Federal Practitioner

Since 1983, the correlation between head and neck squamous cell carcinoma (SCC) and human papillomavirus (HPV) has been of great interest to head and neck oncologists.¹ In 1998, Smith and colleagues provided evidence of HPV as an independent risk factor for the development of head and neck SCC.² HPV-associated head and neck SCC accounts for between 30% and 64% of oropharyngeal SCC, depending on the published study; tonsil primaries account for the majority of these cancers.^3,4

The presence of HPV E6 and E7 oncoproteins leads to the inactivation of p53 and pRb tumor suppressors. Furthermore, Ragin and colleagues discussed a distinct molecular pathway specific to HPV-associated head and neck SCC, which was different from non–HPV-associated head and neck SCC, involving genetic mutations in CDKN2A/p16.⁵

Current methods in correlating the presence of HPV infection in head and neck SCC have centered on p16^INK4a (p16) immunohistochemistry (IHC) staining and DNA in situ hybridization (ISH) for specific HPV DNA types. IHC staining for p16 involves a monoclonal antibody specific to p16. The usefulness of this test relies on p16 overexpression due to the inactivation of pRb by the HPV E7 oncoprotein. This test is readily performed on archived tissue and has a documented sensitivity and specificity of 100% and 79%, respectively, as reported by Singhi and Westra in 2010.⁶ HPV DNA fluorescence in situ hybridization is the gold standard for determining the presence of specific types of HPV DNA; however, p16 IHC can serve as a rapid, less costly means of studying archived tissue, lending its utility to retrospective population-based studies.

METHODS

A retrospective study was designed to determine the proportion of HPV-associated oropharyngeal SCC in a US Department of Veterans Affairs (VA) population, using p16 antigen IHC on paraffin-embedded tissue as the surrogate marker for the presence of HPV infection. Patients consisted of veterans who were treated for oropharyngeal SCC at Veterans Affairs Memphis Healthcare System (VAMHS) in Tennessee between January 1, 2000, and December 31, 2008. This data range allowed for at least 5 years of follow-up. Patients were excluded who lacked enough tissue specimens for analysis. Measurement outcomes included p16 expression, with subset analysis by race and ethnicity, degree of tobacco and alcohol use, tumor location, stage, age at diagnosis, and survival outcome. Microsoft Excel was used to calculate Fisher exact test, Student t test, and χ² statistics. Significance was set at P < .05. This study received institutional review board approval from the University of Tennessee Health Science Center and the VAMHS.

RESULTS

We identified 66 total cases of oropharyngeal SCC; 19 cases (29%) were positive for p16. The mean age at diagnosis for the p16-positive cohort was 59 years vs 61 years for the p16-negative cohort (P = .22; Table 1).

Although the tonsil was the most common site of tumor origin in both the p16-positive and negative cohorts (63% vs 51%, respectively), our analysis showed no statistically significant difference in sites of origin (P = .69) (Table 2).

DISCUSSION

The VAMHS population in our study had a lower proportion of HPV-associated oropharyngeal SCC compared with studies on nonveteran populations (29% vs 40%-80%, respectively).^5,6 This disparity may indicate a true difference in these populations or may be related to a decreased prevalence of HPV infection in the population served by the VAMHS. This single-institution population did not completely correlate with previous population studies. Specifically, age at presentation (equivalent to patients with p16-negative status rather than earlier age at onset), disease stage at presentation (lower stage for patients with p16-positive status), and disease-specific survival (not improved compared with patients with p16-negative status in other studies) were dissimilar to previous investigations.^2,3

The increased age and staging at presentation could be related in these patients with p16-positive status, which may further account for the lack of improved survival. Furthermore, both groups tended to use alcohol at a high proportion; whereas other populations have had a lesser degree of alcohol intake with p16 positivity.^1-4 These differences may be due to variations in the habits and behavior of VA patients compared with non-VA patients.^3,4

HPV-associated oropharyngeal SCC in published data has been associated with high-risk sexual behavior, lower age, and less tobacco and alcohol use.^5,6 No difference was noted in tumor site predilection; however, the small size of our study could explain the lack of finding site preference shown in previous studies.^2,3Other veteran-specific factors are absent in the at-large population, such as Agent Orange exposure. More than 8 million veterans (22%) from the Vietnam era self-reported Agent Orange exposure.⁷ Agent Orange exposure significantly predicted developing upper aerodigestive tract cancer. Oropharyngeal, nasopharyngeal, laryngeal, and thyroid cancers were significantly associated with Agent Orange exposure. Interestingly, these patients experienced an improved 10-year survival rate compared with patients not exposed to Agent Orange. This finding contrasts with our patients, who did not experience improved outcomes vs nonveteran patients with head and neck cancer.⁷

Suicide in veterans with head and neck cancer has been evaluated and was found at an incidence of 0.7%. Survivors of head and neck cancer are almost twice as likely to die by suicide compared with other cancer survivors. These patients have a higher rate of mental health disorders, substance misuse, and use of palliative care services.⁸ Sixty-five of 66 of our patients died during the 5-year observation period, although none died by suicide.

In a 2022 cohort study by Sun and colleagues, upfront surgical treatment was associated with a 23% reduced risk of stroke compared with definitive chemoradiotherapy in US veterans with oropharyngeal carcinoma.⁹ In our study, 58 of 66 patients (88%) received concurrent chemoradiation, possibly reflecting the more advanced stage of diagnosis in our study population. This was due to comorbidities and other health and economic factors. In our study, 43 patients (65%) died of factors not related to the disease, reflecting the overall comorbidity burden of this population. Seven patients (11%) in our 5-year study died of a documented stroke. In the study of veterans by Sun and colleagues, the 10-year cumulative incidence of stroke was 12.5% and death was 57.3%.⁹ Our veteran population experienced a similar incidence of strokes. These findings may need to be included when discussing the risk-benefit aspects of different treatment options with our veteran patients with oropharyngeal cancer.

To understand the influence of HPV infection on the course of oropharyngeal SCC in the VA patient population and to apply this understanding to future individualized treatment paradigms, this study can be expanded to a greater number of VA patients. p16 immunoexpression appears to be a useful surrogate for high-risk HPV infection in oropharyngeal SCC, and its ease of use supports its feasibility in further VA population analysis.¹⁰ While realizing that the veteran HPV-associated oropharyngeal SCC population differs from the civilian HPV-associated oropharyngeal SCC population, we also have realized that other unique considerations in the veteran population, such as chemical warfare exposure, mental illness, and vascular disease, complicate treatment decisions in these patients.

CONCLUSIONS

Disparities in racial distribution and tobacco use between patients with p16-positive and p16-negative status are similar to those reported in non-VA populations. In contrast, the frequently reported younger age at presentation and better disease outcomes seen in non-VA patients were not observed, perhaps due to the lower percentage of p16 expression in VA patients with oropharyngeal SCC. Whereas de-intensification of therapy may be considered for many patients with oropharygeal cancer that is HPV-associated because of improved prognosis, this approach should be undertaken with great care in this group of patients. Personalization of therapy for these HPV-associated oropharyngeal SCC in the veteran population must be adapted to mitigate this critical disparity.

Since 1983, the correlation between head and neck squamous cell carcinoma (SCC) and human papillomavirus (HPV) has been of great interest to head and neck oncologists.¹ In 1998, Smith and colleagues provided evidence of HPV as an independent risk factor for the development of head and neck SCC.² HPV-associated head and neck SCC accounts for between 30% and 64% of oropharyngeal SCC, depending on the published study; tonsil primaries account for the majority of these cancers.^3,4

The presence of HPV E6 and E7 oncoproteins leads to the inactivation of p53 and pRb tumor suppressors. Furthermore, Ragin and colleagues discussed a distinct molecular pathway specific to HPV-associated head and neck SCC, which was different from non–HPV-associated head and neck SCC, involving genetic mutations in CDKN2A/p16.⁵

Current methods in correlating the presence of HPV infection in head and neck SCC have centered on p16^INK4a (p16) immunohistochemistry (IHC) staining and DNA in situ hybridization (ISH) for specific HPV DNA types. IHC staining for p16 involves a monoclonal antibody specific to p16. The usefulness of this test relies on p16 overexpression due to the inactivation of pRb by the HPV E7 oncoprotein. This test is readily performed on archived tissue and has a documented sensitivity and specificity of 100% and 79%, respectively, as reported by Singhi and Westra in 2010.⁶ HPV DNA fluorescence in situ hybridization is the gold standard for determining the presence of specific types of HPV DNA; however, p16 IHC can serve as a rapid, less costly means of studying archived tissue, lending its utility to retrospective population-based studies.

METHODS

A retrospective study was designed to determine the proportion of HPV-associated oropharyngeal SCC in a US Department of Veterans Affairs (VA) population, using p16 antigen IHC on paraffin-embedded tissue as the surrogate marker for the presence of HPV infection. Patients consisted of veterans who were treated for oropharyngeal SCC at Veterans Affairs Memphis Healthcare System (VAMHS) in Tennessee between January 1, 2000, and December 31, 2008. This data range allowed for at least 5 years of follow-up. Patients were excluded who lacked enough tissue specimens for analysis. Measurement outcomes included p16 expression, with subset analysis by race and ethnicity, degree of tobacco and alcohol use, tumor location, stage, age at diagnosis, and survival outcome. Microsoft Excel was used to calculate Fisher exact test, Student t test, and χ² statistics. Significance was set at P < .05. This study received institutional review board approval from the University of Tennessee Health Science Center and the VAMHS.

RESULTS

We identified 66 total cases of oropharyngeal SCC; 19 cases (29%) were positive for p16. The mean age at diagnosis for the p16-positive cohort was 59 years vs 61 years for the p16-negative cohort (P = .22; Table 1).

Although the tonsil was the most common site of tumor origin in both the p16-positive and negative cohorts (63% vs 51%, respectively), our analysis showed no statistically significant difference in sites of origin (P = .69) (Table 2).

DISCUSSION

The VAMHS population in our study had a lower proportion of HPV-associated oropharyngeal SCC compared with studies on nonveteran populations (29% vs 40%-80%, respectively).^5,6 This disparity may indicate a true difference in these populations or may be related to a decreased prevalence of HPV infection in the population served by the VAMHS. This single-institution population did not completely correlate with previous population studies. Specifically, age at presentation (equivalent to patients with p16-negative status rather than earlier age at onset), disease stage at presentation (lower stage for patients with p16-positive status), and disease-specific survival (not improved compared with patients with p16-negative status in other studies) were dissimilar to previous investigations.^2,3

The increased age and staging at presentation could be related in these patients with p16-positive status, which may further account for the lack of improved survival. Furthermore, both groups tended to use alcohol at a high proportion; whereas other populations have had a lesser degree of alcohol intake with p16 positivity.^1-4 These differences may be due to variations in the habits and behavior of VA patients compared with non-VA patients.^3,4

HPV-associated oropharyngeal SCC in published data has been associated with high-risk sexual behavior, lower age, and less tobacco and alcohol use.^5,6 No difference was noted in tumor site predilection; however, the small size of our study could explain the lack of finding site preference shown in previous studies.^2,3Other veteran-specific factors are absent in the at-large population, such as Agent Orange exposure. More than 8 million veterans (22%) from the Vietnam era self-reported Agent Orange exposure.⁷ Agent Orange exposure significantly predicted developing upper aerodigestive tract cancer. Oropharyngeal, nasopharyngeal, laryngeal, and thyroid cancers were significantly associated with Agent Orange exposure. Interestingly, these patients experienced an improved 10-year survival rate compared with patients not exposed to Agent Orange. This finding contrasts with our patients, who did not experience improved outcomes vs nonveteran patients with head and neck cancer.⁷

Suicide in veterans with head and neck cancer has been evaluated and was found at an incidence of 0.7%. Survivors of head and neck cancer are almost twice as likely to die by suicide compared with other cancer survivors. These patients have a higher rate of mental health disorders, substance misuse, and use of palliative care services.⁸ Sixty-five of 66 of our patients died during the 5-year observation period, although none died by suicide.

In a 2022 cohort study by Sun and colleagues, upfront surgical treatment was associated with a 23% reduced risk of stroke compared with definitive chemoradiotherapy in US veterans with oropharyngeal carcinoma.⁹ In our study, 58 of 66 patients (88%) received concurrent chemoradiation, possibly reflecting the more advanced stage of diagnosis in our study population. This was due to comorbidities and other health and economic factors. In our study, 43 patients (65%) died of factors not related to the disease, reflecting the overall comorbidity burden of this population. Seven patients (11%) in our 5-year study died of a documented stroke. In the study of veterans by Sun and colleagues, the 10-year cumulative incidence of stroke was 12.5% and death was 57.3%.⁹ Our veteran population experienced a similar incidence of strokes. These findings may need to be included when discussing the risk-benefit aspects of different treatment options with our veteran patients with oropharyngeal cancer.

To understand the influence of HPV infection on the course of oropharyngeal SCC in the VA patient population and to apply this understanding to future individualized treatment paradigms, this study can be expanded to a greater number of VA patients. p16 immunoexpression appears to be a useful surrogate for high-risk HPV infection in oropharyngeal SCC, and its ease of use supports its feasibility in further VA population analysis.¹⁰ While realizing that the veteran HPV-associated oropharyngeal SCC population differs from the civilian HPV-associated oropharyngeal SCC population, we also have realized that other unique considerations in the veteran population, such as chemical warfare exposure, mental illness, and vascular disease, complicate treatment decisions in these patients.

CONCLUSIONS

Disparities in racial distribution and tobacco use between patients with p16-positive and p16-negative status are similar to those reported in non-VA populations. In contrast, the frequently reported younger age at presentation and better disease outcomes seen in non-VA patients were not observed, perhaps due to the lower percentage of p16 expression in VA patients with oropharyngeal SCC. Whereas de-intensification of therapy may be considered for many patients with oropharygeal cancer that is HPV-associated because of improved prognosis, this approach should be undertaken with great care in this group of patients. Personalization of therapy for these HPV-associated oropharyngeal SCC in the veteran population must be adapted to mitigate this critical disparity.

