| | Sporadic Burkitt's lymphoma of the head and neck in the pediatric populationReceived 25 June 2002; received in revised form 6 August 2002; accepted 7 August 2002. Abstract Burkitt's lymphoma (BL) is one of the fastest growing malignancies in the pediatric population in the United States. BL is a high-grade B-cell Non-Hodgkin's lymphoma (NHL) which exists in endemic, sporadic, and human immunodeficiency-associated subtypes. The African, or endemic, variant usually involves the maxilla and other facial bones while head and neck manifestations in non-endemic BL are rare. We present three unusual present ations of sporadic BL stemming from Waldeyer's ring and the orbit. The clinical and pathologic features of BL are reviewed.
1. Introduction  In 1958, Dennis Burkitt pioneered the association of viruses and cancer in humans with his observations of lymphomatous tumors in the jaws of schoolchildren in equatorial Africa [1]. The Epstein–Barr virus (EBV), a human B lymphotrophic herpes virus, is strongly associated with nasopharyngeal carcinomas as well as with these tumors now known as the endemic form of Burkitt's lymphoma (BL) found in East Africa. BL is a high-grade non-Hodgkin's lymphoma (NHL) of B-cell origin and has been found to occur worldwide as one of three closely related forms. Histologically similar cases of BL occurring outside Africa include the sporadic (or American) form and the AIDS-associated subtype which occurs in the setting of human immunodeficiency virus infection. All forms of the disease are characterized by chromosomal rearrangements involving the c-myc proto-oncogene which result in its inappropriate expression. Burkitt's lymphoma is one of the most aggressive malignancies of lymphoid origin and accounts for 3–5% of all lymphomas. Usually found in the pediatric population, BL represents 40% of childhood NHL [2]. The highest incidence (50–100 cases per million) is found in the endemic form in equatorial regions of Africa and Papua-New Guinea where it accounts for 50–70% of all pediatric malignancies [3]. Found largely in the US and in Europe, sporadic BL is rare with an associated incidence of 2–3 cases per million [4]. Sporadic BL usually involves the abdomen but its presentation in the head and neck region is relatively rare. In a report from Texas Children's hospital three out of 13 patients with sporadic BL had head and neck involvement [5]. Herein we describe three uncommon presentations of sporadic BL arising from Waldeyer's ring and the orbit. 2. Case presentations 2.1. Case 1 An 8 year-old male presented with a 2-week history of a progressive nasal obstruction and hyponasal speech. The patient was otherwise well without symptoms of fevers, weight loss, and night sweats. Complete physical examination revealed a large nasopharyngeal mass. There was no lymphadenopathy or hepatosplenomegaly. A CT scan revealed an 8.5×5.0 cm nasopharyngeal mass obliterating the nasopharynx. The patient underwent an open biopsy of the nasopharyngeal mass which revealed a diffuse sheet of intermediate-sized monomorphous cells amidst macrophages in a ‘starry sky’ pattern consistent with BL. The patient then underwent an extent of disease evaluation. CT scans of the chest and abdomen were normal. Total body PET scanning was consistent with disease localized to the nasopharynx. Bone marrow biopsy and lumbar puncture were negative. The patient underwent several cycles of chemotherapy with cyclophosphamide, vincristine, doxorubicin, methotrexate, and intrathecal cytarabine. He is currently well and disease-free after 3 years. 2.2. Case 2 A 6 year-old female presented with progressive right facial and orbital swelling with loss of vision in the right eye. She was without constitutional symptoms. A complete physical examination was remarkable for a mass involving the right orbit, maxilla, and hard palate with intact mucosa. There was no lymphadenopathy or hepatosplenomegaly. An MRI of the head and neck confirmed the findings (Fig. 1, Fig. 2). The patient underwent an endonasal biopsy of the mass which revealed a sheet of monomorphic cells interspersed with macrophages consistent with Burkitt's lymphoma. The patient then underwent an extent of disease evaluation with CT scans of the chest and abdomen, total body PET scanning, lumbar puncture, and bone marrow evaluation. Findings were consistent with disease localized to the above described areas. Immunogenetic analysis revealed cells bearing the t (8;14) translocation. The patient is currently undergoing chemotherapy with cyclophosphamide, vincristine, doxorubicin, methotrexate, and intrathecal cytarabine. 