Primary Leiomyosarcoma of Bone: Review and Update

Leiomyosarcoma of bone may arise de novo or in association with prior radiation. It typically presents with pain and swelling, and occasionally a palpable mass.¹  The median patient age is 47 years, but cases affecting a wide age range (9–88 years) have been reported.^2,3  In 20% to 40% of cases, patients may present with pathologic fracture.¹  The long bones, particularly distal femur and proximal tibia, account for 70% of cases, whereas the craniofacial bones make up about 20%.^2–7  Imaging studies typically demonstrate an osteolytic, radiolucent intramedullary mass with cortical destruction and soft tissue invasion (Figure 1).^1,3,4  Fifteen percent of cases are associated with prior radiation.^4,8  In contrast to de novo LMBS, 50% of the radiation-associated cases arise in the craniofacial bones.^4,9 

Grossly, LMSB presents as an intramedullary bone tumor with a creamy white, fleshy or fibrous texture; cortical destruction; extension into soft tissue; and frequent pathologic fracture (Figure 2). In most cases, the histopathologic features of LMSB resemble those of its uterine and soft tissue counterparts. It is devoid of malignant osteoid or chondroid matrix production and is composed of long fascicles of spindle cells (Figure 3) permeating through bony trabeculae (Figure 4). In most cases smooth muscle differentiation is evident cytologically by the presence of abundant, deeply eosinophilic cytoplasm and elongated, blunt-ended nuclei with occasional subnuclear vacuoles.

The degree of cytologic atypia varies based on the histologic grade. Lower-grade sarcomas are typically less cellular and consist of spindle cells with uniform, blunt-ended nuclei with cigar-shaped morphology (Figure 5). Necrosis and brisk mitotic activity are usually absent. Higher-grade sarcomas demonstrate overt nuclear pleomorphism, hyperchromasia, and prominent nucleoli (Figure 6). As in any high-grade sarcoma, mitotic figures and tumor necrosis (Figure 7) are common features. Osteoclast-like giant cells may be present in variable quantities (Figure 8) from a scattered few to numerous. Other secondary elements such as prominent, ectatic staghorn vessels have been reported.⁴  In some cases, high-grade sarcomas may present with a less-differentiated morphology and lose some or all recognizable morphologic evidence of smooth muscle differentiation. The extreme cases are those of the pleomorphic variant (Figure 6), characterized by markedly variable nuclei with bizarre and multinucleated forms, resembling undifferentiated pleomorphic sarcoma (UPS). In such cases, immunohistochemical stains are required to make the diagnosis.

Several unique histologic features of LMSB have been described. Some tumors have extensive extracellular stromal matrix, which may consist of homogenized, hyalinizing fibrosis or myxohyaline matrix (Figures 5 and 9) or thick, wirelike collagen bundles (Figure 10).^10,11  Cytologically, the tumoral cells may exhibit an epithelioid (Figure 11) or clear cell (Figure 12) morphology. Epithelioid leiomyosarcoma is a recognized variant that has been described in the uterus and soft tissue as well as bone.^12–14  As its name suggests, the tumor cells are large and rounded. The cytoplasmic borders are well defined, and the cytoplasm is abundant and eosinophilic. The central nuclei often have vesicular chromatin with conspicuous nucleoli. Occasionally, vacuolization may be especially prominent and encompass nearly the entire cytoplasm, imparting a clear cell morphology.^4,15 

Immunohistochemical stains are helpful ancillary studies, particularly in poorly differentiated tumors. Similar to its uterine and soft tissue counterparts, LMSB consistently expresses smooth muscle actin (SMA) (Figure 13) and muscle-specific actin in more than 95% and 93% of cases, respectively.^3,5  However, desmin is positive in only 50% of cases (Figure 14) and thus should not be used as the only primary screening antibody.^3,5  It is worth noting that both cytokeratin and S100 protein expression have been reported. Cytokeratin can be focally positive in more than 30% of cases (Figure 15), especially in the epithelioid variant.^3,4,16  S100 protein was reportedly positive in 4 of 5 cases in one study, and 1 of 20 cases in another.^17,18  Together, absent desmin expression and positive cytokeratin or S100 protein expression are confounding factors that contribute to the difficulty in diagnosing LMSB.

