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FDA approves pembrolizumab/lenvatinib combo for advanced endometrial carcinoma
The Food and Drug Administration has granted accelerated approval to a pembrolizumab (Keytruda) plus lenvatinib (Lenvima) combination for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability high or mismatch repair deficient, and who have disease progression following prior systemic therapy but are not candidates for curative surgery or radiation.
The approval was based on results of KEYNOTE-146, a single-arm, multicenter, open-label, multicohort trial with 108 patients with metastatic endometrial carcinoma; 94 of these were not microsatellite instability high or mismatch repair deficient. The objective response rate in those 94 patients was 38.3% (95% confidence interval, 29%-49%), with 10 complete responses and 26 partial responses. The median duration of response was not reached over the trial period, and 69% of those who responded had a response duration of at least 6 months.
The most common adverse events reported during the trial were fatigue, hypertension, musculoskeletal pain, diarrhea, decreased appetite, hypothyroidism, nausea, stomatitis, vomiting, decreased weight, abdominal pain, headache, constipation, urinary tract infection, dysphonia, hemorrhagic events, hypomagnesemia, palmar-plantar erythrodysesthesia, dyspnea, cough, and rash.
The recommended dosage is lenvatinib 20 mg orally once daily with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks, according to the FDA.
The Food and Drug Administration has granted accelerated approval to a pembrolizumab (Keytruda) plus lenvatinib (Lenvima) combination for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability high or mismatch repair deficient, and who have disease progression following prior systemic therapy but are not candidates for curative surgery or radiation.
The approval was based on results of KEYNOTE-146, a single-arm, multicenter, open-label, multicohort trial with 108 patients with metastatic endometrial carcinoma; 94 of these were not microsatellite instability high or mismatch repair deficient. The objective response rate in those 94 patients was 38.3% (95% confidence interval, 29%-49%), with 10 complete responses and 26 partial responses. The median duration of response was not reached over the trial period, and 69% of those who responded had a response duration of at least 6 months.
The most common adverse events reported during the trial were fatigue, hypertension, musculoskeletal pain, diarrhea, decreased appetite, hypothyroidism, nausea, stomatitis, vomiting, decreased weight, abdominal pain, headache, constipation, urinary tract infection, dysphonia, hemorrhagic events, hypomagnesemia, palmar-plantar erythrodysesthesia, dyspnea, cough, and rash.
The recommended dosage is lenvatinib 20 mg orally once daily with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks, according to the FDA.
The Food and Drug Administration has granted accelerated approval to a pembrolizumab (Keytruda) plus lenvatinib (Lenvima) combination for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability high or mismatch repair deficient, and who have disease progression following prior systemic therapy but are not candidates for curative surgery or radiation.
The approval was based on results of KEYNOTE-146, a single-arm, multicenter, open-label, multicohort trial with 108 patients with metastatic endometrial carcinoma; 94 of these were not microsatellite instability high or mismatch repair deficient. The objective response rate in those 94 patients was 38.3% (95% confidence interval, 29%-49%), with 10 complete responses and 26 partial responses. The median duration of response was not reached over the trial period, and 69% of those who responded had a response duration of at least 6 months.
The most common adverse events reported during the trial were fatigue, hypertension, musculoskeletal pain, diarrhea, decreased appetite, hypothyroidism, nausea, stomatitis, vomiting, decreased weight, abdominal pain, headache, constipation, urinary tract infection, dysphonia, hemorrhagic events, hypomagnesemia, palmar-plantar erythrodysesthesia, dyspnea, cough, and rash.
The recommended dosage is lenvatinib 20 mg orally once daily with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks, according to the FDA.
Nivolumab may be beneficial for recurrent or metastatic cervical cancer
The checkpoint inhibitor nivolumab may hold some promise for treating women with metastatic gynecologic cancers, especially cervical disease, according to cohort results from the phase 1/2 CheckMate 358 trial.
Of twenty-four patients enrolled in the recurrent/metastatic cervical and vaginal/vulvar carcinoma cohorts, 26.3% of patients with cervical cancer and 20% with vaginal/vulvar cancers experienced an objective response, R. Wendel Naumann, MD, and colleagues reported in the Journal of Clinical Oncology.
Median overall survival was 21.9 months (95% confidence interval, 15.1 months to not reached) among patients with cervical cancer. Because of the small size of the vaginal/vulvar cohort, median overall survival was not calculated.
“Given the lack of effective therapy and low survival rates for patients with metastatic disease in these gynecologic cancers, the results reported here are of strong clinical interest and underscore the growing role of immune checkpoint inhibitors in this patient population,” the investigators wrote.
Checkmate 358 is investigating nivolumab in patients with virus-associated cancers. Patients receive nivolumab monotherapy (240 mg intravenously every 2 weeks for 2 years) until disease progression, unacceptable side effects, or withdrawal of consent.
The median age was 51 years in the cervical cohort (n = 19) and 59 in the vaginal/vulvar cohort (n = 5). HPV status was positive in 83.3% of those with cervical disease and 40% of those with vaginal/vulvar disease. Ten cervical tumors and four vaginal/vulvar tumors expressed PD-L1.
The median duration of nivolumab treatment was 5.6 months in the cervical cohort and 6.7 months in the vaginal/vulvar cohort. Median follow-up was 19 months and 10 months, respectively.
At 12 months and 18 months, 40.0% of the cervical cohort and 20% of the vaginal/vulvar cohort were still alive.
The most common treatment-related adverse effects were diarrhea and decreased appetite. One patient in the cervical cohort discontinued treatment because of pneumonitis, which was considered treatment related.
Bristol-Myers Squibb funded the study. Several of Dr. Naumann’s associates reported relationships with the company and four others are employed by Bristol-Myers Squibb.
SOURCE: Naumann RW et al. J Clin Oncol. 2019 Sep 5. doi: 10.1200JCP.19.00739.
The checkpoint inhibitor nivolumab may hold some promise for treating women with metastatic gynecologic cancers, especially cervical disease, according to cohort results from the phase 1/2 CheckMate 358 trial.
Of twenty-four patients enrolled in the recurrent/metastatic cervical and vaginal/vulvar carcinoma cohorts, 26.3% of patients with cervical cancer and 20% with vaginal/vulvar cancers experienced an objective response, R. Wendel Naumann, MD, and colleagues reported in the Journal of Clinical Oncology.
Median overall survival was 21.9 months (95% confidence interval, 15.1 months to not reached) among patients with cervical cancer. Because of the small size of the vaginal/vulvar cohort, median overall survival was not calculated.
“Given the lack of effective therapy and low survival rates for patients with metastatic disease in these gynecologic cancers, the results reported here are of strong clinical interest and underscore the growing role of immune checkpoint inhibitors in this patient population,” the investigators wrote.
Checkmate 358 is investigating nivolumab in patients with virus-associated cancers. Patients receive nivolumab monotherapy (240 mg intravenously every 2 weeks for 2 years) until disease progression, unacceptable side effects, or withdrawal of consent.
The median age was 51 years in the cervical cohort (n = 19) and 59 in the vaginal/vulvar cohort (n = 5). HPV status was positive in 83.3% of those with cervical disease and 40% of those with vaginal/vulvar disease. Ten cervical tumors and four vaginal/vulvar tumors expressed PD-L1.
The median duration of nivolumab treatment was 5.6 months in the cervical cohort and 6.7 months in the vaginal/vulvar cohort. Median follow-up was 19 months and 10 months, respectively.
At 12 months and 18 months, 40.0% of the cervical cohort and 20% of the vaginal/vulvar cohort were still alive.
The most common treatment-related adverse effects were diarrhea and decreased appetite. One patient in the cervical cohort discontinued treatment because of pneumonitis, which was considered treatment related.
Bristol-Myers Squibb funded the study. Several of Dr. Naumann’s associates reported relationships with the company and four others are employed by Bristol-Myers Squibb.
SOURCE: Naumann RW et al. J Clin Oncol. 2019 Sep 5. doi: 10.1200JCP.19.00739.
The checkpoint inhibitor nivolumab may hold some promise for treating women with metastatic gynecologic cancers, especially cervical disease, according to cohort results from the phase 1/2 CheckMate 358 trial.
Of twenty-four patients enrolled in the recurrent/metastatic cervical and vaginal/vulvar carcinoma cohorts, 26.3% of patients with cervical cancer and 20% with vaginal/vulvar cancers experienced an objective response, R. Wendel Naumann, MD, and colleagues reported in the Journal of Clinical Oncology.
Median overall survival was 21.9 months (95% confidence interval, 15.1 months to not reached) among patients with cervical cancer. Because of the small size of the vaginal/vulvar cohort, median overall survival was not calculated.
“Given the lack of effective therapy and low survival rates for patients with metastatic disease in these gynecologic cancers, the results reported here are of strong clinical interest and underscore the growing role of immune checkpoint inhibitors in this patient population,” the investigators wrote.
Checkmate 358 is investigating nivolumab in patients with virus-associated cancers. Patients receive nivolumab monotherapy (240 mg intravenously every 2 weeks for 2 years) until disease progression, unacceptable side effects, or withdrawal of consent.
The median age was 51 years in the cervical cohort (n = 19) and 59 in the vaginal/vulvar cohort (n = 5). HPV status was positive in 83.3% of those with cervical disease and 40% of those with vaginal/vulvar disease. Ten cervical tumors and four vaginal/vulvar tumors expressed PD-L1.
The median duration of nivolumab treatment was 5.6 months in the cervical cohort and 6.7 months in the vaginal/vulvar cohort. Median follow-up was 19 months and 10 months, respectively.
At 12 months and 18 months, 40.0% of the cervical cohort and 20% of the vaginal/vulvar cohort were still alive.
The most common treatment-related adverse effects were diarrhea and decreased appetite. One patient in the cervical cohort discontinued treatment because of pneumonitis, which was considered treatment related.
Bristol-Myers Squibb funded the study. Several of Dr. Naumann’s associates reported relationships with the company and four others are employed by Bristol-Myers Squibb.
SOURCE: Naumann RW et al. J Clin Oncol. 2019 Sep 5. doi: 10.1200JCP.19.00739.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Minimally invasive surgery for cervical cancer: Is surgeon volume a factor?
The role of minimally invasive surgery for early-stage cervical cancer has been the subject of heated debate since the presentation of the results of the Laparoscopic Approach to Cervical Cancer (LACC) Trial at the Society of Gynecologic Oncology Annual Meeting on Women’s Cancer in 2018. This was an international, randomized, phase 3 trial comparing minimally invasive radical hysterectomy (MH) to open radical hysterectomy (OH) in the treatment of early-stage cervical cancer. The trial was closed early by the study’s Data and Safety Monitoring Committee due to an imbalance of deaths between the groups, with a higher rate in the minimally invasive arm. The final results, which were largely unexpected by the medical community, showed that the disease-free survival (DFS) at 4.5 years was 86.0% in the MH arm and 96.5% in the OH arm, which was a larger difference than their noninferiority cutoff of -7.2 percentage points.1 Results of an epidemiologic study, which used data from the Surveillance, Epidemiology, and End Results (SEER) program and the National Cancer Database, also were presented at this meeting, and they reinforced the findings of the LACC trial.2
The combined results have caused significant concern and confusion from the medical community regarding the clinical implication that minimally invasive surgery may be an unacceptable approach for radical hysterectomy in cervical cancer. Prior to this study, retrospective data supported similar outcomes between the two approaches.3 Additionally, robotic surgery has made radical hysterectomy an option for those with a higher body mass index, as an open radical hysterectomy can be technically challenging in larger patients and result in a higher rate of adverse outcomes.
LACC trial questioned by US surgeons
Many in the United States have questioned the design and conclusions of the LACC trial. This trial was conducted primarily outside of North America and utilized conventional laparoscopic surgery 85% of the time as opposed to robotic surgery. Additionally, the found difference in DFS between MH and OH may have been driven more by the superior performance of the OH group (compared with historical data) than the poorly performing MH group.4 Other criticisms have touched on the low number of overall survival events, the low bar for surgeon volume or skill assessment, and the inability to make conclusions regarding “low-risk” lesions (<2 cm, no lymphovascular space invasion, <1 cm depth of invasion).
Were requirements for surgical skill adequate? Regarding surgeon skill, the LACC trial required documentation of the perioperative outcomes from 10 laparoscopic or robotic radical hysterectomies, as well as 2 unedited videos of each surgeon participating in the study to verify their technique, which some have considered inadequate to sufficiently vet a surgeon’s ability. Additionally, 14 of the 33 centers enrolled in the study accrued 71% of the patients, and concerns about the surgeon volume of the remaining 19 centers have been raised. Finally, there has been discussion about whether the variance in surgical approach can even be adequately assessed in a trial of this nature, as surgical skill is not a binary variable that is easily amenable to randomization. Unlike other trials, which have clear exposure and control arms, no 2 surgeries are exactly alike, and surgical technique is highly variable between surgeons, institutions, and countries.
Continue to: New data evaluate for surgeon volume
New data evaluate for surgeon volume
In an effort to address the concerns regarding surgical approach and expertise, the recently published study by Cusimano and colleagues uses population-based data from Ontario for all women undergoing radical hysterectomy for cervical cancer over a 10-year period from 2006 through 2016.5 The primary outcome was all-cause death, but the study also sought to address whether surgeon volume has an impact on recurrence rates for patients undergoing MH versus OH. To measure this impact the authors stratified surgeon characteristics by technique-specific volume and cervical cancer volume, splitting these volumes at the 50% percentile for low- and high-volume surgeons. They defined technique-specific volume as the number of simple and radical hysterectomies performed in the prior year using the selected approach (MH or OH). Cervical cancer volume was calculated as the number of hysterectomies of any type for cervical cancer in the previous 2 years. The technique-specific volume variable was subsequently re-categorized into tertiles, examined as a continuous variable, and analyzed at the 50th percentile for each year of the study.
Death and recurrence rates better in the OH group. The final cohort included 958 women that were relatively evenly split between MH and OH procedures. Results from their analysis show no difference in terms of all-cause death, cervical cancer–specific death, or recurrence. However, all 3 of these parameters were significantly different in favor of the OH group in women with Stage IB disease, which comprised over half of the overall cohort. Importantly, neither technique-specific volume nor cervical cancer volume had an effect on death or recurrence in Stage IB patients in any of the investigators’ analyses.
Important limitations. There are several limitations to this study that have to be taken into account before drawing any conclusions. Pathologic data were obtained from the database and did not include some important details about the tumor specimens (including specifying subgroups of Stage IA and IB disease, tumor size, presence of lymphovascular space invasion, and depth of stromal invasion). All of these details have been shown to be important prognostic variables in early-stage cervical cancer. Additionally, the MH group included a predominantly laparoscopic approach with only 10% of cases performed robotically, which again brings into question the generalizability of the data.
However, despite some of these shortcomings, the study authors do make a compelling argument that surgeon volume alone does not seem to play a significant role in cancer outcomes after MH.
With surgical approaches hard to compare, turn to careful patient counseling
Definitive assessment of the impact of surgical skill and experience on cervical cancer outcomes is probably an impossible task, as even a perfectly designed trial cannot entirely account for the intricacies of a complex surgical procedure. Variations in tumor characteristics and patient anatomy that affect operative decision making are not likely to be reflected when a patient’s outcome is plugged into a database. As a result, some surgeons and departments have turned to reporting personal or institutional recurrence rates for MH, which they believe may b
- Ramirez PT, Frumovitz M, Pareja R, et al. Minimally invasive versus abdominal radical hysterectomy for cervical cancer. N Engl J Med. 2018;379:1895-1904.
- Melamed A, Margul DJ, Chen L, et al. Survival after minimally invasive radical hysterectomy for early-stage cervical cancer. N Engl J Med. 2018;379:1905-1914.
- Wang Y, Deng L, Cao L, et al. The outcome of laparoscopy versus laparotomy for the management of early stage cervical cancer-meta analysis. J Minim Invasive Gynecol. 2015;22:S4-S5.
- Leitao MM Jr. The LACC Trial: has minimally invasive surgery for early-stage cervical cancer been dealt a knockout punch? Int J Gynecol Cancer. 2018;28:1248-1250.
- Cusimano MC, Baxter NN, Gien LT, et al. Impact of surgical approach on oncologic outcomes in women undergoing radical hysterectomy for cervical cancer. Am J Obstet Gynecol. July 6, 2019. doi:10.1016/j.ajog.2019.07.009.
David W. Doo, MD
Dr. Doo is Fellow, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alabama at Birmingham.
Warner K. Huh, MD
Dr. Huh is Division Director and Professor, Division of Gynecologic Oncology, Margaret Cameron Spain Endowed Chair in Obstetrics/Gynecology, University of Alabama at Birmingham.
The authors report no financial relationships relevant to this article.
David W. Doo, MD
Dr. Doo is Fellow, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alabama at Birmingham.
Warner K. Huh, MD
Dr. Huh is Division Director and Professor, Division of Gynecologic Oncology, Margaret Cameron Spain Endowed Chair in Obstetrics/Gynecology, University of Alabama at Birmingham.
The authors report no financial relationships relevant to this article.
David W. Doo, MD
Dr. Doo is Fellow, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alabama at Birmingham.
Warner K. Huh, MD
Dr. Huh is Division Director and Professor, Division of Gynecologic Oncology, Margaret Cameron Spain Endowed Chair in Obstetrics/Gynecology, University of Alabama at Birmingham.
The authors report no financial relationships relevant to this article.
The role of minimally invasive surgery for early-stage cervical cancer has been the subject of heated debate since the presentation of the results of the Laparoscopic Approach to Cervical Cancer (LACC) Trial at the Society of Gynecologic Oncology Annual Meeting on Women’s Cancer in 2018. This was an international, randomized, phase 3 trial comparing minimally invasive radical hysterectomy (MH) to open radical hysterectomy (OH) in the treatment of early-stage cervical cancer. The trial was closed early by the study’s Data and Safety Monitoring Committee due to an imbalance of deaths between the groups, with a higher rate in the minimally invasive arm. The final results, which were largely unexpected by the medical community, showed that the disease-free survival (DFS) at 4.5 years was 86.0% in the MH arm and 96.5% in the OH arm, which was a larger difference than their noninferiority cutoff of -7.2 percentage points.1 Results of an epidemiologic study, which used data from the Surveillance, Epidemiology, and End Results (SEER) program and the National Cancer Database, also were presented at this meeting, and they reinforced the findings of the LACC trial.2
The combined results have caused significant concern and confusion from the medical community regarding the clinical implication that minimally invasive surgery may be an unacceptable approach for radical hysterectomy in cervical cancer. Prior to this study, retrospective data supported similar outcomes between the two approaches.3 Additionally, robotic surgery has made radical hysterectomy an option for those with a higher body mass index, as an open radical hysterectomy can be technically challenging in larger patients and result in a higher rate of adverse outcomes.
LACC trial questioned by US surgeons
Many in the United States have questioned the design and conclusions of the LACC trial. This trial was conducted primarily outside of North America and utilized conventional laparoscopic surgery 85% of the time as opposed to robotic surgery. Additionally, the found difference in DFS between MH and OH may have been driven more by the superior performance of the OH group (compared with historical data) than the poorly performing MH group.4 Other criticisms have touched on the low number of overall survival events, the low bar for surgeon volume or skill assessment, and the inability to make conclusions regarding “low-risk” lesions (<2 cm, no lymphovascular space invasion, <1 cm depth of invasion).
Were requirements for surgical skill adequate? Regarding surgeon skill, the LACC trial required documentation of the perioperative outcomes from 10 laparoscopic or robotic radical hysterectomies, as well as 2 unedited videos of each surgeon participating in the study to verify their technique, which some have considered inadequate to sufficiently vet a surgeon’s ability. Additionally, 14 of the 33 centers enrolled in the study accrued 71% of the patients, and concerns about the surgeon volume of the remaining 19 centers have been raised. Finally, there has been discussion about whether the variance in surgical approach can even be adequately assessed in a trial of this nature, as surgical skill is not a binary variable that is easily amenable to randomization. Unlike other trials, which have clear exposure and control arms, no 2 surgeries are exactly alike, and surgical technique is highly variable between surgeons, institutions, and countries.
Continue to: New data evaluate for surgeon volume
New data evaluate for surgeon volume
In an effort to address the concerns regarding surgical approach and expertise, the recently published study by Cusimano and colleagues uses population-based data from Ontario for all women undergoing radical hysterectomy for cervical cancer over a 10-year period from 2006 through 2016.5 The primary outcome was all-cause death, but the study also sought to address whether surgeon volume has an impact on recurrence rates for patients undergoing MH versus OH. To measure this impact the authors stratified surgeon characteristics by technique-specific volume and cervical cancer volume, splitting these volumes at the 50% percentile for low- and high-volume surgeons. They defined technique-specific volume as the number of simple and radical hysterectomies performed in the prior year using the selected approach (MH or OH). Cervical cancer volume was calculated as the number of hysterectomies of any type for cervical cancer in the previous 2 years. The technique-specific volume variable was subsequently re-categorized into tertiles, examined as a continuous variable, and analyzed at the 50th percentile for each year of the study.
Death and recurrence rates better in the OH group. The final cohort included 958 women that were relatively evenly split between MH and OH procedures. Results from their analysis show no difference in terms of all-cause death, cervical cancer–specific death, or recurrence. However, all 3 of these parameters were significantly different in favor of the OH group in women with Stage IB disease, which comprised over half of the overall cohort. Importantly, neither technique-specific volume nor cervical cancer volume had an effect on death or recurrence in Stage IB patients in any of the investigators’ analyses.
Important limitations. There are several limitations to this study that have to be taken into account before drawing any conclusions. Pathologic data were obtained from the database and did not include some important details about the tumor specimens (including specifying subgroups of Stage IA and IB disease, tumor size, presence of lymphovascular space invasion, and depth of stromal invasion). All of these details have been shown to be important prognostic variables in early-stage cervical cancer. Additionally, the MH group included a predominantly laparoscopic approach with only 10% of cases performed robotically, which again brings into question the generalizability of the data.
However, despite some of these shortcomings, the study authors do make a compelling argument that surgeon volume alone does not seem to play a significant role in cancer outcomes after MH.
With surgical approaches hard to compare, turn to careful patient counseling
Definitive assessment of the impact of surgical skill and experience on cervical cancer outcomes is probably an impossible task, as even a perfectly designed trial cannot entirely account for the intricacies of a complex surgical procedure. Variations in tumor characteristics and patient anatomy that affect operative decision making are not likely to be reflected when a patient’s outcome is plugged into a database. As a result, some surgeons and departments have turned to reporting personal or institutional recurrence rates for MH, which they believe may b
The role of minimally invasive surgery for early-stage cervical cancer has been the subject of heated debate since the presentation of the results of the Laparoscopic Approach to Cervical Cancer (LACC) Trial at the Society of Gynecologic Oncology Annual Meeting on Women’s Cancer in 2018. This was an international, randomized, phase 3 trial comparing minimally invasive radical hysterectomy (MH) to open radical hysterectomy (OH) in the treatment of early-stage cervical cancer. The trial was closed early by the study’s Data and Safety Monitoring Committee due to an imbalance of deaths between the groups, with a higher rate in the minimally invasive arm. The final results, which were largely unexpected by the medical community, showed that the disease-free survival (DFS) at 4.5 years was 86.0% in the MH arm and 96.5% in the OH arm, which was a larger difference than their noninferiority cutoff of -7.2 percentage points.1 Results of an epidemiologic study, which used data from the Surveillance, Epidemiology, and End Results (SEER) program and the National Cancer Database, also were presented at this meeting, and they reinforced the findings of the LACC trial.2
The combined results have caused significant concern and confusion from the medical community regarding the clinical implication that minimally invasive surgery may be an unacceptable approach for radical hysterectomy in cervical cancer. Prior to this study, retrospective data supported similar outcomes between the two approaches.3 Additionally, robotic surgery has made radical hysterectomy an option for those with a higher body mass index, as an open radical hysterectomy can be technically challenging in larger patients and result in a higher rate of adverse outcomes.
LACC trial questioned by US surgeons
Many in the United States have questioned the design and conclusions of the LACC trial. This trial was conducted primarily outside of North America and utilized conventional laparoscopic surgery 85% of the time as opposed to robotic surgery. Additionally, the found difference in DFS between MH and OH may have been driven more by the superior performance of the OH group (compared with historical data) than the poorly performing MH group.4 Other criticisms have touched on the low number of overall survival events, the low bar for surgeon volume or skill assessment, and the inability to make conclusions regarding “low-risk” lesions (<2 cm, no lymphovascular space invasion, <1 cm depth of invasion).
