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Primary Fallopian Tube Malignancies in BRCA-Positive Women Undergoing Surgery for Ovarian Cancer Risk Reduction

Michael J. Callahan, Christopher P. Crum, Fabiola Medeiros, David W. Kindelberger, Julia A. Elvin, Judy E. Garber, Colleen M. Feltmate, Ross S. Berkowitz, Michael G. Muto

From the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, and Division of Women's and Perinatal Pathology, Department of Pathology Brigham and Women's Hospital; and Cancer Risk and Prevention Program, Dana-Farber Cancer Institute, Boston, MA

Address reprint requests to Michael G. Muto, MD, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115; e-mail: mmuto{at}partners.org

	ABSTRACT

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Purpose To review the frequency and location of malignancies detected after prophylactic salpingo-oophorectomy in women with BRCA mutations.

Methods Medical records and pathology findings were reviewed from BRCA-positive women undergoing prophylactic surgery for ovarian cancer risk reduction who underwent complete examination of the adnexa. Patients undergoing this procedure between January 1999 and January 2007 were identified.

Results From January 1999 to January 2007, 122 BRCA-positive patients underwent prophylactic surgery in the Division of Gynecologic Oncology at Brigham and Women's Hospital. The median age was 46.5 years (range, 33 to 76 years). Seven (5.7%) were found to have an early malignancy in the upper genital tract and all patients were age 44 years at diagnosis. Of seven consecutive cancers culled between January 1999 and January 2007, all (100%) originated in the fimbrial or ampullary region of the tube; six had an early (intraepithelial) component. Two were associated with surface implants on the ovary and two required repeated sectioning to detect microscopic carcinomas in the fimbria.

Conclusion The distal fallopian tube seems to be the dominant site of origin for early malignancies detected in approximately 6% of women undergoing ovarian cancer risk-reduction surgery. The greatest proportion of serous cancer risk in BRCA mutation–positive women should be assigned to the fimbria rather than the ovary, and future clinical and research protocols should employ thorough examination of the fimbria, including multiple sections from each tissue block, to maximize detection of early malignancies in this population.

	INTRODUCTION

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In the United States, epithelial ovarian cancer has the highest mortality rate of any female genital tract malignancy.¹ Because of a paucity of effective screening methods, the majority of patients are diagnosed at an advanced stage when the opportunity for cure is reduced drastically.² In the United States, the average lifetime risk of ovarian cancer is approximately 1.4%.² However, if a woman carries a germline mutation in BRCA 1 or 2, the lifetime risk ranges from 16% to 54%.^3-6

Because of the lack of effective screening modalities, many women with a hereditary predisposition to ovarian cancer may opt for risk-reducing surgery. Prior studies have demonstrated up to a 96% risk reduction in ovarian cancer for at-risk women undergoing prophylactic surgery.^7,8 However, at the time of prophylactic surgery, occult carcinoma will be identified in 2.3% to 17% of patients.^7,9-13 Earlier reports focused mainly on occult carcinoma in the ovary, and in the last decade, the fallopian tube has become recognized as an important site of occult disease in these patients.^14-17

At Brigham and Women's Hospital (BWH; Boston, MA), the protocol for pathologic examination of the tubes and ovaries has dictated the entire submission of the adnexal tissues since 1998. In February 2005, the Division of Women's and Perinatal Pathology at BWH refined this protocol to ensure that the distal fallopian tube (fimbria) was examined thoroughly (Sectioning and Extensively Examining the Fimbria [SEE-FIM] protocol).¹⁸ The focus of this report was to update our experience with this population, determine the risk of and identify risk factors for occult neoplasia in BRCA mutation–positive women undergoing prophylactic surgery, and more precisely clarify the role of the fallopian tube in the pathogenesis of early pelvic cancer in this high-risk population.

	METHODS

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A review of BRCA mutation–positive patients undergoing prophylactic surgery for ovarian cancer risk reduction in the Division of Gynecologic Oncology at BWH was undertaken. Data from medical records, operative notes, and pathology reports were abstracted on patients who had undergone prophylactic surgery from January 1999 to January 2007. All data were obtained under the approval of the institutional review board.

