Clear cell carcinoma of the uterine corpus arising in long-standing adenomyosis after menopause: a case report

A 60-year-old woman (gravida 1, para 0) presented for evaluation following the incidental discovery of a pelvic mass. The patient was 164 cm tall and weighed 49 kg, with a body mass index of 18 kg/m 2 . Medical history included hypertension and benign paroxysmal positional vertigo; she had never smoked. Approximately 20 years earlier, the patient had been treated for dysmenorrhea and an approximately 5 cm cystic pelvic lesion that was clinically diagnosed at that time from magnetic resonance imaging (MRI) as an ovarian endometrioma ( Fig. 1 A). She received low-dose estrogen-progestin combinations and gonadotropin-releasing hormone (GnRH) agonists until treatment was discontinued at age 48 years. After menopause at age 50 years, the patient did not undergo gynecological follow-up for approximately 10 years. Following the postoperative histopathological diagnosis of EC-AIA, retrospective review of the earlier MRI findings showed that the cystic lesion corresponded anatomically to the current uterine lesion and was therefore interpreted as pre-existing adenomyosis. Fig. 1 Serial pelvic MRI findings over a 20-year interval. (A) Sagittal T2-weighted image obtained approximately 20 years before presentation, showing a cystic lesion at the same anatomical site as the current uterine lesion. (B) Sagittal T2-weighted image. (C) Axial diffusion-weighted image showing high signal intensity in the solid component of the mass. (D) ADC map demonstrating decreased ADC in the corresponding area. (E) Axial contrast-enhanced T1-weighted image showing enhancement of the solid component. Arrowheads: mass; arrows: solid component. MRI, magnetic resonance imaging; ADC, apparent diffusion coefficient. Fig. 1 Serial pelvic MRI findings over a 20-year interval. (A) Sagittal T2-weighted image obtained approximately 20 years before presentation, showing a cystic lesion at the same anatomical site as the current uterine lesion. (B) Sagittal T2-weighted image. (C) Axial diffusion-weighted image showing high signal intensity in the solid component of the mass. (D) ADC map demonstrating decreased ADC in the corresponding area. (E) Axial contrast-enhanced T1-weighted image showing enhancement of the solid component. Arrowheads: mass; arrows: solid component. MRI, magnetic resonance imaging; ADC, apparent diffusion coefficient. At a routine health screening, transabdominal ultrasonography incidentally revealed a 7 cm pelvic mass. Given the mass enlargement and suspicion of malignancy, the patient was referred for further evaluation. Transvaginal ultrasonography demonstrated a 7 cm hypervascular mass within the posterior wall of the uterine corpus, without ascites. Both cervical and endometrial cytology were negative. Contrast-enhanced pelvic MRI ( Fig. 1 B) revealed an approximately 7 cm mass in the right posterior uterine wall with mixed cystic and solid components. The solid portion featured restricted diffusion on diffusion-weighted imaging ( Fig. 1 C, D) and prominent contrast enhancement ( Fig. 1 E). Contrast-enhanced computed tomography (CT) of the chest and abdomen showed no evidence of lymphadenopathy or distant metastasis. Upper and lower gastrointestinal endoscopy was unremarkable. Serum tumor markers (CA125, carbohydrate antigen 19–9 [CA19–9], and carcinoembryonic antigen [CEA]) and lactate dehydrogenase (LDH) levels were all within reference ranges. Laparotomy was performed for suspected ovarian malignancy. Intraoperatively, a myoma-like mass was found in the posterior wall of the lower uterine corpus. A multilocular cystic mass was also observed in the left ovary. Dense adhesions, consistent with chronic pelvic endometriosis, were present among the posterior uterine mass, the anterior surface of the rectum, and the multilocular left ovarian mass ( Fig. 2 A). Gross examination of the right adnexa and left fallopian tube was unremarkable. A small amount of serosanguinous ascites was present in the pouch of Douglas. Since the mass was determined to be of uterine origin, the patient underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy. Gross examination of the resected specimen ( Fig. 2 B) revealed that the posterior lower uterine mass contained brown mucinous material, while the endometrium appeared unremarkable. The left ovary was multilocular and filled with clear serous fluid. Fig. 2 Intraoperative and gross findings. (A) Intraoperative view showing a myoma-like mass in the posterior wall of the lower uterine corpus (arrow), a multilocular cystic mass in the left ovary (arrowhead), and the anterior surface of the rectum (asterisk). Dense adhesions are present among these structures. (B) Cut surface