Stephanie A. Sullivan, MD

As reviewed in Part 1, surgery is indicated for the staging and treatment of endometrial cancer. Lymph node status is one of the most important factors in determining prognosis and the need for adjuvant treatment. The extent of lymph node evaluation is controversial as full lymphadenectomy carries risks, including increased operative time, blood loss, nerve injury, and lymphedema.

Two trials have found no survival benefit from lymphadenectomy for endometrial cancer; however, other evidence suggests that women without known nodal status may be more likely to receive radiotherapy.^1,2,3

Given these issues, the sentinel lymph node technique strikes a balance between the risks and benefits of lymph node evaluation in endometrial cancer.

Sentinel lymph nodes (SLN) are the first nodes to drain a tumor site, and thus, are typically the first to demonstrate occult malignancy. The use of the SLN technique as an alternative to complete lymphadenectomy in endometrial cancer has been well described, although its accuracy and the validity of its use are still debated.

The viability of the SLN technique is predicated on the ability to achieve mapping of dye or tracer from the tumor to the first lymph node to drain the tumor. The lymphatic drainage of the endometrium is complex and unlike vulvar or breast cancer, endometrial cancer is less accessible for peritumoral injection. Several injection techniques have been described; cervical injection is the easiest to achieve and has been found to have similar or higher SLN detection than hysteroscopic or fundal injections.^4,5

There are a number of techniques for SLN detection, each with unique benefits and risks. Visual identification of blue dye, most frequently isosulfan blue, is the “colorimetric method” and has been used most commonly with cervical injection for endometrial cancer. Injection of isosulfan blue does not require specialized equipment, however visualization in obese patients is inferior.⁶

Technetium sulfur colloid (Tc) is a radioactive tracer that can be detected by gamma probes. A preoperative lymphoscintigraphy and a handheld gamma probe are used to map lymphatics. This technique has limitations, including the additional time and coordination of procedures, as well as some evidence of poor correlation between lymphoscintigraphy and surgical SLN mapping.⁷

Indocyanine green (ICG) is a fluorescent dye that has excellent signal penetration and allows for real-time visual identification using near-infrared fluorescence imaging. The bilateral detection rate with ICG appears comparable or better than blue dye.⁸ Combinations of dye, either ICG plus Tc or Tc plus blue dye, may be also used to increase SLN detection.

The accuracy of the SLN technique is the cornerstone to its success. In a prospective multicenter study – Senti-Endo – patients with early-stage disease underwent pelvic SLN assessment with cervical injection of a combination of dyes followed by systematic pelvic node dissection. The overall negative predictive value was 97% with three patients who had positive lymph nodes that were not detected, all of whom had a type 2 endometrial cancer.⁹

With the uptake of the SLN technique, many institutions have protocols surrounding the technique to ensure appropriate SLN detection and evaluation. Physicians using this technique should adhere to protocols supported by National Comprehensive Cancer Network guidelines, taking care to remove any suspicious lymph nodes and perform a full side-specific lymphadenectomy if bilateral mapping is not achieved.

The extent of lymphadenectomy and application of the SLN technique in high-risk endometrial cancer remains controversial. These patients are at higher risk for unsuccessful mapping and isolated para-aortic metastasis. Retrospective series have suggested equivalent oncologic outcomes for women with high-grade cancers who have been staged by SLN biopsy, compared with selective or complete lymphadenectomy.^10,11

We await the results of a large prospective trial in which patients undergo comprehensive lymphadenectomy in addition to SLN biopsy to assess the accuracy of the technique (NCT01673022).

Pathologic evaluation of SLNs is frequently done with ultrastaging, which describes additional sectioning and staining of the node. This technique frequently identifies isolated tumor cells and micrometastasis (collectively called low-volume disease) in addition to macrometastasis. The clinical and prognostic significance of low-volume disease is unknown and additional investigation is urgently needed to determine appropriate adjuvant therapy and follow-up for these patients.

The SLN technique is an acceptable approach to assess clinical stage I endometrial cancer. Physicians should consider adding the SLN biopsy to their routine staging techniques prior to exclusively adopting the new technique. They should take care to adhere to SLN algorithms and monitor outcomes.

References

1. J Natl Cancer Inst. 2008;100(23):1707-16.

2. Lancet. 2009 Jan;373(9658):125-36.

3. Am J Obstet Gynecol. 2011 Dec;205(6):562.e1–9.

4. Gynecol Oncol. 2013 Nov;131(2):299-303.

5. Int J Gynecol Cancer. 2013 Nov;23(9):1704-11.

6. Gynecol Oncol 2014 Aug;134(2):281-6.

7. Gynecol Oncol. 2009 Feb;112(2):348-352.

8. Gynecol Oncol. 2014 May;133(2):274-7.

9. Lancet Oncol. 2011 May;12(5):469-76.

10. Ann Surg Oncol. 2016 Jan;23(1):196-202.

11. Gynecol Oncol. 2016 Mar;140(3):394-9.

Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina, Chapel Hill. Dr. Sullivan is a clinical fellow in the division of gynecologic oncology at UNC, Chapel Hill. Dr. Rossi and Dr. Sullivan reported having no relevant financial disclosures.

As reviewed in Part 1, surgery is indicated for the staging and treatment of endometrial cancer. Lymph node status is one of the most important factors in determining prognosis and the need for adjuvant treatment. The extent of lymph node evaluation is controversial as full lymphadenectomy carries risks, including increased operative time, blood loss, nerve injury, and lymphedema.

Two trials have found no survival benefit from lymphadenectomy for endometrial cancer; however, other evidence suggests that women without known nodal status may be more likely to receive radiotherapy.^1,2,3

Given these issues, the sentinel lymph node technique strikes a balance between the risks and benefits of lymph node evaluation in endometrial cancer.

Sentinel lymph nodes (SLN) are the first nodes to drain a tumor site, and thus, are typically the first to demonstrate occult malignancy. The use of the SLN technique as an alternative to complete lymphadenectomy in endometrial cancer has been well described, although its accuracy and the validity of its use are still debated.

