Pediatric Annals

Management of Burkitt's Lymphoma

John L Ziegler, MD

Abstract

1. Burkitt, O.P.. and O'Conor, G. T. Malignant lymphoma in African children. I: A clinical syndrome. Cancer 14 (1961), 250.

2. O'Conor, G. T. Malignant lymphoma in African children. Il: A pathological entity. Cancer 14 (1961), 270.

3. Berard, C.W.. et al- Histopathological definition of Burkitt's tumor. Bull. WHO 40 (1969), 601.

4. Burkitt, O.P. Etiology of Burkitt's lymphoma. An alternative hypothesis to a vectored virus. J. Nat. Cancer lnst. 42 (1969), 19.

5. Smith, R. T., and Bausher, J. C. Epstein-Barr virus infection in relation to infectious mononucleosis and Burkitt's lymphoma. Ann. flev. Med. 23 (1972), 39.

6. Ziegler, J. L. Chemotherapy of Burkitt's lymphoma. Cancer 30 (1972), 1534.

7. Hirshaut, Y., Cohen, M. H., and Stevens. D. A. Epstein-Barr-virus antibodies in American and African Burkitt's lymphoma. Lancet 2 (1973). 114.

8. Arseneau, J. C., et al. American Burkitt's lymphoma. A clin ico-pathological study of 30 cases. I: Clinical factors relating to prolonged survival. Amer. J. Med. (In press.)

9. Ziegler, J. L., and Magrath, I. T. Burkitt's lymphoma . I n loachim , H . L . (ed . ) . Pathobiology Annual. 1974. New York: Appleton-Century-Crofts. pp. 129-142.

10. Magiath, I. T., et al. Surgical reduction of tumour bulk in the management of abdominal Burkitt's lymphoma. Brit. Med. J. 2 (1974), 308.

11. Clifford, P., et al. Long-term survival of patients with Burkitt's lymphomas: An assessment of treatment and other factors which may relate to survival- Cancer fíes. 27 (1967). 2587.

12. Williams. E.H. A comparison of results in treating two series of patients with Burkitt's lymphoma. Brit. J. Cancer 25 (1971). 37.

13. Ziegler, J. L., et al. Treatment of Burkitt's tumor with cyclophosphamide. Cancer 26 (1970), 474.

14. Ziegler, J. L., et al. Relapse patterns in Burkitt's lymphoma. Cancer Res. 32 (1972), 1267.

15. Norin, T., et al. Conventional and superfractionated radiation therapy in Burkitt's lymphoma. Acta Radiol. fO(l971), 545.

16. Ziegler, J. L., et al. Central nervous system involvement in Burkitt's lymphoma. Blood 26 (1970). 718.

17. Ziegler, J. L., and Bluming, A.Z. lntrathecal chemotherapy in Burkitt's lymprioma. Brit. Med J. 3 (1971), 508.

18. Magrath, I. T., and Ziegler, J. L. Prophylaxis of meningeal Burkitt's lymphoma with CCNU. Proc. Amer. Assoc. Cancer Res. 14 (1973), 67.

19. !versen, U.. et al. Cell kinetics in African cases of Burkitt's lymphoma. European J. Cancer 8 (1972), 305.

20. Arseneau. J. C., et al. Hyperkalemia. a sequel to chemotherapy of Burkitt's lymphoma. Lancet J (1973), 10.

21. Klein, G. lmmunological studies on a human tumor. Dilemmas of the experimentalist. Israel J. Med. Sci- 7 (1971), 111.

22. Klein, G., et al. EBV-associated seriological patterns in a Burkitt's lymphoma patient during regression and recurrence, Int. J. Cancer 4 (1969), 416.

23. Bluming, A.Z.. et al. Delayed cutaneous sensitivity to autologous Bufkitt lymphoma protein extracts. CWn. Exp lmmunol. 9 (1971). 713.

24. Magrath, I. T. lmmunosuppression in Burkitt's lymphoma. I: Cutaneous reactivity to recall antigens; Alterations induced by a tumor burden and by BCG administration. Int. J. Cancer 13 (1974), 839.

25. Ziegler, J. L., and Magrath, I. T. BCG immunotherapy in Burkitt's lymphoma: Preliminary results of a randomized clinical trial. J. Nat. Cancer lnst. Monogr. 39 (1974), 199.

Acknowledgment. The author wishes to thank his many associates who assisted in the cace of Burkitt's lymphoma patients ai the Uganda Cancer Institute.

