Leiomyosarcoma

LMS should be staged using the sarcoma staging information from the eighth edition (2017) of the Union for International Cancer Control (UICC) TNM classification.

Cytogenetic, molecular cytogenetic, and next-generation sequencing studies show that LMSs display extensive genomic instability, including chromothripsis and whole-genome duplication in subsets of cases. Recurrent DNA copy-number alterations include losses involving tumor suppressors PTEN (10q23.31), RB1 (13q14.2), and TP53 (17p13.1), as well as amplification of MYOCD at 17p12, which encodes a smooth muscle–specific transcriptional coactivator.

Whole-exome/genome and RNA sequencing studies have demonstrated that LMSs are characterized by a modest burden of somatic mutations and substantial mutational heterogeneity. TP53 is mutated in as many as 50% of sporadic LMSs; approximately 90% of samples present with biallelic TP53 inactivation through mutations, deletions, chromosomal rearrangements, or protein-damaging microalterations. Similarly, the function of RB1 is disrupted in nearly all cases of soft tissue LMS by diverse mechanisms that either target RB1 itself or result in altered expression of CDKN2A, CCND1, CCND2, or CDK4. Potentially deleterious ATRX alterations have been observed in 16–49% of cases and probably contribute to the high prevalence of alternative lengthening of telomeres in LMS. ALK rearrangements have been identified in a small subset of LMSs (9 of 377 cases; 2.4%) arising in males and females (soft tissue and uterine), imparting potential for clinically actionable opportunities.

Gene expression studies suggest that there are multiple subgroups of LMS, including a muscle-enriched subtype and less-differentiated groupings, with indications of differing frequencies of specific genomic changes and varying prognoses. Interestingly, some tumors classified as undifferentiated pleomorphic sarcoma cluster closely with a subset of LMSs.

LMS of soft tissue typically forms a fleshy, grey to white to tan mass. A whorled appearance may be evident. Larger examples often display hemorrhage, necrosis, or cystic change. The tumor border frequently appears well circumscribed, although grossly infiltrative tumors are also seen.

Typical LMS shows spindle-shaped cells with plump, blunt-ended nuclei and moderate to abundant, pale to brightly eosinophilic fibrillary cytoplasm. The cells are set in long intersecting fascicles parallel and perpendicular to the plane of section, although this pattern may be ill defined or subtle; some tumors show areas with storiform or palisaded patterns. Moderate nuclear pleomorphism is usually noted, although pleomorphism may be focal, mild, or occasionally absent. Mitotic figures, including atypical ones, are typically easy to find. LMS usually shows diffuse hypercellularity, although focal fibrosis, myxoid change, and hyalinized hypocellular areas can be seen. Tumor cell necrosis is often present in larger tumors. The majority of LMSs are high-grade. Unusual features in soft tissue LMS include myxoid stroma, multinucleated osteoclast-like giant cells, and granular cytoplasmic change. Epithelioid morphology is exceedingly rare. Osseous or chondro-osseous areas are rarely reported in pleomorphic/dedifferentiated LMS. Lymph node metastases are very rare.

By immunohistochemistry, at least one myogenic marker (i.e., SMA, desmin, or h-caldesmon) is positive in 100% of cases, and > 70% of cases are positive for more than one of these markers. None of these is absolutely specific for smooth muscle, and positivity for two myogenic markers is more supportive. Other markers, such as keratin, EMA, and CD34, may also be positive, often focally. In general, the diagnosis of LMS should not be made on the basis of immunohistochemical stains alone in the absence of appropriate morphological features.

As many as 8% of soft tissue LMSs exhibit a nonspecific, poorly differentiated, pleomorphic appearance in addition to typical areas. These tumors are called pleomorphic LMS or dedifferentiated LMS. For this diagnosis to be established, morphological features characteristic of classic LMS must be present, or the patient must have a prior history of LMS. The area of typical LMS may be exceedingly focal, constituting far less than 5% of the tumor. The typical and pleomorphic components may form discrete areas or may comingle. Pleomorphic LMSs most often show polygonal cells, but spindled, epithelioid, and rhabdoid cells may also be seen, and multiple cell types may be present. Pleomorphic areas usually have higher mitotic counts. By immunohistochemistry, about 50–75% of pleomorphic LMSs are positive for at least one myogenic marker, although staining is often weaker and more focal than in the typical leiomyosarcomatous areas. The term “dedifferentiated” has been used for pleomorphic LMSs that lack immunohistochemical staining for myogenic markers in the pleomorphic areas. Dedifferentiation is often seen in the primary tumor, but some cases present in recurrent or metastatic disease.

Not clinically relevant

LMSs are clinically aggressive neoplasms with frequent local recurrences and distant metastases. The most important prognostic factors are histological grade and tumor location and size. Retroperitoneal LMSs are very often fatal; they are typically large (> 10 cm), often difficult or impossible to excise with clear margins, and prone to both local recurrence and metastasis. LMSs of large vessels also tend to have a poor prognosis, although local control rates are higher. Non-retroperitoneal LMSs are generally smaller than those in the retroperitoneum, are more amenable to local control, and have a better prognosis. In some studies, intramuscular rather than subcutaneous location and larger tumor size were related to increased metastasis and poorer survival. Metastases most commonly occur in lung, liver, and soft tissue, and more rarely in bone. LMS is the most common sarcoma to produce skin metastases.

Not clinically relevant

Essential: fascicles of eosinophilic spindled cells with blunt-ended nuclei showing variable pleomorphism; immunolabelling for SMA, desmin, and/or caldesmon.