The viability of the SLN technique is predicated on the ability to achieve mapping of dye or tracer from the tumor to the first lymph node to drain the tumor. The lymphatic drainage of the endometrium is complex and unlike vulvar or breast cancer, endometrial cancer is less accessible for peritumoral injection. Several injection techniques have been described; cervical injection is the easiest to achieve and has been found to have similar or higher SLN detection than hysteroscopic or fundal injections.^4,5

There are a number of techniques for SLN detection, each with unique benefits and risks. Visual identification of blue dye, most frequently isosulfan blue, is the “colorimetric method” and has been used most commonly with cervical injection for endometrial cancer. Injection of isosulfan blue does not require specialized equipment, however visualization in obese patients is inferior.⁶

Technetium sulfur colloid (Tc) is a radioactive tracer that can be detected by gamma probes. A preoperative lymphoscintigraphy and a handheld gamma probe are used to map lymphatics. This technique has limitations, including the additional time and coordination of procedures, as well as some evidence of poor correlation between lymphoscintigraphy and surgical SLN mapping.⁷

Indocyanine green (ICG) is a fluorescent dye that has excellent signal penetration and allows for real-time visual identification using near-infrared fluorescence imaging. The bilateral detection rate with ICG appears comparable or better than blue dye.⁸ Combinations of dye, either ICG plus Tc or Tc plus blue dye, may be also used to increase SLN detection.

The accuracy of the SLN technique is the cornerstone to its success. In a prospective multicenter study – Senti-Endo – patients with early-stage disease underwent pelvic SLN assessment with cervical injection of a combination of dyes followed by systematic pelvic node dissection. The overall negative predictive value was 97% with three patients who had positive lymph nodes that were not detected, all of whom had a type 2 endometrial cancer.⁹

With the uptake of the SLN technique, many institutions have protocols surrounding the technique to ensure appropriate SLN detection and evaluation. Physicians using this technique should adhere to protocols supported by National Comprehensive Cancer Network guidelines, taking care to remove any suspicious lymph nodes and perform a full side-specific lymphadenectomy if bilateral mapping is not achieved.

The extent of lymphadenectomy and application of the SLN technique in high-risk endometrial cancer remains controversial. These patients are at higher risk for unsuccessful mapping and isolated para-aortic metastasis. Retrospective series have suggested equivalent oncologic outcomes for women with high-grade cancers who have been staged by SLN biopsy, compared with selective or complete lymphadenectomy.^10,11

We await the results of a large prospective trial in which patients undergo comprehensive lymphadenectomy in addition to SLN biopsy to assess the accuracy of the technique (NCT01673022).

Pathologic evaluation of SLNs is frequently done with ultrastaging, which describes additional sectioning and staining of the node. This technique frequently identifies isolated tumor cells and micrometastasis (collectively called low-volume disease) in addition to macrometastasis. The clinical and prognostic significance of low-volume disease is unknown and additional investigation is urgently needed to determine appropriate adjuvant therapy and follow-up for these patients.

The SLN technique is an acceptable approach to assess clinical stage I endometrial cancer. Physicians should consider adding the SLN biopsy to their routine staging techniques prior to exclusively adopting the new technique. They should take care to adhere to SLN algorithms and monitor outcomes.

References

1. J Natl Cancer Inst. 2008;100(23):1707-16.

2. Lancet. 2009 Jan;373(9658):125-36.

3. Am J Obstet Gynecol. 2011 Dec;205(6):562.e1–9.

4. Gynecol Oncol. 2013 Nov;131(2):299-303.

5. Int J Gynecol Cancer. 2013 Nov;23(9):1704-11.

6. Gynecol Oncol 2014 Aug;134(2):281-6.

7. Gynecol Oncol. 2009 Feb;112(2):348-352.

8. Gynecol Oncol. 2014 May;133(2):274-7.

9. Lancet Oncol. 2011 May;12(5):469-76.

10. Ann Surg Oncol. 2016 Jan;23(1):196-202.

11. Gynecol Oncol. 2016 Mar;140(3):394-9.

Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina, Chapel Hill. Dr. Sullivan is a clinical fellow in the division of gynecologic oncology at UNC, Chapel Hill. Dr. Rossi and Dr. Sullivan reported having no relevant financial disclosures.

As reviewed in Part 1, surgery is indicated for the staging and treatment of endometrial cancer. Lymph node status is one of the most important factors in determining prognosis and the need for adjuvant treatment. The extent of lymph node evaluation is controversial as full lymphadenectomy carries risks, including increased operative time, blood loss, nerve injury, and lymphedema.

Two trials have found no survival benefit from lymphadenectomy for endometrial cancer; however, other evidence suggests that women without known nodal status may be more likely to receive radiotherapy.^1,2,3

Given these issues, the sentinel lymph node technique strikes a balance between the risks and benefits of lymph node evaluation in endometrial cancer.

Sentinel lymph nodes (SLN) are the first nodes to drain a tumor site, and thus, are typically the first to demonstrate occult malignancy. The use of the SLN technique as an alternative to complete lymphadenectomy in endometrial cancer has been well described, although its accuracy and the validity of its use are still debated.

The viability of the SLN technique is predicated on the ability to achieve mapping of dye or tracer from the tumor to the first lymph node to drain the tumor. The lymphatic drainage of the endometrium is complex and unlike vulvar or breast cancer, endometrial cancer is less accessible for peritumoral injection. Several injection techniques have been described; cervical injection is the easiest to achieve and has been found to have similar or higher SLN detection than hysteroscopic or fundal injections.^4,5

There are a number of techniques for SLN detection, each with unique benefits and risks. Visual identification of blue dye, most frequently isosulfan blue, is the “colorimetric method” and has been used most commonly with cervical injection for endometrial cancer. Injection of isosulfan blue does not require specialized equipment, however visualization in obese patients is inferior.⁶

Technetium sulfur colloid (Tc) is a radioactive tracer that can be detected by gamma probes. A preoperative lymphoscintigraphy and a handheld gamma probe are used to map lymphatics. This technique has limitations, including the additional time and coordination of procedures, as well as some evidence of poor correlation between lymphoscintigraphy and surgical SLN mapping.⁷

Indocyanine green (ICG) is a fluorescent dye that has excellent signal penetration and allows for real-time visual identification using near-infrared fluorescence imaging. The bilateral detection rate with ICG appears comparable or better than blue dye.⁸ Combinations of dye, either ICG plus Tc or Tc plus blue dye, may be also used to increase SLN detection.

