Shock waves moved through the gynecologic oncology world on Oct. 31, 2018, when the New England Journal of Medicine published two papers on survival outcomes for women undergoing surgery for early stage cervical cancer.
Dr. Emma C. Rossi
The first was a randomized controlled trial of laparotomy and minimally invasive surgery (MIS) for radical hysterectomy called the LACC trial.1 In the multicenter, international trial of 631 women, the primary objective was disease-specific survival (cervical cancer–related deaths) and was powered to detect noninferiority of the MIS approach when compared with laparotomy. The trial was closed early when investigators noted a lower than expected rate of 3-year, disease-free survival (91% vs. 97%) from cervical cancer in the MIS group, which was made up of 84% laparoscopic and 16% robotic approaches, versus laparotomy. There were 19 deaths in the MIS group observed versus three in the laparotomy group. The conclusions of the trial were that MIS surgery is associated with inferior cervical cancer survival.
In the second study, authors analyzed data from large U.S. databases – the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) Program – to collect all-cause mortality for patients with early-stage cervical cancer who had undergone radical hysterectomy during 2010-2013.2 Among 2,461 observed results, 1,225 had undergone MIS surgery with the majority (79.8%) via robotic-assistance. Women undergoing MIS approaches had smaller, lower grade tumors; were more likely to be white, privately insured, and of a higher income; and had surgery later in the cohort and by nonacademic centers. The researchers adjusted for risk factors with an analytic process called propensity-score weighting, which matched the groups more closely in an attempt to minimize confounders. They identified higher all-cause mortality among women who were treated with an MIS approach, compared with those treated with laparotomy (hazard ratio, 1.65). They also observed a significant decline in the survival from cervical cancer annually that corresponded to the uptake of MIS radical hysterectomies.
In the wake of these publications, many concluded that gynecologic oncologists should no longer offer a minimally invasive approach for radical hysterectomy. Certainly level I evidence published in a highly influential journal is compelling, and the consistency in findings over two studies adds further weight to the results. However, was this the correct conclusion to draw from these results? Surgeons who had been performing MIS radical hysterectomies for many years with favorable outcomes are challenging this and are raising questions about external generalizability and whether these findings were driven by the surgery itself or by the surgeon.
The studies’ authors proposed hypotheses for their results that implicate the surgical route rather than the surgeon; however, these seem ad hoc and not well supported by data, including the authors’ own data. The first was the hypothesis that cervical tumors were being disrupted and disseminated through the use of uterine manipulators in MIS approaches. However, cervical cancers are fairly routinely “disrupted” by preoperative cone biopsies, loop electrosurgical excision procedures (LEEP), and sharp biopsies, which are arguably more invasive than placement of a manipulator. Uterine manipulators routinely are used in endometrial cancer surgeries, in which the manipulator is embedded within the tumor, without an associated negative survival effect in randomized trials.3 Additionally, not all surgeons utilize manipulators for radical hysterectomies, and these studies did not measure or report on their use; therefore, it is impossible to know whether, and by what magnitude, manipulators played a role. Finally, if uterine manipulators are the explanation for inferior survival, surely the recommendation should be to discourage their use, rather than abandon the MIS approach all together.
The other explanation offered was exposure of the tumor to CO2 gas. This seems an even less plausible explanation because CO2 gas is routinely used in MIS cancer surgeries for endometrial, prostate, gastric, and colorectal surgeries and is used as insufflation for malignant interventional endoscopies without a significant deleterious effect. Additionally, the cervix is not exposed to CO2 until colpotomy at the procedure’s end – and only briefly. The in vitro studies implicating a negative effect of simulated CO2 pneumoperitoneum are neither compelling nor consistent.4,5
I would like to propose another hypothesis for the results: surgical proficiency. Surgery, unlike medical interventions, is not a simple variable that is dichotomous – performed or not. Surgeons do not randomly select operative approaches for patients. We select surgical approaches based on patients’ circumstances and surgeon factors, including our own mastery of the various techniques. Randomized surgical trials rely on the notion that a surgeon is equally skilled in both or all approaches offered, but this is clearly not the case, and any surgeon recognizes this if he or she has observed more than one surgeon or has attempted a procedure via different routes. While some procedures, such as extrafascial hysterectomy for endometrial cancer, are relatively straightforward and surgeon capabilities are more equitable across different approaches, cervical cancer surgery is quite different.
Early-stage cervical cancer primarily exerts radial growth into the cervical stroma and parametria. Curative surgical excision requires broadly negative margins through this tissue, a so called “radical hysterectomy.” The radicality of hysterectomy has been categorized in stages, acknowledging that different sized lesions require different volumes of parametrial resection to achieve adequate clearance from the tumor.6 In doing so, the surgeon must skeletonize and mobilize the distal ureters, cardinal ligament webs, and uterosacral ligaments. These structures are in close proximity to major vascular and neural structures. Hence, the radical hysterectomy is, without dispute, a technically challenging procedure.
Minimally invasive surgery further handicaps the surgeon by eliminating manual contact with tissue, and relying on complex instrumentation, electrosurgical modalities, and loss of haptics. The learning curve for MIS radical hysterectomy is further attenuated by their relative infrequency. Therefore, it makes sense that, when the MIS approach is randomly assigned to surgeons (such as in the LACC trial) or broadly and independently applied (as in the retrospective series), one might see variations in skill, quality, and outcomes, including oncologic outcomes.
The retrospective study by Melamed et al. acknowledged that surgeon skill and volume may contribute to their findings but stated that, because of the nature of their source data, they were unable to explain why they observed their results. The LACC trial attempted to overcome the issue of surgeon skill by ensuring all surgeons were from high-volume sites and had videos reviewed of their cases. However, the videos were chosen by the surgeons themselves and not available for audit in the study’s supplemental material. The LACC trial was conducted over a 9-year period across 33 sites and enrolled a total of 631 subjects. This equates to an enrollment of approximately two patients per site per year and either reflects extremely low-volume sites or highly selective patient enrollment. If the latter, what was different about the unenrolled patients and what was the preferred chosen route of surgery for them?
All 34 recurrences occurred in patients from just 14 of the 33 sites in the LACC trial. That means that less than half of the sites contributed to all of the recurrences. The authors provided no details on the specific sites, surgeons, or accrual rates in their manuscript or supplemental materials. Therefore, readers are unable to know what was different about those sites; whether they contributed the most patients and, therefore, the most recurrences; or whether they were low-volume sites with lower quality.
While margin status, positive or negative, was reported, there was no data captured regarding volume of resected parametrial tissue, or relative distance from tumor to margin, both of which might provide the reader with a better appraisal of surgeon proficiency and consistency in radicality of the two approaches. The incidence of locoregional (pelvic) recurrences were higher in the MIS arm, which is expected if there were inadequate margins around the laparoscopically resected tumors.
Finally, the authors of the LACC trial observed equivalent rates of postoperative complications between the laparotomy and MIS groups. The main virtue for MIS approaches is the reduction in perioperative morbidity. To observe no perioperative morbidity benefit in the MIS group is a red flag suggesting that these surgeons may not have achieved proficiency with the MIS approach.
Despite these arguments, the results of these studies should be taken seriously. Clearly, it is apparent that preservation of oncologic outcomes is not guaranteed with MIS radical hysterectomy, and it should not be the chosen approach for all patients and all surgeons. However, rather than entirely abandoning this less morbid approach, I would argue that it is a call to arms for gynecologic oncologists to self-evaluate. We should know our own data with respect to case volumes, perioperative complications, and cancer-related recurrence and death.
Perhaps MIS radical hysterectomies should be consolidated among high-volume surgeons with demonstrated good outcomes? Just as has been done for rectal cancer surgery with positive effect, we should establish accredited centers of excellence.7 We also need to improve the training of surgeons in novel, difficult techniques, as well as enhance the sophistication of MIS equipment such as improved instrumentation, haptics, and vision-guided surgery (for example, real-time intraoperative assessment of the tumor margins).
Let’s not take a wholesale step backwards to the surgical approaches of a 100 years ago just because they are more straightforward. Let’s do a better job of advancing the quality of what we do for our patients in the future.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no conflicts of interest. Email Dr. Rossi at obnews@mdedge.com.
Shock waves moved through the gynecologic oncology world on Oct. 31, 2018, when the New England Journal of Medicine published two papers on survival outcomes for women undergoing surgery for early stage cervical cancer.
Dr. Emma C. Rossi
The first was a randomized controlled trial of laparotomy and minimally invasive surgery (MIS) for radical hysterectomy called the LACC trial.1 In the multicenter, international trial of 631 women, the primary objective was disease-specific survival (cervical cancer–related deaths) and was powered to detect noninferiority of the MIS approach when compared with laparotomy. The trial was closed early when investigators noted a lower than expected rate of 3-year, disease-free survival (91% vs. 97%) from cervical cancer in the MIS group, which was made up of 84% laparoscopic and 16% robotic approaches, versus laparotomy. There were 19 deaths in the MIS group observed versus three in the laparotomy group. The conclusions of the trial were that MIS surgery is associated with inferior cervical cancer survival.
In the second study, authors analyzed data from large U.S. databases – the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) Program – to collect all-cause mortality for patients with early-stage cervical cancer who had undergone radical hysterectomy during 2010-2013.2 Among 2,461 observed results, 1,225 had undergone MIS surgery with the majority (79.8%) via robotic-assistance. Women undergoing MIS approaches had smaller, lower grade tumors; were more likely to be white, privately insured, and of a higher income; and had surgery later in the cohort and by nonacademic centers. The researchers adjusted for risk factors with an analytic process called propensity-score weighting, which matched the groups more closely in an attempt to minimize confounders. They identified higher all-cause mortality among women who were treated with an MIS approach, compared with those treated with laparotomy (hazard ratio, 1.65). They also observed a significant decline in the survival from cervical cancer annually that corresponded to the uptake of MIS radical hysterectomies.
In the wake of these publications, many concluded that gynecologic oncologists should no longer offer a minimally invasive approach for radical hysterectomy. Certainly level I evidence published in a highly influential journal is compelling, and the consistency in findings over two studies adds further weight to the results. However, was this the correct conclusion to draw from these results? Surgeons who had been performing MIS radical hysterectomies for many years with favorable outcomes are challenging this and are raising questions about external generalizability and whether these findings were driven by the surgery itself or by the surgeon.
The studies’ authors proposed hypotheses for their results that implicate the surgical route rather than the surgeon; however, these seem ad hoc and not well supported by data, including the authors’ own data. The first was the hypothesis that cervical tumors were being disrupted and disseminated through the use of uterine manipulators in MIS approaches. However, cervical cancers are fairly routinely “disrupted” by preoperative cone biopsies, loop electrosurgical excision procedures (LEEP), and sharp biopsies, which are arguably more invasive than placement of a manipulator. Uterine manipulators routinely are used in endometrial cancer surgeries, in which the manipulator is embedded within the tumor, without an associated negative survival effect in randomized trials.3 Additionally, not all surgeons utilize manipulators for radical hysterectomies, and these studies did not measure or report on their use; therefore, it is impossible to know whether, and by what magnitude, manipulators played a role. Finally, if uterine manipulators are the explanation for inferior survival, surely the recommendation should be to discourage their use, rather than abandon the MIS approach all together.
The other explanation offered was exposure of the tumor to CO2 gas. This seems an even less plausible explanation because CO2 gas is routinely used in MIS cancer surgeries for endometrial, prostate, gastric, and colorectal surgeries and is used as insufflation for malignant interventional endoscopies without a significant deleterious effect. Additionally, the cervix is not exposed to CO2 until colpotomy at the procedure’s end – and only briefly. The in vitro studies implicating a negative effect of simulated CO2 pneumoperitoneum are neither compelling nor consistent.4,5
I would like to propose another hypothesis for the results: surgical proficiency. Surgery, unlike medical interventions, is not a simple variable that is dichotomous – performed or not. Surgeons do not randomly select operative approaches for patients. We select surgical approaches based on patients’ circumstances and surgeon factors, including our own mastery of the various techniques. Randomized surgical trials rely on the notion that a surgeon is equally skilled in both or all approaches offered, but this is clearly not the case, and any surgeon recognizes this if he or she has observed more than one surgeon or has attempted a procedure via different routes. While some procedures, such as extrafascial hysterectomy for endometrial cancer, are relatively straightforward and surgeon capabilities are more equitable across different approaches, cervical cancer surgery is quite different.
Early-stage cervical cancer primarily exerts radial growth into the cervical stroma and parametria. Curative surgical excision requires broadly negative margins through this tissue, a so called “radical hysterectomy.” The radicality of hysterectomy has been categorized in stages, acknowledging that different sized lesions require different volumes of parametrial resection to achieve adequate clearance from the tumor.6 In doing so, the surgeon must skeletonize and mobilize the distal ureters, cardinal ligament webs, and uterosacral ligaments. These structures are in close proximity to major vascular and neural structures. Hence, the radical hysterectomy is, without dispute, a technically challenging procedure.
Minimally invasive surgery further handicaps the surgeon by eliminating manual contact with tissue, and relying on complex instrumentation, electrosurgical modalities, and loss of haptics. The learning curve for MIS radical hysterectomy is further attenuated by their relative infrequency. Therefore, it makes sense that, when the MIS approach is randomly assigned to surgeons (such as in the LACC trial) or broadly and independently applied (as in the retrospective series), one might see variations in skill, quality, and outcomes, including oncologic outcomes.
The retrospective study by Melamed et al. acknowledged that surgeon skill and volume may contribute to their findings but stated that, because of the nature of their source data, they were unable to explain why they observed their results. The LACC trial attempted to overcome the issue of surgeon skill by ensuring all surgeons were from high-volume sites and had videos reviewed of their cases. However, the videos were chosen by the surgeons themselves and not available for audit in the study’s supplemental material. The LACC trial was conducted over a 9-year period across 33 sites and enrolled a total of 631 subjects. This equates to an enrollment of approximately two patients per site per year and either reflects extremely low-volume sites or highly selective patient enrollment. If the latter, what was different about the unenrolled patients and what was the preferred chosen route of surgery for them?
All 34 recurrences occurred in patients from just 14 of the 33 sites in the LACC trial. That means that less than half of the sites contributed to all of the recurrences. The authors provided no details on the specific sites, surgeons, or accrual rates in their manuscript or supplemental materials. Therefore, readers are unable to know what was different about those sites; whether they contributed the most patients and, therefore, the most recurrences; or whether they were low-volume sites with lower quality.
While margin status, positive or negative, was reported, there was no data captured regarding volume of resected parametrial tissue, or relative distance from tumor to margin, both of which might provide the reader with a better appraisal of surgeon proficiency and consistency in radicality of the two approaches. The incidence of locoregional (pelvic) recurrences were higher in the MIS arm, which is expected if there were inadequate margins around the laparoscopically resected tumors.
Finally, the authors of the LACC trial observed equivalent rates of postoperative complications between the laparotomy and MIS groups. The main virtue for MIS approaches is the reduction in perioperative morbidity. To observe no perioperative morbidity benefit in the MIS group is a red flag suggesting that these surgeons may not have achieved proficiency with the MIS approach.
Despite these arguments, the results of these studies should be taken seriously. Clearly, it is apparent that preservation of oncologic outcomes is not guaranteed with MIS radical hysterectomy, and it should not be the chosen approach for all patients and all surgeons. However, rather than entirely abandoning this less morbid approach, I would argue that it is a call to arms for gynecologic oncologists to self-evaluate. We should know our own data with respect to case volumes, perioperative complications, and cancer-related recurrence and death.
Perhaps MIS radical hysterectomies should be consolidated among high-volume surgeons with demonstrated good outcomes? Just as has been done for rectal cancer surgery with positive effect, we should establish accredited centers of excellence.7 We also need to improve the training of surgeons in novel, difficult techniques, as well as enhance the sophistication of MIS equipment such as improved instrumentation, haptics, and vision-guided surgery (for example, real-time intraoperative assessment of the tumor margins).
Let’s not take a wholesale step backwards to the surgical approaches of a 100 years ago just because they are more straightforward. Let’s do a better job of advancing the quality of what we do for our patients in the future.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no conflicts of interest. Email Dr. Rossi at obnews@mdedge.com.
Shock waves moved through the gynecologic oncology world on Oct. 31, 2018, when the New England Journal of Medicine published two papers on survival outcomes for women undergoing surgery for early stage cervical cancer.
Dr. Emma C. Rossi
The first was a randomized controlled trial of laparotomy and minimally invasive surgery (MIS) for radical hysterectomy called the LACC trial.1 In the multicenter, international trial of 631 women, the primary objective was disease-specific survival (cervical cancer–related deaths) and was powered to detect noninferiority of the MIS approach when compared with laparotomy. The trial was closed early when investigators noted a lower than expected rate of 3-year, disease-free survival (91% vs. 97%) from cervical cancer in the MIS group, which was made up of 84% laparoscopic and 16% robotic approaches, versus laparotomy. There were 19 deaths in the MIS group observed versus three in the laparotomy group. The conclusions of the trial were that MIS surgery is associated with inferior cervical cancer survival.
In the second study, authors analyzed data from large U.S. databases – the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) Program – to collect all-cause mortality for patients with early-stage cervical cancer who had undergone radical hysterectomy during 2010-2013.2 Among 2,461 observed results, 1,225 had undergone MIS surgery with the majority (79.8%) via robotic-assistance. Women undergoing MIS approaches had smaller, lower grade tumors; were more likely to be white, privately insured, and of a higher income; and had surgery later in the cohort and by nonacademic centers. The researchers adjusted for risk factors with an analytic process called propensity-score weighting, which matched the groups more closely in an attempt to minimize confounders. They identified higher all-cause mortality among women who were treated with an MIS approach, compared with those treated with laparotomy (hazard ratio, 1.65). They also observed a significant decline in the survival from cervical cancer annually that corresponded to the uptake of MIS radical hysterectomies.
In the wake of these publications, many concluded that gynecologic oncologists should no longer offer a minimally invasive approach for radical hysterectomy. Certainly level I evidence published in a highly influential journal is compelling, and the consistency in findings over two studies adds further weight to the results. However, was this the correct conclusion to draw from these results? Surgeons who had been performing MIS radical hysterectomies for many years with favorable outcomes are challenging this and are raising questions about external generalizability and whether these findings were driven by the surgery itself or by the surgeon.
The studies’ authors proposed hypotheses for their results that implicate the surgical route rather than the surgeon; however, these seem ad hoc and not well supported by data, including the authors’ own data. The first was the hypothesis that cervical tumors were being disrupted and disseminated through the use of uterine manipulators in MIS approaches. However, cervical cancers are fairly routinely “disrupted” by preoperative cone biopsies, loop electrosurgical excision procedures (LEEP), and sharp biopsies, which are arguably more invasive than placement of a manipulator. Uterine manipulators routinely are used in endometrial cancer surgeries, in which the manipulator is embedded within the tumor, without an associated negative survival effect in randomized trials.3 Additionally, not all surgeons utilize manipulators for radical hysterectomies, and these studies did not measure or report on their use; therefore, it is impossible to know whether, and by what magnitude, manipulators played a role. Finally, if uterine manipulators are the explanation for inferior survival, surely the recommendation should be to discourage their use, rather than abandon the MIS approach all together.
The other explanation offered was exposure of the tumor to CO2 gas. This seems an even less plausible explanation because CO2 gas is routinely used in MIS cancer surgeries for endometrial, prostate, gastric, and colorectal surgeries and is used as insufflation for malignant interventional endoscopies without a significant deleterious effect. Additionally, the cervix is not exposed to CO2 until colpotomy at the procedure’s end – and only briefly. The in vitro studies implicating a negative effect of simulated CO2 pneumoperitoneum are neither compelling nor consistent.4,5
I would like to propose another hypothesis for the results: surgical proficiency. Surgery, unlike medical interventions, is not a simple variable that is dichotomous – performed or not. Surgeons do not randomly select operative approaches for patients. We select surgical approaches based on patients’ circumstances and surgeon factors, including our own mastery of the various techniques. Randomized surgical trials rely on the notion that a surgeon is equally skilled in both or all approaches offered, but this is clearly not the case, and any surgeon recognizes this if he or she has observed more than one surgeon or has attempted a procedure via different routes. While some procedures, such as extrafascial hysterectomy for endometrial cancer, are relatively straightforward and surgeon capabilities are more equitable across different approaches, cervical cancer surgery is quite different.
Early-stage cervical cancer primarily exerts radial growth into the cervical stroma and parametria. Curative surgical excision requires broadly negative margins through this tissue, a so called “radical hysterectomy.” The radicality of hysterectomy has been categorized in stages, acknowledging that different sized lesions require different volumes of parametrial resection to achieve adequate clearance from the tumor.6 In doing so, the surgeon must skeletonize and mobilize the distal ureters, cardinal ligament webs, and uterosacral ligaments. These structures are in close proximity to major vascular and neural structures. Hence, the radical hysterectomy is, without dispute, a technically challenging procedure.
Minimally invasive surgery further handicaps the surgeon by eliminating manual contact with tissue, and relying on complex instrumentation, electrosurgical modalities, and loss of haptics. The learning curve for MIS radical hysterectomy is further attenuated by their relative infrequency. Therefore, it makes sense that, when the MIS approach is randomly assigned to surgeons (such as in the LACC trial) or broadly and independently applied (as in the retrospective series), one might see variations in skill, quality, and outcomes, including oncologic outcomes.
The retrospective study by Melamed et al. acknowledged that surgeon skill and volume may contribute to their findings but stated that, because of the nature of their source data, they were unable to explain why they observed their results. The LACC trial attempted to overcome the issue of surgeon skill by ensuring all surgeons were from high-volume sites and had videos reviewed of their cases. However, the videos were chosen by the surgeons themselves and not available for audit in the study’s supplemental material. The LACC trial was conducted over a 9-year period across 33 sites and enrolled a total of 631 subjects. This equates to an enrollment of approximately two patients per site per year and either reflects extremely low-volume sites or highly selective patient enrollment. If the latter, what was different about the unenrolled patients and what was the preferred chosen route of surgery for them?
All 34 recurrences occurred in patients from just 14 of the 33 sites in the LACC trial. That means that less than half of the sites contributed to all of the recurrences. The authors provided no details on the specific sites, surgeons, or accrual rates in their manuscript or supplemental materials. Therefore, readers are unable to know what was different about those sites; whether they contributed the most patients and, therefore, the most recurrences; or whether they were low-volume sites with lower quality.
While margin status, positive or negative, was reported, there was no data captured regarding volume of resected parametrial tissue, or relative distance from tumor to margin, both of which might provide the reader with a better appraisal of surgeon proficiency and consistency in radicality of the two approaches. The incidence of locoregional (pelvic) recurrences were higher in the MIS arm, which is expected if there were inadequate margins around the laparoscopically resected tumors.
Finally, the authors of the LACC trial observed equivalent rates of postoperative complications between the laparotomy and MIS groups. The main virtue for MIS approaches is the reduction in perioperative morbidity. To observe no perioperative morbidity benefit in the MIS group is a red flag suggesting that these surgeons may not have achieved proficiency with the MIS approach.
Despite these arguments, the results of these studies should be taken seriously. Clearly, it is apparent that preservation of oncologic outcomes is not guaranteed with MIS radical hysterectomy, and it should not be the chosen approach for all patients and all surgeons. However, rather than entirely abandoning this less morbid approach, I would argue that it is a call to arms for gynecologic oncologists to self-evaluate. We should know our own data with respect to case volumes, perioperative complications, and cancer-related recurrence and death.
Perhaps MIS radical hysterectomies should be consolidated among high-volume surgeons with demonstrated good outcomes? Just as has been done for rectal cancer surgery with positive effect, we should establish accredited centers of excellence.7 We also need to improve the training of surgeons in novel, difficult techniques, as well as enhance the sophistication of MIS equipment such as improved instrumentation, haptics, and vision-guided surgery (for example, real-time intraoperative assessment of the tumor margins).
Let’s not take a wholesale step backwards to the surgical approaches of a 100 years ago just because they are more straightforward. Let’s do a better job of advancing the quality of what we do for our patients in the future.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no conflicts of interest. Email Dr. Rossi at obnews@mdedge.com.
Quality in medicine is a peculiar thing. It is clearly apparent, and yet, can be very difficult to measure and quantify. Surgery, a performance art of sorts, can be even more challenging to qualify or rate. However, as a means to elevate the quality of care for all patients, hospital systems and care providers have aggressively made attempts to do so. This is a noble objective.
U.S. Air Force photo by Staff Sgt. Ciara Gosier
In September 2018, the Committee of Gynecologic Practice of the American College of Obstetricians and Gynecologists released ACOG Committee Opinion Number 750, titled, “Perioperative Pathways: Enhanced Recovery After Surgery.”1
The goals of this committee opinion were to advocate for gynecologic surgeons using the “ERAS” pathways in their perioperative care as part of an evidenced-based approach to quality improvement. ERAS pathways have been previously discussed in this column and feature bundled perioperative pathways that incorporate various concepts such as avoidance of prolonged preoperative fasting, early postoperative feeding, multimodal analgesia (with an avoidance of opiates), and inclusion of antibiotic and antiembolic prophylaxis, among other elements.
