Patient case: 50-year-old male with prostate cancer; genetic feature: ATM deletion

Clinical trial: Comparison Between Fluorescent in Situ Hybridization Panels and Karyotyping in Hematological Neoplasms

Summary: Conventional cytogenetic studies have been the gold standard for more than five decades for detecting genetic alterations that are greater than 10 Mb (mega base pairs) in size (Peterson et al. 2015). Conventional cytogenetic studies have paved the way in identifying specific chromosomal aberrations associated with clinically and morphologically definitive subsets of hematological neoplasms (Sreekantaiah 2007).
  Fluorescence in situ hybridization (FISH) has become a reliable and rapid complementary test in targeting critical genetic events associated with diagnostics and prognosis in hematological neoplasms (Sreekantaiah 2007).
  With the lack of an evidence-based standardized algorithmic approach, misuse and overutilization of laboratory tests are common and result in increased health care costs and patient care complexity. In the current health care environment, which increasingly focuses on value and efficiency, it is critical for pathologists and clinicians to effectively navigate this environment and judiciously incorporate these high-complexity and expensive techniques into routine patient care. Going forward, cost-effective integration and appropriate test utilization will be a top priority across all medical disciplines. While conventional karyotyping provides a comprehensive view of the genome, FISH can detect cryptic or submicro¬scopic genetic abnormalities and identify recurrent genetic abnormalities in nondividing cells. As a consequence, it is commonly extrapolated that FISH will improve the sensitivity of detecting all genetic abnormalities compared with conventional karyotyping analysis. This assumption has then been translated in clinical practice to having clinicians and pathologists routinely ordering both conventional karyotyp¬ing and FISH studies in patients with hematological neoplasms. Depending on how comprehensive the FISH panel is, the cost for this test¬ing may be quite expensive, and its additive value remains questionable (He et al. 2015).
  It is common practice for laboratories to use FISH panels in conjunction with karyotyping both in diagnostic specimens and during follow-up to monitor response to therapy (Wheeler et al. 2018).

Detailed description: Neoplastic hematology is at the forefront of personalized medicine. The World Health Organization (WHO) classification incorporates genetic data with morphologic, immunophenotypic, and clinical features and categorizes hematologic neoplasms into clinically and biologically distinct entities. This system dictates diagnosis and prognosis and guides therapeutic choices, which has become increasingly important with emerging targeted therapies for lymphoma and leukemia. However, laboratory tests for hematologic neoplasms are of high complexity and are generally quite costly (He et al. 2015).
  The initial assessment of many hematologic neoplasms typically includes morphological, histological, immunophenotypic (flow cytometric and/or immunohistochemical), and conventional cytogenetic studies. Data obtained from cytogenetic analysis can be pathognomonic for specific leukemias in the WHO classification (for example, acute myeloid leukemia (AML) with recurrent cytogenetic abnormalities and chronic myelogenous leukemia (CML)) and are likely to assume an even greater role in defining specific entities in future classifications (Wolff et al. 2007).
  It is common practice for laboratories to use FISH panels in conjunction with karyotyping both in diagnostic specimens and during follow-up to monitor response to therapy. FISH is targeted toward specific abnormalities, and results can be evaluated in an automated fashion on interphase nuclei, allowing for examination of more cells than a traditional karyotype. FISH has higher analytic and, in certain circumstances, higher clinical sensitivity compared with karyotype (Wheeler et al. 2018).
  Recent comparative studies in myelodysplastic syndrome (MDS) have showed that FISH panel does not add value to conventional cytogenetic studies findings (He et al. 2016), while a similar study contradicted that both modalities are equally important in prognostication of MDS (Kokate et al. 2017). On the other hand, FISH analysis in lymphoid malignancies have resulted in the expansion and identification of distinct subsets of the disease (Sreekantaiah 2007). Another study also showed that FISH panels showed significantly higher sensitivity in revealing chromosomal abnormalities than that in conventional cytogenetic studies in chronic lymphocytic leukemia (CLL) and multiple myeloma patients while it did not in MDS patients. However, it can increase the detection rate of aberration clones in MDS cases with normal karyotypes or without enough karyotypes to be analysed (Qin et al. 2016). Therefore, the usage of FISH panels in aiding diagnosis or in monitoring follow-up samples of hematologic neoplasms is critical (Ashok et al. 2017).
  The Eastern Collaborative Oncology Group (ECOG) compared conventional cytogenetic studies and FISH in AML patients and found that a probe panel to detect monosomy 5/deletion 5q, monosomy 7/deletion 7q, trisomy 8, t(8;21), t(9;22), MLL rearrangements with various partners, t(15;17), and inv(16)/t(16;16), had a concordance between 98% and 100% (Vance et al. 2007). On the other hand, He et al study demonstrates the limited value of FISH testing in adult AML in the setting of an adequate karyotyping study.
  In spite of many significant technological advances made in recent years in the area of clinical genetic testing, conventional cytogenetic studies and routine FISH studies remain important laboratory testing tools available for evaluating hematologic malignancies. Usually these two testing approaches complement each other and often FISH serves to clarify and better define cytogenetic results. Therefore, there is a very strong expectation that cytogenetic and FISH results should confirm each other in spite of cases that appear to be exceptions. When inconsistent results occur, a suspicion arises that there has been a specimen mix-up and these results are not to be trusted. This can be a source of great confusion even after a confirmatory internal investigation. When conflicting results do occur by these two testing methods on the same specimen, clinical laboratories are challenged to offer explanations based on empirical data beyond simply stating that it was or was not due to laboratory error (Cantu et al. 2018).

Eligibility: Inclusion Criteria:
  -  Adult and pediatric patients with newly diagnosed hematological neoplasms:
  -  Acute Myeloid Leukemia (AML).
  -  Chronic Myeloid Leukemia (CML).
  Exclusion Criteria:
  -  N.A.

Relevance to patient case: not relevant