Special Section—Issues in Gynecologic Pathology
Current Issues in Gynecologic Pathology Fattaneh A. Tavassoli, MD
I
n this issue of Archives of Pathology & Laboratory Medicine, several reviews on various topics in gynecologic pathology are presented, ranging from the spectrum of endocervical adenocarcinomas to ovarian germ cell tumors. Additional reviews discussing these topics will also be presented in the April 2014 issue of the ARCHIVES. Together, the reviews in the March and April issues provide an update on the morphologic features, differential diagnosis, alternate approaches to classification, value of immunohistochemical markers, and potential novel targets for therapy. Endometrial carcinoma is a common gynecologic cancer. Although a vast majority of endometrial carcinomas develop in perimenopausal and postmenopausal women, a very small proportion do develop in women younger than 40 years. Even among younger women, many of the tumors are associated with estrogen excess. Nonetheless, young age at presentation should raise the possibility of DNA mismatch repair abnormalities and Lynch syndrome. A review by Karuna Garg, MD, and Robert Soslow, MD, addresses the association of endometrial carcinomas occurring prior to age 40 years with Lynch syndrome, and how to confirm this with proper use of immunohistochemical stains for DNA mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6). Recognition of Lynch syndrome–associated adenocarcinomas is important for management of these young women; the risk for recurrence and progression requires careful monitoring when conservative therapy is selected. Among the adenocarcinomas that develop in the older age group, the serous papillary carcinomas are particularly aggressive, and identification of novel targets for therapy could potentially result in substantial improvement in survival and quality of life. Encouraged by the results of trastuzumab therapy in management of HER2-positive breast cancers, several recent studies have evaluated HER2 expression and/or amplification in endometrial carcinomas. Natalia Buza, MD, Dana Roque, MD, and Alessandro Santin, MD, address the potential of HER2 as a target for therapy in endometrial carcinomas. It is important to note that conclusions of various studies have been variable in their enthusiasm for routine assessment of HER2 in endometrial cancers and its value as a target for therapy. These differences, at least in part, emanate from inclusion of various subtypes of endometrial carcinoma in some studies, Accepted for publication October 31, 2013. From the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut. doi: 10.5858/arpa.2013-0664-ED Reprints: Fattaneh A. Tavassoli, MD, Department of Pathology, Yale University School of Medicine, Lauder Hall 222, 310 Cedar St, New Haven, CT 06510 (e-mail: [email protected]). Arch Pathol Lab Med—Vol 138, March 2014
whereas others have focused on the serous subtype. Furthermore, most of these studies have basically used variable cutoffs for positivity. It is important to have a largescale, multi-institutional study to look at what should be considered a positive HER2 result immunohistochemically for serous endometrial carcinomas—what level of intensity in what percentage of tumor cells, as well as what ratio of HER2:CEP17 should be required for amplification. Is an equivocal category by immunohistochemistry or fluorescent in situ hybridization even necessary for endometrial carcinomas? The ultimate result should show a positive response to therapy. We also have to agree on what level of therapeutic response is sufficient to treat hundreds of women with this expensive therapeutic option. Francisco Nogales, MD, PhD, Isabel Dulcey, MD, and Ovidiu Preda, MD, PhD, have contributed a superb update on ovarian germ cell tumors. This most useful and wellillustrated review addresses pathogenesis, differential diagnosis, and value of immunohistochemical stains, and it includes a recently described condition of autoimmune encephalitis against N-methyl-D-aspartate receptor that has been noted as the most common autoimmune disorder associated with ovarian teratomas. Also related to ovarian teratomas, gliomatosis peritonei and its possible pathogenetic mechanisms are discussed. Two additional reviews in this special section will appear in the April 2014 issue. Joana Loureiro, MD, and Esther Oliva, MD, have contributed an exceptional review of the variety of glandular lesions of the cervix that will remind pathologists of the wide range of glandular alterations other than neoplastic squamous lesions that occur in the cervix. In my consultation practice, it is not uncommon for a cervical sample to be sent with a question about the changes in the squamous epithelium, whereas the coexisting endocervical glandular alterations that are often equally as important from a clinical standpoint are overlooked. The review illustrates the common and uncommon glandular lesions to remind us of their morphologic characteristics so that they can be recognized, even if the presenting symptoms leading to sampling of the cervix were due to pathology in the squamous epithelium. During the past several decades, the classification of endometrial hyperplasias has gone through several changes, all based purely on morphology. Significant interobserver differences in interpretation have persisted, however, when the current classifications of hyperplasia and atypical hyperplasia (simple and complex) are used. The review prepared by Richard Owings, MD and Charles M. Quick, MD, focuses on Dr Mutter’s concept of endometrial intraepithelial neoplasia (EIN).1,2 The review addresses the molecular alterations, defines diagnostic criteria, and explains Editorial—Tavassoli 333
