BRCA-MutationAssociated Fallopian Tube Carcinoma: A Distinct Clinical Phenotype?

Cass, Ilana MD1; Holschneider, Christine MD2; Datta, Nandini MD1; Barbuto, Denise MD, PhD3; Walts, Ann E. MD3; Karlan, Beth Y. MD1

doi: 10.1097/01.AOG.0000187892.78392.3f
Original Articles

OBJECTIVE: To compare clinical and histologic features between fallopian tube cancers in women with germline BRCA mutations and sporadic cases.

METHODS: Twenty-eight patients with fallopian tube cancer had BRCA mutation testing using multiplex polymerase chain reaction and protein truncation testing. Histologic slides were reviewed by 2 pathologists, and immunohistochemical staining for p53, ki67, estrogen receptor, and progesterone receptor was performed on carcinomas and dysplastic and benign tubal epithelia.

RESULTS: Twelve of 28 (43%) women had BRCA mutations: 11 BRCA1, 1 BRCA2. Excluding 4 cases found at prophylactic surgery, the median age of diagnosis of BRCA mutation carriers was 57 years compared with 65 years among sporadic cases (P = .09). Patients with BRCA-associated fallopian tube cancer had a median survival time of 68 months compared with 37 months when compared with sporadic cases (P = .14). Both groups had predominantly advanced stage, high grade, serous fallopian tube cancers. No patient had exclusively proximal disease. Occult fallopian tube cancer diagnosed at prophylactic surgery in BRCA mutation carriers was exclusively distal. “Skip” areas of high-grade dysplasia were only seen in 2 patients, both of whom were BRCA mutation carriers. There were no differences in the immunohistochemical staining for p53, ki67, estrogen receptor or progesterone receptor in carcinomas and dysplastic or benign epithelia of patients with or without BRCA mutations. Overexpression of p53 was commonly seen in fallopian tube cancers and dysplastic epithelium, but rarely noted in benign epithelium.

CONCLUSION: Fallopian tube cancer is part of the BRCA mutation phenotype and seems to share many clinical features with sporadic fallopian tube cancers, including no exclusively proximal disease. The presentation of BRCA-associated fallopian tube cancers may, however, occur at a younger age and have an improved survival.


Tubal carcinoma is part of the BRCA mutation phenotype and may have an earlier age of onset and improved survival compared with sporadic tubal carcinoma.

From the 1Division of Gynecologic Oncology, Department Obstetrics and Gynecology, University of California Los Angeles and Cedars-Sinai Medical Centers; 2Division of Gynecologic Oncology, Department Obstetrics and Gynecology, Olive View–University of California Los Angeles Medical Center; and 3Department Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California.

Financial support for this study was received from the Women’s Cancer Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA and the California Ovarian Cancer Coalition.

The authors thank Dr. Steven Narod, Center for Research in Women’s Health, Sunnybrook Women’s College Health Science Center, University of Toronto, Toronto, Ontario, Canada, for his significant scientific contribution to the research.

Presented at the Society of Gynecologic Oncologists 36th Annual Meeting, March 20, 2005, Miami Beach, Florida.

Corresponding author: Ilana Cass, MD, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, #160W, Los Angeles, CA 90048; e-mail:

Article Outline

Primary carcinoma of the fallopian tube occurs infrequently, with an annual incidence of 0.3 per 100,000 women compared with an annual incidence of 16 per 100,000 women for ovarian cancer.1,2 The diagnosis of fallopian tube cancer is rarely made preoperatively and is typically made at final pathologic review. Recent evidence supports the finding that fallopian tube carcinoma is a component of the BRCA mutation–associated phenotype. Small case series have reported that fallopian tube carcinoma is part of the BRCA-associated spectrum of gynecologic cancers, and recently 2 large, retrospective studies have found that 16% to 17% of women with tubal cancer harbored BRCA germline mutations.3–9 In a prospective study of 381 female BRCA-1 mutation carriers, Brose et al10 reported a 120-fold increased risk of fallopian tubal cancer compared with the general population. By comparison, the relative risk of ovarian and breast cancer in this cohort was 29-fold and 6-fold higher, respectively, compared with the general population. Based upon these findings, the current recommendation is to include bilateral salpingectomy at the time of prophylactic oophorectomy in women with BRCA germline mutations.5,11

