Background

Burkitt lymphoma is an oncologic emergency when first diagnosed. It along with lymphoblastic lymphomas may grow rapidly and kill the patient if treatment is not started immediately.

Outline

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/Immunohistochemistry/Electron Microscopy
Differential Diagnosis
Prognosis and Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGY	CHARACTERIZATION
GEOGRAPHY
Association of Burkitt's lymphoma with the Epstein-Barr virus in two developing countries. Rao CR, Gutierrez MI, Bhatia K, Fend F, Franklin J, Appaji L, Gallo G, O'Conor G, Lalitha N, Magrath I. Lymphoma Biology Section, Pediatric Branch, National Cancer Institute, USA	Leuk Lymphoma 2000 Oct;39(3-4):329-37 Abstract quote The clinical presentation of Burkitt's lymphoma (BL) and it's association with the Epstein-Barr virus (EBV) varies in different geographic areas, BL in developing countries being "intermediate" between the sporadic and endemic types, both in it's clinical presentation and it's association with EBV, which varies from 25-80%. In this study we have analysed the clinical features, EBV association, subtype and prevalence of the deleted variant of the Latent Membrane Protein-1 (LMP-1) of EBV in forty-two cases from two developing countries- India (n = 25) and Argentina (n = 17). In both countries the abdomen was the site most commonly involved while jaw involvement was rare. EBV was detected by in-situ hybridization using the EBER-1 RNA probe. 47% of cases from Argentina and 80% of cases from India were EBER positive. EBV typing using EBNA-3C primers showed a predominance of Type A in both countries (India-13/16 and Argentina-(7/8)). The 30bp deletion of the LMP-1 gene was detected in all evaluated cases from Argentina while the wild type of the gene was seen in all the evaluable Indian cases. Our study highlights the similarities and differences in the clinical presentation and EBV association of BL in two developing countries and also indicates that the subtype of EBV and prevalence of the LMP-1 deletion may reflect the predominant subtype in a particular population.

 

DISEASE ASSOCIATIONS

CHARACTERIZATION

Primary hepatic Burkitt's lymphoma with chronic hepatitis C. Kuroda J, Omoto A, Fujiki H, Okugawa K, Tamai H, Yamagishi H, Kobayashi Y, Yoshikawa T. First Department of Internal Medicine, Kyoto Prefectural University of Medicine, 465 Kajii Kamigyo-ku, Kyoto 602, Japan.

Acta Haematol 2001;105(4):237-40 Abstract quote The liver is an uncommon primary site for malignant lymphoma, and primary hepatic lymphoma has been found to make up 0.4% of all extranodal lymphomas. We report a rare case of a 75-year-old Japanese male with primary hepatic Burkitt's lymphoma, according to both the revised European-American Lymphoma classification and the new World Health Organization classification. As not only histological findings but also immunological features are deemed essential in the diagnosis of Burkitt's lymphoma, the previous 7 cases of primary hepatic Burkitt's lymphoma were not fully evaluated, using these criteria. As far as we know, this is the first case of primary hepatic Burkitt's lymphoma with typical features on histological, immunological and cytogenetical analysis. He had a history of chronic hepatitis C over several decades with subsequent liver cirrhosis. From our review of the literature and our case, the relationship between hepatitis C virus infection and the development of primary hepatic Burkitt's lymphoma remains obscure.

 