Were requirements for surgical skill adequate? Regarding surgeon skill, the LACC trial required documentation of the perioperative outcomes from 10 laparoscopic or robotic radical hysterectomies, as well as 2 unedited videos of each surgeon participating in the study to verify their technique, which some have considered inadequate to sufficiently vet a surgeon’s ability. Additionally, 14 of the 33 centers enrolled in the study accrued 71% of the patients, and concerns about the surgeon volume of the remaining 19 centers have been raised. Finally, there has been discussion about whether the variance in surgical approach can even be adequately assessed in a trial of this nature, as surgical skill is not a binary variable that is easily amenable to randomization. Unlike other trials, which have clear exposure and control arms, no 2 surgeries are exactly alike, and surgical technique is highly variable between surgeons, institutions, and countries.
Continue to: New data evaluate for surgeon volume
New data evaluate for surgeon volume
In an effort to address the concerns regarding surgical approach and expertise, the recently published study by Cusimano and colleagues uses population-based data from Ontario for all women undergoing radical hysterectomy for cervical cancer over a 10-year period from 2006 through 2016.5 The primary outcome was all-cause death, but the study also sought to address whether surgeon volume has an impact on recurrence rates for patients undergoing MH versus OH. To measure this impact the authors stratified surgeon characteristics by technique-specific volume and cervical cancer volume, splitting these volumes at the 50% percentile for low- and high-volume surgeons. They defined technique-specific volume as the number of simple and radical hysterectomies performed in the prior year using the selected approach (MH or OH). Cervical cancer volume was calculated as the number of hysterectomies of any type for cervical cancer in the previous 2 years. The technique-specific volume variable was subsequently re-categorized into tertiles, examined as a continuous variable, and analyzed at the 50th percentile for each year of the study.
Death and recurrence rates better in the OH group. The final cohort included 958 women that were relatively evenly split between MH and OH procedures. Results from their analysis show no difference in terms of all-cause death, cervical cancer–specific death, or recurrence. However, all 3 of these parameters were significantly different in favor of the OH group in women with Stage IB disease, which comprised over half of the overall cohort. Importantly, neither technique-specific volume nor cervical cancer volume had an effect on death or recurrence in Stage IB patients in any of the investigators’ analyses.
Important limitations. There are several limitations to this study that have to be taken into account before drawing any conclusions. Pathologic data were obtained from the database and did not include some important details about the tumor specimens (including specifying subgroups of Stage IA and IB disease, tumor size, presence of lymphovascular space invasion, and depth of stromal invasion). All of these details have been shown to be important prognostic variables in early-stage cervical cancer. Additionally, the MH group included a predominantly laparoscopic approach with only 10% of cases performed robotically, which again brings into question the generalizability of the data.
However, despite some of these shortcomings, the study authors do make a compelling argument that surgeon volume alone does not seem to play a significant role in cancer outcomes after MH.
With surgical approaches hard to compare, turn to careful patient counseling
Definitive assessment of the impact of surgical skill and experience on cervical cancer outcomes is probably an impossible task, as even a perfectly designed trial cannot entirely account for the intricacies of a complex surgical procedure. Variations in tumor characteristics and patient anatomy that affect operative decision making are not likely to be reflected when a patient’s outcome is plugged into a database. As a result, some surgeons and departments have turned to reporting personal or institutional recurrence rates for MH, which they believe may b
- Ramirez PT, Frumovitz M, Pareja R, et al. Minimally invasive versus abdominal radical hysterectomy for cervical cancer. N Engl J Med. 2018;379:1895-1904.
- Melamed A, Margul DJ, Chen L, et al. Survival after minimally invasive radical hysterectomy for early-stage cervical cancer. N Engl J Med. 2018;379:1905-1914.
- Wang Y, Deng L, Cao L, et al. The outcome of laparoscopy versus laparotomy for the management of early stage cervical cancer-meta analysis. J Minim Invasive Gynecol. 2015;22:S4-S5.
- Leitao MM Jr. The LACC Trial: has minimally invasive surgery for early-stage cervical cancer been dealt a knockout punch? Int J Gynecol Cancer. 2018;28:1248-1250.
- Cusimano MC, Baxter NN, Gien LT, et al. Impact of surgical approach on oncologic outcomes in women undergoing radical hysterectomy for cervical cancer. Am J Obstet Gynecol. July 6, 2019. doi:10.1016/j.ajog.2019.07.009.
- Ramirez PT, Frumovitz M, Pareja R, et al. Minimally invasive versus abdominal radical hysterectomy for cervical cancer. N Engl J Med. 2018;379:1895-1904.
- Melamed A, Margul DJ, Chen L, et al. Survival after minimally invasive radical hysterectomy for early-stage cervical cancer. N Engl J Med. 2018;379:1905-1914.
- Wang Y, Deng L, Cao L, et al. The outcome of laparoscopy versus laparotomy for the management of early stage cervical cancer-meta analysis. J Minim Invasive Gynecol. 2015;22:S4-S5.
- Leitao MM Jr. The LACC Trial: has minimally invasive surgery for early-stage cervical cancer been dealt a knockout punch? Int J Gynecol Cancer. 2018;28:1248-1250.
- Cusimano MC, Baxter NN, Gien LT, et al. Impact of surgical approach on oncologic outcomes in women undergoing radical hysterectomy for cervical cancer. Am J Obstet Gynecol. July 6, 2019. doi:10.1016/j.ajog.2019.07.009.
Perceived discrimination linked to delay in ovarian cancer diagnosis for black women
Perceived everyday discrimination was associated with an extended duration between symptom onset and cancer diagnosis (prolonged symptom duration) in black women with ovarian cancer, according to results from a case-control analysis.
In contrast, another interpersonal factor, trust in physicians, was not associated with prolonged symptom duration.
“We [examined] the association of everyday discrimination and trust in physicians with a prolonged interval between symptom onset and ovarian cancer diagnosis,” wrote Megan A. Mullins, MPH, of the University of Michigan, Ann Arbor, and colleagues. The findings were published in Cancer.
The analysis included 486 cases of black women with newly diagnosed epithelial ovarian cancer, 302 of whom had prolonged symptom duration. Study cases were obtained from the African American Cancer Epidemiology Study that took place from December 2010 to December 2015. Perceived discrimination was evaluated with the five-question version of the Williams Everyday Discrimination Scale.
In the model, adjustments were made for various demographic characteristics, including marital status, body mass index, and age at diagnosis, among other parameters.
After analysis, the researchers found that every 1-unit rise in the frequency of everyday discrimination was associated with a higher likelihood of prolonged symptom duration (odds ratio, 1.74; 95% confidence interval, 1.22-2.49).
No association was found between trust in physicians and prolonged symptom duration (odds ratio, 0.86; 95% CI, 0.66-1.11).
“These results point to the social context in daily life playing a role in receiving optimal ovarian cancer care,” the researchers wrote.
One key limitation of the study was that the data was obtained in a cross-sectional manner, which could introduce bias because of reverse causality.
“This work is a novel first step in understanding the relationship between interpersonal exposures and racial disparities in ovarian cancer care. More equitable access to ovarian cancer care necessitates that women feel comfortable about advocating for their needs and trust their self-assessment of their symptoms,” they concluded.
The study was funded by the National Cancer Institute, the Metropolitan Detroit Cancer Surveillance System, and the Epidemiology Research Core. The authors reported no conflicts of interest.
SOURCE: Mullins MA et al. Cancer. 2019 Aug 15. doi: 10.1002/cncr.32451.
Perceived everyday discrimination was associated with an extended duration between symptom onset and cancer diagnosis (prolonged symptom duration) in black women with ovarian cancer, according to results from a case-control analysis.
In contrast, another interpersonal factor, trust in physicians, was not associated with prolonged symptom duration.
“We [examined] the association of everyday discrimination and trust in physicians with a prolonged interval between symptom onset and ovarian cancer diagnosis,” wrote Megan A. Mullins, MPH, of the University of Michigan, Ann Arbor, and colleagues. The findings were published in Cancer.
The analysis included 486 cases of black women with newly diagnosed epithelial ovarian cancer, 302 of whom had prolonged symptom duration. Study cases were obtained from the African American Cancer Epidemiology Study that took place from December 2010 to December 2015. Perceived discrimination was evaluated with the five-question version of the Williams Everyday Discrimination Scale.
In the model, adjustments were made for various demographic characteristics, including marital status, body mass index, and age at diagnosis, among other parameters.
After analysis, the researchers found that every 1-unit rise in the frequency of everyday discrimination was associated with a higher likelihood of prolonged symptom duration (odds ratio, 1.74; 95% confidence interval, 1.22-2.49).
No association was found between trust in physicians and prolonged symptom duration (odds ratio, 0.86; 95% CI, 0.66-1.11).
“These results point to the social context in daily life playing a role in receiving optimal ovarian cancer care,” the researchers wrote.
One key limitation of the study was that the data was obtained in a cross-sectional manner, which could introduce bias because of reverse causality.
“This work is a novel first step in understanding the relationship between interpersonal exposures and racial disparities in ovarian cancer care. More equitable access to ovarian cancer care necessitates that women feel comfortable about advocating for their needs and trust their self-assessment of their symptoms,” they concluded.
The study was funded by the National Cancer Institute, the Metropolitan Detroit Cancer Surveillance System, and the Epidemiology Research Core. The authors reported no conflicts of interest.
SOURCE: Mullins MA et al. Cancer. 2019 Aug 15. doi: 10.1002/cncr.32451.
Perceived everyday discrimination was associated with an extended duration between symptom onset and cancer diagnosis (prolonged symptom duration) in black women with ovarian cancer, according to results from a case-control analysis.
In contrast, another interpersonal factor, trust in physicians, was not associated with prolonged symptom duration.
“We [examined] the association of everyday discrimination and trust in physicians with a prolonged interval between symptom onset and ovarian cancer diagnosis,” wrote Megan A. Mullins, MPH, of the University of Michigan, Ann Arbor, and colleagues. The findings were published in Cancer.
The analysis included 486 cases of black women with newly diagnosed epithelial ovarian cancer, 302 of whom had prolonged symptom duration. Study cases were obtained from the African American Cancer Epidemiology Study that took place from December 2010 to December 2015. Perceived discrimination was evaluated with the five-question version of the Williams Everyday Discrimination Scale.
In the model, adjustments were made for various demographic characteristics, including marital status, body mass index, and age at diagnosis, among other parameters.
After analysis, the researchers found that every 1-unit rise in the frequency of everyday discrimination was associated with a higher likelihood of prolonged symptom duration (odds ratio, 1.74; 95% confidence interval, 1.22-2.49).
No association was found between trust in physicians and prolonged symptom duration (odds ratio, 0.86; 95% CI, 0.66-1.11).
“These results point to the social context in daily life playing a role in receiving optimal ovarian cancer care,” the researchers wrote.
One key limitation of the study was that the data was obtained in a cross-sectional manner, which could introduce bias because of reverse causality.
“This work is a novel first step in understanding the relationship between interpersonal exposures and racial disparities in ovarian cancer care. More equitable access to ovarian cancer care necessitates that women feel comfortable about advocating for their needs and trust their self-assessment of their symptoms,” they concluded.
The study was funded by the National Cancer Institute, the Metropolitan Detroit Cancer Surveillance System, and the Epidemiology Research Core. The authors reported no conflicts of interest.
SOURCE: Mullins MA et al. Cancer. 2019 Aug 15. doi: 10.1002/cncr.32451.
FROM CANCER
Ovarian cancer and perineal talc exposure: An epidemiologic dilemma
Many readers may be aware of large payments made by such companies as Johnson & Johnson to compensate women with a history of ovarian cancer who have claimed that perineal application of talc played a causative role in their cancer development. This column serves to review the purported role of perineal talc use in the development of ovarian cancer, and explore some of the pitfalls of observational science.
Talc, a hydrated magnesium silicate, is the softest mineral on earth, and has been sold as a personal hygiene product for many decades. Perineal application of talc to sanitary pads, perineal skin, undergarments, and diapers has been a common practice to decrease friction, moisture build-up, and as a deodorant. Talc is chemically similar, although not identical, to asbestos and is geologically located in close proximity to the known carcinogen. In the 1970s, there were concerns raised regarding the possible contamination of cosmetic-grade talc with asbestos, which led to the development of asbestos-free forms of the substance. Given that a strong causal relationship had been established between asbestos exposure and lung and pleural cancers, there was concern that exposure to perineal talc might increase cancer risk.
In the 1980s, an association between perineal talc exposure and ovarian cancer was observed in a case-control study.1 Since that time, multiple other observational studies, predominately case-control studies, have observed an increased ovarian cancer risk among users of perineal talc including the findings of a meta-analysis which estimated a 24%-39% increased risk for ovarian cancer among users.2 Does this establish a causal relationship? For the purposes of legal cases, these associations are adequate. However, science demands a different standard when determining cause and effect.
It is not unusual to rely on observational studies to establish a causal relationship between exposure and disease when it is unethical to randomize subjects in a clinical trial to exposure of the potential harmful agent. This was the necessary methodology behind establishing that smoking causes lung cancer. Several factors must be present when relying on observational studies to establish plausible causation including an observable biologic mechanism, dose-effect response, temporal relationship, consistent effect observed in multiple study populations, and statistical strength of response. These elements should be present in a consistent and powerful enough way to balance the pitfalls of observational studies, namely biases.
A particularly problematic bias is one of recall bias, which plagues case-control studies. Case-control studies are a popular tool to measure a relationship between an exposure and a rare disease, because they are more feasible than the prospective, observational cohort studies that require very large study populations observed over very long periods of time to capture enough events of interest (in this case, cases of ovarian cancer). In case-control studies, researchers identify a cohort of patients with the outcome of interest (ovarian cancer) and compare this population to a control group of similar demographic features. They then survey directly or indirectly (through medical records) for the exposure of interest (perineal talc use).
Recall bias occurs when subjects who have the disease are more likely to have memory of exposure than do control subjects because of the natural instincts individuals have toward attribution. This is emphasized when there is public commentary, justified or not, about the potential risks of that exposure. Given the significant publicity that these lawsuits have had with companies that produced cosmetic talc, it is plausible that ovarian cancer survivors are more likely to remember and negatively attribute their talc exposure to their cancer than are subjects without cancer. Additionally, their memory of volume and duration of exposure generally is enhanced by the same pressures. The potential for this bias is eliminated in prospective, cohort observational studies such as the Women’s Health Initiative Observational Study which, among 61,576 women, half of whom reported perineal talc exposure, did not measure a difference in the development of ovarian cancers during their 12 years of mean follow-up.3
Given these inherent biases, The biologic mechanism of talc carcinogenesis is largely theoretical. As mentioned earlier, prior to the 1970s, there was some observed contamination of talc with asbestos likely caused by the geologic proximity of these minerals. Asbestos is a known carcinogen, and therefore possibly could be harmful if a contaminant of talc. However, it is not known if this level of contamination was enough to be achieve ovarian carcinogenesis. Most theories of talc carcinogenesis are based on foreign body inflammatory reaction via talc particle ascent through the genital tract. This is proposed to induce an inflammatory release of prostaglandins and cytokines, which could cause a mutagenic effect promoting carcinogenesis. The foreign body inflammatory mechanism is further supported by the observation of a decreased incidence of ovarian cancer after hysterectomy or tubal ligation.4 However, inconsistently, a protective effect of NSAIDs has not been observed in ovarian cancer.5
A recent meta-analysis, which reviewed 27 of the largest, best-quality observational studies, identified a dose-effect response with an increased risk for ovarian cancer with greater than 3,600 lifetime applications, compared with less than 3,600 applications.2 The observed association between perineal talc exposure and increased risk of ovarian cancer appears to be consistent across a number of observational studies, including both case-control studies and prospective cohort studies (although somewhat mitigated in the latter). Additionally, there appears to be consistency in the finding that the risk is present for the epithelial subtypes of serous and endometrioid, but not mucinous or clear cell cancer. However, when considering the magnitude of effect, this remains somewhat small (odds ratio, 1.31; 95% confidence interval, 1.24-1.39) when compared with other better established carcinogenic relationships such as smoking and lung cancer where the hazard ratio is 12.12 (95% CI, 6.94-21.17).2,6
If talc does not cause ovarian cancer, why would this association be observed at all? One explanation could be that talc use is a confounder for the true causative mechanism. A theoretical example of this would be if the genital microbiome (a subject we have reviewed previously in this column) was the true culprit. If a particular microbiome profile promotes both oncogenic change in the ovary while also causing vaginal discharge and odor, it might increase the likelihood that perineal talc use is reported in the history of these cancer patients. This is purely speculative, but it always is important to consider the potential for confounding variables when utilizing observational studies to attribute cause and effect.
Therefore, there is a consistently observed association between perineal talc application and ovarian cancer, however, the relationship does not appear to be strong enough, associated with a proven carcinogenic mechanism, or free from interfering recall bias such to definitively state that perineal talc exposure causes ovarian cancer. Given these findings, it is reasonable to recommend patients avoid the use of perineal talc application until further definitive safety evidence is provided. In the meantime, it should be noted that even though talc-containing products are not commercially labeled as carcinogens, many pharmaceutical and cosmetic companies have replaced the mineral talc with corn starch in their powders.
Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She had no relevant financial disclosures. Email her at [email protected].
References
1. Cancer. 1982 Jul 15;50(2):372-6.
2. Epidemiology. 2018 Jan;29(1):41-9.
3. J Natl Cancer Inst. 2014 Sep 10;106(9). pii: dju208.
4. Am J Epidemiol. 1991 Aug 15;134(4):362-9.
5. Int J Cancer. 2008 Jan 1;122(1):170-6.
6. J Natl Cancer Inst. 2018 Nov 1;110(11):1201-7.
Many readers may be aware of large payments made by such companies as Johnson & Johnson to compensate women with a history of ovarian cancer who have claimed that perineal application of talc played a causative role in their cancer development. This column serves to review the purported role of perineal talc use in the development of ovarian cancer, and explore some of the pitfalls of observational science.
Talc, a hydrated magnesium silicate, is the softest mineral on earth, and has been sold as a personal hygiene product for many decades. Perineal application of talc to sanitary pads, perineal skin, undergarments, and diapers has been a common practice to decrease friction, moisture build-up, and as a deodorant. Talc is chemically similar, although not identical, to asbestos and is geologically located in close proximity to the known carcinogen. In the 1970s, there were concerns raised regarding the possible contamination of cosmetic-grade talc with asbestos, which led to the development of asbestos-free forms of the substance. Given that a strong causal relationship had been established between asbestos exposure and lung and pleural cancers, there was concern that exposure to perineal talc might increase cancer risk.
In the 1980s, an association between perineal talc exposure and ovarian cancer was observed in a case-control study.1 Since that time, multiple other observational studies, predominately case-control studies, have observed an increased ovarian cancer risk among users of perineal talc including the findings of a meta-analysis which estimated a 24%-39% increased risk for ovarian cancer among users.2 Does this establish a causal relationship? For the purposes of legal cases, these associations are adequate. However, science demands a different standard when determining cause and effect.
It is not unusual to rely on observational studies to establish a causal relationship between exposure and disease when it is unethical to randomize subjects in a clinical trial to exposure of the potential harmful agent. This was the necessary methodology behind establishing that smoking causes lung cancer. Several factors must be present when relying on observational studies to establish plausible causation including an observable biologic mechanism, dose-effect response, temporal relationship, consistent effect observed in multiple study populations, and statistical strength of response. These elements should be present in a consistent and powerful enough way to balance the pitfalls of observational studies, namely biases.
A particularly problematic bias is one of recall bias, which plagues case-control studies. Case-control studies are a popular tool to measure a relationship between an exposure and a rare disease, because they are more feasible than the prospective, observational cohort studies that require very large study populations observed over very long periods of time to capture enough events of interest (in this case, cases of ovarian cancer). In case-control studies, researchers identify a cohort of patients with the outcome of interest (ovarian cancer) and compare this population to a control group of similar demographic features. They then survey directly or indirectly (through medical records) for the exposure of interest (perineal talc use).
Recall bias occurs when subjects who have the disease are more likely to have memory of exposure than do control subjects because of the natural instincts individuals have toward attribution. This is emphasized when there is public commentary, justified or not, about the potential risks of that exposure. Given the significant publicity that these lawsuits have had with companies that produced cosmetic talc, it is plausible that ovarian cancer survivors are more likely to remember and negatively attribute their talc exposure to their cancer than are subjects without cancer. Additionally, their memory of volume and duration of exposure generally is enhanced by the same pressures. The potential for this bias is eliminated in prospective, cohort observational studies such as the Women’s Health Initiative Observational Study which, among 61,576 women, half of whom reported perineal talc exposure, did not measure a difference in the development of ovarian cancers during their 12 years of mean follow-up.3
Given these inherent biases, The biologic mechanism of talc carcinogenesis is largely theoretical. As mentioned earlier, prior to the 1970s, there was some observed contamination of talc with asbestos likely caused by the geologic proximity of these minerals. Asbestos is a known carcinogen, and therefore possibly could be harmful if a contaminant of talc. However, it is not known if this level of contamination was enough to be achieve ovarian carcinogenesis. Most theories of talc carcinogenesis are based on foreign body inflammatory reaction via talc particle ascent through the genital tract. This is proposed to induce an inflammatory release of prostaglandins and cytokines, which could cause a mutagenic effect promoting carcinogenesis. The foreign body inflammatory mechanism is further supported by the observation of a decreased incidence of ovarian cancer after hysterectomy or tubal ligation.4 However, inconsistently, a protective effect of NSAIDs has not been observed in ovarian cancer.5
A recent meta-analysis, which reviewed 27 of the largest, best-quality observational studies, identified a dose-effect response with an increased risk for ovarian cancer with greater than 3,600 lifetime applications, compared with less than 3,600 applications.2 The observed association between perineal talc exposure and increased risk of ovarian cancer appears to be consistent across a number of observational studies, including both case-control studies and prospective cohort studies (although somewhat mitigated in the latter). Additionally, there appears to be consistency in the finding that the risk is present for the epithelial subtypes of serous and endometrioid, but not mucinous or clear cell cancer. However, when considering the magnitude of effect, this remains somewhat small (odds ratio, 1.31; 95% confidence interval, 1.24-1.39) when compared with other better established carcinogenic relationships such as smoking and lung cancer where the hazard ratio is 12.12 (95% CI, 6.94-21.17).2,6
If talc does not cause ovarian cancer, why would this association be observed at all? One explanation could be that talc use is a confounder for the true causative mechanism. A theoretical example of this would be if the genital microbiome (a subject we have reviewed previously in this column) was the true culprit. If a particular microbiome profile promotes both oncogenic change in the ovary while also causing vaginal discharge and odor, it might increase the likelihood that perineal talc use is reported in the history of these cancer patients. This is purely speculative, but it always is important to consider the potential for confounding variables when utilizing observational studies to attribute cause and effect.
Therefore, there is a consistently observed association between perineal talc application and ovarian cancer, however, the relationship does not appear to be strong enough, associated with a proven carcinogenic mechanism, or free from interfering recall bias such to definitively state that perineal talc exposure causes ovarian cancer. Given these findings, it is reasonable to recommend patients avoid the use of perineal talc application until further definitive safety evidence is provided. In the meantime, it should be noted that even though talc-containing products are not commercially labeled as carcinogens, many pharmaceutical and cosmetic companies have replaced the mineral talc with corn starch in their powders.
Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She had no relevant financial disclosures. Email her at [email protected].
References
1. Cancer. 1982 Jul 15;50(2):372-6.
2. Epidemiology. 2018 Jan;29(1):41-9.
3. J Natl Cancer Inst. 2014 Sep 10;106(9). pii: dju208.
4. Am J Epidemiol. 1991 Aug 15;134(4):362-9.
5. Int J Cancer. 2008 Jan 1;122(1):170-6.
6. J Natl Cancer Inst. 2018 Nov 1;110(11):1201-7.
Many readers may be aware of large payments made by such companies as Johnson & Johnson to compensate women with a history of ovarian cancer who have claimed that perineal application of talc played a causative role in their cancer development. This column serves to review the purported role of perineal talc use in the development of ovarian cancer, and explore some of the pitfalls of observational science.