What was alarming upon closer review of this ACOG Committee Opinion was its omission of the randomized controlled trial by Dickson et al., the only randomized trial published in gynecologic surgery evaluating ERAS pathways.2 This trial compared the length of stay for patients receiving laparotomy for gynecologic cancer surgery who received perioperative care according the ERAS pathway versus those who received standard perioperative care. They found no difference in length of stay – the primary outcome – between the two groups, an impressive 3 days for both. The secondary outcome of postoperative pain was improved for the ERAS group for some of the time points. It was likely that the excellent outcomes in both groups resulted from a Hawthorne effect in which the behavior of study participants is influenced by the fact that they were being observed, in addition to the fact that the physicians involved in the study already were practicing high quality care as part of their “standard” regimen. It simply may be that the act of trying to improve quality is what improves outcomes, not a specific pathway. As senior author, Dr. Peter A. Argenta, explained to me, many of the ERAS elements are “simply good medicine.”
ERAS pathways are an example of process measures of quality. They include elements of care or processes in the delivery of care that are thought to be associated with improved outcomes. Prescription of antibiotics or venous thromboembolism (VTE) prophylaxis are other examples of process measures thought to be associated with improved surgical quality. Rather than rating surgeons’ outcomes (surgical site infection), surgeons are rated on their compliance with a process (the rate of appropriate perioperative antibiotic prescription). However, high compliance with these processes is not automatically associated with improved observed outcomes. For example, hospitals that meet the definition of high quality by virtue of structural measures (such as procedural volume and use of hospital-level quality initiatives) are associated with worse risk-adjusted VTE rates despite demonstrating higher adherence to VTE prophylaxis.3 This is felt to be a function of surveillance bias and the fact that these same hospitals have better capabilities to capture events as part of a feedback mechanism built into their quality initiatives.
What ERAS has favorably done for surgical care is to shine a glaring light on and challenge the unnecessary, old-fashioned, and non–patient-centric interventions that were considered dogma by many. For example, minimizing preoperative fasting is most certainly a patient-friendly adjustment that should absolutely be embraced, regardless of whether or not it speeds up time to discharge. Multimodal approaches to analgesia consistently have been shown to preserve or improve postoperative pain levels with a focus on minimizing opiate use, once again a noble and patient-centered objective.
However, all too many surgical quality interventions focus on their ability to reduce postoperative length of stay. Length of stay is an important driver of health care cost, and an indirect measure of perioperative complications; however, it is not a patient-centered outcome. So long as patients recover from their surgery quickly with respect to pain and function, the location of that recovery (home versus hospital) is less of a focus for most patients. In addition, in the pursuit of shorter hospital stays and less perioperative morbidity, we may encourage practices with unintentional adverse patient-centered outcomes. For example, to preserve a surgeon’s quality metrics, patients who are at high risk for complications may not be offered surgery at all. Long-term ovarian cancer outcomes, such as survival, can be negatively impacted when surgeons opt for less morbid, less radical surgical approaches which have favorable short-term morbidity such as surgical complications and readmissions.4
Ultimately we are most likely to see improvement in quality with a complex, nuanced approach to metrics, not simplistic interventions or pathways. We should recognize interventions that are consistently associated with better outcomes such as high procedural volume, consolidating less common procedures to fewer surgeons, data ascertainment, and reporting data to surgeons.5 Physicians need to take ownership and involvement in the quality metrics that are created to assess the care we provide. Hospital administrators may not fully understand the confounders, such as comorbidities, that contribute to outcomes, which can lead to mischaracterization, cause unfair comparisons between surgeons, or create unintentional incentives that are not patient-centered.6
Dr. Emma C. Rossi
We all need to understand the epidemiologic science behind evidence-based medicine and to be sophisticated in our ability to review and appraise data so that we can be sensible in what interventions we promote as supported by good evidence. If we fail to correctly identify and characterize what is truly good quality, if we miss the point of what is driving outcomes, or overstate the value of certain interventions, we miss the opportunity to intervene in ways that actually do make a meaningful difference.
Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no conflicts of interest. Email Dr. Rossi at obnews@mdedge.com.
Quality in medicine is a peculiar thing. It is clearly apparent, and yet, can be very difficult to measure and quantify. Surgery, a performance art of sorts, can be even more challenging to qualify or rate. However, as a means to elevate the quality of care for all patients, hospital systems and care providers have aggressively made attempts to do so. This is a noble objective.
U.S. Air Force photo by Staff Sgt. Ciara Gosier
In September 2018, the Committee of Gynecologic Practice of the American College of Obstetricians and Gynecologists released ACOG Committee Opinion Number 750, titled, “Perioperative Pathways: Enhanced Recovery After Surgery.”1
The goals of this committee opinion were to advocate for gynecologic surgeons using the “ERAS” pathways in their perioperative care as part of an evidenced-based approach to quality improvement. ERAS pathways have been previously discussed in this column and feature bundled perioperative pathways that incorporate various concepts such as avoidance of prolonged preoperative fasting, early postoperative feeding, multimodal analgesia (with an avoidance of opiates), and inclusion of antibiotic and antiembolic prophylaxis, among other elements.
What was alarming upon closer review of this ACOG Committee Opinion was its omission of the randomized controlled trial by Dickson et al., the only randomized trial published in gynecologic surgery evaluating ERAS pathways.2 This trial compared the length of stay for patients receiving laparotomy for gynecologic cancer surgery who received perioperative care according the ERAS pathway versus those who received standard perioperative care. They found no difference in length of stay – the primary outcome – between the two groups, an impressive 3 days for both. The secondary outcome of postoperative pain was improved for the ERAS group for some of the time points. It was likely that the excellent outcomes in both groups resulted from a Hawthorne effect in which the behavior of study participants is influenced by the fact that they were being observed, in addition to the fact that the physicians involved in the study already were practicing high quality care as part of their “standard” regimen. It simply may be that the act of trying to improve quality is what improves outcomes, not a specific pathway. As senior author, Dr. Peter A. Argenta, explained to me, many of the ERAS elements are “simply good medicine.”
ERAS pathways are an example of process measures of quality. They include elements of care or processes in the delivery of care that are thought to be associated with improved outcomes. Prescription of antibiotics or venous thromboembolism (VTE) prophylaxis are other examples of process measures thought to be associated with improved surgical quality. Rather than rating surgeons’ outcomes (surgical site infection), surgeons are rated on their compliance with a process (the rate of appropriate perioperative antibiotic prescription). However, high compliance with these processes is not automatically associated with improved observed outcomes. For example, hospitals that meet the definition of high quality by virtue of structural measures (such as procedural volume and use of hospital-level quality initiatives) are associated with worse risk-adjusted VTE rates despite demonstrating higher adherence to VTE prophylaxis.3 This is felt to be a function of surveillance bias and the fact that these same hospitals have better capabilities to capture events as part of a feedback mechanism built into their quality initiatives.
What ERAS has favorably done for surgical care is to shine a glaring light on and challenge the unnecessary, old-fashioned, and non–patient-centric interventions that were considered dogma by many. For example, minimizing preoperative fasting is most certainly a patient-friendly adjustment that should absolutely be embraced, regardless of whether or not it speeds up time to discharge. Multimodal approaches to analgesia consistently have been shown to preserve or improve postoperative pain levels with a focus on minimizing opiate use, once again a noble and patient-centered objective.
However, all too many surgical quality interventions focus on their ability to reduce postoperative length of stay. Length of stay is an important driver of health care cost, and an indirect measure of perioperative complications; however, it is not a patient-centered outcome. So long as patients recover from their surgery quickly with respect to pain and function, the location of that recovery (home versus hospital) is less of a focus for most patients. In addition, in the pursuit of shorter hospital stays and less perioperative morbidity, we may encourage practices with unintentional adverse patient-centered outcomes. For example, to preserve a surgeon’s quality metrics, patients who are at high risk for complications may not be offered surgery at all. Long-term ovarian cancer outcomes, such as survival, can be negatively impacted when surgeons opt for less morbid, less radical surgical approaches which have favorable short-term morbidity such as surgical complications and readmissions.4
Ultimately we are most likely to see improvement in quality with a complex, nuanced approach to metrics, not simplistic interventions or pathways. We should recognize interventions that are consistently associated with better outcomes such as high procedural volume, consolidating less common procedures to fewer surgeons, data ascertainment, and reporting data to surgeons.5 Physicians need to take ownership and involvement in the quality metrics that are created to assess the care we provide. Hospital administrators may not fully understand the confounders, such as comorbidities, that contribute to outcomes, which can lead to mischaracterization, cause unfair comparisons between surgeons, or create unintentional incentives that are not patient-centered.6
Dr. Emma C. Rossi
We all need to understand the epidemiologic science behind evidence-based medicine and to be sophisticated in our ability to review and appraise data so that we can be sensible in what interventions we promote as supported by good evidence. If we fail to correctly identify and characterize what is truly good quality, if we miss the point of what is driving outcomes, or overstate the value of certain interventions, we miss the opportunity to intervene in ways that actually do make a meaningful difference.
Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no conflicts of interest. Email Dr. Rossi at obnews@mdedge.com.
Quality in medicine is a peculiar thing. It is clearly apparent, and yet, can be very difficult to measure and quantify. Surgery, a performance art of sorts, can be even more challenging to qualify or rate. However, as a means to elevate the quality of care for all patients, hospital systems and care providers have aggressively made attempts to do so. This is a noble objective.
U.S. Air Force photo by Staff Sgt. Ciara Gosier
In September 2018, the Committee of Gynecologic Practice of the American College of Obstetricians and Gynecologists released ACOG Committee Opinion Number 750, titled, “Perioperative Pathways: Enhanced Recovery After Surgery.”1
The goals of this committee opinion were to advocate for gynecologic surgeons using the “ERAS” pathways in their perioperative care as part of an evidenced-based approach to quality improvement. ERAS pathways have been previously discussed in this column and feature bundled perioperative pathways that incorporate various concepts such as avoidance of prolonged preoperative fasting, early postoperative feeding, multimodal analgesia (with an avoidance of opiates), and inclusion of antibiotic and antiembolic prophylaxis, among other elements.
What was alarming upon closer review of this ACOG Committee Opinion was its omission of the randomized controlled trial by Dickson et al., the only randomized trial published in gynecologic surgery evaluating ERAS pathways.2 This trial compared the length of stay for patients receiving laparotomy for gynecologic cancer surgery who received perioperative care according the ERAS pathway versus those who received standard perioperative care. They found no difference in length of stay – the primary outcome – between the two groups, an impressive 3 days for both. The secondary outcome of postoperative pain was improved for the ERAS group for some of the time points. It was likely that the excellent outcomes in both groups resulted from a Hawthorne effect in which the behavior of study participants is influenced by the fact that they were being observed, in addition to the fact that the physicians involved in the study already were practicing high quality care as part of their “standard” regimen. It simply may be that the act of trying to improve quality is what improves outcomes, not a specific pathway. As senior author, Dr. Peter A. Argenta, explained to me, many of the ERAS elements are “simply good medicine.”
ERAS pathways are an example of process measures of quality. They include elements of care or processes in the delivery of care that are thought to be associated with improved outcomes. Prescription of antibiotics or venous thromboembolism (VTE) prophylaxis are other examples of process measures thought to be associated with improved surgical quality. Rather than rating surgeons’ outcomes (surgical site infection), surgeons are rated on their compliance with a process (the rate of appropriate perioperative antibiotic prescription). However, high compliance with these processes is not automatically associated with improved observed outcomes. For example, hospitals that meet the definition of high quality by virtue of structural measures (such as procedural volume and use of hospital-level quality initiatives) are associated with worse risk-adjusted VTE rates despite demonstrating higher adherence to VTE prophylaxis.3 This is felt to be a function of surveillance bias and the fact that these same hospitals have better capabilities to capture events as part of a feedback mechanism built into their quality initiatives.
What ERAS has favorably done for surgical care is to shine a glaring light on and challenge the unnecessary, old-fashioned, and non–patient-centric interventions that were considered dogma by many. For example, minimizing preoperative fasting is most certainly a patient-friendly adjustment that should absolutely be embraced, regardless of whether or not it speeds up time to discharge. Multimodal approaches to analgesia consistently have been shown to preserve or improve postoperative pain levels with a focus on minimizing opiate use, once again a noble and patient-centered objective.
However, all too many surgical quality interventions focus on their ability to reduce postoperative length of stay. Length of stay is an important driver of health care cost, and an indirect measure of perioperative complications; however, it is not a patient-centered outcome. So long as patients recover from their surgery quickly with respect to pain and function, the location of that recovery (home versus hospital) is less of a focus for most patients. In addition, in the pursuit of shorter hospital stays and less perioperative morbidity, we may encourage practices with unintentional adverse patient-centered outcomes. For example, to preserve a surgeon’s quality metrics, patients who are at high risk for complications may not be offered surgery at all. Long-term ovarian cancer outcomes, such as survival, can be negatively impacted when surgeons opt for less morbid, less radical surgical approaches which have favorable short-term morbidity such as surgical complications and readmissions.4
Ultimately we are most likely to see improvement in quality with a complex, nuanced approach to metrics, not simplistic interventions or pathways. We should recognize interventions that are consistently associated with better outcomes such as high procedural volume, consolidating less common procedures to fewer surgeons, data ascertainment, and reporting data to surgeons.5 Physicians need to take ownership and involvement in the quality metrics that are created to assess the care we provide. Hospital administrators may not fully understand the confounders, such as comorbidities, that contribute to outcomes, which can lead to mischaracterization, cause unfair comparisons between surgeons, or create unintentional incentives that are not patient-centered.6
Dr. Emma C. Rossi
We all need to understand the epidemiologic science behind evidence-based medicine and to be sophisticated in our ability to review and appraise data so that we can be sensible in what interventions we promote as supported by good evidence. If we fail to correctly identify and characterize what is truly good quality, if we miss the point of what is driving outcomes, or overstate the value of certain interventions, we miss the opportunity to intervene in ways that actually do make a meaningful difference.
Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no conflicts of interest. Email Dr. Rossi at obnews@mdedge.com.
Vaginal intraepithelial neoplasia (VAIN) is a condition that frequently poses therapeutic dilemmas for gynecologists. VAIN represents dysplastic changes to the epithelium of the vaginal mucosa, and like cervical neoplasia, the extent of disease is characterized as levels I, II, or III dependent upon the depth of involvement in the epithelial layer by dysplastic cells. While VAIN itself typically is asymptomatic and not a harmful condition, it carries a 12% risk of progression to invasive vaginal carcinoma, so accurate identification, thorough treatment, and ongoing surveillance are essential.1
Dr. Emma C. Rossi
VAIN is associated with high-risk human papillomavirus (HPV) infection, tobacco use, and prior cervical dysplasia. Of women with VAIN, 65% have undergone a prior hysterectomy for cervical dysplasia, which emphasizes the nondefinitive nature of such an intervention.2 These women should be very closely followed for at least 20 years with vaginal cytologic and/or HPV surveillance. High-risk HPV infection is present in 85% of women with VAIN, and the presence of high-risk HPV is a predictor for recurrent VAIN. Recurrent and persistent VAIN also is more common in postmenopausal women and those with multifocal disease.
The most common location for VAIN is at the upper third of the vagina (including the vaginal cuff). It commonly arises within the vaginal fornices, which may be difficult to fully visualize because of their puckered appearance, redundant vaginal tissues, and extensive vaginal rogation.
A diagnosis of VAIN is typically obtained from vaginal cytology which reveals atypical or dysplastic cells. Such a result should prompt the physician to perform vaginal colposcopy and directed biopsies. Comprehensive visualization of the vaginal cuff can be limited in cases where the vaginal fornices are tethered, deeply puckered, or when there is significant mucosal rogation.
The application of 4% acetic acid or Lugol’s iodine are techniques that can enhance the detection of dysplastic vaginal mucosa. Lugol’s iodine selectively stains normal, glycogenated cells, and spares dysplastic glycogen-free cells. The sharp contrast between the brown iodine-stained tissues and the white dysplastic tissues aids in detection of dysplastic areas.
If colposcopic biopsy reveals low grade dysplasia (VAIN I) it does not require intervention, and has a very low rate of conversion to invasive vaginal carcinoma. However moderate- and high-grade vaginal dysplastic lesions should be treated because of the potential for malignant transformation.
Options for treatment of VAIN include topical, ablative, and excisional procedures. Observation also is an option but should be reserved for patients who are closely monitored with repeated colposcopic examinations, and probably should best be reserved for patients with VAIN I or II lesions.
Excisional procedures
The most common excisional procedure employed for VAIN is upper vaginectomy. In this procedure, the surgeon grasps and tents up the vaginal mucosa, incises the mucosa without penetrating the subepithelial tissue layers such as bladder and rectum. The vaginal mucosa then is carefully separated from the underlying endopelvic fascial plane. The specimen should be oriented, ideally on a cork board, with pins or sutures to ascribe margins and borders. Excision is best utilized for women with unifocal disease, or those who fail or do not tolerate ablative or topical interventions.
The most significant risks of excision include the potential for damage to underlying pelvic visceral structures, which is particularly concerning in postmenopausal women with thin vaginal epithelium. Vaginectomy is commonly associated with vaginal shortening or narrowing, which can be deleterious for quality of life. Retrospective series have described a 30% incidence of recurrence after vaginectomy, likely secondary to incomplete excision of all affected tissue.3
Ablation
Ablation of dysplastic foci with a carbon dioxide (CO2) laser is a common method for treatment of VAIN. CO2 laser should ablate tissue to a 1.5 mm minimum depth.3 The benefit of using CO2 laser is its ability to treat multifocal disease in situ without an extensive excisional procedure.
It is technically more straightforward than upper vaginectomy with less blood loss and shorter surgical times, and it can be easily accomplished in an outpatient surgical or office setting. However, one of its greatest limitations is the difficulty in visualizing all lesions and therefore adequately treating all sites. The vaginal rogations also make adequate laser ablation challenging because laser only is able to effectively ablate tissue that is oriented perpendicular to the laser beam.
In addition, there is no pathologic confirmation of adequacy of excision or margin status. These features may contribute to the modestly higher rates of recurrence of dysplasia following laser ablation, compared with vaginectomy.3 It also has been associated with more vaginal scarring than vaginectomy, which can have a negative effect on sexual health.
Topical agents
The most commonly utilized topical therapy for VAIN is the antimetabolite chemotherapeutic agent 5-fluorouracil (5FU). A typical schedule for 5FU treatment is to apply vaginally, at night, once a week for 8 weeks.4 Because it can cause extensive irritation to the vulvar and urethral epithelium, patients are recommended to apply barrier creams or ointments before and following the use of 5FU for several days, wash hands thoroughly after application, and to rinse and shower in the morning after rising. Severe irritation occurs in up to 16% of patients, but in general it is very well tolerated.
Its virtue is that it is able to conform and travel to all parts of the vaginal mucosa, including those that are poorly visualized within the fornices or vaginal folds. 5FU does not require a hospitalization or surgical procedure, can be applied by the patient at home, and preserves vaginal length and function. In recent reports, 5FU is associated with the lowest rates of recurrence (10%-30%), compared with excision or ablation, and therefore is a very attractive option for primary therapy.3 However, it requires patients to have a degree of comfort with vaginal application of drug and adherence with perineal care strategies to minimize the likelihood of toxicity.
The immune response modifier, imiquimod, that is commonly used in the treatment of vulvar dysplasia also has been described in the treatment of VAIN. It appears to have high rates of clearance (greater than 75%) and be most effective in the treatment of VAIN I.5 It requires application under colposcopic guidance three times a week for 8 weeks, which is a laborious undertaking for both patient and physician. Like 5FU, imiquimod is associated with vulvar and perineal irritation.
Vaginal estrogens are an alternative topical therapy for moderate- and high-grade VAIN and particularly useful for postmenopausal patients. They have been associated with a high rate (up to 90%) of resolution on follow-up vaginal cytology testing and are not associated with toxicities of the above stated therapies.6 Vaginal estrogen can be used alone or in addition to other therapeutic strategies. For example, it can be added to the nontreatment days of 5FU or postoperatively prescribed following laser or excisional procedures.
Radiation
Intracavitary brachytherapy is a technique in which a radiation source is placed within a cylinder or ovoids and placed within the vagina.7 Typically 45 Gy is delivered to a depth 0.5mm below the vaginal mucosal surface (“point z”). Recurrence occurs is approximately 10%-15% of patients, and toxicities can be severe, including vaginal stenosis and ulceration. This aggressive therapy typically is best reserved for cases that are refractory to other therapies. Following radiation, subsequent treatments are more difficult because of radiation-induced changes to the vaginal mucosa that can affect healing.
Vaginal dysplasia is a relatively common sequelae of high-risk HPV, particularly among women who have had a prior hysterectomy for cervical dysplasia. Because of anatomic changes following hysterectomy, adequate visualization and comprehensive vaginal treatment is difficult. Therefore, surgeons should avoid utilization of hysterectomy as a routine strategy to “cure” dysplasia as it may fail to achieve this cure and make subsequent evaluations and treatments of persistent dysplasia more difficult. Women who have had a hysterectomy for dysplasia should be closely followed for several decades, and they should be counseled that they have a persistent risk for vaginal disease. When VAIN develops, clinicians should consider topical therapies as primary treatment options because they may minimize toxicity and have high rates of enduring response.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She had no relevant conflicts of interest.
Vaginal intraepithelial neoplasia (VAIN) is a condition that frequently poses therapeutic dilemmas for gynecologists. VAIN represents dysplastic changes to the epithelium of the vaginal mucosa, and like cervical neoplasia, the extent of disease is characterized as levels I, II, or III dependent upon the depth of involvement in the epithelial layer by dysplastic cells. While VAIN itself typically is asymptomatic and not a harmful condition, it carries a 12% risk of progression to invasive vaginal carcinoma, so accurate identification, thorough treatment, and ongoing surveillance are essential.1
Dr. Emma C. Rossi
VAIN is associated with high-risk human papillomavirus (HPV) infection, tobacco use, and prior cervical dysplasia. Of women with VAIN, 65% have undergone a prior hysterectomy for cervical dysplasia, which emphasizes the nondefinitive nature of such an intervention.2 These women should be very closely followed for at least 20 years with vaginal cytologic and/or HPV surveillance. High-risk HPV infection is present in 85% of women with VAIN, and the presence of high-risk HPV is a predictor for recurrent VAIN. Recurrent and persistent VAIN also is more common in postmenopausal women and those with multifocal disease.
The most common location for VAIN is at the upper third of the vagina (including the vaginal cuff). It commonly arises within the vaginal fornices, which may be difficult to fully visualize because of their puckered appearance, redundant vaginal tissues, and extensive vaginal rogation.
A diagnosis of VAIN is typically obtained from vaginal cytology which reveals atypical or dysplastic cells. Such a result should prompt the physician to perform vaginal colposcopy and directed biopsies. Comprehensive visualization of the vaginal cuff can be limited in cases where the vaginal fornices are tethered, deeply puckered, or when there is significant mucosal rogation.
The application of 4% acetic acid or Lugol’s iodine are techniques that can enhance the detection of dysplastic vaginal mucosa. Lugol’s iodine selectively stains normal, glycogenated cells, and spares dysplastic glycogen-free cells. The sharp contrast between the brown iodine-stained tissues and the white dysplastic tissues aids in detection of dysplastic areas.
If colposcopic biopsy reveals low grade dysplasia (VAIN I) it does not require intervention, and has a very low rate of conversion to invasive vaginal carcinoma. However moderate- and high-grade vaginal dysplastic lesions should be treated because of the potential for malignant transformation.
Options for treatment of VAIN include topical, ablative, and excisional procedures. Observation also is an option but should be reserved for patients who are closely monitored with repeated colposcopic examinations, and probably should best be reserved for patients with VAIN I or II lesions.
Excisional procedures
The most common excisional procedure employed for VAIN is upper vaginectomy. In this procedure, the surgeon grasps and tents up the vaginal mucosa, incises the mucosa without penetrating the subepithelial tissue layers such as bladder and rectum. The vaginal mucosa then is carefully separated from the underlying endopelvic fascial plane. The specimen should be oriented, ideally on a cork board, with pins or sutures to ascribe margins and borders. Excision is best utilized for women with unifocal disease, or those who fail or do not tolerate ablative or topical interventions.
The most significant risks of excision include the potential for damage to underlying pelvic visceral structures, which is particularly concerning in postmenopausal women with thin vaginal epithelium. Vaginectomy is commonly associated with vaginal shortening or narrowing, which can be deleterious for quality of life. Retrospective series have described a 30% incidence of recurrence after vaginectomy, likely secondary to incomplete excision of all affected tissue.3
Ablation
Ablation of dysplastic foci with a carbon dioxide (CO2) laser is a common method for treatment of VAIN. CO2 laser should ablate tissue to a 1.5 mm minimum depth.3 The benefit of using CO2 laser is its ability to treat multifocal disease in situ without an extensive excisional procedure.
It is technically more straightforward than upper vaginectomy with less blood loss and shorter surgical times, and it can be easily accomplished in an outpatient surgical or office setting. However, one of its greatest limitations is the difficulty in visualizing all lesions and therefore adequately treating all sites. The vaginal rogations also make adequate laser ablation challenging because laser only is able to effectively ablate tissue that is oriented perpendicular to the laser beam.
In addition, there is no pathologic confirmation of adequacy of excision or margin status. These features may contribute to the modestly higher rates of recurrence of dysplasia following laser ablation, compared with vaginectomy.3 It also has been associated with more vaginal scarring than vaginectomy, which can have a negative effect on sexual health.
Topical agents
The most commonly utilized topical therapy for VAIN is the antimetabolite chemotherapeutic agent 5-fluorouracil (5FU). A typical schedule for 5FU treatment is to apply vaginally, at night, once a week for 8 weeks.4 Because it can cause extensive irritation to the vulvar and urethral epithelium, patients are recommended to apply barrier creams or ointments before and following the use of 5FU for several days, wash hands thoroughly after application, and to rinse and shower in the morning after rising. Severe irritation occurs in up to 16% of patients, but in general it is very well tolerated.
