Burkitt’s lymphoma presenting as mandibular swelling – report of a case and review of publications

British Journal of Oral and Maxillofacial Surgery (2000) 38, 8–11 © 2000 The British Association of Oral and Maxillofacial Surgeons DOI: 10.1054/bjom.1997.0358

BRITISH JOURNAL OF ORAL

& M A X I L L O FA C I A L S U R G E RY

Burkitt’s lymphoma presenting as mandibular swelling – report of a case and review of publications S. H. C. Tsui,* M. H. Wong,† W. Y. Lam‡ *Oral Maxillofacial Surgery and Dental Unit, North District Hospital, Hong Kong; †Oral Maxillofacial Surgery and Dental Unit, Queen Elizabeth Hospital, Hong Kong; ‡Department of Clinical Pathology, Tuen Mun Hospital, Hong Kong SUMMARY. Burkitt’s lymphoma in a 4-year-old Chinese boy presented with acute mandibular swelling but no associated systemic disturbance. A review of published reports shows that the diagnosis should be suspected in jaw lesions with no obvious cause. presentation, it was noted that the developing tooth germ of the permanent second premolar was displaced and enveloped by the lesion. Histological examination of the biopsy specimen showed a diffuse infiltrate of uniform neoplastic lymphoid cells with infiltrative destruction of the jaw bone (Fig. 1). The neoplastic cells were medium-sized with round or slightly indented nuclei containing one of more smallish nucleoli. Nuclear convolution was not a feature. There were also many apoptotic cells, some within histocytes, giving a ‘starry sky’ appearance to the infiltrate. Immunohistochemical stains showed that the neoplastic cells were positive for B-cell markers, including L26 (CD20), 4KB5 (CD45R), and CD21. The features were those of Burkitt’s lymphoma. The boy was then referred to the paediatric department. A computed tomogram (CT) confirmed the presence of an osteolytic lesion in the right mandible (Fig. 2). In addition, a tumour was found in the left infratemporal region that was eroding through the posteromedial wall of the maxillary sinus and directly extending to the adjacent portion of the left maxillary sinus (Fig. 3). One palpable node was also present in the right submandibular region. The abdominal scan was within normal limits. Gallium scan confirmed abnormal uptake at the right mandible and left maxilla. The tumour was stage II and chemotherapy was started according to the United Kingdom Children’s Cancer Study Group 901 protocol which included intrathecal methotrexate. CT about 1 month after chemotherapy showed complete resolution of the lesion in the left maxillary sinus (Fig. 4).

INTRODUCTION Patients with acute swelling in or around the jaws often present to dental or oral surgeons. In most cases, the cause is acute infection of odontogenic origin and appropriate treatment given. In rare cases, the diagnosis is not obvious and the differential diagnosis of a malignancy may be missed if one does not suspect it and if there are no other clinical clues such as loss of weight or neurological deficits. This is particularly so in previously healthy young children. We present a case of malignant lymphoma occurring in a young Chinese boy who was referred to us by his general dental practitioner. The first sign was sudden swelling of the jaw bones of no apparent cause and he had no other systemic complaints. Subsequent investigation and biopsy confirmed Burkitt’s lymphoma, which is a common lesion in the jaws in endemic areas. Early diagnosis of Burkitt’s lymphoma is important because prognosis depends on its extent at the time of diagnosis. We have reviewed other publications about the history, clinical and histological presentation, possible aetiology, and importance of Burkitt’s lymphoma in dental practice. CASE REPORT A 4-year-old Chinese boy was referred to our unit for investigation of a right mandibular swelling of 4 days’ duration. He had had a herniorrhaphy when he was 1 year old, but was otherwise healthy. Clinical examination showed a slightly tender, sessile, firm, non-fluctuant mass 2 cm in diameter in the buccal sulcus opposite the lower first and second deciduous molars in the right mandible. The overlying mucosa looked normal with no ulceration or erythema. The lower right deciduous first and second molars were not carious but were slightly mobile. No periodontal pockets were found. A panoramic and lateral oblique radiographs were taken but showed no abnormality. Aspiration of the lesion was non-productive. Antibiotics were given empirically but there was no response after 4 days. During an incisional biopsy of the lesion under general anaesthesia about 8 days after first

Fig. 1 – Monotonous infiltrate of uniform medium-sized round lymphoid cells with ‘squaring’ of the cytoplasm and nuclei. 8

Burkitt’s lymphoma presenting as mandibular swelling

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Fig. 2 – CT scan showing osteolytic lesion in the right mandible.

