Relation of CD30 Expression to Survival and Morphology in Large Cell B Cell Lymphomas J Clin Pathol: First Published As 10.1136/Jcp.47.1.33 on 1 January 1994

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J Clin Pathol 1994;47:33-37 33 Relation of CD30 expression to survival and morphology in large cell B cell lymphomas J Clin Pathol: first published as 10.1136/jcp.47.1.33 on 1 January 1994. Downloaded from

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

Abstract the nerve growth factor receptor superfamily.3 Aims-To investigate whether CD30 Because these CD30 positive lymphomas expression is correlated with anaplastic seemed to present a specific histological pic- morphology, and whether this correlated ture, this group of lymphomas was called with a better survival in large cell B cell anaplastic large cell (Ki-I +) lymphoma, and lymphomas, as has been described for was incorporated in the updated version of T cell lymphomas. the Kiel classification among the high grade Methods-CD30 expression was investi- category of both B cell and T cell gated using frozen sections in a series of lymphomas.4 Several reports have described 146 large cell B cell lymphomas. Clinical cases or series of these anaplastic large cell data and follow up information were col- lymphomas, most of which have concentrated lected from 25 lymphomas with strong on the T cell variety.2 5 Furthermore, CD30 expression, 30 lymphomas with several morphological subtypes have been partial CD30 expression, and a control described.5 7 17-20 group of 25 lymphomas which did not According to the updated Kiel classifica- express CD30. tion, a lymphoma should not only express Results-Morphological distinction between CD30, but also exhibit a so-called "anaplas- anaplastic and non-anaplastic tumours tic" morphology, to qualify as an anaplastic was difficult. Of the cases with an large cell lymphoma. Some studies mention anaplastic morphology, 50% were CD30 the expression of CD30 in non-anaplastic positive, as were 24% of the polymorphic lymphomas,2782' but none of these studies centroblastic B cell lymphomas. Only has systematically addressed the question of 65% of the morphologically non-anaplas- how frequently CD30 expression occurs in tic tumours were completely CD30 nega- different morphological subtypes of large cell tive. There was no difference in survival non-Hodgkin's lymphoma. In T cell among patients with lymphomas express- lymphomas the relation between anaplastic ing CD30 and those that did not. Patients morphology and CD30 expression seems to http://jcp.bmj.com/ with morphologically anaplastic B cell be fairly good,22 and CD30 expression is lymphomas did not differ in their sur- associated with a relatively benign clinical vivals from those with other high grade B course.22 23 Whether this also holds true for B cell lymphomas. Clinical stage at presen- cell lymphomas is presently unknown. tation was the only variable that was sig- nificantly associated with survival. Department of Conclusions-CD30 expression occurs Methods on October 2, 2021 by guest. Protected copyright. Pathology, Academic frequently in large cell B cell lymphomas In a pilot experiment of 44 large cell B cell Medical Centre, Amsterdam and is poorly related to anaplastic lymphomas CD30 expression, as demon- L A Noorduyn morphology. Morphological distinction strated by Ber-H224 on formalin fixed, paraf- Department of between anaplastic and non-anaplastic fin wax embedded tissue, gave many false Pathology, Free tumours is difficult. In contrast to T cell negative results when compared with frozen University Hospital, B sections we decided to use Amsterdam lymphomas, CD30 positive cell lym- (fig 1). Therefore, P C de Bruin phomas do not show a relatively only those large cell lymphomas from which CJLMMeijer favourable clinical course. The results frozen tissue was available. We therefore col- Netherlands Cancer presented here raise serious doubts as to lected 146 cases of large cell lymphoma from Institute whether large cell B cell lymphoma, the files of the Comprehensive Cancer Centre P van Heerde based on the expression of CD30 or Amsterdam (CCCA). Routinely stained Slotervaart Hospital, and Amsterdam anaplastic morphology, can really be slides (haematoxylin eosin, reticulin, M M van de Sandt termed a separate entity. Giemsa, and periodic acid Schiff), and data Department of on immunohistochemistry were also collected Haematology, Free (3 Clin Pathol 1994;47:33-37) from all cases. University Hospital, Staining with Ber-H2 on frozen sections Amsterdam G J Ossenkoppele was performed according to standard proce- as Correspondence to: In 1982 a monoclonal antibody that reacted dures. Tumours were scored positive (+) Dr L A Noorduyn, selectively with Hodgkin and Reed-Stemnberg if at least 50% of the tumour cells were Department of Pathology, Academic Medical Centre, cells was described by Schwab et al.' Ki-i stained clearly and dubious (+ /-) if less Meibergdreef 9, 1105 AZ (CD30) was subsequently shown to react than 50% of the tumour cells were stained or Amsterdam, The Netherlands with a number of large cell non-Hodgkin's if staining was weak. Morphological investiga- Accepted for publication lymphomas. Recently, it has been shown that tion of the tumours was performed with the 18 August 1993. Ki-i detects an antigen that is a member of help of routinely stained slides, without prior 34 Noorduyn, Bruin, Heerde, Sandt, Ossenkoppele, Meijer

