A rare case of bilateral adnexal Müllerian adenosarcoma arising from endometriosis: A case report and literature review

Abstract

Background

Müllerian adenosarcoma is an uncommon mixed epithelial–mesenchymal neoplasm that predominantly develops in the uterine corpus and rarely occurs in extrauterine sites, including the ovary. Ovarian adenosarcoma is associated with a more aggressive course and is often linked to endometriosis.

Case presentation

We present the case of a nulliparous woman in her early 30s who presented with abdominal bloating, pelvic pain, and significant ascites. Imaging studies revealed bilateral adnexal solid–cystic masses. Histopathologic and immunohistochemical (IHC) evaluation of the resected specimens demonstrated Müllerian adenosarcoma involving both adnexa and peritoneal surfaces, likely arising from endometriosis.

Conclusion

This case highlights the diagnostic difficulty of extrauterine Müllerian adenosarcoma, particularly when presenting as bilateral adnexal Müllerian adenosarcoma with peritoneal involvement arising in the setting of endometriosis. Detailed histopathologic evaluation is essential, especially when glandular elements show mucinous differentiation, which broadens the differential diagnosis.

Introduction

Mullerian adenosarcoma is a rare biphasic tumor composed of benign or mildly atypical Müllerian epithelium and a malignant stromal component. ¹ While it predominantly develops in the uterine corpus, it can also occur in the cervix, ovaries, or even outside the reproductive system. ² Adenosarcoma is recognized as a neoplasm with low malignant potential, primarily associated with local recurrence, though distant metastasis can occasionally occur. ³ Extrauterine cases are frequently associated with endometriosis, supporting a pathogenic link between endometriosis and tumorigenesis.^4–7

The primary symptom of uterine adenosarcoma is abnormal uterine bleeding in postmenopausal women, although it can also occur in younger individuals. ⁸ Extra-uterine adenosarcoma does not have specific features and often presents as abdominal discomfort.^9,10 Unlike uterine adenosarcomas, ovarian adenosarcomas tend to be more aggressive and associated with a worse prognosis.^9,11 They typically present at an advanced stage and are often seen in younger patients.^9,12 Ovarian adenosarcoma usually presents as a unilateral mass, but it rarely involves both ovaries. ⁹

The preferred treatment for uterine adenosarcoma is hysterectomy with bilateral salpingo-oophorectomy, though ovarian preservation may be considered in select premenopausal patients with early-stage disease. The effectiveness of additional radiation therapy and chemotherapy is uncertain and has not been thoroughly assessed. ¹³

Here, we report a rare case of bilateral adnexal Müllerian adenosarcoma with peritoneal involvement arising in the setting of endometriosis.

Methods

The reporting of this study conforms to the CARE guidelines. ¹⁴ Ethical approval was obtained from the Ethics Committee of Shiraz University of Medical Sciences (Approval No: IR.SUMS.MED.REC.1404.126). The study was conducted in accordance with the Helsinki Declaration of 1975, as revised in 2024. The patient details have been de-identified. Written informed consent was obtained from the patient for both treatment and publication.

Case presentation

A premenopausal, nulliparous, Persian woman in her early 30s (BMI: 23.4 kg/m²) presented to the gynecological clinic at our center, complaining of abdominal bloating, intermittent pelvic pain, and unintentional weight loss for approximately 4 months prior to presentation. She had no previous personal or family history of gynecological malignancies.

On physical examination, abdominal palpation revealed moderate ascites and two palpable mass like lesions at both adnexa. Pelvic examination confirmed bilateral enlarged adnexa with associated tenderness. The patient was afebrile and other vital signs were stable.

Abdominopelvic and retroperitoneal sonography depicted two solid-cystic masses measuring 93×66 mm in the left adnexa and 76×60 mm in the right adnexa.

Spiral CT scan of the abdomen and pelvis with and without contrast revealed two large, infiltrative, heterogenous, solid-cystic masses with enhancement, measuring 183×95×102 mm in total, occupying both pelvic sides and the presacral area. The ovaries were not separately identifiable; the masses appeared to arise from the adnexal regions with associated peritoneal thickening and ascites, suggestive of primary adnexal origin with peritoneal seeding (Figure 1).

Figure 1.

