Uterine papillary serous carcinoma (UPSC) is an infrequent but deadly form of endometrial cancer comprising 10% of cases but contributing 40% of deaths from the disease. Recurrence rates are high for this disease. Five-year survival is 55% for all patients and only 70% for stage I disease.1 Patterns of recurrence tend to be distant (extrapelvic and extraabdominal) as frequently as they are localized to the pelvis, and metastases and recurrences are unrelated to the extent of uterine disease (such as myometrial invasion). It is for these reasons that the recommended course of adjuvant therapy for this disease is systemic therapy (typically six doses of carboplatin and paclitaxel chemotherapy) with consideration for radiation to the vagina or pelvis to consolidate pelvic and vaginal control.2 This differs from early-stage high/intermediate–risk endometrioid adenocarcinomas, for which adjuvant chemotherapy has not been found to be helpful.
Dr Joshua Kish
Uterine papillary serous carcinoma, immunohistochemistry strongly positive for HER2.
Because of the lower incidence of UPSC, it frequently has been studied alongside endometrioid cell types in clinical trials which explore novel adjuvant therapies. However, UPSC is biologically distinct from endometrioid endometrial cancers, which likely results in inferior clinical responses to conventional interventions. Fortunately we are beginning to better understand UPSC at a molecular level, and advancements are being made in the targeted therapies for these patients that are unique, compared with those applied to other cancer subtypes.
As discussed above, UPSC is a particularly aggressive form of uterine cancer. Histologically it is characterized by a precursor lesion of endometrial glandular dysplasia progressing to endometrial intraepithelial neoplasia (EIC). Histologically it presents with a highly atypical slit-like glandular configuration, which appears similar to serous carcinomas of the fallopian tube and ovary. Molecularly these tumors commonly manifest mutations in tumor protein p53 (TP53) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), which are both genes associated with oncogenic potential.1 While most UPSC tumors have loss of expression in hormone receptors such as estrogen and progesterone, 25%-30% of cases overexpress the tyrosine kinase receptor human epidermal growth factor receptor 2 (HER2).3-5 This has proven to provide an exciting target for therapeutic interventions.
A target for therapeutic intervention
HER2 is a transmembrane receptor which, when activated, signals complex downstream pathways responsible for cellular proliferation, dedifferentiation, and metastasis. In a recent multi-institutional analysis of early-stage UPSC, HER2 overexpression was identified among 25% of cases.4 Approximately 30% of cases of advanced disease manifest overexpression of this biomarker.5 HER2 overexpression (HER2-positive status) is significantly associated with higher rates of recurrence and mortality, even among patients treated with conventional therapies.3 Thus HER2-positive status is obviously an indicator of particularly aggressive disease.
Fortunately this particular biomarker is one for which we have established and developing therapeutics. The humanized monoclonal antibody, trastuzumab, has been highly effective in improving survival for HER2-positive breast cancer.6 More recently, it was studied in a phase 2 trial with carboplatin and paclitaxel chemotherapy for advanced or recurrent HER2-positive UPSC.5 This trial showed that the addition of this targeted therapy to conventional chemotherapy improved recurrence-free survival from 8 months to 12 months, and improved overall survival from 24.4 months to 29.6 months.5
One discovery leads to another treatment
This discovery led to the approval of trastuzumab to be used in addition to chemotherapy for advanced or recurrent disease.2 The most significant effects appear to be among those who have not received prior therapies, with a doubling of progression-free survival among these patients, and a more modest response among patients treated for recurrent, mostly pretreated disease.
Dr. Emma C. Rossi
Work currently is underway to explore an array of antibody or small-molecule blockades of HER2 in addition to vaccines against the protein or treatment with conjugate compounds in which an antibody to HER2 is paired with a cytotoxic drug able to be internalized into HER2-expressing cells.7 This represents a form of personalized medicine referred to as biomarker-driven targeted therapy, in which therapies are prescribed based on the expression of specific molecular markers (such as HER2 expression) typically in combination with other clinical markers such as surgical staging results, race, age, etc. These approaches can be very effective strategies in rare tumor subtypes with distinct molecular and clinical behaviors.
As previously mentioned, the targeting of HER2 overexpression with trastuzumab has been shown to be highly effective in the treatment of HER2-positive breast cancers where even patients with early-stage disease receive a multimodal therapy approach including antibody, chemotherapy, surgical, and often radiation treatments.6 We are moving towards a similar multimodal comprehensive treatment strategy for UPSC. If it is as successful as it is in breast cancer, it will be long overdue, and desperately necessary given the poor prognosis of this disease for all stages because of the inadequacies of current treatments strategies.
Routine testing of UPSC for HER2 expression is now a part of routine molecular substaging of uterine cancers in the same way we have embraced testing for microsatellite instability and hormone-receptor status. While a diagnosis of HER2 overexpression in UPSC portends a poor prognosis, patients can be reassured that treatment strategies exist that can target this malignant mechanism in advanced disease and more are under further development for early-stage disease.
Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no relevant financial disclosures. Email her at [email protected].
Uterine papillary serous carcinoma (UPSC) is an infrequent but deadly form of endometrial cancer comprising 10% of cases but contributing 40% of deaths from the disease. Recurrence rates are high for this disease. Five-year survival is 55% for all patients and only 70% for stage I disease.1 Patterns of recurrence tend to be distant (extrapelvic and extraabdominal) as frequently as they are localized to the pelvis, and metastases and recurrences are unrelated to the extent of uterine disease (such as myometrial invasion). It is for these reasons that the recommended course of adjuvant therapy for this disease is systemic therapy (typically six doses of carboplatin and paclitaxel chemotherapy) with consideration for radiation to the vagina or pelvis to consolidate pelvic and vaginal control.2 This differs from early-stage high/intermediate–risk endometrioid adenocarcinomas, for which adjuvant chemotherapy has not been found to be helpful.
Dr Joshua Kish
Uterine papillary serous carcinoma, immunohistochemistry strongly positive for HER2.
Because of the lower incidence of UPSC, it frequently has been studied alongside endometrioid cell types in clinical trials which explore novel adjuvant therapies. However, UPSC is biologically distinct from endometrioid endometrial cancers, which likely results in inferior clinical responses to conventional interventions. Fortunately we are beginning to better understand UPSC at a molecular level, and advancements are being made in the targeted therapies for these patients that are unique, compared with those applied to other cancer subtypes.
As discussed above, UPSC is a particularly aggressive form of uterine cancer. Histologically it is characterized by a precursor lesion of endometrial glandular dysplasia progressing to endometrial intraepithelial neoplasia (EIC). Histologically it presents with a highly atypical slit-like glandular configuration, which appears similar to serous carcinomas of the fallopian tube and ovary. Molecularly these tumors commonly manifest mutations in tumor protein p53 (TP53) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), which are both genes associated with oncogenic potential.1 While most UPSC tumors have loss of expression in hormone receptors such as estrogen and progesterone, 25%-30% of cases overexpress the tyrosine kinase receptor human epidermal growth factor receptor 2 (HER2).3-5 This has proven to provide an exciting target for therapeutic interventions.
A target for therapeutic intervention
HER2 is a transmembrane receptor which, when activated, signals complex downstream pathways responsible for cellular proliferation, dedifferentiation, and metastasis. In a recent multi-institutional analysis of early-stage UPSC, HER2 overexpression was identified among 25% of cases.4 Approximately 30% of cases of advanced disease manifest overexpression of this biomarker.5 HER2 overexpression (HER2-positive status) is significantly associated with higher rates of recurrence and mortality, even among patients treated with conventional therapies.3 Thus HER2-positive status is obviously an indicator of particularly aggressive disease.
Fortunately this particular biomarker is one for which we have established and developing therapeutics. The humanized monoclonal antibody, trastuzumab, has been highly effective in improving survival for HER2-positive breast cancer.6 More recently, it was studied in a phase 2 trial with carboplatin and paclitaxel chemotherapy for advanced or recurrent HER2-positive UPSC.5 This trial showed that the addition of this targeted therapy to conventional chemotherapy improved recurrence-free survival from 8 months to 12 months, and improved overall survival from 24.4 months to 29.6 months.5
One discovery leads to another treatment
This discovery led to the approval of trastuzumab to be used in addition to chemotherapy for advanced or recurrent disease.2 The most significant effects appear to be among those who have not received prior therapies, with a doubling of progression-free survival among these patients, and a more modest response among patients treated for recurrent, mostly pretreated disease.
Dr. Emma C. Rossi
Work currently is underway to explore an array of antibody or small-molecule blockades of HER2 in addition to vaccines against the protein or treatment with conjugate compounds in which an antibody to HER2 is paired with a cytotoxic drug able to be internalized into HER2-expressing cells.7 This represents a form of personalized medicine referred to as biomarker-driven targeted therapy, in which therapies are prescribed based on the expression of specific molecular markers (such as HER2 expression) typically in combination with other clinical markers such as surgical staging results, race, age, etc. These approaches can be very effective strategies in rare tumor subtypes with distinct molecular and clinical behaviors.
As previously mentioned, the targeting of HER2 overexpression with trastuzumab has been shown to be highly effective in the treatment of HER2-positive breast cancers where even patients with early-stage disease receive a multimodal therapy approach including antibody, chemotherapy, surgical, and often radiation treatments.6 We are moving towards a similar multimodal comprehensive treatment strategy for UPSC. If it is as successful as it is in breast cancer, it will be long overdue, and desperately necessary given the poor prognosis of this disease for all stages because of the inadequacies of current treatments strategies.
Routine testing of UPSC for HER2 expression is now a part of routine molecular substaging of uterine cancers in the same way we have embraced testing for microsatellite instability and hormone-receptor status. While a diagnosis of HER2 overexpression in UPSC portends a poor prognosis, patients can be reassured that treatment strategies exist that can target this malignant mechanism in advanced disease and more are under further development for early-stage disease.
Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no relevant financial disclosures. Email her at [email protected].
Uterine papillary serous carcinoma (UPSC) is an infrequent but deadly form of endometrial cancer comprising 10% of cases but contributing 40% of deaths from the disease. Recurrence rates are high for this disease. Five-year survival is 55% for all patients and only 70% for stage I disease.1 Patterns of recurrence tend to be distant (extrapelvic and extraabdominal) as frequently as they are localized to the pelvis, and metastases and recurrences are unrelated to the extent of uterine disease (such as myometrial invasion). It is for these reasons that the recommended course of adjuvant therapy for this disease is systemic therapy (typically six doses of carboplatin and paclitaxel chemotherapy) with consideration for radiation to the vagina or pelvis to consolidate pelvic and vaginal control.2 This differs from early-stage high/intermediate–risk endometrioid adenocarcinomas, for which adjuvant chemotherapy has not been found to be helpful.
Dr Joshua Kish
Uterine papillary serous carcinoma, immunohistochemistry strongly positive for HER2.
Because of the lower incidence of UPSC, it frequently has been studied alongside endometrioid cell types in clinical trials which explore novel adjuvant therapies. However, UPSC is biologically distinct from endometrioid endometrial cancers, which likely results in inferior clinical responses to conventional interventions. Fortunately we are beginning to better understand UPSC at a molecular level, and advancements are being made in the targeted therapies for these patients that are unique, compared with those applied to other cancer subtypes.
As discussed above, UPSC is a particularly aggressive form of uterine cancer. Histologically it is characterized by a precursor lesion of endometrial glandular dysplasia progressing to endometrial intraepithelial neoplasia (EIC). Histologically it presents with a highly atypical slit-like glandular configuration, which appears similar to serous carcinomas of the fallopian tube and ovary. Molecularly these tumors commonly manifest mutations in tumor protein p53 (TP53) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), which are both genes associated with oncogenic potential.1 While most UPSC tumors have loss of expression in hormone receptors such as estrogen and progesterone, 25%-30% of cases overexpress the tyrosine kinase receptor human epidermal growth factor receptor 2 (HER2).3-5 This has proven to provide an exciting target for therapeutic interventions.
A target for therapeutic intervention
HER2 is a transmembrane receptor which, when activated, signals complex downstream pathways responsible for cellular proliferation, dedifferentiation, and metastasis. In a recent multi-institutional analysis of early-stage UPSC, HER2 overexpression was identified among 25% of cases.4 Approximately 30% of cases of advanced disease manifest overexpression of this biomarker.5 HER2 overexpression (HER2-positive status) is significantly associated with higher rates of recurrence and mortality, even among patients treated with conventional therapies.3 Thus HER2-positive status is obviously an indicator of particularly aggressive disease.
Fortunately this particular biomarker is one for which we have established and developing therapeutics. The humanized monoclonal antibody, trastuzumab, has been highly effective in improving survival for HER2-positive breast cancer.6 More recently, it was studied in a phase 2 trial with carboplatin and paclitaxel chemotherapy for advanced or recurrent HER2-positive UPSC.5 This trial showed that the addition of this targeted therapy to conventional chemotherapy improved recurrence-free survival from 8 months to 12 months, and improved overall survival from 24.4 months to 29.6 months.5
One discovery leads to another treatment
This discovery led to the approval of trastuzumab to be used in addition to chemotherapy for advanced or recurrent disease.2 The most significant effects appear to be among those who have not received prior therapies, with a doubling of progression-free survival among these patients, and a more modest response among patients treated for recurrent, mostly pretreated disease.
Dr. Emma C. Rossi
Work currently is underway to explore an array of antibody or small-molecule blockades of HER2 in addition to vaccines against the protein or treatment with conjugate compounds in which an antibody to HER2 is paired with a cytotoxic drug able to be internalized into HER2-expressing cells.7 This represents a form of personalized medicine referred to as biomarker-driven targeted therapy, in which therapies are prescribed based on the expression of specific molecular markers (such as HER2 expression) typically in combination with other clinical markers such as surgical staging results, race, age, etc. These approaches can be very effective strategies in rare tumor subtypes with distinct molecular and clinical behaviors.
As previously mentioned, the targeting of HER2 overexpression with trastuzumab has been shown to be highly effective in the treatment of HER2-positive breast cancers where even patients with early-stage disease receive a multimodal therapy approach including antibody, chemotherapy, surgical, and often radiation treatments.6 We are moving towards a similar multimodal comprehensive treatment strategy for UPSC. If it is as successful as it is in breast cancer, it will be long overdue, and desperately necessary given the poor prognosis of this disease for all stages because of the inadequacies of current treatments strategies.
Routine testing of UPSC for HER2 expression is now a part of routine molecular substaging of uterine cancers in the same way we have embraced testing for microsatellite instability and hormone-receptor status. While a diagnosis of HER2 overexpression in UPSC portends a poor prognosis, patients can be reassured that treatment strategies exist that can target this malignant mechanism in advanced disease and more are under further development for early-stage disease.
Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no relevant financial disclosures. Email her at [email protected].
Vulvar intraepithelial neoplasia (VIN) is a distressing condition that may require painful and disfiguring treatments. It is particularly problematic because more than a quarter of patients will experience recurrence of their disease after primary therapy. In this column we will explore the risk factors for recurrence, recommendations for early detection, and options to minimize its incidence.
Dr. Emma C. Rossi
VIN was traditionally characterized in three stages (I, II, III). However, as it became better understood that the previously named VIN I was not, in fact, a precursor for malignancy, but rather a benign manifestation of low-risk human papillomavirus (HPV) infection, it was removed from consideration as VIN. Furthermore, our understanding of VIN grew to recognize that there were two developmental pathways to vulvar neoplasia and malignancy. The first was via high-risk HPV infection, often with tobacco exposure as an accelerating factor, and typically among younger women. This has been named “usual type VIN” (uVIN). The second arises in the background of lichen sclerosus in older women and is named “differentiated type VIN” (dVIN). This type carries with it a higher risk for progression to cancer, coexisting in approximately 80% of cases of invasive squamous cell carcinoma. In addition, the progression to cancer appears to occur more quickly for dVIN lesions (22 months compared with 41 months in uVIN).1
While observation of VIN can be considered for young, asymptomatic women, it is not universally recommended because the risk of progression to cancer is approximately 8% (5% for uVIN and 33% for dVIN).1,2 Both subtypes of VIN can be treated with similar interventions including surgical excision (typically a wide local excision), ablative therapies (such as CO2 laser) or topical medical therapy such as imiquimod or 5-fluorouracil. Excisional surgery remains the mainstay of therapy for VIN because it provides clinicians with certainty regarding the possibility of occult invasive disease (false-negative biopsies), and adequacy of margin status. However, given the proximity of this disease to vital structures such as the clitoris, urethral meatus, and anal verge, as well as issues with wound healing, and difficulty with reapproximation of vulvar tissues – particularly when large or multifocal disease is present – sometimes multimodal treatments or medical therapies are preferred to spare disfigurement or sexual, bladder, or bowel dysfunction.
Excision of VIN need not be deeper than the epidermis, although including a limited degree of dermis protects against incomplete resection of occult, coexisting early invasive disease. However, wide margins should ideally be at least 10 mm. This can prove to be a challenging goal for multiple reasons. First, while there are visual stigmata of VIN, its true extent can be determined only microscopically. In addition, the disease may be multifocal. Furthermore, particularly where it encroaches upon the anus, clitoris, or urethral meatus, resection margins may be limited because of the desire to preserve function of adjacent structures. The application of 2%-5% acetic acid in the operating room prior to marking the planned borders of excision can optimize the likelihood that the incisions will encompass the microscopic extent of VIN. As it does with cervical dysplasia, acetic acid is thought to cause reversible coagulation of nuclear proteins and cytokeratins, which are more abundant in dysplastic lesions, thus appearing white to the surgeon’s eye.
However, even with the surgeon’s best attempts to excise all disease, approximately half of VIN excisions will have positive margins. Fortunately, not all of these patients will go on to develop recurrent dysplasia. In fact, less than half of women with positive margins on excision will develop recurrent VIN disease.2 This incomplete incidence of recurrence may be in part due to an ablative effect of inflammation at the cut skin edges. Therefore, provided that there is no macroscopic disease remaining, close observation, rather than immediate reexcision, is recommended.
Positive excisional margins are a major risk factor for recurrence, carrying an eightfold increased risk, and also are associated with a more rapid onset of recurrence than for those with negative margins. Other predisposing risk factors for recurrence include advancing age, coexistence of dysplasia at other lower genital sites (including vaginal and cervical), immunosuppressive conditions or therapies (especially steroid use), HPV exposure, and the presence of lichen sclerosus.2 Continued tobacco use is a modifiable risk factor that has been shown to be associated with an increased recurrence risk of VIN. We should take the opportunity in the postoperative and surveillance period to educate our patients regarding the importance of smoking cessation in modifying their risk for recurrent or new disease.
HPV infection may not be a modifiable risk factor, but certainly can be prevented by encouraging the adoption of HPV vaccination.
Topical steroids used to treat lichen sclerosus can improve symptoms of this vulvar dystrophy as well as decrease the incidence of recurrent dVIN and invasive vulvar cancer. Treatment should continue until the skin has normalized its appearance and texture. This may involve chronic long-term therapy.3
Recognizing that more than a quarter of patients will recur, the recommended posttreatment follow-up for VIN is at 6 months, 12 months, and then annually. It should include close inspection of the vulva with consideration of application of topical 2%-5% acetic acid (I typically apply this with a soaked gauze sponge) and vulvar colposcopy (a hand-held magnification glass works well for this purpose). Patients should be counseled regarding their high risk for recurrence, informed of typical symptoms, and encouraged to perform regular vulva self-inspection (with use of a hand mirror).
For patients at the highest risk for recurrence (older patients, patients with positive excisional margins, HPV coinfection, lichen sclerosus, tobacco use, and immunosuppression), I recommend 6 monthly follow-up surveillance for 5 years. Most (75%) of recurrences will occur with the first 43 months after diagnosis with half occurring in the first 18 months.2 Patients who have had positive margins on their excisional specimen are at the highest risk for an earlier recurrence.
VIN is an insidious disease with a high recurrence rate. It is challenging to completely resect with negative margins. Patients with a history of VIN should receive close observation in the years following their excision, particularly if resection margins were positive, and clinicians should attempt to modify risk factors wherever possible, paying particularly close attention to older postmenopausal women with a history of lichen sclerosus as progression to malignancy is highest for these women.
Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no relevant financial disclosures. Email Dr. Rossi at [email protected].
Vulvar intraepithelial neoplasia (VIN) is a distressing condition that may require painful and disfiguring treatments. It is particularly problematic because more than a quarter of patients will experience recurrence of their disease after primary therapy. In this column we will explore the risk factors for recurrence, recommendations for early detection, and options to minimize its incidence.