The accuracy of the SLN technique is the cornerstone to its success. In a prospective multicenter study – Senti-Endo – patients with early-stage disease underwent pelvic SLN assessment with cervical injection of a combination of dyes followed by systematic pelvic node dissection. The overall negative predictive value was 97% with three patients who had positive lymph nodes that were not detected, all of whom had a type 2 endometrial cancer.⁹

With the uptake of the SLN technique, many institutions have protocols surrounding the technique to ensure appropriate SLN detection and evaluation. Physicians using this technique should adhere to protocols supported by National Comprehensive Cancer Network guidelines, taking care to remove any suspicious lymph nodes and perform a full side-specific lymphadenectomy if bilateral mapping is not achieved.

The extent of lymphadenectomy and application of the SLN technique in high-risk endometrial cancer remains controversial. These patients are at higher risk for unsuccessful mapping and isolated para-aortic metastasis. Retrospective series have suggested equivalent oncologic outcomes for women with high-grade cancers who have been staged by SLN biopsy, compared with selective or complete lymphadenectomy.^10,11

We await the results of a large prospective trial in which patients undergo comprehensive lymphadenectomy in addition to SLN biopsy to assess the accuracy of the technique (NCT01673022).

Pathologic evaluation of SLNs is frequently done with ultrastaging, which describes additional sectioning and staining of the node. This technique frequently identifies isolated tumor cells and micrometastasis (collectively called low-volume disease) in addition to macrometastasis. The clinical and prognostic significance of low-volume disease is unknown and additional investigation is urgently needed to determine appropriate adjuvant therapy and follow-up for these patients.

The SLN technique is an acceptable approach to assess clinical stage I endometrial cancer. Physicians should consider adding the SLN biopsy to their routine staging techniques prior to exclusively adopting the new technique. They should take care to adhere to SLN algorithms and monitor outcomes.

References

1. J Natl Cancer Inst. 2008;100(23):1707-16.

2. Lancet. 2009 Jan;373(9658):125-36.

3. Am J Obstet Gynecol. 2011 Dec;205(6):562.e1–9.

4. Gynecol Oncol. 2013 Nov;131(2):299-303.

5. Int J Gynecol Cancer. 2013 Nov;23(9):1704-11.

6. Gynecol Oncol 2014 Aug;134(2):281-6.

7. Gynecol Oncol. 2009 Feb;112(2):348-352.

8. Gynecol Oncol. 2014 May;133(2):274-7.

9. Lancet Oncol. 2011 May;12(5):469-76.

10. Ann Surg Oncol. 2016 Jan;23(1):196-202.

11. Gynecol Oncol. 2016 Mar;140(3):394-9.

Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina, Chapel Hill. Dr. Sullivan is a clinical fellow in the division of gynecologic oncology at UNC, Chapel Hill. Dr. Rossi and Dr. Sullivan reported having no relevant financial disclosures.

Cervical intraepithelial neoplasia (CIN) describes a precancerous lesion of the squamous epithelium of the ectocervix. The cervical cancer screening paradigm in the United States begins with collection of cervical cytology with a Pap smear, frequently in conjunction with human papillomavirus testing. Abnormalities will frequently lead to colposcopy with directed biopsy, which can result in a diagnosis of CIN. There are different grades of severity within CIN, which aids in making treatment recommendations.

Pregnancy is a convenient time to capture women for cervical cancer screening, given the increased contact with health care providers. Routine guidelines should be followed for screening women who are pregnant, as collection of cervical cytology and human papillomavirus (HPV) cotesting is safe.

In women who have been found to have abnormal cytology, CIN or malignancy has been identified in up to 19% of cases (Am J Obstet Gynecol. 2004 Jul;191[1]:105-13). High-grade lesions identified in pregnant women create a unique management dilemma.

Terminology

The Bethesda system describes colposcopic abnormalities as CIN and divides premalignant lesions into grades from 1 to 3 with the highest grade representing more worrisome lesions. CIN2 has been found to have poor reproducibility and likely represents a mix of low- and high-grade lesions. In addition, there is concern that HPV-associated lesions of the lower anogenital tract have incongruent terminology among different specialties that may not accurately represent the current understanding of HPV pathogenesis.

In 2012, the Lower Anogenital Squamous Terminology (LAST) project of the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology (ASCCP) advocated for consistent terminology across all lower anogenital tract lesions with HPV, including CIN (Int J Gynecol Pathol. 2013 Jan;32[1]:76-115).

With this new terminology, CIN1 is referred to as low-grade squamous intraepithelial lesion (LSIL). CIN2 is characterized by its p16 immunostaining; lesions that are p16 negative are considered LSIL, while those that are positive are considered HSIL (high-grade squamous intraepithelial lesion). While this staining is not universally performed, physicians will start seeing p16 staining results with increasing frequency on their cervical biopsies. CIN3 lesions are referred to as HSIL.

©monkeybusinessimages/Thinkstock

Given the current understanding of HPV-mediated disease, and a commitment to represent the most up-to-date information, the LAST project terminology of HSIL to represent previously identified CIN2 and CIN3 lesions will be used for the remainder of this text.

Diagnosis

There is little data on the natural history of HSIL diagnosed after colposcopy, as most women get some form of therapy. The information that is available suggests that in patients with untreated HSIL, the cumulative incidence of malignancy is as high as 30% at 30 years (Lancet Oncol. 2008 May;9[5]:425-34). Treatment recommendations for excision are aimed at addressing this alarming number; however, care must be individualized, especially in the setting of pregnancy.

If abnormal cervical cytology is obtained on routine screening, appropriate patients should be referred for colposcopic exam. Physicians performing colposcopy should be familiar with the physiologic effects of pregnancy that can obscure the exam, including the increased cervical mucus production, prominence of endocervical glands, and increased vascularity.

Colposcopic-directed ectocervical biopsies have been found to be safe in pregnancy, and these women should be provided the same care as those who are not pregnant (Obstet Gynecol. 1993 Jun;81[6]:915-8). Endocervical sampling and endometrial sampling should not be performed, however, and physicians should remain dedicated to checking pregnancy tests prior to colposcopy.

HSIL cytology should prompt a biopsy in pregnancy; a decision to skip the biopsy and perform an excisional procedure in this setting is not recommended regardless of patient or gestational age. If LSIL (CIN1) is noted on biopsy, reevaluation post partum should be strongly considered, unless a suspicious lesion was felt to be inadequately biopsied.

