Lead article

Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: leiomyoma

Leiomyomas as clonal tumors: X-inactivation studies

Analyses of multiple leiomyomas from a single uterus have demonstrated that the tumors can harbor different chromosomal changes and suggest that each tumor developed independently [7]. X-inactivation studies, based on the phenomenon of lyonization, i.e., inactivation of one X-chromosome in normal female cells, have demonstrated that leiomyomas develop as clonal lesions. Initially, glucose-6phosphate dehydrogenase (G6PD) isoenzyme analysis was used to demonstrate the independent clonal origin of

Cytogenetic changes in uterine leiomyomata

The pathologic and clinical heterogeneity of leiomyomas is reflected in the cytogenetic findings in these tumors; however, within that heterogeneity exist chromosomally well-defined subgroups [20]. Although the exact significance of these chromosome changes has not been rigorously established in all subgroups, they do serve as a guide to studies attempting to decipher the causative molecular events within subgroups of leiomyoma. The distinct cytogenetic subgroups of leiomyoma imply multiple

FISH studies on leiomyoma

An alphoid DNA probe for chromosome 12 was used by Vanni et al. [87] to determine the possible presence of +12 in interphase nuclei in leiomyoma with normal karyotypes, since cytogenetics revealed this anomaly to be present in 10% of the tumors with abnormal karyotypes. Hayashi et al. [88], [89] utilized alphoid sequences and whole painting probes for chromosomes 12 as a complimentary approach to conventional cytogenetics in the study of the chromosomal changes in leiomyoma. Interphase studies

CGH studies in leiomyoma

CGH studies have revealed gains and losses of chromosomal material that differed from those of LMS [103], [104].

Molecular changes in leiomyoma

A number of molecular methodologies has been applied to the study of genetic events in leiomyoma and individual publications should be consulted for details regarding the techniques used. In this section of the Update, an up-to-date summary of the known molecular events will be presented.

Some miscellaneous biological and genetic aspects of leiomyoma

Caldesmon, a protein present in both smooth and non-smooth muscle cells, and thought to regulate cellular contraction, has been detected immunohistochemically in leiomyoma (3 uterine and 5 non-uterine) and LMS (5 retroperitoneal and 1 uterine), but not in other tumors with smooth muscle cell-like differentiation [247]. Similar results were obtained by Nucci et al. [248].

A number of studies have addressed possible differences (or similarities) in findings of normal myometrium, leiomyomas and LMS

Hereditary leiomyomatosis and renal cell cancer (HLRCC)

HLRCC is an autosomal dominant disorder characterized by smooth muscle tumors of the skin and uterus and/or renal cancer [267], [268], [269]. The renal cancer is of a specific histology, i.e. papillary type II renal cell carcinoma [268], [269]. Predisposition to uterine leiomyosarcoma may also exist.

A germ-line mutation of the fumarate hydratase (fumarase or FH) gene, located at 1q42.3∼q43, has been shown to predispose to HLRCC [270], [271]. Examination of a large number of sporadic tumors

Multiple leiomyomatosis

Multiple leiomyomatosis is a condition consisting of benign tumors arising from the erector pili muscles and uterine leiomyomas. A predisposing gene for multiple leiomyomatosis labeled MCUL1 has been assigned to 1q42.3∼q43 [267], [273]. This gene has yet to be identified rigorously, though Alam et al. [270] suggested possible candidates, e.g., zing-finger protein ZNF124, nidogen, ryanodine receptor R2, and α2-actinin.

In contrast to familial and multiple leiomyomatosis [267], [268], [269], [270]

Angioleiomyoma

Angioleiomyoma (also termed angiomyxoma and vascular leiomyoma) is a relatively common painful, benign subcutaneous or deep dermal tumor composed of mature smooth muscle bundles which surround and intersect vascular channels. These tumors form a morphological continuum with myopericytoma and myofibroma [275].

Most angioleiomyomas occur in the extremities, especially the lower extremity, and other sites include the head, trunk, and other locations [276]. The tumors are characterized by lack of

Disseminated peritoneal leiomyomatosis (DPL)

DPL is a rare condition in females characterized by nodular proliferations of histologically benign smooth muscle throughout the omental and peritoneal surfaces [17]. Some of the characteristics of this unusual condition have been presented by Quade et al. [17]. X-inactivation studies showed a pathogenesis of DPL to be similar to that of uterine leiomyomas. Of interest were the cytogenetic studies which revealed changes in 2 of 6 DPL lesions (Table 1). These changes suggest again a potential

Miscellaneous clinical leiomyoma conditions

Results of twin studies, as well as analysis of individuals with multiple hereditary uterocutaneous leiomyomas, support a role for genetic factors in the pathogenesis of these tumors [285], [286], [287], [288], [289]. Reviews of the epidemiology of uterine leiomyomas have been published [290], [291], [292], [293], [294] and indicate that leiomyomas are at least 3-times more frequent in black than white women [287], [295], [296] and twice as common in monozygotic than dizogotic twins [297].

Comments

As in lipoma, so in leiomyoma, both benign mesenchymal soft tissue tumors not known to become malignant, the genetic changes are complex and intriguing [20], [47], [304]. Such changes are not only complex at the intertumoral level, but also intratumorally [56]. Unless leiomyomas are caused by a cryptic genetic change which has remained unknown, the cytogenetic and molecular genetic abnormalities described to-date indicate a heterogeneity among these tumors. Yet, within this heterogeneity there