Several studies have compared the characteristics of BRCA-associated ovarian cancers with those from patients with sporadic disease. Hereditary BRCA-associated ovarian cancer presents at a younger age and seems to have improved survival compared with sporadic cases. The improved clinical outcome of BRCA-associated ovarian cancer cannot be attributed to less aggressive disease based upon standard histopathologic features, but rather has been attributed to an enhanced chemosensitivity to platinum-based therapy.12,13 A higher proportion of the BRCA1 mutation–associated ovarian cancers have p53 mutations compared with sporadic ovarian cancers.14–16 Increased cellular proliferation rates have also been reported in the ovarian cancers from patients with hereditary BRCA mutations compared with ovarian cancer tissue from sporadic cases using Ki67 and apoptosis assays.17 Molecular analyses of BRCA-associated cancers have suggested potential distinctions between the carcinogenic pathways of BRCA-associated and sporadic breast and ovarian cancers.18,19

Although tubal cancer is staged and treated similarly to ovarian cancer, there is a paucity of information regarding hereditary BRCA-associated tubal cancer. Dysplastic tubal epithelium has been frequently reported in prophylactically removed fallopian tubes of hereditary BRCA mutation carriers.11,20 Given that germline BRCA mutations involve all of the müllerian epithelium, it is possible that mutation carriers who develop tubal cancer may have a field effect with adjacent precursor lesions in their fallopian tubes. If hereditary BRCA-associated tubal cancer has a distinct phenotype compared with sporadic tubal cancer, this could influence recommendations for surgical prophylaxis and screening strategies among high-risk women.

The purpose of this study was to compare the clinical and histologic features of primary fallopian tube cancer in women with BRCA mutations with women without BRCA mutations. Molecular analyses were performed using immunohistochemical staining for p53, Ki67, and estrogen receptor (ER)/progesterone receptor. The location and extent of tubal neoplasia was assessed to estimate whether patterns of tubal involvement differed between the patient cohorts.

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In an institutional review board–approved study, the gynecologic oncology tumor registry and pathology databases at Cedars-Sinai Medical Centers were queried for cases of fallopian tube carcinoma from 1990 to 2004. Patients with incidentally discovered cancers were included in the study. The treating physicians were asked to write letters or contact patients directly to request the patient’s participation in the study. If the treating physician agreed, the patient was approached to participate in the study. If the patient had died of disease, BRCA testing was performed on isolated DNA samples from available tissue blocks of histologically normal tissue from the uterine corpus or cervix. After 1999 the protocol was amended and patients were prospectively identified from the gynecologic oncology tumor registry and invited to participate in the study. Consenting individuals underwent genetic testing to identify germline BRCA mutation carriers immediately after their primary surgery.

A total of 50 consecutive women with fallopian tube carcinoma were identified. Twelve patients were lost to follow-up, and 10 patients were dead of disease according to tumor registry data. Of the patients who had died of disease, tissue blocks were available for DNA isolation from 3 patients. Twenty-five of the remaining patients consented to interviews with a member of the study team and to have a blood sample drawn for genetic testing. Patients were offered the opportunity to receive their BRCA genetic test results at no expense.

