A 39-year-old male, with a past medical history of treated tuberculosis, presented to the emergency department complaining of fever, generalized weakness, vague abdominal pain, vomiting, headache, and generalized body aches of two-week duration with a history of nasal bleeding of moderate severity. Upon examination, there was submandibular lymphadenopathy (2 x 1 cm) and palpable liver (7 cm below the costal margin) and no gastrointestinal manifestations and skin lesions.
Laboratory workup revealed high urea level at 18.84 mmol/L (3.2-7.4), serum creatinine at 141 mumol/l (64-110), lipase at 182 U/L (8-78), myoglobin at 108 ng/ml (1-78), and normal liver function tests.
Further investigations revealed very high ferritin level >40000 mcg/L (24-336), low serum B12 level (<111 pmol/L), normal fibrinogen level at 4.77 gm/L (1.8-3.5), and normal triglyceride level at 0.6 mmol/L (normal: <1.7 mmol/L). Viral serology for hepatitis B and C and HIV was negative.
His complete blood count showed pancytopenia, with hemoglobin of 6.4 gm/dL (13.0-17.0), total white blood count (WBC) of 1.7 x 103/mul (4.0-10.0), absolute neutrophil count (ANC) 0.9 x 103/mul, and platelet count of 2 x 103/mul (150-400). BM failure was suspected, and the patient was admitted for further workup.
Sepsis workup was requested, and the patient was started on antimicrobials and vitamin B12 replacement.
Computerized tomography (CT) scan of the head showed bilateral subdural haemorrhage with no midline shift, and the patient was managed conservatively with transfusion support. Whole body CT scan showed bilateral pleural effusion, extensive pulmonary consolidation, thrombosis of the celiac artery and its branches with splenic infarction, mild hepatomegaly, and massive splenomegaly. The spleen showed poor heterogeneous enhancement suggestive of infarction.
First, peripheral blood smear (PS) was inconclusive as it showed very few circulating atypical cells. Subsequent PS (Figure 1) showed marked leukopenia with some circulating abnormal blastoid cells (13%) of medium size with fine nuclear chromatin and unevenly distributed deeply basophilic/metachromatic coarse granules. Few blasts showed nuclear bilobation.
Bone marrow (BM) aspirate was infiltrated with numerous atypical and immature MCs of blast-like morphology (26%) showing fine nuclear chromatin and few prominent nucleoli. The majority of blasts showed eccentric nuclei with abundant cytoplasm and coarse giant metachromatic/basophilic granules (metachromatic blasts) (Figure 2(a)). Few blasts were agranular with high nucleocytoplasmic ratio and few were spindle-shaped. The majority of neoplastic MCs exhibited marked atypia and pronounced pleomorphism (Figures 2(b) and 2(c)) of (Type I) (Figure 2(b), A-I) with eccentric round/oval nuclei, uneven granules distribution/hypogranulation, and spindle-shaped mast cells with elongated cytoplasmic projections. Neoplastic MCs Type II (promastocytes) (Figure 2(c), A-H), with indented, bilobed nuclei and abundant degranulated/hypogranulated cytoplasm or with coalescent granules and uneven distribution were frequent.
There was trilineage dysplasia with prominent megaloblastic changes mostly in the form of giant granulocytes, megakaryocytes with multilobulation, and some megaloblastic erythroid precursors (composite, Figure 2(d)) with some mitotic figures noted (Figure 2(e)). There was an evident hemophagocytic activity (predominantly erythrophagocytosis) exhibited by histiocytes and neoplastic mast cells (Figure 2(f)).
On H&E, BM biopsy was markedly hypercellular, largely replaced by sheets of neoplastic mast cells showing abundant clear cytoplasm with round/indented nuclei (including many forms with immature nuclear chromatin), and admixed with a reactive background composed of fibroblasts, eosinophils, small lymphocytes, and polyclonal plasma cells (Figure 3(a) and 3(b)). There was a mild increase in reticulin fibres (MF 0-1). By immunohistochemistry (IHC)(Figure 3), the neoplastic MCs were positive for CD45, CD117, mast cell tryptase, CD25, CD43, CD4, and partially positive for CD30 and CD7 while negative for CD2. Histiocytes/macrophages were prominent with evident hemophagocytic activity. Toluidine blue and Giemsa stain highlighted the metachromatic granules of the more differentiated MCs while the majority was negative. Megakaryocytes appeared focally increased with some small hypolobated forms and some degree of morphologic atypia. Serum tryptase level revealed very a high level at 434.00 mcg/L (negative < 11 mcg/L).
Flow cytometry on BM (Figure 4) showed an abnormal population of cells in the blast gate comprising 25%, expressing CD45 (moderate), CD117 (bright), CD33, and HLA-DR with partial aberrant CD25 expression. The neoplastic cells showed aberrant expression of CD4, aberrant partial expression of CD7, and partial expression of CD36. In addition, the analysis showed a small population of cells (~4%) with low side and forward light scatter expressing CD33 and CD4 with a minor subpopulation expressing CD117, CD64, and CD14, possibly representing dysplastic myeloid/hypogranular mast cells. The neoplastic mast cells are negative for cMPO, CD64, CD14, CD19, CD20, cCD3, sCD3, CD5, CD2, CD11c, and CD11b.
Cytogenetic studies showed an abnormal karyotype with isolated trisomy 19 (47, XY, +19[13]).
Molecular analysis of blood confirmed a KIT D816V mutation with negative BCR/ABL-1, consistent with a diagnosis of systemic mastocytosis, mast cell leukaemia.
The patient developed acute kidney injury with progressive deterioration in renal function (serum creatinine at 245 mumol/L) and disseminated intravascular coagulopathy (DIC). Echocardiography showed severe pulmonary hypertension with normal systolic left ventricular function (ejection fraction of 60%).
On the 3rd day after hospitalization, he developed respiratory distress and was started on noninvasive pressure ventilation (NIPV), diuretics, and broad-spectrum antibacterial, antifungal therapy with steroid along with supportive measures after bone marrow results.
The patient developed septic shock with multiorgan failure, so he underwent hemodialysis and was started on prednisone but unfortunately developed cardiac arrest (asystole) and died two weeks after admission.