Epithelial Neoplasms of the Ovary

Gross Findings

Benign serous tumors, frequently bilateral and metachronous (especially in older women), are composed of varying amounts of fibrous stroma (when predominant, serous adenofibroma) and cysts (serous cystadenoma or cystadenofibroma) and range in size from 1 to 10 (rarely up to 30) cm. The cysts are unilocular or multilocular and may contain papillary projections ( Fig. 14.1 ). On occasion, the tumor grows as an excrescence on the ovarian surface (so-called “surface papilloma”).

Microscopic Findings

Benign serous tumors are lined by epithelium that closely recapitulates the ciliated and secretory cells of the fallopian tube ( Fig. 14.2 ). Varying amounts of fibromatous stroma (adenofibroma, cystadenofibroma) and cystic change (cystadenofibroma) are present. Serous surface papillomas are composed of small papillary growths lined by simple bland, serous-type epithelium growing on the surface of the ovary.

Immunohistochemistry

Benign serous tumors have an immunohistochemical profile that is similar to borderline and malignant serous tumors. Like many other ovarian epithelial tumors, they show a CK7-positive, CK20-negative phenotype. In addition, they express PAX8, WT1, ER, BerEP4, and CD15 (Leu-M1).

Gross Findings

Serous borderline tumors are predominantly cystic with variable amounts of papillary epithelial projections that are often soft and delicate ( Fig. 14.3 ) or solid with surface papillary excrescences (or combination thereof).

Microscopic Findings

Serous borderline tumors are characterized by proliferation of the lining epithelium seen as stratification and complex hierarchical branching papillae associated with detached cellular buds. Destructive invasion of the ovarian stroma is not seen. The lining cells are cuboidal to columnar and often ciliated with interspersed eosinophilic (pink) cells, although cilia may not be conspicuous in some cases. The nuclei are uniform and mildly to moderately atypical, and mitotic rate is low. Psammoma bodies may be present but are not diagnostic ( Fig. 14.4 ).

Approximately 5%–10% of all serous borderline tumors contain foci with micropapillary architecture ( Fig. 14.5 ), defined as either nonhierarchical branching of slender, elongated papillae that are at least five times as long as they are wide or a sieve-like cribriform pattern in the surface of the papillae or within glands. When this pattern occupies a continuous area of 5 mm or more, the tumor is designated as serous borderline tumor, micropapillary variant (also referred to as “noninvasive low-grade serous carcinoma”), which is more frequently associated with bilaterality, ovarian surface involvement, and presence of extraovarian implants, a higher proportion of which are invasive.

Foci of stromal microinvasion ( Fig. 14.6 ), defined as individual eosinophilic cells, small cell clusters, or papillae (more frequently small) within the stroma, are found in 10%–15% of serous borderline tumors ( Box 14.1 ). By definition, foci are ≤5 mm in linear extent. The stroma around the epithelial cells/clusters/papillae often retracts, forming a “space.” The tumor cells in microinvasion have more abundant eosinophilic cytoplasm and acquire a round or polygonal shape. However, the nuclei have, at most, mild atypia and are similar to the intraepithelial cells. Stromal microinvasion is more often seen in pregnant women. Although it may be associated with increased long-term risk of disease recurrence, the presence of stromal microinvasion does not warrant a diagnosis of carcinoma. A less common scenario is the presence of microinvasion in the micropapillary variant of serous borderline tumor that has the appearance of a low-grade serous carcinoma but measures ≤5 mm in linear extent. It is unclear what the biologic significance of this finding is; however, some have suggested designating these foci as “microinvasive carcinoma” to separate it from microinvasion as described earlier.

Approximately 30%–40% of serous tumors in the borderline group are associated with similar-appearing lesions in the pelvis and intraabdominal sites, including lymph nodes (high-stage disease) ( Fig. 14.7 ). These lesions, termed implants, may be microscopic or macroscopic and are subclassified into noninvasive ( Fig. 14.8A ,B) and invasive ( Figs. 14.9 and 14.10 ) types, based on the presence of destructive infiltration into underlying normal tissue ( Table 14.5 ). Noninvasive epithelial implants are exclusively composed of glands or cysts with a variable degree of papillary formation present on the peritoneal surfaces. The interface between the implant and surrounding tissue is typically smooth. Noninvasive desmoplastic-type implants may occur over the ovarian surface or between exophytic surface papillae (autoimplants), as well as on the peritoneal surfaces. They form plaques or nodules without associated invasion of underlying organs/tissues and thus are easily removed. They are characterized by prominent desmoplastic reaction and inflammation surrounding single cells or irregular nests of tumor cells, which typically represent a minor component of the lesion. In both types of noninvasive implants, the cytologic features should be similar to those seen in the primary ovarian serous borderline tumor. Invasive implants may also be associated with a desmoplastic response but typically show destructive invasion of underlying tissue in the form of irregularly shaped or confluent glands or tumor cell clusters and often the cells show cytologic features of low-grade carcinoma. Borderline tumors with invasive implants are associated with an increased risk of recurrence and a more aggressive clinical course; thus, these implants are now considered to be low-grade serous carcinoma. Since both types of implants may feature a prominent stromal connective tissue response, occasional implants may be especially difficult to subclassify; in these instances, the implants should probably be classified as indeterminate. Noninvasive implants may appear invasive if they seed the peritoneal surface between omental fat lobules or serosal infoldings, so to determine invasion, it is important to examine the overall distribution (separating fat lobules vs. infiltrating adipose tissue) and cytomorphology of the epithelium (atypia, loss of well-developed gland formation). The presence of micropapillary morphology is considered by some investigators as evidence of invasion in an implant ( Fig. 14.10A ). Rarely, extraovarian invasion by single cells with abundant eosinophilic cytoplasm may be seen ( Fig. 14.10B ). Foci of endosalpingiosis involving extraovarian peritoneum and lymph nodes are common in women with serous borderline tumors. These foci, characterized by simple glands lined by tubal-type epithelium, should be distinguished from extraovarian borderline implants, since the presence of endosalpingiosis does not warrant upstaging of an accompanying ovarian serous borderline tumor ( Fig. 14.11 ).