Since 1983, the correlation between head and neck squamous cell carcinoma (SCC) and human papillomavirus (HPV) has been of great interest to head and neck oncologists.¹ In 1998, Smith and colleagues provided evidence of HPV as an independent risk factor for the development of head and neck SCC.² HPV-associated head and neck SCC accounts for between 30% and 64% of oropharyngeal SCC, depending on the published study; tonsil primaries account for the majority of these cancers.^3,4

The presence of HPV E6 and E7 oncoproteins leads to the inactivation of p53 and pRb tumor suppressors. Furthermore, Ragin and colleagues discussed a distinct molecular pathway specific to HPV-associated head and neck SCC, which was different from non–HPV-associated head and neck SCC, involving genetic mutations in CDKN2A/p16.⁵

Current methods in correlating the presence of HPV infection in head and neck SCC have centered on p16^INK4a (p16) immunohistochemistry (IHC) staining and DNA in situ hybridization (ISH) for specific HPV DNA types. IHC staining for p16 involves a monoclonal antibody specific to p16. The usefulness of this test relies on p16 overexpression due to the inactivation of pRb by the HPV E7 oncoprotein. This test is readily performed on archived tissue and has a documented sensitivity and specificity of 100% and 79%, respectively, as reported by Singhi and Westra in 2010.⁶ HPV DNA fluorescence in situ hybridization is the gold standard for determining the presence of specific types of HPV DNA; however, p16 IHC can serve as a rapid, less costly means of studying archived tissue, lending its utility to retrospective population-based studies.

METHODS

A retrospective study was designed to determine the proportion of HPV-associated oropharyngeal SCC in a US Department of Veterans Affairs (VA) population, using p16 antigen IHC on paraffin-embedded tissue as the surrogate marker for the presence of HPV infection. Patients consisted of veterans who were treated for oropharyngeal SCC at Veterans Affairs Memphis Healthcare System (VAMHS) in Tennessee between January 1, 2000, and December 31, 2008. This data range allowed for at least 5 years of follow-up. Patients were excluded who lacked enough tissue specimens for analysis. Measurement outcomes included p16 expression, with subset analysis by race and ethnicity, degree of tobacco and alcohol use, tumor location, stage, age at diagnosis, and survival outcome. Microsoft Excel was used to calculate Fisher exact test, Student t test, and χ² statistics. Significance was set at P < .05. This study received institutional review board approval from the University of Tennessee Health Science Center and the VAMHS.

RESULTS

We identified 66 total cases of oropharyngeal SCC; 19 cases (29%) were positive for p16. The mean age at diagnosis for the p16-positive cohort was 59 years vs 61 years for the p16-negative cohort (P = .22; Table 1).

Although the tonsil was the most common site of tumor origin in both the p16-positive and negative cohorts (63% vs 51%, respectively), our analysis showed no statistically significant difference in sites of origin (P = .69) (Table 2).

DISCUSSION

The VAMHS population in our study had a lower proportion of HPV-associated oropharyngeal SCC compared with studies on nonveteran populations (29% vs 40%-80%, respectively).^5,6 This disparity may indicate a true difference in these populations or may be related to a decreased prevalence of HPV infection in the population served by the VAMHS. This single-institution population did not completely correlate with previous population studies. Specifically, age at presentation (equivalent to patients with p16-negative status rather than earlier age at onset), disease stage at presentation (lower stage for patients with p16-positive status), and disease-specific survival (not improved compared with patients with p16-negative status in other studies) were dissimilar to previous investigations.^2,3

The increased age and staging at presentation could be related in these patients with p16-positive status, which may further account for the lack of improved survival. Furthermore, both groups tended to use alcohol at a high proportion; whereas other populations have had a lesser degree of alcohol intake with p16 positivity.^1-4 These differences may be due to variations in the habits and behavior of VA patients compared with non-VA patients.^3,4

HPV-associated oropharyngeal SCC in published data has been associated with high-risk sexual behavior, lower age, and less tobacco and alcohol use.^5,6 No difference was noted in tumor site predilection; however, the small size of our study could explain the lack of finding site preference shown in previous studies.^2,3Other veteran-specific factors are absent in the at-large population, such as Agent Orange exposure. More than 8 million veterans (22%) from the Vietnam era self-reported Agent Orange exposure.⁷ Agent Orange exposure significantly predicted developing upper aerodigestive tract cancer. Oropharyngeal, nasopharyngeal, laryngeal, and thyroid cancers were significantly associated with Agent Orange exposure. Interestingly, these patients experienced an improved 10-year survival rate compared with patients not exposed to Agent Orange. This finding contrasts with our patients, who did not experience improved outcomes vs nonveteran patients with head and neck cancer.⁷

Suicide in veterans with head and neck cancer has been evaluated and was found at an incidence of 0.7%. Survivors of head and neck cancer are almost twice as likely to die by suicide compared with other cancer survivors. These patients have a higher rate of mental health disorders, substance misuse, and use of palliative care services.⁸ Sixty-five of 66 of our patients died during the 5-year observation period, although none died by suicide.

In a 2022 cohort study by Sun and colleagues, upfront surgical treatment was associated with a 23% reduced risk of stroke compared with definitive chemoradiotherapy in US veterans with oropharyngeal carcinoma.⁹ In our study, 58 of 66 patients (88%) received concurrent chemoradiation, possibly reflecting the more advanced stage of diagnosis in our study population. This was due to comorbidities and other health and economic factors. In our study, 43 patients (65%) died of factors not related to the disease, reflecting the overall comorbidity burden of this population. Seven patients (11%) in our 5-year study died of a documented stroke. In the study of veterans by Sun and colleagues, the 10-year cumulative incidence of stroke was 12.5% and death was 57.3%.⁹ Our veteran population experienced a similar incidence of strokes. These findings may need to be included when discussing the risk-benefit aspects of different treatment options with our veteran patients with oropharyngeal cancer.

To understand the influence of HPV infection on the course of oropharyngeal SCC in the VA patient population and to apply this understanding to future individualized treatment paradigms, this study can be expanded to a greater number of VA patients. p16 immunoexpression appears to be a useful surrogate for high-risk HPV infection in oropharyngeal SCC, and its ease of use supports its feasibility in further VA population analysis.¹⁰ While realizing that the veteran HPV-associated oropharyngeal SCC population differs from the civilian HPV-associated oropharyngeal SCC population, we also have realized that other unique considerations in the veteran population, such as chemical warfare exposure, mental illness, and vascular disease, complicate treatment decisions in these patients.

CONCLUSIONS

Disparities in racial distribution and tobacco use between patients with p16-positive and p16-negative status are similar to those reported in non-VA populations. In contrast, the frequently reported younger age at presentation and better disease outcomes seen in non-VA patients were not observed, perhaps due to the lower percentage of p16 expression in VA patients with oropharyngeal SCC. Whereas de-intensification of therapy may be considered for many patients with oropharygeal cancer that is HPV-associated because of improved prognosis, this approach should be undertaken with great care in this group of patients. Personalization of therapy for these HPV-associated oropharyngeal SCC in the veteran population must be adapted to mitigate this critical disparity.

Febrile neutropenia (FN) frequently occurs in patients receiving chemotherapy, with the greatest risk of complications occurring in those who experience profound and prolonged neutropenia. Although granulocyte colony-stimulating factor (G-CSF) prophylaxis has been shown to reduce the risk and duration of chemotherapy-induced neutropenia and FN, there is no well-established optimal regimen.¹ The 2022 National Comprehensive Cancer Network guidelines for hematopoietic growth factors recommend prophylaxis with G-CSF in at-risk patients receiving chemotherapy, specifically in chemotherapy regimens considered high risk for FN (incidence > 20%) or intermediate risk for FN (incidence 10%-20%) with additional patient risk factors.² The incidence of developing FN with at least 1 chemotherapy cycle is estimated at 10% to 50% of patients with solid tumors and > 80% of patients with hematologic malignancies.³ The rate of major complications (eg, hypotension, acute renal, respiratory, or heart failure) in the context of FN is 25% to 30%, and mortality is reported up to 11% in this population.⁴

Because of the significant consequences of neutropenia and FN, prevention is imperative due to the increase in morbidity and mortality, including chemotherapy delays, increased hospitalizations, chemotherapy dose reductions, and discontinuations that cause delays in care.⁵ In patients with curative malignancies, these consequences can negatively impact treatment efficacy and overall survival. Additionally, infections occur in 20% to 30% of patients with febrile episodes. Although fever is often the only clinical sign or symptom of infection, patients who are profoundly neutropenic may present with suspected infection and be afebrile or hypothermic.³

For filgrastim, the National Comprehensive Cancer Network guidelines do not specify the total days of required injections but state that a daily dose should be given until the postnadir absolute neutrophil count (ANC) recovers to normal or near normal levels by laboratory standards.² It is uncommon in clinical practice to track postnadir ANCs due to frequent laboratory monitoring. Clinical trial data suggest an average duration of 11 days of daily filgrastim injections for ANC recovery; however, real-world data exist supporting a range from 4 to 10 days with a median of 7 injections per cycle for prevention of neutropenia or FN.^6,7

At the South Texas Veterans Health Care System in San Antonio, daily filgrastim injections are preferred due to cost; patients typically receive a 7-day course for primary prophylaxis for FN. In our study, we aimed to determine the outcomes in patients receiving daily filgrastim injections with a curative cancer diagnosis and a chemotherapy regimen with either high risk for FN, or a chemotherapy regimen with an intermediate risk for FN and additional patient risk factors. Before the initiation of data collection, this study was reviewed and determined to be exempt by the University of Texas Health Science Center at San Antonio Institutional Review Board.

METHODS

Electronic health record reviews at the South Texas Veterans Health Care System were performed to identify patients who received filgrastim primary prophylaxis (defined as filgrastim, tbo-filgrastim, or filgrastim-sndz) for a curative cancer diagnosis. Primary prophylaxis refers to the administration of G-CSF in the first cycle of chemotherapy before the onset of neutropenia. Patients received filgrastim prophylaxis if they were undergoing treatment with a chemotherapy regimen with either high risk for FN or a chemotherapy regimen with an intermediate risk for FN and additional patient risk factors. Risk factors for patients included prior chemotherapy or radiation therapy; persistent neutropenia; bone marrow involvement by tumor; recent surgery and/or open wounds; liver dysfunction (defined as total bilirubin > 2 mg/dL); renal dysfunction (defined as creatinine clearance < 50 mL/min); and those aged > 65 years receiving full chemotherapy dose intensity. Neutropenia is defined as a decrease in ANC < 1000 neutrophils/μL, whereas FN is defined as a single temperature of > 38.3 °C or > 38.0 °C for longer than 1 hour with < 500 neutrophils/μL or < 1000 neutrophils/μL predicted to decline to < 500 neutrophils/μL over the next 48 hours. All patients had their filgrastim dispensed for home administration during their chemotherapy appointment.

Patients were included if they received filgrastim for primary prophylaxis of FN with a curative cancer diagnosis. Patients receiving salvage chemotherapy for hematologic malignancies with intent to proceed to curative transplant were also included. Bone marrow involvement of the tumor is a FN risk factor. Only patients with hematologic malignancies and bone marrow involvement were included. Patients wereexcluded if they received filgrastim for secondary prophylaxis of neutropenia or FN, a noncurative cancer diagnosis, stem cell transplant mobilization and engraftment, or nononcologic neutropenia.

The primary outcome for this study was the incidence of neutropenia or FN leading to treatment delays despite the use of primary prophylaxis with filgrastim. A dose delay was defined as a delay of planned chemotherapy by ≥ 3 days. Secondary outcomes included chemotherapy dose decreases or discontinuations, hospitalizations, days of hospitalization, infections, extended duration of filgrastim, and transitions to pegfilgrastim due to neutropenia or FN. Documented infections were defined in patients with a positive culture, laboratory testing, or imaging consistent with infection. Extended durations of filgrastim or transitions to pegfilgrastim were patient specific and upon clinician discretion.

Descriptive statistics were used to summarize the study population and their health outcomes. Fisher exact test was used to compare FN incidence for high- and intermediate-risk FN groups.

RESULTS

Between September 1, 2015, and September 24, 2020, 381 patients received filgrastim. Of these patients, 59 met the inclusion criteria. Patients receiving filgrastim were excluded due to stem cell transplant mobilization/engraftment (n = 145), a noncurative cancer diagnosis (n = 134), use as a secondary prophylaxis (n = 33), and nononcologic neutropenia (n = 8). Additionally, 2 patients initially received pegfilgrastim and were not included in this data set.

The median (IQR) age was 64 (55-70) years and 42 patients (71%) were male (Table 1).

Ten patients (17%) experienced dose delays despite filgrastim use (Table 2).

DISCUSSION

Real-world data are limited regarding G-CSF practice patterns; however, available data demonstrate patients may receive suboptimal treatment courses of filgrastim leading to increased complications associated with neutropenia and FN, such as dose delays and hospitalizations.^8,9 At the South Texas Veterans Health Care System, 48 patients (81%) received a filgrastim course of ≥ 7 days as an initial course for primary prophylaxis. Multivariate analyses performed by Weycker and colleagues described a decreased risk of hospitalization for neutropenia or FN with each additional day of filgrastim prophylaxis; however, such analysis could not be performed in our data set due to the small sample size.⁸ In this review, 10 patients (17%) experienced treatment delays due to neutropenia or FN, mirroring previously published data. The hospitalization rate of 25% is higher than the published incidence of 5.2% of cancer-related hospitalizations among adults.^7,10 This difference may be explained by a difference in health care access for the veteran population.