Axial CT images of the pelvis. (a) Non-contrast image showing bilateral solid-cystic pelvic masses. (b) Post-contrast image demonstrating heterogeneous enhancement within the masses, with peritoneal thickening and nodularity, suggestive of peritoneal seeding.

Laboratory tests revealed markedly elevated CA-125 (970 U/ml; normal <35 U/ml) and HE4 (119 ρmol/L; normal <70 ρmol/L). LDH was also elevated (350 U/L), while CEA was within normal limits.

A core-needle biopsy of the left adnexal mass under ultrasound guidance revealed a spindle cell tumor covered by bland-looking epithelial components. IHC conducted on the biopsy specimen showed CD10 positivity, CK negativity in stromal cells, focal positivity for SMA (Smooth Muscle Actin), PAX8 positivity in epithelial cells, and a high MIB1 index (50%). Based on the histologic features and IHC results, differential diagnosis included Müllerian adenosarcoma, adenofibroma, low-grade endometrial stromal sarcoma (LGESS) with entrapped epithelium and mucinous neoplasm of the ovary.

Following a course of neoadjuvant chemotherapy with Taxol, Carboplatin, and Bevacizumab, the patient underwent exploratory laparotomy, which included a transabdominal hysterectomy with bilateral salpingoophorectomy (TAH-BSO), bilateral ureter exploration, and resection of peritoneal masses. During surgery, four separate peritoneal nodules were identified and excised, ranging from 1.5 to 3.2 cm in greatest dimension. Endometriotic lesions were also noted on the pelvic peritoneum and ovarian surfaces, consistent with stage III (moderate) endometriosis according to the revised ASRM classification.

On gross examination, the uterus was unremarkable. Both ovaries were enlarged with tumor involving ovarian surfaces and parenchyma. The tumors were centered in both ovaries with surface extension and peritoneal implants, confirming bilateral ovarian adenosarcoma with secondary peritoneal involvement.

Microscopic examination of the peritoneal mass revealed a biphasic pattern of growth composed of benign mucinous epithelial and malignant stromal components along with intraglandular projections and leaf-like (phyllodes-like) architecture that is prominent at low magnification. Also, moderate stromal cytologic atypia, periglandular stromal condensation (periglandular cuffing) and mitotic activity about 3-4 per 10 high power fields in stromal component could be appreciated (Figure 2). Both ovaries showed surface involvement with adenosarcoma and also endometriosis (Figure 3).

Figure 2.

Microscopic features of the tumor. (a and b) Low-power view showing leaf-like (phyllodes-like) architecture (H&E, ×4). (c) Periglandular stromal cuffing (H&E, ×10). (d) Mucinous epithelial lining (H&E, ×40).

Figure 3.

(a) Ovarian surface involvement by adenosarcoma (H&E, ×10). (b and c) Endometriosis with endometrial glands and stroma (H&E, ×10).

The patient’s postoperative recovery was uneventful, and she continued maintenance therapy with Bevacizumab. Surveillance imaging with CT scans at six months post-surgery showed no evidence of disease. However, at the one-year follow-up, a new enhancing pelvic mass was identified on imaging, consistent with disease recurrence. Approximately one year after initial surgery, surveillance imaging identified a new, well-defined subcutaneous mass in the right pelvic sidewall measuring 54 × 35 × 53 mm, exhibiting heterogeneous enhancement with central necrosis on contrast-enhanced CT, and no evidence of intraperitoneal extension (Figure 4(a)). The mass was excised, and histopathological examination revealed a monophasic, high-grade sarcomatous proliferation composed of densely packed spindle cells with marked nuclear atypia, pleomorphism, and frequent mitotic figures (up to 12 per 10 high-power fields). No residual glandular epithelial components were identified, confirming recurrent disease in the form of pure sarcomatous overgrowth (Figure 4(b) and (c)). The patient was subsequently referred for further systemic therapy.

Figure 4.

Radiologic and histopathologic findings at recurrence. (a) Axial contrast-enhanced CT image of the pelvis demonstrates a new, heterogeneously enhancing subcutaneous mass (arrow) in the right pelvic sidewall. (b) Low-power microscopic view (H&E, ×4) of the recurrent mass showing a hypercellular, purely sarcomatous proliferation without an epithelial component. (c) High-power view (H&E, ×40) of the same area confirms high-grade sarcomatous morphology with marked cytologic atypia and increased mitotic activity.