2.3. Case 3 A 14 year-old male presented with a right tonsillar mass increasing in size during a 2-week period and associated with mild dysphagia. The patient denied constitutional symptoms. Examination revealed a large right non-tender tonsillar mass with an area of mucosal ulceration (Fig. 3). There was no palpable lymphadenopathy and no hepatosplenomegaly. A CT scan showed a large mass arising from the right tonsil and an enlarged right jugulodiagastric lymph node (Fig. 4). The patient underwent an open biopsy of the right tonsil which revealed a monomorphic cellular pattern interspersed with pale macrophages in a ‘starry sky’ pattern suggestive of a BL (Fig. 5, Fig. 6). The patient then underwent an extent of disease work-up with lumbar puncture, bone marrow examination, and MRI and PET scanning. Findings were consistent with disease localized to the head and neck. The mass was significantly reduced with just one cycle of cyclophosphamide, vincristine, doxorubicin, methotrexate, and intrathecal cytarabine. The patient, however, is currently completing his treatment course. 3. Discussion Although the diagnostic category of Burkitt's lymphoma encompasses a group of related tumors of lymphoid origin, the differences in the clinicopathologic features of endemic and non-endemic BL merit discussion. Endemic BL is diagnosed at an average age of 9 years and frequently involves the jaw (60–80% of cases) and other facial bones and less commonly involves the abdomen and bone marrow [6]. Endemic BL is virtually always associated with the EBV as positive titers are found in over 90% of cases [7]. In contrast, sporadic BL is associated with slightly older children (average age 12.2 years) and usually presents in the abdomen often involving the terminal ileum, cecum, and/or mesentery [8]. Only approximately one quarter of sporadic BL cases involve the head and neck most commonly in the form of cervical lymphadenopathy which is rarely found in endemic BL. Jaw as well as other facial bone involvement has been reported but is infrequent. In adults, BL occurs mainly in the setting of HIV infection. Although accounting for less than 1% of adult NHL, BL has been reportedly found in as many as 35% of HIV-associated NHL cases [8]. Like sporadic BL, the HIV-associated variant often involves the GI tract and reportedly afflicts the bone marrow in 30% of cases. Unlike in endemic BL, EBV titers are elevated in both sporadic and HIV-associated forms in only 20 and 30% of cases, respectively [9], [10]. Common to all forms of BL, central nervous system involvement has been found in 20–30% of cases [11]. Table 1 tabulates the notable characteristics of BL variants. Both endemic and non-endemic BL usually present as painless masses although clinical symptoms may vary depending upon the site of involvement. In the head and neck region, patients present with signs and symptoms nasal obstruction, facial swelling, unilateral tonsillar enlargement and cervical lympadenopathy. Patients with nasopharyngeal involvement may present with otitis media and hyponasal speech. Imaging modalities with CT and MRI can help determine the extent of primary disease while a total body extent of disease work-up should include PET scans and evaluation of the bone marrow and cerebrospinal fluid. The least invasive procedure should be pursued expeditiously in establishing a diagnosis. Associated with a cell doubling time of 24–26 h, BL ranks amongst the fastest growing of all human tumors and mandates prompt intervention [10]. 3.1. Histopathology Histopathologically, all variants of BL are characterized by sheets of small- to medium-sized monomorphic lymphoid cells with prominent basophilic cytoplasm. Nuclei are round and harbor coarse chromatin. Cells are usually interspersed with scattered benign macrophages containing cellular debris from apoptotic neoplastic cells, yielding a classic ‘starry sky’ appearance when examined under low power magnification [12]. Consistent with a rapid growth pattern, mitotic figures are abundant. Immunophenotypically, BL is a B cell lymphoma expressing cell surface immunoglobulins or B-cell lineage markers including CD19, CD20, CD22, CD74, CD79a, and CD10. Additionally expressed are cell surface Ig heavy chains-most commonly IgM-and either kappa or lambda light chains [13]. 3.2. Molecular and viral pathogenesis 3.2.1. c-myc overexpression At the molecular level, BL is characterized by a translocation between c-myc on chromosome 8 and 1 of the three immunoglobulin chain loci. These translocations occur with a respective frequency of 80, 15, and 5% with chromosomes 14, 2, and 22. The 8q24 locus encodes the c-myc proto-oncogene while the Ig heavy chain locus is on chromosome 14 and the light chains kappa and lambda on chromosomes 2 and 22, respectively [14]. These translocations result in the deregulation of c-myc ultimately yielding its constitutive expression. Hence, overexpression of c-myc appears central to the pathogenesis of BL. Distinct translocation patterns may exist between endemic and sporadic Burkitt's lymphoma. Sporadic cases typically carry translocations involving sequences within or close to c-myc on chromosome 8 and sequences within or near the immunoglobulin heavy chain S region on chromosome 14. In contrast, endemic BL is associated with a translocation involving sequences on chromosome 8 further upstream from c-myc and sequences within or near the JH region on chromosome 14 [15]. These points of chromosomal breakage correlate with the stage of differentiation of the involved cells suggesting that sporadic BL derives from cells more advanced along the B-cell differentiation pathway than those of the endemic variant. 