Müllerian clear cell carcinoma arising from sigmoid endometriosis with pericolic lymph node metastasis in the absence of adnexal disease: a case report

Background: Malignant transformation of endometriosis is rare and most commonly involves the ovary. Extraovarian transformation, particularly in the gastrointestinal tract, is exceptional, and clear cell carcinoma (CCC) arising from intestinal endometriosis is rarely reported. Case presentation: We report a 64-year-old postmenopausal woman with no prior history of endometriosis in whom a sigmoid lesion was incidentally detected during follow-up for a presumed benign ovarian cyst. Colonoscopic biopsy revealed a poorly differentiated carcinoma with clear cell features, and immunohistochemistry (PAX8+, CK7+, HNF1β+, CK20−) supported a Müllerian origin. The patient underwent complete cytoreductive surgery (R0). Final histology confirmed Müllerian clear cell carcinoma arising from sigmoid endometriosis with pericolic lymph node metastasis (pT3N1M0). Integration of the immunophenotypic profile (PAX8+, CK7+, HNF1β+, CK20−), and demonstration of adjacent endometriosis supported the diagnosis of Müllerian clear cell carcinoma arising from endometriosis, fulfilling the Sampson and Scott criteria. She received adjuvant carboplatin and paclitaxel and is disease-free at 6 months.

Müllerian CCC arising from intestinal endometriosis is extremely rare and may occur in postmenopausal women without known endometriosis. Accurate immunohistochemical diagnosis is essential to avoid misclassification and guide appropriate oncologic management.

Endometriosis is a chronic inflammatory condition affecting approximately 10% of women of reproductive age and is characterized by the presence of endometrial-like tissue outside the uterine cavity, leading to inflammation, fibrosis, and adhesions. Although traditionally considered a benign disease, endometriosis exhibits several features of malignancy, including invasive growth, neoangiogenesis, and immune evasion (). Malignant transformation of endometriosis is a rare event, occurring in approximately 0.5–2.5% of cases, and most commonly involves the ovary (). Malignant transformation of endometriosis is thought to involve a multistep process driven by chronic inflammation and oxidative stress, together with the accumulation of molecular alterations affecting pathways involved in cell proliferation, survival, and apoptosis, including alterations in ARID1A and PI3K/AKT/mTOR signaling (–) Extraovarian transformation accounts for approximately 25% of cases and is usually associated with endometrioid histology, whereas clear cell carcinoma (CCC) represents a less frequent but clinically relevant subtype (). The diagnosis of carcinoma arising from endometriosis is based on the Sampson and Scott criteria: 1) coexistence of benign endometriosis and carcinoma, 2) histologic continuity between them, and 3) exclusion of another primary tumor, along with histological evidence of a transition from benign endometriosis to carcinoma (). Müllerian CCC arising from intestinal endometriosis is exceptionally rare, particularly in the absence of ovarian involvement. Moreover, it may occur in postmenopausal women and in the absence of a known history of endometriosis, posing significant diagnostic challenges and a potential risk of misclassification as primary colorectal carcinoma. In these cases, differential diagnosis can be particularly challenging and requires integration of morphological and immunophenotypic findings with histopathological evidence of adjacent endometriosis. In this context, we report a case of Müllerian clear cell carcinoma arising from sigmoid endometriosis with pericolic lymph node metastasis and no evidence of adnexal disease, providing detailed clinicopathological and immunohistochemical characterization and highlighting the diagnostic and therapeutic implications of this rare entity. Case presentation A 64-year-old postmenopausal woman (BMI 23, two vaginal deliveries, spontaneous menopause at 53 years, no prior pelvic surgery, no history of hormone replacement therapy) with a history of hypertension and no prior diagnosis of endometriosis presented to the emergency department in May 2025 with hypertensive crisis and chest