Submitting Author: Wu, Winnie, MD
Institution: UCLA
Additional authors:Sheeja T. Pullarkat
Session: Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1

66 year old male with history of coronary artery disease presented with 6 weeks of fatigue and flu-like symptoms. A CBC was performed, which showed marked leukocytosis with circulating blasts (WBC 34.9 x 10^9/L, Hgb 12.1 g/dl, PLT 199 x 10^9/L).

A bone marrow biopsy was performed.

Biopsy fixation details: Zinc formalin.

Details of microscopic pathology: Peripheral blood smear review showed numerous blasts with a differential count of 30% blasts, 23% neutrophils, 18% bands, 24% lymphocytes, 4% eosinophils, and 1% basophils.

The blasts were large and demonstrated monocytic features, including irregular nuclear contours, moderately dispersed chromatin, variably prominent nucleoli, and abundant light blue occasionally finely granular cytoplasm.

(Figure 1)

No Auer rods were seen. Neutrophils were markedly hypogranular and displayed hyplobation including pseudo Pelger-Huet forms. (Figure 2)

The bone marrow aspirate smears were aparticulate. The bone marrow biopsy-touch preparation revealed 59% blasts similar in morphology to those described in the peripheral smear. The myeloid series displayed dysplasia including hypogranularity and hypolobation. Dysplasia was prominent in the megakaryocytic series, with predominantly small hypolobated forms.

(Figure 3)

The bone marrow trephine biopsy was normocellular (40%) with decreased trilineage hematopoiesis. Sheets of blasts were evident and dysplasia was noted in the myeloid series as described above. The megakaryocytes were small and hypolobated and were seen in clusters. (Figure 4)

Flow cytometric analysis of the bone marrow showed that the blasts constituted 77% of total cells and expressed CD34 (subset), CD117 (subset), CD13, CD15 (subset), CD33, CD11b (subset), CD16 (subset), CD36 (subset), CD71 (dim), HLA-DR (subset), and CD38 (subset), with aberrant expression of CD7. They were negative for all other markers tested including intracellular myeloperoxidase.

Metaphase chromosomal analysis demonstrated the following karyotype: 46,XY,t(4;12)(q12;p13)[8]/46,idem,del(5)(q22q35)[12]

The stemline (20/20) showed a reciprocal translocation between chromosome 4q12 and 12p13, resulting in the fusion of PDGFRα and ETV6. The sideline (12/20) showed an interstitial deletion of 5q. (Figure 5)

FISH analysis of the bone marrow was performed with the standard MDS/AML probes. These studies detected a monoallelic deletion of the 5q31 locus in 91% nuclei examined. In addition, Abbott Molecular-Vysis SCFD2-LNX- PDGFRA tri-color, break-apart probe for the 4q12 region demonstrated PDGFRα rearrangement in 100% of the nuclei (Figure 6a, b), while Abbott Molecular-Vysis ETV6 dual-color, break-apart probe for the 12p13 region demonstrated ETV6 rearrangement in 88% of the nuclei. (Figure 7a, b) This served as a proxy for ETV6-PDGFRα fusions and was consistent translocation (4;12) detected by conventional cytogenetics.

FLT3 negative.

Translocation t(4;12)(q11-q21;p13) is a rare recurrent translocation that results in the fusion of PDGFRα on 4q12 with ETV6 on 12p13. It has been described in acute myeloid leukemia, B-lymphoblastic leukemia, non-Hodgkin lymphoma, and adult T cell leukemia/lymphoma. Some 20 cases of AML with t(4;12)(q11-q21;p13) have been reported, many sharing common characteristics, including:

1) multilineage dysplasia;

2) an immature CD7+/CD34+/CD117+/CD13+/HLA-DR+ immunophenotype suggestive of an early hematopoietic stem cell origin;

3) blasts which morphologically resemble prolymphocytes (pseudo-lymphocytes);

4) absent or low myeloperoxidase; and

5) peripheral blood and marrow basophilia.

Monocytic differentiation, as seen in this case, has been rarely reported. AML with t(4;12)(q11-q21;p13) appear to have a worse clinical outcome. In a review of 15 cases of AML with t(4;12)(q11-q21;p13), complete remission was achieved in 1/3 and overall survival ranged from a few months to 51 months, with median overall survival of 8 months.

Experience with imatinib is limited, but anecdotal evidence suggests refractoriness to tyrosine kinase inhibitors. In the current case, the patient failed induction chemotherapy and imatinib. While he eventually went into morphologic remission, he never achieved cytogenetic remission and succumbed to infectious complications 14 months following allogeneic stem cell transplant.

The entity of myeloid and lymphoid neoplasms with PDGFRα rearrangement is a recently defined category in the WHO. The most common genetic abnormality is the FIPIL1- PDGFRα fusion formed as a result of a cryptic deletion of the CHIC2 gene in 4q12. The FIP1L1-PDGFRα product has been found to be 100-fold more sensitive than BCR-ABL1 to imatinib and even AML’s, in the presence of the FIP1L1-PDGFRα translocation, can achieve sustained complete molecular remission with a tyrosine kinase inhibitor. Several molecular variants with a 4q12 breakpoint can be seen and rearrangement of PDGFRα with ETV6 (12p13), STRN (2p24), CDK5RAP2 (9q33), KIF5B (10p11), and BCR (22q11) are included in the category of myeloid and lymphoid neoplasms with PDGFRα rearrangement according to the current WHO.

The current case is interesting because it raises a couple of issues regarding the classification of neoplasms with PDGFRα rearrangements. According to the current WHO classification, AML’s with t(4;12)(q11-q21;p13) as seen in this case are included in the category of myeloid and lymphoid neoplasms with PDGFRα rearrangements. However, in contrast to the other myeloid and lymphoid neoplasms with PDGFRα rearrangements, which demonstrate no dysplasia, eosinophilia, response to imatinib, and good prognosis, AML’s with t(4;12)(q11-q21;p13) are reported to have multilineage dysplasia, basophilia, distinctive morphology and immunophenotype, poor response to imatinib, and worse prognosis. Hence, there appears to be sufficient histologic and, more importantly, therapeutic and prognostic differences to merit distinguishing these AML’s from the more general category of myeloid and lymphoid neoplasms with PDGFRα rearrangement.

Acute myeloid leukemia with t(4;12)(q12;p13); ETV6-PDGFRA

Case 93