Dr. Emma C. Rossi
VIN was traditionally characterized in three stages (I, II, III). However, as it became better understood that the previously named VIN I was not, in fact, a precursor for malignancy, but rather a benign manifestation of low-risk human papillomavirus (HPV) infection, it was removed from consideration as VIN. Furthermore, our understanding of VIN grew to recognize that there were two developmental pathways to vulvar neoplasia and malignancy. The first was via high-risk HPV infection, often with tobacco exposure as an accelerating factor, and typically among younger women. This has been named “usual type VIN” (uVIN). The second arises in the background of lichen sclerosus in older women and is named “differentiated type VIN” (dVIN). This type carries with it a higher risk for progression to cancer, coexisting in approximately 80% of cases of invasive squamous cell carcinoma. In addition, the progression to cancer appears to occur more quickly for dVIN lesions (22 months compared with 41 months in uVIN).1
While observation of VIN can be considered for young, asymptomatic women, it is not universally recommended because the risk of progression to cancer is approximately 8% (5% for uVIN and 33% for dVIN).1,2 Both subtypes of VIN can be treated with similar interventions including surgical excision (typically a wide local excision), ablative therapies (such as CO2 laser) or topical medical therapy such as imiquimod or 5-fluorouracil. Excisional surgery remains the mainstay of therapy for VIN because it provides clinicians with certainty regarding the possibility of occult invasive disease (false-negative biopsies), and adequacy of margin status. However, given the proximity of this disease to vital structures such as the clitoris, urethral meatus, and anal verge, as well as issues with wound healing, and difficulty with reapproximation of vulvar tissues – particularly when large or multifocal disease is present – sometimes multimodal treatments or medical therapies are preferred to spare disfigurement or sexual, bladder, or bowel dysfunction.
Excision of VIN need not be deeper than the epidermis, although including a limited degree of dermis protects against incomplete resection of occult, coexisting early invasive disease. However, wide margins should ideally be at least 10 mm. This can prove to be a challenging goal for multiple reasons. First, while there are visual stigmata of VIN, its true extent can be determined only microscopically. In addition, the disease may be multifocal. Furthermore, particularly where it encroaches upon the anus, clitoris, or urethral meatus, resection margins may be limited because of the desire to preserve function of adjacent structures. The application of 2%-5% acetic acid in the operating room prior to marking the planned borders of excision can optimize the likelihood that the incisions will encompass the microscopic extent of VIN. As it does with cervical dysplasia, acetic acid is thought to cause reversible coagulation of nuclear proteins and cytokeratins, which are more abundant in dysplastic lesions, thus appearing white to the surgeon’s eye.
However, even with the surgeon’s best attempts to excise all disease, approximately half of VIN excisions will have positive margins. Fortunately, not all of these patients will go on to develop recurrent dysplasia. In fact, less than half of women with positive margins on excision will develop recurrent VIN disease.2 This incomplete incidence of recurrence may be in part due to an ablative effect of inflammation at the cut skin edges. Therefore, provided that there is no macroscopic disease remaining, close observation, rather than immediate reexcision, is recommended.
Positive excisional margins are a major risk factor for recurrence, carrying an eightfold increased risk, and also are associated with a more rapid onset of recurrence than for those with negative margins. Other predisposing risk factors for recurrence include advancing age, coexistence of dysplasia at other lower genital sites (including vaginal and cervical), immunosuppressive conditions or therapies (especially steroid use), HPV exposure, and the presence of lichen sclerosus.2 Continued tobacco use is a modifiable risk factor that has been shown to be associated with an increased recurrence risk of VIN. We should take the opportunity in the postoperative and surveillance period to educate our patients regarding the importance of smoking cessation in modifying their risk for recurrent or new disease.
HPV infection may not be a modifiable risk factor, but certainly can be prevented by encouraging the adoption of HPV vaccination.
Topical steroids used to treat lichen sclerosus can improve symptoms of this vulvar dystrophy as well as decrease the incidence of recurrent dVIN and invasive vulvar cancer. Treatment should continue until the skin has normalized its appearance and texture. This may involve chronic long-term therapy.3
Recognizing that more than a quarter of patients will recur, the recommended posttreatment follow-up for VIN is at 6 months, 12 months, and then annually. It should include close inspection of the vulva with consideration of application of topical 2%-5% acetic acid (I typically apply this with a soaked gauze sponge) and vulvar colposcopy (a hand-held magnification glass works well for this purpose). Patients should be counseled regarding their high risk for recurrence, informed of typical symptoms, and encouraged to perform regular vulva self-inspection (with use of a hand mirror).
For patients at the highest risk for recurrence (older patients, patients with positive excisional margins, HPV coinfection, lichen sclerosus, tobacco use, and immunosuppression), I recommend 6 monthly follow-up surveillance for 5 years. Most (75%) of recurrences will occur with the first 43 months after diagnosis with half occurring in the first 18 months.2 Patients who have had positive margins on their excisional specimen are at the highest risk for an earlier recurrence.
VIN is an insidious disease with a high recurrence rate. It is challenging to completely resect with negative margins. Patients with a history of VIN should receive close observation in the years following their excision, particularly if resection margins were positive, and clinicians should attempt to modify risk factors wherever possible, paying particularly close attention to older postmenopausal women with a history of lichen sclerosus as progression to malignancy is highest for these women.
Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no relevant financial disclosures. Email Dr. Rossi at [email protected].
Vulvar intraepithelial neoplasia (VIN) is a distressing condition that may require painful and disfiguring treatments. It is particularly problematic because more than a quarter of patients will experience recurrence of their disease after primary therapy. In this column we will explore the risk factors for recurrence, recommendations for early detection, and options to minimize its incidence.
Dr. Emma C. Rossi
VIN was traditionally characterized in three stages (I, II, III). However, as it became better understood that the previously named VIN I was not, in fact, a precursor for malignancy, but rather a benign manifestation of low-risk human papillomavirus (HPV) infection, it was removed from consideration as VIN. Furthermore, our understanding of VIN grew to recognize that there were two developmental pathways to vulvar neoplasia and malignancy. The first was via high-risk HPV infection, often with tobacco exposure as an accelerating factor, and typically among younger women. This has been named “usual type VIN” (uVIN). The second arises in the background of lichen sclerosus in older women and is named “differentiated type VIN” (dVIN). This type carries with it a higher risk for progression to cancer, coexisting in approximately 80% of cases of invasive squamous cell carcinoma. In addition, the progression to cancer appears to occur more quickly for dVIN lesions (22 months compared with 41 months in uVIN).1
While observation of VIN can be considered for young, asymptomatic women, it is not universally recommended because the risk of progression to cancer is approximately 8% (5% for uVIN and 33% for dVIN).1,2 Both subtypes of VIN can be treated with similar interventions including surgical excision (typically a wide local excision), ablative therapies (such as CO2 laser) or topical medical therapy such as imiquimod or 5-fluorouracil. Excisional surgery remains the mainstay of therapy for VIN because it provides clinicians with certainty regarding the possibility of occult invasive disease (false-negative biopsies), and adequacy of margin status. However, given the proximity of this disease to vital structures such as the clitoris, urethral meatus, and anal verge, as well as issues with wound healing, and difficulty with reapproximation of vulvar tissues – particularly when large or multifocal disease is present – sometimes multimodal treatments or medical therapies are preferred to spare disfigurement or sexual, bladder, or bowel dysfunction.
Excision of VIN need not be deeper than the epidermis, although including a limited degree of dermis protects against incomplete resection of occult, coexisting early invasive disease. However, wide margins should ideally be at least 10 mm. This can prove to be a challenging goal for multiple reasons. First, while there are visual stigmata of VIN, its true extent can be determined only microscopically. In addition, the disease may be multifocal. Furthermore, particularly where it encroaches upon the anus, clitoris, or urethral meatus, resection margins may be limited because of the desire to preserve function of adjacent structures. The application of 2%-5% acetic acid in the operating room prior to marking the planned borders of excision can optimize the likelihood that the incisions will encompass the microscopic extent of VIN. As it does with cervical dysplasia, acetic acid is thought to cause reversible coagulation of nuclear proteins and cytokeratins, which are more abundant in dysplastic lesions, thus appearing white to the surgeon’s eye.
However, even with the surgeon’s best attempts to excise all disease, approximately half of VIN excisions will have positive margins. Fortunately, not all of these patients will go on to develop recurrent dysplasia. In fact, less than half of women with positive margins on excision will develop recurrent VIN disease.2 This incomplete incidence of recurrence may be in part due to an ablative effect of inflammation at the cut skin edges. Therefore, provided that there is no macroscopic disease remaining, close observation, rather than immediate reexcision, is recommended.
Positive excisional margins are a major risk factor for recurrence, carrying an eightfold increased risk, and also are associated with a more rapid onset of recurrence than for those with negative margins. Other predisposing risk factors for recurrence include advancing age, coexistence of dysplasia at other lower genital sites (including vaginal and cervical), immunosuppressive conditions or therapies (especially steroid use), HPV exposure, and the presence of lichen sclerosus.2 Continued tobacco use is a modifiable risk factor that has been shown to be associated with an increased recurrence risk of VIN. We should take the opportunity in the postoperative and surveillance period to educate our patients regarding the importance of smoking cessation in modifying their risk for recurrent or new disease.
HPV infection may not be a modifiable risk factor, but certainly can be prevented by encouraging the adoption of HPV vaccination.
Topical steroids used to treat lichen sclerosus can improve symptoms of this vulvar dystrophy as well as decrease the incidence of recurrent dVIN and invasive vulvar cancer. Treatment should continue until the skin has normalized its appearance and texture. This may involve chronic long-term therapy.3
Recognizing that more than a quarter of patients will recur, the recommended posttreatment follow-up for VIN is at 6 months, 12 months, and then annually. It should include close inspection of the vulva with consideration of application of topical 2%-5% acetic acid (I typically apply this with a soaked gauze sponge) and vulvar colposcopy (a hand-held magnification glass works well for this purpose). Patients should be counseled regarding their high risk for recurrence, informed of typical symptoms, and encouraged to perform regular vulva self-inspection (with use of a hand mirror).
For patients at the highest risk for recurrence (older patients, patients with positive excisional margins, HPV coinfection, lichen sclerosus, tobacco use, and immunosuppression), I recommend 6 monthly follow-up surveillance for 5 years. Most (75%) of recurrences will occur with the first 43 months after diagnosis with half occurring in the first 18 months.2 Patients who have had positive margins on their excisional specimen are at the highest risk for an earlier recurrence.
VIN is an insidious disease with a high recurrence rate. It is challenging to completely resect with negative margins. Patients with a history of VIN should receive close observation in the years following their excision, particularly if resection margins were positive, and clinicians should attempt to modify risk factors wherever possible, paying particularly close attention to older postmenopausal women with a history of lichen sclerosus as progression to malignancy is highest for these women.
Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no relevant financial disclosures. Email Dr. Rossi at [email protected].
While the incidence of most cancers is falling, endometrial cancer rates continue to rise, in large part because of increasing life expectancy and obesity rates. However, what is even more alarming is the observation that there is a clear disparity in outcomes between black and white women with this disease. But there are things that all health care providers, including nononcologists, can do to help to overcome this disparity.
Black women are nearly twice as likely as non-Hispanic white women to die from the endometrial cancer. The 5-year survival for stage III and IV cancer is 43% for non-Hispanic white women, yet only 25% for black women.1 For a long time, this survival disparity was assumed to be a function of the more aggressive cancer histologies, such as serous, which are more commonly seen in black women. These high-grade cancers are more likely to present in advanced stages and with poorer responses to treatments; however, the predisposition to aggressive cancers tells only part of the story of racial disparities in endometrial cancer and their presentation at later stages. Indeed, fueling the problem are the findings that black women report symptoms less, experience more delays in diagnosis or more frequent deviations from guideline-directed diagnostics, undergo more morbid surgical approaches, receive less surgical staging, are enrolled less in clinical trials, have lower socioeconomic status and lower rates of health insurance, and receive less differential administration of adjuvant therapies, as well as have a background of higher all-cause mortality and comorbidities. While this array of contributing factors may seem overwhelming, it also can be considered a guide for health care providers because most of these factors, unlike histologic cell type, are modifiable, and it is important that we all consider what role we can play in dismantling them.
Black women are less likely to receive guideline-recommended care upon presentation. Research by Kemi M. Doll, MD, from the University of Washington, Seattle, demonstrated that, among women with endometrial cancers, black women were less likely to have documented histories of postmenopausal bleeding within 2 years of the diagnosis, presumably because of factors related to underreporting and inadequate ascertainment by medical professionals of whether or not they had experienced postmenopausal bleeding.2 Additionally, when postmenopausal bleeding was reported by these women, they were less likely to receive the appropriate diagnostic work-up as described by American College of Obstetricians and Gynecologists guidelines, and their bleeding was more likely to be ascribed to nonmalignant pathologies. Her work raises the important question about how black women view the health care profession and their willingness to engage early in good faith that their concerns will be met. These concerns are understandable given the documented different responsiveness of providers to black patients’ symptoms such as pain.3
Once diagnosed with endometrial cancer, black women are less likely to receive comprehensive surgical staging and less likely to have their surgery performed by a minimally invasive route, both of which are considered the standard of care.1,4 Lower rates of minimally invasive surgery expose black women to increased morbidity and are deleterious to quality of life, return to work, and functionality. If surgical staging is omitted, which is more common for these women, clinicians are less able to appropriately prescribe adjuvant therapies which might prevent lethal recurrences from unrecognized advanced cancer or they may overtreat early-stage cancers with adjuvant therapy to make up for gaps in staging information.1,5 However, adjuvant therapy is not a benign intervention, and itself is associated with morbidity.
Dr. Emma C. Rossi
As mentioned earlier, black women are at a higher risk for developing more aggressive cancer subtypes, and this phenomenon may appear unmodifiable. However, important research is looking at the concept of epigenetics and how modifiable environmental factors may contribute to the development of more aggressive types of cancer through gene expression. Additionally, differences in the gene mutations and gene expression of cancers more frequently acquired by black women may negatively influence how these cancers respond to conventional therapies. In the GOG210 study, which evaluated the outcomes of women with comprehensively staged endometrial cancer, black women demonstrated worse survival from cancer, even though they were more likely to receive chemotherapy.5 One explanation for this finding is that these women’s cancers were less responsive to conventional chemotherapy agents.
This raises a critical issue of disparity in clinical trial inclusion. Black women are underrepresented in clinical trials in the United States. There is a dark history in medical research and minority populations, particularly African American populations, which continues to be remembered and felt. However, not all of this underrepresentation may be from unwillingness to participate: For black women, issues of lack of access to or being considered for clinical trials is also a factor. But without adequate representation in trials of novel agents, we will not know whether they are effective for all populations, and indeed it would appear that we should not assume they are equally effective based on the results to date.
So how can we all individually help to overcome these disparities in endometrial cancer outcomes? To begin with, it is important to acknowledge that black women commonly report negative experiences with reproductive health care. From early in their lives, we must sensitively engage all of our patients and ensure they all feel heard and valued. They should know that their symptoms, including pain or bleeding, are taken and treated seriously. If we can do better with this throughout a woman’s earlier reproductive health care experiences, perhaps later in her life, when she experiences postmenopausal bleeding, she will feel comfortable raising this issue with her health care provider who in turn must take this symptom seriously and expeditiously engage all of the appropriate diagnostic resources. Health care delivery is about more than simply offering the best treatment. We also are responsible for education and shared decision making to ensure that we can deliver the best treatment.
We also can support organizations such as ECANA (Endometrial Cancer Action Network for African Americans) which serves to inform black women in their communities about the threat that endometrial cancer plays and empowers them through education about its symptoms and the need to seek care.
Systematically we must ensure black women have access to the same standards in surgical and nonsurgical management of these cancers. This includes referral of all women with cancer, including minorities, to high-volume centers with oncology specialists and explaining to those who may be reluctant to travel that this is associated with improved outcomes in the short and long term. We also must actively consider our black patients for clinical trials, sensitively educate them about their benefits, and overcome barriers to access. One simple way to do this is to explain that the treatments that we have developed for endometrial cancer have mostly been tested on white women, which may explain in part why they do not work so well for nonwhite women.
The racial disparity in endometrial cancer outcomes cannot entirely be attributed to the passive phenomenon of patient and tumor genetics, particularly with consideration that race is a social construct rather than a biological phenomenon. We can all make a difference through advocacy, access, education, and heightened awareness to combat this inequity and overcome these disparate outcomes.
Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no relevant financial disclosures. Email her at [email protected].
While the incidence of most cancers is falling, endometrial cancer rates continue to rise, in large part because of increasing life expectancy and obesity rates. However, what is even more alarming is the observation that there is a clear disparity in outcomes between black and white women with this disease. But there are things that all health care providers, including nononcologists, can do to help to overcome this disparity.
Black women are nearly twice as likely as non-Hispanic white women to die from the endometrial cancer. The 5-year survival for stage III and IV cancer is 43% for non-Hispanic white women, yet only 25% for black women.1 For a long time, this survival disparity was assumed to be a function of the more aggressive cancer histologies, such as serous, which are more commonly seen in black women. These high-grade cancers are more likely to present in advanced stages and with poorer responses to treatments; however, the predisposition to aggressive cancers tells only part of the story of racial disparities in endometrial cancer and their presentation at later stages. Indeed, fueling the problem are the findings that black women report symptoms less, experience more delays in diagnosis or more frequent deviations from guideline-directed diagnostics, undergo more morbid surgical approaches, receive less surgical staging, are enrolled less in clinical trials, have lower socioeconomic status and lower rates of health insurance, and receive less differential administration of adjuvant therapies, as well as have a background of higher all-cause mortality and comorbidities. While this array of contributing factors may seem overwhelming, it also can be considered a guide for health care providers because most of these factors, unlike histologic cell type, are modifiable, and it is important that we all consider what role we can play in dismantling them.
Black women are less likely to receive guideline-recommended care upon presentation. Research by Kemi M. Doll, MD, from the University of Washington, Seattle, demonstrated that, among women with endometrial cancers, black women were less likely to have documented histories of postmenopausal bleeding within 2 years of the diagnosis, presumably because of factors related to underreporting and inadequate ascertainment by medical professionals of whether or not they had experienced postmenopausal bleeding.2 Additionally, when postmenopausal bleeding was reported by these women, they were less likely to receive the appropriate diagnostic work-up as described by American College of Obstetricians and Gynecologists guidelines, and their bleeding was more likely to be ascribed to nonmalignant pathologies. Her work raises the important question about how black women view the health care profession and their willingness to engage early in good faith that their concerns will be met. These concerns are understandable given the documented different responsiveness of providers to black patients’ symptoms such as pain.3
Once diagnosed with endometrial cancer, black women are less likely to receive comprehensive surgical staging and less likely to have their surgery performed by a minimally invasive route, both of which are considered the standard of care.1,4 Lower rates of minimally invasive surgery expose black women to increased morbidity and are deleterious to quality of life, return to work, and functionality. If surgical staging is omitted, which is more common for these women, clinicians are less able to appropriately prescribe adjuvant therapies which might prevent lethal recurrences from unrecognized advanced cancer or they may overtreat early-stage cancers with adjuvant therapy to make up for gaps in staging information.1,5 However, adjuvant therapy is not a benign intervention, and itself is associated with morbidity.
Dr. Emma C. Rossi
As mentioned earlier, black women are at a higher risk for developing more aggressive cancer subtypes, and this phenomenon may appear unmodifiable. However, important research is looking at the concept of epigenetics and how modifiable environmental factors may contribute to the development of more aggressive types of cancer through gene expression. Additionally, differences in the gene mutations and gene expression of cancers more frequently acquired by black women may negatively influence how these cancers respond to conventional therapies. In the GOG210 study, which evaluated the outcomes of women with comprehensively staged endometrial cancer, black women demonstrated worse survival from cancer, even though they were more likely to receive chemotherapy.5 One explanation for this finding is that these women’s cancers were less responsive to conventional chemotherapy agents.
This raises a critical issue of disparity in clinical trial inclusion. Black women are underrepresented in clinical trials in the United States. There is a dark history in medical research and minority populations, particularly African American populations, which continues to be remembered and felt. However, not all of this underrepresentation may be from unwillingness to participate: For black women, issues of lack of access to or being considered for clinical trials is also a factor. But without adequate representation in trials of novel agents, we will not know whether they are effective for all populations, and indeed it would appear that we should not assume they are equally effective based on the results to date.
So how can we all individually help to overcome these disparities in endometrial cancer outcomes? To begin with, it is important to acknowledge that black women commonly report negative experiences with reproductive health care. From early in their lives, we must sensitively engage all of our patients and ensure they all feel heard and valued. They should know that their symptoms, including pain or bleeding, are taken and treated seriously. If we can do better with this throughout a woman’s earlier reproductive health care experiences, perhaps later in her life, when she experiences postmenopausal bleeding, she will feel comfortable raising this issue with her health care provider who in turn must take this symptom seriously and expeditiously engage all of the appropriate diagnostic resources. Health care delivery is about more than simply offering the best treatment. We also are responsible for education and shared decision making to ensure that we can deliver the best treatment.
We also can support organizations such as ECANA (Endometrial Cancer Action Network for African Americans) which serves to inform black women in their communities about the threat that endometrial cancer plays and empowers them through education about its symptoms and the need to seek care.
Systematically we must ensure black women have access to the same standards in surgical and nonsurgical management of these cancers. This includes referral of all women with cancer, including minorities, to high-volume centers with oncology specialists and explaining to those who may be reluctant to travel that this is associated with improved outcomes in the short and long term. We also must actively consider our black patients for clinical trials, sensitively educate them about their benefits, and overcome barriers to access. One simple way to do this is to explain that the treatments that we have developed for endometrial cancer have mostly been tested on white women, which may explain in part why they do not work so well for nonwhite women.
The racial disparity in endometrial cancer outcomes cannot entirely be attributed to the passive phenomenon of patient and tumor genetics, particularly with consideration that race is a social construct rather than a biological phenomenon. We can all make a difference through advocacy, access, education, and heightened awareness to combat this inequity and overcome these disparate outcomes.
Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no relevant financial disclosures. Email her at [email protected].
While the incidence of most cancers is falling, endometrial cancer rates continue to rise, in large part because of increasing life expectancy and obesity rates. However, what is even more alarming is the observation that there is a clear disparity in outcomes between black and white women with this disease. But there are things that all health care providers, including nononcologists, can do to help to overcome this disparity.
Black women are nearly twice as likely as non-Hispanic white women to die from the endometrial cancer. The 5-year survival for stage III and IV cancer is 43% for non-Hispanic white women, yet only 25% for black women.1 For a long time, this survival disparity was assumed to be a function of the more aggressive cancer histologies, such as serous, which are more commonly seen in black women. These high-grade cancers are more likely to present in advanced stages and with poorer responses to treatments; however, the predisposition to aggressive cancers tells only part of the story of racial disparities in endometrial cancer and their presentation at later stages. Indeed, fueling the problem are the findings that black women report symptoms less, experience more delays in diagnosis or more frequent deviations from guideline-directed diagnostics, undergo more morbid surgical approaches, receive less surgical staging, are enrolled less in clinical trials, have lower socioeconomic status and lower rates of health insurance, and receive less differential administration of adjuvant therapies, as well as have a background of higher all-cause mortality and comorbidities. While this array of contributing factors may seem overwhelming, it also can be considered a guide for health care providers because most of these factors, unlike histologic cell type, are modifiable, and it is important that we all consider what role we can play in dismantling them.
Black women are less likely to receive guideline-recommended care upon presentation. Research by Kemi M. Doll, MD, from the University of Washington, Seattle, demonstrated that, among women with endometrial cancers, black women were less likely to have documented histories of postmenopausal bleeding within 2 years of the diagnosis, presumably because of factors related to underreporting and inadequate ascertainment by medical professionals of whether or not they had experienced postmenopausal bleeding.2 Additionally, when postmenopausal bleeding was reported by these women, they were less likely to receive the appropriate diagnostic work-up as described by American College of Obstetricians and Gynecologists guidelines, and their bleeding was more likely to be ascribed to nonmalignant pathologies. Her work raises the important question about how black women view the health care profession and their willingness to engage early in good faith that their concerns will be met. These concerns are understandable given the documented different responsiveness of providers to black patients’ symptoms such as pain.3
Once diagnosed with endometrial cancer, black women are less likely to receive comprehensive surgical staging and less likely to have their surgery performed by a minimally invasive route, both of which are considered the standard of care.1,4 Lower rates of minimally invasive surgery expose black women to increased morbidity and are deleterious to quality of life, return to work, and functionality. If surgical staging is omitted, which is more common for these women, clinicians are less able to appropriately prescribe adjuvant therapies which might prevent lethal recurrences from unrecognized advanced cancer or they may overtreat early-stage cancers with adjuvant therapy to make up for gaps in staging information.1,5 However, adjuvant therapy is not a benign intervention, and itself is associated with morbidity.
Dr. Emma C. Rossi
As mentioned earlier, black women are at a higher risk for developing more aggressive cancer subtypes, and this phenomenon may appear unmodifiable. However, important research is looking at the concept of epigenetics and how modifiable environmental factors may contribute to the development of more aggressive types of cancer through gene expression. Additionally, differences in the gene mutations and gene expression of cancers more frequently acquired by black women may negatively influence how these cancers respond to conventional therapies. In the GOG210 study, which evaluated the outcomes of women with comprehensively staged endometrial cancer, black women demonstrated worse survival from cancer, even though they were more likely to receive chemotherapy.5 One explanation for this finding is that these women’s cancers were less responsive to conventional chemotherapy agents.
This raises a critical issue of disparity in clinical trial inclusion. Black women are underrepresented in clinical trials in the United States. There is a dark history in medical research and minority populations, particularly African American populations, which continues to be remembered and felt. However, not all of this underrepresentation may be from unwillingness to participate: For black women, issues of lack of access to or being considered for clinical trials is also a factor. But without adequate representation in trials of novel agents, we will not know whether they are effective for all populations, and indeed it would appear that we should not assume they are equally effective based on the results to date.
So how can we all individually help to overcome these disparities in endometrial cancer outcomes? To begin with, it is important to acknowledge that black women commonly report negative experiences with reproductive health care. From early in their lives, we must sensitively engage all of our patients and ensure they all feel heard and valued. They should know that their symptoms, including pain or bleeding, are taken and treated seriously. If we can do better with this throughout a woman’s earlier reproductive health care experiences, perhaps later in her life, when she experiences postmenopausal bleeding, she will feel comfortable raising this issue with her health care provider who in turn must take this symptom seriously and expeditiously engage all of the appropriate diagnostic resources. Health care delivery is about more than simply offering the best treatment. We also are responsible for education and shared decision making to ensure that we can deliver the best treatment.
We also can support organizations such as ECANA (Endometrial Cancer Action Network for African Americans) which serves to inform black women in their communities about the threat that endometrial cancer plays and empowers them through education about its symptoms and the need to seek care.
Systematically we must ensure black women have access to the same standards in surgical and nonsurgical management of these cancers. This includes referral of all women with cancer, including minorities, to high-volume centers with oncology specialists and explaining to those who may be reluctant to travel that this is associated with improved outcomes in the short and long term. We also must actively consider our black patients for clinical trials, sensitively educate them about their benefits, and overcome barriers to access. One simple way to do this is to explain that the treatments that we have developed for endometrial cancer have mostly been tested on white women, which may explain in part why they do not work so well for nonwhite women.
The racial disparity in endometrial cancer outcomes cannot entirely be attributed to the passive phenomenon of patient and tumor genetics, particularly with consideration that race is a social construct rather than a biological phenomenon. We can all make a difference through advocacy, access, education, and heightened awareness to combat this inequity and overcome these disparate outcomes.
Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no relevant financial disclosures. Email her at [email protected].
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.
ThitareeSarmkasat/iStock/Getty Images Plus
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, how do studies examining the relationship between talc exposure and ovarian cancer stand up? 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.
Dr. Emma C. Rossi
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].
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.
ThitareeSarmkasat/iStock/Getty Images Plus
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, how do studies examining the relationship between talc exposure and ovarian cancer stand up? 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.
Dr. Emma C. Rossi
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].
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.
ThitareeSarmkasat/iStock/Getty Images Plus
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, how do studies examining the relationship between talc exposure and ovarian cancer stand up? 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.
Dr. Emma C. Rossi
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].
The clinical scenario is as follows: A 62-year-old woman comes to see me for a new diagnosis of grade 1 endometrial cancer. She has a normal body mass index of 24 kg/m2, a history of four prior full-term pregnancies, no family history of malignancy, and no medical comorbidities. She is otherwise a specimen of good health, and has no clear identifiable risk factors for this malignancy. She then reports that she transitioned through menopause at age 52 years and developed severe hot flashes with sleep and mood disturbance. She did not wish to take conventional hormone replacement therapy (HT) because she had heard it causes cancer. She subsequently researched the Internet and found a provider who has been prescribing compounded bioidentical hormone therapy (CBHT) for her for the past 10 years. She submits saliva for testing of her estrogen levels, and the provider uses this data to compound the appropriate doses of “natural” estrogens and testosterone for her which she applies via vaginal or transdermal creams. She has been prescribed a progesterone suppository, but she doesn’t always take that because she doesn’t notice that it has any effect on how she feels. “Doctor, did my bioidentical hormones give me this uterine cancer?”
Alexander Raths/Fotolia
My answer is, of course, I don’t know. Cancer is a complex disease with a complex array of causative and promoting factors. However, we do know that taking estrogen unopposed with adequate progesterone can cause the development of uterine cancer and its precursor state.1 If those bioidentical estrogens were effective at controlling her menopausal symptoms, they likely were effective at stimulating her endometrium at the same time.
What are compounded bioidentical hormones?
The term “bioidentical” refers to having the same molecular structure as that which is found in the human body. Examples of bioidentical estrogens include 17-beta-estradiol, estrone, and estriol – which are produced from yams and soy. Micronized progesterone is an example of a bioidentical progesterone. Many of these drugs are approved by the Food and Drug Administration, and prescribed and dispensed by conventional pharmacies.
An alternative, and increasingly popular, version of bioidentical hormones are CBHs. It should be recognized that this is a marketing, and not a scientific, term. These products utilize hormones, in some cases FDA-approved bioidentical hormones, that are broken down and blended by specialized pharmacies and reconstituted (compounded) into different, and sometimes “customized,” dosing and delivery methods (such as capsules, patches, gels, creams, lozenges, suppositories). Frequently used compounded products utilize multiple formulations of estrogens in doublets and triplets as well as progesterone, testosterone, and dehydroepiandrosterone.
How do they differ from synthetic hormones?
Distributors of CBHs state that they differ from conventional HT (synthetic and bioidentical) because of the customization process from which they promise greater efficacy and a sense of personalized medicine. The distributors frequently utilize assays from saliva, blood, vaginal secretions, and urine to measure a woman’s hormone levels, and titrate her compounded formulation based on those results. It should be noted that there is no data to support that titration of hormones to blood, salivary, or urine levels is efficacious or ensures greater safety than titration based on symptom management.
Critics of CBHT, which includes the North American Menopause Society2 and the American College of Obstetricians and Gynecologists,3 highlight that the main difference between CBHT and HT is lack of FDA regulation over the CBHT industry. Many of these agents are delivered transdermally and therefore are classified as “dietary supplements.” As such, they do not require FDA regulation or proof of safety or efficacy.
Dr. Emma C. Rossi
Lack of FDA approval allows CBHs to be distributed without package inserts and boxed warnings (such as the standard warnings about MI, venous thromboembolic events, and breast cancer). The absence of FDA approval also allows them to avoid FDA-regulated guarantees about purity, potency, and efficacy. Audits of CBHs have shown high rates of discrepancy between stated and measured potency, including observations of both much lower and much higher than stated strength.4
Why would dosing accuracy be important in hormone therapy prescription? If a woman taking estrogen therapy is not receiving adequate cotreatment with progesterone because of either omission or a subtherapeutic product, she increases her risk for endometrial cancer.
What drives patients’ decision to use compounded bioidentical hormones?
After the Womens’ Health Initiative study was published in 20025, all FDA-regulated estrogen preparations were required to carry specific warnings, particularly in relation to the increased risk for MI, venous thromboembolic events, and breast cancer. There was a clear uptake in use of CBHT after this study was reported. By avoiding FDA regulations, distributors of CBHTs may have avoided providing Womens’ Health Initiative information to patients. The absence of an insert with a written warning, in and of itself, makes these preparations seem safer to the patient.
But is it entirely a lack of information that drives demand for CBHTs? Surveys of current or former users suggest the motivations are more complex than that. A survey of 21 past or present CBHT users inquired about reasons for use of CBHT over conventional HT.6 Their responses were categorized as either push motivations away from conventional therapy versus pull motivations toward CBHT. About 95% of current and former users cited distrust of the biomedicine and pharmaceutical industry as reasons for use of CBHT. Fear about the safety of conventional HT, particularly with respect to cancer risk, also was strongly cited at 81%. Motivations pulling toward CBHT included its efficacy (76%) and perception that CBHT is “safer” than conventional HT (76%).
Women in this study also appreciated the tailored, individualized approach that often is associated with CBHT, in which providers spend long consultations discussing individual patient needs and concerns. They enjoy the idea of a customized blend that is created, as opposed to a standard dosing regimen, and intuitively trust the reliability of blood and saliva testing as a prescriptive tool.
Are bioidentical hormones safe with respect to cancer risk?
Hormones themselves are not inert substances, including those derived in vivo and those from plants. They have powerful effects in the human body and can promote malignant transformation or proliferation, alter metabolic pathways, stimulate vascular tone, influence coagulation pathways, along with many other effects. A hormone’s potential for deleterious effect can be present regardless of how that hormone is synthesized, procured, or prepared. While there are no data to suggest that CBHT is associated with increased cancer risk, compared with conventional HT, there are by no means any data to suggest it is safer. Unopposed compounded estrogens place women at increased risk for endometrial cancers, and the prolonged use of hormonal therapy, compounded or otherwise, after menopause increases the risk for breast cancer.
How should we counsel patients?
Patients who desire compounded bioidentical hormone preparations should be counseled that little is known about the safety of these preparations, compared with conventional hormone preparations. The fact that the components are often plant based rather than synthetic does not inherently alter their potential negative impact on biologic pathways. Patients should be educated regarding the difference between FDA-regulated products and nonregulated products so that they can understand that lack of a boxed warning on a non-FDA regulated product does not mean an absence of risk. Women should be informed of the potential inaccuracies in dosing and strength of the CBH preparations they receive.
We should recognize that our patients strongly desire a relationship with their provider in which they are listened to, understood, and treated as individuals. If conversations regarding hormone use are approached with these principles, we will optimize the likelihood our patients are receptive to the highest quality information and not pulled in the direction of unregulated products.
Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She reported that she had no conflicts of interest. Email Dr. Rossi at [email protected].
The clinical scenario is as follows: A 62-year-old woman comes to see me for a new diagnosis of grade 1 endometrial cancer. She has a normal body mass index of 24 kg/m2, a history of four prior full-term pregnancies, no family history of malignancy, and no medical comorbidities. She is otherwise a specimen of good health, and has no clear identifiable risk factors for this malignancy. She then reports that she transitioned through menopause at age 52 years and developed severe hot flashes with sleep and mood disturbance. She did not wish to take conventional hormone replacement therapy (HT) because she had heard it causes cancer. She subsequently researched the Internet and found a provider who has been prescribing compounded bioidentical hormone therapy (CBHT) for her for the past 10 years. She submits saliva for testing of her estrogen levels, and the provider uses this data to compound the appropriate doses of “natural” estrogens and testosterone for her which she applies via vaginal or transdermal creams. She has been prescribed a progesterone suppository, but she doesn’t always take that because she doesn’t notice that it has any effect on how she feels. “Doctor, did my bioidentical hormones give me this uterine cancer?”
Alexander Raths/Fotolia
My answer is, of course, I don’t know. Cancer is a complex disease with a complex array of causative and promoting factors. However, we do know that taking estrogen unopposed with adequate progesterone can cause the development of uterine cancer and its precursor state.1 If those bioidentical estrogens were effective at controlling her menopausal symptoms, they likely were effective at stimulating her endometrium at the same time.
What are compounded bioidentical hormones?
The term “bioidentical” refers to having the same molecular structure as that which is found in the human body. Examples of bioidentical estrogens include 17-beta-estradiol, estrone, and estriol – which are produced from yams and soy. Micronized progesterone is an example of a bioidentical progesterone. Many of these drugs are approved by the Food and Drug Administration, and prescribed and dispensed by conventional pharmacies.
An alternative, and increasingly popular, version of bioidentical hormones are CBHs. It should be recognized that this is a marketing, and not a scientific, term. These products utilize hormones, in some cases FDA-approved bioidentical hormones, that are broken down and blended by specialized pharmacies and reconstituted (compounded) into different, and sometimes “customized,” dosing and delivery methods (such as capsules, patches, gels, creams, lozenges, suppositories). Frequently used compounded products utilize multiple formulations of estrogens in doublets and triplets as well as progesterone, testosterone, and dehydroepiandrosterone.
How do they differ from synthetic hormones?
Distributors of CBHs state that they differ from conventional HT (synthetic and bioidentical) because of the customization process from which they promise greater efficacy and a sense of personalized medicine. The distributors frequently utilize assays from saliva, blood, vaginal secretions, and urine to measure a woman’s hormone levels, and titrate her compounded formulation based on those results. It should be noted that there is no data to support that titration of hormones to blood, salivary, or urine levels is efficacious or ensures greater safety than titration based on symptom management.
Critics of CBHT, which includes the North American Menopause Society2 and the American College of Obstetricians and Gynecologists,3 highlight that the main difference between CBHT and HT is lack of FDA regulation over the CBHT industry. Many of these agents are delivered transdermally and therefore are classified as “dietary supplements.” As such, they do not require FDA regulation or proof of safety or efficacy.
Dr. Emma C. Rossi
Lack of FDA approval allows CBHs to be distributed without package inserts and boxed warnings (such as the standard warnings about MI, venous thromboembolic events, and breast cancer). The absence of FDA approval also allows them to avoid FDA-regulated guarantees about purity, potency, and efficacy. Audits of CBHs have shown high rates of discrepancy between stated and measured potency, including observations of both much lower and much higher than stated strength.4
Why would dosing accuracy be important in hormone therapy prescription? If a woman taking estrogen therapy is not receiving adequate cotreatment with progesterone because of either omission or a subtherapeutic product, she increases her risk for endometrial cancer.
What drives patients’ decision to use compounded bioidentical hormones?
After the Womens’ Health Initiative study was published in 20025, all FDA-regulated estrogen preparations were required to carry specific warnings, particularly in relation to the increased risk for MI, venous thromboembolic events, and breast cancer. There was a clear uptake in use of CBHT after this study was reported. By avoiding FDA regulations, distributors of CBHTs may have avoided providing Womens’ Health Initiative information to patients. The absence of an insert with a written warning, in and of itself, makes these preparations seem safer to the patient.
But is it entirely a lack of information that drives demand for CBHTs? Surveys of current or former users suggest the motivations are more complex than that. A survey of 21 past or present CBHT users inquired about reasons for use of CBHT over conventional HT.6 Their responses were categorized as either push motivations away from conventional therapy versus pull motivations toward CBHT. About 95% of current and former users cited distrust of the biomedicine and pharmaceutical industry as reasons for use of CBHT. Fear about the safety of conventional HT, particularly with respect to cancer risk, also was strongly cited at 81%. Motivations pulling toward CBHT included its efficacy (76%) and perception that CBHT is “safer” than conventional HT (76%).
Women in this study also appreciated the tailored, individualized approach that often is associated with CBHT, in which providers spend long consultations discussing individual patient needs and concerns. They enjoy the idea of a customized blend that is created, as opposed to a standard dosing regimen, and intuitively trust the reliability of blood and saliva testing as a prescriptive tool.
Are bioidentical hormones safe with respect to cancer risk?
Hormones themselves are not inert substances, including those derived in vivo and those from plants. They have powerful effects in the human body and can promote malignant transformation or proliferation, alter metabolic pathways, stimulate vascular tone, influence coagulation pathways, along with many other effects. A hormone’s potential for deleterious effect can be present regardless of how that hormone is synthesized, procured, or prepared. While there are no data to suggest that CBHT is associated with increased cancer risk, compared with conventional HT, there are by no means any data to suggest it is safer. Unopposed compounded estrogens place women at increased risk for endometrial cancers, and the prolonged use of hormonal therapy, compounded or otherwise, after menopause increases the risk for breast cancer.
How should we counsel patients?
Patients who desire compounded bioidentical hormone preparations should be counseled that little is known about the safety of these preparations, compared with conventional hormone preparations. The fact that the components are often plant based rather than synthetic does not inherently alter their potential negative impact on biologic pathways. Patients should be educated regarding the difference between FDA-regulated products and nonregulated products so that they can understand that lack of a boxed warning on a non-FDA regulated product does not mean an absence of risk. Women should be informed of the potential inaccuracies in dosing and strength of the CBH preparations they receive.
We should recognize that our patients strongly desire a relationship with their provider in which they are listened to, understood, and treated as individuals. If conversations regarding hormone use are approached with these principles, we will optimize the likelihood our patients are receptive to the highest quality information and not pulled in the direction of unregulated products.
Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She reported that she had no conflicts of interest. Email Dr. Rossi at [email protected].
The clinical scenario is as follows: A 62-year-old woman comes to see me for a new diagnosis of grade 1 endometrial cancer. She has a normal body mass index of 24 kg/m2, a history of four prior full-term pregnancies, no family history of malignancy, and no medical comorbidities. She is otherwise a specimen of good health, and has no clear identifiable risk factors for this malignancy. She then reports that she transitioned through menopause at age 52 years and developed severe hot flashes with sleep and mood disturbance. She did not wish to take conventional hormone replacement therapy (HT) because she had heard it causes cancer. She subsequently researched the Internet and found a provider who has been prescribing compounded bioidentical hormone therapy (CBHT) for her for the past 10 years. She submits saliva for testing of her estrogen levels, and the provider uses this data to compound the appropriate doses of “natural” estrogens and testosterone for her which she applies via vaginal or transdermal creams. She has been prescribed a progesterone suppository, but she doesn’t always take that because she doesn’t notice that it has any effect on how she feels. “Doctor, did my bioidentical hormones give me this uterine cancer?”
Alexander Raths/Fotolia
My answer is, of course, I don’t know. Cancer is a complex disease with a complex array of causative and promoting factors. However, we do know that taking estrogen unopposed with adequate progesterone can cause the development of uterine cancer and its precursor state.1 If those bioidentical estrogens were effective at controlling her menopausal symptoms, they likely were effective at stimulating her endometrium at the same time.
What are compounded bioidentical hormones?
The term “bioidentical” refers to having the same molecular structure as that which is found in the human body. Examples of bioidentical estrogens include 17-beta-estradiol, estrone, and estriol – which are produced from yams and soy. Micronized progesterone is an example of a bioidentical progesterone. Many of these drugs are approved by the Food and Drug Administration, and prescribed and dispensed by conventional pharmacies.
