438 yj) KRtF 3 eptember 1977 Lymphoma of Large Cells

W. G. STAPLES, E. P. GETAZ

U 11 RY considered more specific. Stem-cell lymphoma, was used tor highly undifferentiated cells, and clasmatocytic Historical aspects of the classification of large-cell lymphoma for well-differentiated cells with phagocytic lymphomas are described. Immunological characteriza­ properties. They introduced the term lymphoblastic tion of the lymphomas has been made possible by lymphoma for the immature lymphoid malignancies. identification of T and B Iymphocytes according to their In 1958 Gall arid Rappaport" changed the terminology cell membrane surface characteristics. The pathogenesis of the previous classification by ubstituting the term of lymphomas has been clarified by the germinal (foili­ histiocytic lymphoma for clasmatocytic lymphoma. A new cular) centre cell concepts of Lennert and Lukes and ~ntity, the histiocytic· lymphocytic (mixed cell) type, was Coliins. The various classifications are presented and Introduced for lymphomas with a mixture of small and compared. Whether these subdivisions will have any large cells. The term lymphoblastic lymphoma was now relevance in the clinical context remains to be seen. changed to lymphocytic type, poorly differentiated. Rappaport's' subsequent classification in 1966 differed in S. Afr. med. l., 52, 438 (1977). only two respects from the earlier one." tem-cell lymphoma was replaced by malignant lymphoma, un­ In 1948 Willis' wrote:' owhere in pathology has a chaos differentiated, and virtually all other large-cell lymphomas of names so clouded clear concept as in the subject of were lumped together as malignant lymphoma, histiocytic. lymphoid tumours.' Unfortunately this position has not Lukes' classification in 1968" omitted mixed histiocytic­ changed, as evidenced by the plethora of classifications lymphocytiC lymphoma because he maintained that it (see Table I) presented in the last 3 years. Architecturally, represented a variation in a single cell, the histiocyte. lymphomas may be diffuse or follicular. ince 1964 Meanwhile, from 1964 to 1966, Lennert et al.,'" as a Lennert et al.,"> on the basis of their electron microscopical result of studies of germinal centres, described three types studies, have steadfastly maintained that follicular lym­ of cells: germinocytes, germinoblasts and reticulum cells. phoma was a distinct pathological entity and this has now They postulated that follicular lymphomas were derived received widespread acknowledgement:"'" 0 matter what from neoplastic proliferations of these three cell lines. terminology is used, there also seems to be general accep' This was the forerunner of the follicular centre cell con­ tance of two types of small-cell lymphoma, one with cept of Lukes and Collins....• normal-appearing lymphocytes and one with pleomorphic Burkitt's tumour, the malignant lymphoma first des­ cleaved lymphocytes, termed well-differentiated lympho­ cribed in Black African children, was first morphologically cytic lymphoma and poorly differentiated lymphocytic characterized by O'Connor" in 1961. A WHO Bulletin" lymphoma respectively.' All classifications also include a issued in 1969 stated that Burkitt's type lymphoma should lymphoma consisting of small Iymphocytes with plasma­ be recognized as a separate entity on clinical and morpho­ cytoid features. The area of greatest controversy concerns logical criteria. This has been generally accepted. the lymphomas of large cells,