BRCA mutation testing was performed on 28 patients. Four patients had testing performed before the diagnosis of tubal carcinoma because of known deleterious family mutation, and the remainder of patients had testing after the diagnosis of carcinoma as part of the study protocol. High molecular weight DNA was isolated from whole blood or paraffin embedded tissue using standard techniques. Because of reports on Ashkenazi Jewish and other founder mutations in non-Ashkenazi Jewish populations, all patients regardless of ancestry were screened using multiplex polymerase chain reaction for BRCA1 mutations 185delAG in exon 2 and 5382insC in exon 20 and exon 13 duplications, as well as the 6174delT mutation in exon 11 of BRCA2. For non-Ashkenazi Jewish patients, protein truncation testing methodology was used to detect truncating mutations in exon 11 of BRCA1 and exons 10 and 11 of BRCA2. This screening effectively includes approximately 58% of the coding region of BRCA1 and 50% of the coding region of BRCA2 (S. Narod, 2004, personal correspondence). All identified mutations were confirmed by sequence analysis.

Epidemiologic data on patient demographics and surgicopathologic characteristics were extracted from hospital records and patient interviews. Patients were asked to complete a questionnaire about their medical and family cancer history and ethnic and religious background. Surgical stage and histologic grade were determined according to the International Federation of Gynecology and Obstetrics and World Health Organization standards and were determined from the review of patient medical records and operative and pathologic reports.

Analysis of patient survival was limited to patients with stage II-III tubal disease. Tumor recurrence was defined as a doubling of CA 125 level to greater than twice the upper limit of normal on 2 consecutive tests, the appearance of a measurable lesion on examination or radiologic imaging, or histologic evidence of recurrent disease.21 Treatment-free intervals were calculated between the date of completion of treatment and date of recurrence. Information on patient survival was extracted from patient charts, patient interviews, or from treating physicians. Patients with a past history of cancer were included in survival analyses.

Histologic material was re-reviewed by 2 gynecologic pathologists (D.B. and A.W.), who were blinded to the BRCA mutation status. Histologic diagnosis of a primary tubal carcinoma was verified in accordance with the criteria of Hu et al,22 then modified by Sedlis23 and Yoonessi.24 Tumor size, histology, and the site of origin within the tube were assessed in available cases. In some cases the site of origin of tubal carcinoma could not be ascertained because of a large carcinoma that involved the entire tube or when only portions of the fallopian tube had been submitted for histologic examination. The presence of other tubal epithelial lesions (tubal atypia, hyperplasia, or dysplasia) and synchronous gynecologic carcinomas was recorded.

Immunohistochemical staining for p53, Ki67, ER, and progesterone receptor expression was performed on available paraffin-embedded tumor samples of fallopian tube carcinoma, dysplasia, and benign tubal epithelium. Slides were prepared and stained according to standard protocol with appropriate positive and negative controls from breast and ovarian carcinomas. Sections of human tonsil were used as positive controls for Ki67 expression.25 Immunohistochemical staining for Ki67, ER, and progesterone receptor was performed according to manufacturer’s recommendations on the Ventana Benchmark XT using the Ventana iVIEW detection system (Ventana Medical Systems, Inc., Tucson, AZ). Estrogen receptor, progesterone receptor, and Ki67 antibodies were prediluted from Ventana Medical Systems, Inc.: Ki67 (clone K-2), ER (clone 6F11), and progesterone receptor (clone 16). Staining for p53 was performed using the P53 antibody (clone DO-7) from Dakocytomation (Carpinteria, CA) at a 1:4K dilution on the Dako autostainer using the Mouse Envision + detection system.20 Two observers independently scored the intensity and distribution of nuclear staining for p53, Ki67, ER, and progesterone receptor without knowledge of the BRCA mutation status of the patients.25

Overall survival and treatment-free survival were estimated using Kaplan Meier methods, and survival curves were compared using the log rank test. Medians for time-independent outcomes such as age were compared using Mann Whitney U nonparametric tests. Proportions and categorical variables were compared using Fisher exact methods (exact χ2). Differences associated with P < .05 were considered statistically significant.

