Mucinous ovarian carcinomas

Incidence/mortality

Mucinous carcinomas of the ovary are a rare subtype of epithelial ovarian carcinomas, accounting for less than 3% of all epithelial ovarian cancers ( Table 5.1 ). Historical studies cite the frequency of primary mucinous ovarian carcinoma ranging from 6% to 25%; however, after excluding tumors of low malignant potential or borderline tumors, and metastatic tumors to the ovary, largely from the GI tract, the true incidence of these tumors is much lower. Therefore, out of the 21,750 new cases of ovarian cancer estimated to be diagnosed in the United States, approximately 650 of these cases will be mucinous ovarian carcinomas. The rarity of these tumors is reflected in the low percentage of primary mucinous ovarian carcinomas represented in clinical trials. In fact, mucinous ovarian carcinomas represented 2–4% of enrolled patients in landmark GOG trials that helped establish current platinum-based treatment paradigms in epithelial ovarian cancer.

Over 80% of mucinous ovarian carcinomas are diagnosed at an early stage, with disease confined to the ovary. The clinical presentation will typically be a young woman reporting pelvic pain or discomfort in the setting of a large (10–15 cm) unilateral ovarian mass. This contrasts with patients who are diagnosed with the more common type of epithelial ovarian cancer, high-grade serous ovarian carcinoma, which tends to present with advanced-stage disease due to the later onset of symptoms. Another feature distinguishing mucinous tumors from the high-grade serous subtype is that they are diagnosed more frequently in younger women, at a median age of 53 years, with 26% diagnosed in women younger than 44 years. In contrast, patients with high-grade serous ovarian carcinoma have a median age at diagnosis of 61 years, with less than 7% being younger than 44 years ( Table 5.2 ).

Women diagnosed with mucinous ovarian carcinoma have an overall better prognosis than those diagnosed with high-grade serous ovarian carcinoma. This is due to the fact that the majority of mucinous ovarian carcinomas are stage I at the time of diagnosis, in contrast to high-grade serous ovarian carcinomas, where stage I disease is rarely diagnosed (83% vs 4%). While early-stage mucinous ovarian carcinomas are associated with a 5-year overall survival exceeding 90%, patients with advanced-stage mucinous carcinomas tend to fare worse than their high-grade serous counterparts, with a median overall survival of less than 15 months. This is largely due to the relative resistance of mucinous ovarian carcinomas to platinum-based chemotherapy regimens ( Table 5.2 ).

Etiology/risk factors

It is now commonly believed that the majority of high-grade serous ovarian carcinomas or tubal carcinomas originate in the fimbriae of the tube and then exfoliate onto the surface of the adjacent ovary. In contrast, mucinous ovarian carcinoma appears to develop as a continuum, arising from benign epithelium, progressing to a mucinous borderline tumor before developing into an invasive malignancy. This is supported by the observation that invasive mucinous carcinomas often coexist with benign mucinous cystadenomas and/or borderline tumors within the same ovarian mass. Mucinous carcinomas can also arise from mature cystic teratomas or Brenner tumors. Histologically, the distinction between these different mucinous entities can be subtle, making an accurate pathologic diagnosis challenging.

Unlike high-grade serous ovarian carcinomas, for which nulliparity, early menarche, late menopause and germline BRCA1 or BRCA2 mutations are established risk factors, smoking is the only known risk factor associated with mucinous ovarian carcinomas ( Table 5.2 ). In a systematic review, current or prior history of smoking was associated with an increased risk for mucinous ovarian carcinoma (RR 2.1, 95% CI 1.7–2.1) but not the other epithelial subtypes of ovarian cancer. Current and former smokers also have worse cancer-specific survival compared with nonsmokers, with a hazard ratio of 1.9 (95% CI 1.01–3.65).

Genetic sequencing can help distinguish mucinous ovarian carcinomas from other epithelial subtypes and from extraovarian primaries. The vast majority of mucinous ovarian carcinomas harbor KRAS mutations (45%–71%), compared with only 10% of endometrioid ovarian carcinomas, 5% of high-grade serous ovarian carcinomas, and 0% of clear cell carcinomas. Notably, the same KRAS mutations have been found in the associated benign and borderline lesions, suggesting that this mutation is a founder event. While TP53 mutations are characteristic of high-grade serous ovarian carcinomas (> 96%), 56%–75% of mucinous ovarian carcinomas harbor these alterations. Additionally, amplification of ERBB2 (HER2) is also seen in 18%–35% of cases. Mutations in ERBB2 (HER2) and TP53 are only observed in the carcinoma component, suggesting that these alterations occur (develop) later in the process of malignant transformation.

