Original article
`
`Annuls of Oncology 12: 853-858. 2001.
`© 2001 Kluwer Academic Publishers. Printed in the Netherlands.
`
`Among diffuse large B-cell lymphomas, T-cell-rich/histiocyte-rich BCL and
`CD30+ anaplastic B-cell subtypes exhibit distinct clinical features
`
`B. Maes,1 A. Anastasopoulou,2 J. C. Kluin-Nelemans,31. Teodorovic,2 R. Achten,1 A. Carbone4"*
`& C DeWolf-Peeters1* on behalf of the EORTC Lymphoma Group
`'Department ofPathology. Catholic University of Leuven; EORTC Data Center. Brussels. Belgium. ' Department of Hematology. Leiden
`University Medical Center, The Netherlands; 4 Department of Pathology. C.R.O. Aviano. Italy
`
`Summary
`
`Background: The EORTC clinical trial 20901, activated in
`1990, was designed to treat non-Hodgkin's lymphomas (NHL)
`of intermediate/high-grade malignancy according to the Work-
`ing Formulation. Established in 1994, the R.E.A.L. Classifica-
`tion on NH L has now replaced all former classifications.
`Patients and methods: We reanalysed all cases (n - 273)
`documented by material available for review according to the
`R.E.A.L. Classification. In addition, we subdivided cases recog-
`nised as diffuse large B-cell lymphoma (DLBCL) into three
`morphologically distinct categories, namely, large cleaved
`DLBCL (LC-DLBCL), T-cell-rich/histiocyte-rich B-cell lym-
`phoma (T-cell-rich/histiocyte-rich BCL) and CD30+ DLBCL
`with anaplastic cell features (CD30+ DLBCL). Finally, T/NULL
`anaplastic large-cell lymphoma (ALCL) cases were subdivided
`into ALK+ and A L K- lymphomas. Review was performed
`independently by two pathologists from two different centres.
`Results: DLBCL (61%), T/NULL ALCL (15%) and mantle-
`cell lymphoma (MCL, 5%) were the main NHL categories
`represented in the study. Fifty-seven of one hundred sixty
`DLBCL cases were further subclassified as LC-DLBCL (33
`
`cases), T-cell-rich/histiocyte-rich BCL (13 cases) or CD30+
`DLBCL (11 cases). The remaining cases were indicated as
`unspecified DLBCL. A clinico-pathological correlation con-
`firmed the findings of previous studies suggesting that MCL,
`DLBCL and ALCL represent distinct entities with MCL being
`characterised by a short survival, in contrast with the longer
`survival and less frequent progression typical of ALK+ com-
`pared to A L K - A L C L. Within DLBCL, T-cell-rich/histiocyte-
`rich BCL showed distinctive features at presentation whereas
`CD30+ DLBCL showed a trend towards a more favourable
`prognosis, that might be comparable to that of ALK+ ALCL.
`Conclusions: Our data further support the usefulness of the
`R.E.A.L. Classification and illustrate the feasibility of DLBCL
`subtyping. Moreover, our results demonstrate the distinct
`clinical characteristics of T-cell-rich/histiocyte-rich BCL and
`CD30+ DLBCL with anaplastic cell features suggesting that
`they may represent clinico-pathologic entities.
`
`Key words: anaplastic large cell lymphoma, diffuse large B-cell
`lymphoma, EORTC, morphology, R.E.A.L. Classification.
`T-cell-rich/histiocyte-rich BCL
`
`Introduction
`
`In 1994 the International Lymphoma Study Group
`(ILSG), introduced the Revised European-American
`Lymphoma (R.E.A.L.) Classification for non-Hodgkin's
`lymphomas (NHL) [1]. It comprises a list of 'real' lym-
`phoma entities that could be defined at that time, using
`morphologic, immunologic and genetic techniques. Sub-
`sequently, various large retrospective studies were per-
`formed in order to evaluate the diagnostic reproducibility
`and the clinical validity of the R.E.A.L. Classification.
