Metastatic and Miscellaneous Primary Neoplasms of the Ovary

Gross Findings

Characteristic gross features of metastases in the ovaries include smaller size (often <10 cm), bilateral involvement, nodular growth, and the presence of tumor on the ovarian surface. Nodular tumors are typically solid or solid and cystic secondary to necrosis; however, it is important to be aware that metastases can be large (>13 cm), unilateral, and cystic, simulating a primary ovarian neoplasm.

As with any ovarian mass, representative sampling of all tumor areas is required, including solid and cystic components, the interface with necrotic and hemorrhagic areas, and the ovarian surface. This is particularly important for mucinous tumors, since many of the features indicative of metastasis are present only focally in this tumor category. Thus, it is generally recommended that mucinous ovarian tumors undergo extensive sampling (at a ratio of one section per centimeter of tumor greatest dimension in tumors less than 10 cm, and two sections per centimeter if the tumor is 10 cm or more in size).

Microscopic Findings

Characteristic histologic features of metastases include nodular architecture with multifocal involvement of the ovarian surface and superficial cortex, hilar, and lymph-vascular spaces. Most metastases have infiltrative growth and stromal desmoplasia. However, some have a confluent glandular or expansile growth simulating either a primary ovarian borderline tumor with intraepithelial carcinoma or a well-differentiated carcinoma, usually of mucinous or endometrioid type. The presence of signet-ring cells strongly suggests metastases, most commonly of gastrointestinal or breast origin. Certain other histologic features are characteristic of particular types of metastatic carcinomas, such as a garland pattern of epithelium surrounding so-called “dirty necrosis” in metastatic colorectal carcinoma. Histologically, benign-appearing and low-grade proliferative mucinous epithelium, simulating cystadenomata and borderline tumor, is characteristic of metastatic mucinous neoplasms of the cecal appendix. Similarly, bland mucinous proliferations associated with stromal luteinization can be seen in metastatic carcinomas of pancreaticobiliary origin.

Clinical Features

Metastases of colorectal adenocarcinoma represent the most common metastatic tumor to the ovary. Most patients have a primary in the rectosigmoid. Patients are typically in their fifth to ninth decades, but occasionally, they can be younger. In some instances, the adnexal mass(es) occurs in patients with a known diagnosis of colorectal carcinoma, but in others (up to 30%), the adnexal mass(es) is the first manifestation of a synchronously or subsequently identified colorectal carcinoma, the latter posing a diagnostic challenge at the time of frozen section evaluation. Patients most commonly present with pelvic or abdominal pain or signs and symptoms related to a colorectal primary, such as rectal bleeding or symptoms of obstruction.

Pathologic Features

Gross Findings

Tumors are bilateral in 25%–60% of patients, with median sizes ranging from 11 cm to 15 cm. The cut surfaces are variably solid and cystic ( Fig. 17.1 ), and hemorrhage and necrosis are common.

Microscopic Findings

Colorectal adenocarcinomas are composed of variably sized glands, ranging from small to large and cystically dilated ( Fig. 17.2 ), or can display complex architecture with cribriforming or papillary patterns ( Fig. 17.3 ). The cells lining the glands are typically columnar, nonstratified, or multilayered and of an “endometrioid” (more frequently) or mucinous appearance, the latter ranging from focal to predominant and diffuse ( Fig. 17.4A,B ). Occasionally, the tumors are associated with abundant extracellular mucin ( Fig. 17.4C ) or have a significant signet-ring cell component. The nuclei are oval to columnar, showing notable cytologic atypia, and there is often brisk mitotic activity ( Fig. 17.5 ). A characteristic (but not pathognomic) histologic finding is the “garland pattern of dirty necrosis,” in which the epithelium is draped along the periphery of luminal eosinophilic necrotic material containing karyorrhectic debris ( Fig. 17.6A ), as well as segmental necrosis ( Fig. 17.6B ). The stroma can sometimes be desmoplastic or edematous, which helps establish the diagnosis of metastatic carcinoma. Stromal luteinization around the neoplastic glands is frequent and can be prominent and should not be interpreted as a sign of a sex cord-stromal ovarian neoplasm.