As an alternative to daily filgrastim injections, the National Comprehensive Cancer Network also recommends a single dose of pegfilgrastim for primary prevention of FN. Efficacy benefits of pegfilgrastim use include increased patient adherence due to a single injection, a reduction in FN incidence and FN-related hospitalizations, and improved time to ANC recovery compared with filgrastim.¹¹ There are reports suggesting pegfilgrastim significantly reduces neutropenia and FN incidence to a greater extent compared with daily filgrastim injections.⁶ In patients with breast cancer receiving dose-dense adjuvant chemotherapy, there are data demonstrating that patients who received filgrastim were more likely to experience severe neutropenia, dose reductions, and treatment delays leading to lower dose density compared with pegfilgrastim.¹² Of the 19 patients with breast cancer included in our population, 26% experienced one of the previously described outcomes leading to either extensions of daily filgrastim injections or transitions to pegfilgrastim to successfully maintain dose density. In patients with acute myeloid leukemia receiving consolidation chemotherapy, filgrastim was found to be associated with a statistically significant increased risk of hospitalizations compared with pegfilgrastim.¹³ The one patient with acute myeloid leukemia included in our study did not require additional hospitalizations for neutropenia or FN after transitioning to pegfilgrastim.

Given the cost advantage, the South Texas Veterans Health Care System continues to prefer daily filgrastim injections. A recent survey demonstrated that 73% of patients at 23 sites in the Veterans Health Administration used filgrastim rather than pegfilgrastim for cost savings, although it is recognized that daily filgrastim injections are less convenient for patients.¹⁴ This analysis did not review costs associated with hospitalization for FN or the appropriateness of G-CSF use. Cancer-related neutropenia accounts for 8.3% of all cancer-related hospitalization costs among adults; the average hospitalization costs nearly $25,000 per stay and about $2.3 billion among adult patients with cancer annually.^10,15

Limitations

This study has limitations that affected the applicability and interpretation of the results. This included the study design since it was a retrospective, single-center, descriptive cohort study. Patient adherence to daily filgrastim injections could not be assessed due to the retrospective nature of the study. The small sample size of 59 patients was prohibitive for utilization of additional analytical tools. Additionally, the predominately male veteran population may make applicability to non-VA populations restrictive.

CONCLUSIONS

Based on the incidence of primary and secondary outcomes associated with using daily filgrastim injections as primary prophylaxis in this study, additional measures such as tracking postnadir ANCs should be performed to ensure patients receive an appropriate number of filgrastim doses to prevent complications associated with neutropenia.

Acknowledgments

We thank Eric Dougherty, PharmD, for assistance in producing granulocyte colony-stimulating factor data.

Febrile neutropenia (FN) frequently occurs in patients receiving chemotherapy, with the greatest risk of complications occurring in those who experience profound and prolonged neutropenia. Although granulocyte colony-stimulating factor (G-CSF) prophylaxis has been shown to reduce the risk and duration of chemotherapy-induced neutropenia and FN, there is no well-established optimal regimen.¹ The 2022 National Comprehensive Cancer Network guidelines for hematopoietic growth factors recommend prophylaxis with G-CSF in at-risk patients receiving chemotherapy, specifically in chemotherapy regimens considered high risk for FN (incidence > 20%) or intermediate risk for FN (incidence 10%-20%) with additional patient risk factors.² The incidence of developing FN with at least 1 chemotherapy cycle is estimated at 10% to 50% of patients with solid tumors and > 80% of patients with hematologic malignancies.³ The rate of major complications (eg, hypotension, acute renal, respiratory, or heart failure) in the context of FN is 25% to 30%, and mortality is reported up to 11% in this population.⁴

Because of the significant consequences of neutropenia and FN, prevention is imperative due to the increase in morbidity and mortality, including chemotherapy delays, increased hospitalizations, chemotherapy dose reductions, and discontinuations that cause delays in care.⁵ In patients with curative malignancies, these consequences can negatively impact treatment efficacy and overall survival. Additionally, infections occur in 20% to 30% of patients with febrile episodes. Although fever is often the only clinical sign or symptom of infection, patients who are profoundly neutropenic may present with suspected infection and be afebrile or hypothermic.³

For filgrastim, the National Comprehensive Cancer Network guidelines do not specify the total days of required injections but state that a daily dose should be given until the postnadir absolute neutrophil count (ANC) recovers to normal or near normal levels by laboratory standards.² It is uncommon in clinical practice to track postnadir ANCs due to frequent laboratory monitoring. Clinical trial data suggest an average duration of 11 days of daily filgrastim injections for ANC recovery; however, real-world data exist supporting a range from 4 to 10 days with a median of 7 injections per cycle for prevention of neutropenia or FN.^6,7

At the South Texas Veterans Health Care System in San Antonio, daily filgrastim injections are preferred due to cost; patients typically receive a 7-day course for primary prophylaxis for FN. In our study, we aimed to determine the outcomes in patients receiving daily filgrastim injections with a curative cancer diagnosis and a chemotherapy regimen with either high risk for FN, or a chemotherapy regimen with an intermediate risk for FN and additional patient risk factors. Before the initiation of data collection, this study was reviewed and determined to be exempt by the University of Texas Health Science Center at San Antonio Institutional Review Board.

METHODS

Electronic health record reviews at the South Texas Veterans Health Care System were performed to identify patients who received filgrastim primary prophylaxis (defined as filgrastim, tbo-filgrastim, or filgrastim-sndz) for a curative cancer diagnosis. Primary prophylaxis refers to the administration of G-CSF in the first cycle of chemotherapy before the onset of neutropenia. Patients received filgrastim prophylaxis if they were undergoing treatment with a chemotherapy regimen with either high risk for FN or a chemotherapy regimen with an intermediate risk for FN and additional patient risk factors. Risk factors for patients included prior chemotherapy or radiation therapy; persistent neutropenia; bone marrow involvement by tumor; recent surgery and/or open wounds; liver dysfunction (defined as total bilirubin > 2 mg/dL); renal dysfunction (defined as creatinine clearance < 50 mL/min); and those aged > 65 years receiving full chemotherapy dose intensity. Neutropenia is defined as a decrease in ANC < 1000 neutrophils/μL, whereas FN is defined as a single temperature of > 38.3 °C or > 38.0 °C for longer than 1 hour with < 500 neutrophils/μL or < 1000 neutrophils/μL predicted to decline to < 500 neutrophils/μL over the next 48 hours. All patients had their filgrastim dispensed for home administration during their chemotherapy appointment.

Patients were included if they received filgrastim for primary prophylaxis of FN with a curative cancer diagnosis. Patients receiving salvage chemotherapy for hematologic malignancies with intent to proceed to curative transplant were also included. Bone marrow involvement of the tumor is a FN risk factor. Only patients with hematologic malignancies and bone marrow involvement were included. Patients wereexcluded if they received filgrastim for secondary prophylaxis of neutropenia or FN, a noncurative cancer diagnosis, stem cell transplant mobilization and engraftment, or nononcologic neutropenia.

The primary outcome for this study was the incidence of neutropenia or FN leading to treatment delays despite the use of primary prophylaxis with filgrastim. A dose delay was defined as a delay of planned chemotherapy by ≥ 3 days. Secondary outcomes included chemotherapy dose decreases or discontinuations, hospitalizations, days of hospitalization, infections, extended duration of filgrastim, and transitions to pegfilgrastim due to neutropenia or FN. Documented infections were defined in patients with a positive culture, laboratory testing, or imaging consistent with infection. Extended durations of filgrastim or transitions to pegfilgrastim were patient specific and upon clinician discretion.

Descriptive statistics were used to summarize the study population and their health outcomes. Fisher exact test was used to compare FN incidence for high- and intermediate-risk FN groups.

RESULTS

Between September 1, 2015, and September 24, 2020, 381 patients received filgrastim. Of these patients, 59 met the inclusion criteria. Patients receiving filgrastim were excluded due to stem cell transplant mobilization/engraftment (n = 145), a noncurative cancer diagnosis (n = 134), use as a secondary prophylaxis (n = 33), and nononcologic neutropenia (n = 8). Additionally, 2 patients initially received pegfilgrastim and were not included in this data set.

The median (IQR) age was 64 (55-70) years and 42 patients (71%) were male (Table 1).

Ten patients (17%) experienced dose delays despite filgrastim use (Table 2).

DISCUSSION

Real-world data are limited regarding G-CSF practice patterns; however, available data demonstrate patients may receive suboptimal treatment courses of filgrastim leading to increased complications associated with neutropenia and FN, such as dose delays and hospitalizations.^8,9 At the South Texas Veterans Health Care System, 48 patients (81%) received a filgrastim course of ≥ 7 days as an initial course for primary prophylaxis. Multivariate analyses performed by Weycker and colleagues described a decreased risk of hospitalization for neutropenia or FN with each additional day of filgrastim prophylaxis; however, such analysis could not be performed in our data set due to the small sample size.⁸ In this review, 10 patients (17%) experienced treatment delays due to neutropenia or FN, mirroring previously published data. The hospitalization rate of 25% is higher than the published incidence of 5.2% of cancer-related hospitalizations among adults.^7,10 This difference may be explained by a difference in health care access for the veteran population.

As an alternative to daily filgrastim injections, the National Comprehensive Cancer Network also recommends a single dose of pegfilgrastim for primary prevention of FN. Efficacy benefits of pegfilgrastim use include increased patient adherence due to a single injection, a reduction in FN incidence and FN-related hospitalizations, and improved time to ANC recovery compared with filgrastim.¹¹ There are reports suggesting pegfilgrastim significantly reduces neutropenia and FN incidence to a greater extent compared with daily filgrastim injections.⁶ In patients with breast cancer receiving dose-dense adjuvant chemotherapy, there are data demonstrating that patients who received filgrastim were more likely to experience severe neutropenia, dose reductions, and treatment delays leading to lower dose density compared with pegfilgrastim.¹² Of the 19 patients with breast cancer included in our population, 26% experienced one of the previously described outcomes leading to either extensions of daily filgrastim injections or transitions to pegfilgrastim to successfully maintain dose density. In patients with acute myeloid leukemia receiving consolidation chemotherapy, filgrastim was found to be associated with a statistically significant increased risk of hospitalizations compared with pegfilgrastim.¹³ The one patient with acute myeloid leukemia included in our study did not require additional hospitalizations for neutropenia or FN after transitioning to pegfilgrastim.

Given the cost advantage, the South Texas Veterans Health Care System continues to prefer daily filgrastim injections. A recent survey demonstrated that 73% of patients at 23 sites in the Veterans Health Administration used filgrastim rather than pegfilgrastim for cost savings, although it is recognized that daily filgrastim injections are less convenient for patients.¹⁴ This analysis did not review costs associated with hospitalization for FN or the appropriateness of G-CSF use. Cancer-related neutropenia accounts for 8.3% of all cancer-related hospitalization costs among adults; the average hospitalization costs nearly $25,000 per stay and about $2.3 billion among adult patients with cancer annually.^10,15

Limitations

This study has limitations that affected the applicability and interpretation of the results. This included the study design since it was a retrospective, single-center, descriptive cohort study. Patient adherence to daily filgrastim injections could not be assessed due to the retrospective nature of the study. The small sample size of 59 patients was prohibitive for utilization of additional analytical tools. Additionally, the predominately male veteran population may make applicability to non-VA populations restrictive.

CONCLUSIONS

Based on the incidence of primary and secondary outcomes associated with using daily filgrastim injections as primary prophylaxis in this study, additional measures such as tracking postnadir ANCs should be performed to ensure patients receive an appropriate number of filgrastim doses to prevent complications associated with neutropenia.

Acknowledgments

We thank Eric Dougherty, PharmD, for assistance in producing granulocyte colony-stimulating factor data.

Febrile neutropenia (FN) frequently occurs in patients receiving chemotherapy, with the greatest risk of complications occurring in those who experience profound and prolonged neutropenia. Although granulocyte colony-stimulating factor (G-CSF) prophylaxis has been shown to reduce the risk and duration of chemotherapy-induced neutropenia and FN, there is no well-established optimal regimen.¹ The 2022 National Comprehensive Cancer Network guidelines for hematopoietic growth factors recommend prophylaxis with G-CSF in at-risk patients receiving chemotherapy, specifically in chemotherapy regimens considered high risk for FN (incidence > 20%) or intermediate risk for FN (incidence 10%-20%) with additional patient risk factors.² The incidence of developing FN with at least 1 chemotherapy cycle is estimated at 10% to 50% of patients with solid tumors and > 80% of patients with hematologic malignancies.³ The rate of major complications (eg, hypotension, acute renal, respiratory, or heart failure) in the context of FN is 25% to 30%, and mortality is reported up to 11% in this population.⁴

Because of the significant consequences of neutropenia and FN, prevention is imperative due to the increase in morbidity and mortality, including chemotherapy delays, increased hospitalizations, chemotherapy dose reductions, and discontinuations that cause delays in care.⁵ In patients with curative malignancies, these consequences can negatively impact treatment efficacy and overall survival. Additionally, infections occur in 20% to 30% of patients with febrile episodes. Although fever is often the only clinical sign or symptom of infection, patients who are profoundly neutropenic may present with suspected infection and be afebrile or hypothermic.³

For filgrastim, the National Comprehensive Cancer Network guidelines do not specify the total days of required injections but state that a daily dose should be given until the postnadir absolute neutrophil count (ANC) recovers to normal or near normal levels by laboratory standards.² It is uncommon in clinical practice to track postnadir ANCs due to frequent laboratory monitoring. Clinical trial data suggest an average duration of 11 days of daily filgrastim injections for ANC recovery; however, real-world data exist supporting a range from 4 to 10 days with a median of 7 injections per cycle for prevention of neutropenia or FN.^6,7

At the South Texas Veterans Health Care System in San Antonio, daily filgrastim injections are preferred due to cost; patients typically receive a 7-day course for primary prophylaxis for FN. In our study, we aimed to determine the outcomes in patients receiving daily filgrastim injections with a curative cancer diagnosis and a chemotherapy regimen with either high risk for FN, or a chemotherapy regimen with an intermediate risk for FN and additional patient risk factors. Before the initiation of data collection, this study was reviewed and determined to be exempt by the University of Texas Health Science Center at San Antonio Institutional Review Board.

