intrODuCtiOn

the aim of a lymphoma classification is to provide a singlelanguage allowing communication between different partiesinvolved in the management of the disease. the classifica-tion should be reproducible and clinically relevant.

hodgkin lymphoma (hl) and non-hodgkin lympho-mas (nhl) are classified separately. two classifications ofhl were proposed since 1925 versus more than 25 classi-fications of nhl. when seeing the diverse courses thatcould follow a nhl, with its different outcomes and sur-

vival as well as response to therapy, many classificationshave been proposed and modified over time.

the term lymphoma was first used in 1858 and the firstclassifications were based on morphology (Americanregistry of pathology in 1934, robb-Smith in 1938, Galland Mallory in 1942 and Jackson and parker in 1939 and1947).

the Classification for hodgkin disease was proposed ina conference in rye (ny) in 1966. it involves a modifica-tion of lukes-Butler classification and divided hodgkindisease into four histologic types: lymphocyte predomi-nance (lp), nodular sclerosis (nS), mixed cellularity (MC)and lymphocyte depleted (lD) [1].

in 1966, rappaport proposed a new classification basedon morphology using cytology and architecture. in 1976, amodified rappaport Classification was established [2,3].

Lebanese Medical Journal 2018 • Volume 66 (1) 21

ARTICLE ORIGINAL / ORIGINAL ARTICLEEPiDEMioLoGy AnD SuBTyPE DiSTRiBuTion oF LyMPHoiD nEoPLASMS FRoM A SinGLE inSTiTuTion in LEBAnon BETWEEn 2010 AnD 2014http://www.lebanesemedicaljournal.org/articles/66-1/original4.pdf

Valerie AftiMOS1,2*, Sahar rASSi-zAnKOul1, zahraa nAJJAr1, Georges AftiMOS1

Aftimos V, rassi-zankoul S, najjar z, Aftimos G. epidemiolo-gy and subtype distribution of lymphoid neoplasms from a singleinstitution in lebanon between 2010 and 2014. J Med liban2018 ; 66 (1) : 21-27.

Aftimos V, rassi-zankoul S, najjar z, Aftimos G. épidémiolo-gie et distribution par sous-type des néoplasies hémato-lympha-tiques au liban entre 2010 et 2014: expérience d’un laboratoire.J Med liban 2018 ; 66 (1) : 21-27.

ABSTRACT • The 2008 WHO classification is the goldstandard for classifying hematopoietic neoplasms. Ourstudy reviewed 1256 cases between the years 2010 and2014. It aimed to establish a descriptive status of lymphomacases in Lebanon. Hodgkin lymphomas (HL) accounted for21% of all cases whereas non-Hodgkin lymphomas (NHL)accounted for 79%. In NHL, mature B-cell neoplasmsaccounted for 85% and mature T-cell neoplasms accountedfor 9%. For mature B-cell neoplasms, the majority of cases(48%) were diffuse large B-cell lymphomas (DLBCL). WithinT-cell lymphomas, anaplastic lymphoma (ALCL 40%) wasthe most prevalent. The distribution within subtypes con-firmed the findings of two previous Lebanese studies. Ourfigures of HL are higher than in Eastern and Western coun-tries. This could probably be related to EBV infection amongother etiologies. Our NHL figures are close to the Westernworld. Westernization of the way of life of the Lebanesesociety could explain this result.

Keywords : hematopoietic neoplams; lymphoma; Hodgkinlymphoma; non Hodgkin lymphoma; epidemiology

