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Burkitt’s lymphoma with loss of the long arm of chromosome 1
Burkitt’s lymphoma with loss of the long arm of chromosome 1 Ioannis Dimitrakopoulos, DDS, MD,a Konstantinos Psomaderis, DDS,b Theodora Katopodi, PhD,c Fotios Iordanidis, MD,d and Ioannis Georgoulis, MD, PhD,e Thessaloniki, Greece ARISTOTLE UNIVERSITY OF THESSALONIKI AND GENERAL HOSPITAL “G. PAPANIKOLAOU”
(Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103:e42-e47)
Burkitt’s lymphoma (BL) is a high-grade non-Hodgkin lymphoma (NHL) of B-cell origin. It was first described by Dennis Burkitt in Uganda in 1958 as a jaw sarcoma occurring at a high frequency in African children.1 It accounts for 3% to 5% of all lymphomas and 40% of NHL in children.2,3 There are 3 clinical variants of BL, each manifesting differences in clinical presentation, morphology, and biology of BL: the endemic (eBL) or African, the sporadic (sBL) or American, and the human immunodeficiency virus–related BL (HIVBL). The eBL appears primarily but not exclusively in equatorial Africa. The sBL affects mostly white people throughout the world, but especially people in northern America and Europe.2 The annual incidence of BL is low, 1% to 10% of all lymphomas in western countries and 20 to 40 times lower than in Africa and northern Brazil.3 Translocation involving MYC is a constant genetic feature, whereas Epstein-Barr virus (EBV) is found in a variable proportion of cases.2-5 In this article we present 2 cases of BL affecting the head and neck areas of 2 white boys. One of them exhibited loss of the long arm of chromosome 1, which, to our knowledge, has never been reported in the international literature. CASE 1 A 14-year-old white boy was referred to our clinic for evaluation of a rapidly enlarging painful swelling on the right side of his face. Twenty days before admission the patient had experienced an intermittent pain on his a
Oral and Maxillofacial Surgeon, Associate Professor, Oral and Maxillofacial Surgery Clinic, Aristotle University of Thessaloniki. b Oral and Maxillofacial Surgeon, Oral and Maxillofacial Surgery Clinic, Aristotle University of Thessaloniki. c Biologist, Laboratory of Biology, Medical School of Aristotle University of Thessaloniki. d Pathologist Specialist, Department of Pathology, General Hospital “G. Papanikolaou.” e Hematologist, Director, Laboratory of Hematology, General Hospital “G. Papanikolaou.” Received for publication Feb 1, 2006; returned for revision Aug 10, 2006; accepted for publication Aug 15, 2006. 1079-2104/$ - see front matter © 2007 Mosby, Inc. All rights reserved. doi:10.1016/j.tripleo.2006.08.011
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right maxilla and a slight swelling of his face in the same area. The family’s dentist diagnosed a maxillary alveolar abscess and prescribed amoxicillin. He also recommended drainage, which was performed 1 day after, but no pus was drained. However, since the swelling increased rapidly in size and the upper teeth of the affected side became loose the patient was referred to us for further evaluation. The patient’s past medical history was unremarkable. He only reported episodes of intermittent paresthesia of the right side of his tongue and the right half of the lower lip over the preceding week. The extraoral examination revealed a painless and firm in consistency swelling over the anterolateral surface of the right maxilla with slight proptosis of the right eye. The intraoral examination demonstrated a diffuse expansion of both the right buccal and palatal maxillary cortical plates, which were not tender to palpation. The overlying mucosa was intact and bluish red in color. The teeth of the affected side (teeth 13 to 17) were loose and displaced; the patient was not able to close his mouth. Regional lymph nodes were not palpable. The radiographic examination disclosed opacification of the right maxillary sinus, which was filled with a soft tissue mass. The antral walls were ill defined. Computed tomography (CT) revealed a contrast-enhancing destructive mass within the right maxillary antrum, extending to palatal and buccal soft tissues. The mass, which also involved the right orbit, was occupying the ipsilateral infratemporal and pterygomandibular space (Fig. 1). Under local anesthesia an intraoral biopsy was performed. The microscopic examination showed that the submucosal tissue was extensively infiltrated by monomorphic medium-sized cells with basophilic cytoplasm and numerous mitotic figures. The nuclei were round with clumped chromatin and relatively clear parachromatin, and contained multiple basophilic medium-sized, centrally situated nucleoli (Fig. 2). A “starry sky” pattern was present, imparted by numerous benign macrophages that had ingested apoptotic tumor cells. Immunohistochemical staining of the tumor cells showed positive expression to CD-20, CD-10, and bcl-6 and negative to CD-3, CD-5, CD-23, TdT, and bcl-2. A very high growth
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Fig. 1. Axial CT. The tumor is marked. Notice the occupation of the whole sinus and the infiltration of the orbital floor.