`These studies have demonstrated the clinical relevance
`of defining new R.E.A.L. entities (e.g., mantle-cell lym-
`phoma, marginal zone cell lymphoma) and the high
`diagnostic accuracy, which was shown to be additionally
`improved by the use of immunophenotyping [2-5]. As
`
`* Both authors contributed equally to this work.
`
`such, they have refuted the criticising reactions on the
`proposal and confirmed the usefulness of the R.E.A.L.
`Classification.
`Its principles have essentially been
`adopted in the forthcoming WHO Classification [6].
`However, to be able to reach their conceptual goal of
`listing only well identifiable entities with a significantly
`distinctive clinical behaviour, the ILSG chose to lump
`together all cases of diffuse
`large B-cell
`lymphoma
`(DLBCL) in one category. Only one subtype, primary
`mediastinal (thymic) large B-cell lymphoma, was recog-
`nised as a separate entity based on its characteristic
`clinico-pathological features [1].
`Despite the grouping of all DLBCL into one R.E.A.L.
`category, various histological identifiable subtypes have
`been described in the past, for which often a distinct
`clinical course was suggested. The Kiel Classification
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`854
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`distinguished immunoblastic from centroblastic lym-
`phoma based on the presence of over 90% immunoblasts
`[7]. Recently, it has been suggested that this particular
`morphological representation indicates an adverse prog-
`nosis when compared with classical centroblastic lym-
`phoma [8].
`In the early nineties, our group described the T-cell-
`rich/histiocyte-rich B-cell lymphoma (T-cell-rich/his-
`tiocyte-rich BCL) and noticed that this DLBCL subtype
`is associated with a characteristic clinical presentation
`and a particularly aggressive course [9].
`Large cleaved DLBCL (LC-DLBCL) was first identi-
`fied by Lukes and Collins [10] and was maintained by
`the Working Formulation as a subcategory 'of interest
`but of uncertain clinical importance' [11]. Whereas it
`was generally accepted that its characteristic nuclear
`morphology as well as the prominent sclerosis enabled
`its recognition, the actual clinical relevance of this sub-
`category has remained controversial, some investigators
`showing a favourable outcome [12-16], while others failed
`to demonstrate any clinical distinctiveness [17-23].
`The implications of CD30+
`immunopositivity in
`large B-cell lymphomas is enigmatic as it has received
`relatively little attention compared with CD30 expres-
`sion inT/null cell lymphomas [24]. CD30 expression in
`DLBCL may be correlated with anaplastic cell features,
`as such delineating another histological
`identifiable
`DLBCL subtype, which may be worthwhile to investigate
`in view of the R.E.A.L. principles.
`All available diagnostic biopsies of patients included
`in EORTC trial 20901 were reviewed. Firstly, all cases
`were reclassified according to the R.E.A.L. Classification.
`Secondly, it was decided to subdivide T/NULL anaplastic
`large-cell lymphoma (ALCL) cases into an ALK + and
`an ALK negative group, as recent studies suggested that
`ALK immunostaining in ALCL may provide crucial
`prognostic information [25, 26]. Finally, we tried to
`recognise the 4 morphologically subcategories of DLBCL
`mentioned above (immunoblastic DLBCL, LC-DLBCL,
`T-cell-rich/histiocyte-rich BCL and CD30+ DLBCL)
`and evaluated both the diagnostic applicability and the
`clinical significance of morphologically subgrouping
`DLBCL.
`
`Patients and methods
`
`Patients
`
`The EORTC clinical trial 20901 included newly diagnosed patients age
`15-60 years with stage 11 — IV NHL. In 1997. the upper age limit was
`increased to 65 years. The NHL was to fulfil the criteria of intermediate
`grade histology according to the Working Formulation. In addition,
`patients with stage I bulky or stage II-IV of the following high grade
`entities were accepted as well: diffuse large-cell immunoblastic. ana-
`plastic large-cell lymphoma, large-cell and small-cell (if containing
`numerous blasts) pleomorphic T-cell lymphoma and AILD-likeT-cell
`lymphoma. Low-grade NHL. lymphoblastic NHL and Burkitt's lym-
`phoma were excluded. A complete staging evaluation was performed.