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Twelve of the 28 (43%) fallopian tube cancer patients had BRCA mutations detected (BRCA heterozygotes). Eleven patients had BRCA1 mutations and 1 patient had a BRCA2 mutation. The remaining 16 fallopian tube cancer patients did not have identified germline BRCA mutations (sporadic cases). Four cases of tubal carcinoma were discovered in asymptomatic germline BRCA mutation carriers at the time of prophylactic bilateral salpingo-oophorectomy: 2 patients had tubal carcinoma in situ and 2 patients had stage IIC disease. The remaining patients were explored for symptomatic disease (Table 1).

Excluding the 4 BRCA germline mutation carriers who had prophylactic surgery, symptomatic patients with hereditary BRCA-associated tubal carcinoma were younger at diagnosis compared with sporadic tubal cases, median age of 57 years compared with 65 years, respectively (P = .09). Sixteen of the 28 patients with fallopian tube cancer were of Jewish origin. A larger proportion of patients with BRCA-associated tubal cancer were of Jewish origin than sporadic tubal cancer patients, 75% compared with 44%. The younger age of diagnosis among patients with BRCA-associated tubal cancer did not achieve statistical significance in this small patient cohort.

The surgical features of the fallopian tube carcinomas among BRCA mutation carriers and sporadic patients were similar. All but 1 patient with visible disease at surgery had optimal surgical cytoreduction to less than 1 cm residual disease. Three germline BRCA mutation carriers did not receive chemotherapy because of early disease: 2 carcinoma in situ and 1 stage IA. The majority of patients in both groups received adjuvant platinum-based chemotherapy. Four patients diagnosed before 1995 were treated with cyclophosphamide and carboplatin, whereas the remaining patients diagnosed after 1995 were treated with paclitaxel and carboplatin (18 patients) or single-agent carboplatin (3 patients). Equivalent numbers of patients in each cohort received second- and third-line chemotherapy.

Median follow-up for the entire cohort of tubal carcinoma patients was 64 months. The median survival time of patients with stage II/III BRCA-associated tubal carcinomas was 68 months compared with 37 months among patients with sporadic cancers (P = .14), although this difference did not achieve statistical significance (Fig. 1). The 2- and 4-year survival rates were slightly higher for patients with BRCA-associated cancers than for sporadic cases (Table 2). The median treatment-free interval among stage II/III BRCA-mutation carriers was 28 months compared with 20 months for sporadic cases (P = .2).

The histopathologic features of fallopian tube carcinomas were similar between patients with BRCA germline mutations and sporadic cases. The majority of patients in each group had high grade, stage II/III, serous carcinomas. All carcinomas were unilateral. No patient in either cohort had exclusively proximal disease. The location and extent of the tubal carcinomas in both groups are summarized in Table 3. Irrespective of BRCA mutation status, fallopian tube carcinoma most often involved the mid or distal segments of the tube. The 3 BRCA mutation carriers with clinically occult fallopian tube cancer diagnosed at prophylactic surgery in which the site of origin of the carcinoma could be ascertained had exclusively distal disease. Two patients in each cohort explored for symptomatic disease had cancer that involved the entire length of the fallopian tube. “Skip” areas of high-grade dysplasia separate from the tubal cancer were only seen in 2 patients, both of whom were BRCA mutation carriers. Potential “precursor” lesions of tubal proliferative epithelium such as atypia, hyperplasia, or dysplasia were seen in 1 or both tubes in 66% of BRCA mutation carriers and in 94% of sporadic patients. Synchronous gynecologic carcinomas were more commonly seen in the patients with sporadic tubal carcinoma than patients with BRCA germline mutations (P = .04). One BRCA mutation carrier had a synchronous ovarian and tubal carcinoma.

