Large B cell diffuse

Authors: Doctors G. Javier1 and R. Ferrés Creation Date: March 2003 Update: March 2004

Scientific Editor: Professor Rafael Fernández-Delgado

1Department of Pediatrics, University Hospital "Germans Trias i Pujol", Cª Canyet s/n, 08916 Badalona, Spain. [email protected]

Abstract Keywords Disease name and synonyms Differential diagnosis Frequency Definition Clinical description Etiology Genetic features Diagnostic methods Staging Prognostic parameters Treatment Survival Keywords References

Abstract Primary diffuse large B-cell (DLB-CL) are aggressive tumors accounting for approximately 40% of the B-cell malignancies. DLB-CL are commonly composed of a mixture of centroblast-like and immunoblast-like cells. These cells express typically the B-cell markers CD19, CD20, and CD22 and the surface immunoglobulin (sIg). DLB-CL are clinically and genetically heterogeneous tumors. The frequently reccurring chromosomal translocations t(3;14), t(8;14) and t(14;18) have been shown to characterize genetic subsets, which together constitute approximately 50% of DLB-CL. However, the genetic basis of the clinical heterogeneity of DLB-CL remains poorly understood. The median age of presentation is in the sixth decade, but the age range is broad, and these tumors may be seen in children. Patients often present with single or multiple rapidly enlarging, symptomatic masses in nodal or extranodal sites; up to 40% of these masses are extranodal. The most common extranodal site is the stomach, although most primary lymphomas of the central nervous system, bone, kidneys and testes are also DLB-CL. Approximately 40% of DLB-CL can be cured with standard therapy. However, 50% of patients relapse after treatment and die of recurrent lymphoma.

Keywords B-cells, non-Hodgkin lymphomas, diffuse large B-cells lymphomas, BCL2, REL, MYC, survivin, apoptosis, chemotherapy

Disease name and synonyms Diffuse large-B cell lymphoma (DLB-CL) Lukes-Collins: Large cleaved or large non- Rappaport: Diffuse histiocytic, occasionally cleaved FCC, B-immunoblastic. diffuse mixed lymphocytic-histiocytic. Working-Formulation: Large-cell cleaved, Kiel: Centroblastic, B- immunoblastic, large-cell noncleaved or immunoblastic; occasionally anaplastic (B cell). diffuse mixed small and large cell.

Javier G and Ferrés R. Large B cell diffuse lymphoma. Orphanet Encyclopedia. March 2004. http://www.orpha.net/data/patho/GB/uk-DLBCL.pdf 1