DISCUSSION Burkitt’s lymphoma is a malignant monoclonal proliferation of early B-lymphocytes that has a potential doubling time of 25.6 h and a growth fraction of nearly 100%,1 making it perhaps the most rapidly dividing tumour known. It was first described by Sir Albert Cook, a British missionary doctor working in Mengo, Uganda, in East Africa at the turn of the century, who noticed a common malignancy among young African children that predominantly affected the jaws and sometimes various abdominal organs.2,3 Half a century later a British surgeon, Denis Burkitt who was working in Kampala, Uganda, East Africa noticed the same lesions on the faces of young African children, and also detected abdominal masses in some cases. He published his findings in 1958, calling the lesion ‘a sarcoma involving the jaws’ and presented detailed analysis of the incidence of jaw involvement and necropsy results.4 With remarkable energy, undivided attention, limited resources, and more than a sense of curiosity, he began to dwell on the geographic distribution of the disease by embarking on a 10 000-mile safari.5 He found that the incidence of the condition was directly related to the altitude of the location. With more information gathered from other parts of Africa, Haddow recognized that the disease is common in areas in which the mean temperature is over 60°F and the rainfall over 20 inches/year.6 The first hypothesis to explain the geographical distribution of the tumour was that it reflected the distribution of some vectored virus.7,8 The discovery of a new strain of virus particles in cultured lymphoblasts from patients with Burkitt’s lymphoma by Epstein et al. in 19649 led to high expectations that the pleiotropic Epstein–Barr virus (EBV) caused Burkitt’s lymphoma. The fact that between 80% and 90% of African cases of Burkitt’s lymphoma contain multiple copies of the EBV DNA genome10,11 and that most of the affected children had raised titres to EBV added credibility to the hypothesis. Further supporting

Fig. 3 – CT scan showing lesion in the posterior wall of the left maxillary sinus.

Fig. 4 – CT scan 1 month after chemotherapy. The lesion in the left sinus has completely resolved.

evidence showed that EBV infection conferred ‘immortality’ on human lymphocytes,12 and that EBV produced lymphoreticular tumours in monkeys.13,14 However, the worldwide ubiquity of EBV infection and also the fact that the virus is not vectored did not support the hypothesis. With time, it was recognized that Burkitt’s lymphoma could occur outside the African continent but

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British Journal of Oral and Maxillofacial Surgery

