Case 5 -

Metastatic Serous Carcinoma Arising in the Tubal Fimbria Christopher P. Crum Brigham & Women’s Hospital Boston, MA

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Case History: A 60-year old woman presented with a history of pelvic discomfort. Physical exam disclosed a large pelvic-abdominal mass. Laparotomy was performed, with bilateral salpingo-oophorectomy, segmental bowel resection, omentectomy and subtotal removal of the tumor. Case 5 - Figure 1 - Ovary Case 5 - Figure 2 - Fallopian Tube Case 5 - Figure 3 - Fallopian Tube Serosa Case 5 - Figure 4 - Omentum Case 5 - Figure 5 - Uterus Case 5 - Figure 6 - Lymph Node Case 5 - Figure 7 - Lymph Node Diagnosis: Metastatic Serous Carcinoma Arising in the Tubal Fimbria Discussion: This case is relatively straightforward, and is presented because it is emblematic of the paradigm shift that is currently taking place with regard to the perceived origin of surface ovarian cancer. This is a consequence of several studies that have continually questioned the time-honored notion that most ovarian serous carcinomas are derived from the ovarian surface epithelium or cortical inclusions. While this pathway is clearly the most plausible for endometrioid and mucinous tumors, high-grade serous carcinomas have rarely been demonstrated to arise on the ovarian surface or within inclusions [1, 2]. Moreover, recent studies have shown that most early cancers detected in BRCA+ women occur in the fallopian tube, specifically in the distal segment [3, 4, 5]. Recently, we discovered that by carefully examining the entire tube, including the fimbria, in salpingooophorectomy specimens from women with ovarian cancer, we could detect early (intraepithelial) carcinomas in a substantial proportion of cases in which the bulk of the tumor was present on the ovaries or pelvic surfaces [6]. This has provided further support to a wide range of pre-existing data that suggested the tube as an important source of pelvic serous carcinoma [7]. For those who must evaluate prophylactic salpingooophorectomy specimens from ovarian cancer-prone populations, two additional tools are helpful, including the method of sectioning and the use of biomarkers in resolving problematic cases. The first is a protocol to maximize the proportion of the fallopian tube mucosa that is accessible for microscopic examination. In this protocol, which includes sectioning and extensively examining the fimbriated end (SEE-FIM), the tubes are sectioned in-toto. The ampullary portion is sectioned at 2-3 mm intervals and the infundibulum is amputated and sectioned longitudinally to maximize exposure of the fimbrial mucosa [8]. This increases the longitudinal surface area of the fimbria that is examined by approximately 60%. In a small series of cases of serous carcinomas detected in the tube in BRCA+ women, three of four were identified in the fimbria and in two, the area involved amounted to one or two discrete foci in individual plicae. Although the fimbria has not been established as the dominant site for early tubal carcinoma, this protocol provides for a more systematic view of this area. The second variable is immunostaining for both p53 and MIB-1. In a recent study, we found that virtually all serous carcinomas of the fallopian tube were intensely p53 positive, presumably due to mutations in the p53 tumor suppressor gene that retard degradation of the protein product. iv However, because p53 immunostaining can occur in non-neoplastic epithelium, a second marker was necessary to increase the specificity for serous carcinoma. support the diagnosis of neoplasia in this setting. Immunostaining for MIB-1 was helpful in this context, because it identified proliferating cells. The combination of a high index (70-80% in at least a portion of the epithelial cells) of both MIB-1 and p53 in the same epithelial focus correlated strongly with cytologic atypia and the diagnosis of serous neoplasia. With the combination of the above biomarkers and histopathology, it is possible to identify three different and overlapping subsets of early serous neoplasia. Whether these comprise stages of the same process is difficult to determine in all cases, but the