An alternative, and increasingly popular, version of bioidentical hormones are CBHs. It should be recognized that this is a marketing, and not a scientific, term. These products utilize hormones, in some cases FDA-approved bioidentical hormones, that are broken down and blended by specialized pharmacies and reconstituted (compounded) into different, and sometimes “customized,” dosing and delivery methods (such as capsules, patches, gels, creams, lozenges, suppositories). Frequently used compounded products utilize multiple formulations of estrogens in doublets and triplets as well as progesterone, testosterone, and dehydroepiandrosterone.
How do they differ from synthetic hormones?
Distributors of CBHs state that they differ from conventional HT (synthetic and bioidentical) because of the customization process from which they promise greater efficacy and a sense of personalized medicine. The distributors frequently utilize assays from saliva, blood, vaginal secretions, and urine to measure a woman’s hormone levels, and titrate her compounded formulation based on those results. It should be noted that there is no data to support that titration of hormones to blood, salivary, or urine levels is efficacious or ensures greater safety than titration based on symptom management.
Critics of CBHT, which includes the North American Menopause Society2 and the American College of Obstetricians and Gynecologists,3 highlight that the main difference between CBHT and HT is lack of FDA regulation over the CBHT industry. Many of these agents are delivered transdermally and therefore are classified as “dietary supplements.” As such, they do not require FDA regulation or proof of safety or efficacy.
Dr. Emma C. Rossi
Lack of FDA approval allows CBHs to be distributed without package inserts and boxed warnings (such as the standard warnings about MI, venous thromboembolic events, and breast cancer). The absence of FDA approval also allows them to avoid FDA-regulated guarantees about purity, potency, and efficacy. Audits of CBHs have shown high rates of discrepancy between stated and measured potency, including observations of both much lower and much higher than stated strength.4
Why would dosing accuracy be important in hormone therapy prescription? If a woman taking estrogen therapy is not receiving adequate cotreatment with progesterone because of either omission or a subtherapeutic product, she increases her risk for endometrial cancer.
What drives patients’ decision to use compounded bioidentical hormones?
After the Womens’ Health Initiative study was published in 20025, all FDA-regulated estrogen preparations were required to carry specific warnings, particularly in relation to the increased risk for MI, venous thromboembolic events, and breast cancer. There was a clear uptake in use of CBHT after this study was reported. By avoiding FDA regulations, distributors of CBHTs may have avoided providing Womens’ Health Initiative information to patients. The absence of an insert with a written warning, in and of itself, makes these preparations seem safer to the patient.
But is it entirely a lack of information that drives demand for CBHTs? Surveys of current or former users suggest the motivations are more complex than that. A survey of 21 past or present CBHT users inquired about reasons for use of CBHT over conventional HT.6 Their responses were categorized as either push motivations away from conventional therapy versus pull motivations toward CBHT. About 95% of current and former users cited distrust of the biomedicine and pharmaceutical industry as reasons for use of CBHT. Fear about the safety of conventional HT, particularly with respect to cancer risk, also was strongly cited at 81%. Motivations pulling toward CBHT included its efficacy (76%) and perception that CBHT is “safer” than conventional HT (76%).
Women in this study also appreciated the tailored, individualized approach that often is associated with CBHT, in which providers spend long consultations discussing individual patient needs and concerns. They enjoy the idea of a customized blend that is created, as opposed to a standard dosing regimen, and intuitively trust the reliability of blood and saliva testing as a prescriptive tool.
Are bioidentical hormones safe with respect to cancer risk?
Hormones themselves are not inert substances, including those derived in vivo and those from plants. They have powerful effects in the human body and can promote malignant transformation or proliferation, alter metabolic pathways, stimulate vascular tone, influence coagulation pathways, along with many other effects. A hormone’s potential for deleterious effect can be present regardless of how that hormone is synthesized, procured, or prepared. While there are no data to suggest that CBHT is associated with increased cancer risk, compared with conventional HT, there are by no means any data to suggest it is safer. Unopposed compounded estrogens place women at increased risk for endometrial cancers, and the prolonged use of hormonal therapy, compounded or otherwise, after menopause increases the risk for breast cancer.
How should we counsel patients?
Patients who desire compounded bioidentical hormone preparations should be counseled that little is known about the safety of these preparations, compared with conventional hormone preparations. The fact that the components are often plant based rather than synthetic does not inherently alter their potential negative impact on biologic pathways. Patients should be educated regarding the difference between FDA-regulated products and nonregulated products so that they can understand that lack of a boxed warning on a non-FDA regulated product does not mean an absence of risk. Women should be informed of the potential inaccuracies in dosing and strength of the CBH preparations they receive.
We should recognize that our patients strongly desire a relationship with their provider in which they are listened to, understood, and treated as individuals. If conversations regarding hormone use are approached with these principles, we will optimize the likelihood our patients are receptive to the highest quality information and not pulled in the direction of unregulated products.
Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She reported that she had no conflicts of interest. Email Dr. Rossi at [email protected].
Pap tests have the reputation of being a simple, noninvasive, low-cost test to offer patients, and, therefore, it is understandable to believe there is no harm in offering it in all situations. However, if inappropriately applied in isolation, performing the Pap test may do more harm than good.
monkeybusinessimages/iStock/Getty Images
I recently saw a patient in consultation for cervical cancer. Her story was similar to one I’ve seen many times before. She was a 30-year-old non–English-speaking Hispanic woman who received regular care from the health department clinics.
In April of the prior year, she had noticed abnormal bleeding symptoms including intermenstrual and postcoital bleeding. She visited the health department and reported these symptoms to the provider who performed an examination. According to the provider’s notes, the cervix appeared “abnormal” and a Pap test was done. The result of this Pap test was high-grade dysplasia. The patient was promptly notified of the result and an appointment was arranged with the local ob.gyn. for a consultation, presumably for colposcopy and subsequent appropriate excisional procedure. Unfortunately, the patient did not attend that scheduled appointment. She later recounted to me that it was because she had not understood that it was important. She had a long history of abnormal Pap tests which, in the past, had only required repeat testing or minor interventions such as “freezing.”
Her bleeding symptoms became worse, and she developed abnormal discharge and pain. In November, she presented again for evaluation to the same provider. Now her cervix appeared very abnormal and was described as a “crater.” Again a Pap test was done. This time the Pap test showed “carcinoma,” and the patient was informed that she had cancer and was referred to gynecologic oncology. When I examined this unfortunate young woman, I discovered a 10 cm, stage IIB very locally advanced tumor. She is currently receiving primary chemotherapy/radiation with an approximately 60% probability of cure, and a high likelihood of lifelong sequelae of this toxic therapy.
This case highlights that, even when patients are engaged within our health care system, we can miss the opportunity to diagnose early-stage cancers if we are not utilizing screening versus diagnostic tests appropriately.
The purpose of a Pap test is as a screening test, which are designed to detect disease in asymptomatic individuals. The accuracy of these tests is determined in low-risk (asymptomatic) populations, which influences the pretest probability of disease. In asymptomatic patients with a normal screening test, it is safe to wait out the interval of time for the repeat screening test, because the combination of a low pretest probability and a high sensitivity of the test in finding disease means that there is a very low chance of missing disease.
Dysplasia rarely causes bleeding. However, invasive cervical cancer does. If a patient has a symptom such as abnormal bleeding, they no longer fit into the population with a low pretest probability for having cervical cancer. This same sensitivity of the Pap test in finding disease, combined with the now-higher pretest probability can raise the level of false-negative results to unacceptably high levels.
Patients with symptoms of cervical cancer should not receive screening tests exclusively; they should receive diagnostic tests. For example, Pap tests should not be used in isolation to diagnose pathology in patients with abnormal bleeding or discharge, just as screening mammograms should not be ordered in patients with symptomatic breast lumps, nipple discharge, retraction, etc. (these women should be referred for diagnostic mammography and ultrasound). It is not unusual for gynecologic oncologists to see patients with visible invasive cervical cancer who have only cervical intraepithelial neoplasia grade 3 on the preceding Pap test. There is a 34% positive predictive value that a cervical cancer will be found with a high-grade dysplastic Pap test.1 Cytology is an inferior diagnostic tool, compared with histology, in determining invasive cancer from preinvasive lesions. Cytology is an inferior diagnostic tool, compared with histology, in determining invasive cancer from preinvasive lesions. It analyzes individual cells rather than a piece of tissue with intercellular relationships.
Dr. Emma C. Rossi
The take-home message for this column is that, if a provider sees an abnormal lesion on a cervix, they should biopsy the visible lesion to obtain a histologic diagnosis. Simply performing a Pap test alone may result in false reassurance and in underestimating the severity of disease.
Some providers will tell me that they have concerns about performing a biopsy on a grossly abnormal cervix for fear that the subsequent bleeding will be difficult to manage in the outpatient setting. This is understandable, although it is unlikely that an office equipped with the ability to perform colposcopy or excisional procedures would not have the necessary equipment to manage this. Prolonged pressure applied to the cervix with topical hemostatic agents or – in extreme cases – vaginal packing with gauze always has been effective for me in these circumstances.
The additional benefit of establishing histologic confirmation prior to referral is expediting care, including additional imaging and referrals to treating providers. If the diagnosis is inadequately established prior to their appointment with a gynecologic oncologist, it can add further delays before definitive surgical or nonsurgical management can be initiated, which is particularly problematic if the patient is experiencing severe bleeding. If the provider feels uncomfortable with proceeding with biopsy, they should inform the patient very clearly that they suspect that there is a cancer of the cervix, and it needs attention from a cancer specialist to confirm the diagnosis. This clear communication will minimize the likelihood that the patient may not show up for the subsequent appointments before her diagnosis is definitively established.
Another common scenario in which Pap tests are inappropriately applied is in the surveillance of endometrial cancer. In 2013, the Society of Gynecologic Oncology released its five “Choosing Wisely” recommendations. This included the recommendation to not perform Pap tests in the surveillance of endometrial cancer. This recommendation was based on a body of evidence that demonstrates screening for endometrial cancer recurrence with Pap smears does not detect vaginal mucosal recurrences any sooner than visualization of lesions on speculum examination.2,3 These Pap-positive recurrences almost always are visible on exam. Additionally, false positives are common in this population, particularly among women who have had radiation or have atrophic tissues.
Using Pap tests for the surveillance of cervical cancer is somewhat more complicated. Similarly, they do not detect cervical cancer recurrence any sooner than comprehensive examination does. However, this population may suffer from chronic human papillomavirus (HPV) infection, and there remains a role of the Pap test in screening for future, new HPV-related preinvasive vaginal disease. Therefore, Pap tests, and/or HPV testing can be offered to cervical cancer survivors in accordance with the American Society for Colposcopy and Cervical Pathology guidelines for noncervical cancer patients, with the caveat that, if radiation has been given, false positives are more likely.2
Pap tests clearly have an important role as a screening test in asymptomatic individuals. However, when the patient has a symptom that might be cervical cancer or a visibly suspicious lesion, she should receive a diagnostic test, and Pap tests are not designed for that purpose.
Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no conflicts of interest. Email Dr. Rossi at [email protected].
Pap tests have the reputation of being a simple, noninvasive, low-cost test to offer patients, and, therefore, it is understandable to believe there is no harm in offering it in all situations. However, if inappropriately applied in isolation, performing the Pap test may do more harm than good.
monkeybusinessimages/iStock/Getty Images
I recently saw a patient in consultation for cervical cancer. Her story was similar to one I’ve seen many times before. She was a 30-year-old non–English-speaking Hispanic woman who received regular care from the health department clinics.
In April of the prior year, she had noticed abnormal bleeding symptoms including intermenstrual and postcoital bleeding. She visited the health department and reported these symptoms to the provider who performed an examination. According to the provider’s notes, the cervix appeared “abnormal” and a Pap test was done. The result of this Pap test was high-grade dysplasia. The patient was promptly notified of the result and an appointment was arranged with the local ob.gyn. for a consultation, presumably for colposcopy and subsequent appropriate excisional procedure. Unfortunately, the patient did not attend that scheduled appointment. She later recounted to me that it was because she had not understood that it was important. She had a long history of abnormal Pap tests which, in the past, had only required repeat testing or minor interventions such as “freezing.”
Her bleeding symptoms became worse, and she developed abnormal discharge and pain. In November, she presented again for evaluation to the same provider. Now her cervix appeared very abnormal and was described as a “crater.” Again a Pap test was done. This time the Pap test showed “carcinoma,” and the patient was informed that she had cancer and was referred to gynecologic oncology. When I examined this unfortunate young woman, I discovered a 10 cm, stage IIB very locally advanced tumor. She is currently receiving primary chemotherapy/radiation with an approximately 60% probability of cure, and a high likelihood of lifelong sequelae of this toxic therapy.
This case highlights that, even when patients are engaged within our health care system, we can miss the opportunity to diagnose early-stage cancers if we are not utilizing screening versus diagnostic tests appropriately.
The purpose of a Pap test is as a screening test, which are designed to detect disease in asymptomatic individuals. The accuracy of these tests is determined in low-risk (asymptomatic) populations, which influences the pretest probability of disease. In asymptomatic patients with a normal screening test, it is safe to wait out the interval of time for the repeat screening test, because the combination of a low pretest probability and a high sensitivity of the test in finding disease means that there is a very low chance of missing disease.
Dysplasia rarely causes bleeding. However, invasive cervical cancer does. If a patient has a symptom such as abnormal bleeding, they no longer fit into the population with a low pretest probability for having cervical cancer. This same sensitivity of the Pap test in finding disease, combined with the now-higher pretest probability can raise the level of false-negative results to unacceptably high levels.
Patients with symptoms of cervical cancer should not receive screening tests exclusively; they should receive diagnostic tests. For example, Pap tests should not be used in isolation to diagnose pathology in patients with abnormal bleeding or discharge, just as screening mammograms should not be ordered in patients with symptomatic breast lumps, nipple discharge, retraction, etc. (these women should be referred for diagnostic mammography and ultrasound). It is not unusual for gynecologic oncologists to see patients with visible invasive cervical cancer who have only cervical intraepithelial neoplasia grade 3 on the preceding Pap test. There is a 34% positive predictive value that a cervical cancer will be found with a high-grade dysplastic Pap test.1 Cytology is an inferior diagnostic tool, compared with histology, in determining invasive cancer from preinvasive lesions. Cytology is an inferior diagnostic tool, compared with histology, in determining invasive cancer from preinvasive lesions. It analyzes individual cells rather than a piece of tissue with intercellular relationships.
Dr. Emma C. Rossi
The take-home message for this column is that, if a provider sees an abnormal lesion on a cervix, they should biopsy the visible lesion to obtain a histologic diagnosis. Simply performing a Pap test alone may result in false reassurance and in underestimating the severity of disease.
Some providers will tell me that they have concerns about performing a biopsy on a grossly abnormal cervix for fear that the subsequent bleeding will be difficult to manage in the outpatient setting. This is understandable, although it is unlikely that an office equipped with the ability to perform colposcopy or excisional procedures would not have the necessary equipment to manage this. Prolonged pressure applied to the cervix with topical hemostatic agents or – in extreme cases – vaginal packing with gauze always has been effective for me in these circumstances.
The additional benefit of establishing histologic confirmation prior to referral is expediting care, including additional imaging and referrals to treating providers. If the diagnosis is inadequately established prior to their appointment with a gynecologic oncologist, it can add further delays before definitive surgical or nonsurgical management can be initiated, which is particularly problematic if the patient is experiencing severe bleeding. If the provider feels uncomfortable with proceeding with biopsy, they should inform the patient very clearly that they suspect that there is a cancer of the cervix, and it needs attention from a cancer specialist to confirm the diagnosis. This clear communication will minimize the likelihood that the patient may not show up for the subsequent appointments before her diagnosis is definitively established.
Another common scenario in which Pap tests are inappropriately applied is in the surveillance of endometrial cancer. In 2013, the Society of Gynecologic Oncology released its five “Choosing Wisely” recommendations. This included the recommendation to not perform Pap tests in the surveillance of endometrial cancer. This recommendation was based on a body of evidence that demonstrates screening for endometrial cancer recurrence with Pap smears does not detect vaginal mucosal recurrences any sooner than visualization of lesions on speculum examination.2,3 These Pap-positive recurrences almost always are visible on exam. Additionally, false positives are common in this population, particularly among women who have had radiation or have atrophic tissues.
Using Pap tests for the surveillance of cervical cancer is somewhat more complicated. Similarly, they do not detect cervical cancer recurrence any sooner than comprehensive examination does. However, this population may suffer from chronic human papillomavirus (HPV) infection, and there remains a role of the Pap test in screening for future, new HPV-related preinvasive vaginal disease. Therefore, Pap tests, and/or HPV testing can be offered to cervical cancer survivors in accordance with the American Society for Colposcopy and Cervical Pathology guidelines for noncervical cancer patients, with the caveat that, if radiation has been given, false positives are more likely.2
Pap tests clearly have an important role as a screening test in asymptomatic individuals. However, when the patient has a symptom that might be cervical cancer or a visibly suspicious lesion, she should receive a diagnostic test, and Pap tests are not designed for that purpose.
Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no conflicts of interest. Email Dr. Rossi at [email protected].
Pap tests have the reputation of being a simple, noninvasive, low-cost test to offer patients, and, therefore, it is understandable to believe there is no harm in offering it in all situations. However, if inappropriately applied in isolation, performing the Pap test may do more harm than good.
monkeybusinessimages/iStock/Getty Images
I recently saw a patient in consultation for cervical cancer. Her story was similar to one I’ve seen many times before. She was a 30-year-old non–English-speaking Hispanic woman who received regular care from the health department clinics.
In April of the prior year, she had noticed abnormal bleeding symptoms including intermenstrual and postcoital bleeding. She visited the health department and reported these symptoms to the provider who performed an examination. According to the provider’s notes, the cervix appeared “abnormal” and a Pap test was done. The result of this Pap test was high-grade dysplasia. The patient was promptly notified of the result and an appointment was arranged with the local ob.gyn. for a consultation, presumably for colposcopy and subsequent appropriate excisional procedure. Unfortunately, the patient did not attend that scheduled appointment. She later recounted to me that it was because she had not understood that it was important. She had a long history of abnormal Pap tests which, in the past, had only required repeat testing or minor interventions such as “freezing.”
Her bleeding symptoms became worse, and she developed abnormal discharge and pain. In November, she presented again for evaluation to the same provider. Now her cervix appeared very abnormal and was described as a “crater.” Again a Pap test was done. This time the Pap test showed “carcinoma,” and the patient was informed that she had cancer and was referred to gynecologic oncology. When I examined this unfortunate young woman, I discovered a 10 cm, stage IIB very locally advanced tumor. She is currently receiving primary chemotherapy/radiation with an approximately 60% probability of cure, and a high likelihood of lifelong sequelae of this toxic therapy.
This case highlights that, even when patients are engaged within our health care system, we can miss the opportunity to diagnose early-stage cancers if we are not utilizing screening versus diagnostic tests appropriately.
The purpose of a Pap test is as a screening test, which are designed to detect disease in asymptomatic individuals. The accuracy of these tests is determined in low-risk (asymptomatic) populations, which influences the pretest probability of disease. In asymptomatic patients with a normal screening test, it is safe to wait out the interval of time for the repeat screening test, because the combination of a low pretest probability and a high sensitivity of the test in finding disease means that there is a very low chance of missing disease.
Dysplasia rarely causes bleeding. However, invasive cervical cancer does. If a patient has a symptom such as abnormal bleeding, they no longer fit into the population with a low pretest probability for having cervical cancer. This same sensitivity of the Pap test in finding disease, combined with the now-higher pretest probability can raise the level of false-negative results to unacceptably high levels.
Patients with symptoms of cervical cancer should not receive screening tests exclusively; they should receive diagnostic tests. For example, Pap tests should not be used in isolation to diagnose pathology in patients with abnormal bleeding or discharge, just as screening mammograms should not be ordered in patients with symptomatic breast lumps, nipple discharge, retraction, etc. (these women should be referred for diagnostic mammography and ultrasound). It is not unusual for gynecologic oncologists to see patients with visible invasive cervical cancer who have only cervical intraepithelial neoplasia grade 3 on the preceding Pap test. There is a 34% positive predictive value that a cervical cancer will be found with a high-grade dysplastic Pap test.1 Cytology is an inferior diagnostic tool, compared with histology, in determining invasive cancer from preinvasive lesions. Cytology is an inferior diagnostic tool, compared with histology, in determining invasive cancer from preinvasive lesions. It analyzes individual cells rather than a piece of tissue with intercellular relationships.
Dr. Emma C. Rossi
The take-home message for this column is that, if a provider sees an abnormal lesion on a cervix, they should biopsy the visible lesion to obtain a histologic diagnosis. Simply performing a Pap test alone may result in false reassurance and in underestimating the severity of disease.
Some providers will tell me that they have concerns about performing a biopsy on a grossly abnormal cervix for fear that the subsequent bleeding will be difficult to manage in the outpatient setting. This is understandable, although it is unlikely that an office equipped with the ability to perform colposcopy or excisional procedures would not have the necessary equipment to manage this. Prolonged pressure applied to the cervix with topical hemostatic agents or – in extreme cases – vaginal packing with gauze always has been effective for me in these circumstances.