HISTORICAL ASPECTS T and B Lymphocytes Before 1930 malignant lymphomas were divided into In the 1950s and 1960s, surgical extirpation of lymphoid Hodgkin's disease and lymphosarcoma, the latter in­ organs in animals wa used to define the various lymphoid 9 populations. and the concept of T and B lymphocytes ,>o cluding many morphological variants, In 1930 Roulet Zl used the term 'Retothelsarkom' for large-cell lymphomas,' arose."' The T cell, or thymus-dependent cell, was asso­ which he thought were derived from reticulum cells not ciated with cellular immunity, and the B cell, or bursa­ classifiable as lymphoid. Thus the term reticulum cell equivalent cell, with humoral immunity. Similar systems sarcoma wa applied to all large-cell lymphomas. exist in man." B lymphocytes are present in the germinal In 1942 Gall and Mallorylt abandoned the term reti­ centres and medullary cords of lymph nodes, while T culum cell sarcoma in favour of two terms which they lymphocytes are in the paracortical areas. In 1960 owell" described the mitogenic effect of phytohaemagglutinin (PHA) on blood lymphocytes. This transformation in­ Department of Haematology, nivcrsity of tcllenbosch and volved the induction and enhancement of RA and Tygerberg Ho pital, Parowvallei, Cl' protein ynthesi and the initiation of cell division. \;j,I. G: STAP~E.S, l\f.MED. PATH. (HAEM.), F.F. PATH. (S.A.), Activated cells tran form into blast-like cells before or SenIOr Specwllst (Present addre,s: Dept of Patholog\· Uni- versity of Cape Town) ., during D TA synthesis. These transformed lymphocytes, E. P. GETAZ, l\f.B. ClI.B.• l\f.R.C.P., Senior Specialist (Present when sta.ined with Giemsa. resemble blast cells with deeply address: Dept of Medical Oncology, Hoswcll Park Memorial basophtllc cytoplasm. and are at least four times the size In titute, Buffalo, Y. USA) of a small Iymphocyte. Date received: 9 February 1977. Different stages in the transformation phenomenon are Reprint requests to: Dr W. G. Staples. Dept of Pathology. University of Cape Town Medical School. Observatory. CP. 7925 RSA. responsible for varying morphological features of Iympho- 3 September 1977 SA MEDICAL JOUR AL 439

TABLE I. COMPARISON OF CLASSIFICATIONS OF LARGE-CELL LYMPHOMAS

Old popular Bennett et al. Lukes and ColJlnS terminology Rappaport (1966) Dorfman (1974) (1974) Kiel (1974) (1974) WHO (1976) Lymphocytic, Atypical small Lymphocytic, Lymphoblastic Lymphosarcoma, poorly lymphocytic poorly diffuse differentiated differentiated

Convoluted Convoluted Convoluted Lymphoblastic Lymphosarcoma lymphocytic cell type lymphocytic convoluted nuclei

Mixed Mixed small Mixed small Centrocytic- Lymphosarcoma, Iymphocytic- and large lymphoid and centroblastic prolymphocytic histiocytic lymphoid undifferentiated and large cell lymphoblastic

Histiocytic, Histiocytic True histiocytic Histiocytic Histiocytic well differentiated

Reticulum cell Histiocytic, Large lymphoid Undifferentiated Centroblastic, Large non-cleaved Lymphosarcoma, sarcoma poorly pyroninophilic large cell immunoblastic immunoblastic immunoblastic differentiated sarcoma

Lymphocytic, Lymphoblastic Small non-cleaved Lymphoblastic poorly differentiated lymphoblastic

Undifferentiated, Undefined, Large cleaved cell Reticulo- pleomorphic undifferentiated sarcoma cytes, which were previously interpreted as different de­ Shevach et al." used these membrane surface markers in grees of Iymphocyte differentiation. In histological sections the identification of the origin of the cells in Iympho­ these cells have a primitive neoplastic appearance and proliferative malignancies. undergo many mitoses, and their cytoplasm stains intensely with methyl green pyronin (pyroninophilia). As a result of the observations of Lukes et al.'""" these cells became TABLE 11. MEMBRANE SURFACE MARKERS known as immunoblasts. They were recognized as normal Cell IgM -EAC IgG-EA constituents of the interfollicular and intrafollicular tissues B Iymphocyte of antigenically stimulated nodes, increasing in regional + T Iymphocyte nodes after smallpox vaccination or in infectious mono­ Monocyte ... nucleosis. + + Macrophage In 1968 Good and Finstad'" documented the association + + of lymphoid malignancy with immunological malfunction. Since then receptors and antigens have been identified on FollicuJar Centre Cell Concept immunologically competent cells, which provide informa­ tion as to their origin (fable 11). In 1970 Raff'6 demon­ Starting in 1971, Lukes and Collins,'·:n on the basis of strated that B lymphocytes had immunoglobulin on their their studies of morphology, proposed the follicular centre surface. In the same year,'most B lymphocytes were shown cell concept. They considered the cells of the follicu1ar to have a receptor for antigen-antibody complement com­ centre to be components of the B cell system and to con­ plexes, which was detected by using red cells (E) coated sist of four types of cells: (i) cleaved nucleated cells; (it) with antibody (A) and complement (C).'" In man, Lay non-cleaved nucleated cells; (iit) tingible body macrophage et al.'" demonstrated rosette formation with T Iymphocytes or 'starry-sky' phagocytes; and (iv) dendritic reticular cells. and sheep red blood cells. Monocytes and macrophages The predominant cells are the cleaved and non-cleaved also bear a receptor for EAC,"" and a receptor for antigen­ cells whose frequency varies with the state of activity of antibody complexes which is detectable by use of red cells the follicle. These cells vary in size and in the stage of coated with immunoglobulin G (EA).'" These membrane nuclear cleavage. Pyroninophilia, scanty in the cleaved surface markers allow the positive identification of T cells, increases in the non-cleaved cell as the nucleu and B lymphocytes, monocytes and macrophages. In 1973, increases in size. Lukes and Collins considered the follicle

