Beyond the Surface: Uncovering the PML::RARA Fusion in Cytogenetically Cryptic and FISH-Negative Acute Promyelocytic Leukemia- A Case Report and Review of the Literature

Abstract Introduction/Objective Chromosomal t(15;17)(q22;q21), resulting in a fusion between the PML gene on chromosome 15q22 and the RARA gene on chromosome 17q21, is the cytogenetic hallmark of acute promyelocytic leukemia (APL). Conventional karyotyping, along with fluorescence in situ hybridization (FISH), can detect the PML/RARA rearrangements in up to 98% of APL cases. Reverse transcriptase-polymerase chain reaction (RT-PCR) is often used to confirm the initial diagnosis. APL with PML::RARA fusion, which is negative with FISH and conventional karyotyping approaches but positive with RT-PCR, is extremely rare. Herein, we report a de novo APL case that was positive by RT-PCR but negative by cytogenetics and FISH studies. A comprehensive review of the literature was also performed. Methods/Case Report A 23-year-old male presented to the ED for left upper extremity weakness 2 days after post- dental cleaning. Upon admission, he developed intracranial hemorrhage, necessitating urgent decompressive hemicraniectomy. Blood smear revealed promyelocytes; flow cytometric analysis showed a CD13+, CD33+, MPO+, CD117+, CD34-, and HLA-DR- abnormal cell population. STAT interphase FISH analyses for PML/RARA fusion and RARA break-apart were negative. A diagnosis of APL was made based on abnormal promyelocytes and characteristic flow cytometry findings. ATRA was immediately administrated. However, the post-operative course was complicated by significant coagulopathy, pancytopenia, and multi-organ failure, and the patient expired 7 days later. RT-PCR returned positive for PML::RARA long fusion transcript; the conventional cytogenetics study was uninformative. The clinical, pathological, and genetic features of 31 cases of FISH/Cytogenetics-negative APL harboring cryptic rearrangements of PML-RARA, detected by RT-PCR in the literature, have been reviewed. Various detection methods were also discussed. Results (if a Case Study enter NA) N/A Conclusion Conventional cytogenetics, FISH and RT-PCR analysis are complementary studies for all clinical suspected APL cases. The clinicopathological characteristics also play critical roles in APL diagnosis when genetic confirmation of the PML::RARA fusion is unavailable.