An In-depth Look at Krukenberg Tumor

An Overview
Osama M. Al-Agha, MD; Anthony D. Nicastri, MD

Krukenberg tumor is an uncommon metastatic tumor of the ovary. This article provides an overview of the major pathologic manifestations of Krukenberg tumor, patient characteristics, clinical and laboratory features of the disease, prognostic factors, and current knowledge about its pathogenesis. Pathologists have to be familiar with the diagnostic histopathologic features of the tumor and its principal differential diagnoses. Awareness of the diagnostic manifestations of the tumor leads to the correct diagnosis and prevents tumor misclassication, thus avoiding improper clinical management. The article also addresses the potential clinical utility of serum CA 125 in patients with Krukenberg tumors. Prognosis of Krukenberg tumor is still very poor but our review of the literature reveals several factors that appear to have an impact on survival. There is no established treatment for Krukenberg tumors. A national registry and prospective studies are needed to set a therapeutic approach for Krukenberg tumors in the hope of improving the survival rate. (Arch Pathol Lab Med. 2006;130:17251730)

and can escape detection. A history of a prior carcinoma of the stomach or another organ can be obtained in only 20% to 30% of the cases.2 It is well recognized that adenocarcinomas composed of signet ring cells of various organs tend to metastasize to the ovaries much more commonly than adenocarcinomas of other histologic types from the same sites. Of these, gastric adenocarcinoma of signet ring cell type (also known as inltrative or diffuse gastric adenocarcinoma), chiey from the pylorus, is the most common nding.3,4 The frequency of Krukenberg tumor varies with that of gastric carcinoma in the population analyzed. For example, in countries such as Japan, which has a high prevalence of gastric carcinoma, Krukenberg tumor accounts for a large proportion (17.8%) of all ovarian cancers.5 ROUTE OF METASTASIS Krukenberg tumor is an example of the selective spread of cancers, most commonly in the stomach-ovarian axis. This axis of tumor spread has historically drawn the attention of many pathologists, especially when it was found that gastric neoplasms selectively metastasize to the ovaries without involvement of other tissues.6 The route of metastasis of gastric carcinoma to the ovaries has been a mystery for a long time, but it is now evident that retrograde lymphatic spread is the most likely route of metastasis as there are several evidences supporting this concept. First, lymphatic permeation at the hilum and cortex is microscopically noted in many cases of Krukenberg tumor. Second, review of the literature reveals 8 reported cases of Krukenberg tumors with primary gastric carcinomas that were conned to the mucosa and submucosa.7 It should be remembered that gastric mucosa and submucosa have a rich lymphatic plexus and their invasion usually accounts for the spread of early gastric cancers. Thus, development of Krukenberg tumors in these cases of early gastric cancers can be explained on the basis of lymphatic spread. Third, some studies showed that the risk of ovarian metastasis in gastric carcinoma increases when there is an increased number of metastatic lymph nodes.8 Last, peritoneal involvement is usually absent and the external surface of the ovaries in Krukenberg tumors often lacks any seedings, adhesions, implantations, or tumor inltrationsan observation that may oppose the peritoneal spread theory and further supports the theory of retrograde lymphatic spread. DOES PRIMARY KRUKENBERG TUMOR EXIST? The primary carcinoma in Krukenberg tumors is sometimes clinically occult. Careful thorough examination of
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rukenberg tumor is a metastatic signet ring cell adenocarcinoma of the ovary. Krukenberg tumor is uncommon, accounting for 1% to 2% of all ovarian tumors. In 1896, Friedrich Krukenberg (18711946), a German gynecologist and pathologist, described what he presumed was a new type of primary ovarian neoplasm. The true metastatic nature of this lesion was established 6 years later. Stomach is the primary site in most Krukenberg tumor cases (70%). Carcinomas of colon, appendix, and breast (mainly invasive lobular carcinoma) are the next most common primary sites. Rare cases of Krukenberg tumor originating from carcinomas of the gallbladder, biliary tract, pancreas, small intestine, ampulla of Vater, cervix, and urinary bladder/urachus have been reported.1 The interval between the diagnosis of a primary carcinoma and the subsequent discovery of ovarian involvement is usually 6 months or less, but longer periods have been reported. In many cases, the primary tumor is very small
Accepted for publication May 12, 2006. From the Department of Pathology, State University of New York, Brooklyn. The authors have no relevant nancial interest in the products or companies described in this article. Reprints: Osama M. Al-Agha, MD, Department of Pathology, State University of New York Downstate Medical Center, 450 Clarkson Ave, Box 25, Brooklyn, NY 11203 (e-mail: osama.al-agha@downstate.edu or osamaalagha@yahoo.com). Arch Pathol Lab MedVol 130, November 2006

