Clinical Review

The ability to find and target specific biomarkers in the DNA of advanced cancers is rapidly changing options and outcomes for patients with locally advanced and metastatic solid tumors. This strategy is the basis for precision oncology, defined here as using predictive biomarkers from tumor and/or germline sequencing to guide therapies. This article focuses specifically on the use of DNA sequencing to find those biomarkers and provides guidance about which test is optimal in a specific situation, as well as interpretation of the results. We emphasize the identification of biomarkers that provide adult patients with advanced solid tumors access to therapies that would not be an option had sequencing not been performed and that have the potential for significant clinical benefit. The best approach is to have an expert team with experience in precision oncology to assist in the interpretation of results.

Which test?

Deciding what test of the array of assays available to use and which tissue to test can be overwhelming, and uncertainty may prevent oncology practitioners from ordering germline or somatic sequencing. For the purposes of this article, we will focus on DNA sequencing for inherited/germline alterations (including mutations, copy number changes, or fusions), which may inform treatment, or alterations that arise in the process of carcinogenesis and tumor evolution (somatic alterations in tumor DNA). This focus is not meant to exclude any specific test but to focus on DNA-based tests in patients with locally advanced or metastatic malignancy.

Germline Testing

Germline testing is the sequencing of inherited DNA in noncancerous cells to find alterations that may play a role in the development of cancers and are actionable in some cases. Germline alterations can inform therapeutic decisions, predict future cancer risk, and provide information that can help family members to better manage their risks of malignancy. Detailed discussions of the importance of germline testing to inform cancer surveillance, risk-reducing interventions, and the testing of relatives to determine who carries inherited alterations (cascade testing) is extremely important with several advantages and is covered in a number of excellent reviews elsewhere.^1-3 Testing of germline DNA in patients with a metastatic malignancy can provide treatment options otherwise not available for patients, particularly for BRCA1/2 and Lynch syndrome–related cancers. Recent studies have shown that 10 to 15% of patients with advanced malignancies of many types have a pathogenic germline alteration.^4,5

Germline DNA is usually acquired from peripheral blood, a buccal swab, or saliva collection and is therefore readily available. This is advantageous because it does not require a biopsy to identify relevant alterations. Germline testing is also less susceptible to the rare situations in which artifacts occur in formalin-fixed tissues and obscure relevant alterations.

The cost of germline testing varies, but most commercial vendor assays for germline testing are significantly less expensive than the cost of somatic testing. The disadvantages include the inability of germline testing to find any alterations that arise solely in tumor tissue and the smaller gene panels included in germline testing as compared to somatic testing panels. Other considerations relate to the inherited nature of pathogenic germline variants and its implications for family members that may affect the patient’s psychosocial health and potentially change the family dynamics.

Deciding who is appropriate for germline testing and when to perform the testing should be individualized to the patient’s wishes and disease status. Treatment planning may be less complicated if testing has been performed and germline status is known. In some cases urgent germline testing is indicated to inform pending procedures and/or surgical decisions for risk reduction, including more extensive tissue resection, such as the removal of additional organs or contralateral tissue. A minor point regarding germline testing is that the DNA of patients with hematologic malignancies may be difficult to sequence because of sample contamination by the circulating malignancy. For this reason, most laboratories will not accept peripheral blood or saliva samples for germline testing in patients with active hematologic malignancies; they often require DNA from another source such as fibroblasts from a skin biopsy or cells from a muscle biopsy. Germline testing is recommended for all patients with metastatic prostate cancer, as well as any patient with any stage of pancreatic cancer or ovarian cancer and patients with breast cancer diagnosed at age ≤ 45 years. More detailed criteria for who is appropriate for germline testing outside of these groups can be found in the appropriate National Comprehensive Cancer Network (NCCN) guidelines.^6-8 In patients with some malignancies such as prostate and pancreatic cancer, approximately half of patients who have a BRCA-related cancer developed that malignancy because of a germline BRCA alteration.^9-11 Testing germline DNA is therefore an easy way to quickly find almost half of all targetable alterations with a treatment approved by the US Food and Drug Administration (FDA) and at low cost, with the added benefit of providing critical information for families who may be unaware that members carry a relevant pathogenic germline alteration. In those families, cascade testing can provide surveillance and intervention strategies that can be lifesaving.

A related and particularly relevant question is when should a result found on a somatic testing panel prompt follow-up germline testing? Some institutions have algorithms in place to automate referral for germline testing based on specific genetic criteria.¹² Excellent reviews are available that outline the following considerations in more detail.¹³ Typically, somatic testing results that would trigger follow-up germline testing would be truncating or deleterious or likely deleterious mutations per germline datasets in high-risk genes associated with highly penetrant autosomal dominant conditions (BRCA1, BRCA2, PALB2, MLH1, MSH2, and MSH6), selected moderate-risk genes (BRIP1, RAD51C, and RAD51D), and specific variants with a high probability of being germline because they are common germline founder mutations. Although the actionability and significance of specific genes remains a matter of some discussion, generally finding a somatic pathogenic sequencing result included in the 59-gene list of the American College of Medical Genetics and Genomics (ACMG) guidelines would be an indication for germline testing. Another indication for germline testing would be finding genes with germline mutations for which the NCCN has specific management guidelines, or the presence of alterations consistent with known founder mutations.¹⁴ When a patient’s tumor has microsatellite instability or is hypermutated (defined as > 10 mutations per megabase), a search for germline alterations is warranted given that about 15% of these patients with these tumors carry a Lynch syndrome gene.¹⁵ Genes that are commonly found as somatic alterations alone (eg, TP53 or APC) are generally not an indication for germline testing unless family history is compelling.

Although some clinicians use the variant allele fraction in the somatic sequencing report to decide whether to conduct germline testing, this approach is suboptimal, as allele fraction may be confounded by assay conditions and a high allele fraction may be found in pure tumors with loss of heterozygosity (LOH) of the other allele. There is also evidence that for a variety of reasons, somatic sequencing panels do not always detect germline alterations in somatic tissues.¹⁶ Reasons for this may include discordance between the genes being tested in the germline vs the somatic panel, technical differences such as interference of formalin-fixed paraffin-embedded (FFPE) artifact with detecting the germline variant, lack of expertise in germline variant interpretation among laboratories doing tumor-only sequencing, and, in rare cases, large deletions in tumor tissue masking a germline point mutation.

Variant Interpretation of Germline Testing

A general understanding of the terminology used for germline variant interpretation allows for the ordering health care practitioner (HCP) to provide the best quality care and an appreciation for the limitations of current molecular testing. Not all variants are associated with disease; the clinical significance of a genetic variant falls on a spectrum. The criteria for determining pathogenicity differ between molecular laboratories, but most are influenced by the standards and guidelines set forth by the ACMG.¹⁴ The clinical molecular laboratory determines variant classification, and a detailed discussion is beyond the scope of this primer. In brief, variant classification is based on evidence of varying strength in different categories including population data, computational and predictive data, functional data, segregation data, de novo data, allelic data, and information from various databases. The ACMG has proposed a 5-tiered classification system, by which most molecular laboratories adhere to in their genetic test reports (Table 1).¹⁴

Pathogenic and likely pathogenic variants are clinically actionable, whereas variants of uncertain significance (VUS) require additional data and/or functional studies before making clinical decisions. Depending on the clinical context and existing supporting evidence, it may be prudent to continue monitoring for worsening or new signs of disease in patients with one or more VUS while additional efforts are underway to understand the variant’s significance.

Somatic Testing

Testing of somatic (tumor) tissue is critical and is the approach most commonly taken in medical oncology (Table 2). Somatic testing may be performed on primary tumor, metastatic biopsy, or circulating tumor DNA (ctDNA, also referred to as cell-free DNA [cfDNA]), with each having its own advantages and disadvantages. Primary tumor tissue is appropriate for testing when the alteration is generally truncal, that is, present at the time that the tumor developed and would be expected to be carried through the evolution of the tumor because of a critical role in carcinogenesis and maintenance of the malignant phenotype. Examples include BRCA1/2, and many tyrosine kinase mutations. Somatic testing at diagnosis is part of standard of care for many malignancies, including adenocarcinoma of the lung, colon cancer, melanoma, and others.^17-19 Testing for specific genes or comprehensive genomic profiling will depend on the tumor histology, stage, and payer coverage.

The advantages of primary tumor are that it is usually in hand as a diagnostic biopsy, acquisition is standard of care, and several targetable alterations are truncal, defined as driver mutations present at the time of tumor development. Also, the potential that the tumor arose in the background of a predisposing germline alteration can be suggested by sequencing primary tumor as discussed above. Moreover, sequencing the primary tumor can be done at any time unless the biopsy sample is considered too old or degraded (per specific platform requirements). The information gained can be used to anticipate additional treatment options that are relevant when patients experience disease progression. Disadvantages include the problem that primary specimens may be old or have limited tumor content, both of which increase the likelihood that sequencing will not be technically successful.

Alterations that are targetable and arise as a result of either treatment pressure or clonal evolution are considered evolutionary. If evolutionary alterations are the main focus for sequencing, then metastasis biopsy or ctDNA are better choices. The advantages of a metastasis biopsy are that tissue is contemporary, tumor content may be higher than in primary tumor, and both truncal and evolutionary alterations can be detected.

For specific tumors, continued analysis of evolving genomic alterations can play a critical role in management. In non–small cell lung cancer (NSCLC), somatic testing is conducted again at progression on repeat biopsies to evaluate for emerging resistance mutations. In epidermal growth factor receptor (EGFR)–mutated lung cancer, the resistance mutation, exon 20 p.T790M (point mutation), can present in patients after treatment with first- or second-generation EGFR tyrosine kinase inhibitors (TKI). Even in patients who are treated with the third-generation EGFR TKI osimertinib that can treat T790M-mutated lung cancer, multiple possible evolutionary mutations can occur at progression, including other EGFR mutations, MET/HER2 amplification, and BRAF V600E, to name a few.²⁰ Resistance mechanisms develop due to treatment selection pressure and the molecular heterogeneity seen in lung cancer.

Disadvantages for metastatic biopsy include the inability to safely access a metastatic site, the time considerations for preauthorization and arrangement of biopsy, and a lower-than-average likelihood of successful sequencing from sites such as bone.^21,22 In addition, there is some concern that a single metastatic site may not capture all relevant alterations for multiple reasons, including tumor heterogeneity.

Selecting the Tissue

Deciding on the tissue to analyze is a critical part of the decision process (Table 3). If the primary tumor tissue is old the likelihood of productive sequencing is lower, although age alone is not the only consideration and the methods of fixation may be just as relevant.

For prostate cancer in particular, the ability to successfully sequence primary tumor tissue decreases as the amount of tumor decreases in low-volume biopsies such as prostate needle biopsies. Generally, if tumor content is < 10% of the biopsy specimen, then sequencing is less likely to be productive.²⁵ Also, if the alteration of interest is not known to be truncal, then a relevant target might be missed by sequencing tissue that does not reflect current biology. Metastasis biopsy may be the most appropriate tissue, particularly if this specimen has already been acquired. As above, a metastasis biopsy may have a higher tumor content, and it should reflect relevant biology if it is recent. However, bone biopsies have a relatively low yield for successful sequencing, so a soft tissue lesion (eg, liver or lymph node metastasis) is generally preferred.

The inability to safely access tissue is often a consideration. Proximity to vital structures such as large blood vessels or the potential for significant morbidity in the event of a complication (liver or lung biopsies, particularly in patients on anticoagulation medications) may make the risk/benefit ratio too high. The inability to conduct somatic testing has been reported to often be due to inadequate tissue sampling.²⁶ ctDNA is an attractive alternative but should typically be drawn when a tumor is progressing with a reasonable tumor burden that is more likely to be shedding DNA. Performing ctDNA analysis in patients without obvious radiographic metastasis or in patients whose tumor is under good control is unlikely to produce interpretable results.

Interpreting the Results

The intent of sequencing tumor tissue is to identify alterations that are biologically important and may provide a point of therapeutic leverage. However, deciding which alterations are relevant is not always straightforward. For example, any normal individual genome contains around 10,000 missense variants, hundreds of insertion/deletion variants, and dozens of protein-truncating variants. Distinguishing these alterations, which are part of the individual, from those that are tumor-specific and have functional significance can be difficult in the absence of paired sequencing of both normal and tissue samples.

Specific Alterations

Although most commercial vendors provide important information in sequencing reports to assist oncology HCPs in deciding which alterations are relevant, the reports are not always clear. In many cases the report will specifically indicate whether the alteration has been reported previously as pathogenic or benign. However, some platforms will report alterations that are not known to be drivers of tumor biology. It is critical to be aware that if variants are not reported as pathogenic, they should not be assumed to be pathogenic simply because they are included in the report. Alterations more likely to be drivers of relevant biology are those that change gene and protein structure and include frameshift (fs*), nonsense (denoted by sequence ending in “X” or “*”), or specific fusions or insertions/deletions (indel) that occur in important domains of the gene.

For some genes, only specific alterations are targetable and not all alterations have the same effect on protein function. Although overexpression of certain genes and proteins are actionable (eg, HER2), amplification of a gene does not necessarily indicate that it is targetable. In NSCLC, specific alterations convey sensitivity to targeted therapies. For example, in EGFR-mutated NSCLC, the sensitizing mutations to EGFR TKIs are exon19 deletions and exon 21 L858R point mutations (the most common mutations), as well as less common mutations found in exon 18-21. Exon 20 mutations, however, are not responsive to EGFR TKIs with a few exceptions.²⁷ Patients who have tumors that do not harbor a sensitizing EGFR mutation should not be treated with an EGFR TKI. In a variety of solid tumors, gene fusions of the NTRK 1/2/3, act as oncogenic drivers. The chromosomal fusion events involving the carboxy-terminal kinase domain of TRK and upstream amino-terminal partners lead to overexpression of the chimeric proteins tropomyosin receptor kinase (TRK) A/B/C, resulting in constitutively active, ligand-independent downstream signaling. In patients with NTRK 1/2/3 gene fusions, larotrectinib and entrectinib, small molecule inhibitors to TRK, have shown antitumor activity.^28,29 No alterations beyond these fusions are known to be targetable.

Allele Fraction

Knowing the fraction (or proportion) of the alteration of interest in the sequenced tissue relative to the estimated tumor content can assist in decision making. Not all platforms will provide this information, which is referred to as mutation allele fraction (MAF) or variant allele fraction (VAF), but sometimes will provide it on request. Platforms will usually provide an estimate of the percent tumor in the tissue being sampled if it is from a biopsy. If the MAF is around 50% in the sequenced tissue (including ctDNA), then there is a reasonable chance that it is a germline variant. However, there are nuances as germline alterations in some genes, such as BRCA1/2, can be accompanied by loss of the other allele of the gene (LOH). In that case, if most of the circulating DNA is from tumor, then the MAF can be > 50%.

If there are 2 alterations of the same gene with MAF percentages that are each half of the total percent tumor, there is a high likelihood of biallelic alteration. These sorts of paired alterations or one mutation with apparent LOH or copy loss would again indicate a high likelihood that the alteration is in fact pathogenic and a relevant driver. Not all pathogenic alterations have to be biallelic to be driver mutations but in BRCA1/2, or mismatch repair deficiency genes, the presence of biallelic alterations increases the likelihood of their being pathogenic.

Tumors that are hypermutated—containing sometimes hundreds of mutations per megabyte of DNA—can be particularly complicated to interpret, because the likelihood increases that many of the alterations are a function of the hypermutation and not a driver mutation. This is particularly important when there are concurrent mutations in mismatch repair genes and genes, such as BRCA1/2. If the tumor is microsatellite instability high or hypermutated, concurrent BRCA1/2 alterations are often passengers as the tumors rarely have coexisting “signatures” suggesting that they have a true deficiency in homologous recombination.³⁰ Large genes such as BRCA1/2 have microsatellite tracts that are prone to frameshift mutations as a result of microsatellite instability, and such mutations in this context are typically subclonal and not drivers. In hypermutated tumors, the likelihood is significantly decreased that any of the mutations other than mismatch repair deficiency or polymerase genes are targetable drivers.

Confounders

In some situations, interpretation can be particularly challenging. For example, several alterations for which there are FDA on-label indications (such as ATM or BRCA2) can be detected in ctDNA that may not be due to the tumor but to CHIP. CHIP represents hematopoietic clones that are dysplastic as a result of exposure to DNA-damaging agents (eg, platinum chemotherapy) or as a result of aging and arise when mutations in hematopoietic stem cells provide a competitive advantage.³¹ The most common CHIP clones that can be detected are DNMT3A, ASXL1, or TET2; because these alterations are not targetable, their importance lies primarily in whether patients have evidence of hematologic abnormality, which might represent an evolving hematopoietic disorder. Because CHIP alterations can overlap with somatic alterations for which FDA-approved drugs exist, such as ATM or CHEK2 (olaparib for prostate cancer) and BRCA2 (poly-ADP-ribose polymerase inhibitors in a range of indications) there is concern that CHIP might result in patient harm from inappropriate treatment of CHIP rather than the tumor, with no likelihood that the treatment would affect the tumor, causing treatment delays.³² General considerations for deciding whether an alteration represents CHIP include excluding alteration in which the VAF is < 1% and when the VAF in the alteration of interest is < 20% of the estimated tumor fraction in the sample. Exceptions to this are found in patients with true myelodysplasia or chronic lymphocytic leukemia, in whom the VAF can be well over 50% because of circulating tumor burden. The only way to be certain that an alteration detected on ctDNA reflects tumor rather than CHIP is to utilize an assay with matched tumor-normal sequencing.

Resources for Assistance

For oncology HCPs, perhaps the best resource to help in selecting and interpreting the appropriate testing is through a dedicated molecular oncology tumor board and subject matter experts who contribute to those tumor boards. In the US Department of Veterans Affairs, the national precision oncology program and its affiliated clinical services, such as the option to order a national consultation and molecular tumor board education, are easily accessible to all HCPs (www.cancer.va.gov). Many commercial vendors provide support to assist with questions of interpretation and to inform clinical decision-making. Other resources that can assist with deciding whether an alteration is pathogenic include extensive curated databases such as ClinVar (www.ncbi.nlm.nih.gov/clinvar) and the Human Genetic Mutation Database (www.hgmd.cf.ac.uk/ac/index.php) for germline alterations or COSMIC (cancer.sanger.ac.uk/cosmic) for somatic alterations. OncoKB (www.oncokb.org) is a resource for assistance in defining levels of evidence for the use of agents to target specific alterations and to assist in assigning pathogenicity to specific alterations. Additional educational resources for training in genomics and genetics are also included in the Appendix.

The rapid growth in technology and ability to enhance understanding of relevant tumor biology continues to improve the therapeutic landscape for men and women dealing with malignancy and our ability to find targetable genetic alterations with the potential for meaningful clinical benefit.

Acknowledgments

Dedicated to Neil Spector.

The ability to find and target specific biomarkers in the DNA of advanced cancers is rapidly changing options and outcomes for patients with locally advanced and metastatic solid tumors. This strategy is the basis for precision oncology, defined here as using predictive biomarkers from tumor and/or germline sequencing to guide therapies. This article focuses specifically on the use of DNA sequencing to find those biomarkers and provides guidance about which test is optimal in a specific situation, as well as interpretation of the results. We emphasize the identification of biomarkers that provide adult patients with advanced solid tumors access to therapies that would not be an option had sequencing not been performed and that have the potential for significant clinical benefit. The best approach is to have an expert team with experience in precision oncology to assist in the interpretation of results.

Which test?

Deciding what test of the array of assays available to use and which tissue to test can be overwhelming, and uncertainty may prevent oncology practitioners from ordering germline or somatic sequencing. For the purposes of this article, we will focus on DNA sequencing for inherited/germline alterations (including mutations, copy number changes, or fusions), which may inform treatment, or alterations that arise in the process of carcinogenesis and tumor evolution (somatic alterations in tumor DNA). This focus is not meant to exclude any specific test but to focus on DNA-based tests in patients with locally advanced or metastatic malignancy.

Germline Testing

Germline testing is the sequencing of inherited DNA in noncancerous cells to find alterations that may play a role in the development of cancers and are actionable in some cases. Germline alterations can inform therapeutic decisions, predict future cancer risk, and provide information that can help family members to better manage their risks of malignancy. Detailed discussions of the importance of germline testing to inform cancer surveillance, risk-reducing interventions, and the testing of relatives to determine who carries inherited alterations (cascade testing) is extremely important with several advantages and is covered in a number of excellent reviews elsewhere.^1-3 Testing of germline DNA in patients with a metastatic malignancy can provide treatment options otherwise not available for patients, particularly for BRCA1/2 and Lynch syndrome–related cancers. Recent studies have shown that 10 to 15% of patients with advanced malignancies of many types have a pathogenic germline alteration.^4,5

Germline DNA is usually acquired from peripheral blood, a buccal swab, or saliva collection and is therefore readily available. This is advantageous because it does not require a biopsy to identify relevant alterations. Germline testing is also less susceptible to the rare situations in which artifacts occur in formalin-fixed tissues and obscure relevant alterations.

The cost of germline testing varies, but most commercial vendor assays for germline testing are significantly less expensive than the cost of somatic testing. The disadvantages include the inability of germline testing to find any alterations that arise solely in tumor tissue and the smaller gene panels included in germline testing as compared to somatic testing panels. Other considerations relate to the inherited nature of pathogenic germline variants and its implications for family members that may affect the patient’s psychosocial health and potentially change the family dynamics.

Deciding who is appropriate for germline testing and when to perform the testing should be individualized to the patient’s wishes and disease status. Treatment planning may be less complicated if testing has been performed and germline status is known. In some cases urgent germline testing is indicated to inform pending procedures and/or surgical decisions for risk reduction, including more extensive tissue resection, such as the removal of additional organs or contralateral tissue. A minor point regarding germline testing is that the DNA of patients with hematologic malignancies may be difficult to sequence because of sample contamination by the circulating malignancy. For this reason, most laboratories will not accept peripheral blood or saliva samples for germline testing in patients with active hematologic malignancies; they often require DNA from another source such as fibroblasts from a skin biopsy or cells from a muscle biopsy. Germline testing is recommended for all patients with metastatic prostate cancer, as well as any patient with any stage of pancreatic cancer or ovarian cancer and patients with breast cancer diagnosed at age ≤ 45 years. More detailed criteria for who is appropriate for germline testing outside of these groups can be found in the appropriate National Comprehensive Cancer Network (NCCN) guidelines.^6-8 In patients with some malignancies such as prostate and pancreatic cancer, approximately half of patients who have a BRCA-related cancer developed that malignancy because of a germline BRCA alteration.^9-11 Testing germline DNA is therefore an easy way to quickly find almost half of all targetable alterations with a treatment approved by the US Food and Drug Administration (FDA) and at low cost, with the added benefit of providing critical information for families who may be unaware that members carry a relevant pathogenic germline alteration. In those families, cascade testing can provide surveillance and intervention strategies that can be lifesaving.

A related and particularly relevant question is when should a result found on a somatic testing panel prompt follow-up germline testing? Some institutions have algorithms in place to automate referral for germline testing based on specific genetic criteria.¹² Excellent reviews are available that outline the following considerations in more detail.¹³ Typically, somatic testing results that would trigger follow-up germline testing would be truncating or deleterious or likely deleterious mutations per germline datasets in high-risk genes associated with highly penetrant autosomal dominant conditions (BRCA1, BRCA2, PALB2, MLH1, MSH2, and MSH6), selected moderate-risk genes (BRIP1, RAD51C, and RAD51D), and specific variants with a high probability of being germline because they are common germline founder mutations. Although the actionability and significance of specific genes remains a matter of some discussion, generally finding a somatic pathogenic sequencing result included in the 59-gene list of the American College of Medical Genetics and Genomics (ACMG) guidelines would be an indication for germline testing. Another indication for germline testing would be finding genes with germline mutations for which the NCCN has specific management guidelines, or the presence of alterations consistent with known founder mutations.¹⁴ When a patient’s tumor has microsatellite instability or is hypermutated (defined as > 10 mutations per megabase), a search for germline alterations is warranted given that about 15% of these patients with these tumors carry a Lynch syndrome gene.¹⁵ Genes that are commonly found as somatic alterations alone (eg, TP53 or APC) are generally not an indication for germline testing unless family history is compelling.

Although some clinicians use the variant allele fraction in the somatic sequencing report to decide whether to conduct germline testing, this approach is suboptimal, as allele fraction may be confounded by assay conditions and a high allele fraction may be found in pure tumors with loss of heterozygosity (LOH) of the other allele. There is also evidence that for a variety of reasons, somatic sequencing panels do not always detect germline alterations in somatic tissues.¹⁶ Reasons for this may include discordance between the genes being tested in the germline vs the somatic panel, technical differences such as interference of formalin-fixed paraffin-embedded (FFPE) artifact with detecting the germline variant, lack of expertise in germline variant interpretation among laboratories doing tumor-only sequencing, and, in rare cases, large deletions in tumor tissue masking a germline point mutation.

Variant Interpretation of Germline Testing

A general understanding of the terminology used for germline variant interpretation allows for the ordering health care practitioner (HCP) to provide the best quality care and an appreciation for the limitations of current molecular testing. Not all variants are associated with disease; the clinical significance of a genetic variant falls on a spectrum. The criteria for determining pathogenicity differ between molecular laboratories, but most are influenced by the standards and guidelines set forth by the ACMG.¹⁴ The clinical molecular laboratory determines variant classification, and a detailed discussion is beyond the scope of this primer. In brief, variant classification is based on evidence of varying strength in different categories including population data, computational and predictive data, functional data, segregation data, de novo data, allelic data, and information from various databases. The ACMG has proposed a 5-tiered classification system, by which most molecular laboratories adhere to in their genetic test reports (Table 1).¹⁴

Pathogenic and likely pathogenic variants are clinically actionable, whereas variants of uncertain significance (VUS) require additional data and/or functional studies before making clinical decisions. Depending on the clinical context and existing supporting evidence, it may be prudent to continue monitoring for worsening or new signs of disease in patients with one or more VUS while additional efforts are underway to understand the variant’s significance.

Somatic Testing

Testing of somatic (tumor) tissue is critical and is the approach most commonly taken in medical oncology (Table 2). Somatic testing may be performed on primary tumor, metastatic biopsy, or circulating tumor DNA (ctDNA, also referred to as cell-free DNA [cfDNA]), with each having its own advantages and disadvantages. Primary tumor tissue is appropriate for testing when the alteration is generally truncal, that is, present at the time that the tumor developed and would be expected to be carried through the evolution of the tumor because of a critical role in carcinogenesis and maintenance of the malignant phenotype. Examples include BRCA1/2, and many tyrosine kinase mutations. Somatic testing at diagnosis is part of standard of care for many malignancies, including adenocarcinoma of the lung, colon cancer, melanoma, and others.^17-19 Testing for specific genes or comprehensive genomic profiling will depend on the tumor histology, stage, and payer coverage.

The advantages of primary tumor are that it is usually in hand as a diagnostic biopsy, acquisition is standard of care, and several targetable alterations are truncal, defined as driver mutations present at the time of tumor development. Also, the potential that the tumor arose in the background of a predisposing germline alteration can be suggested by sequencing primary tumor as discussed above. Moreover, sequencing the primary tumor can be done at any time unless the biopsy sample is considered too old or degraded (per specific platform requirements). The information gained can be used to anticipate additional treatment options that are relevant when patients experience disease progression. Disadvantages include the problem that primary specimens may be old or have limited tumor content, both of which increase the likelihood that sequencing will not be technically successful.

Alterations that are targetable and arise as a result of either treatment pressure or clonal evolution are considered evolutionary. If evolutionary alterations are the main focus for sequencing, then metastasis biopsy or ctDNA are better choices. The advantages of a metastasis biopsy are that tissue is contemporary, tumor content may be higher than in primary tumor, and both truncal and evolutionary alterations can be detected.

For specific tumors, continued analysis of evolving genomic alterations can play a critical role in management. In non–small cell lung cancer (NSCLC), somatic testing is conducted again at progression on repeat biopsies to evaluate for emerging resistance mutations. In epidermal growth factor receptor (EGFR)–mutated lung cancer, the resistance mutation, exon 20 p.T790M (point mutation), can present in patients after treatment with first- or second-generation EGFR tyrosine kinase inhibitors (TKI). Even in patients who are treated with the third-generation EGFR TKI osimertinib that can treat T790M-mutated lung cancer, multiple possible evolutionary mutations can occur at progression, including other EGFR mutations, MET/HER2 amplification, and BRAF V600E, to name a few.²⁰ Resistance mechanisms develop due to treatment selection pressure and the molecular heterogeneity seen in lung cancer.

Disadvantages for metastatic biopsy include the inability to safely access a metastatic site, the time considerations for preauthorization and arrangement of biopsy, and a lower-than-average likelihood of successful sequencing from sites such as bone.^21,22 In addition, there is some concern that a single metastatic site may not capture all relevant alterations for multiple reasons, including tumor heterogeneity.

Selecting the Tissue

Deciding on the tissue to analyze is a critical part of the decision process (Table 3). If the primary tumor tissue is old the likelihood of productive sequencing is lower, although age alone is not the only consideration and the methods of fixation may be just as relevant.

For prostate cancer in particular, the ability to successfully sequence primary tumor tissue decreases as the amount of tumor decreases in low-volume biopsies such as prostate needle biopsies. Generally, if tumor content is < 10% of the biopsy specimen, then sequencing is less likely to be productive.²⁵ Also, if the alteration of interest is not known to be truncal, then a relevant target might be missed by sequencing tissue that does not reflect current biology. Metastasis biopsy may be the most appropriate tissue, particularly if this specimen has already been acquired. As above, a metastasis biopsy may have a higher tumor content, and it should reflect relevant biology if it is recent. However, bone biopsies have a relatively low yield for successful sequencing, so a soft tissue lesion (eg, liver or lymph node metastasis) is generally preferred.

The inability to safely access tissue is often a consideration. Proximity to vital structures such as large blood vessels or the potential for significant morbidity in the event of a complication (liver or lung biopsies, particularly in patients on anticoagulation medications) may make the risk/benefit ratio too high. The inability to conduct somatic testing has been reported to often be due to inadequate tissue sampling.²⁶ ctDNA is an attractive alternative but should typically be drawn when a tumor is progressing with a reasonable tumor burden that is more likely to be shedding DNA. Performing ctDNA analysis in patients without obvious radiographic metastasis or in patients whose tumor is under good control is unlikely to produce interpretable results.

Interpreting the Results

The intent of sequencing tumor tissue is to identify alterations that are biologically important and may provide a point of therapeutic leverage. However, deciding which alterations are relevant is not always straightforward. For example, any normal individual genome contains around 10,000 missense variants, hundreds of insertion/deletion variants, and dozens of protein-truncating variants. Distinguishing these alterations, which are part of the individual, from those that are tumor-specific and have functional significance can be difficult in the absence of paired sequencing of both normal and tissue samples.

Specific Alterations

Although most commercial vendors provide important information in sequencing reports to assist oncology HCPs in deciding which alterations are relevant, the reports are not always clear. In many cases the report will specifically indicate whether the alteration has been reported previously as pathogenic or benign. However, some platforms will report alterations that are not known to be drivers of tumor biology. It is critical to be aware that if variants are not reported as pathogenic, they should not be assumed to be pathogenic simply because they are included in the report. Alterations more likely to be drivers of relevant biology are those that change gene and protein structure and include frameshift (fs*), nonsense (denoted by sequence ending in “X” or “*”), or specific fusions or insertions/deletions (indel) that occur in important domains of the gene.

For some genes, only specific alterations are targetable and not all alterations have the same effect on protein function. Although overexpression of certain genes and proteins are actionable (eg, HER2), amplification of a gene does not necessarily indicate that it is targetable. In NSCLC, specific alterations convey sensitivity to targeted therapies. For example, in EGFR-mutated NSCLC, the sensitizing mutations to EGFR TKIs are exon19 deletions and exon 21 L858R point mutations (the most common mutations), as well as less common mutations found in exon 18-21. Exon 20 mutations, however, are not responsive to EGFR TKIs with a few exceptions.²⁷ Patients who have tumors that do not harbor a sensitizing EGFR mutation should not be treated with an EGFR TKI. In a variety of solid tumors, gene fusions of the NTRK 1/2/3, act as oncogenic drivers. The chromosomal fusion events involving the carboxy-terminal kinase domain of TRK and upstream amino-terminal partners lead to overexpression of the chimeric proteins tropomyosin receptor kinase (TRK) A/B/C, resulting in constitutively active, ligand-independent downstream signaling. In patients with NTRK 1/2/3 gene fusions, larotrectinib and entrectinib, small molecule inhibitors to TRK, have shown antitumor activity.^28,29 No alterations beyond these fusions are known to be targetable.

Allele Fraction

Knowing the fraction (or proportion) of the alteration of interest in the sequenced tissue relative to the estimated tumor content can assist in decision making. Not all platforms will provide this information, which is referred to as mutation allele fraction (MAF) or variant allele fraction (VAF), but sometimes will provide it on request. Platforms will usually provide an estimate of the percent tumor in the tissue being sampled if it is from a biopsy. If the MAF is around 50% in the sequenced tissue (including ctDNA), then there is a reasonable chance that it is a germline variant. However, there are nuances as germline alterations in some genes, such as BRCA1/2, can be accompanied by loss of the other allele of the gene (LOH). In that case, if most of the circulating DNA is from tumor, then the MAF can be > 50%.

If there are 2 alterations of the same gene with MAF percentages that are each half of the total percent tumor, there is a high likelihood of biallelic alteration. These sorts of paired alterations or one mutation with apparent LOH or copy loss would again indicate a high likelihood that the alteration is in fact pathogenic and a relevant driver. Not all pathogenic alterations have to be biallelic to be driver mutations but in BRCA1/2, or mismatch repair deficiency genes, the presence of biallelic alterations increases the likelihood of their being pathogenic.

Tumors that are hypermutated—containing sometimes hundreds of mutations per megabyte of DNA—can be particularly complicated to interpret, because the likelihood increases that many of the alterations are a function of the hypermutation and not a driver mutation. This is particularly important when there are concurrent mutations in mismatch repair genes and genes, such as BRCA1/2. If the tumor is microsatellite instability high or hypermutated, concurrent BRCA1/2 alterations are often passengers as the tumors rarely have coexisting “signatures” suggesting that they have a true deficiency in homologous recombination.³⁰ Large genes such as BRCA1/2 have microsatellite tracts that are prone to frameshift mutations as a result of microsatellite instability, and such mutations in this context are typically subclonal and not drivers. In hypermutated tumors, the likelihood is significantly decreased that any of the mutations other than mismatch repair deficiency or polymerase genes are targetable drivers.

