Unexpected Gynecologic Neoplasms in Patients With Proven or Suspected BRCA-1 or -2 Mutations

Agoff, S. Nicholas; Mendelin, Joel E.; Grieco, Verena S.; Garcia, Rochelle L.

doi:10.1097/00000478-200202000-00003

Cited by 95 publications

(42 citation statements)

References 28 publications

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“…37 Beginning in the late 1990s, investigators began identifying early serous carcinomas of the fallopian tube in prophylactic salpingo-oophorectomies from women with BRCA mutations (BRCA+). [38][39][40] This finding necessitated a shift in management with emphasis on removing both tubes and ovaries from these patients. Since then, early serous carcinoma has been diagnosed in the fallopian tubes from approximately 2% to 10% of BRCA+ patients undergoing prophylactic bilateral salpingo-oophorectomy (table 1).…”

Section: Lessons From the Brca Populationmentioning

confidence: 99%

Lessons from BRCA: The Tubal Fimbria Emerges as an Origin for Pelvic Serous Cancer

Crum¹,

Drapkin²,

Kindelberger³

et al. 2007

Clinical Medicine & Research

313

219

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Ovarian epithelial cancer is diagnosed in approximately 25,000 women yearly in the United States, accounting for approximately 12,500 deaths. Of these tumors, serous cancer is the most lethal, due to its capacity to spread beyond the reproductive tract and involve the peritoneal surfaces or distant organs. Conventional classification systems designate tumor origins principally on the location of the largest tumor. However, despite the fact that the largest tumors typically involve the ovaries, demonstrations of a precise starting point for these tumors, including precursor lesions, have been inconsistent. In recent years, a major effort to prevent serous cancer in genetically susceptible women with mutations in BRCA1 or BRCA2 has spawned the practice of prophylactic salpingo-oophorectomy. This practice has surprisingly revealed that many early cancers in these women arise in the fallopian tube, and further studies have pinpointed the distal (fimbrial) portion as the most common site of origin. Emerging studies that carefully examine the fallopian tubes suggest a high frequency of early cancer in the fimbria in unselected women with ovarian and peritoneal serous carcinoma, raising the distinct possibility that a significant proportion of these tumors have a fimbrial origin.The evidence for these discoveries and their relevance to serous cancer classification, early detection and prevention are addressed in this review. A model for pelvic serous cancer is proposed that takes into account five distinct variables which ultimately impact on origin and tumor distribution: (1) location of target epithelium, (2) genotoxic stress, (3) type of epithelium, (4) mitigating genetic factors, and (5) tumor spread pattern. Ultimately, this model illustrates the importance of identifying cancer precursors, inasmuch as these entities are useful as both surrogate endpoints for their respective malignancies in epidemiologic studies and natural targets for cancer prevention. Ovar ian epithelial cancer is diagnosed in approximately 25,000 women yearly in the United States with approximately one half dying of their disease. 1 It typically afflicts women near to menopause or postmenopause and peaks in the sixth to seventh decades of life. Surgery and chemotherapy will produce a complete response in 70% of patients; however, relapse rates are high, often occurring after a relatively brief respite. Overall long-term survival, but not cure, rates have only begun to improve measurably with the advent of taxol chemotherapy and intraperitoneal routes of instillation. However, the incremental gain in disease-free survival seen with these new therapies is only a few months. 2 Approximately 10% of women with ovarian cancer have a positive family history and most have an inherited heterozygous mutation in the BRCA1 or BRCA2 gene. Women with a hereditary predisposition for ovarian cancer develop the disease on average a decade earlier. 3,4 The lifetime risk of ovarian cancer in women with mutations in BRCA1 or BRCA2 (BRCA+) is estimated to be as h...

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Section: Lessons From the Brca Populationmentioning

confidence: 99%

Lessons from BRCA: The Tubal Fimbria Emerges as an Origin for Pelvic Serous Cancer

Crum¹,

Drapkin²,

Kindelberger³

et al. 2007

Clinical Medicine & Research

313

219

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“…[30][31][32][33][34] These findings have engendered speculation that 'ovarian' carcinomas in women with BRCA1 mutations may originate from undetected exfoliated tubal carcinomas 30,33,35 and have led to the suggestion that ovarian and fallopian tube carcinomas in women with BRCA mutations should be termed 'female adnexal carcinoma'. 24,35 …”

