Systemic Mastocytosis_1113 Derm Clinic
A woman, aged 48 years, complained of a rash on her chest that first appeared rather suddenly two months earlier. The lesions were extremely pruritic and had responded minimally to topical steroids prescribed at an urgent-care center. A review of systems revealed episodic flushing, dizziness, abdominal pain, and diarrhea that seemed to be triggered by alcohol consumption or exercise.
The woman’s medical history was significant for peptic ulcer disease and type 2 diabetes. Physical examination revealed numerous red 3-to-5-mm coalescing macules on the center of the patient’s chest. Vigorous stroking of individual lesions caused the lesions to urticate.
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The combination of systemic symptoms should trigger the clinician to consider a group of unusual conditions associated with the episodic release of vasoactive cytokines; in combination with the highly characteristic rash described in this patient, the most likely diagnosis is systemic mastocytosis (SM). Indeed, a skin biopsy demonstrated large aggregates of mast cells within the dermis. Subsequent studies included a bone marrow biopsy that revealed a dense infiltrate of mast cells and an elevated serum tryptase level >100 ng/mL. This constellation of findings confirmed the diagnosis of SM.
Classified as a myeloproliferative process, mastocytosis develops due to the clonal expansion of normal mast cells in one or more organ systems.1 Because of its rarity and limited epidemiologic data, the true prevalence of mastocytosis is speculative. Overall, the condition is more common in children, but there is a bimodal age of presentation: Approximately 75% of mastocytosis cases occur in infancy or early childhood, with a second peak in the fourth decade of life.2
The World Health Organization categorizes mastocytosis into cutaneous and systemic subtypes. The cutaneous form of mastocytosis is more common in all ages; however, SM and malignant transformation is far more common in the adult population.1,3
Skin findings are usually the first clinical sign of mastocytosis. Urticaria pigmentosa (UP) is the most common of the four major cutaneous subtypes (i.e., UP, solitary mastocytoma, diffuse erythrodermic mastocytosis, and telangiectasia macularis eruptiva perstans). UP typically presents as innumerable 3-to-4-mm, oval-to-round, red-brown macules, or papules, most commonly on the chest and proximal extremities.2 Fine telangiectasias can sometimes be seen in or around primary lesions.4 Solitary mastocytomas, which are more common in children and rare in adults, consist of rather large flesh-colored dermal nodules. Diffuse erythrodermic mastocytosis is also rare but is still more common in children and can be associated with skin thickening and bullae. Telangiectasia macularis eruptiva perstans (TMEP) is similarly rare, more common in adults, and consists of small telangiectasias that can be overlooked because they appear as banal hyperpigmented macules. These macules are also frequently mistaken for spider angiomas or telangiectasias that are attributable to other conditions.2,4,5
Generalized pruritus, dermatographism, and the Darier sign (urtication with light rubbing of the skin) are other clinical clues seen with all mastocytosis subtypes except TMEP.2,6 If firm stroking of a cutaneous lesion results in the formation of a localized hive, the Darier sign is present.
For most patients, mastocytosis is a benign and self-limited condition that is associated with transient symptoms. However, adults with mastocytosis are more likely to have persistent skin findings and are more likely to develop systemic involvement.6 A small percentage of adults may develop an aggressive form of systemic disease, mast-cell leukemia, or sarcoma.2
The symptoms of SM arise when the infiltrating mast cells degranulate and release various cytokine mediators locally and/or systemically.1 Degranulation can be triggered by a number of stimuli, including local trauma, intense physical exercise, alcohol consumption, excessive stress, insect venom, and various drugs (e.g., opioids, inhaled anesthetics, and topical polymyxins).2 Common symptoms of SM include pruritus, flushing, headache, bone pain, dyspepsia, diarrhea, tachycardia, dizziness, syncope, and hypotensive shock.1,2
Physical findings most commonly seen in individuals with SM include hepatomegaly, splenomegly, osteoporosis, gastrointestinal malabsorption, and dysfunction. Such adverse conditions as peptic ulcers, hepatic failure, bone-marrow failure, and leukemia may also develop.1 Fortunately, 90% of patients will have an indolent form of SM with a good prognosis and normal life expectancy; only a few progress to more advanced forms of disease.2,7