Confounders

In some situations, interpretation can be particularly challenging. For example, several alterations for which there are FDA on-label indications (such as ATM or BRCA2) can be detected in ctDNA that may not be due to the tumor but to CHIP. CHIP represents hematopoietic clones that are dysplastic as a result of exposure to DNA-damaging agents (eg, platinum chemotherapy) or as a result of aging and arise when mutations in hematopoietic stem cells provide a competitive advantage.³¹ The most common CHIP clones that can be detected are DNMT3A, ASXL1, or TET2; because these alterations are not targetable, their importance lies primarily in whether patients have evidence of hematologic abnormality, which might represent an evolving hematopoietic disorder. Because CHIP alterations can overlap with somatic alterations for which FDA-approved drugs exist, such as ATM or CHEK2 (olaparib for prostate cancer) and BRCA2 (poly-ADP-ribose polymerase inhibitors in a range of indications) there is concern that CHIP might result in patient harm from inappropriate treatment of CHIP rather than the tumor, with no likelihood that the treatment would affect the tumor, causing treatment delays.³² General considerations for deciding whether an alteration represents CHIP include excluding alteration in which the VAF is < 1% and when the VAF in the alteration of interest is < 20% of the estimated tumor fraction in the sample. Exceptions to this are found in patients with true myelodysplasia or chronic lymphocytic leukemia, in whom the VAF can be well over 50% because of circulating tumor burden. The only way to be certain that an alteration detected on ctDNA reflects tumor rather than CHIP is to utilize an assay with matched tumor-normal sequencing.

Resources for Assistance

For oncology HCPs, perhaps the best resource to help in selecting and interpreting the appropriate testing is through a dedicated molecular oncology tumor board and subject matter experts who contribute to those tumor boards. In the US Department of Veterans Affairs, the national precision oncology program and its affiliated clinical services, such as the option to order a national consultation and molecular tumor board education, are easily accessible to all HCPs (www.cancer.va.gov). Many commercial vendors provide support to assist with questions of interpretation and to inform clinical decision-making. Other resources that can assist with deciding whether an alteration is pathogenic include extensive curated databases such as ClinVar (www.ncbi.nlm.nih.gov/clinvar) and the Human Genetic Mutation Database (www.hgmd.cf.ac.uk/ac/index.php) for germline alterations or COSMIC (cancer.sanger.ac.uk/cosmic) for somatic alterations. OncoKB (www.oncokb.org) is a resource for assistance in defining levels of evidence for the use of agents to target specific alterations and to assist in assigning pathogenicity to specific alterations. Additional educational resources for training in genomics and genetics are also included in the Appendix.

The rapid growth in technology and ability to enhance understanding of relevant tumor biology continues to improve the therapeutic landscape for men and women dealing with malignancy and our ability to find targetable genetic alterations with the potential for meaningful clinical benefit.

Acknowledgments

Dedicated to Neil Spector.

The ability to find and target specific biomarkers in the DNA of advanced cancers is rapidly changing options and outcomes for patients with locally advanced and metastatic solid tumors. This strategy is the basis for precision oncology, defined here as using predictive biomarkers from tumor and/or germline sequencing to guide therapies. This article focuses specifically on the use of DNA sequencing to find those biomarkers and provides guidance about which test is optimal in a specific situation, as well as interpretation of the results. We emphasize the identification of biomarkers that provide adult patients with advanced solid tumors access to therapies that would not be an option had sequencing not been performed and that have the potential for significant clinical benefit. The best approach is to have an expert team with experience in precision oncology to assist in the interpretation of results.

Which test?

Deciding what test of the array of assays available to use and which tissue to test can be overwhelming, and uncertainty may prevent oncology practitioners from ordering germline or somatic sequencing. For the purposes of this article, we will focus on DNA sequencing for inherited/germline alterations (including mutations, copy number changes, or fusions), which may inform treatment, or alterations that arise in the process of carcinogenesis and tumor evolution (somatic alterations in tumor DNA). This focus is not meant to exclude any specific test but to focus on DNA-based tests in patients with locally advanced or metastatic malignancy.

Germline Testing

Germline testing is the sequencing of inherited DNA in noncancerous cells to find alterations that may play a role in the development of cancers and are actionable in some cases. Germline alterations can inform therapeutic decisions, predict future cancer risk, and provide information that can help family members to better manage their risks of malignancy. Detailed discussions of the importance of germline testing to inform cancer surveillance, risk-reducing interventions, and the testing of relatives to determine who carries inherited alterations (cascade testing) is extremely important with several advantages and is covered in a number of excellent reviews elsewhere.^1-3 Testing of germline DNA in patients with a metastatic malignancy can provide treatment options otherwise not available for patients, particularly for BRCA1/2 and Lynch syndrome–related cancers. Recent studies have shown that 10 to 15% of patients with advanced malignancies of many types have a pathogenic germline alteration.^4,5

Germline DNA is usually acquired from peripheral blood, a buccal swab, or saliva collection and is therefore readily available. This is advantageous because it does not require a biopsy to identify relevant alterations. Germline testing is also less susceptible to the rare situations in which artifacts occur in formalin-fixed tissues and obscure relevant alterations.

The cost of germline testing varies, but most commercial vendor assays for germline testing are significantly less expensive than the cost of somatic testing. The disadvantages include the inability of germline testing to find any alterations that arise solely in tumor tissue and the smaller gene panels included in germline testing as compared to somatic testing panels. Other considerations relate to the inherited nature of pathogenic germline variants and its implications for family members that may affect the patient’s psychosocial health and potentially change the family dynamics.

Deciding who is appropriate for germline testing and when to perform the testing should be individualized to the patient’s wishes and disease status. Treatment planning may be less complicated if testing has been performed and germline status is known. In some cases urgent germline testing is indicated to inform pending procedures and/or surgical decisions for risk reduction, including more extensive tissue resection, such as the removal of additional organs or contralateral tissue. A minor point regarding germline testing is that the DNA of patients with hematologic malignancies may be difficult to sequence because of sample contamination by the circulating malignancy. For this reason, most laboratories will not accept peripheral blood or saliva samples for germline testing in patients with active hematologic malignancies; they often require DNA from another source such as fibroblasts from a skin biopsy or cells from a muscle biopsy. Germline testing is recommended for all patients with metastatic prostate cancer, as well as any patient with any stage of pancreatic cancer or ovarian cancer and patients with breast cancer diagnosed at age ≤ 45 years. More detailed criteria for who is appropriate for germline testing outside of these groups can be found in the appropriate National Comprehensive Cancer Network (NCCN) guidelines.^6-8 In patients with some malignancies such as prostate and pancreatic cancer, approximately half of patients who have a BRCA-related cancer developed that malignancy because of a germline BRCA alteration.^9-11 Testing germline DNA is therefore an easy way to quickly find almost half of all targetable alterations with a treatment approved by the US Food and Drug Administration (FDA) and at low cost, with the added benefit of providing critical information for families who may be unaware that members carry a relevant pathogenic germline alteration. In those families, cascade testing can provide surveillance and intervention strategies that can be lifesaving.

A related and particularly relevant question is when should a result found on a somatic testing panel prompt follow-up germline testing? Some institutions have algorithms in place to automate referral for germline testing based on specific genetic criteria.¹² Excellent reviews are available that outline the following considerations in more detail.¹³ Typically, somatic testing results that would trigger follow-up germline testing would be truncating or deleterious or likely deleterious mutations per germline datasets in high-risk genes associated with highly penetrant autosomal dominant conditions (BRCA1, BRCA2, PALB2, MLH1, MSH2, and MSH6), selected moderate-risk genes (BRIP1, RAD51C, and RAD51D), and specific variants with a high probability of being germline because they are common germline founder mutations. Although the actionability and significance of specific genes remains a matter of some discussion, generally finding a somatic pathogenic sequencing result included in the 59-gene list of the American College of Medical Genetics and Genomics (ACMG) guidelines would be an indication for germline testing. Another indication for germline testing would be finding genes with germline mutations for which the NCCN has specific management guidelines, or the presence of alterations consistent with known founder mutations.¹⁴ When a patient’s tumor has microsatellite instability or is hypermutated (defined as > 10 mutations per megabase), a search for germline alterations is warranted given that about 15% of these patients with these tumors carry a Lynch syndrome gene.¹⁵ Genes that are commonly found as somatic alterations alone (eg, TP53 or APC) are generally not an indication for germline testing unless family history is compelling.

Although some clinicians use the variant allele fraction in the somatic sequencing report to decide whether to conduct germline testing, this approach is suboptimal, as allele fraction may be confounded by assay conditions and a high allele fraction may be found in pure tumors with loss of heterozygosity (LOH) of the other allele. There is also evidence that for a variety of reasons, somatic sequencing panels do not always detect germline alterations in somatic tissues.¹⁶ Reasons for this may include discordance between the genes being tested in the germline vs the somatic panel, technical differences such as interference of formalin-fixed paraffin-embedded (FFPE) artifact with detecting the germline variant, lack of expertise in germline variant interpretation among laboratories doing tumor-only sequencing, and, in rare cases, large deletions in tumor tissue masking a germline point mutation.

Variant Interpretation of Germline Testing

A general understanding of the terminology used for germline variant interpretation allows for the ordering health care practitioner (HCP) to provide the best quality care and an appreciation for the limitations of current molecular testing. Not all variants are associated with disease; the clinical significance of a genetic variant falls on a spectrum. The criteria for determining pathogenicity differ between molecular laboratories, but most are influenced by the standards and guidelines set forth by the ACMG.¹⁴ The clinical molecular laboratory determines variant classification, and a detailed discussion is beyond the scope of this primer. In brief, variant classification is based on evidence of varying strength in different categories including population data, computational and predictive data, functional data, segregation data, de novo data, allelic data, and information from various databases. The ACMG has proposed a 5-tiered classification system, by which most molecular laboratories adhere to in their genetic test reports (Table 1).¹⁴

Pathogenic and likely pathogenic variants are clinically actionable, whereas variants of uncertain significance (VUS) require additional data and/or functional studies before making clinical decisions. Depending on the clinical context and existing supporting evidence, it may be prudent to continue monitoring for worsening or new signs of disease in patients with one or more VUS while additional efforts are underway to understand the variant’s significance.

Somatic Testing

Testing of somatic (tumor) tissue is critical and is the approach most commonly taken in medical oncology (Table 2). Somatic testing may be performed on primary tumor, metastatic biopsy, or circulating tumor DNA (ctDNA, also referred to as cell-free DNA [cfDNA]), with each having its own advantages and disadvantages. Primary tumor tissue is appropriate for testing when the alteration is generally truncal, that is, present at the time that the tumor developed and would be expected to be carried through the evolution of the tumor because of a critical role in carcinogenesis and maintenance of the malignant phenotype. Examples include BRCA1/2, and many tyrosine kinase mutations. Somatic testing at diagnosis is part of standard of care for many malignancies, including adenocarcinoma of the lung, colon cancer, melanoma, and others.^17-19 Testing for specific genes or comprehensive genomic profiling will depend on the tumor histology, stage, and payer coverage.

The advantages of primary tumor are that it is usually in hand as a diagnostic biopsy, acquisition is standard of care, and several targetable alterations are truncal, defined as driver mutations present at the time of tumor development. Also, the potential that the tumor arose in the background of a predisposing germline alteration can be suggested by sequencing primary tumor as discussed above. Moreover, sequencing the primary tumor can be done at any time unless the biopsy sample is considered too old or degraded (per specific platform requirements). The information gained can be used to anticipate additional treatment options that are relevant when patients experience disease progression. Disadvantages include the problem that primary specimens may be old or have limited tumor content, both of which increase the likelihood that sequencing will not be technically successful.

Alterations that are targetable and arise as a result of either treatment pressure or clonal evolution are considered evolutionary. If evolutionary alterations are the main focus for sequencing, then metastasis biopsy or ctDNA are better choices. The advantages of a metastasis biopsy are that tissue is contemporary, tumor content may be higher than in primary tumor, and both truncal and evolutionary alterations can be detected.

For specific tumors, continued analysis of evolving genomic alterations can play a critical role in management. In non–small cell lung cancer (NSCLC), somatic testing is conducted again at progression on repeat biopsies to evaluate for emerging resistance mutations. In epidermal growth factor receptor (EGFR)–mutated lung cancer, the resistance mutation, exon 20 p.T790M (point mutation), can present in patients after treatment with first- or second-generation EGFR tyrosine kinase inhibitors (TKI). Even in patients who are treated with the third-generation EGFR TKI osimertinib that can treat T790M-mutated lung cancer, multiple possible evolutionary mutations can occur at progression, including other EGFR mutations, MET/HER2 amplification, and BRAF V600E, to name a few.²⁰ Resistance mechanisms develop due to treatment selection pressure and the molecular heterogeneity seen in lung cancer.

Disadvantages for metastatic biopsy include the inability to safely access a metastatic site, the time considerations for preauthorization and arrangement of biopsy, and a lower-than-average likelihood of successful sequencing from sites such as bone.^21,22 In addition, there is some concern that a single metastatic site may not capture all relevant alterations for multiple reasons, including tumor heterogeneity.

Selecting the Tissue

Deciding on the tissue to analyze is a critical part of the decision process (Table 3). If the primary tumor tissue is old the likelihood of productive sequencing is lower, although age alone is not the only consideration and the methods of fixation may be just as relevant.

For prostate cancer in particular, the ability to successfully sequence primary tumor tissue decreases as the amount of tumor decreases in low-volume biopsies such as prostate needle biopsies. Generally, if tumor content is < 10% of the biopsy specimen, then sequencing is less likely to be productive.²⁵ Also, if the alteration of interest is not known to be truncal, then a relevant target might be missed by sequencing tissue that does not reflect current biology. Metastasis biopsy may be the most appropriate tissue, particularly if this specimen has already been acquired. As above, a metastasis biopsy may have a higher tumor content, and it should reflect relevant biology if it is recent. However, bone biopsies have a relatively low yield for successful sequencing, so a soft tissue lesion (eg, liver or lymph node metastasis) is generally preferred.

The inability to safely access tissue is often a consideration. Proximity to vital structures such as large blood vessels or the potential for significant morbidity in the event of a complication (liver or lung biopsies, particularly in patients on anticoagulation medications) may make the risk/benefit ratio too high. The inability to conduct somatic testing has been reported to often be due to inadequate tissue sampling.²⁶ ctDNA is an attractive alternative but should typically be drawn when a tumor is progressing with a reasonable tumor burden that is more likely to be shedding DNA. Performing ctDNA analysis in patients without obvious radiographic metastasis or in patients whose tumor is under good control is unlikely to produce interpretable results.

Interpreting the Results

The intent of sequencing tumor tissue is to identify alterations that are biologically important and may provide a point of therapeutic leverage. However, deciding which alterations are relevant is not always straightforward. For example, any normal individual genome contains around 10,000 missense variants, hundreds of insertion/deletion variants, and dozens of protein-truncating variants. Distinguishing these alterations, which are part of the individual, from those that are tumor-specific and have functional significance can be difficult in the absence of paired sequencing of both normal and tissue samples.

Specific Alterations

Although most commercial vendors provide important information in sequencing reports to assist oncology HCPs in deciding which alterations are relevant, the reports are not always clear. In many cases the report will specifically indicate whether the alteration has been reported previously as pathogenic or benign. However, some platforms will report alterations that are not known to be drivers of tumor biology. It is critical to be aware that if variants are not reported as pathogenic, they should not be assumed to be pathogenic simply because they are included in the report. Alterations more likely to be drivers of relevant biology are those that change gene and protein structure and include frameshift (fs*), nonsense (denoted by sequence ending in “X” or “*”), or specific fusions or insertions/deletions (indel) that occur in important domains of the gene.

For some genes, only specific alterations are targetable and not all alterations have the same effect on protein function. Although overexpression of certain genes and proteins are actionable (eg, HER2), amplification of a gene does not necessarily indicate that it is targetable. In NSCLC, specific alterations convey sensitivity to targeted therapies. For example, in EGFR-mutated NSCLC, the sensitizing mutations to EGFR TKIs are exon19 deletions and exon 21 L858R point mutations (the most common mutations), as well as less common mutations found in exon 18-21. Exon 20 mutations, however, are not responsive to EGFR TKIs with a few exceptions.²⁷ Patients who have tumors that do not harbor a sensitizing EGFR mutation should not be treated with an EGFR TKI. In a variety of solid tumors, gene fusions of the NTRK 1/2/3, act as oncogenic drivers. The chromosomal fusion events involving the carboxy-terminal kinase domain of TRK and upstream amino-terminal partners lead to overexpression of the chimeric proteins tropomyosin receptor kinase (TRK) A/B/C, resulting in constitutively active, ligand-independent downstream signaling. In patients with NTRK 1/2/3 gene fusions, larotrectinib and entrectinib, small molecule inhibitors to TRK, have shown antitumor activity.^28,29 No alterations beyond these fusions are known to be targetable.

Allele Fraction

Knowing the fraction (or proportion) of the alteration of interest in the sequenced tissue relative to the estimated tumor content can assist in decision making. Not all platforms will provide this information, which is referred to as mutation allele fraction (MAF) or variant allele fraction (VAF), but sometimes will provide it on request. Platforms will usually provide an estimate of the percent tumor in the tissue being sampled if it is from a biopsy. If the MAF is around 50% in the sequenced tissue (including ctDNA), then there is a reasonable chance that it is a germline variant. However, there are nuances as germline alterations in some genes, such as BRCA1/2, can be accompanied by loss of the other allele of the gene (LOH). In that case, if most of the circulating DNA is from tumor, then the MAF can be > 50%.

If there are 2 alterations of the same gene with MAF percentages that are each half of the total percent tumor, there is a high likelihood of biallelic alteration. These sorts of paired alterations or one mutation with apparent LOH or copy loss would again indicate a high likelihood that the alteration is in fact pathogenic and a relevant driver. Not all pathogenic alterations have to be biallelic to be driver mutations but in BRCA1/2, or mismatch repair deficiency genes, the presence of biallelic alterations increases the likelihood of their being pathogenic.

Tumors that are hypermutated—containing sometimes hundreds of mutations per megabyte of DNA—can be particularly complicated to interpret, because the likelihood increases that many of the alterations are a function of the hypermutation and not a driver mutation. This is particularly important when there are concurrent mutations in mismatch repair genes and genes, such as BRCA1/2. If the tumor is microsatellite instability high or hypermutated, concurrent BRCA1/2 alterations are often passengers as the tumors rarely have coexisting “signatures” suggesting that they have a true deficiency in homologous recombination.³⁰ Large genes such as BRCA1/2 have microsatellite tracts that are prone to frameshift mutations as a result of microsatellite instability, and such mutations in this context are typically subclonal and not drivers. In hypermutated tumors, the likelihood is significantly decreased that any of the mutations other than mismatch repair deficiency or polymerase genes are targetable drivers.

Confounders

In some situations, interpretation can be particularly challenging. For example, several alterations for which there are FDA on-label indications (such as ATM or BRCA2) can be detected in ctDNA that may not be due to the tumor but to CHIP. CHIP represents hematopoietic clones that are dysplastic as a result of exposure to DNA-damaging agents (eg, platinum chemotherapy) or as a result of aging and arise when mutations in hematopoietic stem cells provide a competitive advantage.³¹ The most common CHIP clones that can be detected are DNMT3A, ASXL1, or TET2; because these alterations are not targetable, their importance lies primarily in whether patients have evidence of hematologic abnormality, which might represent an evolving hematopoietic disorder. Because CHIP alterations can overlap with somatic alterations for which FDA-approved drugs exist, such as ATM or CHEK2 (olaparib for prostate cancer) and BRCA2 (poly-ADP-ribose polymerase inhibitors in a range of indications) there is concern that CHIP might result in patient harm from inappropriate treatment of CHIP rather than the tumor, with no likelihood that the treatment would affect the tumor, causing treatment delays.³² General considerations for deciding whether an alteration represents CHIP include excluding alteration in which the VAF is < 1% and when the VAF in the alteration of interest is < 20% of the estimated tumor fraction in the sample. Exceptions to this are found in patients with true myelodysplasia or chronic lymphocytic leukemia, in whom the VAF can be well over 50% because of circulating tumor burden. The only way to be certain that an alteration detected on ctDNA reflects tumor rather than CHIP is to utilize an assay with matched tumor-normal sequencing.

Resources for Assistance

For oncology HCPs, perhaps the best resource to help in selecting and interpreting the appropriate testing is through a dedicated molecular oncology tumor board and subject matter experts who contribute to those tumor boards. In the US Department of Veterans Affairs, the national precision oncology program and its affiliated clinical services, such as the option to order a national consultation and molecular tumor board education, are easily accessible to all HCPs (www.cancer.va.gov). Many commercial vendors provide support to assist with questions of interpretation and to inform clinical decision-making. Other resources that can assist with deciding whether an alteration is pathogenic include extensive curated databases such as ClinVar (www.ncbi.nlm.nih.gov/clinvar) and the Human Genetic Mutation Database (www.hgmd.cf.ac.uk/ac/index.php) for germline alterations or COSMIC (cancer.sanger.ac.uk/cosmic) for somatic alterations. OncoKB (www.oncokb.org) is a resource for assistance in defining levels of evidence for the use of agents to target specific alterations and to assist in assigning pathogenicity to specific alterations. Additional educational resources for training in genomics and genetics are also included in the Appendix.

The rapid growth in technology and ability to enhance understanding of relevant tumor biology continues to improve the therapeutic landscape for men and women dealing with malignancy and our ability to find targetable genetic alterations with the potential for meaningful clinical benefit.

Acknowledgments

Dedicated to Neil Spector.

Cervical cancer is an important global health problem with an estimated 604,127 new cases and 341,831 deaths in 2020.¹ Nearly 85% of the disease burden affects individuals from low and middle-income countries. The World Health Organization (WHO) set forth the goal for all countries to reach and maintain an incidence rate of below 4 per 100,000 women by 2030 as part of the Global Strategy to Accelerate the Elimination of Cervical Cancer.

Although traditional Pap cytology has been the cornerstone of screening programs, its poor sensitivity of approximately 50% and limitations in accessibility require new strategies to achieve the elimination of cervical cancer.² The discovery that persistent infection with oncogenic human papillomavirus (HPV) is an essential step in the development of cervical cancer led to the development of diagnostic HPV tests, which have higher sensitivity than cytology (96.1% vs 53.0%) but somewhat lower specificity (90.7% vs 96.3%) for the detection of cervical intraepithelial neoplasia (CIN) 2 or worse lesions.² Initially, HPV testing was incorporated as a method to triage atypical squamous cells of undetermined significance (ASCUS) cytology results.³ Later, the concept of cotesting with cytology emerged,^4,5 and since then, several clinical trials have demonstrated the effectiveness of primary HPV screening.^6-9

In 2020, the WHO recommended HPV DNA testing as the primary screening method starting at the age of 30 years, with regular testing every 5 to 10 years, for the general population.¹⁰ Currently, primary HPV has been adopted in multiple countries, including Australia, the Netherlands, Turkey, England, and Argentina.

In the United States, there are 3 currently acceptable screening strategies: cytology, cytology plus HPV (cotesting), and primary HPV testing (TABLE). The American Cancer Society (ACS) specifically states that HPV testing alone every 5 years is preferred starting at age 25 years; cotesting every 5 years or cytology alone every 3 years are also acceptable.¹¹ The US Preventive Services Task Force (USPSTF) states that cytology alone every 3 years starting at 21 years and then HPV testing alone or cotesting every 5 years or cytology every 3 years starting at age 30 are all acceptable strategies.¹²

When applying these guidelines, it is important to note that they are intended for the screening of patients with all prior normal results with no symptoms. These routine screening guidelines do not apply to special populations, such as those with a history of abnormal results or treatment, a history of immunosuppression,¹³ a history of HPV-related vulvar or vaginal dysplasia,^14-16 or a history of hysterectomy with removal of the cervix and no prior history of cervical dysplasia.^17,18 By contrast, surveillance is interval testing for those who have either an abnormal prior test result or treatment; these may be managed per risk-based estimates provided by the American Society for Colposcopy and Cervical Pathology (ASCCP).^18,19 Finally, diagnosis is evaluation (which may include diagnostic cytology) of a patient with abnormal signs and/or symptoms (such as bleeding, pain, discharge, or cervical mass).

In this Update, we present the evidence for primary HPV testing, the management options for a positive result in the United States, and research that will improve uptake of primary HPV testing as well as accessibility.

Change in screening paradigm: Evidence for primary HPV testing

HPV DNA tests are multiplex assays that detect the DNA of targeted high-risk HPV types, using multiple probes, either by direct genomic detection or by amplification of a viral DNA fragment using polymerase chain reaction (PCR).^20,21 Alternatively, HPV mRNA-based tests detect the expression of E6 and E7 oncoproteins, a marker of viral integration.²⁰ In examining the data from well-conducted clinical trials, 2 important observations are that different HPV assays were used and that direct comparison may not be valid. In addition, not all tests used in the studies are approved by the US Food and Drug Administration (FDA) for primary HPV testing.

Continue to: FDA-approved HPV tests...

 

 

FDA-approved HPV tests

Currently, 2 tests are FDA approved for primary HPV screening. The Cobas HPV test (Roche Molecular Diagnostics) was the first FDA-approved test for primary HPV screening in women aged 25 years and older.⁶ This test reports pooled results from 12 high-risk (hr) HPV types (31/33/35/39/45/51/52/56/58/59/66/68) with reflex genotyping for HPV 16/18, and thus it provides an immediate triage option for HPV-positive women. Of note, it is also approved for cotesting. The second FDA-approved test is the BD Onclarity HPV assay (Becton, Dickinson and Company) for primary HPV screening.²² It detects 14 hrHPV types, types 16/18/45 specifically as well as types 31/33/35/39/51/52/56/58/59/66/68.

Other HPV tests are FDA approved for cotesting and reflex testing but not for primary HPV testing. The Hybrid Capture test, or HC2 (Qiagen Inc), was the first HPV test to be approved by the FDA in 1997 for reflex testing of women with ASCUS cytology. In 2003, it was approved for cotesting along with cytology in women aged 30 years and older.^20,21 In 2009, the Cervista HPV HR test (Hologic Inc) was approved for cotesting. The Aptima HPV assay (Hologic Inc), which is also approved for cotesting, is an RNA-based assay that allows detection of E6/E7 mRNA transcripts of 14 HPV types.²³

Comparing HPV testing with cytology

Ronco and colleagues pooled data from 4 European randomized controlled trials (RCTs)—Swedescreen, POBASCAM, NTCC, ARTISTIC—with a total of 176,464 participants randomly assigned to HPV or cytology screening.²⁴ Swedescreen and POBASCAM used GP5/GP6 PCR, while ARTISTIC and NTCC used HC2 for primary HPV screening. The screening interval was 3 years in all except 5 years in POBASCAM. The pooled detection rate of invasive disease was similar in the 2 arms, with pooled rate ratio for cancer detection being 0.79 (95% confidence interval [CI], 0.46–1.36) in the first 2.5 years, but was 0.45 (95% CI, 0.25–0.81), favoring the HPV arm, after 2.5 years. HPV testing was more effective in preventing cases of adenocarcinoma than squamous cell carcinoma (0.31 [95% CI, 0.14–0.69] vs 0.78 [95% CI, 0.49–1.25]). The authors concluded that HPV-based screening from age 30 years provided 60% to 70% better protection than cytology.

The result of the above meta-analysis was confirmed by the HPV FOCAL RCT that investigated the efficacy of HPV testing (HC2) in comparison with cytology.²⁵ The detection rates for CIN 3 lesions supported primary HPV screening, with an absolute difference in incidence rate of 2.67/1,000 (95% CI, 0.53–4.88) at study randomization and 3.22/1,000 (95% CI, 5.12–1.48) at study exit 4 years later.

Cotesting using HPV and cytology: Marginal benefit

Dillner and colleagues were one of the first groups to report on the risk of CIN 3 based on both HPV and cytology status.²⁶ Using pooled analysis of data from multiple countries, these investigators reported that the cumulative incidence rates (CIR) of CIN 3 after 6 years of follow-up increased consistently in HPV-positive subjects, and an HPV-positive result more accurately predicted CIN 3+ at 5 years than cytology alone. Furthermore, HPV negativity provided greater reassurance than cytology alone. At 5 years of follow-up, the rates of CIN 3+ were 0.25% (0.12%–0.41%) for women negative for HPV compared with 0.83% (0.50%–1.13%) for women with negative cytology results. There was little difference in rates for CIN 3+ between women with negative results on both tests and women who were negative for HPV.

The important question is then the marginal benefit of cotesting, which is the most costly screening option. A study of 331,818 women enrolled for cotesting at Kaiser Permanente found that the risk of CIN 3+ predicted by HPV testing alone when compared with cytology was significantly higher at both 3 years (5.0% vs 3.8%; P = .046) and 5 years (7.6% vs 4.7%; P = .001).²⁷ A negative cytology result did not decrease the risk of CIN 3 further for HPV-negative patients (3 years: 0.047% vs 0.063%, P = .6; 5 years: 0.16% vs 0.17%, P = .8). They concluded that a negative HPV test was enough reassurance for low risk of CIN 3+ and that an additional negative cytology result does not provide extra reassurance.

Furthermore, a systematic meta-analysis of 48 studies, including 8 RCTs, found that the addition of cytology to HPV testing raised the sensitivity by 2% for CIN 3 compared with HPV testing alone. This improvement in sensitivity was at the expense of considerable loss of specificity, with a ratio of 0.93 (95% CI, 0.92–0.95) for CIN 3.²⁸ Schiffman and colleagues also assessed the relative contribution of HPV testing and cytology in detection of CIN 3 and cancer.²⁹ The HPV component alone identified a significantly higher proportion of preinvasive and invasive disease than cytology. Only 3.5% of precancers and 5.9% of cancers were preceded by HPV-negative, cytology-positive results. Thus, cytology contributed only 5 cases per million women per year to the sensitivity of the combined test, at the cost of significantly more colposcopies. Hence, the evidence suggests that there is limited benefit of adding cytology to HPV testing.³⁰

Continue to: Triage of a positive HPV result...

 

 

Triage of a positive HPV result

An important limitation of HPV testing is its inability to discriminate between transient and persistent infections. Referral of all HPV-positive cases to colposcopy would overburden the system with associated unnecessary procedures. Hence, a triage strategy is essential to identify clinically important infections that truly require colposcopic evaluation. The FIGURE illustrates the management of a primary HPV test result performed for screening.

HPV genotyping

One strategy for triaging a positive HPV test result is genotyping. HPV 16 and 18 have the highest risk of persistence and progression and merit immediate referral to colposcopy. In the ATHENA trial, CIN 3 was identified in 17.8% (95% CI, 14.8–20.7%) of HPV 16 positive women at baseline, and the CIR increased to 25.2% (95% CI, 21.7–28.7%) after 3 years. The 3-year CIR of CIN 3 was only 5.4% (95% CI, 4.5–6.3%) in women with HPV genotypes other than 16/18. HPV 18–positive women had a 3-year CIR that was intermediate between women with HPV 16 and women with the 12 other genotypes.⁶ Hence, HPV 16/18–positive cases should be referred for immediate colposcopy, and negative cases should be followed up with cytology and referred for colposcopy if the cytology is ASCUS or worse.³¹

In July 2020, extended genotyping was approved by the FDA with individual detection of HPV 31, 51, 52 (in addition to 16, 18, and 45) and pooled detection of 33/58, 35/39/68, and 56/59/66. One study found that individual genotypes HPV 16 and 31 carry baseline risk values for CIN 3+ (8.1% and 7.5%, respectively) that are above the 5-year risk threshold for referral to colposcopy following the ASCCP risk-based management guideline.³²

Cytology

The higher specificity of cytology makes it an option for triaging HPV-positive cases, and current management guidelines recommend triage to both genotyping and cytology for all patients who are HPV positive, and especially if they are HPV positive but HPV 16/18 negative. Of note, cytology results remain more subjective than those of primary HPV testing, but the combination of initial HPV testing with reflex to cytology is a reasonable and cost effective next step.¹⁸ The VASCAR trial found higher colposcopy referrals in the HPV screening and cytology triage group compared with the cytology alone group (19.36 vs 14.54 per 1,000 women).³³ The ATHENA trial investigated various triage strategies for HPV-positive cases and its impact on colposcopy referrals.⁶ Using HPV genotyping and reflex cytology, if HPV 16/18 was positive, colposcopy was advised, but if any of the other 12 HPV types were positive, reflex cytology was done. If reported as ASCUS or worse, colposcopy was performed; conversely, if it was normal, women were rescreened with cotesting after 1 year. Although this strategy led to a reduction in the number of colposcopies, referrals were still higher in the primary HPV arm (3,769 colposcopies per 294 cases) compared with cytology (1,934 colposcopies per 179 cases) or cotesting (3,097 colposcopies per 240 cases) in women aged 25 years.¹⁴

p16/Ki-67 Dual-Stain

Diffused p16 immunohistochemical staining, as opposed to focal staining, is associated with active HPV infection but can be present in low-grade as well as high-grade lesions.³⁴ Ki-67 is a marker of cellular proliferation. Coexpression of p16 and Ki-67 indicates a loss of cell cycle regulation and is a hallmark of neoplastic transformation. When positive, these tests are supportive of active HPV infection and of a high-grade lesion. Incorporation of these stains to cytology alone provides additional objective reassurance to cytology, where there is much inter- and intra-observer variability. These stains can be done by laboratories using the stains alone or they can use the FDA-approved p16/Ki-67 Dual-Stain immunohistochemistry (DS), CINtec PLUS Cytology (Roche Diagnostics). However, DS is not yet formally incorporated into triage algorithms by national guidelines.

The IMPACT trial assessed the performance of DS compared with cytology in the triage of HPV-positive results, with or without HPV 16/18 genotyping.³⁵ This was a prospective observational screening study of 35,263 women aged 25 to 65 years across 32 sites in the United States. Of the 4,927 HPV-positive patients with DS results, the sensitivity of DS for CIN 3+ was 91.9% (95% CI, 86.1%–95.4%) and 86.0% (95% CI, 77.5%–91.6%) in HPV 16/18–positive and in the 12 other genotypes, respectively. Using DS alone to triage HPV-positive results showed significantly higher sensitivity and specificity than HPV 16/18 genotyping with cytology triage of 12 “other” genotypes, and substantially higher sensitivity but lower specificity than using cytology alone. Of note, triage with DS alone would have referred significantly fewer women to colposcopy than HPV 16/18 genotyping with cytology triage for the 12 other genotypes (48.6% vs 56.0%; P< .0001).

Similarly, a retrospective analysis of the ATHENA trial cohort of HPV-positive results of 7,727 patients aged 25 years or older also demonstrated increased sensitivity of DS compared with cytology (74.9% vs 51.9%; P<.0001) and similar specificities (74.1% vs 75%; P = .3198).³⁶ The European PALMS study, which included 27,349 women aged 18 years or older across 5 countries who underwent routine screening with HPV testing, cytology, and DS, confirmed these findings.³⁷ The sensitivity of DS was higher than that of cytology (86.7% vs 68.5%; P<.001) for CIN 3+ with comparable specificities (95.2% vs 95.4%; P = .15).

