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Systemic mastocytosis (SM) is a clinically heterogeneous disease with prognosis chiefly assigned based on World Health Organization (WHO) morphologic subclassification. We assessed the feasibility of developing contemporary risk models for SM based on clinical and integrated clinical-genetics information. Diagnosis of SM was per WHO criteria, and karyotype and next-generation sequencing data were available in a subset of the total 580 patients (median age, 55 years; range, 18-88 years) seen at the Mayo Clinic between 1968 and 2015. Morphologic subcategories were indolent/smoldering in 291 (50%) and "advanced" in 289 (50%): SM with an associated hematological neoplasm in 199, aggressive SM in 85, and mast cell leukemia in 5. Multivariable analysis of clinical variables identified age >60 years, advanced SM, thrombocytopenia <150 × 109/L, anemia below sex-adjusted normal, and increased alkaline phosphatase (ALP) as independent risk factors for survival; respective hazard ratios (HRs) 95% confidence intervals (95% CIs) were 2.5 (1.9-3.4), 2.7 (1.8-4.0), 2.5 (1.9-3.4), 2.2 (1.6-3.1), and 2.1 (1.5-3.0). In addition, ASXL1 (HR, 4.5; 95% CI, 2.6-7.6), RUNX1 (HR, 4.3; 95% CI, 1.3-10.8), and NRAS (HR, 5.0, 95% CI, 1.5-13.2) mutations were independently associated with inferior survival. Combined clinical, cytogenetic, and molecular risk factor analysis confirmed the independent prognostic contribution of adverse mutations (2.6, 1.6-4.4), advanced SM (4.0, 1.8-10.0), thrombocytopenia (2.8, 1.7-4.5), increased ALP (2.1, 1.2-4.0), and age >60 years (2.2, 1.3-3.6). These data were subsequently used to develop clinical and hybrid clinical-molecular risk models. The current study advances 2 complementary risk models for SM and highlights the independent prognostic contribution of mutations.

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Mast cell leukemia (MCL) is a very rare subtype of systemic mastocytosis (SM). We have identified 13 such patients (5.9%) among 218 patients with SM seen at our institution between 1994 and 2016. Patients with MCL had poor survival (median 31.6 months); response to various therapies was rare and not durable. Clinical course may be affected by concurrent associated hematologic neoplasm and different genetic profiles. More research is required to decipher this rare and enigmatic SM subtype.

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Mast cell leukemia is a rare variant of advanced systemic mastocytosis characterized by at least 20% of mast cells in a bone marrow smear. We evaluated clinical and molecular characteristics of 28 patients with (n=20, 71%) or without an associated hematologic neoplasm. De novo mast cell leukemia was diagnosed in 16 of 28 (57%) patients and secondary mast cell leukemia evolving from other advanced systemic mastocytosis subtypes in 12 of 28 (43%) patients, of which 7 patients progressed while on cytoreductive treatment. Median bone marrow mast cell infiltration was 65% and median serum tryptase was 520 µg/L. C-findings were identified in 26 of 28 (93%) patients. Mutations in KIT (D816V, n=19; D816H/Y, n=5; F522C, n=1) were detected in 25 of 28 (89%) patients and prognostically relevant additional mutations in SRSF2, ASXL1 or RUNX1 (S/A/Rpos) in 13 of 25 (52%) patients. Overall response rate in 18 treatment-naïve patients was 5 of 12 (42%) on midostaurin and 1 of 6 (17%) on cladribine, and after switch 1 of 4 (25%) on midostaurin and 0 of 3 on cladribine, respectively. S/A/Rpos adversely affected response to treatment and progression to secondary mast cell leukemia (n=6) or acute myeloid leukemia (n=3) while on treatment (P<0.05). The median overall survival from mast cell leukemia diagnosis was 17 months as compared to 44 months in a control group of 124 patients with advanced systemic mastocytosis but without mast cell leukemia (P=0.03). In multivariate analyses, S/A/Rpos remained the only independent poor prognostic variable predicting overall survival (P=0.007). In conclusion, the molecular signature should be determined in all patients with mast cell leukemia because of its significant clinical and prognostic relevance.

