Are You Confident of the Diagnosis?
Familial cutaneous leiomyomatosis (FCL) is an autosomal dominant genetic disease. It presents with cutaneous and uterine leiomyomas and is associated with the development of renal cancer.
Characteristic findings on physical examination
See the Leiomyoma chapter for a description of leiomyomas. Typically multiple pink-to-red dermal papules and nodules with minimal to no surface change are seen (Figure 1). They can be tender, and pain can be exacerbated by cold exposure. Pseudo-Darier’s sign can be seen, and when rubbed, the leiomyoma may twitch or fasciculate, mimicking the Darier’s sign of mastocytosis.
According to Pithukpakorn and Toro from the National Institutes of Health, there is currently no consensus for the clinical dermatologic diagnosis of FCL, but the following are helpful diagnostic criteria:
Multiple cutaneous leiomyomas with at least one lesion histologically confirmed
A single cutaneous leiomyoma in the context of a family history of FCL (76% of individuals with FCL will present with at least one cutaneous leiomyoma)
A single cutaneous leiomyoma in the context of a heterozygous mutation in the fumarate hydratase (FH) gene.
A personal or family history of type 2 papillary renal cancer or collecting duct carcinomas, with or without the onset of cutaneous or uterine leiomyomas
Single or multiple cutaneous leiomyomas in association with uterine leiomyomas should encourage the physician to investigate further
Note: uterine leiomyomas are present in all females with this disease, but these are not sufficient for the diagnosis, given that most uterine leiomyomas are spontaneous; however, early onset may be suggestive.
Expected results of diagnostic studies
A skin biopsy will demonstrate a characteristic pink well-differentiated proliferation of smooth muscle bundles (Figure 2). Perinuclear vacuolization is observed. Other stains, such as a Masson trichrome stain (which will stain smooth muscle cells dark red), may highlight the smooth muscle cells. 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.
See the Leiomyoma chapter for a differential diagnosis of leiomyomas.
FCL should not be confused with similar genodermatoses associated with renal cancers such as:
– Birt-Hogg-Dubé syndrome (BHD): patients present with cutaneous fibrofolliculomas, trichodiscomas, and achrocordons. Both fibrofolliculomas and trichodiscomas are skin-colored, circumscribed, smooth, firm facial papules. BHD patients also present with multiple lung cysts and spontaneous pneumothoraces. They are at risk of developing benign renal oncocytomas and/or malignant chromophobe renal cell carcinoma.
– Tuberous sclerosis (TS): patients present with facial angiofibromas (adenoma sebaceum), shagreen patch, and periungual fibromas. They may develop renal angiolipomas and are at higher risk than the general population of developing clear cell renal cell carcinoma.
– Von Hippel-Lindau syndrome (VHL): patients present with capillary malformations (often facial) and café-au-lait spots. They develop benign and malignant tumors of various organs such as central nervous system (CNS) hemangioblastomas, pheochromocytomas, and clear cell renal carcinoma.
Who is at Risk for Developing this Disease?
FCL is an autosomal dominant genetic disease. It occurs in patients who have FH gene mutations inherited from a parent, or a spontaneously developed mutation. The FH gene mutation has high penetrance and is likely to result in phenotypic expression of the disease. Its prevalence in the general population is not known, although one study estimated the presence of this mutation at 1 in 676.
FCL has been diagnosed across different races and ethnicities. It has not been found to have a predilection for either sex. The disease may manifest differently in siblings with the same mutation.
What is the Cause of the Disease?
FCL is caused by a mutation in the FH gene (chromosome 1q42.3-q43), which encodes fumarate hydratase, a mitochondrial enzyme involved in the Krebs cycle.
The FH gene mutation causes a decrease in the enzymatic activity of the enzyme. This important enzyme catalyzes the conversion of fumarate to L-malate. Genetic studies support the role of fumarate hydratase as a tumor suppressor gene. When the latter is deficient to the mutation, intracellular accumulation of fumarate causes decreased hypoxia-inducible factor (HIF) degradation and overexpression of genes downstream. This is the basis for tumor formation and proliferation in FCL.
Systemic Implications and Complications
Leiomyomas in FCL 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 a biopsy of changing or suspicious lesions is necessary to rule out this possibility.
