Increase of bone marrow lymphocytes in systemic mastocytosis: reactive lymphocytosis or malignant lymphoma? Immunohistochemical and molecular findings on routinely processed bone marrow biopsy specimens

Abstract

Aims: To clarify the nature (reactive or neoplastic) of lesional, perifocally aggregated lymphocytes in bone marrow infiltrates of systemic mastocytosis (SM), the histopathology of which can resemble malignant lymphoma with focal bone marrow involvement, particularly low grade malignant B cell lymphoma of lymphoplasmacytic immunocytoma subtype, which frequently exhibits increased mast cell (MC) numbers. Methods: Thirteen cases of SM and three of lymphoplasmacytic immunocytoma with predominant focal bone marrow infiltration were investigated. Immunostaining of formalin fixed, paraffin wax embedded bone marrow specimens was performed using antibodies against CD2, CD5, CD20, CD23, and CD25; κ and λ immunoglobulin light chains; and MC markers chymase, tryptase, and CD117 (KIT). Monoclonal rearrangements of IgH and TCRγ were studied using seminested polymerase chain reaction (PCR). c-kit point mutation Asp816-Val was detected by PNA mediated PCR clamping and hybridisation probes. Results: The lymphocytic clusters in SM contained nearly equal numbers of mature T and B cells, the latter with no coexpression of aberrant antigens, such as CD5 or CD23. Most MCs in SM cases constantly coexpressed tryptase, CD25, and CD117. No monoclonal rearrangements were seen for IgH or TCRγ. In contrast, B cells from immunocytomas showed light chain restriction and monoclonal rearrangement for IgH, confirming their neoplastic nature. c-kit point mutation Asp816-Val was found in ten of 13 SM cases, but in none of the three immunocytomas. Conclusions: Focal accumulations of lymphocytes in the bone marrow of SM are reactive in nature and could be termed lymphocytosis. A diagnosis of SM-AHNMD/immunocytoma should not be made.

Systemic Mastocytosis Presenting with a Prominent B Lymphocyte Proliferation in the Bone Marrow and Extensive Fibrosis of the Spleen

“…Bone marrow infiltrates may be pure mastocytic, mixed mastocytic/lymphocytic or predominantly lymphocytic. The immunohistochemical and molecular studies revealed that the lymphoid infiltration associated with SM is an admixture of T and B lymphocytes or predominantly T-cells and is polyclonal and reactive in nature [6,10]. However in cases with a predominant Bcell infiltration, a diagnosis of low-grade non-Hodgkin lymphoma is often suspected initially, as in our case [6,12].…”

“…Histologically, the infiltration is often focal and dense, especially in the forms that show a malignant course, the MCs are morphologically abnormal and lack metachromatic granules [5,7,13]. Another reason of misdiagnose, is that the underlying histological picture of the bone marrow might be complicated by secondary hematological disorders [3,4,6,[8][9][10]12]. Moreover, it is known that the infiltrates are not composed exclusively of MCs, but also contain eosinophils and lymphocytes [10].…”

“…SM may be associated with myeloid disorders including myeloproliferative diseases, myelodysplastic syndromes, acute myeloid leukemia, and very rarely non-Hodgkin lymphoma, often low grade subtypes, in less than 5% to 20% of cases [3][4][5][6]8,9]. Furthermore, in the bone marrow biopsies of cases with SM, admixture of reactive T and B lymphocytic infiltration may accompany MCs [6,10].…”

“…SM presents with an indolent or aggressive clinical course and may cause considerable diagnostic difficulties. Clinically, various symptoms may be seen such as urticaria, pruritis, abdominal pain, cramping, diarrhea, weight loss, bone pain, headache, and symptoms associated with organ dysfunctions [6]. Histopathologically, it is usually diagnosed by the examination of bone marrow, the site most frequently affected by SM [2][3][4][5].…”

“…Furthermore, in the bone marrow biopsies of cases with SM, admixture of reactive T and B lymphocytic infiltration may accompany MCs [6,10].…”