Management

Managing HSIL in pregnancy focuses on diagnosis and excluding malignancy, while treatment can be reserved for the postpartum period. When choosing a management option, consider individual patient factors such as colposcopic appearance of the lesion, gestational age, and access to health care.

If HSIL is noted on colposcopic-directed biopsy, consider one of several options. The most conservative approach is reevaluation with cytology and colposcopy 6 weeks post partum. This is an option for patients who do not have a colposcopic exam that was concerning for an invasive lesion, were able to be adequately biopsied, and will reliably return for follow-up. Many physicians feel more comfortable with repeat cytology and colposcopy in 3 months from the original biopsy. The most aggressive management would include an excisional procedure during pregnancy.

There are varying rates of regression of biopsy-proven HSIL in pregnancy ranging from 34% to 70% (Obstet Gynecol. 1999 Mar;93[3]:359-62; Acta Obstet Gynecol Scand. 2006;85[9]:1134-7; Reprod Sci. 2009 Nov;16[11]:1034-9). Out of more than 200 patients across these three studies, just two patients were diagnosed with an invasive lesion post partum. Given the low likelihood of progression during pregnancy and the high rate of regression, an excisional procedure should be considered only in cases where there is concern about invasive carcinoma.

In cases where an invasive lesion is suspected, consider an an excisional procedure. While there is some evidence that performing a laser excisional procedure early in pregnancy (18 weeks and earlier) can be safely done, that is not the most common management strategy in the United States (Tumori. 1998 Sep-Oct;84[5]:567-70; Int J Gynecol Cancer. 2007 Jan-Feb;17[1]:127-31). In this circumstance, referral to a gynecologic oncologist is warranted where consideration can be made for performing a cold knife conization. Physicians should be aware of the increased risk of bleeding with this procedure in pregnancy and the potential for preterm birth. There is little literature to guide counseling regarding these risks, and the decision to perform an excisional procedure should be made with a multidisciplinary team (Arch Gynecol Obstet. 2016 Jan 4. doi: 10.1007/s00404-015-3980-y).

The see-and-treat paradigm is not recommended in pregnancy. Those patients with poor follow-up should still undergo colposcopic-directed biopsies prior to any excisional procedure.

Treatment recommendations in pregnancy should be made on the basis of careful consideration of individual patient factors, with strong consideration of repeat testing with cytology and colposcopy prior to an excision procedure.

Dr. Sullivan is a fellow in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Gehrig is professor and director of gynecologic oncology at the university. Dr. Sullivan and Dr. Gehrig reported having no relevant financial disclosures. Email them at obnews@frontlinemedcom.com.

Cervical intraepithelial neoplasia (CIN) describes a precancerous lesion of the squamous epithelium of the ectocervix. The cervical cancer screening paradigm in the United States begins with collection of cervical cytology with a Pap smear, frequently in conjunction with human papillomavirus testing. Abnormalities will frequently lead to colposcopy with directed biopsy, which can result in a diagnosis of CIN. There are different grades of severity within CIN, which aids in making treatment recommendations.

Pregnancy is a convenient time to capture women for cervical cancer screening, given the increased contact with health care providers. Routine guidelines should be followed for screening women who are pregnant, as collection of cervical cytology and human papillomavirus (HPV) cotesting is safe.

In women who have been found to have abnormal cytology, CIN or malignancy has been identified in up to 19% of cases (Am J Obstet Gynecol. 2004 Jul;191[1]:105-13). High-grade lesions identified in pregnant women create a unique management dilemma.

Terminology

The Bethesda system describes colposcopic abnormalities as CIN and divides premalignant lesions into grades from 1 to 3 with the highest grade representing more worrisome lesions. CIN2 has been found to have poor reproducibility and likely represents a mix of low- and high-grade lesions. In addition, there is concern that HPV-associated lesions of the lower anogenital tract have incongruent terminology among different specialties that may not accurately represent the current understanding of HPV pathogenesis.

In 2012, the Lower Anogenital Squamous Terminology (LAST) project of the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology (ASCCP) advocated for consistent terminology across all lower anogenital tract lesions with HPV, including CIN (Int J Gynecol Pathol. 2013 Jan;32[1]:76-115).

With this new terminology, CIN1 is referred to as low-grade squamous intraepithelial lesion (LSIL). CIN2 is characterized by its p16 immunostaining; lesions that are p16 negative are considered LSIL, while those that are positive are considered HSIL (high-grade squamous intraepithelial lesion). While this staining is not universally performed, physicians will start seeing p16 staining results with increasing frequency on their cervical biopsies. CIN3 lesions are referred to as HSIL.

©monkeybusinessimages/Thinkstock

Given the current understanding of HPV-mediated disease, and a commitment to represent the most up-to-date information, the LAST project terminology of HSIL to represent previously identified CIN2 and CIN3 lesions will be used for the remainder of this text.

Diagnosis

There is little data on the natural history of HSIL diagnosed after colposcopy, as most women get some form of therapy. The information that is available suggests that in patients with untreated HSIL, the cumulative incidence of malignancy is as high as 30% at 30 years (Lancet Oncol. 2008 May;9[5]:425-34). Treatment recommendations for excision are aimed at addressing this alarming number; however, care must be individualized, especially in the setting of pregnancy.

If abnormal cervical cytology is obtained on routine screening, appropriate patients should be referred for colposcopic exam. Physicians performing colposcopy should be familiar with the physiologic effects of pregnancy that can obscure the exam, including the increased cervical mucus production, prominence of endocervical glands, and increased vascularity.

Colposcopic-directed ectocervical biopsies have been found to be safe in pregnancy, and these women should be provided the same care as those who are not pregnant (Obstet Gynecol. 1993 Jun;81[6]:915-8). Endocervical sampling and endometrial sampling should not be performed, however, and physicians should remain dedicated to checking pregnancy tests prior to colposcopy.

HSIL cytology should prompt a biopsy in pregnancy; a decision to skip the biopsy and perform an excisional procedure in this setting is not recommended regardless of patient or gestational age. If LSIL (CIN1) is noted on biopsy, reevaluation post partum should be strongly considered, unless a suspicious lesion was felt to be inadequately biopsied.