METHODS

Electronic health record reviews at the South Texas Veterans Health Care System were performed to identify patients who received filgrastim primary prophylaxis (defined as filgrastim, tbo-filgrastim, or filgrastim-sndz) for a curative cancer diagnosis. Primary prophylaxis refers to the administration of G-CSF in the first cycle of chemotherapy before the onset of neutropenia. Patients received filgrastim prophylaxis if they were undergoing treatment with a chemotherapy regimen with either high risk for FN or a chemotherapy regimen with an intermediate risk for FN and additional patient risk factors. Risk factors for patients included prior chemotherapy or radiation therapy; persistent neutropenia; bone marrow involvement by tumor; recent surgery and/or open wounds; liver dysfunction (defined as total bilirubin > 2 mg/dL); renal dysfunction (defined as creatinine clearance < 50 mL/min); and those aged > 65 years receiving full chemotherapy dose intensity. Neutropenia is defined as a decrease in ANC < 1000 neutrophils/μL, whereas FN is defined as a single temperature of > 38.3 °C or > 38.0 °C for longer than 1 hour with < 500 neutrophils/μL or < 1000 neutrophils/μL predicted to decline to < 500 neutrophils/μL over the next 48 hours. All patients had their filgrastim dispensed for home administration during their chemotherapy appointment.

Patients were included if they received filgrastim for primary prophylaxis of FN with a curative cancer diagnosis. Patients receiving salvage chemotherapy for hematologic malignancies with intent to proceed to curative transplant were also included. Bone marrow involvement of the tumor is a FN risk factor. Only patients with hematologic malignancies and bone marrow involvement were included. Patients wereexcluded if they received filgrastim for secondary prophylaxis of neutropenia or FN, a noncurative cancer diagnosis, stem cell transplant mobilization and engraftment, or nononcologic neutropenia.

The primary outcome for this study was the incidence of neutropenia or FN leading to treatment delays despite the use of primary prophylaxis with filgrastim. A dose delay was defined as a delay of planned chemotherapy by ≥ 3 days. Secondary outcomes included chemotherapy dose decreases or discontinuations, hospitalizations, days of hospitalization, infections, extended duration of filgrastim, and transitions to pegfilgrastim due to neutropenia or FN. Documented infections were defined in patients with a positive culture, laboratory testing, or imaging consistent with infection. Extended durations of filgrastim or transitions to pegfilgrastim were patient specific and upon clinician discretion.

Descriptive statistics were used to summarize the study population and their health outcomes. Fisher exact test was used to compare FN incidence for high- and intermediate-risk FN groups.

RESULTS

Between September 1, 2015, and September 24, 2020, 381 patients received filgrastim. Of these patients, 59 met the inclusion criteria. Patients receiving filgrastim were excluded due to stem cell transplant mobilization/engraftment (n = 145), a noncurative cancer diagnosis (n = 134), use as a secondary prophylaxis (n = 33), and nononcologic neutropenia (n = 8). Additionally, 2 patients initially received pegfilgrastim and were not included in this data set.

The median (IQR) age was 64 (55-70) years and 42 patients (71%) were male (Table 1).

Ten patients (17%) experienced dose delays despite filgrastim use (Table 2).

DISCUSSION

Real-world data are limited regarding G-CSF practice patterns; however, available data demonstrate patients may receive suboptimal treatment courses of filgrastim leading to increased complications associated with neutropenia and FN, such as dose delays and hospitalizations.^8,9 At the South Texas Veterans Health Care System, 48 patients (81%) received a filgrastim course of ≥ 7 days as an initial course for primary prophylaxis. Multivariate analyses performed by Weycker and colleagues described a decreased risk of hospitalization for neutropenia or FN with each additional day of filgrastim prophylaxis; however, such analysis could not be performed in our data set due to the small sample size.⁸ In this review, 10 patients (17%) experienced treatment delays due to neutropenia or FN, mirroring previously published data. The hospitalization rate of 25% is higher than the published incidence of 5.2% of cancer-related hospitalizations among adults.^7,10 This difference may be explained by a difference in health care access for the veteran population.

As an alternative to daily filgrastim injections, the National Comprehensive Cancer Network also recommends a single dose of pegfilgrastim for primary prevention of FN. Efficacy benefits of pegfilgrastim use include increased patient adherence due to a single injection, a reduction in FN incidence and FN-related hospitalizations, and improved time to ANC recovery compared with filgrastim.¹¹ There are reports suggesting pegfilgrastim significantly reduces neutropenia and FN incidence to a greater extent compared with daily filgrastim injections.⁶ In patients with breast cancer receiving dose-dense adjuvant chemotherapy, there are data demonstrating that patients who received filgrastim were more likely to experience severe neutropenia, dose reductions, and treatment delays leading to lower dose density compared with pegfilgrastim.¹² Of the 19 patients with breast cancer included in our population, 26% experienced one of the previously described outcomes leading to either extensions of daily filgrastim injections or transitions to pegfilgrastim to successfully maintain dose density. In patients with acute myeloid leukemia receiving consolidation chemotherapy, filgrastim was found to be associated with a statistically significant increased risk of hospitalizations compared with pegfilgrastim.¹³ The one patient with acute myeloid leukemia included in our study did not require additional hospitalizations for neutropenia or FN after transitioning to pegfilgrastim.

Given the cost advantage, the South Texas Veterans Health Care System continues to prefer daily filgrastim injections. A recent survey demonstrated that 73% of patients at 23 sites in the Veterans Health Administration used filgrastim rather than pegfilgrastim for cost savings, although it is recognized that daily filgrastim injections are less convenient for patients.¹⁴ This analysis did not review costs associated with hospitalization for FN or the appropriateness of G-CSF use. Cancer-related neutropenia accounts for 8.3% of all cancer-related hospitalization costs among adults; the average hospitalization costs nearly $25,000 per stay and about $2.3 billion among adult patients with cancer annually.^10,15

Limitations

This study has limitations that affected the applicability and interpretation of the results. This included the study design since it was a retrospective, single-center, descriptive cohort study. Patient adherence to daily filgrastim injections could not be assessed due to the retrospective nature of the study. The small sample size of 59 patients was prohibitive for utilization of additional analytical tools. Additionally, the predominately male veteran population may make applicability to non-VA populations restrictive.

CONCLUSIONS

Based on the incidence of primary and secondary outcomes associated with using daily filgrastim injections as primary prophylaxis in this study, additional measures such as tracking postnadir ANCs should be performed to ensure patients receive an appropriate number of filgrastim doses to prevent complications associated with neutropenia.

Acknowledgments

We thank Eric Dougherty, PharmD, for assistance in producing granulocyte colony-stimulating factor data.

Radiation therapy can cause long-term dysphagia that seriously affects quality of life for survivors of head and neck cancer. ^1-3 Numerous studies have linked pharyngeal constrictor dose to long-term dysphagia, but conclusions about the dose distribution that can be safely tolerated have been inconsistent. For example, a group from the Netherlands found that the mean dose to the superior pharyngeal constrictor muscle and the supraglottic larynx were each predictive of dysphagia. ⁴ A subsequent Vanderbilt study refuted these findings, reporting that these structures were not predictive but that dose to the inferior pharyngeal constrictor muscle was. ⁵ Other studies have connected late dysphagia with dose to the middle pharyngeal constrictor muscle, total larynx, oral cavity, contralateral submandibular gland, contralateral parotid gland, or a combination of these structures. ^6-14 NRG Oncology trials commonly evaluate dose to the “uninvolved pharynx,” which is the total pharyngeal constrictor muscle volume minus the planning target volume (PTV) for the lowest dose target volume. NRG head and neck trials 3, 4, 5, 6, 8, and 9 all use uninvolved pharynx mean dose ≤ 45 Gy as a constraint to judge radiation plan quality.

Differences in methodology or patient population may explain the inconsistency of prior studies on dosimetric predictors of dysphagia, but it is possible that these studies did not evaluate the optimal metric for dysphagia. This study evaluates a novel organ at risk, the contralateral pharyngeal constrictor muscle, to determine whether dose to this structure is predictive of late swallowing function. The study also compares a constraint based on this structure to the NRG uninvolved pharynx constraint mentioned earlier.

Methods

This study is a retrospective review of patients treated at the Richard L. Roudebush Veterans Affairs (VA) Medical Center in Indianapolis, Indiana. Patients were identified by searching the VA Cancer Registry for patients treated for head and neck squamous cell carcinoma between September 1, 2016, and August 30, 2019. Eligible sites included cancers of the nasopharynx, oropharynx, hypopharynx, larynx and oral cavity, as well as head and neck cancer of an unknown primary site. Only patients treated with primary radiation with concurrent systemic therapy were included. Patients were excluded if they had prior surgery or radiation to the head and neck.

The pharyngeal constrictor muscles were contoured per the techniques described by Bhide and colleagues.¹¹ The contralateral constrictor was defined as the half of the constrictor volume contralateral to the primary site. For midline tumors, the side of the neck with a lower volume of lymph node metastases was judged to be the contralateral side.

Results

The VA Cancer Registry identified 113 patients treated for head and neck cancer during the study period. Of these, 55 patients met the inclusion criteria. No patients were lost to follow-up. The median follow-up was 29 months. The median age was 67 years (range, 41-83) (Table 1).

All patients were treated with intensity-modulated radiotherapy. Patients treated with a sequential boost had an initial dose of 54 Gy and/or 50 Gy, followed by a boost to a total of 70 Gy at 2 Gy per fraction. Patients treated with a simultaneous integrated boost (SIB) technique received 70.0 Gy in 33 fractions, with elective volumes treated to 54.5 Gy in 33 fractions. Both patients with nasopharyngeal cancer were treated with SIB plans and had an intermediate dose volume of 59.4 Gy.

Systemic therapy was weekly cisplatin in 41 patients (75%) and cetuximab in 14 (25%). Twenty percent of patients receiving cisplatin switched to an alternative agent during treatment, most commonly carboplatin.

Forty-nine patients (89%) had a G-tube placed before starting radiation. G-tubes were in place for an interval of 0 to 47 months (mean, 8.6); 12 (22%) had a G-tube > 12 months. After completion of radiation, 18 patients (33%) had an abnormal MBS. These were done 1 to 50 months (mean, 14.8) after completion of radiation. Abnormal MBS occurred ≥ 12 months after radiation in 9 patients, 5 of whom had their G-tube in place for less than a year.

Forty-six patients (84%) survived more than 1 year and could be evaluated for late swallowing function. One-year dysphagia was seen in 17 (37%) of these patients. Recurrence was seen in 20 patients (36%), with locoregional recurrence in 12 (60%) of these cases. Recurrence occurred at a range of 0 to 15 months (mean, 5.6). Neither recurrence (P = .69) nor locoregional recurrence (P = .11) was associated with increased dysphagia at 1 year.

In patients who could be evaluated for long-term swallowing function, contralateral constrictor V60 ranged from 0% to 100% (median, 51%). V60 was < 40% in 18 patients (39%). With V60 < 40%, there was a 6% rate of 1-year dysphagia compared with 57% for V60 ≥ 40% (P < .001).

Patients with contralateral constrictor V60 < 40 and V60 ≥ 40 both had a mean age of 65 years. χ² analysis did not show a difference in T stage or systemic treatment but did show that patients with V60 < 40% were more likely to have N1 disease (P = .01), and less likely to have N2 disease (P = .01) compared with patients with V60 ≥ 40%. The difference in 1-year dysphagia between N0 to N1 patients (27%) and N2 to N3 patients (46%) was not statistically significant (P = .19).

In patients who could be evaluated for long-term swallowing function, the uninvolved pharynx volume median of the total constrictor volume was 32% (range, < 1%-62%). The uninvolved pharynx mean dose ranged from 28 to 68 Gy (median, 45). When the uninvolved pharynx mean dose was < 45 Gy, 1-year dysphagia was 22% compared with 52% with a dose ≥ 45 Gy (P = .03).

Discussion

This is the first study to link contralateral constrictor dose to long-term dysphagia in patients treated with radiation for head and neck cancer. Editing the boost volume off air cavities was associated with lower contralateral constrictor V60 and with less long-term dysphagia. This may indicate that optimizing plans to meet a contralateral constrictor constraint can reduce rates of long-term dysphagia.

The most useful clinical predictors are those that identify a patient at low risk for toxicity. These constraints are useful because they reassure physicians that treatments will have a favorable risk/benefit ratio while identifying plans that may need modification before starting treatment.

The contralateral constrictor outperformed the uninvolved pharynx in identifying patients at low risk for long-term dysphagia. This difference could not be overcome by decreasing the threshold of the pharynx constraint, as 17% of patients with dysphagia had a mean dose of < 40 Gy to the uninvolved pharynx, which was not statistically significant. An advantage of contralateral constrictor is that it is independent of PTV size. The uninvolved pharynx structure depends on the PTV contour, so it may obscure a connection between PTV size and dysphagia.

In the context of a clinical trial, only measuring dose to the uninvolved pharynx may allow more plans to meet constraints, but even in NRG trials, physicians have some control over target volumes. For example, NRG HN009, a national trial for patients with head and neck cancer, recommends editing the CTV_7000 (clinical target volume treated to 70 Gy) off air cavities but does not define how much the volume should be cropped or specify protocol violations if the volume is not cropped.¹⁵ Furthermore, constraints used in clinical trials are often adopted for use outside the trial, where physicians have extensive control over target volumes.

The broad range of uninvolved pharynx volume relative to total constrictor volume confounds predictions using this variable. For example, according to the NRG constraint, a patient with an uninvolved pharynx mean dose of 44 Gy will have a low risk of dysphagia even if this structure is only 1% of the total constrictor. The contralateral constrictor is always about 50% of the total constrictor volume, which means that predictions using this structure will not be confounded by the same variation in volume size.

Figure 2 shows a representative patient who met the NRG uninvolved pharynx constraint but developed long-term dysphagia.

Limitations

This study is limited by its single institution, retrospective design, small sample size, and by all patients being male. The high correlation between air cavity editing and the use of SIB makes it impossible to assess the impact of each technique individually. Patients with contralateral constrictor V60 < 40% were less likely to have N2 disease, but N2 to N3 disease did not predict higher 1-year dysphagia, so the difference in N-category cannot fully explain the difference in 1-year dysphagia. It is possible that unreported factors, such as CTV, may contribute significantly to swallowing function. Nevertheless, within the study population, contralateral constrictor dose was able to identify a group with a low rate of long-term dysphagia.

