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 different reports.

References

1. Berezowski K, Stastny JF, Kornstein MJ. Cytokeratins 7 and 20 and carcinoembryonic antigen in ovarian and colonic carcinoma. Mod Pathol 1996;9:426-429.
2. Bullon A Jr, Arseneau J, Prat J, Young RH, Scully RE. Tubular Krukenberg tumor. A problem in histopathologic diagnosis. Am J Surg Pathol 1981;5:225-232.
3. Copeland S, Colvin S. The Krukenberg Tumor. A critique, with the report of an additional four cases, including the smallest on record. Am J Obstet Gynecol 1943;45:59-68.
4. Daya D, Nazerali L, Frank GL. Metastatic ovarian carcinoma of large intestinal origin simulating primary ovarian carcinoma. A clinicopathologic study of 25 cases. Am J Clin Pathol 1992;97:751-758.
5. Demopoulos RI, Touger L, Dubin N. Secondary ovarian carcinoma: a clinical and pathological evaluation. Int J Gynecol Pathol 1987;6:166-175.
6. Diddle A. Krukenberg tumors: diagnositc problem. Cancer 1955;8:1026-1034.
7. Fujiwara K, Ohishi Y, Koike H, Sawada S, Moriya T, Kohno I. Clinical implications of metastases to the ovary. Gynecol Oncol 1995;59:124-128.
8. Groisman GM, Meir A, Sabo E. The value of Cdx2 immunostaining in differentiating primary ovarian carcinomas from colonic carcinomas metastatic to the ovaries. Int J Gynecol Pathol 2004;23:52-57.
9. Guerrieri C, Franlund B, Boeryd B. Expression of cytokeratin 7 in simultaneous mucinous tumors of the ovary and appendix. Mod Pathol 1995;8:573-576.
10. Guerrieri C, Franlund B, Fristedt S, Gillooley JF, Boeryd B. Mucinous tumors of the vermiform appendix and ovary, and pseudomyxoma peritonei: histogenetic implications of cytokeratin 7 expression. Hum Pathol 1997;28:1039-1045.
11. Hale R. Krukenberg tumor of the ovaries. A review of 81 records. Obstet Gynecol 1968;32:221-225.
12. Hoerl HD, Hart WR. Primary ovarian mucinous cystadenocarcinomas. Am J Surg Pathol 1998;22:1449-1462.
13. Holtz F, Hart WR. Krukenberg tumors of the ovary: a clinician analysis of 27 cases. Cancer 1982;50:2438-2447.
14. Ji H, Isacson C, Seidman JD, Kurman RJ, Ronnett BM. Immunohistochemistry for cytokeratins 7 and 20, Dpc4, and MUC5AC in the distinction of metastatic mucinous carcinomas in the ovary from primary ovarian mucinous tumors: Dpc4 assists in the identification of metastatic pancreatic carcinomas. Int J Gynecol Pathol 2002;21:391-400.
15. Joshi V. Primary Krukenberg tumor of the ovary. Review of literature and case report. Cancer 1968;22:1199-1207.
16. Karsh J. Secondary malignant disease of the ovaries. Am J Obstet Gynecol 1951;61:154-160.
17. Krukenberg F. Ueber das Fibrosarcoma ovarii mucocellulare (carcinomatodes). Arch Gynakol 1896;50:287-321.
18. Lagendijk JH, Mullink H, Van Diest PJ, Meijer GA, Meijer CJ. Tracing the origin of adenocarcinomas with unknown primary using immunohistochemistry: differential diagnosis between colonic and ovarian carcinomas as primary sites. Hum Pathol 1998;29:491-497.
19. Lash RH, Hart WR. Intestinal adenocarcinomas metastatic to the ovaries. A clinicopathologic evaluation of 22 cases. Am J Surg Pathol 1987;11:114-121.
20. Lee KR, Scully RE. Mucinous tumors of the ovary: a clinicopathologic study of 196 borderline tumors (of intestinal type) and carcinomas, including an evaluation of 11 cases with "pseudomyxoma peritonei". Am J Surg Pathol 2000;24:1447-1464.