Talc, a hydrated magnesium silicate, is the softest mineral on earth, and has been sold as a personal hygiene product for many decades. Perineal application of talc to sanitary pads, perineal skin, undergarments, and diapers has been a common practice to decrease friction, moisture build-up, and as a deodorant. Talc is chemically similar, although not identical, to asbestos and is geologically located in close proximity to the known carcinogen. In the 1970s, there were concerns raised regarding the possible contamination of cosmetic-grade talc with asbestos, which led to the development of asbestos-free forms of the substance. Given that a strong causal relationship had been established between asbestos exposure and lung and pleural cancers, there was concern that exposure to perineal talc might increase cancer risk.
In the 1980s, an association between perineal talc exposure and ovarian cancer was observed in a case-control study.1 Since that time, multiple other observational studies, predominately case-control studies, have observed an increased ovarian cancer risk among users of perineal talc including the findings of a meta-analysis which estimated a 24%-39% increased risk for ovarian cancer among users.2 Does this establish a causal relationship? For the purposes of legal cases, these associations are adequate. However, science demands a different standard when determining cause and effect.
It is not unusual to rely on observational studies to establish a causal relationship between exposure and disease when it is unethical to randomize subjects in a clinical trial to exposure of the potential harmful agent. This was the necessary methodology behind establishing that smoking causes lung cancer. Several factors must be present when relying on observational studies to establish plausible causation including an observable biologic mechanism, dose-effect response, temporal relationship, consistent effect observed in multiple study populations, and statistical strength of response. These elements should be present in a consistent and powerful enough way to balance the pitfalls of observational studies, namely biases.
A particularly problematic bias is one of recall bias, which plagues case-control studies. Case-control studies are a popular tool to measure a relationship between an exposure and a rare disease, because they are more feasible than the prospective, observational cohort studies that require very large study populations observed over very long periods of time to capture enough events of interest (in this case, cases of ovarian cancer). In case-control studies, researchers identify a cohort of patients with the outcome of interest (ovarian cancer) and compare this population to a control group of similar demographic features. They then survey directly or indirectly (through medical records) for the exposure of interest (perineal talc use).
Recall bias occurs when subjects who have the disease are more likely to have memory of exposure than do control subjects because of the natural instincts individuals have toward attribution. This is emphasized when there is public commentary, justified or not, about the potential risks of that exposure. Given the significant publicity that these lawsuits have had with companies that produced cosmetic talc, it is plausible that ovarian cancer survivors are more likely to remember and negatively attribute their talc exposure to their cancer than are subjects without cancer. Additionally, their memory of volume and duration of exposure generally is enhanced by the same pressures. The potential for this bias is eliminated in prospective, cohort observational studies such as the Women’s Health Initiative Observational Study which, among 61,576 women, half of whom reported perineal talc exposure, did not measure a difference in the development of ovarian cancers during their 12 years of mean follow-up.3
Given these inherent biases, The biologic mechanism of talc carcinogenesis is largely theoretical. As mentioned earlier, prior to the 1970s, there was some observed contamination of talc with asbestos likely caused by the geologic proximity of these minerals. Asbestos is a known carcinogen, and therefore possibly could be harmful if a contaminant of talc. However, it is not known if this level of contamination was enough to be achieve ovarian carcinogenesis. Most theories of talc carcinogenesis are based on foreign body inflammatory reaction via talc particle ascent through the genital tract. This is proposed to induce an inflammatory release of prostaglandins and cytokines, which could cause a mutagenic effect promoting carcinogenesis. The foreign body inflammatory mechanism is further supported by the observation of a decreased incidence of ovarian cancer after hysterectomy or tubal ligation.4 However, inconsistently, a protective effect of NSAIDs has not been observed in ovarian cancer.5
A recent meta-analysis, which reviewed 27 of the largest, best-quality observational studies, identified a dose-effect response with an increased risk for ovarian cancer with greater than 3,600 lifetime applications, compared with less than 3,600 applications.2 The observed association between perineal talc exposure and increased risk of ovarian cancer appears to be consistent across a number of observational studies, including both case-control studies and prospective cohort studies (although somewhat mitigated in the latter). Additionally, there appears to be consistency in the finding that the risk is present for the epithelial subtypes of serous and endometrioid, but not mucinous or clear cell cancer. However, when considering the magnitude of effect, this remains somewhat small (odds ratio, 1.31; 95% confidence interval, 1.24-1.39) when compared with other better established carcinogenic relationships such as smoking and lung cancer where the hazard ratio is 12.12 (95% CI, 6.94-21.17).2,6
If talc does not cause ovarian cancer, why would this association be observed at all? One explanation could be that talc use is a confounder for the true causative mechanism. A theoretical example of this would be if the genital microbiome (a subject we have reviewed previously in this column) was the true culprit. If a particular microbiome profile promotes both oncogenic change in the ovary while also causing vaginal discharge and odor, it might increase the likelihood that perineal talc use is reported in the history of these cancer patients. This is purely speculative, but it always is important to consider the potential for confounding variables when utilizing observational studies to attribute cause and effect.
Therefore, there is a consistently observed association between perineal talc application and ovarian cancer, however, the relationship does not appear to be strong enough, associated with a proven carcinogenic mechanism, or free from interfering recall bias such to definitively state that perineal talc exposure causes ovarian cancer. Given these findings, it is reasonable to recommend patients avoid the use of perineal talc application until further definitive safety evidence is provided. In the meantime, it should be noted that even though talc-containing products are not commercially labeled as carcinogens, many pharmaceutical and cosmetic companies have replaced the mineral talc with corn starch in their powders.
Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She had no relevant financial disclosures. Email her at [email protected].
References
1. Cancer. 1982 Jul 15;50(2):372-6.
2. Epidemiology. 2018 Jan;29(1):41-9.
3. J Natl Cancer Inst. 2014 Sep 10;106(9). pii: dju208.
4. Am J Epidemiol. 1991 Aug 15;134(4):362-9.
5. Int J Cancer. 2008 Jan 1;122(1):170-6.
6. J Natl Cancer Inst. 2018 Nov 1;110(11):1201-7.
Pretreatment CT data may help predict immunotherapy benefit in ovarian cancer
Pretreatment CT data may help identify responders to immunotherapy in ovarian cancer, according to a new study.
Specifically, fewer sites of disease and lower intratumor heterogeneity on contrast-enhanced CT may indicate a higher likelihood of durable response to immune checkpoint inhibitors, according to results of the retrospective study, recently published in JCO Precision Oncology.
“Our results suggest that quantitative analysis of baseline contrast-enhanced CT may facilitate the delivery of precision medicine to patients with ovarian cancer by identifying patients who may benefit from immunotherapy,” wrote Yuki Himoto, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, and colleagues.
The study leverages findings from the emerging field of radiomics, which the investigators note allows for “virtual sampling” of tumor heterogeneity within a single lesion and between lesions.
“This information may complement molecular profiling in personalizing medical decisions,” Dr. Himoto and coauthors explained.
The study cohort included 75 patients with recurrent ovarian cancer who were enrolled in ongoing, prospective trials of immunotherapy, according to the researchers. Of that group, just under one in five derived a durable clinical benefit, defined as progression-free survival lasting at least 24 weeks.
In univariable analysis, they found a number of contrast-enhanced CT variables were linked to durable clinical benefit, including fewer disease sites, lower cluster-site entropy and dissimilarity, which they wrote were an indicator of lower intertumor heterogeneity, and higher energy in the largest-volume lesion, which they described as an indicator of lower intratumor heterogeneity.
However, in multivariable analysis, the only variables that were still associated with durable clinical benefit were fewer disease sites (odds ratio, 1.64; 95% confidence interval, 1.19-2.27; P = .012) and higher energy in the largest lesion (odds ratio, 1.41; 95% CI, 1.11-1.81; P = .006), according to the report.
Those two factors combined were a composite indicator of durable clinical benefit (C-index, 0.821).
These findings could represent a step forward in the provision of immunotherapy in ovarian cancer, which exhibits poor response to immune checkpoint inhibitors, compared with some other cancer types, the investigators wrote.
More insights are needed, however, to help personalize the selection of immunotherapy in ovarian cancer, including a better understanding of cancer immune reactions and retooling of immune response criteria, they added.
“Composite multimodal multifaceted biomarkers that noninvasively capture spatiotemporal tumor heterogeneity will likely be necessary to comprehensively assess immune the tumor microenvironment and serve as clinical decision support for prognosis inference and prediction of response,” Dr. Himoto and associates wrote.
The study was supported by the National Cancer Institute, among other sources. Study authors reported disclosures related to Merck, Bristol-Myers Squibb, Genentech, Celgene, AstraZeneca, Y-mAbs Therapeutics, and others.
SOURCE: Himoto Y et al. JCO Precis Oncol. 2019 Aug 13. doi: 10.1200/PO.19.00038.
Pretreatment CT data may help identify responders to immunotherapy in ovarian cancer, according to a new study.
Specifically, fewer sites of disease and lower intratumor heterogeneity on contrast-enhanced CT may indicate a higher likelihood of durable response to immune checkpoint inhibitors, according to results of the retrospective study, recently published in JCO Precision Oncology.
“Our results suggest that quantitative analysis of baseline contrast-enhanced CT may facilitate the delivery of precision medicine to patients with ovarian cancer by identifying patients who may benefit from immunotherapy,” wrote Yuki Himoto, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, and colleagues.
The study leverages findings from the emerging field of radiomics, which the investigators note allows for “virtual sampling” of tumor heterogeneity within a single lesion and between lesions.
“This information may complement molecular profiling in personalizing medical decisions,” Dr. Himoto and coauthors explained.
The study cohort included 75 patients with recurrent ovarian cancer who were enrolled in ongoing, prospective trials of immunotherapy, according to the researchers. Of that group, just under one in five derived a durable clinical benefit, defined as progression-free survival lasting at least 24 weeks.
In univariable analysis, they found a number of contrast-enhanced CT variables were linked to durable clinical benefit, including fewer disease sites, lower cluster-site entropy and dissimilarity, which they wrote were an indicator of lower intertumor heterogeneity, and higher energy in the largest-volume lesion, which they described as an indicator of lower intratumor heterogeneity.
However, in multivariable analysis, the only variables that were still associated with durable clinical benefit were fewer disease sites (odds ratio, 1.64; 95% confidence interval, 1.19-2.27; P = .012) and higher energy in the largest lesion (odds ratio, 1.41; 95% CI, 1.11-1.81; P = .006), according to the report.
Those two factors combined were a composite indicator of durable clinical benefit (C-index, 0.821).
These findings could represent a step forward in the provision of immunotherapy in ovarian cancer, which exhibits poor response to immune checkpoint inhibitors, compared with some other cancer types, the investigators wrote.
More insights are needed, however, to help personalize the selection of immunotherapy in ovarian cancer, including a better understanding of cancer immune reactions and retooling of immune response criteria, they added.
“Composite multimodal multifaceted biomarkers that noninvasively capture spatiotemporal tumor heterogeneity will likely be necessary to comprehensively assess immune the tumor microenvironment and serve as clinical decision support for prognosis inference and prediction of response,” Dr. Himoto and associates wrote.
The study was supported by the National Cancer Institute, among other sources. Study authors reported disclosures related to Merck, Bristol-Myers Squibb, Genentech, Celgene, AstraZeneca, Y-mAbs Therapeutics, and others.
SOURCE: Himoto Y et al. JCO Precis Oncol. 2019 Aug 13. doi: 10.1200/PO.19.00038.
Pretreatment CT data may help identify responders to immunotherapy in ovarian cancer, according to a new study.
Specifically, fewer sites of disease and lower intratumor heterogeneity on contrast-enhanced CT may indicate a higher likelihood of durable response to immune checkpoint inhibitors, according to results of the retrospective study, recently published in JCO Precision Oncology.
“Our results suggest that quantitative analysis of baseline contrast-enhanced CT may facilitate the delivery of precision medicine to patients with ovarian cancer by identifying patients who may benefit from immunotherapy,” wrote Yuki Himoto, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, and colleagues.
The study leverages findings from the emerging field of radiomics, which the investigators note allows for “virtual sampling” of tumor heterogeneity within a single lesion and between lesions.
“This information may complement molecular profiling in personalizing medical decisions,” Dr. Himoto and coauthors explained.
The study cohort included 75 patients with recurrent ovarian cancer who were enrolled in ongoing, prospective trials of immunotherapy, according to the researchers. Of that group, just under one in five derived a durable clinical benefit, defined as progression-free survival lasting at least 24 weeks.
In univariable analysis, they found a number of contrast-enhanced CT variables were linked to durable clinical benefit, including fewer disease sites, lower cluster-site entropy and dissimilarity, which they wrote were an indicator of lower intertumor heterogeneity, and higher energy in the largest-volume lesion, which they described as an indicator of lower intratumor heterogeneity.
However, in multivariable analysis, the only variables that were still associated with durable clinical benefit were fewer disease sites (odds ratio, 1.64; 95% confidence interval, 1.19-2.27; P = .012) and higher energy in the largest lesion (odds ratio, 1.41; 95% CI, 1.11-1.81; P = .006), according to the report.
Those two factors combined were a composite indicator of durable clinical benefit (C-index, 0.821).
These findings could represent a step forward in the provision of immunotherapy in ovarian cancer, which exhibits poor response to immune checkpoint inhibitors, compared with some other cancer types, the investigators wrote.
More insights are needed, however, to help personalize the selection of immunotherapy in ovarian cancer, including a better understanding of cancer immune reactions and retooling of immune response criteria, they added.
“Composite multimodal multifaceted biomarkers that noninvasively capture spatiotemporal tumor heterogeneity will likely be necessary to comprehensively assess immune the tumor microenvironment and serve as clinical decision support for prognosis inference and prediction of response,” Dr. Himoto and associates wrote.
The study was supported by the National Cancer Institute, among other sources. Study authors reported disclosures related to Merck, Bristol-Myers Squibb, Genentech, Celgene, AstraZeneca, Y-mAbs Therapeutics, and others.
SOURCE: Himoto Y et al. JCO Precis Oncol. 2019 Aug 13. doi: 10.1200/PO.19.00038.
FROM JCO PRECISION ONCOLOGY
Which birth defects are associated with childhood cancer risk?
Morcellation use in gynecologic surgery: Current clinical recommendations and cautions
Morcellation of gynecologic surgical specimens became controversial after concerns arose about the potential for inadvertent spread of malignant cells throughout the abdomen and pelvis during tissue morcellation of suspected benign disease. In 2014, the US Food and Drug Administration (FDA) issued a warningagainst the use of laparoscopic power morcellation specifically for myomectomy or hysterectomy in the treatment of leiomyomas (fibroids) because of the risk of spreading undiagnosed malignancy throughout the abdomen and pelvis.1 This warning was issued after a high-profile case occurred in Boston in which an occult uterine sarcoma was morcellated during a supracervical robot-assisted hysterectomy for suspected benign fibroids.
Recently, the American College of Obstetricians and Gynecologists (ACOG) published a committee opinion with updated recommendations for practice detailing the risks associated with morcellation and suggestions for patient counseling regarding morcellation.2
In this review, we summarize the techniques and risks of morcellation, the epidemiology of undiagnosed uterine malignancies, practice changes noted at our institution, and clinical recommendations moving forward. A case scenario illustrates keys steps in preoperative evaluation and counseling.
Morcellation uses—and risks
Morcellation is the surgical process of dividing a large tissue specimen into smaller pieces to facilitate their removal through the small incisions made in minimally invasive surgery. Morcellation may be performed with a power instrument or manually.
In power morcellation, an electromechanical instrument is used to cut or shave the specimen; in manual morcellation, the surgeon uses a knife to carve the specimen. Power morcellation is performed through a laparoscopic incision, while the manual technique is performed through a minilaparotomy or vaginally after hysterectomy (TABLE). Unlike uncontained morcellation, contained morcellation involves the use of a laparoscopic bag to hold the specimen and therefore prevent tissue dissemination in the abdomen and pelvis.
Morcellation has greatly expanded our ability to perform minimally invasive surgery—for example, in patients with specimens that cannot be extracted en bloc through the vagina after hysterectomy or, in the case of myomectomy or supracervical hysterectomy without a colpotomy, through small laparoscopic ports. Minimally invasive surgery improves patient care, as it is associated with lower rates of infection, blood loss, venous thromboembolism, wound and bowel complications, postoperative pain, and shorter overall recovery time and hospital stay versus traditional open surgery.3,4 Furthermore, laparoscopic hysterectomy has a 3-fold lower risk of mortality compared with open hysterectomy.4 For these reasons, ACOG recommends choosing a minimally invasive approach for all benign hysterectomies whenever feasible.3
With abundant data supporting the use of a minimally invasive approach, laparoscopic morcellation allowed procedures involving larger tissue specimens to be accomplished without the addition of a minilaparotomy for tissue extraction. However, disseminating potentially malignant tissue throughout the abdomen and pelvis during the morcellation process remains a risk. While tissue spread can occur with either power or manual morcellation, the case that drew media attention to the controversy used power morcellation, and thus intense scrutiny focused on this technique. Morcellation has additional risks, including direct injury to surrounding organs, disruption of the pathologic specimen, and distribution of benign tissue throughout the abdomen and pelvis, such as fibroid, endometriosis, and adenomyosis implants.5-7
Continue to: The challenge of leiomyosarcoma...
The challenge of leiomyosarcoma
The primary controversy surrounding morcellation of fibroid tissue specimens is the potential for undiagnosed malignancy, namely uterine leiomyosarcoma or endometrial stromal sarcoma. While other gynecologic malignancies, including cervical and endometrial cancers, are more common and potentially could be disseminated by morcellation, these cancers are more reliably diagnosed preoperatively with cervical and endometrial biopsies, and they do not tend to mimic benign diseases.
Epidemiology and risk factors. Uterine leiomyosarcoma is rare, with an estimated incidence of 0.36 per 100,000 woman-years.8 However, leiomyosarcoma can mimic the appearance and clinical course of benign fibroids, making preoperative diagnosis difficult. Risk factors for leiomyosarcoma include postmenopausal status, with a median age of 54 years at diagnosis, tamoxifen use longer than 5 years, black race, history of pelvic radiation, and certain hereditary cancer syndromes, such as Lynch syndrome.9-11 Because of these risk factors, preoperative evaluation is crucial to determine the most appropriate surgical method for removal of a large, fibroid uterus (see “Employ shared decision making”).
Estimated incidence at benign hysterectomy. The incidence of leiomyosarcoma diagnosed at the time of benign hysterectomy or myomectomy has been studied extensively since the FDA’s 2014 warning was released, with varying rates identified.11,12 The FDA’s analysis cited a risk of 1 in 498 for unsuspected leiomyosarcoma and 1 in 352 for uterine sarcoma.1 Notably, this analysis excluded studies of women undergoing surgery for presumed fibroids in which no leiomyosarcoma was found on pathology, likely inflating the quoted prevalence. The FDA and other entities subsequently performed further analyses, but a systematic literature review and meta-analysis by the Agency for Healthcare Research and Quality (AHRQ) in 2017 is probably the most accurate. That review included 160 studies and reported a prevalence of less than 1 in 10,000 to 1 in 770, lower than the FDA-cited rate.13
Prognosis. The overall prognosis for women with leiomyosarcoma is poor. Studies indicate a 5-year survival rate of only 55.4%, even in stage 1 disease that is apparently confined to the uterus.9 Although evidence is limited linking morcellation to increased recurrence of leiomyosarcoma, data from small, single-center, retrospective studies cite a worse prognosis, higher risk of recurrence, and shorter progression-free survival after sarcoma morcellation compared with patients who underwent en bloc resection.12,14 Of note, these studies evaluated patients who underwent uncontained morcellation of specimens with unsuspected leiomyosarcoma.
CASE Woman with enlarged, irregular uterus and heavy bleeding
A 40-year-old woman (G2P2) with a history of 2 uncomplicated vaginal deliveries presents for evaluation of heavy uterine bleeding. She has regular periods, every 28 days, and she bleeds for 7 days, saturating 6 pads per day. She is currently taking only oral iron therapy as recommended by her primary care physician. Over the last 1 to 2 years she has felt that her abdomen has been getting larger and that her pants do not fit as well. She is otherwise in excellent health, exercises regularly, and has a full-time job. She has not been sexually active in several months.
The patient’s vitals are within normal limits and her body mass index (BMI) is 35 kg/m2.Pelvic examination reveals that she has an enlarged, irregular uterus with the fundus at the level of the umbilicus. The exam is otherwise unremarkable. On further questioning, the patient does not desire future fertility.
What next steps would you include in this patient’s workup, including imaging studies or lab tests? What surgical options would you give her? How would your management differ if this patient were 70 years old (postmenopausal)?
Continue to: Perform a thorough preoperative evaluation to optimize outcomes...
Perform a thorough preoperative evaluation to optimize outcomes
Women like this case patient who present with symptoms that may lead to treatment with myomectomy or hysterectomy should undergo appropriate preoperative testing to evaluate for malignancy.
According to ACOG guidance, patients should undergo a preoperative endometrial biopsy if they15:
- are older than 45 years with abnormal uterine bleeding
- are younger than 45 years with unopposed estrogen exposure (including obesity or polycystic ovary syndrome)
- have persistent bleeding, or
- failed medical management.
Our case patient is younger than 45 but is obese (BMI, 35) and therefore is a candidate for endometrial biopsy. Additionally, all patients should have up-to-date cervical cancer screening. ACOG also recommends appropriate use of imaging with ultrasonography or magnetic resonance imaging (MRI), although imaging is not recommended solely to evaluate for malignancy, as it cannot rule out the diagnosis of many gynecologic malignancies, including leiomyosarcoma.2
Currently, no tests are available to completely exclude a preoperative diagnosis of leiomyosarcoma. While studies have evaluated the use of MRI combined with lactate dehydrogenase isoenzyme testing, the evidence is weak, and this method is not recommended. Sarcoma is detected by endometrial sampling only 30% to 60% of the time, but it should be performed if the patient meets criteria for sampling or if she has other risk factors for malignancy.16 There are no data to support biopsy of presumed benign fibroids prior to surgical intervention. Patients should be evaluated with a careful history and physical examination for other uterine sarcoma risk factors.
Employ shared decision making
Clinicians should use shared decision making with patients to facilitate decisions on morcellation use in gynecologic surgeries for suspected benign fibroids. Informed consent must be obtained after thorough discussion and counseling regarding the literature on morcellation.17 For all patients, including the case patient described, this discussion should include alternative treatment options, surgical approach with associated risks, the use of morcellation, the incidence of leiomyosarcoma with presumed benign fibroids, leiomyosarcoma prognosis, and the risk of disseminating benign or undiagnosed cancerous tissue throughout the abdomen and pelvis.
Some would argue that the risks of laparotomy outweigh the possible risks associated with morcellation during a minimally invasive myomectomy or hysterectomy. However, this risk analysis is not uniform across all patients, and it is likely that in older women, because they have an a priori increased risk of malignancy in general, including leiomyosarcoma, the risks of power morcellation may outweigh the risks of open surgery.18 Younger women have a much lower risk of leiomyosarcoma, and thus discussion and consideration of the patient’s age should be a part of counseling. If the case patient described was 70 years of age, power morcellation might not be recommended, but these decisions require an in-depth discussion with the patient to make an informed decision and ensure patient autonomy.
The contained morcellation approach
Many surgeons who perform minimally invasive procedures use contained morcellation. In this approach, specimens are placed in a containment bag and morcellated with either power instruments or manually to ensure no dissemination of tissue. Manual contained morcellation can be done through a minilaparotomy or the vagina, depending on the procedure performed, while power contained morcellation is performed through a 15-mm laparoscopic incision.
Continue to: Currently, one containment bag has been...
Currently, one containment bag has been FDA approved for use in laparoscopic contained power morcellation.19 Use of a containment bag increases operative time by approximately 20 minutes, due to the additional steps required to accomplish the procedure.20 Its use, however, suggests a decrease in the risk of possible disease spread and it is feasible with appropriate surgeon training.
One study demonstrated the safety and feasibility of power morcellation within an insufflated containment bag, and subsequent follow-up revealed negative intraperitoneal washings.21,22 In another study evaluating tissue dissemination with contained morcellation of tissue stained with dye, the authors noted actual spillage of tissue fragments in only one case.23 Although more information is needed to confirm prevention of tissue dissemination and the safety of contained tissue morcellation, these studies provide promising data supporting the use of tissue morcellation in appropriate cases in order to perform minimally invasive surgery with larger specimens.
