Uterine leiomyosarcoma

Clinical case

A 59-year-old nulliparous woman with history of multiple uterine fibroids status post myomectomy for abnormal uterine bleeding 20 years prior and recent total abdominal hysterectomy and salpingo-oophorectomy for recurrent, intermittent postmenopausal bleeding presented for management of pathological diagnosis of leiomyosarcoma. Workup prior to hysterectomy had included endometrial biopsies (EMBs) which were benign and serial pelvic ultrasounds over 18 months demonstrating a stable 5.4 cm uterine fibroid. MRI prior to surgery demonstrated a dominant 5.4 cm myometrial mass concerning for a degenerating leiomyoma vs leiomyosarcoma ( Fig. 9.1 ). Pathology from her surgery was notable for a 5 cm uterine leiomyosarcoma limited to the myometrium with necrosis, marked cytologic atypia and 14 mitoses/10 high-powered fields. Computed tomography (CT) of the chest, abdomen and pelvis demonstrated multiple 1 to 2 mm indeterminate pulmonary nodules. How would you manage this patient?

Epidemiology

While uterine sarcomas are a rare form of uterine malignancy, making up only 3% to 9% of all uterine cancers, they represent a heterogeneous group of uterine tumors. Uterine leiomyosarcoma is the most common, accounting for approximately 70% of uterine sarcomas. The remaining 30% of uterine sarcomas include other histologies such as endometrial stromal sarcoma, adenosarcoma, and perivascular endothelial cell tumor (PEComa) (see Chapter 10 ).

The median age of diagnosis for uterine leiomyosarcoma is in the mid-50s, and most patients do not have any clear predisposing risk factors. Black women have a two-fold higher risk of uterine leiomyosarcoma than white women, and there have been some reported associations with obesity and diabetes. Hereditary syndromes such as hereditary retinoblastoma have a reported risk of approximately 13% for developing any soft-tissue sarcoma, including uterine leiomyosarcoma, while those with Li–Fraumeni syndrome, a defect in p53, also have a higher risk with one study reporting 7% to 8% of women with Li–Fraumeni syndrome developing leiomyosarcoma. Pelvic radiation exposure has also been reported to increase the risk of developing a uterine sarcoma, as has hormone exposure. In large registry studies, the percentage of women with uterine corpus cancers postpelvic irradiation was 0.08% to 2.4%; of those malignancies, uterine sarcomas made up 18% to 43%. Time interval for postirradiation sarcomas between first and second neoplasm was 132 months (14–396).

Tamoxifen use for greater than 5 years demonstrated significant increase in risk of uterine leiomyosarcoma, while shorter exposure had no association. In one study, the relative risk associated with 5 years of tamoxifen use for all uterine malignancy was 4.1 (1.7–9.5). In National Surgical Adjuvant Breast and Bowel Project (NSABP), secondary malignancies were characterized by organ site and histology specifically; they reported a risk of uterine sarcoma to be 17 per 1000 women years. This compares to a risk of uterine adenocarcinoma reported at 2.2 and 0.71 per 1000 women years for those exposed and unexposed to Tamoxifen respectively. The prognosis of women with uterine sarcoma who had taken tamoxifen was no different than women without exposure to tamoxifen, once stage and histology were controlled for.

Pathology

Leiomyosarcomas (LMS) of the uterus are overall rare but make up the majority of uterine sarcomas. The diagnosis of leiomyosarcoma is based on demonstrating smooth muscle differentiation and criteria for malignancy.

Microscopic description

Overall, the tumor is hypercellular, with a fascicular pattern of growth of elongated, spindled cells, with tumor cells typically easily recognized as with smooth muscle differentiation ( Fig. 9.2 A and B ). The tumors can have spindled, epithelioid, or myxoid features. Other findings such as multinucleated tumor cells, osteoclast-like giant cells, xanthomatous change, and rhabdoid-like cells with inclusion bodies can be seen. While many LMS invade into the surrounding myometrium, some may have a well-circumscribed margin. Lymphovascular invasion can be seen in 10% to 20% of tumors.

The spectrum of smooth muscle neoplasms can range from benign to uncertain malignant potential to malignant. Due to this wide spectrum, diagnostic criteria are applied to smooth muscle neoplasms to arrive at a correct diagnosis and associated prognosis. The histologic features for criteria include nuclear/cytologic atypia, mitotic index and coagulative tumor cell necrosis ( Table 9.1 ). Once a smooth muscle neoplasm reaches any combination of 2 of the following 3, the diagnosis can be made of a leiomyosarcoma: coagulative tumor cell necrosis, mitotic index ≥ 10/10 HPF, and diffuse moderate to severe atypia. It should be noted that these criteria are only for conventional LMS. Different criteria are applied to variants such as epithelioid leiomyosarcoma and myxoid leiomyosarcoma, which are discussed later. If the neoplasm has atypical features but does not meet 2 of the 3 criteria for leiomyosarcoma, the neoplasm may be categorized as a smooth muscle tumors of unknown malignant potential (STUMP), the criteria of which are covered further in a later chapter.

Table 9.1

Histologic criteria for diagnosis of leiomyosarcoma.

Criteria	Two of 3 criteria needed for conventional leiomyosarcoma
Diffuse Atypia	Moderate to Severe
Mitotic activity	≥ 10 mitoses/10 HPF
Coagulative tumor cell necrosis	Present

The correct diagnosis can only be reached if the criteria are appropriately defined and applied. For example, the presence of any necrosis does not suffice for the check box of “necrosis present”, but specifically coagulative tumor cell necrosis is needed. Coagulative tumor cell necrosis is an abrupt transition between normal and necrotic tissue, with the necrotic cells having the appearance of “ghost” cells of dying but recognizable cells ( Fig. 9.3 ). This contrasts with hyaline or infarct type necrosis, which shows areas of necrosis surrounded by a rim of hyalinization separating necrosis from normal tissue.