On being metachromatic: Mystique and misunderstanding in mastocytosis

Among both fellows-in-training and seasoned practitioners, few diseases in hematology evoke as much fascination as systemic mastocytosis (SM). For hematologists who do not specialize in chronic myeloproliferative neoplasms, the ‘‘wow-factor’’ in making a new diagnosis of SM may rival that of equally esoteric diseases such as paroxysmal nocturnal hemoglobinuria or hereditary hemorrhagic telangiectasia. Normally visually absent from the peripheral blood, and represented at a low frequency in the bone marrow, mast cells bear witness to the axiom ‘‘out of sight, out of mind. ’’ This fact, together with the rare incidence of SM, undoubtedly contributes to the mystique of malignant mast cell disease. However, being shrouded in relative obscurity complicates the diagnosis of these mast cell neoplasms. Therefore, a high index of suspicion is required, as well as collaboration with a pathologist with expertise in evaluating the histopathology of these rare tumors. Mast cells under the light microscope can easily be unmasked by use of aniline dyes, such as Giemsa or toluidine blue, which highlight their densely packed metachromatic y granules [1]. Although normal or reactive mast cells are round or oval in shape, malignant mast cells can be recognized by their transformation to atypical, spindled-shape morphology, usually in multifocal, dense aggregates [2]. Mastocytosis may only relinquish its diagnostic identity after a cadré of subspecialty evaluations by dermatologists, immunologists/allergists, and hematologists. The presence of skin manifestations (pruritis, urticaria, and dermatographism) and archetypal mediator signs and symptoms [e.g., flushing, hypotension, tachycardia, syncope, headache, abdominal discomfort, and anaphylaxis (particularly with certain food triggers or insect stings)] facilitate its recognition [3]. Whether these clinical findings present singly or collectively, they are not unique to mastocytosis, and may provoke consideration of many other conditions, including (but not limited to) carcinoid syndrome, pheochromocytomas, and panic attacks. For patients in whom SM can be proven by biopsy, corroboration of longstanding undiagnosed complaints can provide some measure of comfort and direction. Conversely, the inability to diagnose SM in such symptomatic individuals, despite extensive workups, can engender substantial frustration among patients and their physicians. While some undiagnosed patients may indeed have an occult mast cell disorder, others adamantly cling to the diagnosis of SM despite evidence to the contrary. In some instances, their premium of hope may be nourished by well-intentioned internet chat rooms and patient-led mastocytosis meetings. These patients may travel endlessly between doctors with escalating physical and mental disability without an ICD-9 code to validate their complaints. Given this milieu of uncertainty, it is important to revisit some basic facts about mast cell disease. It is defined as a clonal, neoplastic proliferation, and accumulation of mast cells in one or multiple organs. Clinical signs and symptoms result from the release of chemical mediators and by infiltration of tissues (e.g., bone marrow, spleen, lymph nodes, liver, and gastrointestinal tract) by neoplastic mast cells. The World Health Organization (WHO) has incorporated mastocytosis under the umbrella of chronic myeloproliferative neoplasms, and has established specific diagnostic criteria for SM, including one major and one minor criterion, or three minor criteria [2]. The major criterion requires multifocal dense infiltrates of mast cells in the marrow or other extracutaneous organ; minor criteria include: (1) spindleshaped or atypical morphology of mast cells, (2) detection of the D816V KIT mutation, (3) mast cell expression of CD2 and/or CD25 in addition to normal mast cell markers (e.g., tryptase and CD117), and (4) a serum tryptase level >20 ng/ml in the absence of another myeloid disorder [2]. Mastocytosis is a heterogeneous disease. This is reflected by the current 2008 WHO classification which distinguishes cutaneous mastocytosis (CM) from six SM variants: indolent SM, SM with associated clonal hematological nonmast-cell lineage disease (SM-AHNMD), aggressive SM, mast cell leukemia, mast cell sarcoma, and extracutaneous mastocytoma [2]. Skin-only disease usually presents in childhood, but can occur with systemic disease, more commonly with indolent subtypes [4]. Prognosis relates to the SM variant and extends from a normal life expectancy in CM or indolent SM, to only a few months in mast cell leukemia [5]. A critical eye should be lent to whether there is a coexisting WHO-defined hematologic neoplasm (SMAHNMD), since clinical course and prognosis is usually related to the AHNMD component [6]. More indolent forms of SM are characterized by ‘‘B’’ findings (e.g., organ involvement/organomegaly without dysfunction) and should be distinguished from aggressive subtypes categorized by ‘‘C’’ or clinical findings associated with organ dysfunction (e.g., cytopenias related to marrow failure, hepatomegaly with liver function abnormalities and/or ascites/portal hypertension, bone involvement by large osteolyses or fractures, and malabsorption with significant weight loss and/or hypoalbuminemia) [2]. Defining the variant of SM not only aids in assessment of prognosis, but also selection of appropriate treatment: cytoreductive therapies are usually reserved for patients with ‘‘C’’ findings, or for patients with mediator