—  INTERNATIONAL SOCIETY OF GYNECOLOGICAL PATHOLOGISTS   —

Adnexal Pathology in Women at High Familial Risk of Ovarian Cancer


Terence Colgan
Mt. Sinai Hospital
Toronto, Canada


About 5 to 10% of ovarian carcinomas are hereditary in origin. Ovary specific, breast-ovary, and Lynch II (or hereditary non-polyposis cancer) clinical syndromes of hereditary ovarian cancer are recognized. [1, 2, 3, 4] About 95% of hereditary ovarian carcinomas of the ovary specific and breast-ovary types are attributable to BRCA germline mutations, with BRCA1 responsible for a greater proportion than BRCA2. Germline BRCA mutations are responsible for the vast majority of hereditary ovarian cancers. The BRCA genes are responsible for the production of large proteins that have numerous functions, including tumor suppression through the repair of somatically acquired damage in other genes. The development of carcinoma in BRCA germline mutation carriers occurs when the remaining wild-type BRCA allele on the opposite chromosome is inactivated ("biallelic inactivation") and additional genetic mutations occur. This allelic inactivation ("second hit") occurs through genetic recombination, genetic mutations, or epigenetic changes.
  1. Carcinomas and germline BRCA mutations:
    1. Ovarian carcinoma: There are no pathognomonic histopathologic features of hereditary ovarian carcinoma. Studies initially failed to identify any significant differences in pathological features between sporadic and hereditary ovarian carcinomas. [5] Subsequently, most studies have identified that serous ovarian carcinoma is the characteristic histologic type of carcinoma in germline BRCA mutation carriers; typically these carcinomas in BRCA1 mutation carriers occur about 7 years earlier than sporadic tumors. [1, 6, 7, 8, 9, 10, 11, 12, 13] These germline BRCA1 mutation associated serous carcinomas tend to be of a higher grade and stage. [8, 10, 12, 14, 15] A population based study of ovarian carcinomas in the province of Ontario, Canada, identified germline BRCA1/2 mutations in over 16% of ovarian serous carcinomas. [6] With this high prevalence of germline BRCA mutations it is recommended that all women with serous carcinomas undergo genetic assessment in Ontario, regardless of family history or ethnicity. [16]This pathologic indication for assessment may not be appropriate in settings with a lower frequency of germline BRCA mutations. [4]

      Ovarian carcinosarcoma (or malignant mixed mullerian tumour) is a germline BRCA mutation associated malignancy. This tumor been described not only in a germline BRCA2 mutation carrier, [17] but additional molecular studies have shown loss of the wild type of BRCA2 allele, confirming biallelic inactivation/loss of the BRCA genes, and somatic p53 mutations in both the epithelial and sarcomatous elements. Since ovarian carcinosarcomas likely arise from an epithelial cell type with subsequent divergence to two distinct lineages, an association with BRCA germline mutations is not surprising.

      Non-serous carcinomas including endometrioid, clear cell and transitional cell types have been reported in women with germline BRCA mutations. [5, 6, 8, 9, 10, 11, 13, 15, 18] In one study endometrioid adenocarcinomas were over represented in a group of hereditary ovarian cancer patients. [19] The possibility remains that these occurrences may represent sporadic carcinomas. Molecular evidence of definite germline causation of cancer is extremely difficult to obtain (see Dr. Gilks' presentation).

      Although mucinous adenocarcinoma may arise within germline BRCA mutation carriers, [11, 13] mutation carriers are not more prone to the development of mucinous adenocarcinomas. [5, 6, 8, 13, 14] Indeed, there is some evidence that mutation carriers are less likely to develop mucinous carcinomas. [20]

      There is no association between borderline (or low malignant potential, LMP, or atypical proliferating) tumors of the ovary and germline BRCA mutations. There have been isolated reports of clear cell adenofibroma and serous LMP tumors in prophylactic salpingo-oophorectomy specimens, [21, 22] and of LMP tumors in germline BRCA mutation positive women, [13] but these likely represent the occurrence of sporadic tumors. More definitive epidemiologic and clinicopathologic studies have failed to demonstrate any association between germline BRCA mutations and LMP tumors. [6, 8, 9, 13, 15, 23, 24, 25, 26, 27]