the gastrointestinal tract and other sites may also fail to reveal the primary carcinoma. The primary carcinoma sometimes may remain undetected for several years after oophorectomy. Therefore, a diagnosis of primary Krukenberg tumor has been proposed for some cases in which either there is long-term survival after Krukenberg tumor resection without detection of the primary tumor, or a complete autopsy examination fails to reveal an extraovarian primary tumor.9 However, many authors are reluctant to accept the term primary Krukenberg tumor for the following reasons. (1) Primary carcinomas, particularly those arising in the breast and stomach, may be very small, requiring exhaustive sectioning to detect them, and it is possible that tiny primary tumors were missed in the reported cases of primary Krukenberg tumors; (2) it is known that mammary and gastric carcinomas may remain silent for many years. The clinical occultness of the primary tumors probably accounts for some reported primary Krukenberg tumors, especially if one knows that the survival rate of patients with Krukenberg tumor is low (less than 2 years on average) and most of the patients do not live long enough for the primary to become clinically detectable; (3) some primary ovarian tumors may have signet ring cells, and this may be responsible for some reported cases of primary Krukenberg tumor in the earlier literature. These tumors include the primary ovarian, mucinous carcinoid, and the signet ring stromal tumor of the ovary, as will be discussed later. Overall, we believe that, although primary Krukenberg tumor may exist, one should exercise considerable caution before making such a diagnosis or accepting reported cases of primary Krukenberg tumors as valid. CLINICAL PROFILES Women with Krukenberg tumors tend to be unusually young for patients with metastatic carcinoma as they are typically in the fth decade of their lives, with an average age of 45 years. This young age of distribution can be related in part to the increased frequency of gastric signet ring cell carcinomas in young women.10 Common presenting symptoms are usually related to ovarian involvement, the most common of which are abdominal pain and distension (mainly because of the usually bilateral and often large ovarian masses). The remaining patients have nonspecic gastrointestinal symptoms or are asymptomatic. In addition, Krukenberg tumor is reportedly associated with virilization resulting from hormone production by ovarian stroma.11 Ascites is present in 50% of the cases and usually reveals malignant cells. Cetin et al12 have recently reported a case of Krukenberg tumor with right hydrothorax and ascites that revealed no malignant cells. This was referred to as pseudo-Meig syndrome (in contrast to Meig syndrome, which is the triad of benign ovarian tumor, ascites, and right hydrothorax). The diagnosis of the primary carcinoma can be made either preoperatively, during the operation for the ovarian metastasis, or within a few months postoperatively.1 Often, the primary tumor is too small to be detected. In such a situation, diagnosis of Krukenberg tumor warrants careful radiographic and endoscopic exploration of the digestive system in an attempt to detect the primary carcinoma. Radiologically, Krukenberg tumors on abdominopelvic sonography and computed tomographic scans usually appear as bilateral ovarian masses. The masses are usually solid but can also be cystic13 (Figure 1, arrows).
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Figure 1. Abdominopelvic computed tomographic scan of a 67-yearold woman with a Krukenberg tumor originating from a primary gastric carcinoma. The tumor appears radiologically as bilateral, solid ovarian masses.

PATHOLOGIC FEATURES Gross Features Krukenberg tumors are bilateral in more than 80% of the reported cases. The ovaries are usually asymmetrically enlarged, with a bosselated contour. The sectioned surfaces are yellow or white; they are usually solid, although they are occasionally cystic (Figure 2). Importantly, the capsular surface of the ovaries with Krukenberg tumors is typically smooth and free of adhesions or peritoneal deposits. Of note, other metastatic tumors to the ovary tend to be associated with surface implants. This may explain why the gross morphology of Krukenberg tumor can deceptively appear as a primary ovarian tumor. However, bilateralism in Krukenberg tumor is consistent with its metastatic nature. Microscopic Features Microscopically, Krukenberg tumor has 2 components: epithelial and stromal. The epithelial component is composed chiey of mucin-laden signet ring cells with eccentric hyperchromatic nuclei. The cytoplasm of the signet ring cells can be eosinophilic and granular (Figure 3, A), pale and vacuolated (Figure 3, B), or it can have a bulls eye (targetoid) appearance containing a large vacuole with a central to paracentral eosinophilic body composed of a droplet of mucin (Figure 4, arrows). Some tumor cells may lack a mucin vacuole. Mitotic activity is sparse. The signet ring cells can be single, clustered, nested, or they can be arranged in tubules, acini, trabeculae, or cords. Several different patterns can appear in one tumor. Krukenberg tumors displaying a predominantly tubular pattern have been subclassied as tubular Krukenberg to distinguish them from the classic type (Figure 5). In tubular Krukenberg tumors, the signet ring cells are present in tubules and intermingled with stromal cells.14 The histochemical
An In-depth Look at Krukenberg TumorAl-Agha & Nicastri