PATHOGENESIS	CHARACTERIZATION
Genetic alterations of the retinoblastoma-related gene RB2/p130 identify different pathogenetic mechanisms in and among Burkitt's lymphoma subtypes. Cinti C, Leoncini L, Nyongo A, Ferrari F, Lazzi S, Bellan C, Vatti R, Zamparelli A, Cevenini G, Tosi GM, Claudio PP, Maraldi NM, Tosi P, Giordano A. Institute of Normal and Pathologic Cytomorphology, Consiglio Nazionale delle Ricerche, Bologna, Italy.	Am J Pathol 2000 Mar;156(3):751-60 Abstract quote Alterations of cell cycle-associated genes probably contribute to the pathogenesis of Burkitt's Lymphoma (BL), in addition to c-myc translocation. Mutations disrupting the nuclear localization signal of the retinoblastoma-related gene RB2/p130 have been documented recently in BL cell lines and primary tumors. Given the importance of the RB2/p130 gene in controlling cell growth, mutations of this gene may result in uncontrolled cell proliferation. We tested the expression and genomic organization of the RB2/p130 gene in relation to the proliferative features of a series of BL samples collected from the endemic and sporadic regions, regardless of whether the samples were acquired immune deficiency syndrome (AIDS)-related. The expression of the Rb2/p130, p107, and cell proliferation-related proteins (cyclin A and B) was determined by immunohistochemistry. The structures of exons 19 through 22 of the RB2/p130 gene, encoding for the B domain and C terminus, were analyzed by polymerase chain reaction (PCR) analysis and single-strand conformation polymorphism (SSCP) technique. The direct PCR products were sequenced to identify the actual mutations. Our results suggest that BL is composed of a mixture of molecular types with distinct genetic and phenotypic patterns, probably resulting from different pathogenetic mechanisms. In endemic BL, the RB2/p130 gene is mutated in most of the cases, and the protein is restricted to the cytoplasm. In AIDS-related BL, high levels of nuclear expression of the wild-type pRb2/p130, p107, and cell proliferation-related proteins were detected. This finding is in line with the molecular mechanisms observed in virus-linked oncogenesis. Sporadic BLs were mainly characterized by the low nuclear values of the wild-type pRb2/p130 and, conversely, the high values of p107. The increased cell proliferation due to different alterations of cell growth control by Rb-related proteins may be the first step in lymphomagenesis, during which additional genetic changes, including missense mutations of c-myc, may subsequently occur.
c-myc box II mutations in Burkitt's lymphoma-derived alleles reduce cell-transformation activity and lower response to broad apoptotic stimuli. Kuttler F, Ame P, Clark H, Haughey C, Mougin C, Cahn JY, Dang CV, Raffeld M, Fest T. Department of Haematology and Cell Biology, Institut d'Etude et de Transfert de Genes, University Hospital Jean Minjoz, 25030 Cedex Besancon, France.	Oncogene 2001 Sep 20;20(42):6084-94 Abstract quote In addition to c-myc rearrangement, over 50% of Burkitt's lymphoma cases present clustered mutations in exon 2, where many of the functional activities of c-Myc protein are based. This report describes the functional consequences induced by tumour-derived c-myc mutations located in c-myc box II. Two mutated alleles were studied, focusing on the P138C mutation, and compared to wild-type c-myc. The c-Myc transformation, transactivation and apoptosis activities were explored based on cells over-expressing c-Myc. While the transcriptional activation activity was not affected, our experiments exploring the anchorage-independent growth capacity of c-Myc-transfected Rat1a cells showed that c-Myc box II mutants were less potent than wild-type c-Myc in promoting cell transformation. Considering the possibility that these mutations could be interfering with the ability of c-Myc to promote apoptosis, we tested c-Myc-transfected Rat1a fibroblasts under several conditions: serum deprivation-, staurosporine- and TNFalpha-induced cell death. Interestingly, the mutated alleles were characterized by an overall decrease in ability to mediate apoptosis. Our study indicates that point mutations located in c-Myc box II can decrease the ability of the protein to promote both transformation and apoptosis without modifying its transactivating activity.
Antagonistic effects of c-myc and Epstein-Barr virus latent genes on the phenotype of human B cells. Pajic A, Staege MS, Dudziak D, Schuhmacher M, Spitkovsky D, Eissner G, Brielmeier M, Polack A, Bornkamm GW. Institut fur Klinische Molekularbiologie und Tumorgenetik, Hamatologikum der GSF, Munchen, Germany.	Int J Cancer 2001 Sep15;93(6):810-6 Abstract quote Epstein-Barr virus (EBV) immortalized cells and Burkitt lymphoma cells have a completely different growth pattern and phenotype. EBV immortalized cells express a set of 11 viral genes to accommodate B cell activation and proliferation, whereas EBV-positive Burkitt lymphoma cells highly express the c-myc oncogene that is activated through translocation into 1 of the immunoglobulin loci and EBNA1 as the only viral protein. We have developed a primary human B cell line conditionally immortalized by Epstein-Barr virus in which the viral gene program responsible for the induction of proliferation can be switched on and off by the addition or withdrawal of estrogen (cell line EREB2-5). Starting from this cell line we have generated 2 daughter cell lines that proliferate in a c-myc dependent fashion, 1 with a highly active exogenous c-myc gene (cell line A1) and 1 with a regulatable c-myc gene that can be switched on by withdrawal and switched off by addition of tetracycline (cell line P493-6). The comparison of the 3 cell lines has allowed us to dissect the contribution of c-myc and EBV genes to the regulation of the growth pattern and expression of cell surface molecules. We show that MYC and EBNA2 (and their respective target genes) have opposing effects on the expression of several surface markers involved in B cell activation. We show that MYC contributes to the phenotype of Burkitt lymphoma cells by upregulating CD10 and CD38 and downregulating activation markers. The phenotype of the cells is determined on one hand by the absence of the viral gene products EBNA2 and LMP1 that mediate the phenotype of activated lymphoblasts and to a lesser extent by an active contribution of the c-myc gene.
Role of bcl-2 in Epstein-Barr virus-induced malignant conversion of Burkitt's lymphoma cell line Akata. Komano J, Takada K. Department of Tumor Virology, Institute for Genetic Medicine, Hokkaido University, Kita-ku, Sapporo 060-8638, Japan.	J Virol 2001 Feb;75(3):1561-4 Abstract quote We have demonstrated that Epstein-Barr virus (EBV) confers enhanced growth capability in soft agarose, tumorigenesis in the SCID mouse, and resistance to apoptosis in the Burkitt's lymphoma cell line Akata. Subsequently, we have shown that EBV-encoded small RNAs (EBERs) are responsible for these phenotypes. We constantly observed the upregulation of bcl-2 oncoprotein expression upon EBV infection and expression of EBERs. To test whether these phenotypes were due to the upregulation of bcl-2 expression, we introduced bcl-2 into EBV-negative Akata cells at various levels encompassing the range at which EBV-positive cells expressed it. As cells expressed bcl-2 at higher levels, they became more capable of growing in soft agarose and became resistant to apoptosis. However, clones expressing bcl-2 at a higher level than EBV-positive Akata cells were negative in the tumorigenesis assay in the SCID mouse. On the other hand, introduction of bax into EBV-positive Akata cells reduced the resistance to apoptosis; however, it failed to reduce the growth capability in soft agarose. These data indicate that EBV targets not only bcl-2, but also an unknown pathway(s) to enhance the oncogenic potential of Akata cells.

