September 2014 Dermatology CME/CE
A 29-year-old white man presented to the dermatology clinic with multiple lesions on his left arm and shoulder. The lesions had been previously biopsied at an outside dermatology clinic.
The patient reported that the lesions were slightly tender to palpation, but he was otherwise asymptomatic. His medical history was unremarkable. The man’s social history was noncontributory and his family history was significant for a father who had renal cell carcinoma.
The physical exam was notable for many discrete red-brown and skin-colored papules in clusters on the patient’s left scapula, left upper arm, and left forearm, with scattered linear scars at sites of prior excisions.
This Clinical Advisor CME activity consists of 3 articles.To obtain credit, you must also read Ulcerated lesions on the shins and Multiple facial papules on a young girl. Then take the post-test here.
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Multiple cutaneous and uterine leiomyomatosis (MCUL), or Reed syndrome, is a disorder characterized by multiple piloleiomyomas and uterine leiomyomas. Some of these patients also have renal cell carcinoma (RCC), which is diagnosed as hereditary leiomyomatosis and renal cell cancer (HLRCC).1
Leiomyomas are a broad category of neoplasms derived from smooth muscle, of which piloleiomyomas are a variant derived from smooth muscle cells within the arrector pili muscle of the pilosebaceous unit.2-4
MCUL and HLRCC are rare disorders. More than 200 families with HLRCC have been identified, but the exact incidence is unknown. Because of the autosomal-dominant inheritance of these conditions, males and females are equally affected.
This syndrome is inherited in an autosomal-dominant fashion but mutations may occur spontaneously. In both MCUL and HLRCC, mutations have been found in the gene that encodes the fumarate hydratase enzyme in the mitochondrial Krebs cycle.1 The exact mechanism by which this mutation in the Krebs cycle results in cutaneous and visceral tumors is unknown.
Cutaneous leiomyomas are often the first presentation of HLRCC, with a mean age of onset of 25 years.5 Patients present with firm, skin-colored to red-brown papules and nodules. There are usually multiple lesions, ranging from 10 to more than 100, but occasionally only a single lesion is present.5
The majority of patients complain of pain associated with these lesions, especially with palpation.5 The most common locations of involvement are the trunk and extremities, although the face may sometimes be involved.5
The majority of women with HLRCC will also develop uterine leiomyomas (fibroids). Signs and symptoms include irregular menses, menorrhagia, and pain.5 For the majority of these women, the fibroids become so symptomatic that they ultimately require surgical excision.5 Over half of affected women will have a myomectomy or a hysterectomy before they reach age 30 years.5
As many as a quarter of patients with HLRCC develop RCC, which usually is solitary and unilateral.5 The most common type of RCC reported is papillary type II RCC, but renal tumors derived from the collecting duct and oncocytic tumors also have been reported.5
The median age at which patients receive a diagnosis of RCC is 44 years, although cases have been reported in patients as young as age 11 years.5-7 RCCs in patients with HLRCC tend to have an aggressive disease course, and these patients may have advanced disease, including distant metastases, at presentation.5 Leiomyosarcomas have also rarely been seen in patients with HLRCC.8
HLRCC is diagnosed by the presence of multiple cutaneous leiomyomas, with at least one histologically confirmed leiomyoma, or by a single leiomyoma in the presence of a positive family history of HLRCC.9
Diagnosis is confirmed by molecular genetic testing or by demonstrating reduced activity of the fumarate hydratase enzyme in cultured skin fibroblasts or lymphoblastoid cells.9
Histologically, leiomyomas are benign smooth muscle tumors characterized by long, thin, blunt-ended cigar-shaped nuclei. Immunoperoxidase markers for smooth muscle (actin and desmin) are often used.10
The differential diagnosis of painful tumors of the skin can be recalled by the mnemonic “BANGLE,” which stands for blue rubber bleb nevi, angiolipoma, neuroma, glomus tumor, leiomyoma, and eccrine spiradenoma.10
With the exception of blue rubber bleb nevi, which is a venous malformation that gives it a distinct bluish hue, the remainder of the entities in the painful tumor differential can be difficult to distinguish clinically, thereby necessitating a skin biopsy.
The differential diagnosis of hereditary RCC syndromes with cutaneous findings includes Von Hippel-Lindau disease and Birt-Hogg-Dubé syndrome. Most patients with hereditary RCC present with multifocal and/or bilateral renal tumors, whereas HLRCC tends to present with a solitary tumor.