do not show immunoreactivity to vimentin and inhibin.16 The mesenchymal component of Krukenberg tumor is of ovarian stromal origin and is composed of plump and spindle-shaped cells with minimal cytologic atypia or mitotic activity. Stromal edema can be present focally but is sometimes diffuse and marked to the extent of forming pseudocysts. Sometimes the desmoplastic reaction in the stroma can be so intense that it obscures the signet ring pattern of the tumor, rendering its diagnosis challenging, and possibly confused with bromas (Figure 7). Mucinspecial stains can highlight the signet ring cells, facilitating the correct diagnosis.14 CA 125 IN KRUKENBERG TUMOR Preoperative serum CA 125 levels in patients with Krukenberg tumors can be elevated, though they subsequently decrease after tumor resection.17 On the basis of this observation, serum CA 125 level can be used for (1) postoperative follow-up of patients for evaluation of complete resection of the tumor, and (2) follow-up of patients with a history of primary adenocarcinomas (gastrointestinal, in particular) for early detection of ovarian metastasis. Serum CA 125 level also can help predict the prognosis. In a study that investigated serum CA 125 levels in Krukenberg tumors, it was found that the 5-year survival rate was lower in patients in whom preoperative serum CA 125 levels were greater than 75 U/mL compared with patients with CA 125 levels less than 75 U/mL.18 DIFFERENTIAL DIAGNOSIS The diagnosis of Krukenberg tumors largely depends on the recognition of its characteristic light microscopic features with hematoxylin-eosinstained sections. However, Krukenberg tumors may mimic other metastatic or primary ovarian tumors. Distinction from the latter is of great importance as misclassication of Krukenberg tumor as a primary ovarian tumor may lead to suboptimal treatment of the patient. To facilitate discussion of differential diagnosis of Krukenberg tumor, the diagnosis is divided into 2 major parts according to the histologic subtype of Krukenberg tumor. The distinction should be made between (1) classic Krukenberg tumor and ovarian tumors with signet ring cells, and (2) tubular Krukenberg tumors and ovarian tumors with tubular pattern. Differential Diagnosis of Classic Krukenberg Tumor Classic Krukenberg tumors (ie, tumors in which the signet ring cells lack tubular formation) must be distinguished from ovarian tumors that contain signet ring cells lled with either mucinous or nonmucinous material. Ovarian Tumors With Signet Ring Cells Containing Mucin. This group contains primary mucinous carcinoma and mucinous carcinoid tumors. Primary mucinous tumors of the ovary can contain cells with signet ring appearance at least focally. However, these tumors tend to be more commonly unilateral with a complex papillary pattern.19 Mucinous carcinoid tumors (either primary or metastatic, most commonly from appendix) enter the differential diagnosis in this group by having cells that may assume signet ring appearance and resemble Krukenberg tumor cells. Although mucinous carcinoid cells stain with mucin stains similar to Krukenberg tumor cells, immunostains for chromogranin and synaptophysin are usually positive and can easily conrm the diagnosis in favor of mucinous carcinoid.17
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Figure 2. Krukenberg tumor of the same patient as in Figure 1. The ovaries are asymmetrically enlarged with a bosselated contour. Cross section of the ovaries shows predominantly yellow, solid tumor tissue. Figure 3. Krukenberg tumor showing numerous signet ring cells present within a cellular stroma. The cytoplasm of the signet ring cells can be eosinophilic and granular (A) or pale and vacuolated (B) (hematoxylin-eosin, original magnications 600).