`Only patients with a performance status of WHO 0. 1 or 2 in the
`
`absence of severe cardiac, pulmonary, neurologic or metabolic dys-
`function were included
`treatment arms, as
`Patients were randomised to two different
`described elsewhere [27]. A CHOP-like regimen, CHVmP/BV chemo-
`therapy was given. Briefly, patients were randomised after the first
`three CHVmP/BV cycles (reaching a complete or partial remission
`(CR/PR) with a histologically proven negative bone marrow, and no
`contraindications for bone marrow ablative chemotherapy), between
`the ABMTarm (a further 3 cycles CHVmP/BV followed by BEAC
`chemotherapy and autologous stem-cell rescue) or the control arm,
`with further five cycles CHVmP/BV. The protocol also recommended
`radiotherapy for all PR patients
`
`Pathology review
`
`Out of 311 cases included in the trial, 273 were available for the
`present study. Out of these 273 cases, 10 cases were excluded from the
`study due to the insufficient size or quality of the diagnostic biopsy
`specimen.
`The biopsy was taken from a nodal site in 78% of cases (n = 205)
`and from an extranodal site in 22% of cases (;i = 58). All cases were
`independently evaluated by two pathologists (C. de Wolf-Peeters.
`A. Carbone) and subtyped according the R.E.A.L. Classification [1],
`In addition, DLBCL cases were further classified based on the mor-
`phologic criteria described below.
`Immunophenotypic data (including CD20, CD3. CD30, CD15.
`CD5 and bcl-2) were known from the local pathology form in the vast
`majority of cases Since ALK staining was not included in the immuno-
`phenotypic panel performed at diagnosis, ALK staining was addi-
`tionally performed for the T/NULL ALCL cases and the CD30+
`DLBCL cases for which unstained sections were available (25 out of
`38 cases and 9 out of 11 cases, respectively).
`DLBCL cases characterised by neoplastic cells showing an irregular,
`typically indented or cleaved nucleus with evenly dispersed chromatin
`and by a compartmentalising fibrosis were further subtyped as LC-
`DLBCL [10]. Mitotic figures, apoptotic cells, foci of necrosis and an
`accompanying reactive infiltrate composed of small lymphocytes and
`histiocytes were variable features of these cases. DLBCL cases with
`strikingly scarce neoplastic large B-cells, but rich both in small reac-
`tive T lymphocytes and in histiocytes were specified as T-cell-rich/
`histiocyte-rich BCL. These DLBCL are to be distinguished from
`nodular paragranuloma, by the uniform distribution of large cells
`throughout the neoplasm and by the characteristic reactive background
`dominated by small T cells and histiocytes rather than B cells [9].
`DLBCL cases exhibiting both anaplastic cell morphology and CD30
`expression were identified as CD30+ DLBCL. Anaplastic cell features
`included large or very large cells with abundant cytoplasm, with large,
`often reniform or indented nuclei, and usually multiple nucleoli [24],
`DLBCL cases characterised by the predominance of immunoblasts,
`e.g.. more than 90% as defined by the Kiel group [7], were classified as
`immunoblastic DLBCL. DLBCL cases failing to answer the criteria to
`be included into one of these subgroups were left unspecified.
`
`Statistical analysis
`
`All cases analysed were equally distributed over both therapeutic arms.
`Only the cases that were classified under both schemes are included in
`the analysis.
`Progression-free survival (PFS) was calculated as the time interval
`between the date of randomisation and the date of disease progression
`or death, whichever came first. If neither event had been observed,
`then the patient was censored at the dale of the last follow-up.
`Overall survival (OS) was calculated as the time interval between
`the date of randomisation and the date of death due to all causes.