 

LABORATORY/RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
RADIOLOGIC
LABORATORY MARKERS
Serum levels and differential expression of CD44 in childhood leukemia and malignant lymphoma: correlation with prognostic criteria and survival. Tacyildiz N, Cavdar AO, Yavuz G, Gozdasoglu S, Unal E, Ertem U, Duru F, Ikinciogullari A, Babacan E, Kuzu I, Cin S. Department of Pediatric Oncology, Ankara University Medical School, Turkey	Pediatr Int 2001 Aug;43(4):354-60 Abstract quote BACKGROUND: The CD44, a cell surface proteoglycan, participates in a variety of function including tumor dissemination and metastasis. However, there are no available data on the prognostic significance of CD44 expression of tumor tissue correlated with serum sCD44 level in childhood leukemias and lymphomas. METHODS: Serum levels and leukemic cell tumor tissue expression of CD44 were detected in 54 children with acute leukemia and malignant lymphoma. Serum samples were obtained from all patients before treatment and during remission. Twelve age-matched healthy children were included as a control group. RESULTS: The serum CD44 levels were significantly higher in patients with Hodgkin's disease (HD), non-Hodgkin's lymphoma (NHL), Burkitt's lymphoma (BL) and acute lymphoblastic leukemia (ALL) than those in the control group. The median values were 1627.0, 1336.0, 1318.5, 1730.4, 902.7 ng/mL, respectively, and P<0.001, P<0.01, P<0.01, P<0.05 in comparisons, respectively. However, there was no significant difference between acute myeloid leukemia (AML) and the control group (median values: 900.3 and 902.7 ng/mL, respectively, P>0.05). Serum sCD44 levels significantly declined in HD, NHL and ALL patients who were in complete remission (median values: 684.0, 573.8 and 1101.1 ng/mL, respectively, P<0.05 in each comparison). Patients with HD had higher levels of serum sCD44 and correlated well with higher erythrocyte sedimentation rate (ESR), B-symptoms and advanced-stage disease (P<0.05, P<0.05 and P<0.01, respectively). Expression of CD44 was significantly high in patients with HD and NHL who were in advanced stages of disease. High serum CD44 level was also associated with high tumor tissue expression of CD44 in patients with HD and BL. In addition, patients with higher levels of serum sCD44, had a poorer outcome and survival than those with lower sCD44 levels in HD and NHL groups. CONCLUSIONS: A high serum sCD44 level and/or tumor tissue expression at diagnosis is associated with poor prognostic criteria and/or unfavorable outcome in childhood leukemias and lymphomas.

 

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
VARIANTS
Burkitt's lymphoma of the testis: an unusual scrotal mass in childhood. Leonard MP, Schlegel PN, Crovatto A, Gearhart JP. Division of Pediatric Urology, James Buchanan Brady Urological Institute, Johns Hopkins Hospital, Baltimore, Maryland.	J Urol 1990 Jan;143(1):104-6 Abstract quote Burkitt's lymphoma was originally described as a sarcomatous tumor among Ugandan children but it is becoming more prevalent in the United States. We describe a case of Burkitt's lymphoma that presented as a scrotal mass. The management of Burkitt's lymphoma involving the testis is discussed.
Burkitt's lymphoma presenting as ileocaecal intussusception in systemic lupus erythematosus. Chang DK, Yoo DH, Kim TH, Kim IS, Jun KY, Park MH, Kim SY. The Hospital for Rheumatic Diseases, Division of Rheumatology, Hanyang University College of Medicine, Seoul, Korea.	Clin Rheumatol 1999;18(3):253-6 Abstract quote Patients with systemic lupus erythematosus (SLE) are reported to have an increased risk of malignancy, especially lymphoproliferative disorders. We decribe the occurrence of ileocaecal intussusception secondary to Burkitt's lymphoma in a patient with SLE. A 23-year-old woman, who had been diagnosed with SLE 2 years ago, developed intermittent abdominal pain with a palpable mass. Computed tomography and a double-contrast barium enema showed a lobulated mass with intussusception at the ileocaecal junction. Right hemicolectomy and splenectomy was performed after histopathological examinations on colonoscopic biopsy revealed Burkitt's lymphoma. Fourteen months after chemotherapy, there is no evidence of recurrence of the Burkitt's lymphoma. When a patient with SLE has abdominal complaints, besides serositis, lupus enteritis such as peptic ulcer disease, mesenteric vasculitis with or without complications and pancreatitis, we have to consider intussusception secondary to gastrointestinal lymphoma as one of the differential diagnoses. Therefore, we should thoroughly investigate patients with SLE presenting with abdominal pain and not simply consider it afeature of lupus enteritis until other causes have been ruled out.

