A 54-year-old male was originally referred to our institution 2 years prior with a diagnosis of systemic mastocytosis (SM). Past medical history was significant for urticaria pigmentosa, which was diagnosed 15 years prior, and fatigue, diarrhea, and weight loss (∼10%), which were more recent in nature. In addition, a recent computed tomography (CT) scan revealed lymphadenopathy and hepatosplenomegaly.

Mastocytosis is currently defined, according to the 2008 WHO, as a clonal, neoplastic proliferation of mast cells (MCs) in one or multiple organs [1–3]. Clinical symptoms are divided into four separate categories, including (1) constitutional symptoms (i.e., fever, fatigue, and weight loss), (2) skin manifestations (such as urticaria pigmentosa), (3) mediator-related symptoms (to include abdominal pain, flushing, headache, hypotension, tachycardia among others), and (4) musculoskeletal complaints. These are caused by the release of chemical mediators such as histamine, eicosanoids, proteases, and heparin and also by infiltration of tissues by the neoplastic MCs.

In cutaneous mastocytosis, MC infiltration is limited to the skin with a typical presentation in childhood. Urticaria pigmentosa is a macroscopic description of the tendency for the lesions to urticate (sting and blister) and to accumulate intraepidermal pigment. In children, cutaneous mastocytosis typically has a benign clinical course and may regress spontaneously [4]. However, in adults, cutaneous disease is often associated with indolent systemic involvement and skin lesions do not typically regress. The WHO now recognizes three major variants of cutaneous mastocytosis, urticaria pigmentosa/maculopapular cutaneous mastocytosis, diffuse cutaneous mastocytosis, and mastocytoma of skin.

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Figure 1. (a) Peripheral blood smear, performed at the time of referral, revealed absolute monocytosis and dysplastic changes noted in the neutrophils including hypogranular forms. (1,000X, Wright Giemsa). (b) The initial bone marrow aspirate revealed eosinophilia and increased mast cells. Numerous mast cells were atypical and had a spindled morphology. (×400, Wright Giemsa). (c) In addition, dysplasia was pronounced in the megakaryocytes and included atypical clusters of micromegakaryocytes with hypolobated nuclei. (×400, Wright Giemsa). (d) A concurrent bone marrow biopsy showed a marked infiltrate of fibrosis with mast cells (>60% of overall cellularity). (×100, Hematoxylin and Eosin). (e) Many of the mast cells showed an atypical spindled appearance. (×200, Hematoxylin and Eosin). (f) In areas of the biopsy with less involvement by fibrosis and mast cells, eosinophilia was noted and dysplasia was pronounced, especially in the megakaryocytes. (×200, Hematoxylin and Eosin). (g) Mast cell tryptase immunohistochemical stain highlighted the marked involvement by mast cells. (×100). (h) A CD117 immuohistochemical stain also highlighted the mast cell infiltrate (×100), and a CD25 stain helped confirm their neoplastic nature. (insert, ×200). (i) Follow-up bone marrow biopsy 5 revealed multiple neoplastic lymphoid aggregates, which were positive for CD20. (×400, CD20 immunohistochemical stain).

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SM is diagnosed when one major criterion and one minor criterion or at least three minor criteria are present. The major diagnostic criterion for SM is fulfilled by the presence of multifocal dense MC infiltrates (≥15 MCs per aggregate) detected histologically in the bone marrow or in another extracutaneous organ(s). Minor criteria include: (1) ≥25% of the MCs in the infiltrate are spindle-shaped or show atypical morphology or, ≥25% are immature or atypical on BM aspirate smears; (2) a serum tryptase level is persistently greater than 20 ng/mL (this parameter is not valid if there is an associated clonal myeloid disorder); (3) detection of the characteristic D816V KIT mutation and (4) expression of CD2, CD25, or both in neoplastic MCs [1–5]. In these patients, splenomegaly may be appreciated, but is often minimal. However, lymphadenopathy and hepatomegaly are much rarer but were noted in our patient.