Fig. 2. A diffuse monotonous pattern of infiltration composed of medium-sized cells with basophilic cytoplasm and numerous mitotic figures (hematoxylin and eosin [HE] ⫻100).
fraction was observed: nearly 100% of the cells were positive for Ki-67. A diagnosis of Burkitt lymphoma was made. CT examination of the neck, chest, and abdomen did not reveal any pathological alteration such as hepatosplenomegaly or lymphadenopathy. EBV antibodies were not detected in the patient’s serum. The results of routine blood and urine investigations were within normal limits. Examination of the cerebrospinal fluid was within normal limits. Bone marrow biopsy was also negative for any pathology. Chromosome analysis was carried out using the G-banding technique. The patient was found to have a deletion in chromosome 1 that involved loss of the long arm after the band 1q21. The remaining chromosome consisted of its entire short and part of the long arm lying between the
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centromere and band 1q21. This structural chromosomal anomaly can be described as 46, XY, del (1) (pterq21:) (Fig. 3). The patient was referred to the hematology/oncology department of our hospital for further evaluation and treatment. A combination of chemotherapy including cytoxan, prednisone, vincristine, and methotrexate was applied. The patient showed a satisfactory response to the treatment. His condition improved rapidly after chemotherapy. The facial swelling subsided and the teeth became less mobile. Seven weeks later the patient presented with hoarse voice, productive cough, fever up to 38°C, and left facial nerve paresis. The examination of his cerebrospinal fluid revealed the presence of lymphoblasts and infiltration of the central nervous system. A new chemotherapy protocol was used (vincristine, adriamycin, dexamethasone [VAD]) with concurrent lumbar infusion of cytotoxic agents, twice a week, for a total of 10. There was a new recurrence in the next 2 months and radiotherapy of the cranial vault and facial skeleton was performed. The patient finally died from the disease 6 months after the initial diagnosis. CASE 2 An 18-year-old white boy was referred to our clinic for evaluation of an enlarging swelling of his right neck, which had been noticed 20 days earlier. The medical history of the patient revealed that he had suffered from EBV infection 10 years earlier. The physical examination was normal. The clinical evaluation of the mouth, face, and jaws was also normal. The clinical examination of the neck showed a scleroelastic, slightly painful mass, sized 5 ⫻ 7 cm. It occupied a space inferior/medial to the right mandibular angle and anterior to the anterior edge of the sternocleidomastoid muscle. The CT showed an en-block mass of enlarged lymph nodes on the right superior jugular lymph node chain and other enlarged, but smaller than the first ones, lymph nodes on the right anterior and posterior neck triangles as well as on the left anterior neck triangle. Under general anesthesia an excisional biopsy of 2 lymph nodes was performed. The en-block mass had no well-defined borders. The histological examination showed the same findings as the previous report with most prominent starry sky pattern, revealing BL (Figs. 4 and 5). EBV antibodies were detected in the patient’s serum. Chromosome analysis of cultured peripheral blood cells using G-banding technique showed no abnormalities. The patient’s karyotype was normal (46, XY). The patient was referred to the hematology/oncology department for further investigation. The patient died from the disease 7 months after the initial diagnosis.
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Fig. 3. Karyotype of case 1. The deletion of the long arm of chromosome 1 is marked.
Fig. 4. A starry sky pattern is noticed imparted by numerous benign macrophages that had ingested apoptotic tumor cells. The nuclear diameter of the tumor cells is similar to that of the starry sky histiocytesy (lower right area) (HE ⫻400).
DISCUSSION BL is a highly aggressive lymphoma often presenting at extranodal sites or as an acute leukaemia.2,6 The features of the tumor cells and their origin, as well as the prognostic profile of the disease are similar for all patients worldwide. On the contrary, the clinical manifestations of eBL differ from those of sBL. The eBL affects small children at the peak age from 5 to 7 years old and is characterized by jaw tumors in more than
Fig. 5. Immunohistochemical staining of the tumor cells showing positive expression to CD-20.
60% of cases.7 The younger the child, the higher the incidence of jaw involvement, reaching 100% at the age of 3 years old. The maxilla is affected twice as often as the mandible. Paraplegia involving central nervous system infiltration is the prevailing symptom in 35% of cases of the eBL type.8 The peak age of sBL is, however, between 10 and 12 years old.9 The male-tofemale ratio varies between 2:1 and 6.5:1 and is much higher in patients younger than 12 years old.8 It occurs most frequently in white people. Black patients account
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for only 5% of the sBL population. The terminal ileum, the cervical lymph nodes, and the bone marrow are the most frequently involved sites. Cervical lymphadenopathy is present in 16% and the jaw is affected in only 6% to 8% of the cases.4 Perioral anesthesia and localized disease in only 1 quadrant of the mouth are also characteristic features of sBL.9 Clinical signs and symptoms of BL involving the jaws include facial swelling, alveolar and gingival enlargement, mobile teeth, toothache, oral masses, jaw pain, and paresthesia. Toothache is the most common symptom in eBL and is the chief complaint in 90% of adults.8 This unique feature is explained by the infiltration of the tooth pulp by the tumor cells through the apex. In eBL the tumor most commonly involves all 4 quadrants and in 83% of cases infiltrates more than 1 quadrant.10 Maxillary tumors may produce proptosis of the ipsilateral eye. Our first case did appear with these signs but the treatment was delayed because of improper