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Mast cells not only synthesize and release serotonin, but also express and are activated through multiple serotonin receptors. Low blood serotonin level might define a specific subset of patients with systemic mastocytosis (SM) who are more likely to present with neurologic and gastrointestinal complaints. Mast cell leukemia (MCL) is a rare and aggressive type of systemic mastocytosis, and psychiatric manifestations in its course have not been well-characterized. We describe herein a unique patient with a KIT D816V mutation positive a leukemic leukemia variant of systemic mastocytosis with gastrointestinal involvement, presenting with a severe and sustained paranoid delusional illness. While diarrhea improved with the use of histamine H1 and H2 receptor antagonists, the psychosis did not, and the disease followed a dramatic course with a rapidly fatal outcome. As there is paucity of literature, diagnosis of MCL presenting with psychiatric symptoms remains a diagnostic challenge and warrants clinicians to be alert of this rare possibility.

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Reported herein is an autopsy case of mast cell leukemia, a rare form of systemic mastocytosis, complicated with portal hypertension. A 52-year-old woman presented with urticaria-like skin symptoms, anemia, and thrombocytopenia. Atypical mast cells (CD2+, CD25+, CD117+) with toluidine blue metachromasia were found in the peripheral blood and on bone marrow aspiration smears. Chemotherapy with cytosine arabinoside and idarubicin was ineffective and the patient died of multi-organ failure with rapidly progressing hepatosplenomegaly and large-volume ascites 3 months after admission. At autopsy the bone marrow, spleen, liver, and lymph nodes were extensively infiltrated by atypical tumor cells with occasional bi- or multi-lobated nuclei. They were positive for mast cell tryptase and possessed an activating mutation of the c-kitgene (D816V). Ascites (2200 mL) and non-ruptured esophageal varices with submucosal hemorrhage indicated the presence of severe portal hypertension. Although there was no evidence of liver cirrhosis, the hepatic sinusoids were clogged with tumor cells, with a tendency to be more severe in the perivenular areas, and the lumens of central veins were obliterated by tumor cell infiltration. The present case demonstrates that non-cirrhotic portal hypertension due to blocking of sinusoidal and venous flow could be a serious complication in mast cell leukemia.

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Synthesis of histamine in hematopoietic progenitor cells may be one of the earliest events in mastopoiesis. We therefore asked whether the key enzyme involved in histamine production, histidine decarboxylase (HDC), can be used as an immunohistochemical marker for the detection of immature neoplastic mast cells (MC) in patients with MC-proliferative disorders. To address this question, we examined bone marrow biopsy specimens in a cohort of 102 patients with mastocytosis using an antibody against HDC. Independent of the maturation stage of MC, the anti-HDC antibody produced clear diagnostic staining results in all patients with systemic MC disease examined including those with MC leukemia and MC sarcoma, in which MCs are particularly immature. In these patients, expression of HDC was reconfirmed at the messenger RNA level by reverse transcriptase polymerase chain reaction analyses performed with RNA of highly enriched CD117(+) MC. In summary, HDC is expressed in neoplastic MC in patients with systemic mastocytosis independent of the maturation stage of cells or the variant of disease. Histidine decarboxylase should therefore be considered as a new MC marker in the screen panel of antigens used to diagnose high-grade MC malignancies.

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Mastocytosis is a rare disease characterized by an abnormal increase of mast cells in tissues. We report a case of acute myeloid leukemia (AML) with t(8;21) and mast cell leukemia (MCL) in which the mastocytosis persisted after standard chemotherapy and allogeneic stem cell transplantation, although the myeloid leukemia achieved molecular complete remission soon after induction chemotherapy. Donor-type mast cells were noted on d31 after transplant. No c-kit mutation was found before or after the transplant. This represents the first reported case in which rapid engraftment of mast cells of donor origin was documented. Thus, the possibility that the mast cell originates from a common myeloid precursor cell may be questioned and a reactive process should be considered in some cases of systemic mastocytosis.