Eighteen patients had slides available for p53 and Ki67 evaluation and 17 patients had slides available for ER and progesterone receptor evaluation. There were no differences in the immunohistochemical staining for p53, Ki67, ER, and progesterone receptor of carcinomas, or adjacent dysplastic or benign epithelia within the fallopian tubes of the patients with BRCA-associated and sporadic cases (Table 4). Overexpression of p53 was seen in more than 70% of fallopian tube carcinomas of both cohorts. Five patients (1 BRCA mutation carrier and 4 sporadic cases) had areas of carcinoma and adjacent dysplastic epithelia available for p53 expression. Each case had p53 overexpression in both areas (Fig. 2). Epithelium that was Ki67 positive was detected in the majority of carcinomas in both cohorts, but in none of the areas of benign epithelia. Tubal carcinomas and benign epithelia had equally high frequencies of being ER positive. Progesterone receptor–positive immunostaining was present in only one third of tubal cancers, but it was present in 10 of 17 (58%) benign tubal epithelia of evaluable patients, suggesting that there may be some loss of progesterone receptor expression in the process of tubal carcinogenesis.

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We found that 43% of tested women with primary fallopian tube carcinoma from our institution had germline BRCA mutations. BRCA2 mutations may play less of a role in hereditary tubal carcinogenesis than BRCA1 mutations. Only 1 patient in our cohort had a BRCA2 germline mutation. We attribute the higher incidence of BRCA mutations observed in our patients to our patient referral population with a high prevalence of Ashkenazi Jews and by extension, BRCA-related carcinomas. Additionally, our study population included patients with tubal carcinoma-in situ as well as patients of all religious backgrounds. In light of the reported more than 16% prevalence of BRCA mutations in patients with tubal carcinoma both from our institution and the larger, retrospective studies of Levine et al8 and Aziz et al,6 we concur with these authors’ recommendation that genetic testing is appropriate for all affected patients.26 Given that neither a family history of breast or ovary cancer nor a personal history of breast cancer accurately predicted BRCA mutation status in women with fallopian tube cancer, genetic testing is advised regardless of cancer history.

Like its BRCA-associated ovarian counterpart, our data suggest that patients with hereditary BRCA1-associated tubal cancer may be diagnosed at a younger age and have slightly improved survival compared with patients with sporadic disease. Previous studies suggest that BRCA mutation carriers develop tubal cancer approximately 9 years earlier than patients without BRCA mutations.6,8 This finding, in addition to the reported 20% cumulative risk of ovarian cancer among BRCA1 mutation carriers between the 4th and 5th decade, may influence recommendations regarding the optimal timing of surgical prophylaxis among high-risk BRCA1 mutation carriers.27

In our study, the distribution of the carcinomas did not differ between patients with BRCA-associated and sporadic fallopian tube cancer. Carcinoma typically involved the mid and distal segments of the fallopian tube, although 2 patients from each cohort had diffuse disease involving the entire length of fallopian tube. Two of the largest studies of tubal cancer patients with undetermined BRCA mutation status that evaluated the location of tubal disease failed to identify any cases of exclusively proximal tubal disease involving the cornua.28,29 The predominantly distal location of tubal cancer may reflect the anatomy of the fallopian tube, with a larger area of vulnerable epithelium in the ampullary and fimbriated rather than isthmic tubal segments. Careful pathologic assessment of the uterus, cervix, and ovaries is necessary to exclude the presence of synchronous gynecologic cancers, which have been reported to occur in 7–35% of patients with tubal carcinoma.22,30,31

The finding of “skip” areas of high grade dysplasia among only germline BRCA mutation carriers in our study may affect recommendations regarding surgical prophylaxis. There is controversy regarding the optimal prophylactic surgical procedure for high-risk BRCA mutation carriers. Some data suggest that type II endometrial or uterine papillary serous carcinoma is part of the BRCA-associated phenotype and advise that hysterectomy is appropriate despite the additional surgical risk and operative time.32 Recognition of the 100-fold increased risk of tubal cancer among BRCA mutation carriers compared with the general population and the uncertainty about the anatomic distribution of tubal cancer among BRCA mutation carriers has contributed to the clinical dilemma as to whether bilateral salpingo-oophorectomy removes a sufficient portion of the fallopian tube.10,33 Although none of the tubal carcinomas in our study patients exclusively involved the proximal segment of the fallopian tube, there remains a theoretical risk of subsequent tubal carcinoma in the residual interstitial portion of the tube of the uterine cornua after prophylactic bilateral salpingo-oophorectomy when hysterectomy is not performed. Our data support the current recommendation to remove as much fallopian tube as possible at the time of prophylactic oophorectomy while preserving the uterus and rigorous histologic assessment of the adnexa with serial 2-mm sectioning to enhance detection of occult tubal and ovarian carcinomas, which have been reported at the time of risk-reducing salpingo-oophorectomy specimens in 2.5–9% of cases.34