diagnosis. Radiographic findings include osteolytic lesions. Loss of the lamina dura and widening of the periodontal ligament are frequent signs. As the tumor enlarges the teeth and tooth buds are displaced.6,9 In some cases, the mass destruction of the supporting bone gives the impression described as “teeth floating in the air,”3 as it was noticed in our first patient. Whereas the clinical and epidemiologic features of the endemic and sporadic forms of BL differ in many respects, the histopathology is similar in both, representing the unifying feature of the disease.11 All subtypes of BL are histologically identical. The microscope picture is characterized by a diffuse monotonous pattern of infiltration composed of medium-sized B-cells with basophilic cytoplasm and numerous mitotic figures. Since the tumor cells are frequently interspersed with tanglible-body macrophages, a starry-sky appearance is usually demonstrated.2,3,8 In the past, BL that had been described as small-cell noncleaved type lymphoma included both Burkitt and non-Burkitt variants.12-14 However this morphologic classification was not considered entirely satisfactory because of the subjectivity involved in the interpretation of the tissue futures.15 According to the World Health Organization (WHO) recent classification,2 BL depending on its histomorphology is subdivided into classical BL, which includes 2 variants, the atypical Burkitt/Burkitt-like variant and BL with plasmacytoid differentiation. In the morphologic type of the classical BL, which is observed in endemic and, in a high percentage, in the sporadic forms of BL cases, a starry sky pattern is usually evident and often is prominent.2 The histological picture is due to the presence of benign macrophages among the neoplastic cells. The latter cells, which show a diffuse monotonous pattern of infiltration, have round or oval nuclei, are uniform in
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size or shape, and contain 2 to 5 small nucleoli.2,11 The nuclei of the tumor cells approximate in size those of the admixed starry sky histiocytes.2,15 Among the sporadic cases of BL, the type that had been described under the name of the small noncleaved lymphoma of non-Burkitt’s type, and affected older patients more often than BL does, is considered the prominent histological type of the WHO’s atypical Burkitt/Burkitt-like variant that shows similar cytological features to classic BL but greater nuclear pleomorphism. This variant shows sometimes a less evident starry sky pattern and greater pleomorphism in nuclear size and shape with fewer in number (and occasionally 1 single) more prominent nucleoli.2,11 Another characteristic is that non-Burkitt’s variant is not typically associated with c-myc translocation, which is a constant genetic feature of classical BL.2,11 In our cases the histomorphology of the tumors was more consistent with a classic BL with extensive infiltration of the tissues by monomorphic medium-sized cells with basophilic cytoplasm and numerous mitotic figures. The nuclei of the tumor cells were round with clumped chromatin and relatively clear parachromatin that contained multiple basophilic medium-sized, centrally situated nucleoli (Fig. 2). A starry sky pattern was present, imparted by numerous benign macrophages that had ingested apoptotic tumor cells. In some regions the nuclear diameter of the tumor cells was similar to that of the starry sky histiocytes (Fig. 4). Both of our cases lacked translocations involving the c-myc locus indicating that might represent examples of the non-Burkitt variant. However, translocation involving c-myc in endemic cases is found in approximately 80% of the reported cases.16 The rest, a small proportion of BLs (⬍ 20%) without a c-myc translocation, suggests that, according to some authors, there may be some heterogeneity in the chromosomal abnormalities and possibly molecular genetic mechanisms involved in the pathogenesis of Burkitt lymphoma.16 Immunophenotypically, the tumor cells express membrane immunoglobulin M (IgM) with light chain restriction, CD-20, CD-10, and bcl-6. The cells are negative for CD-5, CD-23, TdT, and bcl-2 as it happened in both of our cases. The expression of CD-10 and bcl-6 points toward a germinal center origin for the tumor cells.2-4,17 In lymph nodes and extranodal tissues, the major differential diagnosis of BL is precursor B lymphoblastic leukemia/lymphoblastic lymphoma (B-ALL/LBL). Lymphoblastic lymphoma is the only lymphoma that shows nuclear TdT positivity. Also, myeloblastic infiltration (acute myeloid leukemia-“chloroma”) may be distinguished by chloroacetate esterase or antibodies to myeloperoxidase and lysozyme.2 Activation of a cellular oncogene through chromosomal translocations seems to be basic in the
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tumor genesis of BL. The overexpression of oncogene c-myc on chromosome 8 appears to play an important role in pathogenesis. This overexpression is produced by the translocation between c-myc gene and one of the heavy immunoglobulin chain loci.4,5,16,18-20 Cory21 studied these mutations and identified 3 translocation breakpoints on chromosome 8: (1) within the c-myc gene, (2) immediately to the 5= side of the gene, and (3) distant from the gene. The switch (S) regions were the recombination targets inside the heavy chain gene cluster area in over 80% of cases. The most common translocation is the t(8;14) in 80% of cases, the t(8;2) in 15% of cases, and the t(8;22) in 5% of cases.4,5,16,20,22 Furthermore, in all translocations the c-myc locus on the normal chromosome is silent, whereas c-myc on the translocated chromosome is expressed at high levels. Although the involvement of chromosome 8 is extremely common, there are several reports indicating other chromosomal abnormalities associated with BL. Thus, trisomy of chromosomes 7, 12, 18, 20, and 21 has been documented.2,16,20 Additionally, Lones et al.16 found that in 84% of cases of BL the tumor cells carried more than 1 mutation. Surprisingly, in the same study 1 of 19 patients with BL had a normal karyotype. As far as our first case is