the prevalence was much lower than in Africa. These sporadic cases are of identical histological appearance but differ in a number of other aspects. The mean age of presentation for sporadic cases is usually much higher – from 1115 to 1516 years of age – compared with that of 7 years4 for endemic cases. A notable exception is that of Anavi et al. from Israel who cited a mean age of 7.2 years.17 In addition, the percentage of patients with jaw involvement is much lower in non-endemic areas, about 12.5%17 to 16%.16 This contrasts with the 60–70% in endemic areas. The percentage of cells that contains the EBV DNA genome is also much lower. The role of malaria in the pathogenesis of Burkitt’s lymphoma was first suggested by Dalldorf,18 who observed that intense and persistent malarial infection resulted in hyperplasia of the lymphoreticular system. He postulated that, under these circumstances, the EBV might be oncogenic. By far the most popular hypothesis is that immunodepression is the cause. From a broader perspective, the most common site of tumours in immune-deficient subjects is the lymphoid system.19 Non-Hodgkin’s lymphomas make up 3–4% of all the tumours in the general population, but 26% of the tumours in recipients of renal transplants and 71% in recipients of cardiac transplants.20 In addition, lymphoid tumours are 20 times more common than other tumours in patients with AIDS, who also have Kaposi’s sarcoma.21 This strongly indicates that lymphoid tumours are more to be related to the various states of immune deficiency than any other malignancies. It may be that malaria, in regions of the world where Burkitt’s lymphoma is endemic, increases the incidence of Burkitt’s lymphoma by impairing immune competence, allowing sustained polyclonal B-cell proliferation. Such B-cells are at increased risk of acquiring mutations such as the t(8;14) translocation, which places c-myc close to the immunoglobulin heavy-chain (Cµ) gene and as a result leads to overexpression of c-myc.22 The activation of c-myc by itself is not sufficient for malignant transformation but because of the loss of control of cellular growth the stage is set for additional gene damage (possibly by affecting the N-ras oncogene that occurs in the B-cells immortalized by EBV) that ultimately leads to the emergence of a monoclonal neoplasm. It seems that EBV itself is not directly oncogenic, but rather acts as a polyclonal B-cell mitogen.23 The role of EBV in Burkitt’s lymphoma is particularly relevant in Hong Kong where there is a high incidence of nasopharyngeal carcinoma, which is related to EBV. The fact that Hong Kong has such a rare occurrence of Burkitt’s lymphoma (4–6 cases each year) but many cases of nasopharyngeal carcinoma seems to point to other factors in the pathogenesis of this type of lymphoma.24 Burkitt’s lymphoma is of interest to dental or oral surgeons for a number of reasons. The fact that they may be the first one to come across the lesion cannot be over-emphasized.25 In endemic areas, involvement of the jaw is the presenting feature in 50–70%26,27 of

cases while in non-endemic areas the figure is about 15%.28 In endemic areas the incidence of jaw involvement is highest at the age of 3 years and drops steadily thereafter, and the maxilla is affected more often than the mandible in a ratio of 2:1,29 while in sporadic areas the mandible is more commonly involved.16 The most common oral signs include loosening of teeth, disturbance of eruption, swelling of the jaw, and anaesthesia or paraesthesia when the inferior dental nerve or maxillary nerve are involved.2 Pain is not a prominent feature. The overlying oral mucosa or skin is not usually affected. Rarely, the oral presentation may be periodontal,30 related to tooth extraction,31 or trauma,28 or it may be in the parapharyngeal space.32 Radiologically, the earliest sign is a break in or loss of the lamina dura, followed by enlargement of the developing tooth crypts. Small foci of radiolucent areas then develop, which fuse and enlarge to adjacent areas. Nzeh33 found that radiological changes in the jaws may precede clinical involvement and proposed that all patients with a clinical suspicion of Burkitt’s lymphoma should have radiography of the jaws as the baseline radiological investigation. However, this suggestion is out of date now that CT and bone scans are readily available. Burkitt’s lymphoma is also unique in that it is perhaps the only malignancy that actually infiltrates the dental tissues including the dental pulp, the developing tooth follicle, and the periodontal ligament. Kramer34 speculated that the odontogenic epithelium, which exerts an inductive influence on the mesodermal tissues, may have a role in involving the jaws in Burkitt’s lymphoma. What is peculiar is that after successful chemotherapy, the previously infiltrated dental tissues were able to return to normal. Another point about Burkitt’s lymphoma is that it may be the first indication of HIV infection.35 This is particularly so in homosexual men or those at high risk of acquiring AIDS.36 In our case the age and the clinical presentation were typical of Burkitt’s original description. An occult lesion was developing in the left maxilla when the presenting lesion was in the right mandible, which confirmed other workers’ observations about the multi-jaw propensity of the lesion. In this case, the radiological changes quoted by previous workers were not apparent in the plain film, partly because the patient was not able to cooperate during the radiographic procedures. With hindsight it seems that a lesion was present in the left antrum in the orthopantogram, which was missed. For such a young patient, the possibility of a malignancy should always be borne in mind. In the differential diagnosis of a mass affecting the right mandible, osteomyelitis, osteogenic sarcoma, Langerhan’s disease, malignant lymphoma, giant cell tumour, histoplasmosis37 or other much rarer conditions are all possible. The diagnosis is readily established by histopathological examination of the tumour tissue, which is particularly important as Burkitt’s lymphoma is exquisitely sensitive to chemotherapy with a high 5-year survival (78%) using aggressive chemotherapy.38

Burkitt’s lymphoma presenting as mandibular swelling

Acknowledgement We thank Dr Alfred C. C. Tsang, Consultant Oral and Maxillofacial Surgeon, Tuen Mun Hospital, for his support and advice in the preparation of this article and for his permission to report his patient.