of the hysterectomy specimen showing tumor tissue within the mass in the posterior wall of the lower uterine corpus, while the endometrium (arrowheads) shows no apparent lesion. Fig. 2 Intraoperative and gross findings. (A) Intraoperative view showing a myoma-like mass in the posterior wall of the lower uterine corpus (arrow), a multilocular cystic mass in the left ovary (arrowhead), and the anterior surface of the rectum (asterisk). Dense adhesions are present among these structures. (B) Cut surface of the hysterectomy specimen showing tumor tissue within the mass in the posterior wall of the lower uterine corpus, while the endometrium (arrowheads) shows no apparent lesion. Histopathological examination identified multiple foci showing transition from benign adenomyosis to CCC ( Fig. 3 A, B). Tumor cells with clear cytoplasm proliferated in tubulocystic and solid patterns within the 7 cm intramural mass ( Fig. 3 C), with hobnail cells ( Fig. 3 D). The endometrium was atrophic and free of atypia, with no evidence of continuity with the intramural tumor. The tumor extended beyond the adenomyotic foci and showed extensive invasion into the surrounding myometrium, with cervical stromal involvement. Lymphovascular space invasion was present. Immunohistochemistry showed that the tumor cells were estrogen receptor (ER) negative ( Fig. 3 E), diffusely positive for hepatocyte nuclear factor-1β (HNF-1β) ( Fig. 3 F), and focally positive for vimentin and Napsin A. p53 showed a wild-type staining pattern, whereas Wilms tumor 1 (WT-1) was negative. Based on these histomorphological and immunohistochemical findings, the tumor was diagnosed as CCC. The left ovarian tumor showed morphological features of a seromucinous borderline tumor and was histologically distinct from the uterine CCC. No CCC component was identified in the ovarian tumor. Immunohistochemically, the ovarian tumor was negative for HNF-1β and Napsin A, whereas the uterine CCC was positive for both markers. The ovarian tumor was confined to the ovary, with no anatomical continuity with the uterine lesion and no histopathological evidence of metastatic CCC. Endometriosis was not identified within the ovarian parenchyma, although endometriotic lesions were present in the ipsilateral fallopian tube. Ascitic cytology was negative. Fig. 3 Histopathological and immunohistochemical findings of clear cell carcinoma. (A) HE staining (×40) showing multiple foci of transition from benign adenomyosis to clear cell carcinoma (arrows). (B) HE staining (×100) showing a representative focus of transition from benign adenomyotic epithelium to clear cell carcinoma (arrow). (C) HE staining (×100) showing tumor cells with clear cytoplasm growing in tubulocystic and solid patterns. (D) HE staining (×200) showing hobnail cells. (E) Immunohistochemistry analysis for ER, showing positive staining in adenomyosis (arrowheads) and negative staining in clear cell carcinoma (arrows). (F) Immunohistochemistry analysis for HNF-1β, showing positive staining in clear cell carcinoma (arrows) and negative staining in adenomyosis (arrowheads). HE, hematoxylin-eosin; ER, estrogen receptor; HNF-1β, hepatocyte nuclear factor-1β. Fig. 3 Histopathological and immunohistochemical findings of clear cell carcinoma. (A) HE staining (×40) showing multiple foci of transition from benign adenomyosis to clear cell carcinoma (arrows). (B) HE staining (×100) showing a representative focus of transition from benign adenomyotic epithelium to clear cell carcinoma (arrow). (C) HE staining (×100) showing tumor cells with clear cytoplasm growing in tubulocystic and solid patterns. (D) HE staining (×200) showing hobnail cells. (E) Immunohistochemistry analysis for ER, showing positive staining in adenomyosis (arrowheads) and negative staining in clear cell carcinoma (arrows). (F) Immunohistochemistry analysis for HNF-1β, showing positive staining in clear cell carcinoma (arrows) and negative staining in adenomyosis (arrowheads). HE, hematoxylin-eosin; ER, estrogen receptor; HNF-1β, hepatocyte nuclear factor-1β. After the final postoperative histopathological diagnosis, additional comprehensive staging surgery, including pelvic lymphadenectomy, was proposed; however, the patient declined further surgery because preoperative imaging had shown no suspicious lymphadenopathy. The final diagnosis was International Federation of Gynecology and Obstetrics (FIGO) stage II uterine corpus cancer (pT2NXM0), CCC arising from adenomyosis, and FIGO stage IA ovarian borderline tumor (pT1aNXM0), seromucinous borderline tumor. Given the high risk of recurrence, the patient received six cycles of adjuvant chemotherapy with paclitaxel and carboplatin and remained recurrence-free 5 months after completion of chemotherapy.