Its virtue is that it is able to conform and travel to all parts of the vaginal mucosa, including those that are poorly visualized within the fornices or vaginal folds. 5FU does not require a hospitalization or surgical procedure, can be applied by the patient at home, and preserves vaginal length and function. In recent reports, 5FU is associated with the lowest rates of recurrence (10%-30%), compared with excision or ablation, and therefore is a very attractive option for primary therapy.3 However, it requires patients to have a degree of comfort with vaginal application of drug and adherence with perineal care strategies to minimize the likelihood of toxicity.
The immune response modifier, imiquimod, that is commonly used in the treatment of vulvar dysplasia also has been described in the treatment of VAIN. It appears to have high rates of clearance (greater than 75%) and be most effective in the treatment of VAIN I.5 It requires application under colposcopic guidance three times a week for 8 weeks, which is a laborious undertaking for both patient and physician. Like 5FU, imiquimod is associated with vulvar and perineal irritation.
Vaginal estrogens are an alternative topical therapy for moderate- and high-grade VAIN and particularly useful for postmenopausal patients. They have been associated with a high rate (up to 90%) of resolution on follow-up vaginal cytology testing and are not associated with toxicities of the above stated therapies.6 Vaginal estrogen can be used alone or in addition to other therapeutic strategies. For example, it can be added to the nontreatment days of 5FU or postoperatively prescribed following laser or excisional procedures.
Radiation
Intracavitary brachytherapy is a technique in which a radiation source is placed within a cylinder or ovoids and placed within the vagina.7 Typically 45 Gy is delivered to a depth 0.5mm below the vaginal mucosal surface (“point z”). Recurrence occurs is approximately 10%-15% of patients, and toxicities can be severe, including vaginal stenosis and ulceration. This aggressive therapy typically is best reserved for cases that are refractory to other therapies. Following radiation, subsequent treatments are more difficult because of radiation-induced changes to the vaginal mucosa that can affect healing.
Vaginal dysplasia is a relatively common sequelae of high-risk HPV, particularly among women who have had a prior hysterectomy for cervical dysplasia. Because of anatomic changes following hysterectomy, adequate visualization and comprehensive vaginal treatment is difficult. Therefore, surgeons should avoid utilization of hysterectomy as a routine strategy to “cure” dysplasia as it may fail to achieve this cure and make subsequent evaluations and treatments of persistent dysplasia more difficult. Women who have had a hysterectomy for dysplasia should be closely followed for several decades, and they should be counseled that they have a persistent risk for vaginal disease. When VAIN develops, clinicians should consider topical therapies as primary treatment options because they may minimize toxicity and have high rates of enduring response.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She had no relevant conflicts of interest.
Vaginal intraepithelial neoplasia (VAIN) is a condition that frequently poses therapeutic dilemmas for gynecologists. VAIN represents dysplastic changes to the epithelium of the vaginal mucosa, and like cervical neoplasia, the extent of disease is characterized as levels I, II, or III dependent upon the depth of involvement in the epithelial layer by dysplastic cells. While VAIN itself typically is asymptomatic and not a harmful condition, it carries a 12% risk of progression to invasive vaginal carcinoma, so accurate identification, thorough treatment, and ongoing surveillance are essential.1
Dr. Emma C. Rossi
VAIN is associated with high-risk human papillomavirus (HPV) infection, tobacco use, and prior cervical dysplasia. Of women with VAIN, 65% have undergone a prior hysterectomy for cervical dysplasia, which emphasizes the nondefinitive nature of such an intervention.2 These women should be very closely followed for at least 20 years with vaginal cytologic and/or HPV surveillance. High-risk HPV infection is present in 85% of women with VAIN, and the presence of high-risk HPV is a predictor for recurrent VAIN. Recurrent and persistent VAIN also is more common in postmenopausal women and those with multifocal disease.
The most common location for VAIN is at the upper third of the vagina (including the vaginal cuff). It commonly arises within the vaginal fornices, which may be difficult to fully visualize because of their puckered appearance, redundant vaginal tissues, and extensive vaginal rogation.
A diagnosis of VAIN is typically obtained from vaginal cytology which reveals atypical or dysplastic cells. Such a result should prompt the physician to perform vaginal colposcopy and directed biopsies. Comprehensive visualization of the vaginal cuff can be limited in cases where the vaginal fornices are tethered, deeply puckered, or when there is significant mucosal rogation.
The application of 4% acetic acid or Lugol’s iodine are techniques that can enhance the detection of dysplastic vaginal mucosa. Lugol’s iodine selectively stains normal, glycogenated cells, and spares dysplastic glycogen-free cells. The sharp contrast between the brown iodine-stained tissues and the white dysplastic tissues aids in detection of dysplastic areas.
If colposcopic biopsy reveals low grade dysplasia (VAIN I) it does not require intervention, and has a very low rate of conversion to invasive vaginal carcinoma. However moderate- and high-grade vaginal dysplastic lesions should be treated because of the potential for malignant transformation.
Options for treatment of VAIN include topical, ablative, and excisional procedures. Observation also is an option but should be reserved for patients who are closely monitored with repeated colposcopic examinations, and probably should best be reserved for patients with VAIN I or II lesions.
Excisional procedures
The most common excisional procedure employed for VAIN is upper vaginectomy. In this procedure, the surgeon grasps and tents up the vaginal mucosa, incises the mucosa without penetrating the subepithelial tissue layers such as bladder and rectum. The vaginal mucosa then is carefully separated from the underlying endopelvic fascial plane. The specimen should be oriented, ideally on a cork board, with pins or sutures to ascribe margins and borders. Excision is best utilized for women with unifocal disease, or those who fail or do not tolerate ablative or topical interventions.
The most significant risks of excision include the potential for damage to underlying pelvic visceral structures, which is particularly concerning in postmenopausal women with thin vaginal epithelium. Vaginectomy is commonly associated with vaginal shortening or narrowing, which can be deleterious for quality of life. Retrospective series have described a 30% incidence of recurrence after vaginectomy, likely secondary to incomplete excision of all affected tissue.3
Ablation
Ablation of dysplastic foci with a carbon dioxide (CO2) laser is a common method for treatment of VAIN. CO2 laser should ablate tissue to a 1.5 mm minimum depth.3 The benefit of using CO2 laser is its ability to treat multifocal disease in situ without an extensive excisional procedure.
It is technically more straightforward than upper vaginectomy with less blood loss and shorter surgical times, and it can be easily accomplished in an outpatient surgical or office setting. However, one of its greatest limitations is the difficulty in visualizing all lesions and therefore adequately treating all sites. The vaginal rogations also make adequate laser ablation challenging because laser only is able to effectively ablate tissue that is oriented perpendicular to the laser beam.
In addition, there is no pathologic confirmation of adequacy of excision or margin status. These features may contribute to the modestly higher rates of recurrence of dysplasia following laser ablation, compared with vaginectomy.3 It also has been associated with more vaginal scarring than vaginectomy, which can have a negative effect on sexual health.
Topical agents
The most commonly utilized topical therapy for VAIN is the antimetabolite chemotherapeutic agent 5-fluorouracil (5FU). A typical schedule for 5FU treatment is to apply vaginally, at night, once a week for 8 weeks.4 Because it can cause extensive irritation to the vulvar and urethral epithelium, patients are recommended to apply barrier creams or ointments before and following the use of 5FU for several days, wash hands thoroughly after application, and to rinse and shower in the morning after rising. Severe irritation occurs in up to 16% of patients, but in general it is very well tolerated.
Its virtue is that it is able to conform and travel to all parts of the vaginal mucosa, including those that are poorly visualized within the fornices or vaginal folds. 5FU does not require a hospitalization or surgical procedure, can be applied by the patient at home, and preserves vaginal length and function. In recent reports, 5FU is associated with the lowest rates of recurrence (10%-30%), compared with excision or ablation, and therefore is a very attractive option for primary therapy.3 However, it requires patients to have a degree of comfort with vaginal application of drug and adherence with perineal care strategies to minimize the likelihood of toxicity.
The immune response modifier, imiquimod, that is commonly used in the treatment of vulvar dysplasia also has been described in the treatment of VAIN. It appears to have high rates of clearance (greater than 75%) and be most effective in the treatment of VAIN I.5 It requires application under colposcopic guidance three times a week for 8 weeks, which is a laborious undertaking for both patient and physician. Like 5FU, imiquimod is associated with vulvar and perineal irritation.
Vaginal estrogens are an alternative topical therapy for moderate- and high-grade VAIN and particularly useful for postmenopausal patients. They have been associated with a high rate (up to 90%) of resolution on follow-up vaginal cytology testing and are not associated with toxicities of the above stated therapies.6 Vaginal estrogen can be used alone or in addition to other therapeutic strategies. For example, it can be added to the nontreatment days of 5FU or postoperatively prescribed following laser or excisional procedures.
Radiation
Intracavitary brachytherapy is a technique in which a radiation source is placed within a cylinder or ovoids and placed within the vagina.7 Typically 45 Gy is delivered to a depth 0.5mm below the vaginal mucosal surface (“point z”). Recurrence occurs is approximately 10%-15% of patients, and toxicities can be severe, including vaginal stenosis and ulceration. This aggressive therapy typically is best reserved for cases that are refractory to other therapies. Following radiation, subsequent treatments are more difficult because of radiation-induced changes to the vaginal mucosa that can affect healing.
Vaginal dysplasia is a relatively common sequelae of high-risk HPV, particularly among women who have had a prior hysterectomy for cervical dysplasia. Because of anatomic changes following hysterectomy, adequate visualization and comprehensive vaginal treatment is difficult. Therefore, surgeons should avoid utilization of hysterectomy as a routine strategy to “cure” dysplasia as it may fail to achieve this cure and make subsequent evaluations and treatments of persistent dysplasia more difficult. Women who have had a hysterectomy for dysplasia should be closely followed for several decades, and they should be counseled that they have a persistent risk for vaginal disease. When VAIN develops, clinicians should consider topical therapies as primary treatment options because they may minimize toxicity and have high rates of enduring response.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She had no relevant conflicts of interest.
Cervical dysplasia is commonly diagnosed in women who have completed childbearing and don’t desire future fertility. While diagnostic and/or definitive therapy for cervical dysplasia can include hysterectomy, there are important considerations to make when offering this procedure to patients.
Dr. Emma C. Rossi
Pitfalls
Hysterectomy is commonly requested by patients upon learning of cervical dysplasia, particularly if they have chronic human papillomavirus (HPV) infection and have experienced years of frequent surveillance and interventions. They may see hysterectomy as an option to avoid this close surveillance and to be free of their dysplasia. There are two main concerns with offering hysterectomy as the primary surgical option for the management of dysplasia. Firstly, it may not be curative, and secondly, it may be an inadequate excisional procedure, particularly if the patient has occult invasive disease that has not been adequately diagnosed with a loop electrosurgical excision procedure (LEEP) or a cone biopsy procedure.
It is important to counsel these patients that surgery is not a treatment for high-risk HPV infection, which is the underlying etiology of their disease. With that etiology, HPV infection is likely to persist after hysterectomy and they may develop vaginal or vulvar dysplasia. Therefore, the American Society for Colposcopy and Cervical Pathology recommends that cytology and/or high-risk HPV surveillance continue following hysterectomy if that surgery was performed for dysplasia.1 Hysterectomy is not a means to avoid years of surveillance testing. Approximately 10% of women who have hysterectomy for cervical dysplasia develop vaginal dysplasia or cancer after surgery.2,3 This is similar to the likelihood of recurrent dysplasia after an alternative excisional procedure. In my experience, this diagnosis is often met with enormous frustration for the patient who thought that her hysterectomy would be the cure of her HPV-related disease. Thorough colposcopic evaluation of the vagina can be technically challenging after hysterectomy because of difficulty adequately visualizing lesions within the vaginal rugations, particularly within the puckered lateral vaginal fornices, the most common location for dysplasia.3 We will explore the diagnosis and treatment options for vaginal dysplasia further in a future column.
It is critical that, if patients are offered hysterectomy for treatment of cervical dysplasia, they are counseled that it may not be curative, that they will require long-term vaginal surveillance, and that they are at continued risk for vaginal and vulvar cancer.
An additional concern with performing hysterectomy for definitive management of cervical dysplasia is the concern that occult cancer may be missed preoperatively, and that the hysterectomy is inadequate surgical clearance of the disease. Approximately 2%-5% of patients with a high-grade squamous intraepithelial lesion or equivocal Pap test have occult cervical cancer.4 A similar proportion of patients with cervical intraepithelial neoplasia stage III or adenocarcinoma in situ on colposcopy biopsy have invasive carcinoma on evaluation of an excisional specimen.5 The traditional surgical approach has dictated that a modified (type II) or extended (type III) radical hysterectomy be performed in the setting of FIGO stage IA2 or greater cervical cancer. Radical hysterectomies remove parametrial tissue, effectively achieving a wider margin around the primary lesion. This is important because cervical cancer primarily spreads via direct extension.
The appropriate radicality of surgery for microscopic lesions is debated. It has been proposed that for very small, low-risk lesions, a traditional extrafascial hysterectomy or trachelectomy, or possibly even a large conization, may be adequate.6 However, this is controversial, and National Comprehensive Cancer Network guidelines still advocate for radical procedures for these lesions.7 Certainly an excisional procedure (LEEP or cone) should first be performed to define the size and histologic features of the lesion, and ideally, evaluation and counseling with a gynecologic oncologist should be performed prior to offering patients with a stage IA2 or greater lesion an extrafascial hysterectomy. Additionally, a separate decision would need to be made regarding the need for lymphadenectomy, as this is typically recommended for patients with stage IA2 or greater lesions.
Patients should be counseled that, if extrafascial (simple) hysterectomy is chosen as the primary excisional procedure, they may require additional therapy (additional surgery, or radiation and possibly chemotherapy) if cancer is found in the specimen and the parametrial margin is inadequate. Additionally, and of more concern, if the lesion is a bulky lesion extending into the parametrium and not recognized preoperatively, a “cut-through” hysterectomy will be inadvertently performed (in which margins are grossly positive). These situations typically feature heavy blood loss with patients at increased risk for immediate surgical complications. Postoperatively, prognosis is substantially worse for patients who have had a cut-through hysterectomy, compared stage for stage with patients who primarily received a radical procedure with negative margins or primary chemotherapy and radiation.8 Otherwise said, their risk for death is higher if this error is made. Therefore a thorough examination is essential prior to performing hysterectomy for dysplasia. Any suspicion of bulky cancer should be considered a contraindication for proceeding.
Preoperative evaluation
As a rule, no patient should transition directly from cytologic evaluation with Pap screening to hysterectomy. A colposcopic evaluation of the cervix and vagina accompanied with a thorough bimanual rectovaginal examination should always be performed first. Biopsies of the ectocervix and ideally the endocervix should be obtained because the accuracy of histology is greater than that of cytology. For patients with cervical intraepithelial neoplasia stage I lesions, hysterectomy is not appropriate, as these patients have an extremely low risk for the development of cervical cancer, and the risks and costs of hysterectomy are not justified in such a population.
Surgeons should wait at least 6 weeks following conization or LEEP before performing hysterectomy in order to minimize the likelihood of perioperative complications.9
Substituting LEEP or cone with hysterectomy
In general, it is the most prudent approach to first perform a diagnostic excision with LEEP or cone biopsy before proceeding with hysterectomy for definitive surgery. However, there may be some situations in which this is not feasible. In patients whose cervix is very small and flush with the vagina, an excisional procedure may not be technically possible without concern for damage to adjacent structures. In these patients, after a thorough exam has evaluated for gross disease, a hysterectomy may be the only way to adequately diagnose and treat high-grade dysplasia through excision. For patients with limited access to resources, transportation, or a concern for noncompliance with follow-up, surgeons may wish to offer patients primary hysterectomy rather than a staged procedure.
Hysterectomy remains a potential option for treatment of cervical dysplasia. However, patients should be made aware of the risks of undertreatment of occult cancers, the need for long-term surveillance testing, and the risk for future vaginal dysplasia or cancer. Ideally a comprehensive, stepwise assessment from cytology to colposcopy and examination to diagnostic excisional procedure will first take place to proceed safely with this approach.
References
1. Saslow D et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J Clin. 2012 May-Jun;62(3):147-72.
2. Schockaert S et al. Incidence of vaginal intraepithelial neoplasia after hysterectomy for cervical intraepithelial neoplasia: a retrospective study. Am J Obstet Gynecol. 2008 Aug;199(2):113.e1-5.
3. Kalogirou D et al. Vaginal intraepithelial neoplasia (VAIN) following hysterectomy in patients treated for carcinoma in situ of the cervix. Eur J Gynaecol Oncol. 1997;18(3):188-91.
5. Latif NA et al. Management of adenocarcinoma in situ of the uterine cervix: a comparison of loop electrosurgical excision procedure and cold knife conization. J Low Genit Tract Dis. 2015 Apr;19(2):97-102.
8. Barber HR et al. Operative management of patients previously operated upon for a benign lesion with cervical cancer as a surprise finding. Am J Obstet Gynecol. 1968 Aug 1;101(7):959-65.
9. Sullivan SA et al. Association between timing of cervical excision procedure to minimally invasive hysterectomy and surgical complications. Gynecol Oncol. 2017 Feb;144(2):294-298.
Cervical dysplasia is commonly diagnosed in women who have completed childbearing and don’t desire future fertility. While diagnostic and/or definitive therapy for cervical dysplasia can include hysterectomy, there are important considerations to make when offering this procedure to patients.
Dr. Emma C. Rossi
Pitfalls
Hysterectomy is commonly requested by patients upon learning of cervical dysplasia, particularly if they have chronic human papillomavirus (HPV) infection and have experienced years of frequent surveillance and interventions. They may see hysterectomy as an option to avoid this close surveillance and to be free of their dysplasia. There are two main concerns with offering hysterectomy as the primary surgical option for the management of dysplasia. Firstly, it may not be curative, and secondly, it may be an inadequate excisional procedure, particularly if the patient has occult invasive disease that has not been adequately diagnosed with a loop electrosurgical excision procedure (LEEP) or a cone biopsy procedure.
It is important to counsel these patients that surgery is not a treatment for high-risk HPV infection, which is the underlying etiology of their disease. With that etiology, HPV infection is likely to persist after hysterectomy and they may develop vaginal or vulvar dysplasia. Therefore, the American Society for Colposcopy and Cervical Pathology recommends that cytology and/or high-risk HPV surveillance continue following hysterectomy if that surgery was performed for dysplasia.1 Hysterectomy is not a means to avoid years of surveillance testing. Approximately 10% of women who have hysterectomy for cervical dysplasia develop vaginal dysplasia or cancer after surgery.2,3 This is similar to the likelihood of recurrent dysplasia after an alternative excisional procedure. In my experience, this diagnosis is often met with enormous frustration for the patient who thought that her hysterectomy would be the cure of her HPV-related disease. Thorough colposcopic evaluation of the vagina can be technically challenging after hysterectomy because of difficulty adequately visualizing lesions within the vaginal rugations, particularly within the puckered lateral vaginal fornices, the most common location for dysplasia.3 We will explore the diagnosis and treatment options for vaginal dysplasia further in a future column.
It is critical that, if patients are offered hysterectomy for treatment of cervical dysplasia, they are counseled that it may not be curative, that they will require long-term vaginal surveillance, and that they are at continued risk for vaginal and vulvar cancer.
An additional concern with performing hysterectomy for definitive management of cervical dysplasia is the concern that occult cancer may be missed preoperatively, and that the hysterectomy is inadequate surgical clearance of the disease. Approximately 2%-5% of patients with a high-grade squamous intraepithelial lesion or equivocal Pap test have occult cervical cancer.4 A similar proportion of patients with cervical intraepithelial neoplasia stage III or adenocarcinoma in situ on colposcopy biopsy have invasive carcinoma on evaluation of an excisional specimen.5 The traditional surgical approach has dictated that a modified (type II) or extended (type III) radical hysterectomy be performed in the setting of FIGO stage IA2 or greater cervical cancer. Radical hysterectomies remove parametrial tissue, effectively achieving a wider margin around the primary lesion. This is important because cervical cancer primarily spreads via direct extension.
The appropriate radicality of surgery for microscopic lesions is debated. It has been proposed that for very small, low-risk lesions, a traditional extrafascial hysterectomy or trachelectomy, or possibly even a large conization, may be adequate.6 However, this is controversial, and National Comprehensive Cancer Network guidelines still advocate for radical procedures for these lesions.7 Certainly an excisional procedure (LEEP or cone) should first be performed to define the size and histologic features of the lesion, and ideally, evaluation and counseling with a gynecologic oncologist should be performed prior to offering patients with a stage IA2 or greater lesion an extrafascial hysterectomy. Additionally, a separate decision would need to be made regarding the need for lymphadenectomy, as this is typically recommended for patients with stage IA2 or greater lesions.
Patients should be counseled that, if extrafascial (simple) hysterectomy is chosen as the primary excisional procedure, they may require additional therapy (additional surgery, or radiation and possibly chemotherapy) if cancer is found in the specimen and the parametrial margin is inadequate. Additionally, and of more concern, if the lesion is a bulky lesion extending into the parametrium and not recognized preoperatively, a “cut-through” hysterectomy will be inadvertently performed (in which margins are grossly positive). These situations typically feature heavy blood loss with patients at increased risk for immediate surgical complications. Postoperatively, prognosis is substantially worse for patients who have had a cut-through hysterectomy, compared stage for stage with patients who primarily received a radical procedure with negative margins or primary chemotherapy and radiation.8 Otherwise said, their risk for death is higher if this error is made. Therefore a thorough examination is essential prior to performing hysterectomy for dysplasia. Any suspicion of bulky cancer should be considered a contraindication for proceeding.
Preoperative evaluation
As a rule, no patient should transition directly from cytologic evaluation with Pap screening to hysterectomy. A colposcopic evaluation of the cervix and vagina accompanied with a thorough bimanual rectovaginal examination should always be performed first. Biopsies of the ectocervix and ideally the endocervix should be obtained because the accuracy of histology is greater than that of cytology. For patients with cervical intraepithelial neoplasia stage I lesions, hysterectomy is not appropriate, as these patients have an extremely low risk for the development of cervical cancer, and the risks and costs of hysterectomy are not justified in such a population.
Surgeons should wait at least 6 weeks following conization or LEEP before performing hysterectomy in order to minimize the likelihood of perioperative complications.9
Substituting LEEP or cone with hysterectomy
In general, it is the most prudent approach to first perform a diagnostic excision with LEEP or cone biopsy before proceeding with hysterectomy for definitive surgery. However, there may be some situations in which this is not feasible. In patients whose cervix is very small and flush with the vagina, an excisional procedure may not be technically possible without concern for damage to adjacent structures. In these patients, after a thorough exam has evaluated for gross disease, a hysterectomy may be the only way to adequately diagnose and treat high-grade dysplasia through excision. For patients with limited access to resources, transportation, or a concern for noncompliance with follow-up, surgeons may wish to offer patients primary hysterectomy rather than a staged procedure.
Hysterectomy remains a potential option for treatment of cervical dysplasia. However, patients should be made aware of the risks of undertreatment of occult cancers, the need for long-term surveillance testing, and the risk for future vaginal dysplasia or cancer. Ideally a comprehensive, stepwise assessment from cytology to colposcopy and examination to diagnostic excisional procedure will first take place to proceed safely with this approach.
References
1. Saslow D et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J Clin. 2012 May-Jun;62(3):147-72.
2. Schockaert S et al. Incidence of vaginal intraepithelial neoplasia after hysterectomy for cervical intraepithelial neoplasia: a retrospective study. Am J Obstet Gynecol. 2008 Aug;199(2):113.e1-5.
3. Kalogirou D et al. Vaginal intraepithelial neoplasia (VAIN) following hysterectomy in patients treated for carcinoma in situ of the cervix. Eur J Gynaecol Oncol. 1997;18(3):188-91.
5. Latif NA et al. Management of adenocarcinoma in situ of the uterine cervix: a comparison of loop electrosurgical excision procedure and cold knife conization. J Low Genit Tract Dis. 2015 Apr;19(2):97-102.
8. Barber HR et al. Operative management of patients previously operated upon for a benign lesion with cervical cancer as a surprise finding. Am J Obstet Gynecol. 1968 Aug 1;101(7):959-65.
9. Sullivan SA et al. Association between timing of cervical excision procedure to minimally invasive hysterectomy and surgical complications. Gynecol Oncol. 2017 Feb;144(2):294-298.
Cervical dysplasia is commonly diagnosed in women who have completed childbearing and don’t desire future fertility. While diagnostic and/or definitive therapy for cervical dysplasia can include hysterectomy, there are important considerations to make when offering this procedure to patients.
Dr. Emma C. Rossi
Pitfalls
Hysterectomy is commonly requested by patients upon learning of cervical dysplasia, particularly if they have chronic human papillomavirus (HPV) infection and have experienced years of frequent surveillance and interventions. They may see hysterectomy as an option to avoid this close surveillance and to be free of their dysplasia. There are two main concerns with offering hysterectomy as the primary surgical option for the management of dysplasia. Firstly, it may not be curative, and secondly, it may be an inadequate excisional procedure, particularly if the patient has occult invasive disease that has not been adequately diagnosed with a loop electrosurgical excision procedure (LEEP) or a cone biopsy procedure.