pain. Laboratory findings suggested acute myocardial injury; however, coronary angiography excluded significant coronary artery disease. The patient was discharged on antihypertensive therapy and scheduled for further investigations, including abdominal ultrasound. In June 2025, abdominal ultrasound revealed a suspicious left ovarian cyst, and the patient was referred to our tertiary referral center. Transvaginal ultrasound performed in July 2025 identified a unilocular solid cyst of the left ovary measuring 11 × 11 × 12 mm, with a 5 mm papillary projection and no vascularization (Color Score 1). The patient was asymptomatic, and a 4-month follow-up was planned. At follow-up, the ovarian lesion remained stable. However, a new 12 × 14 × 15 mm solid mass was identified arising from the lateral wall of the sigmoid colon, showing internal vascularization and synchronous movement with the adjacent bowel loop, suggesting an intestinal origin (Figures 1A, B). The patients was asymptomatic for abdominal pain or dyschezia. Contrast-enhanced computed tomography (CT) showed no evidence of ascites, lymphadenopathy, or peritoneal carcinomatosis and did not identify any rectal mass or other suspicious rectal lesion. Serum CA-125 was within the normal range (9 U/mL). Colonoscopy confirmed the presence of an ulcerated sigmoid lesion (Figures 1C, D), and biopsy revealed a poorly differentiated carcinoma with clear cell features and papillary architecture. Immunohistochemistry was positive for PAX8, CK7, and HNF1β, supporting a Müllerian origin. In January 2026, the patient underwent proctosigmoidectomy with total mesorectal excision, modified radical hysterectomy, bilateral salpingo-oophorectomy, omentectomy, peritoneal biopsies, and bilateral pelvic and para-aortic lymphadenectomy. Complete cytoreduction (R0) was achieved. The postoperative course was uneventful, and the patient was discharged on postoperative day 6 without complications. Final histopathological examination revealed Müllerian clear cell carcinoma diffusely infiltrating the sigmoid colon, with full-thickness involvement and lymphovascular invasion. One of seven pericolic lymph nodes was positive for metastatic disease (3.5 mm), while a total of 34 pelvic and para-aortic lymph nodes were negative. Surgical margins were free of disease. Histopathological examination of the left ovarian lesion revealed a serous cystadenofibroma, with no evidence of malignancy. Figure 1 Immunohistochemical analysis (Figure 2) showed positivity for CK7 and SOX17 and negativity for CK20. ARID1A and PTEN expression were preserved, hormone receptors were negative, p53 showed a wild-type pattern, and mismatch repair proteins were proficient. The uterus and adnexa were free of malignancy. Foci of perivisceral endometriosis adjacent to the tumor were identified, fulfilling the Sampson and Scott criteria. The case was discussed at a multidisciplinary tumor board. In the absence of a dedicated staging system, the tumor was classified according to the colorectal TNM system as pT3N1M0 (stage IIIB). The patient completed adjuvant chemotherapy with carboplatin and paclitaxel and is currently alive and disease-free at 6 months of follow-up (Table 1). Figure 2 Table 1 | Time | Clinical event | |---|---| | Initial presentation | Asymptomatic. Incidental finding of ovarian cysts after routine ultrasound | | Diagnostic work-up | Ultrasound. CT scan. Colonoscopy. | | Preoperative assessment | Multidisciplinary evaluation and treatment planning | | Surgery | Total hysterectomy + Bilateral Salpingo-oophorectomy + sigmoid resection + peritonectomy + omentectomy + pelvic and lomboartic lymphadenectomy | | Histopathological examination | Müllerian clear cell carcinoma diffusely infiltrating the sigmoid colon | | Postoperative period | Postoperative course was uneventful, and the patient was discharged on postoperative day 6 without complications | | Follow-up | The case was discussed at a multidisciplinary tumor board. the tumor was classified according to the colorectal TNM system as pT3N1M0 (stage IIIB). The patient was started on adjuvant chemotherapy with carboplatin and paclitaxel and is currently alive and disease-free at 4 months of follow-up | Clinical timeline according to CARE Check list.

