LEIOMYOMA
Cutaneous leiomyomas are uncommon benign tumors of the arrector pili muscle
of the skin. They can occur as a solitary tumor or as multiple lesions. Both
types can be associated with underlying genetic defects. This occurs more
commonly in multiple cutaneous leiomyomatosis, and one needs to look for
systemic findings in affected patients. Other muscle sources of cutaneous
leiomyoma formation include the smooth muscle of blood vessel walls and the
dartos muscle. These rare forms of cutaneous leiomyomas are named
angioleiomyomas and solitary genital leiomyomas, respectively.
Clinical
Findings: Leiomyomas manifest as dermal papules or nodules with a
slight hyperpigmentation of the overlying epidermis. They can also have a
reddish or brownish hue. The tumors are 1 to 2 cm in diameter. They occur
equally in males and females and affect all races. They may occur anywhere on
the skin, but the anterior chest and the genital region are two of the more
common areas of involvement. They typically are tender, and they can be
painful. Most leiomyomas become more painful and more sensitive over time. Cold
temperatures have been shown to exacerbate the pain. The leiomyomas exhibit the
pseudo-Darier’s sign. This sign is elicited by rubbing the leiomyoma; on
manipulation, the lesion begins to twitch or fasciculate. It does not form an
urticarial plaque as would be seen with a true Darier’s sign (e.g., in
cutaneous mastocytosis). Malignant transformation is exceedingly rare.
Multiple cutaneous leiomyomas occur
most commonly on the trunk and proximal extremities. They are the same size as
their solitary counterparts, but they can become so numerous that they appear
to coalesce into large plaques. In most patients, onset occurs in the third to
fifth decades of life. There is a definite autosomal dominant inheritance
pattern to multiple cutaneous leiomyomas. These patients have a genetic defect
in the FH gene (also called MCUL1), which encodes the
Krebs cycle protein fumarate hydratase. The fumarate hydratase protein has been
found to have tumor suppressor functions. Many different types of mutations
have been described, ranging from frameshift mutations to deletion of entire
genes. This most likely explains the variety of phenotypes seen. The most
concerning and life- threatening aspect of this mutation is the possibility of
developing an aggressive and deadly form of papillary renal cell carcinoma.
This tumor in patients with multiple cutaneous leiomyomas tends to be highly
aggressive and metastasizes early. Early screening of the patient and genetic
screening of family members may help decrease the risk of metastatic renal
carcinoma. Patients should be evaluated routinely for kidney disease.
The term Reed syndrome is used
to denote women with cutaneous leiomyomas and uterine leiomyomas.
Pathogenesis: Solitary leiomyomas not associated with the
fumarate hydratase protein defect are believed to be caused by an abnormal
proliferation of myocytes. The cause for this proliferation is unknown.
Fumarate hydratase mutations result in a lack of tumor suppressor function. The
role of this tumor suppressor protein in the production of multiple leiomyomas
has yet to be determined.
Histology: The tumor is located within the dermis and is
composed of interconnected fascicles of spindleshaped cells. The cells are
arranged in a whorl-like pattern. The cells are uniform and bland appearing.
Mitosis should be absent. The cells have been described as cigar shaped,
meaning that they have a long, plump central region with blunt tip ends. The
cell of origin is the myocyte. Immunohistochemical staining can be used to help
differentiate difficult tumors. Leiomyomas stain with muscle markers such as
smooth muscle actin. The overlying epidermis is usually normal.
Treatment: Surgical excision of the solitary form of
leiomyoma is curative. Multiple cutaneous leiomyomatosis can be treated with
a number of medications to help control the discomfort and pain. Use of
α1-adrenergic receptor blockers has been reported most frequently. Doxazosin
and phenoxybenzamine have both been successful. Calcium channel blockers such
as nifedipine have also been successful anecdotally. Gabapentin and botulinum
toxin have been reported to help. Surgical excision is warranted for any lesion
that is painful and not responding to therapy. Patients with multiple cutaneous
leiomyomas should be evaluated for the genetic defect in the fumarate hydratase
protein and should have appropriate screening for kidney disease.
