Differential Diagnoses of Systemic Mastocytosis in Routinely Processed Bone Marrow Biopsy Specimens: A Review

Diagnosis of systemic mastocytosis (SM) is mainly based on the morphological demonstration of compact mast cell infiltrates in various tissue sites. In almost all patients such infiltrates are detected in the bone marrow. Reliable immunohistochemical markers for the diagnosis and grading of SM have been established, but various differential diagnoses including myeloproliferative neoplasms, basophilic and eosinophilic leukemias may be very difficult to delineate. Even more challenging is the recognition of hematological neoplasms with signs of mast cell differentiation but not fulfilling diagnostic criteria for SM, especially the rare myelomastocytic leukemia. It is also important to separate the reactive state of mast cell hyperplasia from indolent variants of SM, especially those with a very low degree of bone marrow infiltration and absence of compact mast cell infiltrates. When the lymphocytic component of the SM infiltrate is very prominent, SM may be confused with an indolent lymphoma, especially lymphoplasmacytic lymphoma which almost always shows a marked reactive increase in mast cells. In aggressive and leukemic variants of SM, mast cells may be very atypical and devoid of metachromatic granules. This hypogranulation can be regarded as cellular atypia and may lead Received: March 18, 2010 Accepted after revision: March 23, 2010 Prof. Dr. med. Hans-Peter Horny Institute of Pathology Ansbach Escherichstr. 6 DE–91522 Ansbach Tel. +49 981 488 830, Fax +49 981 488 8310, E-Mail horny @ patho-ansbach.de © 2010 S. Karger AG, Basel 1015–2008/10/0774–0169$26.00/0 Accessible online at: www.karger.com/pat Horny /Sotlar /Valent Pathobiology 2010;77:169–180 170 disorder can best be shown by the fact that a hemopoietic stem cell-derived disorder in most patients primarily presents as a dermatological disease. The common denominator of mastocytosis is the demonstration of multifocal compact tissue mast cell infiltrates [2] . The presence of such compact mast cell infiltrates outside the skin is the key finding for systemic mastocytosis (SM). Compact mast cell infiltrates are considered as a major diagnostic criterion and represents a crucial indicator for the pathologist to be able to correctly assess or exclude mastocytosis morphologically. The multifaceted features of mastocytosis explain the broad range of differential diagnoses, including reactive and neoplastic states. Moreover, the list of differential diagnoses varies according to the diagnostic approach to the disease. While patients with longstanding adult-type urticaria pigmentosa (the most common form of cutaneous mastocytosis) are staged for the presence of indolent systemic mastocytosis (ISM) by investigation of bone marrow trephine biopsy specimens, isolated bone marrow mastocytosis as a special subvariant of ISM without skin involvement is an incidental finding in a small subgroup of patients with suspected hematological disorders, unexplained osteoporosis, or severe anaphylaxis after bee or wasp stings. In the following, morphological and molecular key features for the diagnosis of mastocytosis are presented together with clues for proper subclassification but also for delineation of mast cell hyperplasia, hematological disorders with signs of mast cell differentiation not fulfilling diagnostic criteria of mastocytosis and the large panel of possible differential diagnoses within the spectrum of hematological neoplasms. Material and Methods The present study is based on archival material gathered in a Center of Reference for Hematopathology of Mastocytosis within the European Competence Network of Mastocytosis (ECNM) located at the Institute of Pathology in Ansbach, Germany. The registry consists of nearly 700 cases of well-documented mastocytosis including immunohistochemical and molecular pathological findings. All subtypes of mastocytosis were recorded. All cases were analyzed immunohistologically with antibodies against the mast cell-related antigens tryptase and CD117 (KIT) but also against CD25 and CD30 to assess an aberrant phenotype of mast cells that is only present in neoplastic states of mastocytosis. Association of SM with a hematological non-mast cell clonal disorder (SM-AHNMD) makes it necessary to apply a larger panel of antibodies to be able to subclassify the ‘AHNMD’ according to WHO criteria. When available, smears of blood and bone marrow were also investigated with special attention to the number and cytomorphological aspects of mast cells. Diagnostic Criteria for Mastocytosis [3] (1) Main criterion. Multifocal compact tissue infiltrate of mast cells. (2) Minor criteria. (2.1) Prominent spindling of mast cells ( 1 25%). (2.2) Aberrant immunophenotype of mast cells with expression of CD25 (and/or CD2). (2.3) Activation point mutations at codon 816 of KIT (usually D816V). (2.4) Chronically elevated serum tryptase ( 1 20 ng/ml). Diagnosis of mastocytosis can be established if the major and at least 1 minor criterion or at least 3 minor criteria are fulfilled. Note that the diagnosis of mastocytosis is only possible when appropriate investigations are performed by the pathologist. Morphological criteria (1, 2.1 and 2.2) alone are sufficient to enable a diagnosis of mastocytosis to be confirmed by the pathologist. In cases where the major criterion is missing, however, at least one additional molecular and/or serological finding has to be considered. Altogether, in about 20% of cases compact mast cell infiltrates cannot be detected and diagnosis of mastocytosis is based on 3 or 4 minor criteria. Immunohistochemical Key Features Immunohistochemical diagnosis of SM in the bone marrow (but also in other tissue sites) requires three antibodies directed against the following antigens: tryptase, CD117 (KIT) and CD25 [4] . In most patients with SM-AHNMD, diagnosis of the ‘AHNMD’ can be achieved only by application of a broader panel of antibodies pending on the suspected subtype of the associated neoplasm. Cases missing any compact mast cell infiltrates cannot be diagnosed without immunohistochemistry. It is essential to be aware that mast cells in reactive and neoplastic states and all stages of maturation coexpress tryptase and CD117. Cells expressing only tryptase or CD117, respectively, are not mast cells. Round tryptase-positive CD117negative cells can be basophilic granulocytes or myeloblasts. An increase in such cells is seen in neoplastic states like basophilic leukemia, chronic myeloid leukemia or myelomastocytic leukemia. Rarely, compact infiltrates consisting exclusively of round tryptase-expressing cells are detected, a finding which has been termed TROCIbm and which is seen only in neoplastic states [5] . TROCI-bm deserves further immunohistochemical clarification using antibodies against CD117, CD25, and CD34.