CASE Next steps and treatment outcome
The patient has up-to-date and negative cervical cancer screening. The complete blood count is notable for a hemoglobin level of 11.0 g/dL (normal range, 12.1 to 15.1 g/dL). You perform an endometrial biopsy; results are negative for malignancy. You order pelvic ultrasonography to better characterize the location and size of the fibroids. It shows multiple leiomyomas throughout the myometrium, with the 2 largest fibroids (measuring 5 and 7 cm) located in the left anterior and right posterolateral aspects of the uterus, respectively. Several 3- to 4-cm fibroids appear to be disrupting the endometrial canal, and there is no evidence of an endometrial polyp. There do not appear to be any cervical or lower uterine segment fibroids, which may have further complicated the proposed surgery.
You discuss treatment options for abnormal uterine bleeding with the patient, including initiation of combined oral contraceptive pills, placement of a levonorgestrel-containing intrauterine device, endometrial ablation, uterine artery embolization, and hysterectomy. You discuss the risks and benefits of each approach, keeping in mind the fibroids that are disrupting the contour of the endometrial canal and causing her bulk symptoms.
The patient ultimately decides to undergo a hysterectomy and would like it to be performed with a minimally invasive procedure, if possible. Because of the size of her uterus, you discuss the use of contained power morcellation, including the risks and benefits. You have a thorough discussion about the risk of occult malignancy, although she is at lower risk because of her age, and she consents.
The patient undergoes an uncomplicated total laparoscopic hysterectomy with bilateral salpingectomy. The specimen is removed using contained power morcellation through the umbilical port site. She has an unremarkable immediate postoperative course and is discharged on postoperative Day 1.
You see the patient in the clinic 2 weeks later. She reports minimal pain or discomfort and has no other complaints. Her abdominal incisions are healing well. You review the final pathology report with her, which showed no evidence of malignancy.
Society guidance on clinical applications
In current clinical practice, many surgeons have converted to exclusively performing contained morcellation in appropriate patients with a low risk of uterine leiomyosarcoma. At our institution, uncontained morcellation has not been performed since the FDA’s 2014 warning.
ACOG and AAGL (formerly the American Association of Gynecologic Laparoscopists) recommend use of containment bags as a solution to continue minimally invasive surgery for large specimens without the risk of possible tissue dissemination, although more in-depth surgeon training is likely required for accurate technique.2,24 The Society of Gynecologic Oncology (SGO) states that power morcellation or any other techniques that divide the uterus in the abdomen are contraindicated in patients with documented or highly suspected malignancy.25
With the presented data of risks associated with uncontained morcellation and agreement of the ACOG, AAGL, and SGO professional societies, we recommend that all morcellation be performed in a contained fashion to prevent the dissemination of benign or undiagnosed malignant tissue throughout the abdomen and pelvis. Shared decision making and counseling on the risks, benefits, and alternatives are paramount for patients to make informed decisions about their medical care. Continued exploration of techniques and methods for safe tissue extraction is still needed to improve minimally invasive surgical options for all women.
1. US Food and Drug Administration. Updated: Laparoscopic uterine power morcellation in hysterectomy and myomectomy: FDA safety communication. November 24, 2014; updated April 7, 2016. https://wayback.archiveit.org/7993/20170404182209/https:/www.fda.gov /MedicalDevices/Safety/AlertsandNotices/ucm424443.htm. Accessed July 23, 2019.
2. American College of Obstetricians and Gynecologists Committee on Gynecologic Practice. ACOG committee opinion no. 770: Uterine morcellation for presumed leiomyomas. Obstet Gynecol. 2019;133:e238-e248.
3. American College of Obstetricians and Gynecologists Committee on Gynecologic Practice. ACOG committee opinion no. 701: Choosing the route of hysterectomy for benign disease. Obstet Gynecol. 2017;129:1149-1150.
4. Wiser A, Holcroft CA, Tolandi T, et al. Abdominal versus laparoscopic hysterectomies for benign diseases: evaluation of morbidity and mortality among 465,798 cases. Gynecol Surg. 2013;10:117-122.
5. Winner B, Biest S. Uterine morcellation: fact and fiction surrounding the recent controversy. Mo Med. 2017;114:176-180.
6. Tulandi T, Leung A, Jan N. Nonmalignant sequelae of unconfined morcellation at laparoscopic hysterectomy or myomectomy. J Minim Invasive Gynecol. 2016;23:331-337.
7. Milad MP, Milad EA. Laparoscopic morcellator-related complications. J Minim Invasive Gynecol. 2014;21:486-491.
8. Toro JR, Travis LB, Wu HJ, et al. Incidence patterns of soft tissue sarcomas, regardless of primary site, in the Surveillance, Epidemiology and End Results program, 1978-2001: an analysis of 26,758 cases. Int J Cancer. 2006;119:2922-2930.
9. Seagle BL, Sobecki-Rausch J, Strohl AE, et al. Prognosis and treatment of uterine leiomyosarcoma: a National Cancer Database study. Gynecol Oncol. 2017;145:61-70.
10. Ricci S, Stone RL, Fader AN. Uterine leiomyosarcoma: epidemiology, contemporary treatment strategies and the impact of uterine morcellation. Gynecol Oncol. 2017;145:208-216.
11. Leibsohn S, d’Ablaing G, Mishell DR Jr, et al. Leiomyosarcoma in a series of hysterectomies performed for presumed uterine leiomyomas. Am J Obstet Gynecol. 1990;162:968-974. Discussion 974-976.
12. Rowland M, Lesnock J, Edwards R, et al. Occult uterine cancer in patients undergoing laparoscopic hysterectomy with morcellation [abstract]. Gynecol Oncol. 2012;127:S29.
13. Hartmann KE, Fonnesbeck C, Surawicz T, et al. Management of uterine fibroids. Comparative effectiveness review no. 195. AHRQ Publication No. 17(18)-EHC028-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2017. https://effectivehealthcare.ahrq.gov/topics/uterine-fibroids /research-2017. Accessed July 23, 2019.
14. Pritts EA, Parker WH, Brown J, et al. Outcome of occult uterine leiomyosarcoma after surgery for presumed uterine fibroids: a systematic review. J Minim Invasive Gynecol. 2015;22:26-33.
15. American College of Obstetricians and Gynecologists Committee on Practice Bulletins–Gynecology. Practice bulletin no. 128: Diagnosis of abnormal uterine bleeding in reproductive-aged women. Obstet Gynecol. 2012;120:197-206.
16. Bansal N, Herzog TJ, Burke W, et al. The utility of preoperative endometrial sampling for the detection of uterine sarcomas. Gynecol Oncol. 2008 Jul;110(1):43–48.
17. American College of Obstetricians and Gynecologists Committee on Ethics. ACOG committee opinion no. 439: Informed consent. Obstet Gynecol. 2009;114:401-408.
18. Wright JD, Cui RR, Wang A, et al. Economic and survival implications of use of electric power morcellation for hysterectomy for presumed benign gynecologic disease. J Natl Cancer Inst. 2015;107:djv251.
19. US Food and Drug Administration. FDA allows marketing of first-of-kind tissue containment system for use with certain laparoscopic power morcellators in select patients [press release]. April 7, 2016. https://www.fda.gov/NewsEvents /Newsroom/PressAnnouncements/ucm494650.htm. Accessed July 23, 2019.
20. Winner B, Porter A, Velloze S, et al. S. Uncontained compared with contained power morcellation in total laparoscopic hysterectomy. Obstet Gynecol. 2015 Oct;126(4):834–8.
21. Cohen SL, Einarsson JI, Wang KC, et al. Contained power morcellation within an insufflated isolation bag. Obstet Gynecol. 2014;124:491-497.
22. Cohen SL, Greenberg JA, Wang KC, et al. Risk of leakage and tissue dissemination with various contained tissue extraction (CTE) techniques: an in vitro pilot study. J Minim Invasive Gynecol. 2014;21:935-939.
23. Cohen SL, Morris SN, Brown DN, et al. Contained tissue extraction using power morcellation: prospective evaluation of leakage parameters. Am J Obstet Gynecol. 2016;214(2):257. e1-257.e6.
24. AAGL. AAGL practice report: morcellation during uterine tissue extraction. J Minim Invasive Gynecol. 2014;21:517-530.
25. Society of Gynecologic Oncology. Position statement: morcellation. 2013. https://www.sgo.org/newsroom /position-statements-2/morcellation/.Accessed July 23, 2019.
Dr. Putman is Chief Resident, Department of Obstetrics and Gynecology, Barnes-Jewish Hospital/Washington University School of Medicine in St. Louis, St. Louis, Missouri.
Dr. Zamorano is Fellow, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine in St. Louis.
Dr. Mutch is Ira C. and Judith Gall Professor of Obstetrics and Gynecology and Vice Chair of Gynecology in the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine in St. Louis and Alvin J. Siteman Cancer Center. He serves on the OBG MANAGEMENT Board of Editors.
Dr. Mutch reports that he receives grant or research support from the National Institutes of Health and the GOG Foundation and that he is a consultant and speaker for Clovis and AstraZeneca. Dr. Putman and Dr. Zamorano report no financial relationships relevant to this article.
Dr. Putman is Chief Resident, Department of Obstetrics and Gynecology, Barnes-Jewish Hospital/Washington University School of Medicine in St. Louis, St. Louis, Missouri.
Dr. Zamorano is Fellow, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine in St. Louis.
Dr. Mutch is Ira C. and Judith Gall Professor of Obstetrics and Gynecology and Vice Chair of Gynecology in the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine in St. Louis and Alvin J. Siteman Cancer Center. He serves on the OBG MANAGEMENT Board of Editors.
Dr. Mutch reports that he receives grant or research support from the National Institutes of Health and the GOG Foundation and that he is a consultant and speaker for Clovis and AstraZeneca. Dr. Putman and Dr. Zamorano report no financial relationships relevant to this article.
Dr. Putman is Chief Resident, Department of Obstetrics and Gynecology, Barnes-Jewish Hospital/Washington University School of Medicine in St. Louis, St. Louis, Missouri.
Dr. Zamorano is Fellow, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine in St. Louis.
Dr. Mutch is Ira C. and Judith Gall Professor of Obstetrics and Gynecology and Vice Chair of Gynecology in the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine in St. Louis and Alvin J. Siteman Cancer Center. He serves on the OBG MANAGEMENT Board of Editors.
Dr. Mutch reports that he receives grant or research support from the National Institutes of Health and the GOG Foundation and that he is a consultant and speaker for Clovis and AstraZeneca. Dr. Putman and Dr. Zamorano report no financial relationships relevant to this article.
Morcellation of gynecologic surgical specimens became controversial after concerns arose about the potential for inadvertent spread of malignant cells throughout the abdomen and pelvis during tissue morcellation of suspected benign disease. In 2014, the US Food and Drug Administration (FDA) issued a warningagainst the use of laparoscopic power morcellation specifically for myomectomy or hysterectomy in the treatment of leiomyomas (fibroids) because of the risk of spreading undiagnosed malignancy throughout the abdomen and pelvis.1 This warning was issued after a high-profile case occurred in Boston in which an occult uterine sarcoma was morcellated during a supracervical robot-assisted hysterectomy for suspected benign fibroids.
Recently, the American College of Obstetricians and Gynecologists (ACOG) published a committee opinion with updated recommendations for practice detailing the risks associated with morcellation and suggestions for patient counseling regarding morcellation.2
In this review, we summarize the techniques and risks of morcellation, the epidemiology of undiagnosed uterine malignancies, practice changes noted at our institution, and clinical recommendations moving forward. A case scenario illustrates keys steps in preoperative evaluation and counseling.
Morcellation uses—and risks
Morcellation is the surgical process of dividing a large tissue specimen into smaller pieces to facilitate their removal through the small incisions made in minimally invasive surgery. Morcellation may be performed with a power instrument or manually.
In power morcellation, an electromechanical instrument is used to cut or shave the specimen; in manual morcellation, the surgeon uses a knife to carve the specimen. Power morcellation is performed through a laparoscopic incision, while the manual technique is performed through a minilaparotomy or vaginally after hysterectomy (TABLE). Unlike uncontained morcellation, contained morcellation involves the use of a laparoscopic bag to hold the specimen and therefore prevent tissue dissemination in the abdomen and pelvis.
Morcellation has greatly expanded our ability to perform minimally invasive surgery—for example, in patients with specimens that cannot be extracted en bloc through the vagina after hysterectomy or, in the case of myomectomy or supracervical hysterectomy without a colpotomy, through small laparoscopic ports. Minimally invasive surgery improves patient care, as it is associated with lower rates of infection, blood loss, venous thromboembolism, wound and bowel complications, postoperative pain, and shorter overall recovery time and hospital stay versus traditional open surgery.3,4 Furthermore, laparoscopic hysterectomy has a 3-fold lower risk of mortality compared with open hysterectomy.4 For these reasons, ACOG recommends choosing a minimally invasive approach for all benign hysterectomies whenever feasible.3
With abundant data supporting the use of a minimally invasive approach, laparoscopic morcellation allowed procedures involving larger tissue specimens to be accomplished without the addition of a minilaparotomy for tissue extraction. However, disseminating potentially malignant tissue throughout the abdomen and pelvis during the morcellation process remains a risk. While tissue spread can occur with either power or manual morcellation, the case that drew media attention to the controversy used power morcellation, and thus intense scrutiny focused on this technique. Morcellation has additional risks, including direct injury to surrounding organs, disruption of the pathologic specimen, and distribution of benign tissue throughout the abdomen and pelvis, such as fibroid, endometriosis, and adenomyosis implants.5-7
Continue to: The challenge of leiomyosarcoma...
The challenge of leiomyosarcoma
The primary controversy surrounding morcellation of fibroid tissue specimens is the potential for undiagnosed malignancy, namely uterine leiomyosarcoma or endometrial stromal sarcoma. While other gynecologic malignancies, including cervical and endometrial cancers, are more common and potentially could be disseminated by morcellation, these cancers are more reliably diagnosed preoperatively with cervical and endometrial biopsies, and they do not tend to mimic benign diseases.
Epidemiology and risk factors. Uterine leiomyosarcoma is rare, with an estimated incidence of 0.36 per 100,000 woman-years.8 However, leiomyosarcoma can mimic the appearance and clinical course of benign fibroids, making preoperative diagnosis difficult. Risk factors for leiomyosarcoma include postmenopausal status, with a median age of 54 years at diagnosis, tamoxifen use longer than 5 years, black race, history of pelvic radiation, and certain hereditary cancer syndromes, such as Lynch syndrome.9-11 Because of these risk factors, preoperative evaluation is crucial to determine the most appropriate surgical method for removal of a large, fibroid uterus (see “Employ shared decision making”).
Estimated incidence at benign hysterectomy. The incidence of leiomyosarcoma diagnosed at the time of benign hysterectomy or myomectomy has been studied extensively since the FDA’s 2014 warning was released, with varying rates identified.11,12 The FDA’s analysis cited a risk of 1 in 498 for unsuspected leiomyosarcoma and 1 in 352 for uterine sarcoma.1 Notably, this analysis excluded studies of women undergoing surgery for presumed fibroids in which no leiomyosarcoma was found on pathology, likely inflating the quoted prevalence. The FDA and other entities subsequently performed further analyses, but a systematic literature review and meta-analysis by the Agency for Healthcare Research and Quality (AHRQ) in 2017 is probably the most accurate. That review included 160 studies and reported a prevalence of less than 1 in 10,000 to 1 in 770, lower than the FDA-cited rate.13
Prognosis. The overall prognosis for women with leiomyosarcoma is poor. Studies indicate a 5-year survival rate of only 55.4%, even in stage 1 disease that is apparently confined to the uterus.9 Although evidence is limited linking morcellation to increased recurrence of leiomyosarcoma, data from small, single-center, retrospective studies cite a worse prognosis, higher risk of recurrence, and shorter progression-free survival after sarcoma morcellation compared with patients who underwent en bloc resection.12,14 Of note, these studies evaluated patients who underwent uncontained morcellation of specimens with unsuspected leiomyosarcoma.
CASE Woman with enlarged, irregular uterus and heavy bleeding
A 40-year-old woman (G2P2) with a history of 2 uncomplicated vaginal deliveries presents for evaluation of heavy uterine bleeding. She has regular periods, every 28 days, and she bleeds for 7 days, saturating 6 pads per day. She is currently taking only oral iron therapy as recommended by her primary care physician. Over the last 1 to 2 years she has felt that her abdomen has been getting larger and that her pants do not fit as well. She is otherwise in excellent health, exercises regularly, and has a full-time job. She has not been sexually active in several months.
The patient’s vitals are within normal limits and her body mass index (BMI) is 35 kg/m2.Pelvic examination reveals that she has an enlarged, irregular uterus with the fundus at the level of the umbilicus. The exam is otherwise unremarkable. On further questioning, the patient does not desire future fertility.
What next steps would you include in this patient’s workup, including imaging studies or lab tests? What surgical options would you give her? How would your management differ if this patient were 70 years old (postmenopausal)?
Continue to: Perform a thorough preoperative evaluation to optimize outcomes...
Perform a thorough preoperative evaluation to optimize outcomes
Women like this case patient who present with symptoms that may lead to treatment with myomectomy or hysterectomy should undergo appropriate preoperative testing to evaluate for malignancy.
According to ACOG guidance, patients should undergo a preoperative endometrial biopsy if they15:
- are older than 45 years with abnormal uterine bleeding
- are younger than 45 years with unopposed estrogen exposure (including obesity or polycystic ovary syndrome)
- have persistent bleeding, or
- failed medical management.
Our case patient is younger than 45 but is obese (BMI, 35) and therefore is a candidate for endometrial biopsy. Additionally, all patients should have up-to-date cervical cancer screening. ACOG also recommends appropriate use of imaging with ultrasonography or magnetic resonance imaging (MRI), although imaging is not recommended solely to evaluate for malignancy, as it cannot rule out the diagnosis of many gynecologic malignancies, including leiomyosarcoma.2
Currently, no tests are available to completely exclude a preoperative diagnosis of leiomyosarcoma. While studies have evaluated the use of MRI combined with lactate dehydrogenase isoenzyme testing, the evidence is weak, and this method is not recommended. Sarcoma is detected by endometrial sampling only 30% to 60% of the time, but it should be performed if the patient meets criteria for sampling or if she has other risk factors for malignancy.16 There are no data to support biopsy of presumed benign fibroids prior to surgical intervention. Patients should be evaluated with a careful history and physical examination for other uterine sarcoma risk factors.
Employ shared decision making
Clinicians should use shared decision making with patients to facilitate decisions on morcellation use in gynecologic surgeries for suspected benign fibroids. Informed consent must be obtained after thorough discussion and counseling regarding the literature on morcellation.17 For all patients, including the case patient described, this discussion should include alternative treatment options, surgical approach with associated risks, the use of morcellation, the incidence of leiomyosarcoma with presumed benign fibroids, leiomyosarcoma prognosis, and the risk of disseminating benign or undiagnosed cancerous tissue throughout the abdomen and pelvis.
Some would argue that the risks of laparotomy outweigh the possible risks associated with morcellation during a minimally invasive myomectomy or hysterectomy. However, this risk analysis is not uniform across all patients, and it is likely that in older women, because they have an a priori increased risk of malignancy in general, including leiomyosarcoma, the risks of power morcellation may outweigh the risks of open surgery.18 Younger women have a much lower risk of leiomyosarcoma, and thus discussion and consideration of the patient’s age should be a part of counseling. If the case patient described was 70 years of age, power morcellation might not be recommended, but these decisions require an in-depth discussion with the patient to make an informed decision and ensure patient autonomy.
The contained morcellation approach
Many surgeons who perform minimally invasive procedures use contained morcellation. In this approach, specimens are placed in a containment bag and morcellated with either power instruments or manually to ensure no dissemination of tissue. Manual contained morcellation can be done through a minilaparotomy or the vagina, depending on the procedure performed, while power contained morcellation is performed through a 15-mm laparoscopic incision.
Continue to: Currently, one containment bag has been...
Currently, one containment bag has been FDA approved for use in laparoscopic contained power morcellation.19 Use of a containment bag increases operative time by approximately 20 minutes, due to the additional steps required to accomplish the procedure.20 Its use, however, suggests a decrease in the risk of possible disease spread and it is feasible with appropriate surgeon training.
One study demonstrated the safety and feasibility of power morcellation within an insufflated containment bag, and subsequent follow-up revealed negative intraperitoneal washings.21,22 In another study evaluating tissue dissemination with contained morcellation of tissue stained with dye, the authors noted actual spillage of tissue fragments in only one case.23 Although more information is needed to confirm prevention of tissue dissemination and the safety of contained tissue morcellation, these studies provide promising data supporting the use of tissue morcellation in appropriate cases in order to perform minimally invasive surgery with larger specimens.
CASE Next steps and treatment outcome
The patient has up-to-date and negative cervical cancer screening. The complete blood count is notable for a hemoglobin level of 11.0 g/dL (normal range, 12.1 to 15.1 g/dL). You perform an endometrial biopsy; results are negative for malignancy. You order pelvic ultrasonography to better characterize the location and size of the fibroids. It shows multiple leiomyomas throughout the myometrium, with the 2 largest fibroids (measuring 5 and 7 cm) located in the left anterior and right posterolateral aspects of the uterus, respectively. Several 3- to 4-cm fibroids appear to be disrupting the endometrial canal, and there is no evidence of an endometrial polyp. There do not appear to be any cervical or lower uterine segment fibroids, which may have further complicated the proposed surgery.
You discuss treatment options for abnormal uterine bleeding with the patient, including initiation of combined oral contraceptive pills, placement of a levonorgestrel-containing intrauterine device, endometrial ablation, uterine artery embolization, and hysterectomy. You discuss the risks and benefits of each approach, keeping in mind the fibroids that are disrupting the contour of the endometrial canal and causing her bulk symptoms.
The patient ultimately decides to undergo a hysterectomy and would like it to be performed with a minimally invasive procedure, if possible. Because of the size of her uterus, you discuss the use of contained power morcellation, including the risks and benefits. You have a thorough discussion about the risk of occult malignancy, although she is at lower risk because of her age, and she consents.
The patient undergoes an uncomplicated total laparoscopic hysterectomy with bilateral salpingectomy. The specimen is removed using contained power morcellation through the umbilical port site. She has an unremarkable immediate postoperative course and is discharged on postoperative Day 1.
You see the patient in the clinic 2 weeks later. She reports minimal pain or discomfort and has no other complaints. Her abdominal incisions are healing well. You review the final pathology report with her, which showed no evidence of malignancy.
Society guidance on clinical applications
In current clinical practice, many surgeons have converted to exclusively performing contained morcellation in appropriate patients with a low risk of uterine leiomyosarcoma. At our institution, uncontained morcellation has not been performed since the FDA’s 2014 warning.
ACOG and AAGL (formerly the American Association of Gynecologic Laparoscopists) recommend use of containment bags as a solution to continue minimally invasive surgery for large specimens without the risk of possible tissue dissemination, although more in-depth surgeon training is likely required for accurate technique.2,24 The Society of Gynecologic Oncology (SGO) states that power morcellation or any other techniques that divide the uterus in the abdomen are contraindicated in patients with documented or highly suspected malignancy.25
With the presented data of risks associated with uncontained morcellation and agreement of the ACOG, AAGL, and SGO professional societies, we recommend that all morcellation be performed in a contained fashion to prevent the dissemination of benign or undiagnosed malignant tissue throughout the abdomen and pelvis. Shared decision making and counseling on the risks, benefits, and alternatives are paramount for patients to make informed decisions about their medical care. Continued exploration of techniques and methods for safe tissue extraction is still needed to improve minimally invasive surgical options for all women.
Morcellation of gynecologic surgical specimens became controversial after concerns arose about the potential for inadvertent spread of malignant cells throughout the abdomen and pelvis during tissue morcellation of suspected benign disease. In 2014, the US Food and Drug Administration (FDA) issued a warningagainst the use of laparoscopic power morcellation specifically for myomectomy or hysterectomy in the treatment of leiomyomas (fibroids) because of the risk of spreading undiagnosed malignancy throughout the abdomen and pelvis.1 This warning was issued after a high-profile case occurred in Boston in which an occult uterine sarcoma was morcellated during a supracervical robot-assisted hysterectomy for suspected benign fibroids.
Recently, the American College of Obstetricians and Gynecologists (ACOG) published a committee opinion with updated recommendations for practice detailing the risks associated with morcellation and suggestions for patient counseling regarding morcellation.2
In this review, we summarize the techniques and risks of morcellation, the epidemiology of undiagnosed uterine malignancies, practice changes noted at our institution, and clinical recommendations moving forward. A case scenario illustrates keys steps in preoperative evaluation and counseling.