identication of intracytoplasmic mucin in the signet ring cells is essential for Krukenberg tumor diagnosis.15 Because the intracytoplasmic mucins of the signet ring cells are neutral and acidic (mostly sialomucins), they stain with Mayer mucicarmine (Figure 6, A), periodic acid Schiff with diastase digestion, and Alcian blue stains. Immunohistochemically, the tumor cells are immunoreactive to epithelial markers, such as cytokeratins (AE1/AE3) (Figure 6, B), and epithelial membrane antigen, and they
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Figure 4. Krukenberg tumor showing some signet ring cells with a bulls eye or targetoid appearance containing a large vacuole with a central or paracentral droplet of mucin that appears as an eosinophilic body (arrows) (hematoxylin-eosin, original magnication 600). Figure 5. Krukenberg tumor cells can be arranged in tubules and cords (arrow). The tubules are lined with round-to-oval nuclei with high-grade cytologic atypia (hematoxylin-eosin, original magnication 400). Figure 6. A, Krukenberg tumor with signet ring cells highlighted with mucicarmine. B, The signet ring cells of Krukenberg tumor are immunoreactive with antibodies against cytokeratins (original magnications 400). Figure 7. At this power of magnication, the appearance of this area of Krukenberg tumor is similar to that of an ovarian broma, but occasional signet ring cells are evident on careful inspection (arrows) (hematoxylin-eosin, original magnication 200).

Ovarian Tumors With Signet Ring Cells Containing Nonmucinous Material. Krukenberg tumors must also be distinguished from ovarian tumors that can contain signet ring cells lled with nonmucinous material, including signet ring stromal tumor, sclerosing stromal cell tumor, and clear cell adenocarcinoma of the ovary. In con1728 Arch Pathol Lab MedVol 130, November 2006

trast to Krukenberg tumor, signet ring stromal tumors are benign, unilateral, devoid of epithelial differentiation, and therefore positive for vimentin but negative for cytokeratins.20 Sclerosing stromal cell tumor can have vacuolated cells with signet ring appearance resembling Krukenberg tumor cells, but sclerosing stromal cell tumor cells contain
An In-depth Look at Krukenberg TumorAl-Agha & Nicastri

