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Urticaria Pigmentosa / Mastocytosis

Key Points

  • Mastocytosis can occur at any age, and may involve the skin, or affect internal organs including the bone marrow and liver/spleen/lymphatic tissues
  • Urticaria pigmentosa is a form of cutaneous mastocytosis most common in childhood, characterized by brown papules, plaques, or nodules, which may urticate when stroked.
  • Patients with cutaneous mastocytosis may have a single isolated mastocytoma, diffuse cutaneous mastocytosis, urticaria pigmentosa, or a rare form of mast cells in the skin seen in adults characterized by telangiectasias and faint lesions, called telangiectasia macularis eruptiva perstans.

Introduction

Mastocytosis includes a wide variety of cutaneous diseases with variable systemic involvement; this chapter will focus specifically on urticaria pigmentosa (UP), with a brief review of other forms of cutaneous mastocytosis. The three most common types of cutaneous mastocytosis are urticaria pigmentosa (UP), diffuse cutaneous mastocytosis, and the presence of a single mastocytoma. Urticaria pigmentosa is most common in childhood, and less likely to have systemic involvement than adult forms of mastocytosis. Most patients develop mastocytosis in childhood, before the age of 2, with 60-80% of patients having lesions during the first year of life; lesions can even be present at birth. UP is the most common form of cutaneous mastocytosis and represents up to 70-90% of cases. Mastocytosis occurs in patients of all ethnic backgrounds and in both men and women. Most cases are sporadic, but there are rare cohorts of familial cases, including disease reported in monozygotic twins. Cases of adult mastocytosis have been identified with alterations in the KIT tyrosine kinase (CD117), particularly point mutations in codon 816 of the c-kit proto-oncogene. This leads to activated KIT, and increased mast cell development. This genetic mutation is less common in children with mastocytosis.

The skin findings of childhood mastocytosis often include isolated tan or brown plaques or nodules (isolated mastocytomas) or variable numbers of brown macules, papules, and small plaques or dermal-based nodules (urticaria pigmentosa); some patients may have extensive, almost erythrodermic involvement with diffuse cutaneous mastocytomas. UP generally appears in childhood, and lesions often develop on the trunk and/or extremities; the face, palms, and soles are generally spared. Adult mastocytosis generally presents with small subcentimeter reddish-brown macules or flat-papules, generally on the trunk and extremities. Telangiectasia macularis eruptiva perstans (TMEP) is a less common presentation seen almost exclusively in adults, where patients have fainter, lighter, more subtle macules and small papules, intermixed with more prominent telangiectasias. While most forms of cutaneous mastocytosis will appear hyperpigmented or brown at times, TMEP is generally flesh colored and indistinct, with a very subtle clinical appearance. Adults may rarely develop diffuse cutaneous mastocytosis.

Mast cells in the skin represent a large concentration of inflammatory mediators, as mast cells often contain granules of histamine. Stroking or rubbing a lesion of cutaneous mastocytosis can elaborate these signaling molecules, and often results in a localized wheal response, where the lesion while form a hive; this is called “Darier’s sign.” Darier’s sign can be seen in isolated mastocytomas, childhood urticaria pigmentosa, and diffuse cutaneous mastocytosis; lesions of TMEP often harbor smaller collections of mast cells and are less apt to urticate when stroked.

In UP, systemic involvement is rare. Most childhood cases will experience a limited course and spontaneous resolution by adolescence. A subset of children whose disease persists may behave more like adult cases of cutaneous mastocytosis, and may warrant c-kit testing or other workup. Adults with cutaneous mastocytosis are at risk for variable amounts of bone marrow involvement. Patients may have hepatic or splenic involvement with mast cell infiltration, and lymph node enlargement may occur. Adults also may develop skeletal lesions due to mastocytosis with opacities or lucencies seen on radiographic imaging; patients may also develop osteosclerosis or osteoporosis. Due to the mast cell burden, patients may occasionally develop gastrointestinal symptoms, including pain, diarrhea, nausea, or vomiting. Patients with mastocytosis should have a thorough physical examination, serum tryptase, blood count with differential, and often a skin biopsy. Patients with an abnormal tryptase level, abnormal blood count, or systemic symptoms warrant further evaluation.

Treatment of mastocytosis is predominantly symptomatic. Indolent cases or cases with isolated, asymptomatic lesions often do not require therapy. As lesions may urticate in response to physical stimulus, patients should be advised to avoid heat and friction to lesions. Patients with mastocytomas, particularly those with high numbers of lesions and disease burden, should avoid mast cell degranulating agents. This list includes alcohol, anticholinergic agents, NSAIDs, aspirin, narcotics, and polymyxin B. Anesthetic agents may trigger anaphylactoid reactions in patients with mastocytosis, and if patients require surgery or general anesthesia, the surgical team and anesthesiologist should be aware of the diagnosis and consulted regarding the safest systemic agents. Histamine receptor antagonists (H1 or H2 blockers, alone or in combination) may help alleviate some of the symptoms of mastocytosis. Cromolyn sodium has been used for GI symptomatic control. Patients with extensive skin disease have been treated with light therapy, including psoralen plus UVA (PUVA) therapy; patients may degranulate during the initiation of such treatment and should be counseled and monitored closely, particularly in cases of high disease burden. Potent topical steroids may eliminate local symptoms and can in some cases resolve the cutaneous lesion entirely. Intralesional steroids may also help with isolated or limited cutaneous mastocytomas. Patients with systemic disease may be at risk for large degranulation episodes and can experience anaphylactoid reactions and life threatening hypotension; patients at risk for this should carry an EpiPen at all times.