concerned, the patient demonstrated a deletion on chromosome 1, without having any other chromosome abnormalities, including chromosome 8. Abnormalities on chromosome 1, such as duplication, associated with BL were reported in the past.16,20 To the best of our knowledge this is the first case of BL demonstrating only a deletion of the long arm of chromosome 1, without any other accompanying chromosomal aberrations. Previous studies have demonstrated that this lost part of the long arm of chromosome 1 either harbors or may be a candidate area for localization of some important tumor suppressor genes. Thus, human malignant melanoma metastases suppressor gene KiSS-1 is localized at 1q32 area,23 whereas the tumor suppressor gene MDA 7/IL-24, which induces apoptosis in human lung, pancreatic, breast, colorectal, and prostate cancer cells as well as melanoma cells is localized in 1q31-32 region.24 Furthermore, a number of studies have shown that both 1q31-32 as well as 1q21-23 regions may harbor putative tumor suppressor genes that may play an important role in the tumorigenesis in a subset of insulinomas25 and correlate with aggressive growth of gastrinomas and postoperative development of liver metastases.26 Other studies on anaplastic thyroid carcinomas and medulloblastomas showed an allelic loss at 1q31-32 and 1q32-43 regions, whereas the hyperparathyroidism-jaw tumor syndrome (HPT-JT) locus has been found within 1q25-q31 region.27,28 These data may indicate that although the c-myc mutation is basic, some other additional chromo-
somal changes might play a role in the development of the disease. Although EBV is related to all subtypes of BL, it is well known that it is present in 90% to 95% of cases of eBL and only in 15% of cases of sBL.3,4,7,8,10,29 The virus colonizes the B-cells and manages to stimulate B-cell proliferation and prevent cell apoptosis. This new genetic environment seems to be optimum for the c-myc transformation and further tumor genesis. It is true that EBV by itself is not directly oncogenic but it provides the proliferating environment for the chromosome translocations. The great difference of EBV presence in eBL and sBL is thought to be the result of different socioeconomic and climatic conditions reflected in poor nutrition, zinc deficiency, and some endemic infectious diseases such as malaria.3,30 On the contrary, the existence of 2 different pathways of pathogenesis but 1 identical histological, immunohistochemical, and karyotypic picture seems unnatural. So, as far as the EBV-negative cases are concerned, there must be a partially effective immune control mechanism that reduces the EBV-positive cells in order to prevent the following tumor genesis procedure. Several authors3,30 suggest that if new, more sophisticated and precise techniques are brought to surface it will be possible to detect the EBV footprints even in all negative cells, revealing finally only 1 identical tumor genesis pathway for both eBL and sBL. BL is the fastest growing tumor in humans. It usually doubles its size in about 24 to 28 hours.2,11 If the patient is left without treatment, death is the final outcome within 5 to 6 months. Nevertheless, the prognosis is extremely good if the disease is detected early. It is of great value for BL to be included in the differential diagnosis spectrum in a patient presenting 1 or more of the signs described above.6 Unfortunately, our first patient lost valuable time, being treated for other benign conditions, reducing his chance for early cure to the minimum. Lones et al.16 suggested that the kind of mutation may be associated with the prognosis of the disease. They concluded that chromosome abnormalities such as in 13q32 and partial duplication of 1q chromosome were associated with poor prognosis. Finally, sBL of head and neck area is rare but does exist. Chromosome transformations such as t(8;14) are related to BL. Our first case demonstrated a karyotype that has never been reported in the past {46,XY,del(1)(pterq21:)}. Many steps have to be taken so that the pathogenesis of BL can be disclosed. REFERENCES 1. Burkitt D. A sarcoma involving the jaws in African children. Br J Surg 1958;46:218-21. 2. Diebold J, Jaffe ES, Raphael M, Warnke RA. Burkitt’s lymphoma. In: Jaffe ES, Harris NL, Stein H, Vardiman JW, editors.
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WHO Classification of tumours. Pathology and genetics of tumours of haematopoietic and lymphoid tissues.Lyon: IARC Press; 2001. p. 181-4. Shapira J, Peylan-Ramu N. Burkitt’s lymphoma. Oral Oncol 1998;34:15-23. Banthia V, Jen A, Kacker A. Sporadic Burkitt’s lymphoma of the head and neck in pediatric population. Int J Pediatric Otorhinolaryngol 2003;67:59-65. Pear WS, Ingnarsson S, Steffen D, Munke M, Francke U, Mazin H, et al. Multiple chromosomal rearrangements in a spontaneously arising t(6;7) rat immunocytoma juxrtrapose c-myc and immunoglobulin heavy chain sequences. Proc Natl Acad Sci U S A 1986;83:7376-80. Landesberg R, Yee H, Datikashvili M, Ahmed ANZ. Unilateral mandibular lip anaesthesia as the sole presenting symptom of Burkitt’s lymphoma: Case report and review of the literature. J Oral Maxillofac Surg 2001;59:322-6. Araujo I, Foss HD, Bittencourt A. Expression of Ebstein-Barr virus gene products in Burkitt’s lymphoma in Northeast Brazil. Blood 1996;87:5279-86. Zarbo RJ. Burkitt’s lymphoma. In: Regezi JA, Scuibba JJ, editors. Oral pathology. Clinical pathologic correlations. 3rd ed. Philadelphia: W.B. Saunders Company; 1999. p. 409-11. Durmus E, Oz G, Guler N, Aunduk M, Caliskan U, Blanchaert RH. Intraosseous mandibular lesion. J Oral Maxillofac Surg 2003;61:246-9. Yih WY, Myers SL, Meshul CK, Bartley MH. African Burkitt’s lymphoma: case report and light and electron microscopic findings. Oral Surg Oral Med Oral Pathol 1990;70:760-4. Ioachim HL, Ratech H, editors. Ioachim’s lymph node pathology. