Institution: Clarient Pathology Services, Inc.
Additional authors:Dennis P. O'Malley, M.D., Michele Hibbard, Ph.D.
Session: AML with myelodysplasia-related changes
HISTORY
67-year-old male with a past medical history of coronary artery disease presents to the emergency room with chest pain. Hemogram: hemoglobin 8.3 g/dL, white blood cells 14.06 k/mm3, platelets 953 k/mm3, mean corpuscular volume 98.9fL, red cell distribution width 22.4%
DETAILS
Bone marrow aspirate; core biopsy and clot section (formalin)
The bone marrow aspirate shows a myeloid: erythroid ratio of 4:1. Myelopoiesis is left-shifted with increased blasts (9%) and a full spectrum of maturation. The erythroid precursors show mild-moderate megaloblastic changes. Megakaryocytes are increased with some megakaryoblasts present.The bone marrow core biopsy is hypercellular (80%), with left-shifted myelopoiesis and markedly increased megakaryopoiesis, including large forms with hyperchromatic nuclei as well as occasional hypolobate nuclei.IMMUNOHISTOCHEMISTRY AND FLOW CYTOMETRY
Flow cytometry shows left-shifted myeloid maturation with about 8% blasts lacking phenotypic aberrancies. Immunohistochemical staining highlights about 5% blasts by CD34, CD117 highlights approximately 20% immature myeloid cells, and CD42b marks increased abnormal megakaryocytes and some megakaryoblasts. The iron stain shows 10% ring sideroblasts and the reticulin stain shows focal moderate fibrosis.
CYTOGENETIC FINDINGS
Conventional cytogenetic analysis shows an interstitial deletion of the long arm of chromosome 5 in all metaphases analyzed: 46,XY,del(5)(q13q33)[20].
Fluorescence in-situ hybridization shows 85.5% of unsorted cells with a 5q33-q34 deletion: nuc ish (CSF1Rx1,D5S23,D5S721x2)[171].FISH is negative for deletions of 7q and 20q, trisomy 8 and the BCR/ABL1 rearrangement.MOLECULAR FINDINGS
A JAK2 V617F mutation is detected by allele-specific polymerase chain reaction.
INTERESTING FEATURES
Our case shows molecular hallmarks and multiple morphologic features of both a myeloproliferative neoplasm (MPN) and myelodysplastic syndrome (MDS). While an isolated 5q abnormality in MDS is associated with low-grade disease and a predictable morphologic phenotype, the myeloproliferative neoplasms associated with a JAK2V617 mutation have a heterogeneous clinical and morphologic presentation, thus in the setting of anemia and dysplasia, the presence of proliferative features should prompt additional investigation for molecular abnormalities that may offer additional therapeutic targets. There are reports of successful lenalidomide treatment for patients with concomittant 5q deletion and JAK2 V617F mutation, thus the addition of a JAK1/JAK2 inhibitor may provide additional therapeutic benefit. Due to cost, our patient has elected to undergo treatment with darbepoetin alfa rather than lenalidomide and has experienced only a slight reduction in platelet count and white blood cells. A comparative genomic hybridization array is pending.
Additional Comments: Included in the MDS/MPN category is the provisional entity ‘refractory anemia with ring sideroblasts associated with marked thrombocytosis’ (RARS-T). Approximately 60% of these reported cases harbor the JAK2 V617F mutation and a small percentage of cases have an MPL mutation. JAK2 V617 positive cases of RARS-T, both with and without 5q deletion, show favorable response to lenalidomide and also may benefit from JAK1/JAK2 inhibitors. Successful dual-therapy of these types of cases might support the establishment of a 5q deletion/ JAK2 V617F positive category within the broader MDS/MPN family.PROPOSED DIAGNOSIS
Myelodysplastic/myeloproliferative neoplasm with del 5q and JAK2 V617F mutation
CONSENSUS DIAGNOSIS
Myelodysplastic syndrome with isolated del(5q) and mutated JAK2 (WHO)
| Bone marrow aspirate: left-shifted myelopoiesis with increased blasts including occasional megakaryoblasts |  |
| Hypercellular bone marrow core biopsy with increased megakaryopoiesis. Some megakaryocytes are large with hyperchromatic nuclei as well as occasional hypolobated nuclei |  |
| Representative karyogram at a 400 G-band resolution depicting an interstitial deletion of the long (q) arm of chromosome 5 |  |
| In a normal cell (upper left diagram), the expected FISH signal pattern is two orange probes (CSF1R) and two green probes (D5S23/D5S721). In a hybridized abnormal cell containing the 5q33-q34 deletion (upper right and below), the one orange, two green signal pattern is observed |  |
| Patient (pictured) and control DNA were amplified by real-time PCR using a single primer set and two fluorogenically-labeled probes specific for the wild-type and V617F mutation on the JAK2 gene. Determination of allele genotype was made by examining the resulting amplification plot and corresponding CT value produced for each sample |  |