Section: Morphologic Datamentioning

confidence: 99%

Origins and molecular pathology of ovarian cancer

2005

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Epithelial ovarian cancer comprises the majority of malignant ovarian tumors in adult women. These neoplasms are classified into distinct morphologic categories based on the appearance of the epithelium into tumors of serous, mucinous, endometrioid, clear cell, transitional, squamous, mixed and undifferentiated type. Current data indicate that each of these histologic subtypes is associated with distinct morphologic and molecular genetic alterations: high-grade serous and possibly endometrioid carcinomas most probably arise from surface epithelial inclusion glands with TP53 mutations and dysfunction of BRCA1 and/or BRCA2; low-grade serous carcinomas probably arise in a stepwise fashion in an adenoma-borderline tumor-carcinoma sequence from typical to micropapillary borderline tumors to low-grade invasive serous carcinoma via activation of the RAS-RAF signaling pathway secondary to mutations in KRAS and BRAF; mucinous carcinomas arise via an adenoma-borderline tumor-carcinoma sequence with mutations in KRAS; low-grade endometrioid carcinomas arise from endometriosis via mutations in CTNNB1 (the gene encoding b-catenin) and PTEN. Although the morphologic data strongly support an origin of clear cell carcinoma from endometriosis, there is limited data on the genetic alterations in these uncommon tumors. Thus it is likely that most low-grade, relatively indolent ovarian carcinomas of serous, mucinous and endometrioid type arise from pre-existing cystadenomas or endometriosis whereas most high-grade serous carcinomas arise without an easily identifiable precursor lesion. Modern Pathology (2005) 18, S19-S32. doi:10.1038/modpathol.3800306Keywords: ovarian cancer; ovarian borderline tumors; histogenesis; molecular pathology Epithelial ovarian cancer comprises the majority of malignant ovarian tumors in adult women. These neoplasms are classified into distinct morphologic categories based on the appearance of the epithelium into tumors of serous, mucinous, endometrioid, clear cell, transitional, squamous, mixed and undifferentiated type. 1,2 Two types of ovarian surface epithelial lesions have been described as possible precursors of these carcinomas: lesions that appear in situ in surface epithelium or surface epithelial inclusion glands (SEIG); and preexisting benign epithelial ovarian tumors and endometriosis. The morphologic and genetic data implicating each as a precursor lesion of the major histologic subtypes of ovarian carcinoma are discussed. Surface epithelium and surface epithelial inclusion glands as precursor lesions Morphologic DataTwo types of morphologic data are available regarding the malignant potential of ovarian surface epithelium and inclusion glands, alterations in these structures and studies on microscopic ovarian carcinoma.Surface epithelium and surface epithelial inclusion glands Despite the widespread acceptance of the origin of surface epithelial cancers from the ovarian surface epithelium and its inclusion glands, only rarely have putative precursor lesions been described at these sites. Two...

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“…The reasons include different histologic and immunophenotypes between ovarian surface epithelium and ovarian epithelial cancers, the pathologic properties of ovarian epithelial cancers showing striking similarities to Mullerian epithelia, 3 and the presence of precancerous lesions of ovarian high-grade serous carcinomas in tubal fimbria but not in the ovary or on ovarian surface. [4][5][6][7][8][9] All these findings, as well as other factors, have led to an increased recognition in recent years that the fallopian tube is the likely source of most pelvic high-grade serous carcinomas. 6,10 Recent molecular studies have suggested that ovarian epithelial cancers can be divided into two broad groups.…”

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confidence: 99%

Tubal origin of ‘ovarian’ low-grade serous carcinoma

et al. 2011

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Ovarian low-grade serous carcinomas are thought to evolve in a stepwise fashion from ovarian epithelial inclusions, cystadenomas, and borderline tumors. The current study was designed to gain insight into the origins of low-grade serous carcinomas (tubal versus ovarian) by comparatively evaluating the morphologic (secretory and ciliated cell distribution) and immunophenotypic (using antibodies to PAX8, tubulin, calretinin, and Ki67) attributes of its putative precursor lesions, the normal tubal epithelium, and the overt malignancy. A total of 226 adnexal tissues from 178 patients were studied, including 98 adnexae removed for non-neoplastic indications, 48 serous cystadenomas, 42 serous borderline tumors, and 38 low-grade serous carcinomas. Normal distal tubal epithelium comprised an admixture of PAX8 þ /tubulinÀ secretory cells and PAX8À/ tubulin þ ciliated cells with a proliferative index of B3%. The vast majority of ovarian surface epithelia displayed a mesothelial phenotype (calretinin þ /PAX8À/tubulinÀ) and low proliferative index (0% (12 per 1000)), although 4% of cases also displayed foci with tubal phenotype (calretininÀ/PAX8 þ /tubulin þ ). In contrast, most (78%) of the ovarian epithelial inclusions displayed a tubal phenotype and had a significantly higher proliferative index (1%) than ovarian surface epithelium, indicating that in most cases, the ovarian surface epithelium and ovarian epithelial inclusions are of different lineages. There was a progressive decrease in the population of ciliated cells, as evidenced by increasing secretory/ciliated cell ratio, from ovarian epithelial inclusions/cystadenomas to borderline tumors to low-grade serous carcinoma, indicating that the latter is a clonal expansion of secretory cells. Overall, the findings make a strong argument that the ovarian epithelial inclusions with a tubal phenotype is likely derived from fallopian tube through an intraovarian endosalpingiosis rather than through Mullerian metaplasia from ovarian surface epithelium. Genetic and molecular studies are needed to further confirm this finding as tubal origination of ovarian serous cancers will have a significant impact on ovarian cancer prevention and management.

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Unexpected Gynecologic Neoplasms in Patients With Proven or Suspected BRCA-1 or -2 Mutations

Cited by 95 publications

References 28 publications

Lessons from BRCA: The Tubal Fimbria Emerges as an Origin for Pelvic Serous Cancer

Lessons from BRCA: The Tubal Fimbria Emerges as an Origin for Pelvic Serous Cancer

Origins and molecular pathology of ovarian cancer

Tubal origin of ‘ovarian’ low-grade serous carcinoma

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