juxtaposition of these entities suggests that they merit consideration. They are as follows: Group I consists of cohesive pseudo-stratified epithelia with absence of cilia and a high MIB-1 and p53 staining index. The epithelia display a variable loss of normal cell polarity and focal nuclear enlargement. Group II display a prominent stratified epithelium with a greater loss of cell polarity. The atypia may or may not be more conspicuous but is accompanied by irregular thickness and loss of cohesion with small linear fractures in the epithelial cell mass. Group III consists of highly disorganized and un-polarized clusters of malignant tumor cells with marked atypia. These tumor cells are frequently seen attached to the tubal mucosa in cases of advanced carcinoma. They are frequently multi-focal and similar to invasive tumor elsewhere in the specimen. In contrast to Groups I and II, tumor cells in Group III while technically "intraepithelial", cannot be readily distinguished from serous carcinoma growing on serosal surfaces [9]. Beyond the diagnostic exercise of locating early cancers in the fallopian tubes of prophylactic salpingo-oophorectomies, the more compelling issue emerges, which is the significance of the fallopian tube in the pathogenesis of pelvic serous carcinoma. If the most recent studies are confirmed, the fallopian tube will become the target for studies of both pathogenesis and prevention of this disease. Practicing pathologists can resolve this at the level of their practice(s) by carefully examining the distal fallopian tube in cases of "ovarian" serous carcinoma. The fact that most fallopian tube carcinomas originate in the distal portion explains the paradox of why ovarian serous carcinoma traditionally been more common than its tubal counterpart. Most serous carcinomas of the tube arise near the fimbria, gain access to the pelvic cavity, and frequently present with ovarian surface and/or peritoneal involvement that exceeds in bulk that found in the tube. Moreover, some of these tumors can spread when very small and would not be appreciated on a cursory exam of the salpinx. In this setting these tumors have often been interpreted as ovarian or peritoneal in origin, as evidenced by this case presentation. Conversely, central tubal carcinomas are uncommon, yet are the most likely to present with a dominant tumor mass in the tube. This explains the perceived rarity of tubal carcinoma in the past, a perception that will change with closer attention to the distal fallopian tube in cases of "ovarian" cancer. References Bell DA, Scully RE. Early de novo ovarian carcinoma. A study of fourteen cases. Cancer. 1994;73:1859-64 Barakat RR, Federici MG, Saigo PE, Robson ME, Offit K, Boyd J. Absence of premalignant histologic, molecular, or cell biologic alterations in prophylactic oophorectomy specimens from BRCA1 heterozygotes. Cancer. 2000;89:383-90 Colgan TJ, Murphy J, Cole DE, Narod S, Rosen B. Occult carcinoma in prophylactic oophorectomy specimens: prevalence and association with BRCA germline mutation status. Am J Surg Pathol. 2001;25:1283-9 Medeiros F, Muto MG, Lee Y, Elvin JA, Callahan MJ, Feltmate C, Garber JE, Cramer DW, Crum CP. The Tubal Fimbria is a Preferred Site for Early Adenocarcinoma in Women with Familial Ovarian Cancer Syndrome. Am J Surg Pathol, 2005, in press Cass I, Holschneider C, Datta N, Barbuto D, Walts AE, Karlan BY. BRCA-Mutation-Associated Fallopian Tube Carcinoma: A Distinct Clinical Phenotype? Obstet Gynecol. 2005;106:1327-1334. Kindelberger D, Lee Y, Hirsch MS, et al. Evidence that surface ovarian carcinomas originate in the distal fallopian tube. Submitted for publication Piek JM, Kenemans P, Verheijen RH. Intraperitoneal serous adenocarcinoma: a critical appraisal of three hypotheses on its cause. Am J Obstet Gynecol. 2004 ;191:718-32 Chang P, Crum CP. The fallopian tube, in Crum CP and Lee KR, eds. Diagnostic Gynecologic and Obstetric Pathology. WB Saunders Elsevier, 2006 Lee Y, Medeiros F, Kindelberger D, Callahan M, Muto M, Crum CP. Advances in the Recognition of Tubal Intraepithelial Carcinoma (TIC): Applications to Cancer Screening and the Pathogenesis of Ovarian Cancer. Adv Anat Pathol , 2006 (in press)