note Blogger's Comment/add yours - abstract: Morphologic spectrum of immunohistochemically characterized clear cell carcinoma of the ovary: a study of 155 cases (references Lynch Syndrome)

Blogger's comment/question: any other survivours (or not) of clear cell ovarian cancer and Lynch Syndrome NOT included in this study?  A missed opportunity.....

 note: absence of a direct reference to Lynch syndrome in abstract

 Morphologic spectrum of immunohistochemically characterized clear cell carcinoma of the ovary: a study of 155 cases.

Delair D, Oliva E, Köbel M, Macias A, Gilks CB, Soslow RA.

*Department of Pathology, Memorial Sloan-Kettering Cancer Center ‡Department of Pathology, Vancouver General Hospital, NY †Department of Pathology, Massachusetts General Hospital, MA §Department of Pathology, University of Calgary, Calgary, Canada.

Abstract

Establishing a diagnosis of ovarian clear cell carcinoma (O-CCC) can be subject to significant interobserver variation. Accurately diagnosing this tumor is important because of its chemoresistance and reported association with Lynch syndrome. The spectrum of the morphologic features of O-CCC has not been well described in a series composed of immunohistochemically characterized cases. A total of 155 cases diagnosed as O-CCC were retrieved from the files of 3 institutions to analyze architectural and cytologic features. The immunohistochemical features of these cases have been reported earlier. A comprehensive list of features was recorded, including, but not limited to, architectural patterns, nuclear appearance, cytoplasmic characteristics, and mitotic index. Between 1 and 13 slides were available for review for each case. The cases were divided into 2 groups based on morphologic characteristics, those with features shared by the large majority (the first group, n=138) and those that showed unusual characteristics (second group, n=17). Tumors in the first group typically showed a mixture of architectural patterns, the most frequent being papillary and tubulocystic. Papillae, usually small and round and lacking hierarchical branching and tufting or stratification of more than 3 cells, were present at least focally in almost 3 of 4 cases. The cell shape was predominantly cuboidal, not columnar. Nuclear pleomorphism and prominent nucleoli were frequently present, but never diffusely. Clear cytoplasm was found in nearly every case and hobnail cells were common. Mitoses exhibited a range from 0 to 13 with an average of 3 to 4 per 10 high power fields. The second group of tumors showed numerous unusual morphologic characteristics, despite the presence of clear cytoplasm, including those typically seen in other ovarian epithelial tumors, such as serous and endometrioid carcinoma. Eighty-nine percent of tumors from the first group showed the expected "O-CCC immunophenotype" [hepatocyte nuclear factor (HNF) positive, and estrogen receptor (ER), progesterone receptor (PR), Wilms tumor 1 (WT1) and p53 negative], whereas 4% of tumors showed HNF positivity along with focal ER or PR expression. Seven percent of tumors were not immunoreactive with these markers. Twenty-nine percent of tumors in the second group showed the O-CCC immunophenotype, whereas 24% of tumors were p53 positive, 5% of tumors were WT1 positive, and the remaining cases were negative for all markers. Ninety-seven percent (112 of 117) of HNF-positive tumors in this series were classical O-CCC. Therefore, O-CCC has characteristic morphologic features and a specific, if not unique, immunophenotype in the vast majority of the cases. Clear cell-rich tumors with features that depart from the classical morphologic appearances described herein should suggest the possibility of an alternative diagnosis.

full free access: 2009 Lynch syndrome (hereditary non-polyposis colorectal cancer) and endometrial carcinoma -- Journal of Clinical Pathology (note reference to clear cell ovarian cancer)

Abstract

Women with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome have a high risk for endometrial cancer (EC) and frequently present with a gynaecological cancer as their first or sentinel malignancy. Identification of these patients is important given their personal and family risk for synchronous and metachronous tumours. Modalities to detect ECs for the possibility of HNPCC include microsatellite instability assay, immunohistochemistry for DNA mismatch repair proteins, MLH1 promoter hypermethylation assay and mutational analysis of DNA mismatch repair genes. The revised Bethesda guidelines provide screening criteria for HNPCC in colorectal cancers (CRCs). However, there are currently no such screening recommendations for women with endometrial carcinoma. While age and family history are useful screening criteria, their sensitivity has been shown to be low for detection of HNPCC in EC. Expansion of these criteria to include tumour morphology (presence of tumour infiltrating lymphocytes and tumour heterogeneity including dedifferentiated/undifferentiated ECs) and topography (lower uterine segment localisation) as well as presence of synchronous ovarian clear cell carcinomas may significantly enhance the detection of patients with EC at risk for HNPCC. Consideration should be given to incorporating these screening criteria into a revision of the Bethesda guidelines for detecting EC patients at highest risk for HNPCC.