References 1. Iversen OH, Iversen U, Ziegler JL, et al. Cell kinetics in Burkitt’s lymphoma. Eur J Cancer 1974; 10: 155–163. 2. Adatia AK. Burkitt’s tumour in the jaws. Br Dent J 1966; 120: 315–326. 3. Burkitt DP. The discovery of Burkitt’s lymphoma. Cancer 1983; 51: 1777–1786. 4. Burkitt DP. A sarcoma involving the jaws in African children. Br J Surg 1958; 46: 218–223. 5. Burkitt DP, Nelson CL, Williams EH. Some geographical variations in diseases patterns in East and Central Africa. East Afr Med J 1963; 40: 1–6. 6. Haddow AJ. An improved map for the study of Burkitt’s lymphoma syndrome in Africa. East Afr Med J 1963; 40: 429–432. 7. Burkitt DP. A lymphoma syndrome in tropical Africa. In: Richter GW, Epstein MA, eds. International review of experimental pathology, vol 2. New York: Academic Press, 1963: 69–136. 8. Burkitt DP. The African lymphoma: epidemiological and therapeutic aspects. In: Zarafonetis CJD, ed. Proceedings of the International Conference on leukaemia and lymphoma. Philadelphia: Lea & Febinger, 1968: 321–330. 9. Epstein MA, Achong BG, Barr YM. Virus particles in cultured lymphoblasts from Burkitt’s lymphoma. Lancet 1964; I: 702–703. 10. Lindahl T, Klein G, Reedman BM, et al. Relationship between Epstein-Barr virus (EBV) DNA and the EBV-determined nuclear antigen (EBNA) in Burkitt lymphoma biopsies and other lymphoproliferative malignancies. Int J Cancer 1974; 13: 764–772. 11. Olweny CLM, Atine I, Kaddu-Makasa A, et al. Epstein-Barr virus genome studies in Burkitt’s lymphoma in Uganda. J Natl Cancer Inst 1977; 58: 1191–1196. 12. Jondal M, Klein G. Surface markers on human B and T lymphocytes. II. Presence of Epstein-Barr virus receptors on B lymphocytes. J Exp Med 1973; 138: 1365–1378. 13. Shope T, Miller G. Epstein-Barr virus – heterophile responses in squirrel monkeys inoculated with virus-transferred autologous leukocytes. J Exp Med 1973; 137: 140–147. 14. Klein G. The Epstein-Barr virus and neoplasia. N Engl J Med 1975; 293: 1353–1357. 15. Levine PH, Kamaraju LS, Connelly RR, et al. The American Burkitt’s lymphoma registry: eight years’ experience. Cancer 1982; 49: 1016–1022. 16. Sariban E, Donahue A, Magrath IT. Jaw involvement in American Burkitt’s lymphoma. Cancer 1984; 53: 1777–1782. 17. Anavi Y, Kaplinsky C, Calderon S, Zaizov R. Head, neck and maxillofacial childhood Burkitt’s lymphoma: a retrospective analysis of 31 patients. J Oral Maxillofac Surg 1990; 48: 708–713. 18. Dalldorf G. Lymphomas of African children with different forms of environmental influences. JAMA 1962; 181: 1026–1028. 19. Iochim HL, Cooper MC, Hellman GC. Lymphomas in men at high risk for acquired immune deficiency syndrome (AIDS). Cancer 1985; 56: 2831–2842. 20. Penn I. Lymphomas complicating transplantation patients. Transpl Proc 1983; 15: 2790–2797. 21. Safai B, Mike V, Giraldo G, et al. Association of Kaposi’s sarcoma with second primary malignancies. Possible etiopathogenic implications. Cancer 1980; 45: 1472–1479.

