Proposal for a revised classification of systemic mastocytosis

To the editor:

Historically, mast cell disease (MCD) signified overt infiltration of one or more organs by cytologically abnormal mast cells.¹  In adults, the condition almost always involves the bone marrow (BM), a cardinal feature of systemic mastocytosis (SM). We now recognize SM as a hematopoietic stem cell disease that often harbors a KIT mutation and is sometimes associated with non–mast cell lineage clonal myeloproliferation. The World Health Organization (WHO) classification system recognizes 4 major SM subcategories: indolent SM (ISM; little or no evidence of organ dysfunction), aggressive SM (ASM; presence of disease-related organopathy), SM associated with a clonal hematologic non–mast cell lineage disease (SM-AHNMD), and mast cell leukemia (MCL; presence of ≥ 20% mast cells in BM aspirate).²  Although we fully endorse the current classification system, it has its limitations, and we hope to initiate a constructive dialogue that may lead to a consideration for revisions.

1. Unlike the case with blast-phase chronic myelogenous leukemia (CML) or leukemic conversion of BCR-ABL1–negative myeloproliferative neoplasms (MPN), most MCL cases develop de novo rather than represent transformation of preexisting SM. Such was the case in the majority of MCL cases identified in a recent review of 342 MCD patients from our institution.³  The mere presence of KITD816V in some MCL cases (the sole MCL case tested in the aforementioned study was negative for the mutation) does not justify the status quo, because the pathogenetic contribution of KITD816V in SM and its use as a therapeutic target are uncertain and definitely not as well defined as they are for BCR-ABL1 or FIP1L1-PDGFRA. From a practical standpoint, the clinical features and treatment of MCL are more akin to acute leukemia than SM.

2. The clinical relevance of the SM-AHNMD subcategory has not been convincingly made, since the SM component is often not the dominant process from the standpoint of clinical features, diagnosis, bone marrow histology, or treatment. Again, for the reasons outlined in the previous paragraph, the presence of KITD816V should not be used as an excuse to lump together a clinicopathologically heterogenous group of diseases that are prognostically diverse. The observations from our recent review of 123 cases with SM associated with other myeloid malignancies underscore this point.⁴ 

3. The current proposal fails to address the prognostic relevance of the provisional ISM subvariants, smoldering SM (SSM) and BM mastocytosis (BMM).

Based on the above discussion, we propose the following revisions to the current SM classification (Table 1):

1. MCL should be eliminated as a subcategory of SM and instead be included under the WHO category of “Acute myeloid leukemia (AML) and related myeloid neoplasms.” The frequent occurrence of KITD816V may be emphasized by naming the entity “MCL with KITD816V,” similar to other entities in the “AML with recurrent genetic abnormalities” subcategory. Similarly, “myelomastocytic leukemia” and “AML with BM mastocytosis” (ie, SM-AML) can be included in the same “AML and related myeloid neoplasms” category.

2. SM-AHNMD should be eliminated as a subcategory of SM; instead, “SM–chronic myelomonocytic leukemia” (SM-CMML) and “SM–myelodysplastic syndrome” (SM-MDS) should be placed under the WHO category of “Myelodysplastic/myeloproliferative neoplasms” (MDS/MPN), given their similar prognosis and morphologic characteristics. In contrast, there is a firm basis for adopting a SM-MPN subcategory: it has been recognized since at least the early 1980s that a proportion of SM patients have BM features that are consistent with a coexisting MPN that is otherwise unclassifiable.⁵  The rare cases of SM with associated lymphoid or plasma cell neoplasm can be classified in the relevant category as, for example, “multiple myeloma with BM mastocytosis.”

3. Given its significantly worse prognosis and different age distribution, as demonstrated in our recent study of 159 cases with ISM,⁶  SSM should be separated from ISM as a distinct entity. In contrast, the clinical relevance of retaining the provisional entity “BMM” as an ISM subvariant is limited and can be removed.

We hope that this document serves to open the dialogue among interested parties regarding the classification of SM, to make it more practical and clinically relevant. In this regard, we strongly believe that the current WHO framework for the classification of hematologic malignancies is the best venue to facilitate the relevant discussions and debates.