The main differential diagnoses of LMSB are metastatic leiomyosarcoma from another site, primary UPS of bone, fibroblastic osteosarcoma, and metastatic sarcomatoid carcinoma. Metastatic leiomyosarcoma can be reliably diagnosed only by clinical history and must be excluded before a diagnosis of primary LMSB can be rendered. Undifferentiated pleomorphic sarcoma describes a group of high-grade pleomorphic sarcomas without a specific line of differentiation. The histomorphology of UPS is commonly a cellular proliferation of spindle and epithelioid cells with high-grade and bizarre cytology and frequent mitoses and necrosis.^19,20  In some cases, focal myxoid stroma, brisk inflammation, and/or giant cells may be prominent features.¹⁹  As alluded to above, despite rigorous histomorphologic and ancillary evaluation, UPS displays ambiguous histomorphologic and immunohistochemical features, and is therefore usually a diagnosis of exclusion.^19,20  The judicious use of immunohistochemical markers such as SMA and desmin is especially helpful in distinguishing UPS from LMSB. Fibroblastic osteosarcoma is an important differential diagnostic consideration. However, identification of focal malignant osteoid formation and lack of myogenic markers are helpful features to distinguish osteosarcoma from LMSB. However, a recent study showed that 20% of LMSB within its cohort contained nonneoplastic or dystrophic calcification, a finding that may be mistaken for true malignant osteoid/bone formation.^7,21  Metastatic sarcomatoid carcinoma may morphologically mimic LMSB, and immunohistochemistry for epithelial markers such as a broad-spectrum cytokeratin or EMA, lack of myogenic markers, and presence of other specific markers such as p63 and PAX-8 to rule out squamous cell and renal cell carcinomas, respectively, as well as a thorough investigation for past malignancy in the clinical history, are effective strategies to discern between metastatic sarcomatoid carcinoma and LMSB. As mentioned above, LMSB may show aberrant focal cytokeratin expression and this should not deter the pathologist from making the diagnosis.

Data on optimal treatment and prognostic factors for LMSB are limited because of its low prevalence. Surgical resection, when possible, remains the primary treatment modality. Radiation has been used to augment surgery for local control with variable results. In a study of 33 patients, Antonescu et al⁴  did not find any difference in survival rates between patients who received surgery alone and patients who received surgery and adjuvant radiation therapy. Unlike primary osteosarcoma, which is generally chemosensitive, multiple studies have reported poor response of LMSB to chemotherapy, as well as minimal impact on overall survival benefit.^5,6  Unfortunately, even fewer data are available in the management of metastatic LMSB. Chemotherapy, albeit suboptimal, is often used in conjunction with patient-centered and goal-oriented management in this setting.¹ 

The 5-year overall survival of LMSB ranges from 62% to 78%, and the 5-year disease-free survival ranges from 45% to 82%.^4–6  However, stratification based on histologic grade reveals notable shifts in prognostic outcomes. Several studies^3–6  have supported the finding that high-stage tumors are associated with poorer outcomes. For example, in an early study, Antonescu et al⁴  reported 60% and 100% 5-year survival rates in patients with high-grade and low-grade tumors, respectively. In a review study by Adelani et al,³  the 5-year overall survival rates in patients with stage I and IIA tumors were 90% and 60%, respectively. In contrast, the numbers were reduced to 29% and 0% in patients with stage IIB and III/IV tumors, respectively. Additionally, negative surgical margins and the absence of metastasis at the time of diagnosis have been linked to better survival outcomes.^5,6  For example, Mori et al⁵  found that for patients without metastasis at initial diagnosis, negative microscopic surgical margins offered better disease-free survival outcome than positive surgical margins. Tumor size (>8 cm) has been reported to be a poor prognostic indicator.^1,3  In general, radiation-associated osseous sarcomas have worse survival outcomes than their primary counterparts, with 5-year survival rates reported by various studies ranging from 20% to 53%.^8,22,23  This also appears to be true for LMSB.⁴  The rate of local recurrence appears to be similar between high-grade and low-grade tumors.^1,5,6  In the study by Antonescu et al,⁴  the local recurrence rates for high- and low-grade tumors were 29% and 33%, respectively. The metastatic rate at 5 years was higher in high-grade tumors (58%) than low-grade tumors (33%).⁴  Highlighting the aggressive behavior of LMSB, in a study by Rekhi et al,⁷  all metastatic cases appeared within the first year of diagnosis. Lung is the most common metastatic site, followed by axial skeleton and liver.³ 

Leiomyosarcoma of bone is a rare but well-recognized primary osseous sarcoma that may arise de novo or in association with radiation. The sarcoma is typically a high-grade tumor with poor survival outcome and limited treatment options, particularly in metastatic cases. Although the diagnostic differential is broad, awareness of this rare bone tumor phenotype and knowledge of its key histomorphologic and immunohistochemical features allow for accurate diagnosis.