.... V4, knowledge of the results of Ber-H2 staining. 9-go" .:. Morphologically, the tumours were graded .* according to the updated Kiel classification.4 i .. Tumours were scored as anaplastic if they

... J Clin Pathol: first published as 10.1136/jcp.47.1.33 on 1 January 1994. Downloaded from met the criteria described by Suchi et al and Lennert.526 In short, anaplastic lymphomas 4 were characterised by large or very large cells, 4. * with abundant cytoplasm, with large, often and usually mul- ...... reniform or indented nuclei, w. tiple, medium sized to large nucleoli. The ._: i :. i. tumour often showed an intrasinusoidal '4 growth pattern. ./:O..§. .... w.s., *: °\ ...... Of the tumours that were scored as + or * .e:*: .S :> ffiW- A">Z:X:.: '4, if}S%;R:. * u R;iu)+ /-)and from a control group of 25 A1 {:Aj.!. *.*..: *, :& * i # tumours that were scored as -, clinical :' # ...... : and follow up data were collected from the .. IP e patients' records. This group of 25 patients whose tumours were completely CD30 nega- : *.z .. , g ...- tive was used as a control group for survival analysis. It included three patients with :. ...:: . anaplastic, but immuno- ...., .":o. ....e..:.A morphologically histochemically CD30 negative, tumours. JR-.if>. ... - .: vR* ..^'w bioi.. Statistical analysis of these data was Figure 1 Polymorphic centroblastic B cell lymphoma. Staining with Be? paraffin wax section is negative. Inset: staining with Ber-H2 onfrozen section is I-Ht2ven performed with the help of a BMDP package.

Results The numbers of positive tumours for each morphological subtype are shown in the Expression ofCD30 (Ber-H2) in 146 large cell B cell table. In most tumours in the CD30+ cate- lymphomas, according to morphological subtype gory, over 80% of tumour cells were positive, and in the CD30 + / - category generally less CD30 than 20% were positive. Only a few tumours + - Total expressed CD30 in tumour cells close to the B cell lymphomas cutoff point of 50%. Follicular centroblastic 2 5 7 14 Of the B cell lymphomas that were mor- Centrocytoid centroblastic 2 10 29 41 Centroblastic 2 5 22 29 phologically scored as anaplastic (fig 2), 50% Polymorphic centroblastic 9 7 21 37 were positive with CD30, but of the