BRCA mutation status was obtained from the medical record. All prophylactic surgeries were performed by the Division of Gynecologic Oncology at BWH. Pathologic review of all removed tissues was performed by members of the Division of Women's and Perinatal Pathology in the Department of Pathology. In all patients, the entire adnexa were submitted for histopathologic examination, with both tubes and ovaries sectioned at 2- to 3-mm intervals before analysis. From February 2005, a modification was introduced in accordance with the SEE-FIM protocol. This modification entailed amputation of the fimbriated end with serial sagittal rather than cross sections of this segment.¹⁸ This resulted in an increase of the surface area examined by approximately 60% (C.P. Crum and E. Prusak, unpublished data).

Tubal abnormalities were classified as described previously into the following categories: normal and minor epithelial abnormalities that did not fulfill the histologic criteria for malignancy¹⁹; malignant epithelial neoplasms confined to the tubal mucosa (intraepithelial carcinoma) or ovarian surface; invasive carcinomas of the tubal mucosa or ovarian cortex; and invasive carcinomas involving mesothelial surfaces, including peritoneum, uterus, and fallopian tube.^20,21 The diagnosis of malignancy was verified by two pathologists (C.P.C. and D.K.).

Fisher's exact test was used to test associations between categoric variables. The Mann-Whitney U test was used to compare medians between two independent samples (continuous variables). All statistical analyses and descriptive statistics were performed with SPSS version 14.0 (SPSS Inc, Chicago, IL). A P value less than .05 (two-sided test) was considered statistically significant.

	RESULTS

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One hundred twenty-two women with BRCA mutations or variants underwent prophylactic surgery for ovarian cancer risk reduction in the Division of Gynecologic Oncology at BWH from January 1999 to January 2007. Sixty women had a BRCA1 mutation, 60 had a BRCA2 mutation, and two had a BRCA mutation that was not specified. The median age of all study patients was 46.5 years (range, 33 to 76 years). The median age of women with a BRCA1 mutation tended to be younger than that of women with a BRCA2 mutation, but the difference was not statistically significant (43.5 v 48.0 years; P = .16, Mann-Whitney U test).

In all patients, the prophylactic operation involved removal of both adnexa; 85 (69.7%) of 122 women had the procedure done laparoscopically. In addition, 31 (25.4%) of 122 patients also had a hysterectomy as part of their risk-reducing surgery, and 26 (21.3%) of 122 had an omentectomy as well. One hundred nineteen (97.5%) patients had peritoneal washings performed.

Seven of the 122 patients (5.7%) had a malignancy discovered at the time of prophylactic surgery (n = 1) or after pathologic review of the adnexa (n = 6). Four patients had a BRCA1 mutation and three had a BRCA2 mutation. The median age of women with malignant findings at the time of prophylactic surgery was greater than that of women with benign pathology (61 v 46 years; P = .019 Mann-Whitney U test). The seven women whose fallopian tubes harbored occult neoplasia were all 44 years of age. Consequently, age 44 years at the time of the procedure was significantly associated with the identification of occult tubal neoplasia (seven of 74 [9.5%] v zero of 48 [0%]; P = .042, Fisher's exact test; Table 1). Four (6.5%) of 62 patients evaluated before March 2005 by the standard pathologic protocol were positive for a malignancy (patients 1, 2, 3, and 5; Table 2). This was similar to the detection rate of malignancy (5%; patients 4, 6, and 7; Table 2) in the 60 specimens evaluated after March 2005 with the SEE-FIM protocol (four of 62 [6.5%] v three of 60 [5%]; P = 1.0, Fisher's exact test).

Patient 1 was a 44-year-old woman with a BRCA2 mutation who underwent laparoscopic bilateral salpingo-oophorectomy (BSO) and peritoneal washings. Intraoperatively, there was no suspicion of malignancy. On histologic review, a fimbrial intraepithelial serous carcinoma of the fallopian tube was noted, with positive peritoneal washings. A subsequent staging operation was negative. She was treated with adjuvant intravenous carboplatin and paclitaxel.

Patient 2 was a 66-year-old woman with a BRCA2 mutation who underwent laparoscopic BSO and peritoneal washings. Intraoperatively there was no suspicion of malignancy, but an ampullary intraepithelial serous carcinoma of the fallopian tube was identified on pathology. No other malignancy was detected on a subsequent staging operation and she was treated with adjuvant intravenous carboplatin and paclitaxel.