To our knowledge, this represents one of the very few reported cases of Müllerian clear cell carcinoma arising from sigmoid endometriosis with pericolic lymph node metastasis, and one of the most comprehensively characterized in terms of immunohistochemical profile. A clinically relevant aspect of this case is the context in which the tumor developed. It demonstrates that malignant transformation of endometriosis may occur in the colon, in a postmenopausal patient, in the absence of a known history of endometriosis, and in the presence of completely normal ovaries. These findings challenge the traditional perception of endometriosis-associated malignancies as predominantly ovarian diseases affecting women of reproductive age. Instead, they support the concept that clinically silent or previously undiagnosed endometriotic foci may persist beyond menopause and retain the potential for malignant transformation. Consequently, Müllerian origin should be considered in the differential diagnosis of atypical colorectal tumors in women, regardless of age or prior clinical history. Clear cell carcinoma involving the colon is an exceptionally rare entity and encompasses two biologically distinct subtypes: intestinal-type and Müllerian-type tumors (). This distinction is clinically crucial, as these entities differ not only in histogenesis but also in diagnostic pathways and therapeutic management. Intestinal-type clear cell carcinoma is typically associated with conventional colorectal adenocarcinoma or adenomatous lesions and expresses markers of intestinal differentiation, such as CK20, CDX2, and CEA (). In contrast, Müllerian-type tumors arise from ectopic endometrial tissue and display a characteristic immunophenotype, including CK7, PAX8, HNF1β, and SOX17 positivity (), with absence of intestinal markers. In the present case, the coexistence of endometriosis adjacent to the tumor, the Müllerian immunoprofile (CK7+/CK20−/PAX8+/SOX17+), and the absence of a primary gynecologic malignancy strongly support the diagnosis of Müllerian clear cell carcinoma arising from intestinal endometriosis, fulfilling Sampson and Scott criteria (). This distinction is not merely academic but has direct clinical implications. Without appropriate immunohistochemical characterization, this tumor could have been misclassified as a primary colorectal carcinoma, potentially leading to an inappropriate therapeutic strategy. The extreme rarity of this condition limits robust comparisons with the literature. Nevertheless, previously reported cases provide a useful framework for contextualizing the present findings (Table 2). Earlier reports by Finkelstein et al., Min et al., and Okazawa et al. described clear cell adenocarcinomas arising in rectal endometriosis, supporting the concept that ectopic endometrial tissue within the colorectal wall can undergo malignant transformation toward a clear cell phenotype (–). More recently, Gaia-Oltean et al. reported a Müllerian clear cell carcinoma developing within rectal endometriosis, further emphasizing the diagnostic importance of demonstrating an association between the tumor and adjacent endometriotic foci (). Table 2 | Features | Lochner et al. (2025) case | Our case | |---|---|---| | Location | Rectum | Sigmoid colon | | Histological Type | Mullerian clear cell carcinoma | Mullerian clear cell carcinoma | | Uterus & adnexa | Disease free | Disease free | | Endometriosis | Yes, on the rectum wall | Yes, on the sigmoid wall perivisceral tissue and parietal peritoneum | | Nodes metastasis | 5 pericolic nodes | 1perisigmoidnode | | Lomboaorticnodes | Not specified | Negative | | ARID1A | Mutationidentified | Preserved function | | PTEN | Not specified | Preserved function | | p53 | Not specified | Wild-type | | MMR | Not specified | Proficient | | Surgery | Total hysterectomy + Bilateral Salpingo-oophorectomy+Proctosigmoidectomy | Total hysterectomy + Bilateral Salpingo-oophorectomy + sigmoid resection + peritonectomy + omentectomy + pelvic and lomboartic lymphadenectomy | | Adjuvant chemotherapy | yes | yes | | Outcome | Disease-free at 4 years follow-up | Disease-free at 4-month follow-up | Comparison between our case and the “twin” case by Lochner at al. (2025). Despite their common association with intestinal endometriosis, the reported cases show considerable heterogeneity in clinical presentation, extent of disease, surgical management, and pathological assessment (Table 2). Notably, most previously described tumors involved the rectum, whereas the present tumor arose in the sigmoid colon, highlighting that malignant transformation may occur at different sites along the rectosigmoid tract. Furthermore, lymph-node metastases were absent in several previously reported cases. The most comparable case is that reported by Lochner et al. (2025) () (Table 2), describing a Müllerian clear cell carcinoma arising from rectal endometriosis with pericolic lymph node metastases and no ovarian involvement. Our case confirms and expands these observations, demonstrating that lymphatic dissemination may occur even in tumors arising from apparently localized intestinal endometriotic foci. The presence of nodal involvement has important surgical implications. Although the available evidence is limited to a very small number of reported cases and does not allow definitive recommendations regarding the optimal surgical approach, these findings suggest that oncologic resection including lymph node assessment should be considered when