Cytology

Positive peritoneal cytologic preparations are characterized by papillary aggregates and/or tight clusters of cells with minimal nuclear atypia and can be difficult to distinguish from benign serous epithelium (endosalpingiosis), reactive mesothelial proliferations, and well-differentiated serous adenocarcinomas. Since further distinction cannot be made on cytologic ground alone, reporting of the previous findings as “serous neoplasm” is prudent. Psammoma bodies may be present but by themselves are not diagnostic. Fine-needle aspiration is only indicated for confirmation of suspected recurrent disease.

Immunohistochemistry

Serous borderline tumors express an immunohistochemical profile that is similar to benign and malignant serous tumors. They are usually CK7 positive and CK20 negative and additionally express PAX8, WT1, ER, BerEP4, and CD15 (Leu-M1).

Molecular analysis

The profile of mRNA expression patterns differs for serous borderline tumors and low-grade serous carcinomas, as well as for low-grade serous carcinomas and high-grade serous carcinomas. The pattern of genetic alterations also differs; e.g., the presence of point mutations in BRAF or (less commonly) KRAS is more frequently associated with borderline tumors, whereas KRAS and NRAS appear to be more frequent in low-grade serous carcinomas, and TP53 mutation and somatic or germline abnormalities of BRCA1 and/or BRCA2 are more frequently associated with high-grade serous carcinoma.

Gross Findings

Low-grade serous carcinomas are typically cystic tumors composed of fine papillary growths ( Fig. 14.13 ). Two-thirds are bilateral, and there is often spread beyond the ovary at the time of diagnosis. Calcifications may be prominent both in the ovarian and the extraovarian lesions.

Microscopic Findings

Low-grade serous carcinoma exhibits low-grade cytologic atypia with destructive invasion of the ovarian stroma. The lining cells are tall to columnar and may or may not display cilia. The nuclei are uniform, nuclear chromatin is evenly distributed, and mitotic activity is low (usually less than 12 mitotic figures per 10 high-power fields [HPFs]). Atypical mitotic figures are absent. A variety of patterns of destructive stromal invasion may be seen, including dense small aggregates of micropapillae ( Fig. 14.14 ), inverted macropapillae ( Fig. 14.15 ), and a mesothelioma-like pattern. Often, an extensive microinvasion-like pattern is seen, which may be deceiving. Psammoma bodies may be present; indeed, a variant of low-grade serous carcinoma with psammomatous calcifications representing ≥75% of the tumor volume has been formerly described under the term “psammomacarcinoma” ( Fig. 14.16 ). Approximately 80% of low-grade serous carcinomas are associated with similar-appearing lesions in the omentum and/or lymph nodes (high-stage disease), which can be microscopic or macroscopic. These need to be distinguished from endosalpingiosis and foci of epithelium with features of noninvasive implants of serous borderline tumor involving extraovarian peritoneum and lymph nodes, since these do not warrant upstaging of the accompanying ovarian low-grade serous carcinoma. Psammomacarcinoma, in particular, can present with extensive extraovarian spread and even as a predominant peritoneal mass.

Cytology

Positive peritoneal cytologic preparations are virtually indistinguishable from serous borderline tumor.

Immunohistochemistry

Low-grade serous carcinomas express an immunohistochemical profile that is similar to other benign and malignant serous tumors. They are usually CK7 positive, CK20 negative, and express PAX8, WT1, BerEP4, ER, and CD15 (Leu-M1). Most low-grade serous carcinomas show normal p53 expression.

Molecular analysis

Compared with serous borderline tumors, low-grade serous carcinomas have a higher prevalence of KRAS and NRAS mutations and lower prevalence of BRAF mutations. Mutations in TP53 , BRCA1 , and BRCA2 are highly uncommon and likely do not play a role in the pathogenesis of low-grade serous ovarian neoplasia, unlike high-grade serous carcinoma.

