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Recent Advances in Diagnosis, Prognosis and Biology of Small B Cell Lymphomas

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Recent Advances in Diagnosis, Prognosis and Biology of Small B Cell Lymphomas Turk J Hematol 2006; 23:173-181 REVIEW ARTICLE © Turkish Society of Hematology Recent advances in diagnosis, prognosis and biology of small B cell lymphomas Gülşah Kaygusuz, Işınsu Kuzu Department of Pathology, Ankara University, Faculty of Medicine, Ankara, Turkey [email protected] INTRODUCTION eral blood, bone marrow, and/or lymph nodes. Small B cell lymphomas are mature B cell lym- The term SLL is used for non-leukemic cases phoid neoplasms arising from the various differ- having the morphology and immunophenotype entiation stages of B cell development. Although of CLL. Many cases of CLL/SLL are thought to in the World Health Organization (WHO) classi- correspond to the recirculating naïve B cells. fication of lymphomas, they are described based Cases that show Ig gene variable region muta- on their morphology, phenotype and genetics, the tions may correspond to a subset of memory B differential diagnosis can be difficult because of cells [1]. some overlapping characteristics. Differences ob- served in the clinical outcome of cases represent- The nodal presentation of CLL/SLL is char- ing the same entity have also made it difficult to acterized by the diffuse infiltration of small lym- understand fully the biology of the small B cell phocytes admixed with prolymphocytes and lymphomas, but interpretation of the results of para-immunoblasts, giving rise to proliferation molecular profiling studies has helped patholo- centers or pseudofollicles. CLL/SLL cells are gists and clinicians in this regard. Some specific small lymphocytes with round nucleus, clumped genetic changes defined on the neoplastic B cells chromatin and scant cytoplasm. Nucleoli are have revealed the route of lymphomagenesis. But generally absent. Prolymphocytes are medium- there are still debates on description, biology and sized cells with dispersed chromatin and small differential diagnosis of some entities. Focusing nucleoli, whereas para-immunoblasts are me- on the interactions between the neoplastic cells dium to large cells with round nuclei, dispersed and the cells or structures of the microenviron- chromatin, central eosinophilic nucleoli and ment is the new concept which holds promise basophilic cytoplasm. The number of para-im- for explaining some of the unresolved questions. munoblasts and size of pseudofollicles vary from Herein, we provide an overview of the recent ad- case to case. Some cases show plasmacytoid dif- vances in the diagnosis, prognosis and biology of ferentiation. small B cell lymphoma entities together with their description in the WHO lymphoma classification. In the spleen, white pulp involvement is usu- ally prominent, but the red pulp may be involved. Bone marrow involvement may be nodular, in- Chronic lymphocytic leukemia/small terstitial, diffuse or a combination of the three; lymphocytic lymphoma (CLL/SLL) pseudofollicles are rarely seen in the marrow [1]. Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) is a hematopoietic Immunophenotypically, CLL/SLL cells are neoplasm of B-lymphocytes found in the periph- positive for IgM, IgM and IgD, CD5, CD19, CD20 173 Kaygusuz G, Kuzu I (weak), CD22 (weak), CD79a, CD23, CD43, and transformation, whereas mutated cases can CD11c (weak) and are negative for CD10, Bcl-1, transform into Hodgkin’s disease or diffuse large FMC7 and CD79b. CD23 and Bcl-1 are useful B cell lymphoma [11]. in distinguishing CLL/SLL from mantle cell lym- phoma [1]. Mantle cell lymphoma (MCL) Some atypical cases that focally express Mantle cell lymphoma (MCL) is a B-cell ne- Cyclin D1 without t(11;14) and are negative for oplasm associated with a very poor prognosis. CD23 have been reported [2]. This kind of aber- The neoplastic cells of MCL are thought to cor- rant expression of Cyclin D1 could represent a respond to pre-germinal center B lymphocytes in source of diagnostic confusion. Additional infor- primary lymphoid follicles and the mantle zones [12] mation, such as immunophenotype, cytogenet- of secondary follicles . Approximately 25% of ics, and molecular findings, should be used to MCL cases bear mutated IgH genes, with rates of resolve such difficult cases. mutations much lower than those observed, for example, in follicular lymphomas, which clearly [13] Although still considered a single disease en- derive from germinal center B cells . tity, it is now known that there are two major types of CLL/SLL: in the first, leukemic cells Lymph nodes, spleen, and bone marrow (with have rearranged VH genes (mutated form), while or without blood involvement) are the most com- in the second, there are few or no mutations (un- monly involved sites. The gastrointestinal tract mutated form). The mutated form of CLL/SLL is and Waldeyer’s ring are the most often involved more indolent whereas unmutated cases have a extranodal sites. more aggressive clinical