505

t4istopathology of Large Cell Lymphomas (Report No 9)* KRISTIN HENRY The purpose of this communication is to discuss and illustrate the different microscopical features of members of this important group of large cell lymphomas and to give some indication of prognosis in relation to histo- pathology. The diffuse large cell lymphoma is a heterogeneous category of tumour previously designated reticulum cell sarcoma in traditional classifications, and 'histiocytic' by Rappaport. The majority are, however, large l ympho id cell tumours which on the basis of their light microscopic anatomy may be subdivided into those of follicle centre (B4ymphocytic) origin, immunoblastic type of either B- or T-lymphocytic origin, and Nndifferentiated' - meaning that although acceptable as lymphoid in nature at light microscopical level there are no further distinguishing features. Plasma cell (extramedullary) lymphomas are separately categorised. A smaller but significant minority group are of histiocytic (mononuclear phagocytic) derivation. Rarely tumours are encountered involving peripheral lymphoreticular tissue but which are derived from other ceil types indigenous to the lymphoreticular and mononuclear and phagocytic system.

The word lymphoma is used here to indicate a tumour arising from cells of the peripheral tympho- reticular and mononuclear and phagocytic system (LRMPS) (Henry, 1975; Henry e t al. 1978a). It thus excludes primary neoplastic proliferations of the bone marrow - the leukaemias. The diffuse large cell lymphomas form an important group of the non- Hodgkin's lymphomas not only because of their relative frequency (24% of the BNLI series and the largest single category of lymphomas amongst Chinese patients (Ho, unpublished), but also because of their relatively poor prognosis. Formerly, large cell lymphomas were referred to as reticulum cell sarcoma (Gall and Mallory, 1942) and later as histiocytic lymphoma by Rappaport (1966). More recently data were presented by Lukes and Collins (1974), Glick et al. (1975), Jaffe et al. (1975), Brouet et al. (1976) and Lennert (1978), that these histiocytic lymphomas were in reality transformed lymphocytes. However, not all workers considered them all to be lymphocytic in nature, and evidence was presented by Henry (1975, 1977), Henry et al. (1978a, b), and Li and Harrison (1978) that some were of true histiocytic (mononuclear phagocytic) origin. There were also yet other large cell tumours considered to be derived from other cells of the LRMPS (Henry, 1975;Henry etal., 1978a). Furthermore, among the large lymphoid category of large cell lymphomas although it is now considered that many are of follicle centre origin, there is no uniformity in nomenclature, varying terms being applied to the cell types according to which classification is used. So that in the Kiel classification (Gerard-Marchant et al., 1974) and Lennert's group (1975, 1978), terms like large centrocytic and centro-

*The work described in this paper was carried out by collaborators in the British National Lymphoma Investigation, referred to in detail on page 482 of this journal. Reprint requests should be see*. to: Dr Gillian Vaughan Hudson, British National Lymphoma Investigation, Department of 0ncology, The Middlesex Hospital, London, W1.

blastic are employed, and in the Lukes and Collins classification (1974) large cleaved and small and large non-cleaved are used to denote a follicle centre origin. The BNLI classification proposed by Bennett et aL (1974) and Henry, e t al. (1978a) refers to large (immunoblastic), small regular and large irregularly nucleated follicle centre cells. Yet other terms are used in Dorfman (1974, 1975) and the WHO classi- fication proposed by Math6 et al. (1976). Most recently a retrospective study of the non-Hodgkin's lymphomas funded by the National Cancer Institute (NCI) have proferred terminology which is a compro- mise between the various classifications but which will enable cross-correlation between the different clinical trials in progress (Report of the NCI study group - see Report No. 7 this issue). Agreement in nomenclature and a working categorisation of the lymphomas acceptable to all members of the British Lymphoma Pathology Group (BLPG) has also been achieved (BLPG publication, 1981, in press). This study sets out to delineate the different histopathol- ogical features of the various groups of tumour com- prising large cell lymphomas and to indicate their relative frequency and prognosis in relation to their histopathology (see also Farrer-Brown, Report No. 8 this issue).