Patient 3 was a 76-year-old woman with a BRCA2 mutation whose surgery initiated as a laparoscopic BSO. A less than 1-cm nodule was noted on the pelvic peritoneum that was confirmed as serous carcinoma by frozen section. The procedure was completed as a laparotomy and the final surgical stage was IIIA, with a primary fimbrial serous carcinoma and positive peritoneal washings. The patient was treated with adjuvant intravenous carboplatin and paclitaxel.

Patient 4 was a 44-year-old woman with a BRCA1 mutation who underwent total abdominal hysterectomy (at the patient's request), BSO, and peritoneal washings. Intraoperatively, there was no suspicion of malignancy. On histologic review, an intraepithelial serous carcinoma was identified in a plica of a single fimbria, with negative peritoneal washings (Fig 1A and 1B). She was treated with adjuvant intravenous carboplatin and paclitaxel.

View larger version (86K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. (A) Distal fallopian tube (patient 4) with a tubal intraepithelial carcinoma (TIC) in a single plica (box), (B) showing epithelial stratification and atypia. (C) Ovarian surface (patient 7) with a small endometrioid carcinoma implant (). (D) The distal fallopian tube contains a microscopic carcinoma () with a flanking TIC ( and inset).

Patient 6 was a 61-year-old woman with a BRCA1 mutation who underwent total abdominal hysterectomy (at the patient's request), BSO, omentectomy, and peritoneal washings. There was no suspicion of malignancy intraoperatively. However, a fimbrial papillary serous carcinoma with focal tubal intraepithelial carcinoma was diagnosed on pathology with focal involvement of the tubal serosa. All other tissues and peritoneal washings were negative. The patient was designated as having stage IC disease and was administered adjuvant intravenous carboplatin and paclitaxel.

Patient 7 was a 51-year-old woman with a BRCA1 mutation who underwent laparoscopic BSO and peritoneal washings. Intraoperatively, there was no suspicion of malignancy. After pathologic evaluation, a 0.1-cm endometrioid adenocarcinoma of the tubal fimbria was diagnosed with a 0.3-cm implant on the surface of one ovary (Fig 1C and 1D). The patient subsequently underwent a robotic-assisted total laparoscopic hysterectomy, BSO, and omentectomy. The final surgical stage was IIA. She received adjuvant intravenous carboplatin and paclitaxel.

In all, only one of the seven malignancies was suspected at the time of surgery; six were accompanied by a noninvasive component, none of the tubal malignancies exceeded 1 cm in size, and five were not appreciated on gross inspection. Of the four malignancies detected by the conventional protocol, two were invasive cancers, one was detected on an ampullary cross-section, and one was detected in the fimbria after three rounds of sectioning. Of the three malignancies detected with the SEE-FIM protocol, one was an invasive cancer, one involved a single plica and was detected on the initial round of sectioning, and one was detected on the ovarian surface on the initial round of sectioning and as a single focus in the fimbria on a second round of sectioning.

	DISCUSSION

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The findings in this study provide additional evidence that the major source of malignancies detected in BRCA mutation–positive women undergoing ovarian cancer risk-reducing surgery is the distal fallopian tube.

Occult malignancy in the tubes or ovaries has been identified in 2.3% to 17% of patients at the time of prophylactic surgery.^7,9-13 Many studies have identified noninvasive carcinomas of the fallopian tube, which, unlike traditional carcinomas in situ in other sites, have the capacity to metastasize without invading the salpinx and are currently referred to as tubal intraepithelial carcinomas (TICs). Paley et al²² reported two BRCA1-positive patients with occult carcinomas of the fallopian tube, including one TIC. Both patients had positive peritoneal cytology. Colgan et al¹² originally described occult carcinoma in five (8.3%) of 60 high-risk women undergoing prophylactic surgery. Two of the patients, both BRCA1 positive, had fallopian tube carcinomas, including one TIC. Both lesions were microscopic and not noted on gross examination at the time of prophylactic surgery. Leeper et al,⁹ reporting on 30 BRCA-positive women, the majority whose fallopian tubes underwent extensive serial sectioning, discovered five patients (17%) with occult malignancy. Three patients (10%) were noted to have primary lesions in the fallopian tube, including two TICs. One of the patients with a TIC had positive peritoneal cytology. All of the women had normal preoperative evaluations.⁹ Finally, Agoff et al²³ reported four occurrences of early fallopian tube carcinoma, including three TICs, in high-risk women undergoing prophylactic surgery. Two of these patients had positive peritoneal cytology. Because of these reports, TIC is viewed as a malignancy and a candidate for adjunctive chemotherapy.

