FMC-7 Expression Identifies Phenotypically Atypical Chronic Lymphocytic Leukemia with Distinct Clinical and Molecular Genetic Features.

Flow cytometric immunophenotyping is critical for accurate diagnosis of CD5-positive chronic lymphocytic leukemia (CLL). CLL is classically positive for CD23 and negative for FMC-7, which are useful markers for distinguishing it from CD5-positive mantle cell lymphoma (MCL). However, a subset of CLLs express FMC-7 and rare cases additionally lack CD23, exhibiting a classic MCL phenotype. While CLL generally has an indolent clinical course, the disease is heterogeneous in clinical behavior and several molecular genetic markers are identified that predict poor prognostic subgroups. Prior studies have shown CLL with atypical phenotypic and morphologic features to be associated with trisomy 12. In this retrospective study, we analyzed a large cohort of consecutive CLL cases to determine if expression of FMC-7 identifies a subset of CLL that differs clinically and genetically from typical CLL.

1848 cases of CLL with complete cytogenetics/FISH and IgVH studies were retrieved from our database over a 2-year period. These cases were divided into three groups based on their imunophenotypes: Group I (1562 cases) with a typical CLL phenotype (CD23+/FMC7-); Group II (238 cases) with co-expression of CD23 and FMC7; and Group III (48 cases) with a mantle-like phenotype (CD23-/FMC7+). Other clinicopathologic parameters obtained for those cases included age, gender, CBC, bone marrow (BM) tumor burden, Zap-70, CD38 and surface light chain intensity.

There were 1144 men and 704 women in age ranging from 30 to 99 years (mean: 70 years). Cytogenetic results showed that group II had a higher percentage of cases with trisomy 12 (50%; p<0.001) and complex cytogenetic abnormalities (9.6%; p=0.005) than group I(14% and 4.8%, respectively). Group III also had a higher percentage of cases with trisomy 12 (29%; p=0.005) and complex cytogenetic abnormalities (14.6%; p<0.001) as compared to group I. However, deletion of 17p was more frequently observed in group III (31%) than in groups I (9%; p<0.001) and II (6%; p<0.001). Deletion of 13q14 occurred more frequently in group I (59%) than in groups II (43%; p=0.002) and III (35%; p<0.001). IgVH hypermutation was more frequent in both groups II (65%; p<0.001) and III (71%; p=0.007) as compared to group I (51%). CD38 expression was higher in group II than group I (45% vs. 25%; p<0.001), but showed no significant difference between groups I and III. FMC7 expression correlated with higher light chain intensity in groups II (66%; p<0.001) and III (72%; p<0.001), compared to group I (43%). Average BM tumor burden was higher in group II than group I (63% vs. 56%; p=0.012) and no significant difference was seen between groups I and III. A low Hb subgroup was identified in the group III (10 vs. 14 g/dL), significantly associated with 17p deletion (p=0.012). In addition group III also showed a lower average platelet count than group I (166k/uL vs. 192k/uL; p=0.04). Notably, 17p deletion was not associated with lower Hb in group I and II CLLs. There was no significant difference in average Hb and platelet count between groups I and II, nor were there significant differences in age, gender, WBC and ZAP-70 between all three groups.

We have identified three groups of CLL based on CD23 and FMC-7 expression. In contrast to group I with typical CLL phenotype, group II (13%) with CD23+/FMC7+ phenotype correlated significantly with higher light chain intensity, trisomy 12, and IgVH hypermutation. Furthermore, group II is more frequently associated with high CD38, complex cytogenetic abnormalities, and a higher BM tumor burden. Thus, FMC7 alone may be sufficient to identify phenotypically atypical CLL with features suggestive of a more aggressive behavior. Group III represents a small subset (2.6%) of CLL with mantle- like phenotype (CD23-/FMC7+). Similar to group II, group III correlated with higher light chain intensity, trisomy 12, complex cytogenetic abnormalities, and IgVH hypermutation. However, group III is highly associated with 17p deletion with lower platelet count and Hb. Group III CLL with mantle-like phenotype is likely biologically to be distinct from group II. Future clinical studies may be warranted to confirm inferior outcome in phenotypically atypical CLL in general and CLL with mantle-like phenotype in particular.

No relevant conflicts of interest to declare.