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2002. p. 428-34. Berard CW, O’Conor GT, Thomas LB. Histo-pathological definition of Burkitt’s tumour. Bull World Health Organ 1969;40:601-7. Miliauskas JR, Berard CW, Young RC, Garvin AJ, Edwards BK, De Vita VT Jr. Undifferentiared non-Hodgkin’s lymphomas (Burkitt’s and non- Burkitt’s types). The relevance of making this histologic distinction. Cancer 1982;50:2115-21. Levine AM, Pavlova Z, Pockros AW, Parker JW, Teitelbaum AH, Paganini-Hill A, et al. Small, noncleaved follicular center cell (FCC) lymphoma: Burkitt and non-Burkitt variants in the United States. I. Clinical features. Cancer 1983;52:1073-9. McClatchey KD, Schnitzer B. Lymphoreticular disorders of the head and neck. In: Thawley SE, Pahje WR, editors. Comprehensive management of head and neck tumors. Philadelphia: W.B. Saunders Co; 1999. p. 1903-17. Lones MA, Sanger WG, Le Beau MM, Heerema NA, Sposto R, Perkins SL, et al. Chromosome abnormalities may correlate with prognosis in Burkitt/Burkitt like lymphomas of children and adolescents. A report from Children’s cancer group study CCGE08. J Pediatr Hematol Oncol 2004;26:169-78. Sandlund JT, Gorban ZI, Berard CW, Sixbey J, Razzouk B,
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Talalayev AG, et al. Large proportion of Epstein-Barr virus-associated small noncleaved cell lymphomas among children with non-Hodgkin’s lymphoma at a single institution in Moscow, Russia. Am J Clin Oncol 1999;22:523-9. Hecht JL, Aster JC. Molecular biology of Burkitt’s lymphoma. J Clin Oncol 2000;18:3707-21. Takada K. Role of Epstein-Barr virus in Burkitt’s lymphoma. Curr Topics Microbiol Immunol 2001;258:141-51. Bauer GP, Volk MS, Siddiqui SY, Brecher ML, Brodsky LS, Stanievich JF, et al. Burkitt’s lymphoma of the parapharyngeal space. Arch Otolaryngol Head Neck Surg 1993;119:117-20. Cory S. Activation of cellular oncogenes in hemopoietic cells by chromosome translocation. Adv Cancer Res 1986;47:189-234. Kornblau SM. Chromosomal abnormality in adult non-endemic Burkitt’s lymphoma and leukemia. Hematol Oncol 1991;9:63-6. West A, Vojta PJ, Welch DR, Welch DR, Weissman BE. Chromosome localization and genomic structure of the KiSS-1 metastasis suppressor gene (KISSI). Genomics 1998;54:145-8. Huang EY, Madireddi MT, Gopalkrishnan RV, Leszczyniecka M, Su Z, Lebedeva IV, et al. Genomic structure, chromosomal localization and expression profile of a novel melanoma differentiation associated (mda-7) gene with cancer specific growth suppressing and apoptosis inducing properties. Oncogene 2001;20:7051-63. Yang YM, Liu TH, Chen YJ, Jiang WJ, Qian JM, Lu X, et al. Chromosome 1q loss of heterozygosity frequently occurs in sporadic insulinomas and is associated with tumor malignancy. Int J Cancer 2005;1172:234-40. Chen YJ, Vortmeyer A, Zhuang Z, Gibril F, Jensen RT. Loss of Heterozygosity of chromosome 1q in Gastrinomas. Cancer Res 2003;63:817-23. Kitamura Y, Shimizu K, Tanaka S, Ito K, Emi M. Allelotyping of anaplastic thyroid carcinoma: frequent allelic losses on 1q, 9p, 11, 17, 19p, and 22q. Genes Chromosomes Cancer 2000;27: 244-51. Hobbs MR, Pole AR, Pidwirny G, Rosen IB, Zarbo RJ, Coon H, et al. Hyperparathroidism–jaw tumor syndrome: the HRPT2 locus is within a 0.7-cM region on chromosome 1q. Am J Hum Genet 1999;64:518-25. Magrath IT. Malignant non-Hodgkin’s lymphomas in children. In: Pizzo PA, Poplack DG, editors. Principles and practice of paediatric oncology. 2nd ed. Philadelphia: JB Lippincott; 1993. p. 537-75. Razzouk BI, Srinivas S, Sample CE, Singh V, Sixbey W. Ebstein-Barr virus DNA recombination and loss in sporadic Burkitt’s lymphoma. J Infect Dis 1996;173:529-35.
Reprint requests: Ioannis Dimitrakopoulos, DDS, MD Pavlou Mela 28 Street, 54351 Thessaloniki, Greece, [email protected]
(Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103:e42-e47)
Burkitt’s lymphoma (BL) is a high-grade non-Hodgkin lymphoma (NHL) of B-cell origin. It was first described by Dennis Burkitt in Uganda in 1958 as a jaw sarcoma occurring at a high frequency in African children.1 It accounts for 3% to 5% of all lymphomas and 40% of NHL in children.2,3 There are 3 clinical variants of BL, each manifesting differences in clinical presentation, morphology, and biology of BL: the endemic (eBL) or African, the sporadic (sBL) or American, and the human immunodeficiency virus–related BL (HIVBL). The eBL appears primarily but not exclusively in equatorial Africa. The sBL affects mostly white people throughout the world, but especially people in northern America and Europe.2 The annual incidence of BL is low, 1% to 10% of all lymphomas in western countries and 20 to 40 times lower than in Africa and northern Brazil.3 Translocation involving MYC is a constant genetic feature, whereas Epstein-Barr virus (EBV) is found in a variable proportion of cases.2-5 In this article we present 2 cases of BL affecting the head and neck areas of 2 white boys. One of them exhibited loss of the long arm of chromosome 1, which, to our knowledge, has never been reported in the international literature. CASE 1 A 14-year-old white boy was referred to our clinic for evaluation of a rapidly enlarging painful swelling on the right side of his face. Twenty days before admission the patient had experienced an intermittent pain on his a
Oral and Maxillofacial Surgeon, Associate Professor, Oral and Maxillofacial Surgery Clinic, Aristotle University of Thessaloniki. b Oral and Maxillofacial Surgeon, Oral and Maxillofacial Surgery Clinic, Aristotle University of Thessaloniki. c Biologist, Laboratory of Biology, Medical School of Aristotle University of Thessaloniki. d Pathologist Specialist, Department of Pathology, General Hospital “G. Papanikolaou.” e Hematologist, Director, Laboratory of Hematology, General Hospital “G. Papanikolaou.” Received for publication Feb 1, 2006; returned for revision Aug 10, 2006; accepted for publication Aug 15, 2006. 1079-2104/$ - see front matter © 2007 Mosby, Inc. All rights reserved. doi:10.1016/j.tripleo.2006.08.011