Ancillary Studies

Immunohistochemistry

Metastatic colorectal adenocarcinomas are typically diffusely and strongly positive for CK20 and CDX2. CK7 is frequently negative; if positive, it tends to be focal except in rectal and right-sided colonic adenocarcinomas, which may exhibit extensive CK7 positivity ( Fig. 17.7 ). CDX2 has limited value in distinguishing metastatic colorectal carcinoma from primary ovarian mucinous tumors; however, it is useful in the distinction from primary ovarian endometrioid carcinomas, which are often negative (with exceptions). SATB2, a transcriptional regulator involved in osteoblastic and neuronal differentiation, has been recently reported to be a relatively sensitive and specific marker for tumors of colorectal or appendiceal origin ( Fig. 17.8 ). Primary endometrioid and mucinous carcinomas of the ovary are negative for this marker, with the important exception of intestinal-type mucinous tumors that arise in the background of a mature cystic teratoma, which are SATB2 positive. Nuclear beta-catenin and MUC2 are positive. PAX8 and ER are negative.

Differential Diagnosis

Metastatic colorectal carcinomas can simulate primary endometrioid and mucinous tumors of the ovary grossly, microscopically, and immunophenotypically. Almost half are unilateral and >13 cm, features usually seen in a primary ovarian neoplasm. In general, there is a discordance between the simple architecture (well-formed glands) and the high-grade nuclear features in metastatic colorectal carcinoma, which contrasts with endometrioid carcinoma, in which the architecture and cytology tend to be concordant. Features favoring a primary endometrioid carcinoma include foci of squamous differentiation, an adenofibromatous background, and associated endometriosis. Furthermore, these tumors are typically positive for PAX8, ER, PR, and CK7 but usually negative for SATB2, CK20, and CDX2 (with exceptions). Beta-catenin is not useful in this differential diagnosis as it can be positive in both.

The distinction of predominantly mucinous metastatic colorectal carcinoma from primary mucinous ovarian neoplasms is more challenging. Ovarian borderline mucinous tumors have low-grade cytomorphology and, although they can display crowded glands, they lack the infiltration and atypical cytomorphology of metastatic colorectal carcinoma. Primary ovarian mucinous carcinomas frequently show benign or borderline components and the general features of metastases as described earlier are typically absent. However, overlap exists: metastases can be purely confluent glandular and primary ovarian mucinous carcinomas can be infiltrative. Compared to endometrioid carcinoma, the immunohistochemical profile of primary ovarian mucinous neoplasms has a greater overlap with that of gastrointestinal tract tumors. First, primary ovarian mucinous tumors are almost always negative for ER, and PAX8 expression is seen in 50%–65% of cases (thus, a significant proportion are negative) and expression may be weak. Unlike most colorectal carcinomas, primary ovarian mucinous tumors are positive for CK7 (patchy or diffuse) and negative for SATB2 and nuclear beta-catenin. CK20 and CDX2 expression tends to be focal in primary ovarian and diffuse in metastatic colorectal tumors. MUC2 and MUC5AC show considerable overlap in staining patterns. Some primary mucinous ovarian carcinomas are associated with a teratoma; if the teratomatous component is identified, it helps establish the tumor as primary. However, an important pitfall to keep in mind is that mucinous carcinomas arising in association with teratomas show an identical immunohistochemical profile to primary intestinal tumors, including positivity for SATB2.

Gross Findings

The tumors are frequently bilateral (80%), but if unilateral, there is a predilection for the right side. The tumor size varies and depends on the histologic type, being larger (usually >10 cm) in LAMN. Adenocarcinoma, especially if nonmucinous, is usually >5 cm. Metastatic carcinoid varies in size, with most measuring from 5 to 10 cm. LAMNs are typically multilocular, with cysts filled with abundant dense inspissated mucin ( Fig. 17.9 ); ovarian surface involvement by mucin deposits is common. Spread from appendiceal carcinoma typically has a solid ( Fig. 17.10 ) to solid and cystic cut surface, which is often gelatinous and can show extensive necrosis.

