The Lymphoblastic Lymphoma of Childhood

LEADING ARTICLES

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causing intussusception. While there is some overlap in organ involvement, the lymphoma of African type, even in non-African children in other continents, commonly affects the jaw bones and ovaries, heart, and other viscera.10 11 This distinction has probably been and

THE LANCET

obscured in the past because, as O’CONOR 29 suggests, the ideas derived from lymphosarcoma in adults have been uncritically carried over to the disease in children; and PULVERTAFT 30 remarks that he had studied only a few childhood in London by the techniques The Lymphoblastic Lymphoma of Childhood he has been lymphomas using in Africa. While the histological SINCE we last discussed the peculiarities of the criteria for the recognition of this neoplasm have been African childhood lymphoma,l further investigation has sharpened, various techniques have been applied to the extended our knowledge of the disease and compelled study of the tumour cells. Histologically,23 31 the pattern some rethinking in other countries. It has long been is uniform: sheets of immature lymphoid cells, interclear that there was nothing uniquely African 2-4 (nor spersed with non-malignant histiocytes, which are often even, it now appears, uniquely human 5) about this childclear and vacuolated and easily fall out in the preparation hood lymphoma; but it is especially common in various of sections-a common cause ofmisdiagnosis in the past. 23 regions of Africa,6 and in New Guinea 7and parts of It is these clear cells which give the characteristic " starry Brazil9 with similar climates. The disease also appears, sky " or " water pot " effect, which again is not peculiar though much less often, in the U.S.A.10 11 and in to this neoplasm.32 These histiocytes commonly contain Britain,12 whose climates are very different from Africa. fat, nuclear debris, red blood-cells, or even tumour In Africa the remarkable features are the great frequency cells which have been phagocytosed. Their function is of the disease (over 70% of childhood malignancies in not clear 2: evident at the growing edge are seldom they Ibadan 13), the predilection for the jaw bones 4 14 15 and of the tumour, but they can be seen in the deeper parts; ovaries,3 16 17 and a clearcut geographical distribution whether they represent a regressive change or some apparently determined by climate.18-20 It may be, immunological response is unknown. Imprints of tumour however, that these geographical limits are not abso- cells stained with Giemsa or Leishman stain suggest lute,21 22 and a long search may be needed to ensure that they are lymphoblasts,23 24 as does the fine structure that occasional cases are not overlooked in other parts displayed by electron microscopy 33 34 (though this has of Africa. been disputed 35). Round the nucleus, a narrow rim The diagnostic criteria of WRIGHT 23-25 and others2 of deep-blue-staining cytoplasm contains many small applied to series of lymphomas in the U.S.A. dis- sudanophilic vacuoles; the nuclei are oval or round, often closed 10 11 a few cases histologically identical with the indented, with a finely stippled chromatin pattern and African variety; and these tumours differ, it seems, 1 to 3 inconspicuous irregular nucleoli.25 The cells conboth clinically and histologically, from the bulk of tain little or no glycogen.25 Chromosome abnormalilymphosarcomas of children. The usual lympho- ties,36 37 when present, are restricted to the tumour cells sarcoma of children 2s-2s is a small-cell lymphocytic and are not detected in blood or bone-marrow; the in the cervical or growth, appearing primarily chromosome counts are around the diploid number with glands, causing mediastinal masses, or affecting the intestines no evidence of polyploid or hypotetraploid cell lines. One 1. Lancet, 1963, ii, 23; see also ibid. 1962, ii, 1363. frequent chromosome abnormality is an abnormal large 2. O’Conor, G. T., Davies, J. N. P.J. Pediat. 1960, 56, 526. 3. O’Conor, G. T. Cancer, 1961, 14, 270. acrocentric chromosome, perhaps replacing a no. 2 4. Burkitt, D. P. Post-grad. med. J. 1962, 38, 71. chromosome. Leukxmic change 3a is much more rarely S. 5. Bras, G., Murray, M., McDonnough, L. T. Lancet, 1965, ii, 619. 6. The Lymphoreticular Tumours in Africa (edited by F. C. Roulet). seen, at least in Africans, than in ordinary lymphosarBasle, 1964. 7. Ryan, B., Campbell, P. E., Farago, C. Med. J. Aust. 1964, i, 436. coma,26 and when it does happen, the nodular character 8. Farago, C. Cancer, 1963, 16, 670. 9. Louisi, A., Bertilli, A. de P., Machado, J. C., Ache de Freitas, J. P. of the visceral deposits persists, together with a diffuse Revta bras. Cirug. 1965, 49, 280. 10. O’Conor, G. T., Rappaport, H., Smith, E. B. Cancer, 1965, 18, 411. superadded leukæmic infiltration of all tissues.31 11. Dorfman, R. F. ibid. p. 418. Mitoses are common, so there is over-production of 12. Wright, D. H. Rep. Br. Emp. Cancer Campn, 1964, p. 585. 13. Edington, G. M., Maclean, C. M. Br. med. J. 1964, i, 264. cells in this lymphoma; whereas (as PULVERTAFT 30 14. Davies, A. G. M., Davies, J. N. P. Acta Un. int. Cancr, 1960, 16, 1320. 15. Cockshott, P. in The Lymphoreticular Tumours in Africa (edited by F. C. Roulet); p. 150. Basle, 1964. remarks) in adult lymphosarcoma and chronic lymphatic 16. Brew, D. St. J., Jackson, J. G. Br. J. Cancer, 1960, 14, 621. leukaemia there is no cytological evidence that the cells 17. Edington, G. M., Maclean, C. M., Okubadejo, C. A. in The Lymphoreticular Tumours in Africa (edited by F. C. Roulet); p. 236. Basle, are neoplastic; they are mature, normal in every way, and 1964. 18. Burkitt, D. P. Br. J. Cancer, 1962, 16, 379. never seen in mitosis, so that these are possibly diseases 19. and LONDON