Challenges and opportunities to improve access to primary HPV screening

The historical success of the Pap test in reducing the incidence of cervical cancer relied on individuals having access to the test. This remains true as screening transitions to primary HPV testing. Limitations of HPV-based screening include provider and patient knowledge; access to tests; cost; need for new laboratory infrastructure; need to leverage the electronic health record to record results, calculate a patient’s risk and determine next steps; and the need to re-educate patients and providers about this new model of care. The American Cancer Society and the Centers for Disease Control and Prevention are currently leading initiatives to help adopt primary HPV screening in the United States and to facilitate new care approaches.

Self-collection and independence from subjective cytology would further improve access. Multiple effectiveness studies and patient acceptability studies have shown that primary HPV screening via self-collection is effective, cost effective, and acceptable to women, especially among underscreened populations.³⁸ Sensitivity is comparable to clinician-obtained samples with polymerase chain reaction–based HPV tests. Furthermore, newer molecular tests that detect methylated target host genes or methylated viral genome can be used to triage HPV-positive cases. Several host methylation markers that identify the specific host genes (for example, CADM1, MAL, and miR-124-2) have been shown to be more specific, reproducible, and can be used in self-collected samples as they are based on molecular methylation analysis.³⁹ The ASCCP monitors these new developments and will incorporate promising tests and approaches once validated and FDA approved into the risk-based management guidelines. An erratum was recently published, and the risk-calculator is also available on the ASCCP website free of charge (https://app.asccp.org).⁴⁰

In conclusion, transition to primary HPV testing from Pap cytology in cervical cancer screening has many challenges but also opportunities. Learning from the experience of countries that have already adopted primary HPV testing is crucial to successful implementation of this new screening paradigm.⁴¹ The evidence supporting primary HPV screening with its improved sensitivity is clear, and the existing triage options and innovations will continue to improve triage of patients with clinically important lesions as well as accessibility. With strong advocacy and sound implementation, the WHO goal of cervical cancer elimination and 70% of women being screened with a high-performance test by age 35 and again by age 45 is achievable. ●

Cervical cancer is an important global health problem with an estimated 604,127 new cases and 341,831 deaths in 2020.¹ Nearly 85% of the disease burden affects individuals from low and middle-income countries. The World Health Organization (WHO) set forth the goal for all countries to reach and maintain an incidence rate of below 4 per 100,000 women by 2030 as part of the Global Strategy to Accelerate the Elimination of Cervical Cancer.

Although traditional Pap cytology has been the cornerstone of screening programs, its poor sensitivity of approximately 50% and limitations in accessibility require new strategies to achieve the elimination of cervical cancer.² The discovery that persistent infection with oncogenic human papillomavirus (HPV) is an essential step in the development of cervical cancer led to the development of diagnostic HPV tests, which have higher sensitivity than cytology (96.1% vs 53.0%) but somewhat lower specificity (90.7% vs 96.3%) for the detection of cervical intraepithelial neoplasia (CIN) 2 or worse lesions.² Initially, HPV testing was incorporated as a method to triage atypical squamous cells of undetermined significance (ASCUS) cytology results.³ Later, the concept of cotesting with cytology emerged,^4,5 and since then, several clinical trials have demonstrated the effectiveness of primary HPV screening.^6-9

In 2020, the WHO recommended HPV DNA testing as the primary screening method starting at the age of 30 years, with regular testing every 5 to 10 years, for the general population.¹⁰ Currently, primary HPV has been adopted in multiple countries, including Australia, the Netherlands, Turkey, England, and Argentina.

In the United States, there are 3 currently acceptable screening strategies: cytology, cytology plus HPV (cotesting), and primary HPV testing (TABLE). The American Cancer Society (ACS) specifically states that HPV testing alone every 5 years is preferred starting at age 25 years; cotesting every 5 years or cytology alone every 3 years are also acceptable.¹¹ The US Preventive Services Task Force (USPSTF) states that cytology alone every 3 years starting at 21 years and then HPV testing alone or cotesting every 5 years or cytology every 3 years starting at age 30 are all acceptable strategies.¹²

When applying these guidelines, it is important to note that they are intended for the screening of patients with all prior normal results with no symptoms. These routine screening guidelines do not apply to special populations, such as those with a history of abnormal results or treatment, a history of immunosuppression,¹³ a history of HPV-related vulvar or vaginal dysplasia,^14-16 or a history of hysterectomy with removal of the cervix and no prior history of cervical dysplasia.^17,18 By contrast, surveillance is interval testing for those who have either an abnormal prior test result or treatment; these may be managed per risk-based estimates provided by the American Society for Colposcopy and Cervical Pathology (ASCCP).^18,19 Finally, diagnosis is evaluation (which may include diagnostic cytology) of a patient with abnormal signs and/or symptoms (such as bleeding, pain, discharge, or cervical mass).

In this Update, we present the evidence for primary HPV testing, the management options for a positive result in the United States, and research that will improve uptake of primary HPV testing as well as accessibility.

Change in screening paradigm: Evidence for primary HPV testing

HPV DNA tests are multiplex assays that detect the DNA of targeted high-risk HPV types, using multiple probes, either by direct genomic detection or by amplification of a viral DNA fragment using polymerase chain reaction (PCR).^20,21 Alternatively, HPV mRNA-based tests detect the expression of E6 and E7 oncoproteins, a marker of viral integration.²⁰ In examining the data from well-conducted clinical trials, 2 important observations are that different HPV assays were used and that direct comparison may not be valid. In addition, not all tests used in the studies are approved by the US Food and Drug Administration (FDA) for primary HPV testing.

Continue to: FDA-approved HPV tests...

 

 

FDA-approved HPV tests

Currently, 2 tests are FDA approved for primary HPV screening. The Cobas HPV test (Roche Molecular Diagnostics) was the first FDA-approved test for primary HPV screening in women aged 25 years and older.⁶ This test reports pooled results from 12 high-risk (hr) HPV types (31/33/35/39/45/51/52/56/58/59/66/68) with reflex genotyping for HPV 16/18, and thus it provides an immediate triage option for HPV-positive women. Of note, it is also approved for cotesting. The second FDA-approved test is the BD Onclarity HPV assay (Becton, Dickinson and Company) for primary HPV screening.²² It detects 14 hrHPV types, types 16/18/45 specifically as well as types 31/33/35/39/51/52/56/58/59/66/68.

Other HPV tests are FDA approved for cotesting and reflex testing but not for primary HPV testing. The Hybrid Capture test, or HC2 (Qiagen Inc), was the first HPV test to be approved by the FDA in 1997 for reflex testing of women with ASCUS cytology. In 2003, it was approved for cotesting along with cytology in women aged 30 years and older.^20,21 In 2009, the Cervista HPV HR test (Hologic Inc) was approved for cotesting. The Aptima HPV assay (Hologic Inc), which is also approved for cotesting, is an RNA-based assay that allows detection of E6/E7 mRNA transcripts of 14 HPV types.²³

Comparing HPV testing with cytology

Ronco and colleagues pooled data from 4 European randomized controlled trials (RCTs)—Swedescreen, POBASCAM, NTCC, ARTISTIC—with a total of 176,464 participants randomly assigned to HPV or cytology screening.²⁴ Swedescreen and POBASCAM used GP5/GP6 PCR, while ARTISTIC and NTCC used HC2 for primary HPV screening. The screening interval was 3 years in all except 5 years in POBASCAM. The pooled detection rate of invasive disease was similar in the 2 arms, with pooled rate ratio for cancer detection being 0.79 (95% confidence interval [CI], 0.46–1.36) in the first 2.5 years, but was 0.45 (95% CI, 0.25–0.81), favoring the HPV arm, after 2.5 years. HPV testing was more effective in preventing cases of adenocarcinoma than squamous cell carcinoma (0.31 [95% CI, 0.14–0.69] vs 0.78 [95% CI, 0.49–1.25]). The authors concluded that HPV-based screening from age 30 years provided 60% to 70% better protection than cytology.

The result of the above meta-analysis was confirmed by the HPV FOCAL RCT that investigated the efficacy of HPV testing (HC2) in comparison with cytology.²⁵ The detection rates for CIN 3 lesions supported primary HPV screening, with an absolute difference in incidence rate of 2.67/1,000 (95% CI, 0.53–4.88) at study randomization and 3.22/1,000 (95% CI, 5.12–1.48) at study exit 4 years later.

Cotesting using HPV and cytology: Marginal benefit

Dillner and colleagues were one of the first groups to report on the risk of CIN 3 based on both HPV and cytology status.²⁶ Using pooled analysis of data from multiple countries, these investigators reported that the cumulative incidence rates (CIR) of CIN 3 after 6 years of follow-up increased consistently in HPV-positive subjects, and an HPV-positive result more accurately predicted CIN 3+ at 5 years than cytology alone. Furthermore, HPV negativity provided greater reassurance than cytology alone. At 5 years of follow-up, the rates of CIN 3+ were 0.25% (0.12%–0.41%) for women negative for HPV compared with 0.83% (0.50%–1.13%) for women with negative cytology results. There was little difference in rates for CIN 3+ between women with negative results on both tests and women who were negative for HPV.

The important question is then the marginal benefit of cotesting, which is the most costly screening option. A study of 331,818 women enrolled for cotesting at Kaiser Permanente found that the risk of CIN 3+ predicted by HPV testing alone when compared with cytology was significantly higher at both 3 years (5.0% vs 3.8%; P = .046) and 5 years (7.6% vs 4.7%; P = .001).²⁷ A negative cytology result did not decrease the risk of CIN 3 further for HPV-negative patients (3 years: 0.047% vs 0.063%, P = .6; 5 years: 0.16% vs 0.17%, P = .8). They concluded that a negative HPV test was enough reassurance for low risk of CIN 3+ and that an additional negative cytology result does not provide extra reassurance.

Furthermore, a systematic meta-analysis of 48 studies, including 8 RCTs, found that the addition of cytology to HPV testing raised the sensitivity by 2% for CIN 3 compared with HPV testing alone. This improvement in sensitivity was at the expense of considerable loss of specificity, with a ratio of 0.93 (95% CI, 0.92–0.95) for CIN 3.²⁸ Schiffman and colleagues also assessed the relative contribution of HPV testing and cytology in detection of CIN 3 and cancer.²⁹ The HPV component alone identified a significantly higher proportion of preinvasive and invasive disease than cytology. Only 3.5% of precancers and 5.9% of cancers were preceded by HPV-negative, cytology-positive results. Thus, cytology contributed only 5 cases per million women per year to the sensitivity of the combined test, at the cost of significantly more colposcopies. Hence, the evidence suggests that there is limited benefit of adding cytology to HPV testing.³⁰

Continue to: Triage of a positive HPV result...

 

 

Triage of a positive HPV result

An important limitation of HPV testing is its inability to discriminate between transient and persistent infections. Referral of all HPV-positive cases to colposcopy would overburden the system with associated unnecessary procedures. Hence, a triage strategy is essential to identify clinically important infections that truly require colposcopic evaluation. The FIGURE illustrates the management of a primary HPV test result performed for screening.

HPV genotyping

One strategy for triaging a positive HPV test result is genotyping. HPV 16 and 18 have the highest risk of persistence and progression and merit immediate referral to colposcopy. In the ATHENA trial, CIN 3 was identified in 17.8% (95% CI, 14.8–20.7%) of HPV 16 positive women at baseline, and the CIR increased to 25.2% (95% CI, 21.7–28.7%) after 3 years. The 3-year CIR of CIN 3 was only 5.4% (95% CI, 4.5–6.3%) in women with HPV genotypes other than 16/18. HPV 18–positive women had a 3-year CIR that was intermediate between women with HPV 16 and women with the 12 other genotypes.⁶ Hence, HPV 16/18–positive cases should be referred for immediate colposcopy, and negative cases should be followed up with cytology and referred for colposcopy if the cytology is ASCUS or worse.³¹

In July 2020, extended genotyping was approved by the FDA with individual detection of HPV 31, 51, 52 (in addition to 16, 18, and 45) and pooled detection of 33/58, 35/39/68, and 56/59/66. One study found that individual genotypes HPV 16 and 31 carry baseline risk values for CIN 3+ (8.1% and 7.5%, respectively) that are above the 5-year risk threshold for referral to colposcopy following the ASCCP risk-based management guideline.³²

Cytology

The higher specificity of cytology makes it an option for triaging HPV-positive cases, and current management guidelines recommend triage to both genotyping and cytology for all patients who are HPV positive, and especially if they are HPV positive but HPV 16/18 negative. Of note, cytology results remain more subjective than those of primary HPV testing, but the combination of initial HPV testing with reflex to cytology is a reasonable and cost effective next step.¹⁸ The VASCAR trial found higher colposcopy referrals in the HPV screening and cytology triage group compared with the cytology alone group (19.36 vs 14.54 per 1,000 women).³³ The ATHENA trial investigated various triage strategies for HPV-positive cases and its impact on colposcopy referrals.⁶ Using HPV genotyping and reflex cytology, if HPV 16/18 was positive, colposcopy was advised, but if any of the other 12 HPV types were positive, reflex cytology was done. If reported as ASCUS or worse, colposcopy was performed; conversely, if it was normal, women were rescreened with cotesting after 1 year. Although this strategy led to a reduction in the number of colposcopies, referrals were still higher in the primary HPV arm (3,769 colposcopies per 294 cases) compared with cytology (1,934 colposcopies per 179 cases) or cotesting (3,097 colposcopies per 240 cases) in women aged 25 years.¹⁴

p16/Ki-67 Dual-Stain

Diffused p16 immunohistochemical staining, as opposed to focal staining, is associated with active HPV infection but can be present in low-grade as well as high-grade lesions.³⁴ Ki-67 is a marker of cellular proliferation. Coexpression of p16 and Ki-67 indicates a loss of cell cycle regulation and is a hallmark of neoplastic transformation. When positive, these tests are supportive of active HPV infection and of a high-grade lesion. Incorporation of these stains to cytology alone provides additional objective reassurance to cytology, where there is much inter- and intra-observer variability. These stains can be done by laboratories using the stains alone or they can use the FDA-approved p16/Ki-67 Dual-Stain immunohistochemistry (DS), CINtec PLUS Cytology (Roche Diagnostics). However, DS is not yet formally incorporated into triage algorithms by national guidelines.

The IMPACT trial assessed the performance of DS compared with cytology in the triage of HPV-positive results, with or without HPV 16/18 genotyping.³⁵ This was a prospective observational screening study of 35,263 women aged 25 to 65 years across 32 sites in the United States. Of the 4,927 HPV-positive patients with DS results, the sensitivity of DS for CIN 3+ was 91.9% (95% CI, 86.1%–95.4%) and 86.0% (95% CI, 77.5%–91.6%) in HPV 16/18–positive and in the 12 other genotypes, respectively. Using DS alone to triage HPV-positive results showed significantly higher sensitivity and specificity than HPV 16/18 genotyping with cytology triage of 12 “other” genotypes, and substantially higher sensitivity but lower specificity than using cytology alone. Of note, triage with DS alone would have referred significantly fewer women to colposcopy than HPV 16/18 genotyping with cytology triage for the 12 other genotypes (48.6% vs 56.0%; P< .0001).

Similarly, a retrospective analysis of the ATHENA trial cohort of HPV-positive results of 7,727 patients aged 25 years or older also demonstrated increased sensitivity of DS compared with cytology (74.9% vs 51.9%; P<.0001) and similar specificities (74.1% vs 75%; P = .3198).³⁶ The European PALMS study, which included 27,349 women aged 18 years or older across 5 countries who underwent routine screening with HPV testing, cytology, and DS, confirmed these findings.³⁷ The sensitivity of DS was higher than that of cytology (86.7% vs 68.5%; P<.001) for CIN 3+ with comparable specificities (95.2% vs 95.4%; P = .15).

Challenges and opportunities to improve access to primary HPV screening

The historical success of the Pap test in reducing the incidence of cervical cancer relied on individuals having access to the test. This remains true as screening transitions to primary HPV testing. Limitations of HPV-based screening include provider and patient knowledge; access to tests; cost; need for new laboratory infrastructure; need to leverage the electronic health record to record results, calculate a patient’s risk and determine next steps; and the need to re-educate patients and providers about this new model of care. The American Cancer Society and the Centers for Disease Control and Prevention are currently leading initiatives to help adopt primary HPV screening in the United States and to facilitate new care approaches.

Self-collection and independence from subjective cytology would further improve access. Multiple effectiveness studies and patient acceptability studies have shown that primary HPV screening via self-collection is effective, cost effective, and acceptable to women, especially among underscreened populations.³⁸ Sensitivity is comparable to clinician-obtained samples with polymerase chain reaction–based HPV tests. Furthermore, newer molecular tests that detect methylated target host genes or methylated viral genome can be used to triage HPV-positive cases. Several host methylation markers that identify the specific host genes (for example, CADM1, MAL, and miR-124-2) have been shown to be more specific, reproducible, and can be used in self-collected samples as they are based on molecular methylation analysis.³⁹ The ASCCP monitors these new developments and will incorporate promising tests and approaches once validated and FDA approved into the risk-based management guidelines. An erratum was recently published, and the risk-calculator is also available on the ASCCP website free of charge (https://app.asccp.org).⁴⁰

In conclusion, transition to primary HPV testing from Pap cytology in cervical cancer screening has many challenges but also opportunities. Learning from the experience of countries that have already adopted primary HPV testing is crucial to successful implementation of this new screening paradigm.⁴¹ The evidence supporting primary HPV screening with its improved sensitivity is clear, and the existing triage options and innovations will continue to improve triage of patients with clinically important lesions as well as accessibility. With strong advocacy and sound implementation, the WHO goal of cervical cancer elimination and 70% of women being screened with a high-performance test by age 35 and again by age 45 is achievable. ●

Cervical cancer is an important global health problem with an estimated 604,127 new cases and 341,831 deaths in 2020.¹ Nearly 85% of the disease burden affects individuals from low and middle-income countries. The World Health Organization (WHO) set forth the goal for all countries to reach and maintain an incidence rate of below 4 per 100,000 women by 2030 as part of the Global Strategy to Accelerate the Elimination of Cervical Cancer.

Although traditional Pap cytology has been the cornerstone of screening programs, its poor sensitivity of approximately 50% and limitations in accessibility require new strategies to achieve the elimination of cervical cancer.² The discovery that persistent infection with oncogenic human papillomavirus (HPV) is an essential step in the development of cervical cancer led to the development of diagnostic HPV tests, which have higher sensitivity than cytology (96.1% vs 53.0%) but somewhat lower specificity (90.7% vs 96.3%) for the detection of cervical intraepithelial neoplasia (CIN) 2 or worse lesions.² Initially, HPV testing was incorporated as a method to triage atypical squamous cells of undetermined significance (ASCUS) cytology results.³ Later, the concept of cotesting with cytology emerged,^4,5 and since then, several clinical trials have demonstrated the effectiveness of primary HPV screening.^6-9

In 2020, the WHO recommended HPV DNA testing as the primary screening method starting at the age of 30 years, with regular testing every 5 to 10 years, for the general population.¹⁰ Currently, primary HPV has been adopted in multiple countries, including Australia, the Netherlands, Turkey, England, and Argentina.

In the United States, there are 3 currently acceptable screening strategies: cytology, cytology plus HPV (cotesting), and primary HPV testing (TABLE). The American Cancer Society (ACS) specifically states that HPV testing alone every 5 years is preferred starting at age 25 years; cotesting every 5 years or cytology alone every 3 years are also acceptable.¹¹ The US Preventive Services Task Force (USPSTF) states that cytology alone every 3 years starting at 21 years and then HPV testing alone or cotesting every 5 years or cytology every 3 years starting at age 30 are all acceptable strategies.¹²

When applying these guidelines, it is important to note that they are intended for the screening of patients with all prior normal results with no symptoms. These routine screening guidelines do not apply to special populations, such as those with a history of abnormal results or treatment, a history of immunosuppression,¹³ a history of HPV-related vulvar or vaginal dysplasia,^14-16 or a history of hysterectomy with removal of the cervix and no prior history of cervical dysplasia.^17,18 By contrast, surveillance is interval testing for those who have either an abnormal prior test result or treatment; these may be managed per risk-based estimates provided by the American Society for Colposcopy and Cervical Pathology (ASCCP).^18,19 Finally, diagnosis is evaluation (which may include diagnostic cytology) of a patient with abnormal signs and/or symptoms (such as bleeding, pain, discharge, or cervical mass).

In this Update, we present the evidence for primary HPV testing, the management options for a positive result in the United States, and research that will improve uptake of primary HPV testing as well as accessibility.

Change in screening paradigm: Evidence for primary HPV testing

HPV DNA tests are multiplex assays that detect the DNA of targeted high-risk HPV types, using multiple probes, either by direct genomic detection or by amplification of a viral DNA fragment using polymerase chain reaction (PCR).^20,21 Alternatively, HPV mRNA-based tests detect the expression of E6 and E7 oncoproteins, a marker of viral integration.²⁰ In examining the data from well-conducted clinical trials, 2 important observations are that different HPV assays were used and that direct comparison may not be valid. In addition, not all tests used in the studies are approved by the US Food and Drug Administration (FDA) for primary HPV testing.

Continue to: FDA-approved HPV tests...

 

 

FDA-approved HPV tests

Currently, 2 tests are FDA approved for primary HPV screening. The Cobas HPV test (Roche Molecular Diagnostics) was the first FDA-approved test for primary HPV screening in women aged 25 years and older.⁶ This test reports pooled results from 12 high-risk (hr) HPV types (31/33/35/39/45/51/52/56/58/59/66/68) with reflex genotyping for HPV 16/18, and thus it provides an immediate triage option for HPV-positive women. Of note, it is also approved for cotesting. The second FDA-approved test is the BD Onclarity HPV assay (Becton, Dickinson and Company) for primary HPV screening.²² It detects 14 hrHPV types, types 16/18/45 specifically as well as types 31/33/35/39/51/52/56/58/59/66/68.

Other HPV tests are FDA approved for cotesting and reflex testing but not for primary HPV testing. The Hybrid Capture test, or HC2 (Qiagen Inc), was the first HPV test to be approved by the FDA in 1997 for reflex testing of women with ASCUS cytology. In 2003, it was approved for cotesting along with cytology in women aged 30 years and older.^20,21 In 2009, the Cervista HPV HR test (Hologic Inc) was approved for cotesting. The Aptima HPV assay (Hologic Inc), which is also approved for cotesting, is an RNA-based assay that allows detection of E6/E7 mRNA transcripts of 14 HPV types.²³

Comparing HPV testing with cytology

Ronco and colleagues pooled data from 4 European randomized controlled trials (RCTs)—Swedescreen, POBASCAM, NTCC, ARTISTIC—with a total of 176,464 participants randomly assigned to HPV or cytology screening.²⁴ Swedescreen and POBASCAM used GP5/GP6 PCR, while ARTISTIC and NTCC used HC2 for primary HPV screening. The screening interval was 3 years in all except 5 years in POBASCAM. The pooled detection rate of invasive disease was similar in the 2 arms, with pooled rate ratio for cancer detection being 0.79 (95% confidence interval [CI], 0.46–1.36) in the first 2.5 years, but was 0.45 (95% CI, 0.25–0.81), favoring the HPV arm, after 2.5 years. HPV testing was more effective in preventing cases of adenocarcinoma than squamous cell carcinoma (0.31 [95% CI, 0.14–0.69] vs 0.78 [95% CI, 0.49–1.25]). The authors concluded that HPV-based screening from age 30 years provided 60% to 70% better protection than cytology.

The result of the above meta-analysis was confirmed by the HPV FOCAL RCT that investigated the efficacy of HPV testing (HC2) in comparison with cytology.²⁵ The detection rates for CIN 3 lesions supported primary HPV screening, with an absolute difference in incidence rate of 2.67/1,000 (95% CI, 0.53–4.88) at study randomization and 3.22/1,000 (95% CI, 5.12–1.48) at study exit 4 years later.

Cotesting using HPV and cytology: Marginal benefit

Dillner and colleagues were one of the first groups to report on the risk of CIN 3 based on both HPV and cytology status.²⁶ Using pooled analysis of data from multiple countries, these investigators reported that the cumulative incidence rates (CIR) of CIN 3 after 6 years of follow-up increased consistently in HPV-positive subjects, and an HPV-positive result more accurately predicted CIN 3+ at 5 years than cytology alone. Furthermore, HPV negativity provided greater reassurance than cytology alone. At 5 years of follow-up, the rates of CIN 3+ were 0.25% (0.12%–0.41%) for women negative for HPV compared with 0.83% (0.50%–1.13%) for women with negative cytology results. There was little difference in rates for CIN 3+ between women with negative results on both tests and women who were negative for HPV.

The important question is then the marginal benefit of cotesting, which is the most costly screening option. A study of 331,818 women enrolled for cotesting at Kaiser Permanente found that the risk of CIN 3+ predicted by HPV testing alone when compared with cytology was significantly higher at both 3 years (5.0% vs 3.8%; P = .046) and 5 years (7.6% vs 4.7%; P = .001).²⁷ A negative cytology result did not decrease the risk of CIN 3 further for HPV-negative patients (3 years: 0.047% vs 0.063%, P = .6; 5 years: 0.16% vs 0.17%, P = .8). They concluded that a negative HPV test was enough reassurance for low risk of CIN 3+ and that an additional negative cytology result does not provide extra reassurance.

Furthermore, a systematic meta-analysis of 48 studies, including 8 RCTs, found that the addition of cytology to HPV testing raised the sensitivity by 2% for CIN 3 compared with HPV testing alone. This improvement in sensitivity was at the expense of considerable loss of specificity, with a ratio of 0.93 (95% CI, 0.92–0.95) for CIN 3.²⁸ Schiffman and colleagues also assessed the relative contribution of HPV testing and cytology in detection of CIN 3 and cancer.²⁹ The HPV component alone identified a significantly higher proportion of preinvasive and invasive disease than cytology. Only 3.5% of precancers and 5.9% of cancers were preceded by HPV-negative, cytology-positive results. Thus, cytology contributed only 5 cases per million women per year to the sensitivity of the combined test, at the cost of significantly more colposcopies. Hence, the evidence suggests that there is limited benefit of adding cytology to HPV testing.³⁰

Continue to: Triage of a positive HPV result...

 

 

Triage of a positive HPV result

An important limitation of HPV testing is its inability to discriminate between transient and persistent infections. Referral of all HPV-positive cases to colposcopy would overburden the system with associated unnecessary procedures. Hence, a triage strategy is essential to identify clinically important infections that truly require colposcopic evaluation. The FIGURE illustrates the management of a primary HPV test result performed for screening.

HPV genotyping

One strategy for triaging a positive HPV test result is genotyping. HPV 16 and 18 have the highest risk of persistence and progression and merit immediate referral to colposcopy. In the ATHENA trial, CIN 3 was identified in 17.8% (95% CI, 14.8–20.7%) of HPV 16 positive women at baseline, and the CIR increased to 25.2% (95% CI, 21.7–28.7%) after 3 years. The 3-year CIR of CIN 3 was only 5.4% (95% CI, 4.5–6.3%) in women with HPV genotypes other than 16/18. HPV 18–positive women had a 3-year CIR that was intermediate between women with HPV 16 and women with the 12 other genotypes.⁶ Hence, HPV 16/18–positive cases should be referred for immediate colposcopy, and negative cases should be followed up with cytology and referred for colposcopy if the cytology is ASCUS or worse.³¹

In July 2020, extended genotyping was approved by the FDA with individual detection of HPV 31, 51, 52 (in addition to 16, 18, and 45) and pooled detection of 33/58, 35/39/68, and 56/59/66. One study found that individual genotypes HPV 16 and 31 carry baseline risk values for CIN 3+ (8.1% and 7.5%, respectively) that are above the 5-year risk threshold for referral to colposcopy following the ASCCP risk-based management guideline.³²

Cytology

The higher specificity of cytology makes it an option for triaging HPV-positive cases, and current management guidelines recommend triage to both genotyping and cytology for all patients who are HPV positive, and especially if they are HPV positive but HPV 16/18 negative. Of note, cytology results remain more subjective than those of primary HPV testing, but the combination of initial HPV testing with reflex to cytology is a reasonable and cost effective next step.¹⁸ The VASCAR trial found higher colposcopy referrals in the HPV screening and cytology triage group compared with the cytology alone group (19.36 vs 14.54 per 1,000 women).³³ The ATHENA trial investigated various triage strategies for HPV-positive cases and its impact on colposcopy referrals.⁶ Using HPV genotyping and reflex cytology, if HPV 16/18 was positive, colposcopy was advised, but if any of the other 12 HPV types were positive, reflex cytology was done. If reported as ASCUS or worse, colposcopy was performed; conversely, if it was normal, women were rescreened with cotesting after 1 year. Although this strategy led to a reduction in the number of colposcopies, referrals were still higher in the primary HPV arm (3,769 colposcopies per 294 cases) compared with cytology (1,934 colposcopies per 179 cases) or cotesting (3,097 colposcopies per 240 cases) in women aged 25 years.¹⁴

p16/Ki-67 Dual-Stain

Diffused p16 immunohistochemical staining, as opposed to focal staining, is associated with active HPV infection but can be present in low-grade as well as high-grade lesions.³⁴ Ki-67 is a marker of cellular proliferation. Coexpression of p16 and Ki-67 indicates a loss of cell cycle regulation and is a hallmark of neoplastic transformation. When positive, these tests are supportive of active HPV infection and of a high-grade lesion. Incorporation of these stains to cytology alone provides additional objective reassurance to cytology, where there is much inter- and intra-observer variability. These stains can be done by laboratories using the stains alone or they can use the FDA-approved p16/Ki-67 Dual-Stain immunohistochemistry (DS), CINtec PLUS Cytology (Roche Diagnostics). However, DS is not yet formally incorporated into triage algorithms by national guidelines.

The IMPACT trial assessed the performance of DS compared with cytology in the triage of HPV-positive results, with or without HPV 16/18 genotyping.³⁵ This was a prospective observational screening study of 35,263 women aged 25 to 65 years across 32 sites in the United States. Of the 4,927 HPV-positive patients with DS results, the sensitivity of DS for CIN 3+ was 91.9% (95% CI, 86.1%–95.4%) and 86.0% (95% CI, 77.5%–91.6%) in HPV 16/18–positive and in the 12 other genotypes, respectively. Using DS alone to triage HPV-positive results showed significantly higher sensitivity and specificity than HPV 16/18 genotyping with cytology triage of 12 “other” genotypes, and substantially higher sensitivity but lower specificity than using cytology alone. Of note, triage with DS alone would have referred significantly fewer women to colposcopy than HPV 16/18 genotyping with cytology triage for the 12 other genotypes (48.6% vs 56.0%; P< .0001).

Similarly, a retrospective analysis of the ATHENA trial cohort of HPV-positive results of 7,727 patients aged 25 years or older also demonstrated increased sensitivity of DS compared with cytology (74.9% vs 51.9%; P<.0001) and similar specificities (74.1% vs 75%; P = .3198).³⁶ The European PALMS study, which included 27,349 women aged 18 years or older across 5 countries who underwent routine screening with HPV testing, cytology, and DS, confirmed these findings.³⁷ The sensitivity of DS was higher than that of cytology (86.7% vs 68.5%; P<.001) for CIN 3+ with comparable specificities (95.2% vs 95.4%; P = .15).

Challenges and opportunities to improve access to primary HPV screening

The historical success of the Pap test in reducing the incidence of cervical cancer relied on individuals having access to the test. This remains true as screening transitions to primary HPV testing. Limitations of HPV-based screening include provider and patient knowledge; access to tests; cost; need for new laboratory infrastructure; need to leverage the electronic health record to record results, calculate a patient’s risk and determine next steps; and the need to re-educate patients and providers about this new model of care. The American Cancer Society and the Centers for Disease Control and Prevention are currently leading initiatives to help adopt primary HPV screening in the United States and to facilitate new care approaches.

Self-collection and independence from subjective cytology would further improve access. Multiple effectiveness studies and patient acceptability studies have shown that primary HPV screening via self-collection is effective, cost effective, and acceptable to women, especially among underscreened populations.³⁸ Sensitivity is comparable to clinician-obtained samples with polymerase chain reaction–based HPV tests. Furthermore, newer molecular tests that detect methylated target host genes or methylated viral genome can be used to triage HPV-positive cases. Several host methylation markers that identify the specific host genes (for example, CADM1, MAL, and miR-124-2) have been shown to be more specific, reproducible, and can be used in self-collected samples as they are based on molecular methylation analysis.³⁹ The ASCCP monitors these new developments and will incorporate promising tests and approaches once validated and FDA approved into the risk-based management guidelines. An erratum was recently published, and the risk-calculator is also available on the ASCCP website free of charge (https://app.asccp.org).⁴⁰

In conclusion, transition to primary HPV testing from Pap cytology in cervical cancer screening has many challenges but also opportunities. Learning from the experience of countries that have already adopted primary HPV testing is crucial to successful implementation of this new screening paradigm.⁴¹ The evidence supporting primary HPV screening with its improved sensitivity is clear, and the existing triage options and innovations will continue to improve triage of patients with clinically important lesions as well as accessibility. With strong advocacy and sound implementation, the WHO goal of cervical cancer elimination and 70% of women being screened with a high-performance test by age 35 and again by age 45 is achievable. ●

ILLUSTRATION BY KIMBERLY MARTENS FOR OBG MANAGEMENT

David G. Mutch, MD: The cervical cancer screening guidelines, using Pap testing, have changed significantly since the times of yearly Paps and exams. Coupled with vaccination and new management guidelines (recommending HPV testing, etc), we actually hope that we are on the way to eradicating cervical cancer from our environment.

Screening: Current recommendations

Dr. Mutch: Warner, the American Society of Colposcopy and Cervical Pathology (ASCCP)¹ endorses the cervical cancer screening guidelines for several professional organizations, including the American Cancer Society (ACS),² the US Preventive Services Task Force (USPSTF),³ and the American College of Obstetricians and Gynecologists (ACOG).⁴ What are the current screening recommendations, as these organizations have disparate views?

Warner Huh, MD: There was a time, around 2012-2013, when for the first time ever, we had significant harmonization of the guidelines between ACOG and the USPSTF and ACS. But in the last 10 years there has been an explosion of data in terms of how to best screen patients.

The move to primary HPV testing. The USPSTF³ initially had recommended looking into primary HPV screening, which is just using HPV testing by itself as the screening modality. But there was a lot of pushback at that time. I think a lot of people thought that we were not prepared to make that leap. Therefore, they endorsed screening with cytology by itself as well as HPV testing by itself, as well as co-testing; but in their recommendations, they made it very clear that they were leaning toward primary HPV screening.

A new patient age to begin screening. In 2020, the ACS put out their new guidelines,² which are a significant departure from what we are used to—they are recommending that we start screening at 25 years of age. Like you said, Dr. Mutch, it doesn’t seem that long ago when we were screening people at age 18, or within 3 years of sexual intercourse. But the reason for it is that the rate of cervical cancer is extremely low under age 25, and other countries like the United Kingdom already do this.

