Systemic Mastocytosis (SM)

Systemic mastocytosis (SM) is characterized by the presence of mast cell (MC) infiltrates in the bone marrow, spleen, lymph nodes, liver, and gastrointestinal tract. In severe cases, mast cell aggregation can hamper normal functioning of the affected tissues or organs.1

A bone marrow examination is usually the initial step in the current diagnostic approach to SM because the bone marrow is involved in most types of adult mastocytosis. In addition, a bone marrow examination makes it possible to detect a second hematologic neoplasm,2 if one is present.

The presence of multifocal, dense MC aggregates (≥15 MCs per aggregate), frequently in perivascular and/or paratrabecular bone marrow locations, is a major criterion for a diagnosis of SM.3

A bone marrow aspirate or a smear from a patient with SM may show multifocal clusters of abnormal MCs, which unlike normal MCs are fusiform (spindle-shaped) with irregularly shaped nuclear outlines and less densely packed cytoplasmic granules.4 Staining with standardized dyes such as Giemsa may not reveal multifocal, dense MC aggregates, particularly when the MCs exhibit marked hypogranulation or abnormal nuclear morphology or the bone marrow is infiltrated by a second hematological neoplasm. A very sensitive immunohistochemical marker, tryptase, allows the detection of even small and/or immature MC infiltrates because this marker is expressed on almost all MCs, irrespective of their stage of maturation, activation status, or tissue of localization.5,6 However, tryptase or KIT/CD117 immunostaining cannot distinguish between normal and neoplastic MCs. In addition, abnormal basophils (seen in chronic myeloid leukemia and some cases of acute or chronic basophilic leukemia) and blasts (seen in acute myeloid leukemia) also stain with tryptase, so that it may be difficult to distinguish MCs.3

In contrast, the immunohistochemical detection of aberrant CD25 expression on bone marrow MCs seems to be a reliable diagnostic tool in SM because it can discriminate abnormal from normal MCs in all subtypes of SM, including the rare cases in which MCs are loosely scattered.7

Systemic Mastocytosis Histological Research

A 2011 study reported a higher degree of expression of CD30 (Ki-1 antigen) in neoplastic MCs in patients with aggressive SM (ASM) or mast cell leukemia (MCL) than in patients with indolent SM (ISM).8

An independent study of 142 patients with SM confirmed aberrant CD30 expression on neoplastic MCs in the majority of patients (80%) when flow cytometry was used. However, the expression of CD30 was similar across SM subcategories in this study.9

The current diagnostic approach to SM considers abnormal expression of CD25 with or without CD2 expression on neoplastic MCs a minor criterion. CD2 expression on abnormal MCs is variable; therefore, CD25 expression is regarded as a more reliable marker for neoplastic MC.

Thus, immunostaining and immunophenotyping studies have improved the ability to distinguish between normal and neoplastic MCs.10,11


  1. Systemic mastocytosis. MedlinePlus Genetics. Accessed April 18, 2022.
  2. Horny HP, Sotlar K, Sperr WR, Valent P. Systemic mastocytosis with associated clonal haematological non-mast cell lineage diseases: a histopathological challenge. J Clin Pathol. 2004;57(6):604-608. doi:10.1136/jcp.2003.014860
  3. Pardanani A. Systemic mastocytosis in adults: 2021 Update on diagnosis, risk stratification and management. Am J Hematol. 2021;96(4):508-525. doi:10.1002/ajh.26118
  4. Stevens EC, Rosenthal NS. Bone marrow mast cell morphologic features and hematopoietic dyspoiesis in systemic mast cell disease. Am J Clin Pathol. 2001;116(2):177-182. doi:10.1309/Q2WJ-46CL-YRFT-M5JF
  5. Horny HP, Sillaber C, Menke D, et al. Diagnostic value of immunostaining for tryptase in patients with mastocytosis. Am J Surg Pathol. 1998;22(9):1132-1140. doi:10.1097/00000478-199809000-00013
  6. Horny HP, Valent P. Histopathological and immunohistochemical aspects of mastocytosis. Int Arch Allergy Immunol. 2002;127(2):115-117. doi:10.1159/000048180
  7. Sotlar K, Horny HP, Simonitsch I, et al. CD25 indicates the neoplastic phenotype of mast cells: a novel immunohistochemical marker for the diagnosis of systemic mastocytosis (SM) in routinely processed bone marrow biopsy specimens. Am J Surg Pathol. 2004;28(10):1319-1325. doi:10.1097/01.pas.0000138181.89743.7b
  8. Sotlar K, Cerny-Reiterer S, Petat-Dutter K, et al. Aberrant expression of CD30 in neoplastic mast cells in high-grade mastocytosis. Mod Pathol. 2011;24(4):585-595. doi:10.1038/modpathol.2010.224
  9. Morgado JM, Perbellini O, Johnson RC, et al. CD30 expression by bone marrow mast cells from different diagnostic variants of systemic mastocytosis. Histopathology. 2013;63(6):780-787. doi:10.1111/his.12221
  10. Escribano L, Garcia Montero AC, Núñez R, Orfao A; Red Española de Mastocitosis. Flow cytometric analysis of normal and neoplastic mast cells: role in diagnosis and follow-up of mast cell disease. Immunol Allergy Clin North Am. 2006;26(3):535-547. doi:10.1016/j.iac.2006.05.008
  11. Pardanani A, Kimlinger T, Reeder T, Li CY, Tefferi A. Bone marrow mast cell immunophenotyping in adults with mast cell disease: a prospective study of 33 patients. Leuk Res. 2004;28(8):777-783. doi:10.1016/j.leukres.2003.10.035

Reviewed by Harshi Dhingra, MD, on 4/25/2022.