The additional benefit of establishing histologic confirmation prior to referral is expediting care, including additional imaging and referrals to treating providers. If the diagnosis is inadequately established prior to their appointment with a gynecologic oncologist, it can add further delays before definitive surgical or nonsurgical management can be initiated, which is particularly problematic if the patient is experiencing severe bleeding. If the provider feels uncomfortable with proceeding with biopsy, they should inform the patient very clearly that they suspect that there is a cancer of the cervix, and it needs attention from a cancer specialist to confirm the diagnosis. This clear communication will minimize the likelihood that the patient may not show up for the subsequent appointments before her diagnosis is definitively established.
Another common scenario in which Pap tests are inappropriately applied is in the surveillance of endometrial cancer. In 2013, the Society of Gynecologic Oncology released its five “Choosing Wisely” recommendations. This included the recommendation to not perform Pap tests in the surveillance of endometrial cancer. This recommendation was based on a body of evidence that demonstrates screening for endometrial cancer recurrence with Pap smears does not detect vaginal mucosal recurrences any sooner than visualization of lesions on speculum examination.2,3 These Pap-positive recurrences almost always are visible on exam. Additionally, false positives are common in this population, particularly among women who have had radiation or have atrophic tissues.
Using Pap tests for the surveillance of cervical cancer is somewhat more complicated. Similarly, they do not detect cervical cancer recurrence any sooner than comprehensive examination does. However, this population may suffer from chronic human papillomavirus (HPV) infection, and there remains a role of the Pap test in screening for future, new HPV-related preinvasive vaginal disease. Therefore, Pap tests, and/or HPV testing can be offered to cervical cancer survivors in accordance with the American Society for Colposcopy and Cervical Pathology guidelines for noncervical cancer patients, with the caveat that, if radiation has been given, false positives are more likely.2
Pap tests clearly have an important role as a screening test in asymptomatic individuals. However, when the patient has a symptom that might be cervical cancer or a visibly suspicious lesion, she should receive a diagnostic test, and Pap tests are not designed for that purpose.
Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no conflicts of interest. Email Dr. Rossi at [email protected].
Shock waves moved through the gynecologic oncology world on Oct. 31, 2018, when the New England Journal of Medicine published two papers on survival outcomes for women undergoing surgery for early stage cervical cancer.
Dr. Emma C. Rossi
The first was a randomized controlled trial of laparotomy and minimally invasive surgery (MIS) for radical hysterectomy called the LACC trial.1 In the multicenter, international trial of 631 women, the primary objective was disease-specific survival (cervical cancer–related deaths) and was powered to detect noninferiority of the MIS approach when compared with laparotomy. The trial was closed early when investigators noted a lower than expected rate of 3-year, disease-free survival (91% vs. 97%) from cervical cancer in the MIS group, which was made up of 84% laparoscopic and 16% robotic approaches, versus laparotomy. There were 19 deaths in the MIS group observed versus three in the laparotomy group. The conclusions of the trial were that MIS surgery is associated with inferior cervical cancer survival.
In the second study, authors analyzed data from large U.S. databases – the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) Program – to collect all-cause mortality for patients with early-stage cervical cancer who had undergone radical hysterectomy during 2010-2013.2 Among 2,461 observed results, 1,225 had undergone MIS surgery with the majority (79.8%) via robotic-assistance. Women undergoing MIS approaches had smaller, lower grade tumors; were more likely to be white, privately insured, and of a higher income; and had surgery later in the cohort and by nonacademic centers. The researchers adjusted for risk factors with an analytic process called propensity-score weighting, which matched the groups more closely in an attempt to minimize confounders. They identified higher all-cause mortality among women who were treated with an MIS approach, compared with those treated with laparotomy (hazard ratio, 1.65). They also observed a significant decline in the survival from cervical cancer annually that corresponded to the uptake of MIS radical hysterectomies.
In the wake of these publications, many concluded that gynecologic oncologists should no longer offer a minimally invasive approach for radical hysterectomy. Certainly level I evidence published in a highly influential journal is compelling, and the consistency in findings over two studies adds further weight to the results. However, was this the correct conclusion to draw from these results? Surgeons who had been performing MIS radical hysterectomies for many years with favorable outcomes are challenging this and are raising questions about external generalizability and whether these findings were driven by the surgery itself or by the surgeon.
The studies’ authors proposed hypotheses for their results that implicate the surgical route rather than the surgeon; however, these seem ad hoc and not well supported by data, including the authors’ own data. The first was the hypothesis that cervical tumors were being disrupted and disseminated through the use of uterine manipulators in MIS approaches. However, cervical cancers are fairly routinely “disrupted” by preoperative cone biopsies, loop electrosurgical excision procedures (LEEP), and sharp biopsies, which are arguably more invasive than placement of a manipulator. Uterine manipulators routinely are used in endometrial cancer surgeries, in which the manipulator is embedded within the tumor, without an associated negative survival effect in randomized trials.3 Additionally, not all surgeons utilize manipulators for radical hysterectomies, and these studies did not measure or report on their use; therefore, it is impossible to know whether, and by what magnitude, manipulators played a role. Finally, if uterine manipulators are the explanation for inferior survival, surely the recommendation should be to discourage their use, rather than abandon the MIS approach all together.
The other explanation offered was exposure of the tumor to CO2 gas. This seems an even less plausible explanation because CO2 gas is routinely used in MIS cancer surgeries for endometrial, prostate, gastric, and colorectal surgeries and is used as insufflation for malignant interventional endoscopies without a significant deleterious effect. Additionally, the cervix is not exposed to CO2 until colpotomy at the procedure’s end – and only briefly. The in vitro studies implicating a negative effect of simulated CO2 pneumoperitoneum are neither compelling nor consistent.4,5
I would like to propose another hypothesis for the results: surgical proficiency. Surgery, unlike medical interventions, is not a simple variable that is dichotomous – performed or not. Surgeons do not randomly select operative approaches for patients. We select surgical approaches based on patients’ circumstances and surgeon factors, including our own mastery of the various techniques. Randomized surgical trials rely on the notion that a surgeon is equally skilled in both or all approaches offered, but this is clearly not the case, and any surgeon recognizes this if he or she has observed more than one surgeon or has attempted a procedure via different routes. While some procedures, such as extrafascial hysterectomy for endometrial cancer, are relatively straightforward and surgeon capabilities are more equitable across different approaches, cervical cancer surgery is quite different.
Early-stage cervical cancer primarily exerts radial growth into the cervical stroma and parametria. Curative surgical excision requires broadly negative margins through this tissue, a so called “radical hysterectomy.” The radicality of hysterectomy has been categorized in stages, acknowledging that different sized lesions require different volumes of parametrial resection to achieve adequate clearance from the tumor.6 In doing so, the surgeon must skeletonize and mobilize the distal ureters, cardinal ligament webs, and uterosacral ligaments. These structures are in close proximity to major vascular and neural structures. Hence, the radical hysterectomy is, without dispute, a technically challenging procedure.
Minimally invasive surgery further handicaps the surgeon by eliminating manual contact with tissue, and relying on complex instrumentation, electrosurgical modalities, and loss of haptics. The learning curve for MIS radical hysterectomy is further attenuated by their relative infrequency. Therefore, it makes sense that, when the MIS approach is randomly assigned to surgeons (such as in the LACC trial) or broadly and independently applied (as in the retrospective series), one might see variations in skill, quality, and outcomes, including oncologic outcomes.
The retrospective study by Melamed et al. acknowledged that surgeon skill and volume may contribute to their findings but stated that, because of the nature of their source data, they were unable to explain why they observed their results. The LACC trial attempted to overcome the issue of surgeon skill by ensuring all surgeons were from high-volume sites and had videos reviewed of their cases. However, the videos were chosen by the surgeons themselves and not available for audit in the study’s supplemental material. The LACC trial was conducted over a 9-year period across 33 sites and enrolled a total of 631 subjects. This equates to an enrollment of approximately two patients per site per year and either reflects extremely low-volume sites or highly selective patient enrollment. If the latter, what was different about the unenrolled patients and what was the preferred chosen route of surgery for them?
All 34 recurrences occurred in patients from just 14 of the 33 sites in the LACC trial. That means that less than half of the sites contributed to all of the recurrences. The authors provided no details on the specific sites, surgeons, or accrual rates in their manuscript or supplemental materials. Therefore, readers are unable to know what was different about those sites; whether they contributed the most patients and, therefore, the most recurrences; or whether they were low-volume sites with lower quality.
While margin status, positive or negative, was reported, there was no data captured regarding volume of resected parametrial tissue, or relative distance from tumor to margin, both of which might provide the reader with a better appraisal of surgeon proficiency and consistency in radicality of the two approaches. The incidence of locoregional (pelvic) recurrences were higher in the MIS arm, which is expected if there were inadequate margins around the laparoscopically resected tumors.
Finally, the authors of the LACC trial observed equivalent rates of postoperative complications between the laparotomy and MIS groups. The main virtue for MIS approaches is the reduction in perioperative morbidity. To observe no perioperative morbidity benefit in the MIS group is a red flag suggesting that these surgeons may not have achieved proficiency with the MIS approach.
Despite these arguments, the results of these studies should be taken seriously. Clearly, it is apparent that preservation of oncologic outcomes is not guaranteed with MIS radical hysterectomy, and it should not be the chosen approach for all patients and all surgeons. However, rather than entirely abandoning this less morbid approach, I would argue that it is a call to arms for gynecologic oncologists to self-evaluate. We should know our own data with respect to case volumes, perioperative complications, and cancer-related recurrence and death.
Perhaps MIS radical hysterectomies should be consolidated among high-volume surgeons with demonstrated good outcomes? Just as has been done for rectal cancer surgery with positive effect, we should establish accredited centers of excellence.7 We also need to improve the training of surgeons in novel, difficult techniques, as well as enhance the sophistication of MIS equipment such as improved instrumentation, haptics, and vision-guided surgery (for example, real-time intraoperative assessment of the tumor margins).
Let’s not take a wholesale step backwards to the surgical approaches of a 100 years ago just because they are more straightforward. Let’s do a better job of advancing the quality of what we do for our patients in the future.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no conflicts of interest. Email Dr. Rossi at [email protected].
Shock waves moved through the gynecologic oncology world on Oct. 31, 2018, when the New England Journal of Medicine published two papers on survival outcomes for women undergoing surgery for early stage cervical cancer.
Dr. Emma C. Rossi
The first was a randomized controlled trial of laparotomy and minimally invasive surgery (MIS) for radical hysterectomy called the LACC trial.1 In the multicenter, international trial of 631 women, the primary objective was disease-specific survival (cervical cancer–related deaths) and was powered to detect noninferiority of the MIS approach when compared with laparotomy. The trial was closed early when investigators noted a lower than expected rate of 3-year, disease-free survival (91% vs. 97%) from cervical cancer in the MIS group, which was made up of 84% laparoscopic and 16% robotic approaches, versus laparotomy. There were 19 deaths in the MIS group observed versus three in the laparotomy group. The conclusions of the trial were that MIS surgery is associated with inferior cervical cancer survival.
In the second study, authors analyzed data from large U.S. databases – the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) Program – to collect all-cause mortality for patients with early-stage cervical cancer who had undergone radical hysterectomy during 2010-2013.2 Among 2,461 observed results, 1,225 had undergone MIS surgery with the majority (79.8%) via robotic-assistance. Women undergoing MIS approaches had smaller, lower grade tumors; were more likely to be white, privately insured, and of a higher income; and had surgery later in the cohort and by nonacademic centers. The researchers adjusted for risk factors with an analytic process called propensity-score weighting, which matched the groups more closely in an attempt to minimize confounders. They identified higher all-cause mortality among women who were treated with an MIS approach, compared with those treated with laparotomy (hazard ratio, 1.65). They also observed a significant decline in the survival from cervical cancer annually that corresponded to the uptake of MIS radical hysterectomies.
In the wake of these publications, many concluded that gynecologic oncologists should no longer offer a minimally invasive approach for radical hysterectomy. Certainly level I evidence published in a highly influential journal is compelling, and the consistency in findings over two studies adds further weight to the results. However, was this the correct conclusion to draw from these results? Surgeons who had been performing MIS radical hysterectomies for many years with favorable outcomes are challenging this and are raising questions about external generalizability and whether these findings were driven by the surgery itself or by the surgeon.
The studies’ authors proposed hypotheses for their results that implicate the surgical route rather than the surgeon; however, these seem ad hoc and not well supported by data, including the authors’ own data. The first was the hypothesis that cervical tumors were being disrupted and disseminated through the use of uterine manipulators in MIS approaches. However, cervical cancers are fairly routinely “disrupted” by preoperative cone biopsies, loop electrosurgical excision procedures (LEEP), and sharp biopsies, which are arguably more invasive than placement of a manipulator. Uterine manipulators routinely are used in endometrial cancer surgeries, in which the manipulator is embedded within the tumor, without an associated negative survival effect in randomized trials.3 Additionally, not all surgeons utilize manipulators for radical hysterectomies, and these studies did not measure or report on their use; therefore, it is impossible to know whether, and by what magnitude, manipulators played a role. Finally, if uterine manipulators are the explanation for inferior survival, surely the recommendation should be to discourage their use, rather than abandon the MIS approach all together.
The other explanation offered was exposure of the tumor to CO2 gas. This seems an even less plausible explanation because CO2 gas is routinely used in MIS cancer surgeries for endometrial, prostate, gastric, and colorectal surgeries and is used as insufflation for malignant interventional endoscopies without a significant deleterious effect. Additionally, the cervix is not exposed to CO2 until colpotomy at the procedure’s end – and only briefly. The in vitro studies implicating a negative effect of simulated CO2 pneumoperitoneum are neither compelling nor consistent.4,5
I would like to propose another hypothesis for the results: surgical proficiency. Surgery, unlike medical interventions, is not a simple variable that is dichotomous – performed or not. Surgeons do not randomly select operative approaches for patients. We select surgical approaches based on patients’ circumstances and surgeon factors, including our own mastery of the various techniques. Randomized surgical trials rely on the notion that a surgeon is equally skilled in both or all approaches offered, but this is clearly not the case, and any surgeon recognizes this if he or she has observed more than one surgeon or has attempted a procedure via different routes. While some procedures, such as extrafascial hysterectomy for endometrial cancer, are relatively straightforward and surgeon capabilities are more equitable across different approaches, cervical cancer surgery is quite different.
Early-stage cervical cancer primarily exerts radial growth into the cervical stroma and parametria. Curative surgical excision requires broadly negative margins through this tissue, a so called “radical hysterectomy.” The radicality of hysterectomy has been categorized in stages, acknowledging that different sized lesions require different volumes of parametrial resection to achieve adequate clearance from the tumor.6 In doing so, the surgeon must skeletonize and mobilize the distal ureters, cardinal ligament webs, and uterosacral ligaments. These structures are in close proximity to major vascular and neural structures. Hence, the radical hysterectomy is, without dispute, a technically challenging procedure.
Minimally invasive surgery further handicaps the surgeon by eliminating manual contact with tissue, and relying on complex instrumentation, electrosurgical modalities, and loss of haptics. The learning curve for MIS radical hysterectomy is further attenuated by their relative infrequency. Therefore, it makes sense that, when the MIS approach is randomly assigned to surgeons (such as in the LACC trial) or broadly and independently applied (as in the retrospective series), one might see variations in skill, quality, and outcomes, including oncologic outcomes.
The retrospective study by Melamed et al. acknowledged that surgeon skill and volume may contribute to their findings but stated that, because of the nature of their source data, they were unable to explain why they observed their results. The LACC trial attempted to overcome the issue of surgeon skill by ensuring all surgeons were from high-volume sites and had videos reviewed of their cases. However, the videos were chosen by the surgeons themselves and not available for audit in the study’s supplemental material. The LACC trial was conducted over a 9-year period across 33 sites and enrolled a total of 631 subjects. This equates to an enrollment of approximately two patients per site per year and either reflects extremely low-volume sites or highly selective patient enrollment. If the latter, what was different about the unenrolled patients and what was the preferred chosen route of surgery for them?
All 34 recurrences occurred in patients from just 14 of the 33 sites in the LACC trial. That means that less than half of the sites contributed to all of the recurrences. The authors provided no details on the specific sites, surgeons, or accrual rates in their manuscript or supplemental materials. Therefore, readers are unable to know what was different about those sites; whether they contributed the most patients and, therefore, the most recurrences; or whether they were low-volume sites with lower quality.
While margin status, positive or negative, was reported, there was no data captured regarding volume of resected parametrial tissue, or relative distance from tumor to margin, both of which might provide the reader with a better appraisal of surgeon proficiency and consistency in radicality of the two approaches. The incidence of locoregional (pelvic) recurrences were higher in the MIS arm, which is expected if there were inadequate margins around the laparoscopically resected tumors.
Finally, the authors of the LACC trial observed equivalent rates of postoperative complications between the laparotomy and MIS groups. The main virtue for MIS approaches is the reduction in perioperative morbidity. To observe no perioperative morbidity benefit in the MIS group is a red flag suggesting that these surgeons may not have achieved proficiency with the MIS approach.
Despite these arguments, the results of these studies should be taken seriously. Clearly, it is apparent that preservation of oncologic outcomes is not guaranteed with MIS radical hysterectomy, and it should not be the chosen approach for all patients and all surgeons. However, rather than entirely abandoning this less morbid approach, I would argue that it is a call to arms for gynecologic oncologists to self-evaluate. We should know our own data with respect to case volumes, perioperative complications, and cancer-related recurrence and death.
Perhaps MIS radical hysterectomies should be consolidated among high-volume surgeons with demonstrated good outcomes? Just as has been done for rectal cancer surgery with positive effect, we should establish accredited centers of excellence.7 We also need to improve the training of surgeons in novel, difficult techniques, as well as enhance the sophistication of MIS equipment such as improved instrumentation, haptics, and vision-guided surgery (for example, real-time intraoperative assessment of the tumor margins).
Let’s not take a wholesale step backwards to the surgical approaches of a 100 years ago just because they are more straightforward. Let’s do a better job of advancing the quality of what we do for our patients in the future.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no conflicts of interest. Email Dr. Rossi at [email protected].
Shock waves moved through the gynecologic oncology world on Oct. 31, 2018, when the New England Journal of Medicine published two papers on survival outcomes for women undergoing surgery for early stage cervical cancer.
Dr. Emma C. Rossi
The first was a randomized controlled trial of laparotomy and minimally invasive surgery (MIS) for radical hysterectomy called the LACC trial.1 In the multicenter, international trial of 631 women, the primary objective was disease-specific survival (cervical cancer–related deaths) and was powered to detect noninferiority of the MIS approach when compared with laparotomy. The trial was closed early when investigators noted a lower than expected rate of 3-year, disease-free survival (91% vs. 97%) from cervical cancer in the MIS group, which was made up of 84% laparoscopic and 16% robotic approaches, versus laparotomy. There were 19 deaths in the MIS group observed versus three in the laparotomy group. The conclusions of the trial were that MIS surgery is associated with inferior cervical cancer survival.
In the second study, authors analyzed data from large U.S. databases – the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) Program – to collect all-cause mortality for patients with early-stage cervical cancer who had undergone radical hysterectomy during 2010-2013.2 Among 2,461 observed results, 1,225 had undergone MIS surgery with the majority (79.8%) via robotic-assistance. Women undergoing MIS approaches had smaller, lower grade tumors; were more likely to be white, privately insured, and of a higher income; and had surgery later in the cohort and by nonacademic centers. The researchers adjusted for risk factors with an analytic process called propensity-score weighting, which matched the groups more closely in an attempt to minimize confounders. They identified higher all-cause mortality among women who were treated with an MIS approach, compared with those treated with laparotomy (hazard ratio, 1.65). They also observed a significant decline in the survival from cervical cancer annually that corresponded to the uptake of MIS radical hysterectomies.
In the wake of these publications, many concluded that gynecologic oncologists should no longer offer a minimally invasive approach for radical hysterectomy. Certainly level I evidence published in a highly influential journal is compelling, and the consistency in findings over two studies adds further weight to the results. However, was this the correct conclusion to draw from these results? Surgeons who had been performing MIS radical hysterectomies for many years with favorable outcomes are challenging this and are raising questions about external generalizability and whether these findings were driven by the surgery itself or by the surgeon.
The studies’ authors proposed hypotheses for their results that implicate the surgical route rather than the surgeon; however, these seem ad hoc and not well supported by data, including the authors’ own data. The first was the hypothesis that cervical tumors were being disrupted and disseminated through the use of uterine manipulators in MIS approaches. However, cervical cancers are fairly routinely “disrupted” by preoperative cone biopsies, loop electrosurgical excision procedures (LEEP), and sharp biopsies, which are arguably more invasive than placement of a manipulator. Uterine manipulators routinely are used in endometrial cancer surgeries, in which the manipulator is embedded within the tumor, without an associated negative survival effect in randomized trials.3 Additionally, not all surgeons utilize manipulators for radical hysterectomies, and these studies did not measure or report on their use; therefore, it is impossible to know whether, and by what magnitude, manipulators played a role. Finally, if uterine manipulators are the explanation for inferior survival, surely the recommendation should be to discourage their use, rather than abandon the MIS approach all together.
