BRCA germline mutations in Jewish women with uterine serous papillary carcinoma
Introduction
Uterine serous papillary carcinoma (USPC) is a relatively new entity that was first introduced as a distinct histologic subtype of endometrial carcinoma by Lauchlan [1] and Hendrickson et al. [2] in 1982. USPC constitutes less than 10% of all uterine epithelial adenocarcinomas, occurs in older women, and is not associated with conditions of excess estrogen exposure [3].
Although this disease originates in the endometrium, histopathologically, its papillary growth and cellular formation resemble the pattern of serous papillary carcinoma of the ovary or the peritoneum. Clinically, USPC is more aggressive than endometroid-type endometrial carcinoma [4], [5], is diagnosed at an advanced stage [4], and results in a poor prognosis very similar to serous papillary carcinoma of the ovary or the peritoneum [6]. From the treatment perspective, USPC responds to agents that are being used in the management of carcinoma of the ovary and the peritoneum [6].
These contrasts raise the question whether USPC can be considered a manifestation of the hereditary breast ovarian cancer syndrome as previously shown in papillary serous cancer of fallopian tubes [7] and in primary peritoneal cancer [8], [9].
Recently, different findings were published concerning the relationship between BRCA germline mutations and the USPC.
It all started from a family pedigree published by Hornreich et al. [10] in which a young USPC patient was found to be a BRCA1 (5382insC) carrier. Analysis of her family tree revealed two first-degree relatives with ovarian carcinoma and five second-degree relatives with breast carcinoma who were diagnosed at an early age, suggesting the first hint for a possible hereditary USPC and breast ovarian syndrome.
Our previous publication described a founder BRCA1 mutation in two of nine unselected Ashkenazi Jewish women with USPC [11]. Although this was a small series, a strong history of familial breast ovarian cancer was documented in this group of patients, and in addition, a loss of heterozygosity (LOH) analysis using USPC tumor DNA from the two BRCA1 carriers showed loss of the wild-type allele, suggesting a causal relationship between the germline BRCA1 mutation and USPC.
Geisler et al. [12] suggested an increased synchronous or subsequent breast cancer development in patients with USPC as compared to patients with endometroid carcinoma (25% vs. 3.2%, respectively P < 0.001).
On the other hand, Goshen et al. [13] failed to detect a BRCA1 or BRCA2 mutation in a panel of 56 unselected cases of USPC; however, they did find a high proportion of cases of USPC having a history of breast cancer or having a close family member with breast carcinoma. Levine et al. [14] suggested that the lifetime risk for endometrial carcinoma is not increased for individuals with a germline BRCA mutation. In a subgroup of 17 USPC cases, no BRCA mutations were found.
These differences in findings are the background of our current study; our objective was to determine the incidence of BRCA1 and BRCA2 mutation in an enlarged series of USPC patients, and in addition, to determine if patients with USPC are at increased risk of breast carcinoma.
Section snippets
Materials and methods
We reviewed all consecutive cases that were diagnosed as USPC in three gynecologic oncology units in Israel between December 1999 and July 2002. All cases were reevaluated pathologically to meet the pathologic criteria of USPC which included papillary structures with well defined complex fibrovascular cores lined by pleomorphic tumor cells with marked luminal exfoliation resulting in an irregular border, densed and eosinophilic cytoplasm, and tumor cells with large hyperchromatic irregular
Results
We identified 27 consecutive cases with USPC from three different gynecological oncology units in Israel.
Patients (20) were found to be Jews of Ashkenazi origin and this formed our group study. The other patients were Jews of Iraqi, Arabic, and Yemenite origin.
The mean age of our Ashkenazi patients was 71.96, ranging from 56 to 91.
Stage distribution revealed 30% at stage I, 15% at stage II, 40% at stage III, and 15% at stage IV.
Personal and familial history of breast and ovarian carcinoma of
Discussion
USPC shares morphological and biological features with ovarian serous papillary carcinoma.
In Ashkenazi Jews in Israel, 30% of ovarian cancers are associated with one of the three common BRCA1 and BRCA2 germline mutations [15], [16]. The similarity between USPC and ovarian serous papillary carcinoma raises the question whether USPC can be considered as a malignancy, which is expressed in the familial breast–ovarian cancer syndrome.
Our recent publication [11] suggested a high incidence of BRCA1
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