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right maxilla and a slight swelling of his face in the same area. The family’s dentist diagnosed a maxillary alveolar abscess and prescribed amoxicillin. He also recommended drainage, which was performed 1 day after, but no pus was drained. However, since the swelling increased rapidly in size and the upper teeth of the affected side became loose the patient was referred to us for further evaluation. The patient’s past medical history was unremarkable. He only reported episodes of intermittent paresthesia of the right side of his tongue and the right half of the lower lip over the preceding week. The extraoral examination revealed a painless and firm in consistency swelling over the anterolateral surface of the right maxilla with slight proptosis of the right eye. The intraoral examination demonstrated a diffuse expansion of both the right buccal and palatal maxillary cortical plates, which were not tender to palpation. The overlying mucosa was intact and bluish red in color. The teeth of the affected side (teeth 13 to 17) were loose and displaced; the patient was not able to close his mouth. Regional lymph nodes were not palpable. The radiographic examination disclosed opacification of the right maxillary sinus, which was filled with a soft tissue mass. The antral walls were ill defined. Computed tomography (CT) revealed a contrast-enhancing destructive mass within the right maxillary antrum, extending to palatal and buccal soft tissues. The mass, which also involved the right orbit, was occupying the ipsilateral infratemporal and pterygomandibular space (Fig. 1). Under local anesthesia an intraoral biopsy was performed. The microscopic examination showed that the submucosal tissue was extensively infiltrated by monomorphic medium-sized cells with basophilic cytoplasm and numerous mitotic figures. The nuclei were round with clumped chromatin and relatively clear parachromatin, and contained multiple basophilic medium-sized, centrally situated nucleoli (Fig. 2). A “starry sky” pattern was present, imparted by numerous benign macrophages that had ingested apoptotic tumor cells. Immunohistochemical staining of the tumor cells showed positive expression to CD-20, CD-10, and bcl-6 and negative to CD-3, CD-5, CD-23, TdT, and bcl-2. A very high growth
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Fig. 1. Axial CT. The tumor is marked. Notice the occupation of the whole sinus and the infiltration of the orbital floor.
Fig. 2. A diffuse monotonous pattern of infiltration composed of medium-sized cells with basophilic cytoplasm and numerous mitotic figures (hematoxylin and eosin [HE] ⫻100).
fraction was observed: nearly 100% of the cells were positive for Ki-67. A diagnosis of Burkitt lymphoma was made. CT examination of the neck, chest, and abdomen did not reveal any pathological alteration such as hepatosplenomegaly or lymphadenopathy. EBV antibodies were not detected in the patient’s serum. The results of routine blood and urine investigations were within normal limits. Examination of the cerebrospinal fluid was within normal limits. Bone marrow biopsy was also negative for any pathology. Chromosome analysis was carried out using the G-banding technique. The patient was found to have a deletion in chromosome 1 that involved loss of the long arm after the band 1q21. The remaining chromosome consisted of its entire short and part of the long arm lying between the
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centromere and band 1q21. This structural chromosomal anomaly can be described as 46, XY, del (1) (pterq21:) (Fig. 3). The patient was referred to the hematology/oncology department of our hospital for further evaluation and treatment. A combination of chemotherapy including cytoxan, prednisone, vincristine, and methotrexate was applied. The patient showed a satisfactory response to the treatment. His condition improved rapidly after chemotherapy. The facial swelling subsided and the teeth became less mobile. Seven weeks later the patient presented with hoarse voice, productive cough, fever up to 38°C, and left facial nerve paresis. The examination of his cerebrospinal fluid revealed the presence of lymphoblasts and infiltration of the central nervous system. A new chemotherapy protocol was used (vincristine, adriamycin, dexamethasone [VAD]) with concurrent lumbar infusion of cytotoxic agents, twice a week, for a total of 10. There was a new recurrence in the next 2 months and radiotherapy of the cranial vault and facial skeleton was performed. The patient finally died from the disease 6 months after the initial diagnosis. CASE 2 An 18-year-old white boy was referred to our clinic for evaluation of an enlarging swelling of his right neck, which had been noticed 20 days earlier. The medical history of the patient revealed that he had suffered from EBV infection 10 years earlier. The physical examination was normal. The clinical evaluation of the mouth, face, and jaws was also normal. The clinical examination of the neck showed a scleroelastic, slightly painful mass, sized 5 ⫻ 7 cm. It occupied a space inferior/medial to the right mandibular angle and anterior to the anterior edge of the sternocleidomastoid muscle. The CT showed an en-block mass of enlarged lymph nodes on the right superior jugular lymph node chain and other enlarged, but smaller than the first ones, lymph nodes on the right anterior and posterior neck triangles as well as on the left anterior neck triangle. Under general anesthesia an excisional biopsy of 2 lymph nodes was performed. The en-block mass had no well-defined borders. The histological examination showed the same findings as the previous report with most prominent starry sky pattern, revealing BL (Figs. 4 and 5). EBV antibodies were detected in the patient’s serum. Chromosome analysis of cultured peripheral blood cells using G-banding technique showed no abnormalities. The patient’s karyotype was normal (46, XY). The patient was referred to the hematology/oncology department for further investigation. The patient died from the disease 7 months after the initial diagnosis.
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Fig. 3. Karyotype of case 1. The deletion of the long arm of chromosome 1 is marked.
Fig. 4. A starry sky pattern is noticed imparted by numerous benign macrophages that had ingested apoptotic tumor cells. The nuclear diameter of the tumor cells is similar to that of the starry sky histiocytesy (lower right area) (HE ⫻400).