The other explanation offered was exposure of the tumor to CO2 gas. This seems an even less plausible explanation because CO2 gas is routinely used in MIS cancer surgeries for endometrial, prostate, gastric, and colorectal surgeries and is used as insufflation for malignant interventional endoscopies without a significant deleterious effect. Additionally, the cervix is not exposed to CO2 until colpotomy at the procedure’s end – and only briefly. The in vitro studies implicating a negative effect of simulated CO2 pneumoperitoneum are neither compelling nor consistent.4,5
I would like to propose another hypothesis for the results: surgical proficiency. Surgery, unlike medical interventions, is not a simple variable that is dichotomous – performed or not. Surgeons do not randomly select operative approaches for patients. We select surgical approaches based on patients’ circumstances and surgeon factors, including our own mastery of the various techniques. Randomized surgical trials rely on the notion that a surgeon is equally skilled in both or all approaches offered, but this is clearly not the case, and any surgeon recognizes this if he or she has observed more than one surgeon or has attempted a procedure via different routes. While some procedures, such as extrafascial hysterectomy for endometrial cancer, are relatively straightforward and surgeon capabilities are more equitable across different approaches, cervical cancer surgery is quite different.
Early-stage cervical cancer primarily exerts radial growth into the cervical stroma and parametria. Curative surgical excision requires broadly negative margins through this tissue, a so called “radical hysterectomy.” The radicality of hysterectomy has been categorized in stages, acknowledging that different sized lesions require different volumes of parametrial resection to achieve adequate clearance from the tumor.6 In doing so, the surgeon must skeletonize and mobilize the distal ureters, cardinal ligament webs, and uterosacral ligaments. These structures are in close proximity to major vascular and neural structures. Hence, the radical hysterectomy is, without dispute, a technically challenging procedure.
Minimally invasive surgery further handicaps the surgeon by eliminating manual contact with tissue, and relying on complex instrumentation, electrosurgical modalities, and loss of haptics. The learning curve for MIS radical hysterectomy is further attenuated by their relative infrequency. Therefore, it makes sense that, when the MIS approach is randomly assigned to surgeons (such as in the LACC trial) or broadly and independently applied (as in the retrospective series), one might see variations in skill, quality, and outcomes, including oncologic outcomes.
The retrospective study by Melamed et al. acknowledged that surgeon skill and volume may contribute to their findings but stated that, because of the nature of their source data, they were unable to explain why they observed their results. The LACC trial attempted to overcome the issue of surgeon skill by ensuring all surgeons were from high-volume sites and had videos reviewed of their cases. However, the videos were chosen by the surgeons themselves and not available for audit in the study’s supplemental material. The LACC trial was conducted over a 9-year period across 33 sites and enrolled a total of 631 subjects. This equates to an enrollment of approximately two patients per site per year and either reflects extremely low-volume sites or highly selective patient enrollment. If the latter, what was different about the unenrolled patients and what was the preferred chosen route of surgery for them?
All 34 recurrences occurred in patients from just 14 of the 33 sites in the LACC trial. That means that less than half of the sites contributed to all of the recurrences. The authors provided no details on the specific sites, surgeons, or accrual rates in their manuscript or supplemental materials. Therefore, readers are unable to know what was different about those sites; whether they contributed the most patients and, therefore, the most recurrences; or whether they were low-volume sites with lower quality.
While margin status, positive or negative, was reported, there was no data captured regarding volume of resected parametrial tissue, or relative distance from tumor to margin, both of which might provide the reader with a better appraisal of surgeon proficiency and consistency in radicality of the two approaches. The incidence of locoregional (pelvic) recurrences were higher in the MIS arm, which is expected if there were inadequate margins around the laparoscopically resected tumors.
Finally, the authors of the LACC trial observed equivalent rates of postoperative complications between the laparotomy and MIS groups. The main virtue for MIS approaches is the reduction in perioperative morbidity. To observe no perioperative morbidity benefit in the MIS group is a red flag suggesting that these surgeons may not have achieved proficiency with the MIS approach.
Despite these arguments, the results of these studies should be taken seriously. Clearly, it is apparent that preservation of oncologic outcomes is not guaranteed with MIS radical hysterectomy, and it should not be the chosen approach for all patients and all surgeons. However, rather than entirely abandoning this less morbid approach, I would argue that it is a call to arms for gynecologic oncologists to self-evaluate. We should know our own data with respect to case volumes, perioperative complications, and cancer-related recurrence and death.
Perhaps MIS radical hysterectomies should be consolidated among high-volume surgeons with demonstrated good outcomes? Just as has been done for rectal cancer surgery with positive effect, we should establish accredited centers of excellence.7 We also need to improve the training of surgeons in novel, difficult techniques, as well as enhance the sophistication of MIS equipment such as improved instrumentation, haptics, and vision-guided surgery (for example, real-time intraoperative assessment of the tumor margins).
Let’s not take a wholesale step backwards to the surgical approaches of a 100 years ago just because they are more straightforward. Let’s do a better job of advancing the quality of what we do for our patients in the future.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no conflicts of interest. Email Dr. Rossi at [email protected].
Quality in medicine is a peculiar thing. It is clearly apparent, and yet, can be very difficult to measure and quantify. Surgery, a performance art of sorts, can be even more challenging to qualify or rate. However, as a means to elevate the quality of care for all patients, hospital systems and care providers have aggressively made attempts to do so. This is a noble objective.
U.S. Air Force photo by Staff Sgt. Ciara Gosier
In September 2018, the Committee of Gynecologic Practice of the American College of Obstetricians and Gynecologists released ACOG Committee Opinion Number 750, titled, “Perioperative Pathways: Enhanced Recovery After Surgery.”1
The goals of this committee opinion were to advocate for gynecologic surgeons using the “ERAS” pathways in their perioperative care as part of an evidenced-based approach to quality improvement. ERAS pathways have been previously discussed in this column and feature bundled perioperative pathways that incorporate various concepts such as avoidance of prolonged preoperative fasting, early postoperative feeding, multimodal analgesia (with an avoidance of opiates), and inclusion of antibiotic and antiembolic prophylaxis, among other elements.
What was alarming upon closer review of this ACOG Committee Opinion was its omission of the randomized controlled trial by Dickson et al., the only randomized trial published in gynecologic surgery evaluating ERAS pathways.2 This trial compared the length of stay for patients receiving laparotomy for gynecologic cancer surgery who received perioperative care according the ERAS pathway versus those who received standard perioperative care. They found no difference in length of stay – the primary outcome – between the two groups, an impressive 3 days for both. The secondary outcome of postoperative pain was improved for the ERAS group for some of the time points. It was likely that the excellent outcomes in both groups resulted from a Hawthorne effect in which the behavior of study participants is influenced by the fact that they were being observed, in addition to the fact that the physicians involved in the study already were practicing high quality care as part of their “standard” regimen. It simply may be that the act of trying to improve quality is what improves outcomes, not a specific pathway. As senior author, Dr. Peter A. Argenta, explained to me, many of the ERAS elements are “simply good medicine.”
ERAS pathways are an example of process measures of quality. They include elements of care or processes in the delivery of care that are thought to be associated with improved outcomes. Prescription of antibiotics or venous thromboembolism (VTE) prophylaxis are other examples of process measures thought to be associated with improved surgical quality. Rather than rating surgeons’ outcomes (surgical site infection), surgeons are rated on their compliance with a process (the rate of appropriate perioperative antibiotic prescription). However, high compliance with these processes is not automatically associated with improved observed outcomes. For example, hospitals that meet the definition of high quality by virtue of structural measures (such as procedural volume and use of hospital-level quality initiatives) are associated with worse risk-adjusted VTE rates despite demonstrating higher adherence to VTE prophylaxis.3 This is felt to be a function of surveillance bias and the fact that these same hospitals have better capabilities to capture events as part of a feedback mechanism built into their quality initiatives.
What ERAS has favorably done for surgical care is to shine a glaring light on and challenge the unnecessary, old-fashioned, and non–patient-centric interventions that were considered dogma by many. For example, minimizing preoperative fasting is most certainly a patient-friendly adjustment that should absolutely be embraced, regardless of whether or not it speeds up time to discharge. Multimodal approaches to analgesia consistently have been shown to preserve or improve postoperative pain levels with a focus on minimizing opiate use, once again a noble and patient-centered objective.
However, all too many surgical quality interventions focus on their ability to reduce postoperative length of stay. Length of stay is an important driver of health care cost, and an indirect measure of perioperative complications; however, it is not a patient-centered outcome. So long as patients recover from their surgery quickly with respect to pain and function, the location of that recovery (home versus hospital) is less of a focus for most patients. In addition, in the pursuit of shorter hospital stays and less perioperative morbidity, we may encourage practices with unintentional adverse patient-centered outcomes. For example, to preserve a surgeon’s quality metrics, patients who are at high risk for complications may not be offered surgery at all. Long-term ovarian cancer outcomes, such as survival, can be negatively impacted when surgeons opt for less morbid, less radical surgical approaches which have favorable short-term morbidity such as surgical complications and readmissions.4
Ultimately we are most likely to see improvement in quality with a complex, nuanced approach to metrics, not simplistic interventions or pathways. We should recognize interventions that are consistently associated with better outcomes such as high procedural volume, consolidating less common procedures to fewer surgeons, data ascertainment, and reporting data to surgeons.5 Physicians need to take ownership and involvement in the quality metrics that are created to assess the care we provide. Hospital administrators may not fully understand the confounders, such as comorbidities, that contribute to outcomes, which can lead to mischaracterization, cause unfair comparisons between surgeons, or create unintentional incentives that are not patient-centered.6
Dr. Emma C. Rossi
We all need to understand the epidemiologic science behind evidence-based medicine and to be sophisticated in our ability to review and appraise data so that we can be sensible in what interventions we promote as supported by good evidence. If we fail to correctly identify and characterize what is truly good quality, if we miss the point of what is driving outcomes, or overstate the value of certain interventions, we miss the opportunity to intervene in ways that actually do make a meaningful difference.
Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no conflicts of interest. Email Dr. Rossi at [email protected].
Quality in medicine is a peculiar thing. It is clearly apparent, and yet, can be very difficult to measure and quantify. Surgery, a performance art of sorts, can be even more challenging to qualify or rate. However, as a means to elevate the quality of care for all patients, hospital systems and care providers have aggressively made attempts to do so. This is a noble objective.
U.S. Air Force photo by Staff Sgt. Ciara Gosier
In September 2018, the Committee of Gynecologic Practice of the American College of Obstetricians and Gynecologists released ACOG Committee Opinion Number 750, titled, “Perioperative Pathways: Enhanced Recovery After Surgery.”1
The goals of this committee opinion were to advocate for gynecologic surgeons using the “ERAS” pathways in their perioperative care as part of an evidenced-based approach to quality improvement. ERAS pathways have been previously discussed in this column and feature bundled perioperative pathways that incorporate various concepts such as avoidance of prolonged preoperative fasting, early postoperative feeding, multimodal analgesia (with an avoidance of opiates), and inclusion of antibiotic and antiembolic prophylaxis, among other elements.
What was alarming upon closer review of this ACOG Committee Opinion was its omission of the randomized controlled trial by Dickson et al., the only randomized trial published in gynecologic surgery evaluating ERAS pathways.2 This trial compared the length of stay for patients receiving laparotomy for gynecologic cancer surgery who received perioperative care according the ERAS pathway versus those who received standard perioperative care. They found no difference in length of stay – the primary outcome – between the two groups, an impressive 3 days for both. The secondary outcome of postoperative pain was improved for the ERAS group for some of the time points. It was likely that the excellent outcomes in both groups resulted from a Hawthorne effect in which the behavior of study participants is influenced by the fact that they were being observed, in addition to the fact that the physicians involved in the study already were practicing high quality care as part of their “standard” regimen. It simply may be that the act of trying to improve quality is what improves outcomes, not a specific pathway. As senior author, Dr. Peter A. Argenta, explained to me, many of the ERAS elements are “simply good medicine.”
ERAS pathways are an example of process measures of quality. They include elements of care or processes in the delivery of care that are thought to be associated with improved outcomes. Prescription of antibiotics or venous thromboembolism (VTE) prophylaxis are other examples of process measures thought to be associated with improved surgical quality. Rather than rating surgeons’ outcomes (surgical site infection), surgeons are rated on their compliance with a process (the rate of appropriate perioperative antibiotic prescription). However, high compliance with these processes is not automatically associated with improved observed outcomes. For example, hospitals that meet the definition of high quality by virtue of structural measures (such as procedural volume and use of hospital-level quality initiatives) are associated with worse risk-adjusted VTE rates despite demonstrating higher adherence to VTE prophylaxis.3 This is felt to be a function of surveillance bias and the fact that these same hospitals have better capabilities to capture events as part of a feedback mechanism built into their quality initiatives.
What ERAS has favorably done for surgical care is to shine a glaring light on and challenge the unnecessary, old-fashioned, and non–patient-centric interventions that were considered dogma by many. For example, minimizing preoperative fasting is most certainly a patient-friendly adjustment that should absolutely be embraced, regardless of whether or not it speeds up time to discharge. Multimodal approaches to analgesia consistently have been shown to preserve or improve postoperative pain levels with a focus on minimizing opiate use, once again a noble and patient-centered objective.
However, all too many surgical quality interventions focus on their ability to reduce postoperative length of stay. Length of stay is an important driver of health care cost, and an indirect measure of perioperative complications; however, it is not a patient-centered outcome. So long as patients recover from their surgery quickly with respect to pain and function, the location of that recovery (home versus hospital) is less of a focus for most patients. In addition, in the pursuit of shorter hospital stays and less perioperative morbidity, we may encourage practices with unintentional adverse patient-centered outcomes. For example, to preserve a surgeon’s quality metrics, patients who are at high risk for complications may not be offered surgery at all. Long-term ovarian cancer outcomes, such as survival, can be negatively impacted when surgeons opt for less morbid, less radical surgical approaches which have favorable short-term morbidity such as surgical complications and readmissions.4
Ultimately we are most likely to see improvement in quality with a complex, nuanced approach to metrics, not simplistic interventions or pathways. We should recognize interventions that are consistently associated with better outcomes such as high procedural volume, consolidating less common procedures to fewer surgeons, data ascertainment, and reporting data to surgeons.5 Physicians need to take ownership and involvement in the quality metrics that are created to assess the care we provide. Hospital administrators may not fully understand the confounders, such as comorbidities, that contribute to outcomes, which can lead to mischaracterization, cause unfair comparisons between surgeons, or create unintentional incentives that are not patient-centered.6
Dr. Emma C. Rossi
We all need to understand the epidemiologic science behind evidence-based medicine and to be sophisticated in our ability to review and appraise data so that we can be sensible in what interventions we promote as supported by good evidence. If we fail to correctly identify and characterize what is truly good quality, if we miss the point of what is driving outcomes, or overstate the value of certain interventions, we miss the opportunity to intervene in ways that actually do make a meaningful difference.
Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no conflicts of interest. Email Dr. Rossi at [email protected].
Quality in medicine is a peculiar thing. It is clearly apparent, and yet, can be very difficult to measure and quantify. Surgery, a performance art of sorts, can be even more challenging to qualify or rate. However, as a means to elevate the quality of care for all patients, hospital systems and care providers have aggressively made attempts to do so. This is a noble objective.
U.S. Air Force photo by Staff Sgt. Ciara Gosier
In September 2018, the Committee of Gynecologic Practice of the American College of Obstetricians and Gynecologists released ACOG Committee Opinion Number 750, titled, “Perioperative Pathways: Enhanced Recovery After Surgery.”1
The goals of this committee opinion were to advocate for gynecologic surgeons using the “ERAS” pathways in their perioperative care as part of an evidenced-based approach to quality improvement. ERAS pathways have been previously discussed in this column and feature bundled perioperative pathways that incorporate various concepts such as avoidance of prolonged preoperative fasting, early postoperative feeding, multimodal analgesia (with an avoidance of opiates), and inclusion of antibiotic and antiembolic prophylaxis, among other elements.
What was alarming upon closer review of this ACOG Committee Opinion was its omission of the randomized controlled trial by Dickson et al., the only randomized trial published in gynecologic surgery evaluating ERAS pathways.2 This trial compared the length of stay for patients receiving laparotomy for gynecologic cancer surgery who received perioperative care according the ERAS pathway versus those who received standard perioperative care. They found no difference in length of stay – the primary outcome – between the two groups, an impressive 3 days for both. The secondary outcome of postoperative pain was improved for the ERAS group for some of the time points. It was likely that the excellent outcomes in both groups resulted from a Hawthorne effect in which the behavior of study participants is influenced by the fact that they were being observed, in addition to the fact that the physicians involved in the study already were practicing high quality care as part of their “standard” regimen. It simply may be that the act of trying to improve quality is what improves outcomes, not a specific pathway. As senior author, Dr. Peter A. Argenta, explained to me, many of the ERAS elements are “simply good medicine.”
ERAS pathways are an example of process measures of quality. They include elements of care or processes in the delivery of care that are thought to be associated with improved outcomes. Prescription of antibiotics or venous thromboembolism (VTE) prophylaxis are other examples of process measures thought to be associated with improved surgical quality. Rather than rating surgeons’ outcomes (surgical site infection), surgeons are rated on their compliance with a process (the rate of appropriate perioperative antibiotic prescription). However, high compliance with these processes is not automatically associated with improved observed outcomes. For example, hospitals that meet the definition of high quality by virtue of structural measures (such as procedural volume and use of hospital-level quality initiatives) are associated with worse risk-adjusted VTE rates despite demonstrating higher adherence to VTE prophylaxis.3 This is felt to be a function of surveillance bias and the fact that these same hospitals have better capabilities to capture events as part of a feedback mechanism built into their quality initiatives.
What ERAS has favorably done for surgical care is to shine a glaring light on and challenge the unnecessary, old-fashioned, and non–patient-centric interventions that were considered dogma by many. For example, minimizing preoperative fasting is most certainly a patient-friendly adjustment that should absolutely be embraced, regardless of whether or not it speeds up time to discharge. Multimodal approaches to analgesia consistently have been shown to preserve or improve postoperative pain levels with a focus on minimizing opiate use, once again a noble and patient-centered objective.
However, all too many surgical quality interventions focus on their ability to reduce postoperative length of stay. Length of stay is an important driver of health care cost, and an indirect measure of perioperative complications; however, it is not a patient-centered outcome. So long as patients recover from their surgery quickly with respect to pain and function, the location of that recovery (home versus hospital) is less of a focus for most patients. In addition, in the pursuit of shorter hospital stays and less perioperative morbidity, we may encourage practices with unintentional adverse patient-centered outcomes. For example, to preserve a surgeon’s quality metrics, patients who are at high risk for complications may not be offered surgery at all. Long-term ovarian cancer outcomes, such as survival, can be negatively impacted when surgeons opt for less morbid, less radical surgical approaches which have favorable short-term morbidity such as surgical complications and readmissions.4
Ultimately we are most likely to see improvement in quality with a complex, nuanced approach to metrics, not simplistic interventions or pathways. We should recognize interventions that are consistently associated with better outcomes such as high procedural volume, consolidating less common procedures to fewer surgeons, data ascertainment, and reporting data to surgeons.5 Physicians need to take ownership and involvement in the quality metrics that are created to assess the care we provide. Hospital administrators may not fully understand the confounders, such as comorbidities, that contribute to outcomes, which can lead to mischaracterization, cause unfair comparisons between surgeons, or create unintentional incentives that are not patient-centered.6
Dr. Emma C. Rossi
We all need to understand the epidemiologic science behind evidence-based medicine and to be sophisticated in our ability to review and appraise data so that we can be sensible in what interventions we promote as supported by good evidence. If we fail to correctly identify and characterize what is truly good quality, if we miss the point of what is driving outcomes, or overstate the value of certain interventions, we miss the opportunity to intervene in ways that actually do make a meaningful difference.
Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no conflicts of interest. Email Dr. Rossi at [email protected].
Vaginal intraepithelial neoplasia (VAIN) is a condition that frequently poses therapeutic dilemmas for gynecologists. VAIN represents dysplastic changes to the epithelium of the vaginal mucosa, and like cervical neoplasia, the extent of disease is characterized as levels I, II, or III dependent upon the depth of involvement in the epithelial layer by dysplastic cells. While VAIN itself typically is asymptomatic and not a harmful condition, it carries a 12% risk of progression to invasive vaginal carcinoma, so accurate identification, thorough treatment, and ongoing surveillance are essential.1
Dr. Emma C. Rossi
VAIN is associated with high-risk human papillomavirus (HPV) infection, tobacco use, and prior cervical dysplasia. Of women with VAIN, 65% have undergone a prior hysterectomy for cervical dysplasia, which emphasizes the nondefinitive nature of such an intervention.2 These women should be very closely followed for at least 20 years with vaginal cytologic and/or HPV surveillance. High-risk HPV infection is present in 85% of women with VAIN, and the presence of high-risk HPV is a predictor for recurrent VAIN. Recurrent and persistent VAIN also is more common in postmenopausal women and those with multifocal disease.
The most common location for VAIN is at the upper third of the vagina (including the vaginal cuff). It commonly arises within the vaginal fornices, which may be difficult to fully visualize because of their puckered appearance, redundant vaginal tissues, and extensive vaginal rogation.