A complete blood count, at the time of referral, showed a normal hemoglobin (14.6 g/dL) and platelet count (326 × 109/L), and a leukocytosis (17.1 × 109/L) with increased monocytes (absolute monocytes: 1.4 × 109/L). A lymphocytosis was not present, and his monocytosis had lasted more than 3 months. The bone marrow (BM) aspiration/biopsy slides revealed a normocellular marrow with moderate dysplasia including hypogranular neutrophils, micromegakaryocytes, small hypolobated megakaryocytes, and megakaryocytes with multiple discrete nuclei (Fig. 1). Myeloblasts, monoblasts, and promonocytes were enumerated at less than 5%. In addition, ∼50% of the overall cellularity was replaced with atypical mast cells, which were spindled in shape with elongated nuclei. These mast cells, by immunohistochemistry, were positive for mast cell tryptase, CD117, and CD25. In addition, diffusely increased fibrosis was highlighted by reticulin staining. Per outside report, flow cytometry failed to reveal an abnormal immunophenotype, including a light chain restricted B-cell population. In addition, karyotype and florescent in situ hybridization (FISH) with probes specific for myelodysplastic syndrome and platelet derived growth factor receptor-alpha (PDGFRA) were normal. The regions/loci represented in these probe mixes for MDS were a dual color dual fusion ETO/RUNX1 to detect t(8;21), 5p15.2 (D5S721), 5q33-34 (CSFIR), centromeric region of chromosome 7, 7q31(D7S486) to detect copy number/deletion of chromosomes 5 and 7, CEP12 to detect copy number of chromosome 12, 13q14, and 13q34 region specific probes to detect deletion/loss of chromosome 13, and 20q13 (AURKA) regions to detect deletion/copy number of chromosome 20. Finally, a KIT (D816V) point mutation was noted by polymerase chain reaction, which was performed on the bone marrow aspirate and serum tryptase was elevated at 601 ng/mL. The patient was then diagnosed with SM with an associated clonal hematologic non-mast cell lineage disease (SM-AHNMD), namely SM with chronic myelomonocytic leukemia-1 (SM-CMML-1).

SM-AHNMD is a disorder where the patient meets criteria for SM as well as another hematologic neoplasm recognized by the WHO [1]. Surprisingly up to 30% of patients with SM are noted to have AHNMD at some point during their disease course. Almost all hematologic malignancies except for Hodgkin lymphoma have been reported as an associated hematologic malignancy with SM [6–10]. The most frequently associated malignancies are myelogenous including acute myelogenous leukemia, chronic myelomonocytic leukemia (CMML), and myelodysplastic syndrome [6]; of these, CMML is the most common. Fittingly, our patient met criteria for CMML.

CMML is defined by the WHO as (1) persistent peripheral blood monocytosis (>1 × 109 /L); (2) no Philadelphia chromosome or BCR-ABL1 fusion gene; (3) no rearrangement of PDGFRA or PDGFRB; (4) fewer than 20% blasts in blood and bone marrow; and (5) dysplasia noted in one or more myeloid lineages [11]. However, criterion 5 is not required if an acquired clonal cytogenetic or molecular genetic abnormality is present or the monocytosis is persistent for 3 months and other causes of monocytosis have been excluded.

A fine needle aspiration performed on an enlarged cervical lymph node revealed mildly increased mast cells with admixed mature lymphocytes, consistent with involvement by mastocytosis.

Lymph nodes, which are rarely involved by SM, show preferential infiltration into the paracortical areas with typical preservation of the nodal architecture. Follicular hyperplasia may be noted along with increased plasma cells, eosinophils, and fibrosis [12]. In CMML, generalized lymphadenopathy may be noted, which is characteristically secondary to proliferations of plasmacytoid dendritic cells. It has been proposed that when associated with this disorder, these cells are clonal and related to the myeloid neoplasm [13, 14].

The patient was initially started on dasatinib, which was discontinued due to gastrointestinal discomfort. Later the patient was initiated on phase II trail with a tyrosine kinase inhibitor (TKI), PKC412 (midostaurin).