Immunoblastic 2 1 6 9 http://jcp.bmj.com/ Anaplastic 8 2 6 16 immunoblastic and polymorphic centroblastic Total 25 30 91 146 tumours, 22% and 24%, respectively, were + > 50% of the tumour cells positive; + < 50% of the also positive. Even the other groups of large tumour cells positive, or weak staining; - tumour cells cell B cell lymphoma included cases which negative. were positive with CD30, and a considerable percentage of these tumours showed partial or weak staining of the tumour cells. Only 65% of the morphologically non-anaplastic on October 2, 2021 by guest. Protected copyright. tumours were completely negative with CD30. In reviewing the morphology of the tumours, it was often difficult to differentiate anaplastic and non-anaplastic tumours. In particular, the distinction between poly- .S.. : 0, morphic centroblastic lymphomas and X.! t. immunoblastic B cell lymphomas on the one ::: ::. hand, and anaplastic large cell B cell lym- *:::: :.: phomas on the other, was hard to make when the lymph node was completely invaded, and *# ,u.if > >ak therefore, the characteristic intrasinusoidal .:: i:. growth pattern of anaplastic large cell lymphoma could not be seen. All these types of :*b. .U. ..f e.: f lymphoma were composed of large cells,

.Z:z,:2' 'S usually with abundant cytoplasm, and .- :.e t: .: .:.' : anaplastic nuclei were detected in varying !§2 '' amounts in all of them. Therefore, the dis- .: .S.:e,:....w. tinction was made by estimating the propor- tion of anaplastic nuclei, but we felt that

... : placing these tumours in one category or

:... '' another was often arbitrary. Of the cases that expressed CD30, 25 4. .'. patients were men, 10 of whom were in ....Figure: S.t,:^:;*t. e |.... r... .:.... ::: ae:., .% 's3':.2'....,.... ' :.:.... '° 3..Anaplastic<... : ...... : nsslt.?.: .X. :e ffly:.:::; .. . s::. : large cell lymphoma, B cell type (haematoxylin and eosin). the CD30 + category, with 15 in the Relation ofCD30 expression to survival and morphology in large cell B cell lymphomas 35