Burkitt, 1963.

D. P. in

11

DECEMBER

Viruses, Nucleic Acids

1965

Cancer; p. 615. Baltimore,

20. Haddow, A. J. E. Afr. med. J. 1963, 40, 429. 21. Gluckman, J. S. Afr. Cancer Bull. 1963, 7, 7. 22. Dalldorf, G., Linsell, C. A., Barnhart, F. E., Martyn, R. Perspect. Biol. Med. 1964, 7, 435. 23. Wright, D. H. Br. J. Cancer, 1963, 17, 50. 24. Wright, D. H. in The Lymphoreticular Tumours in Africa (edited by F. C. Roulet); p. 291. Basle, 1964. 25. Wright, D. H. M.D. Thesis, Bristol University, 1964. 26. Jones, B., Klingberg, W. G. J. Pediat. 1963, 63, 11. 27. Rosenberg, S. A., Diamond, H. D., Dargeon, H. W., Jaslowitz, B., Carver, L. F. New Engl. med. J. 1961, 40, 31. 28. Charache, H. Am. J. Rœntg. 1956, 76, 794.

29. 30. 31. 32. 33. 34.

O’Conor, G. T. Cancer Res. 1963, 23, 1514. Pulvertaft, R. J. V. J. clin. Path. 1965, 18, 261. Wright, D. H. Br. J. Surg. 1964, 51, 245. Diamundopoules, G. T., Smith, E. B. Cancer, 1964, 17, 329. Epstein, M. A., Barr, Y. M. Lancet, 1964, i, 252. Epstein, M. A., Barr, Y. M., Achong, B. C. Path. Biol., Paris, 1964, 12, 1232.

Bernhard, W., Lambert, D. in The Lymphoreticular Tumours in Africa (edited by F. C. Roulet); p. 270. Basle, 1964. 36. Jacobs, P. A., Tough, I. M., Wright, D. H. Lancet, 1963, ii, 1144. 37. Stewart, S. E., Lovelace, E., Whang, J. J., Ngu, V. J. natl. Cancer Inst. 1965, 34, 319. 38. Clift, R. A., Wright, D. H., Clifford, P. Blood, 1963, 22, 243. 35.