Conclusions

Contralateral constrictor dose is a promising predictor of late dysphagia for patients with head and neck cancer treated with radiation with concurrent systemic therapy. Contralateral constrictor V60 < 40% was able to identify a group of patients with a low rate of 1-year dysphagia in this single-center retrospective study. The correlation between air cavity editing and contralateral constrictor V60 suggests that contralateral constrictor dose may depend partly on technique. Further studies are needed to see if the contralateral constrictor dose can be used to predict long-term dysphagia prospectively and in other patient populations.

Radiation therapy can cause long-term dysphagia that seriously affects quality of life for survivors of head and neck cancer. ^1-3 Numerous studies have linked pharyngeal constrictor dose to long-term dysphagia, but conclusions about the dose distribution that can be safely tolerated have been inconsistent. For example, a group from the Netherlands found that the mean dose to the superior pharyngeal constrictor muscle and the supraglottic larynx were each predictive of dysphagia. ⁴ A subsequent Vanderbilt study refuted these findings, reporting that these structures were not predictive but that dose to the inferior pharyngeal constrictor muscle was. ⁵ Other studies have connected late dysphagia with dose to the middle pharyngeal constrictor muscle, total larynx, oral cavity, contralateral submandibular gland, contralateral parotid gland, or a combination of these structures. ^6-14 NRG Oncology trials commonly evaluate dose to the “uninvolved pharynx,” which is the total pharyngeal constrictor muscle volume minus the planning target volume (PTV) for the lowest dose target volume. NRG head and neck trials 3, 4, 5, 6, 8, and 9 all use uninvolved pharynx mean dose ≤ 45 Gy as a constraint to judge radiation plan quality.

Differences in methodology or patient population may explain the inconsistency of prior studies on dosimetric predictors of dysphagia, but it is possible that these studies did not evaluate the optimal metric for dysphagia. This study evaluates a novel organ at risk, the contralateral pharyngeal constrictor muscle, to determine whether dose to this structure is predictive of late swallowing function. The study also compares a constraint based on this structure to the NRG uninvolved pharynx constraint mentioned earlier.

Methods

This study is a retrospective review of patients treated at the Richard L. Roudebush Veterans Affairs (VA) Medical Center in Indianapolis, Indiana. Patients were identified by searching the VA Cancer Registry for patients treated for head and neck squamous cell carcinoma between September 1, 2016, and August 30, 2019. Eligible sites included cancers of the nasopharynx, oropharynx, hypopharynx, larynx and oral cavity, as well as head and neck cancer of an unknown primary site. Only patients treated with primary radiation with concurrent systemic therapy were included. Patients were excluded if they had prior surgery or radiation to the head and neck.

The pharyngeal constrictor muscles were contoured per the techniques described by Bhide and colleagues.¹¹ The contralateral constrictor was defined as the half of the constrictor volume contralateral to the primary site. For midline tumors, the side of the neck with a lower volume of lymph node metastases was judged to be the contralateral side.

Results

The VA Cancer Registry identified 113 patients treated for head and neck cancer during the study period. Of these, 55 patients met the inclusion criteria. No patients were lost to follow-up. The median follow-up was 29 months. The median age was 67 years (range, 41-83) (Table 1).

All patients were treated with intensity-modulated radiotherapy. Patients treated with a sequential boost had an initial dose of 54 Gy and/or 50 Gy, followed by a boost to a total of 70 Gy at 2 Gy per fraction. Patients treated with a simultaneous integrated boost (SIB) technique received 70.0 Gy in 33 fractions, with elective volumes treated to 54.5 Gy in 33 fractions. Both patients with nasopharyngeal cancer were treated with SIB plans and had an intermediate dose volume of 59.4 Gy.

Systemic therapy was weekly cisplatin in 41 patients (75%) and cetuximab in 14 (25%). Twenty percent of patients receiving cisplatin switched to an alternative agent during treatment, most commonly carboplatin.

Forty-nine patients (89%) had a G-tube placed before starting radiation. G-tubes were in place for an interval of 0 to 47 months (mean, 8.6); 12 (22%) had a G-tube > 12 months. After completion of radiation, 18 patients (33%) had an abnormal MBS. These were done 1 to 50 months (mean, 14.8) after completion of radiation. Abnormal MBS occurred ≥ 12 months after radiation in 9 patients, 5 of whom had their G-tube in place for less than a year.

Forty-six patients (84%) survived more than 1 year and could be evaluated for late swallowing function. One-year dysphagia was seen in 17 (37%) of these patients. Recurrence was seen in 20 patients (36%), with locoregional recurrence in 12 (60%) of these cases. Recurrence occurred at a range of 0 to 15 months (mean, 5.6). Neither recurrence (P = .69) nor locoregional recurrence (P = .11) was associated with increased dysphagia at 1 year.

In patients who could be evaluated for long-term swallowing function, contralateral constrictor V60 ranged from 0% to 100% (median, 51%). V60 was < 40% in 18 patients (39%). With V60 < 40%, there was a 6% rate of 1-year dysphagia compared with 57% for V60 ≥ 40% (P < .001).

Patients with contralateral constrictor V60 < 40 and V60 ≥ 40 both had a mean age of 65 years. χ² analysis did not show a difference in T stage or systemic treatment but did show that patients with V60 < 40% were more likely to have N1 disease (P = .01), and less likely to have N2 disease (P = .01) compared with patients with V60 ≥ 40%. The difference in 1-year dysphagia between N0 to N1 patients (27%) and N2 to N3 patients (46%) was not statistically significant (P = .19).

In patients who could be evaluated for long-term swallowing function, the uninvolved pharynx volume median of the total constrictor volume was 32% (range, < 1%-62%). The uninvolved pharynx mean dose ranged from 28 to 68 Gy (median, 45). When the uninvolved pharynx mean dose was < 45 Gy, 1-year dysphagia was 22% compared with 52% with a dose ≥ 45 Gy (P = .03).

Discussion

This is the first study to link contralateral constrictor dose to long-term dysphagia in patients treated with radiation for head and neck cancer. Editing the boost volume off air cavities was associated with lower contralateral constrictor V60 and with less long-term dysphagia. This may indicate that optimizing plans to meet a contralateral constrictor constraint can reduce rates of long-term dysphagia.

The most useful clinical predictors are those that identify a patient at low risk for toxicity. These constraints are useful because they reassure physicians that treatments will have a favorable risk/benefit ratio while identifying plans that may need modification before starting treatment.

The contralateral constrictor outperformed the uninvolved pharynx in identifying patients at low risk for long-term dysphagia. This difference could not be overcome by decreasing the threshold of the pharynx constraint, as 17% of patients with dysphagia had a mean dose of < 40 Gy to the uninvolved pharynx, which was not statistically significant. An advantage of contralateral constrictor is that it is independent of PTV size. The uninvolved pharynx structure depends on the PTV contour, so it may obscure a connection between PTV size and dysphagia.

In the context of a clinical trial, only measuring dose to the uninvolved pharynx may allow more plans to meet constraints, but even in NRG trials, physicians have some control over target volumes. For example, NRG HN009, a national trial for patients with head and neck cancer, recommends editing the CTV_7000 (clinical target volume treated to 70 Gy) off air cavities but does not define how much the volume should be cropped or specify protocol violations if the volume is not cropped.¹⁵ Furthermore, constraints used in clinical trials are often adopted for use outside the trial, where physicians have extensive control over target volumes.

The broad range of uninvolved pharynx volume relative to total constrictor volume confounds predictions using this variable. For example, according to the NRG constraint, a patient with an uninvolved pharynx mean dose of 44 Gy will have a low risk of dysphagia even if this structure is only 1% of the total constrictor. The contralateral constrictor is always about 50% of the total constrictor volume, which means that predictions using this structure will not be confounded by the same variation in volume size.

Figure 2 shows a representative patient who met the NRG uninvolved pharynx constraint but developed long-term dysphagia.

Limitations

This study is limited by its single institution, retrospective design, small sample size, and by all patients being male. The high correlation between air cavity editing and the use of SIB makes it impossible to assess the impact of each technique individually. Patients with contralateral constrictor V60 < 40% were less likely to have N2 disease, but N2 to N3 disease did not predict higher 1-year dysphagia, so the difference in N-category cannot fully explain the difference in 1-year dysphagia. It is possible that unreported factors, such as CTV, may contribute significantly to swallowing function. Nevertheless, within the study population, contralateral constrictor dose was able to identify a group with a low rate of long-term dysphagia.

Conclusions

Contralateral constrictor dose is a promising predictor of late dysphagia for patients with head and neck cancer treated with radiation with concurrent systemic therapy. Contralateral constrictor V60 < 40% was able to identify a group of patients with a low rate of 1-year dysphagia in this single-center retrospective study. The correlation between air cavity editing and contralateral constrictor V60 suggests that contralateral constrictor dose may depend partly on technique. Further studies are needed to see if the contralateral constrictor dose can be used to predict long-term dysphagia prospectively and in other patient populations.

Radiation therapy can cause long-term dysphagia that seriously affects quality of life for survivors of head and neck cancer. ^1-3 Numerous studies have linked pharyngeal constrictor dose to long-term dysphagia, but conclusions about the dose distribution that can be safely tolerated have been inconsistent. For example, a group from the Netherlands found that the mean dose to the superior pharyngeal constrictor muscle and the supraglottic larynx were each predictive of dysphagia. ⁴ A subsequent Vanderbilt study refuted these findings, reporting that these structures were not predictive but that dose to the inferior pharyngeal constrictor muscle was. ⁵ Other studies have connected late dysphagia with dose to the middle pharyngeal constrictor muscle, total larynx, oral cavity, contralateral submandibular gland, contralateral parotid gland, or a combination of these structures. ^6-14 NRG Oncology trials commonly evaluate dose to the “uninvolved pharynx,” which is the total pharyngeal constrictor muscle volume minus the planning target volume (PTV) for the lowest dose target volume. NRG head and neck trials 3, 4, 5, 6, 8, and 9 all use uninvolved pharynx mean dose ≤ 45 Gy as a constraint to judge radiation plan quality.

Differences in methodology or patient population may explain the inconsistency of prior studies on dosimetric predictors of dysphagia, but it is possible that these studies did not evaluate the optimal metric for dysphagia. This study evaluates a novel organ at risk, the contralateral pharyngeal constrictor muscle, to determine whether dose to this structure is predictive of late swallowing function. The study also compares a constraint based on this structure to the NRG uninvolved pharynx constraint mentioned earlier.

Methods

This study is a retrospective review of patients treated at the Richard L. Roudebush Veterans Affairs (VA) Medical Center in Indianapolis, Indiana. Patients were identified by searching the VA Cancer Registry for patients treated for head and neck squamous cell carcinoma between September 1, 2016, and August 30, 2019. Eligible sites included cancers of the nasopharynx, oropharynx, hypopharynx, larynx and oral cavity, as well as head and neck cancer of an unknown primary site. Only patients treated with primary radiation with concurrent systemic therapy were included. Patients were excluded if they had prior surgery or radiation to the head and neck.

The pharyngeal constrictor muscles were contoured per the techniques described by Bhide and colleagues.¹¹ The contralateral constrictor was defined as the half of the constrictor volume contralateral to the primary site. For midline tumors, the side of the neck with a lower volume of lymph node metastases was judged to be the contralateral side.

Results

The VA Cancer Registry identified 113 patients treated for head and neck cancer during the study period. Of these, 55 patients met the inclusion criteria. No patients were lost to follow-up. The median follow-up was 29 months. The median age was 67 years (range, 41-83) (Table 1).

All patients were treated with intensity-modulated radiotherapy. Patients treated with a sequential boost had an initial dose of 54 Gy and/or 50 Gy, followed by a boost to a total of 70 Gy at 2 Gy per fraction. Patients treated with a simultaneous integrated boost (SIB) technique received 70.0 Gy in 33 fractions, with elective volumes treated to 54.5 Gy in 33 fractions. Both patients with nasopharyngeal cancer were treated with SIB plans and had an intermediate dose volume of 59.4 Gy.

Systemic therapy was weekly cisplatin in 41 patients (75%) and cetuximab in 14 (25%). Twenty percent of patients receiving cisplatin switched to an alternative agent during treatment, most commonly carboplatin.

Forty-nine patients (89%) had a G-tube placed before starting radiation. G-tubes were in place for an interval of 0 to 47 months (mean, 8.6); 12 (22%) had a G-tube > 12 months. After completion of radiation, 18 patients (33%) had an abnormal MBS. These were done 1 to 50 months (mean, 14.8) after completion of radiation. Abnormal MBS occurred ≥ 12 months after radiation in 9 patients, 5 of whom had their G-tube in place for less than a year.

Forty-six patients (84%) survived more than 1 year and could be evaluated for late swallowing function. One-year dysphagia was seen in 17 (37%) of these patients. Recurrence was seen in 20 patients (36%), with locoregional recurrence in 12 (60%) of these cases. Recurrence occurred at a range of 0 to 15 months (mean, 5.6). Neither recurrence (P = .69) nor locoregional recurrence (P = .11) was associated with increased dysphagia at 1 year.

In patients who could be evaluated for long-term swallowing function, contralateral constrictor V60 ranged from 0% to 100% (median, 51%). V60 was < 40% in 18 patients (39%). With V60 < 40%, there was a 6% rate of 1-year dysphagia compared with 57% for V60 ≥ 40% (P < .001).

Patients with contralateral constrictor V60 < 40 and V60 ≥ 40 both had a mean age of 65 years. χ² analysis did not show a difference in T stage or systemic treatment but did show that patients with V60 < 40% were more likely to have N1 disease (P = .01), and less likely to have N2 disease (P = .01) compared with patients with V60 ≥ 40%. The difference in 1-year dysphagia between N0 to N1 patients (27%) and N2 to N3 patients (46%) was not statistically significant (P = .19).

In patients who could be evaluated for long-term swallowing function, the uninvolved pharynx volume median of the total constrictor volume was 32% (range, < 1%-62%). The uninvolved pharynx mean dose ranged from 28 to 68 Gy (median, 45). When the uninvolved pharynx mean dose was < 45 Gy, 1-year dysphagia was 22% compared with 52% with a dose ≥ 45 Gy (P = .03).

