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Ovarian epithelial carcinoma with pelvic endometriosis: Wang et al
Journal Club
www.AJOG .org
Ovarian epithelial carcinoma with pelvic endometriosis: Wang et al Linda Van Le, MD; George A. Macones, MD, MSCE, Associate Editor The article below summarizes a roundtable discussion of a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. Article discussed: Wang S, Qui L, Lang JH, et al. Clinical analysis of ovarian epithelial carcinoma with coexisting pelvic endometriosis. Am J Obstet Gynecol 2013;208:413.e1-5.
DISCUSSION QUESTIONS -
Why is this study question important?
-
What was the study design?
-
What were the results?
-
What were the study’s strengths and limitations?
-
What is the clinical impact of this study?
From the Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, NC:
Moderator Linda Van Le, MD Professor Discussants Amanda Jackson, MD Second Year Fellow Kevin Schuler, MD Third Year Fellow Anuj Suri, MD Third Year Fellow Kemi Doll, MD First Year Fellow Jessica Stine, MD First Year Fellow Kenneth Kim, MD Assistant Professor L. V. L. is on the Advisory board for Biologics Inc., Speaker’s Bureau for Eisai, Inc. Funded research by Abbott Labs. The other authors report no conflict of interest. 0002 9378/free ª 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2013.03.004
See related article, page 413
E
pithelial ovarian cancers are uncommon but lethal. They include 5 general histologic types: serous, endometrioid, mucinous, clear cell, and Brenner tumors. Serous histology is most often encountered. In contrast, clear cell carcinomas represent 5-25% of ovarian cancers, and afflicted patients comprise 5% of clinical trial participants. Thus, the infrequent occurrence of clear cell cancers makes it difficult to study this particular ovarian cancer. Clear cell cancers appear to present at earlier stages and are associated with endometriosis; it is said that if one looks long enough, a component of endometriosis will always be associated with clear cell cancer at pathology review. The genetics of these cancers also differ from usual garden-variety carcinomas. Additionally, there is concern that these tumors are not as responsive to platinum-based chemotherapy as their serous counterpart. Given the many clinical questions regarding clear cell cancer of the ovary and its relative rarity, all studies of these tumors are valuable.
Uniformity, please This month, Journal Club members discussed a retrospective review of ovarian cancer patients over a 1-year period. Wang and colleagues set out to determine the relationship between endometriosis-associated ovarian cancer and “typical” epithelial carcinoma of the ovary. From March 2011 to March 2012, 226 patients, a fairly large population of women with ovarian cancer, were identified. Of these, 17 had cancer that was related to endometriosis; 209 did not. Endometriosis-associated ovarian carcinoma (EAOC) was defined as the
presence of ovarian cancer and endometriosis, and the disease could be identified in the same ovary or in the contralateral ovary. The researchers also included patients in this group if they had extra-ovarian pelvic endometriosis. Journal Club members were concerned that the third group might not truly qualify as having EAOC, since this definition is not uniformly accepted. While clinically it makes sense to include women with extra-ovarian pelvic endometriosis in the EAOC group, the concept should be reviewed in order to standardize the definition of EAOC. Unfortunately, given the small number of patients with EAOC, it was difficult to determine whether the authors’ observations would hold up if they had eliminated patients who had only extraovarian manifestations of endometriosis from analysis.
Uncharted opportunity Journal Club participants were impressed with the size of the patient population seen at Peking Union Medical Hospital. However, the authors looked at data amassed during 1 year, and discussants wondered whether an assessment carried out over several years would have provided more insight into EAOC. Given the single hospital site and uniformity of care, this would be a database worth exploring. For example, had the time span and patient pool been increased, it might have been possible to learn more about treatment results. One controversy that merits examination is how well clear cell ovarian cancers respond to platinum agents. Another potential area of investigation is genetic analysis. Mutations in the ARID1A and PIK3CA genes are
MAY 2013 American Journal of Obstetrics & Gynecology
415
Journal Club suspected to play a role in clear cell carcinoma of the ovary. Among patients with clear cell carcinomas, ARID1A is mutated in 46%; PIK3CA in 33%. In contrast, these are not considered significant mutations in patients with serous tumors. A trial by the Gynecologic Oncology Group (GOG)—GOG 268—will determine the frequency with which components of the mTOR signaling pathway are expressed and whether these elements are associated with clinical outcome. Thus, there is a wealth of genetic information to be studied in clear cell cancers. Wang and coworkers did not perform any genetic analyses. When researchers plan new studies, they should consider that Asian women appear to be especially vulnerable to clear cell cancers. Over the last decade, studies have consistently indicated that
www.AJOG.org clear cell carcinoma rates are higher in Japan. It has also been observed that among patients with ovarian cancer in the United States, Asian women are more often given a diagnosis of clear cell cancer than are non-Asian patients. Wang and colleagues demonstrated that the incidence of clear cell tumors is also higher in Chinese women, emphasizing the unique propensity for the clear cell variant in Asian women with ovarian cancer. It would be important to stratify analysis for Asian ethnicity when studying clear cell cancers in future clinical trials.