Differential diagnosis The most common extranodal site is the The differential diagnosis of large B-cell stomach, although most primary lymphomas of lymphoma includes nonlymphoid tumors such as the central nervous system, bone, kidneys and poorly differentiated carcinoma, germ cell tumor, testes are also DLB-CL. glioma, melanoma and sarcoma. Lymphoma is Rare cases present with predominantly often suspected in the differential diagnosis intravascular involvement -the so-called when patients present with lymphadenopathy; intravascular lymphoma, angiotropic lymphoma, however, the disease may not be suspected or malignant angioendotheliomatosis- producing when patient present with extranodal ischemic changes in a variety of organs, involvement. particularly in the central nervous system, Clinical features that support the diagnosis of kidneys and skin. lymphoma include: The large cell lymphomas of childhood are presence of multiple, noncontiguous lesions. clinically, histologically and immunologically characteristic radiographic findings (permeative more heterogeneous that the other subtypes of lesions in bone, ring-enhancing lesions in the NHL. Because of the relative rarity of large cell central nervous system). lymphomas in children, most of the available additional involvement of lymphoid organs. data derive from studies in adult patients. systemic symptoms such as fever and weight The onset of the clinical manifestations may be loss. sudden, and the duration of symptoms is characteristically short. Initial symptoms Frequency (including cough, sore throat, abdominal pain, DLB-CL is one of the most common lymphoid vomiting, and adenopathies) are nonspecific and malignancy in adults, representing about 30- may be indistinguishable from those of a variety 40 % of adult non-Hodgkin’s lymphoma (NHL) of common childhood illnesses. Constitutional diagnosed de novo on basis of morphology and symptoms such as fever, night sweats, and immunophenotype. weight loss are more common in patients with Large cell lymphomas in children are relatively high-grade lymphomas. Rarely, children present rare as they represent less than 5% of NHL in with widely disseminated disease in which the childhood. site of origin cannot be determined. Clinical manifestations in children with DLB-CL are less Definition predictable, and these tumors tend to arise in NHL constitute an heterogeneous group of lymph nodes and in the lymphoid tissue of the neoplasms and among high-grade malignant gastrointestinal tract, bone, mediastinum, and NHL, the updated Kiel classification (Engelhard skin. et al., 1997) identifies three major B-cell entities: Mediastinal large B-cell lymphoma (MLB-CL) centroblastic (CB), B-immunoblastic (B-IB), and has been recently identified as a subgroup of B-large cell anaplastic (Ki-1+), now termed DLB-CL that affects especially young female anaplastic large cell [CD30+], [B-ALC]. The patients. The molecular characteristics of MLB- revised European-American Lymphoma (REAL) CL differ from these of classical DLB-CL and classification proposed in 1994 by the share features with classical . International Lymphoma Study Group unified these lymphomas in the single category of Tumor morphology and immunophenotype diffuse large-B cell lymphomas, as there are no DLB-CL are composed of layers of large cells major differences in the clinical behavior or that resemble centroblasts or immunoblasts, the approach to therapy of these three entities. most common finding being a mixture of Diffuse large-B cell lymphomas were previously centroblast-like and immunoblast-like cells. thought to represent malignant counterparts of Other cells types include large cleaved or B-cells. However recent analysis multilobated cells and anaplastic cells identical using microarrays suggested that there are at to those of T- or null cell-anaplastic large cell least two subsets, with gene expression patterns lymphoma. Some large B-cell lymphoma may be similar either to germinal center B-cells or to rich in small T lymphocytes or histiocytes, activated B-cells. thereby resembling either T-cell lymphoma or Hodgkin’s disease (lymphocyte predominance Clinical description type). The median age of presentation is in the sixth Diffuse large B-cells typically express the B-cell decade, but the age range at onset is broad, and markers CD19, CD20, and CD22 and the these tumors may be seen in children. surface immunoglobulin (sIg). The tumor cells Patients often present with single or multiple are larger and more irregular than immunoblasts rapidly enlarging, symptomatic masses in nodal and the cytoplasm is less basophilic. An or extranodal sites; up to 40% of these masses additional characteristic feature is the cohesive are extranodal. growth pattern of the blasts, which can