Management

Managing HSIL in pregnancy focuses on diagnosis and excluding malignancy, while treatment can be reserved for the postpartum period. When choosing a management option, consider individual patient factors such as colposcopic appearance of the lesion, gestational age, and access to health care.

If HSIL is noted on colposcopic-directed biopsy, consider one of several options. The most conservative approach is reevaluation with cytology and colposcopy 6 weeks post partum. This is an option for patients who do not have a colposcopic exam that was concerning for an invasive lesion, were able to be adequately biopsied, and will reliably return for follow-up. Many physicians feel more comfortable with repeat cytology and colposcopy in 3 months from the original biopsy. The most aggressive management would include an excisional procedure during pregnancy.

There are varying rates of regression of biopsy-proven HSIL in pregnancy ranging from 34% to 70% (Obstet Gynecol. 1999 Mar;93[3]:359-62; Acta Obstet Gynecol Scand. 2006;85[9]:1134-7; Reprod Sci. 2009 Nov;16[11]:1034-9). Out of more than 200 patients across these three studies, just two patients were diagnosed with an invasive lesion post partum. Given the low likelihood of progression during pregnancy and the high rate of regression, an excisional procedure should be considered only in cases where there is concern about invasive carcinoma.

In cases where an invasive lesion is suspected, consider an an excisional procedure. While there is some evidence that performing a laser excisional procedure early in pregnancy (18 weeks and earlier) can be safely done, that is not the most common management strategy in the United States (Tumori. 1998 Sep-Oct;84[5]:567-70; Int J Gynecol Cancer. 2007 Jan-Feb;17[1]:127-31). In this circumstance, referral to a gynecologic oncologist is warranted where consideration can be made for performing a cold knife conization. Physicians should be aware of the increased risk of bleeding with this procedure in pregnancy and the potential for preterm birth. There is little literature to guide counseling regarding these risks, and the decision to perform an excisional procedure should be made with a multidisciplinary team (Arch Gynecol Obstet. 2016 Jan 4. doi: 10.1007/s00404-015-3980-y).

The see-and-treat paradigm is not recommended in pregnancy. Those patients with poor follow-up should still undergo colposcopic-directed biopsies prior to any excisional procedure.

Treatment recommendations in pregnancy should be made on the basis of careful consideration of individual patient factors, with strong consideration of repeat testing with cytology and colposcopy prior to an excision procedure.

Dr. Sullivan is a fellow in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Gehrig is professor and director of gynecologic oncology at the university. Dr. Sullivan and Dr. Gehrig reported having no relevant financial disclosures. Email them at obnews@frontlinemedcom.com.

Cervical intraepithelial neoplasia (CIN) describes a precancerous lesion of the squamous epithelium of the ectocervix. The cervical cancer screening paradigm in the United States begins with collection of cervical cytology with a Pap smear, frequently in conjunction with human papillomavirus testing. Abnormalities will frequently lead to colposcopy with directed biopsy, which can result in a diagnosis of CIN. There are different grades of severity within CIN, which aids in making treatment recommendations.

Pregnancy is a convenient time to capture women for cervical cancer screening, given the increased contact with health care providers. Routine guidelines should be followed for screening women who are pregnant, as collection of cervical cytology and human papillomavirus (HPV) cotesting is safe.

In women who have been found to have abnormal cytology, CIN or malignancy has been identified in up to 19% of cases (Am J Obstet Gynecol. 2004 Jul;191[1]:105-13). High-grade lesions identified in pregnant women create a unique management dilemma.

Terminology

The Bethesda system describes colposcopic abnormalities as CIN and divides premalignant lesions into grades from 1 to 3 with the highest grade representing more worrisome lesions. CIN2 has been found to have poor reproducibility and likely represents a mix of low- and high-grade lesions. In addition, there is concern that HPV-associated lesions of the lower anogenital tract have incongruent terminology among different specialties that may not accurately represent the current understanding of HPV pathogenesis.

In 2012, the Lower Anogenital Squamous Terminology (LAST) project of the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology (ASCCP) advocated for consistent terminology across all lower anogenital tract lesions with HPV, including CIN (Int J Gynecol Pathol. 2013 Jan;32[1]:76-115).

With this new terminology, CIN1 is referred to as low-grade squamous intraepithelial lesion (LSIL). CIN2 is characterized by its p16 immunostaining; lesions that are p16 negative are considered LSIL, while those that are positive are considered HSIL (high-grade squamous intraepithelial lesion). While this staining is not universally performed, physicians will start seeing p16 staining results with increasing frequency on their cervical biopsies. CIN3 lesions are referred to as HSIL.

©monkeybusinessimages/Thinkstock

Given the current understanding of HPV-mediated disease, and a commitment to represent the most up-to-date information, the LAST project terminology of HSIL to represent previously identified CIN2 and CIN3 lesions will be used for the remainder of this text.

Diagnosis

There is little data on the natural history of HSIL diagnosed after colposcopy, as most women get some form of therapy. The information that is available suggests that in patients with untreated HSIL, the cumulative incidence of malignancy is as high as 30% at 30 years (Lancet Oncol. 2008 May;9[5]:425-34). Treatment recommendations for excision are aimed at addressing this alarming number; however, care must be individualized, especially in the setting of pregnancy.

If abnormal cervical cytology is obtained on routine screening, appropriate patients should be referred for colposcopic exam. Physicians performing colposcopy should be familiar with the physiologic effects of pregnancy that can obscure the exam, including the increased cervical mucus production, prominence of endocervical glands, and increased vascularity.

Colposcopic-directed ectocervical biopsies have been found to be safe in pregnancy, and these women should be provided the same care as those who are not pregnant (Obstet Gynecol. 1993 Jun;81[6]:915-8). Endocervical sampling and endometrial sampling should not be performed, however, and physicians should remain dedicated to checking pregnancy tests prior to colposcopy.

HSIL cytology should prompt a biopsy in pregnancy; a decision to skip the biopsy and perform an excisional procedure in this setting is not recommended regardless of patient or gestational age. If LSIL (CIN1) is noted on biopsy, reevaluation post partum should be strongly considered, unless a suspicious lesion was felt to be inadequately biopsied.

Management

Managing HSIL in pregnancy focuses on diagnosis and excluding malignancy, while treatment can be reserved for the postpartum period. When choosing a management option, consider individual patient factors such as colposcopic appearance of the lesion, gestational age, and access to health care.

