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F. Autore et al.
Here, we review the unique morphological, immunophenotypic, and genetic characteristics of patients with CLL carrying +12.
Cytogenetic abnormalities concomitant with +12
+12 is the second most frequent cytogenetic abnormal- ity identified by FISH in patients with CLL, occurring in 16% of these patients at the time of initial evaluation.18 When identified by FISH, +12 is the sole aberration in approximately 70% of +12 CLL cases; +12 has been asso- ciated with del13q, del11q, or del17p in 18%, 8%, and 4% of +12 CLL cases, respectively.18,19,22,24 When identified by chromosome banding analysis, +12 is the sole abnor- mality in 30% of +12 CLL cases, but it can be associated with trisomy 18 (5% of cases) or del14q (3% of cases); associations with t(14;19)(q32;q13), trisomy 19, del17p, del13q, and del11q have also been reported.11,25-27
+12 is even more frequent in patients with small lym- phocytic leukemia than in those with CLL (28-36% vs. 13-16%).28,29 In fact, increased +12 frequency and reduced del13q frequency may represent specific features of small lymphocytic lymphoma with a different prognosis and may distinguish it from classical CLL.28
+12 as a single aberration in CLL confers an intermedi- ate prognostic risk, with a median time to first treatment (TTFT) of 33 months and a median overall survival time (OS) of 114 months.18 +12 that is associated with addi- tional chromosomal abnormalities, including t(14;18)(q32;q21) and trisomy 18, portends a poor prog- nosis independent of NOTCH1 mutation, which is more common in cases with isolated +12.30 Patients with CLL who develop Richter syndrome have a particularly poor prognosis, and +12 is frequent in patients with this syn- drome, with an incidence of up to 50%.31 Yi et al. have ret- rospectively analyzed 330 non-selected CLL patients, using a panel DNA probe to detect cytogenetic abnormal- ities by FISH, 70 patients were positive for +12. In patients who carried a favorable or neutral cytogenetic abnormality, including +12, the co-occurrence of several chromosome abnormalities associated with shorter TTFT and OS. However, in patients with adverse cytogenetic abnormalities, such as del17p or del11q, the co-occur- rence of a favorable or neutral clone, including again +12, portended an improved prognosis. This study challenged the classical hierarchical FISH classification used in CLL, highlighting the prognostic relevance of the intra-tumoral cytogenetic heterogeneity.32
+12 is not related to a specific abnormality. However, +12 as a 'driver' mutation can facilitate the appearance of NOTCH1 and FBXW7 mutations: disruptions of FBXW7 function may lead to constitutional activation of NOTCH1 and then to cell proliferation and evasion from apoptosis. The presence of abnormalities of FBXW7 may be implicated in the pathogenesis of the CLL and deter- mine the selection of treatment-resistant clones.33,34
Cytopenia in patients with +12 CLL
Cytopenias are common in patients with +12 CLL. It has been reported that up to 24% of patients with +12 CLL will develop cytopenias during the course of their disease.35 Cytopenias in CLL can result from either bone marrow failure or autoimmune disease.36,37 Two studies showed that CLL patients with +12 have a higher inci-
dence of autoimmune cytopenias than infiltrative cytope- nias.36,37
Morphological features of patients with +12 CLL
Atypical morphology, defined as the presence of cleaved nuclei and/or lymphoplasmacytoid features in more than 15% of cells, can be observed in up to 20% of patients with CLL.38,39 Several studies have revealed that +12 is the most common cytogenetic abnormality in these cases.38
Athanasiadou et al. evaluated the presence of atypical and typical CLL morphology in a population of 100 CLL patients.38 In the +12 subgroup, 17 of the 23 cases ana- lyzed (74%) were considered morphologically atypical. Atypical morphology was also frequent in the del11q/del17p subgroup (5 of 7 cases, 71%). All del13q cases and 45 of 51 cases (88%) with normal karyotypes had typical morphology.38
Ruptured B cells, or smudge cells, are commonly seen in blood smears of patients with CLL.40 Levels of smudge cells have been correlated with low CD45 expression on CLL cells by flow cytometry.41 Smudge cells are believed to reflect intrinsic CLL cell fragility and cytoskeletal abnormalities, linked to reduced expression of vimentin, and some authors have proposed using percentages of smudge cells to stage CLL.42 In patients with +12 CLL, fewer smudge cells are observed than in patients with CLL overall, along with normal levels of CD45 expres- sion.43
Immunophenotype of patients with +12 CLL
Chronic lymphocytic leukemia patients show an immunophenotypic panel that is typically CD5+, CD23+, FMC7-, surface immunoglobulin (sIg)dim, CD22dim-, and CD79bdim-. Quijano et al.19 established the presence of an atypical immunophenotypic pattern in some subgroups of 180 CLL patients by using combinations of monoclonal antibodies. The atypical immunophenotypic pattern was characterized by a distinct and unusual pattern of expres- sion regarding CD22, CD20, CD79d, FMC7, sIgM, sIgj, sIgk, and CD38. Cases with +12 (23% of the series), com- pared with cases with normal karyotypes (38%), showed significantly higher expression of CD19, CD22, CD20, CD79b, CD24, CD27, CD38, sIgM, sIgk, and sIgλ and lower expression of CD43. Among various cytogenetic subgroups, the atypical immunophenotypic pattern iden- tified in overall CLL patients was more frequent in the +12 and del17p subgroups and less frequent in the del13q subgroup; the del11q subgroup presented an equal distri- bution of the typical and atypical patterns.19
An atypical immunophenotype can be defined using the Matutes score,39 which is calculated from the follow- ing cell surface markers: positive expression of CD5 and CD23, negative expression of FMC7, and weak expres- sion of CD22 and sIg. A modification of the scoring sys- tem, called the modified Matutes score, replaces CD22 with CD79b, and this score is considered atypical if less than 4.39 Interestingly, with the modified Matutes score, +12 defines a subgroup of CLL with more frequent atyp- ical morphology than with the original scoring system.39,44
CD38
CD38 expression45 is significantly more frequent in the +12 and del11q/del17p subgroups of CLL patients (10 of 26 cases and 5 of 10 cases, respectively) than in patients with normal karyotype or in the del13q subgroup of CLL patients (10 of 72 cases and 1 of 5 cases, respectively).38 High CD38 expression on CLL cells has been used as a
haematologica | 2018; 103(6)