Javier G and Ferrés R. Large B cell diffuse lymphoma. Orphanet Encyclopedia. March 2004. http://www.orpha.net/data/patho/GB/uk-DLBCL.pdf 2 frequently only be recognized in the well-fixed lymphomas is the t(14;18)(q32;q21), which areas of the slides. appears in about 25-30% of patients. These translocations deregulate the expression Etiology of BCL6 (3q27), MYC (8q24), and bcl-2(18q21) The extent to which malignant B-cell migration genes, as a result of their juxtaposition to the Ig mimics that of its normal putative counterpart, genes. the mature B-cells, remains to be defined. However, the genetic basis underlying the Mature B-cells migrate to secondary lymphoid clinical heterogenicity of DLB-CL remains poorly organs, where they encounter antigens, engage understood. their B-cell receptors, and subsequently move to Gene amplification is a genetic lesion frequently the germinal center where they undergo associated with progression of the tumor (Rao et hypermutation and affinity maturation. al., 1998). The commonly recurring Ig gene site- Events in DLB-CL indicate that the tumor cell associated translocations leading to deregulation population is arrested at a stage where both of specific genes occurs only in a proportion of somatic mutations and isotype switch can cases. continue after malignant transformation. Most of Recent studies suggest that REL, MYC, and the mutational activity appears to be finished by bcl-2 genes may be more frequently involved in the IgMD+ stage, although there may be few DLB-CL than the frequency of their disruption by further mutations following the isotype switch. chromosomal rearrangement seems to indicate. The IgG isotype variants probably reflect an The role of aberrant expression of these genes influence of Th1 cells. These variants appear (due to cytogenetic translocations or DNA functional at the RNA level, and protein rearrangements) in lymphomatogenesis is expression is seen at least for some of the important. transcripts. Mutational patterns are consistent with the existence of subpopulations within the BCL6 tumor and with parallel switch events to either BCL6 is one of the three genes deregulated by IgG3 or IgG1, which can then switch to IgA such translocations, plays an important role in (Ottensmeier et al., 2000). These findings do not the genesis of DLB-CL. In addition, BCL6 necessarily reflect deregulation, but rather undergoes mutations (hypermutations) in the 5’ indicate that the tumor cells respond to normal regulatory region in more than 70% of the cases signals without being able to achieve a fully of DLB-CL, providing another possible differentiated state. mechanism for the gene deregulation. A subset of DLB-CLs is thought to derive from mature effector cells that left the germinal center MYC and re-entered the circulation. The mechanisms MYC deregulation has been suggested to that govern the migration of normal antigen- compromise a second and contributing event in activated B-cells and their malignant the progression of bcl-2-deregulated follicular counterparts are currently under intense center cell lymphoma into DLB-CL. investigation. bcl-2 Genetic features bcl-2(18q21) overexpression itself has been Although most DLB-CL arise de novo, a subset associated with adverse clinical outcome. of them may result from the transformation of indolent lymphomas, including immunocytoma, REL , and marginal zone REL amplification may be associated with lymphoma; these transformed lymphomas often extranodal presentation. have a prognosis worse than that associated with de novo large B-cell lymphomas. Diagnostic methods In DLB-CL the Ig variable region genes Overcoming the difficulties in distinguishing the commonly undergo somatic mutations three main types of large B-cell lymphomas (Taniguchi et al., 1998; Lossos et al., 2000), and requires experience and sensitive histological this applies also to the morphologically different techniques. subsets of DLB-CL that are located in the central Histopathologic diagnosis should always be nervous system or the skin, and to the T-cell-rich based on microscopic examination of B-cell lymphoma. appropriated selected tissue sections obtained The frequently recurring chromosomal by biopsy, fine-needle aspiration or cytologic translocations, t(3;14)(q27;q32), t(8;14)(q24;q32) examination of appropriate body fluids. and t(14;18)(q32;q21), have been shown to The diagnostic slides are prepared for optimal characterize genetic subsets, which together Giemsa staining and the procedure is correspond to approximately 50% of DLB-CL. supplemented by immunohistochemistry and The most common cytogenetic abnormality in molecular genetic methods, to study the patterns patients diagnosed with diffuse large cell