TABLE 1

REVISED STAGING OF BURKITT'S LYMPHOMA…

INTRODUCTION

Burkitt's lymphoma has been the subject of considerable investigation since the original recognition of the disease in Uganda and the subsequent delineation of a distinct clinical1 and pathologic2'3 syndrome. Epidemiologie studies lend support to the theory of infectious causative agents,4 and the possible oncogenic role of the EpsteinBarr (EB) virus is under intensive study.5 Clinical features suggesting an immune response to the tumor have been described, and a long-term survival rate of up to 67 per cent of patients who achieved complete remission after chemotherapy has been reported.6 These events have provided a basis for optimism in the chemotherapeutic management of patients with cancer, and indicate new directions in the chemical and possible immunologie control of disseminated cancer.

The incidence of Burkitt's lymphoma is highest in tropical countries; in some areas this tumor accounts for over half of childhood malignancies. In African cases, a strong association of Burkitt's lymphoma with high EB virus antibody liters and endemic malaria has been noted.4-5 Patients with histologically identical tumors have been identified in a world-wide distribution, but the association with malaria and the EB virus is lacking.4'7 Nevertheless, these nonendemic cases have clinical features indistinguishable from the African cases and demonstrate similar therapeutic responses.8

DIAGNOSIS

In current nomenclature, Burkitt's iymphoma is defined as a "malignant lymphoma, undifferentiated, Burkitt's type."3 The histologie features are shown in Figure 1 . The malignant cells are undifferentiated lymphoblasts of uniform size and shape. The nuclei are round and primitive and contain prominent nucleoli; the cytoplasm is basophilic, and small vacuoles may be detected. Large pale histiocytes are scattered throughout the tumor, and contain ingested tumor debris. Periodic acid-Schiff (glycogen) stains are negative, and oil-red-O stains (fat) are positive.3 Cytology of the malignant cells, obtained by fine-needle aspiration or by tumor imprint preparation, reveals typical diagnostic features (Figure 2). The tumor cells are round or oval, with finely reticular nuclear chromatin that condenses around several prominent nucleoli. The cytoplasm is deeply basophilic and contains prominent vacuoles. The lack of appreciable pleomorphism and absence of lymphoid or histiocytic differentiation distinguish Burkitt's lymphoma from other types of malignant !ymphoma.

Presenting features and clinical staging. The plethora of clinical manifestations of Burkitt's lymphoma is attributable to the disease's multicentric nature and propensity to develop in extranodal tissues. In endemic areas, the commonest presentation (60 per cent) is a tumor in the mandible, maxilla, or both, producing a typical soft-tissue enlargement (Figure 3), Osteolytic lesions in the facial bones are characteristic, with loss of the lamina dura and displacement and loosening of the teeth. Orbital tumors are common, presenting as proptosis and chemosis (Figure 4), Facial tumors are usually painless, rarely ulcerate, and rapidly enlarge within weeks. The differential diagnosis includes embryonal rhabdomyosarcoma, dentigerous cyst, ossifying fibroma, ameloblastoma, chloroma, phycomycosis, and various ocular disorders. Occasionally facial tumors may be a presenting feature of other types of malignant lymphoma.

Figure 1 . Histopathology of Burkitt's lymphoma. The tumor cells are of uniform size and shape, and show no evidence of histiocytic or lymphocytic differentiation; scattered macrophages are prominent, giving the "starry sky" appearance. (H and E stain, XIOO.)

Figure 1 . Histopathology of Burkitt's lymphoma. The tumor cells are of uniform size and shape, and show no evidence of histiocytic or lymphocytic differentiation; scattered macrophages are prominent, giving the "starry sky" appearance. (H and E stain, XIOO.)

Figura 2. Cytology of Burkitt's lymphoma. Note the prominent cytoplasmic basophilia and vacuolization. The nuclei are primitive and contain prominent nucleoli. Wrlght's stain. X800.)

Figura 2. Cytology of Burkitt's lymphoma. Note the prominent cytoplasmic basophilia and vacuolization. The nuclei are primitive and contain prominent nucleoli. Wrlght's stain. X800.)

Figura 3. Appearance of Burkitt's lymphoma In the left maxilla of a four-year-old girl.

Figura 3. Appearance of Burkitt's lymphoma In the left maxilla of a four-year-old girl.

Figure 4. Invasion of the left orbit by Burkitl's lympnoma In a nine-year-old boy.

Figure 4. Invasion of the left orbit by Burkitl's lympnoma In a nine-year-old boy.

