What Caused This Blister on the Hand?

A healthy 3-month-old male infant was brought in by his mother for evaluation of a recurrent blister on his right dorsal hand. Pregnancy and delivery were uneventful, and family history was unremarkable. Three weeks after birth, the parents noted a light pink, thin plaque on the infant’s right dorsal hand that gradually transformed into a small bulla. He was prescribed a short course of oral cephalexin by a physician for suspected impetigo; however, the blister continued to wax and wane over the next several weeks. On examination, there was a multilobulated, reddish-brown bulla measuring 3 cm in diameter at its largest point and draining clear, yellowish fluid (Figure 1). Gentle stroking of the lesion with a cotton tip applicator did not cause swelling or urticarial reaction. A punch biopsy of the lesion was performed. 

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Solitary Bullous Mastocytoma 

Biopsy revealed a dense, diffuse infiltrate of cells with granular cytoplasm present beneath an epidermal blister, associated with eosinophils and neutrophils. The cells stained positively with tryptase (Figure 2) and negatively with CD1a and S100, confirming the diagnosis of solitary mastocytoma. The presence of a blister in both the clinical and histologic specimen further specified the diagnosis as solitary bullous mastocytoma. 

Mastocytosis is an umbrella term for a series of disorders marked by an abnormal rise in mast cells within the skin and internal organs, including the liver, spleen, bone marrow, and lymph nodes, with an approximate prevalence of 1 case per 10,000 persons.^1,2 Mastocytosis can be further divided into cutaneous and systemic subtypes, each with distinct clinical manifestations, disease patterns, and prognoses. Most of the subtypes occurring in the pediatric population are self-limited with a benign disease course, whereas many of the adult-onset subtypes may carry a more aggressive disease process.³ The most common type of pediatric-onset mastocytosis is urticaria pigmentosa, accounting for approximately 60% of cases.² It is estimated that solitary mastocytomas account for 10% to 15% of all cases of pediatric-onset mastocytosis.^4,5 Lesions may urticate and blister at any time due to release of histamine, which can cause the bullous appearance. Onset is typically within the first 6 months of life, and congenital cases have also been described.⁵ For the World Health Organization’s updated classification of mastocytosis, see eTable 1.⁶ 

In cases of cutaneous mastocytosis, 4 different dermoscopic patterns have been identified, including light brown and yellow-orange blots, pigment network, and reticular vascular forms.⁷ However, it has been reported that in the bullous form, a central vascular structure surrounded by a yellow hue can be observed in dermatoscopy.⁸ 

Mast cells store histamine in intracellular granules and will release large amounts of histamine in response to certain triggers through the process of degranulation. There are many well-documented mast cell triggers, including aspirin, radiocontrast dye, polymyxin, opioids, and others (eTable 2).⁹ Urticaria may appear in areas surrounding mastocytosis lesions, and bullae may occur due to intracellular swelling secondary to histamine. Gentle rubbing of mastocytosis lesions can also trigger histamine release and ensuing urticarial eruptions or bullae, a bedside test known as Darier sign, which can be elicited in 50% to 90% of mastocytosis cases.^5,10 When this bedside test is positive, it can increase the index of suspicion for mastocytosis; however, histologic investigation may still be necessary to rule out other causes of localized urticaria, and Darier sign may be negative if degranulation has already occurred.¹¹ Given the large bulla present on our patient’s hand during his presentation, we hypothesize that Darier sign was negative in this case as degranulation had already occurred. 

The c-KIT proto-oncogene, located on chromosome 4q12, encodes KIT (also known as CD117), a receptor tyrosine kinase that binds to stem cell factor, a protein which promotes cell proliferation.^12,13 Mutations in the c-KIT proto-oncogene, both activating and more rarely nonactivating mutations, have been observed to induce an irregular multiplication of mast cells and melanocytes. The prevalence of KIT mutations in mastocytosis is controversial, as recent studies have shown that these mutations are more common in adult-onset mastocytosis.¹³ However, the discovery of this genetic locus has facilitated the development of targeted gene therapies for certain mutations, such as avapritinib, which targets the mutated tyrosine kinase in advanced systemic mastocytosis.¹⁴ 

There are several entities that can be considered on the differential diagnosis for solitary bullous mastocytoma, including sucking blister, coma blister, bullous impetigo, and bullous Langerhans cell histiocytosis.^15-19 Their characteristic clinical and histologic features are summarized in eTable 3. 

