Introduction

The distinction between primary and secondary tumors of the ovary is one of the more difficult morphologic dilemmas in gynecologic pathology, because there are similarities in both clinical and histologic features in many cases. The reported frequency of metastatic tumors in the ovary varies with the study design (e.g., autopsy vs. surgical material) and the country of origin ( Table 28.1 ); however, it ranges between 15% and 25% of all malignancies involving the ovary. Among cases that clinically or pathologically mimic a primary ovarian tumor, most originate from the endometrium, the gastrointestinal tract, the pancreas, and the breast. Metastases to the ovary connote a poor prognosis, with overall 5-year survival of approximately 20%.

Gross Evaluation of Ovarian Masses

Gross pathologic analysis can often be helpful in distinguishing a primary ovarian from a metastatic tumor to the ovary. This subject is discussed more fully in Chapter 25 , but here is a brief summary:

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  Primary mucinous tumors of the ovary are often larger (frequently 10 cm to 30 cm) than metastatic mucinous tumors, which are often 10 cm or less in greatest dimension.

  
  
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  Metastatic neoplasms often affect both ovaries, whereas most primary ovarian neoplasms are unilateral, except for high-grade serous carcinomas, which are often bilateral and unlikely to be confused with metastatic disease.

  
  
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  Multinodular cortical involvement and surface implants can be suggestive of a metastasis.

  
  
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  Homogeneous expansion of the ovarian parenchyma without cyst formation occurs with metastatic breast cancer, signet ring cell tumors, and lymphomas, and it is less common in primary epithelial ovarian carcinomas.

  
  
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  Large tumors with conspicuous necrosis and hemorrhage are common in metastatic colonic carcinomas (which are frequently bilateral).

Metastatic Tumors From the Gynecologic Tract

Metastatic Uterine Sarcoma

The frequency of a uterine leiomyosarcoma metastasizing to the ovary is only 3.9%. Metastatic endometrial stromal sarcomas is also infrequent. In a series of 10 metastatic endometrial stromal sarcomas, only one involved the ovary ( Fig. 28.1 ). Nevertheless, if one encounters either a leiomyosarcoma or an endometrial stromal sarcoma in the ovary, a metastasis from the uterus (possibly remote or unrecognized) should always be excluded before making a primary diagnosis.

Metastatic low-grade endometrial stromal sarcoma with bland nuclei and prominent spiral arterioles.

Metastatic Cervical Carcinoma

Cervical carcinomas metastasize to the ovary in less than 5% of cases, with the majority of these being adenocarcinomas. Regardless, as endocervical and endometrioid carcinomas of the ovary have morphological overlap, the former should be considered when an adenocarcinoma is encountered in the ovary, especially in a younger woman with or without a history of a cervical primary carcinoma. The primary tumor is usually unremarkable ( Fig. 28.2A ), but when cervical carcinoma involves the ovary, it often lacks gross and microscopic features classically seen in metastatic disease. The tumor may be cystic, and the ovarian surface is often smooth (33%), disease is often unilateral (55%), and mass size can be larger than 10 cm (25%) (see Fig. 28.2B ). Nevertheless, there are morphologic features/clues that suggest a cervical primary, including high nuclear grade, luminal cytoplasmic eosinophilia with apically situated mitoses, and minimal stratification (see Fig. 28.2C ). Patterns resembling mucinous and intestinal carcinomas may also be seen (see Fig. 28.2D and E ). In rare cases, extensive adenocarcinoma in situ or minimally invasive cervical adenocarcinomas have been documented to spread to the ovary. Human papillomavirus (HPV) analysis of the ovarian tumor is a valuable adjunct in difficult cases, because metastatic cervical adenocarcinomas are positive for high-risk HPV, and primary ovarian carcinomas are not. The pathologist should be aware of the possibility of tubal involvement; the presence of diffuse and strong p16 is supportive of a cervical primary (see Fig. 28.2F ). It should be noted that serous and endometrioid carcinomas in the ovary can also express diffuse and patchy p16, respectively, so that such results would require additional morphologic and clinical correlation.

Metastatic cervical adenocarcinoma. A, A high-grade tumor, with both glandular and more solid areas. Note the juxtaposition of both eosinophilic areas (mucin) and high-grade nuclei. B, A sectioned fixed cystic ovarian tumor found to be a metastatic cervical adenocarcinoma. C, A well-differentiated metastatic adenocarcinoma. D, Note the apical eosinophilia with suspended mitoses. E, Metastatic cervical adenocarcinoma with an intestinal pattern. F, Metastatic cervical adenocarcinoma involving tubal mucosa. There is strong staining for p16 (inset).

