J Clin Pathol 1994;47:33-37

Relation of CD30 expression to survival andmorphology in large cell B cell lymphomas

L A Noorduyn, P C de Bruin, P van Heerde, MM van de Sandt, G J Ossenkoppele,CJLMMeijer

AbstractAims-To investigate whether CD30expression is correlated with anaplasticmorphology, and whether this correlatedwith a better survival in large cell B celllymphomas, as has been described forT cell lymphomas.Methods-CD30 expression was investi-gated using frozen sections in a series of146 large cell B cell lymphomas. Clinicaldata and follow up information were col-lected from 25 lymphomas with strongCD30 expression, 30 lymphomas withpartial CD30 expression, and a controlgroup of 25 lymphomas which did notexpress CD30.Results-Morphological distinction betweenanaplastic and non-anaplastic tumourswas difficult. Of the cases with ananaplastic morphology, 50% were CD30positive, as were 24% of the polymorphiccentroblastic B cell lymphomas. Only65% of the morphologically non-anaplas-tic tumours were completely CD30 nega-tive. There was no difference in survivalamong patients with lymphomas express-ing CD30 and those that did not. Patientswith morphologically anaplastic B celllymphomas did not differ in their sur-vivals from those with other high grade Bcell lymphomas. Clinical stage at presen-tation was the only variable that was sig-nificantly associated with survival.Conclusions-CD30 expression occursfrequently in large cell B cell lymphomasand is poorly related to anaplasticmorphology. Morphological distinctionbetween anaplastic and non-anaplastictumours is difficult. In contrast to T celllymphomas, CD30 positive B cell lym-phomas do not show a relativelyfavourable clinical course. The resultspresented here raise serious doubts as towhether large cell B cell lymphoma,based on the expression of CD30 oranaplastic morphology, can really betermed a separate entity.

(3 Clin Pathol 1994;47:33-37)

In 1982 a monoclonal antibody that reactedselectively with Hodgkin and Reed-Stemnbergcells was described by Schwab et al.' Ki-i(CD30) was subsequently shown to reactwith a number of large cell non-Hodgkin'slymphomas. Recently, it has been shown thatKi-i detects an antigen that is a member of

the nerve growth factor receptor superfamily.3Because these CD30 positive lymphomas

seemed to present a specific histological pic-ture, this group of lymphomas was calledanaplastic large cell (Ki-I +) lymphoma, andwas incorporated in the updated version ofthe Kiel classification among the high gradecategory of both B cell and T celllymphomas.4 Several reports have describedcases or series of these anaplastic large celllymphomas, most of which have concentratedon the T cell variety.2 5 Furthermore,several morphological subtypes have beendescribed.5 7 17-20

According to the updated Kiel classifica-tion, a lymphoma should not only expressCD30, but also exhibit a so-called "anaplas-tic" morphology, to qualify as an anaplasticlarge cell lymphoma. Some studies mentionthe expression of CD30 in non-anaplasticlymphomas,2782' but none of these studieshas systematically addressed the question ofhow frequently CD30 expression occurs indifferent morphological subtypes of large cellnon-Hodgkin's lymphoma. In T celllymphomas the relation between anaplasticmorphology and CD30 expression seems tobe fairly good,22 and CD30 expression isassociated with a relatively benign clinicalcourse.22 23 Whether this also holds true for Bcell lymphomas is presently unknown.

MethodsIn a pilot experiment of 44 large cell B celllymphomas CD30 expression, as demon-strated by Ber-H224 on formalin fixed, paraf-fin wax embedded tissue, gave many falsenegative results when compared with frozensections (fig 1). Therefore, we decided to useonly those large cell lymphomas from whichfrozen tissue was available. We therefore col-lected 146 cases of large cell lymphoma fromthe files of the Comprehensive Cancer CentreAmsterdam (CCCA). Routinely stainedslides (haematoxylin and eosin, reticulin,Giemsa, and periodic acid Schiff), and dataon immunohistochemistry were also collectedfrom all cases.

Staining with Ber-H2 on frozen sectionswas performed according to standard proce-dures. Tumours were scored as positive (+)if at least 50% of the tumour cells werestained clearly and dubious (+ /-) if lessthan 50% of the tumour cells were stained orif staining was weak. Morphological investiga-tion of the tumours was performed with thehelp of routinely stained slides, without prior

Department ofPathology, AcademicMedical Centre,AmsterdamLA NoorduynDepartment ofPathology, FreeUniversity Hospital,AmsterdamP C de BruinCJLMMeijerNetherlands CancerInstituteP van HeerdeSlotervaart Hospital,AmsterdamMM van de SandtDepartment ofHaematology, FreeUniversity Hospital,AmsterdamG J OssenkoppeleCorrespondence to:Dr L A Noorduyn,Department of Pathology,Academic Medical Centre,Meibergdreef 9, 1105 AZAmsterdam, TheNetherlandsAccepted for publication18 August 1993.