the value of PTEN immunostain both as a surrogate for inactivation of the tumor suppressor gene PTEN and as an aid or confirmatory step in the hope of not only reducing some of the interobserver variability, but also finding a more reliable separation of the monoclonal proliferations that reflect precursors of endometrial carcinoma from those that are simply physiologic variations. Although technical difficulties with PTEN immunostaining have been noted as a limiting factor in the use of EIN, it is quite possible that with widespread use of EIN classification of endometrial proliferations, improved techniques will evolve that would obviate any difficulties associated with PTEN immunostaining. It is anticipated that molecular analysis of many gynecologic tumors and diseases will open new avenues for management of a variety of highly aggressive gynecologic cancers. In future issues, we hope to address some of the novel concepts regarding the origin of ovarian carcinomas. As pathologists interested in gynecologic pathology are aware, the origin of ovarian cancers has now shifted from the ovarian surface epithelium to the fallopian tube mucosa, at least for the high-grade serous variant. This could have significant implications, particularly in the management of women with BRCA1/BRCA2 mutations; rather than having bilateral salpingo-oopherectomy as a prophylactic proce-
dure when childbearing is complete, these women could potentially get similar benefits with prophylactic bilateral salpingectomy. The addition of molecular analysis has expanded our field, providing novel explanations for old problems. As we learn to judiciously apply molecular techniques to our routine practice, it is important to keep in mind that we still rely on morphology for diagnosis, for differentiating cancer from noncancer, and for recognition of morphologic risk factors. We should also apply these novel technologies to prevent disease by modifying disordered pathways, although this may be more challenging than finding targets for therapy. It is important to incorporate technologic advances into our practice, periodically reassess our approaches, and keep an open mind to all options and possibilities that can help our patients. As aptly expressed before, the mind and a parachute function best only when fully open. References 1. Monte NM, Webster KA, Neuberg D, Dressler GR, Mutter GL. Joint loss of PAX2 and PTEN expression in endometrial precancer and cancer. Cancer Res. 2010;70:6225–6232. 2. Mutter GL, Zaino RJ, Baak JP, Bentley RC, Robboy SJ. Benign endometrial hyperplasia sequence and endometrial intraepithelial neoplasia. Int J Gynecol Pathol. 2007;26:103–114.
Fattaneh A. Tavassoli, MD, received her doctor of medicine degree from St Louis University. She remained in St Louis for her residency in anatomic pathology at Washington University School of Medicine and her fellowship training in gynecologic pathology with Fredrick Kraus, MD, at St John’s Mercy Medical Center. She then joined the Gynecologic and Breast Pathology Department at the Armed Forces Institute of Pathology (AFIP; Washington, DC) as a staff pathologist; subsequently, she was appointed the vice chairman and, in 1994, chairman of that department. While at AFIP, she also served as clinical professor of pathology at George Washington University (Washington, DC), and the Uniformed Services University of Health Sciences in Bethesda, Maryland. She was also a consultant to the National Institutes of Health and has served on National Cancer Institute committees related to breast cancer. In 2003, she moved to Yale University School of Medicine (New Haven, Connecticut), where she continues to practice as professor of pathology and reproductive sciences and as director of the Women’s Health Program in the Department of Pathology.
Fattaneh A. Tavassoli, MD
334 Arch Pathol Lab Med—Vol 138, March 2014
Dr Tavassoli’s interest in breast and gynecologic pathology has resulted in more than 200 peer-reviewed publications and multiple book chapters. She is also the author of two editions of Pathology of the Breast, coeditor of the World Health Organization’s 2003 Classification of Tumours of the Breast and Female Genital Tract, coauthor of the AFIP 2009 fascicle on Tumors of the Mammary Gland (fourth series), and coauthor of an interactive expert system on pathology of the breast. She is an advocate for the term intraepithelial neoplasia (ductal, lobular, and papillary variants) as a replacement for in situ carcinoma in the breast. She serves on the editorial board of multiple pathology journals and is an associate editor in anatomic pathology for the Archives of Pathology & Laboratory Medicine. Her interest in education has resulted in presentation of short and long courses at both the American Society of Clinical Pathology and the United States and Canadian Academy of Pathology. Interested in pathology education on a global level, Dr Tavassoli has given more than 300 presentations in gynecologic and breast pathology in the form of lectures, slide seminars, and short and long courses around the United States and worldwide.