MATERIALS AND METHODS Material which forms the basis for this study was

derived from 798 patients entered in the BNLI non- Hodgkin's trial and from 1153 patients in the NCI retrospective study of the non-Hodgkin's lymphomas, as well as from a personal series. In the BNLI trial and personal series light microscopy evaluation has depended upon high quality well-stained sections using, in addition to H & E, methyl green pyronin (MGP) staining, Giemsa, periodic acid-Schiff (PAS) technique and reticulin/neutral red preparation. Also material from more recently entered patients has been subjected to peroxidase/antiperoxidase tech-

506 C L I N I C A L R A D I O L O G Y

niques, as described by Taylor (1980) and cytohisto- chemical techniques (Li and Harrison, 1978). Material from BNLI trial patients for electron microscopic studies has been limited and has had to rely on formalin-fixed material. In the NCI investigation no ultrastructural or immunocytochemical studies were available. Thus, recognition and categorisation of this group of tumours has largely relied on their light microscopical appearances, but has drawn also on the results and experience with collateral studies using electron microscopical and immunocytochemical techniques (Henry, 1975; Henry and Farrer-Brown, 1977, 1981; Henry e t al., 1978b; Ho and Henry, in preparation).

RESULTS Lymphomas are designated large cell types if the

nuclear volume is the same or greater than that of macrophages or endothelial cell nucleii. Actual measurements are meaningless since there is consid- erable difference in cell size in different blocks due to variability shrinkage or in expansion of tissue (Figs la, b).

In the BNLI series 22.7% of 798 lymphomas were diagnosed as large lymphoid cell lymphomas as com- pared to 18.7% of the 1153 patients studied by Henry, applying the BNLI classification in the NCI retrospective study. These lymphomas were then

broken down into subtypes according to whether they were of follicle centre origin, of immunoblastic type, or 'undifferentiated'. Plasma cell tumours were separately categorised if the majority of cells Were thought to be of plasma cell nature (Henry and Farrer-Brown, 1977). In the BNLI series less than 1% of the large cell lymphomas were considered to be of plasma cell type, though many large lymphoid tumours showed plasma cell differentiation. Histio. cytic lymphomas accounted for 5.7% in the BNLI series but only 1.1% in the NCI study, and with only light microscopical slides available it was not possible to indicate tumours of other cellular origins, and these were therefore categorised as unclassified. Amongst the large lymphoid cell lymphomas it was however possible with light microscopy alone to indicate a B-cell origin, and more specifically a follicular derivation, in contrast to T-cell lymphomas. Large cell lymphomas were often composed of large immunoblast-like cells (Fig. la) as defined by cells with round to ovoid vesicular nuclei and one to two nucleoli either centrally placed or abutting on the nuclear membrane, and with a regular and intensely pyroninophilic cytoplasm. If there was evidence of plasma cell differentiation (Fig. la) then by infer- ence the lymphoma is of B-lymphocytic type. If on the other hand the large cells were seen amongst a

Figs la, b - Diffuse lymphocytic lymphoma of large regulary nucleated cell type. (a) illustrates a large cell variant composed of immunoblastqike cells. The nuclei are round to ovoid and regular, with prominent nucleoli either centrally placed or located against the nuclear membrane. Plasma cell differentiation is present. (b) shows a smaller cell variant, again with round regular nuclei but with several nucleoli arranged peripherally in the manner of germinal-centre centroblasts. Note the cell nuclei are about the same or larger in volume than the macrophage (M) nucleus. H & E, × 1250.

Fig. 2 - Diffuse lymphocytic lymphoma of pleomorphic Fig. 3 - Diffuse lymphoma of large irregularly nucleated type. Against a heterogeneous cellular background are large lymphoid cell type, in which the majority of cells conform lymphoid cells. This lymphoma is of T-cell type and charac- to the large irregular follicle centre (large cleaved) cells, thus teristically the cytoplasm of the large ceils is relatively 'clear' indicating not only a B-ceU tymphoma but one of follicular (arrow) and poorly pyroninophilic in contrast to the B-cell . centre origin. H & E, × 1250. type of large ceil. H & E, × 1250.

Figs 4a, b - Diffuse lymphocytic lymphoma of plasma cell (extramedullary) type. (a) shows a lymphoma in which although the component cells are large they are manifestly of plasma cell type. A conspicuous feature is the presence of intracytoplasmic immunoglobulin crystals (arrow), in this case IgG. (b) illustrates a testicular lymphoma composed almost exclusively of plasmablasts. Note the relatively abundant nuclear chromatin, large centrally placed nucleoli and occasional binucleate forms (arrow). H & E, X 1250.

