Fanconi anemia presenting as an “evolving” acute leukemia-diagnostic challenges
A 14-year-old male patient presented with the complaints of generalized weakness and off and on high grade fever for 6 months. On examination, he was well-looking, afebrile and had pallor without any evidence of mucocutaneous bleeding. There was no lymphadenopathy or organomegaly. His complete blood counts (CBC) showed a hemoglobin (Hb) of 8.7 g/dl, total leucocyte count (TLC) of 1.5 × 109/L and a platelet count of 38 × 109/L. Red cell indices showed hematocrit of 25.2 %, mean corpuscular volume of 102.5 fl, mean corpuscular Hb of 35.3 pg and mean corpuscular Hb concentration of 34.4 g/dl. A clinical diagnosis of aplastic anemia (AA) was made and bone marrow examination was carried out. The marrow aspirate smears were hemodilute and pauci-particulate with very few marrow cell trails showing presence of blast cells, mature monocytes and cells with promonocytoid features (~10%, ~13% and ~4% of the evaluable marrow cells, respectively) []. Erythroid cells showed megaloblastic erythropoiesis with dyserythropoiesis. There was a prominence of macrophages with hemophagocytosis. The blast cells were negative for myeloperoxidase (MPO) cytochemical staining. Bone marrow trephine biopsy was suboptimal and insufficient for opinion. In view of the hemodilution and lack of appreciable dyshemopoietic features, a diagnosis of an “evolving” MPO negative acute leukemia was given and flowcytometric immunophenotyping (FCIM) was suggested for further evaluation. Meanwhile, the clinical course of patient was apparently uneventful except for an acute onset submandibular swelling that subsided with antibiotic therapy. His subsequent CBC at next presentation after 2 weeks showed persistent pancytopenia with Hb of 10.2 g/dl, TLC of 2.3 × 109/L and 21 × 109/L platelets. At this time, his marrow aspirate smears showed hypocellular marrow cell trails with myelogram comprising 18% blasts, 10% promonocytes, 04% monocytes, 10% polymorphs, 01% metamyelocytes, 03% eosinophils, 42% lymphocytes, 04% plasma cells and 08% erythroid precursor cells []. A diagnosis of hypocellular marrow with AML was made. The conventional cytogenetics revealed a normal karyotype []. At subsequent presentation, the patient was apparently maintained except for worsening anemia and thrombocytopenia. There was no bleeding and his clinical examination did not reveal any new findings. His peripheral blood was sent for the stress cytogenetics and human leukocyte antigen (HLA) typing. However, after 3 months from initial presentation, he came with high grade fever and bone pains and finally consented for admission. His CBC showed 6.6 g/dl Hb, 0.8 × 109/L leucocytes and 3 × 109/L platelets. Bone marrow aspirate revealed hypocellular particles with ~68% blasts and promonocytes. ~3% blast cells showed MPO positivity. The 6-color FCIM (FACS Canto II, BD Biosciences) on bone marrow revealed significant replacement by a prominent cell population (red) with variable CD45 expression. This abnormal cluster spanned from the blast region into the monocyte position with bulk of the neoplastic cells falling into the medium cell size range []. A small number of lymphocytes (blue), few residual myeloid precursors (purple) as well as maturing monocytic elements (green) were also present. The leukemic cells comprised ~45% of the cells in the sample and showed homogeneously bright expression of CD33, variable expression of CD13, CD34 and displayed a complex pattern of CD14/CD64 co-expression, indicating monocytic maturation [Figure and ]. These blast cells also showed heterogeneous expression of CD11b, CD15, CD4 and bright HLA DR []. The maturing monocytic elements (comprising ~3% of cells in the sample) showed normal expression of brighter CD33, CD16, CD13, HLA DR and CD11b. Based on the shape of the abnormal cell cluster on Side Scatter/CD45 dot-plot and immunophenotypic findings including pattern of CD14/CD64 co-expression, diagnosis of AML with monocytic differentiation was made. Stress cytogenetics [] showed 88% chromosome breaks and rearrangements in patient's peripheral lymphocytes with mitomycin C (MMC) []. The diagnosis of FA was thus established. Patient consequently received packed red cell and platelet support and was started on a low dose cytosine arabinoside 100 mg/M2/daily (adverse drug event induction therapy). Subsequently, he developed typhlitis and was conservatively managed until he left the hospital care against medical advice.