Microscopic Findings

Secondary involvement by LAMN typically shows irregularly shaped, cystically dilated glands with abundant intraluminal mucin. The glands often have undulating outlines and subepithelial clefting (separation of the mucinous epithelium from the underlying stroma). Shallow outpouchings (“scalloped borders”) are characteristic as well as tall “hypermucinous” cells, which are two to three times taller than conventional ovarian mucinous epithelium ( Fig. 17.11A ). The cells are cytologically bland, with mild to moderately atypical and well-polarized nuclei with only subtle nuclear stratification and infrequent mitotic activity. Acellular mucin often dissects through the stroma (“pseudomyxoma ovarii”) and involves the ovarian surface as well as peritoneal surfaces (“pseudomyxoma peritonei”) ( Fig. 17.11B ). Metastases of appendiceal carcinomas may be of the intestinal (with variable amounts of mucin), colloid, Krukenberg type, or mixtures thereof and show a variety of growths including individual signet-ring cells within a cellular stroma (Krukenberg tumor) to small- and medium-sized glands (intestinal) to single cells and nests floating in pools of mucin (colloid) ( Figs. 17.12–17.14 ). Tubules, cords, and trabeculae may also be seen. Cytologic atypia and brisk mitotic activity are common.

Immunohistochemistry

LAMNs are typically positive for SATB2, CK20, CDX2, and villin in a diffuse and strong fashion. CK7 may be variably positive but is usually focal. In general, MUC2 is typically positive, MUC1 and MUC5AC may be positive, and MUC6 is negative. Appendiceal adenocarcinomas also express CK20, CDX2 (diffusely), and SATB2. CK7 is more often negative, but it can be seen in approximately 40% of cases, including signet-ring cells, and may be patchy or diffuse (it is generally somewhat weaker than CK20 expression) ( Fig. 17.15A,B ). MUC2 is typically positive, MUC1 and MUC5AC may be positive, and MUC6 is negative.

Gross Findings

Tumors are commonly bilateral (80%) especially if poorly cohesive (signet-ring) cell carcinoma. Although size of tumors may be quite variable (up to 18 cm), the average is 6 cm for tubular (intestinal-type) and 10 cm for poorly cohesive (diffuse-type) carcinomas. Most signet-ring cell carcinomas are solid and bosselated with a multinodular cut surface that has alternating white to yellow and glistening areas ( Fig. 17.16 ). Foci of hemorrhage and necrosis are commonly present. In contrast, intestinal-type carcinomas are solid and cystic; the cysts can be quite large (up to 6 cm) and often filled with mucinous secretions or hemorrhage.

Microscopic Findings

Carcinoma metastatic from the stomach is usually of the poorly cohesive (diffuse signet-ring cell type). Thus, most metastatic gastric tumors fulfill the definition of Krukenberg tumor (metastatic adenocarcinoma with signet-ring cells that comprise >10% of the tumor). At low-power scrutiny, cellular and hypocellular areas often alternate, imparting a pseudolobular architecture. The former imparts a fibroma-like appearance ( Fig. 17.17A ), whereas the latter is secondary to edema and/or myxoid stroma. The neoplastic cells predominate in the hypercellular areas ( Fig. 17.17B ). Not infrequently, there is an abrupt transition between the two components ( Fig. 17.17C ). Classically, the signet-ring cells are arranged individually or in clusters; however, they may form glands ( Fig. 17.18A ), hollow or solid tubules, and trabeculae ( Fig. 17.18B ). Less commonly, an insular, lobular, or diffuse growth may be seen ( Fig. 17.19 ). Extracellular mucin is frequently conspicuous and may be admixed with acellular collagen. The presence of cellular fibromatous stroma with luteinization is common, especially in pregnant patients. Metastatic gastric carcinoma of tubular (intestinal type) is typically composed of medium to large tubular glands ( Fig. 17.20 ) that may be dilated and have a pseudoendometrioid appearance; other less common patterns include cribriform, trabecular, and insular. Metastatic gastric carcinoma of the papillary type may also occur. A minor (<10%) signet-ring cell component may be seen. Segmental and “dirty” necrosis is frequent. In either diffuse or intestinal-type carcinomas, the signet-ring cells typically have crescentic or oval hyperchromatic nuclei and abundant eosinophilic to vacuolated cytoplasm. Rarely, their cytoplasm may have a targetoid appearance (clear vacuole with central eosinophilic body; Fig. 17.19 ). Cystic areas of intestinal-type carcinomas may be lined by bland to highly atypical cells with variable amounts of mucin. Desmoplasia is variably present.