Fig. 5 - D i f f u s e lymphocytic lymphoma of pleomorphic plasma cell (extramedullary) type. There is a wide range in cell size with frequent binucleate forms and plasmablasts (arrow) in addition to more mature plasma ceils. The cyto- plasm which often appears eosinophilic in H & E preparations is intensely pyroninophilic. Clear paranuclear zones (G) identify the site of Golgi apparatus. H & E, × 1250.

Fig. 6 - Histiocytic lymphoma. The large cells are relatively well-differentiated histiocytic cells with ovoid and lobated vesicular nuclei, relatively small nucleoli and abundant ill- defined and granular (eosinophilic) cytoplasm. A few small residual lymphocytes are present in this field. H & E, × 1250~

Figs 7a, b -His t iocyt ic lymphoma. (a) demonstrates the superior morphology resulting from processing through plastic. (b) is a PAP preparation showing the presence of dark reaction products identifying the lysosyme content of this relatively well-differentiated histiocytic lymphoma, and which is characteristically aggregated in the vicinity of the Golgi apparatus, (a) toluidine blue, × 125 0; (b) PAP enzyme bridge technique for lysozyme, × 125 0.

B R I T I S H N A T I O N A L L Y M P H O M A I N V E S T I G A T I O N 5 0 9

Fig. 8 -Electromicrograph of a histiocytic lymphoma. The cytoplasm is abundant with prominent peripheral infoldings (arrow) and contains a variety of cell organelles including electron-dense lysosomal structures. Nuclear chromatin is dispersed with accentuation at the nuclear margin, and there is considerable variation in nuclear size and shape. X 3000.

more pleomorphic mixture of cells, and their cytoplasm only poorly pyroninophilic, locking in optical density and appearing clear (Fig. 2), then a T-cell lymphoma was considered. Large lymphoid cell lymphomas may also be composed of cells with strongly pyroninophilic cytoplasm and round regular

AGE DIST. 0 0

O~ 40 h i

< L) Ll_ 20

t~ Z

0

- rV _

YEARS20 40 60 80

MEDIAN AGE - 5 7 , 0 YRS

80

60 u3 uJ

,~ 40 (.3

Z r o lOO

nuclei showing several peripherally arranged nucleoli (Fig. lb) resembling germinal-centre centroblasts. There is thus strong circumstantial evidence, as with the diffuse large cell lymphomas composed predom- inantly of irregularly nucleated follicle centre (large cleaved) cells (Fig. 3), or those with a mixture of regular

PATH. STAGE DIST.

Fq : I I I I l l I V

187. 28% g7. 457.

B I O P S Y SITES NSDAL 677.

NODAL ONLY 517.

EXTRA NODAL

SITES OF INITIAL

INVOLVEMENT 34 LIVER 44 SPLEEN

24 BONE MARROW I BRAIN

1 SPINAL CORD I00

80

g

< m60

~ n

~ Ld

~ 2O

0

" I.'..',..' ' I .... I .... I'"

YEARS 2 4 6 8

SEX RATIO 3 EPIDURAL M : F - 13 : 1 7 RT LUNG

6 LT LUNG

6 RT PLEURA

SURVIVAL & RELAPSE 7 LT PLEURA

FREE SURVIVAL 12 BONEII~SSEOUS) 19 SKINISUBCUT.TISSUE)

MEDIAN SURVIVAL - 1.5 YRS 25 STOMACH 5 YR SURVIVAL - 32 % SO SM INTESTINE

COMPLETE RESPONSE 14 LG BBWEL NAIE - 54 % 29 WALDEYERS

MEDIAN TIME TO RELAPSE 3 ~EST]S 3 BREAST ~JF COMPLETE RESP ) 8.2 YRS 3 THYRB]D --4 1 ~RBIT 2 NOSE OR PARANAS. SIN. 4,1 OTHER 10

Fig. 9 - BNLI classification. Large lymphoid cell lymphoma with or without plasma cell differentiation, 216 cases, 18.7% (NCI retrospective study).

