Uterine sarcomas

Uterine sarcomas are rare malignant tumors arising from the mesenchymal tissues of the uterus, i.e. the endometrial stroma, uterine muscle and connective tissue.  They represent 1% of female genital tract malignancies and 3-7% of all uterine malignances¹. Population-based estimates of uterine sarcoma incidence range from 1.55 to 1.95 per 100,000 women per year. It is estimated that ≤0.1% of patients operated on for presumed uterine leiomyoma have a uterine sarcoma². According to the 2011 WHO classification, uterine sarcomas are classified as leiomyosarcomas, endometrial stromal sarcoma or undifferentiated endometrial sarcoma^3,4. The median age of women with leiomyosarcomas was 50-56 years at diagnosis⁵, endometrial stromal sarcomas 40-55 years and undifferentiated stromal sarcomas 55-60 years⁴.

Age adjusted incidence of leiomyosarcoma was twice as high in black compared to white women⁵. Other risk factors were advanced age and postmenopausal status. Associations between endometrial stromal sarcoma and exposure to tamoxifen, unop­posed estrogen⁵ and polycystic ovary syndrome have also been reported. Endometrial stromal sarcoma is more common in women with past history of pelvic radiation⁵.

Leiomyosarcomas average 6-9 cm in diameter and the cut surface is typically soft, bulging, fleshy, necrotic and hemorrhagic with irregular margins⁶. Infiltrative growth into the myometrium is often noted grossly (or under the microscope), but some leiomyosarcomas may be relatively well circumscribed. About two-thirds are intramural, one-fifth submucosal and one tenth subserosal⁶. They are often single masses (50-75% of cases)⁴ If a leiomyosasrcoma is associated with leiomyomas, the sarcoma is usually the largest mass⁶. Leiomyosarcomas tend to be larger and softer than leiomyomas⁴. Endometrial stromal sarcomas have an irregular nodular growth involving the endometrium, myometrium, or both. Size is variable but most range from 5 to 10 cm. They typically have a yellow to tan fleshy cut surface with hemorrhage and necrosis occasionally seen⁶.

Undifferentiated endometrial sarcomas grow as soft polypoid tumors that bulge into the endometrial cavity and invade the underlying myometrium. Hemorrhage and necrosis are frequently present⁶.

Histopathological diagnosis of uterine sarcomas has always been a challenge, because many benign variants of smooth muscle tumors, e.g. mitotically active leiomyomas, apoplepletic leiomyomas and leiomyomas with bizarre nuclei, can simulate leiomyosarcormas. Diagnosis of endometrial stromal is also difficult which is reflected if frequent changes in their classification. The histopathologic diagnosis of uterine leiomyosarcoma is based upon mitotic count exceeding 10 mitotic figures per 10 high-power-fields (MF/10 HPF), cellular atypia, and the presence of coagulative necrosis⁷.  Leiomyosarcomas are composed of fascicles of spindle cells with abundant eosinophilic cytoplasm⁷ Cellular pleomorphism can be marked in poorly differentiated neoplasms. The mitotic index is usually high⁶. Tumor cell necrosis occurs in one third and is characterized by an abrupt transition from viable to not viable tissue. Both cytological atypia and mitotic activity should usually be present to diagnose leiomyosarcomas, because of the difficulty in reliably distinguishing between necrosis due to infarction and tumor cell necrosis⁶. The term endometrial stromal sarcoma is applied to neoplasms composed of cells that resemble endometrial stromal cells of the proliferative endometrium⁶. Endometrial stromal sarcomas are low grade tumors with cells of relatively uniform size and shape. They typically show < 3 MF/10 HPF, but there can also be greater mitotic activity¹ Proliferation of small vessels and arterioles resembling endometrial spiral arterioles is a characteristic finding. Cluster of differentiation 10 (CD10) - a metalloproteinase - is the most specific biomarker of endometrial stromal sarcoma. 

In undifferentiated endometrial sarcomas, tumor cell necrosis is generally present and can be extensive. Mitotic activity is variable but there are usually > 10 MF/10 HPF¹. These tumors should be diagnosed only after extensive sampling has excluded smooth muscle or skeletal muscle differentiation or small foci of carcinoma, because findings of these would result in a diagnosis of carcinosarcoma.

