Non-Hodgkin malignant lymphomas. Clinico-pathologic correlations with the Kiel classification

Europ. J. Cancer Vol. 14, pp. 587-592. Pergamon Press t978. Printed in Great Britain

Non-Hodgkin Malignant Lymphomas. Clinico-Pathologic Correlations with the Kiel Classification Retrospective Analysis of a Series of 274 Cases C. MEUG~2, B. HOERNI, A. DE MASCAREL, M. DURAND, P. R I C H A U D , G. H O E R N I - S I M O N , J. CHAUVERGNE and C. LAGARDE Fondation Bergonii, Cancer Center, 180, rue de Saint-Gen~s, 33076 Bordeaux Cedex, France A b s t r a c t - - T h r e e hundred and sixty case histories of patients Jbllowedjbr non-Hodgkin lymphoma between 1965 and 1976 were reviewed from the hi~tologic point of view for classification according to Kiel's nomenclature. The diagnosis was rectified for 86 patients and confirmedJbr the 274 remaining ones; these latter cases were classified and their clinicopathologic and evolutive correlations studied. The most striking fact is a very distinct difference between the so-called low gradeforms, which have a non-corrected median survival of four and a haljyears, whereas in the high grade forms it is 7 months. Except for a few minor differences, the observations noted in this series cross-check those previously published.

specimens, tissue sections improperly fixed or too thick, only one slide). Consequently only 360 case histories could be considered. Throughout the period studied the patients were submitted to the same simple routine investigations according to the recommendations of Rye's symposium for Hodgkin's disease [5] with a complete clinical examination, a thoracic X-ray and tomography of the mediastinum, an abdominal lymphography and the usual biologic investigations. There were no exploratory laparotomies. Bone marrow biopsy was done only when clinical and/or biological data were considered suspicious for bone marrow involvement. On the other hand, the treatments varied considerably during the period studied, with particular improvement in chemotherapy and more frequent indication of radiochemotherapeutic associations; but these treatments were never conditioned by the histologic type. All histologic specimens were examined after routine staining by Hematoxylin-eosin, Gomori, PAS and Giemsa. In all cases the specimen reviewed was the one on which the initial diagnosis was based. The pathologist who reviewed the slides knew the age of each patient and the site of the biopsy. For 86 patients the initial diagnosis of N H M L was modified as indicated in Table 1. For the 274

INTRODUCTION The ItISTOLOGIC classification of non-Hodgkin malignant lymphoma ( N H M L ) has been, for a long time, submitted to numerous variations. During the last few years the most frequently used classification has been the one of Rappaport [1]. As for as we are concerned, we have applied this classification for several years without obtaining a distinct clinic0-pathologic correlation [2]. We therefore decided to try Kiel's new classification, first proposed by Lennert [3], then by several European pathologists [4] in order to test its validity. This classification was applied, in a retrospective manner, to all cases observed during the last 12yr; clinico-pathologic and evolutive correlations were particularly investigated. The results of this study are presented in this paper.

MATERIAL AND METHODS This study included 434 case histories (with histologic documents that could be reviewed) of patients treated and followed up at the Fondation Bergonid for N H M L between J a n u a r y 1965 and December 1976. Seventy-four cases were eliminated due to insufficient material for review (incomplete Accepted 24 October 1977. 587

588

C. Meugi et al. Table 1. Diagnosis of 86 excluded patienls

73 malignant 40 carcinomas 27 undifferentiated 1 adenocarcinoma 1 Regaud lymphoepithelioma 11 undetermined 18 blood malignancies 6 malignant histiocytosis 5 lympho-epithelioid lymphomas 2 mycosis thngoides 2 angio-immunoblastic lymphadenopathy 3 miscellaneous 15 miscellaneous and undetermined malignancies 13 benign

7able 2.

Kid classification

I,ow grade Lymphocytic (LC) Lymphoplasmocytoid (LP) Centrocytic (CC) Centroblasto-Centrocytic (CB-CC) High grade Centrnblastic (CB) l,ymphoblastic (LB) Immunoblastic (IB) Unclassifiable

Table 3.

Distribution oj histologic types 165

Low grade Lymphocytic Lymphoplasmocytoid Centrocytic Centroblasto-centrocytic High grade Centroblastic Lymphoblastic hnmunoblastic Unclassifiable

23 31 10 101 91 2 39 50 18

Table 4.

