"Early" Clear Cell Proliferations (Clear Cell Carcinoma in Situ) in Ovarian Endometriotic Cysts: Report of a Case Series With Recommendations for Terminology

Nesa Samuel Karunadhas, Nesa S Karunadhas, Karunadhas NS, Mark Catherwood, Catherwood M, Stringfellow H, Helen F. Stringfellow, Helen Stringfellow, Arora R, Rupali Arora, W. Glenn McCluggage, McCluggage WG
The American journal of surgical pathology · 2025 · vol. 49(9) , pp. 901–908 · doi:10.1097/pas.0000000000002415 · PMID:40326407 · W4410127740
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⚙ AI-generated summary by gemini-2.5-flash-lite, 2026-06-26 ⓘ

This case series identified "CCC in situ" as non-invasive clear cell proliferations in ovarian endometriotic cysts, suggesting this terminology and careful sampling to rule out invasive cancer.

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⚙ AI-generated deep summary by qwen3.7-flash, 2026-08-16 · read from full text ⓘ

This case series analyzed six instances of clear cell proliferations within ovarian endometriotic cysts that exhibited malignant features but lacked stromal invasion. The atypical cells displayed specific immunophenotypic profiles, including positivity for Napsin A and HNF-1beta, while genetic testing revealed a pathogenic MSH6 variant in one patient. With no tumor recurrence observed during follow-up periods up to 24 months, the authors propose the term "clear cell carcinoma in situ" to accurately describe these early lesions. This terminology aims to guide pathologists in recommending extensive sampling to exclude invasive components and to prevent overtreatment through better clinician-patient communication. This paper is centrally about endometriosis — specifically the malignant transformation of endometriotic cysts into clear cell carcinoma in situ.