Editorial—Tavassoli
Copyright of Archives of Pathology & Laboratory Medicine is the property of College of American Pathologists and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Current Issues in Gynecologic Pathology Fattaneh A. Tavassoli, MD
I
n this issue of Archives of Pathology & Laboratory Medicine, several reviews on various topics in gynecologic pathology are presented, ranging from the spectrum of endocervical adenocarcinomas to ovarian germ cell tumors. Additional reviews discussing these topics will also be presented in the April 2014 issue of the ARCHIVES. Together, the reviews in the March and April issues provide an update on the morphologic features, differential diagnosis, alternate approaches to classification, value of immunohistochemical markers, and potential novel targets for therapy. Endometrial carcinoma is a common gynecologic cancer. Although a vast majority of endometrial carcinomas develop in perimenopausal and postmenopausal women, a very small proportion do develop in women younger than 40 years. Even among younger women, many of the tumors are associated with estrogen excess. Nonetheless, young age at presentation should raise the possibility of DNA mismatch repair abnormalities and Lynch syndrome. A review by Karuna Garg, MD, and Robert Soslow, MD, addresses the association of endometrial carcinomas occurring prior to age 40 years with Lynch syndrome, and how to confirm this with proper use of immunohistochemical stains for DNA mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6). Recognition of Lynch syndrome–associated adenocarcinomas is important for management of these young women; the risk for recurrence and progression requires careful monitoring when conservative therapy is selected. Among the adenocarcinomas that develop in the older age group, the serous papillary carcinomas are particularly aggressive, and identification of novel targets for therapy could potentially result in substantial improvement in survival and quality of life. Encouraged by the results of trastuzumab therapy in management of HER2-positive breast cancers, several recent studies have evaluated HER2 expression and/or amplification in endometrial carcinomas. Natalia Buza, MD, Dana Roque, MD, and Alessandro Santin, MD, address the potential of HER2 as a target for therapy in endometrial carcinomas. It is important to note that conclusions of various studies have been variable in their enthusiasm for routine assessment of HER2 in endometrial cancers and its value as a target for therapy. These differences, at least in part, emanate from inclusion of various subtypes of endometrial carcinoma in some studies, Accepted for publication October 31, 2013. From the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut. doi: 10.5858/arpa.2013-0664-ED Reprints: Fattaneh A. Tavassoli, MD, Department of Pathology, Yale University School of Medicine, Lauder Hall 222, 310 Cedar St, New Haven, CT 06510 (e-mail: [email protected]). Arch Pathol Lab Med—Vol 138, March 2014
whereas others have focused on the serous subtype. Furthermore, most of these studies have basically used variable cutoffs for positivity. It is important to have a largescale, multi-institutional study to look at what should be considered a positive HER2 result immunohistochemically for serous endometrial carcinomas—what level of intensity in what percentage of tumor cells, as well as what ratio of HER2:CEP17 should be required for amplification. Is an equivocal category by immunohistochemistry or fluorescent in situ hybridization even necessary for endometrial carcinomas? The ultimate result should show a positive response to therapy. We also have to agree on what level of therapeutic response is sufficient to treat hundreds of women with this expensive therapeutic option. Francisco Nogales, MD, PhD, Isabel Dulcey, MD, and Ovidiu Preda, MD, PhD, have contributed a superb update on ovarian germ cell tumors. This most useful and wellillustrated review addresses pathogenesis, differential diagnosis, and value of immunohistochemical stains, and it includes a recently described condition of autoimmune encephalitis against N-methyl-D-aspartate receptor that has been noted as the most common autoimmune disorder associated with ovarian teratomas. Also related to ovarian teratomas, gliomatosis peritonei and its possible pathogenetic mechanisms are discussed. Two additional reviews in this special section will appear in the April 2014 issue. Joana Loureiro, MD, and Esther Oliva, MD, have contributed an exceptional review of the variety of glandular lesions of the cervix that will remind pathologists of the wide range of glandular alterations other than neoplastic squamous lesions that occur in the cervix. In my consultation practice, it is not uncommon for a cervical sample to be sent with a question about the changes in the squamous epithelium, whereas the coexisting endocervical glandular alterations that are often equally as important from a clinical standpoint are overlooked. The review illustrates the common and uncommon glandular lesions to remind us of their morphologic characteristics so that they can be recognized, even if the presenting symptoms leading to sampling of the cervix were due to pathology in the squamous epithelium. During the past several decades, the classification of endometrial hyperplasias has gone through several changes, all based purely on morphology. Significant interobserver differences in interpretation have persisted, however, when the current classifications of hyperplasia and atypical hyperplasia (simple and complex) are used. The review prepared by Richard Owings, MD and Charles M. Quick, MD, focuses on Dr Mutter’s concept of endometrial intraepithelial neoplasia (EIN).1,2 The review addresses the molecular alterations, defines diagnostic criteria, and explains Editorial—Tavassoli 333