    2. Fallopian tube carcinoma: Both molecular and epidemiologic studies have now shown a strong association between germline BRCA mutations and fallopian tube carcinoma. [28, 29, 30, 31, 32, 33, 34, 35, 36] Preliminary evidence consisted of reports of fallopian tube carcinoma arising in germline BRCA mutation carriers, or in women who had undergone prophylactic oophorectomy only. [29, 32, 34] Subsequent molecular and epidemiologic evidence provided conclusive proof of an association between the development of fallopian tube carcinoma and the presence of a germline BRCA mutation. A causal relationship between the germline mutation and the subsequent development of the tubal malignancy has been shown through loss of heterozygosity studies of the BRCA1 gene within two tubal carcinomas. [35] A population-based study of fallopian tube carcinoma has revealed the presence of a germline BRCA1/2 mutation in over 15% of tubal carcinoma cases. [36]

    3. Peritoneal papillary serous carcinoma: Germline BRCA mutation carriers are also at increased risk for the development of peritoneal serous carcinomas. [37, 38, 39, 40, 41] A recent study of Israeli women with ovarian and peritoneal serous carcinomas showed a similar prevalence of the three common founder Ashkenazi mutations of BRCA1 and BRCA2 in the different types of carcinomas. [39] Germline BRCA1 mutation associated primary peritoneal carcinomas are more likely to be multiclonal, suggesting multifocality, than sporadic peritoneal carcinomas. [40, 41, 42, 43, 44]

      Women who have undergone prophylactic salpingo-oophorectomy still remain at risk for the development of peritoneal serous adenocarcinomas. Since there is this persisting risk of peritoneal carcinomatosis, the preferred term for this prophylactic surgery is "risk reducing salpingo-oophorectomy" (RRSO). [1] The cumulative risk of developing peritoneal carcinomatosis subsequent to RRSO may be as high as 10%. [45, 46, 47, 48]

    4. Endometrial carcinoma: There is not a strong association between germline BRCA mutations and endometrial carcinoma. [49] In a study of 56 patients with endometrial serous carcinomas no germline BRCA1 or BRCA2 mutations were found, although no Ashkenazi Jewish patients with familial cancer clustering were included in the cohort. [50] Nevertheless, a small number of cases of endometrial carcinomas have been causally linked to the presence of a BRCA germline mutation providing some evidence that BRCA1 and 2 germline mutations may predispose to a small increase in the lifetime risk of developing endometrial carcinoma. A study of first-degree relatives of BRCA1/2 positive ovarian carcinoma patients has shown an increased relative risk of developing endometrial carcinoma, although the absolute number of endometrial carcinoma cases (4) was small. [10] Molecular study of a case of uterine serous carcinoma has shown both a germline mutation in BRCA1 and loss of the wild type allele in the tumor, suggesting a causal association. [51] The tumors of two other uterine serous carcinoma patients with BRCA1 germline mutations were characterized by loss of heterozygosity in the tumours - suggesting that the BRCA germline mutation may have a causal link to the endometrial carcinoma. [49] Finally, in a study of 199 endometrial carcinoma cases of all histologic types in Ashkenazi Jewish women, three BRCA germline mutation carriers (1 BRCA1 and 2 BRCA2) were identified in endometrioid carcinomas with two showing loss of the wild-type BRCA allele. [52]

    5. Cervical cancer: Only a single case report of papillary serous adenocarcinoma of the endocervix in a woman whose twin sister had ovarian carcinoma and mother had peritoneal carcinoma has been made. [53]

    6. The BRCA germline mutations – the concept of tissue susceptibility: The inheritance of a germline BRCA mutation is neither a necessary nor sufficient cause for the development of malignancy. A number of factors influence the penetrance of BRCA germline mutations. [1] Different BRCA mutations confer different risks of cancer. Environmental factors may modify the progression to malignancy. [54] Use of the oral contraceptive pill, number of pregnancies or parity, and tubal ligation have all been shown to independently reduce the risk of development of hereditary ovarian carcinoma. A birth cohort (age) effect has also recently been noted to play a role as a determinant of malignancy. [55]

      In addition to these environmental factors, tissue susceptibility to germline BRCA mutation induced malignancy should be recognized. In some tissues the penetrance of the BRCA germline mutation is high (e.g. breast, ovary, and fallopian tube). In other tissues penetrance is intermediate or low. In still other tissues penetrance is negligible or absent. The development of rare malignancies in germline BRCA carriers, such as dysgerminoma, may be a reflection of the variable tissue penetrance by BRCA germline mutations. [56]