10 A MEDIESE fYDSKRIF :3 September 1977

to be the site of normal lymphocyte transformation, pro­ Classification of Bennett et al. ceecling from small cleaved, large cleaved, small non­ cleaved to large non-cleaved cells. Only the non-cleaved In June 1973, at a workshop on the classification of cells possess nucleoli and are the dividing cells of the non-Hodgkin's lymphoma, Bennett el at: presented their foLlicular centre. Thus transformation proceeds from the classification. Their lymphocytic, poorly differentiated small dormant lymphocyte to the large, metabolically group incorporated the lymphoblastic lymphomas, which active clivicling form. From their morphological studies of corresponded to the similarly designated group in Lennert's the malignant lymphomas of follicular centre cell, Lukes classification. The undifferentiated large-cell group con­ and Collins suggested evidence of blocks in transforma­ si ted of large lymphoid cells, i.e. transformed lymphocytes tion of 'switch on' (derepression) from the cleaved to the with strongly basophilic (pyroninophilic) cytoplasm. non-cleaved cells. The lymphomas of follicular centre cells were divided into four categories: (i) small cleaved; Dorfman's Classification (ii) large cleaved; (iii) small non-cleaved; and (iv) large In 1974, Dorfman" proposed a classification that did non-cleaved. Later this concept was expanded by means not differ fundamentally from that of Rappaport.s How­ of immunological studies and the lymphomas were clivided ever, he included the lymphoblastic group with the atypical into T and B cell types.",33 On the basis of their classifica­ small lymphocytic group, and the large-cell lymphomas tion the large-cell lymphoma were mainly of B cell origin, were known as large lymphoid (pyroninophilic) lympho­ i.e. large cleaved and large non-cleaved follicular centre mas. types. Immunoblastic sarcoma could be of both Band T cell origin. WHO Classification In 1976 Mathe el aC issued the WHO classification of Lennert's Germinal Centre Concept haematological malignancies. Using cytological and histo­ logical criteria, they divided the large-cell lymphomas During the same period (1971 - 1974) Lennert'··36 ex­ into lymphoblastic and immunoblastic lymphomas and panded on his concept of cells arising from the germinal reticulosarcomas. The latter term is used for malignant centre; this idea had many similarities to the follicular tumours which show evidence of production of argyro­ centre cell concept. The large cells in the germinal centre philic fibres or phagocytosis, or both, and in which there were named gerrninoblasts. In 1974 he put out a new are conspicuous variations in cellular and nuclear shapes. classification, in which he divided lymphomas into those of low-grade and those of high-grade malignancy.'" The lymphomas of high-grade malignancy consisted of large UNIFICATION cells and were subclivided into germinoblastoma, lympho­ Of the above six classifications, those of Dorfman: blastoma and irnmunoblastoma. In 1974 Lennert'S issued Bennett,' Lennert" and Lukes and Collins" recognize the Kiel classification, in which the term germinoblastoma histiocytic lymphoma as a very rare entity, with positive was changed to centroblastoma. In using the term centro­ alpha-naphthyl-acetate esterase staining"·... on lymph node blastoma, Lennert has further subdivided the transformed imprints. Rappaport's classificationS included many mor­ lymphocyte group. The centroblast in many respects re­ phological variants under the term histiocytic. In the WHO sembles the immunoblast, but it is slightly smaller. Both classification,' histiocytic lymphoma is not mentioned. It is cells have basophilic cytoplasm with large nuclei. The now realized that most cases termed 'histiocytic' lymphoma centroblast has nucleoli along the nuclear membrane while are in reality transformed Iymphocytes or immunoblasts. the immunoblast has a much larger central nucleolus. The This type of large-cell lymphoma has been called histiocytic centroblast is the precursor of the immunoblast during (Rappaport), large lymphoid (Dorfman), undifferentiated lymphocyte transformation," This tumour represents the large cell (Bennett), centroblastic, immunoblastic (Lennert) anaplastic end phase of follicular lymphoma." It is the immunoblastic sarcoma (Lukes and Collins) and immuno­ equivalent of Lukes and Collins' large non-cleaved lym­ blastic (WHO). phoma. The term lymphoblastic lymphoma, as proposed by Lennert states that he has often seen a combination of Gall and Mallory," has now been reintroduced and is used centrocytes, centroblasts and immunoblasts in lymphoid by Bennett, Lennert and the WHO classification. Dorfman tumours. Since the majority of the cells in these tumours includes it under atypical small lymphocytic tumours, are centroblasts, he classifies them as centroblastic lym­ Rappaport as poorly differentiated lymphocytic lymphoma, phomas. The