Figures. Burkitt's lymphoma presenting as a facial tumor and abdominal mass in a six- year-old boy.

Figures. Burkitt's lymphoma presenting as a facial tumor and abdominal mass in a six- year-old boy.

Abdominal tumors are next in presenting frequency (25 per cent) and usually affect ovaries, mesentery, kidneys, and/or retroperitoneal structures with accompanying ascites. Liver and spleen are rarely affected. Patients most usually complain of progressive abdominal enlargement, although emergent symptoms due to ovarian torsion, intussusception, or intestinal obstruction may occur. Many patients present with both facial and abdominal tumors (Figure 5), and it is the facial distortion that occasions the presenting complaint.

Several extranodal anatomic sites may be afflicted with tumor deposits, and no tissue appears exempt. Paraplegia, with or without tumor in other areas, is a common presenting feature (15 per cent) and is attributable to paraspinal tumor compressing the spinal cord or its vascuïature. Other organs that may contain tumor include the parotid gland, the thyroid gland, testes, skin, bone (often the epiphyseal portion), mediastinum, and soft tissues (often in the shoulder or thigh).

Diffuse bone marrow involvement, though rare in African cases, may produce a leukoerythroblastic blood picture or pancytopenia. Central nervous system involvement (aside from paraplegia) is usually manifest clinically as peripheral neuropathy, often leading to a diagnosis of mononeuritis multiplex. Patients occasionally have altered consciousness and intracranial hypertension due to malignant pleocytosis.

American patients with Burkitt's lymphoma have a clinical tumor distribution that is skewed towards advanced abdominal disease, with a relative infrequency of jaw tumors. In a recently reported series of 30 patients, 25 had intra-abdominal involvement, while only five had localized or regional disease elsewhere.8

The clinical staging of Burkitt's lymphoma (Table 1) has recently been revised.9 The staging scheme is designed to reflect tumor burden. In a retrospective analysis of a large series of patients who were uniformly examined and treated, the staging was shown to correlate with the frequency of relapse and survival.

Accurate clinical staging includes the following procedures: complete history and physical examination, hemogram, renal and liver function studies, chest x-ray, intravenous pyelogram, bone survey, liver-spleen-bone and gallium scans (if available), bone marrow aspiration and biopsy, and lumbar puncture with cerebrospinal fluid cytology. Other procedures - such as lymphangiogram, liver biopsy, wholechest tomography, and myelography - may also be indicated.

MANAGEMENT

The first physician to encounter a patient with Burkitt's lymphoma is usually a surgeon, consulted because of an enlarging tumor mass that causes physical or obstructive symptoms. Lymphoma may be suspected in the differential diagnosis, but Burkitt's lymphoma is a rare preoperative diagnosis in the absence of a classic jaw tumor. The surgeon should attempt to remove as much tumor bulk as possible, even in the presence of malignant ascites or obvious foci of metastatic tumor. Such operations usually entail resection of mesenteric masses, along with a portion of bowel, or removal of one or both ovaries. A "debulking" procedure has important prognostic implications in that eight of nine Ugandan patients who underwent resection of over 90 per cent of intra-abdominal tumor mass are long-term survivors. This statistic is compared with longterm survival of 45 per cent in similar patients who underwent less extensive procedures and 37 per cent who did not have surgery at all.10 While these patients are select, the safe removal of tumor bulk is clearly beneficial.

Following excisional or diagnostic surgery, systemic chemotherapy is indicated. The best treatment is cyclophosphamide, 40 mg./kg., in a single intravenous dose, repeated for at least three to six courses at two-week intervals until complete remission has been achieved.6 Patients who relapse while being treated with multiple-dose cyclophosphamide usually fail to respond to further courses of the drug but will demonstrate regression after treatment with vincristine, methotrexate, or cytosine arabinoside. Vincristine, 1.4 mg./sq.m. given intravenously on day 1, and methotrexate, 15 mg./sq.m. given orally on days 1 through 4, seem to be a particularly effective combination, given alternately with cytosine arabinoside 250 mg./sq.m. daily in sixhourly divided subcutaneous doses for three days.6 Orthomerphelan, in single doses of 0.8 mg./kg. given intravenously every two to three weeks, has also yielded a high remission rate,11 as has cyclophosphamide, 40 mg. /pound (total dose) given orally daily for five days.12 Other agents with some degree of activity include daunorubicin, Lasparaginase, actinomycin D, procarbazine, and adriamycin. While these drugs have been tried largely in patients with relapsing, resistant tumors, their use in a primary treatment regimen is discouraged in view of the outstanding results obtained by cyclophosphamide.