Müllerian clear cell carcinoma arising from intestinal endometriosis is suspected. Limited or segmental resections without nodal assessment may be insufficient, given the potential for lymphatic spread. This reinforces the need to manage these tumors according to oncologic principles rather than as benign or borderline lesions. Staging and management remain challenging due to the absence of dedicated guidelines. In clinical practice, staging is generally based on colorectal TNM classification (), reflecting the anatomical origin and pattern of dissemination. However, treatment strategies are largely derived from gynecologic oncology, particularly ovarian clear cell carcinoma, given the shared biological features. This distinction is critical, as therapeutic approaches differ significantly depending on tumor origin. In this context, complete cytoreductive surgery followed by platinum-based chemotherapy represents the most widely adopted strategy (). From a therapeutic perspective, molecular overlap with ovarian clear cell carcinoma may open future avenues for targeted treatment strategies. Alterations involving chromatin remodeling genes such as ARID1A and signaling pathways such as PI3K/AKT/mTOR have been associated with potential sensitivity to targeted therapies and immune checkpoint inhibitors in Müllerian tumors (, ). Although these alterations were not identified in our case, the underlying biological similarity suggests that molecular profiling may play an increasingly important role in guiding treatment in selected patients. Finally, this case highlights the importance of a multidisciplinary approach. The integration of imaging, endoscopy, pathology, and gynecologic oncology expertise was essential to achieve an accurate diagnosis and define the most appropriate management strategy. However it has also inherent limitations. Given the exceptional rarity of Müllerian clear cell carcinoma arising from intestinal endometriosis, the available evidence is largely restricted to individual case reports, limiting meaningful comparisons and precluding definitive conclusions regarding optimal surgical and systemic treatment. Furthermore, the relatively short follow-up period of 6 months in the present case does not allow assessment of long-term oncologic outcomes. In conclusion, this case expands the current spectrum of endometriosis-associated extragonadal malignancies and underscores several clinically relevant points: the potential for malignant transformation in asymptomatic endometriosis, even in postmenopausal women; the critical importance of accurate diagnosis to avoid misclassification and inappropriate treatment; and the need for an oncologically adequate surgical and therapeutic approach tailored to Müllerian origin. Its rarity, diagnostic complexity, and therapeutic implications make this entity highly relevant and deserving of further investigation. Statements Data availability statement The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors. Ethics statement Ethical approval was not required for the study involving humans in accordance with the local legislation and institutional requirements. Written informed consent to participate in this study was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and the institutional requirements. Author contributions MG: Writing – original draft, Data curation, Writing – review & editing. JG: Supervision, Investigation, Writing – review & editing, Data curation. CR: Methodology, Writing – review & editing, Data curation. AL: Project administration, Supervision, Writing – review & editing, Data curation. FM: Visualization, Methodology, Project administration, Supervision, Investigation, Writing – review & editing. PI: Validation, Project administration, Writing – review & editing, Supervision. AP: Supervision, Project administration, Writing – review & editing, Conceptualization, Methodology, Validation, Data curation. Funding The author(s) declared that financial support was not received for this work and/or its publication. Conflict of interest The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Generative AI statement The author(s) declared that generative AI was not used in the creation of this manuscript. Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us. Publisher’s note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Supplementary material The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2026.1945284/full#supplementary-material

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clear cell carcinoma, endometriosis, extragenital endometriosis, Mullerian tumor, sigmoid colon Citation Girlando M, Garcia JM, Ravaioli C, De Leo A, Mezzapesa F, De Iaco P and Perrone AM (2026) Müllerian clear cell carcinoma arising from sigmoid endometriosis with pericolic lymph node metastasis in the absence of adnexal disease: a case report. Front. Oncol. 16:1945284. doi: 10.3389/fonc.2026.1945284 Received 22 July 2026 Revised 11 August 2026 Accepted 17 August 2026 Published 27 August 2026 Volume 16 - 2026 Edited by Robert Fruscio, University of Milano Bicocca, Italy Reviewed by Endeshaw Kindie, University of Gondar, Ethiopia Radomir Gelevski, Kumanovo General Hospital, North Macedonia Updates Copyright © 2026 Girlando, Garcia, Ravaioli, De Leo, Mezzapesa, De Iaco and Perrone. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Matteo Girlando, [email protected]; Jose Manuel Garcia, [email protected] Disclaimer All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.