If HSIL is noted on colposcopic-directed biopsy, consider one of several options. The most conservative approach is reevaluation with cytology and colposcopy 6 weeks post partum. This is an option for patients who do not have a colposcopic exam that was concerning for an invasive lesion, were able to be adequately biopsied, and will reliably return for follow-up. Many physicians feel more comfortable with repeat cytology and colposcopy in 3 months from the original biopsy. The most aggressive management would include an excisional procedure during pregnancy.

There are varying rates of regression of biopsy-proven HSIL in pregnancy ranging from 34% to 70% (Obstet Gynecol. 1999 Mar;93[3]:359-62; Acta Obstet Gynecol Scand. 2006;85[9]:1134-7; Reprod Sci. 2009 Nov;16[11]:1034-9). Out of more than 200 patients across these three studies, just two patients were diagnosed with an invasive lesion post partum. Given the low likelihood of progression during pregnancy and the high rate of regression, an excisional procedure should be considered only in cases where there is concern about invasive carcinoma.

In cases where an invasive lesion is suspected, consider an an excisional procedure. While there is some evidence that performing a laser excisional procedure early in pregnancy (18 weeks and earlier) can be safely done, that is not the most common management strategy in the United States (Tumori. 1998 Sep-Oct;84[5]:567-70; Int J Gynecol Cancer. 2007 Jan-Feb;17[1]:127-31). In this circumstance, referral to a gynecologic oncologist is warranted where consideration can be made for performing a cold knife conization. Physicians should be aware of the increased risk of bleeding with this procedure in pregnancy and the potential for preterm birth. There is little literature to guide counseling regarding these risks, and the decision to perform an excisional procedure should be made with a multidisciplinary team (Arch Gynecol Obstet. 2016 Jan 4. doi: 10.1007/s00404-015-3980-y).

The see-and-treat paradigm is not recommended in pregnancy. Those patients with poor follow-up should still undergo colposcopic-directed biopsies prior to any excisional procedure.

Treatment recommendations in pregnancy should be made on the basis of careful consideration of individual patient factors, with strong consideration of repeat testing with cytology and colposcopy prior to an excision procedure.

Dr. Sullivan is a fellow in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Gehrig is professor and director of gynecologic oncology at the university. Dr. Sullivan and Dr. Gehrig reported having no relevant financial disclosures. Email them at obnews@frontlinemedcom.com.

Vulvar cancer is a rare gynecologic cancer comprising only 5% of gynecologic malignancies. Given the low incidence of disease, many primary providers and even obstetricians and gynecologists many never encounter a case. Increased awareness of vulvar cancer and vulvar dysplasia among patients and physicians may decrease diagnostic delays and expedite patient therapy.

Diagnosis

There is a well documented delay in diagnosis of vulvar cancer that is attributed to both the patient and the physician. Patients may feel uncomfortable or embarrassed telling their physicians about vulvar symptoms and providers may not recognize the risk for malignancy and provide alternative therapies prior to biopsy (J Reprod Med. 1999;44[9]:766-8.).

Risk factors for vulvar cancer include human papillomavirus (HPV) infection, a history of smoking, immunosuppression, and a history of an abnormal pap smear. Vulvar dystrophy, lichen sclerosis, and squamous intraepithelial lesions have also been suggested as precursor lesions of invasive cancers. The key to early diagnosis and treatment is immediate in-office biopsy.

When evaluating a patient with a vulvar lesion, the initial evaluation should include a thorough exam with a measurement of the lesion and evaluation of inguinal lymph nodes. Also, a detailed description of a lesion’s relationship to the midline (how many centimeters away) and other vital structures (clitoris, urethra, anus) is important.

An in-office biopsy can be done on initial presentation and should include the lesion in question and underlying stroma in an effort to delineate depth of invasion. While shave biopsies may be appropriate for some skin lesions, if there is any concern for malignancy, a punch biopsy is preferred.

Pathology

Squamous cell carcinoma is the most common histologic subtype (greater than 90%) followed by malignant melanoma. Malignant melanoma poses a diagnostic challenge as 25% may present with nonpigmented lesions. These lesions may arise from a junctional nevus and are more common in postmenopausal white women.

The measurement of tumor thickness is essential in evaluation of melanoma. A diagnosis of vulvar melanoma should be referred to a gynecologic oncologist for further evaluation and treatment. Frequently these patients require a multidisciplinary approach with other medical and surgical subspecialties consulting.

Adenocarcinoma of the vulva frequently arises within the Bartholin glands. Bartholin gland disease is typically a disease of young women. Any abscess or lesion in the bartholin gland in women older than 50 years should raise awareness of the possibility of malignancy. Providers should have a low threshold for biopsy of any Bartholin lesion in older women and for any Bartholin gland lesion or cyst that returns or persists after initial drainage.

Staging pearls

Vulvar cancer spreads by direct extension, lymphatic embolization and hematogenous spread. Lymphatic spread can occur early in the disease and portends a much worse prognosis. In 2009, the International Federation of Gynecology and Obstetrics (FIGO) revised the staging system. The most significant change was in stage III disease, which now includes any patient with lymph node involvement. This change emphasizes lymph node status as the single most important prognostic factor. The 5-year overall survival of patients with locally advanced tumors but negative regional lymph nodes (62%) has been found to be significantly better than those with positive nodal status (39%, P value less than.0001) (Gynecol Oncol. 2008;110[1]:83-6.).

In patients with stage IA disease, which includes lesions less than 2 cm in size with stromal invasion of less than 1 mm, the risk of lymph node metastasis is low. These patients do not require inguinal lymph node dissection. If lesions are greater than 2 cm and/or have greater than 1 mm depth of invasion, a lymph node dissection is indicated. Lymph node dissection is performed on the ipsilateral side of the lesion as long as the lesion is more than 2 cm from a midline structure. If the lesion is in the midline or within 2 cm of the midline, a bilateral inguinal lymph node dissection is recommended.

There has been a recent uptake of the sentinel inguinal lymph node biopsy technique after two large prospective studies (the GROINSS V trial and GOG 173) validated this methodology (Lancet Oncol. 2010 Jul;11[7]:646-52 and Gynecol Oncol. 2013 Feb;128[2]:155-9).

