Case 9

Submitting Author: Uherova, Patricia, MD
Institution: Esoterix Pathology Practice Group, PC
Additional authors:Ron Thomason, Xiao-Xlang Zhang
Session: AML with recurrent genetic abnormalities Part I

HISTORY

A 55-year-old male with leukopenia and thrombocytopenia. Possible leukemia or aplastic anemia.

DETAILS

Bone marrow biopsy and aspiration (R iliac); core fixed in formalin:

Aspirate smears reveal that the vast majority of myeloid cells are atypical promyelocytes. These cells exhibit irregularly contoured nuclei with fine chromatin and prominent nucleoli. They exhibit abundant granular cytoplasm. Occasional Auer rods are noted. The atypical promyelocytes account for ~80% of the nucleated cells on these preparations.

The core biopsy sections reveal a core of cortical bone and a small amount of subcortical bone and bone marrow tissue. The small marrow sample exhibits an average cellularity of ~60-70%. Normal myelopoiesis is markedly diminished within this sample. There is a prominent infiltrate of atypical immature mononuclear myeloid cells consistent with atypical promyelocytes. This infiltrate occupies ~75% of the sampled marrow space.

IMMUNOHISTOCHEMISTRY AND FLOW CYTOMETRY

Immunohistochemical Studies:

CD34 This stain highlights a few CD34+ blasts within the core biopsy sample. These cells account for <3% of the nucleated cells. The atypical cells do not express this marker.

CD61 (GPIIIA) This stain highlights megakaryocytes within the core biopsy sample. Unremarkable megakaryocytes are observed within focal areas of marrow exhibiting trilineage hematopoiesis. They are decreased within areas occupied by the infiltrate.

Myeloperoxidase (MPX) The infiltrating cells within the core biopsy sample strongly express this marker.

Flow cytometry shows abnormal immature myeloid cells (89%) with the following immunophenotype: CD45+, CD13+, CD33+, CD34-, CD117+, HLA-DR-, CD11b-, CD11c-, CD14-, CD64+, CD10-, CD19-, CD20-, CD2-, CD4-, CD5-, CD7-, CD8-, CD38+, CD56-, cCD3-, cCD79a-, CD41-, CD62-, CD71+/-, GlyA-,

MPO+, TdT-.

CYTOGENETIC FINDINGS

Cytogenetic study: Normal Male Karyotype 46,XY[20]

MOLECULAR FINDINGS

FISH study: No evidence of a PML/RARA translocation detected by FISH analysis

Molecular study (RT-PCR): Positive for PML-RARA (bcr1) transcript (19%)

INTERESTING FEATURES

This case is an example of rare APL lacking t(15;17) on routine cytogenetic study. 4% of these cases represent cryptic/masked APL with submicroscopic insertion of RARA into PML leading to the expression of PML-RARA transcript. FISH is often not sensitive enough to detect small cryptic insertions.

PROPOSED DIAGNOSIS

Acute promyelocytic leukemia (APL) (positive quantitative molecular assay for PML bcr1 RARA transcripts)

Comments: The morphologic and flow cytometric findings are indicative of acute myeloid leukemia consistent with APL. Notably, a FISH assay for PML/RARA is negative and the cytogenetic assay reveals a normal karyotype. However, a quantitative molecular assay for PML/RARA is positive and confirms the diagnosis of APL with PML/RARA.

CONSENSUS DIAGNOSIS

Acute promyelocytic leukemia with cryptic t(15;17)(q22;q12); PML-RARA