`Patients who were still alive when last traced are censored at the date
`of last follow-up. Survival curves were estimated using the Kaplan-
`Meier method. Due to small numbers, not all subtypes could be
`analysed so comparisons are only visually allowed.
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`Table I Baseline characteristics of patients subtyped as MCL,
`DLBCL or ALCL.
`
`MCL DLBCL ALCL ALK+ ALK-
`
`13(5)
`
`160(61)
`
`38(15)
`
`11(29)
`
`14(37)
`
`32-60
`51
`1.6
`
`18-64
`45
`16
`
`16-58
`30
`1.6
`
`16-45
`28
`4.5
`
`17-43
`30
`0.7
`
`8
`15
`8
`69
`
`38
`54
`8
`
`61
`39
`
`92
`8
`
`38
`62
`
`9
`32
`21
`38
`
`81
`16
`3
`
`65
`34
`I
`
`84
`10
`6
`
`76
`20
`4
`
`3
`47
`28
`22
`
`92
`8
`
`53
`47
`
`91
`3
`6
`
`86
`11
`3
`
`0
`27
`46
`27
`
`91
`9
`
`64
`36
`
`91
`9
`
`82
`18
`
`7
`64
`7
`22
`
`93
`7
`
`50
`50
`
`93
`0
`7
`
`93
`7
`
`H ( %)
`Age (years)
`Range
`Median
`Sex ratio (M: F)
`Ann Arbor stage (%)
`I
`II
`III
`IV
`Bone marrow
`involvement (%)
`Negative
`Positive
`Unknown
`Systemic symptoms
`
`Absent
`Present
`Unknown
`Hepatomegaly (%)
`Absent
`Present
`Unknown
`Splenomegaly (%)
`Absent
`Present
`Unknown
`
`Results
`
`Pathology review
`
`Full agreement among both pathologists was reached
`for R.E.A.L. subtyping and for further subdividing
`DLBCL cases, in all except two cases, which were
`excluded from further analysis.
`The R.E.A.L. subtypes mainly represented in the
`study were DLBCL (61%), T/NULL ALCL (15%) and
`MCL (5%). The remaining cases were either follicle
`centre cell lymphoma (4.7%), marginal zone cell lym-
`phoma (3.5%), Burkitt's or Burkitt's like lymphoma
`(2%), T-cell lymphoma (peripheral, not otherwise speci-
`fied or angioimmunoblastic) (3%), primary mediastinal
`large B-cell lymphoma (2%) and chronic lymphocytic
`leukemia (3.8%).
`Based on the morphologic features as described above
`(methods section), the group of DLBCL cases (n = 160)
`comprised 11 CD30+ DLBCL cases (7%), 13 cases of
`T-cell-rich/histiocyte-rich BCL (8%) and 33 LC-DLBCL
`cases (21%). None of the CD30+ DLBCL cases for
`which ALK staining was performed (9 of a total of 11
`cases) showed ALK expression. No more than two cases
`were composed of a sufficient number of immunoblasts
`to qualify as immunoblastic DLBCL. These two cases
`were analysed together with the remaining unspecified
`DLBCL subgroup (103 cases).
`For the 38 cases diagnosed as T/NULL ALCL, ALK
`
`v....
`
`% 100
`
`9 0-
`
`SO-
`
`7 0-
`
`6 0-
`
`5 0-
`
`4 0-
`
`3 0-
`
`2 0-
`
`10 -
`
`855
`
`(a)
`
`- MCL
`DLBCL
`. ALCL
`
`(b)
`
`Figure I. Overall survival (a) and progression-free survival (b)' com-
`parison of MCL patients (H = 13). DLBCL patients (;i = 160) and
`ALCL patients {n = 38).
`
`9 yean
`
`immunostaining was positive, negative or not done in
`respectively 11, 14 and 13 cases.