Von Hippel-Lindau disease is characterized by retinal angiomas, cerebellar tumors, pancreatic cysts, and renal tumors and cysts. A minority of patients will present with angiomas on the posterior neck and scalp.4 Birt-Hogg-Dubé syndrome is notable for trichodiscomas, fibrofolliculomas, skin tags, spontaneous pneumothorax, and chromophobe RCC.
Patients with trichodiscomas and fibrofolliculomas present with skin-colored papules, most commonly on the face and upper trunk.4
Cutaneous leiomyomas can be treated with surgical excision, but it is usually reserved for patients with only a few lesions or for particular lesions that are severely symptomatic.9
Since most patients tend to have multiple leiomyomas, and the surgical scars following multiple excisions can be as cosmetically displeasing as the lesions themselves, reassurance is often the best management. Cryoablation and/or laser excision have been reported, but their efficacy is unclear.9
Uterine fibroids are most commonly treated with myomectomy or hysterectomy, but gonadotropin-releasing hormone agonists, anti-hormonal medications, and pain relievers can be used for minimally symptomatic fibroids or for patients who are poor candidates for surgery.9
Total nephrectomy should be considered for patients with kidney tumors, because RCC in patients with HLRCC tends to follow an aggressive course.9
In terms of surveillance for HLRCC, there are no consensus guidelines. Provisional recommendations are as follows: a full skin examination every 1 to 2 years, an annual gynecologic exam for female patients, and a magnetic resonance imaging or computed tomography scan of the abdomen and pelvis every 1 to 2 years.9
When HLRCC is confirmed in a patient, it is recommended that relatives who are at risk undergo molecular genetic testing for early surveillance and treatment.9
Our patient opted not to treat his leiomyomas, as we advised him that no effective treatments currently exist and that he was not a good surgical candidate due to the number of lesions. The patient will follow up with his primary-care physician for RCC surveillance.
Audrey Chan, MD, is a pediatric dermatology fellow at Texas Children’s Hospital in Houston.
This Clinical Advisor CME activity consists of 3 articles. To obtain credit, you must also read Ulcerated lesions on the shins and Multiple facial papules on a young girl. Then take the post-test here.
- Alam NA, Olpin S, Leigh IM. Fumarate hydratase mutations and predisposition to cutaneous leiomyomas, uterine leiomyomas and renal cancer. Br J Dermatol. 2005;153(1):11-17.
- Bolognia JL, Jorizzo JL, Rapini RP. Dermatology. 2nd ed. St. Louis, Mo.: Elsevier Mosby;2008:1831-1833.
- Rapini R. Practical Dermatopathology. 1st ed. St. Louis, Mo.: Elsevier Mosby;2005:366-368.
- James WD, Berger T, Elston D. Andrews’ Diseases of the Skin: Clinical Dermatology. 11th ed. Philadelphia, Pa.: Saunders Elsevier; 2011:614-615.
- van Spaendonck-Zwarts KY, Badeloe S, Oosting SF, et al. Hereditary leiomyomatosis and renal cell cancer presenting as metastatic kidney cancer at 18 years of age. Fam Cancer. 2012;11(1):123-129.
- Refae MA, Wong N, Patenaude F, et al. Hereditary leiomyomatosis and renal cell cancer: an unusual and aggressive form of hereditary renal carcinoma. Nat Clin Pract Oncol. 2007;4(4):256-261.
- Alrashdi I, Levine S, Paterson J, et al. Hereditary leiomyomatosis and renal cell carcinoma: very early diagnosis of renal cancer in a paediatric patient. Fam Cancer. 2010;9(2):239-243.
- Varol A, Stapleton K, Roscioli T. The syndrome of hereditary leiomyomatosis and renal cell cancer (HLRCC): the clinical features of an individual with a fumarate hydratase gene mutation. Australas J Dermatol. 2006;47(4):247-276.
- Pagon RA, Adam MP, Bird TD, et al., eds. GeneReviews. Seattle, Wash.: University of Washington; 1993-2014.
- Elston D, Ferringer T, Peckham S, et al., eds. Dermatopathology. 2nd ed. St. Louis, Mo.: Elsevier Saunders; 2014: chap. 21