It is important to counsel these patients that surgery is not a treatment for high-risk HPV infection, which is the underlying etiology of their disease. With that etiology, HPV infection is likely to persist after hysterectomy and they may develop vaginal or vulvar dysplasia. Therefore, the American Society for Colposcopy and Cervical Pathology recommends that cytology and/or high-risk HPV surveillance continue following hysterectomy if that surgery was performed for dysplasia.1 Hysterectomy is not a means to avoid years of surveillance testing. Approximately 10% of women who have hysterectomy for cervical dysplasia develop vaginal dysplasia or cancer after surgery.2,3 This is similar to the likelihood of recurrent dysplasia after an alternative excisional procedure. In my experience, this diagnosis is often met with enormous frustration for the patient who thought that her hysterectomy would be the cure of her HPV-related disease. Thorough colposcopic evaluation of the vagina can be technically challenging after hysterectomy because of difficulty adequately visualizing lesions within the vaginal rugations, particularly within the puckered lateral vaginal fornices, the most common location for dysplasia.3 We will explore the diagnosis and treatment options for vaginal dysplasia further in a future column.
It is critical that, if patients are offered hysterectomy for treatment of cervical dysplasia, they are counseled that it may not be curative, that they will require long-term vaginal surveillance, and that they are at continued risk for vaginal and vulvar cancer.
An additional concern with performing hysterectomy for definitive management of cervical dysplasia is the concern that occult cancer may be missed preoperatively, and that the hysterectomy is inadequate surgical clearance of the disease. Approximately 2%-5% of patients with a high-grade squamous intraepithelial lesion or equivocal Pap test have occult cervical cancer.4 A similar proportion of patients with cervical intraepithelial neoplasia stage III or adenocarcinoma in situ on colposcopy biopsy have invasive carcinoma on evaluation of an excisional specimen.5 The traditional surgical approach has dictated that a modified (type II) or extended (type III) radical hysterectomy be performed in the setting of FIGO stage IA2 or greater cervical cancer. Radical hysterectomies remove parametrial tissue, effectively achieving a wider margin around the primary lesion. This is important because cervical cancer primarily spreads via direct extension.
The appropriate radicality of surgery for microscopic lesions is debated. It has been proposed that for very small, low-risk lesions, a traditional extrafascial hysterectomy or trachelectomy, or possibly even a large conization, may be adequate.6 However, this is controversial, and National Comprehensive Cancer Network guidelines still advocate for radical procedures for these lesions.7 Certainly an excisional procedure (LEEP or cone) should first be performed to define the size and histologic features of the lesion, and ideally, evaluation and counseling with a gynecologic oncologist should be performed prior to offering patients with a stage IA2 or greater lesion an extrafascial hysterectomy. Additionally, a separate decision would need to be made regarding the need for lymphadenectomy, as this is typically recommended for patients with stage IA2 or greater lesions.
Patients should be counseled that, if extrafascial (simple) hysterectomy is chosen as the primary excisional procedure, they may require additional therapy (additional surgery, or radiation and possibly chemotherapy) if cancer is found in the specimen and the parametrial margin is inadequate. Additionally, and of more concern, if the lesion is a bulky lesion extending into the parametrium and not recognized preoperatively, a “cut-through” hysterectomy will be inadvertently performed (in which margins are grossly positive). These situations typically feature heavy blood loss with patients at increased risk for immediate surgical complications. Postoperatively, prognosis is substantially worse for patients who have had a cut-through hysterectomy, compared stage for stage with patients who primarily received a radical procedure with negative margins or primary chemotherapy and radiation.8 Otherwise said, their risk for death is higher if this error is made. Therefore a thorough examination is essential prior to performing hysterectomy for dysplasia. Any suspicion of bulky cancer should be considered a contraindication for proceeding.
Preoperative evaluation
As a rule, no patient should transition directly from cytologic evaluation with Pap screening to hysterectomy. A colposcopic evaluation of the cervix and vagina accompanied with a thorough bimanual rectovaginal examination should always be performed first. Biopsies of the ectocervix and ideally the endocervix should be obtained because the accuracy of histology is greater than that of cytology. For patients with cervical intraepithelial neoplasia stage I lesions, hysterectomy is not appropriate, as these patients have an extremely low risk for the development of cervical cancer, and the risks and costs of hysterectomy are not justified in such a population.
Surgeons should wait at least 6 weeks following conization or LEEP before performing hysterectomy in order to minimize the likelihood of perioperative complications.9
Substituting LEEP or cone with hysterectomy
In general, it is the most prudent approach to first perform a diagnostic excision with LEEP or cone biopsy before proceeding with hysterectomy for definitive surgery. However, there may be some situations in which this is not feasible. In patients whose cervix is very small and flush with the vagina, an excisional procedure may not be technically possible without concern for damage to adjacent structures. In these patients, after a thorough exam has evaluated for gross disease, a hysterectomy may be the only way to adequately diagnose and treat high-grade dysplasia through excision. For patients with limited access to resources, transportation, or a concern for noncompliance with follow-up, surgeons may wish to offer patients primary hysterectomy rather than a staged procedure.
Hysterectomy remains a potential option for treatment of cervical dysplasia. However, patients should be made aware of the risks of undertreatment of occult cancers, the need for long-term surveillance testing, and the risk for future vaginal dysplasia or cancer. Ideally a comprehensive, stepwise assessment from cytology to colposcopy and examination to diagnostic excisional procedure will first take place to proceed safely with this approach.
References
1. Saslow D et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J Clin. 2012 May-Jun;62(3):147-72.
2. Schockaert S et al. Incidence of vaginal intraepithelial neoplasia after hysterectomy for cervical intraepithelial neoplasia: a retrospective study. Am J Obstet Gynecol. 2008 Aug;199(2):113.e1-5.
3. Kalogirou D et al. Vaginal intraepithelial neoplasia (VAIN) following hysterectomy in patients treated for carcinoma in situ of the cervix. Eur J Gynaecol Oncol. 1997;18(3):188-91.
5. Latif NA et al. Management of adenocarcinoma in situ of the uterine cervix: a comparison of loop electrosurgical excision procedure and cold knife conization. J Low Genit Tract Dis. 2015 Apr;19(2):97-102.
8. Barber HR et al. Operative management of patients previously operated upon for a benign lesion with cervical cancer as a surprise finding. Am J Obstet Gynecol. 1968 Aug 1;101(7):959-65.
9. Sullivan SA et al. Association between timing of cervical excision procedure to minimally invasive hysterectomy and surgical complications. Gynecol Oncol. 2017 Feb;144(2):294-298.
We classify endometrial cancer so that we can communicate and define each patient’s disease status, the potential for harm, and the likelihood that adjuvant therapies might provide help. Traditional forms of classification have clearly fallen short in achieving this aim, as we all know of patients with apparent low-risk disease (such as stage IA grade 1 endometrioid carcinoma) who have had recurrences and died from their disease, and we know that many patients have been subjected to overtreatment for their cancer and have acquired lifelong toxicities of therapy. This column will explore the newer, more sophisticated molecular-based classifications that are being validated for endometrial cancer, and the ways in which this promises to personalize the treatment of endometrial cancer.
Dr. Emma C. RossiWe historically considered endometrial cancer with respect to “types”: type 1 cancer being estrogen dependent, featuring PTEN mutations, and affecting more obese patients; type 2 cancer being associated with p53 mutations, not estrogen dependent, and affecting older, less obese individuals.1 These categories were reasonable guides but ultimately oversimplified the disease and its affected patients. Additionally we have used histologic types, International Federation of Gynecology and Obstetrics grading, and surgical staging to categorize tumors. Unfortunately, histologic cell type and grade are limited by poor agreement among pathologists, with up to 50% discordance between readers, and surgical staging information may be limited in its completeness.2 Therefore, these categorizations lack the precision and accuracy to serve as prognosticators or to direct therapy. Reliance upon these inaccurate and imprecise methods of characterization may be part of the reason why most major clinical trials have failed to identify survival benefits for experimental therapies in early-stage disease. We may have been indiscriminately applying therapies instead of targeting the patients who are the most likely to derive benefit.
Breast cancer and melanoma are examples of the inclusion of molecular data such as hormone receptor status, HER2/neu status, or BRAF positivity resulting in advancements in personalizing therapeutics. We are now moving toward this for endometrial cancer.
What is the Cancer Genome Atlas?
In 2006 the National Institutes of Health announced an initiative to coordinate work between the National Cancer Institute and the National Human Genome Research Institute taking information about the human genome and analyzing it for key genomic alterations found in 33 common cancers. These data were combined with clinical information (such as survival) to classify the behaviors of those cancers with respect to their individual genomic alternations, in order to look for patterns in mutations and behaviors. The goal of this analysis was to shift the paradigm of cancer classification from being centered around primary organ site toward tumors’ shared genomic patterns.
In 2013 the Cancer Genome Atlas published their results of complete gene sequencing in endometrial cancer.3 The authors identified four discrete subgroups of endometrial cancer with distinct molecular mutational profiles and distinct clinical outcomes: polymerase epsilon (POLE, pronounced “pole-ee”) ultramutated, microsatellite instability (MSI) high, copy number high, and copy number low.
POLE ultramutated
An important subgroup identified in the Cancer Genome Atlas was a group of patients with a POLE ultramutated state. POLE encodes for a subunit of DNA polymerase, the enzyme responsible for replicating the leading DNA strand. Nonfunctioning POLE results in proofreading errors and a subsequent ultramutated cellular state with a predominance of single nucleotide variants. POLE proofreading domain mutations in endometrial cancer and colon cancer are associated with excellent prognosis, likely secondary to the immune response that is elicited by this ultramutated state from creation of “antigenic neoepitopes” that stimulate T-cell response. Effectively, the very mutated cell is seen as “more foreign” to the body’s immune system.
Approximately 10% of patients with endometrial cancer have a POLE ultramutated state, and, as stated above, prognosis is excellent, even if coexisting with a histologic cell type (such as serous) that is normally associated with adverse outcomes. These women tend to be younger, with a lower body mass index, higher-grade endometrioid cell type, the presence of lymphovascular space invasion, and low stage.
MSI high
MSI (microsatellite instability) is a result of epigenetic/hypermethylations or loss of expression in mismatch repair genes (such as MLH1, MSH2, MSH6, PMS2). These genes code for proteins critical in the repair of mismatches in short repeated sequences of DNA. Loss of their function results in an accumulation of errors in these sequences: MSI. It is a feature of the Lynch syndrome inherited state, but is also found sporadically in endometrial tumors. These tumors accumulate a number of mutations during cell replication that, as in POLE hypermutated tumors, are associated with eliciting an immune response.
These tumors tend to be associated with a higher-grade endometrioid cell type, the presence of lymphovascular space invasion, and an advanced stage. Patients with tumors that have been described as MSI high are candidates for “immune therapy” with the PDL1 inhibitor pembrolizumab because of their proinflammatory state and observed favorable responses in clinical trials.4
Copy number high/low
Copy number (CN) high and low refers to the results of microarrays in which hierarchical clustering was applied to identify reoccurring amplification or deletion regions. The CN-high group was associated with the poorest outcomes (recurrence and survival). There is significant overlap with mutations in TP53. Most serous carcinomas were CN high; however, 25% of patients with high-grade endometrioid cell type shared the CN-high classification. These tumors shared great molecular similarity to high-grade serous ovarian cancers and basal-like breast cancer.
Those patients who did not possess mutations that classified them as POLE hypermutated, MSI high, or CN high were classified as CN low. This group included predominantly grades 1 and 2 endometrioid adenocarcinomas of an early stage and had a favorable prognostic profile, though less favorable than those with a POLE ultramutated state, which appears to be somewhat protective.
Molecular/metabolic interactions
While molecular data are clearly important in driving a cancer cell’s behavior, other clinical and metabolic factors influence cancer behavior. For example, body mass index, adiposity, glucose, and lipid metabolism have been shown to be important drivers of cellular behavior and responsiveness to targeted therapies.5,6 Additionally age, race, and other metabolic states contribute to oncologic behavior. Future classifications of endometrial cancer are unlikely to use molecular profiles in isolation but will need to incorporate these additional patient-specific data to better predict and prognosticate outcomes.
Clinical applications
If researchers can better define and describe a patient’s endometrial cancer from the time of their biopsy, important clinical decisions might be able to be tackled. For example, in a premenopausal patient with an endometrial cancer who is considering fertility-sparing treatments, preoperative knowledge of a POLE ultramutated state (and therefore an anticipated good prognosis) might favor fertility preservation or avoid comprehensive staging which may be of limited value. Similarly, if an MSI-high profile is identified leading to a Lynch syndrome diagnosis, she may be more inclined to undergo a hysterectomy with bilateral salpingo-oophorectomy and staging as she is at known increased risk for a more advanced endometrial cancer, as well as the potential for ovarian cancer.
Postoperative incorporation of molecular data promises to be particularly helpful in guiding adjuvant therapies and sparing some women from unnecessary treatments. For example, women with high-grade endometrioid tumors who are CN high were historically treated with radiotherapy but might do better treated with systemic adjuvant therapies traditionally reserved for nonendometrioid carcinomas. Costly therapies such as immunotherapy can be directed toward those with MSI-high tumors, and the rare patient with a POLE ultramutated state who has a recurrence or advanced disease. Clinical trials will be able to cluster enrollment of patients with CN-high, serouslike cancers with those with serous cancers, rather than combining them with patients whose cancers predictably behave much differently.
Much work is still needed to validate this molecular profiling in endometrial cancer and define the algorithms associated with treatment decisions; however, it is likely that the way we describe endometrial cancer in the near future will be quite different.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no disclosures.
2. Clarke BA et al. Endometrial carcinoma: controversies in histopathological assessment of grade and tumour cell type. J Clin Pathol. 2010;63(5):410-5.
3. Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67-73.
5. Roque DR et al. Association between differential gene expression and body mass index among endometrial cancers from the Cancer Genome Atlas Project. Gynecol Oncol. 2016;142(2):317-22.
6. Talhouk A et al. New classification of endometrial cancers: The development and potential applications of genomic-based classification in research and clinical care. Gynecol Oncol Res Pract. 2016 Dec;3:14.
We classify endometrial cancer so that we can communicate and define each patient’s disease status, the potential for harm, and the likelihood that adjuvant therapies might provide help. Traditional forms of classification have clearly fallen short in achieving this aim, as we all know of patients with apparent low-risk disease (such as stage IA grade 1 endometrioid carcinoma) who have had recurrences and died from their disease, and we know that many patients have been subjected to overtreatment for their cancer and have acquired lifelong toxicities of therapy. This column will explore the newer, more sophisticated molecular-based classifications that are being validated for endometrial cancer, and the ways in which this promises to personalize the treatment of endometrial cancer.
Dr. Emma C. RossiWe historically considered endometrial cancer with respect to “types”: type 1 cancer being estrogen dependent, featuring PTEN mutations, and affecting more obese patients; type 2 cancer being associated with p53 mutations, not estrogen dependent, and affecting older, less obese individuals.1 These categories were reasonable guides but ultimately oversimplified the disease and its affected patients. Additionally we have used histologic types, International Federation of Gynecology and Obstetrics grading, and surgical staging to categorize tumors. Unfortunately, histologic cell type and grade are limited by poor agreement among pathologists, with up to 50% discordance between readers, and surgical staging information may be limited in its completeness.2 Therefore, these categorizations lack the precision and accuracy to serve as prognosticators or to direct therapy. Reliance upon these inaccurate and imprecise methods of characterization may be part of the reason why most major clinical trials have failed to identify survival benefits for experimental therapies in early-stage disease. We may have been indiscriminately applying therapies instead of targeting the patients who are the most likely to derive benefit.
Breast cancer and melanoma are examples of the inclusion of molecular data such as hormone receptor status, HER2/neu status, or BRAF positivity resulting in advancements in personalizing therapeutics. We are now moving toward this for endometrial cancer.
What is the Cancer Genome Atlas?
In 2006 the National Institutes of Health announced an initiative to coordinate work between the National Cancer Institute and the National Human Genome Research Institute taking information about the human genome and analyzing it for key genomic alterations found in 33 common cancers. These data were combined with clinical information (such as survival) to classify the behaviors of those cancers with respect to their individual genomic alternations, in order to look for patterns in mutations and behaviors. The goal of this analysis was to shift the paradigm of cancer classification from being centered around primary organ site toward tumors’ shared genomic patterns.
In 2013 the Cancer Genome Atlas published their results of complete gene sequencing in endometrial cancer.3 The authors identified four discrete subgroups of endometrial cancer with distinct molecular mutational profiles and distinct clinical outcomes: polymerase epsilon (POLE, pronounced “pole-ee”) ultramutated, microsatellite instability (MSI) high, copy number high, and copy number low.
POLE ultramutated
An important subgroup identified in the Cancer Genome Atlas was a group of patients with a POLE ultramutated state. POLE encodes for a subunit of DNA polymerase, the enzyme responsible for replicating the leading DNA strand. Nonfunctioning POLE results in proofreading errors and a subsequent ultramutated cellular state with a predominance of single nucleotide variants. POLE proofreading domain mutations in endometrial cancer and colon cancer are associated with excellent prognosis, likely secondary to the immune response that is elicited by this ultramutated state from creation of “antigenic neoepitopes” that stimulate T-cell response. Effectively, the very mutated cell is seen as “more foreign” to the body’s immune system.
Approximately 10% of patients with endometrial cancer have a POLE ultramutated state, and, as stated above, prognosis is excellent, even if coexisting with a histologic cell type (such as serous) that is normally associated with adverse outcomes. These women tend to be younger, with a lower body mass index, higher-grade endometrioid cell type, the presence of lymphovascular space invasion, and low stage.
MSI high
MSI (microsatellite instability) is a result of epigenetic/hypermethylations or loss of expression in mismatch repair genes (such as MLH1, MSH2, MSH6, PMS2). These genes code for proteins critical in the repair of mismatches in short repeated sequences of DNA. Loss of their function results in an accumulation of errors in these sequences: MSI. It is a feature of the Lynch syndrome inherited state, but is also found sporadically in endometrial tumors. These tumors accumulate a number of mutations during cell replication that, as in POLE hypermutated tumors, are associated with eliciting an immune response.
These tumors tend to be associated with a higher-grade endometrioid cell type, the presence of lymphovascular space invasion, and an advanced stage. Patients with tumors that have been described as MSI high are candidates for “immune therapy” with the PDL1 inhibitor pembrolizumab because of their proinflammatory state and observed favorable responses in clinical trials.4
Copy number high/low
Copy number (CN) high and low refers to the results of microarrays in which hierarchical clustering was applied to identify reoccurring amplification or deletion regions. The CN-high group was associated with the poorest outcomes (recurrence and survival). There is significant overlap with mutations in TP53. Most serous carcinomas were CN high; however, 25% of patients with high-grade endometrioid cell type shared the CN-high classification. These tumors shared great molecular similarity to high-grade serous ovarian cancers and basal-like breast cancer.
Those patients who did not possess mutations that classified them as POLE hypermutated, MSI high, or CN high were classified as CN low. This group included predominantly grades 1 and 2 endometrioid adenocarcinomas of an early stage and had a favorable prognostic profile, though less favorable than those with a POLE ultramutated state, which appears to be somewhat protective.
Molecular/metabolic interactions
While molecular data are clearly important in driving a cancer cell’s behavior, other clinical and metabolic factors influence cancer behavior. For example, body mass index, adiposity, glucose, and lipid metabolism have been shown to be important drivers of cellular behavior and responsiveness to targeted therapies.5,6 Additionally age, race, and other metabolic states contribute to oncologic behavior. Future classifications of endometrial cancer are unlikely to use molecular profiles in isolation but will need to incorporate these additional patient-specific data to better predict and prognosticate outcomes.
Clinical applications
If researchers can better define and describe a patient’s endometrial cancer from the time of their biopsy, important clinical decisions might be able to be tackled. For example, in a premenopausal patient with an endometrial cancer who is considering fertility-sparing treatments, preoperative knowledge of a POLE ultramutated state (and therefore an anticipated good prognosis) might favor fertility preservation or avoid comprehensive staging which may be of limited value. Similarly, if an MSI-high profile is identified leading to a Lynch syndrome diagnosis, she may be more inclined to undergo a hysterectomy with bilateral salpingo-oophorectomy and staging as she is at known increased risk for a more advanced endometrial cancer, as well as the potential for ovarian cancer.
Postoperative incorporation of molecular data promises to be particularly helpful in guiding adjuvant therapies and sparing some women from unnecessary treatments. For example, women with high-grade endometrioid tumors who are CN high were historically treated with radiotherapy but might do better treated with systemic adjuvant therapies traditionally reserved for nonendometrioid carcinomas. Costly therapies such as immunotherapy can be directed toward those with MSI-high tumors, and the rare patient with a POLE ultramutated state who has a recurrence or advanced disease. Clinical trials will be able to cluster enrollment of patients with CN-high, serouslike cancers with those with serous cancers, rather than combining them with patients whose cancers predictably behave much differently.
Much work is still needed to validate this molecular profiling in endometrial cancer and define the algorithms associated with treatment decisions; however, it is likely that the way we describe endometrial cancer in the near future will be quite different.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no disclosures.
2. Clarke BA et al. Endometrial carcinoma: controversies in histopathological assessment of grade and tumour cell type. J Clin Pathol. 2010;63(5):410-5.
3. Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67-73.
5. Roque DR et al. Association between differential gene expression and body mass index among endometrial cancers from the Cancer Genome Atlas Project. Gynecol Oncol. 2016;142(2):317-22.
6. Talhouk A et al. New classification of endometrial cancers: The development and potential applications of genomic-based classification in research and clinical care. Gynecol Oncol Res Pract. 2016 Dec;3:14.
We classify endometrial cancer so that we can communicate and define each patient’s disease status, the potential for harm, and the likelihood that adjuvant therapies might provide help. Traditional forms of classification have clearly fallen short in achieving this aim, as we all know of patients with apparent low-risk disease (such as stage IA grade 1 endometrioid carcinoma) who have had recurrences and died from their disease, and we know that many patients have been subjected to overtreatment for their cancer and have acquired lifelong toxicities of therapy. This column will explore the newer, more sophisticated molecular-based classifications that are being validated for endometrial cancer, and the ways in which this promises to personalize the treatment of endometrial cancer.
Dr. Emma C. RossiWe historically considered endometrial cancer with respect to “types”: type 1 cancer being estrogen dependent, featuring PTEN mutations, and affecting more obese patients; type 2 cancer being associated with p53 mutations, not estrogen dependent, and affecting older, less obese individuals.1 These categories were reasonable guides but ultimately oversimplified the disease and its affected patients. Additionally we have used histologic types, International Federation of Gynecology and Obstetrics grading, and surgical staging to categorize tumors. Unfortunately, histologic cell type and grade are limited by poor agreement among pathologists, with up to 50% discordance between readers, and surgical staging information may be limited in its completeness.2 Therefore, these categorizations lack the precision and accuracy to serve as prognosticators or to direct therapy. Reliance upon these inaccurate and imprecise methods of characterization may be part of the reason why most major clinical trials have failed to identify survival benefits for experimental therapies in early-stage disease. We may have been indiscriminately applying therapies instead of targeting the patients who are the most likely to derive benefit.
Breast cancer and melanoma are examples of the inclusion of molecular data such as hormone receptor status, HER2/neu status, or BRAF positivity resulting in advancements in personalizing therapeutics. We are now moving toward this for endometrial cancer.
What is the Cancer Genome Atlas?
In 2006 the National Institutes of Health announced an initiative to coordinate work between the National Cancer Institute and the National Human Genome Research Institute taking information about the human genome and analyzing it for key genomic alterations found in 33 common cancers. These data were combined with clinical information (such as survival) to classify the behaviors of those cancers with respect to their individual genomic alternations, in order to look for patterns in mutations and behaviors. The goal of this analysis was to shift the paradigm of cancer classification from being centered around primary organ site toward tumors’ shared genomic patterns.
In 2013 the Cancer Genome Atlas published their results of complete gene sequencing in endometrial cancer.3 The authors identified four discrete subgroups of endometrial cancer with distinct molecular mutational profiles and distinct clinical outcomes: polymerase epsilon (POLE, pronounced “pole-ee”) ultramutated, microsatellite instability (MSI) high, copy number high, and copy number low.
POLE ultramutated
An important subgroup identified in the Cancer Genome Atlas was a group of patients with a POLE ultramutated state. POLE encodes for a subunit of DNA polymerase, the enzyme responsible for replicating the leading DNA strand. Nonfunctioning POLE results in proofreading errors and a subsequent ultramutated cellular state with a predominance of single nucleotide variants. POLE proofreading domain mutations in endometrial cancer and colon cancer are associated with excellent prognosis, likely secondary to the immune response that is elicited by this ultramutated state from creation of “antigenic neoepitopes” that stimulate T-cell response. Effectively, the very mutated cell is seen as “more foreign” to the body’s immune system.
Approximately 10% of patients with endometrial cancer have a POLE ultramutated state, and, as stated above, prognosis is excellent, even if coexisting with a histologic cell type (such as serous) that is normally associated with adverse outcomes. These women tend to be younger, with a lower body mass index, higher-grade endometrioid cell type, the presence of lymphovascular space invasion, and low stage.
MSI high
MSI (microsatellite instability) is a result of epigenetic/hypermethylations or loss of expression in mismatch repair genes (such as MLH1, MSH2, MSH6, PMS2). These genes code for proteins critical in the repair of mismatches in short repeated sequences of DNA. Loss of their function results in an accumulation of errors in these sequences: MSI. It is a feature of the Lynch syndrome inherited state, but is also found sporadically in endometrial tumors. These tumors accumulate a number of mutations during cell replication that, as in POLE hypermutated tumors, are associated with eliciting an immune response.