Frequent Mutations of Chromatin Remodeling Gene ARID1A in Ovarian Clear Cell Carcinoma (note: 2nd study)

Note: this is a second study regarding clear cell ovarian cancer/ARID1A

"The nature and pattern of the mutations suggest that PPP2R1A functions as an oncogene and ARID1A as a tumor suppressor gene. In a total of 42 OCCCs, 7% had mutations in PPP2R1A and 57% had mutations in ARID1A. These results suggest that aberrant chromatin remodeling contributes to the pathogenesis of OCCC."

Making strides in ovarian cancer research « BC Cancer Foundation's Blog - re: clear cell ovarian cancer/endometriosis

"We were able to show that ARID1A mutated in close to 50 per cent of clear cell carcinomas of the ovary and in a slightly fewer number of the related endometrioid carcinomas.
When we studied in detail two cases where there was endometriosis attached to the tumour, we found that the mutation was present even before the cells in endometriosis looked like cancer cells. This suggests that ARID1A mutations are a very early event and likely critical to the transformation of a non-cancerous disease into cancer.
We are fully confident that this discovery marks the start of finding real treatments for clear cell carcinoma – but there is still a lot of work to do in the future...."

2 Genes Have Possible Link to Deadly Ovarian Cancer - clear cell ovarian cancer

"Mutations in two genes may be associated with one of the most deadly types of ovarian cancer, U.S. researchers have found.

In the study, researchers at the Johns Hopkins Kimmel Cancer Center looked for mutations in 18,000 protein-encoding genes in ovarian clear cell tumors from eight patients. The investigators found 268 mutations in 253 genes, with an average of 20 mutations per tumor......Further investigation revealed that two genes -- ARID1A and PPP2R1A -- were more commonly mutated than other genes..ARID1A is a gene whose product normally suppresses tumors. PPP2R1A is a gene that, when altered, helps turn normal cells into tumor cells. The genes had not previously been linked to ovarian cancer, the researchers explained in a news release from the Johns Hopkins Kimmel Cancer Center....."cont'd

abstract: Sorafenib efficacy in ovarian clear cell carcinoma revealed by transcriptome profiling. - in research- Cancer Science

Targeting annexin A4 to counteract chemoresistance in clear cell carcinoma of the ovary

Take home message: Annexin A4 enhances cancer cell chemoresistance and is overexpressed in tumors of patients with ovarian CCC. Targeting of annexin A4 may represent a future strategy to counteract resistance to chemotherapy in ovarian CCC.

Vascular Endothelial Growth Factor Is a Promising ... [Mol Cancer Ther. 2010] - PubMed result

Mol Cancer Ther. 2010 Jul 27. [Epub ahead of print]

Vascular Endothelial Growth Factor Is a Promising Therapeutic Target for the Treatment of Clear Cell Carcinoma of the Ovary.

Mabuchi S, Kawase C, Altomare DA, Morishige K, Hayashi M, Sawada K, Ito K, Terai Y, Nishio Y, Klein-Szanto AJ, Burger RA, Ohmichi M, Testa JR, Kimura T.

Authors' Affiliations: 1Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine; 2Department of Obstetrics and Gynecology, Osaka Police Hospital; 3Department of Obstetrics and Gynecology, Osaka Medical College, Osaka, Japan; 4Women's Cancer Program, 5Cancer Genetics and Signaling Program, and 6Department of Surgery, Fox Chase Cancer Center, Philadelphia, Pennsylvania; and 7Department of Obstetrics and Gynecology, Kansai Rosai Hospital, Amagasaki, Japan.

Abstract

This study examines the role of vascular endothelial growth factor (VEGF) as a therapeutic target in clear cell carcinoma (CCC) of the ovary, which has been regarded as a chemoresistant histologic subtype. Immunohistochemical analysis using tissue microarrays of 98 primary ovarian cancers revealed that VEGF was strongly expressed both in early-stage and advanced-stage CCC of the ovary. In early-stage CCCs, patients who had tumors with high levels of VEGF had significantly shorter survival than those with low levels of VEGF. In vitro experiments revealed that VEGF expression was significantly higher in cisplatin-refractory human CCC cells (RMG1-CR and KOC7C-CR), compared with the respective parental cells (RMG1 and KOC7C) in the presence of cisplatin. In vivo treatment with bevacizumab (Avastin) markedly inhibited the growth of both parental CCC cell-derived (RMG1 and KOC7C) and cisplatin-refractory CCC cell-derived (RMG1-CR and KOC7C-CR) tumors as a result of inhibition of tumor angiogenesis.
The results of the current study indicate that VEGF is frequently expressed and can be a promising therapeutic target in the management of CCC. Bevacizumab may be efficacious not only as a first-line treatment but also as a second-line treatment of recurrent disease in patients previously treated with cisplatin.
Mol Cancer Ther; 9(8); OF1-12. (c)2010 AACR.