RÉSUMÉ • La classification de l’OMS de 2008 est actuelle-ment la référence standard pour la classification des néopla-sies hémato-lymphatiques. Notre étude est une étude descrip-tive des cas de lymphomes au Liban, dans laquelle 1256cas de lymphomes diagnostiqués entre 2010 et 2014 ont étérevus. Elle a démontré que le lymphome de Hodgkin estestimé à 21% de tous les cas de lymphomes alors que leslymphomes non hodgkiniens représentent 79% des cas. Ausein de ces derniers, les lymphomes B matures représentent85% alors que les lymphomes T matures représentent 9%. Lesous-type prédominant des lymphomes B matures est le lym-phome diffus à grandes cellules B (48% des lymphomes B)alors que le lymphome T le plus fréquent s’est avéré être lelymphome anaplasique (40% des lymphomes T). La distribu-tion entre les différents sous-types a confirmé les résultatsdes deux plus grandes études libanaises qui ont précédé.L’incidence du lymphome de Hodgkin est plus élevée auLiban par rapport aux pays occidentaux et de l’Extrême-Orient. Ceci peut être expliqué par une étiologie liée au virusEpstein Barr. Par contre, l’incidence des lymphomes nonhodgkiniens se rapproche de celle des pays d’Occident. Uneoccidentalisation du mode de vie libanais pourrait être à l’ori-gine de cette tendance.

Mots-clés : néoplasies hémato-lymphatiques; lymphomes;Hodgkin; non Hodgkinien; épidémiologie

1 national institute of pathology, faculty of Medicine, lebanese university, rafic hariri Campus, Baabda, hadath, lebanon.2 institut Jules Bordet, Service d’anatomie pathologie, Bruxelles, Belgique.

*Corresponding author : Valerie Aftimos, MD e-mail: vaftimos@gmail.com

abbReviations

Hl: Hodgkin lymphomaNHl: non Hodgkin lymphomaDlbCl: diffuse large b-cell lymphomaFl: follicular lymphomaMZl: marginal zone lymphomaalCl: anaplastic t-cell lymphomaPTl, NOS: peripheral t-cell lymphoma, unspecified

in 1974, Kiel, as did lukes and Collins, added immuno-phenotype to the morphological classification. Kiel classi-fied lymphomas according to cell origin and differentia-tion. this classification was updated in 1992 [4]. lukesand Collins proposed a scheme for B-cell types [5,6]. in1982, the united States national Cancer institute pro-posed the working formulation, which emphasized ongrouping according to morphology and clinical prognosis,to translate among the various lymphoma classificationsin use at the time (e.g., rappaport, lukes-Collins, andKiel). it divided lymphomas into grades based on clinicalbehavior [7].

prior to 1994, the working formulation was adoptedin the united States, whereas the updated Kiel classifica-tion was used in europe. in 1994, the working formula-tion and Kiel classifications were replaced with therevised european-American lymphoma (reAl) classi-

fication, which incorporated morphology, immunopheno-type, genotype, normal cell counterpart, clinical presenta-tion and course of the disease into subtype definitions [8].

the world health Organization (whO) classificationintroduced in 2001 and modified in 2008 was built on thereAl classification and is the current gold standard forclassifying all hematopoietic neoplasms. the whO sys-tem distinguishes hematologic malignancies according tocell lineage. within the lymphoid neoplasms, morphologyand immunophenotype distinguish hl from the nhl.Differentiation and additional morphologic, phenotypic,genotypic and clinical features distinguish among thenhl subtypes. the 2008 whO classification also drawsattention to early events in lymphomagenesis and definesseveral entities according to age and site in addition tobiologic underpinnings. it defines as well borderlinelesions. the whO classification is found in table i [9].

22 Lebanese Medical Journal 2018 • Volume 66 (1) V. AFTIMOS et al – Lymphoid neoplasms in Lebanon between 2010 & 2014

Tableau I WHo classification of lympHoid neoplasms [9]

WORlD HEAlTH ORGANIZATION OF lYMPHOID NEOPlASMS

PRECURSOR B- AND T-CEll NEOPlASMSprecursor b-lymphoblastic leukemia/lymphoblastic lymphoma (precursor b-cell acute lymphoblastic leukemia)precursor t-lymphoblastic leukemia/lymphoblastic lymphoma (precursor t-cell acute lymphoblastic leukemia)