DISCUSSION BL is a highly aggressive lymphoma often presenting at extranodal sites or as an acute leukaemia.2,6 The features of the tumor cells and their origin, as well as the prognostic profile of the disease are similar for all patients worldwide. On the contrary, the clinical manifestations of eBL differ from those of sBL. The eBL affects small children at the peak age from 5 to 7 years old and is characterized by jaw tumors in more than
Fig. 5. Immunohistochemical staining of the tumor cells showing positive expression to CD-20.
60% of cases.7 The younger the child, the higher the incidence of jaw involvement, reaching 100% at the age of 3 years old. The maxilla is affected twice as often as the mandible. Paraplegia involving central nervous system infiltration is the prevailing symptom in 35% of cases of the eBL type.8 The peak age of sBL is, however, between 10 and 12 years old.9 The male-tofemale ratio varies between 2:1 and 6.5:1 and is much higher in patients younger than 12 years old.8 It occurs most frequently in white people. Black patients account
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for only 5% of the sBL population. The terminal ileum, the cervical lymph nodes, and the bone marrow are the most frequently involved sites. Cervical lymphadenopathy is present in 16% and the jaw is affected in only 6% to 8% of the cases.4 Perioral anesthesia and localized disease in only 1 quadrant of the mouth are also characteristic features of sBL.9 Clinical signs and symptoms of BL involving the jaws include facial swelling, alveolar and gingival enlargement, mobile teeth, toothache, oral masses, jaw pain, and paresthesia. Toothache is the most common symptom in eBL and is the chief complaint in 90% of adults.8 This unique feature is explained by the infiltration of the tooth pulp by the tumor cells through the apex. In eBL the tumor most commonly involves all 4 quadrants and in 83% of cases infiltrates more than 1 quadrant.10 Maxillary tumors may produce proptosis of the ipsilateral eye. Our first case did appear with these signs but the treatment was delayed because of improper diagnosis. Radiographic findings include osteolytic lesions. Loss of the lamina dura and widening of the periodontal ligament are frequent signs. As the tumor enlarges the teeth and tooth buds are displaced.6,9 In some cases, the mass destruction of the supporting bone gives the impression described as “teeth floating in the air,”3 as it was noticed in our first patient. Whereas the clinical and epidemiologic features of the endemic and sporadic forms of BL differ in many respects, the histopathology is similar in both, representing the unifying feature of the disease.11 All subtypes of BL are histologically identical. The microscope picture is characterized by a diffuse monotonous pattern of infiltration composed of medium-sized B-cells with basophilic cytoplasm and numerous mitotic figures. Since the tumor cells are frequently interspersed with tanglible-body macrophages, a starry-sky appearance is usually demonstrated.2,3,8 In the past, BL that had been described as small-cell noncleaved type lymphoma included both Burkitt and non-Burkitt variants.12-14 However this morphologic classification was not considered entirely satisfactory because of the subjectivity involved in the interpretation of the tissue futures.15 According to the World Health Organization (WHO) recent classification,2 BL depending on its histomorphology is subdivided into classical BL, which includes 2 variants, the atypical Burkitt/Burkitt-like variant and BL with plasmacytoid differentiation. In the morphologic type of the classical BL, which is observed in endemic and, in a high percentage, in the sporadic forms of BL cases, a starry sky pattern is usually evident and often is prominent.2 The histological picture is due to the presence of benign macrophages among the neoplastic cells. The latter cells, which show a diffuse monotonous pattern of infiltration, have round or oval nuclei, are uniform in
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size or shape, and contain 2 to 5 small nucleoli.2,11 The nuclei of the tumor cells approximate in size those of the admixed starry sky histiocytes.2,15 Among the sporadic cases of BL, the type that had been described under the name of the small noncleaved lymphoma of non-Burkitt’s type, and affected older patients more often than BL does, is considered the prominent histological type of the WHO’s atypical Burkitt/Burkitt-like variant that shows similar cytological features to classic BL but greater nuclear pleomorphism. This variant shows sometimes a less evident starry sky pattern and greater pleomorphism in nuclear size and shape with fewer in number (and occasionally 1 single) more prominent nucleoli.2,11 Another characteristic is that non-Burkitt’s variant is not typically associated with c-myc translocation, which is a constant genetic feature of classical BL.2,11 In our cases the histomorphology of the tumors was more consistent with a classic BL with extensive infiltration of the tissues by monomorphic medium-sized cells with basophilic cytoplasm and numerous mitotic figures. The nuclei of the tumor cells were round with clumped chromatin and relatively clear parachromatin that contained multiple basophilic medium-sized, centrally situated nucleoli (Fig. 2). A starry sky pattern was present, imparted by numerous benign macrophages that had ingested apoptotic tumor cells. In some regions the nuclear diameter of the tumor cells was similar to that of the starry sky histiocytes (Fig. 4). Both of our cases lacked translocations involving the c-myc locus indicating that might represent examples of the non-Burkitt variant. However, translocation involving c-myc in endemic cases is found in approximately 80% of the reported cases.16 The rest, a small proportion of BLs (⬍ 20%) without a c-myc translocation, suggests that, according to some authors, there may be some heterogeneity in the chromosomal abnormalities and possibly molecular genetic mechanisms involved in the pathogenesis of Burkitt lymphoma.16 Immunophenotypically, the tumor cells express membrane immunoglobulin M (IgM) with light chain restriction, CD-20, CD-10, and bcl-6. The cells are negative for CD-5, CD-23, TdT, and bcl-2 as it happened in both of our cases. The expression of CD-10 and bcl-6 points toward a germinal center origin for the tumor cells.2-4,17 In lymph nodes and extranodal tissues, the major differential diagnosis of BL is precursor B lymphoblastic leukemia/lymphoblastic lymphoma (B-ALL/LBL). Lymphoblastic lymphoma is the only lymphoma that shows nuclear TdT positivity. Also, myeloblastic infiltration (acute myeloid leukemia-“chloroma”) may be distinguished by chloroacetate esterase or antibodies to myeloperoxidase and lysozyme.2 Activation of a cellular oncogene through chromosomal translocations seems to be basic in the