The other major departure in the ACS guidelines is that they really are asking clinicians and screeners to focus on primary HPV screening. Overall, they have sort of doubled down on why they think primary HPV screening is so important.

ACOG sits sort of in the middle of the other recommendations. ACOG understands the value of primary HPV screening, but I don’t think that they are quite ready to recommend screening at age 25. If you look at their updated guidelines from April 2021,⁴ they state that we should continue a screening-starting age of 21 years. So there are some disparate views, but I am confident, Dr. Mutch, that in the next 2 to 3 years, there will be greater harmonization of these guidelines and less confusion for our providers. The greatest barrier is understanding the science and the comfort level of clinicians to go with just an HPV test, since for the last 40 years the Pap test has anchored gynecologic care in this country. And it took at least 10 years to get to what I consider to be widespread adoption to co-testing. The other thing that readers should recognize is that the Task Force is actually revisiting their cervical cancer screening guidance now, so expect another major revision.

Reimbursement and access are barriers. Reimbursement is a further real issue. We are now using one less test, but insurance companies may not reimburse when just the HPV test is used. The other issue is access to labs that can do the HPV testing.

Dr. Mutch: We used to see patients yearly and picked up a lot of adjunctive or additional illnesses. Now they are not being seen yearly it could impact negatively their overall health care. We need to understand that cervical cancer screening is simply a test, which should not eliminate other health care.

Dr. Huh: Yes, I think the extended interval between recommended HPV screenings scares people. I have been involved in these screening guidelines (and I can only speak for myself, not for my colleagues), but even I do think we made a leap to a longer interval way too quickly in this country. Screening changes are slow, and sometimes a glacial process. I think it can worry providers when we make rapid changes.

But this is a test that should not anchor the yearly visit. There are plenty of other reasons—and ACOG actually states this⁴—why patients should come for a wellness exam on a yearly basis. So I think our ObGyns in the United States need to recognize that, but I understand there are underlying concerns that if you extend intervals too long, (a) will patients come back, and (b), as a consequence, is the interval going to miss something in between? Those are real legitimate concerns.

Continue to: Management guidelines...

 

 

Management guidelines: The latest

Dr. Mutch: The ASCCP issued new management guidelines in 2019.⁵ Can you address what you feel are the most important updates?

Dr. Huh: Going back to 2002, we have revised these guidelines every 5 years. For this one, the revision came out a little bit later for various reasons, but the reason we revised it is because we collect new data that we think markedly changes our understanding of the disease process and natural history and the interventions for women that have preinvasive disease of the cervix.

Briefly, I think the biggest changes based on what we were hearing from our providers and users of our apps and algorithms was that our algorithms were becoming way too complicated, and they were. If you look over the last 10 years, the number of branch points on our algorithms basically quadrupled. If we incorporated the new data this time, the algorithms would be unworkable, and you could not use them on your phone because they would be too complicated.

So, we created a system where, in essence, providers have 5 choices for patients:

• treatment
• colposcopy
• follow-up in 1 year
• follow-up in 3 years
• follow-up in 5 years.

Those recommendations are based on what we call “clinically actionable thresholds”—basically, the percent chance of developing immediate CIN3 or worse. That threshold will probably change over time, but what we did is create a system that (a) makes it easier for the provider, (although they have to trust the system—and they can look under the hood and understand how we did this) and (b) allows us to create a foundation where we can add future technologies that use the same rubric or paradigm so that they still wind up getting the same result without having to go to another algorithm.

This new system is probably the most marked change in the history of the ASCCP management guidelines, but we did it to make it ultimately easier for providers going forward for the next 10 to 20 years. There are real opportunities, Dr. Mutch, in terms of how do we integrate this into the electronic medical record (EMR), and how do we pull data so clinicians don’t have to manually enter it.

The other difference is now there is a web-based application. Back in 2012, there were a lot of people that were not using EMRs. Now the majority of the country is, and so they actually are on a browser more than they are on their phone. We actually have an equally robust web platform that allows them to get the information that they need.

Dr. Mutch: I think that is really important—the utility of utilizing a mobile app, if you will, for triaging your patient with a specific test result so that patients are followed up at the proper interval, and that ultimately becomes cost-effective.

Dr. Huh: Yes, the app now is very different than the app that I think people are used to using for the last almost 10 years. You don’t put inputs, pull up the algorithm, and look at the outcome. This is different. You enter the patient’s age. You add their cytology, their HPV results, the clinical scenario that you are in, and then it puts out a recommendation of what to do next. Over time, we want to get away from an algorithm and for our providers to understand what the risk is and how that risk calculation then translates into a clinical recommendation.

Dr. Mutch: I think to utilize an app is almost necessary given the complexity of the triaging process so that it does become, in fact, the most cost-effective way to screen patients.

Dr. Huh: I would agree with that. There is a learning curve for whenever you see new technology. There was a learning curve for even ASCCP leadership as they tried to educate providers. I think people will ultimately see that this is a much better way of managing patients with cervical abnormalities, and I am hoping actually that we will use a similar platform for many other diseases that we manage in women’s health.

Continue to: Chipping away of the yearly exam...

 

 

Chipping away of the yearly exam

Dr. Mutch: With this moving away from the yearly exam and Pap test, women may not get yearly examinations. Do you feel that this could affect a stage migration to a higher stage at diagnosis, for instance, of a cervical cancer? Or that it might adversely impact other health issues?

Dr. Huh: I think that’s a good question. I am worried about the interval—I think 5 years is a bit long. I am more worried that patients will miss out on visits because they may think that they need to only come back for their Pap, even though they should be re-educated on that.

COVID-19 has made this a little hard for us to analyze because, clearly, we have had access to care issues. But I am a little concerned that we could see an uptick in invasive cancer rates in this country, including an uptick in the stage and more locally advanced cervical cancer because of the changes in the screening paradigms. But we don’t know that to be the case.

As with all screenings, the bottom line is you have to worry about what the false-negative and false-positive rates of screening are, and that affects everything. I want the readers to know that primary HPV should be used for screenings. It is not perfect, but it is much better than cytology alone. We need to think about how to better adapt screening in the age that we live in.

HPV self-sampling

Dr. Mutch: Could self-sampling for HPV testing, which obviously would be easier for the patient, and certainly useful in terms of screening, address some health care disparities with regard to cervical cancer?

Dr. Huh: The short answer is, yes. Self-sampling is not US Food and Drug Administration-approved in this country. It’s not being widely used without that approval. But there are multiple countries, including the United States, that have done lots of studies on this topic. There are many public health experts and champions for HPV self-sampling. I think we have learned, based on some studies, that the sensitivity is reasonable.⁶

I live in a part of the country that is woefully underserved; where you are there are pockets in Missouri that are woefully underserved as well. So the issue is, can we reduce these disparities and access to care with something like self-sampling? My personal feeling is I think that we can make a dent in that, and it is never going to fully replace screening, but it at least will allow us to reallocate our resources and attention to those women that are at highest risk for developing cervical cancer or precancer based on the self-sampling result.

I don’t think it will ever replace screening per se, but if we have an abnormal self-sampling test, we might say to that patient, “You really do need to come in to get re-tested or to get re-evaluated.” So it could be a better resource and use of our health care dollars and investments in terms of trying to reduce the incidence of cervical cancer. Of course the verdict is out, but I think there are a lot of people who would love to see this scenario.

If we screen and treat perfectly in this country, we would not even need the HPV vaccine when it comes to cervical cancer. That is how effective screening is. But, up to 50% to 60% of women in this country now still are underscreened or unscreened. We were talking about that number almost 25-30 years ago, Dr. Mutch. So access to screening is a big problem, but the other problem is how do you get patients in to be seen if they have an abnormal screening test? It’s not just about screening. It’s about screening, evaluation, and treatment; all 3 components are really important.

Continue to: Where do we stand with HPV vaccination?...

 

 

Where do we stand with HPV vaccination?

Dr. Mutch: Those are great points.

You brought up vaccination. We have a long way to go with regard to that, certainly in the United States, because of the various factions opposed to vaccination and so on. But do you think that vaccination has allowed us to decrease the incidence of cervical cancer?

Dr. Huh: Yes. There is clear evidence from the Nordic countries.⁷ There is emerging evidence from Australia.⁸ There is emerging evidence from other industrialized nations that clearly demonstrate vaccination’s positive effect in reducing the incidence of cervical cancer. None of this should be a surprise. Every population-based study that has been published with the HPV vaccine in populations that have a low frequency of vaccination have demonstrated substantial reductions in things like genital warts, abnormal Pap tests, precancer, and now evidence that there is a downward trend in terms of the incidence of cervical cancer.⁹

I don’t think that there is any debate anymore that vaccination is the way to go. Our challenge is about implementation and getting the vaccine to people. We still have a long way to go with that. There are parts of the world that are so affected by invasive cervical cancers; we need to get the vaccine to those parts of the world.

Dr. Mutch: What are the barriers to vaccination? How can we overcome those barriers?

Dr. Huh: There is a lot of criticism that we are not vaccinating more in the United States. However, the rates of vaccination are going up every single year. The pandemic may have blunted that rise a bit, but if you look at the vaccination curves, they are going up, not down. We need to continue to educate patients, parents, and pediatricians on the importance of vaccination.

Boys still get vaccinated less frequently than girls, so we have some work to do there. I think globally it is the issue of getting the vaccine to people, making sure that vaccine is available. The thing that I think will be the game-changer going forward is whether or not we will have evidence to indicate that 1 dose is as effective as 2 doses or 3 doses. If we can vaccinate boys and girls with just 1 dose, then in the next generation or two, we seriously might eradicate not just cervical cancer but a lot of HPV-related malignancies worldwide.

Educating patients, clinicians is key

Dr. Mutch: So it seems education, education, education, with regard to screening guidelines, with regard to the need for continued examinations, and that HPV testing is only a test, it does not supplant overall care. Finally, education regarding eradication of cervical cancer through vaccination.

Dr. Huh: That summarizes it well. We are still going to screen for cervical cancer. We are still going to vaccinate, and providers are still going to manage abnormal Pap tests. It is confusing because we are changing it up it seems every year or 2, so this conversation you and I are having is particularly important for clinicians to understand the basis of that. There has been an explosion of data that has come out in this area in the last decade.

Dr. Mutch: Thank you, Dr. Huh. I really appreciate your thoughts on this. As you all know, Dr. Huh has been President of the ASCCP and is instrumental in writing and disseminating these guidelines, so we are very grateful that he has consented to agree to come and talk with us today.

Dr. Huh: My pleasure. Thank you for inviting me. This was fun, and I have really enjoyed talking to you and participating. ●

ILLUSTRATION BY KIMBERLY MARTENS FOR OBG MANAGEMENT

David G. Mutch, MD: The cervical cancer screening guidelines, using Pap testing, have changed significantly since the times of yearly Paps and exams. Coupled with vaccination and new management guidelines (recommending HPV testing, etc), we actually hope that we are on the way to eradicating cervical cancer from our environment.

Screening: Current recommendations

Dr. Mutch: Warner, the American Society of Colposcopy and Cervical Pathology (ASCCP)¹ endorses the cervical cancer screening guidelines for several professional organizations, including the American Cancer Society (ACS),² the US Preventive Services Task Force (USPSTF),³ and the American College of Obstetricians and Gynecologists (ACOG).⁴ What are the current screening recommendations, as these organizations have disparate views?

Warner Huh, MD: There was a time, around 2012-2013, when for the first time ever, we had significant harmonization of the guidelines between ACOG and the USPSTF and ACS. But in the last 10 years there has been an explosion of data in terms of how to best screen patients.

The move to primary HPV testing. The USPSTF³ initially had recommended looking into primary HPV screening, which is just using HPV testing by itself as the screening modality. But there was a lot of pushback at that time. I think a lot of people thought that we were not prepared to make that leap. Therefore, they endorsed screening with cytology by itself as well as HPV testing by itself, as well as co-testing; but in their recommendations, they made it very clear that they were leaning toward primary HPV screening.

A new patient age to begin screening. In 2020, the ACS put out their new guidelines,² which are a significant departure from what we are used to—they are recommending that we start screening at 25 years of age. Like you said, Dr. Mutch, it doesn’t seem that long ago when we were screening people at age 18, or within 3 years of sexual intercourse. But the reason for it is that the rate of cervical cancer is extremely low under age 25, and other countries like the United Kingdom already do this.

The other major departure in the ACS guidelines is that they really are asking clinicians and screeners to focus on primary HPV screening. Overall, they have sort of doubled down on why they think primary HPV screening is so important.

ACOG sits sort of in the middle of the other recommendations. ACOG understands the value of primary HPV screening, but I don’t think that they are quite ready to recommend screening at age 25. If you look at their updated guidelines from April 2021,⁴ they state that we should continue a screening-starting age of 21 years. So there are some disparate views, but I am confident, Dr. Mutch, that in the next 2 to 3 years, there will be greater harmonization of these guidelines and less confusion for our providers. The greatest barrier is understanding the science and the comfort level of clinicians to go with just an HPV test, since for the last 40 years the Pap test has anchored gynecologic care in this country. And it took at least 10 years to get to what I consider to be widespread adoption to co-testing. The other thing that readers should recognize is that the Task Force is actually revisiting their cervical cancer screening guidance now, so expect another major revision.

Reimbursement and access are barriers. Reimbursement is a further real issue. We are now using one less test, but insurance companies may not reimburse when just the HPV test is used. The other issue is access to labs that can do the HPV testing.

Dr. Mutch: We used to see patients yearly and picked up a lot of adjunctive or additional illnesses. Now they are not being seen yearly it could impact negatively their overall health care. We need to understand that cervical cancer screening is simply a test, which should not eliminate other health care.

Dr. Huh: Yes, I think the extended interval between recommended HPV screenings scares people. I have been involved in these screening guidelines (and I can only speak for myself, not for my colleagues), but even I do think we made a leap to a longer interval way too quickly in this country. Screening changes are slow, and sometimes a glacial process. I think it can worry providers when we make rapid changes.

But this is a test that should not anchor the yearly visit. There are plenty of other reasons—and ACOG actually states this⁴—why patients should come for a wellness exam on a yearly basis. So I think our ObGyns in the United States need to recognize that, but I understand there are underlying concerns that if you extend intervals too long, (a) will patients come back, and (b), as a consequence, is the interval going to miss something in between? Those are real legitimate concerns.

Continue to: Management guidelines...

 

 

Management guidelines: The latest

Dr. Mutch: The ASCCP issued new management guidelines in 2019.⁵ Can you address what you feel are the most important updates?

Dr. Huh: Going back to 2002, we have revised these guidelines every 5 years. For this one, the revision came out a little bit later for various reasons, but the reason we revised it is because we collect new data that we think markedly changes our understanding of the disease process and natural history and the interventions for women that have preinvasive disease of the cervix.

Briefly, I think the biggest changes based on what we were hearing from our providers and users of our apps and algorithms was that our algorithms were becoming way too complicated, and they were. If you look over the last 10 years, the number of branch points on our algorithms basically quadrupled. If we incorporated the new data this time, the algorithms would be unworkable, and you could not use them on your phone because they would be too complicated.

So, we created a system where, in essence, providers have 5 choices for patients:

• treatment
• colposcopy
• follow-up in 1 year
• follow-up in 3 years
• follow-up in 5 years.

Those recommendations are based on what we call “clinically actionable thresholds”—basically, the percent chance of developing immediate CIN3 or worse. That threshold will probably change over time, but what we did is create a system that (a) makes it easier for the provider, (although they have to trust the system—and they can look under the hood and understand how we did this) and (b) allows us to create a foundation where we can add future technologies that use the same rubric or paradigm so that they still wind up getting the same result without having to go to another algorithm.

This new system is probably the most marked change in the history of the ASCCP management guidelines, but we did it to make it ultimately easier for providers going forward for the next 10 to 20 years. There are real opportunities, Dr. Mutch, in terms of how do we integrate this into the electronic medical record (EMR), and how do we pull data so clinicians don’t have to manually enter it.

The other difference is now there is a web-based application. Back in 2012, there were a lot of people that were not using EMRs. Now the majority of the country is, and so they actually are on a browser more than they are on their phone. We actually have an equally robust web platform that allows them to get the information that they need.

Dr. Mutch: I think that is really important—the utility of utilizing a mobile app, if you will, for triaging your patient with a specific test result so that patients are followed up at the proper interval, and that ultimately becomes cost-effective.

Dr. Huh: Yes, the app now is very different than the app that I think people are used to using for the last almost 10 years. You don’t put inputs, pull up the algorithm, and look at the outcome. This is different. You enter the patient’s age. You add their cytology, their HPV results, the clinical scenario that you are in, and then it puts out a recommendation of what to do next. Over time, we want to get away from an algorithm and for our providers to understand what the risk is and how that risk calculation then translates into a clinical recommendation.

Dr. Mutch: I think to utilize an app is almost necessary given the complexity of the triaging process so that it does become, in fact, the most cost-effective way to screen patients.

Dr. Huh: I would agree with that. There is a learning curve for whenever you see new technology. There was a learning curve for even ASCCP leadership as they tried to educate providers. I think people will ultimately see that this is a much better way of managing patients with cervical abnormalities, and I am hoping actually that we will use a similar platform for many other diseases that we manage in women’s health.

Continue to: Chipping away of the yearly exam...

 

 

Chipping away of the yearly exam

Dr. Mutch: With this moving away from the yearly exam and Pap test, women may not get yearly examinations. Do you feel that this could affect a stage migration to a higher stage at diagnosis, for instance, of a cervical cancer? Or that it might adversely impact other health issues?

Dr. Huh: I think that’s a good question. I am worried about the interval—I think 5 years is a bit long. I am more worried that patients will miss out on visits because they may think that they need to only come back for their Pap, even though they should be re-educated on that.

COVID-19 has made this a little hard for us to analyze because, clearly, we have had access to care issues. But I am a little concerned that we could see an uptick in invasive cancer rates in this country, including an uptick in the stage and more locally advanced cervical cancer because of the changes in the screening paradigms. But we don’t know that to be the case.

As with all screenings, the bottom line is you have to worry about what the false-negative and false-positive rates of screening are, and that affects everything. I want the readers to know that primary HPV should be used for screenings. It is not perfect, but it is much better than cytology alone. We need to think about how to better adapt screening in the age that we live in.

HPV self-sampling

Dr. Mutch: Could self-sampling for HPV testing, which obviously would be easier for the patient, and certainly useful in terms of screening, address some health care disparities with regard to cervical cancer?

Dr. Huh: The short answer is, yes. Self-sampling is not US Food and Drug Administration-approved in this country. It’s not being widely used without that approval. But there are multiple countries, including the United States, that have done lots of studies on this topic. There are many public health experts and champions for HPV self-sampling. I think we have learned, based on some studies, that the sensitivity is reasonable.⁶

I live in a part of the country that is woefully underserved; where you are there are pockets in Missouri that are woefully underserved as well. So the issue is, can we reduce these disparities and access to care with something like self-sampling? My personal feeling is I think that we can make a dent in that, and it is never going to fully replace screening, but it at least will allow us to reallocate our resources and attention to those women that are at highest risk for developing cervical cancer or precancer based on the self-sampling result.

I don’t think it will ever replace screening per se, but if we have an abnormal self-sampling test, we might say to that patient, “You really do need to come in to get re-tested or to get re-evaluated.” So it could be a better resource and use of our health care dollars and investments in terms of trying to reduce the incidence of cervical cancer. Of course the verdict is out, but I think there are a lot of people who would love to see this scenario.

If we screen and treat perfectly in this country, we would not even need the HPV vaccine when it comes to cervical cancer. That is how effective screening is. But, up to 50% to 60% of women in this country now still are underscreened or unscreened. We were talking about that number almost 25-30 years ago, Dr. Mutch. So access to screening is a big problem, but the other problem is how do you get patients in to be seen if they have an abnormal screening test? It’s not just about screening. It’s about screening, evaluation, and treatment; all 3 components are really important.

Continue to: Where do we stand with HPV vaccination?...

 

 

Where do we stand with HPV vaccination?

Dr. Mutch: Those are great points.

You brought up vaccination. We have a long way to go with regard to that, certainly in the United States, because of the various factions opposed to vaccination and so on. But do you think that vaccination has allowed us to decrease the incidence of cervical cancer?

Dr. Huh: Yes. There is clear evidence from the Nordic countries.⁷ There is emerging evidence from Australia.⁸ There is emerging evidence from other industrialized nations that clearly demonstrate vaccination’s positive effect in reducing the incidence of cervical cancer. None of this should be a surprise. Every population-based study that has been published with the HPV vaccine in populations that have a low frequency of vaccination have demonstrated substantial reductions in things like genital warts, abnormal Pap tests, precancer, and now evidence that there is a downward trend in terms of the incidence of cervical cancer.⁹

I don’t think that there is any debate anymore that vaccination is the way to go. Our challenge is about implementation and getting the vaccine to people. We still have a long way to go with that. There are parts of the world that are so affected by invasive cervical cancers; we need to get the vaccine to those parts of the world.

Dr. Mutch: What are the barriers to vaccination? How can we overcome those barriers?

Dr. Huh: There is a lot of criticism that we are not vaccinating more in the United States. However, the rates of vaccination are going up every single year. The pandemic may have blunted that rise a bit, but if you look at the vaccination curves, they are going up, not down. We need to continue to educate patients, parents, and pediatricians on the importance of vaccination.

Boys still get vaccinated less frequently than girls, so we have some work to do there. I think globally it is the issue of getting the vaccine to people, making sure that vaccine is available. The thing that I think will be the game-changer going forward is whether or not we will have evidence to indicate that 1 dose is as effective as 2 doses or 3 doses. If we can vaccinate boys and girls with just 1 dose, then in the next generation or two, we seriously might eradicate not just cervical cancer but a lot of HPV-related malignancies worldwide.

Educating patients, clinicians is key

Dr. Mutch: So it seems education, education, education, with regard to screening guidelines, with regard to the need for continued examinations, and that HPV testing is only a test, it does not supplant overall care. Finally, education regarding eradication of cervical cancer through vaccination.

Dr. Huh: That summarizes it well. We are still going to screen for cervical cancer. We are still going to vaccinate, and providers are still going to manage abnormal Pap tests. It is confusing because we are changing it up it seems every year or 2, so this conversation you and I are having is particularly important for clinicians to understand the basis of that. There has been an explosion of data that has come out in this area in the last decade.

Dr. Mutch: Thank you, Dr. Huh. I really appreciate your thoughts on this. As you all know, Dr. Huh has been President of the ASCCP and is instrumental in writing and disseminating these guidelines, so we are very grateful that he has consented to agree to come and talk with us today.

Dr. Huh: My pleasure. Thank you for inviting me. This was fun, and I have really enjoyed talking to you and participating. ●

ILLUSTRATION BY KIMBERLY MARTENS FOR OBG MANAGEMENT

David G. Mutch, MD: The cervical cancer screening guidelines, using Pap testing, have changed significantly since the times of yearly Paps and exams. Coupled with vaccination and new management guidelines (recommending HPV testing, etc), we actually hope that we are on the way to eradicating cervical cancer from our environment.

Screening: Current recommendations

Dr. Mutch: Warner, the American Society of Colposcopy and Cervical Pathology (ASCCP)¹ endorses the cervical cancer screening guidelines for several professional organizations, including the American Cancer Society (ACS),² the US Preventive Services Task Force (USPSTF),³ and the American College of Obstetricians and Gynecologists (ACOG).⁴ What are the current screening recommendations, as these organizations have disparate views?

Warner Huh, MD: There was a time, around 2012-2013, when for the first time ever, we had significant harmonization of the guidelines between ACOG and the USPSTF and ACS. But in the last 10 years there has been an explosion of data in terms of how to best screen patients.

The move to primary HPV testing. The USPSTF³ initially had recommended looking into primary HPV screening, which is just using HPV testing by itself as the screening modality. But there was a lot of pushback at that time. I think a lot of people thought that we were not prepared to make that leap. Therefore, they endorsed screening with cytology by itself as well as HPV testing by itself, as well as co-testing; but in their recommendations, they made it very clear that they were leaning toward primary HPV screening.

A new patient age to begin screening. In 2020, the ACS put out their new guidelines,² which are a significant departure from what we are used to—they are recommending that we start screening at 25 years of age. Like you said, Dr. Mutch, it doesn’t seem that long ago when we were screening people at age 18, or within 3 years of sexual intercourse. But the reason for it is that the rate of cervical cancer is extremely low under age 25, and other countries like the United Kingdom already do this.

The other major departure in the ACS guidelines is that they really are asking clinicians and screeners to focus on primary HPV screening. Overall, they have sort of doubled down on why they think primary HPV screening is so important.

ACOG sits sort of in the middle of the other recommendations. ACOG understands the value of primary HPV screening, but I don’t think that they are quite ready to recommend screening at age 25. If you look at their updated guidelines from April 2021,⁴ they state that we should continue a screening-starting age of 21 years. So there are some disparate views, but I am confident, Dr. Mutch, that in the next 2 to 3 years, there will be greater harmonization of these guidelines and less confusion for our providers. The greatest barrier is understanding the science and the comfort level of clinicians to go with just an HPV test, since for the last 40 years the Pap test has anchored gynecologic care in this country. And it took at least 10 years to get to what I consider to be widespread adoption to co-testing. The other thing that readers should recognize is that the Task Force is actually revisiting their cervical cancer screening guidance now, so expect another major revision.

Reimbursement and access are barriers. Reimbursement is a further real issue. We are now using one less test, but insurance companies may not reimburse when just the HPV test is used. The other issue is access to labs that can do the HPV testing.

Dr. Mutch: We used to see patients yearly and picked up a lot of adjunctive or additional illnesses. Now they are not being seen yearly it could impact negatively their overall health care. We need to understand that cervical cancer screening is simply a test, which should not eliminate other health care.

Dr. Huh: Yes, I think the extended interval between recommended HPV screenings scares people. I have been involved in these screening guidelines (and I can only speak for myself, not for my colleagues), but even I do think we made a leap to a longer interval way too quickly in this country. Screening changes are slow, and sometimes a glacial process. I think it can worry providers when we make rapid changes.

But this is a test that should not anchor the yearly visit. There are plenty of other reasons—and ACOG actually states this⁴—why patients should come for a wellness exam on a yearly basis. So I think our ObGyns in the United States need to recognize that, but I understand there are underlying concerns that if you extend intervals too long, (a) will patients come back, and (b), as a consequence, is the interval going to miss something in between? Those are real legitimate concerns.

Continue to: Management guidelines...

 

 

Management guidelines: The latest

Dr. Mutch: The ASCCP issued new management guidelines in 2019.⁵ Can you address what you feel are the most important updates?

Dr. Huh: Going back to 2002, we have revised these guidelines every 5 years. For this one, the revision came out a little bit later for various reasons, but the reason we revised it is because we collect new data that we think markedly changes our understanding of the disease process and natural history and the interventions for women that have preinvasive disease of the cervix.

Briefly, I think the biggest changes based on what we were hearing from our providers and users of our apps and algorithms was that our algorithms were becoming way too complicated, and they were. If you look over the last 10 years, the number of branch points on our algorithms basically quadrupled. If we incorporated the new data this time, the algorithms would be unworkable, and you could not use them on your phone because they would be too complicated.

So, we created a system where, in essence, providers have 5 choices for patients:

• treatment
• colposcopy
• follow-up in 1 year
• follow-up in 3 years
• follow-up in 5 years.

Those recommendations are based on what we call “clinically actionable thresholds”—basically, the percent chance of developing immediate CIN3 or worse. That threshold will probably change over time, but what we did is create a system that (a) makes it easier for the provider, (although they have to trust the system—and they can look under the hood and understand how we did this) and (b) allows us to create a foundation where we can add future technologies that use the same rubric or paradigm so that they still wind up getting the same result without having to go to another algorithm.

This new system is probably the most marked change in the history of the ASCCP management guidelines, but we did it to make it ultimately easier for providers going forward for the next 10 to 20 years. There are real opportunities, Dr. Mutch, in terms of how do we integrate this into the electronic medical record (EMR), and how do we pull data so clinicians don’t have to manually enter it.

The other difference is now there is a web-based application. Back in 2012, there were a lot of people that were not using EMRs. Now the majority of the country is, and so they actually are on a browser more than they are on their phone. We actually have an equally robust web platform that allows them to get the information that they need.

Dr. Mutch: I think that is really important—the utility of utilizing a mobile app, if you will, for triaging your patient with a specific test result so that patients are followed up at the proper interval, and that ultimately becomes cost-effective.

Dr. Huh: Yes, the app now is very different than the app that I think people are used to using for the last almost 10 years. You don’t put inputs, pull up the algorithm, and look at the outcome. This is different. You enter the patient’s age. You add their cytology, their HPV results, the clinical scenario that you are in, and then it puts out a recommendation of what to do next. Over time, we want to get away from an algorithm and for our providers to understand what the risk is and how that risk calculation then translates into a clinical recommendation.

Dr. Mutch: I think to utilize an app is almost necessary given the complexity of the triaging process so that it does become, in fact, the most cost-effective way to screen patients.

Dr. Huh: I would agree with that. There is a learning curve for whenever you see new technology. There was a learning curve for even ASCCP leadership as they tried to educate providers. I think people will ultimately see that this is a much better way of managing patients with cervical abnormalities, and I am hoping actually that we will use a similar platform for many other diseases that we manage in women’s health.

Continue to: Chipping away of the yearly exam...

 

 

Chipping away of the yearly exam

Dr. Mutch: With this moving away from the yearly exam and Pap test, women may not get yearly examinations. Do you feel that this could affect a stage migration to a higher stage at diagnosis, for instance, of a cervical cancer? Or that it might adversely impact other health issues?

Dr. Huh: I think that’s a good question. I am worried about the interval—I think 5 years is a bit long. I am more worried that patients will miss out on visits because they may think that they need to only come back for their Pap, even though they should be re-educated on that.

COVID-19 has made this a little hard for us to analyze because, clearly, we have had access to care issues. But I am a little concerned that we could see an uptick in invasive cancer rates in this country, including an uptick in the stage and more locally advanced cervical cancer because of the changes in the screening paradigms. But we don’t know that to be the case.

As with all screenings, the bottom line is you have to worry about what the false-negative and false-positive rates of screening are, and that affects everything. I want the readers to know that primary HPV should be used for screenings. It is not perfect, but it is much better than cytology alone. We need to think about how to better adapt screening in the age that we live in.

HPV self-sampling

Dr. Mutch: Could self-sampling for HPV testing, which obviously would be easier for the patient, and certainly useful in terms of screening, address some health care disparities with regard to cervical cancer?

Dr. Huh: The short answer is, yes. Self-sampling is not US Food and Drug Administration-approved in this country. It’s not being widely used without that approval. But there are multiple countries, including the United States, that have done lots of studies on this topic. There are many public health experts and champions for HPV self-sampling. I think we have learned, based on some studies, that the sensitivity is reasonable.⁶

I live in a part of the country that is woefully underserved; where you are there are pockets in Missouri that are woefully underserved as well. So the issue is, can we reduce these disparities and access to care with something like self-sampling? My personal feeling is I think that we can make a dent in that, and it is never going to fully replace screening, but it at least will allow us to reallocate our resources and attention to those women that are at highest risk for developing cervical cancer or precancer based on the self-sampling result.

I don’t think it will ever replace screening per se, but if we have an abnormal self-sampling test, we might say to that patient, “You really do need to come in to get re-tested or to get re-evaluated.” So it could be a better resource and use of our health care dollars and investments in terms of trying to reduce the incidence of cervical cancer. Of course the verdict is out, but I think there are a lot of people who would love to see this scenario.

If we screen and treat perfectly in this country, we would not even need the HPV vaccine when it comes to cervical cancer. That is how effective screening is. But, up to 50% to 60% of women in this country now still are underscreened or unscreened. We were talking about that number almost 25-30 years ago, Dr. Mutch. So access to screening is a big problem, but the other problem is how do you get patients in to be seen if they have an abnormal screening test? It’s not just about screening. It’s about screening, evaluation, and treatment; all 3 components are really important.

Continue to: Where do we stand with HPV vaccination?...

 

 

Where do we stand with HPV vaccination?

Dr. Mutch: Those are great points.

You brought up vaccination. We have a long way to go with regard to that, certainly in the United States, because of the various factions opposed to vaccination and so on. But do you think that vaccination has allowed us to decrease the incidence of cervical cancer?

Dr. Huh: Yes. There is clear evidence from the Nordic countries.⁷ There is emerging evidence from Australia.⁸ There is emerging evidence from other industrialized nations that clearly demonstrate vaccination’s positive effect in reducing the incidence of cervical cancer. None of this should be a surprise. Every population-based study that has been published with the HPV vaccine in populations that have a low frequency of vaccination have demonstrated substantial reductions in things like genital warts, abnormal Pap tests, precancer, and now evidence that there is a downward trend in terms of the incidence of cervical cancer.⁹

I don’t think that there is any debate anymore that vaccination is the way to go. Our challenge is about implementation and getting the vaccine to people. We still have a long way to go with that. There are parts of the world that are so affected by invasive cervical cancers; we need to get the vaccine to those parts of the world.

Dr. Mutch: What are the barriers to vaccination? How can we overcome those barriers?

Dr. Huh: There is a lot of criticism that we are not vaccinating more in the United States. However, the rates of vaccination are going up every single year. The pandemic may have blunted that rise a bit, but if you look at the vaccination curves, they are going up, not down. We need to continue to educate patients, parents, and pediatricians on the importance of vaccination.

Boys still get vaccinated less frequently than girls, so we have some work to do there. I think globally it is the issue of getting the vaccine to people, making sure that vaccine is available. The thing that I think will be the game-changer going forward is whether or not we will have evidence to indicate that 1 dose is as effective as 2 doses or 3 doses. If we can vaccinate boys and girls with just 1 dose, then in the next generation or two, we seriously might eradicate not just cervical cancer but a lot of HPV-related malignancies worldwide.

Educating patients, clinicians is key

Dr. Mutch: So it seems education, education, education, with regard to screening guidelines, with regard to the need for continued examinations, and that HPV testing is only a test, it does not supplant overall care. Finally, education regarding eradication of cervical cancer through vaccination.

Dr. Huh: That summarizes it well. We are still going to screen for cervical cancer. We are still going to vaccinate, and providers are still going to manage abnormal Pap tests. It is confusing because we are changing it up it seems every year or 2, so this conversation you and I are having is particularly important for clinicians to understand the basis of that. There has been an explosion of data that has come out in this area in the last decade.

Dr. Mutch: Thank you, Dr. Huh. I really appreciate your thoughts on this. As you all know, Dr. Huh has been President of the ASCCP and is instrumental in writing and disseminating these guidelines, so we are very grateful that he has consented to agree to come and talk with us today.

Dr. Huh: My pleasure. Thank you for inviting me. This was fun, and I have really enjoyed talking to you and participating. ●

Children who have greater acute appendicitis pain may be less likely to improve if they’re treated with antibiotics alone, according to a secondary analysis of a nonrandomized clinical trial.