I

I1 II1 IV Undetermined Total

RESULTS

T h e distribution of the 274 N H M L , confirmed by the histologic revision, according to Kiel's classification, is indicated in T a b l e 3. T h e most i m p o r t a n t groups of centroblastocentrocytic (CB-CC) l y m p h o m a s could be divided into three subgroups: nodular CB-CC (59 patients); nodular CB-CC with sclerosis (18 patients); diffuse CB-CC (24 patients). T h e distribution according to age and sex is shown in Fig. 1. Low grade l y m p h o m a s are rarely observed before 3 0 y r and never before 2 0 y r ; the sex ratio is 1.2. T h e distribution by clinical stage prior to any treatment is indicated in T a b l e 4. O n one hand the patients are equally divided between stages I and II and stages I I I and IV. T h e r e is no difference according to the hist01ogic type, except for lymphocytic forms where stages I I I and I V p r e d o m i n a t e and l y m p h o p l a s m o c y t o i d t~)rms where stages I and II predominate. T a b l e 4 gives the main initial tumoral sites. T h e [i~equency of visceral localizations and Waldeyer's ring in lymphoplasmocytoid forms and of mediastinal lesions in lymphoblastic fbrms, may be pointed out. O n the whole, lymph nodes opacified by l y m p h o g r a p h y , are more often involved in low grade forms than in high grade ones. During evolution, 19 secondary leukemias were observed; 9 in the LC, 3 in the CB-CC, 7 in the LB and 1 in the unclassifiable. T h e distribution of 23 cases with positive Coombs' test and 4 cases with monoclonal dysglobulinemia shows no significant difference.

Distribution by clinical stage High grade

Low grade 25~.tgtS

cases in which the diagnosis of N H M L was confirmed, Kiel's classification was applied (Table 2). Fifty of these patients had been priorly treated and were taken in charge by the F o n d a t i o n Bergonia at the time of a relapse; the other 224 were seen as soon as the diagnosis was established, prior to any treatment.

LC

LP

CC

CB-CC

CB

LB

IB

4 2 9 6 2 23

l0 13 3 4 1 31

1 2 5 1 1 10

26 18 37 15 5 101

0 0 1 l 0 2

9 12 8 10 0 39

12 13 13 8 4 50

Unclassifiable 3 3 8 2 2 18

Total 65 63 84 47 15 274

Non-Hodgkin Malignant Lymphomas

20

10

numberof ~tlents

10

91 HIGH GRADE * 18 Unclassifiable

589

20

i!

m

Wi

LB (39)

[]

Unclass(m)

[~

CS(2)

Fig. 1. Di'stribution of main histologic subtypes accordingto age and sex.

Table 5.

Initial locali,,ation

Low grade

Total Waldeyer Mediastinum Spleen Lymphography Visceral localization Bone marrow

High grade

LC

LP

CC

CB-CC

CB

LB

IB

Unclassifiable

Total

23 4 4 5 11 3 7

31 8 1 2 6 18 1

I0 4 1 2 4 0 1

10l 11 12 14 51 8 8

2 0 1 1 2 1 0

39 3 17 4 10 13 7

50 7 4 1 21 15 1

18 4 5 3 11 1 2

274 41 45 32 116 59 27

Table 6.

Survival of patients as of April l s t J 9 7 7 Low grade

Alive in complete remission Alive with evolutive disease Dead of lymphoma Dead of intercurrent disease Dead of undetermined cause Total

High grade

LC

LP

CB-CC

CB

LB

IB

Unclassifiable

Total

6 6 4 3 4 23

11 5 12 2 1 31

44 10 40 4 3 101

0 1 1 0 0 2

7 2 27 0 3 39

4 3 38 2 3 50

2 1 8 3 4 18

72 28 130 14 18 274

T h e e v o l u t i o n is i n d i c a t e d b y u n c o r r e c t e d a c t u a r i a l survival curves. T h e state o f the patients as o f April 1st 1977 is i n d i c a t e d in T a b l e 6. T h e r e is a h i g h d e a t h r a t e d u e to i n t e r c u r r e n t causes or to u n d e t e r m i n e d cause in r e l a t i o n to the old age o f m a n y patients. T h e Figs. 2 - 5 s h o w a v e r y clear difference b e t w e e n the low g r a d e forms w h i c h h a v e a m e d i a n survival o f 4.5 y r w h e r e a s t h a t o f the h i g h g r a d e ones is o f 7 m o n t h s , closely related to the unclassifiable forms. T h e r e is no definite

difference b e t w e e n the m a i n s u b g r o u p s for the h i g h g r a d e (Fig. 3) n o r for the low g r a d e (Fig. 4). O n the c o n t r a r y , the subdivision o f the C B - C C forms shows a less f a v o r a b l e e v o l u t i o n tbr the diffuse forms (0.025 < P < 0.05) situating t h e m as i n t e r m e d i a r y b e t w e e n the h i g h g r a d e a n d the low g r a d e , with a m e d i a n survival o f 2 yr. Lastly, Fig. 6 shows the e v o l u t i o n o f survivals for the 224 p a t i e n t s w h o r e c e i v e d their first t r e a t m e n t at the F o n d a t i o n Bergonifi, in f u n c t i o n

C. Meugi et

590 1.0

al.