course [3,4]. A more ag- gressive type of CLL/SLL is also recognized by Nodal involvement generally adopts mantle expression of the activation marker CD38 and zone, nodular or diffuse growth patterns. MCL the T- and natural killer cell-associated ZAP- is usually composed of monomorphic, uniform, 70 tyrosine kinase [5,6]. Gene expression profiles small-medium sized B lymphocytes with scant demonstrate that unmutated CLL cells express cytoplasm, irregular nuclei and inconspicuous more ZAP-70 mRNA than mutated CLL cells. nucleoli. Although transformation into a diffuse large B cell lymphoma is rarely seen, transfor- In cases of CLL/SLL, chromosomal transloca- mation into a higher grade tumor may occur and tions are rare, and no specific mutations have these cases are described as ‘blastoid variant’ been identified. Although cytogenetic lesions are of MCL [1]. Several MCL cytologic variants have rare in the early course of the disease, some ap- been described, but the classic and pleomorphic pear as the disease progresses. The most com- blastoid variants are the most relevant because mon is a deletion at 13q14.3, which occurs in they often show genetic abnormalities and po- more than 50% of cases. This deleted region con- tentially correlate with a worse prognosis [14]. tains two micro-RNA genes, miR-15a and miR- 16-1. miR-15a and miR-16-1, which negatively Rare cases of ‘in situ-like MCL’ without asso- regulate bcl-2, are frequently deleted and/or ciating the localized disease have been described downregulated in patients with CLL. Mutations recently [15]. in miRNA transcripts may have functional im- portance and may predispose to CLL [7]. Other cy- Several types of B cell lymphomas show plas- togenetic abnormalities in CLL/SLL are trisomy macytic differentiation. Although this phenom- 12 and deletions at 11q22-23, 6q21 or 17p13. enon is not usual, a few cases of MCL exhibiting clonal plasma cell differentiation have also been Richter syndrome, transformation of CLL/ reported [16]. SLL into aggressive B cell lymphoma, occurs in up to 10% of the cases, most representing a dif- The tumor cells are positive for CD20, CD22, fuse large B cell lymphoma and 0.5-2% being a CD79a, CD5, CD43, surface IgM and IgD, FMC7, Hodgkin’s disease variant [8]. It has been shown and bcl-2 and usually negative for CD10, CD23, that in some cases, Epstein-Barr virus (EBV) in- and bcl-6. Virtually all cases show nuclear ex- fection and fludarabine treatment may lead to pression of Cyclin D1. Cyclin D1 is overexpressed Hodgkin transformation of CLL/SLL [9,10]. It has as a consequence of t(11;14), which juxtaposes been speculated that unmutated cases can show the Cyclin D1 gene next to the immunoglobulin diffuse large B cell lymphoma variant of Richter heavy chain gene [1]. Phenotypic variants may in- 174 Turkish Journal of Hematology Recent advances in diagnosis, prognosis and biology of small B cell lymphomas clude negativity for CD5 or Cyclin D1, and rare Cases of ‘in situ localization of FL’ have been expression of CD10, CD23, bcl-6 or the T-cell reported in the literature [22]. It appears to repre- markers CD8 or CD7 [17,18]. sent early microscopic involvement of FL within the lymph nodes. The clinical significance of The t(11;14)(q13;q32) is the genetic hallmark these cases without other evidence of lymphoma of MCL [1]. This abnormality can be demonstrat- is not known yet. ed by cytogenetics and/or fluorescent in situ hy- bridization (FISH). Many cases also have point The tumor cells are positive for CD19, CD20, mutations and/or deletion of the ATM (ataxia CD22, CD79a, surface Ig (IgM+/IgG-, IgG or telangiectasia mutated) gene. The blastoid vari- rarely IgA), bcl-2, CD10, and bcl-6 and negative ant of MCL frequently shows additional chromo- for CD5, CD43, CD23 and Cyclin D1 [1]. somal abnormalities, such as 13q14 deletions, trisomy 12, as well as the deletion or inactivation The genetic hallmark of FL, t(14;18)(q32;q21), of p53, p16 and p18 loci [19]. which juxtaposes the bcl-2 gene with the IgH gene, is seen in 80-90% of FLs [23]. It is not as- Variable region genes are unmutated in the sociated with the prognosis. Bcl-2 protein is ex- majority of the cases, but a subset of the cases pressed in the majority of the cases, and its ex- show somatic mutation. However, unlike the pression reduces as histological grade increases. situation in CLL, the hypermutational status of Although FL is rarely seen in pediatric patients, the Ig genes in MCL is not of prognostic signifi- it should be noted that bcl-2 expression in pedi- cance and is not associated with ZAP-70 expres- atric FL is relatively infrequent in contrast to its [24,25] sion [20]. adult counterpart . Primary cutaneous fol- licle center cell lymphoma is a variant of FL and is often bcl-2-negative as well [26]. Follicular lymphoma (FL) Follicular lymphoma (FL) is the most common The proliferation index, as determined by Ki- type of low-grade B cell lymphoma, characterized 67 immunohistochemistry on tissue sections, by a clinically indolent course.
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