Mastocytosis is defined as infiltration of atypical mast cells (MCs) in one or more organs (1, 2). In the patients with systemic mastocytosis (SM), neoplastic MCs constitute focal or diffuse infiltrates in various internal organs such as bone marrow (BM), spleen, liver and gastrointestinal tract (1). Parwaresch et al., (3) and Horny HP et al., (4) also stated that MC neoplasia is generally confined to the dermis. Cutaneous mastocytoses are called benign mastocytoma when localized and urticaria pigmentosa when disseminated. The generalized mastocytosis involves extra-cutaneous tissue irrespective of skin involvement.
According to the 2016 updated WHO classification, two major subtypes are Cutaneous Mastocytosis (CM), and Systemic Mastocytosis (SM). In systemic type, neoplastic mast cells involve internal organs with or without cutaneous involvement. SM is subdivided into Indolent SM (ISM), Smoldering SM (SSM), SM with an associated hematologic neoplasm (SM-AHN), aggressive SM (ASM), mast cell leukemia (MCL), mast cell sarcoma, and extra cutaneous mastocytoma (1). Arber DA et al., (5) found that the 2016 edition represented a revision of the prior classification rather than an entirely new classification. Thus, they attempted to incorporate new clinical, prognostic, morphologic, immune-phenotypic, and genetic data that have emerged since the last edition.
WHO recommendations for the diagnosis of SM are considering detection of the following major criteria with at least one major criterion or three minor criteria (1, 6, 7).
Major criterion is characterized by the observation of aggregates (more than 15 cells) of mast cells in bone marrow or extra cutaneous organs. Minor criteria include more than 25% immature spindle-shaped or atypical mast cells in BM or extra cutaneous organs, the presence of KIT D816V point mutation, and phenotypic expression of CD2 or CD25, more than 20 ng/ml serum Tryptase level in the absence of clonal myeloid disorder (1, 6).
MCL, less than 0.5% of mastocytosis, is the leukemic spreading of atypical mast cells, involving more than 20% of bone marrow hematopoietic cells in aspirate or biopsy, with aleukemic variant that shows less than 10 percent mast cells in WBC count of blood (2). Valentini CG et al., (8) and Swerdlow H et al., (9) described the same viewpoints in the previous parallel studies.
Recently, Valent P et al., (10) classified MCL into two categories in a new study to refine diagnostic criteria and classification of mast cell leukemia (MCL) and myelomastocytic leukemia (MML).They proposed a chronic form without obvious organ damage (no C findings present) and a more aggressive variant, and acute MCL where organ damage (C findings) is present.
Literatures state that c-KIT mutation is the most frequent abnormality encountered and a hallmark of the disease.Mast/stem cell growth factor receptor (SCFR), also known as proto-oncogene c-Kit or tyrosine-protein kinase Kit or CD117, is a receptor tyrosine kinase protein that is encoded by the KIT gene in humans (11). Positive IHC staining for CD117/kit in bone marrow is supposed to be essential for the diagnosis of MCL. We describe one case of MCL with insignificant reactivity for CD117. Joris M et al., (12) and Georgin-Lavialle S (13) also showed that non-KIT D816V mutations are unexpectedly frequent and therefore, complete gene sequencing is necessary.
The study illustrates a very rare case of aleukemic variant of acute mast cell leukemia with weight loss, ascites and multiple organs involvement including liver, peritoneum and lymph nodes.
A 57-year-old man was referred to our center with the history of anemia and ascites for two years. He complained from weakness, periodic headache, occasional vomiting and significant weight loss.
His vital signs were within normal ranges on systemic physical examination. Cervical lymphadenopathy was remarkable. Chest and lungs auscultation revealed faded respiratory sounds over middle and lower lobes of the right lung. The liver edge was palpable 3 cm below the right costal margin and evidences of spleen enlargement with mild abdominal distention were identified.
Further evaluations including laboratory tests on serum and ascites fluid, and radiologic investigations were done. Abdominal ultrasound showed multiple para aortic enlarged lymph nodes, splenomegaly (166 mm), and free intraperitoneal fluid. In chest and abdominopelvic CT scan the same findings were distinguished such as hepatosplenomegaly and para aortic lymphadenopathy. Anemia was confirmed by CBC (WBC:6600, Hb:9.8, Plt:307000). Ascites fluid and other laboratory data were unremarkable.
During hospitalization, bone marrow aspiration and biopsy were done with simultaneous PBS preparation, and stained by Giemsa stain.
Peripheral blood showed hypochromia, anisocytosis, and poikilocytosis of red blood cells. WBC differential count was within normal range (51% PMN, 32% lymph, 2% monocyte, 1% eosinophil and 14% activated lymphoid cells).
Giemsa-stained bone marrow aspiration revealed many three-dimentional clusters of de-granulated or hypogranulated mast cells with spindle-shaped nuclei, clear or eosinophilic granular cytoplasm, with no other hematopoietic cells presence andmature mast cells absence, supported by Toluidine blue stain (Figure 1).
Bone marrow biopsies were stained by H&E, Giemsa, and Toluidine blue stains and showed about 100% cellularity with the aggregates of atypical spindle-shaped mast cells that represent hypogranulation. Several megakaryocytes with dysplastic figures were also identified. Immunohistochemistery evaluation of bone marrow biopsy demonstrated low expression of CD117 and CD45 (Figure 2, 3).
After achieving these findings, the serum Tryptase level was checked in the patient. It was markedly elevated above the normal limit (465 ng/ml).
Figure 1. Bone marrow smear showed numerous metachromatic blast cells with vacuolated cytoplasm containing varying numbers of metachromatic granules and spindle-shaped nuclei. (Giemsa, 1000×)
Figure 2. Bone marrow biopsy showed the sheet of spindle-shaped mast cells. (Hematoxylin and eosin, 400×)
Figure 3. Bone marrow biopsy revealed numerous mast cells with metachromatic granules. (Toluidine blue stain, 400×)
Figure 4. Liver biopsy showed peri-portal mast cell infiltration. (H&E, 400×)
Due to massive hepatosplenomegay and generalized lymphadenopathy, liver biopsy and lymphadenectomy were done by the surgeon. The specimens were stained by H&E and Giemsa stains. Liver tissue showed dense portal, sinusoidal, and micronodular mast cells infiltration with portal fibrosis. (Figure 4,5). Lymph nodes also showed mast cells distribution through subcapsular and sinus spaces. (Figure 6,7).