Clinical and Biological Diversity of Clonal Hematological Non-Mast Cell Lineage Neoplasms Associated with Mastocytosis.

Mastocytosis has many features in common with other myeloproliferative neoplsms (MPN) and is recognized by the 2008 World Health Organization (WHO) as a major subgroup of MPNs. In 20-30% of patients with systemic mastocytosis (SM), an associated clonal hematological non mast cell lineage disease (AHNMD) is also diagnosed, and such an occurrence is recognized by WHO classification system as SM-AHNMD. The latter (AHNMD) includes predominantly myeloid neoplasms, but also rarely non-myeloid hematologic neoplasms. SM-AHMD often creates a clinicopathologic diagnostic challenge due to diverse clinical presentation and sometimes subtle morphologic findings. We reviewed the clinicopathologic features, cytogenetic and molecular findings, and clinical course of eight patients with SM-AHNMD.

Approximately 30,000 bone marrow biopsy reports recorded in the institutional electronic database at Moffitt Cencer Center from January 1996 to July 2009 were reviewed. Thirty patients with SM- were identified. Diagnosis was confirmed by bone marrow (BM) histology; SM- and AHNMD-components were classified according to WHO criteria. Immunophenotypic analyses were performed on fresh samples using flow cytometry and on paraffin-embedded samples using immunohistochemistry. Molecular analyses for assessment of immunoglobulin heavy and light chain gene rearrangement and for detection of activating c-Kit D816V point mutation, as well as cytogenetic study by karyotyping and FISH analysis were performed on available skin punch biopsy and bone marrow aspirate samples. Clinical presentation, laboratory and imaging data, therapeutic regimen and clinical course were reviewed.

SM was diagnosed in 30 bone marrow biopsies (0.1 %). SM-AHNMD was diagnosed in 8 patients (27% of SM) over a 13 year period. The AHNMD was MDS (3 cases: 1 refractory anemia, 2 cases of refractory anemia with ringed sideroblasts), MDS/MPN (2 cases, CMML), AML (1 case), marginal zone lymphoma (1 case) and plasma cell myeloma (1 case, IgD monoclonal). Patients ranged in age from 54 to 78 years (average 57), with a male to female ratio of 1:1. At presentation, all patients (8/8) had cytopenia; two patients (2/8) additionally had monocytosis. Cytogenetic abnormalities were identified in 3 cases (3/4) [t(8;21), t(3;5), isochromsme 14, deletion 5q, trisomy 4]. Activating c-Kit (D816V) point mutation was detected in 3 cases (3/4). In six patients (6/8), SM was diagnosed concurrently with the AHNMD and the aberrant mast cell proliferation was observed only after complete histopathologic examination. One patient (1/8) had long-standing indolent SM with cutaneous manifestation, and a second patient (1/8) suffered from recurrent “hives” for 12-15 years which was later diagnosed as cutaneous mastocytosis, prior to the development of an AHNMD. These two patients were treated with Gleevec and/or antihistamines. Upon diagnosis, all patients (8/8) were managed according to standard treatment protocols for their AHNMD. The patient with AML with t(8;21) received daunrubicin and cytarabine induction chemotherapy and intrathecal methotrexate. She achieved remission, followed by multiple relapses.

SM-AHNMD is uncommon. AHNMD is usually myeloid, but can also be a lymphoid/plasma cell neoplasm. In the majority of our cases, mastocytosis was not clinically suspected and the patient's clinical presentation was related to the associated non-mast cell lineage neoplasm. SM-AHNMD might pose a histopathologic challenge that potentially could be missed; for the most part it is a histological diagnosis based on a combination of morphologic features and ancillary studies. Patients are managed according to the current protocols for their AHNMD. Symptoms related to mastocytosis are treated with antihistamines, as needed. Of note, unlike most patients with AML with t(8;21), the patient in our case series fared poorly with standard chemotherapy. The prognostic relevance and therapeutic implications of detecting SM associated with another hematologic malignancy and warrants further studies and remains to be clarified.

No relevant conflicts of interest to declare.