Javier G and Ferrés R. Large B cell diffuse lymphoma. Orphanet Encyclopedia. March 2004. http://www.orpha.net/data/patho/GB/uk-DLBCL.pdf 3 of immunoglobulin and receptor genes overexpression or p53 mutation, have emerged rearrangements. as important prognostic indicators of DLB-CL. The most important factors in establishing the Survivin, a member of the inhibitor of apoptosis diagnosis are a high index of suspicion and a gene family has been recently identified as a recognition of the morphologic spectrum of candidate molecule involved in the apoptotic diffuse large B-cell lymphoma. balance (Ambrosini et al. 1997). Recent studies In most cases, immunoperoxidase stains on demonstrate that survivin expression influenced paraffin sections enable definitive diagnosis; unfavorably overall survival, but had no effect on however, a panel of several antibodies may be the response to treatment, being a new required (cytokeratin, EMA, CD45, pan-B and independent prognostic factor of poor outcome pan-T antigens, Ig light chains, and if relevant, in DLB-CL (Adida et al., 2000). S-100 and HMB-45). The newly identified B-aggressive lymphoma (BAL) gene encodes a protein that is significantly Staging more abundant in high-risk DLB-CLs than in low- Recommended staging studies include careful risk tumors (Aguiar et al., 2000). BAL physical examination with attention to all sites of overexpression increases the rate of migration of palpable disease, a complete blood cell count B-cell lymphoma transfectants, suggesting that including platelets and differential, bone marrow the risk-related protein may promote the aspiration, and lumbar puncture with dissemination of high risk DLB-CL. cytocentrifuge examination of the cerebrospinal fluid and measurement of serum lactic Treatment dehydrogenase. Although approximately 40% of DLB-CL can be Clinical studies include computed tomography cured with standard therapy, the majority of adult (TC), magnetic resonance imaging (MRI) and patients will ultimately die of their disease. radionuclide bone scans for unsuspected bony Approximately 50% of patients relapse after lesions. treatment and succumb to recurrent lymphoma. The most commonly used staging system for A comprehensive experience in the childhood NHL is the St Jude staging system management of clinically aggressive NHL has (Shad et al. 1997). In general the prognosis been accumulated internationally, and a worsens with increasing stage of the tumor. multitude of treatment protocols have been developed and successfully applied. The Prognostic parameters different treatment approaches include: Although combination chemotherapy has Chemotherapy with or without radiation therapy improved the disease outcome, many patients for stage I disease. do not achieve complete remission and they Multiagent doxorubicin-containing chemotherapy ultimately relapse, prompting the search for regimen for stages II through IV: parameters that enable the identification of - MBACOD (doxorubicin, cyclophosfamide, patients at risk of recurrent disease. bleomycin, methotrexate, Deadron). The formulation of an International Prognostic - ACVB (doxorubicin, cyclophosfamide, Index (IPI) has provided a widely accepted set of vindesine, bleomycin, prednisone). criteria to predict the evolution of aggressive In pediatric patients large B-cell diffuse lymphomas and thus to design appropriate lymphomas are treated with the same regimes therapies (The International Non-Hodgkin's used for treatment of the other B NHL ( Prognostic Factors Project, 1993). type). The most extended therapeutic regimes in IPI delineates DLB-CL patients with low (L), low- pediatrics are: intermediate (LI), high-intermediate (HI), and - Total B (St. Jude Children's Research Hospital) high (H) risk disease, and associated differences - BFM 86 in overall survival. - LMB 89 (SFOP) IPI takes into account factors that are mostly Overall survival with these regimes is over 60- linked to the patient’s characteristics or to the 70%, depending on the initial stage of the disease extension and growth, including age, disease. The reported event free survival (EFS) lactate dehydrogenase level, performance of patients treated bay the Spanish Cooperative status, clinical stage, and number of extranodal Group (SHOP), using de LMB89 protocol is sites. 0.77± 012. However one limitation of this prediction strategy For second-line therapies, a variety of is that IPI does not encompass molecular combination regimes such as ifosfamide, abnormalities of tumor cells, which can lead to methotrexate, and etoposide or dexamethasone, different clinical outcomes in patients within the cytarabine, and cisplatin can induce second same group defined by IPI. remissions. Molecular abnormalities of the cell death-cell - VIM3 (mitoxantrone, ifosfamide, methyl-GAG, viability balance, as reflected in bcl-2 Vehem, prednisone, methrotexate) - VIM (mitoxantrone, vepesid, methrotexate)

Javier G and Ferrés R. Large B cell diffuse lymphoma. Orphanet Encyclopedia. March 2004. http://www.orpha.net/data/patho/GB/uk-DLBCL.pdf 4

