Are You Confident of the Diagnosis?
What to be alert for in the history
Characteristic findings on physical examination
Leiomyomas are rare benign tumors that derive from the proliferation of smooth muscle cells. They present as firm, skin colored, light brown or reddish brown papules less than 2cm in size in any distribution (solitary, clustered, segmental, disseminated) on the trunk and/or extremities, but can also be found on the face (Figure 1).
Onset occurs in the twenties, but the range extends from the teen years to the forties. When solitary, they are more likely to appear later in life. Once they present, they are likely to increase in size and number. A majority of patients with cutaneous leiomyomas complain of episodic pain triggered by sensitivity to touch and changes in temperature.
There are three types of leiomyomas based on the source of the smooth muscle cells from which the lesion is derived:
Piloleiomyomas are the most common type and are derived from the arrector pili muscle.
Angioleiomyomas are derived from the walls of arteries and veins.
Genital leiomyomas (most rare) derive from the dartos muscle of the scrotum and labia majora.
Solitary leiomyomas can be sporadic, but multiple lesions are usually associated with systemic implications. However, even a single cutaneous leiomyoma may be the only dermatologic sign of Familial Cutaneous Leiomyomatosis (FCL). Sporadic leiomyomas and leiomyomas associated with FCL cannot be differentiated clinically or histologically. Therefore, other parts of the history and physical examination will steer the physician in the appropriate direction. See Familial Cutaneous Leiomyomatosis Chapter for diagnostic criteria suspicious for FCL
Expected results of diagnostic studies
A skin biopsy will demonstrate a characteristic pink well differentiated proliferation of smooth muscle bundles with blunt ended or “cigar-shaped” nuclei seen using the hematoxylin and eosin stain (Figure 2). Perinuclear vacuolization is observed. Other stains may highlight the smooth muscle cells, such as a Masson trichrome stain, which will stain smooth muscle cells dark red. Fumarate hydratase enzymatic activity in cultured skin fibroblasts or progenitor lymphocytic cells will show reduced activity in all cases.
Genetic sequence analysis of the FH gene will demonstrate sequence variants (deletions, insertions, missense, nonsense, splice site mutations) in most cases. Large deletions are rare
Cutaneous leiomyomas are clinically very similar to other lesions and require a biopsy and histologic evaluation for confirmation.
The clinical differential diagnosis includes nevus, dermatofibroma, neurofibroma, glomus tumor, angiolipoma, and other benign growths, hamartomas or neoplastic lesions.
Who is at Risk for Developing this Disease?
Leiomyomas may develop sporadically or as part of FCL. Their prevalence in the general population is not known. Leiomyomas occur equally across different races and ethnicities. Overall, leiomyomas have not been found to have a predilection for either sex. When exploring different subtypes, piloleiomyomas occur equally in men and women, whereas angioleiomyomas are more common in women than men by a factor of 2 to 1. Genital leiomyomas are rare and no sex predilection has been observed.
What is the Cause of the Disease?
The formation of a leiomyoma may be sporadic or part of a genetic mutation. In the former, no specific cause is identified. In the latter, the leiomyoma forms because of an FH gene mutation that was inherited or spontaneously developed. See the Familial Cutaneous Leiomyomatosis chapter for details on the etiology and pathophysiology of leiomyoma formation when it is part of this genetic disease.
Systemic Implications and Complications
Leiomyomas are benign lesions and do not, in and of themselves, usually affect mortality. However, they can cause complications based on their location, distribution, and symptoms. A full skin examination by a dermatologist or other trained physician is necessary to locate them. A skin biopsy with histologic evaluation is necessary to confirm the initial diagnosis.
Cutaneous leiomyomas can enlarge and become disfiguring. Also, most of them are associated with episodic pain triggered by trauma or cold.
Malignant transformation of cutaneous leiomyomas into leiomyosarcoma, although rare, has been reported. Dermatologic evaluation with biopsy of changing or suspicious lesions is necessary to rule out this possibility.
Leiomyomas may present as part of FCL. in those cases, they can be associated with renal cancer in about 10% of affected individuals (with a range of 6% to 16%). See the Familial Cutaneous Leiomyomatosis chapter for details on the systemic implications of this genetic disease.
