Lavie, Ofer MD*; Ben-Arie, Alon MD†; Segev, Yakir MD*; Faro, Jonathan BSc*; Barak, Frida MD†; Haya, Nir MD*; Auslender, Ron MD*; Gemer, Ofer MD‡
From the *Department of Obstetrics and Gynecology, Carmel Medical Center, Haifa; †Kaplan Medical Center, Rehovot; and ‡Barzilai Medical Center, Ashkelon, Israel.
Received August 22, 2009, and in revised form November 18, 2009.
Accepted for publication November 30, 2009.
Address correspondence and reprint requests to Ofer Lavie, MD, Gyn-Oncology Unit, Carmel Medical Center, 7 Michal St, Haifa 34362, Israel. E-mail: email@example.com.
The authors declare that there are no conflicts of interest.
Objective: To determine the incidence of BRCA1 and BRCA2 mutations in an enlarged series of uterine serous carcinoma (USC) patients and to determine whether patients with USC are associated with a personal or familial history of breast or ovarian carcinoma.
Methods: A cohort of all consecutive patients with diagnosed USC was identified for 9 years. Family pedigrees were drawn as far back and laterally as possible. In all patients, genomic DNA was extracted from peripheral blood samples and analyzed for the 3 mutations common in Ashkenazi Jewish patients. All patients went through total abdominal hysterectomy, bilateral salpingo-oophorectomy, and omentectomy. Tubal, ovarian, and peritoneal carcinoma were ruled out clinically and pathologically in all patients.
Results: Of 51 consecutive patients with USC in Ashkenazi Jews studied, we identified 13 patients (25.5%) who were previously found to have breast carcinoma, 17 patients (33.3%) who had a first-degree relative with breast or ovarian carcinoma, and 8 patients (15.7%) who were found to be carriers of 1 of the 3 BRCA germline mutations.
Conclusions: This series of USC patients, the largest consecutive series to date, suggests a higher incidence of BRCA carriers among Ashkenazi Jews as compared with the general population. This high rate of BRCA germline mutations in USC patients coupled with a high rate of personal and familial cancer histories may suggest that USC is associated with the hereditary breast-ovarian syndrome. This potential association of USC to the BRCA-associated cancer spectrum may have implications for the clinical management and intervention of unaffected BRCA1-2 germline mutation carriers. However, at the current time, there are insufficient data to provide evidence-based guidelines regarding the optimal timing or specific intervention to prevent cancers in these high-risk women.
Uterine serous carcinoma (USC) is an aggressive histological variant of endometrial cancer constituting less than 10% of all uterine epithelial adenocarcinomas.1,2 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. Uterine serous carcinoma occurs in older women and is not associated with conditions of excess estrogen exposure.3 It is often diagnosed at an advanced stage4 and results in a poor prognosis, comparable to serous papillary carcinoma of the ovary.5 From the treatment perspective, USC responds to agents that are being used in the management of carcinoma of the ovary and the peritoneum.6
The histological and clinical similarities between USC and serous papillary carcinoma of the ovary or the peritoneum have prompted the question, "Can USC be considered a manifestation of the hereditary breast ovarian cancer syndrome as previously shown in papillary serous cancer of fallopian tubes7 and in primary peritoneal cancer?"8,9 Several case reports and small series have suggested a relationship between BRCA germline mutations and USC.10-19
Our previous cohort, 20 USC patients of Ashkenazi Jewish descent, were tested for 1 of 3 BRCA founder mutations (185delAG and 5382insC in BRCA1 and 6174delT in BRCA2). In this cohort, 4 patients (20.0%) were found as carriers, 7 (35.0%) had had a diagnosis of breast carcinoma before USC diagnosis, and 12 (60.0%) had family histories with at least 1 first-degree relative with breast or ovarian carcinoma. Tumor tissue heterozygosity analysis found a loss of the wild-type BRCA1 allele in 3 of the 4 primary uterine tumors that were examined.16
In another study comprising 22 Jewish patients with USC, 7 (31.8%) had a previous personal history of breast cancer, 5 (22.7%) had a family history of breast or ovarian carcinoma, and 6 (27.3%) were carriers of 1 of the 3 BRCA1-2 germline mutations.18 On the other hand, Goshen et al13 failed to detect a BRCA1 or BRCA2 mutation in a panel of 56 unselected patients with USC; however, they did find a high proportion of patients with USC having a personal history of breast cancer or a close family member with breast carcinoma. Levine et al14 suggested that the lifetime risk for endometrial carcinoma is not increased for individuals with a germline BRCA mutation. In this study, no BRCA mutations were found in a subgroup of 17 USC patients.