Discussion

This is the first study to link contralateral constrictor dose to long-term dysphagia in patients treated with radiation for head and neck cancer. Editing the boost volume off air cavities was associated with lower contralateral constrictor V60 and with less long-term dysphagia. This may indicate that optimizing plans to meet a contralateral constrictor constraint can reduce rates of long-term dysphagia.

The most useful clinical predictors are those that identify a patient at low risk for toxicity. These constraints are useful because they reassure physicians that treatments will have a favorable risk/benefit ratio while identifying plans that may need modification before starting treatment.

The contralateral constrictor outperformed the uninvolved pharynx in identifying patients at low risk for long-term dysphagia. This difference could not be overcome by decreasing the threshold of the pharynx constraint, as 17% of patients with dysphagia had a mean dose of < 40 Gy to the uninvolved pharynx, which was not statistically significant. An advantage of contralateral constrictor is that it is independent of PTV size. The uninvolved pharynx structure depends on the PTV contour, so it may obscure a connection between PTV size and dysphagia.

In the context of a clinical trial, only measuring dose to the uninvolved pharynx may allow more plans to meet constraints, but even in NRG trials, physicians have some control over target volumes. For example, NRG HN009, a national trial for patients with head and neck cancer, recommends editing the CTV_7000 (clinical target volume treated to 70 Gy) off air cavities but does not define how much the volume should be cropped or specify protocol violations if the volume is not cropped.¹⁵ Furthermore, constraints used in clinical trials are often adopted for use outside the trial, where physicians have extensive control over target volumes.

The broad range of uninvolved pharynx volume relative to total constrictor volume confounds predictions using this variable. For example, according to the NRG constraint, a patient with an uninvolved pharynx mean dose of 44 Gy will have a low risk of dysphagia even if this structure is only 1% of the total constrictor. The contralateral constrictor is always about 50% of the total constrictor volume, which means that predictions using this structure will not be confounded by the same variation in volume size.

Figure 2 shows a representative patient who met the NRG uninvolved pharynx constraint but developed long-term dysphagia.

Limitations

This study is limited by its single institution, retrospective design, small sample size, and by all patients being male. The high correlation between air cavity editing and the use of SIB makes it impossible to assess the impact of each technique individually. Patients with contralateral constrictor V60 < 40% were less likely to have N2 disease, but N2 to N3 disease did not predict higher 1-year dysphagia, so the difference in N-category cannot fully explain the difference in 1-year dysphagia. It is possible that unreported factors, such as CTV, may contribute significantly to swallowing function. Nevertheless, within the study population, contralateral constrictor dose was able to identify a group with a low rate of long-term dysphagia.

Conclusions

Contralateral constrictor dose is a promising predictor of late dysphagia for patients with head and neck cancer treated with radiation with concurrent systemic therapy. Contralateral constrictor V60 < 40% was able to identify a group of patients with a low rate of 1-year dysphagia in this single-center retrospective study. The correlation between air cavity editing and contralateral constrictor V60 suggests that contralateral constrictor dose may depend partly on technique. Further studies are needed to see if the contralateral constrictor dose can be used to predict long-term dysphagia prospectively and in other patient populations.

Primary hepatic lymphoma (PHL) is a rare, malignant lymphoma of the liver. It differs from the predominantly lymph nodal or splenic involvement associated with other types of lymphoma. It is usually detected incidentally on imaging examination, commonly computed tomography (CT), for nonspecific clinical presentation. However, it has important clinical implications for early diagnosis and treatment as indicated in our case.

Case Presentation

An 84-year-old man presented to the emergency department for evaluation of upper back pain. The patient had a history of hypertension, diabetes mellitus, and was a former smoker. He had normal vital signs, an unremarkable physical examination, and a body mass index of 25. His laboratory studies showed a normal blood cell count and serum chemistry, including serum calcium level and α-fetoprotein, but mildly elevated liver function tests.

The patient’s chest CT angiography showed no evidence of thoracic aortic dissection, penetrating atherosclerotic ulceration, or pulmonary artery embolism. Besides emphysematous changes in the lung, the chest CT was within normal limits.

Discussion

Lymphoma is a tumor that originates from hematopoietic cells typically presented as a circumscribed solid tumor of lymphoid cells.¹ Lymphomas are usually seen in the lymph nodes, spleen, blood, bone marrow, brain, gastrointestinal tract, skin, or other normal structures where lymphoreticular cells exist but very rarely in the liver.² PHL is extremely rare due to the lack of abundant lymphoid tissue in the normal liver.³ It accounts for 0.4% of extra-nodal lymphomas and 0.016% of non-Hodgkin lymphoma.^4-6 The etiology of PHL is unknown but usually it develops in patients with previous liver disease: viral infection (hepatitis B and C, Epstein-Barr, and HIV), autoimmune disease, immunosuppression, or liver cirrhosis.^5-7

The diagnosis of PHL can be challenging due to its rarity, vague clinical features, and nonspecific radiologic findings. The common presenting symptoms are usually vague and include abdominal pain or discomfort, fatigue, jaundice, weight loss, and fever.⁵ Liver biopsy is essential to its diagnosis. The disease course is usually indolent among most patients with PHL. In our case, the patient presented with upper back pain but his condition deteriorated rapidly, likely due to the advanced stage of the disease. Diagnosis of liver lymphoma depends on a liver biopsy that should be compatible with the lymphoma. The criteria for diagnosis of PHL defined by Lei include (1) symptoms caused mainly by liver involvement at presentation; (2) absence of distant lymphadenopathy, palpable clinically at presentation or detected during staging radiologic studies; and (3) absence of leukemic blood involvement in the peripheral blood smear.⁷ Other authors define PHL as having major liver involvement without evidence of extrahepatic involvement for at least 6 months.⁸ In our case, the multiple large lesions of the liver are consistent with advanced stage PHL with retroperitoneal lymph nodes and right lung metastasis. DLBCL is the most common histopathological type of lymphoma (65.9%). Other types have been described less commonly, including diffuse mixed large- and small-cell, lymphoblastic, diffuse histiocytic, mantle cell, and small noncleaved or Burkitt lymphoma.^5-7

Currently, there is no consensus on PHL treatment. The therapeutic options include surgery, chemotherapy, radiation therapy, or a combination of therapies.⁷ Most evidence regarding treatment and tumor response comes from case series, as PHLs are rare. Surgical resection in a series of 8 patients showed a cumulative 1- and 2-year survival rate of 66.7% and 55.6%, respectively.⁹ Chemotherapy is the recommended treatment option for extra-nodal DLBCL, making it a choice also for the treatment of PHL.¹⁰ Page and colleagues demonstrated that combination chemotherapy regimens helped achieve remission for 83.3% of patients.¹¹ Since PHL is chemo-sensitive, most patients are treated with chemotherapy alone or in combination with surgery and radiotherapy. The most common chemotherapy regimen is R-CHOP for CD20-positive B-cell lymphoma. The use of the R-CHOP regimen has been reported to achieve complete remission in primary DLBCL of the liver.¹²

Conclusions

Primary DLBCL of the liver is a very rare disease without specific clinical manifestations, biochemical indicators, or radiologic features except for space-occupying liver lesions. However, patients’ conditions can deteriorate rapidly at an advanced stage, as demonstrated in our case. DLBCL requires a high level of suspicion for its early diagnosis and treatment and should be considered in the differential diagnosis for any hepatic space-occupying lesions.

Acknowledgments

We appreciate Lynne Dryer, ARNP, for her clinical assistance with this patient and in the preparation of the manuscript.

Primary hepatic lymphoma (PHL) is a rare, malignant lymphoma of the liver. It differs from the predominantly lymph nodal or splenic involvement associated with other types of lymphoma. It is usually detected incidentally on imaging examination, commonly computed tomography (CT), for nonspecific clinical presentation. However, it has important clinical implications for early diagnosis and treatment as indicated in our case.

Case Presentation

An 84-year-old man presented to the emergency department for evaluation of upper back pain. The patient had a history of hypertension, diabetes mellitus, and was a former smoker. He had normal vital signs, an unremarkable physical examination, and a body mass index of 25. His laboratory studies showed a normal blood cell count and serum chemistry, including serum calcium level and α-fetoprotein, but mildly elevated liver function tests.

The patient’s chest CT angiography showed no evidence of thoracic aortic dissection, penetrating atherosclerotic ulceration, or pulmonary artery embolism. Besides emphysematous changes in the lung, the chest CT was within normal limits.

Discussion

Lymphoma is a tumor that originates from hematopoietic cells typically presented as a circumscribed solid tumor of lymphoid cells.¹ Lymphomas are usually seen in the lymph nodes, spleen, blood, bone marrow, brain, gastrointestinal tract, skin, or other normal structures where lymphoreticular cells exist but very rarely in the liver.² PHL is extremely rare due to the lack of abundant lymphoid tissue in the normal liver.³ It accounts for 0.4% of extra-nodal lymphomas and 0.016% of non-Hodgkin lymphoma.^4-6 The etiology of PHL is unknown but usually it develops in patients with previous liver disease: viral infection (hepatitis B and C, Epstein-Barr, and HIV), autoimmune disease, immunosuppression, or liver cirrhosis.^5-7

The diagnosis of PHL can be challenging due to its rarity, vague clinical features, and nonspecific radiologic findings. The common presenting symptoms are usually vague and include abdominal pain or discomfort, fatigue, jaundice, weight loss, and fever.⁵ Liver biopsy is essential to its diagnosis. The disease course is usually indolent among most patients with PHL. In our case, the patient presented with upper back pain but his condition deteriorated rapidly, likely due to the advanced stage of the disease. Diagnosis of liver lymphoma depends on a liver biopsy that should be compatible with the lymphoma. The criteria for diagnosis of PHL defined by Lei include (1) symptoms caused mainly by liver involvement at presentation; (2) absence of distant lymphadenopathy, palpable clinically at presentation or detected during staging radiologic studies; and (3) absence of leukemic blood involvement in the peripheral blood smear.⁷ Other authors define PHL as having major liver involvement without evidence of extrahepatic involvement for at least 6 months.⁸ In our case, the multiple large lesions of the liver are consistent with advanced stage PHL with retroperitoneal lymph nodes and right lung metastasis. DLBCL is the most common histopathological type of lymphoma (65.9%). Other types have been described less commonly, including diffuse mixed large- and small-cell, lymphoblastic, diffuse histiocytic, mantle cell, and small noncleaved or Burkitt lymphoma.^5-7

Currently, there is no consensus on PHL treatment. The therapeutic options include surgery, chemotherapy, radiation therapy, or a combination of therapies.⁷ Most evidence regarding treatment and tumor response comes from case series, as PHLs are rare. Surgical resection in a series of 8 patients showed a cumulative 1- and 2-year survival rate of 66.7% and 55.6%, respectively.⁹ Chemotherapy is the recommended treatment option for extra-nodal DLBCL, making it a choice also for the treatment of PHL.¹⁰ Page and colleagues demonstrated that combination chemotherapy regimens helped achieve remission for 83.3% of patients.¹¹ Since PHL is chemo-sensitive, most patients are treated with chemotherapy alone or in combination with surgery and radiotherapy. The most common chemotherapy regimen is R-CHOP for CD20-positive B-cell lymphoma. The use of the R-CHOP regimen has been reported to achieve complete remission in primary DLBCL of the liver.¹²

Conclusions

Primary DLBCL of the liver is a very rare disease without specific clinical manifestations, biochemical indicators, or radiologic features except for space-occupying liver lesions. However, patients’ conditions can deteriorate rapidly at an advanced stage, as demonstrated in our case. DLBCL requires a high level of suspicion for its early diagnosis and treatment and should be considered in the differential diagnosis for any hepatic space-occupying lesions.

Acknowledgments

We appreciate Lynne Dryer, ARNP, for her clinical assistance with this patient and in the preparation of the manuscript.

Primary hepatic lymphoma (PHL) is a rare, malignant lymphoma of the liver. It differs from the predominantly lymph nodal or splenic involvement associated with other types of lymphoma. It is usually detected incidentally on imaging examination, commonly computed tomography (CT), for nonspecific clinical presentation. However, it has important clinical implications for early diagnosis and treatment as indicated in our case.

Case Presentation

An 84-year-old man presented to the emergency department for evaluation of upper back pain. The patient had a history of hypertension, diabetes mellitus, and was a former smoker. He had normal vital signs, an unremarkable physical examination, and a body mass index of 25. His laboratory studies showed a normal blood cell count and serum chemistry, including serum calcium level and α-fetoprotein, but mildly elevated liver function tests.

The patient’s chest CT angiography showed no evidence of thoracic aortic dissection, penetrating atherosclerotic ulceration, or pulmonary artery embolism. Besides emphysematous changes in the lung, the chest CT was within normal limits.