Morcellation uses—and risks
Morcellation is the surgical process of dividing a large tissue specimen into smaller pieces to facilitate their removal through the small incisions made in minimally invasive surgery. Morcellation may be performed with a power instrument or manually.
In power morcellation, an electromechanical instrument is used to cut or shave the specimen; in manual morcellation, the surgeon uses a knife to carve the specimen. Power morcellation is performed through a laparoscopic incision, while the manual technique is performed through a minilaparotomy or vaginally after hysterectomy (TABLE). Unlike uncontained morcellation, contained morcellation involves the use of a laparoscopic bag to hold the specimen and therefore prevent tissue dissemination in the abdomen and pelvis.
Morcellation has greatly expanded our ability to perform minimally invasive surgery—for example, in patients with specimens that cannot be extracted en bloc through the vagina after hysterectomy or, in the case of myomectomy or supracervical hysterectomy without a colpotomy, through small laparoscopic ports. Minimally invasive surgery improves patient care, as it is associated with lower rates of infection, blood loss, venous thromboembolism, wound and bowel complications, postoperative pain, and shorter overall recovery time and hospital stay versus traditional open surgery.3,4 Furthermore, laparoscopic hysterectomy has a 3-fold lower risk of mortality compared with open hysterectomy.4 For these reasons, ACOG recommends choosing a minimally invasive approach for all benign hysterectomies whenever feasible.3
With abundant data supporting the use of a minimally invasive approach, laparoscopic morcellation allowed procedures involving larger tissue specimens to be accomplished without the addition of a minilaparotomy for tissue extraction. However, disseminating potentially malignant tissue throughout the abdomen and pelvis during the morcellation process remains a risk. While tissue spread can occur with either power or manual morcellation, the case that drew media attention to the controversy used power morcellation, and thus intense scrutiny focused on this technique. Morcellation has additional risks, including direct injury to surrounding organs, disruption of the pathologic specimen, and distribution of benign tissue throughout the abdomen and pelvis, such as fibroid, endometriosis, and adenomyosis implants.5-7
Continue to: The challenge of leiomyosarcoma...
The challenge of leiomyosarcoma
The primary controversy surrounding morcellation of fibroid tissue specimens is the potential for undiagnosed malignancy, namely uterine leiomyosarcoma or endometrial stromal sarcoma. While other gynecologic malignancies, including cervical and endometrial cancers, are more common and potentially could be disseminated by morcellation, these cancers are more reliably diagnosed preoperatively with cervical and endometrial biopsies, and they do not tend to mimic benign diseases.
Epidemiology and risk factors. Uterine leiomyosarcoma is rare, with an estimated incidence of 0.36 per 100,000 woman-years.8 However, leiomyosarcoma can mimic the appearance and clinical course of benign fibroids, making preoperative diagnosis difficult. Risk factors for leiomyosarcoma include postmenopausal status, with a median age of 54 years at diagnosis, tamoxifen use longer than 5 years, black race, history of pelvic radiation, and certain hereditary cancer syndromes, such as Lynch syndrome.9-11 Because of these risk factors, preoperative evaluation is crucial to determine the most appropriate surgical method for removal of a large, fibroid uterus (see “Employ shared decision making”).
Estimated incidence at benign hysterectomy. The incidence of leiomyosarcoma diagnosed at the time of benign hysterectomy or myomectomy has been studied extensively since the FDA’s 2014 warning was released, with varying rates identified.11,12 The FDA’s analysis cited a risk of 1 in 498 for unsuspected leiomyosarcoma and 1 in 352 for uterine sarcoma.1 Notably, this analysis excluded studies of women undergoing surgery for presumed fibroids in which no leiomyosarcoma was found on pathology, likely inflating the quoted prevalence. The FDA and other entities subsequently performed further analyses, but a systematic literature review and meta-analysis by the Agency for Healthcare Research and Quality (AHRQ) in 2017 is probably the most accurate. That review included 160 studies and reported a prevalence of less than 1 in 10,000 to 1 in 770, lower than the FDA-cited rate.13
Prognosis. The overall prognosis for women with leiomyosarcoma is poor. Studies indicate a 5-year survival rate of only 55.4%, even in stage 1 disease that is apparently confined to the uterus.9 Although evidence is limited linking morcellation to increased recurrence of leiomyosarcoma, data from small, single-center, retrospective studies cite a worse prognosis, higher risk of recurrence, and shorter progression-free survival after sarcoma morcellation compared with patients who underwent en bloc resection.12,14 Of note, these studies evaluated patients who underwent uncontained morcellation of specimens with unsuspected leiomyosarcoma.
CASE Woman with enlarged, irregular uterus and heavy bleeding
A 40-year-old woman (G2P2) with a history of 2 uncomplicated vaginal deliveries presents for evaluation of heavy uterine bleeding. She has regular periods, every 28 days, and she bleeds for 7 days, saturating 6 pads per day. She is currently taking only oral iron therapy as recommended by her primary care physician. Over the last 1 to 2 years she has felt that her abdomen has been getting larger and that her pants do not fit as well. She is otherwise in excellent health, exercises regularly, and has a full-time job. She has not been sexually active in several months.
The patient’s vitals are within normal limits and her body mass index (BMI) is 35 kg/m2.Pelvic examination reveals that she has an enlarged, irregular uterus with the fundus at the level of the umbilicus. The exam is otherwise unremarkable. On further questioning, the patient does not desire future fertility.
What next steps would you include in this patient’s workup, including imaging studies or lab tests? What surgical options would you give her? How would your management differ if this patient were 70 years old (postmenopausal)?
Continue to: Perform a thorough preoperative evaluation to optimize outcomes...
Perform a thorough preoperative evaluation to optimize outcomes
Women like this case patient who present with symptoms that may lead to treatment with myomectomy or hysterectomy should undergo appropriate preoperative testing to evaluate for malignancy.
According to ACOG guidance, patients should undergo a preoperative endometrial biopsy if they15:
- are older than 45 years with abnormal uterine bleeding
- are younger than 45 years with unopposed estrogen exposure (including obesity or polycystic ovary syndrome)
- have persistent bleeding, or
- failed medical management.
Our case patient is younger than 45 but is obese (BMI, 35) and therefore is a candidate for endometrial biopsy. Additionally, all patients should have up-to-date cervical cancer screening. ACOG also recommends appropriate use of imaging with ultrasonography or magnetic resonance imaging (MRI), although imaging is not recommended solely to evaluate for malignancy, as it cannot rule out the diagnosis of many gynecologic malignancies, including leiomyosarcoma.2
Currently, no tests are available to completely exclude a preoperative diagnosis of leiomyosarcoma. While studies have evaluated the use of MRI combined with lactate dehydrogenase isoenzyme testing, the evidence is weak, and this method is not recommended. Sarcoma is detected by endometrial sampling only 30% to 60% of the time, but it should be performed if the patient meets criteria for sampling or if she has other risk factors for malignancy.16 There are no data to support biopsy of presumed benign fibroids prior to surgical intervention. Patients should be evaluated with a careful history and physical examination for other uterine sarcoma risk factors.
Employ shared decision making
Clinicians should use shared decision making with patients to facilitate decisions on morcellation use in gynecologic surgeries for suspected benign fibroids. Informed consent must be obtained after thorough discussion and counseling regarding the literature on morcellation.17 For all patients, including the case patient described, this discussion should include alternative treatment options, surgical approach with associated risks, the use of morcellation, the incidence of leiomyosarcoma with presumed benign fibroids, leiomyosarcoma prognosis, and the risk of disseminating benign or undiagnosed cancerous tissue throughout the abdomen and pelvis.
Some would argue that the risks of laparotomy outweigh the possible risks associated with morcellation during a minimally invasive myomectomy or hysterectomy. However, this risk analysis is not uniform across all patients, and it is likely that in older women, because they have an a priori increased risk of malignancy in general, including leiomyosarcoma, the risks of power morcellation may outweigh the risks of open surgery.18 Younger women have a much lower risk of leiomyosarcoma, and thus discussion and consideration of the patient’s age should be a part of counseling. If the case patient described was 70 years of age, power morcellation might not be recommended, but these decisions require an in-depth discussion with the patient to make an informed decision and ensure patient autonomy.
The contained morcellation approach
Many surgeons who perform minimally invasive procedures use contained morcellation. In this approach, specimens are placed in a containment bag and morcellated with either power instruments or manually to ensure no dissemination of tissue. Manual contained morcellation can be done through a minilaparotomy or the vagina, depending on the procedure performed, while power contained morcellation is performed through a 15-mm laparoscopic incision.
Continue to: Currently, one containment bag has been...
Currently, one containment bag has been FDA approved for use in laparoscopic contained power morcellation.19 Use of a containment bag increases operative time by approximately 20 minutes, due to the additional steps required to accomplish the procedure.20 Its use, however, suggests a decrease in the risk of possible disease spread and it is feasible with appropriate surgeon training.
One study demonstrated the safety and feasibility of power morcellation within an insufflated containment bag, and subsequent follow-up revealed negative intraperitoneal washings.21,22 In another study evaluating tissue dissemination with contained morcellation of tissue stained with dye, the authors noted actual spillage of tissue fragments in only one case.23 Although more information is needed to confirm prevention of tissue dissemination and the safety of contained tissue morcellation, these studies provide promising data supporting the use of tissue morcellation in appropriate cases in order to perform minimally invasive surgery with larger specimens.
CASE Next steps and treatment outcome
The patient has up-to-date and negative cervical cancer screening. The complete blood count is notable for a hemoglobin level of 11.0 g/dL (normal range, 12.1 to 15.1 g/dL). You perform an endometrial biopsy; results are negative for malignancy. You order pelvic ultrasonography to better characterize the location and size of the fibroids. It shows multiple leiomyomas throughout the myometrium, with the 2 largest fibroids (measuring 5 and 7 cm) located in the left anterior and right posterolateral aspects of the uterus, respectively. Several 3- to 4-cm fibroids appear to be disrupting the endometrial canal, and there is no evidence of an endometrial polyp. There do not appear to be any cervical or lower uterine segment fibroids, which may have further complicated the proposed surgery.
You discuss treatment options for abnormal uterine bleeding with the patient, including initiation of combined oral contraceptive pills, placement of a levonorgestrel-containing intrauterine device, endometrial ablation, uterine artery embolization, and hysterectomy. You discuss the risks and benefits of each approach, keeping in mind the fibroids that are disrupting the contour of the endometrial canal and causing her bulk symptoms.
The patient ultimately decides to undergo a hysterectomy and would like it to be performed with a minimally invasive procedure, if possible. Because of the size of her uterus, you discuss the use of contained power morcellation, including the risks and benefits. You have a thorough discussion about the risk of occult malignancy, although she is at lower risk because of her age, and she consents.
The patient undergoes an uncomplicated total laparoscopic hysterectomy with bilateral salpingectomy. The specimen is removed using contained power morcellation through the umbilical port site. She has an unremarkable immediate postoperative course and is discharged on postoperative Day 1.
You see the patient in the clinic 2 weeks later. She reports minimal pain or discomfort and has no other complaints. Her abdominal incisions are healing well. You review the final pathology report with her, which showed no evidence of malignancy.
Society guidance on clinical applications
In current clinical practice, many surgeons have converted to exclusively performing contained morcellation in appropriate patients with a low risk of uterine leiomyosarcoma. At our institution, uncontained morcellation has not been performed since the FDA’s 2014 warning.
ACOG and AAGL (formerly the American Association of Gynecologic Laparoscopists) recommend use of containment bags as a solution to continue minimally invasive surgery for large specimens without the risk of possible tissue dissemination, although more in-depth surgeon training is likely required for accurate technique.2,24 The Society of Gynecologic Oncology (SGO) states that power morcellation or any other techniques that divide the uterus in the abdomen are contraindicated in patients with documented or highly suspected malignancy.25
With the presented data of risks associated with uncontained morcellation and agreement of the ACOG, AAGL, and SGO professional societies, we recommend that all morcellation be performed in a contained fashion to prevent the dissemination of benign or undiagnosed malignant tissue throughout the abdomen and pelvis. Shared decision making and counseling on the risks, benefits, and alternatives are paramount for patients to make informed decisions about their medical care. Continued exploration of techniques and methods for safe tissue extraction is still needed to improve minimally invasive surgical options for all women.
1. US Food and Drug Administration. Updated: Laparoscopic uterine power morcellation in hysterectomy and myomectomy: FDA safety communication. November 24, 2014; updated April 7, 2016. https://wayback.archiveit.org/7993/20170404182209/https:/www.fda.gov /MedicalDevices/Safety/AlertsandNotices/ucm424443.htm. Accessed July 23, 2019.
2. American College of Obstetricians and Gynecologists Committee on Gynecologic Practice. ACOG committee opinion no. 770: Uterine morcellation for presumed leiomyomas. Obstet Gynecol. 2019;133:e238-e248.
3. American College of Obstetricians and Gynecologists Committee on Gynecologic Practice. ACOG committee opinion no. 701: Choosing the route of hysterectomy for benign disease. Obstet Gynecol. 2017;129:1149-1150.
4. Wiser A, Holcroft CA, Tolandi T, et al. Abdominal versus laparoscopic hysterectomies for benign diseases: evaluation of morbidity and mortality among 465,798 cases. Gynecol Surg. 2013;10:117-122.
5. Winner B, Biest S. Uterine morcellation: fact and fiction surrounding the recent controversy. Mo Med. 2017;114:176-180.
6. Tulandi T, Leung A, Jan N. Nonmalignant sequelae of unconfined morcellation at laparoscopic hysterectomy or myomectomy. J Minim Invasive Gynecol. 2016;23:331-337.
7. Milad MP, Milad EA. Laparoscopic morcellator-related complications. J Minim Invasive Gynecol. 2014;21:486-491.
8. Toro JR, Travis LB, Wu HJ, et al. Incidence patterns of soft tissue sarcomas, regardless of primary site, in the Surveillance, Epidemiology and End Results program, 1978-2001: an analysis of 26,758 cases. Int J Cancer. 2006;119:2922-2930.
9. Seagle BL, Sobecki-Rausch J, Strohl AE, et al. Prognosis and treatment of uterine leiomyosarcoma: a National Cancer Database study. Gynecol Oncol. 2017;145:61-70.
10. Ricci S, Stone RL, Fader AN. Uterine leiomyosarcoma: epidemiology, contemporary treatment strategies and the impact of uterine morcellation. Gynecol Oncol. 2017;145:208-216.
11. Leibsohn S, d’Ablaing G, Mishell DR Jr, et al. Leiomyosarcoma in a series of hysterectomies performed for presumed uterine leiomyomas. Am J Obstet Gynecol. 1990;162:968-974. Discussion 974-976.
12. Rowland M, Lesnock J, Edwards R, et al. Occult uterine cancer in patients undergoing laparoscopic hysterectomy with morcellation [abstract]. Gynecol Oncol. 2012;127:S29.
13. Hartmann KE, Fonnesbeck C, Surawicz T, et al. Management of uterine fibroids. Comparative effectiveness review no. 195. AHRQ Publication No. 17(18)-EHC028-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2017. https://effectivehealthcare.ahrq.gov/topics/uterine-fibroids /research-2017. Accessed July 23, 2019.
14. Pritts EA, Parker WH, Brown J, et al. Outcome of occult uterine leiomyosarcoma after surgery for presumed uterine fibroids: a systematic review. J Minim Invasive Gynecol. 2015;22:26-33.
15. American College of Obstetricians and Gynecologists Committee on Practice Bulletins–Gynecology. Practice bulletin no. 128: Diagnosis of abnormal uterine bleeding in reproductive-aged women. Obstet Gynecol. 2012;120:197-206.
16. Bansal N, Herzog TJ, Burke W, et al. The utility of preoperative endometrial sampling for the detection of uterine sarcomas. Gynecol Oncol. 2008 Jul;110(1):43–48.
17. American College of Obstetricians and Gynecologists Committee on Ethics. ACOG committee opinion no. 439: Informed consent. Obstet Gynecol. 2009;114:401-408.
18. Wright JD, Cui RR, Wang A, et al. Economic and survival implications of use of electric power morcellation for hysterectomy for presumed benign gynecologic disease. J Natl Cancer Inst. 2015;107:djv251.
19. US Food and Drug Administration. FDA allows marketing of first-of-kind tissue containment system for use with certain laparoscopic power morcellators in select patients [press release]. April 7, 2016. https://www.fda.gov/NewsEvents /Newsroom/PressAnnouncements/ucm494650.htm. Accessed July 23, 2019.
20. Winner B, Porter A, Velloze S, et al. S. Uncontained compared with contained power morcellation in total laparoscopic hysterectomy. Obstet Gynecol. 2015 Oct;126(4):834–8.
21. Cohen SL, Einarsson JI, Wang KC, et al. Contained power morcellation within an insufflated isolation bag. Obstet Gynecol. 2014;124:491-497.
22. Cohen SL, Greenberg JA, Wang KC, et al. Risk of leakage and tissue dissemination with various contained tissue extraction (CTE) techniques: an in vitro pilot study. J Minim Invasive Gynecol. 2014;21:935-939.
23. Cohen SL, Morris SN, Brown DN, et al. Contained tissue extraction using power morcellation: prospective evaluation of leakage parameters. Am J Obstet Gynecol. 2016;214(2):257. e1-257.e6.
24. AAGL. AAGL practice report: morcellation during uterine tissue extraction. J Minim Invasive Gynecol. 2014;21:517-530.
25. Society of Gynecologic Oncology. Position statement: morcellation. 2013. https://www.sgo.org/newsroom /position-statements-2/morcellation/.Accessed July 23, 2019.
1. US Food and Drug Administration. Updated: Laparoscopic uterine power morcellation in hysterectomy and myomectomy: FDA safety communication. November 24, 2014; updated April 7, 2016. https://wayback.archiveit.org/7993/20170404182209/https:/www.fda.gov /MedicalDevices/Safety/AlertsandNotices/ucm424443.htm. Accessed July 23, 2019.
2. American College of Obstetricians and Gynecologists Committee on Gynecologic Practice. ACOG committee opinion no. 770: Uterine morcellation for presumed leiomyomas. Obstet Gynecol. 2019;133:e238-e248.
3. American College of Obstetricians and Gynecologists Committee on Gynecologic Practice. ACOG committee opinion no. 701: Choosing the route of hysterectomy for benign disease. Obstet Gynecol. 2017;129:1149-1150.
4. Wiser A, Holcroft CA, Tolandi T, et al. Abdominal versus laparoscopic hysterectomies for benign diseases: evaluation of morbidity and mortality among 465,798 cases. Gynecol Surg. 2013;10:117-122.
5. Winner B, Biest S. Uterine morcellation: fact and fiction surrounding the recent controversy. Mo Med. 2017;114:176-180.
6. Tulandi T, Leung A, Jan N. Nonmalignant sequelae of unconfined morcellation at laparoscopic hysterectomy or myomectomy. J Minim Invasive Gynecol. 2016;23:331-337.
7. Milad MP, Milad EA. Laparoscopic morcellator-related complications. J Minim Invasive Gynecol. 2014;21:486-491.
8. Toro JR, Travis LB, Wu HJ, et al. Incidence patterns of soft tissue sarcomas, regardless of primary site, in the Surveillance, Epidemiology and End Results program, 1978-2001: an analysis of 26,758 cases. Int J Cancer. 2006;119:2922-2930.
9. Seagle BL, Sobecki-Rausch J, Strohl AE, et al. Prognosis and treatment of uterine leiomyosarcoma: a National Cancer Database study. Gynecol Oncol. 2017;145:61-70.
10. Ricci S, Stone RL, Fader AN. Uterine leiomyosarcoma: epidemiology, contemporary treatment strategies and the impact of uterine morcellation. Gynecol Oncol. 2017;145:208-216.
11. Leibsohn S, d’Ablaing G, Mishell DR Jr, et al. Leiomyosarcoma in a series of hysterectomies performed for presumed uterine leiomyomas. Am J Obstet Gynecol. 1990;162:968-974. Discussion 974-976.
12. Rowland M, Lesnock J, Edwards R, et al. Occult uterine cancer in patients undergoing laparoscopic hysterectomy with morcellation [abstract]. Gynecol Oncol. 2012;127:S29.
13. Hartmann KE, Fonnesbeck C, Surawicz T, et al. Management of uterine fibroids. Comparative effectiveness review no. 195. AHRQ Publication No. 17(18)-EHC028-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2017. https://effectivehealthcare.ahrq.gov/topics/uterine-fibroids /research-2017. Accessed July 23, 2019.
14. Pritts EA, Parker WH, Brown J, et al. Outcome of occult uterine leiomyosarcoma after surgery for presumed uterine fibroids: a systematic review. J Minim Invasive Gynecol. 2015;22:26-33.
15. American College of Obstetricians and Gynecologists Committee on Practice Bulletins–Gynecology. Practice bulletin no. 128: Diagnosis of abnormal uterine bleeding in reproductive-aged women. Obstet Gynecol. 2012;120:197-206.
16. Bansal N, Herzog TJ, Burke W, et al. The utility of preoperative endometrial sampling for the detection of uterine sarcomas. Gynecol Oncol. 2008 Jul;110(1):43–48.
17. American College of Obstetricians and Gynecologists Committee on Ethics. ACOG committee opinion no. 439: Informed consent. Obstet Gynecol. 2009;114:401-408.
18. Wright JD, Cui RR, Wang A, et al. Economic and survival implications of use of electric power morcellation for hysterectomy for presumed benign gynecologic disease. J Natl Cancer Inst. 2015;107:djv251.
19. US Food and Drug Administration. FDA allows marketing of first-of-kind tissue containment system for use with certain laparoscopic power morcellators in select patients [press release]. April 7, 2016. https://www.fda.gov/NewsEvents /Newsroom/PressAnnouncements/ucm494650.htm. Accessed July 23, 2019.
20. Winner B, Porter A, Velloze S, et al. S. Uncontained compared with contained power morcellation in total laparoscopic hysterectomy. Obstet Gynecol. 2015 Oct;126(4):834–8.
21. Cohen SL, Einarsson JI, Wang KC, et al. Contained power morcellation within an insufflated isolation bag. Obstet Gynecol. 2014;124:491-497.
22. Cohen SL, Greenberg JA, Wang KC, et al. Risk of leakage and tissue dissemination with various contained tissue extraction (CTE) techniques: an in vitro pilot study. J Minim Invasive Gynecol. 2014;21:935-939.
23. Cohen SL, Morris SN, Brown DN, et al. Contained tissue extraction using power morcellation: prospective evaluation of leakage parameters. Am J Obstet Gynecol. 2016;214(2):257. e1-257.e6.
24. AAGL. AAGL practice report: morcellation during uterine tissue extraction. J Minim Invasive Gynecol. 2014;21:517-530.
25. Society of Gynecologic Oncology. Position statement: morcellation. 2013. https://www.sgo.org/newsroom /position-statements-2/morcellation/.Accessed July 23, 2019.
Office hysteroscopic evaluation of postmenopausal bleeding
Postmenopausal bleeding (PMB) is the presenting sign in most cases of endometrial carcinoma. Prompt evaluation of PMB can exclude, or diagnose, endometrial carcinoma.1 Although no general consensus exists for PMB evaluation, it involves endometrial assessment with transvaginal ultrasonography (TVUS) and subsequent endometrial biopsy when a thickened endometrium is found. When biopsy results reveal insufficient or scant tissue, further investigation into the etiology of PMB should include office hysteroscopy with possible directed biopsy. In this article I discuss the prevalence of PMB and steps for evaluation, providing clinical takeaways.
Postmenopausal bleeding: Its risk for cancer
Abnormal uterine bleeding (AUB) in a postmenopausal woman is of particular concern to the gynecologist and the patient because of the increased possibility of endometrial carcinoma in this age group. AUB is present in more than 90% of postmenopausal women with endometrial carcinoma, which leads to diagnosis in the early stages of the disease. Approximately 3% to 7% of postmenopausal women with PMB will have endometrial carcinoma.2 Most women with PMB, however, experience bleeding secondary to atrophic changes of the vagina or endometrium and not to endometrial carcinoma. (FIGURE 1, VIDEO 1) In addition, women who take gonadal steroids for hormone replacement therapy (HRT) may experience breakthrough bleeding that leads to initial investigation with TVUS.
