Mastocytosis

Introduction

Background

Mastocytosis is a disorder characterized by mast cell proliferation and accumulation within various organs, most commonly the skin.

The World Health Organization (WHO) classification of mastocytosis includes the following^1,2 :

• Cutaneous mastocytosis
  • Urticaria pigmentosa
  • Maculopapular cutaneous mastocytosis
  • Diffuse cutaneous mastocytosis
  • Mastocytoma of skin
• Indolent systemic mastocytosis
• Systemic mastocytosis with an associated (clonal) hematologic non–mast cell lineage disease
• Aggressive systemic mastocytosis
• Mast cell leukemia
• Mast cell sarcoma
• Extracutaneous mastocytoma^1,2

This article focuses on cutaneous mastocytosis (CM). Types of CM include solitary mastocytoma, diffuse erythrodermic mastocytosis, paucicellular mastocytosis (also termed telangiectasia macularis eruptiva perstans [TMEP]), and urticaria pigmentosa (UP). UP is the most common form and is characterized by oval or round red-brown macules, papules, or plaques ranging in number from a few to thousands (see Media Files 1-2). Lesions may vesiculate in infancy (see Media File 3).

When a UP or mastocytoma lesion is stroked, it typically urticates, becoming pruritic, edematous, and erythematous. This change is referred to as the Darier sign, which is explainable on the basis of mast cell degranulation induced by physical stimulation. Uncontrolled stroking of mastocytomas should be avoided in patients who have had a systemic reaction such as miosis and asthmalike symptoms in their past.³

Pathophysiology

Whether mastocytosis is a hyperplastic reaction to an unknown stimulus or whether it is a neoplastic condition is unknown. Increased local concentrations of soluble mast cell growth factor in lesions of CM are believed to stimulate mast cell proliferation, melanocyte proliferation, and melanin pigment production. The induction of melanocytes explains the hyperpigmentation that commonly is associated with cutaneous mast cell lesions. Impaired mast cell apoptosis has been postulated to be involved, as evidenced by up-regulation of the apoptosis-preventing protein BCL-2 demonstrated in patients with mastocytosis. Activating mutations of the proto-oncogene c-kit have been identified but do not explain the initiation of the disease.⁴ Interleukin 6 levels have been shown to be elevated and correlated with disease severity, indicating interleukin 6 is involved in the pathophysiology of mastocytosis.⁵

Associated systemic manifestations are believed to reflect the release of mast cell–derived mediators, such as histamine, prostaglandins, heparin, neutral proteases, and acid hydrolases. Symptoms and signs induced by mediators may include headache, flushing, dizziness, tachycardia, hypotension, syncope, anorexia, nausea, vomiting, abdominal pain, and diarrhea. The skeletal, hematopoietic, gastrointestinal (GI), cardiopulmonary, and central nervous systems may be involved either directly, via mast cell infiltration, or indirectly, via mast cell mediator release.

Frequency

United States

Of new patients visiting dermatology clinics, 0.1-0.8% have some form of mastocytosis.

International

The international incidence is not known to differ from the incidence observed in the United States.

Mortality/Morbidity

Most cases of UP in children resolve spontaneously, although acute extensive degranulation rarely can cause life-threatening episodes of shock. Patients with adult- or adolescent-onset UP are more likely to have persistent disease and are at greater risk for systemic involvement. Juvenile-onset systemic mastocytosis has a malignant transformation rate as high as 7%, while adult-onset systemic mastocytosis has a malignant transformation rate as high as 30%.

Race

Most reported cases are in whites. The cutaneous lesions of most types of mastocytosis are less visible in persons with more heavily pigmented skin.

Sex

Mastocytosis affects males and females equally (no known sex predilection).

Age

Most patients with mastocytosis are children; 75% of cases occur during infancy or early childhood. Incidence peaks again in patients aged 30-49 years.

Clinical

History

Patients may present with cutaneous lesions, systemic symptoms of an acute nature, and/or chronic systemic symptoms.

• Most patients have pruritic cutaneous lesions.
• Some patients, especially those with extensive cutaneous disease, experience acute systemic symptoms exacerbated by certain activities or ingestion of certain drugs or foods. Possible systemic symptoms include flushing, headache, dyspnea, wheezing, rhinorrhea, nausea, vomiting, diarrhea, and syncope.
• Patients also may have chronic systemic symptoms involving various organ systems.
  • Involvement of the skeletal system may be manifested as bone pain or the new onset of a fracture.
  • Involvement of the central nervous system may produce neuropsychiatric symptoms, as well as nonspecific changes such as malaise and irritability.
  • GI involvement may yield weight loss, diarrhea, nausea/vomiting, and abdominal cramps.
  • Cardiovascular effects can include shock, syncope (resulting from vascular dilatation), or angina.
  • Anaphylactic reactions to hymenoptera stings may be the first sign of mastocytosis.

Physical

The most common physical findings in mastocytosis involve the skin, liver, spleen, and cardiovascular system.

• Skin - Lesion types
• Macules, papules, nodules, and plaques (see Media File 4)
• Blisters and bullae in children (see Media File 5)
• Diffuse induration
• Isolated nodule or tumor
• Skin - Distribution
• Widespread symmetric distribution
• Trunk involved more than extremities
• Tendency to spare the face, scalp, palms, and soles; however, a patient with scarring alopecia has been reported⁶
• Skin - Lesion color, quantity, and size
• Yellow-tan to red-brown
• From 1 to more than 1000
• From 1 mm to several centimeters
• Skin - Special characteristics
• Darier sign: Wheal and surrounding erythema develop in a lesion after rubbing it.
• Dermatographism: In approximately half the patients, stroking macroscopically uninvolved skin produces dermographia.
• Flushing: Flushing may occur spontaneously following skin stroke or after ingesting a mast cell degranulating agent.
• Liver - Possible hepatomegaly (present in 40% of adult patients with systemic mastocytosis)
• Spleen - Possible splenomegaly (present in 50% of patients with systemic mastocytosis)
• Cardiovascular - Hypotension and tachycardia

Causes

Mastocytosis probably is a hyperplastic response to an abnormal stimulus. Rare cases of familial UP have been recorded.⁷