Initial Evaluation

Differential diagnosis

Urticaria

Café-au-lait macules

Arthropod bites

Treatment

First-line therapy: Avoiding triggers of mast cell degranulation. Patients should avoid extremes of temperature, particularly heat, and should be careful jumping into extremely hot baths or showers, cold swimming pools, or extremely cool air conditioned rooms. Patients should avoid direct physical stimulation to the mastocytomas, and ideally anxiety and stress should be limited.

First steps

  • Avoid direct physical stimulation of mastocytoma lesions.
  • Avoid hot temperatures or rapid temperature swings.
  • H1 antihistamines can offer symptomatic relief.
  • Topical steroids, particularly potent topical steroids under occlusion, may help individual lesions fade and resolve faster.

Ancillary steps

  • H1 antihistamines can decrease itching, flushing, urticaria, and tachycardia. Both sedating and non-sedating antihistamines may offer some relief (diphenhydramine or hydroxyzine and cetirizine, respectively).
  • Combination H1 and H2 antihistamine blockade can be helpful for more severe cases with extensive pruritus or cutaneous whealing (ranitidine or famotidine).

Subsequent steps

  • Oral cromolyn sodium can aid in controlling some of the GI symptoms of mast cell disease.
  • Oral psoralen and UVA (PUVA) therapy can be effective in cases of widespread cutaneous mastocytosis.
  • Many cases of childhood UP will self-resolve and fade away by puberty, and aggressive systemic therapy including cytoreductive therapy/chemotherapy is often unnecessary.

Pitfalls

  • Patients with systemic symptoms, abnormal blood counts, or elevated tryptase levels warrant more thorough investigation for potential systemic mastocytosis.
  • Patients with cutaneous or systemic mastocytosis may be at risk of anaphylaxis. Patients with high burdens of disease warrant consideration for prophylactic EpiPen prescriptions and instructions on warning signs and symptoms of anaphylaxis.
  • Widespread use of potent topical steroids in very small patients, particularly infants, can lead to systemic absorption and HPA-axis suppression.
  • Signs of systemic mastocytosis may include hepatomegaly (with or without ascites or portal hypertension), splenomegaly, lymphadenopathy, severe GI involvement with malabsorption, lytic lesions or pathologic skeletal fractures, markedly elevated tryptase, or abnormal bone marrow with cytopenias. If present, these signs and symptoms warrant thorough investigation.
  • All patients with UP should be followed regularly by their physician and counseled about signs and symptoms suggestive of systemic disease.

Clinical Case

Case 1

  • 10-month-old healthy boy
  • No significant past medical history
  • Review of systems is noncontributory, notably negative for signs of fatigue, diarrhea, nausea, vomiting
  • Social history is unremarkable
  • Presents for evaluation of multiple, widespread brownish papules and plaques. The lesions were first noted about 4-5 months ago, largely on the trunk and extremities, sparing the face, palms, and soles. The lesions don’t appear to be uncomfortable. The patient’s mother tried over the counter topical corticosteroids without relief

Initial evaluation

  • Healthy appearing male
  • Numerous red-to-brown, slightly hyperpigmented, papules and plaques on the trunk and extremities
  • When one lesion was vigorously rubbed, it appeared to swell up and resemble a wheal
  • There is no lymphadenopathy or hepatosplenomegaly on exam
  • No other skin lesions

Diagnosis: Urticaria Pigmentosa

  • Recommend avoiding excess rubbing, friction, or pressure, along with avoidance of extreme temperatures, particularly extreme heat
  • Non-sedating H1 antihistamine trial initiated
  • Counseled about signs and symptoms of systemic mastocytosis, including findings of vomiting, diarrhea, dyspnea, fatigue, or signs of systemic anaphylaxis
  • Counseled about mast cell degranulators and need to inform physicians and particularly anesthesiologists/surgeons about the diagnosis prior to new prescriptions, particularly if general anesthesia is required
  • Complete blood count is sent and normal, and serum tryptase is not elevated. A confirmatory skin biopsy is offered but the mother declines

Follow-up evaluation

  • Follow-up in 6 months for recheck, and every 6-12 months thereafter
  • The family notes the lesions seem less noticeable and seem to cause fewer symptoms with the avoidance measures
  • The lesions seem to be slowly fading on their own
  • As the child reaches adolescence, the lesions seem to be self-resolving

References

Bains SN, Hsieh FH (2010). Current approaches to the diagnosis and treatment of systemic mastocytosis. Ann Allergy Asthma Immunol, 104, 1-10.

Caplan RM (1963). The natural course of urticarial pigmentosa. Analysis and follow-up of 112 cases. Arch Dermatol, 87, 146-157.

Castells M, Metcalfe DD, Escribano L (2011). Guidelines for the diagnosis and treatment of cutaneous mastocytosis in children. Am J Clin Dermatol 12, 259-270.

Fett NM, Teng J, Longley BJ (2013). Familial urticarial pigmentosa: report of a family and review of the role of KIT mutations. Am J Dermatopathol, 35, 113-116

Frieri M, Quershi M (2013). Pediatric mastocytosis: a review of the literature. Pediatr Allergy Immunol Pulmonol, 26, 175-180.

Worobec AS (2000). Treatment of systemic mast cell disorders. Hematol Oncol Clin North Am, 14, 659-687.