Treatment

Surgical management of stage I and II disease involves a wide radical excision of the tumor with a 1-cm circumferential margin. Tumors with a depth of invasion of less than 1 mm do not require lymphadenectomy (Gynecol Oncol. 1992 Mar;44[3]:240-4). Stage I/II disease with deeper than 1-mm invasion requires a 2-cm margin and either sentinel node evaluation or lymphadenectomy. Survival for women with adequate resection of primary squamous carcinoma with negative lymph node involvement is greater than 90%.

Patients with metastasis to the groin frequently receive bilateral groin and pelvic radiation; however, recommendations are individualized based on size and number of metastasis. Patients should expect to receive recommendations for therapy after pathologic review and multidisciplinary consultation; therapy should be individualized for each clinical situation.

This disease is one of the elderly, but it is important to remember that treatment recommendations should not be made according to age alone. A British study found that when women over the age of 80 received standard treatment, their recurrence rate was 25% compared with a 53% recurrence rate in those whose treatment was modified (Int J Gynecol Cancer. 2009;19[4]:752-5.). In patients with advanced disease, preoperative radiation, with or without chemotherapy, is frequently regarded as the treatment of choice and may eliminate the need for radical surgery.

While vulvar cancer is a rare gynecologic malignancy, it can be devastating for patients and families, especially at late stages. Early diagnosis and treatment is imperative for improved patient outcomes. An increased awareness among patients and physicians alike may allow for earlier diagnosis and treatment.

Dr. Sullivan is a fellow in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Gehrig is professor and director of gynecologic oncology at the university. Dr. Sullivan and Dr. Gehrig reported having no relevant financial disclosures.

Vulvar cancer is a rare gynecologic cancer comprising only 5% of gynecologic malignancies. Given the low incidence of disease, many primary providers and even obstetricians and gynecologists many never encounter a case. Increased awareness of vulvar cancer and vulvar dysplasia among patients and physicians may decrease diagnostic delays and expedite patient therapy.

Diagnosis

There is a well documented delay in diagnosis of vulvar cancer that is attributed to both the patient and the physician. Patients may feel uncomfortable or embarrassed telling their physicians about vulvar symptoms and providers may not recognize the risk for malignancy and provide alternative therapies prior to biopsy (J Reprod Med. 1999;44[9]:766-8.).

Risk factors for vulvar cancer include human papillomavirus (HPV) infection, a history of smoking, immunosuppression, and a history of an abnormal pap smear. Vulvar dystrophy, lichen sclerosis, and squamous intraepithelial lesions have also been suggested as precursor lesions of invasive cancers. The key to early diagnosis and treatment is immediate in-office biopsy.

When evaluating a patient with a vulvar lesion, the initial evaluation should include a thorough exam with a measurement of the lesion and evaluation of inguinal lymph nodes. Also, a detailed description of a lesion’s relationship to the midline (how many centimeters away) and other vital structures (clitoris, urethra, anus) is important.

An in-office biopsy can be done on initial presentation and should include the lesion in question and underlying stroma in an effort to delineate depth of invasion. While shave biopsies may be appropriate for some skin lesions, if there is any concern for malignancy, a punch biopsy is preferred.

Pathology

Squamous cell carcinoma is the most common histologic subtype (greater than 90%) followed by malignant melanoma. Malignant melanoma poses a diagnostic challenge as 25% may present with nonpigmented lesions. These lesions may arise from a junctional nevus and are more common in postmenopausal white women.

The measurement of tumor thickness is essential in evaluation of melanoma. A diagnosis of vulvar melanoma should be referred to a gynecologic oncologist for further evaluation and treatment. Frequently these patients require a multidisciplinary approach with other medical and surgical subspecialties consulting.

Adenocarcinoma of the vulva frequently arises within the Bartholin glands. Bartholin gland disease is typically a disease of young women. Any abscess or lesion in the bartholin gland in women older than 50 years should raise awareness of the possibility of malignancy. Providers should have a low threshold for biopsy of any Bartholin lesion in older women and for any Bartholin gland lesion or cyst that returns or persists after initial drainage.

Staging pearls

Vulvar cancer spreads by direct extension, lymphatic embolization and hematogenous spread. Lymphatic spread can occur early in the disease and portends a much worse prognosis. In 2009, the International Federation of Gynecology and Obstetrics (FIGO) revised the staging system. The most significant change was in stage III disease, which now includes any patient with lymph node involvement. This change emphasizes lymph node status as the single most important prognostic factor. The 5-year overall survival of patients with locally advanced tumors but negative regional lymph nodes (62%) has been found to be significantly better than those with positive nodal status (39%, P value less than.0001) (Gynecol Oncol. 2008;110[1]:83-6.).

In patients with stage IA disease, which includes lesions less than 2 cm in size with stromal invasion of less than 1 mm, the risk of lymph node metastasis is low. These patients do not require inguinal lymph node dissection. If lesions are greater than 2 cm and/or have greater than 1 mm depth of invasion, a lymph node dissection is indicated. Lymph node dissection is performed on the ipsilateral side of the lesion as long as the lesion is more than 2 cm from a midline structure. If the lesion is in the midline or within 2 cm of the midline, a bilateral inguinal lymph node dissection is recommended.

There has been a recent uptake of the sentinel inguinal lymph node biopsy technique after two large prospective studies (the GROINSS V trial and GOG 173) validated this methodology (Lancet Oncol. 2010 Jul;11[7]:646-52 and Gynecol Oncol. 2013 Feb;128[2]:155-9).

Treatment

Surgical management of stage I and II disease involves a wide radical excision of the tumor with a 1-cm circumferential margin. Tumors with a depth of invasion of less than 1 mm do not require lymphadenectomy (Gynecol Oncol. 1992 Mar;44[3]:240-4). Stage I/II disease with deeper than 1-mm invasion requires a 2-cm margin and either sentinel node evaluation or lymphadenectomy. Survival for women with adequate resection of primary squamous carcinoma with negative lymph node involvement is greater than 90%.

Patients with metastasis to the groin frequently receive bilateral groin and pelvic radiation; however, recommendations are individualized based on size and number of metastasis. Patients should expect to receive recommendations for therapy after pathologic review and multidisciplinary consultation; therapy should be individualized for each clinical situation.

