Am J Cancer Res 2013;3(1):70-95
Original Article
Morphologic and other clinicopathologic features of endometrial clear cell
carcinoma: a comprehensive analysis of 50 rigorously classified cases
Oluwole Fadare, Wenxin Zheng, Marta A Crispens, Howard W Jones III, Dineo Khabele, Katja Gwin, Sharon X Liang, Khaled
Moham-med, Mohamed M Desouki, Vinita Parkash, Jonathan L Hecht
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA; Department of
Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Pathology and Department
of Obstetrics & Gynecology, University of Arizona College of Medicine, Tucson, AZ, USA; Department of Pathology, University of
Chicago, Chicago, IL, USA; Department of Pathology and Laboratory Medicine, North Shore-LIJ Health System and Hofstra North
Shore-LIJ School of Medicine, New Hyde Park, NY, USA; Department of Gastroenterology, University of Pittsburgh Medical
Center, Pittsburgh, PA, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT, USA and Department
of Pathology, Bridgeport Hospital, Bridgeport, CT, USA; Department of Pathology, Beth Israel Deaconess Medical Center and
Harvard Medical School, Boston, MA, USA
Received November 5, 2012; Accepted December 18, 2012; Epub January 18, 2013; Published January 25, 2013
Abstract: Clear cell carcinoma of the endometrium (CCC) is an uncommon histotype whose analyses have generally been
hampered by its rarity and issues of interobserver diagnostic variability. In this study, we analyzed the clinicopathologic features
of 50 CCCs that were assembled from multiple institutions and which we considered to be morphologically unambiguous after
a rigorous review process for diagnostic accuracy. Forty-four (88%) of the 50 CCC cases showed an admixture of the classic
architectural patterns (glandular, papillary, solid and cystic in decreasing order of prevalence). Mitotic indices were variable but
were generally low: 60% of cases had a mitotic index of 3 or lower. The predominant cell type lining glands and papillae was
invariably hobnail and/or cuboidal. Stratification of nuclei (greater than 3 cells) or columnar cells on glands and papillae were
uncommon and never diffusely present. 82% of cases showed an admixture of polygonal cells with clear and eosinophilic
cytoplasm; only clear cells were present in 4% and only eosinophilic cells were present in 10%. Hobnail cells were common,
being identifiable in 86% of cases, and being diffuse in 60%. Only 2 cases had a predominance of nuclear grade 3 cells.
Psammoma, hyaline and targetoid bodies were identified in 32%, 52% and 20% of cases respectively. Clear cell endometrial
intraepithelial carcinoma was identified in 41.7% of cases with evaluable background endometrium. The 5-year progression free
survival (PFS) for the entire cohort was 61%, and was 88%, 75%, 22% and 28.6% for stages I to IV respectively. On univariate
analyses, age >65 years, advanced FIGO stage, and the presence of any lymph node metastases were associated with reduced
PFS (p=0.02, 0.002, and 0.002 respectively). On multivariate analyses, the only variable associated with reduced PFS was age
>65 years. The 5-year overall survival (OS) for the entire cohort was 78%, and was 94%, 87.5%, 66.7%, and 42.8% for stages I to
IV respectively. On univariate analyses, the following factors were associated with reduced OS: age >65 years (p=0.04),
advanced FIGO stage (p=0.003), distant metastases (p=0.003), myometrial invasion >30% (p=0.01), a mitotic index >4
(p=0.014), and a specific architectural pattern (at least 10% of the tumor composed of solid masses or individual infiltrating
tumor cells, p=0.02). On multivariate analyses, only age >65 years and advanced stage were associated with reduced OS
(p=0.023 and 0.022 respectively). In summary, endometrial CCC has a wide morphologic spectrum that is detailed and
illustrated herein, but also has core cytoarchitectural features that are of high diagnostic utility. Morphologically unambiguous
CCC apparently have patient outcomes that are more favorable than has previously been reported, indicating that ambiguous
tumors should be classified separately. The existence of morphologically ambiguous clear-cell rich carcinomas that do not fit the
conventional histotypic groupings, is a likely reflection of the biologic complexity of endometrial carcinomas in general; these
cases should be reported descriptively, and studied separately from conventional CCC. (ajcr0000159).
Keywords: Clear cell carcinoma, endometrium, morphologic features
Address all correspondence to:
Dr. Oluwole Fadare
Department of Pathology, Microbiology and Immunology
MCN C-2310D, Vanderbilt University Medical Center
1161 21st Avenue S, Nashville, TN 37232, USA.