`
`Clinical data
`
`Clinical characteristics at patient entry of the three
`mainly represented R.E.A.L. categories (MCL, DLBCL,
`T/NULL ALCL) are summarised in Table l.The ALCL
`group included patients on the average 15-20 years
`younger when compared with MCL and DLBCL (median
`age 30 years vs. 51 and 45 years). Ann Arbor stages 111
`and IV were observed in 77% of MCL cases compared
`to 59% and 50% of respectively DLBCL and ALCL
`cases. Bone marrow involvement was found in more than
`half of the MCL cases (54%) and was rare in DLBCL
`and ALCL (respectively, 16% and 8%). Systemic symp-
`toms were more frequently present in ALCL (47%)
`compared to MCL (39%) and DLBCL (34%). Moreover,
`besides the important differences in clinical presentation,
`these three lymphomas appear to behave differently,
`MCL displaying a tendency towards an inferior prognosis
`in terms of progression-free survival (Figures la and b).
`ALK staining divides T/NULL ALCL in two distinct
`subentities in terms of prognosis as demonstrated by a
`different overall survival and progression-free survival
`(Figures 2a and b). Moreover, the ALK positive and the
`ALK negative subgroups show distinctive clinical charac-
`teristics at entry, with a marked male predominance and
`a higher incidence of aggressive stages HI and IV among
`ALK + ALCL (Table I).
`Among the DLBCL subgroups, T-cell-rich/histiocyte-
`rich BCL shows highly characteristic clinical features at
`presentation as shown in Table 2. A clear male prepon-
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`856
`
`00
`90-
`
`70-
`
`60 -
`50-
`
`40-
`
`30-
`
`20-
`10 -
`
`0 -
`
`Figure 2 Overall survival (a) and progression-free survival (b) of
`CD30 + DLBCL patients (;i = II), compared to ALCL patients,
`divided into ALK+ (n = 11). A L K- cases (n - 14) and cases without
`available ALK staining (n = 13).
`
`(a)
`
`LC-DLBCL
`CD30* DLBCL
`T cd rkfc/kWiocTtt ricti BCL
`nmr«rffl1 DLBCL
`
`9 yon
`
`LC-OLBCL
`CD3** DLBCL
`T «D ricWUBlocrU-rich BCL
`
`9 y««n
`
`Figure 3. Overall survival (a) and progression-free survival (b) of
`DLBCL patients, divided into LC-DLBCL (n = 33),T-cell-rich/histio-
`cyte-rich BCL (n = 13), CD30+ DLBCL (n = II) and unspecified
`DLBCL (n = 103)
`
`derance (ratio M : F = 5.5) was noted in this category,
`compared to an almost equal distribution between both
`sexes in the other DLBCL. T-cell-rich/histiocyte-rich
`BCL patients presented more often with advanced Ann
`Arbor stages (III and IV) (84% vs. 55%, 45% and 62% in
`
`Discussion
`
`The morphological review of cases included in the
`EORTC trial 20901, allowed to address three issues of
`special current interest.
`Firstly, it was ascertained that the R.E.A.L. Classifi-
`cation [1] defines clinically distinct entities within a
`subpopulation of patients affected by intermediate/
`high-grade NHL. DLBCL, ALCL and MCL were the
`
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`
`(a)
`
`Table 2. Baseline characteristics for DLBCL subtypes.
