Two Cases of Extrauterine Müllerian Adenosarcoma Arising from Pelvic Endometriosis

Introduction

AMüllerian adenosarcoma is a rare entity. It was initially described in 1974. ¹ Histologic features are intermediate between a benign adenofibroma and a malignant carcinosarcoma, usually comprised of a benign epithelial component with a malignant mesenchymal component. ² This adenosarcoma arises most commonly in the uterus (95%). Extrauterine locations are less common and include the ovary, cervix, vagina, adnexae, pelvic peritoneum, rectovaginal septum, and intestinal serosa.^3–7 This article reports 2 cases of extrauterine Müllerian adenosarcoma arising from pelvic endometriosis, and discusses the clinical and histopathologic features of this exceedingly rare condition.

Cases and Results

Case 1

A 63-year-old nulliparous woman presented in June 2013 with abdominal discomfort and vaginal bleeding. A rectovaginal nodule was palpable on examination. Pelvic sonography revealed a 4-cm solid–cystic lesion with prominent vascularity. Magnetic resonance imaging (MRI) showed a solid mass in the rectouterine pouch; this mass was inseparable from the posterior vaginal wall.

Differential diagnoses included a rectovaginal septal tumor or an endometriotic deposit with possible malignant changes. Examination under anesthesia, hysteroscopy, and colonoscopy yielded unremarkable results apart from a 6-cm mass in the rectouterine pouch involving the upper third of the vagina and extending toward the parametria. Endometrial biopsy revealed atrophic endometrium.

This patient underwent a modified radical hysterectomy, bilateral salpingo-oophorectomy (BSO), resection of the rectovaginal mass, anterior resection, and diverting ileostomy in August 2013. Operative findings were a 6-cm mass in the rectovaginal septum that was inseparable from the rectum and upper vagina. The uterus and ovaries were normal. Frozen section and histology only showed endometriosis. The patient recovered uneventfully, with subsequent reversal of the ileostomy.

In May 2015, this patient presented with bloating, anorexia, and constipation. Examination revealed a grossly distended abdomen. Computed tomography (CT) showed a 25-cm solid–cystic mass extending from the rectosigmoid colon to the liver and a second 15-cm mass in the left lower abdomen. There were multiple hepatic hypodensities suspicious of metastases, but there was no ascites. Given this diagnostic uncertainty, ultrasound-guided biopsy of the larger mass was performed, revealing mixed features between endometriosis and a low-grade adenosarcoma. She underwent open surgical resection, small-bowel resection, and reanastomosis in June 2015. Intraoperatively, the masses were found arising from the pelvis on the right side of the rectum and adherent to the abdominal wall; and in the left iliac fossa extending to the left hypochondrium, densely adherent to the omentum and surrounding bowel. Adhesiolysis was performed, and chocolate-colored hemorrhagic material was seen. The resection was suboptimal, with residual disease left in the right pararectal space and liver edge. Histology of the specimens was reported as an adenosarcoma with sarcomatous overgrowth (Fig 1A and B).

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FIG. 1.

Case 1: (A) Staghorn and irregular glands surrounded by cellular and atypical stroma at 2× magnification. (B) Areas of high-grade sarcomatous overgrowth at 40× magnification. Case 2: (C) Cystic and irregular glands with stromal condensation at 2× magnification. (D) Mild stromal atypia with mitoses at 40× magnification.

A gynecologic tumor board recommended adjuvant chemotherapy. However, her postoperative course was complicated by right lower-limb venous thrombosis. Interval CT showed progressive disease although she had received 2 cycles of gemcitabine and doxorubicin. She opted to stop chemotherapy and was given supportive care. She died in November 2015.

Discussion

An extrauterine Müllerian adenosarcoma is a rare mixed epithelial–mesenchymal neoplasm, comprised of a mixture of benign glandular and malignant, usually-low grade, sarcomatous stromal components. There are three main theories for its pathogenesis. First, it can be associated with, or arise from, underlying endometriosis. Second, especially in cases with no endometriosis, this kind of adenosarcoma can arise from pluripotent mesothelial or mesenchymal cells within the pelvic cavity. Finally, this kind of adenosarcoma can also arise from Müllerian-duct remnants.^2,4

Malignant change is sometimes seen in endometriosis, although this is more common in ovarian endometriosis.^8,9 Adenosarcoma is the second most-common malignancy to arise from extraovarian endometriosis after clear-cell carcinoma.^10,11 Risk factors for malignant transformation include pelvic irradiation and prolonged estrogen exposure, such as with combined oral contraceptive, hormone-replacement therapy, or tamoxifen use.^5,12

The clinical presentation of an extrauterine Müllerian adenosarcoma is variable and reflects the wide range of locations it can affect.^3–6 It might present with vaginal bleeding, a pelvic mass, or simply be an incidental finding on cross-sectional imaging.