These tumors tend to be associated with a higher-grade endometrioid cell type, the presence of lymphovascular space invasion, and an advanced stage. Patients with tumors that have been described as MSI high are candidates for “immune therapy” with the PDL1 inhibitor pembrolizumab because of their proinflammatory state and observed favorable responses in clinical trials.4
Copy number high/low
Copy number (CN) high and low refers to the results of microarrays in which hierarchical clustering was applied to identify reoccurring amplification or deletion regions. The CN-high group was associated with the poorest outcomes (recurrence and survival). There is significant overlap with mutations in TP53. Most serous carcinomas were CN high; however, 25% of patients with high-grade endometrioid cell type shared the CN-high classification. These tumors shared great molecular similarity to high-grade serous ovarian cancers and basal-like breast cancer.
Those patients who did not possess mutations that classified them as POLE hypermutated, MSI high, or CN high were classified as CN low. This group included predominantly grades 1 and 2 endometrioid adenocarcinomas of an early stage and had a favorable prognostic profile, though less favorable than those with a POLE ultramutated state, which appears to be somewhat protective.
Molecular/metabolic interactions
While molecular data are clearly important in driving a cancer cell’s behavior, other clinical and metabolic factors influence cancer behavior. For example, body mass index, adiposity, glucose, and lipid metabolism have been shown to be important drivers of cellular behavior and responsiveness to targeted therapies.5,6 Additionally age, race, and other metabolic states contribute to oncologic behavior. Future classifications of endometrial cancer are unlikely to use molecular profiles in isolation but will need to incorporate these additional patient-specific data to better predict and prognosticate outcomes.
Clinical applications
If researchers can better define and describe a patient’s endometrial cancer from the time of their biopsy, important clinical decisions might be able to be tackled. For example, in a premenopausal patient with an endometrial cancer who is considering fertility-sparing treatments, preoperative knowledge of a POLE ultramutated state (and therefore an anticipated good prognosis) might favor fertility preservation or avoid comprehensive staging which may be of limited value. Similarly, if an MSI-high profile is identified leading to a Lynch syndrome diagnosis, she may be more inclined to undergo a hysterectomy with bilateral salpingo-oophorectomy and staging as she is at known increased risk for a more advanced endometrial cancer, as well as the potential for ovarian cancer.
Postoperative incorporation of molecular data promises to be particularly helpful in guiding adjuvant therapies and sparing some women from unnecessary treatments. For example, women with high-grade endometrioid tumors who are CN high were historically treated with radiotherapy but might do better treated with systemic adjuvant therapies traditionally reserved for nonendometrioid carcinomas. Costly therapies such as immunotherapy can be directed toward those with MSI-high tumors, and the rare patient with a POLE ultramutated state who has a recurrence or advanced disease. Clinical trials will be able to cluster enrollment of patients with CN-high, serouslike cancers with those with serous cancers, rather than combining them with patients whose cancers predictably behave much differently.
Much work is still needed to validate this molecular profiling in endometrial cancer and define the algorithms associated with treatment decisions; however, it is likely that the way we describe endometrial cancer in the near future will be quite different.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no disclosures.
2. Clarke BA et al. Endometrial carcinoma: controversies in histopathological assessment of grade and tumour cell type. J Clin Pathol. 2010;63(5):410-5.
3. Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67-73.
5. Roque DR et al. Association between differential gene expression and body mass index among endometrial cancers from the Cancer Genome Atlas Project. Gynecol Oncol. 2016;142(2):317-22.
6. Talhouk A et al. New classification of endometrial cancers: The development and potential applications of genomic-based classification in research and clinical care. Gynecol Oncol Res Pract. 2016 Dec;3:14.
One-quarter of patients with breast cancer are diagnosed at a premenopausal age and these young women may be directed to discuss oophorectomy with their ob.gyn. This may be because of the discovery of a deleterious BRCA gene mutation, which places them at increased risk for ovarian cancer, but oophorectomy may also be a therapeutic option for their breast cancer: 60% of premenopausal breast cancers are hormone receptor–positive. Ovarian ablation has been associated with improved overall survival and disease-free survival among these patients.1
Estrogen is an important promoter of breast cancer and is predominantly derived from ovarian tissue in premenopausal women. However, in postmenopausal women, the majority of estrogen is produced peripherally through the conversion of androgens to estrogen via the enzyme aromatase. Aromatase inhibitors, such as exemestane, anastrazole, and letrazole, are drugs which block this conversion in peripheral tissues. They are contraindicated in premenopausal women with intact ovarian function, because there is a reflex pituitary stimulation of ovarian estrogen release in response to suppression of peripheral conversion of androgens. For such patients, ovarian function must be ablated either with surgery or with gonadotropin-releasing hormone (GnRH) analogues such as leuprorelin and goserelin if aromatase inhibitors are desired.
Dr. Emma C. RossiTwo major clinical trials, the SOFT and TEXT trials, explored the benefit of ovarian ablation in the adjuvant treatment of early stage premenopausal breast cancer. The SOFT trial included 3,066 women randomized to receive tamoxifen, tamoxifen with ovarian suppression, or an aromatase inhibitor with ovarian suppression.2 In the TEXT trial, 2,672 patients were randomized to receive either an aromatase inhibitor with ovarian suppression or tamoxifen with ovarian suppression.3 Results of the two trials showed that there was greatest treatment effect when ovarian suppression is added to tamoxifen, or in patients receiving an aromatase inhibitor with ovarian suppression. This effect appeared to be dominant among women who had received prior chemotherapy and were at higher risk for recurrence, and who remained premenopausal after completion of their primary therapy. While ovarian suppression was associated with improved disease-free survival, it was not associated with an increased overall survival.
In these trials, ovarian ablation was achieved either reversibly with GnRH analogues or permanently and irreversibly with oophorectomy. No studies have compared the survival benefit of these two approaches; however, surgical ovarian ablation is immediate, reliable, and has been shown to be the most cost-effective method.4 It is a good option for women who struggle with adherence to repeated appointments for injections. It also substantially reduces the risk for ovarian cancer, which is elevated among this population of patients, even among those without a deleterious BRCA gene mutation.
BRCA populations
For women with BRCA germline mutations and a history of breast cancer, oophorectomy is associated with a 70% risk of all-cause mortality, including a 60% reduction in breast cancer mortality. This effect is inclusive of patients with “triple-negative,” hormone receptor–negative tumors. The positive effect on breast cancer mortality is predominantly seen among BRCA-1 mutation carriers, and if the oophorectomy is performed within 2 years of diagnosis.5
Technique
When performing oophorectomy either for breast cancer or because of a hereditary cancer syndrome such as BRCA mutation, it is important to ensure that the ovarian vessel pedicle is transected at least 2 cm from its insertion in the ovary. This prevents leaving a residual ovarian remnant. In order to do this, it may be necessary to skeletonize the ovarian vessels free from their physiological attachments to the sigmoid colon on the left, and terminal ileum and cecum on the right. It is also important to ensure that the ureter is not invested in this more proximal segment of ovarian vessels. To prevent this, the retroperitoneal space can be opened lateral to and parallel with the ovarian vessels, and the “medial leaf” of the broad ligament swept medially to expose the ureter as it crosses the bifurcation of the external and internal iliac arteries at the pelvic brim. With the ureter in view, a window can then be made in the “medial leaf” above the ureter and below the ovary and ovarian vessels, in doing so creating a skeletonized ovarian vessel segment which can be sealed and cut 2 cm or more from its insertion in the ovary.
The fallopian tubes should be removed with the ovarian specimens, with attention made to removing the fallopian tube at its junction with the uterine cornua. It should be noted that the majority of fallopian tube cancers arise in the fimbriated end of the tube, and cornual tubal malignancies are fairly uncommon.
The decision about whether or not to perform hysterectomy at the time of salpingo-oophorectomy is complex. In patients without hereditary cancer syndromes, such as BRCA or Lynch syndrome, hysterectomy likely offers no benefit to the patient who is undergoing a procedure for the purpose of ovarian ablation. An argument has been made that hysterectomy can eliminate the increased endometrial cancer risk associated with tamoxifen. However, given the previously discussed data, after oophorectomy, aromatase inhibitors are the preferred treatment option, and tamoxifen can be avoided. If a patient has unrelated underlying uterine pathology a hysterectomy might be indicated. Women with BRCA germline mutations, particularly women with BRCA-1 mutations, may be at increased risk for uterine serous carcinoma, and in these patients, hysterectomy at the time of oophorectomy can be discussed and offered, though as yet, it is not a guideline recommendation for all patients.6 Patients who ask to “just take everything out while you are there” without a clear indication for hysterectomy should be counseled that hysterectomy is associated with increased risk, recovery, and cost, compared with bilateral salpingo-oophorectomy. Among patients with elevated surgical risk (such as morbid obesity, known adhesive disease, increased venous thromboembolism risk, diabetes, and so on) it may not always be appropriate to extend the complexity of the procedure given the limited benefit.
Consequences of ovarian ablation
It should be noted that ovarian ablation in the TEXT and SOFT trials was not associated with an increase in overall survival for women with premenopausal breast cancer. Alternatively, large, observational studies such as the Nurses’ Health Study have shown that premenopausal oophorectomy without hormone replacement therapy is associated with increased all-cause mortality. This is primarily driven by the increased cardiopulmonary risk (heart attack and stroke), deaths after osteoporotic hip fractures, and the increased risk for lung and colon cancer.7,8
It is normal for young patients to have heightened concerns regarding their risk of recurrence from their cancer, and less concerned by threats to their health in decades to come. However, it is important to discuss this data with the patient and allow for her to make an informed decision about her immediate versus future risks. If she determines that she is not interested in permanent ovarian ablation with oophorectomy because of either surgical risks, concerns regarding permanent infertility, or increased all-cause mortality, she still has an option for medical ovarian ablation with GnRH analogues in the treatment of her breast cancer.
Hormone replacement therapy postoperatively
Women who undergo oophorectomy for the treatment of breast cancer should not be offered hormone replacement therapy. This is true even for “triple-negative” or hormone receptor–negative breast cancers as there is still some observed benefit of ovarian ablation, and risk from exogenous hormone administration in these women. Alternatively, postoperative hormone replacement therapy remains safe until the age of natural menopause among premenopausal patients with BRCA germline mutations without a preceding breast cancer diagnosis.
Surgical ovarian ablation with bilateral salpingo-oophorectomy is a valuable strategy in the adjuvant therapy of premenopausal breast cancer, particularly among BRCA mutation carriers and women with hormone receptor–positive disease, or among women who find adherence to medical ablation difficult. Patients should be carefully counseled that this may introduce increased long-term cardiovascular risks for them.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill.
One-quarter of patients with breast cancer are diagnosed at a premenopausal age and these young women may be directed to discuss oophorectomy with their ob.gyn. This may be because of the discovery of a deleterious BRCA gene mutation, which places them at increased risk for ovarian cancer, but oophorectomy may also be a therapeutic option for their breast cancer: 60% of premenopausal breast cancers are hormone receptor–positive. Ovarian ablation has been associated with improved overall survival and disease-free survival among these patients.1
Estrogen is an important promoter of breast cancer and is predominantly derived from ovarian tissue in premenopausal women. However, in postmenopausal women, the majority of estrogen is produced peripherally through the conversion of androgens to estrogen via the enzyme aromatase. Aromatase inhibitors, such as exemestane, anastrazole, and letrazole, are drugs which block this conversion in peripheral tissues. They are contraindicated in premenopausal women with intact ovarian function, because there is a reflex pituitary stimulation of ovarian estrogen release in response to suppression of peripheral conversion of androgens. For such patients, ovarian function must be ablated either with surgery or with gonadotropin-releasing hormone (GnRH) analogues such as leuprorelin and goserelin if aromatase inhibitors are desired.
Dr. Emma C. RossiTwo major clinical trials, the SOFT and TEXT trials, explored the benefit of ovarian ablation in the adjuvant treatment of early stage premenopausal breast cancer. The SOFT trial included 3,066 women randomized to receive tamoxifen, tamoxifen with ovarian suppression, or an aromatase inhibitor with ovarian suppression.2 In the TEXT trial, 2,672 patients were randomized to receive either an aromatase inhibitor with ovarian suppression or tamoxifen with ovarian suppression.3 Results of the two trials showed that there was greatest treatment effect when ovarian suppression is added to tamoxifen, or in patients receiving an aromatase inhibitor with ovarian suppression. This effect appeared to be dominant among women who had received prior chemotherapy and were at higher risk for recurrence, and who remained premenopausal after completion of their primary therapy. While ovarian suppression was associated with improved disease-free survival, it was not associated with an increased overall survival.
In these trials, ovarian ablation was achieved either reversibly with GnRH analogues or permanently and irreversibly with oophorectomy. No studies have compared the survival benefit of these two approaches; however, surgical ovarian ablation is immediate, reliable, and has been shown to be the most cost-effective method.4 It is a good option for women who struggle with adherence to repeated appointments for injections. It also substantially reduces the risk for ovarian cancer, which is elevated among this population of patients, even among those without a deleterious BRCA gene mutation.
BRCA populations
For women with BRCA germline mutations and a history of breast cancer, oophorectomy is associated with a 70% risk of all-cause mortality, including a 60% reduction in breast cancer mortality. This effect is inclusive of patients with “triple-negative,” hormone receptor–negative tumors. The positive effect on breast cancer mortality is predominantly seen among BRCA-1 mutation carriers, and if the oophorectomy is performed within 2 years of diagnosis.5
Technique
When performing oophorectomy either for breast cancer or because of a hereditary cancer syndrome such as BRCA mutation, it is important to ensure that the ovarian vessel pedicle is transected at least 2 cm from its insertion in the ovary. This prevents leaving a residual ovarian remnant. In order to do this, it may be necessary to skeletonize the ovarian vessels free from their physiological attachments to the sigmoid colon on the left, and terminal ileum and cecum on the right. It is also important to ensure that the ureter is not invested in this more proximal segment of ovarian vessels. To prevent this, the retroperitoneal space can be opened lateral to and parallel with the ovarian vessels, and the “medial leaf” of the broad ligament swept medially to expose the ureter as it crosses the bifurcation of the external and internal iliac arteries at the pelvic brim. With the ureter in view, a window can then be made in the “medial leaf” above the ureter and below the ovary and ovarian vessels, in doing so creating a skeletonized ovarian vessel segment which can be sealed and cut 2 cm or more from its insertion in the ovary.
The fallopian tubes should be removed with the ovarian specimens, with attention made to removing the fallopian tube at its junction with the uterine cornua. It should be noted that the majority of fallopian tube cancers arise in the fimbriated end of the tube, and cornual tubal malignancies are fairly uncommon.
The decision about whether or not to perform hysterectomy at the time of salpingo-oophorectomy is complex. In patients without hereditary cancer syndromes, such as BRCA or Lynch syndrome, hysterectomy likely offers no benefit to the patient who is undergoing a procedure for the purpose of ovarian ablation. An argument has been made that hysterectomy can eliminate the increased endometrial cancer risk associated with tamoxifen. However, given the previously discussed data, after oophorectomy, aromatase inhibitors are the preferred treatment option, and tamoxifen can be avoided. If a patient has unrelated underlying uterine pathology a hysterectomy might be indicated. Women with BRCA germline mutations, particularly women with BRCA-1 mutations, may be at increased risk for uterine serous carcinoma, and in these patients, hysterectomy at the time of oophorectomy can be discussed and offered, though as yet, it is not a guideline recommendation for all patients.6 Patients who ask to “just take everything out while you are there” without a clear indication for hysterectomy should be counseled that hysterectomy is associated with increased risk, recovery, and cost, compared with bilateral salpingo-oophorectomy. Among patients with elevated surgical risk (such as morbid obesity, known adhesive disease, increased venous thromboembolism risk, diabetes, and so on) it may not always be appropriate to extend the complexity of the procedure given the limited benefit.
Consequences of ovarian ablation
It should be noted that ovarian ablation in the TEXT and SOFT trials was not associated with an increase in overall survival for women with premenopausal breast cancer. Alternatively, large, observational studies such as the Nurses’ Health Study have shown that premenopausal oophorectomy without hormone replacement therapy is associated with increased all-cause mortality. This is primarily driven by the increased cardiopulmonary risk (heart attack and stroke), deaths after osteoporotic hip fractures, and the increased risk for lung and colon cancer.7,8
It is normal for young patients to have heightened concerns regarding their risk of recurrence from their cancer, and less concerned by threats to their health in decades to come. However, it is important to discuss this data with the patient and allow for her to make an informed decision about her immediate versus future risks. If she determines that she is not interested in permanent ovarian ablation with oophorectomy because of either surgical risks, concerns regarding permanent infertility, or increased all-cause mortality, she still has an option for medical ovarian ablation with GnRH analogues in the treatment of her breast cancer.
Hormone replacement therapy postoperatively
Women who undergo oophorectomy for the treatment of breast cancer should not be offered hormone replacement therapy. This is true even for “triple-negative” or hormone receptor–negative breast cancers as there is still some observed benefit of ovarian ablation, and risk from exogenous hormone administration in these women. Alternatively, postoperative hormone replacement therapy remains safe until the age of natural menopause among premenopausal patients with BRCA germline mutations without a preceding breast cancer diagnosis.
Surgical ovarian ablation with bilateral salpingo-oophorectomy is a valuable strategy in the adjuvant therapy of premenopausal breast cancer, particularly among BRCA mutation carriers and women with hormone receptor–positive disease, or among women who find adherence to medical ablation difficult. Patients should be carefully counseled that this may introduce increased long-term cardiovascular risks for them.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill.
One-quarter of patients with breast cancer are diagnosed at a premenopausal age and these young women may be directed to discuss oophorectomy with their ob.gyn. This may be because of the discovery of a deleterious BRCA gene mutation, which places them at increased risk for ovarian cancer, but oophorectomy may also be a therapeutic option for their breast cancer: 60% of premenopausal breast cancers are hormone receptor–positive. Ovarian ablation has been associated with improved overall survival and disease-free survival among these patients.1
Estrogen is an important promoter of breast cancer and is predominantly derived from ovarian tissue in premenopausal women. However, in postmenopausal women, the majority of estrogen is produced peripherally through the conversion of androgens to estrogen via the enzyme aromatase. Aromatase inhibitors, such as exemestane, anastrazole, and letrazole, are drugs which block this conversion in peripheral tissues. They are contraindicated in premenopausal women with intact ovarian function, because there is a reflex pituitary stimulation of ovarian estrogen release in response to suppression of peripheral conversion of androgens. For such patients, ovarian function must be ablated either with surgery or with gonadotropin-releasing hormone (GnRH) analogues such as leuprorelin and goserelin if aromatase inhibitors are desired.
Dr. Emma C. RossiTwo major clinical trials, the SOFT and TEXT trials, explored the benefit of ovarian ablation in the adjuvant treatment of early stage premenopausal breast cancer. The SOFT trial included 3,066 women randomized to receive tamoxifen, tamoxifen with ovarian suppression, or an aromatase inhibitor with ovarian suppression.2 In the TEXT trial, 2,672 patients were randomized to receive either an aromatase inhibitor with ovarian suppression or tamoxifen with ovarian suppression.3 Results of the two trials showed that there was greatest treatment effect when ovarian suppression is added to tamoxifen, or in patients receiving an aromatase inhibitor with ovarian suppression. This effect appeared to be dominant among women who had received prior chemotherapy and were at higher risk for recurrence, and who remained premenopausal after completion of their primary therapy. While ovarian suppression was associated with improved disease-free survival, it was not associated with an increased overall survival.
In these trials, ovarian ablation was achieved either reversibly with GnRH analogues or permanently and irreversibly with oophorectomy. No studies have compared the survival benefit of these two approaches; however, surgical ovarian ablation is immediate, reliable, and has been shown to be the most cost-effective method.4 It is a good option for women who struggle with adherence to repeated appointments for injections. It also substantially reduces the risk for ovarian cancer, which is elevated among this population of patients, even among those without a deleterious BRCA gene mutation.
BRCA populations
For women with BRCA germline mutations and a history of breast cancer, oophorectomy is associated with a 70% risk of all-cause mortality, including a 60% reduction in breast cancer mortality. This effect is inclusive of patients with “triple-negative,” hormone receptor–negative tumors. The positive effect on breast cancer mortality is predominantly seen among BRCA-1 mutation carriers, and if the oophorectomy is performed within 2 years of diagnosis.5
Technique
When performing oophorectomy either for breast cancer or because of a hereditary cancer syndrome such as BRCA mutation, it is important to ensure that the ovarian vessel pedicle is transected at least 2 cm from its insertion in the ovary. This prevents leaving a residual ovarian remnant. In order to do this, it may be necessary to skeletonize the ovarian vessels free from their physiological attachments to the sigmoid colon on the left, and terminal ileum and cecum on the right. It is also important to ensure that the ureter is not invested in this more proximal segment of ovarian vessels. To prevent this, the retroperitoneal space can be opened lateral to and parallel with the ovarian vessels, and the “medial leaf” of the broad ligament swept medially to expose the ureter as it crosses the bifurcation of the external and internal iliac arteries at the pelvic brim. With the ureter in view, a window can then be made in the “medial leaf” above the ureter and below the ovary and ovarian vessels, in doing so creating a skeletonized ovarian vessel segment which can be sealed and cut 2 cm or more from its insertion in the ovary.
The fallopian tubes should be removed with the ovarian specimens, with attention made to removing the fallopian tube at its junction with the uterine cornua. It should be noted that the majority of fallopian tube cancers arise in the fimbriated end of the tube, and cornual tubal malignancies are fairly uncommon.
The decision about whether or not to perform hysterectomy at the time of salpingo-oophorectomy is complex. In patients without hereditary cancer syndromes, such as BRCA or Lynch syndrome, hysterectomy likely offers no benefit to the patient who is undergoing a procedure for the purpose of ovarian ablation. An argument has been made that hysterectomy can eliminate the increased endometrial cancer risk associated with tamoxifen. However, given the previously discussed data, after oophorectomy, aromatase inhibitors are the preferred treatment option, and tamoxifen can be avoided. If a patient has unrelated underlying uterine pathology a hysterectomy might be indicated. Women with BRCA germline mutations, particularly women with BRCA-1 mutations, may be at increased risk for uterine serous carcinoma, and in these patients, hysterectomy at the time of oophorectomy can be discussed and offered, though as yet, it is not a guideline recommendation for all patients.6 Patients who ask to “just take everything out while you are there” without a clear indication for hysterectomy should be counseled that hysterectomy is associated with increased risk, recovery, and cost, compared with bilateral salpingo-oophorectomy. Among patients with elevated surgical risk (such as morbid obesity, known adhesive disease, increased venous thromboembolism risk, diabetes, and so on) it may not always be appropriate to extend the complexity of the procedure given the limited benefit.
Consequences of ovarian ablation
It should be noted that ovarian ablation in the TEXT and SOFT trials was not associated with an increase in overall survival for women with premenopausal breast cancer. Alternatively, large, observational studies such as the Nurses’ Health Study have shown that premenopausal oophorectomy without hormone replacement therapy is associated with increased all-cause mortality. This is primarily driven by the increased cardiopulmonary risk (heart attack and stroke), deaths after osteoporotic hip fractures, and the increased risk for lung and colon cancer.7,8
It is normal for young patients to have heightened concerns regarding their risk of recurrence from their cancer, and less concerned by threats to their health in decades to come. However, it is important to discuss this data with the patient and allow for her to make an informed decision about her immediate versus future risks. If she determines that she is not interested in permanent ovarian ablation with oophorectomy because of either surgical risks, concerns regarding permanent infertility, or increased all-cause mortality, she still has an option for medical ovarian ablation with GnRH analogues in the treatment of her breast cancer.
Hormone replacement therapy postoperatively
Women who undergo oophorectomy for the treatment of breast cancer should not be offered hormone replacement therapy. This is true even for “triple-negative” or hormone receptor–negative breast cancers as there is still some observed benefit of ovarian ablation, and risk from exogenous hormone administration in these women. Alternatively, postoperative hormone replacement therapy remains safe until the age of natural menopause among premenopausal patients with BRCA germline mutations without a preceding breast cancer diagnosis.
Surgical ovarian ablation with bilateral salpingo-oophorectomy is a valuable strategy in the adjuvant therapy of premenopausal breast cancer, particularly among BRCA mutation carriers and women with hormone receptor–positive disease, or among women who find adherence to medical ablation difficult. Patients should be carefully counseled that this may introduce increased long-term cardiovascular risks for them.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill.
Ovarian cancer most commonly follows a pattern of intraperitoneal spread, and even in the setting of bulky extra-ovarian disease, it can be thought of as being largely localized to the peritoneal compartment. This forms some of the rationale for performing extensive cytoreductive surgery (CRS) on ovarian cancer metastatic within the peritoneal cavity, and also some of the rationale for delivery of cytotoxic therapy directly to this compartment (intraperitoneal or “IP” chemotherapy). To be most effective, IP chemotherapy should be able to contact all peritoneal surfaces and be exposed to very low volume tumors (ideally no thicker than 2-mm implants).
Dr. Emma C. Rossi
There is a large body of evidence demonstrating the benefits of conventional IP chemotherapy in women who have received complete or “optimal” CRS to disease measuring less than 1 cm3.1 However, IP chemotherapy is complicated by difficult administration and can be difficult for patients to tolerate. It is associated with significant toxicity, more so than what is seen from intravenous chemotherapy, and this toxicity is drawn out over the 18 (or more) weeks of therapy. It requires placement of an intraperitoneal port, and there are many problems associated with this foreign body including infection, malposition, and even erosions into underlying visceral structures. There are also concerns regarding the ability of the intraperitoneal infusions to reach all peritoneal surfaces when postoperative adhesions may have formed to pocket-off areas of the peritoneal cavity.