`
`Unspecified
`CD30+ T-cell-rich/ LC-
`DLBCL histiocyte- DLBCL DLBCL
`rich BCL
`
`n (%)
`Age (year)
`Range
`Median
`Sex ratio (M : F)
`Ann Arbor stage (%)
`
`11(7)
`
`13(8)
`
`33(21)
`
`103(64)
`
`18-52
`41
`1.7
`
`24-52
`41
`5.5
`
`19-64
`44
`1 3
`
`18-64
`47
`1.3
`
`7
`31
`24
`38
`
`82
`15
`3
`
`65
`34
`I
`
`84
`12
`4
`
`79
`19
`2
`
`12
`43
`12
`33
`
`82
`15
`3
`
`67
`33
`0
`
`94
`
`0 6
`
`82
`
`9 9
`
`15
`69
`
`54
`38
`
`46
`54
`0
`
`69
`23
`
`30
`62
`
`18
`27
`18
`37
`
`90
`10
`0
`
`73
`27
`0
`
`73
`9
`18
`
`82
`18
`0
`
`II
`
`I
`III
`IV
`Bone marrow
`involvement (%)
`Negative
`Positive
`Unknown
`Systemic symptoms (%)
`Absent
`Present
`Unknown
`Hepatomegaly (%)
`Absent
`Present
`Unknown
`Splenomegaly (%)
`Absent
`Present
`Unknown
`
`CD30+ DLBCL, LC-DLBCL and unspecified DLBCL,
`respectively). Approximately 40 % of patients presented
`with bone marrow invasion at diagnosis, which is rather
`rare in the other subtypes and
`in the unspecified
`DLBCL. In addition, hepatosplenomegaly and systemic
`symptoms were more frequent findings in T-cell-rich/
`histiocyte-rich BCL at presentation. The survival curves
`of the DLBCL subtypes do not show a clear disadvantage
`for T-cell-rich/histiocyte-rich BCL patients (Figures 3a
`and b). The small number of T-cell-rich/histiocyte-rich
`BCL patients included in the analysis may provide a
`reasonable explanation for this unexpected observation.
`CD30+ DLBCL, on the other hand, can be clearly
`distinguished from the other subtypes with respect to
`clinical behaviour. Overall and disease-free survival
`curves suggest that the clinical course of CD30+ DLBCL
`may be comparable to that of ALK+ ALCL (Figure 2a
`and b).
`
`i
`
`AUUAIXL
`ALK-ALCL
`
`CW0+ DLBCL
`
`9 ye«n
`
`(b)
`
`AJJUALCL
`ALK-ALCL
`ALKirinlaf
`• "- CDSftt DLBCL
`
`9 yem
`
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`857
`
`three major categories represented in the study. These
`three lymphomas show a distinct clinical behaviour with
`MCL being the most aggressive. These findings confirm
`the data of other large studies [3,4], and underscore that
`lymphomas that were originally lumped together as
`'intermediate/high-grade', according to the Working
`Formulation, show marked differences in survival.
`Despite the low percentage of T-cell lymphoma cases
`represented in the study, partially due to the inclusion
`criteria of the trial, a relatively high number of cases
`diagnosed as T/NULL ALCL was found. Since they
`represented 38 out of a total of 261 cases analysed (15%),
`a second issue, the prognostic significance of ALK
`expression in this particular group of lymphomas, could
`be investigated. ALK expression results from the trans-
`location t(2;5) or from other chromosomal rearrange-
`ments involving the ALK gene [28]. t(2;5) has been
`demonstrated in 15%-85% of ALCL cases, an impres-
`sive variability that has been ascribed to differences in
`methodology applied, inclusion criteria, patient charac-
`teristics and the presence of variant translocations [25,
`26, 28-31]. In our study, of 25 cases that were stained for
`ALK, 11 cases showed positivity. Visual comparison of
`the survival curves, showed a clearly better clinical
`behaviour of ALK positive ALCL cases as compared to
`ALK negative cases, in terms of both overall survival
`and progression free survival (Figure 2). These results
`confirm those of Falini et al. who reported a signifi-
`cantly better prognosis of ALK positive cases in a series
`comprising 96 ALCL [25].
`Finally, we decided to assess whether previously de-
`scribed, morphologically distinct DLBCL subgroups
`may be adopted for subclassification. In the R.E.A.L.
`Classification, subdividing DLBCL was considered im-
`practical for the lack of both diagnostic reproducibility
`as well as clinical relevance. Our results show that three
`previously described DLBCL, being LC-DLBCL, T-cell-
`rich/histiocyte-rich BCL and CD30+ DLBCL can be
`recognised and distinguished from one another. In addi-
`tion, our data indicate that these entities have clinically
`distinct features, either because of the characteristics
`at presentation (T-cell-rich/histiocyte-rich BCL), or for
`prognostic reasons (CD30+ DLBCL). It has to be em-
`phasised that the latter findings merely represent observed
`trends in an analysis that, due to low patient numbers,
`lacked the power to reach the level of statistical signifi-
`cance.
