Definition

Systemic mastocytosis (SM) is a clonal disease derived from transformed bone marrow (BM) progenitor cells, histologically characterized by accumulations of atypical mast cells in various tissue sites. SM presents an unusually broad spectrum of morphological and clinical features. In approximately 30% of SM patients, a systemic mastocytosis-associated hematologic non-mast cell disorder (SM-AHNMD) is diagnosed simultaneously, before or after SM diagnosis.

Introduction

SM diagnosis is based on morphology and cannot be established on the basis of clinical findings alone. Therefore, the pathologist should be familiar with the diagnostic criteria defined for mastocytosis and also to recognize its mimickers.^1,2 Important mimickers of mastocytosis are reactive states of mast cell hyperplasia and a few rare neoplastic hematological disorders such as tryptase-positive acute myeloid leukemia (AML) or myelomastocytic leukemia. Diagnostic criteria of SM are given in Box 26.1.

The major and two of four minor diagnostic criteria are morphology-based. Diagnosis of SM can be established if the major and one minor criterion are fulfilled. In cases lacking the major criterion, SM diagnosis can be established if at least three minor criteria are found.^1,2 Most cases of SM can be easily diagnosed when focal compact infiltrates with a significant proportion of spindle-shaped mast cells are present. SM exhibiting exclusively round mast cells can be diagnosed after demonstration of an atypical immunophenotype with expression of CD25, which is not present in normal mast cells.³ If compact mast cell infiltrates are missing, diffusely scattered spindle-shaped mast cells with CD25 expression alone are not enough to establish a diagnosis of mastocytosis. In these patients, demonstration of the KIT^D816V mutation and/or chronically elevated serum tryptase enables diagnosis of mastocytosis since three of four minor criteria are fulfilled.^4,5,6

BM is the main tissue where diagnosis of SM can be established. However, demonstration of compact mast cell infiltrates in extramedullary tissues like lymph node, spleen, liver and/or mucosa should also be regarded as strong indication for SM.^7,8,9 Rarely, the diagnosis of mastocytosis is first established in the mucosa of the gastrointestinal (GI) tract and BM involvement is confirmed later. It is rather unlikely that pure GI form exists. In all patients with GI involvement, the meticulous investigation of the BM should be performed using immunohistochemistry and molecular biology. In a considerable proportion of SM patients, the degree of tissue infiltration is very low. The WHO 2008 classification of mastocytosis is given in Box 26.2.² The approach to the diagnosis of mastocytosis is complex and considering its relatively low incidence, the diagnosis is usually more difficult than in most other hematological malignancies. The different forms of SM can only be recognized when the pathologist is aware of important clinical findings, especially the so-called ‘B-findings’, including organomegaly, and ‘C-findings’, indicating organ dysfunction due to widespread mast cell infiltration (Box 26.2).

Molecular genetics aspects

Mast cells of most patients with SM carry the activating point mutation KIT^D816V of the c-kit gene.¹⁰ However, the frequency of KIT^D816V varies between subtypes of the disease. It has been found in almost 100% of patients with SM-AHNMD but only in about 50–60% of patients with aggressive SM and mast cell leukemia (MCL). Indolent SM assumes an intermediate position. Other than D816V point mutations of c-kit (e.g. D816Y or D816H) do occur but are rarely detected in SM.¹¹ A considerable number of patients with SM-AHNMD were found to carry KIT^D816V not only in the SM but also in the AHNMD compartment of the disease. The frequency of KIT^D816V depends on the subtype of hematological disorder. SM-associated chronic myelomonocytic leukemia (CMML) exhibits KIT^D816V in almost all cases. The mutation is found both in the SM and the AHNMD compartment of the disease, which underlines a close clonal relationship between SM and CMML in the setting of SM-AHNMD. In SM associated with a myeloproliferative neoplasm with eosinophilia (MPNEo), KIT^D816V is usually not found in the MPNEo. Very surprisingly, it is also lacking in the SM compartment, although compact infiltrates of CD25⁺ mast cells are present in a few cases thus enabling the morphological diagnosis of SM.¹² In other types of SM-AHNMD (SM with myelodysplastic syndrome (SM-MDS), SM-AML, and SM with myeloproliferative neoplasms (SM-MPN)), the incidence of KIT^D816V in the associated disorder varies between 20% and 60% of patients. Interestingly, it has been shown that in cases of SM-MPN (e.g. primary myelofibrosis), both mast cells and cells of neutrophilic lineage could carry both activating point mutations KIT^D816V and JAK-2^V617F, further indicating the close relationship between SM and ‘AHNMD’.¹³

Routine work-up of cases with suspected systemic mastocytosis

To be able to establish a proper diagnosis including classification of SM, the hematopathologist must be provided with clinical data concerning presence of urticaria pigmentosa or another mastocytosis-related rash, hepatosplenomegaly and/or lymphadenopathy, cytopenia or increase in blood cells such as thrombocytosis, allergy, and elevated serum tryptase.