 

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL	Diffuse infiltrate of monotonous medium-sized cells Many interspersed macrophage imparting a starry sky pattern Lymphoma cells are medium sized with brisk mitotic activity Nuclei and cytoplasm show squaring of their contours Chromatin in coarse and multiple nucleoli seen with many apoptotic bodies Some cells show small cytoplasmic vacuoles, consistent with lipid vacuoles
VARIANTS
BURKITT-LIKE LYMPHOMA	Also known as a small non-cleaved cell lymphoma Currently, recommended that the term be restricted to lymphomas believed to be related to Burkitt lymphoma with proven or strong presumptive evidence of c-myc gene translocation Morphologically similar to Burkitt lymphoma, except that there is somewhat greater pleomorphism of nuclear size and shape, and nucleoli are more prominent and fewer in number Almost 100% of the cells are Ki67 positive
Burkitt-like lymphomas in AIDS patients: characterization within a series of 103 human immunodeficiency virus-associated non-Hodgkin's lymphomas. Burkitt's Lymphoma Study Group. Davi F, Delecluse HJ, Guiet P, Gabarre J, Fayon A, Gentilhomme O, Felman P, Bayle C, Berger F, Audouin J, Bryon PA, Diebold J, Raphael M. Departement d'Hematologie and Unite Recherche Associee du Centre National de la Recherche Scientifique 625, Hopital Pitie-Salpetriere, Paris, France.	J Clin Oncol 1998 Dec;16(12):3788-95 Abstract quote PURPOSE: Burkitt-like lymphoma (BLL) is a tumor with morphologic features intermediate between Burkitt's lymphoma (BL) and large-cell lymphoma, but its relationship with these lymphomas is currently unclear. We have therefore analyzed its characteristics within a large series of human immunodeficiency virus (HIV)-associated lymphomas. MATERIALS AND METHODS: Clinical, histologic, immunophenotypic, and molecular analyses were performed on 103 patients with AIDS lymphomas. RESULTS: Nineteen cases (18.4%) were identified as BLL. They were monoclonal B-cell proliferations, as evaluated by immunoglobulin (Ig) gene rearrangement analyses, and had rearrangement of the c-myc oncogene in 68% of cases but not the bcl-2 gene, in contrast to a previous study on non-HIV-associated BLL. This molecular pattern was therefore identical to that of typical BL, suggesting that they represented tumors of similar origin. However, some features could clearly differentiate BLL from BL and were similar to those seen in the diffuse large-cell immunoblastic lymphomas (DLC-IBL) group. These included a greater frequency of Epstein-Barr Virus (EBV) infection (79% v 48%, P = .04), an upregulation of CD39 (50% v 0%, P = .0007) and CD70 (75% v 15%, P = .003) activation antigens and of the CD11a/LFA-1 adhesion molecule (83% v30%, P = .05), and, finally, a lower CD4 count (mean, 119/microL v 270/microL, P = .04). CONCLUSION: BLL is a frequent entity among AIDS lymphomas and should be considered as a morphologic variant of BL in the context of severe immunodepression that occurs in HIV-infected patients.

 

SPECIAL STAINS/IMMUNOPEROXIDASE/ OTHER	CHARACTERIZATION
SPECIAL STAINS
IMMUNOPEROXIDASE	CD20+ CD10+ CD3- Tdt- Ki-67 index ~100%
CD5+ Burkitt lymphoma/leukemia. Lin CW, O'Brien S, Faber J, Manshouri T, Romaguera J, Huh YO, Kantarjian H, Keating M, Albitar M. Department of Laboratory Medicine, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA. .	Am J Clin Pathol 1999 Dec;112(6):828-35 Abstract quote CD5 is a T-cell marker aberrantly expressed in B-cell chronic lymphocytic leukemia and mantle cell lymphoma. Other B-cell neoplasms, including Burkitt lymphoma, are usually CD5-. We report 4 cases of de novo CD5+ Burkitt lymphoma/leukemia in elderly patients, all of whom were in a leukemic phase and had variable lymph node and splenic involvement. The blasts were typically medium sized, with folded nuclei, distinct but not prominent nucleoli, and moderate amounts of somewhat vacuolated basophilic cytoplasm; they were terminal deoxynucleotidyl transferase--negative and surface immunoglobulin--positive. All 4 cases demonstrated c-myc rearrangement, but none had t(14;18), t(11;14), or cyclin D1 overexpression or rearrangement. Only 1 patient achieved complete remission after hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone) therapy. One patient responded poorly to hyper-CVAD, and 2 patients died during induction chemotherapy. These rare cases of aggressive lymphoid malignancy with CD5 positivity and molecular features associated with Burkitt lymphoma/leukemia are best classified as Burkitt leukemia. However, the morphologic and immunophenotypic similarity to the blastoid variant of mantle cell lymphoma are diagnostically challenging. The diseases can be distinguished at the genetic level, since Burkitt lymphoma involves the rearrangement of c-myc, and mantle cell lymphoma usually the overexpression or rearrangement of cyclin D1.
Burkitt lymphoma is immunophenotypically different from Burkitt-like lymphoma in young persons. Hutchison RE, Finch C, Kepner J, Fuller C, Bowman P, Link M, Schwenn M, Laver J, Desai S, Barrett D, Murphy SB. State University of New York Health Science Center, Syracuse, USA.	Ann Oncol 2000;11 Suppl 1:35-8 Abstract quote INTRODUCTION: Burkitt-like lymphoma (BLL) is a provisional category of B-cell lymphoma which is morphologically intermediate between Burkitt lymphoma (BL) and large B-cell lymphoma (LBCL). The clinical significance of this morphology is controversial. PATIENTS AND METHODS: We examined 41 cases of pediatric B-cell lymphoma by immunohistochemistry for proteins associated with proto-oncogenes c-myc, BCL-2 and BCL-6 and a subset of cases (with adequate slides) for a proliferation-associated marker (Ki-67) and for apoptosis (Apop-Tag). Sixteen cases of BLL, thirteen cases of BL and twelve cases of LBCL were examined. RESULTS: Our results showed BCL-6 expression in 16 of 16 BLL, 4 of 13 BL, and 9 of 12 LBCL; c-myc expression in 14 of 15 BLL, 9 of 13 BL, and 12 of 12 LBCL; and BCL-2 expression in 2 of 16 BLL, 9 of 13 BL, and 6 of 12 LBCL. Mean apoptotic index for BLL was 10.3% (n = 6); for BL was 17.1% (n = 5); and for LBCL was 10.9% (n = 6). Ki-67 was diffusely reactive in all cases tested. There was a significantly higher proportion of BLL than BL which expressed BCL-6 (P = 0.0001). CONCLUSIONS: Labeling for BCL-6 distinguishes BLL from BL. It is likely that in children in North America, BLL is biologically distinct from BL and more closely resembles a subset of LBCL