Video 1
The risk of malignancy in polyps in postmenopausal women over the age of 59 who present with PMB is approximately 12%, and hysteroscopic resection should routinely be performed. For asymptomatic patients, the risk of a malignant lesion is low—approximately 3%—and for these women intervention should be assessed individually for the risks of carcinoma and benefits of hysteroscopic removal.3
Clinical takeaway. The high possibility of endometrial carcinoma in postmenopausal women warrants that any patient who is symptomatic with PMB should be presumed to have endometrial cancer until the diagnostic evaluation process proves she does not.
Evaluation of postmenopausal bleeding
Transvaginal ultrasound
As mentioned, no general consensus exists for the evaluation of PMB; however, initial evaluation by TVUS is recommended. The American College of Obstetricians and Gynecologists (ACOG) concluded that when the endometrium measures ≤4 mm with TVUS, the likelihood that bleeding is secondary to endometrial carcinoma is less than 1% (negative predictive value 99%), and endometrial biopsy is not recommended.3 Endometrial sampling in this clinical scenario likely will result in insufficient tissue for evaluation, and it is reasonable to consider initial management for atrophy. A thickened endometrium on TVUS (>4 mm in a postmenopausal woman with PMB) warrants additional evaluation with endometrial sampling (FIGURE 2).
Clinical takeaway. A thickened endometrium on TVUS ≥4 mm in a postmenopausal woman with PMB warrants additional evaluation with endometrial sampling.
Endometrial biopsy
An endometrial biopsy is performed to determine whether endometrial cancer or precancer is present in women with AUB. ACOG recommends that endometrial biopsy be performed for women older than age 45. It is also appropriate in women younger than 45 years if they have risk factors for developing endometrial cancer, including unopposed estrogen exposure (obesity, ovulatory dysfunction), failed medical management of AUB, or persistence of AUB.4
Continue to: Endometrial biopsy has some...
Endometrial biopsy has some diagnostic shortcomings, however. In 2016 a systematic review and meta-analysis found that, in women with PMB, the specificity of endometrial biopsy was 98% to 100% (accurate diagnosis with a positive result). The sensitivity (ability to make an accurate diagnosis) of endometrial biopsy to identify endometrial pathology (carcinoma, atypical hyperplasia, and polyps) is lower than typically thought. These investigators found an endometrial biopsy failure rate of 11% (range, 1% to 53%) and rate of insufficient samples of 31% (range, 7% to 76%). In women with insufficient or failed samples, endometrial cancer or precancer was found in 7% (range, 0% to 18%).5 Therefore, a negative tissue biopsy result in women with PMB is not considered to be an endpoint, and further evaluation with hysteroscopy to evaluate for focal disease is imperative. The results of endometrial biopsy are only an endpoint to the evaluation of PMB when atypical hyperplasia or endometrial cancer is identified.
Clinical takeaway. A negative tissue biopsy result in women with PMB is not considered to be an endpoint, and further evaluation with hysteroscopy to evaluate for focal disease is imperative.
Hysteroscopy
Hysteroscopy is the gold standard for evaluating the uterine cavity, diagnosing intrauterine pathology, and operative intervention for some causes of AUB. It also is easily performed in the office. This makes the hysteroscope an essential instrument for the gynecologist. Dr. Linda Bradley, a preeminent leader in hysteroscopic surgical education, has coined the phrase, “My hysteroscope is my stethoscope.”6 As gynecologists, we should be as adept at using a hysteroscope in the office as the cardiologist is at using a stethoscope.
It has been known for some time that hysteroscopy improves our diagnostic capabilities over blinded procedures such as endometrial biopsy and dilation and curettage (D&C). As far back as 1989, Dr. Frank Loffer reported the increased sensitivity (ability to make an accurate diagnosis) of hysteroscopy with directed biopsy over blinded D&C (98% vs 65%) in the evaluation of AUB.7 Evaluation of the endometrium with D&C is no longer recommended; yet today, few gynecologists perform hysteroscopic-directed biopsy for AUB evaluation instead of blinded tissue sampling despite the clinical superiority and in-office capabilities (FIGURE 3).
Continue to: Hysteroscopy and endometrial carcinoma...
Hysteroscopy and endometrial carcinoma
The most common type of gynecologic cancer in the United States is endometrial adenocarcinoma (type 1 endometrial cancer). There is some concern about the effect of hysteroscopy on endometrial cancer prognosis and the spread of cells to the peritoneum at the time of hysteroscopy. A large meta-analysis found that hysteroscopy performed in the presence of type 1 endometrial cancer statistically significantly increased the likelihood of positive intraperitoneal cytology; however, it did not alter the clinical outcome. It was recommended that hysteroscopy not be avoided for this reason and is helpful in the diagnosis of endometrial cancer, especially in the early stages of disease.8
For endometrial cancer type 2 (serous carcinoma, clear cell carcinoma, and carcinosarcoma), Chen and colleagues reported a statistically significant increase in positive peritoneal cytology for cancers evaluated by hysteroscopy versus D&C. The disease-specific survival for the hysteroscopy group was 60 months, compared with 71 months for the D&C group. While this finding was not statistically significant, it was clinically relevant, and the effect of hysteroscopy on prognosis with type 2 endometrial cancer is unclear.9
A common occurrence in the evaluation of postmenopausal bleeding (PMB) is an initial TVUS finding of an enlarged endometrium and an endometrial biopsy that is negative or reveals scant or insufficient tissue. Unfortunately, the diagnostic evaluation process often stops here, and a diagnosis for the PMB is never actually identified. Here are several clinical scenarios that highlight the need for hysteroscopy in the initial evaluation of PMB, especially when there is a discordance between transvaginal ultrasonography (TVUS) and endometrial biopsy findings.
Patient 1: Discordant TVUS and biopsy, with benign findings
The patient is a 52-year-old woman who presented to her gynecologist reporting abnormal uterine bleeding (AUB). She has a history of breast cancer, and she completed tamoxifen treatment. Pelvic ultrasonography was performed; an enlarged endometrial stripe of 1.3 cm was found (FIGURE 4A). Endometrial biopsy was performed, showing adequate tissue but with a negative result. The patient is told that she is likely perimenopausal, which is the reason for her bleeding.
At the time of referral, the patient is evaluated with in-office hysteroscopy. Diagnosis of a 5 cm x 7 cm benign endometrial polyp is made. An uneventful hysteroscopic polypectomy is performed (VIDEO 2).
Video 2
This scenario illustrates the shortcoming of initial evaluation by not performing a hysteroscopy, especially in a woman with a thickened endometrium with previous tamoxifen therapy. Subsequent visits failed to correlate bleeding etiology with discordant TVUS and endometrial biopsy results with hysteroscopy, and no hysteroscopy was performed in the operating room at the time of D&C.
Patient 2: Discordant TVUS and biopsy, with premalignant findings
The patient is a 62-year-old woman who had incidental findings of a thickened endometrium on computed tomography scan of the pelvis. TVUS confirmed a thickened endometrium measuring 17 mm, and an endometrial biopsy showed scant tissue.
At the time of referral, a diagnostic hysteroscopy was performed in the office. Endometrial atrophy, a large benign appearing polyp, and focal abnormal appearing tissue were seen (FIGURE 5). A decision for polypectomy and directed biopsy was made. Histology findings confirmed benign polyp and atypical hyperplasia (VIDEO 3).
Video 3
This scenario illustrates that while the patient was asymptomatic, there was discordance between the TVUS and endometrial biopsy. Hysteroscopy identified a benign endometrial polyp, which is common in asymptomatic postmenopausal patients with a thickened endometrium and endometrial biopsy showing scant tissue. However, addition of the diagnostic hysteroscopy identified focal precancerous tissue, removed under directed biopsy.
Patient 3: Discordant TVUS and biopsy, with malignant findings
The patient is a 68-year-old woman with PMB. TVUS showed a thickened endometrium measuring 14 mm. An endometrial biopsy was negative, showing scant tissue. No additional diagnostic evaluation or management was offered.
Video 4A
At the time of referral, the patient was evaluated with in-office diagnostic hysteroscopy, and the patient was found to have endometrial atrophy, benign appearing polyps, and focal abnormal tissue (FIGURE 6). A decision for polypectomy and directed biopsy was made. Histology confirmed benign polyps and grade 1 adenocarcinoma (VIDEOS 4A, 4B, 4C).
Video 4B
This scenario illustrates the possibility of having multiple endometrial pathologies present at the time of discordant TVUS and endometrial biopsy. Hysteroscopy plays a critical role in additional evaluation and diagnosis of endometrial carcinoma with directed biopsy, especially in a symptomatic woman with PMB.
Video 4C
Conclusion
Evaluation of PMB begins with a screening TVUS. Findings of an endometrium of ≤4 mm indicate a very low likelihood of the presence of endometrial cancer, and treatment for atrophy or changes to hormone replacement therapy regimen is reasonable first-line management; endometrial biopsy is not recommended. For patients with persistent PMB or thickened endometrium ≥4 mm on TVUS, biopsy sampling of the endometrium should be performed. If the endometrial biopsy does not explain the etiology of the PMB with atypical hyperplasia or endometrial cancer, then hysteroscopy should be performed to evaluate for focal endometrial disease and possible directed biopsy.
- ACOG Committee Opinion no. 734: the role of transvaginal ultrasonography in evaluating the endometrium of women with postmenopausal bleeding. Obstet Gynecol. 2018;131:e124-e129.
- Goldstein SR. Appropriate evaluation of postmenopausal bleeding. Menopause. 2018;25:1476-1478.
- Bel S, Billard C, Godet J, et al. Risk of malignancy on suspicion of polyps in menopausal women. Eur J Obstet Gynecol Reprod Biol. 2017;216:138-142.
- Practice bulletin no. 128: diagnosis of abnormal uterine bleeding in reproductive-aged women. Obstet Gynecol. 2012;120:197-206.
- van Hanegem N, Prins MM, Bongers MY. The accuracy of endometrial sampling in women with postmenopausal bleeding: a systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2016;197:147-155.
- Embracing hysteroscopy. September 6, 2017. https://consultqd.clevelandclinic.org/embracing-hysteroscopy/. Accessed July 22, 2019.
- Loffer FD. Hysteroscopy with selective endometrial sampling compared with D&C for abnormal uterine bleeding: the value of a negative hysteroscopic view. Obstet Gynecol. 1989;73:16-20.
- Chang YN, Zhang Y, Wang LP, et al. Effect of hysteroscopy on the peritoneal dissemination of endometrial cancer cells: a meta-analysis. Fertil Steril. 2011;96:957-961.
- Chen J, Clark LH, Kong WM, et al. Does hysteroscopy worsen prognosis in women with type II endometrial carcinoma? PLoS One. 2017;12:e0174226.
Dr. Garcia is Medical Director, Garcia Sloan Centers and Center for Women’s Surgery and Clinical Assistant Professor, Department of Obstetrics and Gynecology, University of New Mexico, Albuquerque. She serves on the OBG
The author reports being a consultant to Karl Storz Endoscopy and UVision360 and having other current financial relationships with Minerva Surgical and Gynesonics.
Dr. Garcia is Medical Director, Garcia Sloan Centers and Center for Women’s Surgery and Clinical Assistant Professor, Department of Obstetrics and Gynecology, University of New Mexico, Albuquerque. She serves on the OBG
The author reports being a consultant to Karl Storz Endoscopy and UVision360 and having other current financial relationships with Minerva Surgical and Gynesonics.
Dr. Garcia is Medical Director, Garcia Sloan Centers and Center for Women’s Surgery and Clinical Assistant Professor, Department of Obstetrics and Gynecology, University of New Mexico, Albuquerque. She serves on the OBG
The author reports being a consultant to Karl Storz Endoscopy and UVision360 and having other current financial relationships with Minerva Surgical and Gynesonics.
Postmenopausal bleeding (PMB) is the presenting sign in most cases of endometrial carcinoma. Prompt evaluation of PMB can exclude, or diagnose, endometrial carcinoma.1 Although no general consensus exists for PMB evaluation, it involves endometrial assessment with transvaginal ultrasonography (TVUS) and subsequent endometrial biopsy when a thickened endometrium is found. When biopsy results reveal insufficient or scant tissue, further investigation into the etiology of PMB should include office hysteroscopy with possible directed biopsy. In this article I discuss the prevalence of PMB and steps for evaluation, providing clinical takeaways.
Postmenopausal bleeding: Its risk for cancer
Abnormal uterine bleeding (AUB) in a postmenopausal woman is of particular concern to the gynecologist and the patient because of the increased possibility of endometrial carcinoma in this age group. AUB is present in more than 90% of postmenopausal women with endometrial carcinoma, which leads to diagnosis in the early stages of the disease. Approximately 3% to 7% of postmenopausal women with PMB will have endometrial carcinoma.2 Most women with PMB, however, experience bleeding secondary to atrophic changes of the vagina or endometrium and not to endometrial carcinoma. (FIGURE 1, VIDEO 1) In addition, women who take gonadal steroids for hormone replacement therapy (HRT) may experience breakthrough bleeding that leads to initial investigation with TVUS.
Video 1
The risk of malignancy in polyps in postmenopausal women over the age of 59 who present with PMB is approximately 12%, and hysteroscopic resection should routinely be performed. For asymptomatic patients, the risk of a malignant lesion is low—approximately 3%—and for these women intervention should be assessed individually for the risks of carcinoma and benefits of hysteroscopic removal.3
Clinical takeaway. The high possibility of endometrial carcinoma in postmenopausal women warrants that any patient who is symptomatic with PMB should be presumed to have endometrial cancer until the diagnostic evaluation process proves she does not.
Evaluation of postmenopausal bleeding
Transvaginal ultrasound
As mentioned, no general consensus exists for the evaluation of PMB; however, initial evaluation by TVUS is recommended. The American College of Obstetricians and Gynecologists (ACOG) concluded that when the endometrium measures ≤4 mm with TVUS, the likelihood that bleeding is secondary to endometrial carcinoma is less than 1% (negative predictive value 99%), and endometrial biopsy is not recommended.3 Endometrial sampling in this clinical scenario likely will result in insufficient tissue for evaluation, and it is reasonable to consider initial management for atrophy. A thickened endometrium on TVUS (>4 mm in a postmenopausal woman with PMB) warrants additional evaluation with endometrial sampling (FIGURE 2).
Clinical takeaway. A thickened endometrium on TVUS ≥4 mm in a postmenopausal woman with PMB warrants additional evaluation with endometrial sampling.
Endometrial biopsy
An endometrial biopsy is performed to determine whether endometrial cancer or precancer is present in women with AUB. ACOG recommends that endometrial biopsy be performed for women older than age 45. It is also appropriate in women younger than 45 years if they have risk factors for developing endometrial cancer, including unopposed estrogen exposure (obesity, ovulatory dysfunction), failed medical management of AUB, or persistence of AUB.4
Continue to: Endometrial biopsy has some...
Endometrial biopsy has some diagnostic shortcomings, however. In 2016 a systematic review and meta-analysis found that, in women with PMB, the specificity of endometrial biopsy was 98% to 100% (accurate diagnosis with a positive result). The sensitivity (ability to make an accurate diagnosis) of endometrial biopsy to identify endometrial pathology (carcinoma, atypical hyperplasia, and polyps) is lower than typically thought. These investigators found an endometrial biopsy failure rate of 11% (range, 1% to 53%) and rate of insufficient samples of 31% (range, 7% to 76%). In women with insufficient or failed samples, endometrial cancer or precancer was found in 7% (range, 0% to 18%).5 Therefore, a negative tissue biopsy result in women with PMB is not considered to be an endpoint, and further evaluation with hysteroscopy to evaluate for focal disease is imperative. The results of endometrial biopsy are only an endpoint to the evaluation of PMB when atypical hyperplasia or endometrial cancer is identified.
Clinical takeaway. A negative tissue biopsy result in women with PMB is not considered to be an endpoint, and further evaluation with hysteroscopy to evaluate for focal disease is imperative.
Hysteroscopy
Hysteroscopy is the gold standard for evaluating the uterine cavity, diagnosing intrauterine pathology, and operative intervention for some causes of AUB. It also is easily performed in the office. This makes the hysteroscope an essential instrument for the gynecologist. Dr. Linda Bradley, a preeminent leader in hysteroscopic surgical education, has coined the phrase, “My hysteroscope is my stethoscope.”6 As gynecologists, we should be as adept at using a hysteroscope in the office as the cardiologist is at using a stethoscope.
It has been known for some time that hysteroscopy improves our diagnostic capabilities over blinded procedures such as endometrial biopsy and dilation and curettage (D&C). As far back as 1989, Dr. Frank Loffer reported the increased sensitivity (ability to make an accurate diagnosis) of hysteroscopy with directed biopsy over blinded D&C (98% vs 65%) in the evaluation of AUB.7 Evaluation of the endometrium with D&C is no longer recommended; yet today, few gynecologists perform hysteroscopic-directed biopsy for AUB evaluation instead of blinded tissue sampling despite the clinical superiority and in-office capabilities (FIGURE 3).
Continue to: Hysteroscopy and endometrial carcinoma...
Hysteroscopy and endometrial carcinoma
The most common type of gynecologic cancer in the United States is endometrial adenocarcinoma (type 1 endometrial cancer). There is some concern about the effect of hysteroscopy on endometrial cancer prognosis and the spread of cells to the peritoneum at the time of hysteroscopy. A large meta-analysis found that hysteroscopy performed in the presence of type 1 endometrial cancer statistically significantly increased the likelihood of positive intraperitoneal cytology; however, it did not alter the clinical outcome. It was recommended that hysteroscopy not be avoided for this reason and is helpful in the diagnosis of endometrial cancer, especially in the early stages of disease.8
For endometrial cancer type 2 (serous carcinoma, clear cell carcinoma, and carcinosarcoma), Chen and colleagues reported a statistically significant increase in positive peritoneal cytology for cancers evaluated by hysteroscopy versus D&C. The disease-specific survival for the hysteroscopy group was 60 months, compared with 71 months for the D&C group. While this finding was not statistically significant, it was clinically relevant, and the effect of hysteroscopy on prognosis with type 2 endometrial cancer is unclear.9
A common occurrence in the evaluation of postmenopausal bleeding (PMB) is an initial TVUS finding of an enlarged endometrium and an endometrial biopsy that is negative or reveals scant or insufficient tissue. Unfortunately, the diagnostic evaluation process often stops here, and a diagnosis for the PMB is never actually identified. Here are several clinical scenarios that highlight the need for hysteroscopy in the initial evaluation of PMB, especially when there is a discordance between transvaginal ultrasonography (TVUS) and endometrial biopsy findings.
Patient 1: Discordant TVUS and biopsy, with benign findings
The patient is a 52-year-old woman who presented to her gynecologist reporting abnormal uterine bleeding (AUB). She has a history of breast cancer, and she completed tamoxifen treatment. Pelvic ultrasonography was performed; an enlarged endometrial stripe of 1.3 cm was found (FIGURE 4A). Endometrial biopsy was performed, showing adequate tissue but with a negative result. The patient is told that she is likely perimenopausal, which is the reason for her bleeding.
At the time of referral, the patient is evaluated with in-office hysteroscopy. Diagnosis of a 5 cm x 7 cm benign endometrial polyp is made. An uneventful hysteroscopic polypectomy is performed (VIDEO 2).
Video 2
This scenario illustrates the shortcoming of initial evaluation by not performing a hysteroscopy, especially in a woman with a thickened endometrium with previous tamoxifen therapy. Subsequent visits failed to correlate bleeding etiology with discordant TVUS and endometrial biopsy results with hysteroscopy, and no hysteroscopy was performed in the operating room at the time of D&C.
Patient 2: Discordant TVUS and biopsy, with premalignant findings
The patient is a 62-year-old woman who had incidental findings of a thickened endometrium on computed tomography scan of the pelvis. TVUS confirmed a thickened endometrium measuring 17 mm, and an endometrial biopsy showed scant tissue.
At the time of referral, a diagnostic hysteroscopy was performed in the office. Endometrial atrophy, a large benign appearing polyp, and focal abnormal appearing tissue were seen (FIGURE 5). A decision for polypectomy and directed biopsy was made. Histology findings confirmed benign polyp and atypical hyperplasia (VIDEO 3).
Video 3
This scenario illustrates that while the patient was asymptomatic, there was discordance between the TVUS and endometrial biopsy. Hysteroscopy identified a benign endometrial polyp, which is common in asymptomatic postmenopausal patients with a thickened endometrium and endometrial biopsy showing scant tissue. However, addition of the diagnostic hysteroscopy identified focal precancerous tissue, removed under directed biopsy.
Patient 3: Discordant TVUS and biopsy, with malignant findings
The patient is a 68-year-old woman with PMB. TVUS showed a thickened endometrium measuring 14 mm. An endometrial biopsy was negative, showing scant tissue. No additional diagnostic evaluation or management was offered.
Video 4A
At the time of referral, the patient was evaluated with in-office diagnostic hysteroscopy, and the patient was found to have endometrial atrophy, benign appearing polyps, and focal abnormal tissue (FIGURE 6). A decision for polypectomy and directed biopsy was made. Histology confirmed benign polyps and grade 1 adenocarcinoma (VIDEOS 4A, 4B, 4C).
Video 4B
This scenario illustrates the possibility of having multiple endometrial pathologies present at the time of discordant TVUS and endometrial biopsy. Hysteroscopy plays a critical role in additional evaluation and diagnosis of endometrial carcinoma with directed biopsy, especially in a symptomatic woman with PMB.
Video 4C
Conclusion
Evaluation of PMB begins with a screening TVUS. Findings of an endometrium of ≤4 mm indicate a very low likelihood of the presence of endometrial cancer, and treatment for atrophy or changes to hormone replacement therapy regimen is reasonable first-line management; endometrial biopsy is not recommended. For patients with persistent PMB or thickened endometrium ≥4 mm on TVUS, biopsy sampling of the endometrium should be performed. If the endometrial biopsy does not explain the etiology of the PMB with atypical hyperplasia or endometrial cancer, then hysteroscopy should be performed to evaluate for focal endometrial disease and possible directed biopsy.
Postmenopausal bleeding (PMB) is the presenting sign in most cases of endometrial carcinoma. Prompt evaluation of PMB can exclude, or diagnose, endometrial carcinoma.1 Although no general consensus exists for PMB evaluation, it involves endometrial assessment with transvaginal ultrasonography (TVUS) and subsequent endometrial biopsy when a thickened endometrium is found. When biopsy results reveal insufficient or scant tissue, further investigation into the etiology of PMB should include office hysteroscopy with possible directed biopsy. In this article I discuss the prevalence of PMB and steps for evaluation, providing clinical takeaways.
Postmenopausal bleeding: Its risk for cancer
Abnormal uterine bleeding (AUB) in a postmenopausal woman is of particular concern to the gynecologist and the patient because of the increased possibility of endometrial carcinoma in this age group. AUB is present in more than 90% of postmenopausal women with endometrial carcinoma, which leads to diagnosis in the early stages of the disease. Approximately 3% to 7% of postmenopausal women with PMB will have endometrial carcinoma.2 Most women with PMB, however, experience bleeding secondary to atrophic changes of the vagina or endometrium and not to endometrial carcinoma. (FIGURE 1, VIDEO 1) In addition, women who take gonadal steroids for hormone replacement therapy (HRT) may experience breakthrough bleeding that leads to initial investigation with TVUS.
Video 1
The risk of malignancy in polyps in postmenopausal women over the age of 59 who present with PMB is approximately 12%, and hysteroscopic resection should routinely be performed. For asymptomatic patients, the risk of a malignant lesion is low—approximately 3%—and for these women intervention should be assessed individually for the risks of carcinoma and benefits of hysteroscopic removal.3
Clinical takeaway. The high possibility of endometrial carcinoma in postmenopausal women warrants that any patient who is symptomatic with PMB should be presumed to have endometrial cancer until the diagnostic evaluation process proves she does not.
Evaluation of postmenopausal bleeding
Transvaginal ultrasound
As mentioned, no general consensus exists for the evaluation of PMB; however, initial evaluation by TVUS is recommended. The American College of Obstetricians and Gynecologists (ACOG) concluded that when the endometrium measures ≤4 mm with TVUS, the likelihood that bleeding is secondary to endometrial carcinoma is less than 1% (negative predictive value 99%), and endometrial biopsy is not recommended.3 Endometrial sampling in this clinical scenario likely will result in insufficient tissue for evaluation, and it is reasonable to consider initial management for atrophy. A thickened endometrium on TVUS (>4 mm in a postmenopausal woman with PMB) warrants additional evaluation with endometrial sampling (FIGURE 2).