centrocytes indicate that they are germinal and Lukes and Collins as small non-cleaved cell tumour. centre tumours. The immunoblasts present in the tumour It is interesting to note that recently Nathwani el at:' may develop from the centroblasts. Lennert used to in­ have used the term malignant lymphoma, lymphoblastic, clude this group of tumours in the group of immuno­ as a variant of poorly differentiated lymphocytic lym­ blastic lymphomas because he believed that the immuno­ phoma to describe convoluted and non-convoluted forms blast was the cell with the highest degree of differentiation. in children and adolescents, and sometimes associated with However, he has now removed these tumours from the acute lymphoblastic leukaemia. immunoblastic group, since they differ from the other All the classifications except that of Lennert allow for irnmunoblastic lymphomas in that their tumour cells form an unclassifiable or undefined group, to which Rappaport EAC rosettes.'" simply refers as unclifferentiated, pleomorphic. The Lukes :3 September 1977 SA MEDICAL JOUR TAL 44i and Collins classification describes the large cleaved cell is a transformed Iymphocyte and is a large cell with a as an entity. It is difficult to fit this cell, as described, into moderate amount of strongly basophilic (pyroninophilic) the other classifications. Presumably it would fit into the cytoplasm. It has a large nucleus, usually with a single unclassified undefined or undifferentiated types. The WHO prominent nucleolus (Fig. ]). The centrobla t is a cell classification would probably include it in the reticulo­ type described only by Lennert. It is a medium-sized to sarcoma group, providing it produced reticulin or exhibited large cell with scanty basophilic cytoplasm and it has two phagocytosis. Many of these irregular or large cleaved to three meduim-sized nucleoli situated at the nuclear cells may result from technical inadequacies in fixation membrane (Fig. 2). and processing: as their imprints show normal rounded cells. It must be pointed out that imprints obtained with the convoluted type of lymphoblastic lymphoma n exhibit convolutions of the nuclei of the lymphoblastic cells. In Lennert's classification there is no group which corresponds with tbe large cleaved cell of Lukes and Collins; he believes that these cells may be unclassified lymphoblastic lymphomas which often have cleaved nuclei.'" Braylan e! al."' have divided the large-cell Iympbomas into three major categories: L Monomorphic cells with round to oval vesicular nuclei, one to three eosinophilic nucleoli, and pyronino­ philic cytoplasm. These cells most closely resemble immunoblasts or transformed lympbocytes. 2. Uniform cells with indented or lobulated nuclei and usually single and moderately prominent nucleoli. The cytoplasm is relatively abundant and only faintly pyro­ ninophilic. This description is most like that of the large cleaved cell of Lukes and Collins.33 3. A very pleomorphic and bizarre group which in­ Fig. 2. Centroblasts - Lennert describes this cell as a cludes multinucleate giant cells. Foci of necrosis, inter­ distinctive cell type and regards it as the precursor cell stitial fibrosis and inflammatory elements suggest of the immunoblast. It is a medium.to-Iarge cell with scanty basophilic cytoplasm, a large nucleus and two to Hodgkin's disease. three small nucleoli situated at the nuclear membrane. Most classifications include three basic cell types com­ (H and E x 400.) prising the common large-cell lymphomas: Immunoblastic, a term used by Lennert, Lukes and Taylor" has used immunoperoxidase techniques for the Coli ins, and Mathe (WHO), which was labelled as histio­ demonstration of intracellular immunoglobulins in certa-in cytic by Rappaport, as large lymphoid by Dorfman and large-cell lymphomas, thereby confirming their B cell 3 3 as undifferentiated large cell by Bennett et al. This cell origin. Like Lennert •• • and Lukes and Collins: he relates the various histological types of Iymphoreticular neo­ plasms to morphological forms of the lymphocyte which are assumed during transformation. The fact that one may see several cell types in a lymphomatous neoplasm is well known, hence the terms polymorphic reticulo­ sarcoma..·•• and polymorphic immunocytoma'" (Fig. 3). Recently Fisher et al:· described a case of immuno­ blastic lymphadenopathy which evo!':yed into a malignant lymphoma with plasmacytoid features. This malignancy fitted in well with the description applied to immuno­ blastic sarcoma as described by Lukes and Collins." Mathe et al." have described an immunoblastic lymphoma which quickly evolved into a leukaemic phase. In the des­ cription of Lukes and Collins14 these cells may occasionally include prominent abnormal plasma cells. Electron micro­ scopy of the tumour in Fisher's case revealed a prominent rough endoplasmic reticulum lined with ribosomal particles.'· The tumour in Mathe's case