As illustrated by the reports described in the preceding paragraph and the patient characteristics listed in Table 2, both detection of an early malignancy in a BRCA mutation–positive specimen and assignment of a primary site are highly dependent on the thoroughness with which the pathologic examination is performed. TICs are sufficiently small to escape both gross and microscopic examination while cells that are capable of forming tumor masses on the ovarian or peritoneal surfaces are exfoliated (Fig 1). In a follow-up to the study by Colgan et al,²⁰ Finch et al¹¹ performed both a careful examination of the tubes and ovaries and described the location of seven early malignancies in their BRCA mutation–positive population. On the basis of their descriptions, the distal fallopian tube was a credible source in at least five of seven patients. Although larger numbers of patients must be examined to establish the exact percentage of malignancies arising from the fallopian tube in these high-risk women, the present study and that of Finch et al¹¹ suggest the tube may harbor the primary carcinoma in approximately 85% of tumors.

It is important to emphasize that both methods (conventional analysis and SEE-FIM protocol) of pathologic examination used in our series to examine the adnexa included the entire tubal fimbria for analysis. On the discovery of microscopic, noninvasive serous carcinomas in the fimbria, we designed the SEE-FIM protocol, which increases the surface area of the fimbria available for examination on the first round of sectioning by approximately 60%. However, the gain in detection sensitivity of this protocol will likely vary according to the size of the tumor. In the first cohort, before the institution of the SEE-FIM protocol, two tumors were invasive and one involved the ampulla, all of which would likely be detected as easily with either protocol. Detection of a fourth tumor, which was suspected only because of the positive peritoneal cytology, required three rounds of sectioning. Similarly, one invasive cancer detected by the SEE-FIM protocol would likely have been detected by either method, whereas detection of the TIC in the single plica would be facilitated by the SEE-FIM protocol. Nevertheless, one extremely small fimbrial lesion, suspected only because of a microscopic ovarian implant, required a second round of sectioning for detection. Because of this, a protocol augmenting the current protocol with multiple sections from each tissue block should be considered.

Recent reports also indicate that the distal tube is a source of tumors in both BRCA mutation–positive and BRCA mutation–negative women, and may account for malignancies previously attributed to the ovaries or peritoneum. Cass et al²⁴ showed that when cancers arose in the fallopian tube, the fimbria was a preferred site in both BRCA mutation–positive and BRCA mutation–negative women. Kindelberger et al²⁵ recently showed that the endosalpinx was involved in 75% of women with pelvic serous cancer and that TICs were associated with approximately 50% of presumed ovarian and primary peritoneal serous carcinomas. A follow-up study has shown that the detection frequency of TICs in patients with primary peritoneal serous carcinoma increased from 35% to 50% when random sampling was replaced by the SEE-FIM protocol (J.W. Carlson, C.P. Crum, and D. Kindelberger, unpublished data). They and others demonstrated that identical p53 mutations were shared by both TICs and remote tumors in such cases, confirming a genetic relationship between the two entities.^19,25,26 A recent report has also described a putative precursor to TIC in the distal tube, termed the p53 signature, which shares location, cell type, evidence of DNA damage, and presence of p53 mutations with TICs, and is commonly present in women with early tubal cancer.¹⁹ These studies have strengthened the link between the tubal fimbria and pelvic epithelial carcinogenesis in women with and without BRCA mutations.