A different level of danger While ovarian cancers are generally lethal, clear cell histology has been associated with worse progression-free and overall survival. To date, many of our studies have lumped data collected from
women who have clear cell carcinomas with that gathered from patients with more common histologic types, such as serous carcinomas. It is finally understood that rare histologic types should be studied separately; their susceptibility to standard chemotherapeutic agents is different, as are long-term outcomes. The GOG has introduced studies specific to rare cell types, including clear cell cancers and mucinous adenocarcinomas. Given the scarcity of these cancers, findings will take some time to accrue. Meanwhile, the collective information we can gain from active gynecology services will have to suffice. If investigators at institutions with large databases stepped up evaluation of their patients with clear cell cancers, we might gain some partial understanding of these unusual cell types while we await results from prospective studies.
Our publisher A global family of outstanding imprints Elsevier, which publishes the American Journal of Obstetrics & Gynecology, is the world’s largest scientific, technical, and medical publisher. Founded in 1880 in Leiden, the Netherlands, and now based in Amsterdam, the company maintains more than 60 offices in 20 countries and publishes 2000 journals and 2000 new books annually. Elsevier’s global scholarly community comprises 7000 journal editors, 70,000 editorial board members, 300,000 reviewers, and 600,000 authors. Elsevier’s namesake was the venerable House of Elzevir, a 7-generation family publishing business from 1580 to 1712, during which the company produced more than 2000 titles. Its diminutive volumes became so popular that “an Elzevir” became common parlance in the late 19th century for a pocketbook-sized collector’s edition of the classics. The founding family dared to publish Galileo’s Two New Sciences, the first important treatise on modern physics, in 1638. With the author under house arrest, the manuscript, banned by the Inquisition, was smuggled out of Italy. Subsequent visionaries published by Elsevier include Jules Verne, Alexander Fleming, Stephen W. Hawking, and numerous Nobel recipients.
416 American Journal of Obstetrics & Gynecology MAY 2013
www.AJOG .org
Ovarian epithelial carcinoma with pelvic endometriosis: Wang et al Linda Van Le, MD; George A. Macones, MD, MSCE, Associate Editor The article below summarizes a roundtable discussion of a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. Article discussed: Wang S, Qui L, Lang JH, et al. Clinical analysis of ovarian epithelial carcinoma with coexisting pelvic endometriosis. Am J Obstet Gynecol 2013;208:413.e1-5.
DISCUSSION QUESTIONS -
Why is this study question important?
-
What was the study design?
-
What were the results?
-
What were the study’s strengths and limitations?
-
What is the clinical impact of this study?
From the Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, NC:
Moderator Linda Van Le, MD Professor Discussants Amanda Jackson, MD Second Year Fellow Kevin Schuler, MD Third Year Fellow Anuj Suri, MD Third Year Fellow Kemi Doll, MD First Year Fellow Jessica Stine, MD First Year Fellow Kenneth Kim, MD Assistant Professor L. V. L. is on the Advisory board for Biologics Inc., Speaker’s Bureau for Eisai, Inc. Funded research by Abbott Labs. The other authors report no conflict of interest. 0002 9378/free ª 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2013.03.004
See related article, page 413
E
pithelial ovarian cancers are uncommon but lethal. They include 5 general histologic types: serous, endometrioid, mucinous, clear cell, and Brenner tumors. Serous histology is most often encountered. In contrast, clear cell carcinomas represent 5-25% of ovarian cancers, and afflicted patients comprise 5% of clinical trial participants. Thus, the infrequent occurrence of clear cell cancers makes it difficult to study this particular ovarian cancer. Clear cell cancers appear to present at earlier stages and are associated with endometriosis; it is said that if one looks long enough, a component of endometriosis will always be associated with clear cell cancer at pathology review. The genetics of these cancers also differ from usual garden-variety carcinomas. Additionally, there is concern that these tumors are not as responsive to platinum-based chemotherapy as their serous counterpart. Given the many clinical questions regarding clear cell cancer of the ovary and its relative rarity, all studies of these tumors are valuable.
