Solitary mastocytomas most frequently occur in infants and children under 2 years of age, with the highest prevalence in the first month of life.^1,3 True solitary mastocytomas (isolated lesions without systemic disease) are only very rarely seen in adults and children over the age of 16, with only a handful of cases reported in the literature.^3,4 Solitary mastocytomas account for approximately 20% of cutaneous mastocytosis cases (with the remaining 80% of cases representing urticaria pigmentosa [UP] and disseminated cutaneous mastocytosis).^5,6

Although their etiology is not fully understood, mastocytomas often show activating mutations in the KIT gene.⁷ KIT is a receptor tyrosine kinase and proto-oncogene that is normally expressed by mast cells.⁷ KIT activating mutations are key molecular carcinogenic events in gastrointestinal stromal tumors (GISTs), as well as some melanomas and acute myeloid leukemias.⁷ Contrary to the previously held notion that KIT mutations are generally only associated with adult mastocytosis, many recent studies have demonstrated KIT mutations in childhood mastocytosis.^7,8,9,10 Mastocytomas specifically have been found to have mutations in KIT, with one study reporting identifiable mutations in 67% of solitary mastocytomas.⁷

Mastocytomas are typically brown or yellow-brown macules, plaques, or nodules.^11,12 The lesions are most commonly distributed on the trunk, but also occur frequently on the face and limbs.¹³ Typically, solitary mastocytomas are 1 cm in diameter or less.¹ The surface of the lesions may be smooth, or may have a characteristic orange peel (peau d’orange) appearance.¹¹ Rubbing of the lesions often causes mast cell degranulation, resulting in localized swelling or wheal formation (referred to clinically as Darier sign).^3,11 Extralesional symptoms such as generalized flushing, pruritus, nausea, vomiting, and headaches may occur in a small subset of patients with mastocytomas and are due to the release of mast cell mediators into the circulation.^11,14,15

Patients with solitary mastocytomas have an excellent prognosis. Strictly speaking, cutaneous mastocytomas are a form of isolated cutaneous mastocytosis. Thus, by definition, patients do not have systemic disease. The majority of mastocytomas will resolve spontaneously—in most cases within 4 to 10 years, and often by the time the patient reaches puberty.^1,3,13 Adult-onset mastocytomas are less likely to spontaneously involute than the typical pediatric mastocytomas.³ However, mastocytomas that persist in any age group are often cured with complete excision.¹ Malignant transformation of solitary mastocytomas to primary mast cell sarcoma (MCS) is rare, but has been described in at least one case report in the literature.¹⁶

Histologic sections of mastocytomas show a dense, nodular aggregate of mature mast cells in the dermis (Fig. 66-1), with occasional extension into the deeper levels of the dermis and subcutaneous tissues.¹⁸ The mast cells are often ovoid with abundant cytoplasm and contain round-to-oval nuclei with inconspicuous nucleoli.¹¹ The mast cell cytoplasm contains small amphophilic granules which contain bioactive chemicals such as histamine.¹¹

Mastocytomas express normal mast cell markers such as CD33, CD5, CD68, CD117, tryptase, and chymase.^19,20 Mast cells also express CD45 (common leukocyte antigen).¹⁹ Histochemical stains such as Toluidine blue, Giemsa, and chloroacetate esterase (the Leder stain) may also be used to highlight mast cells.^1,19 CD117 is the most sensitive marker for mast cells but is not entirely specific. Conversely, chymase is highly specific for mast cells, but less sensitive.¹⁹ Childhood mastocytoses very rarely express aberrant immunohistochemical markers such as CD25 or CD2, with very few reported cases in the literature.^21,22 Aberrant antigen expression in solitary mastocytomas specifically is not well characterized. However, as a whole, the limited cutaneous mastocytoses (including solitary mastocytomas) express aberrant CD25 much less often than the cutaneous lesions of systemic mastocytosis.²³

The genetic and molecular findings of solitary mastocytomas specifically are not well characterized. In one small study, 67% of solitary mastocytomas had mutations in the KIT proto-oncogene.⁷

Mast cells are derived from CD34⁺ pluripotent bone marrow precursor cells and belong to the larger family of CD45⁺ hematopoietic cells.¹⁹

