, . 182: 125–127 (1997)

EDITORIAL

WHAT IS BURKITT’S LYMPHOMA?

SUMMARY

Burkitt’s lymphoma (BL) has been defined on the basis of its characteristic cytomorphology. Although histologically identical,endemic BL and sporadic BL are distinct clinico-anatomical entities. Their morphological identity probably relates to similarchromosomal translocations in both tumours, resulting in c-myc de-regulation and consequent unrestrained proliferation withoutdifferentiation. Similar gene rearrangements are found in a proportion of AIDS-related lymphomas that are predominantly extranodaland have the cytomorphology of BL. The term ‘‘Burkitt-like lymphoma’’ (BLL) has been applied to a group of high-grade B-celllymphomas that appear morphologically intermediate between BL and centroblastic/immunoblastic lymphomas, as detailed in anaccompanying paper in this issue. These tumours do not usually show c-myc gene rearrangements. The association of Burkitt’s namewith such a disparate group of tumours is confusing and new terminology for sporadic BL, AIDS-related BL and BLL is desirable. Itis important that clinico-anatomical features, as well as cytomorphology, should be taken into account in the diagnosis of endemic BL.The origin of a case from tropical Africa does not, in itself, imply that it is endemic BL, even more since the AIDS epidemic in thatcontinent. ? 1997 by John Wiley & Sons, Ltd.

J. Pathol. 182: 125–127, 1997.No. of Figures: 0. No. of Tables: 0. No. of References: 21.

KEY WORDS—Burkitt’s lymphoma; c-myc; AIDS-related lymphomas

INTRODUCTION

The eponym Burkitt’s lymphoma (BL) recognizes theunique contribution of Denis Burkitt in describing theclinical features of this tumour, delineating its geo-graphical distribution and pioneering its treatment withchemotherapy.1,2 The use of an eponym without adefinition, however, led to confusion, particularly in thewake of numerous reports (often of single cases of BL)from many non-African countries. In order to clarify thesituation, the World Health Organisation, in collabor-ation with the International Agency for Research onCancer, organized a meeting of 18 haematopathologistswith a particular interest in BL, with the purpose offormulating a definition of this tumour.3 The con-clusions of this meeting were ‘the eponym Burkitt’stumour is best applied to a malignant neoplasm of thehaematopoietic system composed of a predominant andcharacteristic cell type’. The detailed histomorphologyof the tumour was described with an emphasis on thenecessity for high-quality histological preparations andthe use of imprint cytology when possible. The groupconcluded that ‘Burkitt’s tumour, as defined above, isnot limited to Africa and occurs in many parts of theworld’. It should be noted that two members of thegroup dissented from this view, regarding BL as aclinico-pathological concept only and rejecting the con-cept that BL exists in a specific histological and cytologi-cal sense. With almost 30 years of hindsight, one canrecognize that this minority view was, at least partly,correct.The establishment of the American BL registry led to

the collection of a substantial number of cases of BL, asdefined by histology. It soon became apparent that theAmerican cases of BL, although occasionally closelyresembling African cases, differed as a group by having

a lower incidence of jaw tumours and a higher incidenceof abdominal involvement.4 In a recent study ofchildhood non-Hodgkin’s lymphoma in the U.K. 130of 308 cases (42·2 per cent) were categorized as BL. Ofthese, 87 had abdominal tumours with 37 specified asbeing in the ileocaecal region. Nine cases involvedWaldeyer’s ring and none had jaw involvement.5 Thisanatomical distribution is unlike that of African BL,which rarely involves the ileocaecal region or Waldeyer’sring.6,7 These two diseases, designated as endemic BL(eBL) and sporadic BL (sBL), are clearly differentclinico-pathological entities sharing a common cytomor-phology. The reason for this histological identity may bedue to the fact that both tumours show translocations ofthe c-myc oncogene and the immunoglobulin genes.Consequent deregulation of c-myc leads to continuousreplication of cells that are unable to differentiate and,therefore, appear cytologically indistinguishable. eBLand sBL usually differ in the position of the breakpoints,in relation to both c-myc and the immunoglobulingenes,8 although this varies in different parts of theworld, with intermediate patterns of breakpoints occur-ring in South America.9 The position of the breakpointon the immunoglobulin gene in sBL suggests that thistumour may arise later in B-cell ontogeny than eBL.10The histogenesis of eBL and sBL probably differs.