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Figure 1 Polymorphic centroblastic B cell lymphoma. Staining with Be?wax section is negative. Inset: staining with Ber-H2 on frozen section is I

knowledge of the results of Ber-H2 staining.Morphologically, the tumours were graded

according to the updated Kiel classification.4Tumours were scored as anaplastic if theymet the criteria described by Suchi et al andLennert.526 In short, anaplastic lymphomaswere characterised by large or very large cells,

* with abundant cytoplasm, with large, oftenreniform or indented nuclei, and usually mul-tiple, medium sized to large nucleoli. Thetumour often showed an intrasinusoidalgrowth pattern.

...... ... Of the tumours that were scored as + orR;iu)+/-)and from a control group of 25

tumours that were scored as -, clinicaland follow up data were collected from thepatients' records. This group of 25 patientswhose tumours were completely CD30 nega-tive was used as a control group for survivalanalysis. It included three patients withmorphologically anaplastic, but immuno-histochemically CD30 negative, tumours.

Statistical analysis of these data was

-Ht2ven paraffin performed with the help of a BMDP package.

Expression ofCD30 (Ber-H2) in 146 large cell B celllymphomas, according to morphological subtype

CD30

+ - Total

B cell lymphomasFollicular centroblastic 2 5 7 14Centrocytoid centroblastic 2 10 29 41Centroblastic 2 5 22 29Polymorphic centroblastic 9 7 21 37Immunoblastic 2 1 6 9Anaplastic 8 2 6 16Total 25 30 91 146

+ > 50% of the tumour cells positive; + < 50% of thetumour cells positive, or weak staining; - tumour cellsnegative.

.S..

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Figure 2 Anaplastic large cell lymphoma, B cell type (haematoxylin and eosin).

ResultsThe numbers of positive tumours for eachmorphological subtype are shown in thetable. In most tumours in the CD30+ cate-gory, over 80% of tumour cells were positive,and in the CD30 + / - category generally lessthan 20% were positive. Only a few tumoursexpressed CD30 in tumour cells close to thecutoff point of 50%.Of the B cell lymphomas that were mor-

phologically scored as anaplastic (fig 2), 50%were positive with CD30, but of theimmunoblastic and polymorphic centroblastictumours, 22% and 24%, respectively, werealso positive. Even the other groups of largecell B cell lymphoma included cases whichwere positive with CD30, and a considerablepercentage of these tumours showed partialor weak staining of the tumour cells. Only65% of the morphologically non-anaplastictumours were completely negative withCD30. In reviewing the morphology of thetumours, it was often difficult to differentiateanaplastic and non-anaplastic tumours. Inparticular, the distinction between poly-morphic centroblastic lymphomas andimmunoblastic B cell lymphomas on the onehand, and anaplastic large cell B cell lym-phomas on the other, was hard to make whenthe lymph node was completely invaded, andtherefore, the characteristic intrasinusoidalgrowth pattern of anaplastic large cell lym-phoma could not be seen. All these types oflymphoma were composed of large cells,usually with abundant cytoplasm, andanaplastic nuclei were detected in varyingamounts in all of them. Therefore, the dis-tinction was made by estimating the propor-tion of anaplastic nuclei, but we felt thatplacing these tumours in one category oranother was often arbitrary.Of the cases that expressed CD30, 25

patients were men, 10 of whom were inthe CD30 + category, with 15 in the

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Relation ofCD30 expression to survival and morphology in large cell B cell lymphomas

- CD30 +It-I --- CD30 +/-

.CD30-§

-

:...'.n = 25.............. n= 25

r- ~~~~~n= 18

30 _-

20 _

10n%0 12 24 36 48 60 72

Months

CD30 +I- category. Thirty patiwomen, 15 of whom were in thecategory, with 15 in the CD30 Agory. The patients were treated witexcision, radiotherapy, chemothercombination of these treatments. Bpatients were treated in several inand because treatment varied withwere not treated uniformly. We hasons, however, to assume that theretematic differences in treatmnent begroups of patients investigated.

Twelve patients in the CD30 ++/- group were excluded from tianalysis, either because the clinicalnot be found (n = 10), or becauseof causes unrelated to their non-

lymphoma (n = 2). The survival anperformed on a total of 68 patient:CD30 + lymphomas, 25 with C]lymphomas, and a control grotpatients with CD30- lymphomas.68 patients had primary large cell I

phoma, without evidence of a pregrade lymphoma.

Nine of the 18 patients withlymphomas (50%) died of their disa mean survival of nine months.

nine patients were alive, with a mi

up of 45 months. Nine of thepatients with CD30 + / - lymphorrtheir disease, with a mean survimonths. The other 16 patients v

with a mean followup of 43 montdof the 25 (44%) patients with

Figure 4 Survival curvesoflarge cellB celllymphomas presenting withstage I or II, comparedwith stage III or IVdisease. The difference issignificant (p = 0O01).