The etiology of SM is not completely understood. Most of the patients studied have had an activating mutation in codon 816 of the c-kit gene, which encodes for the KIT tyrosine kinase receptor. Mast-cell growth and differentiation is triggered when this KIT receptor is bound by a ligand known as stem cell factor; mutation of the KIT receptor leads to constitutive activation.1,8 Because a relatively small percentage of patients with SM do not possess this mutation, the mutation is considered only a minor diagnostic criterion.1
The differential diagnosis for SM depends on the cutaneous and/or systemic clinical presentation. For UP, the differential diagnosis includes lentigines and atypical melanocytic nevi. A positive Darier sign would differentiate UP from these conditions. The clinician should be aware that a positive Darier sign may cause UP to be mistaken for urticaria.9 Persistence of hyperpigmented lesions once the hive resolves should be a clinical clue that simple urticaria is not the diagnosis.2,6
Conditions to be considered when a patient presents with systemic symptoms may vary considerably depending on which organ systems are affected. In these cases, recognizing the significance of a rash can be vital in securing the correct diagnosis. Akin et al reported that a subset of 12 patients referred for recurrent idiopathic anaphylaxis actually had SM; of these, physical examination revealed UP in eight individuals.10
Making the diagnosis of SM typically requires suspicion of the condition. Skin biopsies are often the first diagnostic test. Identifying aggregates of mast cells is fairly straightforward, but sometimes the collections are small and require confirming immunohistochemical staining with cell surface markers, tryptase, and, if available, staining for the KIT mutation. All individuals diagnosed with cutaneous mastocytosis should have a complete blood count and have their serum tryptase levels measured. If elevated, the clinician should consider a bone-marrow biopsy, which aids in diagnosis and is necessary for staging the disease. Since children only rarely have extracutaneous involvement, a bone-marrow biopsy should be considered only if the tryptase level is >100 ng/mL or if there are other clinical signs of systemic disease.11
Unfortunately, there is currently no cure for SM. The goal of treatment is symptom control and relief. To avoid triggering symptomatic episodes, patients should always be educated regarding the agents and events that cause mast-cell mediator release. Such symptoms as pruritus, flushing, and tachycardia can be ameliorated with the use of histamine-1 blockers; histamine-2 blockers help mitigate the GI symptoms. Oral cromolyn sodium (Gastrocrom), a specific mast-cell stabilizer, can be used to prevent future GI symptoms. Other medications that can help with symptomatic relief or moderate end-organ damage include glucocorticoids, bisphosphonates, proton-pump inhibitors, and self-injectable epinephrine for severe anaphylaxis.11 Psoralen with UVA (PUVA) phototherapy has been shown to be highly effective in treating UP and associated pruritus.12 Patients with more aggressive forms of SM may require cytoreductive therapy.11
The patient in this case was placed on cromolyn for control of her GI symptoms. Her skin showed rapid clearing once PUVA was initiated.
Dustin Larsen is a third-year student at Medical College of Virginia Hospitals, Virginia Commonwealth University, in Richmond, where Julia R. Nunley, MD, is a professor of dermatology.
- Valent P, Horny HP, Escribano L, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res. 2001;25:603-625.
- Brockow K. Urticaria pigmentosa. Immunol Allergy Clin North Am. 2004;24:287-316.
- Berezowska S, Flaig MJ, Ruëff F, et al. Adult-onset mastocytosis in the skin is highly suggestive of systemic mastocytosis. Mod Pathol. 2013 Jun 28. Epub ahead of print.
- Soter NA. Mastocytosis and the skin. Hematol Oncol Clin North Am. 2000;14:537-555.
- Gordon Spratt EA, DeFelice T, O’Reilly K, et al. Generalized essential telangiectasia. Dermatol Online J. 2012;18:13. Available at escholarship.org/uc/item/0hx273p5.
- Caplan RM. The natural course of urticaria pigmentosa. Arch Dermatol. 1963;87:146-157.
- Pardanani A, Tefferi A. Systemic mastocytosis in adults: a review on prognosis and treatment based on 342 Mayo Clinic patients and current literature. Curr Opin Hematol. 2010;17:125-132.
- Pardanani A, Akin C, Valent P. Pathogenesis, clinical features, and treatment advances in mastocytosis. Best Pract Res Clin Haematol. 2006;19:595-615.
- Goldsmith LA, Katz SI, Gilchrest BA, et al, eds. Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York, N.Y.: McGraw-Hill; 2012.
- Akin C, Scott LM, Kocabas CN, et al. Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with “idiopathic” anaphylaxis. Blood. 2007;110:2331-2333. Available at bloodjournal.hematologylibrary.org/content/110/7/2331.long.
- Valent P, Akin C, Escribano L, et al. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest. 2007;37:435-453.
- Godt O, Proksch E, Streit V, Christophers E. Short- and long-term effectiveness of oral and bath PUVA therapy in urticaria pigmentosa and systemic mastocytosis. Dermatology. 1997;195:35-39.
All electronic documents accessed October 15, 2013.