title: Most morphologic features in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) do not reliably predict underlying FISH genetics or immunoglobulin heavy chain variable region somatic mutational status.
abstract: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is common in the Western world. Genetic abnormalities detected by fluorescence in situ hybridization (FISH) and immunoglobulin heavy chain variable gene region (IGHV) mutational status are well-known independent prognostic indicators in CLL/SLL. Given the requirement for specialized testing to detect such aberrations, we investigated whether morphologic features may predict the presence of a more or less favorable genetic profile. Forty-one SLL cases were morphologically evaluated for expanded proliferation centers, increased large cells outside of proliferation centers, and nuclear contour irregularities (NCI) in small and large tumor cells. ZAP-70 immunohistochemistry and FISH (deletions of 13q14, p53 and ATM and trisomy 12) were successful in all cases. IGHV mutational status was determined in 26/41 cases. Significant NCI in both small and large cells correlated with the presence of an unfavorable FISH abnormality (ie, ATM or p53 deletions). However, despite good specificity (94%), the sensitivity (57%) of this finding is inadequate for routine use. No other significant associations with morphologic features were identified. Strong ZAP-70 positivity correlated with unmutated IGHV (P=0.001), rendering ZAP-70 IHC a useful surrogate for IGHV mutational status. ZAP-70 positivity predicted against finding a favorable FISH deletion 13q14 (P=0.023). Although we only studied 41 cases, we corroborated their validity using Kaplan-Meier overall survival analysis. In conclusion, morphologic features in SLL are not a reliable predictor of underlying genetic status. Thus, we propose a practical, cost-effective approach to the work-up of these cases, which should be driven by clinical necessity.
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Christine F
authors.initials: CF
authors.lastname: Garcia
authors.forename: Kristin E
authors.initials: KE
authors.lastname: Hunt
authors.forename: Huining
authors.initials: H
authors.lastname: Kang
authors.forename: Amy
authors.initials: A
authors.lastname: Babb
authors.forename: James M
authors.initials: JM
authors.lastname: Gale
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Vasef
authors.forename: Kaaren K
authors.initials: KK
authors.lastname: Reichard
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D048429:Cell Size; D002869:Chromosome Aberrations; D003584:Cytological Techniques; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D011237:Predictive Value of Tests; D011379:Prognosis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C529133:IGH-CCND1 fusion protein, human; D015514:Oncogene Proteins, Fusion; D016159:Tumor Suppressor Protein p53; D051746:ZAP-70 Protein-Tyrosine Kinase