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tumor genesis of BL. The overexpression of oncogene c-myc on chromosome 8 appears to play an important role in pathogenesis. This overexpression is produced by the translocation between c-myc gene and one of the heavy immunoglobulin chain loci.4,5,16,18-20 Cory21 studied these mutations and identified 3 translocation breakpoints on chromosome 8: (1) within the c-myc gene, (2) immediately to the 5= side of the gene, and (3) distant from the gene. The switch (S) regions were the recombination targets inside the heavy chain gene cluster area in over 80% of cases. The most common translocation is the t(8;14) in 80% of cases, the t(8;2) in 15% of cases, and the t(8;22) in 5% of cases.4,5,16,20,22 Furthermore, in all translocations the c-myc locus on the normal chromosome is silent, whereas c-myc on the translocated chromosome is expressed at high levels. Although the involvement of chromosome 8 is extremely common, there are several reports indicating other chromosomal abnormalities associated with BL. Thus, trisomy of chromosomes 7, 12, 18, 20, and 21 has been documented.2,16,20 Additionally, Lones et al.16 found that in 84% of cases of BL the tumor cells carried more than 1 mutation. Surprisingly, in the same study 1 of 19 patients with BL had a normal karyotype. As far as our first case is concerned, the patient demonstrated a deletion on chromosome 1, without having any other chromosome abnormalities, including chromosome 8. Abnormalities on chromosome 1, such as duplication, associated with BL were reported in the past.16,20 To the best of our knowledge this is the first case of BL demonstrating only a deletion of the long arm of chromosome 1, without any other accompanying chromosomal aberrations. Previous studies have demonstrated that this lost part of the long arm of chromosome 1 either harbors or may be a candidate area for localization of some important tumor suppressor genes. Thus, human malignant melanoma metastases suppressor gene KiSS-1 is localized at 1q32 area,23 whereas the tumor suppressor gene MDA 7/IL-24, which induces apoptosis in human lung, pancreatic, breast, colorectal, and prostate cancer cells as well as melanoma cells is localized in 1q31-32 region.24 Furthermore, a number of studies have shown that both 1q31-32 as well as 1q21-23 regions may harbor putative tumor suppressor genes that may play an important role in the tumorigenesis in a subset of insulinomas25 and correlate with aggressive growth of gastrinomas and postoperative development of liver metastases.26 Other studies on anaplastic thyroid carcinomas and medulloblastomas showed an allelic loss at 1q31-32 and 1q32-43 regions, whereas the hyperparathyroidism-jaw tumor syndrome (HPT-JT) locus has been found within 1q25-q31 region.27,28 These data may indicate that although the c-myc mutation is basic, some other additional chromo-
somal changes might play a role in the development of the disease. Although EBV is related to all subtypes of BL, it is well known that it is present in 90% to 95% of cases of eBL and only in 15% of cases of sBL.3,4,7,8,10,29 The virus colonizes the B-cells and manages to stimulate B-cell proliferation and prevent cell apoptosis. This new genetic environment seems to be optimum for the c-myc transformation and further tumor genesis. It is true that EBV by itself is not directly oncogenic but it provides the proliferating environment for the chromosome translocations. The great difference of EBV presence in eBL and sBL is thought to be the result of different socioeconomic and climatic conditions reflected in poor nutrition, zinc deficiency, and some endemic infectious diseases such as malaria.3,30 On the contrary, the existence of 2 different pathways of pathogenesis but 1 identical histological, immunohistochemical, and karyotypic picture seems unnatural. So, as far as the EBV-negative cases are concerned, there must be a partially effective immune control mechanism that reduces the EBV-positive cells in order to prevent the following tumor genesis procedure. Several authors3,30 suggest that if new, more sophisticated and precise techniques are brought to surface it will be possible to detect the EBV footprints even in all negative cells, revealing finally only 1 identical tumor genesis pathway for both eBL and sBL. BL is the fastest growing tumor in humans. It usually doubles its size in about 24 to 28 hours.2,11 If the patient is left without treatment, death is the final outcome within 5 to 6 months. Nevertheless, the prognosis is extremely good if the disease is detected early. It is of great value for BL to be included in the differential diagnosis spectrum in a patient presenting 1 or more of the signs described above.6 Unfortunately, our first patient lost valuable time, being treated for other benign conditions, reducing his chance for early cure to the minimum. Lones et al.16 suggested that the kind of mutation may be associated with the prognosis of the disease. They concluded that chromosome abnormalities such as in 13q32 and partial duplication of 1q chromosome were associated with poor prognosis. Finally, sBL of head and neck area is rare but does exist. Chromosome transformations such as t(8;14) are related to BL. Our first case demonstrated a karyotype that has never been reported in the past {46,XY,del(1)(pterq21:)}. Many steps have to be taken so that the pathogenesis of BL can be disclosed. REFERENCES 1. Burkitt D. A sarcoma involving the jaws in African children. Br J Surg 1958;46:218-21. 2. Diebold J, Jaffe ES, Raphael M, Warnke RA. Burkitt’s lymphoma. In: Jaffe ES, Harris NL, Stein H, Vardiman JW, editors.
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