21. Lee KR, Young RH. The distinction between primary and metastatic mucinous carcinomas of the ovary: gross and histologic findings in 50 cases. Am J Surg Pathol 2003;27:281-292.
22. Leffel J, Dockerty M. Krukenberg's tumors. A survey of forty-four cases. Ann Surg 1942;115:102-113.
23. Loy TS, Calaluce RD, Keeney GL. Cytokeratin immunostaining in differentiating primary ovarian carcinoma from metastatic colonic adenocarcinoma. Mod Pathol 1996;9:1040-1044.
24. Loy TS, Quesenberry JT, Sharp SC. Distribution of CA 125 in adenocarcinomas. An immunohistochemical study of 481 cases. Am J Clin Pathol 1992;98:175-179.
25. Mazur MT, Hsueh S, Gersell DJ. Metastases to the female genital tract. Analysis of 325 cases. Cancer 1984;53:1978-1984.
26. Merino MJ, Edmonds P, LiVolsi V. Appendiceal carcinoma metastatic to the ovaries and mimicking primary ovarian tumors. Int J Gynecol Pathol 1985;4:110-120.
27. Moll R, Lowe A, Laufer J, Franke WW. Cytokeratin 20 in human carcinomas. A new histodiagnostic marker detected by monoclonal antibodies. Am J Pathol 1992;140:427-447.
28. Novak E, Gray L. Krukenberg tumors of the ovary. Clinical and pathological study of 21 cases. Surg Gynecol Obstet 1938;66:157-165.
29. Park SY, Kim HS, Hong EK, Kim WH. Expression of cytokeratins 7 and 20 in primary carcinomas of the stomach and colorectum and their value in the differential diagnosis of metastatic carcinomas to the ovary. Hum Pathol 2002;33:1078-1085.
30. Prayson RA, Hart WR, Petras RE. Pseudomyxoma peritonei. A clinicopathologic study of 19 cases with emphasis on site of origin and nature of associated ovarian tumors. Am J Surg Pathol 1994;18:591-603.
31. Ramaekers F, van Niekerk C, Poels L, Schaafsma E, Huijsmans A, Robben H, Schaart G, Vooijs P. Use of monoclonal antibodies to keratin 7 in the differential diagnosis of adenocarcinomas. Am J Pathol 1990;136:641-655.
32. Riopel MA, Ronnett BM, and Kurman RJ. Evaluation of diagnostic criteria and behavior of ovarian intestinal-type mucinous tumors: borderline, microinvasive, invasive and metastatic. Am J Surg Pathol 1999;23:617-635.
33. Rodriguez IM, Prat J. Mucinous tumors of the ovary: a clinicopathologic analysis of 75 borderline tumors (of intestinal type) and carcinomas. Am J Surg Pathol 2002;26:139-152.
34. Ronnett BM, Kurman RJ, Zahn CM, Shmookler BM, Jablonski K, Kass M, Sugarbaker PH. Pseudomyxoma peritonei in women: a clinicopathologic analysis of 30 cases with emphasis on site of origin, prognosis, and relationship to ovarian mucinous tumors of low malignant potential. Hum Pathol 1995;26:509-524.
35. Ronnett BM, Zahn CM, Kurman RJ, Kass ME, Sugarbaker PH, Shmookler BM. Disseminated peritoneal adenomucinosis and peritoneal mucinous carcinomatosis. A clinicopathologic analysis of 109 cases with emphasis on distinguishing pathologic features, site of origin, prognosis, and relationship to "pseudomyxoma peritonei". Am J Surg Pathol 1995;19:1390-1408.
36. Ronnett BM, Shmookler BM, Diener-West M, Sugarbaker PH, Kurman RJ. Immunohistochemical evidence supporting the appendiceal origin of pseudomyxoma peritonei in women. Int J Gynecol Pathol 1997;16:1-9.
