Pathologic and Immunohistochemical Distinction of
Metastatic Gastrointestinal Carcinomas in the Ovaries from Primary Ovarian Mucinous Tumors
Johns Hopkins Hospital
Frequencies and sites of origin of metastases in the ovary:
|Metastatic carcinomas account for approximately 15% of malignant neoplasms involving the ovary.|
|The most common primary sites include colorectum, breast, endometrium, stomach, cervix, pancreas, appendix, and biliary tract.|
|30% of metastatic cancers in the ovary present as possible primary ovarian neoplasms; 90% of these are derived from extragenital sites.|
|80% of ovarian metastases from extragenital sites are derived from gastrointestinal tract carcinomas.|
|Metastatic carcinomas derived from the gastrointestinal tract are the most common neoplasms to mimic a primary ovarian neoplasm.|
Distinction of primary ovarian mucinous neoplasms
from metastatic mucinous carcinomas involving the ovary:
|Metastatic mucinous carcinomas involving the ovary are more common than primary ovarian mucinous carcinomas.|
|Mucinous neoplasms pose the greatest difficulty because metastatic mucinous carcinomas and primary ovarian mucinous neoplasms can share gross and microscopic features. In addition, certain metastatic carcinomas have the same immunophenotype as primary ovarian mucinous tumors (see below).|
|The metastatic mucinous carcinomas that most frequently simulate primary ovarian mucinous tumors include pancreaticobiliary, colorectal, appendiceal, gastric, and endocervical.|
|The majority of ovaries that contain metastatic neoplasms are bilaterally involved (ranging from ~50-80%) and modestly enlarged ( ≤ 10 cm), whereas primary ovarian mucinous neoplasms are typically large (>10 cm), unilateral (>90%), and most often stage I. Therefore, the finding of bilateral ovarian involvement and/or extra-ovarian mucinous tumor strongly suggests that the ovarian tumor is metastatic from another site. However, metastases can be large and unilateral (ovarian metastases of colorectal adenocarcinomas have a greater tendency to be unilateral and large compared to metastases from other sites) and can simulate the histologic appearance of primary ovarian mucinous tumors (atypical proliferative mucinous tumors with intraepithelial carcinoma and mucinous carcinomas).|
|Metastases often have a nodular growth pattern in which the nodules involve the surface and/or superficial cortex of the ovary. The nodules are typically surrounded by preserved ovarian stroma, which is sometimes compressed by the nodules. This nodular pattern can be subtle in some cases and is best appreciated at very low magnification.|
|The presence of cysts does not reliably distinguish primary from metastatic tumors.|
|Hormonal symptoms (virilization) can result from metastatic mucinous adenocarcinomas and do not prove that the tumor is a primary ovarian sex cord-stromal tumor. This is particularly true for the Krukenberg tumor in which the hypercellular stroma can obscure the malignant signet ring cells and suggest a primary ovarian stromal tumor.|
Metastatic colorectal carcinoma
|Metastatic colorectal carcinoma has a tendency to produce larger, multicystic tumors that are unilateral more often than other metastases and thus can easily simulate the gross appearance of a primary ovarian tumor.|
|Sometimes colorectal carcinoma displays mucinous rather than the typical "endometrioid"-type differentiation and simulates a primary ovarian mucinous tumor histologically (atypical proliferative mucinous tumor with intraepithelial carcinoma or mucinous carcinoma).|
|A characteristic feature of metastatic colorectal carcinoma that assists in distinction from primary ovarian mucinous tumors is the presence of atypical glandular epithelium draped around the periphery of cystic spaces which are filled with dense, eosinophilic, necrotic cellular material ("garland pattern" with "dirty necrosis"). In addition, the mucinous epithelium typically displays greater cytologic atypia than most primary ovarian mucinous tumors.|
|The finding of abundant extracellular mucin containing floating glands or epithelial fragments of mucinous carcinoma is a feature of some metastatic colorectal carcinomas (and other metastatic gastrointestinal mucinous adenocarcinomas) and is distinctly unusual for a primary ovarian mucinous tumor.|
Metastatic pancreatic carcinoma
|Metastatic pancreatic carcinoma typically produces enlarged, multicystic ovarian tumors that simulate primary ovarian atypical proliferative mucinous tumors or mucinous carcinomas both grossly and histologically. These metastases are typically bilateral and tend to be somewhat smaller than primary ovarian mucinous tumors.|
|Metastatic pancreatic carcinoma often displays a spectrum of mucinous epithelium ranging from histologically bland (simulating cystadenoma) to proliferative with tufts and crypts (simulating atypical proliferative tumor) to carcinomatous (smaller infiltrative glands with cytologic atypia). This histologic spectrum suggests "tumor progression" within a primary ovarian mucinous tumor but is actually quite characteristic of metastatic pancreatic carcinoma. Thus, areas resembling mucinous cystadenoma and atypical proliferative mucinous tumor adjacent to areas of infiltrative well differentiated carcinoma do not necessarily represent a precursor tumor from which the carcinoma arose and thus do not prove that the carcinoma had its origin in the ovary.|
|The combination of a haphazard pattern of larger, often dilated bland glands composed of very low-grade mucinous epithelium admixed with foci of small, infiltrative, atypical glands and a nodular growth pattern are features that can help to distinguish metastatic pancreatic carcinoma from primary ovarian mucinous tumors. Primary ovarian mucinous tumors (atypical proliferative and well differentiated carcinoma) typically have a more regularly, organized growth pattern. The atypical proliferative tumors are characterized by mucinous cysts with peripheral crypts and intraglandular epithelial proliferation (tufts, papillae) and the well differentiated mucinous carcinomas more often have a confluent glandular pattern rather than haphazardly arranged infiltrative glands.|