Mann et al.11 studying American cases of BL, noted anapparent transition between reactive follicles and follicu-lar and diffuse BL, and proposed that BL was of folliclecentre cell derivation. This hypothesis is supported bythe expression of CD10 on some BL cells.12 This transi-tion from follicular to diffuse growth is not seen in eBL,which I have proposed may be of MALT derivation.13This hypothesis is based on the mainly extranodaldistribution of BL and, in particular, the massive breastinvolvement seen in pregnant and lactating females with

CCC 0022–3417/97/060125–03 $17·50 Received 26 November 1996? 1997 by John Wiley & Sons, Ltd. Accepted 16 January 1997

BL, a feature reminiscent of the migration of MALTB-cells to the breast in adoptive transfer experiments insyngeneic mice. Evidence of epitheliotropism by BL cellsmay also support this hypothesis.Our understanding of BL has been somewhat con-

fused by the use of the term ‘Burkitt-like lymphoma’(BLL) (small non-cleaved cell, non-Burkitt, in theRappaport classification). These tumours often showmoderate degrees of nuclear pleomorphism and appearto be intermediate in appearance between BL andcentroblastic/immunoblastic lymphomas. They oftenshow cytogenetic and molecular characteristics of fol-licle centre cell lymphomas, rather than BL.14 TheInternational Lymphoma Study Group (ILSG), whichformulated the revised European/American lymphomaclassification, found that they could not reliably distin-guish BLL from other types of diffuse, large B-celllymphoma.15 A high proportion of AIDs-associatedNHLs are extranodal and are histologically categorizedas BL or BLL.16 Many of these have c-myc generearrangements, similar to those seen in sBL.17 EBV isdetected in 40–67 per cent of AIDs-associated NHL,although this association appears to be more commonin the category of immunoblastic lymphoma than in BLor BLL.18In this issue of the journal, Spina et al.19 have

compared the cell kinetics and immunophenotype of teneBLs collected from the lowland areas of Kenya, whereBL is endemic, and ten sBLs and 12 BLLs from northernItaly. Differences between the groups emerge, with eBLand BLL having higher mitotic and lower apoptoticindices, suggesting that they grow faster than sBL.Labelling indices for bcl-2 were higher in BLL than ineBL or sBL, whereas those for c-myc and bcl-6 showedthe reverse trend. Nine of the ten eBLs were EBV-positive, as determined by EBER expression, whereasthree of the ten sBLs were positive, consistent withprevious studies of sBL. A major problem with thisstudy is the apparent assumption that all the casesderived from lowland Kenya are eBL because of theirgeographical location. Three cases stand out from therest in being HIV-positive, in their 20s, and havingtumours in the cervical lymph nodes in two cases and inthe ileum in one. These clearly do not conform to thetumour syndrome described by Denis Burkitt and areprobably better designated as AIDs-related BL. If thesepatients are removed from the eBL cases, the mean agedrops from 13·5 to 7 years and the four youngest of theremaining patients have jaw/orbit involvement, consist-ent with eBL. The sBL patients had a mean age of 22years; five had involvement of the cervical lymph nodesand five had tumours of the ileum (the paper does notdistinguish between tumours of the terminal ileum,characteristic of sBL, and tumour nodules, throughoutthe small bowel, which are seen in eBL). It is importantthat the definition of eBL should take into accountmore than the geographical location of the case. Wehave no reason to suppose that sBL does not occur inendemic areas and the high prevalence of HIV infectionin Africa will undoubtedly result in many AIDs-relatedBLs that probably have a different aetiopathogenesisfrom eBL.

Undoubtedly, many people have been confused by theuse of the terms ‘eBL’, ‘sBL’, and ‘BLL’ (and theirsynonyms). The minority group on the Working Partythat defined BL3 were correct in demanding that clinico-pathological features, as well as histology, were requiredfor the definition of this tumour. Most cases of sBL havecharacteristic clinico-pathological features, with a highincidence of tumour in the ileocaecal region andoropharynx, unlike eBL, although rare cases of sBLhave jaw tumours and other features characteristic ofthe endemic tumour.20 It would be of interest andimportance to study the molecular genetics of suchcases. It is unfortunate that the eponym BL is used forthe sporadic form of the disease. Perhaps the ILSGcould follow-up their spectacular success with mantlecell lymphoma21 in finding an appropriate name for thistumour. This same group proposes the term ‘high-gradeB-cell lymphoma, Burkitt-like’ as a provisional categoryfor tumours that have a morphology intermediatebetween centroblastic/immunoblastic lymphomas andBL. It is a pity that the name Burkitt is again attached toa tumour that, in general, does not have the clinico-pathological or molecular genetic characteristics ofBL.15 It is uncertain whether this tumour has anyunifying characteristics, other than morphology, andit might be better designated as ‘high-grade B-celllymphoma, basophilic’, eliminating the term ‘BLL’.

D. H. WDepartment of Pathology,University of Southampton,Level E (813) South Block,

Southampton General Hospital,Tremona Road,

Southampton SO16 6YD

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? 1997 by John Wiley & Sons, Ltd. J. Pathol. 182: 125–127 (1997)