“While approximately 35% of families chose nonoperative management, a high pain score between 7-10 on a 10-point scale nearly doubled in-hospital treatment failure,” Rebecca M. Rentea, MD, a pediatric surgeon and the director of the Comprehensive Colorectal Center at Children’s Mercy Kansas City, Mo., told this news organization in an email.

“Even if nonoperative management of pediatric appendicitis did not work – resulting in the need to remove the appendix in 34% of cases – families were happy with their decisions 1 year later,” added Dr. Rentea, who coauthored an invited commentary about the study.

Lead study author Peter C. Minneci, MD, MHSc, a pediatric surgeon at Nationwide Children’s Hospital, Columbus, Ohio, and colleagues analyzed a subgroup of patients from a larger study in 10 tertiary children’s hospitals in the Midwest Pediatric Surgery Consortium.

As they reported in JAMA Network Open, the larger prospective, nonrandomized clinical trial enrolled 1,068 children between 2015 and 2018. The children ranged in age from 7 to 17 years, and they had imaging-confirmed appendicitis with an appendix diameter of 1.1 cm or less, no abscess, no appendicolith, and no phlegmon. White blood cell count was between 5,000 and 18,000 cells/μL, and abdominal pain began less than 48 hours before they received antibiotic therapy.

Caregivers chose either surgery or nonoperative antibiotic management. Patients who were treated first with antibiotics alone and who did not undergo appendectomy within 1 year were considered to have successfully completed nonoperative treatment.

The secondary analysis included the 370 children enrolled in the nonoperative group. Of these, 229 were boys, and the median age was 12.3 years. In this subgroup, the researchers compared outcomes after nonoperative, antibiotic management vs. surgery.

At 1 year, treatment failure had occurred in 125 patients, with 53 having undergone appendectomy during their first hospitalization, and 72 having experienced delayed treatment failure after being discharged.

• Higher patient-reported pain at presentation was linked to higher risk for in-hospital treatment failure (relative risk, 2.1; 95% confidence interval, 1.0-4.4) but not for delayed treatment failure (RR, 1.3; 95% CI, 0.7-2.3) or overall treatment failure at 1 year (RR, 1.5; 95% CI, 1.0-2.2).
• Pain lasting longer than 24 hours was linked to lower risk for delayed treatment failure (RR, 0.3; 95% CI, 0.1-1.0) but not for in-hospital treatment failure (RR, 1.2; 95% CI, 0.5-2.7) or treatment failure at 1 year (RR, 0.7; 95% CI, 0.4-1.2).
• Satisfaction with the decision was higher with successful nonoperative management at 30 days (28.0 vs. 27.0; difference, 1.0; 95% CI, 0.01-2.0) and at 1 year (28.1 vs 27.0; difference, 1.1; 95% CI, 0.2-2.0).

The researchers found no increased risk for treatment failure based on age, sex, race, ethnicity, white blood cell count, primary language, insurance status, transfer status, presentation symptoms, or imaging results.

Antibiotics-only is a safe option for children

“This study suggests that pediatric patients with uncomplicated acute appendicitis should be offered treatment options, including nonoperative management,” the authors write. “Treatment with antibiotics alone is a safe and equitable option for children, with no increased risk of treatment failure based on sociodemographic or objective clinical characteristics at presentation.”

But, the authors advise: “Families need to be made aware that treatment failure is not uncommon, and they should be provided with anticipatory guidance on how to proceed should symptoms recur.”

The investigators acknowledged limitations to the study, including the nonrandomized design that may have introduced bias, the loss to follow-up, and the study population being U.S. Midwest children, who may differ from children elsewhere in the country.

Shawn D. St Peter, MD, a pediatric surgeon, medical chair, and a senior vice president at Children’s Mercy Kansas City told this news organization in an email that having a nonoperative alternative to surgical appendectomy is important.

“Antibiotics are the initial treatment for appendicitis and can be the definitive treatment,” he said.

“Surprisingly, no sociodemographic or clinical characteristics were associated with an increased risk of nonoperative appendicitis treatment failure,” added Dr. St Peter, who coauthored the commentary with Dr. Rentea.

Howard C. Jen, MD, a pediatric surgeon at University of California, Los Angeles, Mattel Children’s Hospital, was not surprised by the findings.

“Nonoperative management for acute noncomplicated appendicitis in children continues to be safe and effective in highly selected patients,” he said in an email. “This alternative to surgery should be offered routinely to patients with early acute appendicitis.” 

Dr. Jen, who was not involved with the current study, noted that it did not address the impact and costs to families of nonoperative management vs. surgery.

“For the most vulnerable children who had difficulties accessing medical care, what is the best treatment option? What factors are important to the families when making this decision?” he asked.

All study and editorial authors report no relevant financial relationships. The study was funded by the Patient-Centered Outcomes Research Institute and the National Center for Advancing Translational Sciences.

A version of this article first appeared on Medscape.com.

Children who have greater acute appendicitis pain may be less likely to improve if they’re treated with antibiotics alone, according to a secondary analysis of a nonrandomized clinical trial.

“While approximately 35% of families chose nonoperative management, a high pain score between 7-10 on a 10-point scale nearly doubled in-hospital treatment failure,” Rebecca M. Rentea, MD, a pediatric surgeon and the director of the Comprehensive Colorectal Center at Children’s Mercy Kansas City, Mo., told this news organization in an email.

“Even if nonoperative management of pediatric appendicitis did not work – resulting in the need to remove the appendix in 34% of cases – families were happy with their decisions 1 year later,” added Dr. Rentea, who coauthored an invited commentary about the study.

Lead study author Peter C. Minneci, MD, MHSc, a pediatric surgeon at Nationwide Children’s Hospital, Columbus, Ohio, and colleagues analyzed a subgroup of patients from a larger study in 10 tertiary children’s hospitals in the Midwest Pediatric Surgery Consortium.

As they reported in JAMA Network Open, the larger prospective, nonrandomized clinical trial enrolled 1,068 children between 2015 and 2018. The children ranged in age from 7 to 17 years, and they had imaging-confirmed appendicitis with an appendix diameter of 1.1 cm or less, no abscess, no appendicolith, and no phlegmon. White blood cell count was between 5,000 and 18,000 cells/μL, and abdominal pain began less than 48 hours before they received antibiotic therapy.

Caregivers chose either surgery or nonoperative antibiotic management. Patients who were treated first with antibiotics alone and who did not undergo appendectomy within 1 year were considered to have successfully completed nonoperative treatment.

The secondary analysis included the 370 children enrolled in the nonoperative group. Of these, 229 were boys, and the median age was 12.3 years. In this subgroup, the researchers compared outcomes after nonoperative, antibiotic management vs. surgery.

At 1 year, treatment failure had occurred in 125 patients, with 53 having undergone appendectomy during their first hospitalization, and 72 having experienced delayed treatment failure after being discharged.

• Higher patient-reported pain at presentation was linked to higher risk for in-hospital treatment failure (relative risk, 2.1; 95% confidence interval, 1.0-4.4) but not for delayed treatment failure (RR, 1.3; 95% CI, 0.7-2.3) or overall treatment failure at 1 year (RR, 1.5; 95% CI, 1.0-2.2).
• Pain lasting longer than 24 hours was linked to lower risk for delayed treatment failure (RR, 0.3; 95% CI, 0.1-1.0) but not for in-hospital treatment failure (RR, 1.2; 95% CI, 0.5-2.7) or treatment failure at 1 year (RR, 0.7; 95% CI, 0.4-1.2).
• Satisfaction with the decision was higher with successful nonoperative management at 30 days (28.0 vs. 27.0; difference, 1.0; 95% CI, 0.01-2.0) and at 1 year (28.1 vs 27.0; difference, 1.1; 95% CI, 0.2-2.0).

The researchers found no increased risk for treatment failure based on age, sex, race, ethnicity, white blood cell count, primary language, insurance status, transfer status, presentation symptoms, or imaging results.

Antibiotics-only is a safe option for children

“This study suggests that pediatric patients with uncomplicated acute appendicitis should be offered treatment options, including nonoperative management,” the authors write. “Treatment with antibiotics alone is a safe and equitable option for children, with no increased risk of treatment failure based on sociodemographic or objective clinical characteristics at presentation.”

But, the authors advise: “Families need to be made aware that treatment failure is not uncommon, and they should be provided with anticipatory guidance on how to proceed should symptoms recur.”

The investigators acknowledged limitations to the study, including the nonrandomized design that may have introduced bias, the loss to follow-up, and the study population being U.S. Midwest children, who may differ from children elsewhere in the country.

Shawn D. St Peter, MD, a pediatric surgeon, medical chair, and a senior vice president at Children’s Mercy Kansas City told this news organization in an email that having a nonoperative alternative to surgical appendectomy is important.

“Antibiotics are the initial treatment for appendicitis and can be the definitive treatment,” he said.

“Surprisingly, no sociodemographic or clinical characteristics were associated with an increased risk of nonoperative appendicitis treatment failure,” added Dr. St Peter, who coauthored the commentary with Dr. Rentea.

Howard C. Jen, MD, a pediatric surgeon at University of California, Los Angeles, Mattel Children’s Hospital, was not surprised by the findings.

“Nonoperative management for acute noncomplicated appendicitis in children continues to be safe and effective in highly selected patients,” he said in an email. “This alternative to surgery should be offered routinely to patients with early acute appendicitis.” 

Dr. Jen, who was not involved with the current study, noted that it did not address the impact and costs to families of nonoperative management vs. surgery.

“For the most vulnerable children who had difficulties accessing medical care, what is the best treatment option? What factors are important to the families when making this decision?” he asked.

All study and editorial authors report no relevant financial relationships. The study was funded by the Patient-Centered Outcomes Research Institute and the National Center for Advancing Translational Sciences.

A version of this article first appeared on Medscape.com.

Children who have greater acute appendicitis pain may be less likely to improve if they’re treated with antibiotics alone, according to a secondary analysis of a nonrandomized clinical trial.

“While approximately 35% of families chose nonoperative management, a high pain score between 7-10 on a 10-point scale nearly doubled in-hospital treatment failure,” Rebecca M. Rentea, MD, a pediatric surgeon and the director of the Comprehensive Colorectal Center at Children’s Mercy Kansas City, Mo., told this news organization in an email.

“Even if nonoperative management of pediatric appendicitis did not work – resulting in the need to remove the appendix in 34% of cases – families were happy with their decisions 1 year later,” added Dr. Rentea, who coauthored an invited commentary about the study.

Lead study author Peter C. Minneci, MD, MHSc, a pediatric surgeon at Nationwide Children’s Hospital, Columbus, Ohio, and colleagues analyzed a subgroup of patients from a larger study in 10 tertiary children’s hospitals in the Midwest Pediatric Surgery Consortium.

As they reported in JAMA Network Open, the larger prospective, nonrandomized clinical trial enrolled 1,068 children between 2015 and 2018. The children ranged in age from 7 to 17 years, and they had imaging-confirmed appendicitis with an appendix diameter of 1.1 cm or less, no abscess, no appendicolith, and no phlegmon. White blood cell count was between 5,000 and 18,000 cells/μL, and abdominal pain began less than 48 hours before they received antibiotic therapy.

Caregivers chose either surgery or nonoperative antibiotic management. Patients who were treated first with antibiotics alone and who did not undergo appendectomy within 1 year were considered to have successfully completed nonoperative treatment.

The secondary analysis included the 370 children enrolled in the nonoperative group. Of these, 229 were boys, and the median age was 12.3 years. In this subgroup, the researchers compared outcomes after nonoperative, antibiotic management vs. surgery.

At 1 year, treatment failure had occurred in 125 patients, with 53 having undergone appendectomy during their first hospitalization, and 72 having experienced delayed treatment failure after being discharged.

• Higher patient-reported pain at presentation was linked to higher risk for in-hospital treatment failure (relative risk, 2.1; 95% confidence interval, 1.0-4.4) but not for delayed treatment failure (RR, 1.3; 95% CI, 0.7-2.3) or overall treatment failure at 1 year (RR, 1.5; 95% CI, 1.0-2.2).
• Pain lasting longer than 24 hours was linked to lower risk for delayed treatment failure (RR, 0.3; 95% CI, 0.1-1.0) but not for in-hospital treatment failure (RR, 1.2; 95% CI, 0.5-2.7) or treatment failure at 1 year (RR, 0.7; 95% CI, 0.4-1.2).
• Satisfaction with the decision was higher with successful nonoperative management at 30 days (28.0 vs. 27.0; difference, 1.0; 95% CI, 0.01-2.0) and at 1 year (28.1 vs 27.0; difference, 1.1; 95% CI, 0.2-2.0).

The researchers found no increased risk for treatment failure based on age, sex, race, ethnicity, white blood cell count, primary language, insurance status, transfer status, presentation symptoms, or imaging results.

Antibiotics-only is a safe option for children

“This study suggests that pediatric patients with uncomplicated acute appendicitis should be offered treatment options, including nonoperative management,” the authors write. “Treatment with antibiotics alone is a safe and equitable option for children, with no increased risk of treatment failure based on sociodemographic or objective clinical characteristics at presentation.”

But, the authors advise: “Families need to be made aware that treatment failure is not uncommon, and they should be provided with anticipatory guidance on how to proceed should symptoms recur.”

The investigators acknowledged limitations to the study, including the nonrandomized design that may have introduced bias, the loss to follow-up, and the study population being U.S. Midwest children, who may differ from children elsewhere in the country.

Shawn D. St Peter, MD, a pediatric surgeon, medical chair, and a senior vice president at Children’s Mercy Kansas City told this news organization in an email that having a nonoperative alternative to surgical appendectomy is important.

“Antibiotics are the initial treatment for appendicitis and can be the definitive treatment,” he said.

“Surprisingly, no sociodemographic or clinical characteristics were associated with an increased risk of nonoperative appendicitis treatment failure,” added Dr. St Peter, who coauthored the commentary with Dr. Rentea.

Howard C. Jen, MD, a pediatric surgeon at University of California, Los Angeles, Mattel Children’s Hospital, was not surprised by the findings.

“Nonoperative management for acute noncomplicated appendicitis in children continues to be safe and effective in highly selected patients,” he said in an email. “This alternative to surgery should be offered routinely to patients with early acute appendicitis.” 

Dr. Jen, who was not involved with the current study, noted that it did not address the impact and costs to families of nonoperative management vs. surgery.

“For the most vulnerable children who had difficulties accessing medical care, what is the best treatment option? What factors are important to the families when making this decision?” he asked.

All study and editorial authors report no relevant financial relationships. The study was funded by the Patient-Centered Outcomes Research Institute and the National Center for Advancing Translational Sciences.

A version of this article first appeared on Medscape.com.

Muraca GM, Boutin A, Razaz N, et al. Maternal and neonatal trauma following operative vaginal delivery. CMAJ. 2022;194:E1-E12. doi: 10.1503/cmaj.210841.
 

EXPERT COMMENTARY 

Operative vaginal delivery is used to achieve and expedite safe vaginal birth while avoiding CD and its associated morbidities.^1,2 Despite support from the American College of Obstetricians and Gynecologists (ACOG) for the use of OVD as an alternative to CD, OVD was used in only 3% of all US births in 2013, a shift from approximately 30% in 1987.^1,3 Reported complications of OVD are biased by the level of experience of the operator, changes in practice, and by misinterpretation of the counterfactual.¹

Outcomes of OVD should be compared with appropriate reference groups, namely, with second-stage CD births rather than with spontaneous vaginal births.⁴ With decreasing rates of OVD, evidence of contemporary data is needed on appropriately compared perinatal outcomes.⁴
 

Details of the study 

Muraca and colleagues conducted an observational cohort study of births in Canada between 2013 and 2019 to assess the incidence of maternal and neonatal trauma following OVD. They used composites defined a priori— stratified by instrument, region, level of obstetric care, and institutional OVD volume. 

Results. Among 1,326,191 live or stillbirths, 2.9% were attempted forceps deliveries and 8.4% were attempted vacuum deliveries. Following forceps delivery, the maternal trauma rate was 25.3% (95% confidence interval [CI], 24.8%–25.7%), and the neonatal trauma rate was 9.6 per 1,000 live births (95% CI, 8.6–10.6). Following vacuum delivery, maternal and neonatal trauma rates were 13.2% (95% CI, 13.0%–13.4%) and 9.6 per 1,000 live births (95% CI, 9.0–10.2), respectively. Maternal trauma was driven by higher order perineal lacerations. Some association was seen between increased forceps volume and decreased maternal trauma rates. 

The authors concluded that in Canada, rates of maternal and neonatal trauma following OVD are higher than previously reported in consensus statements.

Study strengths and limitations

This large contemporary study uniquely stratified perinatal outcomes following OVD. The outcomes are well defined and meaningful, but some limitations affect the generalizability of the findings. 

First, stillbirths were included for the maternal composite outcome, yet the incidence of this within the study population is not reported. Operative vaginal deliveries that involve stillbirths can be complex; a subgroup analysis excluding these would aid in interpretation.

Second, complicated OVDs, including sequential use of forceps and vacuum and OVDs from midpelvic station, were included; ACOG recommends against both these practices in routine circumstances due to known increases in maternal and neonatal morbidity.¹ As such, the inclusion of these OVDs may bias results away from the null. 

Finally, despite discussing the role of episiotomy, the episiotomy rate in this cohort is not reported.

Despite these limitations, the study by Muraca and colleagues is a positive step forward toward understanding the role of OVD in contemporary obstetric practice, and it uniquely ascertains the impact of OVD volume outcomes that previously had been an elusive exposure ●
 

Muraca GM, Boutin A, Razaz N, et al. Maternal and neonatal trauma following operative vaginal delivery. CMAJ. 2022;194:E1-E12. doi: 10.1503/cmaj.210841.
 

EXPERT COMMENTARY 

Operative vaginal delivery is used to achieve and expedite safe vaginal birth while avoiding CD and its associated morbidities.^1,2 Despite support from the American College of Obstetricians and Gynecologists (ACOG) for the use of OVD as an alternative to CD, OVD was used in only 3% of all US births in 2013, a shift from approximately 30% in 1987.^1,3 Reported complications of OVD are biased by the level of experience of the operator, changes in practice, and by misinterpretation of the counterfactual.¹

Outcomes of OVD should be compared with appropriate reference groups, namely, with second-stage CD births rather than with spontaneous vaginal births.⁴ With decreasing rates of OVD, evidence of contemporary data is needed on appropriately compared perinatal outcomes.⁴
 

Details of the study 

Muraca and colleagues conducted an observational cohort study of births in Canada between 2013 and 2019 to assess the incidence of maternal and neonatal trauma following OVD. They used composites defined a priori— stratified by instrument, region, level of obstetric care, and institutional OVD volume. 

Results. Among 1,326,191 live or stillbirths, 2.9% were attempted forceps deliveries and 8.4% were attempted vacuum deliveries. Following forceps delivery, the maternal trauma rate was 25.3% (95% confidence interval [CI], 24.8%–25.7%), and the neonatal trauma rate was 9.6 per 1,000 live births (95% CI, 8.6–10.6). Following vacuum delivery, maternal and neonatal trauma rates were 13.2% (95% CI, 13.0%–13.4%) and 9.6 per 1,000 live births (95% CI, 9.0–10.2), respectively. Maternal trauma was driven by higher order perineal lacerations. Some association was seen between increased forceps volume and decreased maternal trauma rates. 

The authors concluded that in Canada, rates of maternal and neonatal trauma following OVD are higher than previously reported in consensus statements.

Study strengths and limitations

This large contemporary study uniquely stratified perinatal outcomes following OVD. The outcomes are well defined and meaningful, but some limitations affect the generalizability of the findings. 

First, stillbirths were included for the maternal composite outcome, yet the incidence of this within the study population is not reported. Operative vaginal deliveries that involve stillbirths can be complex; a subgroup analysis excluding these would aid in interpretation.

Second, complicated OVDs, including sequential use of forceps and vacuum and OVDs from midpelvic station, were included; ACOG recommends against both these practices in routine circumstances due to known increases in maternal and neonatal morbidity.¹ As such, the inclusion of these OVDs may bias results away from the null. 

Finally, despite discussing the role of episiotomy, the episiotomy rate in this cohort is not reported.

Despite these limitations, the study by Muraca and colleagues is a positive step forward toward understanding the role of OVD in contemporary obstetric practice, and it uniquely ascertains the impact of OVD volume outcomes that previously had been an elusive exposure ●
 

Muraca GM, Boutin A, Razaz N, et al. Maternal and neonatal trauma following operative vaginal delivery. CMAJ. 2022;194:E1-E12. doi: 10.1503/cmaj.210841.
 

EXPERT COMMENTARY 

Operative vaginal delivery is used to achieve and expedite safe vaginal birth while avoiding CD and its associated morbidities.^1,2 Despite support from the American College of Obstetricians and Gynecologists (ACOG) for the use of OVD as an alternative to CD, OVD was used in only 3% of all US births in 2013, a shift from approximately 30% in 1987.^1,3 Reported complications of OVD are biased by the level of experience of the operator, changes in practice, and by misinterpretation of the counterfactual.¹

Outcomes of OVD should be compared with appropriate reference groups, namely, with second-stage CD births rather than with spontaneous vaginal births.⁴ With decreasing rates of OVD, evidence of contemporary data is needed on appropriately compared perinatal outcomes.⁴
 

Details of the study 

Muraca and colleagues conducted an observational cohort study of births in Canada between 2013 and 2019 to assess the incidence of maternal and neonatal trauma following OVD. They used composites defined a priori— stratified by instrument, region, level of obstetric care, and institutional OVD volume. 

Results. Among 1,326,191 live or stillbirths, 2.9% were attempted forceps deliveries and 8.4% were attempted vacuum deliveries. Following forceps delivery, the maternal trauma rate was 25.3% (95% confidence interval [CI], 24.8%–25.7%), and the neonatal trauma rate was 9.6 per 1,000 live births (95% CI, 8.6–10.6). Following vacuum delivery, maternal and neonatal trauma rates were 13.2% (95% CI, 13.0%–13.4%) and 9.6 per 1,000 live births (95% CI, 9.0–10.2), respectively. Maternal trauma was driven by higher order perineal lacerations. Some association was seen between increased forceps volume and decreased maternal trauma rates. 

The authors concluded that in Canada, rates of maternal and neonatal trauma following OVD are higher than previously reported in consensus statements.

Study strengths and limitations

This large contemporary study uniquely stratified perinatal outcomes following OVD. The outcomes are well defined and meaningful, but some limitations affect the generalizability of the findings. 

First, stillbirths were included for the maternal composite outcome, yet the incidence of this within the study population is not reported. Operative vaginal deliveries that involve stillbirths can be complex; a subgroup analysis excluding these would aid in interpretation.

Second, complicated OVDs, including sequential use of forceps and vacuum and OVDs from midpelvic station, were included; ACOG recommends against both these practices in routine circumstances due to known increases in maternal and neonatal morbidity.¹ As such, the inclusion of these OVDs may bias results away from the null. 

Finally, despite discussing the role of episiotomy, the episiotomy rate in this cohort is not reported.

Despite these limitations, the study by Muraca and colleagues is a positive step forward toward understanding the role of OVD in contemporary obstetric practice, and it uniquely ascertains the impact of OVD volume outcomes that previously had been an elusive exposure ●
 

Artificial intelligence (AI) in medicine has shown significant promise, particularly in neuroimaging. AI refers to computer systems designed to perform tasks that normally require human intelligence.¹ Machine learning (ML), a field in which computers learn from data without being specifically programmed, is the AI subset responsible for its success in matching or even surpassing humans in certain tasks.²

Supervised learning, a subset of ML, uses an algorithm with annotated data from which to learn.³ The program will use the characteristics of a training data set to predict a specific outcome or target when exposed to a sample data set of the same type. Unsupervised learning finds naturally occurring patterns or groupings within the data.⁴ With deep learning (DL) algorithms, computers learn the features that optimally represent the data for the problem at hand.⁵ Both ML and DL are meant to emulate neural networks in the brain, giving rise to artificial neural networks composed of nodes structured within input, hidden, and output layers.

The DL neural network differs from a conventional one by having many hidden layers instead of just 1 layer that extracts patterns within the data.⁶ Convolutional neural networks (CNNs) are the most prevalent DL architecture used in medical imaging. CNN’s hidden layers apply convolution and pooling operations to break down an image into features containing the most valuable information. The connecting layer applies high-level reasoning before the output layer provides predictions for the image. This framework has applications within radiology, such as predicting a lesion category or condition from an image, determining whether a specific pixel belongs to background or a target class, and predicting the location of lesions.¹

AI promises to increase efficiency and reduces errors. With increased data processing and image interpretation, AI technology may help radiologists improve the quality of patient care.⁶ This article discusses the current applications and future integration of AI in neuroradiology.

Neuroimaging Applications

AI can improve the quality of neuroimaging and reduce the clinical and systemic loads of other imaging modalities. AI can predict patient wait times for computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, and X-ray imaging.⁷ A ML-based AI has detected the variables that most affected patient wait times, including proximity to federal holidays and severity of the patient’s condition, and calculated how long patients would be delayed after their scheduled appointment time. This AI modality could allow more efficient patient scheduling and reveal areas of patient processing that could be changed, potentially improving patient satisfaction and outcomes for time-sensitive neurologic conditions.

AI can save patient and health care practitioner time for repeat MRIs. An estimated 20% of MRI scans require a repeat series—a massive loss of time and funds for both patients and the health care system.⁸ A DL approach can determine whether an MRI is usable clinically or unclear enough to require repetition.⁹ This initial screening measure can prevent patients from making return visits and neuroradiologists from reading inconclusive images. AI offers the opportunity to reduce time and costs incurred by optimizing the health care process before imaging is obtained.

Speeding Up Neuroimaging

AI can reduce the time spent performing imaging. Because MRIs consume time and resources, compressed sensing (CS) is commonly used. CS preferentially maintains in-plane resolution at the expense of through-plane resolution to produce a scan with a single, usable viewpoint that preserves signal-to-noise ratio (SNR). CS, however, limits interpretation to single directions and can create aliasing artifacts. An AI algorithm known as synthetic multi-orientation resolution enhancement works in real time to reduce aliasing and improve resolution in these compressed scans.¹⁰ This AI improved resolution of white matter lesions in patients with multiple sclerosis (MS) on FLAIR (fluid-attenuated inversion recovery) images, and permitted multiview reconstruction from these limited scans.

Tasks of reconstructing and anti-aliasing come with high computational costs that vary inversely with the extent of scanning compression, potentially negating the time and resource savings of CS. DL AI modalities have been developed to reduce operational loads and further improve image resolution in several directions from CS. One such deep residual learning AI was trained with compressed MRIs and used the framelet method to create a CNN that could rapidly remove global and deeply coherent aliasing artifacts.¹¹ This system, compared with synthetic multi-orientation resolution enhancement, uses a pretrained, pretested AI that does not require additional time during scanning for computational analysis, thereby multiplying the time benefit of CS while retaining the benefits of multidirectional reconstruction and increased resolution. This methodology suffers from inherent degradation of perceptual image quality in its reconstructions because of the L2 loss function the CNN uses to reduce mean squared error, which causes blurring by averaging all possible outcomes of signal distribution during reconstruction. To combat this, researchers have developed another AI to reduce reconstruction times that uses a different loss function in a generative adversarial network to retain image quality, while offering reconstruction times several hundred times faster than current CS-MRI structures.¹² So-called sparse-coding methods promise further reduction in reconstruction times, with the possibility of processing completed online with a lightweight architecture rather than on a local system.¹³

Neuroimaging of acute cases benefits most directly from these technologies because MRIs and their high resolution and SNR begin to approach CT imaging time scales. This could have important implications in clinical care, particularly for stroke imaging and evaluating spinal cord compression. CS-MRI optimization represents one of the greatest areas of neuroimaging cost savings and neurologic care improvement in the modern radiology era.

Reducing Contrast and Radiation Doses

AI has the ability to read CT, MRI, and positron emission tomography (PET) with reduced or without contrast without significant loss in sensitivity for detecting lesions. With MRI, gadolinium-based contrast can cause injection site reactions, allergic reactions, metal deposition throughout the body, and nephrogenic systemic fibrosis in the most severe instances.¹⁴ DL has been applied to brain MRIs performed with 10% of a full dose of contrast without significant degradation of image quality. Neuroradiologists did not rate the AI-synthesized images for several MRI indications lower than their full-dose counterparts.¹⁵ Low-dose contrast imaging, regardless of modality, generates greater noise with a significantly reduced signal. However, with AI applied, researchers found that the software suppressed motion and aliasing artifacts and improved image quality, perhaps evidence that this low-dose modality is less vulnerable to the most common pitfalls of MRI.

Recently, low-dose MRI moved into the spotlight when Subtle Medical SubtleGAD software received a National Institutes of Health grant and an expedited pathway to phase 2 clinical trials.¹⁶ SubtleGAD, a DL AI that enables low-dose MRI interpretation, might allow contrast MRI for patients with advanced kidney disease or contrast allergies. At some point, contrast with MRI might not be necessary because DL AI applied to noncontrast MRs for detecting MS lesions was found to be preliminarily effective with 78% lesion detection sensitivity.¹⁷

PET-MRI combines simultaneous PET and MRI and has been used to evaluate neurologic disorders. PET-MRI can detect amyloid plaques in Alzheimer disease 10 to 20 years before clinical signs of dementia emerge.¹⁸ PET-MRI has sparked DL AI development to decrease the dose of the IV radioactive tracer 18F-florbetaben used in imaging to reduce radiation exposure and imaging costs.This reduction is critical if PET-MRI is to become used widely.^19-21

An initial CNN could reconstruct low-dose amyloid scans to full-dose resolution, albeit with a greater susceptibility to some artifacts and motion blurring.²² Similar to the synthetic multi-orientation resolution enhancement CNN, this program showed signal blurring from the L2 loss function, which was corrected in a later AI that used a generative adversarial network to minimize perceptual loss.²³ This new AI demonstrated greater image resolution, feature preservation, and radiologist rating over the previous AI and was capable of reconstructing low-dose PET scans to full-dose resolution without an accompanying MRI. Applications of this algorithm are far-reaching, potentially allowing neuroimaging of brain tumors at more frequent intervals with higher resolution and lower total radiation exposure.

AI also has been applied to neurologic CT to reduce radiation exposure.²⁴ Because it is critical to abide by the principles of ALARA (as low as reasonably achievable), the ability of AI to reduce radiation exposure holds significant promise. A CNN has been used to transform low-dose CTs of anthropomorphic models with calcium inserts and cardiac patients to normal-dose CTs, with the goal of improving the SNR.²⁵ By training a noise-discriminating CNN and a noise-generating CNN together in a generative adversarial network, the AI improved image feature preservation during transformation. This algorithm has a direct application in imaging cerebral vasculature, including calcification that can explain lacunar infarcts and tracking systemic atherosclerosis.²⁶

Another CNN has been applied to remove more complex noise patterns from the phenomena of beam hardening and photon starvation common in low-dose CT. This algorithm extracts the directional components of artifacts and compares them to known artifact patterns, allowing for highly specific suppression of unwanted signals.²⁷ In June 2019, the US Food and Drug Administration (FDA) approved ClariPi, a deep CNN program for advanced denoising and resolution improvement of low- and ultra low-dose CTs.²⁸ Aside from only low-dose settings, this AI could reduce artifacts in all CT imaging modalities and improve therapeutic value of procedures, including cerebral angiograms and emergency cranial scans. As the average CT radiation dose decreased from 12 mSv in 2009 to 1.5 mSv in 2014 and continues to fall, these algorithms will become increasingly necessary to retain the high resolution and diagnostic power expected of neurologic CTs.^29,30

Downstream Applications

Downstream applications refer to AI use after a radiologic study is acquired, mostly image interpretation. More than 70% of FDA-approved AI medical devices are in radiology, and many of these relate to image analysis.^6,31 Although AI is not limited to black-and-white image interpretation, it is hypothesized that one of the reasons radiology is inviting to AI is because gray-scale images lend themselves to standardization.³ Moreover, most radiology departments already use AI-friendly picture archiving and communication systems.^31,32

AI has been applied to a range of radiologic modalities, including MRI, CT, ultrasonography, PET, and mammography.^32-38 AI also has been specifically applied to radiography, including the interpretation of tuberculosis, pneumonia, lung lesions, and COVID-19.^33,39-45 AI also can assist triage, patient screening, providing a “second opinion” rapidly, shortening the time needed for attaining a diagnosis, monitoring disease progression, and predicting prognosis.^{37-39,43,45-47} Downstream applications of AI in neuroradiology and neurology include using CT to aid in detecting hemorrhage or ischemic stroke; using MRI to automatically segment lesions, such as tumors or MS lesions; assisting in early diagnosis and predicting prognosis in MS; assisting in treating paralysis, including from spinal cord injury; determining seizure type and localizing area of seizure onset; and using cameras, wearable devices, and smartphone applications to diagnose and assess treatment response in neurodegenerative disorders, such as Parkinson or Alzheimer diseases (Figure).^37,48-56

Practical and Ethical Considerations

In any discussion of the benefits of AI, it is prudent to address its shortcomings. Chief among these is overfitting, which occurs when an AI is too closely aligned with its training dataset and prone to error when applied to novel cases. Often this is a byproduct of a small training set.⁶⁰ Neuroradiology, particularly with uncommon, advanced imaging methods, has a smaller number of available studies.⁶¹ Even with more prevalent imaging modalities, such as head CT, the work of collecting training scans from patients with the prerequisite disease processes, particularly if these processes are rare, can limit the number of datapoints collected. Neuroradiologists should understand how an AI tool was generated, including the size and variety of the training dataset used, to best gauge the clinical applicability and fitness of the system.

Another point of concern for AI clinical decision support tools’ implementation is automation bias—the tendency for clinicians to favor machine-generated decisions and ignore contrary data or conflicting human decisions.⁶² This situation often arises when radiologists experience overwhelming patient loads or are in underresourced settings, where there is little ability to review every AI-based diagnosis. Although AI might be of benefit in such conditions by reducing physician workload and streamlining the diagnostic process, there is the propensity to improperly rely on a tool meant to augment, not replace, a radiologist’s judgment. Such cases have led to adverse outcomes for patients, and legal precedence shows that this constitutes negligence.⁶³ Maintaining awareness of each tool’s limitations and proper application is the only remedy for such situations.