Hyperthermic intraperitoneal chemotherapy (HIPEC), at the time of CRS, is a strategy that has been explored to overcome some of these challenges.2 HIPEC has the most history as an adjunct to the surgical management of gastrointestinal cancers (particularly appendiceal and colorectal). The technique first described by Dr. Paul H. Sugarbaker for gastrointestinal tumors remains similar to that performed in ovarian cancer.3 Patients first undergo extensive CRS until there is no macroscopic residual disease. Immediately following cytoreduction, catheters are placed into the peritoneal cavity, the main incision is temporarily closed (to prevent spillage), and an infusion of cytotoxic agents (commonly cisplatin, often with a second agent such as mitomycin C or doxorubicin) is warmed and then distilled into the peritoneal cavity until it is “moderately distended.” The patient’s body is then rolled back and forth to “wash” down the entire peritoneal cavity. All peritoneal surfaces can be touched by the agent as this procedure is happening intraoperatively prior to adhesion formation.
The “H” in HIPEC stands for hyperthermic, which is a key differentiator from traditional intraperitoneal and intravenous chemotherapy administration. Some chemotherapy agents, such as cisplatin, have a synergistic effect with hyperthermia. Some of these effects include increased oxygen free radical formation, increased cellular uptake of drug, reversal of mechanisms of drug resistance, and increases in DNA damage. The ideal range of hyperthermia is between 41° C and 44° C. At higher temperatures, infusions rates can be faster; however, higher temperatures are associated with more toxicity, particularly of the small bowel.4
Toxicity is a concern with HIPEC.5 Cytoreductive surgery for ovarian cancer can be associated with substantial morbidity, and exposing patients to prolonged operative time, extended periods of hyperthermia, and high doses of cytotoxic agents is a concern. When performed by high volume, experienced practitioners, approximately 12% of patients experience serious (grade 3-5) toxicity after CRS with HIPEC, with a procedure-related mortality of 1.2%. The majority of major toxicities were bone marrow suppression and nephrotoxicity (which in some cases can result in patients requiring hemodialysis in the immediate postoperative period). It is for this reason that most HIPEC protocols include a routine ICU admission postoperatively to closely monitor patients for major renal toxicity and electrolyte disturbances. These complications are associated with higher doses of administered cisplatin. Febrile neutropenia and gastrointestinal complications (such as bowel perforation, fistula, or anastomotic leak) also comprise the most common major toxicities. Patient factors to consider as higher risk for morbidity and mortality include underlying cardiac or pulmonary disease, poor performance status, extreme obesity, and preexisting renal disease.
While the history of HIPEC was focused around the treatment of GI peritoneal malignancies, in more recent years, the technique has been applied and studied in women with ovarian cancer.
The indications for use can vary from the upfront setting (at the time of primary CRS), following neoadjuvant chemotherapy (at the time of interval CRS), or in the recurrent setting (at the time of secondary CRS).2 Possibly the most compelling study exploring HIPEC in ovarian cancer was published earlier this year in the New England Journal of Medicine.6 This study explored the use of HIPEC at the time of interval CRS following three cycles of neoadjuvant platinum and taxane intravenous chemotherapy. Two hundred and forty-five patients were randomly assigned at the time of optimal interval CRS to either CRS alone or CRS with HIPEC with cisplatin administered over 90 minutes. All patients received three additional cycles of intravenous platinum and taxane chemotherapy. Death was observed in a significantly higher proportion of patients in the non-HIPEC group (62% versus 50%). HIPEC was associated with a hazard ratio for death of 0.67 (P = .02). In this study, a similar number of severe adverse outcomes were observed in the two groups, though specific information was lacking, particularly with respect to renal toxicity.
These findings are intriguing and have energized interest in HIPEC by many gynecologic oncology providers; however, there are some concerns regarding the results. Patients in this study received not one intervention, but in fact three interventions (hyperthermia, an additional cycle of chemotherapy, and the peritoneal administration of chemotherapy). Any one of these three variables could explain the outcomes and it is difficult to know if all three (in the form of HIPEC) are necessary to see this observed benefit. Others have questioned the finding of no added toxicity when HIPEC is applied. This is inconsistent with what has been presented elsewhere. It is unclear from the data whether or not the nephrotoxicity was comparable between the two groups or more severe among those who received HIPEC.
An additional concern regarding HIPEC is the feasibility. Additional operative times (by up to 90 minutes), increased duration of hospitalization (including ICU admission), and additional equipment and specialized personnel are required for this technique. This may further hinder its uptake and routine practice. In the meantime, we continue to await further clinical trials that will better define the ovarian cancer patient population who might benefit from this technique and provide further data regarding its risk/benefit profile.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill.
References
1. Armstrong DK et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354:34-43.
2. Helm CW et al. Hyperthermic intraperitoneal chemotherapy with and without cytoreductive surgery for epithelial ovarian cancer. J Surg Oncol. 2008;98(4):283-90.
3. Glehen O et al. Hyperthermic intraperitoneal chemotherapy: nomenclature and modalities of perfusion. J Surg Oncol. 2008;98(4):242-6.
4. Kusamura S et al. Drugs, carrier solutions and temperature in hyperthermic intraperitoneal chemotherapy. J Surg Oncol. 2008;98(4):247-52.
5. Kusamura S et al. Impact of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy on systemic toxicity. Ann Surg Oncol. 2007;14(9):2550-8.
Ovarian cancer most commonly follows a pattern of intraperitoneal spread, and even in the setting of bulky extra-ovarian disease, it can be thought of as being largely localized to the peritoneal compartment. This forms some of the rationale for performing extensive cytoreductive surgery (CRS) on ovarian cancer metastatic within the peritoneal cavity, and also some of the rationale for delivery of cytotoxic therapy directly to this compartment (intraperitoneal or “IP” chemotherapy). To be most effective, IP chemotherapy should be able to contact all peritoneal surfaces and be exposed to very low volume tumors (ideally no thicker than 2-mm implants).
Dr. Emma C. Rossi
There is a large body of evidence demonstrating the benefits of conventional IP chemotherapy in women who have received complete or “optimal” CRS to disease measuring less than 1 cm3.1 However, IP chemotherapy is complicated by difficult administration and can be difficult for patients to tolerate. It is associated with significant toxicity, more so than what is seen from intravenous chemotherapy, and this toxicity is drawn out over the 18 (or more) weeks of therapy. It requires placement of an intraperitoneal port, and there are many problems associated with this foreign body including infection, malposition, and even erosions into underlying visceral structures. There are also concerns regarding the ability of the intraperitoneal infusions to reach all peritoneal surfaces when postoperative adhesions may have formed to pocket-off areas of the peritoneal cavity.
Hyperthermic intraperitoneal chemotherapy (HIPEC), at the time of CRS, is a strategy that has been explored to overcome some of these challenges.2 HIPEC has the most history as an adjunct to the surgical management of gastrointestinal cancers (particularly appendiceal and colorectal). The technique first described by Dr. Paul H. Sugarbaker for gastrointestinal tumors remains similar to that performed in ovarian cancer.3 Patients first undergo extensive CRS until there is no macroscopic residual disease. Immediately following cytoreduction, catheters are placed into the peritoneal cavity, the main incision is temporarily closed (to prevent spillage), and an infusion of cytotoxic agents (commonly cisplatin, often with a second agent such as mitomycin C or doxorubicin) is warmed and then distilled into the peritoneal cavity until it is “moderately distended.” The patient’s body is then rolled back and forth to “wash” down the entire peritoneal cavity. All peritoneal surfaces can be touched by the agent as this procedure is happening intraoperatively prior to adhesion formation.
The “H” in HIPEC stands for hyperthermic, which is a key differentiator from traditional intraperitoneal and intravenous chemotherapy administration. Some chemotherapy agents, such as cisplatin, have a synergistic effect with hyperthermia. Some of these effects include increased oxygen free radical formation, increased cellular uptake of drug, reversal of mechanisms of drug resistance, and increases in DNA damage. The ideal range of hyperthermia is between 41° C and 44° C. At higher temperatures, infusions rates can be faster; however, higher temperatures are associated with more toxicity, particularly of the small bowel.4
Toxicity is a concern with HIPEC.5 Cytoreductive surgery for ovarian cancer can be associated with substantial morbidity, and exposing patients to prolonged operative time, extended periods of hyperthermia, and high doses of cytotoxic agents is a concern. When performed by high volume, experienced practitioners, approximately 12% of patients experience serious (grade 3-5) toxicity after CRS with HIPEC, with a procedure-related mortality of 1.2%. The majority of major toxicities were bone marrow suppression and nephrotoxicity (which in some cases can result in patients requiring hemodialysis in the immediate postoperative period). It is for this reason that most HIPEC protocols include a routine ICU admission postoperatively to closely monitor patients for major renal toxicity and electrolyte disturbances. These complications are associated with higher doses of administered cisplatin. Febrile neutropenia and gastrointestinal complications (such as bowel perforation, fistula, or anastomotic leak) also comprise the most common major toxicities. Patient factors to consider as higher risk for morbidity and mortality include underlying cardiac or pulmonary disease, poor performance status, extreme obesity, and preexisting renal disease.
While the history of HIPEC was focused around the treatment of GI peritoneal malignancies, in more recent years, the technique has been applied and studied in women with ovarian cancer.
The indications for use can vary from the upfront setting (at the time of primary CRS), following neoadjuvant chemotherapy (at the time of interval CRS), or in the recurrent setting (at the time of secondary CRS).2 Possibly the most compelling study exploring HIPEC in ovarian cancer was published earlier this year in the New England Journal of Medicine.6 This study explored the use of HIPEC at the time of interval CRS following three cycles of neoadjuvant platinum and taxane intravenous chemotherapy. Two hundred and forty-five patients were randomly assigned at the time of optimal interval CRS to either CRS alone or CRS with HIPEC with cisplatin administered over 90 minutes. All patients received three additional cycles of intravenous platinum and taxane chemotherapy. Death was observed in a significantly higher proportion of patients in the non-HIPEC group (62% versus 50%). HIPEC was associated with a hazard ratio for death of 0.67 (P = .02). In this study, a similar number of severe adverse outcomes were observed in the two groups, though specific information was lacking, particularly with respect to renal toxicity.
These findings are intriguing and have energized interest in HIPEC by many gynecologic oncology providers; however, there are some concerns regarding the results. Patients in this study received not one intervention, but in fact three interventions (hyperthermia, an additional cycle of chemotherapy, and the peritoneal administration of chemotherapy). Any one of these three variables could explain the outcomes and it is difficult to know if all three (in the form of HIPEC) are necessary to see this observed benefit. Others have questioned the finding of no added toxicity when HIPEC is applied. This is inconsistent with what has been presented elsewhere. It is unclear from the data whether or not the nephrotoxicity was comparable between the two groups or more severe among those who received HIPEC.
An additional concern regarding HIPEC is the feasibility. Additional operative times (by up to 90 minutes), increased duration of hospitalization (including ICU admission), and additional equipment and specialized personnel are required for this technique. This may further hinder its uptake and routine practice. In the meantime, we continue to await further clinical trials that will better define the ovarian cancer patient population who might benefit from this technique and provide further data regarding its risk/benefit profile.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill.
References
1. Armstrong DK et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354:34-43.
2. Helm CW et al. Hyperthermic intraperitoneal chemotherapy with and without cytoreductive surgery for epithelial ovarian cancer. J Surg Oncol. 2008;98(4):283-90.
3. Glehen O et al. Hyperthermic intraperitoneal chemotherapy: nomenclature and modalities of perfusion. J Surg Oncol. 2008;98(4):242-6.
4. Kusamura S et al. Drugs, carrier solutions and temperature in hyperthermic intraperitoneal chemotherapy. J Surg Oncol. 2008;98(4):247-52.
5. Kusamura S et al. Impact of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy on systemic toxicity. Ann Surg Oncol. 2007;14(9):2550-8.
Ovarian cancer most commonly follows a pattern of intraperitoneal spread, and even in the setting of bulky extra-ovarian disease, it can be thought of as being largely localized to the peritoneal compartment. This forms some of the rationale for performing extensive cytoreductive surgery (CRS) on ovarian cancer metastatic within the peritoneal cavity, and also some of the rationale for delivery of cytotoxic therapy directly to this compartment (intraperitoneal or “IP” chemotherapy). To be most effective, IP chemotherapy should be able to contact all peritoneal surfaces and be exposed to very low volume tumors (ideally no thicker than 2-mm implants).
Dr. Emma C. Rossi
There is a large body of evidence demonstrating the benefits of conventional IP chemotherapy in women who have received complete or “optimal” CRS to disease measuring less than 1 cm3.1 However, IP chemotherapy is complicated by difficult administration and can be difficult for patients to tolerate. It is associated with significant toxicity, more so than what is seen from intravenous chemotherapy, and this toxicity is drawn out over the 18 (or more) weeks of therapy. It requires placement of an intraperitoneal port, and there are many problems associated with this foreign body including infection, malposition, and even erosions into underlying visceral structures. There are also concerns regarding the ability of the intraperitoneal infusions to reach all peritoneal surfaces when postoperative adhesions may have formed to pocket-off areas of the peritoneal cavity.
Hyperthermic intraperitoneal chemotherapy (HIPEC), at the time of CRS, is a strategy that has been explored to overcome some of these challenges.2 HIPEC has the most history as an adjunct to the surgical management of gastrointestinal cancers (particularly appendiceal and colorectal). The technique first described by Dr. Paul H. Sugarbaker for gastrointestinal tumors remains similar to that performed in ovarian cancer.3 Patients first undergo extensive CRS until there is no macroscopic residual disease. Immediately following cytoreduction, catheters are placed into the peritoneal cavity, the main incision is temporarily closed (to prevent spillage), and an infusion of cytotoxic agents (commonly cisplatin, often with a second agent such as mitomycin C or doxorubicin) is warmed and then distilled into the peritoneal cavity until it is “moderately distended.” The patient’s body is then rolled back and forth to “wash” down the entire peritoneal cavity. All peritoneal surfaces can be touched by the agent as this procedure is happening intraoperatively prior to adhesion formation.
The “H” in HIPEC stands for hyperthermic, which is a key differentiator from traditional intraperitoneal and intravenous chemotherapy administration. Some chemotherapy agents, such as cisplatin, have a synergistic effect with hyperthermia. Some of these effects include increased oxygen free radical formation, increased cellular uptake of drug, reversal of mechanisms of drug resistance, and increases in DNA damage. The ideal range of hyperthermia is between 41° C and 44° C. At higher temperatures, infusions rates can be faster; however, higher temperatures are associated with more toxicity, particularly of the small bowel.4
Toxicity is a concern with HIPEC.5 Cytoreductive surgery for ovarian cancer can be associated with substantial morbidity, and exposing patients to prolonged operative time, extended periods of hyperthermia, and high doses of cytotoxic agents is a concern. When performed by high volume, experienced practitioners, approximately 12% of patients experience serious (grade 3-5) toxicity after CRS with HIPEC, with a procedure-related mortality of 1.2%. The majority of major toxicities were bone marrow suppression and nephrotoxicity (which in some cases can result in patients requiring hemodialysis in the immediate postoperative period). It is for this reason that most HIPEC protocols include a routine ICU admission postoperatively to closely monitor patients for major renal toxicity and electrolyte disturbances. These complications are associated with higher doses of administered cisplatin. Febrile neutropenia and gastrointestinal complications (such as bowel perforation, fistula, or anastomotic leak) also comprise the most common major toxicities. Patient factors to consider as higher risk for morbidity and mortality include underlying cardiac or pulmonary disease, poor performance status, extreme obesity, and preexisting renal disease.
While the history of HIPEC was focused around the treatment of GI peritoneal malignancies, in more recent years, the technique has been applied and studied in women with ovarian cancer.
The indications for use can vary from the upfront setting (at the time of primary CRS), following neoadjuvant chemotherapy (at the time of interval CRS), or in the recurrent setting (at the time of secondary CRS).2 Possibly the most compelling study exploring HIPEC in ovarian cancer was published earlier this year in the New England Journal of Medicine.6 This study explored the use of HIPEC at the time of interval CRS following three cycles of neoadjuvant platinum and taxane intravenous chemotherapy. Two hundred and forty-five patients were randomly assigned at the time of optimal interval CRS to either CRS alone or CRS with HIPEC with cisplatin administered over 90 minutes. All patients received three additional cycles of intravenous platinum and taxane chemotherapy. Death was observed in a significantly higher proportion of patients in the non-HIPEC group (62% versus 50%). HIPEC was associated with a hazard ratio for death of 0.67 (P = .02). In this study, a similar number of severe adverse outcomes were observed in the two groups, though specific information was lacking, particularly with respect to renal toxicity.
These findings are intriguing and have energized interest in HIPEC by many gynecologic oncology providers; however, there are some concerns regarding the results. Patients in this study received not one intervention, but in fact three interventions (hyperthermia, an additional cycle of chemotherapy, and the peritoneal administration of chemotherapy). Any one of these three variables could explain the outcomes and it is difficult to know if all three (in the form of HIPEC) are necessary to see this observed benefit. Others have questioned the finding of no added toxicity when HIPEC is applied. This is inconsistent with what has been presented elsewhere. It is unclear from the data whether or not the nephrotoxicity was comparable between the two groups or more severe among those who received HIPEC.
An additional concern regarding HIPEC is the feasibility. Additional operative times (by up to 90 minutes), increased duration of hospitalization (including ICU admission), and additional equipment and specialized personnel are required for this technique. This may further hinder its uptake and routine practice. In the meantime, we continue to await further clinical trials that will better define the ovarian cancer patient population who might benefit from this technique and provide further data regarding its risk/benefit profile.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill.
References
1. Armstrong DK et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354:34-43.
2. Helm CW et al. Hyperthermic intraperitoneal chemotherapy with and without cytoreductive surgery for epithelial ovarian cancer. J Surg Oncol. 2008;98(4):283-90.
3. Glehen O et al. Hyperthermic intraperitoneal chemotherapy: nomenclature and modalities of perfusion. J Surg Oncol. 2008;98(4):242-6.
4. Kusamura S et al. Drugs, carrier solutions and temperature in hyperthermic intraperitoneal chemotherapy. J Surg Oncol. 2008;98(4):247-52.
5. Kusamura S et al. Impact of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy on systemic toxicity. Ann Surg Oncol. 2007;14(9):2550-8.
There is an increased focus on reducing the costs of health care delivery, and one major driver of surgical cost is length of hospitalization. A minimally invasive surgical approach to hysterectomy is a strategy that significantly enhances recovery and shortens hospital stay, although many patients who can safely be considered for same-day discharge (SDD), including many with cancer, are still admitted to the hospital overnight. Much has been published on the predictors and pathways for successful same-day discharge after minimally invasive hysterectomy, and in this column we will review how to best predict who is a good candidate for SDD and how to optimize the success of this approach with respect to safety and patient satisfaction.
What are the benefits to SDD?
Dr. Emma C. Rossi
Certainly, decreased hospitalization costs are an attractive feature of SDD following hysterectomy, although surgeons should also be mindful that patient-centered outcomes, such as pain control, managing nausea, and patient satisfaction, also are considered with equal emphasis. Several studies have shown that, in appropriate candidates and when proactive pathways are used, patient satisfaction is preserved with SDD following hysterectomy.1
Choosing patient candidates
Same day discharge is most successfully accomplished in patients of good general baseline health.2 Diabetic patients, particularly those on insulin, are generally not good candidates for SDD because it is important to monitor and intervene in blood glucose changes that are influenced by a nothing-by-mouth status and surgical stress. We recommend observing patients overnight with a history of pulmonary disease who may have transient increased postoperative O2 needs. Similarly, patients with significant cardiac disease (including heart failure and coronary disease) may benefit from prolonged overnight observation.
Particular caution should be paid to patients with obstructive sleep apnea, which may be occult but anticipated in patients with very high body mass indexes (greater than 40 kg/m2). General anesthetic drugs, the trauma of intubation, and opioids all couple with the underlying airway compromise such that these patients are at risk for postoperative apnea, which, in severe cases, can result in anoxia and death. These patients should be considered for continuous pulse-ox monitoring for at least 12-24 hours postoperatively and are not good candidates for same-day discharge.
Patients who have baseline anticoagulation that has been stopped or bridged preoperatively should have prolonged observation with recheck of their postoperative hemoglobin prior to discharge.
Patients who live alone or are very elderly with baseline frailty are poor candidates for SDD and may benefit from nursing observation overnight while they metabolize their anesthesia. Patients who have chronic opioid dependency present a greater challenge to control postoperative pain; these patients are generally less good candidates for SDD.
Studies have shown that the indication for the procedure (for example, cancer with staging, fibroids, endometriosis) is less critical in determining who is a good candidate for SDD.3 However, successful SDD rates are highest in more straightforward cases with few or no prior surgeries, small uteri (less than 14 weeks), a surgical duration of less than 3 hours, and a surgical start time before 2 p.m. Longer, more complex cases are typically associated with more blood loss, higher risk for occult complications, and more time under anesthesia (and in Trendelenburg), which can exacerbate airway edema. In preparation for such cases, it might be wise to prepare patients for the possibility that they may not be good candidates for discharge on the same day. In general, most SDD pathways exclude patients with very high BMI (greater than 50 kg/m2) because of concern for airway patency and because these cases may be more complex with higher underlying risk. In addition, many of these patients have diabetes and require perioperative metabolic interventions.
Patient preparation
A key component to successful SDD is setting patient expectations. Patients should be informed at their preoperative visit that, unless there is an unexpected occurrence or response to the surgery, they will be discharged to home the same day. This allows them to prepare their home (including transportation needs) in advance. They should be provided with information about what to expect that first night after surgery (including potential residual drowsiness or nausea from anesthesia and immediate postoperative pain).
On the day of surgery, under the influence of anesthesia and pain medication, patients will have difficulty retaining complex discharge instructions. The preoperative visit is critically important because it’s the best time to provide them with this information, including postoperative activity limitations, wound and dressing care, and follow-up instructions. This is also the best time to provide prescriptions for postoperative pain, nausea, and constipation prophylaxis with detailed instructions about best use. Patients should be encouraged to fill these prescriptions preoperatively so that they have these medications on hand on the evening of their discharge.
Many programs utilize a combination of educational strategies (in person, written, video) to maximize the likelihood of retention.1 It is also important to offer an opportunity for patients to ask questions about this information after they have received it (for example, by phoning the patients prior to their procedure).
Preoperative strategies
Postoperative pain and nausea can be preempted with immediate preoperative doses of dexamethasone, gabapentin, ondansetron, celecoxib, and acetaminophen. Postoperative nausea is associated with dehydration; therefore, ensure patients are well hydrated preoperatively by avoiding bowel preparations and minimizing the duration of nothing-by-mouth status. Multimodal pain strategies have consistently shown improved perioperative pain control and decreased GI dysfunction.4
Intraoperative strategies
Consider in-and-out catheterization rather than placement of an indwelling catheter for anticipated short cases without complex bladder dissection.5 Minimize blood loss and maximally evacuate blood and clots with suction because hemoperitoneum can induce nausea and pain.
Pain from retained gas under the diaphragm can be reduced by bathing the diaphragms with 400 cc of dilute local anesthetic made by mixing 50 mL of 0.5% bupivacaine in 1000 mL normal saline prior to removal of pneumoperitoneum and while still in Trendelenburg. Ensure there is minimal retained intraperitoneal CO2 at the completion of the surgery by asking the anesthesiologists to perform positive pressure ventilations prior to fascial closure. Consider injecting port sites (including the peritoneal and fascial layers) with a mixture of immediate and long-acting local anesthetics. Request that the anesthesia staff administer intraoperative doses of IV ketorolac, acetaminophen, and tramadol (in preference to opioids) and an aggressive perioperative cocktail of antiemetics.
Management in the recovery room
Surgeons should ensure that recovery room staff are well versed in the pathway for patients who are selected for SDD to ensure proactive implementation of analgesic and antiemetic regimens and to fast-track the various tasks and education required for discharge.5
Patients should be started on their home postoperative medication regimen in the recovery room, including an anti-inflammatory such as diclofenac, sublingual tramadol (in preference to an opioid, such as hydrocodone), docusate, and sennosides. IV opioids should be avoided because they can result in somnolence and nausea.
If placed intraoperatively, the Foley catheter should be removed early to allow adequate time to void. Backfilling the bladder prior to removal can hasten the urge to void and help objectively document completeness of evacuation. All patients should be seen by the anesthesiologist and/or surgeon prior to discharge.
For patients who are discharged same day, a follow-up phone call on postoperative day 1 is valuable to ensure that they have continued their successful postoperative transition to the home and to intervene early if there are concerns for patient satisfaction.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill.
2. Rivard C et al. Factors influencing same-day hospital discharge and risk factors for readmission after robotic surgery in the gynecologic oncology patient population. J Minim Invasive Gynecol. 2015 Feb;22(2):219-26.
3. Lee SJ et al. The feasibility and safety of same-day discharge after robotic-assisted hysterectomy alone or with other procedures for benign and malignant indications. Gynecol Oncol. 2014 Jun;133(3):552-5.
4. Elia N et al. Does multimodal analgesia with acetaminophen, nonsteroidal antiinflammatory drugs, or selective cyclooxygenase-2 inhibitors and patient-controlled analgesia morphine offer advantages over morphine alone? Meta-analyses of randomized trials. Anesthesiology. 2005 Dec;103(6):1296-304.