Discussion

Lymphoma is a tumor that originates from hematopoietic cells typically presented as a circumscribed solid tumor of lymphoid cells.¹ Lymphomas are usually seen in the lymph nodes, spleen, blood, bone marrow, brain, gastrointestinal tract, skin, or other normal structures where lymphoreticular cells exist but very rarely in the liver.² PHL is extremely rare due to the lack of abundant lymphoid tissue in the normal liver.³ It accounts for 0.4% of extra-nodal lymphomas and 0.016% of non-Hodgkin lymphoma.^4-6 The etiology of PHL is unknown but usually it develops in patients with previous liver disease: viral infection (hepatitis B and C, Epstein-Barr, and HIV), autoimmune disease, immunosuppression, or liver cirrhosis.^5-7

The diagnosis of PHL can be challenging due to its rarity, vague clinical features, and nonspecific radiologic findings. The common presenting symptoms are usually vague and include abdominal pain or discomfort, fatigue, jaundice, weight loss, and fever.⁵ Liver biopsy is essential to its diagnosis. The disease course is usually indolent among most patients with PHL. In our case, the patient presented with upper back pain but his condition deteriorated rapidly, likely due to the advanced stage of the disease. Diagnosis of liver lymphoma depends on a liver biopsy that should be compatible with the lymphoma. The criteria for diagnosis of PHL defined by Lei include (1) symptoms caused mainly by liver involvement at presentation; (2) absence of distant lymphadenopathy, palpable clinically at presentation or detected during staging radiologic studies; and (3) absence of leukemic blood involvement in the peripheral blood smear.⁷ Other authors define PHL as having major liver involvement without evidence of extrahepatic involvement for at least 6 months.⁸ In our case, the multiple large lesions of the liver are consistent with advanced stage PHL with retroperitoneal lymph nodes and right lung metastasis. DLBCL is the most common histopathological type of lymphoma (65.9%). Other types have been described less commonly, including diffuse mixed large- and small-cell, lymphoblastic, diffuse histiocytic, mantle cell, and small noncleaved or Burkitt lymphoma.^5-7

Currently, there is no consensus on PHL treatment. The therapeutic options include surgery, chemotherapy, radiation therapy, or a combination of therapies.⁷ Most evidence regarding treatment and tumor response comes from case series, as PHLs are rare. Surgical resection in a series of 8 patients showed a cumulative 1- and 2-year survival rate of 66.7% and 55.6%, respectively.⁹ Chemotherapy is the recommended treatment option for extra-nodal DLBCL, making it a choice also for the treatment of PHL.¹⁰ Page and colleagues demonstrated that combination chemotherapy regimens helped achieve remission for 83.3% of patients.¹¹ Since PHL is chemo-sensitive, most patients are treated with chemotherapy alone or in combination with surgery and radiotherapy. The most common chemotherapy regimen is R-CHOP for CD20-positive B-cell lymphoma. The use of the R-CHOP regimen has been reported to achieve complete remission in primary DLBCL of the liver.¹²

Conclusions

Primary DLBCL of the liver is a very rare disease without specific clinical manifestations, biochemical indicators, or radiologic features except for space-occupying liver lesions. However, patients’ conditions can deteriorate rapidly at an advanced stage, as demonstrated in our case. DLBCL requires a high level of suspicion for its early diagnosis and treatment and should be considered in the differential diagnosis for any hepatic space-occupying lesions.

Acknowledgments

We appreciate Lynne Dryer, ARNP, for her clinical assistance with this patient and in the preparation of the manuscript.

Many patients with asymptomatic renal stones can qualify for an active surveillance program, Swiss researchers report at the American Urological Association 2023 Annual Meeting.

Kevin Stritt, MD, chief resident in the urology department at Lausanne University Hospital, said kidney stones often pass without symptoms. But until now, data on the frequency of asymptomatic, spontaneous passage of stones have been lacking.

The new data come from the NOSTONE trial, a prospective, multicenter, double-blind, placebo-controlled randomized trial to assess the efficacy of hydrochlorothiazide in the prevention of recurrence in patients with recurrent calcium-containing kidney stones.

Dr. Stritt and colleagues evaluated the natural history of asymptomatic renal stones during a median follow-up of 35 months. “We found for the first time that a relevant number of kidney stone passages [39%] were asymptomatic, spontaneous stone passages,” Dr. Stritt told this news organization.

All asymptomatic spontaneous stone passages were analyzed in a comparison of the total number of kidney stones on low-dose, nonintravenous contrast CT imaging at the beginning and end of the 3-year follow-up.

Of the 403 stones passed spontaneously, 61% (245) were symptomatic stone passages and 39% (158) were asymptomatic stone passages, Dr. Stritt told this news organization.

Asymptomatic stones were a median size of 2.4 mm, and symptomatic stones were 2.15 mm, which was not significantly different (P = .366), according to the researchers. Dr. Stritt said the spontaneous passage of asymptomatic stones was largely influenced by a higher number of stones on CT imaging at randomization (P = .001) and a lower total stone volume (P = .001).

Ephrem Olweny, MD, an assistant professor of urology and section chief of endourology at Rush University Medical Center in Chicago, said previous studies have found that the rate of spontaneous passage of kidney stones ranges from 3% to 29%.

“But this secondary analysis of data from a prior multicenter prospective randomized trial offers higher-quality data that will be of value in guiding patient counseling,” Dr. Olweny said.

“Observation should be initially offered to these patients. However, patients should be informed that 52% are likely to develop symptoms, and some may indeed opt for preemptive surgical removal,” he added.

David Schulsinger, MD, an associate professor in the department of urology at Stony Brook (N.Y.) University Hospital, said the incidence of kidney stones has been increasing worldwide, affecting approximately 12% of men and 6% of women. Dehydration and diets high in sodium and calcium are major factors, he said.

Patients with a history of stones have a 50% risk of recurrence in the next 5 years, and an 80% risk in their lifetime, he added.

Dr. Schulsinger said the message from the Swiss study is that urologists can be “comfortable” watching small stones, those averaging 2.4 mm or less in size. “But if a patient has a 7- or  8-mm stone, you might be more inclined to manage that patient a little bit more aggressively.”

Roughly half of patients with stones less than 2 mm will pass it in about 8 days, he said. 

Dr. Olweny noted that the study was a secondary analysis of data from a randomized controlled trial that evaluated the efficacy of thiazides in preventing the recurrence of calcium stones. “The original study was not specifically designed to look at asymptomatic stone passage rates for small renal stones, and therefore, the observed rates may not reflect the most precise estimates,” he said.

Dr. Stritt said his group has not studied the size limit of stones that pass spontaneously without symptoms. “This study could serve to construct recurrence prediction models based on medical history and stone burden on CT imaging. More well-designed research on this topic is urgently needed,” he said. “These results should encourage urologists to counsel patients about the possibility of an active surveillance strategy when smaller kidney stones are present.”

The author and independent commentators have reported no relevant financial relationships.

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

Many patients with asymptomatic renal stones can qualify for an active surveillance program, Swiss researchers report at the American Urological Association 2023 Annual Meeting.

Kevin Stritt, MD, chief resident in the urology department at Lausanne University Hospital, said kidney stones often pass without symptoms. But until now, data on the frequency of asymptomatic, spontaneous passage of stones have been lacking.

The new data come from the NOSTONE trial, a prospective, multicenter, double-blind, placebo-controlled randomized trial to assess the efficacy of hydrochlorothiazide in the prevention of recurrence in patients with recurrent calcium-containing kidney stones.

Dr. Stritt and colleagues evaluated the natural history of asymptomatic renal stones during a median follow-up of 35 months. “We found for the first time that a relevant number of kidney stone passages [39%] were asymptomatic, spontaneous stone passages,” Dr. Stritt told this news organization.

All asymptomatic spontaneous stone passages were analyzed in a comparison of the total number of kidney stones on low-dose, nonintravenous contrast CT imaging at the beginning and end of the 3-year follow-up.

Of the 403 stones passed spontaneously, 61% (245) were symptomatic stone passages and 39% (158) were asymptomatic stone passages, Dr. Stritt told this news organization.

Asymptomatic stones were a median size of 2.4 mm, and symptomatic stones were 2.15 mm, which was not significantly different (P = .366), according to the researchers. Dr. Stritt said the spontaneous passage of asymptomatic stones was largely influenced by a higher number of stones on CT imaging at randomization (P = .001) and a lower total stone volume (P = .001).

Ephrem Olweny, MD, an assistant professor of urology and section chief of endourology at Rush University Medical Center in Chicago, said previous studies have found that the rate of spontaneous passage of kidney stones ranges from 3% to 29%.

“But this secondary analysis of data from a prior multicenter prospective randomized trial offers higher-quality data that will be of value in guiding patient counseling,” Dr. Olweny said.

“Observation should be initially offered to these patients. However, patients should be informed that 52% are likely to develop symptoms, and some may indeed opt for preemptive surgical removal,” he added.

David Schulsinger, MD, an associate professor in the department of urology at Stony Brook (N.Y.) University Hospital, said the incidence of kidney stones has been increasing worldwide, affecting approximately 12% of men and 6% of women. Dehydration and diets high in sodium and calcium are major factors, he said.

Patients with a history of stones have a 50% risk of recurrence in the next 5 years, and an 80% risk in their lifetime, he added.

Dr. Schulsinger said the message from the Swiss study is that urologists can be “comfortable” watching small stones, those averaging 2.4 mm or less in size. “But if a patient has a 7- or  8-mm stone, you might be more inclined to manage that patient a little bit more aggressively.”

Roughly half of patients with stones less than 2 mm will pass it in about 8 days, he said. 

Dr. Olweny noted that the study was a secondary analysis of data from a randomized controlled trial that evaluated the efficacy of thiazides in preventing the recurrence of calcium stones. “The original study was not specifically designed to look at asymptomatic stone passage rates for small renal stones, and therefore, the observed rates may not reflect the most precise estimates,” he said.

Dr. Stritt said his group has not studied the size limit of stones that pass spontaneously without symptoms. “This study could serve to construct recurrence prediction models based on medical history and stone burden on CT imaging. More well-designed research on this topic is urgently needed,” he said. “These results should encourage urologists to counsel patients about the possibility of an active surveillance strategy when smaller kidney stones are present.”

The author and independent commentators have reported no relevant financial relationships.

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

Many patients with asymptomatic renal stones can qualify for an active surveillance program, Swiss researchers report at the American Urological Association 2023 Annual Meeting.

Kevin Stritt, MD, chief resident in the urology department at Lausanne University Hospital, said kidney stones often pass without symptoms. But until now, data on the frequency of asymptomatic, spontaneous passage of stones have been lacking.

The new data come from the NOSTONE trial, a prospective, multicenter, double-blind, placebo-controlled randomized trial to assess the efficacy of hydrochlorothiazide in the prevention of recurrence in patients with recurrent calcium-containing kidney stones.

Dr. Stritt and colleagues evaluated the natural history of asymptomatic renal stones during a median follow-up of 35 months. “We found for the first time that a relevant number of kidney stone passages [39%] were asymptomatic, spontaneous stone passages,” Dr. Stritt told this news organization.

All asymptomatic spontaneous stone passages were analyzed in a comparison of the total number of kidney stones on low-dose, nonintravenous contrast CT imaging at the beginning and end of the 3-year follow-up.

Of the 403 stones passed spontaneously, 61% (245) were symptomatic stone passages and 39% (158) were asymptomatic stone passages, Dr. Stritt told this news organization.

Asymptomatic stones were a median size of 2.4 mm, and symptomatic stones were 2.15 mm, which was not significantly different (P = .366), according to the researchers. Dr. Stritt said the spontaneous passage of asymptomatic stones was largely influenced by a higher number of stones on CT imaging at randomization (P = .001) and a lower total stone volume (P = .001).

Ephrem Olweny, MD, an assistant professor of urology and section chief of endourology at Rush University Medical Center in Chicago, said previous studies have found that the rate of spontaneous passage of kidney stones ranges from 3% to 29%.

“But this secondary analysis of data from a prior multicenter prospective randomized trial offers higher-quality data that will be of value in guiding patient counseling,” Dr. Olweny said.

“Observation should be initially offered to these patients. However, patients should be informed that 52% are likely to develop symptoms, and some may indeed opt for preemptive surgical removal,” he added.

David Schulsinger, MD, an associate professor in the department of urology at Stony Brook (N.Y.) University Hospital, said the incidence of kidney stones has been increasing worldwide, affecting approximately 12% of men and 6% of women. Dehydration and diets high in sodium and calcium are major factors, he said.

Patients with a history of stones have a 50% risk of recurrence in the next 5 years, and an 80% risk in their lifetime, he added.

Dr. Schulsinger said the message from the Swiss study is that urologists can be “comfortable” watching small stones, those averaging 2.4 mm or less in size. “But if a patient has a 7- or  8-mm stone, you might be more inclined to manage that patient a little bit more aggressively.”

Roughly half of patients with stones less than 2 mm will pass it in about 8 days, he said. 

Dr. Olweny noted that the study was a secondary analysis of data from a randomized controlled trial that evaluated the efficacy of thiazides in preventing the recurrence of calcium stones. “The original study was not specifically designed to look at asymptomatic stone passage rates for small renal stones, and therefore, the observed rates may not reflect the most precise estimates,” he said.

Dr. Stritt said his group has not studied the size limit of stones that pass spontaneously without symptoms. “This study could serve to construct recurrence prediction models based on medical history and stone burden on CT imaging. More well-designed research on this topic is urgently needed,” he said. “These results should encourage urologists to counsel patients about the possibility of an active surveillance strategy when smaller kidney stones are present.”

The author and independent commentators have reported no relevant financial relationships.

