White : Diseases of the Skin - Cellular and Metabolic Cutaneous Infiltrates

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Gary M. White & Neil H. Cox

Diseases of the Skin

11	Cellular and Metabolic Cutaneous Infiltrates

MASTOCYTOSIS

Etiology and pathogenesis

Mastocytoses are the deposition of abnormal numbers of mast cells in skin or other organs. Most cases are sporadic, a few are familial, and some are associated with other myeloproliferative disease. It is now known that adults, and a small proportion of children, with sporadic mastocytosis have mutations in the protooncogene c-kit. The product of this gene, KIT, is expressed on mast cell surface membranes and is normally activated by stem cell factor, leading to cell growth and increased survival. Mutations in c-kit lead to constitutive activation of KIT.

In addition to the well-known histamine content of mast cells, numerous other chemicals from mast cell granules play a part in producing the symptoms of mastocytosis. These include proteases, carboxypeptidase A, heparin, leukotrienes, prostaglandins (leukotriene B4, leukotriene C4, prostaglandin D2, and platelet-activating factor), and cytokines (interleukin [IL]-1, IL-3, IL-4, IL-5, IL-6, granulocyte–monocyte colony-stimulating factor, and tumor necrosis factor). Release of IL-5 leads to eosinophilia, which may be prominent in some cases.

    Mastocytosis is divided on clinical grounds into the following types.

  •   Type Ia: indolent mastocytosis, no systemic disease.

  •   Type Ib: indolent mastocytosis, with systemic disease.

  •   Type II: mastocytosis associated with a myeloproliferative (IIa) or myelodysplastic (IIb) disorder (skin lesions may or may not be present; urticaria, dermographism, or flushing usually occur).

  •   Type III: lymphadenopathic mastocytosis with eosinophilia (also termed aggressive mastocytosis; rare, usually no skin lesions).

  •   Type IV: mast cell leukemia (rare, usually no skin lesions). This text will concentrate on the skin lesions.

Clinical

Cutaneous mastocytosis presents with several different morphologies (Table 11.6and described later), each of which has a different age group of predilection (Fig. 11.45 – 11.50). Lesions in children contain many more mast cells than those in adults, hence the greater tendency for lesional urtication or blistering in the younger age group. Clinical features of the lesions include itch, urtication when rubbed (Darier sign), bliste ring in some cases, and pigmentation. Dermographism and urticarial lesions may occur more widely. Systemic symptoms include flushing (Ch.12), alcohol intolerance, headache (especially in adults), and peptic ulceration (Table 11.7).

Table 11.6 CLINICAL VARIANTS OF CUTANEOUS MASTOCYTOSIS

Pattern	Description	Differential diagnosis
Solitary mastocytoma	Yellow-brown plaque (may be macular or papular morphology). Urticates or blisters easily. Virtually always in children.	Early macular lesions may resemble a café-au-lait patch or congenital nevus. Congenital or early-onset lesions are often confused with a variety of birthmarks, or with some form of intrauterine or perinatal trauma. Juvenile xanthogranuloma may have a similar yellowish color. Bullous lesions may be confused with impetigo, burns, or child abuse.
Urticaria pigmentosa: childhood pattern	Variable number of yellow-brown macules, plaques; usually fewer if later age of onset. Usually urticate easily; especially if extensive and young age. Larger lesions (may be 1–2 cm) compared with the adult pattern	Includes café-au-lait patches, bite reactions, pseudolymphomas, ordinary and Spitz nevi, impetigo, other pediatric bullous disorders (all rare), burns, child abuse.
Urticaria pigmentosa: adult pattern	Numerous red-brown macules or papules, usually each < 0.5 cm, mainly on trunk. May be difﬁcult to urticate.	Lichen planus, freckles, nevi.
Diffuse cutaneous mastocytosis	Semiconfluent yellow–pale brown plaques, skin may be wrinkled and doughy. Rare; usually children.	May be confused with immunobullous disorders, impetigo, erythema multiforme if there is extensive blistering. Flushing episodes may suggest carcinoid syndrome.
Telangiectasia macularis eruptive perstans	Telangiectatic macules; may be discrete or semiconfluent. Urtication is often subtle. Usually adults.	Usually non-speciﬁc description of telangiectasia or red patches; may be assumed to represent aging or solar damage.
Xanthelasmoid pattern	Yellowish plaques; may urticate. Rare.	Xanthomatoses, pseudoxanthoma elasticum.
No skin lesions	Systemic disease may occur without skin lesions	Depends on organ(s) involved and symptoms; see Table 11.7