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of under-elimination. In acute lymphatic leukaemia there is over-production; the cells are obviously abnormal, and mitoses are frequent, but the cells are quite different from those of the African lymphoblastic lymphoma. These observations may be generally accepted, and most workers agree on the histological and cytochemical findings in the tumour cells in sections and imprints; but there are discrepancies in the reported behaviour of the cells in culture. It has been possible to establish several cell-lines in culture. 30 33 39 40 PULVERTAFT 30 had not seen cells in London behaving like the cells he cultured in Africa, which autolysed rapidly in salt mixtures at 37°C, were considerably larger than small lymphocytes, had a very characteristic cytoplasmic granularity, and (in contrast to lymphocytes) often had an indented nucleus, trefoil in outline. The cells adhered to collagen but not to glass. In most respects it seems that the cell-lines established by PULVERTAFT in Nigeria are similar to those from Uganda studied by EpSTEIN and his collaborators, but they seem to differ in many ways from those established by FoGH et a1.40 from a Kenya case and others established in South Africa. The cell-lines cultured by EPSTEIN all appear to carry an intracellular structure which is regarded as viral, and which is not seen in most other cell-lines. 4But STEWART et a1.37 have established from a Nigerian child flown to Washington a cell-line which carries what seem to be the same bodies. Their nature is disputable, though their appearances seem No successful cultures seem to have been constant. made from this material, and no lesions produced in animals. 39 Mycoplasmas have now been identified in cases of leukxmia 41-43 and isolated from human tumours,44 but EPSTEIN and his colleagues 39 do not accept that these bodies could be mycoplasmal in origin. Meanwhile, from the tumours themselves, viruses of the herpes group have been repeatedly isolated, as have some as yet unidentified agents, by DALLDORF and BERGAMINI.45 BELL et al.4s 4’ have made several isolations of reovirus III. Immunological tests have indicated differences between control and affected children, but their significance is uncertain. The bodies identified in the celllines are said not to resemble reovirus III morpho-

logically.39s An alternative approach by FINK and her co-workers 48 offers distinct possibilities. Unidentified particles have often been seen in the plasma ofleukaemic patients. Concentration of such particles has enabled an antiserum to be made and conjugated with fluorescent dyes. An antiserum to the Rauscher strain of murine leukaemia virus has also been made and similarly conjugated. Applications of these conjugated antisera to cultured 39. 40. 41. 42. 43. 44.

45. 46. 47.

48.

Epstein, M. A., Henle, G., Achong, B. C., Barr, Y. M. J. exp. Med. 1965, 121, 171. Fogh, J., Anderson, H. C., Allen, B., Petursson, G., Saunders, E. L., Dalldorf, G. Cancer Res. 1964, 24, 416. Negroni, G. Br. med. J. 1964, i, 927. Fallon, R. J., Grist, N. R., Inman, D. R., Lemcke, R. M., Negroni, G., Woods, D. A. Br. med. J. Aug. 14, 1965, p. 388. Hayflick, L., Koprowski, H. Nature, Lond. 1965, 205, 713. Armstrong, D., Henle, G., Somerson, N. L., Hayflick, L. J. Bact. 1965, 90, 418. Dalldorf, G., Bergamini, F. Proc. nat. Acad. Sci. U.S.A. 1964, 51, 263. Bell, T. M., Massie, A., Ross, M. G. R., Williams, M. C. Br. med. J. 1964, i, 1212. Rep. E. Afr. Virus Res. Inst. July 1963-Dec. 1964, pp. 24-26. Fink, A. M., Malmgren, R. A., Rauscher, F. J., Orr, H. C., Karom, M. J. Natn. Cancer Inst. 1964, 33, 581.

cells from two African cases of lymphoblastic lymphoma has disclosed that the cells fluoresce strongly, and they react less strongly to the murine virus antiserum. Cells from some human cases of leukaemia and erythroleukaemia also react. In view of the current difficulties in culturing the presumed viral agent 39 49 and the uncertainty whether tumours can be produced in animals,45 50 51 this approach deserves repetition with more specific antisera. The laboratory findings are compatible with some transmissible agent being responsible for this lymphoma, and the original idea that it might be a virus-induced tumour spread by an insect vector 52 has been supported by other clinical and epidemiological evidence. Areas of high frequency in Africa have been defined, and the distribution seems to be determined by factors connected with rainfall and temperature.19 53 HADDOW 20 has shown by means of grid maps that over 90% of African cases lie in areas where the mean temperature of the coolest month is 60°F (about 15’5°C) and with an annual rainfall of 20 in. (about 500 mm.); and he observes that with this annual rainfall many mosquito species rely for survival on drought-resistant eggs, adults dying out completely so that there would be a break in transmission if mosquitoes were involved. He has found nothing in the peculiar agedistribution to conflict, from the viewpoint of a virologist, with the idea that an arthropod-borne virus could be involved,54 and he wonders whether a very widely disseminated virus might occasionally produce these tumours. Although no vector has yet been incriminated,45 there is some evidence that local epidemics do arise,19 and failure of the rains seems to lead to a dearth of cases with a fresh crop following a rainy period or inundations. The disease is commoner in adults than was at first supposed, and the histological changes and organ involvement, including jaw lesions, are the same as in children; but many of these adult cases come from areas where the disease is not seen in children.31 The response to chemotherapy 55 56 has also given some immunological pointers: some children respond favourably to adequate chemotherapy, certainly by comparison with other lymphomas in children, and others show remission when quite inadequate amounts of chemotherapy are given. Fresh information is arriving so fast that any positive statement is unsafe, but the cumulative data strongly suggest that a virus is the cause. 57 Nevertheless, other possibilities cannot be excluded. It seems unlikely that the disease is caused by a mixture of infections common in children living in the tropics, unless some other factors are involved-consumption of beans, 58 for example, or a fungal toxin. But even if a causal virus should be demonstrated, other mysteries may well remain.59 One is the high frequency of jaw-bone involvement in younger children. For one thing, the 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59.