Cio

C'E0)Cu

a)cJa)

0)

100

90

80

70

60

50

40

30

L

Stage I/I|4+- Stage III/IV

IL n = 36

-I

n = 32

20 _-10

10 12 24 36 48 60 72

Months

tumours died of their disease, with a meansurvival of 13 months. The other 14 patientswith CD30- lymphomas were alive with amean follow up of 47 months. There was nosignificant difference in survival betweenpatients with CD30 + and those withCD30- tumours (p = 0 55), nor was there asignificant difference between CD30 + /-and CD30- tumours (p = 0-41), or betweenCD30 + and CD30 +/- tumours (p =0 27). A survival curve is shown in fig 3.Of the 12 patients with an anaplastic

tumour morphology, six (50%) had died of84 96 their lymphoma, with a mean survival of six

months. The other patients had a mean fol-low up of 52 months. Of the 56 patients witha lymphoma without anaplastic morphology,23 (41%) had died, with a mean survival of

ients were 16 months. The other 33 patients were aliveCD30 + with a mean follow up of 44 months. Survivalt/- cate- analysis did not show a significant differenceth surgical between these groups of patients.apy, or a Of the seven patients with an anaplasticecause the morphology in the CD30 + category, threeistitutions, (43%) had died, with a mean survival of twotime, they months; the other four had a mean follow upve no rea- of 49 months. Although this does not seem towere sys- indicate a different survival for this subgroup,tween the the number of patients is clearly too small for

definitive conclusions to be drawn.or CD30 Survival was also correlated with stage of

ie survival disease at presentation. Eleven of the 36data could (31%) patients presenting with stage I or IIthey died disease died of their disease, with a mean sur-Hodgkin's vival of 19 months. The other 25 patients hadLalysis was a mean follow up of 45 months. Eighteen ofs, 18 with the 32 (56%) patients presenting with stageD30 +/- III or IV disease died of their disease, with aap of 25 mean survival of 11 months. The other 14All those patients had a mean follow up of 45 months.

3 cell lym- Survival analysis showed this difference to bevious low significant (p = 0-01). A survival curve is

shown in fig 4.CD30 +

;ease, withThe other Discussionean follow In our hands staining of B cell lymphomas25 (36%) with Ber-H2 on formalin fixed, paraffin waxias died of embedded tissue seemed to be more variableival of 20 than on frozen tissue. This discrepancy wasvere alive, not seen in T cell lymphomas (data noths. Eleven shown). Other investigators have alsoCD30 - reported difficulties in obtaining satisfying

results with the Ber-H2 antibody on paraffinwax embedded material.27 28 Therefore, fordiagnostic purposes, we think it is safer to useBer-H2 on frozen tissue.

Recently, it has been reported that Ki-1(CD30) detects two unrelated molecules, a120 kilodalton membrane bound protein anda 57 kilodalton intracellular protein.29 In thisreport two Hodgkin's disease derived celllines expressed both antigens, while amyeloma cell line expressed only the intracel-lular antigen. Therefore it might be possiblethat CD30 positive B cell lymphomas expressone of the antigens, and that CD30 positiveT cell lymphomas the other, or both. If the

84 96 antigen expressed by B cell lymphomas is lessresistant to formalin fixation this could

lOOrFigure 3 Survival curvesofCD30 +, CD30 +/-,and CD30 - large cellBcell lymphomas. Nosignificant difference wasseen between any of thegroups.

90

80

70

60

50

40

C'7

4-a)CDa1)

a)0L

n

n

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explain the discrepancy in the effect offixation on CD30 expression between largecell B cell lymphomas and large cell T celllymphomas.CD30 expression in B cell lymphomas has

received relatively little attention comparedwith CD30 expression in T cell lymphomas.Stein et a12 reported nine CD30 positivetumours in 62 (15%) large cell B cell lym-phomas, of which two showed animmunoblastic and seven an anaplastic mor-phology. Tashiro et a17 found two CD30 pos-itive tumours in 45 (4%) B cell lymphomas,but this study included small cell lymphomas.Several other studies only report the inci-dence of CD30 positive B cell lymphomas inrelation to T cell and non-B, non-T cell lym-phoma,'689101421 but the generally low inci-dence indicates that the percentage of B celllymphomas expressing CD30 is also low inthese studies. The highest incidence of CD30expression reported is by Pallesen,2' whofound CD30 expression in 14 of 41immunoblastic and 16 of 73 (26%) centro-blastic B cell lymphomas, while the numberof anaplastic B cell lymphomas was not given.This last figure is in the same range as ourfindings, with 25 of 146 (17%) large celltumours showing strong CD30 expression,and 30 (21%) showing partial or weak stain-ing.