TKIs have been investigated in patients with SM because more than 90% of patients with SM contain an activating point mutation within KIT [15–19]. KIT is a proto-oncogene, which encodes for a class III receptor tyrosine kinase. This protein consists of an extracellular domain with five immunoglobulin-like repeats, a single transmembrane domain, a juxtamembrane domain, and a cytoplasmic tyrosine kinase domain [15]. The most common point mutation, KITD816V, results from substitution of valine for asparagine at codon 816 within KIT exon 17 [20]. This mutation causes a resistance to apoptosis, leading to a neoplastic clone.

Response to TKIs is more interesting in patients with SM-AHNMD. In some reports, there is evidence that the associated non-mast cell hematologic malignant cells have the same KIT mutation [18, 21–25]. This finding supports the belief that there is a common neoplastic progenitor from which malignant mast cells and the non-mast cell hematologic malignancy arise. Therefore it can be assumed that SM as well as the associated non-mast cell hematologic malignancy may improve by using TKIs in patients with SM-AHNMD [26, 27].

Follow-up has included five additional BM biopsies; all of which have continued to show involvement by atypical mast cells in varying degrees [follow-up BM (1) 50% of overall cellularity, (2) 80%, (3) 15%, (4) 30%, and (5) 60%]. The first 2 BM biopsies were performed prior to treatment with PKC412, and the last 3 are subsequent to his new treatment after 3, 6, and 12 cycles. Serial CT scans have shown stable disease without increase in lymphadenopathy or liver and spleen size. Overall, his serum tryptase levels have trended down, and most importantly, he reports less diarrhea and fatigue. In addition, he has been able to gain weight since he began the trial. Interestingly, his monocyte counts as well white blood cell counts decreased significantly as a response to the TKI.

Prognosis in patients with SM-AHNMD is variable due to the vast variety of associated disorders, but a recent study showed median survival to be 2 years overall [28]. Our patient is alive over 2 years after diagnosis, leading to some support for the use of TKI therapy in these patients, particularly in combination with other more systemic therapies or alone if more intensive therapies cannot be tolerated. Furthermore, the improving monocytosis raises the possibility of a similar KITD816V clone being present in the neoplastic cells of his CMML.

Follow-up BM 5, performed ∼2 years after initial diagnosis also revealed multiple non-paratrabecular lymphoid aggregates composed of small, round, mature lymphocytes. By immunohistochemistry, the lymphoid cells were CD20 positive and negative for CD3, CD43, CD5, CD23, CD10, BCL-2, and BCL-1. Flow cytometry performed on the BM aspirate revealed a monoclonal B-cell population expressing CD19 and CD20 with kappa light chain restriction. These cells were negative for CD5 and CD10. Karyotyping on the aspirate was normal. Follow-up FISH, performed on peripheral blood, with probes specific for recurring abnormalities in non-Hodgkin lymphoma (NHL) was negative. The regions/loci represented in these probe mixes for NHL were a tri-color dual fusion CMYC/IGH probe specific for detection of t(8;14) and copy number of chromosome 8, a dual color dual fusion IGH/BCL1 and IGH/BCL2 probe to detect t(11;14) and t(14;18), respectively, and a dual color break-apart BCL6 probe to detect deletion/rearrangement at 3q27.

The finding of two separate non-mast cell hematologic malignancies in a patient with SM is exceedingly rare. Recently, Du et al. reported a SM patient with two concurrent non-mast cell hematologic malignancies, chronic lymphocytic leukemia and multiple myeloma [29]. To our knowledge, this is the only other patient in the literature with two non-mast cell lineage hematologic malignancies in association with SM. However, patients with myeloproliferative neoplasms are believed to have a higher incidence of developing monoclonal B cell populations than the general patient population [30]. Given our patients known myelodysplastic/myeloproliferative disorder, namely CMML, he may have been predisposed to developing his third hematologic neoplasm.


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