Mastocytosis_0813 Derm Clinic 1
Piloleiomyoma_0813 Derm Clinic 2
A man, aged 43 years, presented with a pruritic eruption that had been present for three months. The eruption began on his trunk and then spread to the proximal extremities. Extreme temperature changes and alcohol consumption aggravated the lesions. A review of systems was otherwise normal. Medical and family histories were unremarkable. Physical exam revealed reddish-brown macules and papules on the trunk and proximal extremities that would urticate when stroked. No lymphadenopathy or hepatosplenomegaly was appreciated.
A 22-year-old woman presented to the clinic complaining of “lumps” on her back. The lesions had been present for five months and were occasionally associated with pain, especially in cold weather. There was no associated pruritus. A review of systems was otherwise negative. Medical and family histories revealed a prior diagnosis of uterine leiomyomas in the woman and her mother. On physical examination, a group of erythematous firm papules was appreciated on the left mid-back. After gentle stroking, the lesions appeared to urticate.
Select your diagnoses for both cases from the options on the right. Read the explanation, then follow the link to complete the post test and claim your certificate.
Submit your diagnosis to see full explanation.
CASE #1: Mastocytosis
Mastocytosis is a term used to describe a spectrum of clinical disorders that have local and/or systemic accumulations of mast cells. In 1869, Nettleship and Tay first described mastocytosis in a young girl with hyperpigmented papules that urticated.1
Eight years later, Erlich discovered the mast cell. Unna was the first to identify mast cells as the responsible entity in cutaneous mastocytosis. However, it was not until nearly 60 years later, in 1949, that Ellis reported the first patient with systemic disease.
The World Health Organization classifies mastocytosis into cutaneous and systemic forms. These include cutaneous mastocytosis (urticaria pigmentosa, diffuse cutaneous mastocytosis, and mastocytoma of the skin), indolent systemic mastocytosis, systemic mastocytosis with an associated clonal hematologic non-mast cell lineage disease, aggressive systemic mastocytosis, mast-cell leukemia, mast-cell sarcoma, and extracutaneous mastocytoma.2
If extracutaneous involvement is present, the skeletal system, bone marrow, lymph nodes, spleen, liver, GI system, and central nervous system are the most commonly affected organs. This article will primarily address cutaneous mastocytosis.
Mastocytosis may be present at birth or develop anytime thereafter. Approximately 55% of patients develop the disease prior to age 2 years, and another 10% develop the disease between age 2 years and age 15 years. Most patients with mastocytosis have no family history of the disease; however, a small number of familial cases have been described.3 Women and men are equally affected, and there is no racial predilection.
There are both childhood and adult forms of mastocytosis, and they vary in clinical presentation, prognosis, and pathogenesis. Many cases of adult mastocytosis result from a neoplastic proliferation of mast cells caused by a mutation at codon 816 in the c-KIT gene. c-KIT is a proto-oncogene whose protein product is the transmembrane tyrosine kinase KIT receptor (CD117) and whose ligand is stem-cell factor. This mutation leads to constitutive activation of KIT, thereby causing continued mast-cell development.
Childhood mastocytosis is defined as disease onset prior to puberty. Interestingly, childhood and familial cases of mastocytosis do not usually harbor the c-KIT mutation. Childhood disease is thought to arise from mutations other than the 816 type, from cytokine-derived hyperplasias, or from other yet unidentified mutations.
Urticaria pigmentosa represents 60% to 90% of childhood cases of cutaneous mastocytosis. The most common clinical presentation is that of tan, brown, or rose-colored macules and papules that have a predilection for the trunk, sparing the central face, scalp, palms, and soles. Solitary mastocytomas, which present as a yellow-brown papule or plaque, comprise 10% to 40% of childhood mastocytoses.
Diffuse cutaneous mastocytosis is a rare form of childhood mastocytosis in which the entire skin is thickened and infiltrated with mast cells. The skin often has a peau d’orange appearance, and generalized bullae and erosions may develop. In children, systemic involvement is rarely seen. Most cases of early-onset, skin-limited disease will resolve spontaneously or markedly improve by adolescence. Individuals who have lesions that persist into adulthood are thought to possess the c-KIT activating mutation and have the same prognosis as adult-onset mastocytosis patients.
Adult-onset mastocytosis most commonly presents as a generalized eruption that favors the trunk and proximal extremities. Characteristic lesions are pink or reddish-brown macules and papules that measure 1 cm or less in diameter. Telangiectasia macularis eruptive perstans is a form of adult mastocytosis that most commonly presents with persistent, asymptomatic, reddish-brown macules and patches with telangiectasias that usually measure less than 0.5 cm.
Erythrodermic mastocytosis presents as generalized erythroderma and the skin has a leather-grain appearance. In adults with the c-KIT activating mutation, lesions tend to persist throughout life and the likelihood of systemic involvement is higher.