Gross

Majority of primary ovarian mucinous carcinomas are grossly large unilateral masses. This appearance is different from metastatic tumors involving the ovary, which are frequently bilateral; and the ovaries are small and multinodular with a bosselated surface. While the aforementioned appearance is typical, on occasion large unilateral tumors may represent metastasis from the gastrointestinal (GI) tract or pancreas rather than ovarian primaries; therefore, careful histologic evaluation is necessary.

Microscopic findings

Histologically primary ovarian mucinous carcinomas usually show a heterogeneous appearance with areas of cystadenoma, borderline tumor, and carcinoma. The majority of mucinous carcinomas are of intestinal type with the lining epithelium containing goblet cells. Mucinous ovarian carcinomas show two patterns of invasion, i.e., expansile type and infiltrative type. In the expansile pattern the glands are back to back with minimal or no intervening stroma, and this area should measure at least 5 mm in one dimension; importantly there is no stromal invasion or desmoplastic reaction around the glands ( Fig. 5.2 ). Infiltrative invasion is characterized by haphazard glands surrounded by desmoplastic stroma, measuring at least 5 mm in one linear dimension ( Fig. 5.3 ). If the infiltrative pattern of invasion is focal and measures < 5 mm, in a background of a mucinous borderline tumor, the term microinvasive carcinoma is used. The size criteria are based on the WHO Classification of Tumors of the Female Reproductive Organs. Of note, intestinal-type mucinous carcinomas may arise in a background of an ovarian teratoma and mimic metastasis due to extensive pseudomyxoma ovarii/peritonei.

A subset of mucinous carcinomas have mural nodules which may be composed of anaplastic carcinoma, or sarcoma. These two components have histologic overlap but the anaplastic carcinoma is diffusely positive for keratin markers, while negative in sarcoma. The presence of anaplastic carcinoma and sarcoma may be associated with an adverse outcome but some studies have not shown this to be the case in stage IA tumors; however, experience is limited. Sarcoma-like mural nodule, on the other hand, is a reactive proliferation composed of mitotically active spindle cells with numerous osteoclast-like giant cells, and as such is a benign proliferation that does not alter the outcome.

Ancillary testing

Primary ovarian mucinous tumors are usually positive for CK7 (diffuse) ( Fig. 5.4 ). CK20 ( Fig. 5.5 ), PAX-8 and ER show variable staining ranging from negative to focal or patchy staining but are not usually diffuse and strong. Markers of intestinal differentiation such as SATB2 are negative in the surface epithelial tumors, but can be positive in mucinous tumors arising in a background of teratoma. Distinction from metastasis can be challenging on histologic evaluation hence, doing a panel of immunostains is prudent.

Differential diagnosis

The differential diagnosis for ovarian mucinous carcinoma is quite diverse. Among other ovarian primaries, endometrioid carcinoma and clear cell carcinoma can show extensive mucinous differentiation and may be classified as mucinous carcinoma. Diffuse strong expression of ER and PR favors endometrioid carcinoma over mucinous carcinoma. Expression of HNF-1B and napsin-A would support clear cell carcinoma. Distinguishing metastatic mucinous ovarian carcinoma from a primary ovarian mucinous carcinoma can be particularly challenging. Histologic features such as dirty necrosis are typical of metastatic colonic adenocarcinoma, and the presence of pseudomyxoma ovarii/peritonei is almost always associated with an appendiceal primary. But in many cases there are overlapping histologic features and immunohistochemical (IHC) stains are necessary to make the correct diagnosis. The two most important markers are CK7 and CK20, the former being diffusely positive in ovarian mucinous carcinomas and the latter in tumors of the lower GI tract. However, right-sided colonic adenocarcinomas that are microsatellite unstable may be diffusely CK7 positive and negative for CK20, and most ovarian mucinous carcinomas can show focal CK20 staining; these factors must be considered when interpreting the stains. CDX2 is often positive in ovarian mucinous carcinomas which limits its utility in this differential. Other metastatic tumors that are morphologically virtually indistinguishable from ovarian mucinous carcinomas are tumors of the pancreaticobiliary tract and some cervical carcinomas. Pancreaticobiliary tract tumors show loss of DPC4 in about 50% of cases and this marker may facilitate the diagnosis as other markers are not specific in this differential. Unlike primary ovarian mucinous carcinomas, HPV-associated cervical carcinoma will be diffusely positive for p16 and show positivity for high risk HPV by in-situ hybridization. Despite the use of immunomarkers, in a subset of cases, distinguishing primary from metastatic tumors is not possible, and correlation with clinical and radiologic findings is necessary to determine the primary site of origin.