A diagnosis of VAIN is typically obtained from vaginal cytology which reveals atypical or dysplastic cells. Such a result should prompt the physician to perform vaginal colposcopy and directed biopsies. Comprehensive visualization of the vaginal cuff can be limited in cases where the vaginal fornices are tethered, deeply puckered, or when there is significant mucosal rogation.
The application of 4% acetic acid or Lugol’s iodine are techniques that can enhance the detection of dysplastic vaginal mucosa. Lugol’s iodine selectively stains normal, glycogenated cells, and spares dysplastic glycogen-free cells. The sharp contrast between the brown iodine-stained tissues and the white dysplastic tissues aids in detection of dysplastic areas.
If colposcopic biopsy reveals low grade dysplasia (VAIN I) it does not require intervention, and has a very low rate of conversion to invasive vaginal carcinoma. However moderate- and high-grade vaginal dysplastic lesions should be treated because of the potential for malignant transformation.
Options for treatment of VAIN include topical, ablative, and excisional procedures. Observation also is an option but should be reserved for patients who are closely monitored with repeated colposcopic examinations, and probably should best be reserved for patients with VAIN I or II lesions.
Excisional procedures
The most common excisional procedure employed for VAIN is upper vaginectomy. In this procedure, the surgeon grasps and tents up the vaginal mucosa, incises the mucosa without penetrating the subepithelial tissue layers such as bladder and rectum. The vaginal mucosa then is carefully separated from the underlying endopelvic fascial plane. The specimen should be oriented, ideally on a cork board, with pins or sutures to ascribe margins and borders. Excision is best utilized for women with unifocal disease, or those who fail or do not tolerate ablative or topical interventions.
The most significant risks of excision include the potential for damage to underlying pelvic visceral structures, which is particularly concerning in postmenopausal women with thin vaginal epithelium. Vaginectomy is commonly associated with vaginal shortening or narrowing, which can be deleterious for quality of life. Retrospective series have described a 30% incidence of recurrence after vaginectomy, likely secondary to incomplete excision of all affected tissue.3
Ablation
Ablation of dysplastic foci with a carbon dioxide (CO2) laser is a common method for treatment of VAIN. CO2 laser should ablate tissue to a 1.5 mm minimum depth.3 The benefit of using CO2 laser is its ability to treat multifocal disease in situ without an extensive excisional procedure.
It is technically more straightforward than upper vaginectomy with less blood loss and shorter surgical times, and it can be easily accomplished in an outpatient surgical or office setting. However, one of its greatest limitations is the difficulty in visualizing all lesions and therefore adequately treating all sites. The vaginal rogations also make adequate laser ablation challenging because laser only is able to effectively ablate tissue that is oriented perpendicular to the laser beam.
In addition, there is no pathologic confirmation of adequacy of excision or margin status. These features may contribute to the modestly higher rates of recurrence of dysplasia following laser ablation, compared with vaginectomy.3 It also has been associated with more vaginal scarring than vaginectomy, which can have a negative effect on sexual health.
Topical agents
The most commonly utilized topical therapy for VAIN is the antimetabolite chemotherapeutic agent 5-fluorouracil (5FU). A typical schedule for 5FU treatment is to apply vaginally, at night, once a week for 8 weeks.4 Because it can cause extensive irritation to the vulvar and urethral epithelium, patients are recommended to apply barrier creams or ointments before and following the use of 5FU for several days, wash hands thoroughly after application, and to rinse and shower in the morning after rising. Severe irritation occurs in up to 16% of patients, but in general it is very well tolerated.
Its virtue is that it is able to conform and travel to all parts of the vaginal mucosa, including those that are poorly visualized within the fornices or vaginal folds. 5FU does not require a hospitalization or surgical procedure, can be applied by the patient at home, and preserves vaginal length and function. In recent reports, 5FU is associated with the lowest rates of recurrence (10%-30%), compared with excision or ablation, and therefore is a very attractive option for primary therapy.3 However, it requires patients to have a degree of comfort with vaginal application of drug and adherence with perineal care strategies to minimize the likelihood of toxicity.
The immune response modifier, imiquimod, that is commonly used in the treatment of vulvar dysplasia also has been described in the treatment of VAIN. It appears to have high rates of clearance (greater than 75%) and be most effective in the treatment of VAIN I.5 It requires application under colposcopic guidance three times a week for 8 weeks, which is a laborious undertaking for both patient and physician. Like 5FU, imiquimod is associated with vulvar and perineal irritation.
Vaginal estrogens are an alternative topical therapy for moderate- and high-grade VAIN and particularly useful for postmenopausal patients. They have been associated with a high rate (up to 90%) of resolution on follow-up vaginal cytology testing and are not associated with toxicities of the above stated therapies.6 Vaginal estrogen can be used alone or in addition to other therapeutic strategies. For example, it can be added to the nontreatment days of 5FU or postoperatively prescribed following laser or excisional procedures.
Radiation
Intracavitary brachytherapy is a technique in which a radiation source is placed within a cylinder or ovoids and placed within the vagina.7 Typically 45 Gy is delivered to a depth 0.5mm below the vaginal mucosal surface (“point z”). Recurrence occurs is approximately 10%-15% of patients, and toxicities can be severe, including vaginal stenosis and ulceration. This aggressive therapy typically is best reserved for cases that are refractory to other therapies. Following radiation, subsequent treatments are more difficult because of radiation-induced changes to the vaginal mucosa that can affect healing.
Vaginal dysplasia is a relatively common sequelae of high-risk HPV, particularly among women who have had a prior hysterectomy for cervical dysplasia. Because of anatomic changes following hysterectomy, adequate visualization and comprehensive vaginal treatment is difficult. Therefore, surgeons should avoid utilization of hysterectomy as a routine strategy to “cure” dysplasia as it may fail to achieve this cure and make subsequent evaluations and treatments of persistent dysplasia more difficult. Women who have had a hysterectomy for dysplasia should be closely followed for several decades, and they should be counseled that they have a persistent risk for vaginal disease. When VAIN develops, clinicians should consider topical therapies as primary treatment options because they may minimize toxicity and have high rates of enduring response.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She had no relevant conflicts of interest.
Vaginal intraepithelial neoplasia (VAIN) is a condition that frequently poses therapeutic dilemmas for gynecologists. VAIN represents dysplastic changes to the epithelium of the vaginal mucosa, and like cervical neoplasia, the extent of disease is characterized as levels I, II, or III dependent upon the depth of involvement in the epithelial layer by dysplastic cells. While VAIN itself typically is asymptomatic and not a harmful condition, it carries a 12% risk of progression to invasive vaginal carcinoma, so accurate identification, thorough treatment, and ongoing surveillance are essential.1
Dr. Emma C. Rossi
VAIN is associated with high-risk human papillomavirus (HPV) infection, tobacco use, and prior cervical dysplasia. Of women with VAIN, 65% have undergone a prior hysterectomy for cervical dysplasia, which emphasizes the nondefinitive nature of such an intervention.2 These women should be very closely followed for at least 20 years with vaginal cytologic and/or HPV surveillance. High-risk HPV infection is present in 85% of women with VAIN, and the presence of high-risk HPV is a predictor for recurrent VAIN. Recurrent and persistent VAIN also is more common in postmenopausal women and those with multifocal disease.
The most common location for VAIN is at the upper third of the vagina (including the vaginal cuff). It commonly arises within the vaginal fornices, which may be difficult to fully visualize because of their puckered appearance, redundant vaginal tissues, and extensive vaginal rogation.
A diagnosis of VAIN is typically obtained from vaginal cytology which reveals atypical or dysplastic cells. Such a result should prompt the physician to perform vaginal colposcopy and directed biopsies. Comprehensive visualization of the vaginal cuff can be limited in cases where the vaginal fornices are tethered, deeply puckered, or when there is significant mucosal rogation.
The application of 4% acetic acid or Lugol’s iodine are techniques that can enhance the detection of dysplastic vaginal mucosa. Lugol’s iodine selectively stains normal, glycogenated cells, and spares dysplastic glycogen-free cells. The sharp contrast between the brown iodine-stained tissues and the white dysplastic tissues aids in detection of dysplastic areas.
If colposcopic biopsy reveals low grade dysplasia (VAIN I) it does not require intervention, and has a very low rate of conversion to invasive vaginal carcinoma. However moderate- and high-grade vaginal dysplastic lesions should be treated because of the potential for malignant transformation.
Options for treatment of VAIN include topical, ablative, and excisional procedures. Observation also is an option but should be reserved for patients who are closely monitored with repeated colposcopic examinations, and probably should best be reserved for patients with VAIN I or II lesions.
Excisional procedures
The most common excisional procedure employed for VAIN is upper vaginectomy. In this procedure, the surgeon grasps and tents up the vaginal mucosa, incises the mucosa without penetrating the subepithelial tissue layers such as bladder and rectum. The vaginal mucosa then is carefully separated from the underlying endopelvic fascial plane. The specimen should be oriented, ideally on a cork board, with pins or sutures to ascribe margins and borders. Excision is best utilized for women with unifocal disease, or those who fail or do not tolerate ablative or topical interventions.
The most significant risks of excision include the potential for damage to underlying pelvic visceral structures, which is particularly concerning in postmenopausal women with thin vaginal epithelium. Vaginectomy is commonly associated with vaginal shortening or narrowing, which can be deleterious for quality of life. Retrospective series have described a 30% incidence of recurrence after vaginectomy, likely secondary to incomplete excision of all affected tissue.3
Ablation
Ablation of dysplastic foci with a carbon dioxide (CO2) laser is a common method for treatment of VAIN. CO2 laser should ablate tissue to a 1.5 mm minimum depth.3 The benefit of using CO2 laser is its ability to treat multifocal disease in situ without an extensive excisional procedure.
It is technically more straightforward than upper vaginectomy with less blood loss and shorter surgical times, and it can be easily accomplished in an outpatient surgical or office setting. However, one of its greatest limitations is the difficulty in visualizing all lesions and therefore adequately treating all sites. The vaginal rogations also make adequate laser ablation challenging because laser only is able to effectively ablate tissue that is oriented perpendicular to the laser beam.
In addition, there is no pathologic confirmation of adequacy of excision or margin status. These features may contribute to the modestly higher rates of recurrence of dysplasia following laser ablation, compared with vaginectomy.3 It also has been associated with more vaginal scarring than vaginectomy, which can have a negative effect on sexual health.
Topical agents
The most commonly utilized topical therapy for VAIN is the antimetabolite chemotherapeutic agent 5-fluorouracil (5FU). A typical schedule for 5FU treatment is to apply vaginally, at night, once a week for 8 weeks.4 Because it can cause extensive irritation to the vulvar and urethral epithelium, patients are recommended to apply barrier creams or ointments before and following the use of 5FU for several days, wash hands thoroughly after application, and to rinse and shower in the morning after rising. Severe irritation occurs in up to 16% of patients, but in general it is very well tolerated.
Its virtue is that it is able to conform and travel to all parts of the vaginal mucosa, including those that are poorly visualized within the fornices or vaginal folds. 5FU does not require a hospitalization or surgical procedure, can be applied by the patient at home, and preserves vaginal length and function. In recent reports, 5FU is associated with the lowest rates of recurrence (10%-30%), compared with excision or ablation, and therefore is a very attractive option for primary therapy.3 However, it requires patients to have a degree of comfort with vaginal application of drug and adherence with perineal care strategies to minimize the likelihood of toxicity.
The immune response modifier, imiquimod, that is commonly used in the treatment of vulvar dysplasia also has been described in the treatment of VAIN. It appears to have high rates of clearance (greater than 75%) and be most effective in the treatment of VAIN I.5 It requires application under colposcopic guidance three times a week for 8 weeks, which is a laborious undertaking for both patient and physician. Like 5FU, imiquimod is associated with vulvar and perineal irritation.
Vaginal estrogens are an alternative topical therapy for moderate- and high-grade VAIN and particularly useful for postmenopausal patients. They have been associated with a high rate (up to 90%) of resolution on follow-up vaginal cytology testing and are not associated with toxicities of the above stated therapies.6 Vaginal estrogen can be used alone or in addition to other therapeutic strategies. For example, it can be added to the nontreatment days of 5FU or postoperatively prescribed following laser or excisional procedures.
Radiation
Intracavitary brachytherapy is a technique in which a radiation source is placed within a cylinder or ovoids and placed within the vagina.7 Typically 45 Gy is delivered to a depth 0.5mm below the vaginal mucosal surface (“point z”). Recurrence occurs is approximately 10%-15% of patients, and toxicities can be severe, including vaginal stenosis and ulceration. This aggressive therapy typically is best reserved for cases that are refractory to other therapies. Following radiation, subsequent treatments are more difficult because of radiation-induced changes to the vaginal mucosa that can affect healing.
Vaginal dysplasia is a relatively common sequelae of high-risk HPV, particularly among women who have had a prior hysterectomy for cervical dysplasia. Because of anatomic changes following hysterectomy, adequate visualization and comprehensive vaginal treatment is difficult. Therefore, surgeons should avoid utilization of hysterectomy as a routine strategy to “cure” dysplasia as it may fail to achieve this cure and make subsequent evaluations and treatments of persistent dysplasia more difficult. Women who have had a hysterectomy for dysplasia should be closely followed for several decades, and they should be counseled that they have a persistent risk for vaginal disease. When VAIN develops, clinicians should consider topical therapies as primary treatment options because they may minimize toxicity and have high rates of enduring response.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She had no relevant conflicts of interest.
Vaginal intraepithelial neoplasia (VAIN) is a condition that frequently poses therapeutic dilemmas for gynecologists. VAIN represents dysplastic changes to the epithelium of the vaginal mucosa, and like cervical neoplasia, the extent of disease is characterized as levels I, II, or III dependent upon the depth of involvement in the epithelial layer by dysplastic cells. While VAIN itself typically is asymptomatic and not a harmful condition, it carries a 12% risk of progression to invasive vaginal carcinoma, so accurate identification, thorough treatment, and ongoing surveillance are essential.1
Dr. Emma C. Rossi
VAIN is associated with high-risk human papillomavirus (HPV) infection, tobacco use, and prior cervical dysplasia. Of women with VAIN, 65% have undergone a prior hysterectomy for cervical dysplasia, which emphasizes the nondefinitive nature of such an intervention.2 These women should be very closely followed for at least 20 years with vaginal cytologic and/or HPV surveillance. High-risk HPV infection is present in 85% of women with VAIN, and the presence of high-risk HPV is a predictor for recurrent VAIN. Recurrent and persistent VAIN also is more common in postmenopausal women and those with multifocal disease.
The most common location for VAIN is at the upper third of the vagina (including the vaginal cuff). It commonly arises within the vaginal fornices, which may be difficult to fully visualize because of their puckered appearance, redundant vaginal tissues, and extensive vaginal rogation.
A diagnosis of VAIN is typically obtained from vaginal cytology which reveals atypical or dysplastic cells. Such a result should prompt the physician to perform vaginal colposcopy and directed biopsies. Comprehensive visualization of the vaginal cuff can be limited in cases where the vaginal fornices are tethered, deeply puckered, or when there is significant mucosal rogation.
The application of 4% acetic acid or Lugol’s iodine are techniques that can enhance the detection of dysplastic vaginal mucosa. Lugol’s iodine selectively stains normal, glycogenated cells, and spares dysplastic glycogen-free cells. The sharp contrast between the brown iodine-stained tissues and the white dysplastic tissues aids in detection of dysplastic areas.
If colposcopic biopsy reveals low grade dysplasia (VAIN I) it does not require intervention, and has a very low rate of conversion to invasive vaginal carcinoma. However moderate- and high-grade vaginal dysplastic lesions should be treated because of the potential for malignant transformation.
Options for treatment of VAIN include topical, ablative, and excisional procedures. Observation also is an option but should be reserved for patients who are closely monitored with repeated colposcopic examinations, and probably should best be reserved for patients with VAIN I or II lesions.
Excisional procedures
The most common excisional procedure employed for VAIN is upper vaginectomy. In this procedure, the surgeon grasps and tents up the vaginal mucosa, incises the mucosa without penetrating the subepithelial tissue layers such as bladder and rectum. The vaginal mucosa then is carefully separated from the underlying endopelvic fascial plane. The specimen should be oriented, ideally on a cork board, with pins or sutures to ascribe margins and borders. Excision is best utilized for women with unifocal disease, or those who fail or do not tolerate ablative or topical interventions.
The most significant risks of excision include the potential for damage to underlying pelvic visceral structures, which is particularly concerning in postmenopausal women with thin vaginal epithelium. Vaginectomy is commonly associated with vaginal shortening or narrowing, which can be deleterious for quality of life. Retrospective series have described a 30% incidence of recurrence after vaginectomy, likely secondary to incomplete excision of all affected tissue.3
Ablation
Ablation of dysplastic foci with a carbon dioxide (CO2) laser is a common method for treatment of VAIN. CO2 laser should ablate tissue to a 1.5 mm minimum depth.3 The benefit of using CO2 laser is its ability to treat multifocal disease in situ without an extensive excisional procedure.
It is technically more straightforward than upper vaginectomy with less blood loss and shorter surgical times, and it can be easily accomplished in an outpatient surgical or office setting. However, one of its greatest limitations is the difficulty in visualizing all lesions and therefore adequately treating all sites. The vaginal rogations also make adequate laser ablation challenging because laser only is able to effectively ablate tissue that is oriented perpendicular to the laser beam.
In addition, there is no pathologic confirmation of adequacy of excision or margin status. These features may contribute to the modestly higher rates of recurrence of dysplasia following laser ablation, compared with vaginectomy.3 It also has been associated with more vaginal scarring than vaginectomy, which can have a negative effect on sexual health.
Topical agents
The most commonly utilized topical therapy for VAIN is the antimetabolite chemotherapeutic agent 5-fluorouracil (5FU). A typical schedule for 5FU treatment is to apply vaginally, at night, once a week for 8 weeks.4 Because it can cause extensive irritation to the vulvar and urethral epithelium, patients are recommended to apply barrier creams or ointments before and following the use of 5FU for several days, wash hands thoroughly after application, and to rinse and shower in the morning after rising. Severe irritation occurs in up to 16% of patients, but in general it is very well tolerated.
Its virtue is that it is able to conform and travel to all parts of the vaginal mucosa, including those that are poorly visualized within the fornices or vaginal folds. 5FU does not require a hospitalization or surgical procedure, can be applied by the patient at home, and preserves vaginal length and function. In recent reports, 5FU is associated with the lowest rates of recurrence (10%-30%), compared with excision or ablation, and therefore is a very attractive option for primary therapy.3 However, it requires patients to have a degree of comfort with vaginal application of drug and adherence with perineal care strategies to minimize the likelihood of toxicity.
The immune response modifier, imiquimod, that is commonly used in the treatment of vulvar dysplasia also has been described in the treatment of VAIN. It appears to have high rates of clearance (greater than 75%) and be most effective in the treatment of VAIN I.5 It requires application under colposcopic guidance three times a week for 8 weeks, which is a laborious undertaking for both patient and physician. Like 5FU, imiquimod is associated with vulvar and perineal irritation.
Vaginal estrogens are an alternative topical therapy for moderate- and high-grade VAIN and particularly useful for postmenopausal patients. They have been associated with a high rate (up to 90%) of resolution on follow-up vaginal cytology testing and are not associated with toxicities of the above stated therapies.6 Vaginal estrogen can be used alone or in addition to other therapeutic strategies. For example, it can be added to the nontreatment days of 5FU or postoperatively prescribed following laser or excisional procedures.
Radiation
Intracavitary brachytherapy is a technique in which a radiation source is placed within a cylinder or ovoids and placed within the vagina.7 Typically 45 Gy is delivered to a depth 0.5mm below the vaginal mucosal surface (“point z”). Recurrence occurs is approximately 10%-15% of patients, and toxicities can be severe, including vaginal stenosis and ulceration. This aggressive therapy typically is best reserved for cases that are refractory to other therapies. Following radiation, subsequent treatments are more difficult because of radiation-induced changes to the vaginal mucosa that can affect healing.
Vaginal dysplasia is a relatively common sequelae of high-risk HPV, particularly among women who have had a prior hysterectomy for cervical dysplasia. Because of anatomic changes following hysterectomy, adequate visualization and comprehensive vaginal treatment is difficult. Therefore, surgeons should avoid utilization of hysterectomy as a routine strategy to “cure” dysplasia as it may fail to achieve this cure and make subsequent evaluations and treatments of persistent dysplasia more difficult. Women who have had a hysterectomy for dysplasia should be closely followed for several decades, and they should be counseled that they have a persistent risk for vaginal disease. When VAIN develops, clinicians should consider topical therapies as primary treatment options because they may minimize toxicity and have high rates of enduring response.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She had no relevant conflicts of interest.
Cervical dysplasia is commonly diagnosed in women who have completed childbearing and don’t desire future fertility. While diagnostic and/or definitive therapy for cervical dysplasia can include hysterectomy, there are important considerations to make when offering this procedure to patients.
Dr. Emma C. Rossi
Pitfalls
Hysterectomy is commonly requested by patients upon learning of cervical dysplasia, particularly if they have chronic human papillomavirus (HPV) infection and have experienced years of frequent surveillance and interventions. They may see hysterectomy as an option to avoid this close surveillance and to be free of their dysplasia. There are two main concerns with offering hysterectomy as the primary surgical option for the management of dysplasia. Firstly, it may not be curative, and secondly, it may be an inadequate excisional procedure, particularly if the patient has occult invasive disease that has not been adequately diagnosed with a loop electrosurgical excision procedure (LEEP) or a cone biopsy procedure.