Metastatic appendiceal mucinous tumors
|Appendiceal mucinous carcinomas can have a variety of histologic patterns and can demonstrate mixtures of these patterns. These include pure signet ring cell carcinomas (often Krukenberg type tumor), carcinomas with goblet cell carcinoid-type patterns of differentiation ("adenocarcinoid" type, sometimes with tubular Krukenberg tumor pattern), well differentiated mucinous carcinomas resembling primary ovarian atypical proliferative mucinous tumors and well differentiated carcinomas, and adenocarcinomas of typical colorectal type.|
|Low-grade mucinous tumors (adenomas) of the appendix can secondarily involve the ovaries in the clinical syndrome of pseudomyxoma peritonei (PMP). The ovarian tumors are usually bilateral and smaller than primary ovarian mucinous tumors, histologically low-grade, associated with extensive pseudomyxoma ovarii, and often demonstrate ovarian surface and/or superficial cortical involvement. Morphologic, immunohistochemical, and molecular genetic data support the concept that the ovarian tumors are secondarily derived form the appendiceal tumors in these cases.|
|The primary appendiceal tumors in both carcinoma cases and adenoma-associated PMP can be relatively small and inconspicuous whereas the ovarian tumors can be large and typically are responsible for the clinical presentation.|
Immunohistochemistry in the distinction of metastatic carcinomas
from primary ovarian neoplasms
|No single antibody is entirely specific for tumors of ovarian origin and it is best to use a panel of antibodies to evaluate a given tumor.|
|The most common immunophenotypes (with frequencies of positivity) for tumors in the common differential diagnoses are listed in the tables below.|
|Cytokeratins 7 (CK 7) and 20 (CK 20) are very useful in certain situations (colon versus ovary) and not helpful in others (ovary versus pancreas).|
|Primary ovarian mucinous tumors (atypical proliferative and carcinoma) are always diffusely positive for CK 7 and are variably positive for CK 20—the rare exception is mucinous tumors arising in ovarian mature cystic teratomas, which are CK 20-positive and CK 7-negative).|
|For those tumors that can share expression of CK 7 and/or CK 20, the patterns of staining for CK 7 and CK 20 can be helpful for suggesting that one primary site is more likely than the other. Primary ovarian mucinous tumors are always diffusely positive (staining of 100% of the tumor cells) for CK 7 and are variably positive for CK 20 (most often positive, often with patchy rather than diffuse staining). Appendiceal adenomas and colon carcinomas are usually negative for CK 7 and diffusely positive for CK 20. Some appendiceal adenomas (~20%), a higher percentage of appendiceal carcinomas (~40%), and a small percentage of colon carcinomas can express CK 7 but the staining pattern is almost always patchy rather than diffuse. The patchy staining can be strong and involve more than 50% of the tumor but it is not 100% in these tumors, with the exception of some appendiceal carcinomas. Therefore, positivity for CK 7 should not be considered either proof of ovarian origin or evidence against intestinal origin without considering the staining distribution in the tumor. In addition, it is critical to avoid letting immunohistochemical results determine that the ovary is the site of origin when the morphology clearly favors a metastasis (for example, CK 7-positive signet ring cell carcinoma from the appendix or colon carcinoma with patchy strong positivity for CK 7).|
|Dpc4 is a relatively new marker that is expressed by all primary ovarian mucinous tumors but expression is lost in ~50% of metastatic pancreatic carcinomas. Thus, lack of staining with Dpc4 distinguishes metastatic pancreatic carcinoma from primary ovarian mucinous tumors. This is useful because both ovarian and pancreatic mucinous tumors share the same pattern of CK 7 and CK 20 expression (diffuse positivity for CK 7 and variably positivity for CK 20). In addition, loss of Dpc4 expression appears to be rather specific for pancreatic carcinomas since colorectal, appendiceal, gastric, and endocervical carcinomas appear to retain expression.|
|Cdx2 is useful for distinguishing ovarian serous and endometrioid carcinomas from metastatic colorectal carcinomas but does not distinguish the latter from ovarian mucinous carcinomas.|
|CA125 is produced by some adenocarcinomas from many nongynecologic sites and thus immunoreactivity is not specific to ovarian tumors.|
Ovary versus colon:
|Tumor type || CK 7|| CK 20|
|Ovary: non-mucinous || Positive (100%)|| Negative (70-100%)|
|Ovary: mucinous || Positive (100%)|| Positive (70%)|
|Colon|| Negative (90%)|| Positive (75-85%)|
Ovary versus pancreas:
|Tumor type || CK 7 || CK 20|| Dpc4|
|Ovary: mucinous || Positive (100%)|| Positive (70%)|| Positive (100%)|
|Pancreas ||Positive (95%)|| Positive (75%)|| Negative (50%)|
Ovary versus stomach:
|Tumor type || CK 7 ||CK 20|
|Ovary: mucinous || Positive (100%)|| Positive (70%)|
|Stomach || Positive (75%)|| Positive (45%)|
Ovary versus appendix:
|Tumor type || CK 7|| CK 20|
|Ovary: mucinous || Positive (100%)|| Positive (70%)|
|Appendix: adenoma ||Negative (80%)|| Positive (100%)|
|Appendix: carcinoma || Negative (60%)|| Positive (100%)|
Percentages listed in the tables are based on studies of both primary and metastatic GI
adenocarcinomas; some reflect combined results from several studies with rounding to the nearest 5% or
10% value for practical purposes and some are reported as ranges to reflect different results from
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