MATURE B-CEll NEOPlASMSchronic lymphocytic leukemia/small lymphocytic lymphomab-cell prolymphocytic leukemialymphoplasmacytic lymphomasplenic marginal zone lymphomaHairy cell leukemiaplasma cell myelomamonoclonal gammopathy of undetermined significancesolitary plasmacytoma of boneextraosseous plasmacytomaprimary amyloidosisHeavy chain diseasesextranodal marginal zone b-cell lymphoma of mucosa-associated lymphoid tissuenodal marginal zone b-cell lymphomafollicular lymphomaprimary cutaneous follicle centre lymphomamantle cell lymphomadiffuse large b-cell lymphomadiffuse large b-cell lymphoma associated with chronic inflammationlymphomatoid granulomatosismediastinal (thymic) large b-cell lymphomaintravascular large b-cell lymphomaalK positive large b-cell lymphomaplasmablastic lymphomalarge b-cell lymphoma arising in HHv8-associated multicentric castleman diseaseprimary effusion lymphomaburkitt lymphoma/leukemia

b-cell lymphoma, unclassifiable, with features intermediate between diffuse large b-cell lymphoma and burkitt lymphomab-cell lymphoma, unclassifiable, with features intermediate between diffuse large b-cell lymphoma andclassical Hodgkin lymphoma

MAteriAl AnD MethODS

Our study is a cross-sectional study between the years2010 and 2014, which aimed to establish a descriptivestatus of lymphoma cases in lebanon. Our database camefrom a private pathology laboratory receiving cases fromthe entire lebanese territory. the specimens consisted ofbiopsies of various lesions or excision of lymph nodes.they were fixed in formalin at 10% and embedded inparaffin. Charged slides were cut at 5 microns and stainedby hematoxylin & eosin, Giemsa stain and reticulin stain.After a preliminary diagnosis by one pathologist, an im-munohistochemichal study was performed.

the cases were then classified following the 2008whO Classification shown in table i. the panel of im-munohistochemical stains used varied widely but thechoice of antibodies was restricted and oriented by themorphological features to avoid the misinterpretation andthe overlapping positivity. the most used antibodieswere CD20, CD79a and pAX5 for identifying B-cell,CD3 and CD5 for t-cell along with CD23, CD21, tdt,Cyclin D1, Bcl2, Bcl6, lCA, OCt2, BOB1, lCA andKi67. A second pathologist reviewed cases that werejudged ambiguous or difficult.

1468 cases over five years diagnosed as lymphomaswere selected. those where the immunohistochemichalstudy was not done (except for gastric MAlt lympho-mas, mycosis fungoid and hodgkin, nodular sclerosingvariant) or was inconclusive were excluded as well asrelapses and secondary localizations, leaving us with a

total of 1256 new cases. Data including the age and thesex of the patients, the localization of the biopsies takenand the lymphoma subtypes diagnosed were collectedand then analyzed.

reSultS

within the final 1256 cases that we studied, we found46.33% of women (581) and 53.67% of men (673), withan age varying between 1 and 98 years old and a meanage of 53 years old. for hl, two age peaks were found:one between 20-30 years (55 cases) and the second lessprominent between 60 and 70 years of age (23 cases).Sex ratio and age distribution within the different lym-phoma subtypes are found in table ii.

V. AFTIMOS et al – Lymphoid neoplasms in Lebanon between 2010 & 2014 Lebanese Medical Journal 2018 • Volume 66 (1) 23

Tableau IIage & sex distRibution foR most common lympHoma subtypes

Subtype Sex Ratio age

M/F Min-Max Mean

HodgKin 1.3 2 _ 88 37 ± 18dlbcl 0.9 4 _ 98 60 ± 18fl 0.9 15 _ 86 59 ± 14mZl 1.3 5 _ 89 54 ± 17malt 0.8 7 _ 87 56 ± 17alcl 1.7 19 _ 85 52 ± 21ptl, nos 1.3 12 _ 88 50 ± 21

MATURE T-CEll AND NK-CEll NEOPlASMSleukemic/disseminated

t-cell prolymphocytic leukemiat-cell large granular lymphocytic leukemiaaggressive nK-cell leukemia

Cutaneousmycosis fungoidessezary syndromeprimary cutaneous anaplastic large cell lymphomaprimary cutaneous gamma-delta t-cell lymphomalymphomatoid papulosis