Figure 3 Survival curves tumours died of their disease, with a mean ofCD30 +, CD30 +/-, lOOr - CD30 + and CD30 - large cell B 90 It-I --- CD30 +/- survival of 13 months. The other 14 patients cell lymphomas. No .CD30- with CD30- lymphomas were alive with a 80 - significant difference was § mean follow up of 47 months. There was no seen between any ofthe 70 :...'.n = 25 J Clin Pathol: first published as 10.1136/jcp.47.1.33 on 1 January 1994. Downloaded from groups. C'7 significant difference in survival between 60 patients with CD30 + and those with ...... 4 - n= 25 = a) 50 CD30- tumours (p 0 55), nor was there a CD significant difference between CD30 + /- ~~~~~n= 18 a1) 40 r- and CD30- tumours (p = 0-41), or between a) 30 _- CD30 + and CD30 +/- tumours (p = 0L 20 _ 0 27). A survival curve is shown in fig 3. Of the 12 patients with an anaplastic 10 tumour morphology, six (50%) had died of nn% 0 12 24 36 48 60 72 84 96 their lymphoma, with a mean survival of six Months months. The other patients had a mean follow up of 52 months. Of the 56 patients with a lymphoma without anaplastic morphology, 23 (41%) had died, with a mean survival of CD30 +I- category. Thirty patiients were 16 months. The other 33 patients were alive women, 15 of whom were in the CD30 + with a mean follow up of 44 months. Survival category, with 15 in the CD30 At/- cate- analysis did not show a significant difference gory. The patients were treated witth surgical between these groups of patients. excision, radiotherapy, chemotherapy, or a Of the seven patients with an anaplastic combination of these treatments. Because the morphology in the CD30 + category, three patients were treated in several inistitutions, (43%) had died, with a mean survival of two and because treatment varied with time, they months; the other four had a mean follow up were not treated uniformly. We have no rea- of 49 months. Although this does not seem to sons, however, to assume that there were sys- indicate a different survival for this subgroup, tematic differences in treatmnent between the the number of patients is clearly too small for groups of patients investigated. definitive conclusions to be drawn. Twelve patients in the CD30 + or CD30 Survival was also correlated with stage of +/- group were excluded from ti ie survival disease at presentation. Eleven of the 36 analysis, either because the clinical data could (31%) patients presenting with stage I or II not be found (n = 10), or because they died disease died of their disease, with a mean sur- of causes unrelated to their non-Hodgkin's vival of 19 months. The other 25 patients had lymphoma (n = 2). The survival anLalysis was a mean follow up of 45 months. Eighteen of performed on a total of 68 patient:s, 18 with the 32 (56%) patients presenting with stage CD30 + lymphomas, 25 with C]D30 +/- III or IV disease died of their disease, with a http://jcp.bmj.com/ lymphomas, and a control grotap of 25 mean survival of 11 months. The other 14 patients with CD30- lymphomas. All those patients had a mean follow up of 45 months. 68 patients had primary large cell I3 cell lym- Survival analysis showed this difference to be phoma, without evidence of a pre vious low significant (p = 0-01). A survival curve is grade lymphoma. shown in fig 4. Nine of the 18 patients with CD30 + died of their dis;ease, with lymphomas (50%) on October 2, 2021 by guest. Protected copyright. a mean survival of nine months. The other Discussion nine patients were alive, with a miean follow In our hands staining of B cell lymphomas up of 45 months. Nine of the 25 (36%) with Ber-H2 on formalin fixed, paraffin wax patients with CD30 + / - lymphorrias died of embedded tissue seemed to be more variable their disease, with a mean surviival of 20 than on frozen tissue. This discrepancy was months. The other 16 patients vvere alive, not seen in T cell lymphomas (data not with a mean followup of 43 montdhs. Eleven shown). Other investigators have also of the 25 (44%) patients with CD30 - reported difficulties in obtaining satisfying results with the Ber-H2 antibody on paraffin wax embedded material.27 28 Therefore, for Figure 4 Survival curves 100 diagnostic purposes, we think it is safer to use oflarge cell B cell L 90 Stage I/I| Ber-H2 on frozen tissue. lymphomas presenting with Recently, it has been reported that Ki-1 stage I or II, compared 80 4+- Stage III/IV with stage III or IV Cio (CD30) detects two unrelated molecules, a disease. The difference is 70 IL n = 36 120 kilodalton membrane bound protein and significant (p = 0O01). C'E 60 a 57 kilodalton intracellular protein.29 In this Cu two disease derived cell 0) 50 -I report Hodgkin's 40 lines expressed both antigens, while a cJa) a) myeloma cell line expressed only the intracel- 30 n = 32 0) lular antigen. Therefore it might be possible 20 _- that CD30 positive B cell lymphomas express 10 one of the antigens, and that CD30 positive n 1 T cell lymphomas the other, or both. If the 0 12 24 36 48 60 72 84 96 antigen expressed by B cell lymphomas is less Months resistant to formalin fixation this could 36 Noorduyn, Bruin, Heerde, Sandt, Ossenkoppele, Meijer