 

DIFFERENTIAL DIAGNOSIS

KEY DIFFERENTIATING FEATURES

	LYMPHOBLASTIC LYMPHOMA	BURKITT LYMPHOMA
NUCLEI	Round or convoluted, usually no significant molding	Usually round, but occasionally may show nuclear protrusions Prominent nuclear molding, with squaring of nuclear membrane
CHROMATIN PATTERN	Fine, dusty	Coarsely granular
NUCLEOLI	Inconspicuous	Distinct, 2-5 nucleoli, often not membrane bound
CYTOPLASM	Scanty and barely visible in routine histologic sections In Giemsa stained touch preparations, cytoplasm is apparently found only around part of the perimeter of the nucleus	Definite rim of basophilic to plasmacytoid cytoplasm, with squaring of cytoplasmic outline In Giemsa-stained touch preparations, small lipid vacuoles are found in the basophilic cytoplasm
LINEAGE	Usually T-lineage, sometimes B or NK lineage	Always B lineage
TdT	Positive	Negative
Ki-67	High, usually <80%	~100%

ADDITIONAL DISEASES
DIFFUSE LARGE B-CELL LYMPHOMA
The Distinction between Burkitt Lymphoma and Diffuse Large B-Cell Lymphoma with c-myc Rearrangement. Nakamura N, Nakamine H, Tamaru J, Nakamura S, Yoshino T, Ohshima K, Abe M. Department of Pathology, Fukushima Medical University School of Medicine (NN, MA), Japan.	Mod Pathol 2002 Jul;15(7):771-6 Abstract quote To compare immunophenotypic and molecular features between Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) with c-myc rearrangements (c-myc(R) DLBCL), we analyzed 18 cases of B-cell non-Hodgkin's lymphoma with c-myc(R) that were confirmed by chromosomal and/or Southern blotting analyses. The cases were histologically classified into 10 BLs and five DLBCLs. The remaining three cases could not be classified because of suboptimal quality of the surgical materials. BLs were from five adults and five children, whereas all DLBCLs were from adults. BLs were positive for CD20 (10/10 cases examined), CD10 (9/10), Bcl-2 (1/9), and Bcl-6 (10/10), whereas they were negative for CD3 (0/10) and EBV (0/8), by Epstein-Barr virus (EBV) EBER-1 RNA in situ hybridization. c-Myc(R) DLBCLs were positive for CD20 (5/5), CD10 (2/5), Bcl-2 (3/4), and Bcl-6 (4/4), whereas none of them were positive for CD3 and EBV. A mean of MIB-1 index (MIB-1(+) cells/neoplastic cells, %) of BLs (98.1%) was higher than that of c-myc(R) DLBCLs (66.3%; P <.0001). Somatic mutation of immunoglobulin heavy-chain gene variable region (VH gene) in BLs (four cases) ranged from 0.7 to 4.9% with an average value of 2.3%, whereas those in DLBCLs (three cases) from 8.2 to 32.0% with an average value of 17.0%. It is, therefore, concluded that a growth fraction of nearly 100%, as well as a monotonous proliferation of medium-sized cells and c-myc(R), should be of value in the diagnosis of BL, which is probably different from c-myc(R) DLBCL. In addition, CD10(+), Bcl-2(-), and low frequency of mutation of the VH gene could be helpful for the histologic distinction of BL from (c-myc(R)) DLBCL.