cyto i . These are large cells with a narrow rim of ba 0­ philic (pyroninophilic) cytoplasm. and a large cleaved nucleus with an inconspicuous nucleolus (Fig. 5). They may sometimes appear rounded on imprint preparation.

Fig. 3. A spectrum of cells, from large cells with vesicular nuclei and prominent nucleoli to smaller cells in which the nuclear chromatin becomes clumped and the nucleoli indistinct. This entity has been described as a poly­ morphic reticulosarcoma (Robb-Smith), polymorphic immunocytoma (Lennert) and immunoblastic sarcoma with plasmacytoid features (Lukes and Coliins). (H and Fig. 5. Large cleaved cell - the classification of Lukes and ColJins is the only one to recognize this cell as E x 500.) forming a distinct type. This large cell has an irregular cleaved nucleus and fairly prominent cytoplasm. lymphoma, Dorfman, who classifies it with his atypical (H and E x 400.) small lymphocytic group, and Lukes and Collins, who call it small non-cleaved lymphoma. These are medium­ The histiocytic group is mentioned by all except the sized cells with scanty basophilic cytoplasm which re­ WHO classification. Morphologically it resembles the semble the lymphoblasts of acute lymphoblastic leukae­ imrnunoblast but has abundant acidophilic amorphous mia. They have large nuclei with fine chromatin and with cytoplasm, a smaller nucleus and less marked nucleoli small or medium-sized nucleoli (Fig. 4). Among these (Fig. 6). The nuclear chromatin tends to be more clumped cells are often found macrophages exhibiting phagocytosis, than in the immunoblast.39 Lukes and Collins33 maintain giving the characteristic 'starry sky' appearance. that it cannot always be differentiated morphologically from an immunoblast. On lymph node imprints it is positive on alpha-naphthyl-acetate esterase staining.33

Fig. 4. Lymphoblasts these medium-sized cells have scanty basophilic cytoplasm. The nuclei are fairly large with fine chromatin and with small or medium-sized nucleoli. (H and E x 400.) Fig. 6. Histiocytes - these cells differ in appearance from the immunoblasts. They have abundant acidophilic Large cleaved cell. This term is used only by Lukes cytoplasm, a smaller nucleus and less prominent nucleoli. Their nuclei are sometimes indented aDd also vary in and Collins. Mathe would include it in the reticulosarcoma size. On lymph node imprints they are positive with group, providing it formed reticulin or exhibited phago- alpha-naphthyl-acetate esterase stains. (H and E x 500.) 3 September 1977 SA MEDICAL JOURNAL 443