On the basis of this and prior studies, the age at which risk of pelvic serous cancer justifies risk-reducing surgery is early in the fifth decade. Lamb et al²⁷ and Powell et al¹⁰ correlated increasing age with the likelihood of detecting occult malignancy in high-risk women. Finch et al¹¹ detected no occurrences at younger than age 40 years. All of the women with malignancy—including occult carcinoma—in the current series were 44 years of age (median, 61 years; range, 44 to 76 years). As evidenced by the age distribution of women in our study diagnosed with occult tubal cancer, the current recommendation of the Society of Gynecologic Oncologists to offer risk-reducing salpingo-oophorectomy to BRCA1-positive women after the completion of childbearing, and not delayed beyond the age of approximately 40 to 44 years, seems prudent.²⁸ In addition, the risk of carcinoma in BRCA2-positive women increases considerably by age 50 years, and along with the breast cancer protection premenopausal salpingo-oophorectomy allows,^7,29 a similar recommendation for the timing of prophylactic surgery in BRCA2-positive women seems reasonable. The second variable, based on this report and prior studies described previously, is the relationship between careful examination of the distal fallopian tube and the likelihood of detecting early tubal cancer.^10,27

The beneficial effects of adjuvant therapy for women with early cancers of the fallopian tube remain unproven. Leeper et al⁹ treated both women with TICs (one with positive cytology) with adjuvant carboplatin and paclitaxel. In the series studied by Agoff et al,²³ three of four women with occult tubal cancer were treated with adjuvant chemotherapy. One woman experienced disease recurrence 10 months after completion of therapy. However, the three women in that series with TICs only had not experienced recurrence (two were treated and one was not treated with adjuvant chemotherapy). All of the seven patients in our group received adjuvant carboplatin and paclitaxel (one patient received only one cycle secondary to her decision to stop therapy because of toxicities). However, at this point there is insufficient information from this group to ascertain the potential benefits of chemotherapy. In addition, longitudinal follow-up will be required to determine the risk of subsequent peritoneal carcinoma in this cohort of BRCA mutation–positive women that have had detection of primary fallopian tube malignancies in the prophylactic specimens.

It would be premature to assume that the fallopian tube is the only site of origin of occult malignancy in high-risk women, and current management dictates the entire removal of both tubes and ovaries. Nevertheless, a much clearer understanding of the origin of pelvic carcinomas in BRCA-positive women, and the risk of nontubal (ovarian or peritoneal) origins, is attainable, provided the distal fallopian tube is evaluated thoroughly and thorough longitudinal follow-up of each patient is carried out. Another important question that remains unanswered is whether occasional recurrences after prophylactic oophorectomy have been due to unsuspected early malignancies in the fallopian tubes versus de novo carcinomas arising in the pelvic peritoneum.^7,8 Large-scale studies using the SEE-FIM protocol or equivalent scrutiny of the fimbria have the greatest potential to answer these questions, and both determine the optimal management of women who seek pelvic cancer risk reduction and characterize the serous carcinogenesis pathway in the distal tube.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Judy E. Garber, Novartis (C), Myriad Genetics (C) Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

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Conception and design: Michael J. Callahan, Christopher P. Crum, Fabiola Medeiros, Julia A. Elvin, Judy E. Garber, Colleen M. Feltmate, Ross S. Berkowitz, Michael G. Muto

Provision of study materials or patients: Christopher P. Crum, David W. Kindelberger, Julia A. Elvin, Judy E. Garber, Colleen M. Feltmate, Ross S. Berkowitz, Michael G. Muto

Collection and assembly of data: Michael J. Callahan, Christopher P. Crum, Fabiola Medeiros, Julia A. Elvin, Judy E. Garber

Data analysis and interpretation: Michael J. Callahan, Christopher P. Crum, Colleen M. Feltmate, Ross S. Berkowitz, Michael G. Muto

Manuscript writing: Michael J. Callahan, Christopher P. Crum, Ross S. Berkowitz, Michael G. Muto

Final approval of manuscript: Michael J. Callahan, Christopher P. Crum, Fabiola Medeiros, David W. Kindelberger, Julia A. Elvin, Judy E. Garber, Colleen M. Feltmate, Ross S. Berkowitz, Michael G. Muto

	ACKNOWLEDGMENTS

 
We thank Kathryn Stoeckert and Anu Chittenden for their expert assistance.

	NOTES

 
Presented in part at the New England Association of Gynecologic Oncologists 25th Annual Meeting, June 2-5, 2005, Bretton Woods, NH, and the Society of Gynecologic Oncologists 37th Annual Meeting, March 22-26, 2006, Palm Springs, CA.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted April 22, 2007; accepted June 13, 2007.

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