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.

TP53 Staining in Tissue Samples of Chronic Lymphocytic Lymphoma Cases: An Immunohistochemical Survey of 51 Cases

“…For years, researchers believed that the extent of PCs was associated with worse prognosis since PCs are metabolically and mitotically active zones. So far, however, only a limited number of studies showed findings that supported this hypothesis [18], while others usually failed to demonstrate a correlation between the extent of PCs and prognosis [19,20,21]. In our study, we also could not show a significant correlation.…”

High prevalence of adverse prognostic genetic aberrations and unmutated IGHV genes in small lymphocytic lymphoma as compared to chronic lymphocytic leukemia

“…As of yet, only a few molecular-genetic studies in SLL have been reported [21][22][23][24][25], which may be due to the fact that the prevalence of SLL is relatively rare. In addition, lymph node samples from SLL patients are routinely examined in pathology laboratories, instead in immunology/hematology laboratories where testing of CLLassociated molecular-genetic prognostic parameters mostly takes place.…”

“…Our data support the current WHO classification and illustrate that CLL and SLL likely encompass a phenotypic spectrum within one disease entity. Note that lymph node specimens were evaluated by Aoun et al [25], Daudignon et al [23], Garcia et al [24], and the current study. Bone marrow biopsies were evaluated by Tsimberidou et al [22].…”

“…More recently, also multiplex ligation-dependent probe amplification (MLPA [28]) has been used as a comprehensive tool to detect genetic abnormalities in CLL/SLL [29]. Both FISH and MLPA have also been applied to SLL [21][22][23][24][25]. Biased and stereotypic use of heavy chain complementary determining region 3 has been observed in CLL/SLL, particularly for the IGH3-21 and IGH4-34 V-genes, which suggests the occurrence of antigen selection during the course of the disease [30][31][32][33][34].…”

Reassessment of small lymphocytic lymphoma in the era of monoclonal B-cell lymphocytosis

“…The clinical significance of this latter finding is uncertain, as the majority of previous studies did not show a correlation between the extent of proliferation centers and clinical behavior in CLL/SLL. 23,[29][30][31] However, one recent study did suggest that expanded and confluent proliferation centers predict a worse outcome in patients with CLL/SLL. 32 While the proportion of cases with deletion 13q14.3 was relatively lower in our study than in other reports on CLL/SLL and clinical MBL, the proportions of trisomy 12 and deletions of 11q22.3, 17p13.1 and 6q23 were similar.…”