Table

TABLE 1REVISED STAGING OF BURKITT'S LYMPHOMA

TABLE 1

REVISED STAGING OF BURKITT'S LYMPHOMA

The use of "consolidation" or "maintenance" therapy once remission has been achieved has not been clarified. A trial of single- versus multiple-dose cyclophosphamide in Uganda13 revealed a similar frequency of long-term survivors, although multiple-dose therapy prolonged the duration of remission by about six to 10 weeks.

An analysis of relapse revealed that approximately one-third of patients achieve durable first remissions and do not relapse.14 These are patients who have localized or multiple small tumor deposits (stage A or B) on admission or patients who have had extensive surgical removal of tumor. There are several exceptional patients who, in spite of having more advanced tumors (stages C or D), still achieve long remissions, although these are clearly a minority.

About two-thirds of patients who achieve complete remission have relapses. Half of these patients relapse with recurrent tumors and often develop meningeal or neurologic impairment, usually soon after initial treatment. These patients with "early" relapse have a poor prognosis and respond only partially or transiently to continued therapy. The rest of the patients develop a peculiar form of relapse after a prolonged (average: six months) initial remission. This "late" form of relapse is very often manifested as tumor in new, previously unaffected sites, although tumors may recur in the same site. These patients respond well to therapy and may have very prolonged second remissions with a good prognosis. While "early" and "late" may be artificial delineations of relapse type, they do indicate the importance of vigilant surveillance and prompt, aggressive treatment of tumor relapse.

Figure T. Survival in Burkitt's lymphoma, An analysis of 172 patients who achieved complete remissions following cyclophosphamide and have been followed for at least two years.

Figure T. Survival in Burkitt's lymphoma, An analysis of 172 patients who achieved complete remissions following cyclophosphamide and have been followed for at least two years.

While the pathogenesis of the heterogenous relapse patterns in Burkitt's lymphoma is speculative,14 the messages seem to be clear: (1) complete initial remissions are mandatory, and initial treatment must be adequate (multiple doses); (2) relapse in close proximity to initial therapy usually indicates drug resistance, suggesting potential efficacy of combination or sequential therapy using full doses of active agents; (3) meningeal involvement must be recognized and treated (see below) and Js preventable; (4) prolonged maintenance therapy is probably not indicated, since fully one-third of patients are long-term survivors with "minimal" initial therapy; and (5) "late" relapse must be anticipated and treated vigorously because the prognosis may be excellent.

The utility of cyclophosphamide, vincristine, and methotrexate in combination is being explored in current chemotherapy regimens. The "COM" regimen is given as follows:

Cyclophosphamide, 1 gm./sq.m. intravenously on day 1.

Vincristine (Oncovin®, 1.4 mg./sq.m. intravenously on day 3 (maximum: 2 mg.).

Methotrexate, 15 mg./sq.m. on days 14 (days 1 and 4 intrathecally, days 2 and 3 intravenously).

This regimen has yielded a high remission rate in preliminary trials in Uganda, in Ghana, and at the National Cancer Institute, The long-term effects cannot yet be assessed. At the National Cancer Institute, patients who become resistant to the COM regimen receive high-dose methotrexate with leucovorin rescue, followed by cytosine arabinoside, 100 mg./sq.m. in a 12hour infusion dose, in an experimental phase 2 trial.

The role of radiotherapy in Burkitt's lymphoma has not been subjected to critical trials. The tumor is extremely rathosensitive,15 particularly when doses are "superfractionated"; because of the multicentric tumor location, however, radiotherapy alone is not recommended. Radiation treatment may well be effective in the rapid reduction of tumor bulk that endangers life and is surgically inaccessible. Certainly the radiation of paraspinal tumor or obstructive mediastinal masses is a procedure that is indicated in the event of sudden paraplegia or superior vena cava syndrome. Reduction of tumor bulk by radiotherapy during or following chemotherapy is of potential vaJue and is under study. Finally, cranial irradiation for prophylaxis of meningeal involvement is clearly a worthwhile investigation in view of its efficacy in prevention of meningeal leukemia.

