Final Diagnosis -- Systemic Mastocytosis



Mastocytosis is a proliferation of mast cells and their subsequent accumulation in one or more organ systems. Mast cell disease can be limited to the skin, which is referred to as cutaneous mastocytosis, or involve extracutaneous tissue, which is called systemic mastocytosis. Systemic mastocytosis may occur at any age among adults. The male to female ratio has been reported to vary from 1 to 1.3.

Mast Cells
Mast cells are ubiquitous, being found in varying amounts in practically all tissues and organs (1). Mature mast cells are highly granulated, with their content varying by tissue localization (2). They exhibit a variable morphology with sizes up to 25 m. A unilobed nucleus may be round to oval in shape. The cytoplasmic granules range from 0.3 to 0.8 m in size and may occupy the majority of the cell volume. Monoclonal antibodies against the membrane receptor c-kit (CD117) and the granule protease tryptase are useful in the definitive identification of mast cells in situ (3, 4).

The mast cell is derived from a pluripotential CD34-positive stem cell that resides in the bone marrow (5). The basophil represents a terminally differentiated circulating granulocyte which diverges early in development from the mast cell lineage. By comparison, the mast cell leaves the bone marrow as a monocyte-like precursor, circulates briefly, and enters tissue where it undergoes local differentiation and maturation with expression of particular proteases and proteoglycans (6).

They are known to release histamine, proteoglycan, tryptase, chymase and other proinflammatory mediators upon activation (7). Mast cells play a critical role in innate immunity because they are located at the port of entry of pathogens, in mucosal membranes and dermis, and around blood vessels (8). Mast cells also play an important role in host defense against parasitic infections. Pathological functions of mast cells include involvement in immediate hypersensitivity responses, such as asthma, rhinitis, urticaria, and anaphylaxis (9). Classical mast cell activation occurs through the high affinity IgE receptor, which is expressed not only on the surface of mast cells, but also on basophils (10) and Langerhans cells (11).

The pathogenesis of systemic mastocytosis is largely unknown. Activating mutations of the proto-oncogene c-kit tyrosine kinase receptor expressed by mature mast cells as well as an increased production of stem cell factor (SCF), the ligand for c-kit, have been implicated (12, 13). A mutation affects codon 816 with the substitution of valine for aspartate (Asp816Val) in a putative activating loop in the kinase domain. This mutation at codon 816 is present in bone marrow mast cells in 80% of those with the disease (14). C-kit mutations are somatic mutations. Mast cells with mutated c-kit can grow and develop independent of exogenous cytokines. In one study of a patients with aggressive systemic mastocytosis, mast cell hyperplasia was thought to be due to the secretion of SCF by mast cells (13). Rare familial cases are reported.

Clinical presentation and manifestations
Disease manifestations result from a number of pathogenic mechanisms (15). These include increased numbers of mast cells in one or more tissues; local mass effects due to the mast cell accumulation; tissue response to cellular infiltrate; and local and distant effects of released mast cell mediators, such as histamine, eicosanoid, proteases, heparin, platelet-activating factor, cytokine and growth factor (Table 1).

Systemic mastocytosis is characterized pathologically by increased mast cells in the bone marrow, liver, spleen, lymph nodes, gastrointestinal tract, bones, and skin. Some organ systems are commonly spared, as few patients experience pulmonary involvement. Clinical manifestations are grouped into the following categories: 1) constitutional symptoms (fatigue, weight loss, fever, sweats); 2) skin symptoms (pruritus, urticaria, dermatographism); 3) mediator-related events (abdominal pain, nausea, vomiting, diarrhea, gastrointestinal distress, syncope, flushing, hypotension/hypertension, headache, tachycardia, respiratory symptoms); and bone-related complaints (bone pain, fractures, arthralgia). Physical findings may include splenomegaly, lymphadenopathy and hepatomegaly. Patients with the systemic mastocytosis usually show mild symptoms. However, in some patients with the mediator-related events or organ impairment, the disease may be life threatening.

Hematological abnormalities occur in many patients with systemic mastocytosis. Anemia, leukocytosis or leukopenia, and thrombocytopenia or thrombocytosis may occur. Circulating mast cells are infrequently observed. Patients with myelodysplatic/myeloproliferative diseases or lymphoproliferative disorders may have mastocytosis.

The requirements for the diagnosis of systemic mastocytosis according to the WHO classification of tumors (16) are outlined in Table 2. Within bone marrow, multifocal aggregates of more than 15 mast cells are a major criterion. The finding of such aggregates outside of the bone marrow is also diagnostic. In biopsy sections of bone marrow or other extracutaneous organs, more than 25% of the mast cells being immature, spindle-shaped or atypical are a minor criterion. Measurement of serum tryptase most accurately reflect overall mast cell burden and activation. However, one single serum determination of tryptase may not completely reflect the dynamic burden of mast cells. Thus elevations in urine histamine levels are useful for the diagnosis. Detection of KIT point mutation at codon 816 in bone marrow, blood or other organs will be helpful for the diagnosis. The aberrant expression of CD2 and CD25 in tissue mast cells is another feature.

Systemic mastocytosis can be confused either clinically or histologically with a variety of disorders. The differential diagnosis includes: anaphylaxis, angioedema, carcinoid syndrome, pheochromocytoma, and metastatic disease to bone, vasoactive intestinal peptide-secreting tumors, Zollinger-Ellison syndrome, agnogenic myeloid metaplasia and reactive mastocytosis.

This patient has many typical symptoms of mastocytosis that result from release of mast cell mediators, and she is moderately anemic. There are aggregates of more than 15 mast cells in the bone marrow biopsy section, and more than 25% of the mast cells are spindle-shaped. The infiltrates of mast cells express CD117 and tryptase as shown by immunohistochemistry. Therefore, the bone marrow satisfied one major and two minor criteria for a diagnosis of systemic mastocytosis. The bone marrow aspirate and biopsy do not show myelodysplatic, lymphoproliferative or myeloproliferative changes.

There is currently no cure for systemic mastocytosis. For most patients, the goal of treatment is to reduce the release of mast cell mediators and, if released, to counteract the consequences. The initial standard treatment includes the use of anti-H1 and anti-H2 histamine receptor blockers. Aspirin is administered to control flushing. Disodium cromolyn, which is an inhibitor of mast cell degranulation, is also used.


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Contributed by Ming Yin, MD, PhD and Lisa J Robinson, MD

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