Until recently, patients with advanced diffuse histiocytic 18. Mueller, A. P., Wolfe, H. R. and Meyer, R. K. (1960): J. Immunol., 85, 172. lymphoma or reticulum cell sarcoma have been regarded 19. Warner, N. L., Szenberg, A. and Burnetl, F. M. (1962): Aust. J. expo BioI., 40, 373. as having a uniformly fatal disease. In the last decade, the 20. Warner, . L. and Szenberg, A. ill Good, R. A. and Gabrielsen, complete remission rate in the treatment of advanced A. E.• eds (1964): The Thymus ill Immunology. p. 39. 'ew York: Harper & Row. diffuse histiocytic lymphoma has risen from 10% to 78°~ 21. Miller, J. F. A. P. (1961): Lancet, 2, 748. 22. Good, R. A. and Finstad, J. in Zarafonetis, C. J. D., ed. (1968): with the use of combination chemotherapy." S bdivision Op. cir.", p. 175. of the large-cell lymphomas is not as yet of prognostic 23. Nowell, P. C. (1960): Cancer Res., 20, 462. 24. Lukes, R. J., Tindle, B. H. and Parker, J. W. (1969): Lancet, 2, significance, and it remains to be seen whether classifica­ 1003. 25. Tindle, B. H., Parker, J. W. and Lukes, R. J. (1972): Amer. J. tion based on histology, cytology, histochemistry and din. Path., 58, 607. cytochemistry will be of clinical use. 26. Raff, M. C. (1970): Immunology, 19, 637. 27. Bianco, D., Patrick, R. and Nussenzweig, V. (1970): J. expo Med., 132, 70. REFERE ICES 28. Lay, W. H., Mendes, F., Bianco, C. et 01. (1971): attire (Lond.), 230, 531. I. Willis, R. A. (1948): Pathology of Tumours, p. 760. St Louis: C. V. 29. Huber, H., Polley, M. J., Unscot!, W. D. et al. (1968): Science. Mosby. 162, 1281. 2. Lennert, K., Caesar, R. and MUller, K. (1966): Exp. Hematol., 11, 6. 30. Huber, H. and Fudenberg, H. H. (196): Int. Arch. Allergy, 34, 3. Lennert, K. (1964): Pathologie der HalslYl1lphkllotell. Berlin: Springer­ 18. Verlag. 31. Shevach, E. M., Jaffee, E. S. and Green, I. (1973): Transplant. Rev., 4. Lukes, R. J. and Collin , R. D. (1973): New Observatiolls 011 Folli­ 16, 3. cri/ar Lymphoma (GA IN Monographs on Cancer Research, No. 15), 32. Collins, R. D. and Lukes, R. J. (1971): Amer. J. Path., 62, 63a. p. 209. Baltimore: University Park Press. 33. Lukes, R. J. and Collins, R. D. (1975): Brit. J. Cancer, 31, suppl. 5. Bennett, M. H., Farrer-Brown, G., Henry, K. et 01. (1974): Lancet, n, p. I. 2,405. 34. Lennert, K. (1971): Paper presented at a meeting of the European 6. Dorfman, R. F. (1975): The NOII-Hodgkill's Lymphomas, p. 276. Division of the International Society of Haematology. Milan. Baltimore: Williams & Wilkins. 35. Lennert, K., ill Akazaki, K. et al., eds (1973): Malignallt Disease 7. MatM, G., Rappaport, H., O'Connor, G. T. et al. (1976): Histo­ of the Haematopoietic System. Tokyo: University of Tokyo Press. logical and Cytological Typing of Neoplastic Diseases 0/ Haemato­ 36. Idem (1974): Lancet, 2, 586. poietic and Lymphoid Tissues. Geneva: WHO. 37. Lennert. K., Stein, H. and Kaiserling, E. (1975): Brit. J. Cancer, 31, 8. Rappaport, H. (1966): Tumours of the Hematopoietic System (Atlas supp!. IT, p. 29. of Tumor Pathology, fasc. 8). Washington, DC: AFIP. 38. Lennert, K., Mohri, N., Stein, H., et al. (1975): Brit. J. Haemat., 9. Roulet, F. (1930): Virchows Arch. path. Anat., 277, 15. 31, suppl., p. 193. 10. Idem (1932): Ibid., 286, 702. 39. Lennen. K.: Personal communication. I I. Gall, E. A. and Mallory, T. B. (1942): Amer. J. Path., 18, 381. 40. Leder, L. D. (1967): Blut, 16, 86. 12. Gall. E. A. and Rappaport, H. ill McDonald, J. R., ed. (1957): 41. Nathwani, B. I., Kim, H. and Rapp.port. H. (1976): Cancer, 38, 964. Seminar 011 Diseases 0/ Lymph Nodes and Splenic Lesions: New 42. Braylan, R. C., J affe, E. S. and Berard, C. W. (1975): Pathology Orleans: American Society of Clinical Pathologists. Anllual, p. 39. London: W. B. Saunders. 13. Lukes, R. J. ill Zarafonetis, C. J. D., ed. (1968): Proceedillgs of 43. TaYlor, C. R. (1976): Europ. J. Cancer, 12, 61. the International Conference Oil Leukaemia-Lymphoma, p. 333. Phila­ 44. Robb-Smith, A. H. T. (1938): J. Path. Bact., 47, 457. delphia: Lea & Febiger. 45. Idem (1974): Lancet, ], 513. 14. Lukes, R. J. and Collins, R. D. (1974): Cancer, 34, 1488. 46. Fisher, R. I., Jaffe, 1::. S., Braylan. R. C. et al. (1975): Amer. J. 15. O'Connor. G. T. (1961): Ibid., 14, 270. Med., 61, 553. 16. Berard, C., O'Connor, G. T., Thomas, L. B. et al. (1969): Bull. 47. Mathe. G., Belpomrne. D., Dantchev, D. et al. (1972): Biomedicine, WHO, 40, 601. 20, 333. 17. Glick, B., Chang, T. S. and Jaap, R. G. (1956): Poult. SeL, 35, 48. Sweet, D. L., Golomb, H. M. and Uitmann, J. E. (1976): Ann. 224. intern. Med., 85, 521.