Medical management of cutaneous leiomyomas has no effect on the appearance of the lesions but may improve the symptoms associated with them.
NSAIDS and other analgesics: ibuprofen, Tylenol, other.
Gabapentin: 300mg orally initially, 300mg twice daily on day 2, then 300mg orally three times daily. Increase three times daily dose gradually until symptoms improve. Do not exceed 3600mg a day. Taper dose over 7 days to discontinue.
Pregabalin: 150mg orally daily gradually increased to 600mg orally daily.
Pregabalin in combination with duloxetine 60mg orally daily.
Pregabalin in combination with venlafaxine 75mg orally daily gradually increased to 600mg (300mg orally twice daily).
Calcium channel blockers such as:
-Nifedipine immediate-release form: start at 10mg orally three times daily. May increase dose every 7 to 14 days. Up to 40mg orally three times daily.
-Nifedipine extended-release form: 30 to 60mg orally daily.
Alpha blockers such as:
-Doxazosin: start at 1mg orally daily. Increase dose by 1mg each week until symptoms improve. Dose up to 4mg orally daily.
-Phenoxybenzamine: start at 10mg orally twice daily, increase by 10mg every other day until symptoms improve.
Surgical excision of symptomatic, changing, disfiguring, or otherwise bothersome cutaneous leiomyomas is the treatment of choice.
Cryosurgery: using liquid nitrogen, two freeze-thaw cycles analogous to the technique used to freeze actinic keratoses or warts.
Carbon dioxide laser (10,600nm)
Botulinum toxin intralesional therapy: in one report, 100 units of a 100u/mL preparation of Botox® was injected into 15 lesions; all lesions were injected only once and received 5 to 15 units. In another report, a total of 200 units of Botox® was used to treat multiple lesions.
Optimal Therapeutic Approach for this Disease
Cutaneous leiomyomas should be approached on a case-by-case basis given the number, distribution and symptoms associated with the lesions. Treatment of a solitary lesion with surgical excision may be the most effective treatment when this is feasible. Although there is a risk of recurrence, complete surgical excision usually resolves the patient’s symptoms.
A changing cutaneous leiomyoma should be biopsied or surgically excised to rule out the risk of malignant transformation to leiomyosarcoma.
Treatment of painful cutaneous leiomyomas depends on the extent of the pain and patient co-morbidities. NSAIDS might provide adequate relief if surgical excision is not possible given the location or number of lesions. The next step might include cryosurgery as a low-risk treatment with the potential to relieve symptoms. However, the risk of pain recurrence is high. Carbon dioxide laser ablation could provide benefit at this point, but this option is not readily available.
Botulinum toxin A (BT-A) injection therapy may be considered at this point given the increasing number of case reports demonstrating success, but the pain may return after a few months and necessitates another round of injections. Botox injections have not been associated with serious systemic side effects at the doses described above, but cost might be prohibitive.
Next, gabapentin or its more potent successor pregabalin alone or in combination with other medication may be used if no contraindications exist. High doses are necessary, which increases the risk of side effects, and resolution of pain is often partial.
The use of calcium channel blockers might decrease painful or temperature-sensitive lesions, presumably by blocking the contraction of those smooth muscles. Use of nifedipine may result in swelling, flushing, headaches as well as cardiac side effects and hypotension.
The next lesser option might be doxazosin, a reversible alpha-1 receptor blocker which, through its alpha adrenergic blockade, may also alleviate symptoms by decreasing the smooth muscles’ reaction to sympathetic stimuli; headaches, dizziness, and gastrointestinal upset are common. After that, phenoxybenzamine might be chosen; it is an irreversible nonselective alpha blocker that can cause postural hypotension and reflex tachycardia, in addition to gastrointestinal side effects.
Hyoscine butyl bromide, although found in the literature as a treatment option for painful cutaneous leiomyomas, is not recommended given the significant risk of central nervous system side effects, including confusion, agitation, hallucinations, delusions, blurred vision, and other behavioral changes.
For patients with one or multiple cutaneous leiomyomas, the following evaluations are needed:
-an annual dermatologic full skin examination to evaluate new or symptomatic lesions, and/or to biopsy lesions suspicious for malignant transformation to leiomyosarcoma.