165 19~

~\,, 08

LOW

GRADE

08

122

~

64

97

9v~

71 06

X

7 G*ade --

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o

X

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-- --

CB.CC

~o~

04

8

•

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~'~

Unclass.

High Grade

\~ 4 1

Fig. 2.

", LP

Crude actuarial survival curvesfor all patients.

Fig. 4.

2

3

;y

4

Crude actuarial survival curvesfor low grade types.

1.0.

50

CB CC HIGH GRADE

14

13

o cccno O~

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~ 15

>-

-N O

CC n ~ . X ~"

o6

0.4.

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CB CC diff.

\

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3

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LB IB 1

Fig. 3.

Crude actuarial survival curvesfor high grade types.

of the period of treatment; it demonstrates a moderate but regular improvement, in the results between the beginning and the end of the decade in consideration, comparable in the two main histologic groups.

Fig. 5.

2

3

4

5y

Crude actuarial survival curves for CB-CC subtypes (nodular, with or without sclerosis, and di/Ji*se).

DISCUSSION The histologic revision of 360 case histories of patients who had initially been diagnosed as having N H M L first led to the exclusion of 84 cases; the diagnosis of these cases has been

Non-Hodgkin Malignant Lymphomas

\'~. ~ 'l~ -'~.'.~''-..._ ~

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i~l~

0.2.

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k'~

i O.4,

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High Grade Fig. 6.

LOW Grade ~ 197476

'\.\~" 1971.73

1974_76 " ~ 1965_70 1971_73

Crude actuarial survival curves according to the year o/ diagnosis and J%~t treatment.

modified (Table 1). For forty of them it was really lymph node metastases ofundifferenciated carcinoma (anaplastic carcinoma, oat cell carcinoma of the lung, nasopharyngeal carcinoma) or even thymona, melanoma, seminoma, embryonal sarcoma or neuroblastoma. These diagnostic readjustments were largely facilitated during the second reading by the routine use of special stains and, in particular, slow staining Giemsa; this stain only weakly colors metastatic cells, while the cytoplasm of the lymphoid elements are generally bluish or dark blue. The good technical quality of the sections and the stains is the first condition necessary in order to reduce classification difficulties. Kiel's classification is sufficiently explicit to avoid problems in the large majority of the cases. There may be some hesitations between LC, LP or diffuse CBCC types, or between LB and IB types; however, there is rarely a hesitation between low grade and high grade forms. Each of these two main groups is characterized by definite cytologic criteria which are based on the size of the cellular elements and their nucleus, the staining characteristics of the cytoplasm, the outline of their nucleus (round, clived, convoluted) the character of their chromatin and the presence or absence ofnucleolus, their size and number [3]. The main criticism which can be attributed to our work lies in the fact that the slides were read by only one pathologist. It would have been preferable, of course, to have the slides read by two or three different pathologists. Our results may be confi'onted with those previously published concerning the same histologic classification [6-9]. We have thus observed a relatively higher proportion of high grade forms in comparison with most of the other series. The distribution

59l

according to sex and age for each histologic subgroup is, on the contrary, comparable in all series. All forms are more frequent in elderly patients. Low grade forms were not observed in children. For the high grade forms, the distribution of the LB is bimodal with two peaks, one around 20 yr and another around 70yr, while the frequency of the IB increases with age. It is more difficult to compare the distribution by stages; in other series, there was a pathologic staging according to Ann Arbor Symposium [10], whereas we have used a clinical staging according to Rye Symposium [5]. This fact explains why we have almost as many ! and II stages as III and IV stages, whereas in other series stages III and IV clearly predominate. In all series, the correlation between evolution and histology demonstrates a very significant difference between the low grade and the high grade forms. This difference is more striking in our series than in preceding ones. In all series the CC have a prognosis slightly less favorable than the other low grade forms. The difference, which is especially distinct, between the nodular CBCC and the diffuse CB-CC is significant in our series. This difference had not previously been observed by the German investigators, but appears here particularly important. In contrast with other data [11], there is no difference in our series between survival of patients with nodular CB-CC, with or without sclerosis. Like Brittinger et al. [8], we did not observe a difference between LB and IB, while Musshoff et al. [7] observe a more favorable evolution for the LB than for the IB. At last, in all series the survival regularly decreases for the low grade forms, while it has a tendency to stabilize after an initial rapid deterioration for the high grade ones. This tendency which begins to appear in our series is particularly evident in the one of Diihmke and Qu~ick [9] in which the two curves meet at 10yr. As far as we are concerned, this classification gave us a histoprognostic correlation which was much more interesting than the one obtained with Rappaport's classification [2]. It is close to the one independently proposed by Lukes [12] and indicate two very distinct categories of N H M L for which a different therapeutic attitude must be proposed. The evolution, very different between these two types of N H M L effectively calls for a treatment adapted to the gravity of the disease [ 13]. Only the subgroup of diffuse CB-CC lymphomas has an intermediary prognosis but it represents less than 10~) of the patients (24/274). The group of histologically unclassifiable cases shares the poor prognosis of the high grade forms. Consequently, our results confirm that Kiel's