Uniformity, please This month, Journal Club members discussed a retrospective review of ovarian cancer patients over a 1-year period. Wang and colleagues set out to determine the relationship between endometriosis-associated ovarian cancer and “typical” epithelial carcinoma of the ovary. From March 2011 to March 2012, 226 patients, a fairly large population of women with ovarian cancer, were identified. Of these, 17 had cancer that was related to endometriosis; 209 did not. Endometriosis-associated ovarian carcinoma (EAOC) was defined as the
presence of ovarian cancer and endometriosis, and the disease could be identified in the same ovary or in the contralateral ovary. The researchers also included patients in this group if they had extra-ovarian pelvic endometriosis. Journal Club members were concerned that the third group might not truly qualify as having EAOC, since this definition is not uniformly accepted. While clinically it makes sense to include women with extra-ovarian pelvic endometriosis in the EAOC group, the concept should be reviewed in order to standardize the definition of EAOC. Unfortunately, given the small number of patients with EAOC, it was difficult to determine whether the authors’ observations would hold up if they had eliminated patients who had only extraovarian manifestations of endometriosis from analysis.
Uncharted opportunity Journal Club participants were impressed with the size of the patient population seen at Peking Union Medical Hospital. However, the authors looked at data amassed during 1 year, and discussants wondered whether an assessment carried out over several years would have provided more insight into EAOC. Given the single hospital site and uniformity of care, this would be a database worth exploring. For example, had the time span and patient pool been increased, it might have been possible to learn more about treatment results. One controversy that merits examination is how well clear cell ovarian cancers respond to platinum agents. Another potential area of investigation is genetic analysis. Mutations in the ARID1A and PIK3CA genes are
MAY 2013 American Journal of Obstetrics & Gynecology
415
Journal Club suspected to play a role in clear cell carcinoma of the ovary. Among patients with clear cell carcinomas, ARID1A is mutated in 46%; PIK3CA in 33%. In contrast, these are not considered significant mutations in patients with serous tumors. A trial by the Gynecologic Oncology Group (GOG)—GOG 268—will determine the frequency with which components of the mTOR signaling pathway are expressed and whether these elements are associated with clinical outcome. Thus, there is a wealth of genetic information to be studied in clear cell cancers. Wang and coworkers did not perform any genetic analyses. When researchers plan new studies, they should consider that Asian women appear to be especially vulnerable to clear cell cancers. Over the last decade, studies have consistently indicated that
www.AJOG.org clear cell carcinoma rates are higher in Japan. It has also been observed that among patients with ovarian cancer in the United States, Asian women are more often given a diagnosis of clear cell cancer than are non-Asian patients. Wang and colleagues demonstrated that the incidence of clear cell tumors is also higher in Chinese women, emphasizing the unique propensity for the clear cell variant in Asian women with ovarian cancer. It would be important to stratify analysis for Asian ethnicity when studying clear cell cancers in future clinical trials.
A different level of danger While ovarian cancers are generally lethal, clear cell histology has been associated with worse progression-free and overall survival. To date, many of our studies have lumped data collected from
women who have clear cell carcinomas with that gathered from patients with more common histologic types, such as serous carcinomas. It is finally understood that rare histologic types should be studied separately; their susceptibility to standard chemotherapeutic agents is different, as are long-term outcomes. The GOG has introduced studies specific to rare cell types, including clear cell cancers and mucinous adenocarcinomas. Given the scarcity of these cancers, findings will take some time to accrue. Meanwhile, the collective information we can gain from active gynecology services will have to suffice. If investigators at institutions with large databases stepped up evaluation of their patients with clear cell cancers, we might gain some partial understanding of these unusual cell types while we await results from prospective studies.
Our publisher A global family of outstanding imprints Elsevier, which publishes the American Journal of Obstetrics & Gynecology, is the world’s largest scientific, technical, and medical publisher. Founded in 1880 in Leiden, the Netherlands, and now based in Amsterdam, the company maintains more than 60 offices in 20 countries and publishes 2000 journals and 2000 new books annually. Elsevier’s global scholarly community comprises 7000 journal editors, 70,000 editorial board members, 300,000 reviewers, and 600,000 authors. Elsevier’s namesake was the venerable House of Elzevir, a 7-generation family publishing business from 1580 to 1712, during which the company produced more than 2000 titles. Its diminutive volumes became so popular that “an Elzevir” became common parlance in the late 19th century for a pocketbook-sized collector’s edition of the classics. The founding family dared to publish Galileo’s Two New Sciences, the first important treatise on modern physics, in 1638. With the author under house arrest, the manuscript, banned by the Inquisition, was smuggled out of Italy. Subsequent visionaries published by Elsevier include Jules Verne, Alexander Fleming, Stephen W. Hawking, and numerous Nobel recipients.
416 American Journal of Obstetrics & Gynecology MAY 2013