E-mail: oluwolefadare@yahoo.com
Original Article
Morphologic and other clinicopathologic features of endometrial clear cell
carcinoma: a comprehensive analysis of 50 rigorously classified cases
Oluwole Fadare, Wenxin Zheng, Marta A Crispens, Howard W Jones III, Dineo Khabele, Katja Gwin, Sharon X Liang, Khaled
Moham-med, Mohamed M Desouki, Vinita Parkash, Jonathan L Hecht
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA; Department of
Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Pathology and Department
of Obstetrics & Gynecology, University of Arizona College of Medicine, Tucson, AZ, USA; Department of Pathology, University of
Chicago, Chicago, IL, USA; Department of Pathology and Laboratory Medicine, North Shore-LIJ Health System and Hofstra North
Shore-LIJ School of Medicine, New Hyde Park, NY, USA; Department of Gastroenterology, University of Pittsburgh Medical
Center, Pittsburgh, PA, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT, USA and Department
of Pathology, Bridgeport Hospital, Bridgeport, CT, USA; Department of Pathology, Beth Israel Deaconess Medical Center and
Harvard Medical School, Boston, MA, USA
Received November 5, 2012; Accepted December 18, 2012; Epub January 18, 2013; Published January 25, 2013
Abstract: Clear cell carcinoma of the endometrium (CCC) is an uncommon histotype whose analyses have generally been
hampered by its rarity and issues of interobserver diagnostic variability. In this study, we analyzed the clinicopathologic features
of 50 CCCs that were assembled from multiple institutions and which we considered to be morphologically unambiguous after
a rigorous review process for diagnostic accuracy. Forty-four (88%) of the 50 CCC cases showed an admixture of the classic
architectural patterns (glandular, papillary, solid and cystic in decreasing order of prevalence). Mitotic indices were variable but
were generally low: 60% of cases had a mitotic index of 3 or lower. The predominant cell type lining glands and papillae was
invariably hobnail and/or cuboidal. Stratification of nuclei (greater than 3 cells) or columnar cells on glands and papillae were
uncommon and never diffusely present. 82% of cases showed an admixture of polygonal cells with clear and eosinophilic
cytoplasm; only clear cells were present in 4% and only eosinophilic cells were present in 10%. Hobnail cells were common,
being identifiable in 86% of cases, and being diffuse in 60%. Only 2 cases had a predominance of nuclear grade 3 cells.
Psammoma, hyaline and targetoid bodies were identified in 32%, 52% and 20% of cases respectively. Clear cell endometrial
intraepithelial carcinoma was identified in 41.7% of cases with evaluable background endometrium. The 5-year progression free
survival (PFS) for the entire cohort was 61%, and was 88%, 75%, 22% and 28.6% for stages I to IV respectively. On univariate
analyses, age >65 years, advanced FIGO stage, and the presence of any lymph node metastases were associated with reduced
PFS (p=0.02, 0.002, and 0.002 respectively). On multivariate analyses, the only variable associated with reduced PFS was age
>65 years. The 5-year overall survival (OS) for the entire cohort was 78%, and was 94%, 87.5%, 66.7%, and 42.8% for stages I to
IV respectively. On univariate analyses, the following factors were associated with reduced OS: age >65 years (p=0.04),
advanced FIGO stage (p=0.003), distant metastases (p=0.003), myometrial invasion >30% (p=0.01), a mitotic index >4
(p=0.014), and a specific architectural pattern (at least 10% of the tumor composed of solid masses or individual infiltrating
tumor cells, p=0.02). On multivariate analyses, only age >65 years and advanced stage were associated with reduced OS
(p=0.023 and 0.022 respectively). In summary, endometrial CCC has a wide morphologic spectrum that is detailed and
illustrated herein, but also has core cytoarchitectural features that are of high diagnostic utility. Morphologically unambiguous
CCC apparently have patient outcomes that are more favorable than has previously been reported, indicating that ambiguous
tumors should be classified separately. The existence of morphologically ambiguous clear-cell rich carcinomas that do not fit the
conventional histotypic groupings, is a likely reflection of the biologic complexity of endometrial carcinomas in general; these
cases should be reported descriptively, and studied separately from conventional CCC. (ajcr0000159).
Keywords: Clear cell carcinoma, endometrium, morphologic features
Address all correspondence to:
Dr. Oluwole Fadare
Department of Pathology, Microbiology and Immunology
MCN C-2310D, Vanderbilt University Medical Center
1161 21st Avenue S, Nashville, TN 37232, USA.
E-mail: oluwolefadare@yahoo.com
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American Journal of Cancer Research
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