Leiomyosarcoma

Leiomyosarcoma (LMS) is a group of tumors that comprises one of the most common subtypes of soft tissue sarcoma. Many of these tumors arise in the uterus and beyond the scope of this chapter. Also, some recent evidence suggests that uterine LMS may represent a distinct disease possessing different genomic alterations compared to extra-uterine tumors. Another relatively common anatomic location for these tumors is in the skin or subcutaneous tissue. The incidence of these tumors arising in the extremities is relatively rare. As noted in our soft tissue tumor summary chapter, cutaneous leiomyosarcoma is a special variant showing morphology similar to leiomyosarcomas of other locations but has an excellent prognosis (almost no distant metastasis) because of its superficial location and limited clinical stage. Thus, these tumors were reclassified as “atypical intradermal smooth muscle neoplasm” by the World Health Organization (WHO) and the term leiomyosarcoma is utilized for these tumors when they occur in deeper tissues. Our emphasis in this chapter will concentrate on those tumors originating in the extremities but also applies to those tumors arising in the extra-uterine abdomen and pelvis.

Epidemiology

Leiomyosarcomas arise anywhere in the body and are derived from smooth muscle cells. In addition to the uterus, other sites include the retroperitoneum, and, less commonly, the extremities. While they are occasionally seen in patients with a history of genetic syndromes such as Li-Fraumeni, most occur sporadically with no evidence of hereditary propensity. These tumors are most common in older patients with a median age of approximately 60 years.

Clinical Features

As is the case for most soft tissue sarcomas, LMS tends to present as a painless mass which is typically firm and non-mobile on exam. When seen in the extremities, most are deep seated. The duration of the mass may be prolonged but is typically short as is the case for many high grade, rapidly growing tumors.

Radiologic Features

These tumors may not be seen on plain x-rays which may, at most, show some unusual soft tissue contours. MRI scanning, with and without contrast, is the most useful study to delineate the size and anatomic orientation of the lesion. As is typical for most soft tissue sarcomas, these tumors will be dark on T1 weighted images, bright on fat suppressed T2 and STIR images, and enhance with contrast administration. Large high-grade lesions may have extensive necrosis which will give a heterogeneous enhancement pattern as the necrotic areas will not actively enhance. Calcifications are rare.

Pathology

All smooth muscle tumors (benign or malignant) demonstrate elongated spindle cells with abundant eosinophilic cytoplasm running in fascicles that intersect at right angles (Figure 1). Nuclei show blunted ends (cigar shaped) and perinuclear vacuoles. Smooth muscle tumors should demonstrate strong and diffuse immunoreactivity to desmin and/or Smooth Muscle Actin (SMA). SMA is also positive in (myo) fibroblasts and is not as specific as desmin.

Figure 1: H&E stained histology slide of leiomyosarcoma, demonstrating fascicles of cells intersecting at right angles, with eosinophilic cytoplasm and cigar-shaped nuclei. (Courtesy of Dr. Gord Zhu)

Pathology of benign leiomyomas and variants:

These are extremely common in the uterus, but much less commonly seen in soft tissue and skin. Outside the uterus, they are believed to arise from the smooth muscle cells of blood vessels (angioleiomyoma) or pili erector muscle in the skin (cutaneous leiomyoma) at these uncommon locations. Leiomyomas outside of the gynecologic tract should demonstrate minimal cytologic atypia, no necrosis, and very low mitotic activity (fewer than 1 mitotic figure / 50 HPF). These tumors are difficult to recognize histologically, so positive staining with desmin and SMA are critical to making the diagnosis.

Pathology of leiomyosarcomas:

Leiomyosarcomas often develop in the retroperitoneum, lower extremities, or along blood vessels. Deep extremity leiomyosarcomas are usually high grade and demonstrate significant pleomorphism (similar to but typically less than UPS), increased mitotic rate (more than 1 mitotic figure / 10 HPF) and/or tumor necrosis. Being derived from smooth muscle cells, these tumors are composed of elongated spindle cells with abundant eosinophilic cytoplasm and cigar-shaped nuclei, running in fascicles which intersect at right angles. In light of their smooth muscle derivation, these tumors should demonstrate strong and diffuse immunoreactivity to desmin and/or SMA, though SMA positivity in these tumors is not as specific as desmin positivity.

Differential Diagnosis

The initial differential diagnosis associated with large, deep, enhancing, non-fatty soft tissue masses includes primarily the whole range of soft tissue sarcomas but also includes benign lesions such as desmoid tumors, etc.

Disease Course: Treatment and Prognosis

As with most high-grade soft tissue sarcomas, the prognosis is usually worse in patients with large, deep tumors and certainly for those who demonstrate metastatic disease at presentation. Despite this, the 10-year disease free survival for extremity non-metastatic LMS approaches 70%. The standard treatment involves wide margin surgery in association with pre- or post-operative radiation therapy. Chemotherapy is frequently utilized, especially for large, deep tumors or for those which have developed metastases. However, the effectiveness of this systemic therapy is limited, and the rarity of this disease makes it difficult to assemble large series.

An important member of the leiomyosarcoma family to understand is the cutaneous leiomyosarcoma, a special variant showing morphology similar to leiomyosarcomas of other locations, but has an excellent prognosis (almost no distant metastasis) because of its superficial location and limited clinical stage. Thus, these tumors were reclassified in 2020 as “atypical intradermal smooth muscle neoplasm” by WHO. As with leiomyomas, this diagnosis is difficult to make histologically so again, look for desmin and SMA positivity.

Key Test Topics

Smooth muscle tumors, both benign and malignant, show elongated spindle cells with cigar-shaped nuclei and strong immunoreactivity to desmin and/or SMA.
Leiomyosarcoma resembles undifferentiated pleomorphic sarcoma (UPS) morphologically but is distinguished by strong desmin and SMA positivity
Standard treatment involves wide margin surgery and radiation. Chemotherapy may be employed but demonstrates limited efficacy
Cutaneous leiomyosarcoma has good prognosis.