Immunohistochemistry

Strong CK7 expression is seen in most cases, along with CK8, CK19, and CDX2. CK20 and SATB2 show variable expression but tend to be positive (patchy). Focal positivity for chromogranin, NSE, and synaptophysin can be seen. Expression of mucins is variable, with MUC5AC being more consistently positive compared to MUC1, MUC4, and MUC6. Hormone receptors, PAX8, calretinin, inhibin, and SF1 are negative.

Gross Findings

The tumors are typically bilateral (75%–100%), often show surface involvement, and vary greatly in size, measuring up to 20 cm. The cut surfaces are more commonly solid and cystic but may be predominantly solid or multicystic. The solid areas range from white to tan or red and may be firm or spongy. Multicystic tumors filled with mucin are more often seen in metastases from the pancreas.

Microscopic Findings

At low power, surface involvement may be identified ( Fig. 17.21 ), and varying degrees of differentiation, ranging from “benign appearing” to frankly malignant, are present ( Fig. 17.22A–C ). Admixtures of simple or cystically dilated glands, complex glands (including cribriforming), villiform, complex papillae, or micropapillae are characteristic. Irregularly infiltrative and relatively small glands with desmoplastic stroma are also frequently seen. Metastatic pancreaticobiliary carcinoma most often displays mucinous differentiation, including goblet cells, and is characterized by cuboidal to columnar cells showing basal to pseudostratified nuclei with varying degrees of nuclear pleomorphism and mitotic activity ( Fig. 17.23A–C ). Occasionally, tumor is more poorly differentiated and contains signet-ring cells as well as minor foci of nests, trabeculae, and single cells free floating within pools of mucin (colloid carcinoma). Although rare, pseudomyxoma ovarii may occur. The nonmucinous component is nonspecific cuboidal to columnar, sometimes with pseudoendometrioid features including secretory or hobnail appearance. The stroma varies greatly both within and among tumors; the most common is a fibromatous appearance, but a desmoplastic to hyalinized or collagenous stroma may also be seen. Stromal luteinization may also occasionally occur.

Immunohistochemistry

Tumors are typically diffusely positive for CK7 and frequently positive for CDX2, CK8, CK17, CK18, and CK19; CK20 usually shows patchy staining. About 70% of tumors are CK7/CK20 positive, with the remainder showing a CK7-positive/CK20-negative profile. They are also positive for MUC1, MUC4, and MUC5AC. Dpc4 is inactivated (and consequently with loss of expression) in approximately 55% of pancreatic carcinomas and 35% of bile and ampullary carcinomas ( Fig. 17.24 ).

Gross Findings

In approximately two-thirds of cases, metastases are bilateral. The tumors are usually <5 cm, multinodular and solid ( Fig. 17.25 ); cystic and papillary tumors are unusual.

Microscopic Findings

A variety of patterns can be encountered that often merge, with ductal carcinomas often displaying glandular, papillary, cribriform, or diffuse growth(s), and lobular carcinomas exhibiting characteristic single-file, cords, trabeculae, insular, nests, and diffuse growth ( Figs. 17.26–17.29 ). The tumor cells tend to have pale to eosinophilic cytoplasm and display round to oval nuclei with variable nuclear enlargement (usually not prominent). The stroma, which varies in amount, can be fibromatous, collagenous or edematous. Signet-ring cells are more often seen in lobular carcinoma and, when extensively present, often show a diffuse or corded architecture and are associated with striking edema; however, extracellular mucin is not observed (unlike Krukenberg tumors from the gastrointestinal tract). Single cells and follicle-like structures may be seen.

