Case 1 -

Tubal Intra-Epithelial Carcinoma, Metastatic to the Ovary (Fimbrial-Ovarian Carcinoma) Christopher Crum Brigham & Women’s Hospital Boston, MA

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Case History: The patient is a 78 year old woman with a history of invasive ductal breast carcinoma 5 years prior with metastasis to the right clavicle 2 years later. She was in good health and undergoing routine radiologic surveillance when a 3cm left adnexal mass was identified on PET/CT scan, and confirmed to be cystic on ultrasound. Left salpingo-oophorectomy was performed, with omental and retroperitoneal lymph node biopsies. Exam of the left adnexa revealed a grossly unremarkable fallopian tube and an adherent ovarian mass. The omental and lymph node biopsies were negative. The uterus and right adnexa had been removed previously, with a diagnosis of dermoid cyst. The section submitted is from the left ovarian mass. Case 1 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 1 - Figure 1 Low power image of the ovarian tumor, showing sharply demarcated neoplastic glands with cytoplasmic clearing. Case 1 - Figure 2 Medium power image of the ovarian tumor. Case 1 - Figure 3 Medium power image of the ovarian tumor. Case 1 - Figure 4 High power image of the ovarian tumor. Note the uniform pattern of supranuclear vacuoles. Case 1 - Figure 5 High power image of the ovarian tumor. The cytoplasmic vacuoles were mucicarmine negative and very weakly positive for PAS. Case 1 - Figure 6 CK7 CK7 immunostain is diffusely positive in this tumor, supporting a Mullerian origin. Case 1 - Figure 7 CK20 CK20 immunostain is heterogenous, which does not support a colon primary but would not exclude an upper gastrointestinal or pancreatic primary. Case 1 - Figure 8 CDX2 CDX2 immunostain is heterogenous, which does not support a colon primary but would not exclude an upper gastrointestinal or pancreatic primary. Case 1 - Figure 9 SMAD4 SMAD4 immunostain is positive. This is non-diagnostic for a metastatic tumor of the pancreas. Case 1 - Figure 10 p16 p16 immunostain is diffuse and strongly positive. This is unusual for a well differentiated endometrioid or mucinous carcinoma and suggests an unusual variant. Case 1 - Figure 11 p53 p53 immunostain is diffusely positive. This is unusual for a well differentiated endometrioid or mucinous carcinoma and suggests an unusual variant of non-serous Mullerian carcinoma. Discussion: The case in question raises the common dilemma of ascertaining the site of origin for a well differentiated ovarian tumor that has abundant cytoplasmic vacuoles, reflecting a secretory or mucinous product. The differential diagnosis in a case such as this includes the following: A metastatic tumor from the gastrointestinal or pancreatico-biliary tracts A primary tumor of the ovary An implant or metastasis from another Mullerian site, such as the cervix, endometrium or fallopian tube Did this tumor arise in a remote, non-Mullerian site? The presentation of this tumor, as a large, non-necrotic, well to moderately-differentiated gland-forming, expansile mass with a smooth surface, does not strongly support a metastasis from the gastro-intestinal tract. Nevertheless, immunostains for CK7, CK20, SMAD4 and CDX2 were ordered. The immunophenotype was as follows: CK7(+++), CK20(+), CDX2 (+) and SMAD4 (+++). Based on this and the tumor morphology, a primary tumor arising in the gastrointestinal tract was considered unlikely; a primary in the pancreatico-biliary tracts could not be excluded but a CT scan of that region was negative. Did this tumor arise from the ovary or from another Mullerian site? Four potential Mullerian primary sites must be considered in cases such as this, and include the following: Cervix: Approximately 5% of cervical adenocarcinomas will metastasize to the ovary, including occasional tumors that have minimal or no histologic evidence of cervical stromal invasion. In our experience, younger age (under 50 years of age), the presence of nuclear hyperchromasia exceeding that typically seen in gland forming endometrioid carcinomas, apical eosinophilia and mitoses that appear "suspended" in the apical cytoplasm, are helpful distinguishing features. Such tumors are typically HPV positive and will immunostain strongly and diffusely for p16. However, p16 immunostaining is not specific for metastatic cervix carcinomas and although less diffuse in endometrioid carcinomas, it will not distinguish these tumors from some upper genital tract (serous) carcinomas. Endometrium: Approximately 12% of endometrioid carcinomas of the ovary are associated with a synchronous endometrial primary; the proportion of well-differentiated endometrioid tumors of the ovary that are metastases from the endometrium is very low. Fallopian tube: There is increasing evidence that a subset of pelvic serous carcinomas originate in the distal fallopian tube as a serous tubal intraepithelial carcinoma (STIC). Approximately 80% of pelvic serous carcinomas detected in risk-reducing salpingo-oophorectomies in women with BRCA1 or BRCA2 mutations arise as STICs in or near the fimbria. The percentage of unselected (and advanced) ovarian or peritoneal serous cancers that arise in the tube is less clear, but from 35-47% are associated with a STIC. A precursor (the p53 signature) has been described in the fimbria and linked to STIC, further implicating the salpinx in the genesis of many "ovarian" serous carcinomas. Perhaps relevant to this case, early endometrioid carcinomas have been identified in the fimbria in association with similar carcinomas in the ovary, implying a source in the tube. The ovary: Unilateral carcinomas of the ovary, or those forming a dominant mass, support an ovarian origin. In order of decreasing frequency, mucinous, endometrioid