Systemic mastocytosis with an associated hematological neoplasms: One or two entities?

Mastocytosis refers to a group of disorders characterized by excessive mast-cell accumulation in one or multiple tissues. The WHO classification [1] splits mastocytosis from the myeloproliferative neoplasms as a distinctive entity group. SM-AHN was introduced as abbreviation of “systemic mastocytosis with associated clonal hematological non-mast-cell lineage disease" (SH-AHNMD) and recognized as a subgroup of systemic mastocytosis. Approximately 5% of SM cases are with myeloid malignancies, according to the classification, the most detected AHN is CMML [1]. Here, we report a case with the diagnosis of SM-AHN combining SM and CMML. We aim to show that SM-AHN with CMML may be overestimated, and that monocytosis may be an integral component of the SM.


Systemic mastocytosis with an associated hematological neoplasms: One or two entities?
Mastocytosis refers to a group of disorders characterized by excessive mast-cell accumulation in one or multiple tissues. The WHO classification [1] splits mastocytosis from the myeloproliferative neoplasms as a distinctive entity group. SM-AHN was introduced as abbreviation name of the 2008 category of "systemic mastocytosis with associated clonal hematological non-mast-cell lineage disease" (SH-AHNMD) and recognized as a subgroup of systemic mastocytosis. Approximately 5% of SM cases are associated with myeloid malignancies, according to the WHO classification, the most commonly detected AHN is CMML [1]. Here, we report a case with the diagnosis of SM-AHN combining SM and CMML. We aim to show that SM-AHN with CMML may be overestimated, and that monocytosis may be an integral component of the SM.
A 62-year-old caucasian man was referred to our outpatient clinic in July 2018 with suspicion of myeloid disease. The patient complained about episodes of extreme fatigue, drenching night sweats, fever, skin hematomas, and weight loss of about 8 kg within 6 months.
The initial blood examinations documented a hemoglobin level of 10.5 g/dL, platelet count of 98 × 10 9 /L, and white blood cell count of 13.5 × 10 9 /L showing a differential count with 8.47 × 10 9 /L neutrophils, 0.98 × 10 9 /L lymphocytes, and 2.29 × 10 9 /L monocytes (17% of total leukocytes), no eosinophilia or basophilia. Serum tryptase level was increased at 139 µg/L (normal < 13 µg/L) with a normal serum lactate dehydrogenase of 313 U/L. A full-body computed-tomography scan revealed homogenous splenomegaly with a bipolar diameter of 18.5 cm.
The morphological examination of the initial bone marrow (BM) aspirate and trephine biopsy performed in July 2018, revealed hypercellularity for his age with marked proliferation of dysplastic granulopoiesis and megakaryopoiesis, reduced erythropoiesis and the presence of dense mast cell aggregates with atypical spindle-shape.
The blast count was not increased. BM fibrosis was evident (MF-2). SM was diagnosed (major criterion and four minor criteria) ( Figure 1). The diagnostic criteria of CMML were additionally met (all five criteria) and fittingly, the diagnosis of SM-AHN was assumed. Cytogenetic testing For the molecular analysis, only those mutations identified previously in the BM were investigated in the sorted monocytes ( Table 1).
The monocytes harbored the following mutations: KIT D816V with VAF of 47%, ASXL1 with a VAF of 52%, SRSF2 with a VAF of 53% and TET2 mutation with a VAF of 100%. Moreover, the high allele burden of TET2 mutation suggested a germline mutation, so we additionally tested the TET2 variant p(Asn275Ilefs*18) in a saliva sample using Sanger Sequencing. This was positive with a VAF of 50% suggesting a somatic mutation.
The patient developed a rapidly progressive splenomegaly  For NGS, we used the Ion Torrent S5 platform (Thermo Fisher Scientific, Reinach, Switzerland) including IonChef, and the human genome assembly GRCh37 (hg19) for variant calling. The original bone marrow sample was sequenced using the Ampliseq Oncomine myeloid panel (40 genes/hotspots; Thermo Fisher Scientific, Reinach, Switzerland). VAF, variant allele frequency. All molecular investigations were done before the patient received the hypomethylating treatment and also before he underwent an allogeneic hematopoietic stem cell transplantation.
four-quadrant ascites after three cycles of hypomethylated therapy.
On May 2019, the patient underwent an allogeneic hematopoietic stem cell transplantation from his human leukocyte antigen genoidentical brother. To date, the patient is alive, however without achieving hematologic remission, and has extensive cutaneous graft-versus-host disease.
The definition of the role of monocytosis in the diagnosis of myeloid diseases has been topic of discussion for a long time. Monocytosis may accompany many myeloid diseases; the latest WHO update considered this aspect particularly for the diagnosis of CMML, defining that monocytosis not only has to be greater than 1.0 × 10 9 /L, but also has to exceed 10% of the total leukocytes count [1]. This new cutoff should certainly contribute to a better differentiation of many myeloid entities; however, it remains arbitrary and may not be valid in all cases. The identification of BCR-ABL1, PDGFRA, PDGFRB FGFR1 PCM1-JAK2 mutations together with the criteria for the diagnosis of specific diseases like chronic myeloid leukemia, primary myelofibrosis, polycythemia vera, and essential thrombocythemia will rule out the diagnosis of CMML. In all these diseases, monocytosis per se as a criterion is therefore overruled. Mastocytosis is currently not included in this consideration.
Some authors described that multilineage KIT involvement and multi-mutated clones are characteristic of advanced SM, and mentioned that this is particularly true when associated with hematologic neoplasms [2][3][4]. The presence of KIT D816V was first reported in monocytic cell of BM [2] and a further publication also identified KIT D816V mutation in variable myeloid subtypes of marrow cells of AHN [3]. Among multilineage SM patients, the presence of the KIT D816V mutation is typically detected in genomic DNA (gDNA) of CD34 + hematopoietic stem and precursor cells, eosinophils, monocytes, and maturing neutrophils, and, to a less extent, also in T lymphocytes, in addition to bone marrow mast cells [5]. Historically, monocytosis has proven to be a great confounder. The advances in molecular diagnostics and the improvement of the diagnostic criteria for myeloid neoplasms in the past two decades have contributed to delimiting some myeloid neoplasms even with noticeable monocytosis from CMML [1,[7][8][9]. In the case presented, the disease that drove the clinical picture was clearly the SM. Formally, the persistent monocytosis allowed the diagnosis of CMML. The confirmation that the isolated monocyte harbored all mutations found in BM inclusive KIT (Table 1) suggests that the monocytes might be rather the expression of the SM and may perhaps not represent a second disease. Associating other diseases with systemic mastocytosis can be a distracting factor to focus treatment properly [10]. We consider that a most appropriate nomenclature for such cases needs to be defined.