510 C L I N I C A L R A D I O L O G Y

and irregularly nucleated lymphoid cells, that these tumours are also of follicle centre origin. As with the B-immunoblastic tumours, any lymphoma of follicle centre origin might show plasma cell differentiation. The 'undifferentiated' large lymphoid category is a convenient label to retain as long as it is understood that without the benefit of electron microscopy and immunocytochemistry that some anaplastic carcin- omas and even true histiocytic lymphomas may be wrongly placed in this category. Plasma cell lym- phomas if of lymphoplasmacytoid type or showing good differentiation either without or with cyto- plasmic secretory products (Fig. 4a), were easily recognised. The less well-differentiated categories were composed generally of plasmablasts (Fig. 4b) or of a pleomorphic mixture of plasma cells with frequent giant cell forms (Fig. 5). Such plasma cell lymphomas form less than 1% of tumours in the BNLI series as compared to 2.1% of 24 cases diag- nosed by K.H. in the NCI retrospective study. This difference may possibly reflect a much larger number of extranodal sites included in the NCI material, Histiocytic (mononuclear phagocytic) lymphomas were conveniently separated into well-differentiated histiocytic tumours (Fig. 6) in which the cells approxi- mated quite closely to tissue histiocytes except that the nuclei were generally larger and more lobated and the cytoplasm much more abundant and foamy. In this type of tumour staining for lysozyme (Fig. 7b) and anti-alpha-1 chymotrypsin were positive. Less well-differentiated histiocytic lymphomas such as the

AGE DIST.

(-) 4 LI. Q

2

Z

0 YEARs2O 4Q 90 BO

MEDIAN AGE - 58.3 YRS

L II III I

IO0

CO Ld CO < U LL

Z

Table 1 - Large cell l ymphomas

Large lymphoid cell lymphoma -~ 1. Predominantly large regularly nucleated lymphoid ceils

(B*-or T-immunoblasts, B*-centroblasts). Those showiag a rather clear cytoplasm are likely to be of T-lymphocYtic type.

2. Large irregularly nucleated follicle centre (large cleaved) B*-lymphocytes

3. Mixtures of large regularly and irregularly nucleated follicle centre B*-lymphocytes

4. Large 'undifferentiated' cells thought to be lymphoid in origin but with few distinguishing features

Plasma cell (extramedullary) lymphoma 1. Well-differentiated (mature) type 2. Lymphoplasmacytoid type 3. Plasmablastic type 4. Pleomorphic type

Histiocytic (mononuclear phagocytic) lymphoma 1. Well-differentiated type 2. Blast cell (histioblast) type 3. Pleomorphic type

*All may show plasma cell differentiation but this is most pronounced in B4mmunoblastic lymphomas.

histioblastic and pleomorphic variants showed a much more variable appearance and enzyme staining was frequently negative. However, processing through plastic (Fig. 7a) and ultrastructural studies were extremely helpful in identifying the histiocytic nature of the cells. These different ~roups are shown in Table 1. The actuarial survival curves of the NCI/ Stanford study on large cell lymphomas are shown in Figs 9-11 and it can be seen that there is no obvious

PATH. STAGE DIST. BIBPSY SITES NBDAL 637. NODAL ONLY 337.

EXTRA NODAL

SITES OF INITIAL

' INVBLVEHENT

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SEX RATIB H:F- 0.6:1

SURVIVAL & RELAPSE

FREE SURVIVAL

MEDIAN S U R V I V A L = I . I YRS

5 YR S U R V I V A L = 2 8 %

C@MF'LETE R E S P g N S E RATE ~ 9 7 7.

MI IIIAN TIME TO RELAPSE ~I: CL<IHPLETE RESP - 1,0 YRS

1 RT PLEURA I LT PLEURA I B@NEIBGSEOUS) I SKIN{SUBCUT.TISSUE) I srONA~H

4 SM INTESTINE

1 LG BOWEL 2 ~ALDEYERS 2 BREAST

O BTHER

0 YEARS 2 4 6 8 lO

Fig. 10 -BNLI classification. Plasma cell lymphoma, 24 cases, 2.1% (NCI retrospective study).

co

B R I T I S H N A T I O N A L L Y M P H O M A I N V E S T I G A T I O N 511

100

80

AGE DIST.

~6o ~o

~o

~ 20

c)

[ . , , , , O I I , I I I I I

YEARS 20 40 150 80 I00

MEDIAN AGE - 42.1 YRS

3 " 1 ' 1 ] ' i " I'" "1. , F - - ~ I . , L .I, 1 1 . . I . . I . "

0 ,,,, I, I I ~ l_Li' I I I , O YEARS 2 4 15

PA FH. STAGE DIST. :12.5

zo.oy .sp

o:o-. V-7 ]

8Z

I I I 8 10

l I Ill IV 0% 07. g2%

SEX RATII~ M:F- 2.3:1

SURVIVAL & RELAPSE FREE SURVIVAL

MEDIAN SURVIVAL - 1.2 YRS

5 YR SURVIVAL -

C~JMPLETE RESPONSE RATE ~ 0 7.