Clinical takeaway. A thickened endometrium on TVUS ≥4 mm in a postmenopausal woman with PMB warrants additional evaluation with endometrial sampling.
Endometrial biopsy
An endometrial biopsy is performed to determine whether endometrial cancer or precancer is present in women with AUB. ACOG recommends that endometrial biopsy be performed for women older than age 45. It is also appropriate in women younger than 45 years if they have risk factors for developing endometrial cancer, including unopposed estrogen exposure (obesity, ovulatory dysfunction), failed medical management of AUB, or persistence of AUB.4
Continue to: Endometrial biopsy has some...
Endometrial biopsy has some diagnostic shortcomings, however. In 2016 a systematic review and meta-analysis found that, in women with PMB, the specificity of endometrial biopsy was 98% to 100% (accurate diagnosis with a positive result). The sensitivity (ability to make an accurate diagnosis) of endometrial biopsy to identify endometrial pathology (carcinoma, atypical hyperplasia, and polyps) is lower than typically thought. These investigators found an endometrial biopsy failure rate of 11% (range, 1% to 53%) and rate of insufficient samples of 31% (range, 7% to 76%). In women with insufficient or failed samples, endometrial cancer or precancer was found in 7% (range, 0% to 18%).5 Therefore, a negative tissue biopsy result in women with PMB is not considered to be an endpoint, and further evaluation with hysteroscopy to evaluate for focal disease is imperative. The results of endometrial biopsy are only an endpoint to the evaluation of PMB when atypical hyperplasia or endometrial cancer is identified.
Clinical takeaway. A negative tissue biopsy result in women with PMB is not considered to be an endpoint, and further evaluation with hysteroscopy to evaluate for focal disease is imperative.
Hysteroscopy
Hysteroscopy is the gold standard for evaluating the uterine cavity, diagnosing intrauterine pathology, and operative intervention for some causes of AUB. It also is easily performed in the office. This makes the hysteroscope an essential instrument for the gynecologist. Dr. Linda Bradley, a preeminent leader in hysteroscopic surgical education, has coined the phrase, “My hysteroscope is my stethoscope.”6 As gynecologists, we should be as adept at using a hysteroscope in the office as the cardiologist is at using a stethoscope.
It has been known for some time that hysteroscopy improves our diagnostic capabilities over blinded procedures such as endometrial biopsy and dilation and curettage (D&C). As far back as 1989, Dr. Frank Loffer reported the increased sensitivity (ability to make an accurate diagnosis) of hysteroscopy with directed biopsy over blinded D&C (98% vs 65%) in the evaluation of AUB.7 Evaluation of the endometrium with D&C is no longer recommended; yet today, few gynecologists perform hysteroscopic-directed biopsy for AUB evaluation instead of blinded tissue sampling despite the clinical superiority and in-office capabilities (FIGURE 3).
Continue to: Hysteroscopy and endometrial carcinoma...
Hysteroscopy and endometrial carcinoma
The most common type of gynecologic cancer in the United States is endometrial adenocarcinoma (type 1 endometrial cancer). There is some concern about the effect of hysteroscopy on endometrial cancer prognosis and the spread of cells to the peritoneum at the time of hysteroscopy. A large meta-analysis found that hysteroscopy performed in the presence of type 1 endometrial cancer statistically significantly increased the likelihood of positive intraperitoneal cytology; however, it did not alter the clinical outcome. It was recommended that hysteroscopy not be avoided for this reason and is helpful in the diagnosis of endometrial cancer, especially in the early stages of disease.8
For endometrial cancer type 2 (serous carcinoma, clear cell carcinoma, and carcinosarcoma), Chen and colleagues reported a statistically significant increase in positive peritoneal cytology for cancers evaluated by hysteroscopy versus D&C. The disease-specific survival for the hysteroscopy group was 60 months, compared with 71 months for the D&C group. While this finding was not statistically significant, it was clinically relevant, and the effect of hysteroscopy on prognosis with type 2 endometrial cancer is unclear.9
A common occurrence in the evaluation of postmenopausal bleeding (PMB) is an initial TVUS finding of an enlarged endometrium and an endometrial biopsy that is negative or reveals scant or insufficient tissue. Unfortunately, the diagnostic evaluation process often stops here, and a diagnosis for the PMB is never actually identified. Here are several clinical scenarios that highlight the need for hysteroscopy in the initial evaluation of PMB, especially when there is a discordance between transvaginal ultrasonography (TVUS) and endometrial biopsy findings.
Patient 1: Discordant TVUS and biopsy, with benign findings
The patient is a 52-year-old woman who presented to her gynecologist reporting abnormal uterine bleeding (AUB). She has a history of breast cancer, and she completed tamoxifen treatment. Pelvic ultrasonography was performed; an enlarged endometrial stripe of 1.3 cm was found (FIGURE 4A). Endometrial biopsy was performed, showing adequate tissue but with a negative result. The patient is told that she is likely perimenopausal, which is the reason for her bleeding.
At the time of referral, the patient is evaluated with in-office hysteroscopy. Diagnosis of a 5 cm x 7 cm benign endometrial polyp is made. An uneventful hysteroscopic polypectomy is performed (VIDEO 2).
Video 2
This scenario illustrates the shortcoming of initial evaluation by not performing a hysteroscopy, especially in a woman with a thickened endometrium with previous tamoxifen therapy. Subsequent visits failed to correlate bleeding etiology with discordant TVUS and endometrial biopsy results with hysteroscopy, and no hysteroscopy was performed in the operating room at the time of D&C.
Patient 2: Discordant TVUS and biopsy, with premalignant findings
The patient is a 62-year-old woman who had incidental findings of a thickened endometrium on computed tomography scan of the pelvis. TVUS confirmed a thickened endometrium measuring 17 mm, and an endometrial biopsy showed scant tissue.
At the time of referral, a diagnostic hysteroscopy was performed in the office. Endometrial atrophy, a large benign appearing polyp, and focal abnormal appearing tissue were seen (FIGURE 5). A decision for polypectomy and directed biopsy was made. Histology findings confirmed benign polyp and atypical hyperplasia (VIDEO 3).
Video 3
This scenario illustrates that while the patient was asymptomatic, there was discordance between the TVUS and endometrial biopsy. Hysteroscopy identified a benign endometrial polyp, which is common in asymptomatic postmenopausal patients with a thickened endometrium and endometrial biopsy showing scant tissue. However, addition of the diagnostic hysteroscopy identified focal precancerous tissue, removed under directed biopsy.
Patient 3: Discordant TVUS and biopsy, with malignant findings
The patient is a 68-year-old woman with PMB. TVUS showed a thickened endometrium measuring 14 mm. An endometrial biopsy was negative, showing scant tissue. No additional diagnostic evaluation or management was offered.
Video 4A
At the time of referral, the patient was evaluated with in-office diagnostic hysteroscopy, and the patient was found to have endometrial atrophy, benign appearing polyps, and focal abnormal tissue (FIGURE 6). A decision for polypectomy and directed biopsy was made. Histology confirmed benign polyps and grade 1 adenocarcinoma (VIDEOS 4A, 4B, 4C).
Video 4B
This scenario illustrates the possibility of having multiple endometrial pathologies present at the time of discordant TVUS and endometrial biopsy. Hysteroscopy plays a critical role in additional evaluation and diagnosis of endometrial carcinoma with directed biopsy, especially in a symptomatic woman with PMB.
Video 4C
Conclusion
Evaluation of PMB begins with a screening TVUS. Findings of an endometrium of ≤4 mm indicate a very low likelihood of the presence of endometrial cancer, and treatment for atrophy or changes to hormone replacement therapy regimen is reasonable first-line management; endometrial biopsy is not recommended. For patients with persistent PMB or thickened endometrium ≥4 mm on TVUS, biopsy sampling of the endometrium should be performed. If the endometrial biopsy does not explain the etiology of the PMB with atypical hyperplasia or endometrial cancer, then hysteroscopy should be performed to evaluate for focal endometrial disease and possible directed biopsy.
- ACOG Committee Opinion no. 734: the role of transvaginal ultrasonography in evaluating the endometrium of women with postmenopausal bleeding. Obstet Gynecol. 2018;131:e124-e129.
- Goldstein SR. Appropriate evaluation of postmenopausal bleeding. Menopause. 2018;25:1476-1478.
- Bel S, Billard C, Godet J, et al. Risk of malignancy on suspicion of polyps in menopausal women. Eur J Obstet Gynecol Reprod Biol. 2017;216:138-142.
- Practice bulletin no. 128: diagnosis of abnormal uterine bleeding in reproductive-aged women. Obstet Gynecol. 2012;120:197-206.
- van Hanegem N, Prins MM, Bongers MY. The accuracy of endometrial sampling in women with postmenopausal bleeding: a systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2016;197:147-155.
- Embracing hysteroscopy. September 6, 2017. https://consultqd.clevelandclinic.org/embracing-hysteroscopy/. Accessed July 22, 2019.
- Loffer FD. Hysteroscopy with selective endometrial sampling compared with D&C for abnormal uterine bleeding: the value of a negative hysteroscopic view. Obstet Gynecol. 1989;73:16-20.
- Chang YN, Zhang Y, Wang LP, et al. Effect of hysteroscopy on the peritoneal dissemination of endometrial cancer cells: a meta-analysis. Fertil Steril. 2011;96:957-961.
- Chen J, Clark LH, Kong WM, et al. Does hysteroscopy worsen prognosis in women with type II endometrial carcinoma? PLoS One. 2017;12:e0174226.
- ACOG Committee Opinion no. 734: the role of transvaginal ultrasonography in evaluating the endometrium of women with postmenopausal bleeding. Obstet Gynecol. 2018;131:e124-e129.
- Goldstein SR. Appropriate evaluation of postmenopausal bleeding. Menopause. 2018;25:1476-1478.
- Bel S, Billard C, Godet J, et al. Risk of malignancy on suspicion of polyps in menopausal women. Eur J Obstet Gynecol Reprod Biol. 2017;216:138-142.
- Practice bulletin no. 128: diagnosis of abnormal uterine bleeding in reproductive-aged women. Obstet Gynecol. 2012;120:197-206.
- van Hanegem N, Prins MM, Bongers MY. The accuracy of endometrial sampling in women with postmenopausal bleeding: a systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2016;197:147-155.
- Embracing hysteroscopy. September 6, 2017. https://consultqd.clevelandclinic.org/embracing-hysteroscopy/. Accessed July 22, 2019.
- Loffer FD. Hysteroscopy with selective endometrial sampling compared with D&C for abnormal uterine bleeding: the value of a negative hysteroscopic view. Obstet Gynecol. 1989;73:16-20.
- Chang YN, Zhang Y, Wang LP, et al. Effect of hysteroscopy on the peritoneal dissemination of endometrial cancer cells: a meta-analysis. Fertil Steril. 2011;96:957-961.
- Chen J, Clark LH, Kong WM, et al. Does hysteroscopy worsen prognosis in women with type II endometrial carcinoma? PLoS One. 2017;12:e0174226.
Why do so many women aged 65 years and older die of cervical cancer?
Surprisingly, the cervical cancer death rate is greater among women aged >65 years than among younger women1,2 (FIGURE). Paradoxically, most of our screening programs focus on women <65 years of age. A nationwide study from Denmark estimated that the cervical cancer death rate per 100,000 women at ages 40 to 44 and 65 to 69 was 3.8 and 9.0, respectively.1 In other words, the cervical cancer death rate at age 65 to 69 years was 2.36 times higher than at age 40 to 44 years.1
A study from the United States estimated that the cervical cancer death rate per 100,000 white women at ages 40 to 44 and 65 to 69 was 3.3 and 8.6, respectively,2 very similar to the findings from Denmark. The same US study estimated that the cervical cancer death rate per 100,000 black women at ages 40 to 44 and 65 to 69 was 5.3 and 23.8, highlighting the fact that, in the United States, cervical cancer disease burden is disproportionately greater among black than among white women.2 In addition, the cervical cancer death rate among black women at age 65 to 69 was 4.49 times higher than at age 40 to 44 years.2
Given the high death rate from cervical cancer in women >65 years of age, it is paradoxical that most professional society guidelines recommend discontinuing cervical cancer screening at 65 years of age, if previous cervical cancer screening is normal.3,4 Is the problem due to an inability to implement the current guidelines? Or is the problem that the guidelines are not optimally designed to reduce cervical cancer risk in women >65 years of age?
The American College of Obstetricians and Gynecologists (ACOG) and the US Preventive Services Task Force (USPSTF) recommend against cervical cancer screening in women >65 years of age who have had adequate prior screening and are not otherwise at high risk for cervical cancer. However, ACOG and the USPSTF caution that there are many groups of women that may benefit from continued screening after 65 years of age, including women with HIV infection, a compromised immune system, or previous high-grade precancerous lesion or cervicalcancer; women with limited access to care; women from racial/ethnic minority groups; and migrant women.4 Many clinicians remember the guidance, “discontinue cervical cancer screening at 65 years” but do not recall all the clinical factors that might warrant continued screening past age 65. Of special concern is that black,2 Hispanic,5 and migrant women6 are at much higher risk for invasive cervical cancer than white or US-born women.
The optimal implementation of the ACOG and USPSTF guidelines are undermined by a fractured health care system, where key pieces of information may be unavailable to the clinician tasked with making a decision about discontinuing cervical cancer screening. Imagine the case in which a 65-year-old woman pre‑sents to her primary care physician for cervical cancer screening. The clinician performs a cervical cytology test and obtains a report of “no intraepithelial lesion or malignancy.” The clinician then recommends that the patient discontinue cervical cancer screening. Unbeknownst to the clinician, the patient had a positive HPV 16/18/45 test within the past 10 years in another health system. In this case, it would be inappropriate to terminate the patient from cervical cancer screening.
Continue to: Testing for hrHPV is superior to cervical cytology in women >65 years...
Testing for hrHPV is superior to cervical cytology in women >65 years
In Sweden, about 30% of cervical cancer cases occur in women aged >60 years.7 To assess the prevalence of oncogenic high-risk HPV (hrHPV), women at ages 60, 65, 70, and 75 years were invited to send sequential self-collected vaginal samples for nucleic acid testing for hrHPV. The prevalence of hrHPV was found to be 4.4%. Women with a second positive, self-collected, hrHPV test were invited for colposcopy, cervical biopsy, and cytology testing. Among the women with two positive hrHPV tests, cervical biopsy revealed 7 cases of cervical intraepithelial neoplasia grade 2 (CIN2), 6 cases of CIN1, and 4 biopsies without CIN. In these women 94% of the cervical cytology samples returned, “no intraepithelial lesion or malignancy” and 6% revealed atypical squamous cells of undetermined significance. This study suggests that, in women aged >65 years, cervical cytology may have a high rate of false-negative results, possibly due to epithelial atrophy. An evolving clinical pearl is that, when using the current cervical cancer screening guidelines, the final screen for cervical cancer must include a nucleic acid test for hrHPV.
In women 65 to 90 years, the prevalence of hrHPV is approximately 5%
In a study of 40,382 women aged 14 to 95 years, the prevalence of hrHPV was 46% in 20- to 23-year-old women and 5.7% in women older than 65 years of age.8 In a study of more than 108,000 women aged 69 to >89 years the prevalence of hrHPV was 4.3%, and similar prevalence rates were seen across all ages from 69 to >89 years.9 The carcinogenic role of persistent hrHPV infection in women >65 years is an important area for future research.
Latent HPV virus infection
Following a primary varicella-zoster infection (chickenpox), the virus may remain in a latent state in sensory ganglia, reactivating later in life to cause shingles. Thirty percent of people who have a primary chickenpox infection eventually will develop a case of shingles. Immunocompromised populations are at an increased risk of developing shingles because of reduced T-cell mediated immunity.
A recent hypothesis is that in immunocompromised and older women, latent HPV can reactivate and cause clinically significant infection.10 Following renal transplantation investigators have reported a significant increase in the prevalence of genital HPV, without a change in sexual behavior.11 In cervical tissue from women with no evidence of active HPV infection, highly sensitive PCR-based assays detected HPV16 virus in a latent state in some women, possibly due to disruption of the viral E2 gene.12 If latent HPV infection is a valid biological concept, it suggests that there is no “safe age” at which to discontinue screening for HPV infection because the virus cannot be detected in screening samples while it is latent.
Options for cervical cancer screening in women >65 years
Three options might reduce the morbidity and mortality associated with cervical cancer in women >65 years.
Option 1: Double-down on trying to effectively implement current guidelines. The high rate of cervical cancer mortality in women >65 years of age indicates that the current guidelines, as implemented in real clinical practice, are not working. A problem with the current screening guidelines is that clinicians are expected to be capable of finding all relevant cervical cancer test results and properly interpreting the results. Clinicians are over-taxed and fallible, and the current approach is not likely to be successful unless additional information technology solutions are implemented.
Continue to: Health systems could use information...
Health systems could use information technology to mitigate these problems. For example, health systems could deploy software to assemble every cervical screening result on each woman and pre‑sent those results to clinicians in a single integrated view in the electronic record. Additionally, once all lifetime screening results are consolidated in one view, artificial intelligence systems could be used to analyze the totality of results and identify women who would benefit by continued screening past age 65 and women who could safely discontinue screening.
Option 2: Adopt the Australian approach to cervical cancer screening. The current Australian approach to cervical cancer screening is built on 3 pillars: 1) school-based vaccination of all children against hrHPV, 2) screening all women from 25 to 74 years of age every 5 years using nucleic acid testing for hrHPV, and 3) providing a system for the testing of samples self-collected by women who are reluctant to visit a clinician for screening.13 Australia has one of the lowest cervical cancer death rates in the world.
Option 3: Continue screening most women past age 65. Women >65 years of age are known to be infected with hrHPV genotypes. hrHPV infection causes cervical cancer. Cervical cancer causes many deaths in women aged >65 years. There is no strong rationale for ignoring these three facts. hrHPV screening every 5 years as long as the woman is healthy and has a reasonable life expectancy is an option that could be evaluated in randomized studies.
Given the high rate of cervical cancer death in women >65 years of age, I plan to be very cautious about discontinuing cervical cancer screening until I can personally ensure that my patient has no evidence of hrHPV infection.
In 2008, Harald zur Hausen, MD, received the Nobel Prize in Physiology or Medicine for discovering that human papilloma virus (HPV) caused cervical cancer. In a recent study, 74% of cervical cancers were associated with HPV 16 or 18 infections. A total of 89% of the cancers were associated with one of the high-risk HPV genotypes, including HPV 16/18/31/33/45/52/58.1
Recently, HPV has been shown to be a major cause of oropharyngeal cancer. The Centers for Disease Control and Prevention calculated that in CY2015 in the United States there were 18,917 cases of HPV-associated oropharyngeal squamous cell cancer and 11,788 cases of cervical cancer.2 Most cases of HPV-associated oropharyngeal cancer occur in men, and HPV vaccination of boys may help to prevent this cancer type. Oncogenic HPV produce two proteins (E6 and E7) that promote viral replication and squamous cell growth by inhibiting the function of p53 and retinoblastoma protein. The immortalized HeLa cell line, derived from Ms. Henrietta Lack's cervical cancer, contains integrated HPV18 nucleic acid sequences.3,4
The discovery that HPV causes cancer catalyzed the development of nucleic acid tests to identify high-risk oncogenic HPV and vaccines against high-risk oncogenic HPV genotypes that prevent cervical cancer. From a public health perspective, it is more effective to vaccinate the population against oncogenic HPV genotypes than to screen and treat cancer. In the United States, vaccination rates range from a high of 92% (District of Columbia) and 89% (Rhode Island) to a low of 47% (Wyoming) and 50% (Kentucky and Mississippi).5 To reduce HPV-associated cancer mortality, the gap in vaccination compliance must be closed.
References
- Kjaer SK, Munk C, Junge J, et al. Carcinogenic HPV prevalence and age-specific type distribution in 40,382 women with normal cervical cytology, ACSUC/LSIL, HSIL, or cervical cancer: what is the potential for prevention? Cancer Causes Control. 2014;25:179-189.
- Van Dyne EA, Henley SJ, Saraiya M, et al. Trends in human papillomavirus-associated cancers - United States, 1999-2015. MMWR Morb Mortal Wkly Rep. 2018;67:918-924.
- Rosl F, Westphal EM, zur Hausen H. Chromatin structure and transcriptional regulation of human papillomavirus type 18 DNA in HeLa cells. Mol Carcinog. 1989;2:72-80.
- Adey A, Burton JN, Kitzman, et al. The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line. Nature. 2013;500:207-211.
- Walker TY, Elam-Evans LD, Singleton JA, et al. National, regional, state, and selected local area vaccination coverage among adolescents aged 13-17 years - United States, 2016. MMWR Morb Mortal Wkly Rep. 2017;66:874-882.
- Hammer A, Kahlert J, Gravitt PE, et al. Hysterectomy-corrected cervical cancer mortality rates in Denmark during 2002-2015: a registry-based cohort study. Acta Obstet Gynecol Scand. 2019;98:1063-1069.
- Beavis AL, Gravitt PE, Rositch AF. Hysterectomy-corrected cervical cancer mortality rates reveal a larger racial disparity in the United States. Cancer. 2017;123:1044-1050.
- American College of Obstetricians and Gynecologists Committee on Practice Bulletins--Gynecology. Practice Bulletin No. 168: cervical cancer screening and prevention. Obstet Gynecol. 2016;128:e111-30.
- Curry SJ, Krist AH, Owens DK, et al; US Preventive Services Task Force. Screening for cervical cancer: US Preventive Services Task Force recommendation statement. JAMA. 2018;320:674-686.
- Stang A, Hawk H, Knowlton R, et al. Hysterectomy-corrected incidence rates of cervical and uterine cancers in Massachusetts, 1995-2010. Ann Epidemiol. 2014;24:849-854.
- Hallowell BD, Endeshaw M, McKenna MT, et al. Cervical cancer death rates among U.S.- and foreign-born women: U.S., 2005-2014. Am J Prev Med. 2019;56:869-874.
- Lindström AK, Hermansson RS, Gustavsson I, et al. Cervical dysplasia in elderly women performing repeated self-sampling for HPV testing. PLoS One. 2018;13:e0207714.
- Kjaer SK, Munk C, Junge J, et al. Carcinogenic HPV prevalence and age-specific type distribution in 40,382 women with normal cervical cytology, ACSUC/LSIL, HSIL, or cervical cancer: what is the potential for prevention? Cancer Causes Control. 2014;25:179-189.
- Andersen B, Christensen BS, Christensen J, et al. HPV-prevalence in elderly women in Denmark. Gynecol Oncol. 2019;154:118-123.
- Gravitt PE, Winer RL. Natural history of HPV infection across the lifespan: role of viral latency. Viruses. 2017;9:E267.
- Hinten F, Hilbrands LB, Meeuwis KAP, et al. Reactivation of latent HPV infections after renal transplantation. Am J Transplant. 2017;17:1563-1573.
- Leonard SM, Pereira M, Roberts S, et al. Evidence of disrupted high-risk human papillomavirus DNA in morphologically normal cervices of older women. Sci Rep. 2016;6:20847.
- Cervical cancer screening. Cancer Council website. https://www.cancer.org.au/about-cancer/early-detection/screening-programs/cervical-cancer-screening.html. Updated March 15, 2019. Accessed July 23, 2019.
Robert L. Barbieri, MD
Editor in Chief, OBG MANAGEMENT
Chair, Obstetrics and Gynecology
Brigham and Women’s Hospital
Kate Macy Ladd Professor of Obstetrics,
Gynecology and Reproductive Biology
Harvard Medical School
Dr. Barbieri reports no financial relationships relevant to this article.
Robert L. Barbieri, MD
Editor in Chief, OBG MANAGEMENT
Chair, Obstetrics and Gynecology
Brigham and Women’s Hospital
Kate Macy Ladd Professor of Obstetrics,
Gynecology and Reproductive Biology
Harvard Medical School
Dr. Barbieri reports no financial relationships relevant to this article.
Robert L. Barbieri, MD
Editor in Chief, OBG MANAGEMENT
Chair, Obstetrics and Gynecology
Brigham and Women’s Hospital
Kate Macy Ladd Professor of Obstetrics,
Gynecology and Reproductive Biology
Harvard Medical School
Dr. Barbieri reports no financial relationships relevant to this article.
