Section 3 -

Synchronous and Metachronous Appendiceal and Ovarian Mucinous Tumors Brigitte M. Ronnett The Johns Hopkins University School of Medicine Baltimore, MD USA

Women with appendiceal mucinous tumors often have synchronous or metachronous ovarian mucinous tumors; these tumors usually have similar histologic appearances, which has lead to much speculation regarding the relationship between them. The appendiceal tumors can be broadly classified into two types, including low-grade adenomatous mucinous tumors and mucinous carcinomas. In most cases these women have one of two clinical scenarios, namely, pseudomyxoma peritonei (PMP) or peritoneal mucinous carcinomatosis (PMCA). The former is associated with the low-grade adenomatous tumors and the latter, the carcinomas. The ovarian tumors often are responsible for the clinical presentation. The appendiceal tumor is often identified synchronously with the ovarian tumor(s) but sometimes is discovered metachronously (often later, prompted by features of the ovarian tumor suggesting it is not primary) or is never identified due to obliteration of the appendix by the tumor. These ovarian tumors often had been interpreted as independent primary ovarian "borderline" mucinous tumors or carcinomas and were thought to be responsible for PMP and PMCA, not only when an appendiceal tumor had not been identified but even at times when one had been found. However, recent morphologic, immunohistochemical, and molecular genetic studies have demonstrated that in virtually all cases, the appendiceal tumors are primary and the ovarian tumors are secondary both in PMP and PMCA. Clinicopathologic scenarios Pseudomyxoma peritonei (PMP): mucinous ascites accompanied by low-grade adenomatous mucinous neoplasm (derived from a ruptured appendiceal mucinous adenoma), diagnosed pathologically as "disseminated peritoneal adenomucinosis" (DPAM)* Peritoneal mucinous carcinomatosis (PMCA): disseminated/metastatic mucinous carcinoma (architectural patterns and cytologic features of carcinoma) with abundant extracellular mucin production (* a term created, with the assistance of Robert J. Kurman and John Yardley, to provide a unique diagnostic label for this condition characterized by disseminated peritoneal mucinous tumor caused by ruptured appendiceal low-grade adenomatous mucinous tumors, associated with a unique clinical syndrome (-"osis") of mucinous ascites (PMP); ovarian involvement may simulate primary ovarian mucinous tumors but tumors in the ovaries should not be labeled with "ovarian-type" diagnostic terms due to distinct clinical, morphologic, and immunohistochemical features) Morphologic varieties of appendiceal and ovarian mucinous tumors Low-grade adenomatous mucinous neoplasms (mucinous adenomas) Mucinous carcinomas: Signet ring cell carcinomas (pure) Adenocarcinomas with "goblet cell carcinoid-like" patterns Well differentiated glandular adenocarcinomas Mixtures of the above types (including some with adenoma) Obstacles to understanding the relationship between primary ovarian mucinous tumors and PMP Synchronous appendiceal and ovarian mucinous tumors are common Appendix can appear "normal" or be obscured by peritoneal disease; it is not always removed or completely examined microscopically Ovarian tumors can be large and responsible for the clinical presentation (encountered by gynecologist or gynecologic oncologist due to pelvic/adnexal mass) Default is to interpret ovarian mucinous tumor as primary and at least "borderline" due to the presence of extraovarian disease ("implants"), especially when the appendiceal tumor is not identified Keys to understanding the relationship between "borderline" (low malignant potential/atypical proliferative) mucinous tumors and PMP: The facts Virtually all mucinous "borderline" tumors are stage I (recent studies with rigorously classified tumors) Survival for stage I is virtually 100% "Advanced stage disease" has a significantly worse prognosis (~ 50% survival); interestingly, this is associated with PMP in ~90% of cases Rupture of bona fide primary ovarian mucinous borderline tumors has not been demonstrated to lead to subsequent PMP