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22. Sheer D. Chromosomes and cancer. In: Franks LM, Teich NM eds. Introduction to the cellular and molecular biology of cancer, 2nd edn. Oxford: Oxford University Press, 1991: 276. 23. Cotran RS, Kumar V, Robbins SL, Schoen FL. Robbins pathologic basis of disease. 5th edn. Philadelphia: WB Saunders Co. 1985, P.264, 287–289. 24. Raab-Traub N. Epstein-Barr virus and nasopharyngeal carcinoma. Semin Cancer Biol 1992; 3: 297–307. 25. Burkitt D. Malignant lymphoma of the jaws. J Dent Res 1966; 45(suppl 3): 554–559. 26. Burkitt D, O’Conor GT. Malignant lymphoma in African children. Cancer 1961; 14: 258–269. 27. Biggar RJ, Nkrumah FK, Perkins IV. Presenting clinical features of Burkitt’s lymphoma in Ghana, West Africa. J Trop Pediatr 1979; 6: 157–161. 28. Svoboda WE, Aaron GR, Albano EA. North American Burkitt’s lymphoma presenting with intraoral symptoms. Pediatr Dent 1991; 13: 52–58. 29. Adatia AK, Dental tissues and Burkitt’s tumour. Oral Med Oral Surg Oral Pathol 1968; 25: 221–234. 30. Vallejo GH, Garcia MD, Lopez A, et al. Unusual periodontal findings in an AIDS patient with Burkitt’s lymphoma – a case report. J Periodontol 1989; 60: 723–727. 31. Baden E, Carter R. Intraoral presentation of American Burkitt’s lymphoma after extraction of a mandibular left third molar. J Oral Maxillofac Surg 1987; 45: 689–693. 32. Bauer GP, Volk MS, Siddiqui SY, et al. Burkitt’s lymphoma of the parapharyngeal space. Arch Otolaryngol Head Neck Surg 1993; 119: 117–120. 33. Nzeh DA. Importance of the jaw radiograph in diagnosis of Burkitt’s lymphoma. Clin Radiol 1987; 38: 519–522. 34. Kramer IRH. Malignant lymphoma of children in Africa. Int Dent J 1965; 15: 200–208. 35. Mukerji PK, Hilfer CL. Burkitt’s lymphoma with mandible, intra-abdominal and renal involvement – initial presentation of HIV infection in a 4-year old child. Pediatr Radiol 1993; 23: 76–77. 36. Ziegler JL, Drew WL, Miner RC, et al. Outbreak of Burkitt’slike lymphoma in homosexual men. Lancet 1982; II: 631–633. 37. Adekeye EO, Edwards MB, Williams HK. Mandibular African histoplasmosis: imitation of neoplasia or giant-cell granuloma? Oral Surg Oral Med Oral Pathol 1988; 65: 81–84. 38. Lopez TM, Hagemeister FB, McLaughlin P. Small noncleaved cell lymphoma in adults. Superior results for stage I–III disease. J Clin Oncol 1990; 8: 615–622.

The Authors Sunny H. C. Tsui BDS, FRACDS, FDSRCS(Eng), FHKAM(Dental Surgery) Oral Maxillofacial Surgery and Dental Unit North District Hospital Hong Kong M. H. Wong BDS, FRACDS Oral Maxillofacial Surgery and Dental Unit Queen Elizabeth Hospital Gascoigne Road Hong Kong W. Y. Lam MBBS, MRCPath, FHKAM(Path), FIAC(Cytology) Department of Clinical Pathology Tuen Mun Hospital Tuen Mun Hong Kong Correspondence and requests for offprints to: Dr Sunny H. C. Tsui, Oral Maxillofacial Surgery & Dental Unit, North District Hospital, 9 PoKin Road, Fanling, NT, Hong Kong. Paper received 9 July 1997 Accepted 16 September 1997