Histologically, differential diagnoses include adenofibroma, polypoid endometriosis, carcinosarcoma, endometrial stromal sarcoma, and fibrosarcoma.^1,13 Extrauterine adenofibroma is rare and is composed of cytologically bland epithelial and stromal components, with no evidence of mitoses, periglandular hypercellularity, or stromal overgrowth. The histologic criteria used to distinguish between an extrauterine adenofibroma and a low-grade adenosarcoma are based on criteria defined for uterine lesions.

Polypoid endometriosis is a variant of endometriosis characterized by polypoidal architecture resembling endometrial polyps with prominent blood vessels. Endometrial stromal sarcoma has sheets of uniform cells resembling stromal cells of proliferative endometrium, with a prominent network of small arterioles. Cluster designation (CD)–10 is a useful immunohistochemical marker for confirming this diagnosis. Fibrosarcoma is extremely rare and is a cellular lesion composed of fascicles of atypical spindle cells, with prominent mitoses and areas of hemorrhage and necrosis. Fibrosarcoma is often a diagnosis of exclusion, as there are no specific immunohistochemical stains or molecular profiles for this tumor. A standardized method of staging extrauterine adenosarcomas does not exist, although the International Federation of Gynecology and Obstetrics staging for uterine adenosarcoma would be a reasonable surrogate. ¹³

Surgical resection is the mainstay of treatment for extrauterine Müllerian adenosarcomas. Fertility-sparing surgery may be an option when there is early disease with no evidence of sarcomatous overgrowth, but radical surgery with adjuvant chemotherapy or radiotherapy is otherwise recommended.^6,10,11 Conventionally, surgery is performed via laparotomy, although laparoscopic treatment of vaginal adenosarcoma was described by Pontrelli and colleagues in 2016. ⁵ In addition to the attendant benefits of minimally invasive surgery, this approach also allowed better visualization of the patient's anatomy with more accurate and complete resection. ⁵ With further refinement in surgical techniques and equipment, laparoscopy may emerge as the preferred surgical approach in selected cases of this rare condition.

Varying combinations of adjuvant therapy are described in the literature. Doxorubicin-based chemotherapy has been suggested, as was used in the first case. ¹⁴ Alternatives include a combination of ifosfamide and cisplatin, or gemcitabine with docetaxel. ⁷ Adjuvant therapy with aromatase inhibitors has also been described. ¹⁵ Adjuvant radiotherapy may be included as part of a combined regimen if there is an increased recurrence risk, although there is a paucity of evidence for this. ¹¹

Although extrauterine Müllerian adenosarcoma is generally low-grade, it appears to occur in patients in a younger age group and to behave more aggressively than uterine adenosarcoma does. ¹⁶ Several factors have been illustrated to influence prognosis.

First, an extrauterine location has been shown to confer a worse prognosis (35% versus 10% mortality) and a greater likelihood of recurrence after primary surgery (50% versus 25%), compared to an uterine adenosarcoma. This aggressive behavior may be explained by the tumor's free access to the peritoneal cavity, with transcoelomic spread not hampered by the myometrium, compared to an uterine adenosarcoma. ⁷ A poorer prognosis may also be attributable to the increased risk of local complications at extrauterine sites, such as bowel obstruction; later presentation and, therefore, more advanced disease at diagnosis; and greater difficulty in achieving complete surgical clearance.^6,17

Second, the absence of underlying endometriosis confers a worse prognosis.^4,7 This may be explained by the lower disease aggressiveness and lower mitotic rate in the stromal component of an adenosarcoma if it has arisen from endometriosis. ⁷

Third, coexistent sarcomatous overgrowth, in which the tumor is composed of more than 25% of pure—usually poorly or undifferentiated—sarcoma, and a higher grade of the stromal component of the adenosarcoma, suggests more-aggressive disease with a worse prognosis.^4,7

Finally, disease recurrence following primary treatment portends a grave prognosis. ¹⁸

Conclusions

Further research is needed to better define the optimum screening, treatment, and follow-up for extrauterine Müllerian adenosarcoma. Despite its rarity, clinicians should be aware of this condition as a possibility in a woman presenting with a pelvic mass or abnormal vaginal bleeding with a history of endometriosis.