5. Donnez O et al. Low pain score after total laparoscopic hysterectomy and same-day discharge within less than 5 hours: Results of a prospective observational study. J Minim Invasive Gynecol. 2015 Nov-Dec;22(7):1293-9.
There is an increased focus on reducing the costs of health care delivery, and one major driver of surgical cost is length of hospitalization. A minimally invasive surgical approach to hysterectomy is a strategy that significantly enhances recovery and shortens hospital stay, although many patients who can safely be considered for same-day discharge (SDD), including many with cancer, are still admitted to the hospital overnight. Much has been published on the predictors and pathways for successful same-day discharge after minimally invasive hysterectomy, and in this column we will review how to best predict who is a good candidate for SDD and how to optimize the success of this approach with respect to safety and patient satisfaction.
What are the benefits to SDD?
Dr. Emma C. Rossi
Certainly, decreased hospitalization costs are an attractive feature of SDD following hysterectomy, although surgeons should also be mindful that patient-centered outcomes, such as pain control, managing nausea, and patient satisfaction, also are considered with equal emphasis. Several studies have shown that, in appropriate candidates and when proactive pathways are used, patient satisfaction is preserved with SDD following hysterectomy.1
Choosing patient candidates
Same day discharge is most successfully accomplished in patients of good general baseline health.2 Diabetic patients, particularly those on insulin, are generally not good candidates for SDD because it is important to monitor and intervene in blood glucose changes that are influenced by a nothing-by-mouth status and surgical stress. We recommend observing patients overnight with a history of pulmonary disease who may have transient increased postoperative O2 needs. Similarly, patients with significant cardiac disease (including heart failure and coronary disease) may benefit from prolonged overnight observation.
Particular caution should be paid to patients with obstructive sleep apnea, which may be occult but anticipated in patients with very high body mass indexes (greater than 40 kg/m2). General anesthetic drugs, the trauma of intubation, and opioids all couple with the underlying airway compromise such that these patients are at risk for postoperative apnea, which, in severe cases, can result in anoxia and death. These patients should be considered for continuous pulse-ox monitoring for at least 12-24 hours postoperatively and are not good candidates for same-day discharge.
Patients who have baseline anticoagulation that has been stopped or bridged preoperatively should have prolonged observation with recheck of their postoperative hemoglobin prior to discharge.
Patients who live alone or are very elderly with baseline frailty are poor candidates for SDD and may benefit from nursing observation overnight while they metabolize their anesthesia. Patients who have chronic opioid dependency present a greater challenge to control postoperative pain; these patients are generally less good candidates for SDD.
Studies have shown that the indication for the procedure (for example, cancer with staging, fibroids, endometriosis) is less critical in determining who is a good candidate for SDD.3 However, successful SDD rates are highest in more straightforward cases with few or no prior surgeries, small uteri (less than 14 weeks), a surgical duration of less than 3 hours, and a surgical start time before 2 p.m. Longer, more complex cases are typically associated with more blood loss, higher risk for occult complications, and more time under anesthesia (and in Trendelenburg), which can exacerbate airway edema. In preparation for such cases, it might be wise to prepare patients for the possibility that they may not be good candidates for discharge on the same day. In general, most SDD pathways exclude patients with very high BMI (greater than 50 kg/m2) because of concern for airway patency and because these cases may be more complex with higher underlying risk. In addition, many of these patients have diabetes and require perioperative metabolic interventions.
Patient preparation
A key component to successful SDD is setting patient expectations. Patients should be informed at their preoperative visit that, unless there is an unexpected occurrence or response to the surgery, they will be discharged to home the same day. This allows them to prepare their home (including transportation needs) in advance. They should be provided with information about what to expect that first night after surgery (including potential residual drowsiness or nausea from anesthesia and immediate postoperative pain).
On the day of surgery, under the influence of anesthesia and pain medication, patients will have difficulty retaining complex discharge instructions. The preoperative visit is critically important because it’s the best time to provide them with this information, including postoperative activity limitations, wound and dressing care, and follow-up instructions. This is also the best time to provide prescriptions for postoperative pain, nausea, and constipation prophylaxis with detailed instructions about best use. Patients should be encouraged to fill these prescriptions preoperatively so that they have these medications on hand on the evening of their discharge.
Many programs utilize a combination of educational strategies (in person, written, video) to maximize the likelihood of retention.1 It is also important to offer an opportunity for patients to ask questions about this information after they have received it (for example, by phoning the patients prior to their procedure).
Preoperative strategies
Postoperative pain and nausea can be preempted with immediate preoperative doses of dexamethasone, gabapentin, ondansetron, celecoxib, and acetaminophen. Postoperative nausea is associated with dehydration; therefore, ensure patients are well hydrated preoperatively by avoiding bowel preparations and minimizing the duration of nothing-by-mouth status. Multimodal pain strategies have consistently shown improved perioperative pain control and decreased GI dysfunction.4
Intraoperative strategies
Consider in-and-out catheterization rather than placement of an indwelling catheter for anticipated short cases without complex bladder dissection.5 Minimize blood loss and maximally evacuate blood and clots with suction because hemoperitoneum can induce nausea and pain.
Pain from retained gas under the diaphragm can be reduced by bathing the diaphragms with 400 cc of dilute local anesthetic made by mixing 50 mL of 0.5% bupivacaine in 1000 mL normal saline prior to removal of pneumoperitoneum and while still in Trendelenburg. Ensure there is minimal retained intraperitoneal CO2 at the completion of the surgery by asking the anesthesiologists to perform positive pressure ventilations prior to fascial closure. Consider injecting port sites (including the peritoneal and fascial layers) with a mixture of immediate and long-acting local anesthetics. Request that the anesthesia staff administer intraoperative doses of IV ketorolac, acetaminophen, and tramadol (in preference to opioids) and an aggressive perioperative cocktail of antiemetics.
Management in the recovery room
Surgeons should ensure that recovery room staff are well versed in the pathway for patients who are selected for SDD to ensure proactive implementation of analgesic and antiemetic regimens and to fast-track the various tasks and education required for discharge.5
Patients should be started on their home postoperative medication regimen in the recovery room, including an anti-inflammatory such as diclofenac, sublingual tramadol (in preference to an opioid, such as hydrocodone), docusate, and sennosides. IV opioids should be avoided because they can result in somnolence and nausea.
If placed intraoperatively, the Foley catheter should be removed early to allow adequate time to void. Backfilling the bladder prior to removal can hasten the urge to void and help objectively document completeness of evacuation. All patients should be seen by the anesthesiologist and/or surgeon prior to discharge.
For patients who are discharged same day, a follow-up phone call on postoperative day 1 is valuable to ensure that they have continued their successful postoperative transition to the home and to intervene early if there are concerns for patient satisfaction.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill.
2. Rivard C et al. Factors influencing same-day hospital discharge and risk factors for readmission after robotic surgery in the gynecologic oncology patient population. J Minim Invasive Gynecol. 2015 Feb;22(2):219-26.
3. Lee SJ et al. The feasibility and safety of same-day discharge after robotic-assisted hysterectomy alone or with other procedures for benign and malignant indications. Gynecol Oncol. 2014 Jun;133(3):552-5.
4. Elia N et al. Does multimodal analgesia with acetaminophen, nonsteroidal antiinflammatory drugs, or selective cyclooxygenase-2 inhibitors and patient-controlled analgesia morphine offer advantages over morphine alone? Meta-analyses of randomized trials. Anesthesiology. 2005 Dec;103(6):1296-304.
5. Donnez O et al. Low pain score after total laparoscopic hysterectomy and same-day discharge within less than 5 hours: Results of a prospective observational study. J Minim Invasive Gynecol. 2015 Nov-Dec;22(7):1293-9.
There is an increased focus on reducing the costs of health care delivery, and one major driver of surgical cost is length of hospitalization. A minimally invasive surgical approach to hysterectomy is a strategy that significantly enhances recovery and shortens hospital stay, although many patients who can safely be considered for same-day discharge (SDD), including many with cancer, are still admitted to the hospital overnight. Much has been published on the predictors and pathways for successful same-day discharge after minimally invasive hysterectomy, and in this column we will review how to best predict who is a good candidate for SDD and how to optimize the success of this approach with respect to safety and patient satisfaction.
What are the benefits to SDD?
Dr. Emma C. Rossi
Certainly, decreased hospitalization costs are an attractive feature of SDD following hysterectomy, although surgeons should also be mindful that patient-centered outcomes, such as pain control, managing nausea, and patient satisfaction, also are considered with equal emphasis. Several studies have shown that, in appropriate candidates and when proactive pathways are used, patient satisfaction is preserved with SDD following hysterectomy.1
Choosing patient candidates
Same day discharge is most successfully accomplished in patients of good general baseline health.2 Diabetic patients, particularly those on insulin, are generally not good candidates for SDD because it is important to monitor and intervene in blood glucose changes that are influenced by a nothing-by-mouth status and surgical stress. We recommend observing patients overnight with a history of pulmonary disease who may have transient increased postoperative O2 needs. Similarly, patients with significant cardiac disease (including heart failure and coronary disease) may benefit from prolonged overnight observation.
Particular caution should be paid to patients with obstructive sleep apnea, which may be occult but anticipated in patients with very high body mass indexes (greater than 40 kg/m2). General anesthetic drugs, the trauma of intubation, and opioids all couple with the underlying airway compromise such that these patients are at risk for postoperative apnea, which, in severe cases, can result in anoxia and death. These patients should be considered for continuous pulse-ox monitoring for at least 12-24 hours postoperatively and are not good candidates for same-day discharge.
Patients who have baseline anticoagulation that has been stopped or bridged preoperatively should have prolonged observation with recheck of their postoperative hemoglobin prior to discharge.
Patients who live alone or are very elderly with baseline frailty are poor candidates for SDD and may benefit from nursing observation overnight while they metabolize their anesthesia. Patients who have chronic opioid dependency present a greater challenge to control postoperative pain; these patients are generally less good candidates for SDD.
Studies have shown that the indication for the procedure (for example, cancer with staging, fibroids, endometriosis) is less critical in determining who is a good candidate for SDD.3 However, successful SDD rates are highest in more straightforward cases with few or no prior surgeries, small uteri (less than 14 weeks), a surgical duration of less than 3 hours, and a surgical start time before 2 p.m. Longer, more complex cases are typically associated with more blood loss, higher risk for occult complications, and more time under anesthesia (and in Trendelenburg), which can exacerbate airway edema. In preparation for such cases, it might be wise to prepare patients for the possibility that they may not be good candidates for discharge on the same day. In general, most SDD pathways exclude patients with very high BMI (greater than 50 kg/m2) because of concern for airway patency and because these cases may be more complex with higher underlying risk. In addition, many of these patients have diabetes and require perioperative metabolic interventions.
Patient preparation
A key component to successful SDD is setting patient expectations. Patients should be informed at their preoperative visit that, unless there is an unexpected occurrence or response to the surgery, they will be discharged to home the same day. This allows them to prepare their home (including transportation needs) in advance. They should be provided with information about what to expect that first night after surgery (including potential residual drowsiness or nausea from anesthesia and immediate postoperative pain).
On the day of surgery, under the influence of anesthesia and pain medication, patients will have difficulty retaining complex discharge instructions. The preoperative visit is critically important because it’s the best time to provide them with this information, including postoperative activity limitations, wound and dressing care, and follow-up instructions. This is also the best time to provide prescriptions for postoperative pain, nausea, and constipation prophylaxis with detailed instructions about best use. Patients should be encouraged to fill these prescriptions preoperatively so that they have these medications on hand on the evening of their discharge.
Many programs utilize a combination of educational strategies (in person, written, video) to maximize the likelihood of retention.1 It is also important to offer an opportunity for patients to ask questions about this information after they have received it (for example, by phoning the patients prior to their procedure).
Preoperative strategies
Postoperative pain and nausea can be preempted with immediate preoperative doses of dexamethasone, gabapentin, ondansetron, celecoxib, and acetaminophen. Postoperative nausea is associated with dehydration; therefore, ensure patients are well hydrated preoperatively by avoiding bowel preparations and minimizing the duration of nothing-by-mouth status. Multimodal pain strategies have consistently shown improved perioperative pain control and decreased GI dysfunction.4
Intraoperative strategies
Consider in-and-out catheterization rather than placement of an indwelling catheter for anticipated short cases without complex bladder dissection.5 Minimize blood loss and maximally evacuate blood and clots with suction because hemoperitoneum can induce nausea and pain.
Pain from retained gas under the diaphragm can be reduced by bathing the diaphragms with 400 cc of dilute local anesthetic made by mixing 50 mL of 0.5% bupivacaine in 1000 mL normal saline prior to removal of pneumoperitoneum and while still in Trendelenburg. Ensure there is minimal retained intraperitoneal CO2 at the completion of the surgery by asking the anesthesiologists to perform positive pressure ventilations prior to fascial closure. Consider injecting port sites (including the peritoneal and fascial layers) with a mixture of immediate and long-acting local anesthetics. Request that the anesthesia staff administer intraoperative doses of IV ketorolac, acetaminophen, and tramadol (in preference to opioids) and an aggressive perioperative cocktail of antiemetics.
Management in the recovery room
Surgeons should ensure that recovery room staff are well versed in the pathway for patients who are selected for SDD to ensure proactive implementation of analgesic and antiemetic regimens and to fast-track the various tasks and education required for discharge.5
Patients should be started on their home postoperative medication regimen in the recovery room, including an anti-inflammatory such as diclofenac, sublingual tramadol (in preference to an opioid, such as hydrocodone), docusate, and sennosides. IV opioids should be avoided because they can result in somnolence and nausea.
If placed intraoperatively, the Foley catheter should be removed early to allow adequate time to void. Backfilling the bladder prior to removal can hasten the urge to void and help objectively document completeness of evacuation. All patients should be seen by the anesthesiologist and/or surgeon prior to discharge.
For patients who are discharged same day, a follow-up phone call on postoperative day 1 is valuable to ensure that they have continued their successful postoperative transition to the home and to intervene early if there are concerns for patient satisfaction.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill.
2. Rivard C et al. Factors influencing same-day hospital discharge and risk factors for readmission after robotic surgery in the gynecologic oncology patient population. J Minim Invasive Gynecol. 2015 Feb;22(2):219-26.
3. Lee SJ et al. The feasibility and safety of same-day discharge after robotic-assisted hysterectomy alone or with other procedures for benign and malignant indications. Gynecol Oncol. 2014 Jun;133(3):552-5.
4. Elia N et al. Does multimodal analgesia with acetaminophen, nonsteroidal antiinflammatory drugs, or selective cyclooxygenase-2 inhibitors and patient-controlled analgesia morphine offer advantages over morphine alone? Meta-analyses of randomized trials. Anesthesiology. 2005 Dec;103(6):1296-304.
5. Donnez O et al. Low pain score after total laparoscopic hysterectomy and same-day discharge within less than 5 hours: Results of a prospective observational study. J Minim Invasive Gynecol. 2015 Nov-Dec;22(7):1293-9.
Hearing a diagnosis of cancer is one of the most significant moments of a patient’s life and informing a patient of her diagnosis is an emotionally and technically challenging task for an obstetrician gynecologist who is frequently on the front line of making this diagnosis. In this column, we will explore some patient-centered strategies to perform this difficult task well so that patients come away informed but with the highest chance for positive emotional adjustment.
Fewer than 10% of physicians report receiving formal training in techniques of breaking bad news. For the majority of clinicians concerns are centered on being honest and not taking away hope, and in responding to a patient’s emotions.1 The SPIKES approach was developed to arm physicians with strategies to discuss a cancer diagnosis with their patients. This approach includes six key elements to incorporate during the encounter. These strategies are not meant to be formulaic but rather consistent principles that can be adjusted for individual patient needs.
Setting up the discussion
Breaking bad news should not be a one-size-fits-all approach. Age, educational level, culture, religion, race and ethnicity, and socioeconomic opportunities each affects what and how patients may want to have this kind of information communicated to them. So how do you know how best to deliver a patient-centered approach for your patient? I recommend this simple strategy: Ask her. When ordering a test or performing a biopsy, let the patient know then why you are ordering the test and inform her of the possibility that the results may show cancer. Ask her how she would like for you to communicate that result. Would she like to be called by phone, the benefit of which is quick dissemination of information? Or would she like to receive the information face to face in the office? Research supports that most patients prefer to learn the result in the office.2 If so, I recommend scheduling a follow-up appointment in advance to prevent delays. Ask her if she would like a family member or a supportive friend to be present for the conveying of results so that she will have time to make these arrangements. Ask her if she would prefer for an alternate person to be provided with the results on her behalf.
When preparing to speak with the patient, it is valuable to mentally rehearse the words that you’ll use. Arrange for privacy and manage time constraints and interruptions (silence pagers and phones, ensure there is adequate time allocated in the schedule). Sit down to deliver the news and make a connection with eye contact and, if appropriate, touch.
Assessing the patient’s perception. Before you tell, ask. For example, “what is your understanding about why we did the biopsy?” This will guide you in where her head and heart are and can ensure you meet her wherever she is.
Obtaining the patient’s invitation.Ask the patient what she would like to be told and how much information. What would she like you to focus on? What does she not want to hear?
Giving knowledge and information to the patient. Especially now, it is important to avoid jargon and use nontechnical terms. However, do not shy away from using specific words like “cancer” by substituting them for more vague and confusing terms such as “malignancy” or “tumor.” It is important to find the balance between expressing information without being overly emotive, while avoiding excessive bluntness. Word choice is critical. Communication styles in the breaking of bad news can be separated broadly into three styles: disease centered, emotion centered, and patient-centered.3 The patient-centered approach is achieved by balancing emotional connection, information sharing, nondominance, and conveying hope. (For example, “I have some disappointing news to share. Shall we talk about the next steps in treatment? I understand this is that this is difficult for you.”) In general, this approach is most valued by patients and is associated with better information recall.
Addressing the patient’s emotions with empathetic responses. It is important that physicians take a moment to pause after communicating the test result. Even if prepared, most patients will still have a moment of shock, and their minds will likely spin through a multitude of thoughts preventing them from being able to “hear” and focus on the subsequent information. This is a moment to reflect on her reactions, her body language, and nonverbal communications to guide you on how to approach the rest of the encounter. Offer her your comfort and condolence in whichever way feels appropriate for you and her.
Beware of your own inclinations to “soften the blow.” It is a natural, compassionate instinct to follow-up giving a bad piece of information by balancing a good piece of information. For example, after just telling a woman that she has endometrial cancer, following with a statement such as “but it’s just stage 1 and is curable with surgery.” While this certainly may have immediate comforting effects, it has a couple of unintended consequences. First, it can result in difficulties later adjusting to a change in diagnosis when more information comes in (for example, upstaging after surgery or imaging). It is better to be honest and tell patients only what you know for sure in these immediate first moments of diagnosis when complete information is lacking. A more general statement such as “for most women, this is found at an early stage and is highly treatable” may be more appropriate and still provide some comfort. Second, attempts to soften the blow with a qualifying statement of positivity, such as “this is a good kind of cancer to have” might be interpreted by some patients as failing to acknowledge their devastation. She may feel that you are minimizing her condition and not allowing her to grieve or be distressed.
Strategy and summary. Patients who leave the encounter with some kind of plan for the future feel less distressed and anxious. The direction at this point of the encounter should be led by the patient. What are her greatest concerns (such as mortality, loss of fertility, time off work for treatment), and what does she want to know right now? Most patients express a desire to know more about treatment or prognosis.2,4 Unfortunately, it often is not possible to furnish this yet, particularly if this falls into the realm of a subspecialist, and prognostication typically requires more information than a provider has at initial diagnosis. However, leaving these questions unanswered is likely to result in a patient feeling helpless. For example, if an ob.gyn. discovers an apparent advanced ovarian cancer on a CT scan, tell her that, despite its apparent advanced case, it is usually treatable and that a gynecologic oncologist will discuss those best treatment options with her. Assure her that you will expeditiously refer her to a specialist who will provide her with those specifics.
The aftermath
That interval between initial diagnosis and specialist consultation is extraordinarily difficult and a high anxiety time. It is not unreasonable, in such cases, to recommend the patient to reputable online information sources, such as the Society of Gynecologic Oncology or American Cancer Society websites so that she and her family can do some research prior to that visit in order to prepare them better and give them a sense of understanding in their disease.
It is a particularly compassionate touch to reach out to the patient in the days following her cancer diagnosis, even if she has moved on to a specialist. Patients often tell me that they felt enormous reassurance and appreciation when their ob.gyn. reached out to them to “check on how they are doing.” This can usually reasonably be done by phone. This second contact serves another critical purpose: it allows for repetition of the diagnosis and initial plan, and the ability to fill in the blanks of what the patient may have missed during the prior visit, if her mind was, naturally, elsewhere. It also, quite simply, shows that you care.
Dr. Emma C. Rossi Ultimately, none of us can break bad news perfectly every time. We all need to be insightful with each of these encounters as to what we did well, what we did not, and how we can adjust in the future. With respect to the SPIKES approach, patients report that physicians struggle most with the “perception,” “invitation,” and “strategy and summary” components.5 Our objective should be keeping the patient’s needs in mind, rather than our own, to maximize the chance of doing a good job. If this task is done well, not only are patients more likely to have positive emotional adjustments to their diagnosis but also more adherence with future therapies.4 In the end, it is the patient who has the final say on whether it was done well or not.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She reports no relevant financial disclosures.
Hearing a diagnosis of cancer is one of the most significant moments of a patient’s life and informing a patient of her diagnosis is an emotionally and technically challenging task for an obstetrician gynecologist who is frequently on the front line of making this diagnosis. In this column, we will explore some patient-centered strategies to perform this difficult task well so that patients come away informed but with the highest chance for positive emotional adjustment.
Fewer than 10% of physicians report receiving formal training in techniques of breaking bad news. For the majority of clinicians concerns are centered on being honest and not taking away hope, and in responding to a patient’s emotions.1 The SPIKES approach was developed to arm physicians with strategies to discuss a cancer diagnosis with their patients. This approach includes six key elements to incorporate during the encounter. These strategies are not meant to be formulaic but rather consistent principles that can be adjusted for individual patient needs.
Setting up the discussion
Breaking bad news should not be a one-size-fits-all approach. Age, educational level, culture, religion, race and ethnicity, and socioeconomic opportunities each affects what and how patients may want to have this kind of information communicated to them. So how do you know how best to deliver a patient-centered approach for your patient? I recommend this simple strategy: Ask her. When ordering a test or performing a biopsy, let the patient know then why you are ordering the test and inform her of the possibility that the results may show cancer. Ask her how she would like for you to communicate that result. Would she like to be called by phone, the benefit of which is quick dissemination of information? Or would she like to receive the information face to face in the office? Research supports that most patients prefer to learn the result in the office.2 If so, I recommend scheduling a follow-up appointment in advance to prevent delays. Ask her if she would like a family member or a supportive friend to be present for the conveying of results so that she will have time to make these arrangements. Ask her if she would prefer for an alternate person to be provided with the results on her behalf.
When preparing to speak with the patient, it is valuable to mentally rehearse the words that you’ll use. Arrange for privacy and manage time constraints and interruptions (silence pagers and phones, ensure there is adequate time allocated in the schedule). Sit down to deliver the news and make a connection with eye contact and, if appropriate, touch.
Assessing the patient’s perception. Before you tell, ask. For example, “what is your understanding about why we did the biopsy?” This will guide you in where her head and heart are and can ensure you meet her wherever she is.
Obtaining the patient’s invitation.Ask the patient what she would like to be told and how much information. What would she like you to focus on? What does she not want to hear?
Giving knowledge and information to the patient. Especially now, it is important to avoid jargon and use nontechnical terms. However, do not shy away from using specific words like “cancer” by substituting them for more vague and confusing terms such as “malignancy” or “tumor.” It is important to find the balance between expressing information without being overly emotive, while avoiding excessive bluntness. Word choice is critical. Communication styles in the breaking of bad news can be separated broadly into three styles: disease centered, emotion centered, and patient-centered.3 The patient-centered approach is achieved by balancing emotional connection, information sharing, nondominance, and conveying hope. (For example, “I have some disappointing news to share. Shall we talk about the next steps in treatment? I understand this is that this is difficult for you.”) In general, this approach is most valued by patients and is associated with better information recall.
Addressing the patient’s emotions with empathetic responses. It is important that physicians take a moment to pause after communicating the test result. Even if prepared, most patients will still have a moment of shock, and their minds will likely spin through a multitude of thoughts preventing them from being able to “hear” and focus on the subsequent information. This is a moment to reflect on her reactions, her body language, and nonverbal communications to guide you on how to approach the rest of the encounter. Offer her your comfort and condolence in whichever way feels appropriate for you and her.
Beware of your own inclinations to “soften the blow.” It is a natural, compassionate instinct to follow-up giving a bad piece of information by balancing a good piece of information. For example, after just telling a woman that she has endometrial cancer, following with a statement such as “but it’s just stage 1 and is curable with surgery.” While this certainly may have immediate comforting effects, it has a couple of unintended consequences. First, it can result in difficulties later adjusting to a change in diagnosis when more information comes in (for example, upstaging after surgery or imaging). It is better to be honest and tell patients only what you know for sure in these immediate first moments of diagnosis when complete information is lacking. A more general statement such as “for most women, this is found at an early stage and is highly treatable” may be more appropriate and still provide some comfort. Second, attempts to soften the blow with a qualifying statement of positivity, such as “this is a good kind of cancer to have” might be interpreted by some patients as failing to acknowledge their devastation. She may feel that you are minimizing her condition and not allowing her to grieve or be distressed.