 

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSTIC FACTORS
Adult Burkitt's lymphoma: clinical and prognostic evaluation of 20 patients. Zinzani PL, Gherlinzoni F, Bendandi M, Salvucci M, Tura S. Institute of Hematology, L. e A. Seragnoli, University of Bologna, Italy.	Leuk Lymphoma 1994 Aug;14(5-6):465-70 Abstract quote Burkitt's lymphoma (BL), a rapidly growing lymphoma, is recognized by its aggressive course, brief median survival, and low rates of long-term survival for patients. Several polychemotherapeutic approaches are utilized. Twenty adult patients with BL identified according to the Kiel classification were analysed retrospectively. Therapeutic modifications depended upon the different times of the diagnosis. Eight patients received the LSA2-L2 regimen, 11 patients were treated with third generation polychemotherapeutic regimens for high-grade non-Hodgkin's lymphomas: F-MACHOP and MACOP-B, and 1 elderly patient was given the COP regimen. Of the 11 patients treated with cyclic conventional therapy (7 with F-MACHOP and 4 with MACOP-B), 8 achieved a complete response (CR). Of the 8 patients who were given the LSA2-L2 protocol, 4 obtained a CR. One elderly patient treated with the COP regimen obtained a partial response. Early stage of disease, low levels of LDH, and the absence of bone marrow involvement were characteristics of patients with good prognoses. Effective conventional third-generation polychemotherapy regimens (F-MACHOP and MACOP-B), normally used for high-grade non-Hodgkin's lymphomas, were equally effective for a large fraction of adults with BL. Furthermore, our study confirms the important role of LDH level, stage, and bone marrow involvement as prognostic factors in BL as well as the roles of tumor burden in the CR rate and relapse-free survival.
Non-Hodgkin's lymphoma protocols in the treatment of patients with Burkitt's lymphoma and lymphoblastic lymphoma: a report on 58 patients. Kaiser U, Uebelacker I, Havemann K. Philipps-Universitat Marburg, Dept of Hematology/Oncology, Germany.	Leuk Lymphoma 1999 Dec;36(1-2):101-8 Abstract quote Lymphoblastic lymphoma (LBL) and Burkitt's lymphoma belong to the very aggressive lymphomas requiring intensive therapy. We retrospectively analyzed 29 patients with Burkitt's lymphoma and 29 patients with LBL who received induction therapy with a CHOP-like lymphoma protocol. Patients with Burkitt's lymphoma (with a median age of 54.5 years) have a CR rate of 72% and a lymphoma free long-time survival of 55%. The International Prognostic Index was the most valuable prognostic factor for survival. Patients with LBL with a median age of 45 years had a CR rate of 55% and a lymphoma-free survival of 38%. Stage was the most predictive prognostic factor. Our data suggest that for older patients (>50) treatment with lymphoma protocols may yield response rates that are comparable to the results of patients with disseminated diffuse large cell lymphoma. Younger patients with risk factors should be treated with more intensive therapy like ALL-protocols. The role of auto-transplantation after high dose therapy (HDT) however as part of primary treatment still needs to be evaluated in clinical trials. One of four patients with LBL who received HDT and one of four patients with Burkitt's lymphoma who received HDT achieved long-term remission.
Expression of Epstein-Barr virus lytically related genes in African Burkitt's lymphoma: correlation with patient response to therapy. Labrecque LG, Xue SA, Kazembe P, Phillips J, Lampert I, Wedderburn N, Griffin BE. Department of Infectious Diseases (Virology), Imperial College School of Medicine, Hammersmith Hospital, London, UK.	Int J Cancer 1999 Mar 31;81(1):6-11 Abstract quote A study on the Epstein-Barr virus (EBV)-associated malignancy (endemic) Burkitt's lymphoma (BL) was initiated on fine-needle-aspiration biopsies from 46 proven BL cases in Malawi. Gene expression that might correlate with patient serology (where high levels of antibodies to lytically related genes are commonly observed) was explored. In two-thirds of the cases, we identified the EBV BZLF1 replication activator intermediate early protein ZEBRA in varying quantities and to varying extents in cells by immuno-cytochemistry. The early lytic-cycle gene transcript BHLF1 was assessed positively by solid-phase hybridisation in over half of the same tumours. Evidence of transcription of these genes was confirmed on a smaller number of surgically removed fresh biopsies by RT-PCR. We asked whether our findings, which are generally counter to the established notion that EBV gene expression in BLs is restricted to the latent function, EBNA1, might offer some explanation for the differential responses to chemotherapy observed among African patients. Where the duration of follow-up was sufficient to assign the cases (37 in number) to one of 3 categories, namely, complete, partial or no response, a significant correlation between expression of the viral function ZEBRA and a positive patient response to treatment was found. Lack of this was associated with poor prognosis. Clinical data and EBV gene expression results support the postulate of subgroups of African BLs, the intermediate early antigen providing a marker of potential use in patient management.
TREATMENT