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Abstract

Clear cell carcinoma (CCC) is an uncommon malignancy accounting for ∼12% of ovarian carcinomas. Most cases arise from endometriosis, frequently an endometriotic cyst. We report a series of 6 cases where clear cell proliferations, morphologically, and immunophenotypically consistent with CCC, involve the epithelial lining of an endometriotic cyst without invasion into the surrounding stroma. The patients were aged 29 to 63 years (mean 45). In all cases, epithelial proliferations composed of cells with atypical nuclei, sometimes with a hobnail morphology, and clear or eosinophilic cytoplasm involved the epithelial lining of an ovarian endometriotic cyst. In areas, the proliferations comprised a monolayer, but in all cases, there was also significant epithelial stratification and multilayering, sometimes with a pseudopapillary architecture. There was no invasion of the atypical cells into the surrounding ovarian stroma. The proliferations were positive for Napsin A (6 of 6; 4 diffuse, 2 focal), racemase (5 of 5; 3 diffuse, 2 focal), hepatocyte nuclear factor 1-beta (5 of 5; all diffuse), oestrogen receptor (5 of 6; 2 diffuse, 3 focal), and PAX8 (3 of 3; all diffuse). p53 was wild-type in all 6 cases and WT1 and progesterone receptor were negative in the 4 and 6 cases tested, respectively. Mismatch repair immunohistochemistry was retained in the 3 cases tested. Next-generation sequencing was performed in 2 cases. In 1 case, a sole pathogenic MSH6 variant (p.Ser65fs) was identified. Follow-up (2 to 24 months) was available in 5 cases and there was no tumour recurrence. In reporting these "early" clear cell proliferations in endometriotic cysts, we provide recommendations for the reporting pathologist regarding the most appropriate terminology, which is important in patient management. We suggest that these proliferations be termed "CCC in situ" and that identification of such a lesion should prompt extensive sampling in order to exclude an invasive CCC component within the stroma outside the endometriotic cyst lining. We also stress the importance of close dialogue between the pathologist and the clinician and between the clinician and the patient in order to avoid overtreatment in such cases.
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Clear cell carcinoma (CCC) is an uncommon malignancy accounting for ∼12% of ovarian carcinomas. Most cases arise from endometriosis, frequently an endometriotic cyst. We report a series of 6 cases where clear cell proliferations, morphologically, and immunophenotypically consistent with CCC, involve the epithelial lining of an endometriotic cyst without invasion into the surrounding stroma. The patients were aged 29 to 63 years (mean 45). In all cases, epithelial proliferations composed of cells with atypical nuclei, sometimes with a hobnail morphology, and clear or eosinophilic cytoplasm involved the epithelial lining of an ovarian endometriotic cyst. In areas, the proliferations comprised a monolayer, but in all cases, there was also significant epithelial stratification and multilayering, sometimes with a pseudopapillary architecture. There was no invasion of the atypical cells into the surrounding ovarian stroma. The proliferations were positive for Napsin A (6 of 6; 4 diffuse, 2 focal), racemase (5 of 5; 3 diffuse, 2 focal), hepatocyte nuclear factor 1-beta (5 of 5; all diffuse), oestrogen receptor (5 of 6; 2 diffuse, 3 focal), and PAX8 (3 of 3; all diffuse). p53 was wild-type in all 6 cases and WT1 and progesterone receptor were negative in the 4 and 6 cases tested, respectively. Mismatch repair immunohistochemistry was retained in the 3 cases tested. Next-generation sequencing was performed in 2 cases. In 1 case, a sole pathogenic MSH6 variant (p.Ser65fs) was identified. Follow-up (2 to 24 months) was available in 5 cases and there was no tumour recurrence. In reporting these “early” clear cell proliferations in endometriotic cysts, we provide recommendations for the reporting pathologist regarding the most appropriate terminology, which is important in patient management. We suggest that these proliferations be termed “CCC in situ” and that identification of such a lesion should prompt extensive sampling in order to exclude an invasive CCC component within the stroma outside the endometriotic cyst lining. We also stress the importance of close dialogue between the pathologist and the clinician and between the clinician and the patient in order to avoid overtreatment in such cases. “Early” Clear Cell Proliferations (Clear Cell Carcinoma in Situ) in Ovarian Endometriotic Cysts Report of a Case Series With Recommendations for Terminology Plain Language SummaryClear cell carcinoma (CCC) is a rare type of ovarian cancer, often linked to endometriosis. This study examined six cases where CCC-like cell growths were found in the lining of endometriotic cysts, but did not invade surrounding tissue. Patients were aged 29 to 63, and the cell growths showed markers such as Napsin A, racemase, hepatocyte nuclear factor 1-beta, oestrogen receptor, and PAX8. Genetic testing was performed in two cases, revealing a pathogenic MSH6 variant in one case. No recurrence was observed in follow-ups up to 24 months. The study suggests calling these growths "CCC in situ" and recommends thorough examination to rule out invasive cancer, emphasizing careful communication to prevent unnecessary treatment. Text is machine generated and may contain inaccuracies. FAQ

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Condition tags

endometriosis

MeSH descriptors

Adenocarcinoma, Clear Cell Adenocarcinoma, Clear Cell Adenocarcinoma, Clear Cell Adenocarcinoma, Clear Cell Adenocarcinoma, Clear Cell Adenocarcinoma, Clear Cell Adenocarcinoma, Clear Cell Adenocarcinoma, Clear Cell Adenocarcinoma, Clear Cell Adenocarcinoma, Clear Cell Adenocarcinoma, Clear Cell Adenocarcinoma, Clear Cell Adenocarcinoma, Clear Cell Adenocarcinoma, Clear Cell Adenocarcinoma, Clear Cell Adenocarcinoma, Clear Cell Adenocarcinoma, Clear Cell Adenocarcinoma, Clear Cell Adenocarcinoma, Clear Cell Adenocarcinoma, Clear Cell

Citation neighborhood

Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. [ expand to 2 hops ] — adds papers reached through this work's immediate citers/citees. Heavier; up to 60 extra dots.

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