A high frequency of neurologic disease and the development of neuropaîhy and/or meningea! signs as a manifestation of relapse are common findings in Burkitt's lymphoma.16 Presumably tumor cells gain access to the central nervous system via direct spread along peripheral nerves, although blood-borne spread cannot be excluded. The appearance of malignant ceJis in the cerebrospinaJ fluid is an indication for intrathecal chemotherapy. Both methotrexate and cytosine arabinoside arc effective in eradicating these cells, but the optimal schedule has not been worked out. Current approaches employ cytosine arabinoside, 30 mg./sq.m. intrathecally daily for three days, followed by methotrexate, 15 mg./sq.m. intrathecally on the fourth day. Attempts at "prophylaxis" of meningeal impairment by four courses of methotrexate administered intrathecally, alternating with cytosine arabinoside administered intrathecally every four days, were not effective in preventing subsequent meningeal relapse.17 The addition of CCNU, an effective drug that crosses the bloodbrain barrier, did not prevent subsequent malignant pleocytosis when it was administered early in remission." Present attempts at prevention are incorporated in the COM regimen, in which intrathecal methotrexate is given twice with each course of therapy. The efficacy of prophylactic cranial radiation is also under study in a controlled trial.

COMPLICATIONS

Burkitt's lymphoma is the most rapidly growing human neoplasm, with a doubling time of 24 hours and a growth fraction (proportion of actively proliferating cells) approaching 100 per cent.19 When large tumors are present, metabolic complications resulting from hyperuricemia, hypoglycemia, and lactic acidosis may ensue. Appropriate metabolic monitoring and the administration of allopurinol, bicarbonate, and glucose may avert life-threatening events. 8

Following tumor lysis by chemotherapy, electrolyte abnormalities may also present clinical problems.20 The sudden release of intracellular potassium and phosphorus (with subsequent lowering of calcium) may result in cardiac arrest. Renal failure (secondary to hyperuricemia, parenchyma! tumor, or obstructive uropathy) may aggravate these abnormalities. Consequently, close monitoring of serum and urinary electrolytes (at least twice daily) is mandatory in patients with large tumor burden, and judicious management of positive fluid balance and high urine flow is essential. The latter measure is also critical in avoiding the bladder toxicity from cyclophosphamide metabolites.

Other complications of Burkitt's lymphoma include organ dysfunction due to tumor (as in liver and kidneys), obstructive disorders (airway; venous occlusion, intussusception, urinary tract obstruction), pathologic fractures from osseous involvement, and the sequelae of pancytopenia secondary to diffuse bone marrow invasion. The toxic effects of chemotherapy are now well known, but monitoring of the peripheral blood counts and vigilance for supervening infection during periods of leukopenia are important. Blood product replacement therapy is usually unnecessary except in patients with diffuse marrow involvement.

PROGNOSIS

In African cases, the long-term survival rate varies from 20 to 67 per cent.6'11'12 Prognosis is clearly dependent on initial response to chemotherapy; nonresponders usually succumb to their tumor within three months. Survival is critically dependent on the initial clinical stage, which is demonstrated in the life table analysis (Figure 6). Adequately treated patients with local or limited disease (stages A and B) have a survival rate of 67 per cent. Patients with intra-ab dominai tumor with single (stage C) or multiple (stage D) extra-abdominal tumors have a survival expectancy of 50 per cent and 15 per cent respectively.9 Other factors associated with a poor prognosis (dependent on or independent of stage) include older age (above 12 years), low EB virus anti-VCA-antibody titer (stage D only), and male sex (stage B and C only). The exact significance of the latter observations is in doubt.9

IMMUNOLOGY

An abundance of clinical and experimental data support a role for tumordirected immunity in the clinical course of Burkitt's lymphoma (reviewed by Klein21). The identification of humoral and cell-mediated immune reactions to tumor cells or tumor extracts and their fluctuation during remission and relapse strongly suggest host recognition of the tumor.22'23 It is not yet clear whether these reactions are beneficial to the host or whether, under certain circumstances, they promote tumor growth. While some immune reactions are attributable to antigens associated with the EB virus,21 others suggest the presence of tumor-specific antigen.23 The picture is complicated by the apparent nonspecific immunosuppression associated with a large tumor burden24 and by the strong association of the disease with chronic endemic malaria and its immunologie consequences.4 These observations provide a theoretical basis for immunotherapy in Burkitt's lymphoma, though a recent trial of repeated BCG vaccination during remission had no effect on relapse or remission duration." Much has still to be learned regarding the immunology of this disease, and great care must be taken in the design and evaluation of future clinical trials employing immunotherapy.

SUMMARY

Burkitt's lymphoma is a world-wide disease with distinctive morphologic characteristics and clinical behavior. It is remarkably responsive to chemotherapy, and there are strong indications that host immunity may be a determinant in survival.