Discussion

Malignant mesenchymal neoplasms account for approximately 1-3% of all tumors found in the female genital tract, with Mullerian Adenosarcoma comprising about 8-10% of these malignancies. First described in 1974, this uncommon tumor is characterized by both stromal and epithelial components. ⁹ Mullerian adenosarcomas have the potential to occur at various extrauterine locations, with the ovary identified as the most prevalent site. However, other locations have also been reported, including the vagina, fallopian tubes, peritoneal areas such as the pouch of Douglas and intestinal serosa, as well as the intestine and the liver.^15–17 Some extrauterine tumors have shown an association with endometriosis, suggesting a potential link, while others seem unrelated and may originate from the peritoneal mesothelium, possibly as part of the secondary Mullerian system.

In a case series by Eichhorn et al., ⁵ 40 instances of ovarian adenosarcoma were reported, with only one case affecting both ovaries. Similarly, our patient exhibited adenosarcoma in both adnexa, which could also be attributed to endometriosis in both ovaries.

Endometriosis can lead to elevated levels of CA-125 on its own. In this patient, the increased level could be attributed to either endometriosis or her ovarian tumor. Shakuntala et al. noted that elevated levels of CA-125 are uncommon in cases of adenosarcoma. ¹⁸ However, our patient’s laboratory results indicated elevated CA-125 levels, aligning with the findings by Inoue et al., who identified increased CA-125 level as a potential indicator of sarcomatous overgrowth. ¹⁹ Notably, in post-surgery workups, the levels of CA-125 returned to normal in our patient.

Extra-uterine adenosarcoma is generally identified as a large, partially cystic mass with an irregular and lobulated surface. The tumor exhibits a mixed composition, including both epithelial and stromal components, with the stromal elements being more prominent. A key characteristic is the presence of a benign yet neoplastic epithelial element alongside a malignant mesenchymal component. Under low power magnification, the tumor frequently displays a leaf-like or club-like structure, similar to that of a phyllodes tumor found in the breast. The epithelial structures typically appear as glands, which can be either enlarged or narrow, and are significantly spaced apart by a rich stromal background. Additionally, the epithelial layer extends over leaf-shaped projections and is generally made up of cuboidal or low columnar cells. In our case, the cystically dilated glands were lined by bland-looking mucinous-type epithelium. The stromal element, frequently classified as low grade, consists of spindle-shaped and/or rounded cells. A distinctive feature of adenosarcoma is the arrangement of stromal cells around the glandular components, which results in the formation of a cuff known as “periglandular cuffing” or the “cambium” layer. The stromal cells within these regions demonstrate varying degrees of atypical characteristics, with nuclei that are typically hyperchromatic. While it is common to observe a mitotic count of two or more per 10 high-power fields (HPFs) in these tumors, some cases may present with a lower count. Furthermore, in many areas of a single neoplasm, the mitotic count may be reduced. Approximately 25% of adenosarcomas contain heterologous stromal components, mainly featuring Rhabdomyoblasts. However, characteristics of chondrosarcoma and liposarcoma may also be present. ³

Adenosarcoma is not typically a common type of ovarian tumor, so it’s important to consider other potential diagnoses before making a conclusion. Key differential diagnoses include endometrial stromal sarcoma, immature teratoma, malignant mixed Müllerian tumors, and pure sarcomas. However, it could be a reasonable diagnosis for a patient with endometriosis and bilateral ovarian masses. ¹ Other considerations include ovarian adenofibroma, which lacks significant stromal atypia or mitotic activity, and mucinous ovarian neoplasms with mural nodules, where the mesenchymal component is typically high-grade and lacks the biphasic, phyllodes-like architecture of adenosarcoma.

Adenosarcoma is a common gynecological cancer associated with endometriosis, following clear cell and endometrial carcinomas of the ovary. ²⁰ In 2000, Zanetta proposed that persistent stimulation from natural or artificial estrogen could raise the risk of developing cancer associated with endometriosis. ²¹ While endometriosis could contribute to the development of extrauterine adenosarcoma, it is generally viewed as a positive prognostic factor for this type of tumor. ²² Our case also had endometriosis at the surface of the left ovary.