Ethically, we must consider the opaqueness of ML-developed neuroimaging AIs. For many systems, the specific process by which an AI arrives at its conclusions is unknown. This AI “black box” can conceal potential errors and biases that are masked by overall positive performance metrics. The lack of understanding about how a tool functions in the zero-failure clinical setting understandably gives radiologists pause. The question must be asked: Is it ethical to use a system that is a relatively unknown quantity? Entities, including state governments, Canada, and the European Union, have produced an answer. Each of these governments have implemented policies requiring that health care AIs use some method to display to end users the process by which they arrive at conclusions.^64-68

The 21st Century Cures Act declares that to attain approval, clinical AIs must demonstrate this explainability to clinicians and patients.⁶⁹ The response has been an explosion in the development of explainable AI. Systems that visualize the areas where AI attention most often rests with heatmaps, generate labels for the most heavily weighted features of radiographic images, and create full diagnostic reports to justify AI conclusions aim to meet the goal of transparency and inspiring confidence in clinical end users.⁷⁰ The ability to understand the “thought process” of a system proves useful for error correction and retooling. A trend toward under- or overdetecting conditions, flagging seemingly irrelevant image regions, or low reproducibility can be better addressed when it is clear how the AI is drawing its false conclusions. With an iterative process of testing and redesigning, false positive and negative rates can be reduced, the need for human intervention can be lowered to an appropriate minimum, and patient outcomes can be improved.⁷¹

Data collection raises another ethical concern. To train functional clinical decision support tools, massive amounts of patient demographic, laboratory, and imaging data are required. With incentives to develop the most powerful AI systems, record collection can venture down a path where patient autonomy and privacy are threatened. Radiologists have a duty to ensure data mining serves patients and improves the practice of radiology while protecting patients’ personal information.⁶² Policies have placed similar limits on the access to and use of patient records.^64-69 Patients have the right to request explanation of the AI systems their data have been used to train. Approval for data acquisition requires the use of explainable AI, standardized data security protocol implementation, and adequate proof of communal benefit from the clinical decision support tool. Establishment of state-mandated protections bodes well for a future when developers can access enormous caches of data while patients and health care professionals are assured that no identifying information has escaped a well-regulated space. On the level of the individual radiologist, the knowledge that each datum represents a human life. These are people who has made themselves vulnerable by seeking relief for what ails them, which should serve as a lasting reminder to operate with utmost care when handling sensitive information.

Conclusions

The demonstrated applications of AI in neuroimaging are numerous and varied, and it is reasonable to assume that its implementation will increase as the technology matures. AI use for detecting important neurologic conditions holds promise in combatting ever greater imaging volumes and providing timely diagnoses. As medicine witnesses the continuing adoption of AI, it is important that practitioners possess an understanding of its current and emerging uses.

Artificial intelligence (AI) in medicine has shown significant promise, particularly in neuroimaging. AI refers to computer systems designed to perform tasks that normally require human intelligence.¹ Machine learning (ML), a field in which computers learn from data without being specifically programmed, is the AI subset responsible for its success in matching or even surpassing humans in certain tasks.²

Supervised learning, a subset of ML, uses an algorithm with annotated data from which to learn.³ The program will use the characteristics of a training data set to predict a specific outcome or target when exposed to a sample data set of the same type. Unsupervised learning finds naturally occurring patterns or groupings within the data.⁴ With deep learning (DL) algorithms, computers learn the features that optimally represent the data for the problem at hand.⁵ Both ML and DL are meant to emulate neural networks in the brain, giving rise to artificial neural networks composed of nodes structured within input, hidden, and output layers.

The DL neural network differs from a conventional one by having many hidden layers instead of just 1 layer that extracts patterns within the data.⁶ Convolutional neural networks (CNNs) are the most prevalent DL architecture used in medical imaging. CNN’s hidden layers apply convolution and pooling operations to break down an image into features containing the most valuable information. The connecting layer applies high-level reasoning before the output layer provides predictions for the image. This framework has applications within radiology, such as predicting a lesion category or condition from an image, determining whether a specific pixel belongs to background or a target class, and predicting the location of lesions.¹

AI promises to increase efficiency and reduces errors. With increased data processing and image interpretation, AI technology may help radiologists improve the quality of patient care.⁶ This article discusses the current applications and future integration of AI in neuroradiology.

Neuroimaging Applications

AI can improve the quality of neuroimaging and reduce the clinical and systemic loads of other imaging modalities. AI can predict patient wait times for computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, and X-ray imaging.⁷ A ML-based AI has detected the variables that most affected patient wait times, including proximity to federal holidays and severity of the patient’s condition, and calculated how long patients would be delayed after their scheduled appointment time. This AI modality could allow more efficient patient scheduling and reveal areas of patient processing that could be changed, potentially improving patient satisfaction and outcomes for time-sensitive neurologic conditions.

AI can save patient and health care practitioner time for repeat MRIs. An estimated 20% of MRI scans require a repeat series—a massive loss of time and funds for both patients and the health care system.⁸ A DL approach can determine whether an MRI is usable clinically or unclear enough to require repetition.⁹ This initial screening measure can prevent patients from making return visits and neuroradiologists from reading inconclusive images. AI offers the opportunity to reduce time and costs incurred by optimizing the health care process before imaging is obtained.

Speeding Up Neuroimaging

AI can reduce the time spent performing imaging. Because MRIs consume time and resources, compressed sensing (CS) is commonly used. CS preferentially maintains in-plane resolution at the expense of through-plane resolution to produce a scan with a single, usable viewpoint that preserves signal-to-noise ratio (SNR). CS, however, limits interpretation to single directions and can create aliasing artifacts. An AI algorithm known as synthetic multi-orientation resolution enhancement works in real time to reduce aliasing and improve resolution in these compressed scans.¹⁰ This AI improved resolution of white matter lesions in patients with multiple sclerosis (MS) on FLAIR (fluid-attenuated inversion recovery) images, and permitted multiview reconstruction from these limited scans.

Tasks of reconstructing and anti-aliasing come with high computational costs that vary inversely with the extent of scanning compression, potentially negating the time and resource savings of CS. DL AI modalities have been developed to reduce operational loads and further improve image resolution in several directions from CS. One such deep residual learning AI was trained with compressed MRIs and used the framelet method to create a CNN that could rapidly remove global and deeply coherent aliasing artifacts.¹¹ This system, compared with synthetic multi-orientation resolution enhancement, uses a pretrained, pretested AI that does not require additional time during scanning for computational analysis, thereby multiplying the time benefit of CS while retaining the benefits of multidirectional reconstruction and increased resolution. This methodology suffers from inherent degradation of perceptual image quality in its reconstructions because of the L2 loss function the CNN uses to reduce mean squared error, which causes blurring by averaging all possible outcomes of signal distribution during reconstruction. To combat this, researchers have developed another AI to reduce reconstruction times that uses a different loss function in a generative adversarial network to retain image quality, while offering reconstruction times several hundred times faster than current CS-MRI structures.¹² So-called sparse-coding methods promise further reduction in reconstruction times, with the possibility of processing completed online with a lightweight architecture rather than on a local system.¹³

Neuroimaging of acute cases benefits most directly from these technologies because MRIs and their high resolution and SNR begin to approach CT imaging time scales. This could have important implications in clinical care, particularly for stroke imaging and evaluating spinal cord compression. CS-MRI optimization represents one of the greatest areas of neuroimaging cost savings and neurologic care improvement in the modern radiology era.

Reducing Contrast and Radiation Doses

AI has the ability to read CT, MRI, and positron emission tomography (PET) with reduced or without contrast without significant loss in sensitivity for detecting lesions. With MRI, gadolinium-based contrast can cause injection site reactions, allergic reactions, metal deposition throughout the body, and nephrogenic systemic fibrosis in the most severe instances.¹⁴ DL has been applied to brain MRIs performed with 10% of a full dose of contrast without significant degradation of image quality. Neuroradiologists did not rate the AI-synthesized images for several MRI indications lower than their full-dose counterparts.¹⁵ Low-dose contrast imaging, regardless of modality, generates greater noise with a significantly reduced signal. However, with AI applied, researchers found that the software suppressed motion and aliasing artifacts and improved image quality, perhaps evidence that this low-dose modality is less vulnerable to the most common pitfalls of MRI.

Recently, low-dose MRI moved into the spotlight when Subtle Medical SubtleGAD software received a National Institutes of Health grant and an expedited pathway to phase 2 clinical trials.¹⁶ SubtleGAD, a DL AI that enables low-dose MRI interpretation, might allow contrast MRI for patients with advanced kidney disease or contrast allergies. At some point, contrast with MRI might not be necessary because DL AI applied to noncontrast MRs for detecting MS lesions was found to be preliminarily effective with 78% lesion detection sensitivity.¹⁷

PET-MRI combines simultaneous PET and MRI and has been used to evaluate neurologic disorders. PET-MRI can detect amyloid plaques in Alzheimer disease 10 to 20 years before clinical signs of dementia emerge.¹⁸ PET-MRI has sparked DL AI development to decrease the dose of the IV radioactive tracer 18F-florbetaben used in imaging to reduce radiation exposure and imaging costs.This reduction is critical if PET-MRI is to become used widely.^19-21

An initial CNN could reconstruct low-dose amyloid scans to full-dose resolution, albeit with a greater susceptibility to some artifacts and motion blurring.²² Similar to the synthetic multi-orientation resolution enhancement CNN, this program showed signal blurring from the L2 loss function, which was corrected in a later AI that used a generative adversarial network to minimize perceptual loss.²³ This new AI demonstrated greater image resolution, feature preservation, and radiologist rating over the previous AI and was capable of reconstructing low-dose PET scans to full-dose resolution without an accompanying MRI. Applications of this algorithm are far-reaching, potentially allowing neuroimaging of brain tumors at more frequent intervals with higher resolution and lower total radiation exposure.

AI also has been applied to neurologic CT to reduce radiation exposure.²⁴ Because it is critical to abide by the principles of ALARA (as low as reasonably achievable), the ability of AI to reduce radiation exposure holds significant promise. A CNN has been used to transform low-dose CTs of anthropomorphic models with calcium inserts and cardiac patients to normal-dose CTs, with the goal of improving the SNR.²⁵ By training a noise-discriminating CNN and a noise-generating CNN together in a generative adversarial network, the AI improved image feature preservation during transformation. This algorithm has a direct application in imaging cerebral vasculature, including calcification that can explain lacunar infarcts and tracking systemic atherosclerosis.²⁶

Another CNN has been applied to remove more complex noise patterns from the phenomena of beam hardening and photon starvation common in low-dose CT. This algorithm extracts the directional components of artifacts and compares them to known artifact patterns, allowing for highly specific suppression of unwanted signals.²⁷ In June 2019, the US Food and Drug Administration (FDA) approved ClariPi, a deep CNN program for advanced denoising and resolution improvement of low- and ultra low-dose CTs.²⁸ Aside from only low-dose settings, this AI could reduce artifacts in all CT imaging modalities and improve therapeutic value of procedures, including cerebral angiograms and emergency cranial scans. As the average CT radiation dose decreased from 12 mSv in 2009 to 1.5 mSv in 2014 and continues to fall, these algorithms will become increasingly necessary to retain the high resolution and diagnostic power expected of neurologic CTs.^29,30

Downstream Applications

Downstream applications refer to AI use after a radiologic study is acquired, mostly image interpretation. More than 70% of FDA-approved AI medical devices are in radiology, and many of these relate to image analysis.^6,31 Although AI is not limited to black-and-white image interpretation, it is hypothesized that one of the reasons radiology is inviting to AI is because gray-scale images lend themselves to standardization.³ Moreover, most radiology departments already use AI-friendly picture archiving and communication systems.^31,32

AI has been applied to a range of radiologic modalities, including MRI, CT, ultrasonography, PET, and mammography.^32-38 AI also has been specifically applied to radiography, including the interpretation of tuberculosis, pneumonia, lung lesions, and COVID-19.^33,39-45 AI also can assist triage, patient screening, providing a “second opinion” rapidly, shortening the time needed for attaining a diagnosis, monitoring disease progression, and predicting prognosis.^{37-39,43,45-47} Downstream applications of AI in neuroradiology and neurology include using CT to aid in detecting hemorrhage or ischemic stroke; using MRI to automatically segment lesions, such as tumors or MS lesions; assisting in early diagnosis and predicting prognosis in MS; assisting in treating paralysis, including from spinal cord injury; determining seizure type and localizing area of seizure onset; and using cameras, wearable devices, and smartphone applications to diagnose and assess treatment response in neurodegenerative disorders, such as Parkinson or Alzheimer diseases (Figure).^37,48-56

Practical and Ethical Considerations

In any discussion of the benefits of AI, it is prudent to address its shortcomings. Chief among these is overfitting, which occurs when an AI is too closely aligned with its training dataset and prone to error when applied to novel cases. Often this is a byproduct of a small training set.⁶⁰ Neuroradiology, particularly with uncommon, advanced imaging methods, has a smaller number of available studies.⁶¹ Even with more prevalent imaging modalities, such as head CT, the work of collecting training scans from patients with the prerequisite disease processes, particularly if these processes are rare, can limit the number of datapoints collected. Neuroradiologists should understand how an AI tool was generated, including the size and variety of the training dataset used, to best gauge the clinical applicability and fitness of the system.

Another point of concern for AI clinical decision support tools’ implementation is automation bias—the tendency for clinicians to favor machine-generated decisions and ignore contrary data or conflicting human decisions.⁶² This situation often arises when radiologists experience overwhelming patient loads or are in underresourced settings, where there is little ability to review every AI-based diagnosis. Although AI might be of benefit in such conditions by reducing physician workload and streamlining the diagnostic process, there is the propensity to improperly rely on a tool meant to augment, not replace, a radiologist’s judgment. Such cases have led to adverse outcomes for patients, and legal precedence shows that this constitutes negligence.⁶³ Maintaining awareness of each tool’s limitations and proper application is the only remedy for such situations.

Ethically, we must consider the opaqueness of ML-developed neuroimaging AIs. For many systems, the specific process by which an AI arrives at its conclusions is unknown. This AI “black box” can conceal potential errors and biases that are masked by overall positive performance metrics. The lack of understanding about how a tool functions in the zero-failure clinical setting understandably gives radiologists pause. The question must be asked: Is it ethical to use a system that is a relatively unknown quantity? Entities, including state governments, Canada, and the European Union, have produced an answer. Each of these governments have implemented policies requiring that health care AIs use some method to display to end users the process by which they arrive at conclusions.^64-68

The 21st Century Cures Act declares that to attain approval, clinical AIs must demonstrate this explainability to clinicians and patients.⁶⁹ The response has been an explosion in the development of explainable AI. Systems that visualize the areas where AI attention most often rests with heatmaps, generate labels for the most heavily weighted features of radiographic images, and create full diagnostic reports to justify AI conclusions aim to meet the goal of transparency and inspiring confidence in clinical end users.⁷⁰ The ability to understand the “thought process” of a system proves useful for error correction and retooling. A trend toward under- or overdetecting conditions, flagging seemingly irrelevant image regions, or low reproducibility can be better addressed when it is clear how the AI is drawing its false conclusions. With an iterative process of testing and redesigning, false positive and negative rates can be reduced, the need for human intervention can be lowered to an appropriate minimum, and patient outcomes can be improved.⁷¹

Data collection raises another ethical concern. To train functional clinical decision support tools, massive amounts of patient demographic, laboratory, and imaging data are required. With incentives to develop the most powerful AI systems, record collection can venture down a path where patient autonomy and privacy are threatened. Radiologists have a duty to ensure data mining serves patients and improves the practice of radiology while protecting patients’ personal information.⁶² Policies have placed similar limits on the access to and use of patient records.^64-69 Patients have the right to request explanation of the AI systems their data have been used to train. Approval for data acquisition requires the use of explainable AI, standardized data security protocol implementation, and adequate proof of communal benefit from the clinical decision support tool. Establishment of state-mandated protections bodes well for a future when developers can access enormous caches of data while patients and health care professionals are assured that no identifying information has escaped a well-regulated space. On the level of the individual radiologist, the knowledge that each datum represents a human life. These are people who has made themselves vulnerable by seeking relief for what ails them, which should serve as a lasting reminder to operate with utmost care when handling sensitive information.

Conclusions

The demonstrated applications of AI in neuroimaging are numerous and varied, and it is reasonable to assume that its implementation will increase as the technology matures. AI use for detecting important neurologic conditions holds promise in combatting ever greater imaging volumes and providing timely diagnoses. As medicine witnesses the continuing adoption of AI, it is important that practitioners possess an understanding of its current and emerging uses.

Artificial intelligence (AI) in medicine has shown significant promise, particularly in neuroimaging. AI refers to computer systems designed to perform tasks that normally require human intelligence.¹ Machine learning (ML), a field in which computers learn from data without being specifically programmed, is the AI subset responsible for its success in matching or even surpassing humans in certain tasks.²

Supervised learning, a subset of ML, uses an algorithm with annotated data from which to learn.³ The program will use the characteristics of a training data set to predict a specific outcome or target when exposed to a sample data set of the same type. Unsupervised learning finds naturally occurring patterns or groupings within the data.⁴ With deep learning (DL) algorithms, computers learn the features that optimally represent the data for the problem at hand.⁵ Both ML and DL are meant to emulate neural networks in the brain, giving rise to artificial neural networks composed of nodes structured within input, hidden, and output layers.

The DL neural network differs from a conventional one by having many hidden layers instead of just 1 layer that extracts patterns within the data.⁶ Convolutional neural networks (CNNs) are the most prevalent DL architecture used in medical imaging. CNN’s hidden layers apply convolution and pooling operations to break down an image into features containing the most valuable information. The connecting layer applies high-level reasoning before the output layer provides predictions for the image. This framework has applications within radiology, such as predicting a lesion category or condition from an image, determining whether a specific pixel belongs to background or a target class, and predicting the location of lesions.¹

AI promises to increase efficiency and reduces errors. With increased data processing and image interpretation, AI technology may help radiologists improve the quality of patient care.⁶ This article discusses the current applications and future integration of AI in neuroradiology.

Neuroimaging Applications

AI can improve the quality of neuroimaging and reduce the clinical and systemic loads of other imaging modalities. AI can predict patient wait times for computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, and X-ray imaging.⁷ A ML-based AI has detected the variables that most affected patient wait times, including proximity to federal holidays and severity of the patient’s condition, and calculated how long patients would be delayed after their scheduled appointment time. This AI modality could allow more efficient patient scheduling and reveal areas of patient processing that could be changed, potentially improving patient satisfaction and outcomes for time-sensitive neurologic conditions.

AI can save patient and health care practitioner time for repeat MRIs. An estimated 20% of MRI scans require a repeat series—a massive loss of time and funds for both patients and the health care system.⁸ A DL approach can determine whether an MRI is usable clinically or unclear enough to require repetition.⁹ This initial screening measure can prevent patients from making return visits and neuroradiologists from reading inconclusive images. AI offers the opportunity to reduce time and costs incurred by optimizing the health care process before imaging is obtained.

Speeding Up Neuroimaging

AI can reduce the time spent performing imaging. Because MRIs consume time and resources, compressed sensing (CS) is commonly used. CS preferentially maintains in-plane resolution at the expense of through-plane resolution to produce a scan with a single, usable viewpoint that preserves signal-to-noise ratio (SNR). CS, however, limits interpretation to single directions and can create aliasing artifacts. An AI algorithm known as synthetic multi-orientation resolution enhancement works in real time to reduce aliasing and improve resolution in these compressed scans.¹⁰ This AI improved resolution of white matter lesions in patients with multiple sclerosis (MS) on FLAIR (fluid-attenuated inversion recovery) images, and permitted multiview reconstruction from these limited scans.

Tasks of reconstructing and anti-aliasing come with high computational costs that vary inversely with the extent of scanning compression, potentially negating the time and resource savings of CS. DL AI modalities have been developed to reduce operational loads and further improve image resolution in several directions from CS. One such deep residual learning AI was trained with compressed MRIs and used the framelet method to create a CNN that could rapidly remove global and deeply coherent aliasing artifacts.¹¹ This system, compared with synthetic multi-orientation resolution enhancement, uses a pretrained, pretested AI that does not require additional time during scanning for computational analysis, thereby multiplying the time benefit of CS while retaining the benefits of multidirectional reconstruction and increased resolution. This methodology suffers from inherent degradation of perceptual image quality in its reconstructions because of the L2 loss function the CNN uses to reduce mean squared error, which causes blurring by averaging all possible outcomes of signal distribution during reconstruction. To combat this, researchers have developed another AI to reduce reconstruction times that uses a different loss function in a generative adversarial network to retain image quality, while offering reconstruction times several hundred times faster than current CS-MRI structures.¹² So-called sparse-coding methods promise further reduction in reconstruction times, with the possibility of processing completed online with a lightweight architecture rather than on a local system.¹³

Neuroimaging of acute cases benefits most directly from these technologies because MRIs and their high resolution and SNR begin to approach CT imaging time scales. This could have important implications in clinical care, particularly for stroke imaging and evaluating spinal cord compression. CS-MRI optimization represents one of the greatest areas of neuroimaging cost savings and neurologic care improvement in the modern radiology era.

Reducing Contrast and Radiation Doses

AI has the ability to read CT, MRI, and positron emission tomography (PET) with reduced or without contrast without significant loss in sensitivity for detecting lesions. With MRI, gadolinium-based contrast can cause injection site reactions, allergic reactions, metal deposition throughout the body, and nephrogenic systemic fibrosis in the most severe instances.¹⁴ DL has been applied to brain MRIs performed with 10% of a full dose of contrast without significant degradation of image quality. Neuroradiologists did not rate the AI-synthesized images for several MRI indications lower than their full-dose counterparts.¹⁵ Low-dose contrast imaging, regardless of modality, generates greater noise with a significantly reduced signal. However, with AI applied, researchers found that the software suppressed motion and aliasing artifacts and improved image quality, perhaps evidence that this low-dose modality is less vulnerable to the most common pitfalls of MRI.

Recently, low-dose MRI moved into the spotlight when Subtle Medical SubtleGAD software received a National Institutes of Health grant and an expedited pathway to phase 2 clinical trials.¹⁶ SubtleGAD, a DL AI that enables low-dose MRI interpretation, might allow contrast MRI for patients with advanced kidney disease or contrast allergies. At some point, contrast with MRI might not be necessary because DL AI applied to noncontrast MRs for detecting MS lesions was found to be preliminarily effective with 78% lesion detection sensitivity.¹⁷

PET-MRI combines simultaneous PET and MRI and has been used to evaluate neurologic disorders. PET-MRI can detect amyloid plaques in Alzheimer disease 10 to 20 years before clinical signs of dementia emerge.¹⁸ PET-MRI has sparked DL AI development to decrease the dose of the IV radioactive tracer 18F-florbetaben used in imaging to reduce radiation exposure and imaging costs.This reduction is critical if PET-MRI is to become used widely.^19-21

An initial CNN could reconstruct low-dose amyloid scans to full-dose resolution, albeit with a greater susceptibility to some artifacts and motion blurring.²² Similar to the synthetic multi-orientation resolution enhancement CNN, this program showed signal blurring from the L2 loss function, which was corrected in a later AI that used a generative adversarial network to minimize perceptual loss.²³ This new AI demonstrated greater image resolution, feature preservation, and radiologist rating over the previous AI and was capable of reconstructing low-dose PET scans to full-dose resolution without an accompanying MRI. Applications of this algorithm are far-reaching, potentially allowing neuroimaging of brain tumors at more frequent intervals with higher resolution and lower total radiation exposure.

AI also has been applied to neurologic CT to reduce radiation exposure.²⁴ Because it is critical to abide by the principles of ALARA (as low as reasonably achievable), the ability of AI to reduce radiation exposure holds significant promise. A CNN has been used to transform low-dose CTs of anthropomorphic models with calcium inserts and cardiac patients to normal-dose CTs, with the goal of improving the SNR.²⁵ By training a noise-discriminating CNN and a noise-generating CNN together in a generative adversarial network, the AI improved image feature preservation during transformation. This algorithm has a direct application in imaging cerebral vasculature, including calcification that can explain lacunar infarcts and tracking systemic atherosclerosis.²⁶

Another CNN has been applied to remove more complex noise patterns from the phenomena of beam hardening and photon starvation common in low-dose CT. This algorithm extracts the directional components of artifacts and compares them to known artifact patterns, allowing for highly specific suppression of unwanted signals.²⁷ In June 2019, the US Food and Drug Administration (FDA) approved ClariPi, a deep CNN program for advanced denoising and resolution improvement of low- and ultra low-dose CTs.²⁸ Aside from only low-dose settings, this AI could reduce artifacts in all CT imaging modalities and improve therapeutic value of procedures, including cerebral angiograms and emergency cranial scans. As the average CT radiation dose decreased from 12 mSv in 2009 to 1.5 mSv in 2014 and continues to fall, these algorithms will become increasingly necessary to retain the high resolution and diagnostic power expected of neurologic CTs.^29,30

Downstream Applications

Downstream applications refer to AI use after a radiologic study is acquired, mostly image interpretation. More than 70% of FDA-approved AI medical devices are in radiology, and many of these relate to image analysis.^6,31 Although AI is not limited to black-and-white image interpretation, it is hypothesized that one of the reasons radiology is inviting to AI is because gray-scale images lend themselves to standardization.³ Moreover, most radiology departments already use AI-friendly picture archiving and communication systems.^31,32

AI has been applied to a range of radiologic modalities, including MRI, CT, ultrasonography, PET, and mammography.^32-38 AI also has been specifically applied to radiography, including the interpretation of tuberculosis, pneumonia, lung lesions, and COVID-19.^33,39-45 AI also can assist triage, patient screening, providing a “second opinion” rapidly, shortening the time needed for attaining a diagnosis, monitoring disease progression, and predicting prognosis.^{37-39,43,45-47} Downstream applications of AI in neuroradiology and neurology include using CT to aid in detecting hemorrhage or ischemic stroke; using MRI to automatically segment lesions, such as tumors or MS lesions; assisting in early diagnosis and predicting prognosis in MS; assisting in treating paralysis, including from spinal cord injury; determining seizure type and localizing area of seizure onset; and using cameras, wearable devices, and smartphone applications to diagnose and assess treatment response in neurodegenerative disorders, such as Parkinson or Alzheimer diseases (Figure).^37,48-56

Practical and Ethical Considerations

In any discussion of the benefits of AI, it is prudent to address its shortcomings. Chief among these is overfitting, which occurs when an AI is too closely aligned with its training dataset and prone to error when applied to novel cases. Often this is a byproduct of a small training set.⁶⁰ Neuroradiology, particularly with uncommon, advanced imaging methods, has a smaller number of available studies.⁶¹ Even with more prevalent imaging modalities, such as head CT, the work of collecting training scans from patients with the prerequisite disease processes, particularly if these processes are rare, can limit the number of datapoints collected. Neuroradiologists should understand how an AI tool was generated, including the size and variety of the training dataset used, to best gauge the clinical applicability and fitness of the system.

Another point of concern for AI clinical decision support tools’ implementation is automation bias—the tendency for clinicians to favor machine-generated decisions and ignore contrary data or conflicting human decisions.⁶² This situation often arises when radiologists experience overwhelming patient loads or are in underresourced settings, where there is little ability to review every AI-based diagnosis. Although AI might be of benefit in such conditions by reducing physician workload and streamlining the diagnostic process, there is the propensity to improperly rely on a tool meant to augment, not replace, a radiologist’s judgment. Such cases have led to adverse outcomes for patients, and legal precedence shows that this constitutes negligence.⁶³ Maintaining awareness of each tool’s limitations and proper application is the only remedy for such situations.

Ethically, we must consider the opaqueness of ML-developed neuroimaging AIs. For many systems, the specific process by which an AI arrives at its conclusions is unknown. This AI “black box” can conceal potential errors and biases that are masked by overall positive performance metrics. The lack of understanding about how a tool functions in the zero-failure clinical setting understandably gives radiologists pause. The question must be asked: Is it ethical to use a system that is a relatively unknown quantity? Entities, including state governments, Canada, and the European Union, have produced an answer. Each of these governments have implemented policies requiring that health care AIs use some method to display to end users the process by which they arrive at conclusions.^64-68

The 21st Century Cures Act declares that to attain approval, clinical AIs must demonstrate this explainability to clinicians and patients.⁶⁹ The response has been an explosion in the development of explainable AI. Systems that visualize the areas where AI attention most often rests with heatmaps, generate labels for the most heavily weighted features of radiographic images, and create full diagnostic reports to justify AI conclusions aim to meet the goal of transparency and inspiring confidence in clinical end users.⁷⁰ The ability to understand the “thought process” of a system proves useful for error correction and retooling. A trend toward under- or overdetecting conditions, flagging seemingly irrelevant image regions, or low reproducibility can be better addressed when it is clear how the AI is drawing its false conclusions. With an iterative process of testing and redesigning, false positive and negative rates can be reduced, the need for human intervention can be lowered to an appropriate minimum, and patient outcomes can be improved.⁷¹

Data collection raises another ethical concern. To train functional clinical decision support tools, massive amounts of patient demographic, laboratory, and imaging data are required. With incentives to develop the most powerful AI systems, record collection can venture down a path where patient autonomy and privacy are threatened. Radiologists have a duty to ensure data mining serves patients and improves the practice of radiology while protecting patients’ personal information.⁶² Policies have placed similar limits on the access to and use of patient records.^64-69 Patients have the right to request explanation of the AI systems their data have been used to train. Approval for data acquisition requires the use of explainable AI, standardized data security protocol implementation, and adequate proof of communal benefit from the clinical decision support tool. Establishment of state-mandated protections bodes well for a future when developers can access enormous caches of data while patients and health care professionals are assured that no identifying information has escaped a well-regulated space. On the level of the individual radiologist, the knowledge that each datum represents a human life. These are people who has made themselves vulnerable by seeking relief for what ails them, which should serve as a lasting reminder to operate with utmost care when handling sensitive information.

Conclusions

The demonstrated applications of AI in neuroimaging are numerous and varied, and it is reasonable to assume that its implementation will increase as the technology matures. AI use for detecting important neurologic conditions holds promise in combatting ever greater imaging volumes and providing timely diagnoses. As medicine witnesses the continuing adoption of AI, it is important that practitioners possess an understanding of its current and emerging uses.

Selective estrogen receptor modulators (SERMs) are unique synthetic compounds that bind to the estrogen receptor and initiate either estrogenic agonistic or antagonistic activity, depending on the confirmational change they produce on binding to the receptor. Many SERMs have come to market, others have not. Unlike estrogens, which regardless of dose or route of administration all carry risks as a boxed warning on the label, referred to as class labeling,¹ various SERMs exert various effects in some tissues (uterus, vagina) while they have apparent class properties in others (bone, breast).²

The first SERM, for all practical purposes, was tamoxifen (although clomiphene citrate is often considered a SERM). Tamoxifen was approved by the US Food and Drug Administration (FDA) in 1978 for the treatment of breast cancer and, subsequently, for breast cancer risk reduction. It became the most widely prescribed anticancer drug worldwide.

Subsequently, when data showed that tamoxifen could produce a small number of endometrial cancers and a larger number of endometrial polyps,^3,4 there was renewed interest in raloxifene. In preclinical animal studies, raloxifene behaved differently than tamoxifen in the uterus. After clinical trials with raloxifene showed uterine safety,⁵ the drug was FDA approved for prevention of osteoporosis in 1997, for treatment of osteoporosis in 1999, and for breast cancer risk reduction in 2009. Most clinicians are familiar with these 2 SERMs, which have been in clinical use for more than 4 and 2 decades, respectively.

Ospemifene: A third-generation SERM and its indications

Hormone deficiency from menopause causes vulvovaginal and urogenital changes as well as a multitude of symptoms and signs, including vulvar and vaginal thinning, loss of rugal folds, diminished elasticity, increased pH, and most notably dyspareunia. The nomenclature that previously described vulvovaginal atrophy (VVA) has been expanded to include genitourinary syndrome of menopause (GSM).⁶ Unfortunately, many health care providers do not ask patients about GSM symptoms, and few women report their symptoms to their clinician.⁷ Furthermore, although low-dose local estrogens applied vaginally have been the mainstay of therapy for VVA/GSM, only 7% of symptomatic women use any pharmacologic agent,⁸ mainly because of fear of estrogens due to the class labeling mentioned above.

Ospemifene, a newer SERM, improved superficial cells and reduced parabasal cells as seen on a maturation index compared with placebo, according to results of multiple phase 3 clinical trials^9,10; it also lowered vaginal pH and improved most bothersome symptoms (original studies were for dyspareunia). As a result, the FDA approved ospemifene for treatment of moderate to severe dyspareunia from VVA of menopause.

Subsequent studies allowed for a broadened indication to include treatment of moderate to severe dryness due to menopause.¹¹ The ospemifene label contains a boxed warning that states, “In the endometrium, [ospemifene] has estrogen agonistic effects.”¹² Although ospemifene is not an estrogen (it’s a SERM), the label goes on to state, “There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens.” This statement caused The Medical Letter to initially suggest that patients who receive ospemifene also should receive a progestational agent—a suggestion they later retracted.^13,14

To understand why the ospemifene labeling might be worded in such a way, one must review the data regarding the poorly named entity “weakly proliferative endometrium.” The package labeling combines any proliferative endometrium (“weakly” plus “actively” plus “disordered”) that occurred in the clinical trial. Thus, 86.1 per 1,000 of the ospemifene-treated patients (vs 13.3 per 1,000 of those taking placebo) had any one of the proliferative types. The problem is that “actively proliferative” endometrial glands will have mitotic activity in virtually every nucleus of the gland as well as abundant glandular progression (FIGURE 1), whereas “weakly proliferative” is actually closer to inactive or atrophic endometrium with an occasional mitotic figure in only a few nuclei of each gland (FIGURE 2).

In addition, at 1 year, the incidence of active proliferation with ospemifene was 1%.¹⁵ In examining the uterine safety study for raloxifene, both doses of that agent had an active proliferation incidence of 3% at 1 year.⁵ Furthermore, that study had an estrogen-only arm in which, at end point, the incidence of endometrial proliferation was 39%, and hyperplasia, 23%!⁵ It therefore is evident that, in the endometrium, ospemifene is much more like the SERM raloxifene than it is like estrogen. The American College of Obstetricians and Gynecologists (ACOG) endorsed ospemifene (level A evidence) as a first-line therapy for dyspareunia, noting absent endometrial stimulation.¹⁶

Continue to: Ospemifene effects on breast and bone...

 

 

Ospemifene effects on breast and bone

Although ospemifene is approved for treatment of moderate to severe VVA/GSM, it has other SERM effects typical of its class. The label currently states that ospemifene “has not been adequately studied in women with breast cancer; therefore, it should not be used in women with known or suspected breast cancer.”¹² We know that tamoxifen reduced breast cancer 49% in high-risk women in the Breast Cancer Prevention Trial (BCPT).¹⁷ We also know that in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, raloxifene reduced breast cancer 77% in osteoporotic women,¹⁸ and in the Study of Tamoxifen and Raloxifene (STAR) trial, it performed virtually identically to tamoxifen in breast cancer prevention.¹⁹ Previous studies demonstrated that ospemifene inhibits breast cancer cell growth in in vitro cultures as well as in animal studies²⁰ and inhibits proliferation of human breast tissue epithelial cells,²¹ with breast effects similar to those seen with tamoxifen and raloxifene.

Thus, although one would not choose ospemifene as a primary treatment or risk-reducing agent for a patient with breast cancer, the direction of its activity in breast tissue is indisputable and is likely the reason that in the European Union (unlike in the United States) it is approved to treat dyspareunia from VVA/GSM in women with a prior history of breast cancer.