This disease is one of the elderly, but it is important to remember that treatment recommendations should not be made according to age alone. A British study found that when women over the age of 80 received standard treatment, their recurrence rate was 25% compared with a 53% recurrence rate in those whose treatment was modified (Int J Gynecol Cancer. 2009;19[4]:752-5.). In patients with advanced disease, preoperative radiation, with or without chemotherapy, is frequently regarded as the treatment of choice and may eliminate the need for radical surgery.

While vulvar cancer is a rare gynecologic malignancy, it can be devastating for patients and families, especially at late stages. Early diagnosis and treatment is imperative for improved patient outcomes. An increased awareness among patients and physicians alike may allow for earlier diagnosis and treatment.

Dr. Sullivan is a fellow in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Gehrig is professor and director of gynecologic oncology at the university. Dr. Sullivan and Dr. Gehrig reported having no relevant financial disclosures.

Vulvar cancer is a rare gynecologic cancer comprising only 5% of gynecologic malignancies. Given the low incidence of disease, many primary providers and even obstetricians and gynecologists many never encounter a case. Increased awareness of vulvar cancer and vulvar dysplasia among patients and physicians may decrease diagnostic delays and expedite patient therapy.

Diagnosis

There is a well documented delay in diagnosis of vulvar cancer that is attributed to both the patient and the physician. Patients may feel uncomfortable or embarrassed telling their physicians about vulvar symptoms and providers may not recognize the risk for malignancy and provide alternative therapies prior to biopsy (J Reprod Med. 1999;44[9]:766-8.).

Risk factors for vulvar cancer include human papillomavirus (HPV) infection, a history of smoking, immunosuppression, and a history of an abnormal pap smear. Vulvar dystrophy, lichen sclerosis, and squamous intraepithelial lesions have also been suggested as precursor lesions of invasive cancers. The key to early diagnosis and treatment is immediate in-office biopsy.

When evaluating a patient with a vulvar lesion, the initial evaluation should include a thorough exam with a measurement of the lesion and evaluation of inguinal lymph nodes. Also, a detailed description of a lesion’s relationship to the midline (how many centimeters away) and other vital structures (clitoris, urethra, anus) is important.

An in-office biopsy can be done on initial presentation and should include the lesion in question and underlying stroma in an effort to delineate depth of invasion. While shave biopsies may be appropriate for some skin lesions, if there is any concern for malignancy, a punch biopsy is preferred.

Pathology

Squamous cell carcinoma is the most common histologic subtype (greater than 90%) followed by malignant melanoma. Malignant melanoma poses a diagnostic challenge as 25% may present with nonpigmented lesions. These lesions may arise from a junctional nevus and are more common in postmenopausal white women.

The measurement of tumor thickness is essential in evaluation of melanoma. A diagnosis of vulvar melanoma should be referred to a gynecologic oncologist for further evaluation and treatment. Frequently these patients require a multidisciplinary approach with other medical and surgical subspecialties consulting.

Adenocarcinoma of the vulva frequently arises within the Bartholin glands. Bartholin gland disease is typically a disease of young women. Any abscess or lesion in the bartholin gland in women older than 50 years should raise awareness of the possibility of malignancy. Providers should have a low threshold for biopsy of any Bartholin lesion in older women and for any Bartholin gland lesion or cyst that returns or persists after initial drainage.

Staging pearls

Vulvar cancer spreads by direct extension, lymphatic embolization and hematogenous spread. Lymphatic spread can occur early in the disease and portends a much worse prognosis. In 2009, the International Federation of Gynecology and Obstetrics (FIGO) revised the staging system. The most significant change was in stage III disease, which now includes any patient with lymph node involvement. This change emphasizes lymph node status as the single most important prognostic factor. The 5-year overall survival of patients with locally advanced tumors but negative regional lymph nodes (62%) has been found to be significantly better than those with positive nodal status (39%, P value less than.0001) (Gynecol Oncol. 2008;110[1]:83-6.).

In patients with stage IA disease, which includes lesions less than 2 cm in size with stromal invasion of less than 1 mm, the risk of lymph node metastasis is low. These patients do not require inguinal lymph node dissection. If lesions are greater than 2 cm and/or have greater than 1 mm depth of invasion, a lymph node dissection is indicated. Lymph node dissection is performed on the ipsilateral side of the lesion as long as the lesion is more than 2 cm from a midline structure. If the lesion is in the midline or within 2 cm of the midline, a bilateral inguinal lymph node dissection is recommended.

There has been a recent uptake of the sentinel inguinal lymph node biopsy technique after two large prospective studies (the GROINSS V trial and GOG 173) validated this methodology (Lancet Oncol. 2010 Jul;11[7]:646-52 and Gynecol Oncol. 2013 Feb;128[2]:155-9).

Treatment

Surgical management of stage I and II disease involves a wide radical excision of the tumor with a 1-cm circumferential margin. Tumors with a depth of invasion of less than 1 mm do not require lymphadenectomy (Gynecol Oncol. 1992 Mar;44[3]:240-4). Stage I/II disease with deeper than 1-mm invasion requires a 2-cm margin and either sentinel node evaluation or lymphadenectomy. Survival for women with adequate resection of primary squamous carcinoma with negative lymph node involvement is greater than 90%.

Patients with metastasis to the groin frequently receive bilateral groin and pelvic radiation; however, recommendations are individualized based on size and number of metastasis. Patients should expect to receive recommendations for therapy after pathologic review and multidisciplinary consultation; therapy should be individualized for each clinical situation.

This disease is one of the elderly, but it is important to remember that treatment recommendations should not be made according to age alone. A British study found that when women over the age of 80 received standard treatment, their recurrence rate was 25% compared with a 53% recurrence rate in those whose treatment was modified (Int J Gynecol Cancer. 2009;19[4]:752-5.). In patients with advanced disease, preoperative radiation, with or without chemotherapy, is frequently regarded as the treatment of choice and may eliminate the need for radical surgery.

While vulvar cancer is a rare gynecologic malignancy, it can be devastating for patients and families, especially at late stages. Early diagnosis and treatment is imperative for improved patient outcomes. An increased awareness among patients and physicians alike may allow for earlier diagnosis and treatment.

Dr. Sullivan is a fellow in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Gehrig is professor and director of gynecologic oncology at the university. Dr. Sullivan and Dr. Gehrig reported having no relevant financial disclosures.