Case 3 -

High Grade Ovarian Carcinoma with Mixed Endometrioid and Serous Differentiation, Arising in the Setting of Endometriosis Kathleen R. Cho University of Michigan Medical School Ann Arbor, MI

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Click here to download handout in 1-up pdf format for the current section Click here to download handout in 6-up pdf format for the current section Clinical History Clinical History: 46 year old woman with strong family history of ovarian cancer and bilateral ovarian masses. Case 3 - Figure 1 Endometriosis adjacent to fallopian tube Case 3 - Figure 2 Portion of ovary with carcinoma involving endometriotic cyst Case 3 - Figure 3 Photomicrographs show carcinoma with features most pathologists associate with endometrioid differentiation: solid and near-solid areas of growth admixed with well formed glands, many with round/ovoid lumens Case 3 - Figure 4 Photomicrographs show carcinoma with features most pathologists associate with endometrioid differentiation: solid and near-solid areas of growth admixed with well formed glands, many with round/ovoid lumens Case 3 - Figure 5 Photomicrographs show carcinoma with features most pathologists associate with endometrioid differentiation: solid and near-solid areas of growth admixed with well formed glands, many with round/ovoid lumens Case 3 - Figure 6 Photomicrographs show carcinoma with features most pathologists associate with endometrioid differentiation: solid and near-solid areas of growth admixed with well formed glands, many with round/ovoid lumens Introduction: A 46 yo woman presented with bilateral ovarian masses and elevated CA125. TAH/BSO, pelvic and para-aortic lymph node dissection, and optimal debulking were performed. Ovaries showed high grade carcinoma (endometrioid vs. serous). Question: Do high grade endometrioid carcinomas exist, and if so, what are the morphological and molecular features that allow them to be distinguished from high grade serous carcinomas? Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: Pathological findings: Carcinoma was associated with unequivocal endometriosis involving ovary and fallopian tube Immunohistochemical findings: -ER/PR expression variable in different parts of tumor -p53 expression strong and diffuse in nuclei throughout tumor -p16 expression variable in different parts of tumor, some strong and diffuse, others completely negative -WT1 expression strong and diffuse in nuclei throughout tumor Differential Diagnoses: High-grade endometrioid carcinoma High-grade serous carcinoma High-grade carcinoma with mixed differentiation Final Diagnosis: High Grade Ovarian Carcinoma with Mixed Endometrioid and Serous Differentiation, Arising in the Setting of Endometriosis Case Discussion: The morphological and molecular features of high-grade endometrioid and high-grade serous ovarian carcinomas overlap. Indeed, some pathologists now default the vast majority of gland-forming or near-solid cytologically high- grade ovarian carcinomas to the serous category and "true" high-grade endometrioid carcinomas are considered by some to be rare. One could reasonably question whether the latter diagnostic category should even exist. The morphological features traditionally believed to help identify high grade endometrioid carcinomas include: 1) round "punched out" spaces rather than slit-like spaces, 2) longer broader papillae, 3)squamous differentiation, 4) adenofibromatous growth pattern, and 5) endometriosis. However, tumors displaying these features can also have areas indistinguishable from typical high grade serous carcinomas, as seen in this case. Although a number of studies have attempted to identify immunohistochemical stains that help distinguish high grade serous from high grade endometrioid carcinomas (e.g., hormone receptors ER and PR, p53, p16, and WT1), no single immunostain allows absolutely certain distinction between these two entities. Moreover, it should be remembered that immunohistochemistry allows evaluation of how individual proteins are expressed in a given tumor at a single point in time - expression of these proteins often changes as tumors evolve and additional genetic alterations are acquired. Comprehensive gene expression and mutational analyses suggest that many ovarian tumors diagnosed as high grade endometrioid carcinomas are indistinguishable from high grade serous carcinomas based on their molecular profiles. These may indeed be appropriately re-classified as serous. However, there is a small subset that have molecular features typical of low grade endometrioid carcinomas that also acquire mutations more often associated with high grade carcinomas - these may represent "true" high grade endometrioid carcinomas. It remains unclear whether there are morphological features that allow this small subgroup to be recognized as distinct from the other high grade carcinomas. Conclusion(s): Given currently available treatment options, the distinction between high grade endometrioid and high grade serous carcinomas is of limited clinical importance and some have advocated the inclusion of both in a single category of high grade "Mullerian" carcinoma. However, in the relatively near future, distinguishing amongst subsets of high grade tumors may have implications for "personalized" medicine using drugs that target specific molecular defects in a given patient's tumor cells. References: McCluggage WG: My approach to and thoughts on the typing of ovarian carcinomas, J Clin Pathol 2008, 61:152- 163. Gilks CB, Ionescu DN, Kalloger SE, Kobel M, Irving J, Clarke B, Santos J, Le N, Moravan V, Swenerton K: Tumor cell type can be reproducibly diagnosed and is of independent prognostic significance in patients with maximally debulked ovarian carcinoma, Hum Pathol 2008, 39:1239-1251. Lee P, Rosen DG, Zhu C, Silva EG, Liu J: Expression of progesterone receptor is a favorable prognostic marker in ovarian cancer, Gynecol Oncol 2005, 96:671-677. Wu R, Hendrix-Lucas N, Kuick R, Zhai Y, Schwartz DR, Akyol A, Hanash S, Misek DM, Katabuchi H, Williams BO, Fearon ER, Cho KR: Mouse model of human ovarian endometrioid adenocarcinoma based on somatic defects in the Wnt/B-catanin and PI3K/Pten signaling pathways, Cancer Cell 2007, 11:321-333. Phillips V, Kelly P, McCluggage WG: Increased p16 expression in high-grade serous and undifferentiated carcinoma compared with other morphologic types of ovarian carcinoma, Int J Gynecol Pathol 2009, 28:179-186. Stewart CJ, Brennan BA, Chan T, Netreba J: WT1 expression in endometrioid ovarian carcinoma with and without associated endometriosis, Pathology 2008, 40:592- 599. Vang R, Shih Ie M, Kurman RJ: Ovarian low-grade and high-grade serous carcinoma: pathogenesis, clinicopathologic and molecular biologic features, and diagnostic problems, Adv Anat Pathol 2009, 16:267-282. Cho KR, Shih IM: Ovarian Cancer, Annu. Rev. Pathol. Mech. Dis. 2009, 4:287-313.