Henle, G., Henle, W. J. Bact. 1965, 89, 250. Epstein, M. A., Woodall, J., Thomson, A. D. Lancet, 1964, ii, 288. Wright, D. H., Bell, T. M. ibid. p. 969. Burkitt, D. P., Davies, J. N. P. Med. Press, 1961, 245, 367. Chapman, D. S., Jenkins, J. Med. Proc. 1963, 9, 320. Haddow, A. J. E. Afr. med. J. 1964, 41, 1. Oettgen, H. F., Burkitt, D., Burchenal, J. H. Cancer, 1963, 16, 616. Burkitt, D. P., Hutt, M. S. R., Wright, D. H. ibid. 1965, 18, 399. Harris, R. J. C. Br. med. Bull. 1964, 20, 149. Pulvertaft, R. J. V. Lancet, 1964, ii, 552. Rous, P. Nature, Lond. 1965, 207, 457.

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bones in both African adults and children 14 60 are prone to several tumours other than lymphoma. The pathogenesis of the jaw lesions in lymphoblastic lymphoma is disputed6l: certainly the tumours arise in the marrow, and not from any part of the dental apparatus. Whether this is because of a blood-stream dissemination or of penetration of malignant cells along branches of the maxillary artery from an original nidus in the parotid gland is not clear. If tooth-buds are soaked in polyoma virus, and, after washing, reimplanted subcutaneously in mice a variety of tumours may arise, chiefly adamantinomas.62 63 Does some such process as this, but with a different virus, perhaps explain the peculiar liability of the African jaw to neoplasia ? Is neoplasia the only consequence ? Perhaps, however, the true importance of the African lymphoblastic lymphoma lies elsewhere. It is surely a perfect example of pathology related to geography. The possibilities disclosed by the discovery of this cancer have brought to Africa skilled laboratory workers who have stimulated local workers and trained others, and their work has revealed problems for further study in other parts of the world. Leading American centres of pathology have reassessed their lymphomas in the light of African experience, and other centres might well follow their example. Mere data collection and analysis, as FLOREY 64 has sadly noted, has met little approval from fund-granting agencies, which should perhaps reconsider the importance of scientific work with no experimental content. Many of the reported oddities of cancer distribution-for instance, the prevalence of chloroma in African children 65-call for collaboration between experimentalists and epidemiologists. 666 ASPULVERTAFT 30 has remarked, research workers might far more profitably spend their time in tropical Africa than in the thrice ploughed fields of temperate climes ... only the surface has been scratched ; there are still rich seams tobemined."

jaw

"

Respirator Treatment Hyaline-membrane Disease DESPITE the almost embarrassing riches of information on basic physiology and pathology in hyaline-membrane disease (the respiratory distress syndrome), the vital in

link in the setiological chain is missing and the disease remains a common cause of death. Though we have no effective means of influencing the fundamental process, important advances have been made in supporting therapy, such as the correction of acidosis, hypoglycxmia, hypocalcxmia, hypoproteinxmia, and the use of oxygen in high enough concentration. Assisted respiration obviously has a place in supporting therapy for a condition associated with atelectasis, exhaustion, and apnoea. Results were encouraging with positive-pressure respiraDodge, O. G. Cancer, 1965, 18, 205. Lehner, T. J. Path. Bact. 1964, 88, 581. Main, J. H. P., Dawe, C. J., Stanley, H. R. Fedn Proc. Fedn Am. Socs exp. Biol. 1965, 24, 684. Abst. 3066. 63. Stanley, H. R., Dawe, C. J., Law, W. Oral Surg. 1964, 17, 547. 64. Florey, H. Proc. R. Soc. B, 1962, 157, pp. 433, 449. 65. Davies, J. N. P., Owor, R. Br. med. J. Aug. 14, 1965, p. 405. 66. Cancer Res. 1965, 25, 1273. 60. 61. 62.