Metastatic Tumors From the Gastrointestinal and Pancreaticobiliary Tracts

Gastrointestinal carcinomas and carcinoid tumors can metastasize to the ovaries and may be difficult to distinguish from primary ovarian tumors, both histologically and immunohistochemically.

Gastric Carcinoma

The most common pattern of metastatic gastric carcinoma is the signet ring carcinoma (so called Krukenberg tumor ). However, Krukenberg tumors may also originate in the intestine (including the appendix), breast, pancreas, or biliary tract. The majority of cases present with symptoms related to a pelvic mass, because the primary lesion may be occult. Tumors are usually bilateral solid masses that grossly demonstrate a mucoid, glistening cut surface ( Fig. 28.3 ). The signet ring cells are filled with cytoplasmic mucin ( Fig. 28.4A ) and may be present as scattered single cells or in tubular or glandular patterns (tubular Krukenberg tumor) (see Fig. 28.4B ). A subset of cases may contain a prominent spindled cellular stroma. The differential diagnosis for signet ring cell carcinomas in the ovary includes a primary ovarian carcinoma with focal Krukenberg-like areas arising in a background of a more characteristic pattern, such as a mucinous (most common) or endometrioid carcinoma. Pure signet ring cell carcinomas of the ovary exist but are exceedingly rare. When encountering a pure signet ring cell carcinoma in the ovary, a metastasis should always be excluded, and additional sampling should be considered if no classic variant of ovarian carcinoma is identified. In cases with a prominent stroma, the differential diagnosis may also include a luteinized thecoma or a sclerosing stromal tumor. In difficult cases, a mucin stain and/or a keratin immunostain may be useful to accentuate the malignant cells. Cytokeratin 7 (CK7) and CK20 can show overlapping staining patterns in gastric and ovarian tumors and have limited utility in this distinction. The use of MUC antibodies has been proposed to help distinguish gastrointestinal and ovarian mucinous tumors, but none are entirely sensitive or specific.

Gross photograph of metastatic gastric carcinoma (Kruken-berg tumor) with characteristic uniform consistency and replacement of the ovarian cortex.

A, Metastatic gastric carcinoma (Krukenberg tumor) with numerous signet ring cells. B, Metastatic gastric carcinoma (Krukenberg tumor) with signet ring cells in cords and trabeculae.

Colorectal Carcinoma

Colorectal carcinomas are the most common gastrointestinal primary site of origin for a metastasis to the ovary. They characteristically mimic primary endometrioid carcinomas, and awareness of a colonic tumor can help avoid a serious diagnostic error. This topic is reviewed fully in Chapter 25 in the sections on the differential diagnosis of endometrioid and mucinous ovarian carcinomas. Briefly, metastatic colonic carcinomas are typically bilateral (in less than 50% of cases), large, and necrotic ( Fig. 28.5 ). The characteristic histologic findings are garland and cribriform arrangements of pseudostratified epithelial cells with high nuclear grade (greater than that seen in well-differentiated endometrioid adenocarcinomas) and segmental epithelial necrosis with nuclear debris in cystic spaces (“dirty necrosis”) ( Fig. 28.6A and B ). Nuclear staining with beta-catenin is also more frequently observed in colorectal adenocarcinomas (see Fig. 28.6C ). As opposed to primary endometrioid ovarian carcinomas, which are typically positive for CK7 and negative for CK20, CDX-2, and SATB2, most colorectal carcinomas are characteristically negative for CK7, and positive for CK20, CDX-2, and SATB2 (see Fig. 28.6D , Table 28.2 ; also see Chapter 25 ). The presence of PAX8 can be helpful for distinguishing a primary versus metastatic colorectal carcinomas, because it is positive in a subset of endometrioid/mucinous ovarian carcinomas (≈25%) but is negative in colorectal adenocarcinomas (overall, high specificity, but low sensitivity).

Gross photograph of metastatic colon carcinoma. Note the hemorrhagic and focally necrotic cystic and solid mass.

A and B, Metastatic colon carcinoma with a garland-like gland pattern and “dirty necrosis.” C, Beta-catenin stain showing focal nuclear positivity in metastatic colon carcinoma (primary ovary carcinoma would have only cell membrane staining). D, SATB2 staining is quite specific for this tumor.

Table 28.2

Biomarker Expression in Primary and Metastatic Tumors Involving the Ovary

	Ovary a	Uterine a	Colon	Gastric	Appendix	Pancreas	Breast	Lung
CK7	100	100	10	75	30	95	100	70-100
CK20	43	15	95-100	45	96	75	0	0-10
B-CAT(N)	0-10	48	60-100	63	9
SATB2	0-5	0-15	71-100	0	80	0	0-15	0-17
CDX-2 b	10-30	7	90-100	12-50	100	15-60	0	0-30
MUC-2 b	10-38	0	60-100	50	96	0-100	15	4
MUC5AC b	100	14-31	25-40	55-100	85-100	73-92	37	50-100
SMAD4 (intact)			95	17-45	75	50-80
GATA3	0-22 c	0-2	0	0		0	70-100	<1
PAX8	35-100	38-70	0	0	0	0-5	0	0
WT1	0-87	10					2	0-30
TTF1	5	0-23	0	0	0	0	0	10-70

 

^a Percentages vary with tumor subtype.