From the histopathological perspective, the epithelial component appears as benign-looking glandular epithelium, typically of the endometrioid type. ¹⁸ However, in our case, the epithelial lining is of the mucinous type, which poses a diagnostic challenge. The presence of mucinous epithelium in adenosarcoma is uncommon and may lead to diagnostic confusion with mucinous ovarian tumors, particularly mucinous borderline tumors with mural nodules. In such cases, the presence of a low-grade biphasic pattern with periglandular cuffing and absence of high-grade sarcomatous nodules favors adenosarcoma. ²³

In the majority of adenosarcomas that have a low-grade stromal component and lack sarcomatous overgrowth, the stromal elements typically show positive expression of estrogen receptors, progesterone receptors, CD10, and WT1. They are negative for p53 and demonstrate a low MIB1 proliferation index.^24,25

Low-grade endometrial stromal sarcoma (LGESS) shares morphologic and immunophenotypic overlap, typically exhibiting diffuse CD10 and hormone receptor positivity. However, LGESS lacks an epithelial component and demonstrates characteristic tongue-like infiltration and arteriolar networks, aiding distinction.

In contrast, areas characterized by high-grade sarcoma and sarcomatous overgrowth exhibit an increased MIB1 proliferation index and may show positive expression for p53. In our case, we observed sarcomatous overgrowth and an increased MIB1 index in the stromal component.

Typically, a decrease in the expression of cell differentiation markers, such as estrogen and progesterone receptors and CD10, results in an immunophenotype resembling undifferentiated uterine sarcoma. ²⁵

The recurrence rate for uterine adenosarcoma is about 25%, whereas ovarian adenosarcoma has a notably higher recurrence rate of roughly 50%. Additionally, the mortality risk associated with ovarian adenosarcoma is over 35%, which is notably greater than that of uterine adenosarcoma. The management of ovarian adenosarcoma remains challenging due to its rarity and aggressive behavior. Surgical resection with total hysterectomy and bilateral salpingo-oophorectomy represents the cornerstone of treatment, complemented by surgical staging and optimal debulking of extra-ovarian disease.^9,10 In young patients desiring fertility preservation, unilateral salpingo-oophorectomy may be considered in carefully selected early-stage cases, albeit with caution given the higher risk of recurrence. ⁹ The role of adjuvant therapy is not well-established, though platinum-based chemotherapy is often administered in advanced or high-grade tumors, particularly those with sarcomatous overgrowth. ¹⁰ Hormonal therapy has been proposed for ER/PR-positive cases, though evidence is limited to small series and case reports. ²⁴

In the present case, a multimodality approach was employed, consisting of neoadjuvant chemotherapy (carboplatin, paclitaxel, and bevacizumab) followed by optimal surgical cytoreduction (TAH-BSO, ureterolysis, and resection of peritoneal deposits). This regimen initially resulted in significant symptomatic improvement and radiologic resolution of disease, consistent with reports of chemotherapy sensitivity in some advanced adenosarcomas. ¹⁰ However, the patient experienced a recurrence one year post-surgery, underscoring the characteristically high recurrence rate of ovarian adenosarcoma—reported to be approximately 50%—and its often-aggressive clinical course despite maximal initial therapy. ⁹ This outcome highlights the limited durability of current treatment protocols for advanced bilateral disease and emphasizes the need for vigilant long-term surveillance and the development of more effective adjuvant strategies.

Although not standard for ovarian masses due to risk of tumor seeding, biopsy was performed in this case due to the atypical presentation and need for histologic diagnosis prior to neoadjuvant therapy.

This case is notable for its bilateral adnexal involvement, association with endometriosis, and unusual mucinous epithelial differentiation—features that collectively broaden the clinicopathologic spectrum of extrauterine adenosarcoma and underscore diagnostic challenges in young patients with complex pelvic masses.

Conclusion

This case report highlights the rarity and complexity of bilateral ovarian adenosarcoma, a tumor that presents unique diagnostic and therapeutic challenges. It emphasizes the histopathologic and immunohistochemical features of adenosarcoma, which might not be a common diagnosis in ovarian spindle cell tumors especially when the specimen is brought from a tru-cut biopsy.