explain the discrepancy in the effect of the other, however, were not large. fixation on CD30 expression between large Furthermore, even in the morphologically cell B cell lymphomas and large cell T cell anaplastic tumours, a considerable part of the lymphomas. tumours showed partial or weak staining, or CD30 expression in B cell lymphomas has none at all. J Clin Pathol: first published as 10.1136/jcp.47.1.33 on 1 January 1994. Downloaded from received relatively little attention compared Because a favourable prognosis has been with CD30 expression in T cell lymphomas. described for anaplastic CD30 positive T cell Stein et a12 reported nine CD30 positive lymphomas,222' we compared CD30 negative tumours in 62 (15%) large cell B cell lym- (-) CD30 partially positive (+ /-), and phomas, of which two showed an CD30 positive (+) large cell B cell non- immunoblastic and seven an anaplastic mor- Hodgkin's lymphomas, to detect a possible phology. Tashiro et a17 found two CD30 pos- difference in clinical behaviour between those itive tumours in 45 (4%) B cell lymphomas, groups. We could not find any association but this study included small cell lymphomas. between a favourable prognosis and CD30 Several other studies only report the inci- expression. dence of CD30 positive B cell lymphomas in None of the above mentioned studies has relation to T cell and non-B, non-T cell lym- specifically addressed the prognosis of phoma,'689101421 but the generally low inci- anaplastic large cell B cell non-Hodgkin's dence indicates that the percentage of B cell lymphoma, although several studies have lymphomas expressing CD30 is also low in described the clinical outcome of a limited these studies. The highest incidence of CD30 number of patients. Tashiro et al7 reported expression reported is by Pallesen,2' who one large cell and one small cell CD30 + B found CD30 expression in 14 of 41 cell lymphoma; both patients were alive, with immunoblastic and 16 of 73 (26%) centro- a mean follow up of 49 months. In the series blastic B cell lymphomas, while the number of Chan et all two patients died and one was of anaplastic B cell lymphomas was not given. alive after eight months of follow up. Bitter et This last figure is in the same range as our all8 report two patients, who both died. Penny findings, with 25 of 146 (17%) large cell et al described six patients,16 who all were tumours showing strong CD30 expression, alive, but two patients were alive with disease, and 30 (21%) showing partial or weak stain- and three had a follow up of less than a year. ing. Although these numbers are small, they seem Several explanations can be given for our to support our finding that CD30 + large cell relatively high percentage of CD30 positive B cell lymphoma does not have such a lymphomas. First, most studies reporting a favourable prognosis. predominance of T cell anaplastic large cell These findings contrast with the situation lymphomas do not state how they selected in T cell lymphomas, which we have reported cases for staining with CD30, which means before.22 This indicates that there are obvious that a number of B cell anaplastic large cell prognostic implications to establishing the T lymphomas might have been missed. cell or B cell lineage of a morpho- http://jcp.bmj.com/ Moreover, as staining of B cell anaplastic logically anaplastic non-Hodgkin's lym- large cell lymphoma with CD30 seems to be phoma. Research on CD30 expression in unreliable when performed on formalin fixed, lymphomas should also clearly discriminate paraffin wax embedded tissue, investigators between B cell and T cell lymphomas. who did not use frozen tissue will probably In the present version of the Kiel classifica- have underestimated the incidence of CD30 tion4 CD30 positive anaplastic lymphoma is positive B cell lymphoma. incorporated in both the B cell and the T cell on October 2, 2021 by guest. Protected copyright. Finally, although we did not test the inter- categories. In our view, in order to qualify as and intraobserver variability in large cell B a clinicopathological entity, a subtype of lym- cell lymphomas, we found that the morpho- phoma should originate from a particular logical distinction between anaplastic type of lymphocyte, in a particular stage of tumours on the one hand and immunoblastic lymphocyte development. It should show a or polymorphic centroblastic tumours on the distinct, reproducible histology, display a dis- other was very difficult. This indicates that tinct clinical picture in terms of its patient the inter- and intraobserver variability is population, localisation, clinical course, or probably high in the diagnosis of the B cell response to treatment, or, if possible, show a variety of anaplastic large cell lymphoma and combination of these features. Previous stud- suggests that differences in morphological cri- ies have indicated that the T cell variety of teria and the inability to apply them consis- large cell anaplastic CD30 positive lymphoma tently could account for a great deal of the has a distinctive morphology,22 and that its differences in the relative reported prevalence recognition is histologically reproducible.'0 of B cell and T cell anaplastic large cell lym- Furthermore, primary nodal and primary phoma. It also does not support an attempt to cutaneous CD30 positive T cell lymphomas subdivide anaplastic large cell lymphoma run a relatively benign clinical course. For even further, as is advocated by some large cell B cell lymphomas, however, the sit- authors.5 6 17 uation is entirely different. These tumours are In this study, CD30 expression was present morphologically not well demarcated from in all subtypes of B cell large cell lymphoma. other large cell B cell lymphomas, and corre- The differences between polymorphic cen- lation between CD30 expression and mor- troblastic and immunoblastic lymphomas on phology is poor. Neither CD30 expression, the one hand, and anaplastic lymphomas on nor anaplastic morphology was correlated Relation ofCD30 expression to survival and morphology in large cell B cell lymphomas 37

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