Virtually all SERMs have estrogen agonistic activity in bone. Bone is a dynamic organ, constantly being laid down and taken away (resorption). Estrogen and SERMs are potent antiresorptives in bone metabolism. Ospemifene effectively reduced bone loss in ovariectomized rats, with activity comparable to that of estradiol and raloxifene.²² Clinical data from 3 phase 1 or 2 clinical trials found that ospemifene 60 mg/day had a positive effect on biochemical markers for bone turnover in healthy postmenopausal women, with significant improvements relative to placebo and effects comparable to those of raloxifene.²³ Actual fracture or bone mineral density (BMD) data in postmenopausal women are lacking, but there is a good correlation between biochemical markers for bone turnover and the occurrence of fracture.²⁴ Once again, women who need treatment for osteoporosis should not be treated primarily with ospemifene, but women who use ospemifene for dyspareunia can expect positive activity on bone metabolism.

Clinical application

Ospemifene is an oral SERM approved for the treatment of moderate to severe dyspareunia as well as dryness from VVA due to menopause. In addition, it appears one can safely surmise that the direction of ospemifene’s activity in bone and breast is virtually indisputable. The magnitude of that activity, however, is unstudied. Therefore, in selecting an agent to treat women with dyspareunia or vaginal dryness from VVA of menopause, determining any potential add-on benefit for that particular patient in either bone and/or breast is clinically appropriate.

The SERM bazedoxifene

A meta-analysis of 4 randomized, placebo-controlled trials showed that another SERM, bazedoxifene, can significantly decrease the incidence of vertebral fracture in postmenopausal women at follow-up of 3 and 7 years.²⁵ That meta-analysis also confirmed the long-term favorable safety and tolerability of bazedoxifene, with no increase in adverse events, serious adverse events, myocardial infarction, stroke, venous thromboembolic events, or breast carcinoma in patients using bazedoxifene. However, bazedoxifene use did result in an increased incidence of hot flushes and leg cramps across 7 years.²⁵ Bazedoxifene is available in a 20-mg dose for treatment of postmenopausal osteoporosis in Israel and a number of European Union countries.

Continue to: Enter the concept of tissue-selective estrogen complex (TSEC)...

 

 

Enter the concept of tissue-selective estrogen complex (TSEC)

Some postmenopausal women are extremely intolerant of any progestogen added to estrogen therapy to confer endometrial protection in those with a uterus. According to the results of a clinical trial of postmenopausal women, bazedoxifene is the only SERM shown to decrease endometrial thickness compared with placebo.²⁶ This is the basis for thinking that perhaps a SERM like bazedoxifene, instead of a progestogen, could be used to confer endometrial protection.

A further consideration comes out of the evaluation of data derived from the 2 arms of the Women’s Health Initiative (WHI).²⁷ In the arm that combined conjugated estrogen with medroxyprogesterone acetate through 11.3 years, there was a 25% increase in the incidence of invasive breast cancer, which was statistically significant. Contrast that with the arm in hysterectomized women who received only conjugated estrogen (often inaccurately referred to as the “estrogen only” arm of the WHI). In that study arm, the relative risk of invasive breast cancer was reduced 23%, also statistically significant. Thus, the culprit in the breast cancer incidence difference in these 2 arms appears to be the addition of the progestogen medroxyprogesterone acetate.²⁷

Since the progestogen was used only for endometrial protection, could such endometrial protection be provided by a SERM like bazedoxifene? Preclinical trials showed that a combination of bazedoxifene and conjugated estrogen (in various estrogen doses) resulted in uterine wet weight in an ovariectomized rat model that was no different than that with placebo.²⁸

In terms of effects on breast, preclinical models showed that conjugated estrogen use resulted in less mammary duct elongation and end bud proliferation than estradiol by itself, and that the combination of conjugated estrogen and bazedoxifene resulted in mammary duct elongation and end bud proliferation that was similar to that in the ovariectomized animals and considerably less than a combination of estradiol with bazedoxifene.²⁹

Five phase 3 studies known as the SMART (Selective estrogens, Menopause, And Response to Therapy) trials were then conducted. Collectively, these studies examined the frequency and severity of vasomotor symptoms (VMS), BMD, bone turnover markers, lipid profiles, sleep, quality of life, breast density, and endometrial safety with conjugated estrogen/bazedoxifene treatment.³⁰ Based on these trials with more than 7,500 women, in 2013 the FDA approved a compound of conjugated estrogen 0.45 mg and bazedoxifene 20 mg (Duavee in the United States and Duavive outside the United States).

The incidence of endometrial hyperplasia at 12 months was consistently less than 1%, which is the FDA guidance for approval of hormone therapies. The incidence of bleeding or spotting with conjugated estrogen/bazedoxifene (FIGURE 3) in each 4-week interval over 12 months mirror-imaged that of placebo and ranged from 3.9% in the first 4-week interval to 1.7% in the last 4 weeks, compared with conjugated estrogen 0.45 mg/medroxyprogesterone acetate 1.5 mg, which had a 20.8% incidence of bleeding or spotting in the first 4-week interval and was still at an 8.8% incidence in the last 4 weeks.³¹ This is extremely relevant in clinical practice. There was no difference from placebo in breast cancer incidence, breast pain or tenderness, abnormal mammograms, or breast density at month 12.³²

In terms of frequency of VMS, there was a 74% reduction from baseline at 12 weeks compared with placebo (P<.001), as well as a 37% reduction in the VMS severity score (P<.001).³² Statistically significant improvements occurred in lumbar spine and hip BMD (P<.01) for women who were 1 to 5 years since menopause as well as for those who were more than 5 years since menopause.³³

Packaging issue puts TSEC on back order

In May 2020, Pfizer voluntarily recalled its conjugated estrogen/bazedoxifene product after identifying a “flaw in the drug’s foil laminate pouch that introduced oxygen and lowered the dissolution rate of active pharmaceutical ingredient bazedoxifene acetate.”³⁴ The manufacturer then wrote a letter to health care professionals in September 2021 stating, “Duavee continues to be out of stock due to an unexpected and complex packaging issue, resulting in manufacturing delays. This has nothing to do with the safety or quality of the product itself but could affect product stability throughout its shelf life… Given regulatory approval timelines for any new packaging, it is unlikely that Duavee will return to stock in 2022.”³⁵

Other TSECs?

The conjugated estrogen/bazedoxifene combination is the first FDA-approved TSEC. Other attempts have been made to achieve similar results with combined raloxifene and 17β-estradiol.³⁶ That study was meant to be a 52-week treatment trial with either raloxifene 60 mg alone or in combination with 17β-estradiol 1 mg per day to assess effects on VMS and endometrial safety. The study was stopped early because signs of endometrial stimulation were observed in the raloxifene plus estradiol group. Thus, one cannot combine any estrogen with any SERM and assume similar results.

Clinical application

The combination of conjugated estrogen/bazedoxifene is approved for treatment of VMS of menopause as well as prevention of osteoporosis. Although it is not approved for treatment of moderate to severe VVA, in younger women who initiate treatment it should prevent the development of moderate to severe symptoms of VVA.

Finally, this drug should be protective of the breast. Conjugated estrogen has clearly shown a reduction in breast cancer incidence and mortality, and bazedoxifene is a SERM. All SERMs have, as a class effect, been shown to be antiestrogens in breast tissue, and abundant preclinical data point in that direction.

This combination of conjugated estrogen/bazedoxifene, when it is once again clinically available, may well provide a new paradigm of hormone therapy that is progestogen free and has a benefit/risk ratio that tilts toward its benefits.

Potential for wider therapeutic benefits

Newer SERMs like ospemifene, approved for treatment of VVA/GSM, and bazedoxifene/conjugated estrogen combination, approved for treatment of VMS and prevention of bone loss, have other beneficial properties that can and should result in their more widespread use. ●

Selective estrogen receptor modulators (SERMs) are unique synthetic compounds that bind to the estrogen receptor and initiate either estrogenic agonistic or antagonistic activity, depending on the confirmational change they produce on binding to the receptor. Many SERMs have come to market, others have not. Unlike estrogens, which regardless of dose or route of administration all carry risks as a boxed warning on the label, referred to as class labeling,¹ various SERMs exert various effects in some tissues (uterus, vagina) while they have apparent class properties in others (bone, breast).²

The first SERM, for all practical purposes, was tamoxifen (although clomiphene citrate is often considered a SERM). Tamoxifen was approved by the US Food and Drug Administration (FDA) in 1978 for the treatment of breast cancer and, subsequently, for breast cancer risk reduction. It became the most widely prescribed anticancer drug worldwide.

Subsequently, when data showed that tamoxifen could produce a small number of endometrial cancers and a larger number of endometrial polyps,^3,4 there was renewed interest in raloxifene. In preclinical animal studies, raloxifene behaved differently than tamoxifen in the uterus. After clinical trials with raloxifene showed uterine safety,⁵ the drug was FDA approved for prevention of osteoporosis in 1997, for treatment of osteoporosis in 1999, and for breast cancer risk reduction in 2009. Most clinicians are familiar with these 2 SERMs, which have been in clinical use for more than 4 and 2 decades, respectively.

Ospemifene: A third-generation SERM and its indications

Hormone deficiency from menopause causes vulvovaginal and urogenital changes as well as a multitude of symptoms and signs, including vulvar and vaginal thinning, loss of rugal folds, diminished elasticity, increased pH, and most notably dyspareunia. The nomenclature that previously described vulvovaginal atrophy (VVA) has been expanded to include genitourinary syndrome of menopause (GSM).⁶ Unfortunately, many health care providers do not ask patients about GSM symptoms, and few women report their symptoms to their clinician.⁷ Furthermore, although low-dose local estrogens applied vaginally have been the mainstay of therapy for VVA/GSM, only 7% of symptomatic women use any pharmacologic agent,⁸ mainly because of fear of estrogens due to the class labeling mentioned above.

Ospemifene, a newer SERM, improved superficial cells and reduced parabasal cells as seen on a maturation index compared with placebo, according to results of multiple phase 3 clinical trials^9,10; it also lowered vaginal pH and improved most bothersome symptoms (original studies were for dyspareunia). As a result, the FDA approved ospemifene for treatment of moderate to severe dyspareunia from VVA of menopause.

Subsequent studies allowed for a broadened indication to include treatment of moderate to severe dryness due to menopause.¹¹ The ospemifene label contains a boxed warning that states, “In the endometrium, [ospemifene] has estrogen agonistic effects.”¹² Although ospemifene is not an estrogen (it’s a SERM), the label goes on to state, “There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens.” This statement caused The Medical Letter to initially suggest that patients who receive ospemifene also should receive a progestational agent—a suggestion they later retracted.^13,14

To understand why the ospemifene labeling might be worded in such a way, one must review the data regarding the poorly named entity “weakly proliferative endometrium.” The package labeling combines any proliferative endometrium (“weakly” plus “actively” plus “disordered”) that occurred in the clinical trial. Thus, 86.1 per 1,000 of the ospemifene-treated patients (vs 13.3 per 1,000 of those taking placebo) had any one of the proliferative types. The problem is that “actively proliferative” endometrial glands will have mitotic activity in virtually every nucleus of the gland as well as abundant glandular progression (FIGURE 1), whereas “weakly proliferative” is actually closer to inactive or atrophic endometrium with an occasional mitotic figure in only a few nuclei of each gland (FIGURE 2).

In addition, at 1 year, the incidence of active proliferation with ospemifene was 1%.¹⁵ In examining the uterine safety study for raloxifene, both doses of that agent had an active proliferation incidence of 3% at 1 year.⁵ Furthermore, that study had an estrogen-only arm in which, at end point, the incidence of endometrial proliferation was 39%, and hyperplasia, 23%!⁵ It therefore is evident that, in the endometrium, ospemifene is much more like the SERM raloxifene than it is like estrogen. The American College of Obstetricians and Gynecologists (ACOG) endorsed ospemifene (level A evidence) as a first-line therapy for dyspareunia, noting absent endometrial stimulation.¹⁶

Continue to: Ospemifene effects on breast and bone...

 

 

Ospemifene effects on breast and bone

Although ospemifene is approved for treatment of moderate to severe VVA/GSM, it has other SERM effects typical of its class. The label currently states that ospemifene “has not been adequately studied in women with breast cancer; therefore, it should not be used in women with known or suspected breast cancer.”¹² We know that tamoxifen reduced breast cancer 49% in high-risk women in the Breast Cancer Prevention Trial (BCPT).¹⁷ We also know that in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, raloxifene reduced breast cancer 77% in osteoporotic women,¹⁸ and in the Study of Tamoxifen and Raloxifene (STAR) trial, it performed virtually identically to tamoxifen in breast cancer prevention.¹⁹ Previous studies demonstrated that ospemifene inhibits breast cancer cell growth in in vitro cultures as well as in animal studies²⁰ and inhibits proliferation of human breast tissue epithelial cells,²¹ with breast effects similar to those seen with tamoxifen and raloxifene.

Thus, although one would not choose ospemifene as a primary treatment or risk-reducing agent for a patient with breast cancer, the direction of its activity in breast tissue is indisputable and is likely the reason that in the European Union (unlike in the United States) it is approved to treat dyspareunia from VVA/GSM in women with a prior history of breast cancer.

Virtually all SERMs have estrogen agonistic activity in bone. Bone is a dynamic organ, constantly being laid down and taken away (resorption). Estrogen and SERMs are potent antiresorptives in bone metabolism. Ospemifene effectively reduced bone loss in ovariectomized rats, with activity comparable to that of estradiol and raloxifene.²² Clinical data from 3 phase 1 or 2 clinical trials found that ospemifene 60 mg/day had a positive effect on biochemical markers for bone turnover in healthy postmenopausal women, with significant improvements relative to placebo and effects comparable to those of raloxifene.²³ Actual fracture or bone mineral density (BMD) data in postmenopausal women are lacking, but there is a good correlation between biochemical markers for bone turnover and the occurrence of fracture.²⁴ Once again, women who need treatment for osteoporosis should not be treated primarily with ospemifene, but women who use ospemifene for dyspareunia can expect positive activity on bone metabolism.

Clinical application

Ospemifene is an oral SERM approved for the treatment of moderate to severe dyspareunia as well as dryness from VVA due to menopause. In addition, it appears one can safely surmise that the direction of ospemifene’s activity in bone and breast is virtually indisputable. The magnitude of that activity, however, is unstudied. Therefore, in selecting an agent to treat women with dyspareunia or vaginal dryness from VVA of menopause, determining any potential add-on benefit for that particular patient in either bone and/or breast is clinically appropriate.

The SERM bazedoxifene

A meta-analysis of 4 randomized, placebo-controlled trials showed that another SERM, bazedoxifene, can significantly decrease the incidence of vertebral fracture in postmenopausal women at follow-up of 3 and 7 years.²⁵ That meta-analysis also confirmed the long-term favorable safety and tolerability of bazedoxifene, with no increase in adverse events, serious adverse events, myocardial infarction, stroke, venous thromboembolic events, or breast carcinoma in patients using bazedoxifene. However, bazedoxifene use did result in an increased incidence of hot flushes and leg cramps across 7 years.²⁵ Bazedoxifene is available in a 20-mg dose for treatment of postmenopausal osteoporosis in Israel and a number of European Union countries.

Continue to: Enter the concept of tissue-selective estrogen complex (TSEC)...

 

 

Enter the concept of tissue-selective estrogen complex (TSEC)

Some postmenopausal women are extremely intolerant of any progestogen added to estrogen therapy to confer endometrial protection in those with a uterus. According to the results of a clinical trial of postmenopausal women, bazedoxifene is the only SERM shown to decrease endometrial thickness compared with placebo.²⁶ This is the basis for thinking that perhaps a SERM like bazedoxifene, instead of a progestogen, could be used to confer endometrial protection.

A further consideration comes out of the evaluation of data derived from the 2 arms of the Women’s Health Initiative (WHI).²⁷ In the arm that combined conjugated estrogen with medroxyprogesterone acetate through 11.3 years, there was a 25% increase in the incidence of invasive breast cancer, which was statistically significant. Contrast that with the arm in hysterectomized women who received only conjugated estrogen (often inaccurately referred to as the “estrogen only” arm of the WHI). In that study arm, the relative risk of invasive breast cancer was reduced 23%, also statistically significant. Thus, the culprit in the breast cancer incidence difference in these 2 arms appears to be the addition of the progestogen medroxyprogesterone acetate.²⁷

Since the progestogen was used only for endometrial protection, could such endometrial protection be provided by a SERM like bazedoxifene? Preclinical trials showed that a combination of bazedoxifene and conjugated estrogen (in various estrogen doses) resulted in uterine wet weight in an ovariectomized rat model that was no different than that with placebo.²⁸

In terms of effects on breast, preclinical models showed that conjugated estrogen use resulted in less mammary duct elongation and end bud proliferation than estradiol by itself, and that the combination of conjugated estrogen and bazedoxifene resulted in mammary duct elongation and end bud proliferation that was similar to that in the ovariectomized animals and considerably less than a combination of estradiol with bazedoxifene.²⁹

Five phase 3 studies known as the SMART (Selective estrogens, Menopause, And Response to Therapy) trials were then conducted. Collectively, these studies examined the frequency and severity of vasomotor symptoms (VMS), BMD, bone turnover markers, lipid profiles, sleep, quality of life, breast density, and endometrial safety with conjugated estrogen/bazedoxifene treatment.³⁰ Based on these trials with more than 7,500 women, in 2013 the FDA approved a compound of conjugated estrogen 0.45 mg and bazedoxifene 20 mg (Duavee in the United States and Duavive outside the United States).

The incidence of endometrial hyperplasia at 12 months was consistently less than 1%, which is the FDA guidance for approval of hormone therapies. The incidence of bleeding or spotting with conjugated estrogen/bazedoxifene (FIGURE 3) in each 4-week interval over 12 months mirror-imaged that of placebo and ranged from 3.9% in the first 4-week interval to 1.7% in the last 4 weeks, compared with conjugated estrogen 0.45 mg/medroxyprogesterone acetate 1.5 mg, which had a 20.8% incidence of bleeding or spotting in the first 4-week interval and was still at an 8.8% incidence in the last 4 weeks.³¹ This is extremely relevant in clinical practice. There was no difference from placebo in breast cancer incidence, breast pain or tenderness, abnormal mammograms, or breast density at month 12.³²

In terms of frequency of VMS, there was a 74% reduction from baseline at 12 weeks compared with placebo (P<.001), as well as a 37% reduction in the VMS severity score (P<.001).³² Statistically significant improvements occurred in lumbar spine and hip BMD (P<.01) for women who were 1 to 5 years since menopause as well as for those who were more than 5 years since menopause.³³

Packaging issue puts TSEC on back order

In May 2020, Pfizer voluntarily recalled its conjugated estrogen/bazedoxifene product after identifying a “flaw in the drug’s foil laminate pouch that introduced oxygen and lowered the dissolution rate of active pharmaceutical ingredient bazedoxifene acetate.”³⁴ The manufacturer then wrote a letter to health care professionals in September 2021 stating, “Duavee continues to be out of stock due to an unexpected and complex packaging issue, resulting in manufacturing delays. This has nothing to do with the safety or quality of the product itself but could affect product stability throughout its shelf life… Given regulatory approval timelines for any new packaging, it is unlikely that Duavee will return to stock in 2022.”³⁵

Other TSECs?

The conjugated estrogen/bazedoxifene combination is the first FDA-approved TSEC. Other attempts have been made to achieve similar results with combined raloxifene and 17β-estradiol.³⁶ That study was meant to be a 52-week treatment trial with either raloxifene 60 mg alone or in combination with 17β-estradiol 1 mg per day to assess effects on VMS and endometrial safety. The study was stopped early because signs of endometrial stimulation were observed in the raloxifene plus estradiol group. Thus, one cannot combine any estrogen with any SERM and assume similar results.

Clinical application

The combination of conjugated estrogen/bazedoxifene is approved for treatment of VMS of menopause as well as prevention of osteoporosis. Although it is not approved for treatment of moderate to severe VVA, in younger women who initiate treatment it should prevent the development of moderate to severe symptoms of VVA.

Finally, this drug should be protective of the breast. Conjugated estrogen has clearly shown a reduction in breast cancer incidence and mortality, and bazedoxifene is a SERM. All SERMs have, as a class effect, been shown to be antiestrogens in breast tissue, and abundant preclinical data point in that direction.

This combination of conjugated estrogen/bazedoxifene, when it is once again clinically available, may well provide a new paradigm of hormone therapy that is progestogen free and has a benefit/risk ratio that tilts toward its benefits.

Potential for wider therapeutic benefits

Newer SERMs like ospemifene, approved for treatment of VVA/GSM, and bazedoxifene/conjugated estrogen combination, approved for treatment of VMS and prevention of bone loss, have other beneficial properties that can and should result in their more widespread use. ●

Selective estrogen receptor modulators (SERMs) are unique synthetic compounds that bind to the estrogen receptor and initiate either estrogenic agonistic or antagonistic activity, depending on the confirmational change they produce on binding to the receptor. Many SERMs have come to market, others have not. Unlike estrogens, which regardless of dose or route of administration all carry risks as a boxed warning on the label, referred to as class labeling,¹ various SERMs exert various effects in some tissues (uterus, vagina) while they have apparent class properties in others (bone, breast).²

The first SERM, for all practical purposes, was tamoxifen (although clomiphene citrate is often considered a SERM). Tamoxifen was approved by the US Food and Drug Administration (FDA) in 1978 for the treatment of breast cancer and, subsequently, for breast cancer risk reduction. It became the most widely prescribed anticancer drug worldwide.

Subsequently, when data showed that tamoxifen could produce a small number of endometrial cancers and a larger number of endometrial polyps,^3,4 there was renewed interest in raloxifene. In preclinical animal studies, raloxifene behaved differently than tamoxifen in the uterus. After clinical trials with raloxifene showed uterine safety,⁵ the drug was FDA approved for prevention of osteoporosis in 1997, for treatment of osteoporosis in 1999, and for breast cancer risk reduction in 2009. Most clinicians are familiar with these 2 SERMs, which have been in clinical use for more than 4 and 2 decades, respectively.

Ospemifene: A third-generation SERM and its indications

Hormone deficiency from menopause causes vulvovaginal and urogenital changes as well as a multitude of symptoms and signs, including vulvar and vaginal thinning, loss of rugal folds, diminished elasticity, increased pH, and most notably dyspareunia. The nomenclature that previously described vulvovaginal atrophy (VVA) has been expanded to include genitourinary syndrome of menopause (GSM).⁶ Unfortunately, many health care providers do not ask patients about GSM symptoms, and few women report their symptoms to their clinician.⁷ Furthermore, although low-dose local estrogens applied vaginally have been the mainstay of therapy for VVA/GSM, only 7% of symptomatic women use any pharmacologic agent,⁸ mainly because of fear of estrogens due to the class labeling mentioned above.

Ospemifene, a newer SERM, improved superficial cells and reduced parabasal cells as seen on a maturation index compared with placebo, according to results of multiple phase 3 clinical trials^9,10; it also lowered vaginal pH and improved most bothersome symptoms (original studies were for dyspareunia). As a result, the FDA approved ospemifene for treatment of moderate to severe dyspareunia from VVA of menopause.

Subsequent studies allowed for a broadened indication to include treatment of moderate to severe dryness due to menopause.¹¹ The ospemifene label contains a boxed warning that states, “In the endometrium, [ospemifene] has estrogen agonistic effects.”¹² Although ospemifene is not an estrogen (it’s a SERM), the label goes on to state, “There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens.” This statement caused The Medical Letter to initially suggest that patients who receive ospemifene also should receive a progestational agent—a suggestion they later retracted.^13,14

To understand why the ospemifene labeling might be worded in such a way, one must review the data regarding the poorly named entity “weakly proliferative endometrium.” The package labeling combines any proliferative endometrium (“weakly” plus “actively” plus “disordered”) that occurred in the clinical trial. Thus, 86.1 per 1,000 of the ospemifene-treated patients (vs 13.3 per 1,000 of those taking placebo) had any one of the proliferative types. The problem is that “actively proliferative” endometrial glands will have mitotic activity in virtually every nucleus of the gland as well as abundant glandular progression (FIGURE 1), whereas “weakly proliferative” is actually closer to inactive or atrophic endometrium with an occasional mitotic figure in only a few nuclei of each gland (FIGURE 2).

In addition, at 1 year, the incidence of active proliferation with ospemifene was 1%.¹⁵ In examining the uterine safety study for raloxifene, both doses of that agent had an active proliferation incidence of 3% at 1 year.⁵ Furthermore, that study had an estrogen-only arm in which, at end point, the incidence of endometrial proliferation was 39%, and hyperplasia, 23%!⁵ It therefore is evident that, in the endometrium, ospemifene is much more like the SERM raloxifene than it is like estrogen. The American College of Obstetricians and Gynecologists (ACOG) endorsed ospemifene (level A evidence) as a first-line therapy for dyspareunia, noting absent endometrial stimulation.¹⁶

Continue to: Ospemifene effects on breast and bone...

 

 

Ospemifene effects on breast and bone

Although ospemifene is approved for treatment of moderate to severe VVA/GSM, it has other SERM effects typical of its class. The label currently states that ospemifene “has not been adequately studied in women with breast cancer; therefore, it should not be used in women with known or suspected breast cancer.”¹² We know that tamoxifen reduced breast cancer 49% in high-risk women in the Breast Cancer Prevention Trial (BCPT).¹⁷ We also know that in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, raloxifene reduced breast cancer 77% in osteoporotic women,¹⁸ and in the Study of Tamoxifen and Raloxifene (STAR) trial, it performed virtually identically to tamoxifen in breast cancer prevention.¹⁹ Previous studies demonstrated that ospemifene inhibits breast cancer cell growth in in vitro cultures as well as in animal studies²⁰ and inhibits proliferation of human breast tissue epithelial cells,²¹ with breast effects similar to those seen with tamoxifen and raloxifene.

Thus, although one would not choose ospemifene as a primary treatment or risk-reducing agent for a patient with breast cancer, the direction of its activity in breast tissue is indisputable and is likely the reason that in the European Union (unlike in the United States) it is approved to treat dyspareunia from VVA/GSM in women with a prior history of breast cancer.

Virtually all SERMs have estrogen agonistic activity in bone. Bone is a dynamic organ, constantly being laid down and taken away (resorption). Estrogen and SERMs are potent antiresorptives in bone metabolism. Ospemifene effectively reduced bone loss in ovariectomized rats, with activity comparable to that of estradiol and raloxifene.²² Clinical data from 3 phase 1 or 2 clinical trials found that ospemifene 60 mg/day had a positive effect on biochemical markers for bone turnover in healthy postmenopausal women, with significant improvements relative to placebo and effects comparable to those of raloxifene.²³ Actual fracture or bone mineral density (BMD) data in postmenopausal women are lacking, but there is a good correlation between biochemical markers for bone turnover and the occurrence of fracture.²⁴ Once again, women who need treatment for osteoporosis should not be treated primarily with ospemifene, but women who use ospemifene for dyspareunia can expect positive activity on bone metabolism.

Clinical application

Ospemifene is an oral SERM approved for the treatment of moderate to severe dyspareunia as well as dryness from VVA due to menopause. In addition, it appears one can safely surmise that the direction of ospemifene’s activity in bone and breast is virtually indisputable. The magnitude of that activity, however, is unstudied. Therefore, in selecting an agent to treat women with dyspareunia or vaginal dryness from VVA of menopause, determining any potential add-on benefit for that particular patient in either bone and/or breast is clinically appropriate.

The SERM bazedoxifene

A meta-analysis of 4 randomized, placebo-controlled trials showed that another SERM, bazedoxifene, can significantly decrease the incidence of vertebral fracture in postmenopausal women at follow-up of 3 and 7 years.²⁵ That meta-analysis also confirmed the long-term favorable safety and tolerability of bazedoxifene, with no increase in adverse events, serious adverse events, myocardial infarction, stroke, venous thromboembolic events, or breast carcinoma in patients using bazedoxifene. However, bazedoxifene use did result in an increased incidence of hot flushes and leg cramps across 7 years.²⁵ Bazedoxifene is available in a 20-mg dose for treatment of postmenopausal osteoporosis in Israel and a number of European Union countries.

Continue to: Enter the concept of tissue-selective estrogen complex (TSEC)...

 

 

Enter the concept of tissue-selective estrogen complex (TSEC)

Some postmenopausal women are extremely intolerant of any progestogen added to estrogen therapy to confer endometrial protection in those with a uterus. According to the results of a clinical trial of postmenopausal women, bazedoxifene is the only SERM shown to decrease endometrial thickness compared with placebo.²⁶ This is the basis for thinking that perhaps a SERM like bazedoxifene, instead of a progestogen, could be used to confer endometrial protection.

A further consideration comes out of the evaluation of data derived from the 2 arms of the Women’s Health Initiative (WHI).²⁷ In the arm that combined conjugated estrogen with medroxyprogesterone acetate through 11.3 years, there was a 25% increase in the incidence of invasive breast cancer, which was statistically significant. Contrast that with the arm in hysterectomized women who received only conjugated estrogen (often inaccurately referred to as the “estrogen only” arm of the WHI). In that study arm, the relative risk of invasive breast cancer was reduced 23%, also statistically significant. Thus, the culprit in the breast cancer incidence difference in these 2 arms appears to be the addition of the progestogen medroxyprogesterone acetate.²⁷

Since the progestogen was used only for endometrial protection, could such endometrial protection be provided by a SERM like bazedoxifene? Preclinical trials showed that a combination of bazedoxifene and conjugated estrogen (in various estrogen doses) resulted in uterine wet weight in an ovariectomized rat model that was no different than that with placebo.²⁸

In terms of effects on breast, preclinical models showed that conjugated estrogen use resulted in less mammary duct elongation and end bud proliferation than estradiol by itself, and that the combination of conjugated estrogen and bazedoxifene resulted in mammary duct elongation and end bud proliferation that was similar to that in the ovariectomized animals and considerably less than a combination of estradiol with bazedoxifene.²⁹

Five phase 3 studies known as the SMART (Selective estrogens, Menopause, And Response to Therapy) trials were then conducted. Collectively, these studies examined the frequency and severity of vasomotor symptoms (VMS), BMD, bone turnover markers, lipid profiles, sleep, quality of life, breast density, and endometrial safety with conjugated estrogen/bazedoxifene treatment.³⁰ Based on these trials with more than 7,500 women, in 2013 the FDA approved a compound of conjugated estrogen 0.45 mg and bazedoxifene 20 mg (Duavee in the United States and Duavive outside the United States).

The incidence of endometrial hyperplasia at 12 months was consistently less than 1%, which is the FDA guidance for approval of hormone therapies. The incidence of bleeding or spotting with conjugated estrogen/bazedoxifene (FIGURE 3) in each 4-week interval over 12 months mirror-imaged that of placebo and ranged from 3.9% in the first 4-week interval to 1.7% in the last 4 weeks, compared with conjugated estrogen 0.45 mg/medroxyprogesterone acetate 1.5 mg, which had a 20.8% incidence of bleeding or spotting in the first 4-week interval and was still at an 8.8% incidence in the last 4 weeks.³¹ This is extremely relevant in clinical practice. There was no difference from placebo in breast cancer incidence, breast pain or tenderness, abnormal mammograms, or breast density at month 12.³²

In terms of frequency of VMS, there was a 74% reduction from baseline at 12 weeks compared with placebo (P<.001), as well as a 37% reduction in the VMS severity score (P<.001).³² Statistically significant improvements occurred in lumbar spine and hip BMD (P<.01) for women who were 1 to 5 years since menopause as well as for those who were more than 5 years since menopause.³³

Packaging issue puts TSEC on back order

In May 2020, Pfizer voluntarily recalled its conjugated estrogen/bazedoxifene product after identifying a “flaw in the drug’s foil laminate pouch that introduced oxygen and lowered the dissolution rate of active pharmaceutical ingredient bazedoxifene acetate.”³⁴ The manufacturer then wrote a letter to health care professionals in September 2021 stating, “Duavee continues to be out of stock due to an unexpected and complex packaging issue, resulting in manufacturing delays. This has nothing to do with the safety or quality of the product itself but could affect product stability throughout its shelf life… Given regulatory approval timelines for any new packaging, it is unlikely that Duavee will return to stock in 2022.”³⁵

Other TSECs?

The conjugated estrogen/bazedoxifene combination is the first FDA-approved TSEC. Other attempts have been made to achieve similar results with combined raloxifene and 17β-estradiol.³⁶ That study was meant to be a 52-week treatment trial with either raloxifene 60 mg alone or in combination with 17β-estradiol 1 mg per day to assess effects on VMS and endometrial safety. The study was stopped early because signs of endometrial stimulation were observed in the raloxifene plus estradiol group. Thus, one cannot combine any estrogen with any SERM and assume similar results.

Clinical application

The combination of conjugated estrogen/bazedoxifene is approved for treatment of VMS of menopause as well as prevention of osteoporosis. Although it is not approved for treatment of moderate to severe VVA, in younger women who initiate treatment it should prevent the development of moderate to severe symptoms of VVA.

Finally, this drug should be protective of the breast. Conjugated estrogen has clearly shown a reduction in breast cancer incidence and mortality, and bazedoxifene is a SERM. All SERMs have, as a class effect, been shown to be antiestrogens in breast tissue, and abundant preclinical data point in that direction.

This combination of conjugated estrogen/bazedoxifene, when it is once again clinically available, may well provide a new paradigm of hormone therapy that is progestogen free and has a benefit/risk ratio that tilts toward its benefits.