Data from Liu H, Shi J, Wilkerson ML, et al: Immunohistochemical evaluation of GATA3 expression in tumors and normal tissues: a useful immunomarker for breast and urothelial carcinomas. Am J Clin Pathol 138(1):57-64, 2012; Ordóñez NG: Value of GATA3 immunostaining in tumor diagnosis: a review. Adv Anat Pathol 20(5):352-360, 2013; Dragomir A, de Wit M, Johansson C, et al: The role of SATB2 as a diagnostic marker for tumors of colorectal origin: results of a pathology-based clinical prospective study. Am J Clin Pathol 141(5):630-638, 2014; Moh M, Krings G, Ates D, et al: SATB2 expression distinguishes ovarian metastases of colorectal and appendiceal origin from primary ovarian tumors of mucinous or endometrioid type. Am J Surg Pathol 40(3):419-432, 2016.

b Percentage of staining increases in mucinous tumors.

c Positivity was reported mainly in transitional cell carcinoma, proliferating Brenner tumor, and benign Brenner tumor.

Tumors of the Small Bowel

Metastases from the small intestine are most often carcinoid tumors. In the largest series of cases, 40% of the patients had carcinoid syndrome, and most also had extraovarian metastases. The tumors are usually bilateral solid masses with a smooth surface and a white or yellow nodular cut surface. Microscopically, metastatic carcinoids are typically of the insular type ( Fig. 28.7 ), but they may also demonstrate other patterns. Acinar-like spaces typically form at the periphery of the islands; and in some cases, there are rounded nests of cells with many goblet cells accompanying the carcinoid cells (goblet cell carcinoid). A prominent fibromatous stroma is often present. The differential diagnosis includes primary carcinoid tumors, Sertoli cell tumors, granulosa cell tumors, and benign or malignant primary ovarian endometrioid adenofibromas. Special stains for neuroendocrine markers confirm the diagnosis of carcinoid. An absence of other germ cell tumor elements and bilateral tumors strongly indicates a metastatic process. Of note, about 20% of small bowel carcinoid tumors are immunoreactive with PAX8, and therefore this marker is not helpful in distinguishing primary and metastatic carcinoid tumors of the ovary. Metastatic small bowel tumors with a prominent clear cell component are a rare source of confusion with a primary clear cell carcinoma or a secretory endometrioid carcinoma of the ovary ( Fig. 28.8 ).

Metastatic insular carcinoid tumor from the small bowel.

Metastatic clear cell carcinoma from the small bowel. The morphology is similar to early secretory endometrium.

Appendiceal Carcinoma

The subject of metastatic low-grade appendiceal mucinous tumors to the ovary in the setting of pseudomyxoma peritonei is extensively reviewed in Chapter 25 in the section on mucinous ovarian tumors. In the absence of pseudomyxoma peritonei, appendiceal tumors that spread to the ovaries range from the goblet cell carcinoid to intestinal, colloid, or signet ring cell patterns ( Fig. 28.9 ). This diverse array of patterns often leads to confusion with primary ovarian mucinous carcinomas or with metastatic mucinous carcinomas from other sites. This is especially true, because appendiceal lesions may be small and occult, even in the presence of large ovarian masses. Immunohistochemistry may aid in differentiating secondary appendiceal carcinomas (see Table 28.2 ) from primary ovarian carcinomas, because most ovarian mucinous carcinomas are CK7 diffusely positive and CK20 negative to patchy, whereas most appendiceal carcinomas are CK20 diffusely positive and demonstrate variable (often focal or negative) staining for CK7. In addition, MUC-2 and CDX-2 are positive in mucinous appendiceal carcinomas and negative or only focally positive in mucinous ovarian carcinomas ( Fig. 28.10 ). SATB2 is positive in appendiceal tumors and only rarely present in mucinous ovarian carcinomas. Again, the presence of PAX8 in mucinous tumors supports an ovarian primary (although sensitivity is only about 30%) over a metastasis, because appendiceal carcinomas are negative for this marker.

A, Metastatic appendiceal carcinoma with a villous papillary pattern. B, Metastatic mucinous (colloid) appendiceal carcinoma. C, Metastatic appendiceal carcinoma with numerous signet ring cells.

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