Strategy and summary. Patients who leave the encounter with some kind of plan for the future feel less distressed and anxious. The direction at this point of the encounter should be led by the patient. What are her greatest concerns (such as mortality, loss of fertility, time off work for treatment), and what does she want to know right now? Most patients express a desire to know more about treatment or prognosis.2,4 Unfortunately, it often is not possible to furnish this yet, particularly if this falls into the realm of a subspecialist, and prognostication typically requires more information than a provider has at initial diagnosis. However, leaving these questions unanswered is likely to result in a patient feeling helpless. For example, if an ob.gyn. discovers an apparent advanced ovarian cancer on a CT scan, tell her that, despite its apparent advanced case, it is usually treatable and that a gynecologic oncologist will discuss those best treatment options with her. Assure her that you will expeditiously refer her to a specialist who will provide her with those specifics.
The aftermath
That interval between initial diagnosis and specialist consultation is extraordinarily difficult and a high anxiety time. It is not unreasonable, in such cases, to recommend the patient to reputable online information sources, such as the Society of Gynecologic Oncology or American Cancer Society websites so that she and her family can do some research prior to that visit in order to prepare them better and give them a sense of understanding in their disease.
It is a particularly compassionate touch to reach out to the patient in the days following her cancer diagnosis, even if she has moved on to a specialist. Patients often tell me that they felt enormous reassurance and appreciation when their ob.gyn. reached out to them to “check on how they are doing.” This can usually reasonably be done by phone. This second contact serves another critical purpose: it allows for repetition of the diagnosis and initial plan, and the ability to fill in the blanks of what the patient may have missed during the prior visit, if her mind was, naturally, elsewhere. It also, quite simply, shows that you care.
Dr. Emma C. Rossi Ultimately, none of us can break bad news perfectly every time. We all need to be insightful with each of these encounters as to what we did well, what we did not, and how we can adjust in the future. With respect to the SPIKES approach, patients report that physicians struggle most with the “perception,” “invitation,” and “strategy and summary” components.5 Our objective should be keeping the patient’s needs in mind, rather than our own, to maximize the chance of doing a good job. If this task is done well, not only are patients more likely to have positive emotional adjustments to their diagnosis but also more adherence with future therapies.4 In the end, it is the patient who has the final say on whether it was done well or not.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She reports no relevant financial disclosures.
Hearing a diagnosis of cancer is one of the most significant moments of a patient’s life and informing a patient of her diagnosis is an emotionally and technically challenging task for an obstetrician gynecologist who is frequently on the front line of making this diagnosis. In this column, we will explore some patient-centered strategies to perform this difficult task well so that patients come away informed but with the highest chance for positive emotional adjustment.
Fewer than 10% of physicians report receiving formal training in techniques of breaking bad news. For the majority of clinicians concerns are centered on being honest and not taking away hope, and in responding to a patient’s emotions.1 The SPIKES approach was developed to arm physicians with strategies to discuss a cancer diagnosis with their patients. This approach includes six key elements to incorporate during the encounter. These strategies are not meant to be formulaic but rather consistent principles that can be adjusted for individual patient needs.
Setting up the discussion
Breaking bad news should not be a one-size-fits-all approach. Age, educational level, culture, religion, race and ethnicity, and socioeconomic opportunities each affects what and how patients may want to have this kind of information communicated to them. So how do you know how best to deliver a patient-centered approach for your patient? I recommend this simple strategy: Ask her. When ordering a test or performing a biopsy, let the patient know then why you are ordering the test and inform her of the possibility that the results may show cancer. Ask her how she would like for you to communicate that result. Would she like to be called by phone, the benefit of which is quick dissemination of information? Or would she like to receive the information face to face in the office? Research supports that most patients prefer to learn the result in the office.2 If so, I recommend scheduling a follow-up appointment in advance to prevent delays. Ask her if she would like a family member or a supportive friend to be present for the conveying of results so that she will have time to make these arrangements. Ask her if she would prefer for an alternate person to be provided with the results on her behalf.
When preparing to speak with the patient, it is valuable to mentally rehearse the words that you’ll use. Arrange for privacy and manage time constraints and interruptions (silence pagers and phones, ensure there is adequate time allocated in the schedule). Sit down to deliver the news and make a connection with eye contact and, if appropriate, touch.
Assessing the patient’s perception. Before you tell, ask. For example, “what is your understanding about why we did the biopsy?” This will guide you in where her head and heart are and can ensure you meet her wherever she is.
Obtaining the patient’s invitation.Ask the patient what she would like to be told and how much information. What would she like you to focus on? What does she not want to hear?
Giving knowledge and information to the patient. Especially now, it is important to avoid jargon and use nontechnical terms. However, do not shy away from using specific words like “cancer” by substituting them for more vague and confusing terms such as “malignancy” or “tumor.” It is important to find the balance between expressing information without being overly emotive, while avoiding excessive bluntness. Word choice is critical. Communication styles in the breaking of bad news can be separated broadly into three styles: disease centered, emotion centered, and patient-centered.3 The patient-centered approach is achieved by balancing emotional connection, information sharing, nondominance, and conveying hope. (For example, “I have some disappointing news to share. Shall we talk about the next steps in treatment? I understand this is that this is difficult for you.”) In general, this approach is most valued by patients and is associated with better information recall.
Addressing the patient’s emotions with empathetic responses. It is important that physicians take a moment to pause after communicating the test result. Even if prepared, most patients will still have a moment of shock, and their minds will likely spin through a multitude of thoughts preventing them from being able to “hear” and focus on the subsequent information. This is a moment to reflect on her reactions, her body language, and nonverbal communications to guide you on how to approach the rest of the encounter. Offer her your comfort and condolence in whichever way feels appropriate for you and her.
Beware of your own inclinations to “soften the blow.” It is a natural, compassionate instinct to follow-up giving a bad piece of information by balancing a good piece of information. For example, after just telling a woman that she has endometrial cancer, following with a statement such as “but it’s just stage 1 and is curable with surgery.” While this certainly may have immediate comforting effects, it has a couple of unintended consequences. First, it can result in difficulties later adjusting to a change in diagnosis when more information comes in (for example, upstaging after surgery or imaging). It is better to be honest and tell patients only what you know for sure in these immediate first moments of diagnosis when complete information is lacking. A more general statement such as “for most women, this is found at an early stage and is highly treatable” may be more appropriate and still provide some comfort. Second, attempts to soften the blow with a qualifying statement of positivity, such as “this is a good kind of cancer to have” might be interpreted by some patients as failing to acknowledge their devastation. She may feel that you are minimizing her condition and not allowing her to grieve or be distressed.
Strategy and summary. Patients who leave the encounter with some kind of plan for the future feel less distressed and anxious. The direction at this point of the encounter should be led by the patient. What are her greatest concerns (such as mortality, loss of fertility, time off work for treatment), and what does she want to know right now? Most patients express a desire to know more about treatment or prognosis.2,4 Unfortunately, it often is not possible to furnish this yet, particularly if this falls into the realm of a subspecialist, and prognostication typically requires more information than a provider has at initial diagnosis. However, leaving these questions unanswered is likely to result in a patient feeling helpless. For example, if an ob.gyn. discovers an apparent advanced ovarian cancer on a CT scan, tell her that, despite its apparent advanced case, it is usually treatable and that a gynecologic oncologist will discuss those best treatment options with her. Assure her that you will expeditiously refer her to a specialist who will provide her with those specifics.
The aftermath
That interval between initial diagnosis and specialist consultation is extraordinarily difficult and a high anxiety time. It is not unreasonable, in such cases, to recommend the patient to reputable online information sources, such as the Society of Gynecologic Oncology or American Cancer Society websites so that she and her family can do some research prior to that visit in order to prepare them better and give them a sense of understanding in their disease.
It is a particularly compassionate touch to reach out to the patient in the days following her cancer diagnosis, even if she has moved on to a specialist. Patients often tell me that they felt enormous reassurance and appreciation when their ob.gyn. reached out to them to “check on how they are doing.” This can usually reasonably be done by phone. This second contact serves another critical purpose: it allows for repetition of the diagnosis and initial plan, and the ability to fill in the blanks of what the patient may have missed during the prior visit, if her mind was, naturally, elsewhere. It also, quite simply, shows that you care.
Dr. Emma C. Rossi Ultimately, none of us can break bad news perfectly every time. We all need to be insightful with each of these encounters as to what we did well, what we did not, and how we can adjust in the future. With respect to the SPIKES approach, patients report that physicians struggle most with the “perception,” “invitation,” and “strategy and summary” components.5 Our objective should be keeping the patient’s needs in mind, rather than our own, to maximize the chance of doing a good job. If this task is done well, not only are patients more likely to have positive emotional adjustments to their diagnosis but also more adherence with future therapies.4 In the end, it is the patient who has the final say on whether it was done well or not.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She reports no relevant financial disclosures.
Adnexal masses are common findings in women. While the decision to operate on symptomatic adnexal masses is straightforward, the decision-making process for asymptomatic masses is more complicated. Here we address how to approach an asymptomatic adnexal mass, including how to decide when to operate, when to refer, or how to monitor.
Dr. Lisa Jackson-MooreApproximately 200,000 women in the United States undergo surgery for a pelvic mass annually, yet only 21,290 are ultimately found to have ovarian cancer.1 Therefore, only approximately 1 in 10 women in the United States who have surgery for adnexal masses have an underlying malignancy.
It is important to minimize the number of surgeries for benign, asymptomatic adnexal masses because complications are reported in 2%-15% of surgeries for adnexal masses and these can range from minimal to devastating.1 In addition, unnecessary surgery is associated with a burden of cost to the health care system. Therefore, there is a paradigm shift in the management of asymptomatic adnexal masses trending toward surveillance of any masses that are likely to be benign. What becomes critical in this approach is the ability to accurately classify these masses preoperatively.
Determining the malignant potential of a mass
Guidance is provided by the ACOG Practice Bulletin Number 174, which was published in 2016: “Evaluation and Management of Adnexal Masses.”2 These guidelines remind clinicians that:
Most adnexal masses are benign, even in postmenopausal patients.
The recommended imaging modality is quality transvaginal ultrasonography with an ultrasonographer accredited through the American Registry of Diagnostic Medical Sonographers.
Simple cysts up to 10 cm can be monitored using repeat imaging every 6 months without surgical intervention, even in postmenopausal patients. In prospective studies, no cases of malignancy were diagnosed over 6 years of surveillance and most resolved. Those that persist are likely to be serous cystadenomas.
Many benign lesions such as endometriomas and cystic teratomas have characteristic radiologic features. Surgery for these lesions is warranted for large size, symptoms, or growth in size.
Ultrasound characteristics of malignant masses include:
1. Cyst size greater than 10 cm
2. Papillary or solid components
3. Septations
4. Internal blood flow on color Doppler.
Dr. Emma C. RossiAn international multidisciplinary panel of experts has convened on this topic. The panel defined two approaches to diagnosing asymptomatic adnexal masses based on morphologic features on ultrasound. The first approach was a simple risk assessment stratification profile based on pattern recognition.1 This approach categorizes masses as: almost certainly benign, almost certainly malignant, suspicious for malignancy, or indeterminate. Those that are almost certainly malignant or suspicious for malignant can be referred to a gynecologic oncologist for surgical evaluation. Those that are almost certainly benign can be observed. For those in the indeterminate group, further evaluation with MRI, serial ultrasound, tumor marker assessment (for example, CA 125), or application of risk-prediction models (such as the International Ovarian Tumor Analysis Group’s “simple rules”) can be employed to identify candidates for observation or referral. However, there will remain a portion of patients in whom the masses remain “indeterminate.” These patients are typically treated as though they may be malignant, and referral to an oncology specialist is recommended to help decide whether to proceed with surgery or observation.
An alternative approach that has been proposed is an ultrasound scoring system devised by International Ovarian Tumor Analysis Group. The scoring system uses 10 ultrasound findings that are characteristic of malignant and benign and is designed to characterize masses as either benign or malignant.3 This approach is able to correctly classify 77% of masses. The remaining masses with features that do not fit the “simple rules” are considered potentially malignant and should be referred to an oncology specialist for further decision making.
Decision to operate
After referral to gynecologic oncologists, surgery is not always inevitable, particularly for women with indeterminate masses. The gynecologic oncologist uses a decision-making process that factors in the underlying surgical risks for that patient with the likelihood of malignancy based on the features of the mass. The threshold to operate is higher in women with underlying major comorbidities, such as morbid obesity, complex prior surgical history, or cardiopulmonary disease. Healthier surgical candidates are more likely to be considered for a surgery, even if the suspicion for malignancy is lower. However, low surgical risk does not equate to no surgical risk. Therefore, even in apparently “good” surgical candidates, the suspicion for underlying malignancy needs to be reasonably high in order to justify the cost and risk of surgery in an asymptomatic patient. Sometimes it is patient anxiety and a desire to avoid repeated surveillance that prompts a decision to operate.
How to monitor
The role of surveillance and monitoring is to establish a natural history of the lesion or to allow it to reveal itself to be stable or regressive. Surveillance with serial sonography has shown that most asymptomatic adnexal masses with low risk features will resolve over time. Lack of resolution in the setting of stable findings is not a worrisome feature and is not suggestive of malignancy. The mere persistence of an otherwise benign-appearing lesion is not a reason to intervene with surgery.
Unfortunately, there is no clear guidance on the surveillance intervals. Some experts recommend an initial repeat scan in 3 months. If at that point the morphologic features and size are stable or decreasing, ultrasounds can be repeated at annual intervals for 5 years. In one study, masses that became malignant demonstrated growth by 7 months. Other experts recommend limiting the period of surveillance of cystic lesions to 1 year and lesions with solid components to 2 years.
Conclusions
Many asymptomatic adnexal masses discovered on imaging can be monitored with serial sonography. Lesions with more worrisome morphology that’s suggestive of malignancy should prompt referral to a gynecologic oncologist. Surgery on benign masses can be avoided. Outcome data is needed to advise the optimal timing intervals and the limit of follow-up serial ultrasonography. A caveat of this watch-and-see approach is having to allay the patient’s fears of the malignant potential of the mass. This requires conversations with the patient informing them that the stability of the mass will be shown over time and that surgery can be safely avoided.
Dr. Jackson-Moore is an associate professor in gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Rossi is an assistant professor in the division of gynecologic oncology at UNC. They reported having no relevant financial disclosures.
Adnexal masses are common findings in women. While the decision to operate on symptomatic adnexal masses is straightforward, the decision-making process for asymptomatic masses is more complicated. Here we address how to approach an asymptomatic adnexal mass, including how to decide when to operate, when to refer, or how to monitor.
Dr. Lisa Jackson-MooreApproximately 200,000 women in the United States undergo surgery for a pelvic mass annually, yet only 21,290 are ultimately found to have ovarian cancer.1 Therefore, only approximately 1 in 10 women in the United States who have surgery for adnexal masses have an underlying malignancy.
It is important to minimize the number of surgeries for benign, asymptomatic adnexal masses because complications are reported in 2%-15% of surgeries for adnexal masses and these can range from minimal to devastating.1 In addition, unnecessary surgery is associated with a burden of cost to the health care system. Therefore, there is a paradigm shift in the management of asymptomatic adnexal masses trending toward surveillance of any masses that are likely to be benign. What becomes critical in this approach is the ability to accurately classify these masses preoperatively.
Determining the malignant potential of a mass
Guidance is provided by the ACOG Practice Bulletin Number 174, which was published in 2016: “Evaluation and Management of Adnexal Masses.”2 These guidelines remind clinicians that:
Most adnexal masses are benign, even in postmenopausal patients.
The recommended imaging modality is quality transvaginal ultrasonography with an ultrasonographer accredited through the American Registry of Diagnostic Medical Sonographers.
Simple cysts up to 10 cm can be monitored using repeat imaging every 6 months without surgical intervention, even in postmenopausal patients. In prospective studies, no cases of malignancy were diagnosed over 6 years of surveillance and most resolved. Those that persist are likely to be serous cystadenomas.
Many benign lesions such as endometriomas and cystic teratomas have characteristic radiologic features. Surgery for these lesions is warranted for large size, symptoms, or growth in size.
Ultrasound characteristics of malignant masses include:
1. Cyst size greater than 10 cm
2. Papillary or solid components
3. Septations
4. Internal blood flow on color Doppler.
Dr. Emma C. RossiAn international multidisciplinary panel of experts has convened on this topic. The panel defined two approaches to diagnosing asymptomatic adnexal masses based on morphologic features on ultrasound. The first approach was a simple risk assessment stratification profile based on pattern recognition.1 This approach categorizes masses as: almost certainly benign, almost certainly malignant, suspicious for malignancy, or indeterminate. Those that are almost certainly malignant or suspicious for malignant can be referred to a gynecologic oncologist for surgical evaluation. Those that are almost certainly benign can be observed. For those in the indeterminate group, further evaluation with MRI, serial ultrasound, tumor marker assessment (for example, CA 125), or application of risk-prediction models (such as the International Ovarian Tumor Analysis Group’s “simple rules”) can be employed to identify candidates for observation or referral. However, there will remain a portion of patients in whom the masses remain “indeterminate.” These patients are typically treated as though they may be malignant, and referral to an oncology specialist is recommended to help decide whether to proceed with surgery or observation.
An alternative approach that has been proposed is an ultrasound scoring system devised by International Ovarian Tumor Analysis Group. The scoring system uses 10 ultrasound findings that are characteristic of malignant and benign and is designed to characterize masses as either benign or malignant.3 This approach is able to correctly classify 77% of masses. The remaining masses with features that do not fit the “simple rules” are considered potentially malignant and should be referred to an oncology specialist for further decision making.
Decision to operate
After referral to gynecologic oncologists, surgery is not always inevitable, particularly for women with indeterminate masses. The gynecologic oncologist uses a decision-making process that factors in the underlying surgical risks for that patient with the likelihood of malignancy based on the features of the mass. The threshold to operate is higher in women with underlying major comorbidities, such as morbid obesity, complex prior surgical history, or cardiopulmonary disease. Healthier surgical candidates are more likely to be considered for a surgery, even if the suspicion for malignancy is lower. However, low surgical risk does not equate to no surgical risk. Therefore, even in apparently “good” surgical candidates, the suspicion for underlying malignancy needs to be reasonably high in order to justify the cost and risk of surgery in an asymptomatic patient. Sometimes it is patient anxiety and a desire to avoid repeated surveillance that prompts a decision to operate.
How to monitor
The role of surveillance and monitoring is to establish a natural history of the lesion or to allow it to reveal itself to be stable or regressive. Surveillance with serial sonography has shown that most asymptomatic adnexal masses with low risk features will resolve over time. Lack of resolution in the setting of stable findings is not a worrisome feature and is not suggestive of malignancy. The mere persistence of an otherwise benign-appearing lesion is not a reason to intervene with surgery.
Unfortunately, there is no clear guidance on the surveillance intervals. Some experts recommend an initial repeat scan in 3 months. If at that point the morphologic features and size are stable or decreasing, ultrasounds can be repeated at annual intervals for 5 years. In one study, masses that became malignant demonstrated growth by 7 months. Other experts recommend limiting the period of surveillance of cystic lesions to 1 year and lesions with solid components to 2 years.
Conclusions
Many asymptomatic adnexal masses discovered on imaging can be monitored with serial sonography. Lesions with more worrisome morphology that’s suggestive of malignancy should prompt referral to a gynecologic oncologist. Surgery on benign masses can be avoided. Outcome data is needed to advise the optimal timing intervals and the limit of follow-up serial ultrasonography. A caveat of this watch-and-see approach is having to allay the patient’s fears of the malignant potential of the mass. This requires conversations with the patient informing them that the stability of the mass will be shown over time and that surgery can be safely avoided.
Dr. Jackson-Moore is an associate professor in gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Rossi is an assistant professor in the division of gynecologic oncology at UNC. They reported having no relevant financial disclosures.
Adnexal masses are common findings in women. While the decision to operate on symptomatic adnexal masses is straightforward, the decision-making process for asymptomatic masses is more complicated. Here we address how to approach an asymptomatic adnexal mass, including how to decide when to operate, when to refer, or how to monitor.
Dr. Lisa Jackson-MooreApproximately 200,000 women in the United States undergo surgery for a pelvic mass annually, yet only 21,290 are ultimately found to have ovarian cancer.1 Therefore, only approximately 1 in 10 women in the United States who have surgery for adnexal masses have an underlying malignancy.
It is important to minimize the number of surgeries for benign, asymptomatic adnexal masses because complications are reported in 2%-15% of surgeries for adnexal masses and these can range from minimal to devastating.1 In addition, unnecessary surgery is associated with a burden of cost to the health care system. Therefore, there is a paradigm shift in the management of asymptomatic adnexal masses trending toward surveillance of any masses that are likely to be benign. What becomes critical in this approach is the ability to accurately classify these masses preoperatively.
Determining the malignant potential of a mass
Guidance is provided by the ACOG Practice Bulletin Number 174, which was published in 2016: “Evaluation and Management of Adnexal Masses.”2 These guidelines remind clinicians that:
Most adnexal masses are benign, even in postmenopausal patients.
The recommended imaging modality is quality transvaginal ultrasonography with an ultrasonographer accredited through the American Registry of Diagnostic Medical Sonographers.
Simple cysts up to 10 cm can be monitored using repeat imaging every 6 months without surgical intervention, even in postmenopausal patients. In prospective studies, no cases of malignancy were diagnosed over 6 years of surveillance and most resolved. Those that persist are likely to be serous cystadenomas.
Many benign lesions such as endometriomas and cystic teratomas have characteristic radiologic features. Surgery for these lesions is warranted for large size, symptoms, or growth in size.
Ultrasound characteristics of malignant masses include:
1. Cyst size greater than 10 cm
2. Papillary or solid components
3. Septations
4. Internal blood flow on color Doppler.
Dr. Emma C. RossiAn international multidisciplinary panel of experts has convened on this topic. The panel defined two approaches to diagnosing asymptomatic adnexal masses based on morphologic features on ultrasound. The first approach was a simple risk assessment stratification profile based on pattern recognition.1 This approach categorizes masses as: almost certainly benign, almost certainly malignant, suspicious for malignancy, or indeterminate. Those that are almost certainly malignant or suspicious for malignant can be referred to a gynecologic oncologist for surgical evaluation. Those that are almost certainly benign can be observed. For those in the indeterminate group, further evaluation with MRI, serial ultrasound, tumor marker assessment (for example, CA 125), or application of risk-prediction models (such as the International Ovarian Tumor Analysis Group’s “simple rules”) can be employed to identify candidates for observation or referral. However, there will remain a portion of patients in whom the masses remain “indeterminate.” These patients are typically treated as though they may be malignant, and referral to an oncology specialist is recommended to help decide whether to proceed with surgery or observation.
An alternative approach that has been proposed is an ultrasound scoring system devised by International Ovarian Tumor Analysis Group. The scoring system uses 10 ultrasound findings that are characteristic of malignant and benign and is designed to characterize masses as either benign or malignant.3 This approach is able to correctly classify 77% of masses. The remaining masses with features that do not fit the “simple rules” are considered potentially malignant and should be referred to an oncology specialist for further decision making.
Decision to operate
After referral to gynecologic oncologists, surgery is not always inevitable, particularly for women with indeterminate masses. The gynecologic oncologist uses a decision-making process that factors in the underlying surgical risks for that patient with the likelihood of malignancy based on the features of the mass. The threshold to operate is higher in women with underlying major comorbidities, such as morbid obesity, complex prior surgical history, or cardiopulmonary disease. Healthier surgical candidates are more likely to be considered for a surgery, even if the suspicion for malignancy is lower. However, low surgical risk does not equate to no surgical risk. Therefore, even in apparently “good” surgical candidates, the suspicion for underlying malignancy needs to be reasonably high in order to justify the cost and risk of surgery in an asymptomatic patient. Sometimes it is patient anxiety and a desire to avoid repeated surveillance that prompts a decision to operate.
How to monitor
The role of surveillance and monitoring is to establish a natural history of the lesion or to allow it to reveal itself to be stable or regressive. Surveillance with serial sonography has shown that most asymptomatic adnexal masses with low risk features will resolve over time. Lack of resolution in the setting of stable findings is not a worrisome feature and is not suggestive of malignancy. The mere persistence of an otherwise benign-appearing lesion is not a reason to intervene with surgery.
Unfortunately, there is no clear guidance on the surveillance intervals. Some experts recommend an initial repeat scan in 3 months. If at that point the morphologic features and size are stable or decreasing, ultrasounds can be repeated at annual intervals for 5 years. In one study, masses that became malignant demonstrated growth by 7 months. Other experts recommend limiting the period of surveillance of cystic lesions to 1 year and lesions with solid components to 2 years.
Conclusions
Many asymptomatic adnexal masses discovered on imaging can be monitored with serial sonography. Lesions with more worrisome morphology that’s suggestive of malignancy should prompt referral to a gynecologic oncologist. Surgery on benign masses can be avoided. Outcome data is needed to advise the optimal timing intervals and the limit of follow-up serial ultrasonography. A caveat of this watch-and-see approach is having to allay the patient’s fears of the malignant potential of the mass. This requires conversations with the patient informing them that the stability of the mass will be shown over time and that surgery can be safely avoided.
Dr. Jackson-Moore is an associate professor in gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Rossi is an assistant professor in the division of gynecologic oncology at UNC. They reported having no relevant financial disclosures.