3.2.2. Epstein–Barr virus and p53 In addition to translocation events, the molecular pathogenesis of BL also involves EBV infection of tumor cells and p53 inactivation. Although EBV has been associated with BL of all types, its exact role in oncogenesis is not entirely clear. EBV is a human herpes virus which infects most of the world's population subclinically during childhood and thereafter remains in the body. The virus colonizes antibody-producing B cells that serve as ideal sites for residence as they are relatively long-lived. Colonization with EBV and presumably additional genetic events stimulate B cell proliferation and/or inhibit cell apoptosis, thereby optimizing the likelihood for c-myc translocation events and malignant transformation [15], [16]. In the setting of HIV infection, EBV may act as a virulence factor as EBV+HIV-associated BL fares less well clinically and appears morphologically more aggressive with immunoblastic differentiation. As with other tumors associated with p53 tumor suppressor gene mutations, the functional loss of the wild-type p53 gene product may play a role in enhancing the tumorigenicity of BL cells by impairing the host cell's ability to regulate its cycle. Loss or inactivation of the p53 tumor suppressor gene has been detected in 30–40% of BL cases although the rate has been reported to be as high as 60% in HIV-associated BL [17], [18]. 3.3. Treatment The primary therapeutic modality for BL is chemotherapy. As BL is one of the fastest growing tumors with a high mitotic index, neoplastic cells are highly sensitive to cytotoxic agents. As with most cancers, treatment success depends upon the extent of disease. Current chemotherapy regimens in patients with disease limited to the head and neck yield 90% long-term survival [19]. Patients with extensive disease (i.e. involvement of the bone marrow and/or CNS) and those with HIV-associated BL fare less well. The addition of locoregional radiation therapy or surgery, increases morbidity without impacting survival although surgical debulking and the use of radiotherapy to diminish tumor volume have been reported. BL is sensitive to a wide array of chemotherapeutic agents, and clinical experience has shown that combination is superior to single-agent chemotherapy. Because of the high proliferative rate of these tumors and the abundance of cells in various stages of the cell cycle, initiation of successive cycles of treatment imposes greater cytotoxicity than does a traditional fixed-cycle regimen. This approach maximizes dose intensity while minimizing kinetic failures. Furthermore, the use of multiple agents with different mechanisms of action may decrease the chance of drug resistance. Most chemotherapy regimen are Cyclophosphamide based [20]. Currently all patients with BL at our institution receive intrathecal chemoprophylaxis to improve survival as CNS is a common site of relapse of disease [21]. Commonly used chemotherapy cocktails include intravenous cyclophosphamide, vincristine, doxorubicin, methotrexate, and leucovorin rescue with intrathecal cytarabine prophylaxis (CODOX-M) for patients with localized disease [22]. CODOX-M and intravenous ifosfamide, etoposide, and cytarabine (IVAC) (CODOX-M/IVAC) is reserved for patients with extensive disease [22]. The role of steroids is limited to patients treated with certain treatment protocols such as hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD), a high dose-intensive chemotherapy regimen usually used in patients with AIDS related BL [23] or patients with CNS edema or patients with airway compromise. Preoperative steroids may suppress disease (false negative bone marrow or CNS involvement) and may lead to under-staging of disease. 4. Conclusions BL is a NHL of B-cell origin with aggressive growth characteristics that mandate prompt diagnosis and treatment. BL exists as one of three variants (endemic, sporadic, and HIV-associated), and we report herein three cases of sporadic BL with unusual presentations in the head and neck region. 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Cancer. 2002;94(5):1492–1499. Department of Otolaryngology-Head and Neck Surgery, New York-Presbyterian, University Hospitals of Columbia and Cornell, New York, NY, USA  Corresponding author. Present address: 445 E 77th street, Apartment 3B, New York, NY 10021, USA. Tel.: +1-212-746-1485; fax: +1-212-746-2253
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