Histologically, an increased number of mast cells, which have a fried-egg appearance with granules in an amphophilic cytoplasm, will be appreciated. If needed, such special stains as Giemsa, toluidine blue, and Leder or monoclonal antibodies that recognize tryptase or CD117 (KIT) can help to identify tissue mast cells.
Lesions of mastocytosis often exhibit a positive Darier sign (urtication on stroking). Other diseases that may exhibit a positive Darier sign include juvenile xanthogranulomas, histiocytosis X, leukemia cutis and lymphoma. A pseudo-Darier sign, defined as transient piloerection and elevation or increased induration of a lesion after rubbing, clinically resembles Darier sign and may be seen in leiomyomas or smooth-muscle hamartomas.
Other diseases in the clinical differential diagnosis include pigmented nevi, juvenile xanthogranuloma, xanthomas, arthropod bites, and bullous disorders.
Once a diagnosis of mastocytosis is reached, the decision to assess for bone marrow involvement must be made. In general, all adult patients and children with an unexplainable abnormal complete blood count (CBC), hepatomegaly, splenomegaly, lymphadenopathy, or a baseline serum tryptase >20 ng/mL should be offered a bone-marrow biopsy. In adults who do not meet the above criteria, yearly CBC and serum tryptase testing should be performed, along with a complete history and physical examination.
Those with symptomatic mastocytosis should identify and avoid such triggers as temperature extremes, alcohol, and certain medications, including aspirin, nonsteroidal anti-inflammatory drugs, narcotics (e.g. morphine, codeine), anticholinergic medications, polymyxin B sulfate, and some systemic anesthetics. Local injection of lidocaine can be used safely. If needed for symptom control, local therapy includes potent or superpotent topical steroids and intralesional corticosteroids.
Systemic therapy for symptom control includes oral H1 and H2 receptor antagonists, oral cromolyn sodium (Gastrocrom), oral corticosteroids, and oral PUVA. Systemic therapy for severe mastocytosis includes interferon α-2b (Intron A), cladribine (Leustatin), hydroxyurea (Droxia, Hydrea), and specific tyrosine kinase inhibitors, such as imatinib mesylate (Gleevec) (depending on the type of c-KIT mutation).4
In this case, a biopsy confirmed the diagnosis of mastocytosis. History, physical examination, CBC, and serum tryptase were all within normal limits. The patient continues to be followed annually to monitor for disease progression.
CASE #2: Piloleiomyoma
Leiomyomas were first described by Rudolf Virchow in 1854. The three distinct variants of leiomyomas include piloleiomyomas, genital leiomyomas, and angioleiomyomas. Cutaneous leiomyomas are rare neoplasms, and their exact incidence is unknown. One general surgical pathology practice reported the incidence to be as low as 0.04% in approximately 85,000 cases.5
Men and women are equally affected, and there is no racial predilection. Most patients develop the tumors during adolescence or early adulthood; however, rare congenital or pediatric cases have been described.
Cutaneous leiomyomas are benign dermal tumors. Piloleiomyomas are derived from the arrector pili muscles. Genital leiomyomas arise from the dartoic, vulvar, or mammary smooth muscles. The smooth muscles that envelop dermal blood vessels give rise to angioleiomyomas. Individuals with multiple cutaneous leiomyomas may have multiple cutaneous and uterine leiomyomatosis (MCUL) syndrome. This syndrome is also known as multiple leiomyomatosis, Reed’s syndrome, and leiomyomatosis cutis et uteri.
MCUL is an autosomal dominant disorder with germline mutations in the fumarate hydratase gene, located on chromosome 1q42.3-43.6 Fumarate hydratase is an enzyme of the mitochondrial Krebs cycle that catalyzes fumarate to malate. Individuals who have this germline mutation are at high risk for developing MCULs. A small number of these patients are also at risk of developing early-onset papillary renal cell carcinoma.5,6 When associated with renal cell carcinoma, these patients are said to have hereditary leiomyomatosis and renal cell cancer (HLRCC).
Piloleiomyomas present as skin-colored, pink, or reddish-brown dermal papules or nodules that are small and firm and that can be solitary or multiple. Solitary piloleiomyomas are most commonly located on the extremities, whereas multiple piloleiomyomas are most commonly seen on the trunk, with a predilection for the shoulder.