Surprisingly, the cervical cancer death rate is greater among women aged >65 years than among younger women1,2 (FIGURE). Paradoxically, most of our screening programs focus on women <65 years of age. A nationwide study from Denmark estimated that the cervical cancer death rate per 100,000 women at ages 40 to 44 and 65 to 69 was 3.8 and 9.0, respectively.1 In other words, the cervical cancer death rate at age 65 to 69 years was 2.36 times higher than at age 40 to 44 years.1
A study from the United States estimated that the cervical cancer death rate per 100,000 white women at ages 40 to 44 and 65 to 69 was 3.3 and 8.6, respectively,2 very similar to the findings from Denmark. The same US study estimated that the cervical cancer death rate per 100,000 black women at ages 40 to 44 and 65 to 69 was 5.3 and 23.8, highlighting the fact that, in the United States, cervical cancer disease burden is disproportionately greater among black than among white women.2 In addition, the cervical cancer death rate among black women at age 65 to 69 was 4.49 times higher than at age 40 to 44 years.2
Given the high death rate from cervical cancer in women >65 years of age, it is paradoxical that most professional society guidelines recommend discontinuing cervical cancer screening at 65 years of age, if previous cervical cancer screening is normal.3,4 Is the problem due to an inability to implement the current guidelines? Or is the problem that the guidelines are not optimally designed to reduce cervical cancer risk in women >65 years of age?
The American College of Obstetricians and Gynecologists (ACOG) and the US Preventive Services Task Force (USPSTF) recommend against cervical cancer screening in women >65 years of age who have had adequate prior screening and are not otherwise at high risk for cervical cancer. However, ACOG and the USPSTF caution that there are many groups of women that may benefit from continued screening after 65 years of age, including women with HIV infection, a compromised immune system, or previous high-grade precancerous lesion or cervicalcancer; women with limited access to care; women from racial/ethnic minority groups; and migrant women.4 Many clinicians remember the guidance, “discontinue cervical cancer screening at 65 years” but do not recall all the clinical factors that might warrant continued screening past age 65. Of special concern is that black,2 Hispanic,5 and migrant women6 are at much higher risk for invasive cervical cancer than white or US-born women.
The optimal implementation of the ACOG and USPSTF guidelines are undermined by a fractured health care system, where key pieces of information may be unavailable to the clinician tasked with making a decision about discontinuing cervical cancer screening. Imagine the case in which a 65-year-old woman pre‑sents to her primary care physician for cervical cancer screening. The clinician performs a cervical cytology test and obtains a report of “no intraepithelial lesion or malignancy.” The clinician then recommends that the patient discontinue cervical cancer screening. Unbeknownst to the clinician, the patient had a positive HPV 16/18/45 test within the past 10 years in another health system. In this case, it would be inappropriate to terminate the patient from cervical cancer screening.
Continue to: Testing for hrHPV is superior to cervical cytology in women >65 years...
Testing for hrHPV is superior to cervical cytology in women >65 years
In Sweden, about 30% of cervical cancer cases occur in women aged >60 years.7 To assess the prevalence of oncogenic high-risk HPV (hrHPV), women at ages 60, 65, 70, and 75 years were invited to send sequential self-collected vaginal samples for nucleic acid testing for hrHPV. The prevalence of hrHPV was found to be 4.4%. Women with a second positive, self-collected, hrHPV test were invited for colposcopy, cervical biopsy, and cytology testing. Among the women with two positive hrHPV tests, cervical biopsy revealed 7 cases of cervical intraepithelial neoplasia grade 2 (CIN2), 6 cases of CIN1, and 4 biopsies without CIN. In these women 94% of the cervical cytology samples returned, “no intraepithelial lesion or malignancy” and 6% revealed atypical squamous cells of undetermined significance. This study suggests that, in women aged >65 years, cervical cytology may have a high rate of false-negative results, possibly due to epithelial atrophy. An evolving clinical pearl is that, when using the current cervical cancer screening guidelines, the final screen for cervical cancer must include a nucleic acid test for hrHPV.
In women 65 to 90 years, the prevalence of hrHPV is approximately 5%
In a study of 40,382 women aged 14 to 95 years, the prevalence of hrHPV was 46% in 20- to 23-year-old women and 5.7% in women older than 65 years of age.8 In a study of more than 108,000 women aged 69 to >89 years the prevalence of hrHPV was 4.3%, and similar prevalence rates were seen across all ages from 69 to >89 years.9 The carcinogenic role of persistent hrHPV infection in women >65 years is an important area for future research.
Latent HPV virus infection
Following a primary varicella-zoster infection (chickenpox), the virus may remain in a latent state in sensory ganglia, reactivating later in life to cause shingles. Thirty percent of people who have a primary chickenpox infection eventually will develop a case of shingles. Immunocompromised populations are at an increased risk of developing shingles because of reduced T-cell mediated immunity.
A recent hypothesis is that in immunocompromised and older women, latent HPV can reactivate and cause clinically significant infection.10 Following renal transplantation investigators have reported a significant increase in the prevalence of genital HPV, without a change in sexual behavior.11 In cervical tissue from women with no evidence of active HPV infection, highly sensitive PCR-based assays detected HPV16 virus in a latent state in some women, possibly due to disruption of the viral E2 gene.12 If latent HPV infection is a valid biological concept, it suggests that there is no “safe age” at which to discontinue screening for HPV infection because the virus cannot be detected in screening samples while it is latent.
Options for cervical cancer screening in women >65 years
Three options might reduce the morbidity and mortality associated with cervical cancer in women >65 years.
Option 1: Double-down on trying to effectively implement current guidelines. The high rate of cervical cancer mortality in women >65 years of age indicates that the current guidelines, as implemented in real clinical practice, are not working. A problem with the current screening guidelines is that clinicians are expected to be capable of finding all relevant cervical cancer test results and properly interpreting the results. Clinicians are over-taxed and fallible, and the current approach is not likely to be successful unless additional information technology solutions are implemented.
Continue to: Health systems could use information...
Health systems could use information technology to mitigate these problems. For example, health systems could deploy software to assemble every cervical screening result on each woman and pre‑sent those results to clinicians in a single integrated view in the electronic record. Additionally, once all lifetime screening results are consolidated in one view, artificial intelligence systems could be used to analyze the totality of results and identify women who would benefit by continued screening past age 65 and women who could safely discontinue screening.
Option 2: Adopt the Australian approach to cervical cancer screening. The current Australian approach to cervical cancer screening is built on 3 pillars: 1) school-based vaccination of all children against hrHPV, 2) screening all women from 25 to 74 years of age every 5 years using nucleic acid testing for hrHPV, and 3) providing a system for the testing of samples self-collected by women who are reluctant to visit a clinician for screening.13 Australia has one of the lowest cervical cancer death rates in the world.
Option 3: Continue screening most women past age 65. Women >65 years of age are known to be infected with hrHPV genotypes. hrHPV infection causes cervical cancer. Cervical cancer causes many deaths in women aged >65 years. There is no strong rationale for ignoring these three facts. hrHPV screening every 5 years as long as the woman is healthy and has a reasonable life expectancy is an option that could be evaluated in randomized studies.
Given the high rate of cervical cancer death in women >65 years of age, I plan to be very cautious about discontinuing cervical cancer screening until I can personally ensure that my patient has no evidence of hrHPV infection.
In 2008, Harald zur Hausen, MD, received the Nobel Prize in Physiology or Medicine for discovering that human papilloma virus (HPV) caused cervical cancer. In a recent study, 74% of cervical cancers were associated with HPV 16 or 18 infections. A total of 89% of the cancers were associated with one of the high-risk HPV genotypes, including HPV 16/18/31/33/45/52/58.1
Recently, HPV has been shown to be a major cause of oropharyngeal cancer. The Centers for Disease Control and Prevention calculated that in CY2015 in the United States there were 18,917 cases of HPV-associated oropharyngeal squamous cell cancer and 11,788 cases of cervical cancer.2 Most cases of HPV-associated oropharyngeal cancer occur in men, and HPV vaccination of boys may help to prevent this cancer type. Oncogenic HPV produce two proteins (E6 and E7) that promote viral replication and squamous cell growth by inhibiting the function of p53 and retinoblastoma protein. The immortalized HeLa cell line, derived from Ms. Henrietta Lack's cervical cancer, contains integrated HPV18 nucleic acid sequences.3,4
The discovery that HPV causes cancer catalyzed the development of nucleic acid tests to identify high-risk oncogenic HPV and vaccines against high-risk oncogenic HPV genotypes that prevent cervical cancer. From a public health perspective, it is more effective to vaccinate the population against oncogenic HPV genotypes than to screen and treat cancer. In the United States, vaccination rates range from a high of 92% (District of Columbia) and 89% (Rhode Island) to a low of 47% (Wyoming) and 50% (Kentucky and Mississippi).5 To reduce HPV-associated cancer mortality, the gap in vaccination compliance must be closed.
References
- Kjaer SK, Munk C, Junge J, et al. Carcinogenic HPV prevalence and age-specific type distribution in 40,382 women with normal cervical cytology, ACSUC/LSIL, HSIL, or cervical cancer: what is the potential for prevention? Cancer Causes Control. 2014;25:179-189.
- Van Dyne EA, Henley SJ, Saraiya M, et al. Trends in human papillomavirus-associated cancers - United States, 1999-2015. MMWR Morb Mortal Wkly Rep. 2018;67:918-924.
- Rosl F, Westphal EM, zur Hausen H. Chromatin structure and transcriptional regulation of human papillomavirus type 18 DNA in HeLa cells. Mol Carcinog. 1989;2:72-80.
- Adey A, Burton JN, Kitzman, et al. The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line. Nature. 2013;500:207-211.
- Walker TY, Elam-Evans LD, Singleton JA, et al. National, regional, state, and selected local area vaccination coverage among adolescents aged 13-17 years - United States, 2016. MMWR Morb Mortal Wkly Rep. 2017;66:874-882.
Surprisingly, the cervical cancer death rate is greater among women aged >65 years than among younger women1,2 (FIGURE). Paradoxically, most of our screening programs focus on women <65 years of age. A nationwide study from Denmark estimated that the cervical cancer death rate per 100,000 women at ages 40 to 44 and 65 to 69 was 3.8 and 9.0, respectively.1 In other words, the cervical cancer death rate at age 65 to 69 years was 2.36 times higher than at age 40 to 44 years.1
A study from the United States estimated that the cervical cancer death rate per 100,000 white women at ages 40 to 44 and 65 to 69 was 3.3 and 8.6, respectively,2 very similar to the findings from Denmark. The same US study estimated that the cervical cancer death rate per 100,000 black women at ages 40 to 44 and 65 to 69 was 5.3 and 23.8, highlighting the fact that, in the United States, cervical cancer disease burden is disproportionately greater among black than among white women.2 In addition, the cervical cancer death rate among black women at age 65 to 69 was 4.49 times higher than at age 40 to 44 years.2
Given the high death rate from cervical cancer in women >65 years of age, it is paradoxical that most professional society guidelines recommend discontinuing cervical cancer screening at 65 years of age, if previous cervical cancer screening is normal.3,4 Is the problem due to an inability to implement the current guidelines? Or is the problem that the guidelines are not optimally designed to reduce cervical cancer risk in women >65 years of age?
The American College of Obstetricians and Gynecologists (ACOG) and the US Preventive Services Task Force (USPSTF) recommend against cervical cancer screening in women >65 years of age who have had adequate prior screening and are not otherwise at high risk for cervical cancer. However, ACOG and the USPSTF caution that there are many groups of women that may benefit from continued screening after 65 years of age, including women with HIV infection, a compromised immune system, or previous high-grade precancerous lesion or cervicalcancer; women with limited access to care; women from racial/ethnic minority groups; and migrant women.4 Many clinicians remember the guidance, “discontinue cervical cancer screening at 65 years” but do not recall all the clinical factors that might warrant continued screening past age 65. Of special concern is that black,2 Hispanic,5 and migrant women6 are at much higher risk for invasive cervical cancer than white or US-born women.
The optimal implementation of the ACOG and USPSTF guidelines are undermined by a fractured health care system, where key pieces of information may be unavailable to the clinician tasked with making a decision about discontinuing cervical cancer screening. Imagine the case in which a 65-year-old woman pre‑sents to her primary care physician for cervical cancer screening. The clinician performs a cervical cytology test and obtains a report of “no intraepithelial lesion or malignancy.” The clinician then recommends that the patient discontinue cervical cancer screening. Unbeknownst to the clinician, the patient had a positive HPV 16/18/45 test within the past 10 years in another health system. In this case, it would be inappropriate to terminate the patient from cervical cancer screening.
Continue to: Testing for hrHPV is superior to cervical cytology in women >65 years...
Testing for hrHPV is superior to cervical cytology in women >65 years
In Sweden, about 30% of cervical cancer cases occur in women aged >60 years.7 To assess the prevalence of oncogenic high-risk HPV (hrHPV), women at ages 60, 65, 70, and 75 years were invited to send sequential self-collected vaginal samples for nucleic acid testing for hrHPV. The prevalence of hrHPV was found to be 4.4%. Women with a second positive, self-collected, hrHPV test were invited for colposcopy, cervical biopsy, and cytology testing. Among the women with two positive hrHPV tests, cervical biopsy revealed 7 cases of cervical intraepithelial neoplasia grade 2 (CIN2), 6 cases of CIN1, and 4 biopsies without CIN. In these women 94% of the cervical cytology samples returned, “no intraepithelial lesion or malignancy” and 6% revealed atypical squamous cells of undetermined significance. This study suggests that, in women aged >65 years, cervical cytology may have a high rate of false-negative results, possibly due to epithelial atrophy. An evolving clinical pearl is that, when using the current cervical cancer screening guidelines, the final screen for cervical cancer must include a nucleic acid test for hrHPV.
In women 65 to 90 years, the prevalence of hrHPV is approximately 5%
In a study of 40,382 women aged 14 to 95 years, the prevalence of hrHPV was 46% in 20- to 23-year-old women and 5.7% in women older than 65 years of age.8 In a study of more than 108,000 women aged 69 to >89 years the prevalence of hrHPV was 4.3%, and similar prevalence rates were seen across all ages from 69 to >89 years.9 The carcinogenic role of persistent hrHPV infection in women >65 years is an important area for future research.
Latent HPV virus infection
Following a primary varicella-zoster infection (chickenpox), the virus may remain in a latent state in sensory ganglia, reactivating later in life to cause shingles. Thirty percent of people who have a primary chickenpox infection eventually will develop a case of shingles. Immunocompromised populations are at an increased risk of developing shingles because of reduced T-cell mediated immunity.
A recent hypothesis is that in immunocompromised and older women, latent HPV can reactivate and cause clinically significant infection.10 Following renal transplantation investigators have reported a significant increase in the prevalence of genital HPV, without a change in sexual behavior.11 In cervical tissue from women with no evidence of active HPV infection, highly sensitive PCR-based assays detected HPV16 virus in a latent state in some women, possibly due to disruption of the viral E2 gene.12 If latent HPV infection is a valid biological concept, it suggests that there is no “safe age” at which to discontinue screening for HPV infection because the virus cannot be detected in screening samples while it is latent.
Options for cervical cancer screening in women >65 years
Three options might reduce the morbidity and mortality associated with cervical cancer in women >65 years.
Option 1: Double-down on trying to effectively implement current guidelines. The high rate of cervical cancer mortality in women >65 years of age indicates that the current guidelines, as implemented in real clinical practice, are not working. A problem with the current screening guidelines is that clinicians are expected to be capable of finding all relevant cervical cancer test results and properly interpreting the results. Clinicians are over-taxed and fallible, and the current approach is not likely to be successful unless additional information technology solutions are implemented.
Continue to: Health systems could use information...
Health systems could use information technology to mitigate these problems. For example, health systems could deploy software to assemble every cervical screening result on each woman and pre‑sent those results to clinicians in a single integrated view in the electronic record. Additionally, once all lifetime screening results are consolidated in one view, artificial intelligence systems could be used to analyze the totality of results and identify women who would benefit by continued screening past age 65 and women who could safely discontinue screening.
Option 2: Adopt the Australian approach to cervical cancer screening. The current Australian approach to cervical cancer screening is built on 3 pillars: 1) school-based vaccination of all children against hrHPV, 2) screening all women from 25 to 74 years of age every 5 years using nucleic acid testing for hrHPV, and 3) providing a system for the testing of samples self-collected by women who are reluctant to visit a clinician for screening.13 Australia has one of the lowest cervical cancer death rates in the world.
Option 3: Continue screening most women past age 65. Women >65 years of age are known to be infected with hrHPV genotypes. hrHPV infection causes cervical cancer. Cervical cancer causes many deaths in women aged >65 years. There is no strong rationale for ignoring these three facts. hrHPV screening every 5 years as long as the woman is healthy and has a reasonable life expectancy is an option that could be evaluated in randomized studies.
Given the high rate of cervical cancer death in women >65 years of age, I plan to be very cautious about discontinuing cervical cancer screening until I can personally ensure that my patient has no evidence of hrHPV infection.
In 2008, Harald zur Hausen, MD, received the Nobel Prize in Physiology or Medicine for discovering that human papilloma virus (HPV) caused cervical cancer. In a recent study, 74% of cervical cancers were associated with HPV 16 or 18 infections. A total of 89% of the cancers were associated with one of the high-risk HPV genotypes, including HPV 16/18/31/33/45/52/58.1
Recently, HPV has been shown to be a major cause of oropharyngeal cancer. The Centers for Disease Control and Prevention calculated that in CY2015 in the United States there were 18,917 cases of HPV-associated oropharyngeal squamous cell cancer and 11,788 cases of cervical cancer.2 Most cases of HPV-associated oropharyngeal cancer occur in men, and HPV vaccination of boys may help to prevent this cancer type. Oncogenic HPV produce two proteins (E6 and E7) that promote viral replication and squamous cell growth by inhibiting the function of p53 and retinoblastoma protein. The immortalized HeLa cell line, derived from Ms. Henrietta Lack's cervical cancer, contains integrated HPV18 nucleic acid sequences.3,4
The discovery that HPV causes cancer catalyzed the development of nucleic acid tests to identify high-risk oncogenic HPV and vaccines against high-risk oncogenic HPV genotypes that prevent cervical cancer. From a public health perspective, it is more effective to vaccinate the population against oncogenic HPV genotypes than to screen and treat cancer. In the United States, vaccination rates range from a high of 92% (District of Columbia) and 89% (Rhode Island) to a low of 47% (Wyoming) and 50% (Kentucky and Mississippi).5 To reduce HPV-associated cancer mortality, the gap in vaccination compliance must be closed.
References
- Kjaer SK, Munk C, Junge J, et al. Carcinogenic HPV prevalence and age-specific type distribution in 40,382 women with normal cervical cytology, ACSUC/LSIL, HSIL, or cervical cancer: what is the potential for prevention? Cancer Causes Control. 2014;25:179-189.
- Van Dyne EA, Henley SJ, Saraiya M, et al. Trends in human papillomavirus-associated cancers - United States, 1999-2015. MMWR Morb Mortal Wkly Rep. 2018;67:918-924.
- Rosl F, Westphal EM, zur Hausen H. Chromatin structure and transcriptional regulation of human papillomavirus type 18 DNA in HeLa cells. Mol Carcinog. 1989;2:72-80.
- Adey A, Burton JN, Kitzman, et al. The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line. Nature. 2013;500:207-211.
- Walker TY, Elam-Evans LD, Singleton JA, et al. National, regional, state, and selected local area vaccination coverage among adolescents aged 13-17 years - United States, 2016. MMWR Morb Mortal Wkly Rep. 2017;66:874-882.
- Hammer A, Kahlert J, Gravitt PE, et al. Hysterectomy-corrected cervical cancer mortality rates in Denmark during 2002-2015: a registry-based cohort study. Acta Obstet Gynecol Scand. 2019;98:1063-1069.
- Beavis AL, Gravitt PE, Rositch AF. Hysterectomy-corrected cervical cancer mortality rates reveal a larger racial disparity in the United States. Cancer. 2017;123:1044-1050.
- American College of Obstetricians and Gynecologists Committee on Practice Bulletins--Gynecology. Practice Bulletin No. 168: cervical cancer screening and prevention. Obstet Gynecol. 2016;128:e111-30.
- Curry SJ, Krist AH, Owens DK, et al; US Preventive Services Task Force. Screening for cervical cancer: US Preventive Services Task Force recommendation statement. JAMA. 2018;320:674-686.
- Stang A, Hawk H, Knowlton R, et al. Hysterectomy-corrected incidence rates of cervical and uterine cancers in Massachusetts, 1995-2010. Ann Epidemiol. 2014;24:849-854.
- Hallowell BD, Endeshaw M, McKenna MT, et al. Cervical cancer death rates among U.S.- and foreign-born women: U.S., 2005-2014. Am J Prev Med. 2019;56:869-874.
- Lindström AK, Hermansson RS, Gustavsson I, et al. Cervical dysplasia in elderly women performing repeated self-sampling for HPV testing. PLoS One. 2018;13:e0207714.
- Kjaer SK, Munk C, Junge J, et al. Carcinogenic HPV prevalence and age-specific type distribution in 40,382 women with normal cervical cytology, ACSUC/LSIL, HSIL, or cervical cancer: what is the potential for prevention? Cancer Causes Control. 2014;25:179-189.
- Andersen B, Christensen BS, Christensen J, et al. HPV-prevalence in elderly women in Denmark. Gynecol Oncol. 2019;154:118-123.
- Gravitt PE, Winer RL. Natural history of HPV infection across the lifespan: role of viral latency. Viruses. 2017;9:E267.
- Hinten F, Hilbrands LB, Meeuwis KAP, et al. Reactivation of latent HPV infections after renal transplantation. Am J Transplant. 2017;17:1563-1573.
- Leonard SM, Pereira M, Roberts S, et al. Evidence of disrupted high-risk human papillomavirus DNA in morphologically normal cervices of older women. Sci Rep. 2016;6:20847.
- Cervical cancer screening. Cancer Council website. https://www.cancer.org.au/about-cancer/early-detection/screening-programs/cervical-cancer-screening.html. Updated March 15, 2019. Accessed July 23, 2019.
- Hammer A, Kahlert J, Gravitt PE, et al. Hysterectomy-corrected cervical cancer mortality rates in Denmark during 2002-2015: a registry-based cohort study. Acta Obstet Gynecol Scand. 2019;98:1063-1069.
- Beavis AL, Gravitt PE, Rositch AF. Hysterectomy-corrected cervical cancer mortality rates reveal a larger racial disparity in the United States. Cancer. 2017;123:1044-1050.
- American College of Obstetricians and Gynecologists Committee on Practice Bulletins--Gynecology. Practice Bulletin No. 168: cervical cancer screening and prevention. Obstet Gynecol. 2016;128:e111-30.
- Curry SJ, Krist AH, Owens DK, et al; US Preventive Services Task Force. Screening for cervical cancer: US Preventive Services Task Force recommendation statement. JAMA. 2018;320:674-686.
- Stang A, Hawk H, Knowlton R, et al. Hysterectomy-corrected incidence rates of cervical and uterine cancers in Massachusetts, 1995-2010. Ann Epidemiol. 2014;24:849-854.
- Hallowell BD, Endeshaw M, McKenna MT, et al. Cervical cancer death rates among U.S.- and foreign-born women: U.S., 2005-2014. Am J Prev Med. 2019;56:869-874.
- Lindström AK, Hermansson RS, Gustavsson I, et al. Cervical dysplasia in elderly women performing repeated self-sampling for HPV testing. PLoS One. 2018;13:e0207714.
- Kjaer SK, Munk C, Junge J, et al. Carcinogenic HPV prevalence and age-specific type distribution in 40,382 women with normal cervical cytology, ACSUC/LSIL, HSIL, or cervical cancer: what is the potential for prevention? Cancer Causes Control. 2014;25:179-189.
- Andersen B, Christensen BS, Christensen J, et al. HPV-prevalence in elderly women in Denmark. Gynecol Oncol. 2019;154:118-123.
- Gravitt PE, Winer RL. Natural history of HPV infection across the lifespan: role of viral latency. Viruses. 2017;9:E267.
- Hinten F, Hilbrands LB, Meeuwis KAP, et al. Reactivation of latent HPV infections after renal transplantation. Am J Transplant. 2017;17:1563-1573.
- Leonard SM, Pereira M, Roberts S, et al. Evidence of disrupted high-risk human papillomavirus DNA in morphologically normal cervices of older women. Sci Rep. 2016;6:20847.
- Cervical cancer screening. Cancer Council website. https://www.cancer.org.au/about-cancer/early-detection/screening-programs/cervical-cancer-screening.html. Updated March 15, 2019. Accessed July 23, 2019.