592

C. Meugi et al.

classification is useful in indicating the prognosis and guiding the treatment of N H M L . T h e question as to whether these results are reproducible remains unanswered. The convergence of the main series of different teams published

until now seems to indicate that this reproducibility is good; however, only studies presently u n d e r w a y involving comparisons between several pathologists will shed more light on this subject.

REFERENCES

1. H . R . RAPPAPORT,W. J. WINTER and E. B. HICKS,Follicular lymphoma. A reevaluation of its position in the scheme of malignant lymphoma, based on a survey of 253 cases. Cancer (Philad.)9, 792 (1956). 2. B. HOERNI,J. CHAUVERGNE,M. DURAND,G. HOERNI-SIMON,J. TOUCHARD,C. MEUG~ et C. LA6ARDE, Evolution des r~ticulosarcomes et lymphosarcomes. Analyse d'une sfirie de 268 malades. Bull. Cancer 61, 61 (1974). 3. K. LENNERT, N. MOHRI, H. STEIN and E. KAISERLING,The histopathology of malignant lymphoma. Brit. J. Haemat. 31 suppl. II, 193 (1975). 4. R. GERARD-MARCHANT,I. HAMLIN,K. LENNERT,F. RILKE, A. G. STANSFELDand J. A. M. VAN UNNIK, Classification of non-Hodgkin's lymphomas. Lancet fi, 405 (1974). 5. S.A. ROSENBERG,Report of the committee on the staging of Hodgkin's disease. Cancer Res. 26, 1320 (1966). 6. E. D~HMKE, Zur Klinischen Relevanz der histologischen Differenzierung maligner Non-Hodgkin-Lymphome nach der "Kiel-Klassification". Eine retrospektive Studie entsprechender Korrelationen bei 228 FS.11en aus SchleswigHolstein. Strahlentherapie 152, 129 (1976). 7. K. MUSSHOFF, H. SCHMIDT-WOLLMER,K. LENNERT and W. SANDRITTER, Preliminary clinical findings on the Kiel classification of malignant lymphomas. Z. Krebsforsch. 87, 229 (1976). 8. G. BRITTINGER,H. BARTELS,K. BREMER,A. BURGER,E. D/dHMKE,U. GUNZER,E. K6NIG, A. STACHER, H. STEIN, H. TnEML und R. WALDNER, (Kieler Lymphomgruppe), Retrospektive Untersuchungen zur klinischen Bedeutung der Kiel-Klassification der malignen Non-Hodgkin-Lymphome. Strahlentherapie 153, 222 (1977). 9. E. Dt~HMKEund J. QUXCK, Retrospektive Analyse von malignen Non-HodgkinLymphomerkrankungen der Radiologischen Klinik der Universitfit Kiel von 1969 bis 1975. Strahlentherapie 153, 229 (1977). 10. S.A. ROSENBERG,M. BOIRON,V. T. DE VITA,R. E. JOHNSON, B. J. LEE, J. E. ULTMANNand M. JR. VIAMONTE~Report of the committee on Hodgkin's disease staging procedures. Cancer Res. 31, 1862 (1971). 11. M . n . BENNETTand H. L. MILLET,Nodular sclerotic lymphosarcoma. A possible new clinico-pathological entity. Clin. Radiol. 20, 339 (1969). 12. R . J . LUKES and R. D. COLLINS~ New approaches to the classification of the lymphomata. Brit. J. Cancer 31, suppl. II, 1 (1975). 13. C. LAGARDE,J. CHAUVERGNEet B. HOERNI,Les Iymphomes Malins. Masson, Paris (1975).