llEDIAN TIME "H~ RELAPSE

BIOPSY SITES NClDAL 777,

NDDAL ONLY 46%

EXTRA NODAL SITES OF INITIAL

INVOLVEMENT 2 LIVER 4 SPLEEN 4 BONE MARROW I BRAIN 2 RT LUNG I LT LUNG I RT PLEURA ] LT PLEURA 3 BI~NEI~SSEBUS] 3 SKIN~SUBCUT.TISSUE) 2 Oq-ttER

UF COMPLETE RESP~> 0.0 YRS

Fig. 11 - BNLI classification. Hist iocytic l y m p h o m a , 13 cases, 1.1% (NCI re t rospect ive s tudy).

difference between survival in the large lymphoid cell group (with or without plasma cell differentiation), the plasma cell lymphomas, or the histiocytic lym. phomas. However, only very small numbers make up the last two groups. Nor was there any marked differ- ence between the NCI survival curves and those from similar categories of lymphoma analysed in the BNLI trial (see Farrer-Brown, Report No. 8 this issue).

DISCUSSION It is of some importance to attempt to separate,

because of possible difference in prognosis, the differ- ent members of the large lymphoid cell lymphomas as well as to separate them from pure plasma cell tt~mours on the one hand and histiocytic tumours on the other. Although the BNLI has no actuarial survival curves yet available to support this hypothesis, there is some evidence based on personally studied cases, and from the NCI retrospective trial, that large cell lymphomas of irregularly nucleated type (large cleaved cells, large centrocyte, large follicle centre cell) as well as other larg e lymphoid cell lymphomas of probable follicle centre origin have a better prog- nosis. For this reason such turnouts have been placed in the intermediate prognostic category of the Stanford 'formulation'; the Working Party of the NCI study group (1981, in press), in contrast to the immunoblastic lymphomas whether of T- or B-cell origin, and the pleomorphic T-cell lymphoma which were found to carry a much worse prognosis. In the plasma cell group limited studies have indicated a

better prognosis of the lymphoplasmacytoid and well- differentiated groups (Grade 1 in the BNLI series) than for the plasmablastic and pleomorphic plasma cell tumours (BNLI Grade 2). It is not possible, however, to compare the BNLI classified plasma cell tumours with series other than the NCI study since it is only well-differentiated plasmacytomas which have been accepted or recognised as plasmacytoma (Wilt- shaw, 1976), the less well-differentiated plasma cell lymphomas still being currently designated as immuno- blastic sarcoma, or pleomorphic immunoblastic sar- coma. Similarly no comparisons are available between the BNLI histiocytic series and others since the major- ity of classifications either indicate that a true histio- cytic lymphoma is exceptionally rare or that if it does occur it should not be classified as a lymphoma. In our experience the well-differentiated histiocytic lymphomas appear to carry a better (Grade 1) prog- nosis than the histioblastic or pleomorphic histiocytic lymphomas, but further studies with detailed actuarial survival curves are necessary to prove this point. It is not the purpose of this communication to discuss the ultrastructural features of the group of large cell lymphomas. For this information the reader is referred to several ultrastructural studies as follows: Levine and Dorfman (1975), Henry (1975), Henry and Farrer-Brown (1977, 1981), Henry etaL (1978a,b), Lennert (1978) and Rilke et al. (1978). Nor will the various immunocytochemical techniques as described by Isaacson et al. (1980), Mason and Biberfeld (1980) be discussed. In this context, a word of caution should

512 CLINICAL R A D I O L O G Y

be in t roduced in tha t many o f the large cell l ymphomas (Braylen etal., 1975) apparent ly lack surface markers. However , with the advent o f monoc lona l ant ibodies (Warnke and Levy, 1980) such p rob lems may soon be in the past.

Acknowledgements. I gratefully acknowledge the coopera- tion of many colleagues participating in the National Cancer Institute (NCI) retrospective study of the non-Hodgkin's lymphomas and in particular for the computer data used. I should also like to thank Mrs Norma Jackson for the prepara- tion of this manuscript, Miss Phyl Brock and Mr S. J. Kee for technical assistance and the Cancer Research Campaign for their personal grant.

Financial support for the whole study was provided by the Cancer Research Campaign, the NCI, the Cooperative Clinical Cancer Therapy Trust Fund, the Middlesex Hospital Special Trustees, the Isle of Man Anti-Cancer Association and many patients, relatives, friends and well-wishers.

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