  2. The risk-reducing Salpingo-oophorectomy (RRSO) specimen (prophylactic salpingo-oophorectomy specimen): Many high-risk women will elect to undergo RRSO following child-bearing since it significantly reduces the risk of developing carcinoma. [57, 58] Women with BRCA germline mutations who undergo salpingo-oophorectomy also substantially reduce their risk of developing breast carcinoma. [58] Resection of the fallopian tube is included at the time of RRSO since these high-risk women are also at substantial risk of developing tubal carcinoma. [59, 60]


    1. The detection of occult carcinomas in RRSO specimens: Meticulous examination of the RRSO specimen will reveal occult carcinomas involving the ovary, fallopian tube, and/or peritoneum in a small proportion of cases. [59, 61, 62, 63, 64, 65] Ovarian carcinomas may be invasive or surface de-novo (intra-epithelial) in type. Similarly, tubal carcinomas may be invasive carcinomas of serous or clear cell type, or adenocarcinoma-in-situ. The identification of occult carcinomas has been restricted to BRCA mutation positive or unknown patients only. [62, 63, 66] The natural history of these occult ovarian and tubal carcinomas following RRSO is uncertain. Possibly, some peritoneal papillary carcinomas that manifest post-RRSO may actually be metastatic recurrences of prior diagnosed, or undetected, occult carcinomas of the ovary and tube. [59, 61]

      The diagnosis and clinical significance of early invasive tubal carcinomas and preinvasive epithelial tubal lesions present new challenges for gynecologic pathologists. [67] Since the criteria for a diagnosis of tubal epithelial dysplasia/atypical hyperplasia are not well defined, the prevalence and natural history of preinvasive tubal epithelial lesions is uncertain. [68, 69] There are concerns that preinvasive carcinomas may shed malignant cells into the peritoneal cavity even in the absence of invasion. These concerns may prompt the use of post-operative adjuvant chemotherapy following a diagnosis of adenocarcinoma-in-situ of the tube.

    2. Pathologic examination of the RRSO specimen: RRSO alone may be performed laparoscopically as an outpatient procedure. [4] Alternatively, RRSO may be performed in conjunction with selective peritoneal and omental biopsies, so that staging information is available in the event that an occult cancer is subsequently detected at pathologic examination. The entire ovaries and fallopian tubes of RRSO specimens should be examined microscopically. (If fresh tissue is required for research, then a quick section should be taken from the mirror image surface to exclude any occult carcinoma.) The role of intra-operative (quick section) examination of the RRSO specimen is limited. Microscopic examination of the entire RRSO specimen is not feasible at quick section. Macroscopic examination with selective microscopic sectioning of any suspicious RRSO specimens would be useful if the knowledge of malignancy would lead to a complete staging procedure at the time of RRSO, [61] but it can be anticipated that final and complete pathologic examination would subsequently detect occult carcinomas in some additional cases.

    3. Inability to detect ovarian carcinoma precursor lesions: A number of putative pre-neoplastic epithelial and stromal lesions have been described in the ovary including epithelial inclusion cysts, surface epithelial hyperplasia, surface epithelial papillomatosis, deep cortical invaginations with associated papillae, cortical stromal hyperplasia and hyperthecosis, increased follicular activity, and hilar cell hyperplasia. [64] The existence of three or more of these findings in ovaries from high-risk patients has been described as a "cancer prone phenotype". Additional studies have not confirmed that putative preneoplastic changes can be consistently recognized in the ovary. [70, 71, 72, 73, 74]
Four General References on Hereditary Ovarian Carcinoma

  1. Modugno F. and the Ovarian Cancer and High-Risk Women Symposium Presenters. Ovarian cancer and high-risk women – implications for prevention, screening, and early detection. Gynecol Oncol 2003;91:15-31.
  2. Piver SM. Hereditary ovarian cancer. Gynecol Oncol 2002;85:9-17.
  3. Lynch HT et al. Genetics and ovarian carcinoma. Semin Oncol 1998;25:1265-1281.
  4. Levine DA et al. Prophylactic surgery in hereditary breast/ovarian cancer syndrome. Oncology 2003;17:1328- 1329.
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