Diagnostic criteria and classification of mastocytosis: a consensus proposal

Abstract

The term ‘mastocytosis’ denotes a heterogeneous group of disorders characterized by abnormal growth and accumulation of mast cells (MC) in one or more organ systems. Over the last 20 years, there has been an evolution in accepted classification systems for this disease. In light of such developments and novel useful markers, it seems appropriate now to re-evaluate and update the classification of mastocytosis. Here, we propose criteria to delineate categories of mastocytosis together with an updated consensus classification system. In this proposal, the diagnosis cutaneous mastocytosis (CM) is based on typical clinical and histological skin lesions and absence of definitive signs (criteria) of systemic involvement. Most patients with CM are children and present with maculopapular cutaneous mastocytosis (=urticaria pigmentosa, UP). Other less frequent forms of CM are diffuse cutaneous mastocytosis (DCM) and mastocytoma of skin. Systemic mastocytosis (SM) is commonly seen in adults and defined by multifocal histological lesions in the bone marrow (affected almost invariably) or other extracutaneous organs (major criteria) together with cytological and biochemical signs (minor criteria) of systemic disease (SM-criteria). SM is further divided into the following categories: indolent systemic mastocytosis (ISM), SM with an a̱ssociated clonal ẖematologic ṉon-m̱ast cell lineage ḏisease (AHNMD), aggressive systemic mastocytosis (ASM), and mast cell leukemia (MCL). Patients with ISM usually have maculopapular skin lesions and a good prognosis. In the group with associated hematologic disease, the AHNMD should be classified according to FAB/WHO criteria. ASM is characterized by impaired organ-function due to infiltration of the bone marrow, liver, spleen, GI-tract, or skeletal system, by pathologic MC. MCL is a ‘high-grade’ leukemic disease defined by increased numbers of MC in bone marrow smears (≥20%) and peripheral blood, absence of skin lesions, multiorgan failure, and a short survival. In typical cases, circulating MC amount to ≥10% of leukocytes (classical form of MCL). Mast cell sarcoma is a unifocal tumor that consists of atypical MC and shows a destructive growth without (primary) systemic involvement. This high-grade malignant MC disease has to be distinguished from a localized benign mastocytoma in either extracutaneous organs (=extracutaneous mastocytoma) or skin. Depending on the clinical course of mastocytosis and development of an AHNMD, patients can shift from one category of MC disease into another. In all categories, mediator-related symptoms may occur and may represent a serious clinical problem. All categories of mastocytosis should be distinctively separated from reactive MC hyperplasia, MC activation syndromes, and a more or less pronounced increase in MC in myelogenous malignancies other than mastocytosis. Criteria proposed in this article should be helpful in this regard.

Introduction

In 1869, Nettleship and Tay described a unique cutaneous disease that showed a symmetrical spread with pigmented maculopapular lesions and an urticaria-like response to rubbing or scratching [1]. The disease was termed urticaria pigmentosa (UP). Soon after the discovery of the mast cell (MC) by Paul Ehrlich in 1879 [2], the lesions were found to contain focal accumulations of MC. For a long time, it was assumed that such pathologic accumulation of MC, called mastocytosis, is restricted to skin. However, in 1949, Ellis described a systemic form of mastocytosis with involvement of visceral organs [3]. During the last few decades, it was found that systemic mastocytosis (SM) can present with or without skin lesions and may show an either indolent or aggressive clinical course [4], [5], [6], [7]. It was also found that SM might be complicated by an a̱ssociated ẖematologic clonal, ṉon m̱ast cell lineage ḏisease (AHNMD). In most cases, a myeloproliferative syndrome (MPS) or myelodysplastic syndrome (MDS) is diagnosed [4], [5], [8], [9], [10]. In a few cases, acute myeloid leukemia (AML) occurs [8], [9], [10]. In other patients, the MC disease itself was found to develop as a leukemia (mast cell leukemia) [4], [5], [11]. These patients are rare and have a poor prognosis.

Cutaneous mastocytosis (CM) without systemic involvement preferentially develops in childhood and has a favorable prognosis. Spontaneous remissions are often seen during (or shortly after) puberty [12]. The potential of spontaneous regression may have led to the speculation that (pediatric) CM is a non-neoplastic (reactive) disease, and to the use of the suffix — ‘osis’, traditionally used for reactive pathologies. However, recent data suggest that most variants of mastocytosis (at least SM) represent clonal disorders. This assumption has been based primarily on recurrent somatic (gain of function) mutations of c-kit (encoding the SCF receptor) that have been detected in MC in patients with SM [13], [14]. Moreover, specific recurrent abnormalities in the cell surface phenotype of MC have been described [15]. The notion that mastocytosis (at least SM) is a clonal disease process raises several questions. One important question is whether mastocytosis (SM) can be discussed in association with other clonal hematologic disorder. In this regard, it is important to note that MC share a common progenitor as well as differentiation antigens with myelomonocytic cells [16], [17], [18], [19]. In fact, today, MC can be regarded as myeloid cells. Moreover, in patients with SM, c-kit mutations can be detected not only in MC, but also in other myeloid cells, CD34⁺ progenitors, and sometimes even in B-lymphocytes [20]. In light of these findings and the potential occurrence of an AHNMD, systemic mastocytosis may be regarded as related to hematopoietic stem cell disorders — in fact, based on current knowledge, SM may best be addressed as a myeloproliferative disease.

Based on organ involvement, impairment of organ function, and other aspects, a number of classification systems for mastocytosis have been established and have been used [4], [5], [21], [22], [23], [24], [25]. However, the knowledge about MC and mastocytosis has increased in recent years. In addition, a number of useful novel markers have been developed, and re-evaluation of older and new markers of disease has resulted in the potential to introduce well-defined disease criteria [26]. In light of these developments, it now seems justified to reconsider diagnostic aspects and to propose an updated consensus classification system for mastocytosis. In the present article, we propose such a consensus classification system together with consensus criteria to diagnose mastocytosis and to define each category of disease.