Treatment of poor prognosis Burkitt's lymphoma in adults with the Societe Francaise d'Oncologie Pediatrique LMB Protocol--a study of the Federation Nationale des Centres de Lutte Contre le Cancer (FNLCC). Philip T, Meckenstock R, Deconnick E, Carrie C, Bailly C, Colombat P, Dauriac C, Demaille MC, Salles B, Cahn JY, et al.	Eur J Cancer 1992;28A(12):1954-9 Abstract quote 14 adult patients between 16 and 50 years old with small non-cleaved cell lymphoma (Burkitt's lymphoma) were prospectively treated from 1982 to 1990 with the LMB protocols of the Societe Francaise d'Oncologie Pediatrique (SFOP). No HIV-positive patients were included. All patients had extensive disease with bad prognosis factors, i.e. 10 patients had Murphy stage III and 4 had stage IV with bone marrow involvement. The LMB protocols were characterised by high-dose fractionated cyclophosphamide, high-dose methotrexate (HD-MTX), and cytosine arabinoside. No local or central nervous system irradiation was used. Treatment duration ranged from 5 (LMB 84) to 12 (LMB 81) months. There were no therapy-related deaths. All patients achieved complete remission (CR). 6 patients relapsed between 2 and 30 months following CR. 8 of the 14 patients (57%) are still alive and disease-free after treatment by LMB protocol alone. 2 patients were salvaged with bone marrow transplantation after relapse and a total of 10 out of 14 patients (71%) are disease-free at the time of this report. Our results showed the high curability of advanced Burkitt's lymphoma using a paediatric protocol, even in adult patients. The LMB protocol may be applied to adult patients but requires intensive care during the induction period.
Curability of advanced Burkitt's lymphoma in children by intensive short-term chemotherapy. Gasparini M, Rottoli L, Massimino M, Gianni MC, Ballerini E, Ravagnani F, Pupa S, Fossati-Bellani F. Division of Pediatric Oncology, Istituto Nazionale Tumori, Milan, Italy	Eur J Cancer 1993;29A(5):692-8 Abstract quote The treatment programme (regimen I) we designed in 1982 for advanced Burkitt's lymphoma was modified in 1986 as regimen IIA and IIB for patients presenting without or with bone marrow (BM) and/or nervous system involvement, respectively. Following a 5-week course of cytoreductive chemotherapy, including vincristine (VCR), cyclophosphamide (CPM), doxorubicin (DXR), high-dose methotrexate (HDMTX) and intrathecal methotrexate and cytarabine (ARAC), high-dose ARAC and cisplatin were given as a 4-day continuous infusion. Regimen I continued with an additional 3-week course including VCR, CPM, DXR and HDMTX, which was omitted in regimen IIA. In regimen IIB the initial cytoreductive chemotherapy was complemented by adding etoposide and increasing HDMTX doses, and by modifying the high-dose ARAC administration modality and was followed, once the bone marrow had recovered, by ifosfamide that concluded the programme. A total of 44 children (22 in regimen I and 22 in regimens IIA and IIB) were treated, with an overall response rate of 98%. 4 patients died as a result of treatment related complications. Survival, progression-free and event-free survival rates were 73, 70 and 63%, respectively, for regimen I, and 82, 90 and 82%, respectively, for regimen IIA and IIB. A short chemotherapeutic regimen, using alternating phase-specific and non-specific agents, is able to cure the majority of patients with advanced Burkitt's lymphoma.
Aggressive chemotherapy in the treatment of Burkitt's and non-Burkitt's undifferentiated lymphoma. Mazza JJ, Hines JD, Andersen JW, Neiman RS, Mann R, Oken MM, O'Connell MJ. Department of Hematology/Oncology, Marshfield Clinic, WI 54449, USA.	Leuk Lymphoma 1995 Jul;18(3-4):289-96 Abstract quote Because of the aggressive nature and frequent recurrence of malignant lymphomas of the undifferentiated type, we used a multi-drug induction chemotherapy regimen that has met with some success in children with similar type of histopathology followed by intensification and 8 cycles of consolidation chemotherapy in an attempt to prolong the duration of remission and survival in adult patients with this diagnosis. Fifty-one patients (median age 35 years) with undifferentiated malignant lymphoma were collected over a 4 year period (1984-1988) and entered into a phase III protocol done under the auspices of the Eastern Cooperative Oncology Group (ECOG). Six patients who had their diagnosis made at surgery and had resection of their tumor were excluded from analysis of response to therapy. Sixty percent of the patients had Stage IV disease. Sixteen patients had marrow involvement and five had central nervous system (CNS) disease. None of the patients received CNS radiation therapy. The 45 patients evaluated for response showed a response rate of 67% (30/45) and a complete response rate of 40% (18/45). Thirteen responders continue disease-free with a median follow-up of > 40 months and have an estimated 5 year survival of 80%. Only two treatment related deaths were reported for the entire group. Patients with undifferentiated non-Burkitt's lymphoma had a longer survival than those with undifferentiated Burkitt's. We concluded that adult patients with undifferentiated lymphomas could be treated successfully with an aggressive multi-drug chemotherapy regimen, consisting of multiple alternating cycles of non-crossed-resistant chemotherapy. Toxicity with this aggressive prolonged regimen was acceptable.