BIBLIOGRAPHY

1. Burkitt, O.P.. and O'Conor, G. T. Malignant lymphoma in African children. I: A clinical syndrome. Cancer 14 (1961), 250.

2. O'Conor, G. T. Malignant lymphoma in African children. Il: A pathological entity. Cancer 14 (1961), 270.

3. Berard, C.W.. et al- Histopathological definition of Burkitt's tumor. Bull. WHO 40 (1969), 601.

4. Burkitt, O.P. Etiology of Burkitt's lymphoma. An alternative hypothesis to a vectored virus. J. Nat. Cancer lnst. 42 (1969), 19.

5. Smith, R. T., and Bausher, J. C. Epstein-Barr virus infection in relation to infectious mononucleosis and Burkitt's lymphoma. Ann. flev. Med. 23 (1972), 39.

6. Ziegler, J. L. Chemotherapy of Burkitt's lymphoma. Cancer 30 (1972), 1534.

7. Hirshaut, Y., Cohen, M. H., and Stevens. D. A. Epstein-Barr-virus antibodies in American and African Burkitt's lymphoma. Lancet 2 (1973). 114.

8. Arseneau, J. C., et al. American Burkitt's lymphoma. A clin ico-pathological study of 30 cases. I: Clinical factors relating to prolonged survival. Amer. J. Med. (In press.)

9. Ziegler, J. L., and Magrath, I. T. Burkitt's lymphoma . I n loachim , H . L . (ed . ) . Pathobiology Annual. 1974. New York: Appleton-Century-Crofts. pp. 129-142.

10. Magiath, I. T., et al. Surgical reduction of tumour bulk in the management of abdominal Burkitt's lymphoma. Brit. Med. J. 2 (1974), 308.

11. Clifford, P., et al. Long-term survival of patients with Burkitt's lymphomas: An assessment of treatment and other factors which may relate to survival- Cancer fíes. 27 (1967). 2587.

12. Williams. E.H. A comparison of results in treating two series of patients with Burkitt's lymphoma. Brit. J. Cancer 25 (1971). 37.

13. Ziegler, J. L., et al. Treatment of Burkitt's tumor with cyclophosphamide. Cancer 26 (1970), 474.

14. Ziegler, J. L., et al. Relapse patterns in Burkitt's lymphoma. Cancer Res. 32 (1972), 1267.

15. Norin, T., et al. Conventional and superfractionated radiation therapy in Burkitt's lymphoma. Acta Radiol. fO(l971), 545.

16. Ziegler, J. L., et al. Central nervous system involvement in Burkitt's lymphoma. Blood 26 (1970). 718.

17. Ziegler, J. L., and Bluming, A.Z. lntrathecal chemotherapy in Burkitt's lymprioma. Brit. Med J. 3 (1971), 508.

18. Magrath, I. T., and Ziegler, J. L. Prophylaxis of meningeal Burkitt's lymphoma with CCNU. Proc. Amer. Assoc. Cancer Res. 14 (1973), 67.

19. !versen, U.. et al. Cell kinetics in African cases of Burkitt's lymphoma. European J. Cancer 8 (1972), 305.

20. Arseneau. J. C., et al. Hyperkalemia. a sequel to chemotherapy of Burkitt's lymphoma. Lancet J (1973), 10.

21. Klein, G. lmmunological studies on a human tumor. Dilemmas of the experimentalist. Israel J. Med. Sci- 7 (1971), 111.

22. Klein, G., et al. EBV-associated seriological patterns in a Burkitt's lymphoma patient during regression and recurrence, Int. J. Cancer 4 (1969), 416.

23. Bluming, A.Z.. et al. Delayed cutaneous sensitivity to autologous Bufkitt lymphoma protein extracts. CWn. Exp lmmunol. 9 (1971). 713.

24. Magrath, I. T. lmmunosuppression in Burkitt's lymphoma. I: Cutaneous reactivity to recall antigens; Alterations induced by a tumor burden and by BCG administration. Int. J. Cancer 13 (1974), 839.

25. Ziegler, J. L., and Magrath, I. T. BCG immunotherapy in Burkitt's lymphoma: Preliminary results of a randomized clinical trial. J. Nat. Cancer lnst. Monogr. 39 (1974), 199.

Acknowledgment. The author wishes to thank his many associates who assisted in the cace of Burkitt's lymphoma patients ai the Uganda Cancer Institute.

TABLE 1

REVISED STAGING OF BURKITT'S LYMPHOMA

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