lipid as opposed to mucin, which is found in Krukenberg cells, and therefore do not show reactivity to the periodic acidSchiff stain. Moreover, Krukenberg tumor lacks the distinctive microscopic features of sclerosing stromal cell tumor (biphasic pattern composed of highly vascular and cellular areas separated by paucicellular areas). In addition, a positive inhibin stain can help with the diagnosis of sclerosing stromal cell tumor. Clear cell carcinoma of the ovary may have cells with signet ring cell appearance, thus resembling classic Krukenberg tumors, at least focally. In contrast to mucin-laden signet ring cells of Krukenberg tumor, the clear cell cytoplasm contains glycogen, a feature that can be demonstrated with a periodic acid Schiff stain, whose reactivity abolishes with diastase digestion. Besides, the papillary and tubulocystic pattern with hobnail cells characterize the clear cell carcinoma. Differential Diagnosis of Tubular Krukenberg Tumor Tubular Krukenberg tumors (ie, tumors in which the cells are predominantly arranged in tubules) must be distinguished from other ovarian tumors displaying annular or tubular pattern. The major tumor in this group is Sertoli-Leydig cell tumor. The nuclei of tubular Krukenberg tumors are more atypical than those within the tubules of Sertoli-Leydig cell tumors. Presence of signet ring cells within the tubules is inconsistent with Sertoli-Leydig cell tumor. In contrast to Krukenberg tumor, Sertoli-Leydig cell tumor stains positive to inhibin but negative to cytokeratins or epithelial membrane antigen. Other ovarian tumors with a tubular pattern that can enter the differential diagnosis in this group include well-differentiated endometrioid carcinoma (metastatic or primary) and tumors of wolfan origin. Differentiation can be made on the basis of their characteristic histologic features. IMMUNOHISTOCHEMISTRY IN THE DISTINCTION OF METASTATIC CARCINOMAS FROM PRIMARY OVARIAN NEOPLASMS Immunohistochemical evaluation may aid in distinguishing primary ovarian carcinomas from metastatic carcinomas. Cytokeratins 7 and 20 (CK7 and CK20) immunophenotype is the most commonly used analysis. Primary ovarian carcinomas are almost always immunoreactive to CK7 (90%100%) but generally are not immunoreactive to CK20. By contrast, metastatic gastric carcinoma tends to be less frequently positive for CK7 (55%) but is positive for CK20 in approximately 70% of cases. Colorectal adenocarcinomas are usually negative for CK7 but positive for CK20 in most cases. Tumors metastasizing from the appendix are commonly positive for CK20 but positive also for CK7 in 50% of cases. Therefore, a CK7 /CK20 immunophenotype favors a primary ovarian carcinoma, whereas a CK7 /CK20 or CK7 /CK20 immunophenotype (CK20 positivity, in particular) favors a metastatic gastrointestinal carcinoma.2123 Use of source-specic antibodies can increase the diagnostic condence. For example, immunoreactivity for carcinoembryonic antigen and CDX2 together with the immunoexpression pattern of CK7 /CK20 increases the condence in pointing toward the colorectal origin of the primary.24 PROGNOSIS AND MANAGEMENT Patients with Krukenberg tumors have an overall mortality rate that is signicantly high. Authors in almost all
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the reported cases underline the gloomy outcome of this tumor. Most patients die within 2 years (median survival, 14 months).25 Review of the literature showed that the prognostic factors for Krukenberg tumors have not been well established, but we were able to identify a number of diagnostic and management issues that appear to have an impact on survival. Several studies show that the prognosis is poor when the primary tumor is identied after the metastasis to the ovary is discovered, and the prognosis becomes worse if the primary tumor remains covert. This has been supported by a study that showed that the survival rate was low in the patients who underwent surgery on the ovarian tumor simultaneously or before the surgery on the primary carcinoma, compared with the survival rate of patients who underwent surgery on the ovarian tumor after the surgery on the primary carcinoma.18 Our review of the literature did not show large differences in the survival rate in regard to origin of the cancer, except for 1 study that showed that the median survival time of patients with ovarian metastases of gastric carcinoma was lower than that of patients with breast and colorectal carcinoma.26 No optimal treatment strategy for Krukenberg tumors has been clearly established in the literature. Whether a surgical resection should be performed has not been adequately addressed. Lower rate of resectability when the primary tumor metastasizes to other sites (in addition to the ovaries) and the overall dismal prognosis are the 2 major factors that usually dissuade resection of Krukenberg tumors.27 On the contrary, if metastasis is limited to the ovaries, surgery may render the patient free of residual disease and the survival time may increase.28 Hence, the signicance of early detection of ovarian metastasis and the importance of serum CA 125 level monitoring (as discussed previously) are vital. Chemotherapy or radiotherapy has no signicant effect on prognosis of patients with Krukenberg tumors. Because no curative treatment is available, prophylaxis by bilateral oophorectomy at time of operation of the primary tumor has been considered by some authorities,29 but this requires further study and evaluation. CONCLUSIONS Krukenberg tumor is a metastatic ovarian tumor that is histologically characterized by mucin-laden signet ring cells. Stomach is the most common primary site, but other organs can serve as a primary site. The lymphatic system is the most likely route for metastasis. Diagnosis of Krukenberg tumor with unknown primary warrants careful investigation of mainly the digestive tract and other potential sites. CA 125 levels can be used for screening for early detection of ovarian metastasis as well as for monitoring the course of disease. The prognosis of Krukenberg tumor is poor and no curative treatment is currently available.
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carcinomas metastasizing to the ovaries. Gynecol Obstet Invest. 2002;54:221 227. 19. Lee KR, Young RH. The distinction between primary and metastatic mucinous carcinomas of the ovary: gross and histologic ndings in 50 cases. Am J Surg Pathol. 2003;27:281292. 20. Vang R, Bague S, Tavassoli FA, Prat J. Signet ring stromal tumor of the ovary: clinicopathologic analysis and comparison with Krukenberg tumor. Int J Gynecol Pathol. 2004;23:4551. 21. 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; 33:10781085. 22. 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;26:852855. 23. 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;21:11441155. 24. Baker PM, Oliva E. Immunohistochemistry as a tool in the differential diagnosis of ovarian tumors: an update. Int J Gynecol Pathol. 2005;24:3955. 25. Benaaboud I, Ghazli M, Kerroumi M, Mansouri A. Krukenberg tumor: 9 cases report [in French]. J Gynecol Obstet Biol Reprod (Paris). 2002;31:365370. 26. Demopoulos RI, Touger L, Dubin N. Secondary ovarian carcinoma: a clinical and pathological evaluation. Int J Gynecol Pathol. 1987;6:166175. 27. Novak E, Gray LA. Krukenberg tumors of the ovary: clinical and pathological study of 21 cases. Surg Gynecol Obstet. 1938;66:157167. 28. Kim HK, Heo DS, Bang YJ, Kim NK. Prognostic factors of Krukenbergs tumor. Gynecol Oncol. 2001;82:105109. 29. McGill FM, Ritter DB, Rickard CS, Kaleya RN. Krukenberg tumors: can management be improved? Gynecol Obstet Invest. 1999;48:6165.

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