Multiple Cutaneous Leiomyomas

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B

Synonyms:

Multiple cutaneous and uterine leiomyomatosis (MCUL)

syndrome

Hereditary leiomyomatosis renal cell cancer (HLRCC)

syndrome

B

Etiology:

Mutation in fumarate hydratase gene, mapped to chromosome

1q42.3-q43

B

Associations:

Uterine leiomyomas and rarely leiomyosarcomas, renal

carcinoma

B

Clinical:

Red-brown indurated papules, sometimes clustered or in linear

array

B

Histology:

Reticular dermal fascicular tumor with cigar-shaped nuclei,

amphophilic vacuolated cytoplasm, rare mitotic figures

B

IHC:

Smooth muscle actin+, desmin+

B

Evaluation:

Renal, uterine ultrasound, possible evaluation for fumarate

hydratase function or mutation

B

Treatment:

Surgical management of underlying tumors, excision of

painful cutaneous tumors, or nifedipine

B

Prognosis:

Excellent with early detection of underlying malignancy

Cutaneous leiomyomas are uncommon tumors that arise from arrector pili muscle (pilar leiomyoma), genital smooth muscle (genital leiomyoma), or vascular smooth muscle (angioleiomyoma). Angioleiomyomas are histologically distinct, and are not known to occur as multiple lesions. Most pilar leiomyomas occur singly, but can occur as multiple lesions. As multiple lesions, they may occur in association with uterine leiomyomas and, rarely, leiomyosarcomas, in the multiple cutaneous and uterine leiomyomatosis (MCUL) syndrome. More recently, cutaneous and uterine leiomyomas have been reported to occur in association with renal cell carcinoma in the hereditary leiomyomatosis renal cell cancer (HLRCC) syndrome (1). MCUL and HLRCC likely represent part of a spectrum of one disease. These syndromes are both familial and transmitted in an autosomal dominant pattern, with variable penetrance. The implicated gene encodes fumarate hydratase, an enzyme in the Krebs cycle that maps to chromosome 1q42.3-q43 (2). Fumarate hydratase (FH) is distributed predominantly within mitochondria, but also within the cytosol, of mammalian cells. In the cytosol, FH is involved in the purine nucleo tide cycle. In mitochondria, it catalyzes the reversible hydration of fumarate into malate as part of the Krebs cycle. The previous step in the Krebs cycle is the conversion of succinate to fumarate by succinate dehydrogenase. Succinate dehydrogenase mutations are also associated with a cancer predisposition, specifically pheochromocy-toma and paraganglionoma. The mechanism of tumori-genesis is unknown (3).

There is a spectrum of fumarate hydratase gene defects described in different clinical settings, but the type of defect does not appear to correlate with disparate clinical manifestations (4). Fumarate hydratase mutations cause multiple cutaneous and uterine leiomyomatosis (MCUL) syndrome, hereditary leiomyomatosis renal cell cancer (HLRCC) syndrome, and autosomal recessive FH deficiency, which manifests as severe developmental delay, and death in childhood. Autosomal recessive FH deficiency does not appear to be associated with development of malignancy. However, short life expectancy may not allow for its expression. Some parents of FH-deficient children develop leiomyomas as may be expected in the heterozygous state (2). In HLRCC and MCUL, the devel opment of uterine and cutaneous leiomyomas and renal cell cancer occurs with one mutant allele and one wild type (normal) allele. Tumor development requires a "second hit," as suggested in Knudson's theory of tumori-genesis. Loss of expression of the wild type allele may occur by loss of heterozygosity, or second mutation in the previously normal allele. Loss of heterozygosity at the genetic locus for these syndromes is known to occur in the cutaneous and uterine leiomyomas and renal cell carcinomas in patients with the syndrome, supporting a role for FH in tumor suppression (5). Mutations of the FH gene are rare in sporadic leiomyomas, and not found in sporadic leiomyosarcomas. Therefore, the gene does not play a major role in the development of sporadic tumors (6).

Cutaneous leiomyomas usually present as red-brown dome-shaped papules, from several millimeters to approximately one centimeter in diameter (Figure 19.1). When

Leiomyoma The Calf
Figure 19.1. Clustered erythematous papules and small nodules of the calf. Photo courtesy of Cleveland Clinic Foundation, Department of Dermatology.

they are multiple, they may be clustered or form a linear array. Solitary lesions usually occur on the extremities, and multiple lesions may occur on either the trunk or extremities. Pain is commonly reported, and may be precipitated by cold or pressure. The discomfort is described as sharp, burning, or throbbing (7). The differential diagnosis is wide for solitary lesions, and for multiple lesions may include such disparate entities as segmental neurofibromatosis, foreign body granuloma, dermatofibrosar-coma protuberans, and sarcoidosis.

Histopathology reveals a reticular dermal tumor composed of fascicles of smooth muscle bundles, with cigar-shaped nuclei and eosinophilic to amphophilic vacuolated cytoplasm (Figure 19.2A and 19.2B). Tumor cells are highlighted by antibodies to smooth muscle actin and desmin. In one series, 55% of these tumors had epidermal hyperplasia, and 10% had focal infiltration of the fat. Twenty-eight percent had mitotic figures, but these were usually sparse. No recurrences were seen in the mitotically active lesions. A nodular, more circumscribed architecture appears to correlate with the presence of multiple lesions (7). Renal carcinomas occurring in association with FH deficiency are of the Type II papillary or collecting duct type (4).

Multiple leiomyomas are not exclusively a manifestation of fumarate hydratase deficiency. They have also been reported to occur in patients with chronic lympho-cytic leukemia (8) and HIV infection (9). An association of leiomyosarcomas and leiomyomas with HIV infection and other forms of immunosuppression is well-established, and is known to be induced by Epstein-Barr virus (EBV) infection. In these tumors, EBV genomes are detectable within tumor cells by in situ hybridization (10).

Management of multiple leiomyomas is primarily surgical. Excision of symptomatic lesions may be warranted. Nifedipine has been used to alleviate the pain in the setting of multiple painful tumors (11). Affected individuals should undergo renal imaging studies, and in women, uterine imaging because of a risk of development of leiomyosarcoma. Evaluation of family members should also be undertaken. Genetic evaluation for fumarate hydratase mutations or functional assay should be considered.

Multiple cutaneous leiomyomas has recently been added to the list of cancer-susceptibility syndromes that may first present in the skin. These tumors may represent manifestations of multiple cutaneous and uterine leiomyomatosis (MCUL) syndrome or leiomyomatosis renal cell cancer (HLRCC) syndrome, which are closely related, if not the same entity. Recognition of the cutaneous leio-myomas may have life-saving implications for the patient and relatives.

Cutaneous Leiomyomas Pictures
Figure 19.2. (A and B) Dermal tumor composed of fascicles of smooth muscle cells with vacuolated cytoplasm and blunt-ended nuclei.

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