37. Ronnett BM, Kurman RJ, Shmookler BM, Sugarbaker PH, Young RH. The morphologic spectrum of ovarian metastases of appendiceal adenocarcinomas. A clinicopathologic and immunohistochemical analysis of tumors often misinterpreted as primary ovarian tumors or metastatic tumors from other gastrointestinal sites. Am J Surg Pathol 1997;21:1144-1155.
38. Ronnett BM, Yan H, Kurman RJ, Shmookler BM, Wu L, Sugarbaker PH. Pseudomyxoma peritonei associated with disseminated peritoneal adenomucinosis has a significantly more favorable prognosis than peritoneal mucinous carcinomatosis. Cancer 2001;92:85-91.
39. Ronnett BM, Seidman JD. Mucinous tumors arising in ovarian mature cystic teratomas: relationship to the clinical syndrome of pseudomyxoma peritonei. Am J Surg Pathol 2003; 27:650-657.
40. Seidman JD, Kurman RJ, Ronnett BM. Primary and metastatic mucinous adenocarcinomas in the ovaries: incidence in routine practice with a new approach to improve intraoperative diagnosis. Am J Surg Pathol 2003;27:985-993.
41. Szych C, Staebler A, Connolly DC, Wu R, Cho KR, Ronnett BM. Molecular genetic evidence supporting the clonality and appendiceal origin of pseudomyxoma peritonei in women. Am J Pathol 1999;154:1849-1855.
42. Ueda G, Sawada M, Ogawa H, Tanizawa O, Tsujimoto M. Immunohistochemical study of cytokeratin 7 for the differential diagnosis of adenocarcinomas in the ovary. Gynecol Oncol 1993;51:219-223.
43. Ulbright T, Roth L, Stehman F. Secondary ovarian neoplasia. A clinicopathologic study of 35 cases. Cancer 1984;53:1164-1174.
44. Wang N, Zee S, Zarbo R, Bacchi C, Gown A. Coordinate expression of cytokeratins 7 and 20 defines unique subsets of carcinomas. Appl Immunohistochem 1995;3:99-107.
45. Wauters CC, Smedts F, Gerrits LG, Bosman FT, Ramaekers FC. Keratins 7 and 20 as diagnostic markers of carcinomas metastatic to the ovary. Hum Pathol 1995;26:852-855.
46. Wong PC, Ferenczy A, Fan LD, McCaughey E. Krukenberg tumors of the ovary. Ultrastructural, histochemical and immunohistochemical studies of 15 cases. Cancer 1986;57:751-760.
47. Woodruff J, Novak E. The Krukenberg tumor. Study of 48 cases from the Ovarian Tumor Registry. Obstet Gynecol 1960;15:351-360.
48. Young RH, Gilks CB, Scully RE. Mucinous tumors of the appendix associated with mucinous tumors of the ovary and pseudomyxoma peritonei. A clinicopathological analysis of 22 cases supporting an origin in the appendix. Am J Surg Pathol 1991;15:415-429.
49. Young RH, Hart WR. Metastases from carcinomas of the pancreas simulating primary mucinous tumors of the ovary. A report of seven cases. Am J Surg Pathol 1989;13:748-756.
50. Young RH, Hart WR. Metastatic intestinal carcinomas simulating primary ovarian clear cell carcinoma and secretory endometrioid carcinoma. A clinicopathologic and immunohistochemical study of five cases. Am J Surg Pathol 1998;22:805-815.
51. Young RH, Scully RE. Mucinous ovarian tumors associated with mucinous adenocarcinomas of the cervix. A clinicopathological analysis of 16 cases. Int J Gynecol Pathol 1988;7:99-111.
52. Young RH, Scully RE. Ovarian metastases from carcinoma of the gallbladder and extrahepatic bile ducts simulating primary tumors of the ovary. A report of six cases. Int J Gynecol Pathol 1990;9:60-72.
53. Young RH and Scully RE. Metastatic tumors of the ovary. In: Kurman, RJ. Blaustein's Pathology of the Female Genital Tract. 5^th ed., 2002. New York: Springer-Verlag.