tion for short periods from a face-mask, 1 and the striking temporary improvement produced in some infants by endotracheal oxygen paved the way for more ambitious programmes of mechanical ventilation.3 Long-continued respirator treatment poses increasing technical problems the smaller the size of the patient; but they are not insuperable, and intermittent positive-pressure respiration has already been successfully applied in tetanus neonatorum.4 As experience accumulates, smaller and smaller infants are being kept alive for longer periods. The position has now been reachedwhere severely affected babies can be maintained on a respirator for two or three days. Unfortunately, their course does little to support the view that hyaline-membrane disease is a self-limiting condition in which recovery sets in after three days. The use of mechanical ventilation for days or weeks has not only created many new problems but has also led to a new natural history of the disorder. Alveolar thickening with an excess of fibroblasts, collagen, and reticulin fibres has been found on lung biopsy in an eight-week-old baby successfully maintained on an Engstrom respirator for the first month,5and the survivors of hyaline-membrane disease seem to be more susceptible than normal to acute bronchiolitis in the first six months of life. Several reports 6-10 of successful respirator treatment for neonatal respiratory distress have appeared. In the first series 11 only 1 of the 18 infants survived, but there were 7 survivors in a second series of 20 babies.12 All were in terminal respiratory failure when assisted ventilation was started, using a Bird Mark-8 respirator and infant circle, set to deliver 40% oxygen at positive pressures of 30-35 cm. of water and rates of 50-70 per minute via a tracheostomy. Common complications included movement of the tube into the right main bronchus, obstruction by secretion, and pneumonia. Pneumothorax occurred once, death from intracranial haemorrhage twice, and 1 of the 7 survivors is mentally retarded. The experience of THOMAS et a1.13 with a group of infants who were probably less severely affected has also been encouraging. These workers favoured tracheal intubation with a soft plastic tube, which was simpler and less traumatic than tracheostomy and could be maintained for many days without laryngeal spasm or oedema. Mechanical ventilation was performed with the Bennett PR 2 unit delivering 40-100% oxygen at peak pressures of 20-40 cm. of water and rates of 40-70 per minute. Of 26 infants treated, 18 have survived and only 1 shows evidence of residual brain damage. The Donald, I., Lord, J. Lancet, 1953, i, 9. Donald, I. ibid. 1954, i, 895. Donald, I., Kerr, M. M., Macdonald, I. R. Scott. med. J. 1958, 3, 151. Wright, R., Sykes, M. K., Jackson, B. G., Mann, N. M., Adams, E. B. Lancet, 1961, ii, 678. 5. Robertson, B., Tunell, R., Rudhe, U. Acta pœdiat., Stockh. 1964, 53, 433. 6. Benson, F., Celander, O., Haglund, G., Nilsson, L., Paulsen, L., Renck, L. Acta anœsth. scand. 1958, 2, 37. 7. Colgan, F. J., Eldrup-Jørgensen, S., Lawrence, R. M. J. Am. med. Ass. 1960, 173, 1557. 8. Stahlman, M., Young, W., Payne, G. Am. J. Dis. Child. 1962, 104, 1. 2. 3. 4.

526. 9. 10. 11. 12.

Heese, H. de V., Wittman, W., Malan, A. F. S. Afr. med. J. 1963, 37, 123. Reid, D. H. S., Tunstall, M.E. Lancet, 1965, i, 1196. Delivoria-Papadopoulos, M., Swyer, P. Archs Dis. Childh. 1964, 39, 481. Delivoria-Papadopoulos, M., Levinson, H., Swyer, P. ibid. 1965, 40,

13.

Thomas, D. V., Fletcher, G., Sunshine, P., Schaffer, I. A., Klaus, M. H. J. Am. med. Ass. 1965, 193, 183.

474.