# Uncovering the PML::RARA Fusion in Cytogenetically Cryptic and FISH-Negative Acute Promyelocytic Leukemia—A Case Report and Comprehensive Literature Review

## TL;DR

This paper reports a rare case of acute promyelocytic leukemia where the genetic marker was missed by standard tests but detected later with molecular methods.

## Contribution

The paper highlights the importance of molecular testing in diagnosing rare, cytogenetically cryptic APL cases missed by standard FISH and cytogenetics.

## Key findings

- qRT-PCR confirmed the presence of PML::RARA fusion in a FISH-negative APL case.
- A review of 34 similar cases showed RT-PCR reliably detects cryptic fusions.
- Standard diagnostic methods often miss rare APL cases, emphasizing the need for molecular testing.

## Abstract

The PML::RARA fusion resulting from t(15;17) is the genetic hallmark of acute promyelocytic leukemia (APL), typically detected by cytogenetics and/or fluorescence in situ hybridization (FISH) studies. Rarely, APL patients present with normal cytogenetics and FISH findings, complicating diagnosis and delaying life-saving therapy. We report a 23-year-old male with clinical, morphologic and immunophenotypic features consistent with APL but negative for FISH studies. Despite prompt initiation of all-trans retinoic acid (ATRA) based on clinical suspicion, the patient succumbed to intracranial hemorrhage. Quantitative reverse transcriptase PCR (qRT-PCR) confirmed a long isoform PML::RARA fusion. A review of 34 published cytogenetics- and FISH-negative cases since 1995 demonstrates that RT-PCR-based methods reliably detect cryptic fusions. While advanced genomic approaches may identify these fusions at higher resolution, their accessibility, complexity, cost, and turnaround time often limit diagnostic utility in the urgent setting of APL. Given the extreme rarity of this subset, cytogenetics and FISH remain the standard frontline tests; however, these cases underscore the critical need to incorporate molecular testing into routine workflows. Early recognition and timely therapy are essential to reducing mortality in cryptic APL, and these cases also provide insight into mechanisms of atypical leukemia biology.