The clinical significance of associated tubal atypia, hyperplasia, and dysplasia remains controversial. Tubal epithelial proliferations have been reported in up to 18% of routinely accessioned salpingectomy specimens.35–37 Although the pathogenesis of tubal cancer is not clear, it has been suggested that the model of epithelial cancer progression described in other malignancies may apply.38 The recent World Health Organization histologic classification of tubal carcinomas recognizes tubal carcinoma in situ as a specific diagnostic entity and studies of early “occult” tubal carcinomas in BRCA mutation carriers increasingly demonstrate foci of carcinoma in situ that transition to invasive carcinoma.29,34 Piek et al20 reported tubal dysplasia in 50% of 12 patients with a genetic predisposition to ovarian cancer who underwent prophylactic adnexectomy compared with none of 13 control patients whose fallopian tubes were removed for benign gynecologic disease. We found that tubal atypia, hyperplasia, or dysplasia occurred in the majority of BRCA-associated and sporadic tubal cancer patients and involved both tubes despite the unilateral primary location of the tubal carcinomas. Based upon these findings, we advise that any patient found to have occult tubal carcinoma in situ at the time of salpingo-oophorectomy should be counseled to undergo hysterectomy because of the potential for multifocal tubal neoplasia to completely evaluate all segments of the fallopian tubes.

Our findings of coexisting p53 overexpression in carcinoma and dysplastic epithelium, with only rare staining in benign epithelium, support the findings and suggestion of Demopoulos et al39 that these lesions may be precursors to tubal carcinoma. Further data suggesting that tubal dysplasia is a preinvasive lesion comes from the data of Piek et al,20 who found p53 overexpression in areas of tubal dysplasia among the prophylactically removed tubes of patients with germline BRCA1 mutations. He also reported higher levels of Ki67 staining in the benign tubal epithelium of germline BRCA mutation carriers compared with controls. We did not find that Ki67 staining distinguished between the tubal carcinomas or the adjacent benign epithelium of hereditary BRCA-associated and sporadic cases.

As with other reports, the initial retrospective design of our study that examined patient survival suffered from selection bias by including only living cancer patients.12,40–43 We recognize the inherent bias of studying survival as an endpoint in a cohort of cancer survivors. We also recognize the limitation of incomplete BRCA sequencing in the study population and the high frequency of Ashkenazi Jewish women in our patient population. Although the BRCA screening techniques used in the study identify more than 90% of germline BRCA mutations in Jewish patients, a significant proportion of BRCA mutations in non-Jewish populations would not be detected. We have, therefore, amended the study to approach all newly diagnosed tubal cancer patients, and counsel them to have complete genetic evaluation and testing. Prospective multi-institutional studies with larger patient populations are necessary to validate our preliminary observations regarding the prevalence and characteristics of BRCA mutation–associated tubal carcinoma and to define the optimal prophylactic surgical procedure for BRCA mutation carriers to reduce their risk of tubal and ovarian carcinoma.

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International Journal of Gynecological Pathology
Coexisting Intraepithelial Serous Carcinomas of the Endometrium and Fallopian Tube: Frequency and Potential Significance
Jarboe, EA; Miron, A; Carlson, JW; Hirsch, MS; Kindelberger, D; Mutter, GL; Crum, CP; Nucci, MR
International Journal of Gynecological Pathology, 28(4): 308-315.
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© 2005 by The American College of Obstetricians and Gynecologists.