The differential diagnosis includes systemic mastocytosis (SM) with cutaneous involvement and other forms of isolated cutaneous mastocytosis discussed in this chapter. Cutaneous tumors with cell types that resemble mast cells may also be considered in the differential. Mast cells typically have a characteristic histologic appearance with amphophilic cytoplasmic granules that are uncommonly seen in other cell types.¹¹ Nevertheless, in certain cases, mast cells may bear resemblance to melanocytes, histiocytes, and Langerhans cells.²⁴ Langerhans cell histiocytosis (LCH) also frequently presents as a cutaneous tumor in infants and young children.²⁵ However, histologically, Langerhans cells are pale histiocytes devoid of cytoplasmic granules and often demonstrate characteristic folded (or reniform) nuclei.²⁵ Langerhans cells are positive for S100 and CD1a (Langerin), whereas mast cells are negative for these markers.^22,24,25 An eosinophilic infiltrate is common in lesions of LCH,²⁵ but this feature has also rarely been described in cases of mastocytoma.^26,27 Histologically, mastocytomas may also bear resemblance to melanocytic nevi. Rare instances of mastocytomas combined with melanocytic nevi have even been reported (Fig. 66-2).²⁸ Unlike junctional melanocytic nevi, mastocytomas involve only the dermis, and do not typically involve or extend into the epidermis.²⁴ Furthermore, mastocytomas do not generally show the nesting pattern that is characteristic of most melanocytic nevi, and instead are generally composed of a single dense aggregate of cells.²⁴ Immunohistochemical stains for S100 protein, CD117, and melanocyte-specific markers may be used if the distinction cannot be made on histologic examination alone.

In a child or an adult with a presumed solitary cutaneous mastocytoma, cutaneous involvement by SM should also be considered in the differential diagnosis. Aberrant CD25 expression is more commonly seen in cases of systemic mastocytosis, and this marker may be useful for identifying patients with cutaneous mastocytosis who are more likely to have systemic disease and may require further workup.²³

Rare cases of mastocytomas with dense eosinophilic infiltrates have been described (Fig. 66-3).^26,27 The eosinophilic infiltrate may be so dense as to obscure the underlying mast cells, making the diagnosis challenging, and raising the differential consideration of LCH.²⁷ A histiocyte-rich pleomorphic mastocytoma has also been described. This lesion was characterized by a rich histiocytic infiltrate with enlarged, bilobed, and multinucleated mast cells.²²

UP is the most common clinical presentation of cutaneous mastocytosis, representing 75% to 80% of all cases.^5,6 As with other forms of cutaneous mastocytosis, UP most commonly occurs in infants and children, with 80% of cases occurring within the first year of life.^2,29 In adult patients who clinically appear to have UP, further studies frequently show systemic disease, and these patients are better classified as having SM with cutaneous involvement.^29,30 However, rare cases of adults with pure cutaneous UP have been described.^2,30 Studies have shown an equal sex predilection to slight male predominance.^6,29

As with other forms of cutaneous mastocytosis, both sporadic and germline activating mutations in the KIT proto-oncogene have been demonstrated in urticaria pigmentosa.^{31,32,33,34,35,36} Although the disease is usually sporadic, familial forms of UP with a variety of germline mutations in KIT have been described.^{31,32,33,34,35,36} A minority of cases of cutaneous mastocytosis are KIT-negative.⁹ In these cases, it has been suggested that the etiologic agent is the abnormal expression of mast cell growth factors.³¹

The lesions of urticarial pigmentosa are usually red or brown, oval shaped, and typically vary in size.² Most of the lesions are larger than 0.5 mm, and may be macules, papules, nodules, or plaques.² The lesions can be sharply demarcated or have indistinct borders (Fig. 66-3).² The lesions are typically symmetrically distributed on the head, neck, and extremities.^2,11 Rubbing or scratching of the rash usually results in localized swelling, wheal, or blister formation (Darier sign) due to mast cell degranulation.² Generalized itching is a reported symptom in about half of patients.¹¹ UP only very rarely persists into adulthood.² Serum tryptase levels are often measured in patients with mastocytosis. Patients with isolated cutaneous mastocytosis generally have lower serum tryptase levels than those with systemic mastocytosis.³⁷ In children with UP, serum tryptase levels are usually within the normal range,^2,37 which is consistent with the fact that UP in children is frequently a skin-limited process. Some congenital cases of UP can present with alopecia (Fig. 66-4).³⁸

The prognosis in children is good. In most patients, the rash regresses by the time the patient reaches puberty.² On the other hand, adults with UP are more likely to have persistent disease and systemic involvement.²

Biopsies of UP lesions show an increase in dermal mast cells that is “4 to 8 times higher than that seen in normal skin and 2 to 3 times higher than that seen in inflamed skin.”² The mast cells may be spindled or ovoid and show characteristic amphophilic cytoplasmic granules similar to the mast cells seen in other cutaneous mastocytoses.^2,11 The number of dermal mast cells identified histologically can vary significantly from patient to patient.² The infiltrate is predominantly in the upper third of the dermis, at times in proximity to the dermoepidermal junction (Fig. 66-5).³⁹

Mast cells express CD33, CD5, CD68, CD117, tryptase, and chymase, as well as CD45 (leukocyte common antigen).^19,20 Toluidine blue, Giemsa, and chloroacetate esterase (the Leder stain) can also be used to highlight mast cells.^1,19 CD117 is the most sensitive marker for mast cells but is not entirely specific. Conversely, chymase positivity is highly specific for mast cells, but less sensitive.¹⁹ Tryptase has been recommended as the standard immunohistochemical marker for the identification and quantification of mast cells in mastocytosis.²