Krukenberg tumors of colorectal origin: a dismal outcome--experience of a tertiary center.

BACKGROUND: Krukenberg tumor (KT) is described as metastases of the ovary usually from a tumor of gastric origin. As colorectal cancer (CRC) is now the most common cancer in Singapore, we are seeing more KT with colorectal origin. PURPOSE: To determine the pattern of presentation of KT from CRC origin in terms of patient demographics, time of onset related to the diagnosis of CRC, presence of elevated serum tumor markers, carcinomatosis peritoneii, and survival of patients. METHODS: A retrospective database review of all patients diagnosed with KT from CRC treated in a specialized colorectal surgery department between August 1992 and March 2004. RESULTS: Twenty-five patients' records were available for analysis. Median age at diagnosis was 53 years old (range: 38-79). Sixteen patients (64%) had ovarian metastasis at the time of diagnosis of the CRC. Eleven patients (44%) had unilateral ovarian involvement. Nineteen patients (76%) had carcinomatosis peritoneii. Serum Carcinoembryonic antigen (CEA) was available for 21 patients, 18 (86%) were raised; serum cancer antigen-125 (CA-125) was available for seven patients, five (71%) were raised. There were 11 mortalities (44%) and all died of the disease. Median time between diagnosis of KT and death was 19 months. The rest of the patients were alive with existence of disease at last follow-up. CONCLUSION: KT is associated with a dismal outcome and poor prognosis. There was 0% disease-free survival. Serum CEA and CA-125 tend to rise in patients with KT. Patients investigated for elevated CA-125 and unilateral ovarian mass should have the diagnosis of colorectal cancer excluded before treatment of ovarian mass.

Immunohistochemical diagnosis of Krukenberg tumors.

The diagnosis of Krukenberg tumors, as in other types of metastatic tumors of unknown primary origin, can often be a challenge for clinicians. In many cases, traditional diagnostic methods are insufficient, requiring immunohistochemistry analysis for identifying the origin of metastatic tumors. In our study, we examined a total of 34 female patients with Krukenberg tumors with different sites of the primary tumor: gastric (n=18), colorectal (n=6) or breast (n=7) and tumors with unknown origin (n=3). Cytokeratin (CK) 7 and CK20, carcinoembryonic antigen (CEA) and cancer antigen (CA) 125 were applied. The analysis of immunohistochemical profiles for CEA and CA125 showed that, regardless of the histological origin, the predominant immunohistochemical profile was CEA(+)÷CA125(-). CK7÷CK20 profile was different depending on the histological origin of the Krukenberg tumors. Thus, for the cases of gastric origin, CK7(-)÷CK20(-) was present in 66.7% (12÷18) of the cases. For the cases with colorectal origin, the predominant immunohistochemical profile was CK7(-)÷CK20(+), in a percentage of 66.7% (4÷6). The combination CK7(+)÷CK20(-) was found in 85.7% (6÷7) among cases of breast origin. Consequently, the immunohistochemical profile CK7÷CK20 can have a key role in identifying the primary tumor in patients with Krukenberg tumors of unknown origin.

Characteristic mucinous ovarian cancer antigen is expressed in malignantly transformed Bloom's syndrome cells.

Using a double-antibody panning procedure, we separated a unique cancer antigen cell line (BS-SHI-4M OVC-MU) expressing a mucinous ovarian cancer (OVC) antigen from a malignantly transformed Bloom's syndrome cell line. In order to gain information concerning a mucinous OVC antigen, we tested this unique cell line in the reaction to sera from patients with various OVCs, Krukenberg (KR) tumor, and signet ring cell cancer of the stomach under immunofluorescence and Western blotting protocols and determined the mucinous OVC antigen band at M(r) 84,000. We also undertook an immune electron microscopic study to gain information concerning the antigen-antibody reaction [BS-SHI-4M OVC-MU cells-sera from patients with mucinous OVC and KR tumor] and concerning the antigenic determinant of the membrane using preembedding methods. Occasional protein A-gold particles were observed along the cell membrane of BS-SHI-4M OVC-MU cells, when treated with sera from mucinous OVC and KR tumor patients, but no labeling was observed in the cell membrane when treated with sera from normal patients and those with other cancers. Results of the immune electron microscopic study strongly support the data from the antigen-antibody reaction obtained by immunofluorescence and Western blotting analyses. The BS-SHI-4M OVC-MU cells separated here would be useful for serodiagnosis of mucinous OVC and KR tumors and for follow-up of patients after therapy.

Krukenberg tumor. A report of six cases.

The Authors present six cases of ovarian neoplasm with histological characteristics of typical Krukenberg tumor. Usually, Krukenberg Tumor is bilateral and often secondary to gastrointestinal carcinomas. Secondary ovarian neoplasms often become evident a short time after the diagnosis of primary tumor. Moreover, the post ovulatory rearrangement of the ovarian surface could favour the metastatic spread of cancerous cells. In four cases TAG 72 serum levels were useful in the monitoring of relapsing disease.

[Soluble interleukin-2 receptor level in the sera and ascitic fluids in patients with ovarian cancer].

In 31 patients with ovarian cancer, the sIL-2R level of the sera and ascitic fluids were measured by ELISA, to investigate the inhibitive effect of sIL-2R purified from ascitic fluids on normal lymphocyte transformation, stimulated with phytohemagglutinin (PHA). The results showed that the sera sIL-2R levels in the patients were much higher than those in the normal controls (857 +/- 428kU/L vs 235 +/- 90kU/L, P < 0.001). The sera sIL-2R levels in mucinous cancer were significantly higher than those in serous cancer (988 +/- 539kU/L vs 488 +/- 233kU/L P < 0.01). But no obvious correlation was observed with the histopathological grading, nor with metastasis. Higher levels of sIL-2R were also observed in the ascitic. The normal lymphocyte transformation stimulated with PHA was significantly inhibited by high sIL-2R purified from the ascitic fluids.

