Intraepithelial Carcinoma of the Fimbria and Pelvic Serous Carcinoma: Evidence for a Causal Relationship David W. Kindelberger, MD,* Yonghee Lee, MD,* Alexander Miron, PhD,w Michelle S. Hirsch, MD, PhD,* Colleen Feltmate, MD,z Fabiola Medeiros, MD,* Michael J. Callahan, MD,z Elizabeth O. Garner, MD, MPH,z Robert W. Gordon,w Chandler Birch,* Ross S. Berkowitz, MD,z Michael G. Muto, MD,z and Christopher P. Crum, MD* Abstract: Proposed origins of pelvic serous carcinoma include the ovary, fallopian tube, and peritoneum. Prophylactic salpingo-oophorectomies in BRCA+ women have recently identified the fimbria as a site of origin for early serous carcinoma (tubal intraepithelial carcinoma or TIC). We explored the relationship of TIC to pelvic serous carcinomas in consecutive cases with complete adnexal exam (SEE-FIM protocol). Cases positive (group A) or negative (group B) for endosalpinx (including fimbria) involvement, were subclassified as tubal, ovarian, or primary peritoneal in origin. Coexisting TIC was recorded in group A when present and p53 mutation status was determined in 5 cases. Of 55 evaluable cases, 41 (75%) were in group A; including tubal (n = 5), peritoneal (n = 6), and ovarian (n = 30) carcinomas. Foci of TIC were identified in 5 of 5, 4 of 6, and 20 of 30, respectively. Ninety- three percent of TICs involved the fimbriae. Five of 5 TICs and concurrent ovarian carcinomas contained identical p53 muta- tions. Thirteen of 14 cases in group B were classified as primary ovarian carcinomas, 10 with features supporting an origin in the ovary. Overall, 71% and 48% of ‘‘ovarian’’ serous carcinomas had endosalpinx involvement or TIC. TIC coexists with all forms of pelvic serous carcinoma and is a plausible origin for many of these tumors. Further studies are needed to elucidate the etiologic significance of TIC in pelvic serous carcinoma, reevaluate the criteria for tubal, peritoneal, and ovarian serous carcinoma, and define the role of the distal tube in pelvic serous carcinogenesis. Key Words: intraepithelial carcinoma, serous carcinoma, BRCA, fallopian tube neoplasms, ovarian neoplasms (Am J Surg Pathol 2007;31:161–169) O varian cancer is diagnosed in approximately 25,000 women yearly in the United States, accounting for approximately 12,500 deaths. 22 It can be divided into 2 general histopathologic categories, each of which can be distinguished by its molecular pathogenesis and propen- sity for extraovarian spread. The first consists of tumors of borderline malignancy, low-grade serous carcinomas, endometrioid, and mucinous ovarian carcinomas. These tumors predominate in the ovarian parenchyma, are often confined to one or more cysts (intracystic) and do not typically originate from, or involve, the ovarian surface. The pathogenesis of this first type involves multiple biologic events paralleling a histologic progression from benign to malignant. These include microsatellite in- stability and mutations in KRAS, BRAF, b-catenin, and pTEN. 26 The second group consists of serous carcinomas, which have 3 proposed origins, including the ovarian surface epithelium or mullerian inclusions, fallopian tube mucosa, and mullerian epithelium elsewhere in the peritoneal cavity. 12 The pathogenesis of this second group frequently involves mutations in the p53 tumor suppressor gene and typically involves a rapid evolution, often in the absence of a preexisting benign precursor condition. 26 Because of their propensity for serosal organ involvement and rapid peritoneal spread, serous carcino- mas are the most lethal form of pelvic epithelial cancer. 6 Fallopian tube serous carcinomas originate, by definition, from neoplastic transformation of the salpin- geal mucosa (tubal intraepithelial carcinoma or TIC), which must be present to designate the tube as the primary tumor site. In contrast, intraepithelial carcinoma is rarely identified within ovarian or peritoneal carcino- mas and coexisting TIC is likewise considered rare. 2,4,25 Thus, pathologists usually designate a serous tumor as ovarian or peritoneal based on the extent to which these organs are involved and after other sources are excluded (Table 1). 22 Copyright r 2007 by Lippincott Williams & Wilkins From the *Division of Women’s and Perinatal Pathology, Department of Pathology; wBrigham and Women’s Hospital, Division of Cancer Biology, Dana Farber Cancer Institute; and zDivision of Gyneco- logic Oncology, Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, Boston, MA. Supported by a funding (to C. Crum) from NCI [P50 CA10500 (SPORE; D. Cramer, P.I.)], the Francis Ward Paine and TSA Pemberton Funds of the Division of Women’s and Perinatal Pathology (C. Crum), Department of Pathology, Brigham and Women’s Hospital, and a grant from the Columbia Hospital for Women Research Foundation, Washington, DC (to C. Crum). Reprints: Christopher P. Crum, MD, Department of Pathology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115 (e-mail: ccrum@partners.org). ORIGINAL ARTICLE Am J Surg Pathol  Volume 31, Number 2, February 2007 161