According to the most recent revised 2016 WHO classification[1], a diagnosis of SM could be made when the major criterion (≥ 15 MC in clusters) and / or 3 minor criteria (other extracutaneous organs > 25% of the mast cells infiltration, KIT mutation, CD25/CD2 co-expression,) are present. Due to the presence of C-findings (hypohemoglobinemia, thrombocytopenia, splenomegaly, and gastrointestinal dysfunction), a diagnosis of ASM was made. ASM is a hematopoietic neoplasm characterized by infiltration of visceral organs by neoplastic mast cells with consecutive organopathy and respective clinical and laboratory findings (so called C-Findings). In ASM the infiltration of mast cells causes impairment function of involved organs and the clinical picture is charaterized by loss of function of involved organs. In our case, the patient has mild ascites, malabsorption, osteolysis and two cytopenia. The patient also presented with constitutional symptoms (weight loss), extensive lymphadenopathy, eosinophilia and splenomegaly, which mimicking a lymphoma. Lymph nodes involvement in ASM is common. Evidence of lymph nodes involvement includes lymphadenopathy. The main sign of lymph nodes involvement in ASM is the pathological accumulation of mast cells in the lymph nodes.
The histological pattern of the mast cell infiltrate can vary depending on the tissue sampled. On lymph node sample, mast cells aggregate predominantly in paracortical areas. In our case, histology of a cervical lymph node revealed follicular lymphoid hyperplasia with interfollicular infiltration by spindle-shaped mast cells with abundant, lightly staining cytoplasm. The presence of multifocal compact mast cell infiltrates or a diffuse compact mast cell infiltration pattern is highly compatible with the diagnosis of mastocytosis. However, in patients with the diffuse infiltration pattern, it is therefore impossible to establish the diagnosis of mastocytosis without additional studies, including the demonstration of an aberrant immunophenotype and/or detection of an activating point mutation in KIT. In the present case, a core biopsy on the cervical lymph node was nondiagnostic,due to prominent eosinophils, which obscure the mast cells infiltrate. Subsequently, lymphadenectomy showed densely packed, spindled mast cells aggregate predominantly in the parafollicular area, which confirmed the diagnosis of mastocytosis. Four patients with ASM with a presentation similar to the one described in this article were previously reported in the literature. In one patient KIT mutation status was not determined[2], and the other three patients were positive for KITD816V [3–5].
Previous studies have reported GI tract involvement by mastocytosis in small numbers of patients [6–8]. Histologically, involved GI endoscopic biopsy contained scattered single mast cells with expression of both CD117 and CD25, determined to represent minimal involvement by mastocytosis. Due to involvement was very focal and subtle in our case, the diagnosis of mastocytosis in mucosal biopsies was very difficult. The present case was initially diagnosed as chronic gastritis on the basis of the low dense of mast cells, and did not have endoscopic abnormalities, which added to the difficulty of diagnosis. Following recognition of mastocytosis in the lymphadenectomy, described above, the gastric biopsies were retrospectively stained for c-kit, revealing only a few scattered mast cells in the lamina propria, confirming SM in the stomach. The histologic differential diagnosis of mastocytosis in the GI tract is with reactive mast cell hyperplasia. Normal/reactive mast cells are usually loosely scattered throughout the sample and display round to oval nuclei with clumped chromatin, a low nuclear: cytoplasmic ratio, and absent or indistinct nucleoli. They are often appeared in normal mucosa or slightly increased in parasitic infection but do not show coexpression of CD117 and CD25, which can help in the differential diagnosis with mastocytosis.
Immunohistochemically, the CD117 positive mast cells with co-expression of CD2 and / or CD 25 is a sensitive and specific marker in the diagnosis of SM. Compared with normal mast cells, neoplastic mast cells abnormally express CD2 and CD25, but did not express most T or B antigens. Other markers including CD30, CD45, and CD68 are variably positive. In our case, the neoplastic mast cells mainly express CD117 and CD25, aberrant expression of CD2 is not seen in neoplastic mast cells, which is mainly expressed normally on some T lymphocytes. Prior studies have shown an association between CD30/123 expression and advanced disease [9–11],but data on this association is not particularly robust. We did not find CD30 or CD123 expression by neoplastic mast cells in our case.
Most cases of ASM harbor the KIT D816V mutation. The KIT gene, also known as CD117, encodes the KIT proto-oncogene receptor tyrosine kinase (c-KIT), a member of the PDGF receptor type III receptor tyrosine kinase family, which includes PDGFRA, PDGFRB, CSF1R, FLT1, FLT3, FLT4 and KDR[12, 13]. KIT is a receptor for stem cell factor, important in regulating growth and development of hematopoietic cells[14]. The KIT gene is flanked by the PDGFRA and KDR genes on chromosome 4q12. Ligand binding to KIT results in kinase activation and stimulation of downstream pathways including the RAS/RAF/MEK/ERK and PI3K/AKT/MTOR pathways promoting cell proliferation and survival[15]. A common kinase domain mutation that causes ligand-independent constitutive activation, D816V, occurs in 80–93% of aggressive forms of mastocytosis [16, 17]. In our case, some other genetic abnormalities were detected by NGS technology in addition to the KIT mutation, including ARID1A, BARD1, MYD88, TET2, KMT2C, POLE and RNF43 mutations, MSI-H and low tumor mutation burden. TET2 mutation is more frequently identified in SM with an associated haematological neoplasm. To the best of our knowledge, this is the first case of ASM reporting these genes abnormality. The relationship between ASM and these genetic abnormalities has not been documented thus far, so a large number of samples are needed to verify the relationship between ASM and these gene abnormalities.
Rapidly, the patient suffered from tumor dissemination, and finally died from respiratory failure almost 2 months after initial presentation. Several parameters have been described to be associated with an unfavorable prognosis in SM, including an absence of skin lesions, huge osteolyses, weight loss, malabsorption, enlarged liver with portal hypertension, and splenomegaly with hypersplenism[18–21]. In the present patient, absence of skin lesions, multiple bone lesions, weight loss, malabsorption and splenomegaly were observed. In a previous literature reported that lymphadenopathic mastocytosis with eosinophilia” was described as a separate, clinically aggressive variant of ASM[22]. There are also other cases of SM presenting with lymphadenopathy and eosinophilia exhibited a less aggressive course [3, 23]. Lymph node involvement with significant lymphadenopathy is extremely rare; when involved, it can mimic malignant lymphoma, creating a diagnostic challenge.