An in-depth look at Krukenberg tumor: an overview.

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 misclassification, 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.

Carcinoembryonic antigen isotypes in tissue sections and loose cyst fluid cells of ovarian neoplasms.

The aim of this study was to establish whether different subsets of ovarian neoplasms express a restricted isotype of carcinoembryonic antigen (CEA) which can be detected in solid tumors and detached cells. Sixty-one cases of mucinous, serous, endometrioid, and Krukenberg tumors were studied by immunohistochemistry using two monoclonal antibodies (MAbs), commercial anti-CEA and D14 with a higher specificity for colorectal adenocarcinomas. The results with both antibodies showed a considerable degree of heterogeneity between cases of nonserous tumors, with a more restrictive pattern observed with the D14 MAb. The proportion of immunostained cells was comparable in tumors and fluids.

Characterization of Krukenberg tumor cell line, especially the biological relationship between cancer and stromal cells.

The signet-ring cell adenocarcinoma cell line (HSKT-C) and the fibroblast cell strain (HSKT-F) were established from a Krukenberg tumor. The HSKT-C cells are small, roundish or spindle-like in shape and form monolayer sheets of epithelial pavement cells and produce carcinoembryonic proteins such as carbohydrate antigen 19-9 (CA 19-9), carcinoembryonic antigen (CEA), tissue polypeptide antigen (TPA), etc. They show a stable proliferation after successful passages of 45 times within 13 months. The chromosome number varied widely and showed aneuploidy. The HSKT-C cells were transplanted to hamster cheek pouches and produced a tumor (signet-ring cell adenocarcinoma). On the other hand, HSKT-F cells are fibroblast-like. Their chromosome number is 46, and no karyological abnormality was observed. They could not be transplanted in the nude mouse or the hamster and did not produce carcinoembryonic proteins. It should be noted that they produce estrogens (estrone and 17 beta-estradiol). Sarcomatous morphological change of the stromal cells in Krukenberg tumor is considered to be a reactive change against invasion of the signet-ring cell adenocarcinoma into stromal tissues.

[Histomorphological studies of Krukenberg tumor on early ovarian metastatic lesion].

In ten cases of "early" Krukenberg tumor with only slight swelling of the ovary, histomorphological studies were performed to clarify the process of the formation of Krukenberg tumor. 1) The histological features of early metastatic lesion were classified into 3 types; lymph vessel permeation only, solid alveolar structure, and diffuse infiltration type. 2) Lymph vessel permeation in the ovarian hilum was observed in all cases. 3) In the diffuse infiltration type, signet-ring cells extended diffusely and radially via the lymph vessels, and, in the periphery, tumor cells leaked from the lymph vessels, infiltrating the stroma. At this stage, the response of ovarian stroma was slight, and signet-ring cells were present more abundantly in the vicinity of the infiltrated area. 4) In the solid alveolar type, the stroma was interposed in these lesions. 5) CEA staining revealed many CEA positive tumor cells in the proliferated stroma in which tumor cells failed to be detected. In summary, tumor cells infiltrate via the lymph vessels and leak into the stroma. Following the destruction of signet-ring cells, the mucus leaks into the stroma and it produces stromal edema and proliferation, eventually leading to a swollen ovary.

[Sequential measurement of serum CA 125 levels in Krukenberg's tumor].

CA 125 is a tumor marker for ovarian cancer developed by hybridoma technology. In the present study, the levels of CA 125 were sequentially measured in the serum of five patients with Krukenberg's tumor originating in the gastrointestinal tract. Four out of the five (80%) had elevated serum CA 125 levels, i.e., greater than 35 U/ml and, in most cases, these levels decreased after resection of the ovarian tumor. Serum CA 19-9 and CEA levels were also increased in two (40%) and three (60%) patients, respectively, and, in these positive cases, reflected the clinical course. The results indicated the clinical usefulness of these cancer markers in Krukenberg's tumor.

Serum and tissue measurements of CA72-4 in ovarian cancer patients.

Serum levels of cancer-associated antigen 72-4 (CA72-4) (tumor-associated glycoprotein 72; TAG-72) from 106 patients with primary ovarian cancer were measured by an immunoradiometric assay employing the monoclonal antibodies (MAbs) B72.3 and CC49. Immunohistochemical localization of TAG-72 was also investigated using immunoperoxidase methodology in conjunction with both light and electron microscopy. In using a cutoff value of 4.0 U/ml for the serum assay, sensitivity of all primary ovarian carcinomas was 63.2% (67.6% of mucinous cystadenocarcinomas and 66.7% of serous cystadenocarcinomas), while specificity of benign ovarian tumors was 91.1%. Diagnostic characteristics of CA125 and CA72-4 have been demonstrated by receiver-operating-characteristics analysis. Although CA125 expressed a remarkable diagnostic efficiency with serous cystadenocarcinoma, it was less efficient with mucinous cystadenocarcinoma. CA72-4, however, was highly detectable for any histological type of ovarian cancer. Immunohistochemical staining with MAbs B72.3 and CC49 in the cytoplasm was stronger than that in the cell membrane in tissues from mucinous cystadenocarcinomas. Also, histological localization of TAG-72 in the microvilli and apical cytoplasmic membrane was demonstrated by electron microscopy using MAb B72.3 and samples of seromucinous cystadenocarcinoma (mixed type). Consequently, TAG-72 was useful for the detection of ovarian carcinoma, especially for monitoring mucinous cystadenocarcinoma, and it is localized in the microvilli and apical cytoplasmic membrane of cystadenocarcinoma cells.