Fig. 11.45 Examples of extensive neonatal mastocytosis.
(a) This infant had diffuse cutaneous involvement; splenomegaly was a feature when he was a few years older. (b) This child had scattered red patches present at birth, but blisters, as shown here, and generalized flushing were the prominent problems during her early childhood.

Fig. 11.46 Solitary lesions (mastocytoma) are a pattern of mastocytosis that occurs in infants and young children, and often affects the distal part of a limb. In this case, blistering at the ankle was blamed on a name band used in the neonatal unit, but the characteristic brown color of mastocytosis made the diagnosis apparent.

Fig. 11.47 (a) Urticaria pigmentosa is the most frequent type of mastocytosis in the second half of the ﬁrst decade of life. The lesions typically urticate when rubbed, swelling up and developing a flare around them (Darier sign), as shown here. (b) Blistering may occur as a more extreme response to release of inflammatory mediators from mast cells, particularly in infants and young children with widespread lesions.

Fig. 11.48 Mastocytosis in an adult. Pigmentation of lesions may be prominent, as shown here.

Fig. 11.49 Extensive adult mastocytosis lesions. Some such patients have minor symptoms, but in this case there was considerable itch due to the dermographic tendency illustrated.

Mastocytoma

These lesions are generally solitary or few in number, and usually present within the first few months of life. They often cause blistering, and may be a diagnostic challenge until the typical brown pigmentation develops. Most resolve spontaneously.

Urticaria pigmentosa

This is the commonest childhood form of mastocytosis, presenting as scattered (predominantly truncal) reddish brown or yellow-brown plaques that become red and raised, with a surrounding erythematous flare after rubbing. Most of those with early age of onset remit or just leave faint staining by teenage years. Those with onset in the second half of childhood, or in adult years, usually have more, but smaller, lesions, which are more persistent.

Other cutaneous mastocytoses

Telangiectasia macularis eruptiva perstans

Telangiectasia macularis eruptiva perstans (TMEP) is an essentially asymptomatic variant of mastocytosis that usually occurs in middle-aged women and is characterized by prominent telangiectasia. Symptomatic urtication is usually mild, but the telangiectasia or variable redness of lesions causes cosmetic concern (Fig. 11.50).

Fig. 11.50 Telangiectasia macularis eruptiva perstans. Unfortunately, the upper trunk is a common site in female patients, although urtication and symptoms are usually minor.

Table 11.7 SYMPTOMS AND ORGAN-SPECIFIC FEATURES THAT MAY OCCUR IN MASTOCYTOSIS

Organ system	Symptom or feature	Comments
Skin	Itch (mediated by prostaglandin D2),wheals (leukotrienes), flushing (chymase), blisters (histamine)	Wheals in localized disease (mastocytoma, limited urticaria pigmentosa) are at the site of lesions, but they may occur elsewhere in more extensive disease.Blisters are most commonly a feature of extensive mastocytosis in infants and young children, improving with time.
General	General malaise or tiredness, fever	Constitutional symptoms suggest signiﬁcant systemic involvement.
Cardiac	Palpitations, dizziness, fainting, chest pain	Different mediators involved in the different symptoms.
Respiratory	Dyspnea	Uncommon.
Gastrointestinal and abdominal	Nausea or vomiting, diarrhea, cramps, dyspepsia; splenomegaly, hepatomegaly	Epigastric pain suggests peptic ulcer and systemic disease. Splenomegaly probably occurs in about 50% with systemic disease.
Bone and bone marrow	Osteoporosis, bone pain	Focal radiolucent or radiopaque bone lesions are fairly common. Subclinical bone marrow involvement (increased bone marrow mast cells) occurs in most adults with mastocytosis but is rare in children. Bone pain may occur in systemic disease.
Neurologic	Headache	Cognitive impairment may occur in systemic disease.