These reported discrepancies are the background of our current study. Our objective was to determine the incidence of BRCA1 and BRCA2 mutations in an enlarged series of USC patients and to determine whether patients with USC are associated with a personal or familial history of breast or ovarian carcinoma.
We reviewed 59 consecutive patients with diagnosed USC in 3 gynecologic oncology units in Israel between December 1999 and June 2008. All patients underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, and omentectomy. Clinical and pathological evaluation of all patients ruled out tubal, ovarian, and peritoneal carcinoma while meeting the criteria of USC. These criteria include papillary structures with well-defined complex fibrovascular cores lined by pleomorphic tumor cells with marked luminal exfoliation resulting in an irregular border, dense and eosinophilic cytoplasm, and tumor cells with large hyperchromatic irregular nuclei with macronucleoli.
The study was approved by each center's institutional review board, and a written informed consent was obtained for collection of epidemiologic information and blood samples.
All participants received genetic counseling at their respective institutions. Information about ethnic backgrounds and personal/family histories were retrieved from medical records and from individual interviews with all patients and their relatives. Family pedigrees were drawn as far back and laterally as possible. Genomic DNA was extracted from peripheral blood samples and analyzed by a standard salting out procedure15 for the 3 mutations common in Ashkenazi Jews (BRCA1-185delAG, BRCA1-5382insC, and BRCA2-6174delT) using published methods.10
Our study group was made up of 51 of the 59 consecutive USC patients who were Jews of Ashkenazi origin. The other 8 patients were Jews of Iraqi, Moroccan, or Yemenite origin. The median age was 71 years (range, 55-91 years). The stage distribution was 43% at stage I, 10% at stage II, 37% at stage III, and 10% at stage IV.
We identified 13 USC patients (25.5%) who had a previous diagnosis of breast carcinoma; 1 patient (2.0%) had a personal history of ovarian carcinoma. This patient had stage IA1 epithelial ovarian cancer 30 years before the diagnosis of USC and only underwent an oophorectomy at that time to preserve future fertility. Seventeen patients (33.3%) had a first-degree relative with breast or ovarian carcinoma. Eight patients (15%) were found to be carriers of 1 of the 3 BRCA germline mutations evaluated (5 for BRCA1-185delAG, 2 for BRCA1-5382insC, and 1 for BRCA2-6174delT). A comparison of clinical characteristics of the BRCA mutation carriers and noncarriers is shown in Table 1. There was no significant difference in age at diagnosis, the stage distribution, or the incidence of personal history of breast carcinoma between the carriers and noncarriers. Eight (100%) of the BRCA carriers had at least 1 first-degree relative with breast or ovarian carcinoma as compared with only 10 (23.3%) of patients in the noncarrier group.
Uterine serous carcinoma shares morphological and biological features with ovarian serous papillary carcinoma. This similarity raises the question whether USC can be considered as a malignancy that is associated with the familial breast-ovarian cancer syndrome.
In the current extended series of 51 Jews of Ashkenazi origin, 13 (25%) of the USC patients had a previous diagnosis of breast cancer and 1 (2.0%) of ovarian cancer; 17 (33.3%) had at least 1 first-degree relative with breast or ovarian carcinoma. Of these patients, 8 (15.7%) were found to be carriers of the founder BRCA mutation.
Other studies have explored the association of USC with BRCA mutations or with personal or familial history of breast and ovarian cancer (Table 2).
The high incidence of personal history of breast carcinoma coupled with the high incidence of family history of breast carcinoma among patients with USC supports a possibility of a predisposing genetic link between USC and breast carcinoma.