`For LC-DLBCL, some investigators have suggested a
`better prognosis compared to unspecified DLBCL [12-
`16], whereas other could not confirm this finding [17-23].
`In the present study, no obvious difference could be
`observed between the clinical presentation and the sur-
`vival curves of LC-DLBCL on the one hand and
`DLBCL with non-cleaved cell morphology on the other,
`despite its readily identifiable morphology.
`Patients affected by T-cell-rich/histiocyte-rich BCL,
`usually middle-aged men, have been shown to present
`with advanced stage disease, with involvement of the
`spleen, the bone marrow and/or the liver, besides multi-
`
`ple peripheral lymph nodes [9]. The present study again
`highlights, apart from the typical morphology, the spe-
`cific clinical features of this subcategory at presentation,
`but, due to small patient numbers, does not allow to
`adequately judge the patients' prognosis.
`Except for one study by Noorduyn et al., CD30+
`DLBCL have only been found in small numbers in larger
`series essentially focusing on T/NULL-ALCL [24].
`Noorduyn et al. suggested that CD30 expression is not
`restricted to DLBCL with anaplastic morphology. More-
`over, they failed to demonstrate any correlation between
`survival on the one hand and CD30 expression and/or
`anaplastic morphology on the other. Our approach
`essentially differs from the one applied by Noorduyn et
`al. in that we required both anaplastic features and
`CD30 expression to delineate the particular DLBCL
`subtype. However, the observed trend towards a better
`prognosis comparable with ALK+ ALCL, requires con-
`firmation in a larger study.
`The low number (no more than two) of immunoblastic
`DLBCL cases identifiable in our study, corroborates the
`forthcoming WHO Classification that will not incorpo-
`rate this subtype. It was believed that neither reliable
`pathological or biological criteria for subclassification,
`nor distinctive therapies are available at this time to
`justify a distinction between immunoblastic and centro-
`blastic lymphoma [11].
`The WHO Advisory Committee has recommended to
`lump all DLBCL together [11], in the forthcoming clas-
`sification of NHL. Nevertheless, it was acknowledged
`that a further subclassification is mandatory, in order to
`identify subgroups of patients that might benefit from
`alternative therapies. Our data support the feasibility
`of subtyping DLBCL according previously described
`morphological entities. They further indicate that T-cell-
`rich/histiocyte-rich BCL and CD30+ DLBCL with ana-
`plastic cytology may have clinical distinct features.
`Recently DLBCL have been divided into two prog-
`nostically distinct subgroups
`(germinal centre
`like
`DLBCL and activated B-cell like DLBCL) using a
`DNA microarray for the analysis of lymphoid cells
`(Lymphochip) [32]. These techniques should be applied
`to DLBCL subtypes identified by morphology, in order
`to investigate the correlation between immunomorpho-
`logical findings and molecular data. Such analysis will
`hopefully result in less complicated utilities to be used in
`daily practice.
`
`Acknowledgements
`
`Supported by grants number 5U10 CA11488-21 through
`5U10 CA11488-29 from the National Cancer Institute
`(Bethesda, Maryland, USA). Its contents are solely the
`responsibility of the authors and do not necessarily
`represent the official views of the National Cancer
`Institute. Supported by a grant from the Associazione
`Italiana per la Ricerca sul Cancro (AIRC), Milan, Italy,
`to A. Carbone.
`
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`858
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`Received 31 October 2000; accepted 21 February 2001.
`
`Correspondence lo
`Dr B. Maes
`Department of Pathology
`University Hospitals, Catholic University of Leuven
`Minderbroedersstraat 12
`3000 Leuven
`Belgium
`E-mail: Brigitte.Maes@uz.kuleuven.ac.be
`
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