It is important to counsel these patients that surgery is not a treatment for high-risk HPV infection, which is the underlying etiology of their disease. With that etiology, HPV infection is likely to persist after hysterectomy and they may develop vaginal or vulvar dysplasia. Therefore, the American Society for Colposcopy and Cervical Pathology recommends that cytology and/or high-risk HPV surveillance continue following hysterectomy if that surgery was performed for dysplasia.1 Hysterectomy is not a means to avoid years of surveillance testing. Approximately 10% of women who have hysterectomy for cervical dysplasia develop vaginal dysplasia or cancer after surgery.2,3 This is similar to the likelihood of recurrent dysplasia after an alternative excisional procedure. In my experience, this diagnosis is often met with enormous frustration for the patient who thought that her hysterectomy would be the cure of her HPV-related disease. Thorough colposcopic evaluation of the vagina can be technically challenging after hysterectomy because of difficulty adequately visualizing lesions within the vaginal rugations, particularly within the puckered lateral vaginal fornices, the most common location for dysplasia.3 We will explore the diagnosis and treatment options for vaginal dysplasia further in a future column.
It is critical that, if patients are offered hysterectomy for treatment of cervical dysplasia, they are counseled that it may not be curative, that they will require long-term vaginal surveillance, and that they are at continued risk for vaginal and vulvar cancer.
An additional concern with performing hysterectomy for definitive management of cervical dysplasia is the concern that occult cancer may be missed preoperatively, and that the hysterectomy is inadequate surgical clearance of the disease. Approximately 2%-5% of patients with a high-grade squamous intraepithelial lesion or equivocal Pap test have occult cervical cancer.4 A similar proportion of patients with cervical intraepithelial neoplasia stage III or adenocarcinoma in situ on colposcopy biopsy have invasive carcinoma on evaluation of an excisional specimen.5 The traditional surgical approach has dictated that a modified (type II) or extended (type III) radical hysterectomy be performed in the setting of FIGO stage IA2 or greater cervical cancer. Radical hysterectomies remove parametrial tissue, effectively achieving a wider margin around the primary lesion. This is important because cervical cancer primarily spreads via direct extension.
The appropriate radicality of surgery for microscopic lesions is debated. It has been proposed that for very small, low-risk lesions, a traditional extrafascial hysterectomy or trachelectomy, or possibly even a large conization, may be adequate.6 However, this is controversial, and National Comprehensive Cancer Network guidelines still advocate for radical procedures for these lesions.7 Certainly an excisional procedure (LEEP or cone) should first be performed to define the size and histologic features of the lesion, and ideally, evaluation and counseling with a gynecologic oncologist should be performed prior to offering patients with a stage IA2 or greater lesion an extrafascial hysterectomy. Additionally, a separate decision would need to be made regarding the need for lymphadenectomy, as this is typically recommended for patients with stage IA2 or greater lesions.
Patients should be counseled that, if extrafascial (simple) hysterectomy is chosen as the primary excisional procedure, they may require additional therapy (additional surgery, or radiation and possibly chemotherapy) if cancer is found in the specimen and the parametrial margin is inadequate. Additionally, and of more concern, if the lesion is a bulky lesion extending into the parametrium and not recognized preoperatively, a “cut-through” hysterectomy will be inadvertently performed (in which margins are grossly positive). These situations typically feature heavy blood loss with patients at increased risk for immediate surgical complications. Postoperatively, prognosis is substantially worse for patients who have had a cut-through hysterectomy, compared stage for stage with patients who primarily received a radical procedure with negative margins or primary chemotherapy and radiation.8 Otherwise said, their risk for death is higher if this error is made. Therefore a thorough examination is essential prior to performing hysterectomy for dysplasia. Any suspicion of bulky cancer should be considered a contraindication for proceeding.
Preoperative evaluation
As a rule, no patient should transition directly from cytologic evaluation with Pap screening to hysterectomy. A colposcopic evaluation of the cervix and vagina accompanied with a thorough bimanual rectovaginal examination should always be performed first. Biopsies of the ectocervix and ideally the endocervix should be obtained because the accuracy of histology is greater than that of cytology. For patients with cervical intraepithelial neoplasia stage I lesions, hysterectomy is not appropriate, as these patients have an extremely low risk for the development of cervical cancer, and the risks and costs of hysterectomy are not justified in such a population.
Surgeons should wait at least 6 weeks following conization or LEEP before performing hysterectomy in order to minimize the likelihood of perioperative complications.9
Substituting LEEP or cone with hysterectomy
In general, it is the most prudent approach to first perform a diagnostic excision with LEEP or cone biopsy before proceeding with hysterectomy for definitive surgery. However, there may be some situations in which this is not feasible. In patients whose cervix is very small and flush with the vagina, an excisional procedure may not be technically possible without concern for damage to adjacent structures. In these patients, after a thorough exam has evaluated for gross disease, a hysterectomy may be the only way to adequately diagnose and treat high-grade dysplasia through excision. For patients with limited access to resources, transportation, or a concern for noncompliance with follow-up, surgeons may wish to offer patients primary hysterectomy rather than a staged procedure.
Hysterectomy remains a potential option for treatment of cervical dysplasia. However, patients should be made aware of the risks of undertreatment of occult cancers, the need for long-term surveillance testing, and the risk for future vaginal dysplasia or cancer. Ideally a comprehensive, stepwise assessment from cytology to colposcopy and examination to diagnostic excisional procedure will first take place to proceed safely with this approach.
References
1. Saslow D et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J Clin. 2012 May-Jun;62(3):147-72.
2. Schockaert S et al. Incidence of vaginal intraepithelial neoplasia after hysterectomy for cervical intraepithelial neoplasia: a retrospective study. Am J Obstet Gynecol. 2008 Aug;199(2):113.e1-5.
3. Kalogirou D et al. Vaginal intraepithelial neoplasia (VAIN) following hysterectomy in patients treated for carcinoma in situ of the cervix. Eur J Gynaecol Oncol. 1997;18(3):188-91.
5. Latif NA et al. Management of adenocarcinoma in situ of the uterine cervix: a comparison of loop electrosurgical excision procedure and cold knife conization. J Low Genit Tract Dis. 2015 Apr;19(2):97-102.
8. Barber HR et al. Operative management of patients previously operated upon for a benign lesion with cervical cancer as a surprise finding. Am J Obstet Gynecol. 1968 Aug 1;101(7):959-65.
9. Sullivan SA et al. Association between timing of cervical excision procedure to minimally invasive hysterectomy and surgical complications. Gynecol Oncol. 2017 Feb;144(2):294-298.
Cervical dysplasia is commonly diagnosed in women who have completed childbearing and don’t desire future fertility. While diagnostic and/or definitive therapy for cervical dysplasia can include hysterectomy, there are important considerations to make when offering this procedure to patients.
Dr. Emma C. Rossi
Pitfalls
Hysterectomy is commonly requested by patients upon learning of cervical dysplasia, particularly if they have chronic human papillomavirus (HPV) infection and have experienced years of frequent surveillance and interventions. They may see hysterectomy as an option to avoid this close surveillance and to be free of their dysplasia. There are two main concerns with offering hysterectomy as the primary surgical option for the management of dysplasia. Firstly, it may not be curative, and secondly, it may be an inadequate excisional procedure, particularly if the patient has occult invasive disease that has not been adequately diagnosed with a loop electrosurgical excision procedure (LEEP) or a cone biopsy procedure.
It is important to counsel these patients that surgery is not a treatment for high-risk HPV infection, which is the underlying etiology of their disease. With that etiology, HPV infection is likely to persist after hysterectomy and they may develop vaginal or vulvar dysplasia. Therefore, the American Society for Colposcopy and Cervical Pathology recommends that cytology and/or high-risk HPV surveillance continue following hysterectomy if that surgery was performed for dysplasia.1 Hysterectomy is not a means to avoid years of surveillance testing. Approximately 10% of women who have hysterectomy for cervical dysplasia develop vaginal dysplasia or cancer after surgery.2,3 This is similar to the likelihood of recurrent dysplasia after an alternative excisional procedure. In my experience, this diagnosis is often met with enormous frustration for the patient who thought that her hysterectomy would be the cure of her HPV-related disease. Thorough colposcopic evaluation of the vagina can be technically challenging after hysterectomy because of difficulty adequately visualizing lesions within the vaginal rugations, particularly within the puckered lateral vaginal fornices, the most common location for dysplasia.3 We will explore the diagnosis and treatment options for vaginal dysplasia further in a future column.
It is critical that, if patients are offered hysterectomy for treatment of cervical dysplasia, they are counseled that it may not be curative, that they will require long-term vaginal surveillance, and that they are at continued risk for vaginal and vulvar cancer.
An additional concern with performing hysterectomy for definitive management of cervical dysplasia is the concern that occult cancer may be missed preoperatively, and that the hysterectomy is inadequate surgical clearance of the disease. Approximately 2%-5% of patients with a high-grade squamous intraepithelial lesion or equivocal Pap test have occult cervical cancer.4 A similar proportion of patients with cervical intraepithelial neoplasia stage III or adenocarcinoma in situ on colposcopy biopsy have invasive carcinoma on evaluation of an excisional specimen.5 The traditional surgical approach has dictated that a modified (type II) or extended (type III) radical hysterectomy be performed in the setting of FIGO stage IA2 or greater cervical cancer. Radical hysterectomies remove parametrial tissue, effectively achieving a wider margin around the primary lesion. This is important because cervical cancer primarily spreads via direct extension.
The appropriate radicality of surgery for microscopic lesions is debated. It has been proposed that for very small, low-risk lesions, a traditional extrafascial hysterectomy or trachelectomy, or possibly even a large conization, may be adequate.6 However, this is controversial, and National Comprehensive Cancer Network guidelines still advocate for radical procedures for these lesions.7 Certainly an excisional procedure (LEEP or cone) should first be performed to define the size and histologic features of the lesion, and ideally, evaluation and counseling with a gynecologic oncologist should be performed prior to offering patients with a stage IA2 or greater lesion an extrafascial hysterectomy. Additionally, a separate decision would need to be made regarding the need for lymphadenectomy, as this is typically recommended for patients with stage IA2 or greater lesions.
Patients should be counseled that, if extrafascial (simple) hysterectomy is chosen as the primary excisional procedure, they may require additional therapy (additional surgery, or radiation and possibly chemotherapy) if cancer is found in the specimen and the parametrial margin is inadequate. Additionally, and of more concern, if the lesion is a bulky lesion extending into the parametrium and not recognized preoperatively, a “cut-through” hysterectomy will be inadvertently performed (in which margins are grossly positive). These situations typically feature heavy blood loss with patients at increased risk for immediate surgical complications. Postoperatively, prognosis is substantially worse for patients who have had a cut-through hysterectomy, compared stage for stage with patients who primarily received a radical procedure with negative margins or primary chemotherapy and radiation.8 Otherwise said, their risk for death is higher if this error is made. Therefore a thorough examination is essential prior to performing hysterectomy for dysplasia. Any suspicion of bulky cancer should be considered a contraindication for proceeding.
Preoperative evaluation
As a rule, no patient should transition directly from cytologic evaluation with Pap screening to hysterectomy. A colposcopic evaluation of the cervix and vagina accompanied with a thorough bimanual rectovaginal examination should always be performed first. Biopsies of the ectocervix and ideally the endocervix should be obtained because the accuracy of histology is greater than that of cytology. For patients with cervical intraepithelial neoplasia stage I lesions, hysterectomy is not appropriate, as these patients have an extremely low risk for the development of cervical cancer, and the risks and costs of hysterectomy are not justified in such a population.
Surgeons should wait at least 6 weeks following conization or LEEP before performing hysterectomy in order to minimize the likelihood of perioperative complications.9
Substituting LEEP or cone with hysterectomy
In general, it is the most prudent approach to first perform a diagnostic excision with LEEP or cone biopsy before proceeding with hysterectomy for definitive surgery. However, there may be some situations in which this is not feasible. In patients whose cervix is very small and flush with the vagina, an excisional procedure may not be technically possible without concern for damage to adjacent structures. In these patients, after a thorough exam has evaluated for gross disease, a hysterectomy may be the only way to adequately diagnose and treat high-grade dysplasia through excision. For patients with limited access to resources, transportation, or a concern for noncompliance with follow-up, surgeons may wish to offer patients primary hysterectomy rather than a staged procedure.
Hysterectomy remains a potential option for treatment of cervical dysplasia. However, patients should be made aware of the risks of undertreatment of occult cancers, the need for long-term surveillance testing, and the risk for future vaginal dysplasia or cancer. Ideally a comprehensive, stepwise assessment from cytology to colposcopy and examination to diagnostic excisional procedure will first take place to proceed safely with this approach.
References
1. Saslow D et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J Clin. 2012 May-Jun;62(3):147-72.
2. Schockaert S et al. Incidence of vaginal intraepithelial neoplasia after hysterectomy for cervical intraepithelial neoplasia: a retrospective study. Am J Obstet Gynecol. 2008 Aug;199(2):113.e1-5.
3. Kalogirou D et al. Vaginal intraepithelial neoplasia (VAIN) following hysterectomy in patients treated for carcinoma in situ of the cervix. Eur J Gynaecol Oncol. 1997;18(3):188-91.
5. Latif NA et al. Management of adenocarcinoma in situ of the uterine cervix: a comparison of loop electrosurgical excision procedure and cold knife conization. J Low Genit Tract Dis. 2015 Apr;19(2):97-102.
8. Barber HR et al. Operative management of patients previously operated upon for a benign lesion with cervical cancer as a surprise finding. Am J Obstet Gynecol. 1968 Aug 1;101(7):959-65.
9. Sullivan SA et al. Association between timing of cervical excision procedure to minimally invasive hysterectomy and surgical complications. Gynecol Oncol. 2017 Feb;144(2):294-298.
Cervical dysplasia is commonly diagnosed in women who have completed childbearing and don’t desire future fertility. While diagnostic and/or definitive therapy for cervical dysplasia can include hysterectomy, there are important considerations to make when offering this procedure to patients.
Dr. Emma C. Rossi
Pitfalls
Hysterectomy is commonly requested by patients upon learning of cervical dysplasia, particularly if they have chronic human papillomavirus (HPV) infection and have experienced years of frequent surveillance and interventions. They may see hysterectomy as an option to avoid this close surveillance and to be free of their dysplasia. There are two main concerns with offering hysterectomy as the primary surgical option for the management of dysplasia. Firstly, it may not be curative, and secondly, it may be an inadequate excisional procedure, particularly if the patient has occult invasive disease that has not been adequately diagnosed with a loop electrosurgical excision procedure (LEEP) or a cone biopsy procedure.
It is important to counsel these patients that surgery is not a treatment for high-risk HPV infection, which is the underlying etiology of their disease. With that etiology, HPV infection is likely to persist after hysterectomy and they may develop vaginal or vulvar dysplasia. Therefore, the American Society for Colposcopy and Cervical Pathology recommends that cytology and/or high-risk HPV surveillance continue following hysterectomy if that surgery was performed for dysplasia.1 Hysterectomy is not a means to avoid years of surveillance testing. Approximately 10% of women who have hysterectomy for cervical dysplasia develop vaginal dysplasia or cancer after surgery.2,3 This is similar to the likelihood of recurrent dysplasia after an alternative excisional procedure. In my experience, this diagnosis is often met with enormous frustration for the patient who thought that her hysterectomy would be the cure of her HPV-related disease. Thorough colposcopic evaluation of the vagina can be technically challenging after hysterectomy because of difficulty adequately visualizing lesions within the vaginal rugations, particularly within the puckered lateral vaginal fornices, the most common location for dysplasia.3 We will explore the diagnosis and treatment options for vaginal dysplasia further in a future column.
It is critical that, if patients are offered hysterectomy for treatment of cervical dysplasia, they are counseled that it may not be curative, that they will require long-term vaginal surveillance, and that they are at continued risk for vaginal and vulvar cancer.
An additional concern with performing hysterectomy for definitive management of cervical dysplasia is the concern that occult cancer may be missed preoperatively, and that the hysterectomy is inadequate surgical clearance of the disease. Approximately 2%-5% of patients with a high-grade squamous intraepithelial lesion or equivocal Pap test have occult cervical cancer.4 A similar proportion of patients with cervical intraepithelial neoplasia stage III or adenocarcinoma in situ on colposcopy biopsy have invasive carcinoma on evaluation of an excisional specimen.5 The traditional surgical approach has dictated that a modified (type II) or extended (type III) radical hysterectomy be performed in the setting of FIGO stage IA2 or greater cervical cancer. Radical hysterectomies remove parametrial tissue, effectively achieving a wider margin around the primary lesion. This is important because cervical cancer primarily spreads via direct extension.
The appropriate radicality of surgery for microscopic lesions is debated. It has been proposed that for very small, low-risk lesions, a traditional extrafascial hysterectomy or trachelectomy, or possibly even a large conization, may be adequate.6 However, this is controversial, and National Comprehensive Cancer Network guidelines still advocate for radical procedures for these lesions.7 Certainly an excisional procedure (LEEP or cone) should first be performed to define the size and histologic features of the lesion, and ideally, evaluation and counseling with a gynecologic oncologist should be performed prior to offering patients with a stage IA2 or greater lesion an extrafascial hysterectomy. Additionally, a separate decision would need to be made regarding the need for lymphadenectomy, as this is typically recommended for patients with stage IA2 or greater lesions.
Patients should be counseled that, if extrafascial (simple) hysterectomy is chosen as the primary excisional procedure, they may require additional therapy (additional surgery, or radiation and possibly chemotherapy) if cancer is found in the specimen and the parametrial margin is inadequate. Additionally, and of more concern, if the lesion is a bulky lesion extending into the parametrium and not recognized preoperatively, a “cut-through” hysterectomy will be inadvertently performed (in which margins are grossly positive). These situations typically feature heavy blood loss with patients at increased risk for immediate surgical complications. Postoperatively, prognosis is substantially worse for patients who have had a cut-through hysterectomy, compared stage for stage with patients who primarily received a radical procedure with negative margins or primary chemotherapy and radiation.8 Otherwise said, their risk for death is higher if this error is made. Therefore a thorough examination is essential prior to performing hysterectomy for dysplasia. Any suspicion of bulky cancer should be considered a contraindication for proceeding.
Preoperative evaluation
As a rule, no patient should transition directly from cytologic evaluation with Pap screening to hysterectomy. A colposcopic evaluation of the cervix and vagina accompanied with a thorough bimanual rectovaginal examination should always be performed first. Biopsies of the ectocervix and ideally the endocervix should be obtained because the accuracy of histology is greater than that of cytology. For patients with cervical intraepithelial neoplasia stage I lesions, hysterectomy is not appropriate, as these patients have an extremely low risk for the development of cervical cancer, and the risks and costs of hysterectomy are not justified in such a population.
Surgeons should wait at least 6 weeks following conization or LEEP before performing hysterectomy in order to minimize the likelihood of perioperative complications.9
Substituting LEEP or cone with hysterectomy
In general, it is the most prudent approach to first perform a diagnostic excision with LEEP or cone biopsy before proceeding with hysterectomy for definitive surgery. However, there may be some situations in which this is not feasible. In patients whose cervix is very small and flush with the vagina, an excisional procedure may not be technically possible without concern for damage to adjacent structures. In these patients, after a thorough exam has evaluated for gross disease, a hysterectomy may be the only way to adequately diagnose and treat high-grade dysplasia through excision. For patients with limited access to resources, transportation, or a concern for noncompliance with follow-up, surgeons may wish to offer patients primary hysterectomy rather than a staged procedure.
Hysterectomy remains a potential option for treatment of cervical dysplasia. However, patients should be made aware of the risks of undertreatment of occult cancers, the need for long-term surveillance testing, and the risk for future vaginal dysplasia or cancer. Ideally a comprehensive, stepwise assessment from cytology to colposcopy and examination to diagnostic excisional procedure will first take place to proceed safely with this approach.
References
1. Saslow D et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J Clin. 2012 May-Jun;62(3):147-72.
2. Schockaert S et al. Incidence of vaginal intraepithelial neoplasia after hysterectomy for cervical intraepithelial neoplasia: a retrospective study. Am J Obstet Gynecol. 2008 Aug;199(2):113.e1-5.
3. Kalogirou D et al. Vaginal intraepithelial neoplasia (VAIN) following hysterectomy in patients treated for carcinoma in situ of the cervix. Eur J Gynaecol Oncol. 1997;18(3):188-91.
5. Latif NA et al. Management of adenocarcinoma in situ of the uterine cervix: a comparison of loop electrosurgical excision procedure and cold knife conization. J Low Genit Tract Dis. 2015 Apr;19(2):97-102.
8. Barber HR et al. Operative management of patients previously operated upon for a benign lesion with cervical cancer as a surprise finding. Am J Obstet Gynecol. 1968 Aug 1;101(7):959-65.
9. Sullivan SA et al. Association between timing of cervical excision procedure to minimally invasive hysterectomy and surgical complications. Gynecol Oncol. 2017 Feb;144(2):294-298.
