A 18 year-old male has a history of constant non-productive cough, low grade fever, decreased appetite, swollen face and 10 Lb weight loss for 2-3 months after long trip to India. Antibiotics and prednisone therapy improved his symptom, however his symptoms returned after finishing the steroid course. He visited urgent care facility. Chest X-ray and CT scan showed a large mediastinal mass causing a mass effect and a solid nodule in right lower lobe, and no lymphadenopathy or organomegaly.
Initial complete blood counts showed WBC 7.0 x 109/L, Hb 12.9 g/dl, MCV 82.9 fL, RDW 15.1%, and platelet 90 x 109/L. Peripheral blood (PB) smear reported no circulating blasts or atypical cells. Coagulation tests showed normal PT and APTT. Chemistry tests showed abnormal results in serum LDH 913 (normal 135-225 U/L), C-reactive protein 74.5 (normal <0.9 mg/dL), AFP 3805 (normal <11 ng/mL), and beta HCG 731 (normal 0-3 IU/L). Virus tests for hepatitis A, B and C, human immunodeficiency viruses, Epstein-Barr virus and Mycobacterium tuberculosis were negative.
Needle core biopsy of the mass and bone marrow (BM) biopsy were performed. Needle core biopsy demonstrated necrosis and viable tissue with myxoid background and atypical cells with eccentric nuclei and dense eosinophilic cytoplasm, which are positive for SALL-4 (focal), myogenin and desmin by immunohistochemistry. The diagnosis of the mediastinal mass was germ cell tumor with rhabdomyoblastic differentiation. BM aspiration and biopsy with immunohistochemistry are showed in Figures 1-3.
BM aspiration (Figure 1; Wright stain X500) showed immature cells/blasts with large size, high nuclear to cytoplasmic ratio, irregular or lobulated nuclei, basophilic cytoplasm with occasional cytoplasmic blebs, reticular chromatin and prominent nucleoli.
BM core biopsy (Figure 2; H&E x400) showed 80-90% cellularity, trilineage hematopoiesis and left-shift in maturation with large immature cells/blasts with a similar morphology seen in the aspirate smears.
Immunohistochemistry (Figure 3) on the BM core biopsy showed these cells are positive for dim CD117 and CD61, and negative for CD3, CD10, CD15, CD20, CD30, CD34 (positive for 1-2% blasts), CD99, PAX5, MPO, TdT, AFP, PLAP and HCG.
Flow cytometry on this BM specimen reported 22% immature cells/blasts by dim CD45 and high forward scatter, which are positive for CD36, CD38, CD117, CD56, CD40, CD41, CD42a, CD42b and CD61, and are negative for MPO, cytoplasmic CD3, TdT, and other myeloid and lymphoid markers.
Conventional cytogenetics showed a complex karyotype with hyperdiploidy and no recurrent cytogenetic abnormality: 90-91,XY,-X,-Y,+1,+1,-2,-3,+6,+7,-9,-11,-12,-13,-13,+14,-18,+19,+21,+21,+22,+1-2mar/46,XY.
Clinical Followup and Prognosis:
After diagnosis of acute megakaryoblastic leukemia and concomitant germ cell tumor, the patient is receiving chemotherapy.
Acute megakaryoblastic leukemia (AMegL) comprised approximately 1% of acute myeloid leukemia (AML) in adult, and occurs with proliferation of abnormal megakaryoblasts. Diagnosis of AMegL requires >=20% blasts, of which >= 50% are of megakaryocyte lineage. The AMegL cannot be diagnosed in AML cases with recurrent genetic abnormalities, AML with myelodysplasia-related changes or therapy-related AML. The patients typically present with cytopenias and extramedullary manifestation. However, the patient sometimes have thrombocytosis. The bone marrow shows increased blasts of megakaryocytic lineage with various stages of maturation and often extensive fibrosis, which can cause dry taps and make difficult to make correct diagnosis.
Immunohistochemistry and flow cytometry have significantly improved an accurate diagnosis of this disease. Megakaryoblasts express one or more platelet glycoproteins: CD41, CD42b and CD61. Myeloid markers CD13 and CD33 may be positive. However, CD34, HLADR, MPO, TdT, and lymphoid markers are negative. AMegL patients have often highly complexed abnormal karyotype, but there are no specific cytogenetic abnormalities associated with AMegL.
AMegL has unusual association with mediastinal germ cell tumors (MGCT) in young adult males. AMegL occurs concomitantly in 30% of MGCT patients or shortly after diagnosis of MGCT in 46% (median 5 months). Approximately 5.9% of MGCT patients develop AML, most commonly AMegL. The leukemic cells in MGCT are suggested to originate from the vascular structures of the mesenchyme-like component. Among MGCT, embryonal carcinoma with significantly elevated serum AFP are most common. AMegL and MGCT patients share common cytogenetic abnormalities including isochromosome (12p) (38%), trisomy 8 (16%) and Klinefelter syndrome (XXY; 14%), and harbor TP53 and TPEN mutations.
AMegL is the most common AML in children with Down syndrome. 5-10% of Down syndrome infant experience transient abnormal myelopoiesis, which is self-limiting and abnormal myeloproliferation, and resolves within 3-4 months of birth. Trisomy 21 and GATA1 mutation are considered pathognomonic in this disease. 20-30% of Down syndrome children with transient abnormal myelopoiesis will develop AMegL.
Differential diagnosis includes AML with myelodysplasia-related changes, AML with panmyelosis with myelofibrosis, lymphoblastic leukemia, pure erythroid leukemia, blast crisis from chronic myeloid leukemia or myeloproliferative neoplasms, and metastatic tumors. Prognosis of AMegL is poorer than other type of AMLs with median overall survival of 4-10 months. However, AMegL in children with Down syndrome has a favorable prognosis with a better response to chemotherapy.
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