Immunohistochemistry

Breast carcinomas are typically positive for CK7 and GATA3 ( Fig. 17.30 ) but negative for CK20 and PAX8. Expression of ER, PR, GCDFP-15 (BRST-2), and mammaglobin is more often seen in low- to intermediate-grade ductal carcinomas and in a significant number of lobular carcinomas. It is important to note that triple negative breast carcinomas can be negative for GATA3. GCDFP-15 positivity typically establishes the diagnosis of breast carcinoma (with rare exceptions), but negative staining does not exclude this diagnosis. Most tumors do not express WT1 (seen in ∼20%).

Gross Findings

The tumors are commonly unilateral, but may be bilateral (one-third), with a mean size of 10 cm. The external surface is typically smooth (surface involvement is rare) and intact, whereas the cut surface is firm or soft, lobulated, white to yellow/tan, hemorrhagic, and/or necrotic with secondary cyst formation, the latter feature more often seen in small cell carcinoma ( Fig. 17.31 ).

Microscopic Findings

Among all histologic subtypes of lung carcinoma, small cell carcinoma most commonly metastasizes to the ovary. The tumor cells may be arranged in sheets, trabeculae, or nests. They are small to intermediate in size and have a high nuclear-to-cytoplasmic ratio, hyperchromatic nuclei, nuclear molding, inconspicuous nucleoli, and brisk mitotic activity. Other histologic types include adenocarcinoma, large cell carcinoma not otherwise specified (NOS), and, rarely, squamous cell carcinoma ( Fig. 17.32–17.33 ).

Immunohistochemistry

Small cell carcinoma expresses low-molecular-weight cytokeratin (CK8/18), TTF1, chromogranin, synaptophysin, and CD56. TTF1 is also expressed in 75% of adenocarcinomas, which are also typically positive for CK7 and Napsin-A ( Figs. 17.34 and 17.35 ). Approximately half of large cell carcinomas express TTF1 and can be positive for Napsin-A, whereas squamous cell carcinomas are typically positive for CK5/6, p63, and p40 but negative for Napsin-A and TTF1.

Gross Findings

The majority of tumors are unilateral (mean 13 cm). They are frequently cystic but may have a solid component.

Microscopic Findings

The most common histologic type to metastasize to the ovary is papillary urothelial carcinoma, which is characterized by large papillae projecting into cystic spaces and lined by atypical (low- or high-grade) stratified epithelium. Infiltrating nests with central cystic change secondary to necrosis and desmoplastic stroma may also be seen ( Fig. 17.36 ). Importantly, these tumors may show squamous and/or glandular differentiation. The next most common histologic type is adenocarcinoma with signet-ring cells (signet-ring cell carcinoma), in which the cells infiltrate individually or form trabeculae or sheets; a minor glandular component can also be seen. Rarely, urachal adenocarcinoma (with variable degrees of mucinous differentiation) metastasizes to the ovaries and has the appearance of a mucinous carcinoma.

Immunohistochemistry

Urothelial carcinomas of the urinary bladder express CK7 and CK20, usually at significant levels ( Fig. 17.37 ). They also express GATA3, uroplakin, and thrombomodulin, but are negative for WT1 (N-terminus).

Gross Findings

Approximately 20% of tumors are bilateral, ranging from 7 cm to 18 cm. They are typically solid but may have a cystic component. The cut surface is nodular, tan, yellow or brown, and shows variable amounts of hemorrhage.

Microscopic Findings

Conventional (clear cell) carcinoma is the most common histologic subtype of renal cell carcinoma that metastasizes to the ovary. It is typically composed of nests or tubules, some cystically dilated, associated with a conspicuous sinusoidal vasculature ( Fig. 17.38 ). Alveolar and solid growth patterns may also be seen. The tumor cells are polyhedral, cuboidal, and/or columnar with abundant clear cytoplasm and nuclei of varying sizes ( Figs. 17.39 and 17.40 ). The tubules and cysts may contain colloid-like secretions or blood.