Other extranodalextranodal nK/t-cell lymphoma, nasal typeenteropathy-associated t-cell lymphomaHepatosplenic t-cell lymphomasubcutaneous panniculitis-like t-cell lymphoma

Nodalangioimmunoblastic t-cell lymphomaperipheral t-cell lymphoma, unspecifiedanaplastic large cell lymphoma

HODGKIN lYMPHOMAnodular lymphocyte predominant Hodgkin lymphomaclassical Hodgkin lymphoma

Nodular scelrosis classical Hodgkin lymphomaMixed cellularity classical Hodgkin lymphomaLymphocyte-rich classical Hodgkin lymphoma

the incidence per year is shown in fig. 1. hodgkinlymphomas accounted for 21% (258 cases) whereas nhlaccounted for 79% (996 cases). within hodgkin lym-phomas, the nodular sclerosing variant accounted for mostof the cases, summing up to 81% (210 cases) (fig. 2a).when considering nhl, mature B-cell neoplasms accountfor 85% (853 cases), mature t-cell neoplasms account for9% (87 cases). the remaining 6% are distributed betweenprecursors lymphoid neoplasms, composite lymphomasand grey zone lymphomas (fig. 2b). for mature B-cell neo-plasms, the majority of cases 48% (406 cases) are diffuselarge B-cell lymphomas (DlBCl), followed by follicularlymphomas (fl) (16%, 136 cases), and mucosa-associatedlymphoid tissue (MAlt) and marginal zone lymphoma(Mzl) accounting for 9% each (75 cases of MAlt and 74cases of Mzl). to note, 12 cases of composite lymphomaswere DlBCl and fl lymphomas (fig. 2c). when consid-ering mature t-cell neoplasms, the majority of cases aredistributed between anaplastic lymphomas (AlCl 40%,35 cases) and peripheral t-cell lymphomas, nOS (ptCl,nOS 34%, 30 cases) (fig. 2d).

hl, Mzl, AnCl and ptCl,nOS showed a male pre-dominance while DlBCl, fl and MAlt showed a slightfemale predominance. nhl’s mean age varied from 50- to60-year-old while hl arise in younger people with a meanage around 37-year-old (table ii). Concerning localiza-tion, 54% of lymphomas were nodal (680 cases). theextra-nodal localization was mainly found in the stomach(8.7%) followed by the bone marrow (6.6%) with 18.3%of miscellaneous locations (fig. 3).

DiSCuSSiOn

when comparing to previous studies, we will direct ourattention first to the two largest lebanese studies cover-ing lymphoid malignancies: Sader-Ghorra C. et al. [10]and Otrock zK et al. [11]. Our study covers 1256 newcases whereas the two other studies covered 502 and 272new cases respectively. Our rates of hl and nhl are in

24 Lebanese Medical Journal 2018• Volume 66 (1) V. AFTIMOS et al – Lymphoid neoplasms in Lebanon between 2010 & 2014

Figure 2aSubtype distribution of HL

(cHL,NS: Hodgkin lymphoma, nodular sclerosis; cHL,LR: Hodgkin

lymphoma, lymphocyte-rich; cHL,MC: Hodgkin lymphoma, mixed

cellularity; cHL,unspecified: classical Hodgkin lymphoma, unspecified

type; NLPHL: Nodular lymphocyte predominant Hodgkin lymphoma.

No cases of lymphocyte depleted HL were diagnosed.)

Figure 2bSubtype distribution of NHL

(OTHER subtypes includes 1 case of grey zone lymphoma and

18 cases of composite lymphomas out of 996 cases.)