-an initial gynecologic evaluation looking for uterine fibroids and monitoring of mass effect as well as potential malignant transformation.
-if patient’s presentation is suspicious for FCL, an abdominal/pelvic computed tomographic (CT) scan with contrast or magnetic resonance imaging (MRI) looking for renal tumors is needed. A repeat imaging study every 2 years is recommended if a diagnosis of FCL is made. See the Famillial Cutaneous Leiomyomatosis chapter for details.
Any patient with a solitary leiomyoma should undergo screening to look for other cutaneous leiomyomas, a consultation with a geneticist can be obtained to screen for FCL. If FCL is discovered these patients need lifelong follow-up (See Familial Cutaneous Leiomyomatosis chapter for details.
Unusual Clinical Scenarios to Consider in Patient Management
Polycythemia and hypercalcemia may be associated with multiple leiomyomas as a result of ectopic erythropoietin- and parathyroid hormone-related peptide production.
What is the Evidence?
Alam, NA, Olpin, S, Leigh, IM. ” Fumarate hydratase mutations and predisposition to cutaneous leiomyomas, uterine leiomyomas and renal cancer”. Br J Dermatol. vol. 153. 2005. pp. 11-7. (A review of the genetics of the different potential FH gene mutations and their association with Familial Cutaneous Leiomyomatosis. The discussion also includes recommendations for screening and for monitoring.)
Batchelor, RJ, Lyon, CC, Highet, AS. ” Successful treatment of pain in two patients with cutaneous leiomyomata with the oral alpha-1 adrenoceptor antagonist, doxazosin”. Br J Dermatol. vol. 150. 2004. pp. 775-6. (Two case reports detailing the successful treatment of painful leiomyomas with doxazosin.)
Christenson, LJ, Smith, K, Arpey, CJ. ” Treatment of multiple cutaneous leiomyomas with CO2 laser ablation”. Dermatol Surg. vol. 26. 2000. pp. 319-22. (A case report detailing the settings and technique used in the successful treatment of multiple cutaneous leiomyomas with CO2 laser. Carbon dioxide laser (10,600nm) with setting of 10W total power output and a spot size of 0.2cm. Two passes over the cutaneous leiomyomas with exposure duration alternated between 0.5s and continuous with a laser-to-target distance of 5cm.
Ferzli, PG, Millett, CR, Newman, MD, Heymann, WR. ” The dermatologist's guide to hereditary syndromes with renal tumors”. Cutis. vol. 81. 2008. pp. 41-8. (A comprehensive review of the dermatologic manifestations of four hereditary syndromes with renal tumors, with a discussion of the appropriate screening tests for patients with these findings.)
Horner, KL, Raugi, GJ, Miethke, MC. “Leiomyoma”. Emedicine. 2009. A complete discussion of the different types of leiomyomas. The implications and epidemiology of each type of leiomyoma is explored, and a presentation of the necessary tests and treatment modalities is outlined.)
Kostopanagiotou, G, Arvaniti, C, Kitsiou, MC, Apostolaki, S, Chatzimichael, K, Matsota, P. ” Successful pain relief of cutaneous leiomyomata due to Reed syndrome with the combination treatment of pregabalin and duloxetine”. J Pain Symptom Manage. vol. 38. 2009. pp. e3-5. (A case report detailing successful pharmacologic treatment of symptomatic cutaneous leiomyomas with the use of pregabalin in combination with duloxetine versus venlafaxine.)
Onder, M, Adisen, E. ” A new indication of botulinum toxin: Leiomyoma-related pain”. J Am Acad Dermatol. vol. 60. 2009. pp. 325-8. (A case report detailing the technique and dosage used to treat painful cutaneous leiomyomas with botulinum toxin injections, and documentation of the patient's need for fewer oral medications as a result of the treatment.)
Pithukpakorn, M, Toro, JR. “Hereditary leiomyomatosis and renal cell cancer”. Gene Reviews. 2006. (An in-depth explanation of the most recent management and diagnostic recommendations as well as a presentation of the specifics of genetic counseling and testing availability.)
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