Genichiro To: Writing – original draft, Data curation, Conceptualization. Ai Shinto: Writing – review & editing, Investigation, Data curation. Asako Fukuda: Writing – review & editing, Investigation, Data curation. Mariko Hashiguchi: Writing – review & editing, Investigation. Seiichi Kato: Writing – review & editing, Investigation. Yasushi Umezaki: Writing – review & editing, Investigation, Data curation. Kaoru Okugawa: Writing – review & editing, Supervision, Investigation, Data curation.

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Written informed consent was obtained from the patient for publication of the case report and accompanying images.

The estimated rate of malignant transformation of ovarian endometrioma ranges from 0.7% to 1.6% [5] , and this transformation is associated mainly with CCC and endometrioid carcinoma [1] . In contrast, endometrial carcinoma arising in adenomyosis (EC-AIA) is exceedingly rare [6] . The present case is clinically important because CCC arose within long-standing adenomyosis and was diagnosed after menopause, while preoperative diagnosis remained difficult despite suspicious imaging findings. As EC-AIA arises within the myometrium, patients often lack classic symptoms such as abnormal uterine bleeding, and routine cervical and endometrial cytology may remain negative, making preoperative diagnosis particularly challenging [3] , [4] . In their systematic review, Raffone et al. reported that 86% of cases ultimately diagnosed as EC-AIA postoperatively had been preoperatively suspected to represent other conditions, including uterine sarcoma, uterine leiomyoma, and ovarian cancer [3] . Similarly, in the present case, EC-AIA was not suspected preoperatively and the diagnosis was established only after surgical resection of a pelvic mass that had been incidentally detected during routine health screening. Specific transvaginal ultrasonography and pelvic MRI findings for EC-AIA have not been established [3] , [4] . In the present case, transvaginal ultrasonography demonstrated mass enlargement and increased vascularity, while pelvic MRI showed mixed cystic and solid components, with restricted diffusion and contrast enhancement in the solid portion. Although EC-AIA was not included in the preoperative differential diagnosis, these findings were suggestive of malignancy in a pelvic mass [7] , [8] , leading to surgical intervention. MRI obtained approximately 20 years earlier demonstrated a smaller cystic lesion at the same anatomical site, which had originally been clinically interpreted as an ovarian endometrioma. Following the postoperative histopathological diagnosis of CCC arising in adenomyosis, this earlier lesion was retrospectively interpreted as pre-existing adenomyosis. At presentation, the lesion had enlarged and developed solid components showing contrast enhancement and diffusion restriction. Although the exact timing of malignant transformation cannot be determined because regular gynecological follow-up was not performed after menopause, these interval imaging changes may raise suspicion for malignant change in a long-standing cystic adenomyotic lesion. Although imaging findings may raise suspicion for EC-AIA, the diagnosis ultimately depends on histopathological examination. The histopathological diagnosis is generally based on the Colman and Rosenthal criteria [9] : (1) no carcinoma in the endometrium or other pelvic tissues; (2) evidence of tumor origin from adenomyosis rather than invasion from another site; (3) endometrial stromal cells surrounding the glands to support the diagnosis of adenomyosis; and (4) histologic identification of a transition from benign adenomyosis to malignancy. The present case fulfilled all four criteria, including multiple transition foci from benign adenomyosis to CCC in the absence of endometrial involvement. Another noteworthy finding in the present case was the concomitant left ovarian seromucinous borderline tumor. The ovarian tumor was histologically and immunohistochemically distinct from the uterine CCC, with no CCC component, anatomical continuity, or evidence of metastatic involvement. These findings support the interpretation that the ovarian seromucinous borderline tumor and uterine CCC represented independent primary tumors. Although both tumor types have been reported in association with endometriosis [10] , [11] , no histopathological evidence of a direct relationship between the two tumors in this patient was observed. Nevertheless, their coexistence may reflect a shared endometriosis-related background. Adenomyosis is a common benign condition, occurring in approximately 40% of women who undergo hysterectomy for symptoms [12] . The present case adds to the literature on EC-AIA by demonstrating serial MRI changes over approximately two decades in a histologically confirmed case of CCC arising in adenomyosis. The exact timing of malignant transformation remains unknown. Nevertheless, careful assessment of interval changes in a long-standing cystic adenomyotic lesion, particularly the development of solid components, contrast enhancement, and diffusion restriction, may facilitate recognition of malignant change even in the absence of uterine bleeding or cytological abnormalities.

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Ovarian cancer, particularly endometrioid carcinoma and clear cell carcinoma (CCC), is well known to arise from ovarian endometrioma [1] . However, endometrial carcinoma arising in adenomyosis (EC-AIA) is exceedingly rare, accounting for less than 1% of all endometrial cancer cases [2] , [3] . CCC reportedly comprises 6–14% of EC-AIA cases [3] , [4] . As EC-AIA develops within the myometrium without involvement of the endometrium, abnormal uterine bleeding may be absent and cervical and endometrial cytology are frequently negative, rendering the preoperative diagnosis challenging [3] , [4] . This report describes a rare case of CCC arising in long-standing adenomyosis diagnosed after menopause and is presented in accordance with the CARE reporting guideline.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.