Gross Findings

High-grade serous carcinomas are large tumors (usually >10 cm). The fallopian tube may be adherent to the mass or may be partially or completely embedded in it. The cut surface shows solid and cystic areas, both composed of friable tan tissue with hemorrhage and necrosis ( Fig. 14.17 ). Cystic spaces contain excrescences of soft and friable tumoral tissue. Surface involvement and bilateral ovarian disease is common.

Microscopic Findings

In their classic form, high-grade serous carcinomas are characterized by complex branching papillae and glands lined by a population of pleomorphic cells with loss of polarity. The cells grow in tufts and micropapillae forming narrow, slit-like spaces within the lumen. The interface with the stroma shows destructive stromal invasion, which is recognized by confluent growth of malignant cells or irregularly arranged glands, papillae, and/or nests of tumor cells with desmoplasia ( Fig. 14.18 ). Cytologically, the cells display pronounced nuclear atypia noticeable at low-power magnification, which includes bizarre cells showing large and pleomorphic round nuclei with high nuclear-to-cytoplasmic ratio, coarse to open chromatin and prominent nucleoli (many times with a cherry red appearance). Mitotic activity is usually brisk (>12 mitoses per 10 HPFs) and abnormal figures are common. Some tumors show alternative architectural patterns, including solid, endometrioid, and transitional (known as “SET”), either predominantly or exclusively ( Fig. 14.19 ). These patterns appear to be more common in BRCA mutation carriers. Although deceiving and suggestive of other types of malignancy, they display the same severe nuclear atypia and mitotic activity seen in classic forms of this tumor. Tumor cell necrosis is common and can be extensive. Psammoma bodies may be seen.

The evaluation of pathologic response to neoadjuvant chemotherapy in patients with tubo-ovarian and peritoneal high-grade serous carcinoma has prognostic significance as it correlates with progression-free survival and response to first-line platinum therapy. To this end, the Chemotherapy Response Score (CRS) system was developed to assess and document response. The system is simple and has good interobserver reproducibility especially after online training. The CRS has three categories:

• CRS score 1: No or minimal tumor response

  • Mainly viable tumor

  • No or minimal regression-associated fibro-inflammatory changes, limited to a few foci

• CRS score 2: Appreciable tumor response with residual tumor

  • Multifocal or diffuse fibro-inflammatory regressive changes with tumor in sheets, streaks or nodules

  • Extensive regression-associated fibro-inflammatory changes with multifocal residual tumor, which is regularly distributed and easily identifiable

• CRS score 3: Complete or near-complete response

  • Mainly regression associated fibro-inflammatory changes

  • Absent or minimal tumor, the latter defined as very few, irregularly scattered individual tumor cells or cell groups or nodules up to 2 mm

Importantly, response in the omentum appears to have better correlation with patient outcome, in contrast to response assessed in the ovary, and the omentum is the site of choice for chemotherapy response scoring. Reporting the CRS in the ovary, if available, is also encouraged.

Cytology

Cytologic examination of ascitic fluid or abdominal/pelvic peritoneal washings is part of the formal staging of ovarian epithelial carcinoma. Positive peritoneal cytologic preparations (seen in up to 95% of cases) are characterized by loose papillary aggregates and/or tight clusters of cells with cytoplasmic vacuolization and hyperchromatic and/or pleomorphic nuclei ( Fig. 14.18D ). Fine-needle aspiration is indicated only for the diagnosis of an inoperable cancer or confirmation of suspected recurrent disease.

Immunohistochemistry

Serous carcinomas are positive for CK7, PAX8, WT1, Ber-EP4, and CD15 (Leu-M1) but negative for CK20. In addition, high-grade serous carcinomas usually exhibit abnormal p53 expression, defined as strong, diffuse nuclear staining in ≥80% of tumor cells or complete absence of expression in tumor cells (null pattern). A third, and much less frequent, abnormal p53 pattern is cytoplasmic staining. There must be at least some p53 expression in adjacent normal cells in order to accurately interpret the null pattern of abnormal p53 expression. About 4% of tumors have wild type p53 staining pattern; these have TP53 mutations that do not translate into abnormal protein expression. ER expression is present in most tumors, although intensity and distribution vary.

Molecular Studies

Marked genomic instability, with complex karyotypic abnormalities and aneuploidy, is the norm.

High-grade serous carcinoma usually exhibits TP53 mutations and somatic or germline abnormalities of BRCA1 and/or BRCA2 or related genes. Detection of BRCA1/2 mutations may be useful to instate Poly ADP-ribose polymerase (PARP) inhibitor therapy, which is indicated in mutation carriers.

Gross Findings

Benign seromucinous tumors are composed of varying amounts of fibromatous stroma (when predominant, serous adenofibroma) and cysts (which are typically less prominent).