Morphologic, immunohistochemical, and molecular genetic data provide evidence that the ovarian mucinous tumors in PMP are secondarily derived from appendiceal low-grade adenomatous mucinous tumors (ruptured mucinous adenomas) PMP is of appendiceal, not ovarian, origin and is not an advanced stage ovarian mucinous tumor (rare exception: mucinous tumors arising in ovarian mature cystic teratomas) Distinction of primary and metastatic mucinous tumors in the ovary Metastatic mucinous carcinomas are more common than primary ovarian mucinous carcinomas Carcinomas of colorectum, appendix, pancreas, biliary tract/gallbladder, stomach, and endocervix can simulate primary ovarian mucinous tumors Characteristic features of primary ovarian mucinous tumors:unilateral, large (>15 cm), lack of surface or superficial cortical tumor, multicystic and/or solid without parenchymal nodules, typically stage I Characteristic features of metastatic mucinous carcinomas: often bilateral, typically smaller (<15 cm) but can be large, tumor involving ovarian surface and/or superficial cortex, nodular pattern with preserved intervening stroma but can be multicystic, presence of extraovarian tumor (peritoneum, omentum) Problematic features of some metastatic mucinous carcinomas in the ovary that render distinction from primary ovarian mucinous tumors difficult include: Initial clinical presentation in the ovary (occult primary tumor) Unilateral large tumor with cyst formation Deceptive patterns of invasion (simulating "borderline" tumor with intraepithelial carcinoma or confluent glandular pattern of invasive mucinous carcinoma) Greater differentiation than the primary tumor Highly differentiated areas simulating a benign mucinous tumor, suggesting origin in the ovary Hormonal symptoms (virilization) suggesting a primary ovarian sex cord-stromal tumor Immunohistochemical distinction of primary ovarian and appendiceal mucinous tumors Tumor type CK7 CK20 Primary ovarian mucinous tumors^ Positive* (>95%) Positive* (~70-80%) Appendiceal low-grade adenomatous mucinous tumors Negative** (~80-90%) Positive** (100%) Appendiceal adenocarcinomas Negative** (~70%) Positive** (100%) ^ exception: some mucinous tumors arising in ovarian mature cystic teratomas have the CK7-/CK20+ immunoprofile * CK7 pattern is usually diffuse, CK20 pattern is usually focal/patchy ** CK7 pattern is usually focal/patchy; CK20 pattern is usually diffuse Selected References: Cuatrecasas M, Matias-Guiu X, Prat J. 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A clinicopathologic and immunohistochemical analysis of tumors often misinterpreted as primary ovarian tumors or metastatic tumors from other gastrointestinal sites. Am J Surg Pathol 1997;21:1144-1155. Ronnett BM, Kurman RJ, Zahn CM et al. Pseudomyxoma peritonei in women: A clinicopathologic analysis of 30 cases with emphasis on site of origin, prognosis, and relationship to ovarian mucinous tumors of low malignant potential. Hum Pathol 1995;26:509-524. Ronnett BM, Seidman JD. Mucinous tumors arising in ovarian mature cystic teratomas: relationship to the clinical syndrome of pseudomyxoma peritonei. Am J Surg Pathol 2003;27:650-657. Ronnett BM, Shmookler BM, Diener-West M, Sugarbaker PH, Kurman RJ. Immunohistochemical evidence supporting the appendiceal origin of pseudomyxoma peritonei in women. Int J Gynecol Pathol 1997;16:1-9. Ronnett BM, Yan H, Kurman RJ, Shmookler BM, Wu L, Sugarbaker PH. 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Cytokeratins 7 and 20 in primary and secondary mucinous tumors of the ovary: analysis of coordinate immunohistochemical expression profiles and staining distribution in 174 cases. Am J Surg Pathol 2006 (In Press). Vang R, Ronnett BM. Distinction of primary ovarian mucinous tumors and mucinous tumors metastatic to the ovary: a practical approach with guidelines for prediction of primary site for metastases of uncertain origin. Pathol Case Rev 2006;11:18-30. Young RH, Gilks CB, Scully RE. Mucinous tumors of the appendix associated with mucinous tumors of the ovary and pseudomyxoma peritonei. A clinicopathological analysis of 22 cases supporting an origin in the appendix. Am J Surg Pathol 1991;15:415-429.