Potential for wider therapeutic benefits

Newer SERMs like ospemifene, approved for treatment of VVA/GSM, and bazedoxifene/conjugated estrogen combination, approved for treatment of VMS and prevention of bone loss, have other beneficial properties that can and should result in their more widespread use. ●

ILLUSTRATION BY KIMBERLY MARTENS FOR OBG MANAGEMENT

While its etiology remains uncertain, cesarean scar niche (CSN) is well publicized, as are its pathological clinical manifestations. In a future pregnancy, they include cesarean scar pregnancy (CSP), which in turn can lead to placenta accreta spectrum, and possible uterine rupture/dehiscence of a residual thin myometrial layer. CSP refers to the implantation of an early pregnancy on the scar or in the niche at the site of a prior cesarean delivery (CD); it has an incidence of 1 per 1,000 pregnancies. An estimated 52% of CSPs occur after even just one CD.¹ CSP has been linked to placenta accreta spectrum and has been shown to be its precursor.² Both CSP and placenta accreta spectrum can be consequences of CD and share a common histology of villous or placental attachment/invasion into the cesarean scar.³ The incidence of placenta accreta spectrum has risen from about 1 in 4,000 live births in the 1970s to 1 in 2,500 in the 1980s; in 2016, the incidence of placenta accreta spectrum was reported as 1 per 272 live births.⁴

Placenta accreta spectrum denotes the attachment of the placenta into and through the myometrium,⁵ and it can result in severe complications, including hemorrhage, hysterectomy, and intensive care treatment. The increasing rate of placenta accreta spectrum parallels the increasing CD rate, which rose from 5.8% in 1970 to 31.9% in 2016.⁶ Multiple repeat CDs are increasing in frequency as well. At the beginning of the century, placenta accreta spectrum mainly occurred after manual removal of the placenta, uterine curettage, or endometritis. Recently, experts are in agreement that the main determinant of placenta accreta spectrum is the uterine scar and niche formation after a previous CD.⁵ Larger niches are associated with an increased incidence of uterine rupture or dehiscence in a subsequent pregnancy.⁷

In the nonpregnant state, such niches are associated with intermenstrual bleeding, pelvic pain, painful intercourse, painful menses, and subfertility, becoming increasingly more severe in women with greater numbers of CDs.^8-10 Conception rate with assisted reproductive treatment is notably reduced.¹¹

Understanding its etiology

Monteagudo and colleagues first described a “niche” in 100% of 44 women evaluated for postmenopausal bleeding who had a prior CD.¹² CSN has been the subject of well over 3,000 publications over the past 30 years. While the topic generates much interest among researchers, it is garnering little traction among practicing obstetricians. Such “niches,” also referred to as isthmocele, cesarean scar defect, or a diverticulum, was first described in 1961¹³ and later defined on ultrasonography as a hypoechoic triangular-shaped uterine defect outlined by saline instillation sonohysterogram (SIS), reflecting a discontinuation of the myometrium at the site of a previous CD.¹² In 2019, a European task force further defined a CSN as an “indentation at the site in the cesarean section scar with a depth of at least 2 mm” and extended the classification to include branches as extensions toward the anterior uterine serosa.¹⁴ Using this criterion, sonographic postoperative evaluation after one CD revealed a CSN in 68.9% of women with one single-layer uterine closure and in 73.6% of women after a double-layer closure.¹⁵ Larger niche sizes with thinner residual myometrial thickness appeared more frequently when a single-layer closure technique was used, without closure of the peritoneum. Its prevalence varies from 56% to 84%.^16,17

Etiology of CSN formation: Our hypotheses

The precise pathophysiology of CSN remains elusive. Speculations attributed niche formation to numerous factors: timing of surgery, cervical incision, incomplete closure of the uterine incision, adhesion formation between the CD scar and the abdominal wall, and inherent maternal conditions which may impair healing, such as smoking, obesity, diabetes, maternal age, and labor status.^18-20 Retroflexion of the uterus is reportedly associated with increased incidence and size of the niche, with CSN 50% more likely to develop in women with a retroflexed versus an anteverted uterus.²¹ We demonstrated the origin of niche formation in real-time from the start to the completion of uterine closure by a video capture of a single-layer closure followed by an immediate SIS of the ex vivo hysterectomized uterus, and histopathologic proof of the presence of endometrial cells defining the “niche.”²² This case exposes the misalignment of the uterine wall, while including the endometrium in the closure (FIGURE 1). Similarly, pathologic studies of hysteroscopy-resected isthmocele ridges of symptomatic women with niche-related subfertility revealed the tissue edges lined by endocervical, endometrial, or isthmic mucosa either combined or isolated in the scar.²³ The presence of endometrial/cervical tissue in the myometrial closure has been debated for over a century.^24,25

Continue to: Uterine closure techniques...

 

 

Uterine closure techniques: Historical perspective

In 1882, Max Sanger introduced a vertical uterine closure of a classical cesarean operation in response to hysterectomy as the contemporaneous alternative to prevent infection, bleeding, and death.²⁴ Dr. Sanger emphasized layer approximation, suturing, and the avoidance of decidua in the first layer (FIGURE 2). This became the teaching of the classical CD until the 1970s. In 1926, Munro Kerr addressed uterine rupture with labor after a classical CD by introducing the lower uterine segment transverse incision. He cautioned to maintain the decidua inside the uterine 2-layer closure of the cavity.²⁵ These pioneers were joined by others to rally for endometrium exclusion while promoting layer approximation. These techniques became universally standard and were taught across teaching medical centers in the United States and abroad until about 50 years ago.

In the 1970s, newer developments brought significant changes to uterine closure techniques. Initiated by Joel-Cohen,²⁶ blunt dissection of the abdominal incision was adapted by Michael Stark, creating what came to be known as the Misgav-Ladach cesarean technique.²⁷ Stark emphasized blunt dissection and introduced single-layer closure. Thereby the exclusion of the endometrium, used for more than 70 years, was abandoned by the present-day single- or double-layer uterine closure in favor of cost and time savings. Systematic reviews and meta-analyses comparing the two contrasting techniques were inconclusive, noting that the niche prevalence and size were similar in both groups. These studies did not take into account the variety of individual techniques or the position of the endometrium in the final closures.²⁸

Endometrium and uterine closure

Our recent study examining uterine scar defect in women after one primary CD by SIS concluded that a specific endometrium-free closure technique (EFCT) (FIGURE 3) is associated with fewer and less severe defects and a thicker residual myometrial thickness when compared with closures with unknown or endometrium inclusion.²⁹ The study found non-specific closure techniques to be 6 times more likely to form a niche of 2-mm deep or greater than the EFCT.

Furthermore, we surveyed the diversity of uterine closures and the location of the endometrium among obstetricians in one institution.³⁰ Presence of endometrium on the surface of the final uterine closure was reported by 20% of respondents (see Figure 1). When asked for their opinion on the impact of CD techniques on placenta accreta spectrum, without available evidence 80% of the survey respondents reported no relationship to techniques, and only 20% suggested an association. This particular study demonstrates that the surgical techniques just described are random, unfettered, and applied without consideration of clinical outcomes.

Our recent retrospective study that spanned 30 years and examined the EFCT—per­formed anywhere between 3 to 9 consecutive CDs—revealed no abnormal placentation in any subsequent pregnancies.³¹ This was one of the few clinical studies of the long-term consequences of a uterine closure technique. In this study, the endometrium was excluded during the uterine closure, allowing its free edges to abut and heal. This step avoids scarring the endometrial-myometrial (EM) interface and unintentional inclusion of endometrium in the closed uterine wall. In this context, Jauniaux and colleagues cited the destruction of the EM interface as the main factor for placenta-adherent disorders.³² Sholapurkar and others highlight the need to further examine intrinsic details of uterine closure beyond single- and double-layer techniques to better understand the etiology of cesarean scar formation.¹⁹ The search for the pathophysiology of CSN continues to present significant challenges imposed by the variety of currently practiced uterine closures.

Continue to: Focus on prevention...

 

 

Research: Focus on prevention

Our research aims to address the endometrium, a specific layer that was the topic of concern in nascent CD techniques, as a renewed and contemporary one. The presence of the endometrium in ectopic locations or its destruction from intrauterine surgeries or infections has been implicated in abnormal placentation.^13,24 Our approach, in theory, is to limit the position of the endometrium to its innermost location and avoid its iatrogenic suturing and inclusion into the uterine wall closure. The rationale of sparing the endometrium in a layer-by-layer approximation is to allow for a closer restoration to normal anatomy and physiology than a random “en masse” uterine wall closure would permit. For this reason, the EM junction, the perimetrium, and the serosa must be identified and realigned for a more effective closure that incorporates the entire myometrial thickness. As evidence supports technical impact on the development of uterine scar defect in women after one CD, future studies are needed to evaluate uterine integrity by saline infusion sonohysterography in multiparous women with a prior random closure technique or a prior EFCT.

The potential long-term risks of blunt dissection for opening the uterus have not been studied. There are no physiologic lines in the uterine wall to facilitate a regular-bordered uterine stretch. The tissue stretch, which depends on the individual surgeon’s strength applied during the procedure and patient’s labor status, may result in an irregular tear and a difficult repair. The EFCT technique shows a more optimized risk-benefit ratio for an anatomical repair and is replicable. The safety of uterine layer re-approximation has been demonstrated and can be studied in large populations using strict uniform criteria.

Current and future challenges

Residency training

Most recently, teachers of resident trainees are mostly familiar with blunt dissection, techniques of which are passed on unchallenged from resident to resident. The endometrium and peritoneum are neither identified nor treated as separate layers, thus becoming obsolete as surgical and anatomical landmarks.

Standardization of CD techniques

Front-line obstetricians are persuaded to practice a standardized approach that relies on the benefits of cost related to operating room turnover as well as surgeons’ time savings without consideration of outcomes in subsequent pregnancies. Sholapurkar has warned that “wrong standardization” is far worse than no standardization, worse for the training of junior obstetricians, as it can inhibit critical reasoning about safe surgical techniques that can optimize outcomes of the condition of the lower uterine segment.³³

Emergence of cost and time savings in clinical practice

A time-cost savings argument is relatively negligeable in an estimated 40-minute CD. By contrast, deliberate surgical technique and carrying out the appropriate steps for the particular condition at hand to achieve the best outcomes assume more weight.³² Furthermore, this short-term cost benefit is challenged by the comparatively larger costs associated with the diagnosis, the treatment of post-CD adverse consequences (outlined above), as well as the emotional impact on women and their families. Additionally, the emphasis on time savings creates a generation of surgeons fixated with total operative time without consideration of long-term risks and adverse maternal outcomes.

Physician autonomy has led to the unmonitored freedom of obstetricians to choose their own technique for a CD, with some employing the commonly practiced culture of fastest turnaround even in nonurgent circumstances.

Documentation and terminology

Current documenting systems are not detail-oriented enough to assist in a thorough correlation between surgical techniques and outcomes. The use of single- or double-layer closure terminology is insufficient and has proven to be flawed, without describing the handling of the endometrium in terms of its inclusion or exclusion in the closure.

Quality improvement feedback

Long-term post-CD complications are often not reported to the physician or institution involved in the prior CD. In our opinion, some sort of registry would be of value. Perhaps then subsequent CD outcomes could be traced back and reported to the prior institution and surgeon. Feedback is critical to understanding the correlation between techniques and outcomes and more specifically to gathering learning points and using data for quality improvement of future cases.

Patient education

While women continue to have complications following the presently used surgical techniques, they often have expectations not discussed with their obstetricians. Women should be educated and empowered to realize the different approaches to all aspects and consequences of CDs.

Conclusion

The technique of excluding the endometrium in closing the uterine incision appears to reduce subsequent abnormal placentation and diminish the frequency and size of post-CD scar defect. The revival of the endometrium-free closure technique may allow significant change in the postoperative results. Currently, standardization of CD technique is being promoted on the basis of time- and cost-savings rather than clinical outcomes. Simultaneously, inroads are being made to better understand the risks and consequences of CD.

Emerging evidence suggests that a post-CD niche is the result of poor layer approximation as well as inclusion of the endometrium, which prevent healing of the uterine wall and often enables faulty implantation of the fertilized oocyte in the next pregnancy, potentially giving rise to placenta accreta spectrum. The prevalence and size of the defect can be minimized by techniques aimed at restoring the anatomy of the uterine wall and the physiology of the endometrium. Specialized training and education are necessary to stress the importance of anatomical assessment and decision making at the time of uterine closure. ●

ILLUSTRATION BY KIMBERLY MARTENS FOR OBG MANAGEMENT

While its etiology remains uncertain, cesarean scar niche (CSN) is well publicized, as are its pathological clinical manifestations. In a future pregnancy, they include cesarean scar pregnancy (CSP), which in turn can lead to placenta accreta spectrum, and possible uterine rupture/dehiscence of a residual thin myometrial layer. CSP refers to the implantation of an early pregnancy on the scar or in the niche at the site of a prior cesarean delivery (CD); it has an incidence of 1 per 1,000 pregnancies. An estimated 52% of CSPs occur after even just one CD.¹ CSP has been linked to placenta accreta spectrum and has been shown to be its precursor.² Both CSP and placenta accreta spectrum can be consequences of CD and share a common histology of villous or placental attachment/invasion into the cesarean scar.³ The incidence of placenta accreta spectrum has risen from about 1 in 4,000 live births in the 1970s to 1 in 2,500 in the 1980s; in 2016, the incidence of placenta accreta spectrum was reported as 1 per 272 live births.⁴

Placenta accreta spectrum denotes the attachment of the placenta into and through the myometrium,⁵ and it can result in severe complications, including hemorrhage, hysterectomy, and intensive care treatment. The increasing rate of placenta accreta spectrum parallels the increasing CD rate, which rose from 5.8% in 1970 to 31.9% in 2016.⁶ Multiple repeat CDs are increasing in frequency as well. At the beginning of the century, placenta accreta spectrum mainly occurred after manual removal of the placenta, uterine curettage, or endometritis. Recently, experts are in agreement that the main determinant of placenta accreta spectrum is the uterine scar and niche formation after a previous CD.⁵ Larger niches are associated with an increased incidence of uterine rupture or dehiscence in a subsequent pregnancy.⁷

In the nonpregnant state, such niches are associated with intermenstrual bleeding, pelvic pain, painful intercourse, painful menses, and subfertility, becoming increasingly more severe in women with greater numbers of CDs.^8-10 Conception rate with assisted reproductive treatment is notably reduced.¹¹

Understanding its etiology

Monteagudo and colleagues first described a “niche” in 100% of 44 women evaluated for postmenopausal bleeding who had a prior CD.¹² CSN has been the subject of well over 3,000 publications over the past 30 years. While the topic generates much interest among researchers, it is garnering little traction among practicing obstetricians. Such “niches,” also referred to as isthmocele, cesarean scar defect, or a diverticulum, was first described in 1961¹³ and later defined on ultrasonography as a hypoechoic triangular-shaped uterine defect outlined by saline instillation sonohysterogram (SIS), reflecting a discontinuation of the myometrium at the site of a previous CD.¹² In 2019, a European task force further defined a CSN as an “indentation at the site in the cesarean section scar with a depth of at least 2 mm” and extended the classification to include branches as extensions toward the anterior uterine serosa.¹⁴ Using this criterion, sonographic postoperative evaluation after one CD revealed a CSN in 68.9% of women with one single-layer uterine closure and in 73.6% of women after a double-layer closure.¹⁵ Larger niche sizes with thinner residual myometrial thickness appeared more frequently when a single-layer closure technique was used, without closure of the peritoneum. Its prevalence varies from 56% to 84%.^16,17

Etiology of CSN formation: Our hypotheses

The precise pathophysiology of CSN remains elusive. Speculations attributed niche formation to numerous factors: timing of surgery, cervical incision, incomplete closure of the uterine incision, adhesion formation between the CD scar and the abdominal wall, and inherent maternal conditions which may impair healing, such as smoking, obesity, diabetes, maternal age, and labor status.^18-20 Retroflexion of the uterus is reportedly associated with increased incidence and size of the niche, with CSN 50% more likely to develop in women with a retroflexed versus an anteverted uterus.²¹ We demonstrated the origin of niche formation in real-time from the start to the completion of uterine closure by a video capture of a single-layer closure followed by an immediate SIS of the ex vivo hysterectomized uterus, and histopathologic proof of the presence of endometrial cells defining the “niche.”²² This case exposes the misalignment of the uterine wall, while including the endometrium in the closure (FIGURE 1). Similarly, pathologic studies of hysteroscopy-resected isthmocele ridges of symptomatic women with niche-related subfertility revealed the tissue edges lined by endocervical, endometrial, or isthmic mucosa either combined or isolated in the scar.²³ The presence of endometrial/cervical tissue in the myometrial closure has been debated for over a century.^24,25

Continue to: Uterine closure techniques...

 

 

Uterine closure techniques: Historical perspective

In 1882, Max Sanger introduced a vertical uterine closure of a classical cesarean operation in response to hysterectomy as the contemporaneous alternative to prevent infection, bleeding, and death.²⁴ Dr. Sanger emphasized layer approximation, suturing, and the avoidance of decidua in the first layer (FIGURE 2). This became the teaching of the classical CD until the 1970s. In 1926, Munro Kerr addressed uterine rupture with labor after a classical CD by introducing the lower uterine segment transverse incision. He cautioned to maintain the decidua inside the uterine 2-layer closure of the cavity.²⁵ These pioneers were joined by others to rally for endometrium exclusion while promoting layer approximation. These techniques became universally standard and were taught across teaching medical centers in the United States and abroad until about 50 years ago.

In the 1970s, newer developments brought significant changes to uterine closure techniques. Initiated by Joel-Cohen,²⁶ blunt dissection of the abdominal incision was adapted by Michael Stark, creating what came to be known as the Misgav-Ladach cesarean technique.²⁷ Stark emphasized blunt dissection and introduced single-layer closure. Thereby the exclusion of the endometrium, used for more than 70 years, was abandoned by the present-day single- or double-layer uterine closure in favor of cost and time savings. Systematic reviews and meta-analyses comparing the two contrasting techniques were inconclusive, noting that the niche prevalence and size were similar in both groups. These studies did not take into account the variety of individual techniques or the position of the endometrium in the final closures.²⁸

Endometrium and uterine closure

Our recent study examining uterine scar defect in women after one primary CD by SIS concluded that a specific endometrium-free closure technique (EFCT) (FIGURE 3) is associated with fewer and less severe defects and a thicker residual myometrial thickness when compared with closures with unknown or endometrium inclusion.²⁹ The study found non-specific closure techniques to be 6 times more likely to form a niche of 2-mm deep or greater than the EFCT.

Furthermore, we surveyed the diversity of uterine closures and the location of the endometrium among obstetricians in one institution.³⁰ Presence of endometrium on the surface of the final uterine closure was reported by 20% of respondents (see Figure 1). When asked for their opinion on the impact of CD techniques on placenta accreta spectrum, without available evidence 80% of the survey respondents reported no relationship to techniques, and only 20% suggested an association. This particular study demonstrates that the surgical techniques just described are random, unfettered, and applied without consideration of clinical outcomes.

Our recent retrospective study that spanned 30 years and examined the EFCT—per­formed anywhere between 3 to 9 consecutive CDs—revealed no abnormal placentation in any subsequent pregnancies.³¹ This was one of the few clinical studies of the long-term consequences of a uterine closure technique. In this study, the endometrium was excluded during the uterine closure, allowing its free edges to abut and heal. This step avoids scarring the endometrial-myometrial (EM) interface and unintentional inclusion of endometrium in the closed uterine wall. In this context, Jauniaux and colleagues cited the destruction of the EM interface as the main factor for placenta-adherent disorders.³² Sholapurkar and others highlight the need to further examine intrinsic details of uterine closure beyond single- and double-layer techniques to better understand the etiology of cesarean scar formation.¹⁹ The search for the pathophysiology of CSN continues to present significant challenges imposed by the variety of currently practiced uterine closures.

Continue to: Focus on prevention...

 

 

Research: Focus on prevention

Our research aims to address the endometrium, a specific layer that was the topic of concern in nascent CD techniques, as a renewed and contemporary one. The presence of the endometrium in ectopic locations or its destruction from intrauterine surgeries or infections has been implicated in abnormal placentation.^13,24 Our approach, in theory, is to limit the position of the endometrium to its innermost location and avoid its iatrogenic suturing and inclusion into the uterine wall closure. The rationale of sparing the endometrium in a layer-by-layer approximation is to allow for a closer restoration to normal anatomy and physiology than a random “en masse” uterine wall closure would permit. For this reason, the EM junction, the perimetrium, and the serosa must be identified and realigned for a more effective closure that incorporates the entire myometrial thickness. As evidence supports technical impact on the development of uterine scar defect in women after one CD, future studies are needed to evaluate uterine integrity by saline infusion sonohysterography in multiparous women with a prior random closure technique or a prior EFCT.

The potential long-term risks of blunt dissection for opening the uterus have not been studied. There are no physiologic lines in the uterine wall to facilitate a regular-bordered uterine stretch. The tissue stretch, which depends on the individual surgeon’s strength applied during the procedure and patient’s labor status, may result in an irregular tear and a difficult repair. The EFCT technique shows a more optimized risk-benefit ratio for an anatomical repair and is replicable. The safety of uterine layer re-approximation has been demonstrated and can be studied in large populations using strict uniform criteria.

Current and future challenges

Residency training

Most recently, teachers of resident trainees are mostly familiar with blunt dissection, techniques of which are passed on unchallenged from resident to resident. The endometrium and peritoneum are neither identified nor treated as separate layers, thus becoming obsolete as surgical and anatomical landmarks.

Standardization of CD techniques

Front-line obstetricians are persuaded to practice a standardized approach that relies on the benefits of cost related to operating room turnover as well as surgeons’ time savings without consideration of outcomes in subsequent pregnancies. Sholapurkar has warned that “wrong standardization” is far worse than no standardization, worse for the training of junior obstetricians, as it can inhibit critical reasoning about safe surgical techniques that can optimize outcomes of the condition of the lower uterine segment.³³

Emergence of cost and time savings in clinical practice

A time-cost savings argument is relatively negligeable in an estimated 40-minute CD. By contrast, deliberate surgical technique and carrying out the appropriate steps for the particular condition at hand to achieve the best outcomes assume more weight.³² Furthermore, this short-term cost benefit is challenged by the comparatively larger costs associated with the diagnosis, the treatment of post-CD adverse consequences (outlined above), as well as the emotional impact on women and their families. Additionally, the emphasis on time savings creates a generation of surgeons fixated with total operative time without consideration of long-term risks and adverse maternal outcomes.

Physician autonomy has led to the unmonitored freedom of obstetricians to choose their own technique for a CD, with some employing the commonly practiced culture of fastest turnaround even in nonurgent circumstances.

Documentation and terminology

Current documenting systems are not detail-oriented enough to assist in a thorough correlation between surgical techniques and outcomes. The use of single- or double-layer closure terminology is insufficient and has proven to be flawed, without describing the handling of the endometrium in terms of its inclusion or exclusion in the closure.

Quality improvement feedback

Long-term post-CD complications are often not reported to the physician or institution involved in the prior CD. In our opinion, some sort of registry would be of value. Perhaps then subsequent CD outcomes could be traced back and reported to the prior institution and surgeon. Feedback is critical to understanding the correlation between techniques and outcomes and more specifically to gathering learning points and using data for quality improvement of future cases.

Patient education

While women continue to have complications following the presently used surgical techniques, they often have expectations not discussed with their obstetricians. Women should be educated and empowered to realize the different approaches to all aspects and consequences of CDs.

Conclusion

The technique of excluding the endometrium in closing the uterine incision appears to reduce subsequent abnormal placentation and diminish the frequency and size of post-CD scar defect. The revival of the endometrium-free closure technique may allow significant change in the postoperative results. Currently, standardization of CD technique is being promoted on the basis of time- and cost-savings rather than clinical outcomes. Simultaneously, inroads are being made to better understand the risks and consequences of CD.

Emerging evidence suggests that a post-CD niche is the result of poor layer approximation as well as inclusion of the endometrium, which prevent healing of the uterine wall and often enables faulty implantation of the fertilized oocyte in the next pregnancy, potentially giving rise to placenta accreta spectrum. The prevalence and size of the defect can be minimized by techniques aimed at restoring the anatomy of the uterine wall and the physiology of the endometrium. Specialized training and education are necessary to stress the importance of anatomical assessment and decision making at the time of uterine closure. ●

ILLUSTRATION BY KIMBERLY MARTENS FOR OBG MANAGEMENT

While its etiology remains uncertain, cesarean scar niche (CSN) is well publicized, as are its pathological clinical manifestations. In a future pregnancy, they include cesarean scar pregnancy (CSP), which in turn can lead to placenta accreta spectrum, and possible uterine rupture/dehiscence of a residual thin myometrial layer. CSP refers to the implantation of an early pregnancy on the scar or in the niche at the site of a prior cesarean delivery (CD); it has an incidence of 1 per 1,000 pregnancies. An estimated 52% of CSPs occur after even just one CD.¹ CSP has been linked to placenta accreta spectrum and has been shown to be its precursor.² Both CSP and placenta accreta spectrum can be consequences of CD and share a common histology of villous or placental attachment/invasion into the cesarean scar.³ The incidence of placenta accreta spectrum has risen from about 1 in 4,000 live births in the 1970s to 1 in 2,500 in the 1980s; in 2016, the incidence of placenta accreta spectrum was reported as 1 per 272 live births.⁴

Placenta accreta spectrum denotes the attachment of the placenta into and through the myometrium,⁵ and it can result in severe complications, including hemorrhage, hysterectomy, and intensive care treatment. The increasing rate of placenta accreta spectrum parallels the increasing CD rate, which rose from 5.8% in 1970 to 31.9% in 2016.⁶ Multiple repeat CDs are increasing in frequency as well. At the beginning of the century, placenta accreta spectrum mainly occurred after manual removal of the placenta, uterine curettage, or endometritis. Recently, experts are in agreement that the main determinant of placenta accreta spectrum is the uterine scar and niche formation after a previous CD.⁵ Larger niches are associated with an increased incidence of uterine rupture or dehiscence in a subsequent pregnancy.⁷

In the nonpregnant state, such niches are associated with intermenstrual bleeding, pelvic pain, painful intercourse, painful menses, and subfertility, becoming increasingly more severe in women with greater numbers of CDs.^8-10 Conception rate with assisted reproductive treatment is notably reduced.¹¹

Understanding its etiology

Monteagudo and colleagues first described a “niche” in 100% of 44 women evaluated for postmenopausal bleeding who had a prior CD.¹² CSN has been the subject of well over 3,000 publications over the past 30 years. While the topic generates much interest among researchers, it is garnering little traction among practicing obstetricians. Such “niches,” also referred to as isthmocele, cesarean scar defect, or a diverticulum, was first described in 1961¹³ and later defined on ultrasonography as a hypoechoic triangular-shaped uterine defect outlined by saline instillation sonohysterogram (SIS), reflecting a discontinuation of the myometrium at the site of a previous CD.¹² In 2019, a European task force further defined a CSN as an “indentation at the site in the cesarean section scar with a depth of at least 2 mm” and extended the classification to include branches as extensions toward the anterior uterine serosa.¹⁴ Using this criterion, sonographic postoperative evaluation after one CD revealed a CSN in 68.9% of women with one single-layer uterine closure and in 73.6% of women after a double-layer closure.¹⁵ Larger niche sizes with thinner residual myometrial thickness appeared more frequently when a single-layer closure technique was used, without closure of the peritoneum. Its prevalence varies from 56% to 84%.^16,17

Etiology of CSN formation: Our hypotheses

The precise pathophysiology of CSN remains elusive. Speculations attributed niche formation to numerous factors: timing of surgery, cervical incision, incomplete closure of the uterine incision, adhesion formation between the CD scar and the abdominal wall, and inherent maternal conditions which may impair healing, such as smoking, obesity, diabetes, maternal age, and labor status.^18-20 Retroflexion of the uterus is reportedly associated with increased incidence and size of the niche, with CSN 50% more likely to develop in women with a retroflexed versus an anteverted uterus.²¹ We demonstrated the origin of niche formation in real-time from the start to the completion of uterine closure by a video capture of a single-layer closure followed by an immediate SIS of the ex vivo hysterectomized uterus, and histopathologic proof of the presence of endometrial cells defining the “niche.”²² This case exposes the misalignment of the uterine wall, while including the endometrium in the closure (FIGURE 1). Similarly, pathologic studies of hysteroscopy-resected isthmocele ridges of symptomatic women with niche-related subfertility revealed the tissue edges lined by endocervical, endometrial, or isthmic mucosa either combined or isolated in the scar.²³ The presence of endometrial/cervical tissue in the myometrial closure has been debated for over a century.^24,25

Continue to: Uterine closure techniques...

 

 

Uterine closure techniques: Historical perspective

In 1882, Max Sanger introduced a vertical uterine closure of a classical cesarean operation in response to hysterectomy as the contemporaneous alternative to prevent infection, bleeding, and death.²⁴ Dr. Sanger emphasized layer approximation, suturing, and the avoidance of decidua in the first layer (FIGURE 2). This became the teaching of the classical CD until the 1970s. In 1926, Munro Kerr addressed uterine rupture with labor after a classical CD by introducing the lower uterine segment transverse incision. He cautioned to maintain the decidua inside the uterine 2-layer closure of the cavity.²⁵ These pioneers were joined by others to rally for endometrium exclusion while promoting layer approximation. These techniques became universally standard and were taught across teaching medical centers in the United States and abroad until about 50 years ago.

In the 1970s, newer developments brought significant changes to uterine closure techniques. Initiated by Joel-Cohen,²⁶ blunt dissection of the abdominal incision was adapted by Michael Stark, creating what came to be known as the Misgav-Ladach cesarean technique.²⁷ Stark emphasized blunt dissection and introduced single-layer closure. Thereby the exclusion of the endometrium, used for more than 70 years, was abandoned by the present-day single- or double-layer uterine closure in favor of cost and time savings. Systematic reviews and meta-analyses comparing the two contrasting techniques were inconclusive, noting that the niche prevalence and size were similar in both groups. These studies did not take into account the variety of individual techniques or the position of the endometrium in the final closures.²⁸

Endometrium and uterine closure

Our recent study examining uterine scar defect in women after one primary CD by SIS concluded that a specific endometrium-free closure technique (EFCT) (FIGURE 3) is associated with fewer and less severe defects and a thicker residual myometrial thickness when compared with closures with unknown or endometrium inclusion.²⁹ The study found non-specific closure techniques to be 6 times more likely to form a niche of 2-mm deep or greater than the EFCT.

Furthermore, we surveyed the diversity of uterine closures and the location of the endometrium among obstetricians in one institution.³⁰ Presence of endometrium on the surface of the final uterine closure was reported by 20% of respondents (see Figure 1). When asked for their opinion on the impact of CD techniques on placenta accreta spectrum, without available evidence 80% of the survey respondents reported no relationship to techniques, and only 20% suggested an association. This particular study demonstrates that the surgical techniques just described are random, unfettered, and applied without consideration of clinical outcomes.

Our recent retrospective study that spanned 30 years and examined the EFCT—per­formed anywhere between 3 to 9 consecutive CDs—revealed no abnormal placentation in any subsequent pregnancies.³¹ This was one of the few clinical studies of the long-term consequences of a uterine closure technique. In this study, the endometrium was excluded during the uterine closure, allowing its free edges to abut and heal. This step avoids scarring the endometrial-myometrial (EM) interface and unintentional inclusion of endometrium in the closed uterine wall. In this context, Jauniaux and colleagues cited the destruction of the EM interface as the main factor for placenta-adherent disorders.³² Sholapurkar and others highlight the need to further examine intrinsic details of uterine closure beyond single- and double-layer techniques to better understand the etiology of cesarean scar formation.¹⁹ The search for the pathophysiology of CSN continues to present significant challenges imposed by the variety of currently practiced uterine closures.

Continue to: Focus on prevention...

 

 

Research: Focus on prevention

Our research aims to address the endometrium, a specific layer that was the topic of concern in nascent CD techniques, as a renewed and contemporary one. The presence of the endometrium in ectopic locations or its destruction from intrauterine surgeries or infections has been implicated in abnormal placentation.^13,24 Our approach, in theory, is to limit the position of the endometrium to its innermost location and avoid its iatrogenic suturing and inclusion into the uterine wall closure. The rationale of sparing the endometrium in a layer-by-layer approximation is to allow for a closer restoration to normal anatomy and physiology than a random “en masse” uterine wall closure would permit. For this reason, the EM junction, the perimetrium, and the serosa must be identified and realigned for a more effective closure that incorporates the entire myometrial thickness. As evidence supports technical impact on the development of uterine scar defect in women after one CD, future studies are needed to evaluate uterine integrity by saline infusion sonohysterography in multiparous women with a prior random closure technique or a prior EFCT.

The potential long-term risks of blunt dissection for opening the uterus have not been studied. There are no physiologic lines in the uterine wall to facilitate a regular-bordered uterine stretch. The tissue stretch, which depends on the individual surgeon’s strength applied during the procedure and patient’s labor status, may result in an irregular tear and a difficult repair. The EFCT technique shows a more optimized risk-benefit ratio for an anatomical repair and is replicable. The safety of uterine layer re-approximation has been demonstrated and can be studied in large populations using strict uniform criteria.

Current and future challenges

Residency training

Most recently, teachers of resident trainees are mostly familiar with blunt dissection, techniques of which are passed on unchallenged from resident to resident. The endometrium and peritoneum are neither identified nor treated as separate layers, thus becoming obsolete as surgical and anatomical landmarks.

Standardization of CD techniques

Front-line obstetricians are persuaded to practice a standardized approach that relies on the benefits of cost related to operating room turnover as well as surgeons’ time savings without consideration of outcomes in subsequent pregnancies. Sholapurkar has warned that “wrong standardization” is far worse than no standardization, worse for the training of junior obstetricians, as it can inhibit critical reasoning about safe surgical techniques that can optimize outcomes of the condition of the lower uterine segment.³³

Emergence of cost and time savings in clinical practice

A time-cost savings argument is relatively negligeable in an estimated 40-minute CD. By contrast, deliberate surgical technique and carrying out the appropriate steps for the particular condition at hand to achieve the best outcomes assume more weight.³² Furthermore, this short-term cost benefit is challenged by the comparatively larger costs associated with the diagnosis, the treatment of post-CD adverse consequences (outlined above), as well as the emotional impact on women and their families. Additionally, the emphasis on time savings creates a generation of surgeons fixated with total operative time without consideration of long-term risks and adverse maternal outcomes.

Physician autonomy has led to the unmonitored freedom of obstetricians to choose their own technique for a CD, with some employing the commonly practiced culture of fastest turnaround even in nonurgent circumstances.

Documentation and terminology

Current documenting systems are not detail-oriented enough to assist in a thorough correlation between surgical techniques and outcomes. The use of single- or double-layer closure terminology is insufficient and has proven to be flawed, without describing the handling of the endometrium in terms of its inclusion or exclusion in the closure.

Quality improvement feedback

Long-term post-CD complications are often not reported to the physician or institution involved in the prior CD. In our opinion, some sort of registry would be of value. Perhaps then subsequent CD outcomes could be traced back and reported to the prior institution and surgeon. Feedback is critical to understanding the correlation between techniques and outcomes and more specifically to gathering learning points and using data for quality improvement of future cases.

Patient education

While women continue to have complications following the presently used surgical techniques, they often have expectations not discussed with their obstetricians. Women should be educated and empowered to realize the different approaches to all aspects and consequences of CDs.

Conclusion

The technique of excluding the endometrium in closing the uterine incision appears to reduce subsequent abnormal placentation and diminish the frequency and size of post-CD scar defect. The revival of the endometrium-free closure technique may allow significant change in the postoperative results. Currently, standardization of CD technique is being promoted on the basis of time- and cost-savings rather than clinical outcomes. Simultaneously, inroads are being made to better understand the risks and consequences of CD.

Emerging evidence suggests that a post-CD niche is the result of poor layer approximation as well as inclusion of the endometrium, which prevent healing of the uterine wall and often enables faulty implantation of the fertilized oocyte in the next pregnancy, potentially giving rise to placenta accreta spectrum. The prevalence and size of the defect can be minimized by techniques aimed at restoring the anatomy of the uterine wall and the physiology of the endometrium. Specialized training and education are necessary to stress the importance of anatomical assessment and decision making at the time of uterine closure. ●