Solitary piloleiomyomas tend to be bigger than those of multiple piloleiomyomas but rarely grow larger than 2 cm in diameter. Piloleiomyomas are frequently associated with spontaneous or induced pain. Known triggers include pressure, trauma, emotion, and cold temperatures. The exact pathogenesis of the pain is unknown. However, several hypotheses have been proposed, including contraction of smooth muscle, compression of nearby nerves, or an increased number of nerve bundles.7
Genital leiomyomas usually present as solitary interdermal papules or nodules that may be pedunculated and are usually smaller than 2 cm in diameter. Genital leiomyomas can be located on the labia majora, the vulva, the scrotum, and occasionally the nipple. In contrast to other leiomyomas, most genital lesions are asymptomatic. Angioleiomyomas usually present as firm subcutaneous nodules on the lower extremities. These nodules are usually solitary and do not exceed 4 cm in diameter.
In all leiomyomas, the major constituent cell is the myocyte. Myoctes are fusiform and have centrally located elongated nuclei with blunt ends (cigar-shaped). Often, perinuclear vacuoles can be appreciated. If smooth-muscle differentiation is not obvious on hematoxylin-and-eosin-stained tissue, Masson trichrome stain (which will stain muscle red) or immunohistochemistry that demonstrates antibodies against smooth-muscle actin and/or desmin may prove helpful.
Piloleiomyomas tend to be poorly demarcated and are composed of intersecting smooth-muscle bundles centered in the reticular dermis with varying amounts of intermingled collagen at the periphery. The tumors can extend into the fat and the overlying epidermis may be normal, effaced, or hyperplastic. Genital leiomyomas are often larger and better circumscribed than are piloleiomyomas. Tumors of the scrotum are usually homogeneous spindle cell tumors, whereas tumors involving the vulva can show hyalinization, myxoid change, or epithelioid cytology. Nipple leiomyomas most closely resemble piloleiomyomas. Angioleiomyomas are usually encapsulated and well-circumscribed nodules located in the lower reticular dermis and subcutis. These tumors contain smooth-muscle bundles that surround numerous thick-walled vessels.
Because of the wide spectrum of clinical presentations (solitary, linear, clustered, and so forth) the differential diagnosis is broad. Dermal neoplasms, including dermatofibromas, dermatofibrosarcoma protuberans, schwannomas, neurofibromas, adnexal tumors, and cutaneous metastases, are often considered.
Leiomyomas may present with a pseudo-Darier sign due to muscle-fiber contraction, which may help to differentiate these tumors from other entities in the differential. If needed, a biopsy will provide a definitive diagnosis.
Since leiomyomas are benign tumors, the extent of treatment will be solely dependent on the severity of symptoms. Solitary or limited tumors may be surgically removed. Tumors that are not amenable to surgical excision may be treated with such off-label therapies as nitroglycerin (Nitrolingual, Nitromist, Nitrostat), nifedipine, doxazosin (Cardura), phenoxybenzamine (Dibenzyline), topical 9% hyoscine hydrobromide, gabapentin (Horizant, Neurontin), or CO2 laser ablation.6,8
Malignant transformation of cutaneous leiomyomas is rare, and the prognosis is generally good. However, the clinician must not forget to take a detailed family history, offer genetic counseling, and arrange for additional screening for uterine leiomyomas and renal cell cancer in those at risk for MCUL and HLRCC.
In this case, an excisional biopsy revealed the diagnosis of piloleiomyoma. The woman was referred to genetics and advised to undergo regular screenings for uterine leiomyomas and renal cell cancer.
Kerri Robbins is an instructor in the Department of Dermatology at Baylor College of Medicine in Houston.
- Nettleship E, Tay W. Rare forms of urticaria. Br Med J. 1869;2:323-324.
- Valent P. Diagnostic evaluation and classification of mastocytosis. Immunol Allergy Clin North Am. 2006;26:515-534.
- Longley BJ Jr, Metcalfe DD, Tharp M, et al. Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis. Proc Natl Acad Sci USA. 1999;96:1609-1614. Avaialable at www.pnas.org/content/96/4/1609.long.
- Pardanani A. Systemic mastocytosis: disease overview, pathogenesis, and treatment. Hematol Oncol Clin North Am. 2012;26:117-28.
- Stewart L, et al: Association of germline mutations in the fumararte hydratase gene and uterine fibroids in women with hereditary leiomyomatosis and renal cell cancer. Arch Dermatol. 2008;144:1584-1592.
- Choudhary S, McLeod M, Torchia D, Romanelli P. Multiple cutaneous and uterine leiomyomatosis syndrome: a review. J Clin Aesthet Dermatol. 2013;6:16-21. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3638850/.
- Raj S, Calonje E, Kraus M, et al. Cutaneous pilar leiomyoma: clinicopathologic analysis of 53 lesions in 45 patients. Am J Dermatopathol. 1997;19:2-9.
- Christenson LJ, Smith K, Arpey CJ. Treatment of multiple cutaneous leiomyomas with CO2 laser ablation. Dermatol Surg. 2000;26:319-322.
All electronic documents accessed August 9, 2013.