or serous can present as a unilateral or unilaterally dominant mass. Additional biomarker information and its significance in this case p16: This tumor is strongly p16 immunopositive. This is consistent with either a metastasis from a primary cervical tumor, an unusual variant of serous carcinoma or high grade endometrioid carcinoma. HPV: This tumor was tested for HPV by PCR and scored negative. This is strong evidence against a cervical primary. P53: Although this tumor has prominent cytoplasmic vacuoles, the p53 immunostain is strongly and diffusely positive. Based on what we know about the molecular pathways to mucinous and well differentiated endometrioid carcinomas of the ovary, the presence of strong p53 immunostaining usually excludes these tumor types. It does not exclude a colonic, gastric, lung or pancreatic primary, but these are unlikely in view of the other findings. This leaves open the possibility of an unusual variant of mullerian carcinoma in which the p53 immunophenotype is at odds with the histopathology. Co-existing tubal intraepithelial carcinoma Examination of the ipsilateral fallopian tube in this case revealed an unusual finding, which was an intra-epithelial carcinoma with a focally secretory pattern (figure at right). Like the ovarian tumor, the tubal lesion was diffusely positive for p16 and p53. There was no lamina propria invasion of the fallopian tube. Could both the ovary and tubal neoplasms represent metastases from another site, such as the gastro-intestinal or pancreatico-biliary tracts? There is scant conclusive evidence in the literature of gastro-intestinal or pancreatic tumors metastasizing to the mucosal surface of the fallopian tube. Could both tumors signify separate primary neoplasms (ie a multi-focal carcinoma of the genital tract)? Separate primary neoplasms of the tube have been reported in cases of endometriod carcinoma of the endometrium. Rare examples of multifocal mucinous tumors of the cervix, endometrium, tube and ovary have been reported, but there is no molecular evidence confirming that these are indeed separate primaries. P53 mutation analysis of paired STICs and remote serous tumors in the ovary or peritoneum has invariably confirmed identical p53 mutations, consistent with a single source for both tumors. Is it possible that a primary gynecologic tumor has metastasized to the fallopian tube (ie from ovary to fimbria, not the reverse)? Although serous carcinomas frequently metastasize to the serosal surface of the tubes, there is no conclusive evidence that they implant and spread along the tubal epithelium. Nevertheless, this is a possibility, particularly in advanced carcinomas. Studies of early carcinomas arising in BRCA+ women suggest the opposite is usually the case due to the fact that a high proportion emerge in the fimbria rather than ovarian surface or ovarian cortical inclusions.. A non-serous immunophenotype The tumor is negative (or very focally positive) for WT-1 and PAX 8, excluding a conventional serous carcinoma. The tumor is muci-carmine negative, and weakly PAS and PAS-D positive. Diagnosis: Tubal intra-epithelial carcinoma, metastatic to the ovary (Fimbrial-ovarian carcinoma). Final Comments: This case is unusual because of the following: The tumor forms uniform (grade 1) glands with grade 2 nuclear features. It is strongly p53 positive, highlighting a disparity between glandular differentiation and p53 immunophenotype Despite the presence of p53, it is WT-1 and PAX8 negative, consistent with a non-serous lineage. Bibliography: Armes JE, Lourie R, de Silva M, Stamaratis G, Boyd A, Kumar B, Price G, Hyde S, Allen D, Grant P, Venter DJ. Abnormalities of the RB1 pathway in ovarian serous papillary carcinoma as determined by overexpression of the p16(INK4A) protein. Int J Gynecol Pathol. 2005;24:363-8. Jarboe E, Folkins A, Nucci MR, Kindelberger D, Drapkin R, Miron A, Lee Y, Crum CP. Serous carcinogenesis in the fallopian tube: a descriptive classification. Int J Gynecol Pathol. 2008;27:1-9 Kindelberger DW, Lee Y, Miron A, Hirsch MS, Feltmate C, Medeiros F, Callahan MJ, Garner EO, Gordon RW, Birch C, Berkowitz RS, Muto MG, Crum CP Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship. Am J Surg Pathol. 2007;31:161-9 Lee KR, Young RH. The distinction between primary and metastatic mucinous carcinomas of the ovary: gross and histologic findings in 50 cases. Am J Surg Pathol. 2003;27:281-92. Lee Y, Miron A, Drapkin R, Nucci MR, Medeiros F, Saleemuddin A, Garber J, Birch C, Mou H, Gordon RW, Cramer DW, McKeon FD, Crum CP. A candidate precursor to serous carcinoma that originates in the distal fallopian tube. J Pathol. 2007 Jan;211(1):26-35. Erratum in: J Pathol. 2007;213:116 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. 2006 ;30:230-6. Roh MH, Kindelberger D, Crum CP. Serous Tubal Intraepithelial Carcinoma and the Dominant Ovarian Mass: Clues to Serous Tumor Origin? Am J Surg Pathol. 2008 Nov 13 Ronnett BM, Yemelyanova AV, Vang R, Gilks CB, Miller D, Gravitt PE, Kurman RJ. Endocervical adenocarcinomas with ovarian metastases: analysis of 29 cases with emphasis on minimally invasive cervical tumors and the ability of the metastases to simulate primary ovarian neoplasms. Am J Surg Pathol. 2008;32:1835-53 Seidman JD, Kurman RJ, Ronnett BM. Primary and metastatic mucinous adenocarcinomas in the ovaries: incidence in routine practice with a new approach to improve intraoperative diagnosis. Am J Surg Pathol. 2003;27:985-93. Vang R, Gown AM, Farinola M, Barry TS, Wheeler DT, Yemelyanova A, Seidman JD, Judson K, Ronnett BM. p16 expression in primary ovarian mucinous and endometrioid tumors and metastatic adenocarcinomas in the ovary: utility for identification of metastatic HPV-related endocervical adenocarcinomas. Am J Surg Pathol. 2007;31:653-63