The difference between our findings and the reports (which could not demonstrate this high incidence of BRCA carriers among USC patients) may be related to a population bias. BRCA1 and BRCA2 mutation analysis has revealed more than 100 pathogenic mutations in each gene. These mutations are usually "private," that is, unique to a single family.20,21 In the Ashkenazi Jewish population, only 3 mutations have been found to be recurrent on the BRCA1 and BRCA2 genes; therefore, identification of these 3 mutations in the Ashkenazi group can represent the incidence of the mutated BRCA genes. However, in the non-Ashkenazi Jews examined, these 3 mutations cannot represent the incidence of mutations on BRCA genes. Therefore, sequencing the relevant genes could reveal a higher incidence of BRCA carrier mutations among USC patients who are non-Ashkenazi Jews. This concept is supported by the report of Goldman et al22 who performed full BRCA1 and BRCA2 sequencing on 9 patients with USC (only 2 were of Ashkenazi ancestry). In this report, 3 of the 9 patients had nonfounder mutations on the BRCA2 gene (N1880K, IVS11-19A>G, 12944F).
Our cohort is the largest consecutive series evaluating the incidence of BRCA carriers among USC patients of Ashkenazi origin. Although the incidence of BRCA carriers among the current cohort of USC patients was lower than in our previous report (8 of 51 [15.7%] vs 4 of 20 [20%]),16 it is nevertheless much higher than the 2.5% incidence of BRCA carriers in the general population of Ashkenazi origin.23,24 This incidence is lower than the 30% reported incidence of the 3 common BRCA1 and BRCA2 germline mutations among Ashkenazi ovarian cancer patients24-26 and is comparable to the 10% incidence of these gene mutations among the Ashkenazi breast carcinoma.26
In our study, 13 (25.5%) of all the USC patients compared with 3 (37.5%) of USC patients who are BRCA mutation carriers had previous breast cancer. The proportion of breast cancer in individuals with USC in this study is 2.5 times higher than the expected incidence in the general Ashkenazi Jewish population in Israel.
Additionally, all 8 mutation carriers had at least 1 first-degree relative with a breast and/or ovarian carcinoma, a relationship previously noted by us and by others.16,18 This combination of a high ratio of personal breast cancer and family history of breast and/or ovarian cancer suggests a possible genetic association between breast cancer, ovarian cancer, and USC in the Ashkenazi Jewish population.
A comparison of the clinical characteristics between the USC BRCA mutation carriers and the noncarriers did not single out significant differences. The preponderance towards earlier stage at the time of diagnosis among mutation carriers in our series contrasts with other data.18 In our series, 5 patients (62.5%) of the BRCA mutation carrier group had a diagnosis of stage I disease as compared with only 17 (39.5%) who had a diagnosis at an early stage among the noncarrier group with USC. However, these statistics did not reach a significant difference (P = 0.2). The early stage of USC at the time of diagnosis may be a reflection of intensive gynecological surveillance of patients with a known history of breast cancer.
As expected with USC patients, the median age at diagnosis in our cohort was high (71 years). The median age of the mutation group did not differ significantly from the nonmutated group (68.8 vs 72, respectively; P = 0.2). This age similarity contrasts with the general tendency of familial cancer cases to occur at a younger patient age.
Kwon et al19 reported on prolonged survival in 4 cases of advanced-stage USC BRCA mutation carriers. The small numbers in all series hamper meaningful comparison of the prognosis in carriers and noncarriers.
In conclusion, the high rate of BRCA germline mutations in USC patients observed in this extended series coupled with a high rate of personal and familial cancer histories may suggest that USC is associated with the hereditary breast-ovarian syndrome.
This potential association of USC to the BRCA-associated cancer spectrum may have implications on the clinical management and intervention of unaffected BRCA1-2 germline mutation carriers.9 At this time, a definitive recommendation for hysterectomy to prevent primary uterine tumors as part of the BRCA-associated cancer spectrum does not seem warranted. However, in the clinical decision of whether to recommend a hysterectomy in addition to bilateral salpingo-oophorectomy, other important clinical issues need to be considered. These include a potential need for tamoxifen administration, the presence of other uterine pathologic conditions, and the ability to administer estrogen without progesterone as hormone replacement. At the current time, there are insufficient data to provide evidence-based guidelines regarding the optimal timing or specific intervention necessary to prevent cancers in these high-risk women.
Further molecular characterization of the USC's tumors including loss of heterozygosity and an understanding of the natural history of these cancers may provide additional insight into the significance of BRCA gene mutations and may direct us to effective noninvasive prevention modalities in the future.
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