Biopsy may be needed to confirm the diagnosis in atypical cases. Although mast cells can be identified on hematoxylin-eosin stain with their characteristic “fried egg” appearance, special stains can be helpful in identifying subtle mast cell infiltrates. A mixed infiltrate composed of eosinophils, neutrophils, and others may be present, especially if the lesion has been traumatized, as in our case. Common mast cell stains include tryptase, CD117, Giemsa, toluidine blue, and chloroacetate esterase (Leder).²⁰ Among these, only tryptase and CD117 will be positive at all times, even after degranulation.²¹ 

Any patients exhibiting signs of systemic involvement, such as recurrent wheezing, whole-body flushing, splenomegaly, or excessive diarrhea, should be evaluated for systemic mastocytosis. Workup may involve bone marrow biopsy, serum tryptase, molecular testing for KITD816V mutation, and/or appropriate imaging and organ biopsies.¹ In these cases, skin biopsy is typically preferred due to accessibility of tissue and low potential for morbidity from the procedure.^1,6,12 

Treatment for isolated mastocytoma is largely symptomatic and does not alter the course of the disease.⁵ Studies indicate that the complete resolution rate for isolated mastocytoma is 10% per year.² Patients and their families should be counseled to avoid mast cell degranulating agents, including opioids, nonsteriodal anti-inflammatory drugs, aspirin, radiocontrast dye, and certain anesthetics. H1-blocking agents, such as fexofenadine or loratadine, may be used for symptomatic pruritus or flushing, and H2-blocking agents such as cimetidine may be added as adjunctive therapy in severe cases. Oral cromolyn sodium has been used effectively for gastrointestinal manifestations of mastocytosis; however, there is mixed evidence as to whether oral or topical cromolyn sodium is effective for cutaneous disease.²² Topical antihistamines and topical steroids may also be used for symptomatic pruritus. 

The patient was largely asymptomatic and showed no signs of distress, such as pain, discomfort, or pruritus, from the mastocytoma. The patient was treated with 1 mL of liquid fexofenadine given orally for 2 weeks, as well as topical fluocinonide ointment applied daily on the lesion. After 3 weeks, the bulla had resolved and there was a residual pink-brown plaque on the right dorsal hand that remained asymptomatic (Figure 3). 

Solitary mastocytoma is an uncommon presentation of pediatric-onset cutaneous mastocytosis and may present as an isolated bullous lesion in a young infant. Most cases are sporadic rather than inherited, and generally occur within 3 months of birth. Diagnostic evaluation may involve cutaneous rubbing of lesions (testing for Darier sign) and skin biopsy; however, more extensive evaluation is indicated for suspected systemic mastocytosis. Patients and their families should be counseled to avoid known mast cell degranulators. Treatment is largely supportive, and many cases resolve spontaneously within the first few years of life. 

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14. Baird JH, Gotlib J. Clinical validation of KIT inhibition in advanced systemic mastocytosis. Curr Hematol Malig Rep. 2018;13(5):407-416. doi:10.1007/s11899- 018-0469-3 

15. Afsar FS, Cun S, Seremet S. Neonatal sucking blister. Dermatol Online J. 2019;25(11):13030/qt33b1w59j. 

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20. Patterson J. Weedon’s Skin Pathology. 4th edition. Elsevier; 2015. 

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22. Horan RF, Sheffer AL, Austen KF. Cromolyn sodium in the management of systemic mastocytosis. J Allergy Clin Immunol. 1990;85(5):852-855. doi:10.1016/0091- 6749(90)90067-e