Several explanations can be given for ourrelatively high percentage of CD30 positivelymphomas. First, most studies reporting apredominance of T cell anaplastic large celllymphomas do not state how they selectedcases for staining with CD30, which meansthat a number of B cell anaplastic large celllymphomas might have been missed.Moreover, as staining of B cell anaplasticlarge cell lymphoma with CD30 seems to beunreliable when performed on formalin fixed,paraffin wax embedded tissue, investigatorswho did not use frozen tissue will probablyhave underestimated the incidence of CD30positive B cell lymphoma.

Finally, although we did not test the inter-and intraobserver variability in large cell Bcell lymphomas, we found that the morpho-logical distinction between anaplastictumours on the one hand and immunoblasticor polymorphic centroblastic tumours on theother was very difficult. This indicates thatthe inter- and intraobserver variability isprobably high in the diagnosis of the B cellvariety of anaplastic large cell lymphoma andsuggests that differences in morphological cri-teria and the inability to apply them consis-tently could account for a great deal of thedifferences in the relative reported prevalenceof B cell and T cell anaplastic large cell lym-phoma. It also does not support an attempt tosubdivide anaplastic large cell lymphomaeven further, as is advocated by someauthors.5 6 17

In this study, CD30 expression was presentin all subtypes of B cell large cell lymphoma.The differences between polymorphic cen-troblastic and immunoblastic lymphomas onthe one hand, and anaplastic lymphomas on

the other, however, were not large.Furthermore, even in the morphologicallyanaplastic tumours, a considerable part of thetumours showed partial or weak staining, ornone at all.

Because a favourable prognosis has beendescribed for anaplastic CD30 positive T celllymphomas,222' we compared CD30 negative(-) CD30 partially positive (+ /-), andCD30 positive (+) large cell B cell non-Hodgkin's lymphomas, to detect a possibledifference in clinical behaviour between thosegroups. We could not find any associationbetween a favourable prognosis and CD30expression.None of the above mentioned studies has

specifically addressed the prognosis ofanaplastic large cell B cell non-Hodgkin'slymphoma, although several studies havedescribed the clinical outcome of a limitednumber of patients. Tashiro et al7 reportedone large cell and one small cell CD30 + Bcell lymphoma; both patients were alive, witha mean follow up of 49 months. In the seriesof Chan et all two patients died and one wasalive after eight months of follow up. Bitter etall8 report two patients, who both died. Pennyet al described six patients,16 who all werealive, but two patients were alive with disease,and three had a follow up of less than a year.Although these numbers are small, they seemto support our finding that CD30 + large cellB cell lymphoma does not have such afavourable prognosis.

These findings contrast with the situationin T cell lymphomas, which we have reportedbefore.22 This indicates that there are obviousprognostic implications to establishing the Tcell or B cell lineage of a morpho-logically anaplastic non-Hodgkin's lym-phoma. Research on CD30 expression inlymphomas should also clearly discriminatebetween B cell and T cell lymphomas.

In the present version of the Kiel classifica-tion4 CD30 positive anaplastic lymphoma isincorporated in both the B cell and the T cellcategories. In our view, in order to qualify asa clinicopathological entity, a subtype of lym-phoma should originate from a particulartype of lymphocyte, in a particular stage oflymphocyte development. It should show adistinct, reproducible histology, display a dis-tinct clinical picture in terms of its patientpopulation, localisation, clinical course, orresponse to treatment, or, if possible, show acombination of these features. Previous stud-ies have indicated that the T cell variety oflarge cell anaplastic CD30 positive lymphomahas a distinctive morphology,22 and that itsrecognition is histologically reproducible.'0Furthermore, primary nodal and primarycutaneous CD30 positive T cell lymphomasrun a relatively benign clinical course. Forlarge cell B cell lymphomas, however, the sit-uation is entirely different. These tumours aremorphologically not well demarcated fromother large cell B cell lymphomas, and corre-lation between CD30 expression and mor-phology is poor. Neither CD30 expression,nor anaplastic morphology was correlated

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Relation ofCD30 expression to survival and morphology in large cell B cell lymphomas

with a difference in survival in the presentstudy.

These clinicopathological data raise thequestion as to whether CD30 + anaplasticlarge cell lymphomas of the B cell varietyshould be considered a separate clinicopatho-logical entity. Of course, one study and a lim-ited number of patients do not preclude slightdifferences. In particular, in this study thenumber of patients with CD30 + tumoursthat were also morphologically anaplastic wastoo small for definite conclusions to bedrawn. We feel, however, that our resultsraise serious doubts about whether CD30expression and anaplastic morphology doreally define a separate entity in large cell Bcell lymphomas, as they do in large cell T celllymphomas.

This study was supported by the Comprehensive CancerCentre, Amsterdam.

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