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

Cholangiocarcinoma is a heterogeneous, highly aggressive cancer of the biliary tract epithelium with an overall 5-year relative survival rate of only 9%.^1,2 Although surgical resection of localized, intrahepatic cholangiocarcinoma is associated with improved overall survival, most patients present with advanced disease not amenable to surgery due to a late onset of symptoms.² Recently, an increased incidence of cholangiocarcinoma has been reported in the United States.³ Although relatively rare in the US, cholangiocarcinoma is prevalent across large parts of Asia, including China, Vietnam, Thailand, South Korea, and Taiwan.²

Risk Factors

To date, risk factors for developing cholangiocarcinoma have not been elucidated. ^4,5 However, a growing body of literature suggests that chronic infection of genetically susceptible human subjects with Clonorchis sinensis ( C sinensis ) and Opisthorchis viverrini ( O viverrini ) plays a role. ^6,7 The life cycle of these food-borne zoonotic trematodes involves eggs discharged in the stool of infected humans, the definitive host. ^6,7 In nature, these eggs are ingested by freshwater snails, the intermediate host, where they undergo several developmental stages to form cercariae. Once released from snails into the water, free-swimming cercariae come in contact and penetrate freshwater fish where they encyst as metacercariae. Infection of humans occurs by ingesting undercooked, salted, pickled, or smoked freshwater fish infested with metacercariae. After ingestion, metacercariae excyst in the duodenum and ascend the biliary tract through the ampulla of Vater. They then mature into adult flukes that reside in small- and medium-sized intrahepatic biliary ducts. ^6,7

Although most infected people remain asymptomatic, untreated indolent infections with C sinensis and O viverrini may persist in peripheral intrahepatic bile ducts for as long as 30 years, which is the lifespan of the trematodes.^6,7 During this prolonged period, C sinensis and O viverrini feeding activities and their excretory-secretory products may damage bile duct epithelium and promote intense local inflammation.^6,7 Conceivably, these pathological processes could then provoke the epithelial desquamation, adenomatous hyperplasia, goblet cell metaplasia, periductal fibrosis, and granuloma formation that are conducive to initiation and progression of cholangiocarcinoma in genetically susceptible people.⁸ Accordingly, the International Agency for Research on Cancer (IARC) has determined that there is sufficient evidence for the carcinogenicity of chronic infections with C sinensis and O viverrini in humans and that chronic infections with these trematodes cause cholangiocarcinoma.⁹ The IARC concluded that chronic infections with C sinensis and O viverrini are carcinogenic to humans (Group 1).⁹

Diagnosis

Presently, the diagnosis of C sinensis and O viverrini infection is based on microscopic identification and enumeration of the parasites’ eggs in weighted stool specimens using a formalin-ethyl acetate sedimentation concentration technique. ^6,7 This approach requires a labor-intensive test that is conducted by an experienced technician. The test has low specificity and sensitivity because eggs could be confused with those of nonpathogenic intestinal flukes that are morphologically similar and because eggs are not present in feces during all stages of the infection. Although diffuse dilatation of intrahepatic bile ducts by screening sonography is used to diagnose clonorchiasis in endemic areas, it has low sensitivity, particularly in patients with low-level C sinensis and O viverrin i infections. ¹⁰

To address the current diagnostic gap, several enzyme-linked immunosorbent assays (ELISA) have been developed for the diagnosis of C sinensis, including monoclonal antibody-based (mAb) ELISA and indirect antibody ELISA.^11,12 However, both have important limitations. The mAb ELISA detects only active infections while indirect antibody ELISA cross-reacts with other liver flukes.^11,12 Taken together, these data illustrate the difficulties in diagnosing asymptomatic individuals with low-burden C sinensis or O viverrini infections by existing laboratory methods.

Timely serodiagnosis of indolent C sinensis and O viverrini infections is important because these parasites have recently been raised as a risk factor for cholangiocarcinoma in veterans who served in Vietnam.¹³ The American War Library estimates that as of February 28, 2019, about 610,000 Americans who served on land in Vietnam or in the air over Vietnam between 1954 and 1975 are alive, and about 164,000 Americans who served at sea in Vietnam waters are alive.¹⁴ To that end, Psevdos and colleagues screened 97 US veterans who served in Vietnam and identified 50 who reported exposure to raw or undercooked fish while there.¹³ None had evidence of active C sinensis or O viverrini infection. Blood samples obtained from these veterans were analyzed for circulating C sinensis and O viverrini antibodies using an ELISA developed in South Korea and 12 blood samples tested positive for the trematodes. Imaging of extrahepatic and intrahepatic bile ducts was unyielding in all cases. One veteran diagnosed with cholangiocarcinoma had repeated negative tests. However, the results of this study were challenged by several experts in this field because the authors did not report the sensitivity and specificity of the ELISA assay used.¹⁵

Serologic testing of US veterans who served in C sinensis and O viverrini–endemic countries for indolent infections with these parasites is not recommended at present.¹⁵ Nevertheless, there is an urgent need to develop sensitive and specific serologic assays, such as ELISA tests with recombinant antigens, to detect both acute and indolent infections caused by each biliary liver fluke in the US, including in patients diagnosed with cholangiocarcinoma. We posit that testing and treatment of high-risk populations could lead to earlier detection and treatment of cholangiocarcinoma, leading to improved overall survival in the population at risk.

Cholangiocarcinoma is a heterogeneous, highly aggressive cancer of the biliary tract epithelium with an overall 5-year relative survival rate of only 9%.^1,2 Although surgical resection of localized, intrahepatic cholangiocarcinoma is associated with improved overall survival, most patients present with advanced disease not amenable to surgery due to a late onset of symptoms.² Recently, an increased incidence of cholangiocarcinoma has been reported in the United States.³ Although relatively rare in the US, cholangiocarcinoma is prevalent across large parts of Asia, including China, Vietnam, Thailand, South Korea, and Taiwan.²

Risk Factors

To date, risk factors for developing cholangiocarcinoma have not been elucidated. ^4,5 However, a growing body of literature suggests that chronic infection of genetically susceptible human subjects with Clonorchis sinensis ( C sinensis ) and Opisthorchis viverrini ( O viverrini ) plays a role. ^6,7 The life cycle of these food-borne zoonotic trematodes involves eggs discharged in the stool of infected humans, the definitive host. ^6,7 In nature, these eggs are ingested by freshwater snails, the intermediate host, where they undergo several developmental stages to form cercariae. Once released from snails into the water, free-swimming cercariae come in contact and penetrate freshwater fish where they encyst as metacercariae. Infection of humans occurs by ingesting undercooked, salted, pickled, or smoked freshwater fish infested with metacercariae. After ingestion, metacercariae excyst in the duodenum and ascend the biliary tract through the ampulla of Vater. They then mature into adult flukes that reside in small- and medium-sized intrahepatic biliary ducts. ^6,7

Although most infected people remain asymptomatic, untreated indolent infections with C sinensis and O viverrini may persist in peripheral intrahepatic bile ducts for as long as 30 years, which is the lifespan of the trematodes.^6,7 During this prolonged period, C sinensis and O viverrini feeding activities and their excretory-secretory products may damage bile duct epithelium and promote intense local inflammation.^6,7 Conceivably, these pathological processes could then provoke the epithelial desquamation, adenomatous hyperplasia, goblet cell metaplasia, periductal fibrosis, and granuloma formation that are conducive to initiation and progression of cholangiocarcinoma in genetically susceptible people.⁸ Accordingly, the International Agency for Research on Cancer (IARC) has determined that there is sufficient evidence for the carcinogenicity of chronic infections with C sinensis and O viverrini in humans and that chronic infections with these trematodes cause cholangiocarcinoma.⁹ The IARC concluded that chronic infections with C sinensis and O viverrini are carcinogenic to humans (Group 1).⁹

Diagnosis

Presently, the diagnosis of C sinensis and O viverrini infection is based on microscopic identification and enumeration of the parasites’ eggs in weighted stool specimens using a formalin-ethyl acetate sedimentation concentration technique. ^6,7 This approach requires a labor-intensive test that is conducted by an experienced technician. The test has low specificity and sensitivity because eggs could be confused with those of nonpathogenic intestinal flukes that are morphologically similar and because eggs are not present in feces during all stages of the infection. Although diffuse dilatation of intrahepatic bile ducts by screening sonography is used to diagnose clonorchiasis in endemic areas, it has low sensitivity, particularly in patients with low-level C sinensis and O viverrin i infections. ¹⁰

To address the current diagnostic gap, several enzyme-linked immunosorbent assays (ELISA) have been developed for the diagnosis of C sinensis, including monoclonal antibody-based (mAb) ELISA and indirect antibody ELISA.^11,12 However, both have important limitations. The mAb ELISA detects only active infections while indirect antibody ELISA cross-reacts with other liver flukes.^11,12 Taken together, these data illustrate the difficulties in diagnosing asymptomatic individuals with low-burden C sinensis or O viverrini infections by existing laboratory methods.

Timely serodiagnosis of indolent C sinensis and O viverrini infections is important because these parasites have recently been raised as a risk factor for cholangiocarcinoma in veterans who served in Vietnam.¹³ The American War Library estimates that as of February 28, 2019, about 610,000 Americans who served on land in Vietnam or in the air over Vietnam between 1954 and 1975 are alive, and about 164,000 Americans who served at sea in Vietnam waters are alive.¹⁴ To that end, Psevdos and colleagues screened 97 US veterans who served in Vietnam and identified 50 who reported exposure to raw or undercooked fish while there.¹³ None had evidence of active C sinensis or O viverrini infection. Blood samples obtained from these veterans were analyzed for circulating C sinensis and O viverrini antibodies using an ELISA developed in South Korea and 12 blood samples tested positive for the trematodes. Imaging of extrahepatic and intrahepatic bile ducts was unyielding in all cases. One veteran diagnosed with cholangiocarcinoma had repeated negative tests. However, the results of this study were challenged by several experts in this field because the authors did not report the sensitivity and specificity of the ELISA assay used.¹⁵

Serologic testing of US veterans who served in C sinensis and O viverrini–endemic countries for indolent infections with these parasites is not recommended at present.¹⁵ Nevertheless, there is an urgent need to develop sensitive and specific serologic assays, such as ELISA tests with recombinant antigens, to detect both acute and indolent infections caused by each biliary liver fluke in the US, including in patients diagnosed with cholangiocarcinoma. We posit that testing and treatment of high-risk populations could lead to earlier detection and treatment of cholangiocarcinoma, leading to improved overall survival in the population at risk.

Cholangiocarcinoma is a heterogeneous, highly aggressive cancer of the biliary tract epithelium with an overall 5-year relative survival rate of only 9%.^1,2 Although surgical resection of localized, intrahepatic cholangiocarcinoma is associated with improved overall survival, most patients present with advanced disease not amenable to surgery due to a late onset of symptoms.² Recently, an increased incidence of cholangiocarcinoma has been reported in the United States.³ Although relatively rare in the US, cholangiocarcinoma is prevalent across large parts of Asia, including China, Vietnam, Thailand, South Korea, and Taiwan.²

Risk Factors

To date, risk factors for developing cholangiocarcinoma have not been elucidated. ^4,5 However, a growing body of literature suggests that chronic infection of genetically susceptible human subjects with Clonorchis sinensis ( C sinensis ) and Opisthorchis viverrini ( O viverrini ) plays a role. ^6,7 The life cycle of these food-borne zoonotic trematodes involves eggs discharged in the stool of infected humans, the definitive host. ^6,7 In nature, these eggs are ingested by freshwater snails, the intermediate host, where they undergo several developmental stages to form cercariae. Once released from snails into the water, free-swimming cercariae come in contact and penetrate freshwater fish where they encyst as metacercariae. Infection of humans occurs by ingesting undercooked, salted, pickled, or smoked freshwater fish infested with metacercariae. After ingestion, metacercariae excyst in the duodenum and ascend the biliary tract through the ampulla of Vater. They then mature into adult flukes that reside in small- and medium-sized intrahepatic biliary ducts. ^6,7

Although most infected people remain asymptomatic, untreated indolent infections with C sinensis and O viverrini may persist in peripheral intrahepatic bile ducts for as long as 30 years, which is the lifespan of the trematodes.^6,7 During this prolonged period, C sinensis and O viverrini feeding activities and their excretory-secretory products may damage bile duct epithelium and promote intense local inflammation.^6,7 Conceivably, these pathological processes could then provoke the epithelial desquamation, adenomatous hyperplasia, goblet cell metaplasia, periductal fibrosis, and granuloma formation that are conducive to initiation and progression of cholangiocarcinoma in genetically susceptible people.⁸ Accordingly, the International Agency for Research on Cancer (IARC) has determined that there is sufficient evidence for the carcinogenicity of chronic infections with C sinensis and O viverrini in humans and that chronic infections with these trematodes cause cholangiocarcinoma.⁹ The IARC concluded that chronic infections with C sinensis and O viverrini are carcinogenic to humans (Group 1).⁹

Diagnosis

Presently, the diagnosis of C sinensis and O viverrini infection is based on microscopic identification and enumeration of the parasites’ eggs in weighted stool specimens using a formalin-ethyl acetate sedimentation concentration technique. ^6,7 This approach requires a labor-intensive test that is conducted by an experienced technician. The test has low specificity and sensitivity because eggs could be confused with those of nonpathogenic intestinal flukes that are morphologically similar and because eggs are not present in feces during all stages of the infection. Although diffuse dilatation of intrahepatic bile ducts by screening sonography is used to diagnose clonorchiasis in endemic areas, it has low sensitivity, particularly in patients with low-level C sinensis and O viverrin i infections. ¹⁰

To address the current diagnostic gap, several enzyme-linked immunosorbent assays (ELISA) have been developed for the diagnosis of C sinensis, including monoclonal antibody-based (mAb) ELISA and indirect antibody ELISA.^11,12 However, both have important limitations. The mAb ELISA detects only active infections while indirect antibody ELISA cross-reacts with other liver flukes.^11,12 Taken together, these data illustrate the difficulties in diagnosing asymptomatic individuals with low-burden C sinensis or O viverrini infections by existing laboratory methods.

Timely serodiagnosis of indolent C sinensis and O viverrini infections is important because these parasites have recently been raised as a risk factor for cholangiocarcinoma in veterans who served in Vietnam.¹³ The American War Library estimates that as of February 28, 2019, about 610,000 Americans who served on land in Vietnam or in the air over Vietnam between 1954 and 1975 are alive, and about 164,000 Americans who served at sea in Vietnam waters are alive.¹⁴ To that end, Psevdos and colleagues screened 97 US veterans who served in Vietnam and identified 50 who reported exposure to raw or undercooked fish while there.¹³ None had evidence of active C sinensis or O viverrini infection. Blood samples obtained from these veterans were analyzed for circulating C sinensis and O viverrini antibodies using an ELISA developed in South Korea and 12 blood samples tested positive for the trematodes. Imaging of extrahepatic and intrahepatic bile ducts was unyielding in all cases. One veteran diagnosed with cholangiocarcinoma had repeated negative tests. However, the results of this study were challenged by several experts in this field because the authors did not report the sensitivity and specificity of the ELISA assay used.¹⁵

Serologic testing of US veterans who served in C sinensis and O viverrini–endemic countries for indolent infections with these parasites is not recommended at present.¹⁵ Nevertheless, there is an urgent need to develop sensitive and specific serologic assays, such as ELISA tests with recombinant antigens, to detect both acute and indolent infections caused by each biliary liver fluke in the US, including in patients diagnosed with cholangiocarcinoma. We posit that testing and treatment of high-risk populations could lead to earlier detection and treatment of cholangiocarcinoma, leading to improved overall survival in the population at risk.