Myelomonocytic leukemia with intracytoplasmic crystalline inclusions, double minute chromosomes and MYC amplification

Excerpt

The patient is an 83-year-old man with a history of coronary artery disease status post two bypass surgeries. Shortly after admission, he was found to have severe anemia requiring blood transfusions. The patient also noted easy bruising. A CBC revealed a hemoglobin of 8.6 g/dL, a platelet count of 12 × 10³/μL and a white blood cell count of 7.0 × 10³/μL with an absolute monocytosis (1.5 × 10³/μL). Bone marrow biopsy showed a myelomonocytic neoplasm with increased blasts. Precise enumeration of blasts, immature myeloid precursors and immature monocytes was difficult due to the presence of marked dysgranulopoiesis (Fig. 1, top panel). Immature myeloid cells contained peculiar rectangular-shaped salmon-pink inclusions (Fig. 1, top panel). Conventional cytogenetic analysis demonstrated a simple karyotype with 3–24 copies of double minutes composed of amplified MYC verified by interphase FISH (Fig. 1, bottom panel). A next-generation sequencing panel revealed mutations in DNMT3A, NRAS, TET2, U2AF1, and WT1. Double minutes are small chromatin particles that lack a centromere and represent a form of extrachromosomal gene amplification. They are occasionally seen in hematologic malignancies and are frequently associated with MYC amplification. Presence of double minutes has been reported predominantly in AML, followed by MDS, and, rarely, CMML. In this patient, the sudden clinical presentation, presence of double minutes, and the molecular genetic profile favor AML with monocytic differentiation over CMML. Similar intracytoplasmic crystalline inclusions have been reported in two patients with AML-M4, one patient with CMML [1], and two acute promyelocytic leukemia patients with variant RARA translocations: t(X;17)(p11;q12); BCOR-RARA [2] and t(11;17)(q23;q21); ZBTB16-RARA [3]. Of note, immunoglobulin-containing intracytoplasmic crystals in lymphocytes of patients with chronic lymphocytic leukemia may have a virtually identical morphologic appearance [4]. The most recently reported case of CMML also showed evidence of double minutes with MYC amplification. The treatment outcome was poor, including in the patient reported here, who did not respond to DNA methyltransferase inhibitor and was put on comfort care 6 months after diagnosis. Thus, presence of intracytoplasmic crystalline inclusions in myeloid cells may be a feature of aggressive myelomonocytic neoplasms with double minutes composed of amplified MYC.

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