LMSs are characteristically solitary, intramural masses and are usually not associated with leiomyomas. The gross appearance of LMSs has significant differentiating features from that of leiomyomas in most of the cases. They are large tumors averaging 10 cm in diameter with poorly circumscribed borders that appear to irregularly infiltrate the adjacent myometrium. Leiomyomas, on the other hand, characteristically have a sharp line of demarcation separating the tumor from the myometrium. LMSs that present as a circumscribed mass are not usually recognized grossly as a malignant tumor because of the overlap in appearance between malignant change and the various forms of degeneration. The macroscopic features that are suspicious of malignancy and require thorough sampling of the tumor are: loss of whorled pattern, heterogeneity, irregular, merging, blurred or poorly defined margins, yellow, tan or gray color, softer tumors that lack a rubbery, resilient feel, and absence of a bulging surface. The cut surface may also show irregular areas of hemorrhage and necrosis.

LMSs exhibit hypercellularity, severe nuclear atypia, geographic foci of tumor cell necrosis, and a high mitotic rate including atypical mitotic figures, generally exceeding 15 mitotic figures per 10 high-power fields (Fig. 11.1a). Mitosis is counted in the most mitotically active areas in ten successive HPFs using an 40× objective and a standard 10× eyepiece. The poorly differentiated tumors show nuclear pleomorphism, hyperchromasia, prominent nucleoli, and tumor giant cells, features that indicate increasing anaplasia of the tumor (Fig. 11.1b). Well-differentiated LMS on the other hand consist of elongated smooth muscle cells with regular nuclei that differ little from those of a leiomyoma (Fig. 11.1c). Areas of coagulative necrosis and hemorrhage are seen (Fig. 11.1d). The tumors, in most cases, would have invaded the adjacent myometrial tissue at the time of diagnosis and may have perforated the serosal surface of the uterus with involvement of other pelvic organs. Vascular invasion may also be seen.

If a smooth muscle tumor is well circumscribed, composed of cells that are uniform in size and shape, has no intravascular component, cytological atypia or necrosis, and with a mitotic count of less than 5 mitotic figures per 10 HPFs, then the tumor is a leiomyoma. On the other hand, when a tumor has infiltrative margins (Fig. 11.1e), intravascular growth, marked cytological atypia, coagulative tumor cell necrosis, a mitotic count greater than 10 mitosis per 10 HPFs and abnormal mitotic figures, then the tumor is an LMS. Most of the smooth muscle tumors belong to the two extremes of the spectrum and are either clearly benign or malignant. It is the tumors that fall in the intermediate category that require careful consideration to reliably categorize them, to predict prognosis, and to decide on further treatment. Numerous studies have been undertaken during the past three decades to define the histological criteria that would help to correctly categorize these tumors and to differentiate them from leiomyomas with atypical histological features like the mitotically active leiomyoma, cellular leiomyoma, atypical leiomyoma, myxoid leiomyoma, epithelioid leiomyoma, hemorrhagic leiomyoma, leiomyoma with hormone-induced changes, and from leiomyomas with unusual growth patterns like disseminated peritoneal leiomyomatosis, benign metastasizing leiomyoma, intravenous leiomyomatosis, and lymphangioleiomyomatosis. Of the many histological features that were assessed, mitotic index, the degree of cytological atypia, and the presence or absence of coagulative tumor cell necrosis have emerged as the most important predictors of behavior [7]. No single histological feature, with the exception of tumor cell necrosis, is diagnostic of malignancy. By employing three variables in the assessment of smooth muscle tumors, this diagnostic strategy moves away from complete dependence on mitotic count [8].

Other features that need to be considered are age of the patient, the size of the tumor and its gross appearance, the tumor’s margins, and presence of vascular invasion.

The epithelioid and myxoid variants of LMS are rare tumors that exhibit malignant biologic behavior despite low mitotic counts and mild nuclear atypia.

LMSs are immunoreactive to smooth muscle markers such as smooth muscle actin, desmin, and h-caldesmon and histone deacetylace. Epithelioid LMS can express epithelial markers such as keratin and epithelial membrane antigen and are often immunoreactive to CD10.

Mutation and over expression of p53 and p16 has been described in a significant minority of LMS and in STUMPs that are at an increased risk of aggressive behavior but not in leiomyomas [9]. However other studies have shown that there is significant overlap in the Ki-67, p16, and p53 expression patterns in the atypical leiomyoma to LMS spectrum precluding its routine use for diagnostic purpose.