Initial management of advanced Burkitt lymphoma in children: is there still a place for surgery? Miron I, Frappaz D, Brunat-Mentigny M, Combaret V, Buclon M, Bouffet E, Thiesse P, Ragg S, Bailly C, Philip T. Pediatric Department, Centre L. Berard, Lyon, France.	Pediatr Hematol Oncol 1997 Nov-Dec;14(6):555-61 Abstract quote This retrospective study compared the overall survival, the event-free survival, and the timing of chemotherapy in patients with advanced Burkitt lymphoma with and without laparotomy. Thirty-five patients with advanced abdominal Burkitt lymphoma treated at least partially at the Centre Leon Berard between 1981 and 1992 were included in this study. The diagnosis was obtained by laparotomy (LAP group) in 21 patients (17 stage III, 4 stage IV) and by other methods (non-LAP group) in 14 patients (5 stage III, 9 stage IV). The overall survival (71 and 93%) and the event-free survival (66 and 79%) were similar in the LAP and non-LAP groups, and the relapse rate was five (three local) in the LAP group compared with three (none local) in the non-LAP group. The local complication rate (9 of 21 versus 2 of 14) and the toxic death rate (2 of 21 versus 1 of 14) were slightly higher in the LAP group. Laparotomy also caused delays in therapy and increased the overall hospital stay. The mean interval from diagnosis to the start of the fourth course of chemotherapy was 57 days compared with 48 days and the average hospital stay was 44.4 days compared with 39 days for the LAP and non-LAP groups, respectively. Because advanced Burkitt lymphoma can be diagnosed by fine-needle aspiration, and chemotherapy cures more than 80% of the patients, there is no need for initial surgery, apart from acute emergencies. Furthermore, laparotomy delay chemotherapy and might reduce the survival rate.
Eighty-one percent event-free survival in advanced Burkitt's lymphoma/leukemia: no differences in outcome between pediatric and adult patients treated with the same intensive pediatric protocol. Todeschini G, Tecchio C, Degani D, Meneghini V, Marradi P, Balter R, Zanotti R, Ricetti M, Franchini M, Perona G. Department of Hematology, University of Verona School of Medicine, Italy.	Ann Oncol 1997;8 Suppl 1:77-81 Abstract quote BACKGROUND: Advanced Burkitt's lymphoma (BL) has an extremely poor prognosis in adults. With a previous protocol including CNS prophylaxis, 40% of our adult patients achieved CR and only 13% became long survivors. In 1988, following this poor experience, we adopted a very intensive pediatric-derived protocol. PATIENTS AND METHODS: Twenty-one consecutive patients, 8 adults (median age 35, stage III: 1; IV: 7; leukemias: 6) and 13 children (median age 10, state III: 8; IV: 5; leukemias: 4) were treated with the same protocol (POG 8617), based on alternate two-phase cycles with sequential high-dose CTX, VCR, ADM + CNS chemoprophylaxis (phase A) and HD MTX + HiDAC (phase B). Adults received 6 cycles, children 8; i.t. prophylaxis in phase B was omitted in adults. RESULTS: Twenty of 21 (95%) patients achieved CR (adults 100%, children 92%). Two patients died early; 2 relapsed at 4 and 9 months. With a median follow-up of 28 months (4-96), 17 patients (81%) are event free (adults 75%, children 85%). Severe infections affected 62% of adults and 15% of children. CONCLUSIONS: (1) The prognosis of adult advanced BL definitely improved with this intensive protocol. (2) There were no differences in outcome between adults and children. (3) Outcome of lymphoma and leukemia was similar. (4) Severe infections occurred frequently in adults. This intensive pediatric protocol requires a careful supportive therapy.
Hyper-CVAD program in Burkitt's-type adult acute lymphoblastic leukemia. Thomas DA, Cortes J, O'Brien S, Pierce S, Faderl S, Albitar M, Hagemeister FB, Cabanillas FF, Murphy S, Keating MJ, Kantarjian H. Departments of Leukemia, Hematopathology, and Lymphoma, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.	J Clin Oncol 1999 Aug;17(8):2461-70 Abstract quote PURPOSE: To evaluate response and outcome with a front-line intensive multiagent chemotherapy regimen in adults with Burkitt's-type acute lymphoblastic leukemia (B-ALL). PATIENTS AND METHODS: From September 1992 to June 1997, 26 consecutive adults with newly diagnosed untreated B-ALL received hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD). Their median age was 58 years (range, 17 to 79 years), and 46% were > or = 60 years. Patients received Hyper-CVAD alternated with courses of high-dose methotrexate and cytarabine. Granulocyte colony-stimulating factor and prophylactic antibiotics were administered for all eight planned courses. CNS prophylaxis alternated intrathecal methotrexate and cytarabine on days 2 and 7 of each course. RESULTS: Complete remission (CR) was obtained in 21 patients (81%). There were five induction deaths (19%). The median time to CR was 22 days (range, 15 to 89 days); 70% achieved CR within 4 weeks. The 3-year survival rate was 49% (+/- 11%); the 3-year continuous CR rate was 61% (+/- 11%). Twelve CR patients (57%) were in continuous CR at a median follow-up of 3+ years (range, 13+ months to 6.5+ years). Characteristics predicting for worse survival were age > or = 60 years, poor performance status, anemia, thrombocytopenia, peripheral blasts, and increased lactate dehydrogenase level. The 3-year survival rate was 77% for 14 patients younger than 60 years and 17% for 12 patients > or = 60 years (P <.01). Regression analysis identified older age, anemia, and presence of peripheral blasts as independent factors associated with shorter survival. Patients could be stratified according to (1) no or one adverse feature, (2) two adverse features, and (3) all adverse features. The 3-year survival rates were 89%, 47%, and 0%, respectively (P <.01). CONCLUSION: Hyper-CVAD is effective in adult B-ALL. Identification of patients with high risk for relapse and improved methods to detect residual disease may result in risk-oriented approaches.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Eight Edition. Mosby 1996.
Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Taken from Chan JKC. Practical Lymphoma Diagnosis: A Simplified Approach. Presented at the 111th Semi-Annual California Tumor Tissue Registry. December 2001.

Lymphoma

Last Updated 8/19/2002

Send mail to psdermpath@earthlink.net with questions or comments about this web site.
Copyright © 2002 The Doctor's Doctor