the value of PTEN immunostain both as a surrogate for inactivation of the tumor suppressor gene PTEN and as an aid or confirmatory step in the hope of not only reducing some of the interobserver variability, but also finding a more reliable separation of the monoclonal proliferations that reflect precursors of endometrial carcinoma from those that are simply physiologic variations. Although technical difficulties with PTEN immunostaining have been noted as a limiting factor in the use of EIN, it is quite possible that with widespread use of EIN classification of endometrial proliferations, improved techniques will evolve that would obviate any difficulties associated with PTEN immunostaining. It is anticipated that molecular analysis of many gynecologic tumors and diseases will open new avenues for management of a variety of highly aggressive gynecologic cancers. In future issues, we hope to address some of the novel concepts regarding the origin of ovarian carcinomas. As pathologists interested in gynecologic pathology are aware, the origin of ovarian cancers has now shifted from the ovarian surface epithelium to the fallopian tube mucosa, at least for the high-grade serous variant. This could have significant implications, particularly in the management of women with BRCA1/BRCA2 mutations; rather than having bilateral salpingo-oopherectomy as a prophylactic proce-
dure when childbearing is complete, these women could potentially get similar benefits with prophylactic bilateral salpingectomy. The addition of molecular analysis has expanded our field, providing novel explanations for old problems. As we learn to judiciously apply molecular techniques to our routine practice, it is important to keep in mind that we still rely on morphology for diagnosis, for differentiating cancer from noncancer, and for recognition of morphologic risk factors. We should also apply these novel technologies to prevent disease by modifying disordered pathways, although this may be more challenging than finding targets for therapy. It is important to incorporate technologic advances into our practice, periodically reassess our approaches, and keep an open mind to all options and possibilities that can help our patients. As aptly expressed before, the mind and a parachute function best only when fully open. References 1. Monte NM, Webster KA, Neuberg D, Dressler GR, Mutter GL. Joint loss of PAX2 and PTEN expression in endometrial precancer and cancer. Cancer Res. 2010;70:6225–6232. 2. Mutter GL, Zaino RJ, Baak JP, Bentley RC, Robboy SJ. Benign endometrial hyperplasia sequence and endometrial intraepithelial neoplasia. Int J Gynecol Pathol. 2007;26:103–114.
Fattaneh A. Tavassoli, MD, received her doctor of medicine degree from St Louis University. She remained in St Louis for her residency in anatomic pathology at Washington University School of Medicine and her fellowship training in gynecologic pathology with Fredrick Kraus, MD, at St John’s Mercy Medical Center. She then joined the Gynecologic and Breast Pathology Department at the Armed Forces Institute of Pathology (AFIP; Washington, DC) as a staff pathologist; subsequently, she was appointed the vice chairman and, in 1994, chairman of that department. While at AFIP, she also served as clinical professor of pathology at George Washington University (Washington, DC), and the Uniformed Services University of Health Sciences in Bethesda, Maryland. She was also a consultant to the National Institutes of Health and has served on National Cancer Institute committees related to breast cancer. In 2003, she moved to Yale University School of Medicine (New Haven, Connecticut), where she continues to practice as professor of pathology and reproductive sciences and as director of the Women’s Health Program in the Department of Pathology.
Fattaneh A. Tavassoli, MD
334 Arch Pathol Lab Med—Vol 138, March 2014
Dr Tavassoli’s interest in breast and gynecologic pathology has resulted in more than 200 peer-reviewed publications and multiple book chapters. She is also the author of two editions of Pathology of the Breast, coeditor of the World Health Organization’s 2003 Classification of Tumours of the Breast and Female Genital Tract, coauthor of the AFIP 2009 fascicle on Tumors of the Mammary Gland (fourth series), and coauthor of an interactive expert system on pathology of the breast. She is an advocate for the term intraepithelial neoplasia (ductal, lobular, and papillary variants) as a replacement for in situ carcinoma in the breast. She serves on the editorial board of multiple pathology journals and is an associate editor in anatomic pathology for the Archives of Pathology & Laboratory Medicine. Her interest in education has resulted in presentation of short and long courses at both the American Society of Clinical Pathology and the United States and Canadian Academy of Pathology. Interested in pathology education on a global level, Dr Tavassoli has given more than 300 presentations in gynecologic and breast pathology in the form of lectures, slide seminars, and short and long courses around the United States and worldwide.
Editorial—Tavassoli
Copyright of Archives of Pathology & Laboratory Medicine is the property of College of American Pathologists and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