Figure 1Incidence per year of HL and NHL between 2010 and 2014

240

180

120

60

02010 2011 2012 2013 2014

Num

ber

of c

ases

/yea

r

HL NHL

168

217

175

207

229

46 37

7061

44

cHL,unspecified

2%

cHL,LR

3%

cHL,MC

8%

NLPHL

6%

cHL,NS

81%

PRECURSOR

LYMPHOID

NEOPLASMS

4%

OTHER

2%

MATURE B-CELL

NEOPLASMS

85%

MATURE T-CELL

&

NK NEOPLASMS

9%

between both results: we found 21% hl vs. 79% nhl,whereas Sader-Ghorra C. et al. [10] found 24% hl vs.76% nhl and Otrock zK et al. [11] 32.7% hl vs. 67.3%nhl. nodular sclerosing variant was predominant inboth our study and Otrock zK et al’s [11]. Among nhl,all studies demonstrated that mature B-cell lymphomasrepresented the largest portion with very close resultswhile mature t-cell lymphomas represented 9% in allthree studies. within mature B-cell lymphomas, all threestudies showed a predominance of DlBCl with closeresults followed by fl, which was estimated at 17% inour study but at a higher proportion in the two otherstudies (20% in Sader-Ghorra C. et al. [10] and 23% inOtrock zn et al. [11]).

worldwide, the incidence of lymphoma seems to beincreasing and this is mainly true for the incidence oflymphoma in the western world such as the uS andeurope [12,13]. this is also true for lebanon [14]. whilenhl ranks 12th in incidence in europe [13], the inci-dence in lebanon mirrors that of the uS: 5th in men and

Figure 2cSubtype distribution of mature B-cell neoplasms

(DLBCL: Diffuse large b-cell lymphoma; BUR: burkitt lymphoma;

MCL: Mantle cell lymphoma; FL: Follicular lymphoma; MZL: Marginal

zone b-cell lymphoma; MALT: Extranodal marginal zone b-cell

lymphoma of mucosa-associated lymphoid tissue; CLL: Chronic

lymphocytic leukemia/small lymphocytic lymphoma; PMBL: Primary

mediastinal large b-cell lymphoma; OTHER includes: 5 cases of

splenic marginal zone lymphoma, 5 cases of lymphoplasmacytic

lymphoma, 3 cases of plasmablastic lymphoma, 2 cases of intra-

vascular large b-cell lymphoma, one case of extra-osseous plasma-

cytoma, one case of primary cutaneous follicle centre lymphoma

and one case of b-cell lymphoma unclassifiable with features

between diffuse large b-cell lymphoma and burkitt lymphoma.)

Figure 2dSubtype distribution of mature T-cell & NK neoplasms

(ALCL: Anaplastic large cell lymphoma; ATL: Angioimmunoblastic

T-cell lymphoma; PTCL,NOS: Peripheral T-cell lymphoma, unspecified;

PCAL: Primary cutaneous anaplastic large cell lymphoma; MF:

Mycosis fungoide; EATL: Enteropathy-associated T-cell lymphoma;

NK/T: Extra-nodal NK/T-cell lymphoma, nasal type.)

Figure 3Nodal vs extra-nodal localization

(BM: bone marrow; COL: colon; SI: small intestine; SK: skin;

SP: spleen; ST: stomach; MD: mediastinum; MIS: miscellaneous;

NOS: unspecified.)

COL

0.40%NOS

0.72%BM

6.62%

MIS

18.26%

SK

3.75%

MD

4.78%

SI

1.43% ST

8.69%

SP

1.12%

PMBL

2%

OTHER

2%CLL

7%

MALT

9%

MZL

9%

FL

16%

MCL

6%

DLBCL

48%

BUR

1%

ALCL

40%

NK/T

2%

EATL

6%

MF

7%

PCAL

6%

PTCL,NOS

34%

ATL

5%

V. AFTIMOS et al – Lymphoid neoplasms in Lebanon between 2010 & 2014 Lebanese Medical Journal 2018 • Volume 66 (1) 25

4th in women in lebanon [14] and 6th in men and womenin the uS [12]. when comparing to lymphoid malignan-cies around the world, hl (21% in our study) seemsmore frequent than in western and far eastern countries(11.6% in the uS [15], 14.4% in the uK [16], 5.19% inChina [17] and 5.9% in Japan [15]), and approaches thenumbers in turkey (17%) [18] and in irak (24%) [19].Saudi Arabia has the highest rate with 32% [20]. innhl, t-cell lymphomas are more frequent in our series(9%) than in western countries (5.3% in the uK [16])but less frequent than in far eastern countries (16.51%in China [17]). we found that turkey (8%) [18], irak(9%) [19] and Algeria (12.7%) [21], had close figures.