Autologous bone marrow transplantation in Ambrosini G., Adibe C., Altieri D.C. A novel chemotherapy-sensitive relapsed disease. antiapoptosis gene, survivin, expressed in Chemotherapy administered at the standard cancer and lymphoma. Nat Med., 1997. 3: 917- doses is rarely effective to cure patients with 921. relapsed or refractory diffuse LDB-CL. High-dose Engelhard M., Brittinger G., Huhn D. chemotherapy or radiation therapy followed by Subclassification of Diffuse Large B-cell autologous or allogeneic bone marrow Lymphomas according to the Kiel Classification: transplantation can cure some patients. Distinction of centroblastic and immunoblastic Further candidate gene and/or positional cloning lymphomas is a significant prognostic risk factor. approaches should help identifying additional Blood, 1997. 89: 2291-2297. genes mapping to the amplified chromosomal Javier G., Estella J., Fernández-Delgado R. Et regions identified, thereby providing new clues to al. Linfoma difuso de célula grande B en la the genetic basis of progression and clinical infancia. Haematologica 2003. 88 (Sup7):88. behavior of DLB-CL. Li F., Ambrosini G., Chu E.Y. et al. Control of Molecular targeting of bcl-2 and survivin apoptosis and mitotic sprindle checkpoint by improved disease in vivo and caused survivin. Nature, 1998. 396: 580-584. spontaneous apoptosis in vitro, thus suggesting Li F., Ackermann E.J., Bennett C.F. et al. that manipulation of this antiapoptotic pathway Pleotropic cell-division defects and apoptosis may offer a potential therapeutic strategy to induced by interference with survivin function. achieve stable remission in lymphoma (Li et al. Nat Cell Biol., 1999. 1: 461-466. 1998, 1999). Lossos I.S., et al. Molecular analysis of immunoglobulin genes in diffuse large B-cell Survival lymphomas. Blood, 2000. 95: 1797-1803. The survival of patients with DLB-CL is both age- Ottensmeier C.H., Stevenson F.K. Isotype and stage- dependent. Even in patients with switch variants reveal clonally related advanced disease, about 30% to 60% may have subpopulations in diffuse large B-cell lymphoma. prolonged survival with effective combination Blood, 2000. 96: 2550-2556. chemotherapy regimes. Rao P.H., et al. Chromosomal and gene Up to 80% of patients who present with minimal amplification in diffuse large B-cell lymphoma. disease at diagnosis can be long-term disease Blood, 1998. 92: 234-240. free survivors. Savage K.J., Monti S., Kutok J.L. et al. The After patients achieve complete remission with molecular signature of mediastinal large B-cell an aggressive combination of chemotherapy lymphoma differs from that of other diffuse large regimes, 30-50% eventually suffer a relapse. B-cell lymphomas and shares features with Most relapses occur within the first 2 years after classical Hodgkin lymphoma. Blood, 2003. therapy has been finished. 102:3871-9. Patients who remain in complete remission for Shad A., Magrath I. Malignant non-Hodgkin's more than 2 years have 70% to 90% probability lymphomas in children. In "Principles and of being cured. Practice of Pediatric Oncology". Pizzo P.A., Poplack D.G. Lippincott-Ravers Pub. References Philadelphia 1997; 545-588. Adida C., et al. Prognostic significance of Taniguchi M. et al. De novo CD5+ diffuse large survivin expression in diffuse large B-cell B-cell lymphomas express VH genes with lymphomas. Blood, 2000. 96: 1921-1925. somatic mutation. Blood, 1998. 91: 1145-1151. Aguiar R.C., Yakushijin Y., Kharbanda S., The International Non-Hodgkin's Lymphoma Salgia R., Fletcher J.A., Shipp M.A. BAL is a Prognostic Factors Project. A predictive model novel risk-related gene in diffuse large B-cell for aggressive non-Hodgkin's lymphoma. N Eng lymphomas that enhances cellular migration. J Med. 1993; 329: 987-994. Blood, 2000. 96: 4328-4234.

Javier G and Ferrés R. Large B cell diffuse lymphoma. Orphanet Encyclopedia. March 2004. http://www.orpha.net/data/patho/GB/uk-DLBCL.pdf 5