FCL is associated with renal cancer in about 10% of affected individuals (with a range of 6%-16%). FCL-associated renal cancer is aggressive and specific in type; these are type 2 papillary renal cancers in the majority of cases, but they may also present as collecting duct carcinomas.
Unlike sporadic renal cancer, which develops in the sixth and seventh decades of life, hereditary cancers can develop much earlier. Patients present in their forties with one or several symptoms characteristic of renal tumors (eg. low back pain, hematuria, palpable mass).
As papillary renal cancer can be difficult to identify on ultrasound, an abdominal/pelvic computed tomography (CT) scan with contrast or magnetic resonance imaging (MRI) is needed to find renal tumors. Evaluation by a urologic oncology specialist is appropriate.
Medical management of cutaneous leiomyomas has no effect on the appearance of the lesions, but may improve the symptoms associated with them.
Non-steroid anti-inflammatory drugs (NSAIDS) and other analgesics: ibuprofen, Tylenol, other.
Gabapentin: 300mg PO initially, 300mg twice daily on day two, 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: 30-60mg 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.
Surgical excision of symptomatic or changing uterine fibroids not responsive to medical therapy is the treatment of choice.
Early total nephrectomy is highly encouraged in FCL patients with renal tumors, given the aggressive nature of these renal cancers and the fact that only 20% respond to chemotherapy, radiation therapy, or immunotherapy.
Cryosurgery using liquid nitrogen, two freeze-thaw cycles analogous to the technique used to freeze actinic keratoses or warts
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.
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, based on the number and distribution of lesions and the symptoms associated with them. 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 comorbidities. NSAIDS might provide adequate relief if surgical excision is not possible, depending on the location and 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 will necessitate another round of injections. Botox® injections have not been associated with serious systemic side effects at the doses described above, but the cost might be prohibitive.
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. The high dose 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, and headaches, as well as cardiac side effects and hypotension.
The next lesser option might be doxazosin, a reversible alpha-1 receptor blocker that acts as an 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, as well as gastrointestinal side effects.
Hyoscine butylbromide, although found in the literature as a treatment option for painful cutaneous leiomyomas, is not recommended, given the significant risk of CNS side effects, including confusion, agitation, hallucinations, delusions, blurred vision, and other behavioral changes.
If a renal tumor is present, early surgical total nephrectomy is necessary, given the aggressive nature of these tumors in FCL patients.
For patients with a diagnosis of FCL or family members with a risk of carrying the mutation, the following monitoring measures are recommended:
An evaluation by a geneticist that includes family screening, education, and counseling.
An annual dermatologic full-skin examination to evaluate new or symptomatic lesions, and/or to biopsy suspicious lesions for malignant transformation to leiomyosarcoma.
An annual gynecologic evaluation of uterine fibroids and monitoring of mass effect as well as potential malignant transformation.
An annual urologic examination with special attention directed at screening and monitoring for renal tumor development. This can be performed by a urologist or a nephrologist.
An abdominal/pelvic CT scan with contrast or MRI every two years to look for renal tumors. As renal tumors can appear in teenage years, screening should start in childhood.
An annual complete blood count (CBC) and calcium level should be considered, to screen for the rare association with polycythemia and hypercalcemia respectively.
When an individual is diagnosed with FCL, genetic testing of asymptomatic relatives is recommended and increases the likelihood of finding malignancies early and preventing complications. The siblings and children of an affected individual have a 50% chance of having the same FH mutation.
Prenatal diagnosis is now possible if the specific FH mutation of the parent is known.
Given that FCL is an autosomal dominant disease with high penetrance, finding affected individuals may have a significant impact on their morbidity and mortality.
Genetic counseling would also help future parents understand prenatal testing options and risks.
Unusual Clinical Scenarios to Consider in Patient Management
Some patients with FCL have developed other solid organ tumors, including gastrointestinal, testicular, ovarian, breast, and bladder tumors. It is too early to tell if these tumors are also associated with the genetic defect in FCL or are incidental findings.
Polycythemia and hypercalcemia may be associated with multiple leiomyomas as a result of ectopic erythropoietin and parathyroid hormone-related peptide production.
Positron emission tomography (PET) and CT may be used in conjunction with the other imaging modalities to identify proliferating or metabolically active renal lesions. These scans should be performed under the recommendation of the consulting urologist or nephrologist.
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.)
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.)
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. (Acase reportdetailing 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. (Acase reportdetailing thetechnique 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”. (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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