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Mast cell leukemia is a rare, severe disease that may manifest through an array of clinical presentations, including vasomotor flushing and hypotension. Leukemic infiltrate of muscle and bone may rarely occur, resulting in nonspecific myalgias, bony pain, and neuropathic pain secondary to compression of nerves by bone. Mast cell leukemia as a clinical entity has not been well described. We present the case of a 25-year-old man with a remote medical history of germ cell tumor who was initially diagnosed with mast cell leukemia after presenting with low back pain. One and a half years later, the patient presented with a chief complaint of back pain and myalgias and was found to have relapsed mast cell leukemia. Medical management and, specifically, rehabilitation of these patients can be extremely difficult. This report shows the complex management of patients with mast cell leukemia.

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INTRODUCTION: Acute mast cell leukemia is a rare and severe disease. We report herein a case associated with a flush syndrome. CASE REPORT: A 44-year-old man, presented with a flush of face and trunk. Bone marrow was infiltrated with immature mast cells. In spite of chemotherapy and bone marrow transplantation the patient deceased. DISCUSSION: Pheochromocytoma, carcinoid tumor, and mastocytosis are associated with a flush syndrome. In our patient the diagnosis was an acute mast cell leukemia. Acute mast cell leukemia can follow systemic mastocytosis or occur de novo. This disease is of poor prognosis. No treatment is available.

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Abdominal malignant mesothelioma was found in a 17-year-old, spayed female Japanese domestic cat with mast cell leukaemia. The mesothelioma was mainly located at the periphery of the pancreas, spleen and stomach, and showed metastases to the lung, an anterior mediastinal lymph node and lymph ducts in the tracheal mucosa. Micro-circulatory defects caused by the mast cell leukaemia may have been partly responsible for the distant metastases.

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Blood findings in 61 cases of generalized mastocytosis (GM) were evaluated. The cases were divided into two major variants: Systemic mastocytosis (SM; n = 34) with urticaria pigmentosa-like skin lesions, and malignant mastocytosis (MM; n = 27), without skin involvement. The following results were obtained: (1) Significant differences between MM and SM were found in the main haematological parameters (erythrocyte, platelet and leucocyte counts and haemoglobin level); normal values were found in 16 of the SM cases, but never in MM. (2) The main pathological findings were: in SM, anaemia (9/34) and leucocytosis (5/34); and in MM, leucocytosis (19/27), monocytosis (14/27), eosinophilia (12/27), bicytopenia (12/27, mostly anaemia with thrombocytopenia), basophilia (10/27) and isolated anaemia (7/27). (3) The major finding was a significant difference between MM and SM in the incidence of myeloproliferative disorders (MPD), myelodysplasia and mast cell leukaemia (MCL): these disorders occurred in 23 (92%) MM patients, but only in two (6%) SM patients (P less than 0.001). The four instances of MCL and two of myelodysplasia all occurred with MM. Of the 19 cases of MPD, six (SM, 1; MM, 5) were acute variants (acute myeloid and myelomonocytic leukaemias) and 13 (SM, 1; MM, 12) were chronic variants. No case of malignant lymphoma was noted. (4) The blood picture in 10 of 13 chronic MPD cases represented an atypical chronic myeloid leukaemia for which the preliminary descriptive term 'mastocytosis-associated MPD' is proposed. (5) A survey of 103 published cases (SM, 77; MM, 26) yielded similar findings, including a high incidence of MPD and MCL in MM. These findings add further weight to the argument for recognizing SM and MM as two separate entities.

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An adult patient with multiple unusual histiocytic tumors of the skin is described. As shown by immunohistologic study, electron microscopy, and immunoelectron microscopy, the tumors represent circumscribed proliferations of the Langerhans cell-related indeterminate dendritic cells of the skin. This distinct cutaneous histiocytosis may represent a paraneoplastic syndrome.

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