Books Received • Boeke Ontvang

Techniqnes in Clinical Immunology. Ed. by R. A. Thompson. Operath'e Surgery Revision. 3rd ed. By J. J. Shipman. Pp. Pp. ix + 241. Illustrated. £6,25. Oxford: Blackwell v + 183. £5,00. London: H. K. Lewis. 1977. Scientific Publications. ]977. Medical Selection of Life Risks. By R. D. C. Brackenridge. Acoustic Impedance and Admittance - The l\1easurement of Pp. xii + 765. London: The Undershaft Press. 1977. Middle Ear Function. Bd. by A. S. Feldman and Lama A. Wilber. Pp. viii + 383. illustrated. $23,50. Baltimore: Williams & Wilkins. ]976. Health Aspects of Human Settlements. (WHO Public Health Papers, O. 66). Ed. by A. E. Martin. Pp. 57. Sw. fr. 8,-. Geneva: World Health Organization. 1977. Available The Clinical Management of l\1uscle Disease. A Practical from Van Schaik's Bookstore (Ply) Ltd, PO Box 724, Manual of Diagnosis and Treatment. By 1. M. Siege!. Pretoria, 0001. Pp. xii + ]62. Illustrated. £3,75. London: William Heinemann Medical Books. 1977. Methods Used in Est.ablishing Permissible Levels in Occu­ pational Exposure to Harmful Agents. (WHO Technical The Essentials of Cardiac Pacing. By G. Fontaine, Y. Report Series, o. 601.) Report of a WHO Expert Grosgogeat and J. J. Welti. Pp. 79. Illustrated. £5,50. Committee. Pp. 68. Sw.fr. 8,-. Geneva: World Health London: Cedig Publisher, distributed by William Organization. 1977. Available from Van Schaik's Book­ Heinemann. 1976. store (Pty) Ltd, PO Box 724, Pretoria, 0001.