Diffuse cutaneous mastocytosis

This rare pattern usually presents in the first few years of life, typically in infancy. The skin may exhibit thickening, with a doughy peau d’orange texture, but in the earliest stages there may be blistering with little else visibly abnormal. Flushing and diarrhea are common, but improvement within a few years is anticipated.

Xanthelasmoid pattern

Rare, and may be confused with xanthomatoses or with pseudoxanthoma elasticum.

Systemic mastocytosis and investigations

About 20% of adults with urticaria pigmentosa will have some involvement of bone marrow or gastrointestinal tract, causing systemic features such as headache, diarrhea, or flushing. A small proportion, probably less than 2%, develop more aggressive disease associated with myeloproliferative features, lymphoma, neutropenia, lymphadenopathy and eosinophilia, or even mast cell leukemia. Such developments may be accompanied by an apparently paradoxical improvement in skin symptoms, which presumably reflects development of a less well-differentiated mast cell population.

Measurement of mast cell tryptase or of urinary histamine or its metabolites (N-methyl histamine, 1,4-methylimidazole acetic acid, MeImAA) may be useful in assessment of systemic symptoms. A radiologic or isotope skeletal assessment is recommended in adults with mastocytosis, even in the absence of overt systemic disease, and a bone marrow biopsy is also recommended if there is either an abnormal complete blood count or evidence of bone lesions.

Differential diagnosis

This is discussed for each pattern of skin lesions in Table 11.6. Biopsy of skin lesions will usually confirm the diagnosis, but additional investigations as described earlier for systemic disease may also be useful.

Treatment

This falls into three main categories for cutaneous disease.

•	Avoid triggers of mast cell degranulation. This is especially important if there are signiﬁcant systemic features due to widespread skin lesions. Friction is an important factor in causing urtication or blistering of lesions in children. More important is the potential for signiﬁcant mediator release due to drugs such as opiates, aspirin, NSAIDs, alcohol, and many anesthetics (propofol, vecuronium, and fentanyl appear to be safe).
•	Local treatments. These include topical corticosteroids, PUVA, and UVA1 (the last is not widely available). If using topical corticosteroids, potent agents are required, so there is a risk of atrophy with prolonged use. Short-term use under occlusion may be worthwhile, or intralesional depot steroid (usually for localized mastocytomas). Rarely, troublesome mastocytomas may be treated by excision.
•	Systemic treatments. In patients with more widespread urticaria pigmentosa, or with systemic symptoms, symptomatic treatment with oral H1 antihistamines is usually required. H2 antagonists are also useful, especially if there is associated peptic ulcer disease. Mast cell stabilizing agents, such as ketotifen and sodium cromoglycate, are also useful in some cases, as is doxepin (which has powerful antihistaminic activity).

PRACTICE POINTS

•	In childhood mastocytosis (and less reliably in adult forms), lesions are usually brown but become edematous, itchy, and with a surrounding red flare when rubbed.
•	Patients with systemic symptoms such as flushing or urticaria associated with cutaneous mastocytosis should avoid drugs that cause mast cell degranulation; opiates and anesthetic agents are of particular importance.
•	In adults with mastocytosis, any abnormality of blood counts is an indication that a bone marrow biopsy should be performed.

•	Type Ia: indolent mastocytosis, no systemic disease.
•	Type Ib: indolent mastocytosis, with systemic disease.
•	Type II: mastocytosis associated with a myeloproliferative (IIa) or myelodysplastic (IIb) disorder (skin lesions may or may not be present; urticaria, dermographism, or flushing usually occur).
•	Type III: lymphadenopathic mastocytosis with eosinophilia (also termed aggressive mastocytosis; rare, usually no skin lesions).
•	Type IV: mast cell leukemia (rare, usually no skin lesions). This text will concentrate on the skin lesions.