hl seems to be higher in lebanon versus the rest ofthe world. in fact, a study by GlOBOCAn 2012 showedthat israel and lebanon seemed to have the highest inci-dence of hl around the Mediterranean Basin [22]. theetiological factors involved in the pathogenesis of hl aremultifactorial and include both genetic and environmen-tal risk factors. these risk factors include eBV infection.eBV-positivity was found to be 90% in Greece, 61.5% inturkey, 50% in egypt, 48% in italy and 30% in israel[23-27]. in lebanon, the study by Otrock zK et al. [11]showed that 39 out of 43 patients having hl had positiveeBV igG antibodies. furthermore, 54.5 % of eBV sero-positive hl cases were positive for latent eBV expres-sion using in situ hybridization for eBer. these findingsare a proof that further exploration of the relationship be-tween eBV and hl needs to be investigated.

Another association was found with tuberculosis. itseems that hl’s incidence is higher in areas where tuber-culosis is endemic. tuberculosis precedes, is concomi-tant or follows hl [26,28,29]. in lebanon, the declaredprevalence of tuberculosis was estimated at 12/100,000inhabitants in 2009 [30]. in 2011, the estimated preva-lence was 19/100,000 in lebanon. Since then, 630 newcases were declared in 2012 and 689 new cases in 2013,including non-lebanese residents [31], showing that in-cidence of tuberculosis in lebanon seems to be on the rise.

As shown by roman e. and Smith A., we also had abimodal age distribution for hl [32]. Our first peak wasin young adults (20-30 years) and the second in theelderly (60-70 years).

Concerning nhl, the most common subtype in thecurrent study was found to be DlBCl with a rate of40.7%. this rate is close to the one found in the uK(40.9%) [16] and in france (41%) [33] and is lower thanthe one found in Algeria (52.8%) [21], Saudi Arabia(51%) [20], irak (52.2%) [19] and China (53.5%) [17].fl is close to western incidence with a rate of 13.6%(uK 15.9% [16], uS 17% [15]. this rate is lower in irak(2.9%) [19] and in Saudi Arabia (7%) [20] but almostsimilar in Algeria (13.2%) [21].

numbers in the current study approach the westerncountries statistics. DlBCl and fl are the most com-mon subtypes in our study as well as in the western coun-tries [34]. however t-cell lymphoma rates seem to behalfway between the eastern and the western world, con-

sidering that rare t-cell neoplasms are more common inAsia than in the rest of the world [34]. it seems to berelated to the htlV-1 virus, which is more common inJapan and the Caribbean and rare in europe and the uSA[35]. Genetic factors play an important role in the etiol-ogy of nhl: chromosomal translocations have been ob-served in up to 90% of nhl cases [36,37]. however, theuniform rise of nhl throughout the world implicates therole of environmental agents [34]. Some studies haveshown that higher consumption of meat and dairy prod-ucts is associated with an increased risk of nhl, whereashigher consumption of vegetables and fruits reduces nhlrisk [38,39]. particularly for DlBCl, an associationwith a high body mass index has been found [40]. fl onthe other hand has been linked to tobacco smoking, asthe latter appears to induce the BCL2 translocation (14,18) found in fl [41]. these environmental agents arefound mostly in the western world but also in lebanonas westernization of the way of life occurs and couldexplain our numbers.

COnCluSiOn

Despite the numerous studies conducted to search for anetiology for lymphomas, the latter remain poorly under-stood. however, it seems that westernization may play animportant part in explaining the distribution of the differ-ent subtypes in lebanon. this would explain the similarnumbers in non-hodgkin B-cell lymphomas. lebanon,being a Mediterranean country, the relationship to eBVvirus can explain the higher figures of hl in the currentstudy.

ACKnOwleDGeMentS

the authors would like to thank the institut national depathologie and Dr. philippe Aftimos.

COnfliCtS Of intereStS

the authors declare that there is no conflict of interestsregarding this paper.

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