Leiomyosarcomas often present with symptoms of abnormal uterine bleeding (56%) either in the pre- or post-menopausal period, a palpable pelvic mass (54%), or abdominal pain (22%)¹. Signs and symptoms resemble those of benign leiomyomas, and preoperative distinction on the basis of clinical information between the two may be difficult. Malignancy should be suspected in case of tumor growth in menopausal women who are not on hormonal replacement therapy⁸ Occasionally, the presenting symptoms are explained by tumor rupture (hemoperitoneum), extrauterine growth (one-third to one-half of cases), or metastases⁶. Patients with endometrial stromal sarcomas often present with abnormal uterine bleeding and/or pelvic pain, but as many as 25% are asymptomatic⁹.

Recently Ludovisi et al¹⁰ retrospectively collected the preoperative ultrasound reports of 195 patients with a histological diagnosis of uterine sarcomas from 13 ultrasound centers: 116 leiomyosarcomas, 48 endometrial stromal sarcomas and 31 undifferentiated endometrial sarcomas. Median age of the patients was 56 (range, 26-86) years and most patients were postmenopausal (111/195, 56.9%).

Median largest tumor diameter was 91 (range 7-321) mm. According to the assessment by the original examiners (first step of analysis), all but one sarcoma with reliable information on tumor type (n = 172) contained solid components and the vast majority were solid tumors (155/172, 90%). Most sarcomas manifested inhomogeneous echogenicity of the solid tissue (151/195, 77.4%), cystic areas were described in 87/195 (44.6%), and most of the cystic areas had irregular walls (67/87, 77.0%). Internal shadows were found in 42/192 (21.5%) of cases, while fan shaped shadowing was rare (4/192, 2.1%).

Tumor borders were found to be irregular in 103/195 (52.8%) cases. Moderate or rich vascularization was observed in 127/187 (67.9%) tumors with reliable color Doppler information.

Leiomyosarcomas were larger than endometrial stromal sarcomas and undifferentiated endometrial sarcomas (median largest diameter 106 mm vs 68 vs 70). Endometrial stromal sarcomas manifested the highest percentage of visible normal endometrium (44/48, 91.7%) and regular tumor borders (29/48, 60.4%) and were less vascularized than the other sarcomas (score 1-2 in 20 of 47 tumors with reliable color Doppler information, 42.5%). Undifferentiated endometrial sarcomas manifested the highest percentage of absent shadowing (27/31, 87.1%), irregular tumor borders (23/31, 74.2%), and hemorrhagic or ground glass echogenicity of cyst fluid (6/15, 40%).

Leiomyosarcomas are very aggressive tumors with poor prognosis⁶. The treatment includes total abdominal hysterectomy and debulking of tumor outside the uterus. Oophorectomy is generally recommended, but it might not be necessary in patients of reproductive age with early stage disease. Lymph node dissection is controversial, but if there are no signs of metastatic lymph nodes, lymph node dissection can be spared¹¹. The role of adjuvant radiation therapy for patients with Stage I/II leiomyosarcoma is highly controversial, because it does not seem to affect either progression or survival¹². Occasionally, estrogen-receptor positive tumors will respond to hormonal treatment, for example progestin, aromatase inhibitor, Gonadotrophin Releasing Hormone (GnRH) analogues or GnRH analogues plus megestrol acetate.

Endometrial stromal sarcomas are indolent tumors with a favorable prognosis. Stage is the most important prognostic factor. The 5-year disease specific survival for stage I and II tumors is 90% compared to 50% for stage III and IV¹³. Surgical treatment of endometrial stromal sarcomas is hysterectomy and bilateral salpingo-oophorectomy¹⁴. However, in young patients affected by early stage endometrial stromal sarcoma who wish to preserve reproductive function, fertility sparing surgery (hysteroscopic removal of the lesion and sparing of uterus and ovaries) is an option. Endometrial stromal sarcomas are usually hormone receptor‑positive, and progestins and aromatase inhibitors are used as adjuvant treatment for this disease.

Undifferentiated endometrial sarcomas have very poor prognosis, and most patients die of the disease within 2 years from diagnosis⁶. Treatment is primarily surgical with or without adjuvant radiotherapy or chemotherapy.

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