Abstract
Burkitt’s lymphoma (BL) is a non-Hodgkin Lymphoma (NHL) type fast growing neoplasm of the B-cells and is one of the most common subtypes of paediatric lymphomas. A case of 5 years old female presenting with pain and abnormal teeth mobility in the mandible and swelling of right eye. The initial presentation coincided with multiple organ involvement and urgent referral to Oncology was made. Chemotherapy was initiated and patient was in remission within two months, remains in remission 22 months later. This case reports stresses on dentists and GP recognising signs of abnormal presentations and referring to relevant specialities to ensure early detection and management.
1
Introduction
Burkitt’s lymphoma (BL) is a non-Hodgkin Lymphoma (NHL) type fast growing neoplasm of the B-cells and is one of the most common subtypes of paediatric lymphomas [ ]. Despite its rarity, BL accounts for about 2% of all non-Hodgkin lymphomas, with varying occurrence depending on the subtype [ ]. Burkitt’s lymphoma was first described in 1958, by Dr. Denis Burkitt, who while working in Uganda, noted a high incidence of African children presenting with rapidly growing mandibular tumours [ , ]. Mature B-cell non-Hodgkin lymphomas (B-NHLs) constitute approximately 60% of all paediatric NHL diagnoses and 7% of all paediatric cancers [ ]. Paediatric orofacial tumours studies reveal that BL was the most common malignant lesion, while Ameloblastoma was the commonest benign tumour [ ]. Although rare, Burkitt’s lymphoma affects children more frequently, accounting for 30–50% of paediatric lymphomas in some studies and is more prevalent in males than females [ ]. This review delves into the literature on the oral manifestations of Burkitt’s lymphoma, focusing on various clinical presentations, diagnostic challenges, and management strategies.
Burkitt’s lymphoma exhibits specific chromosomal translocations, most commonly involving the MYC gene [ , ]. A translocation between MYC gene and an immunoglobulin promoter leads to the constitutive expression of MYC and is found in all cases [ ]. BL may present as bony or visceral organ involvement including maxillofacial bones, mediastinum, pelvis, abdomen, kidneys, spleen, ovaries [ , , ]. Bone marrow involvement is quite rare and approximately 20% of patients with BL exhibit sporadic bone marrow involvement. Advanced mature B‐cell NHL (≥25% bone marrow blasts cells and/or central nervous system involvement) is categorised as highly aggressive. BL with bone marrow involvement is classified as stage IV mature B‐cell NHL, while BL with 5%–25% blasts in the bone marrow is classified as Burkitt’s lymphoma with bone marrow involvement [ , ].
Although primarily a haematological disorder, BL presents significant oral manifestations, and have a significant debilitating impact on quality of life [ ]. This rapidly growing malignant tumour with high proliferative potential manifests in three primary subtypes: endemic, sporadic, and immunodeficiency associated [ , ]. Endemic BL primarily occurs in equatorial Africa and is closely linked to Epstein-Barr virus infection (EBV) [ ]. It often manifests in the jaw or facial bones, primarily affecting children. The Epstein – Barr virus (EBV) plays a notable role in the pathogenesis of Burkitt’s Lymphoma, particularly in the endemic form. While the precise mechanism by which EBV contributes to Burkitt’s Lymphoma is complex, it is thought to involve the virus’s ability to inhibit programmed cell death, thereby fostering the survival and proliferation of infected cells [ ]. EBV infection often coincides with a higher incidence of Burkitt’s Lymphoma, highlighting the virus’s influence in specific geographical and environmental settings. Sporadic BL is more commonly found in the western world and typically involved visceral organs such as abdomen, spleen, kidneys, pelvis etc. and may present as an abdominal mass, although involvement of the jaw and facial soft tissues may also be found [ , ]. Immunodeficiency-associated BL primarily affects individuals with immunocompromised conditions, such as HIV/AIDS, and has a propensity of involving extra-nodal sites [ ].
Oral manifestations of Burkitt’s Lymphoma can frequently mimic commonly occurring dental conditions, leading to misdiagnosis, and delaying appropriate treatment [ , , ]. These include gingival or soft tissue swelling, pain, tooth mobility and displacement, and paraesthesia. Facial asymmetry arising from intra-oral or extra-oral swelling may prompt patients to seek dental evaluation [ , ]. The swelling may involve the facial bones, soft tissues such as tongue, oro-pharynx, and gingivae and can progress rapidly [ , ]. This can be mistaken for other odontogenic lesions or infections [ ]. Localized pain is frequently reported and might be due to the tumour infiltration and invasion into dental pulp or alveolar bone, which impacts developing teeth. As the lymphoma progresses, affected teeth may exhibit increasing abnormal tooth mobility secondary to underlying bone and periodontal destruction [ , , ]. Altered sensation or paraesthesia, particularly in areas innervated by the inferior alveolar and mental nerves, is a particularly alarming symptom. While paraesthesia can be a rare presentation, its presence suggests possible nerve involvement by the lymphoma, signalling an advanced stage of disease. When paraesthesia occurs without an apparent cause, especially in a young, fit, and healthy patient, it necessitates further investigation to rule out possible malignancy, including Burkitt’s Lymphoma. Early identification and referral for appropriate oncological assessment can significantly impact prognosis and treatment outcomes. Painful ulcerative lesions may be present, particularly in advanced stages. These lesions are often painful and may resemble aphthous ulcers or other infectious lesions. Changes in the oral mucosa such as localised or diffused erythema, pallor, or the appearance of petechial (which may reflect systemic involvement) [ , ]. Cervical lymphadenopathy is a common finding in BL due to its malignant and invasive nature and may extend into the oral cavity and nasopharynx, causing further swelling and discomfort.
Radiographic examination is a pivotal tool in differentiating Burkitt’s Lymphoma from other conditions [ ]. Typical radiographic features associated with BL include areas of diffuse generalised bone resorption or loss which are crucial in identifying the extent of the disease [ , ]. These radiolucent areas indicate profuse trabecular bone loss, leaving teeth appearing to be ‘floating’. Jaw involvement with Burkitt’s lymphoma is more commonly seen with the endemic form though a case describing “floating teeth”. Historically, “floating teeth” in paediatric patients have been thought to be almost pathognomonic of Langerhans cell histiocytosis, though this finding may also reflect any destructive process in the mandible, including infectious, hematologic, metabolic, or neoplastic aetiology [ ]. Loss of Lamina Dura can mimic periodontal diseases, making imaging an important diagnostic tool. Widening of Periodontal Ligament Space is another diagnostic clue, as it might indicate invasive or malignant processes rather than a localised benign inflammation. Roots of teeth may appear shorter and resorbed and teeth may appear displaced due to lack of bony support. Radiographically, BL causes generalised destruction of crypts of teeth with loss of lamina dura and trabecular pattern in the jaws [ , ] and may present as tumour of the jaws or facial bones with metastatic potential [ ]. A detailed radiographic evaluation, alongside a thorough clinical examination, can help distinguish Burkitt’s Lymphoma from other dental pathologies [ ].
Visceral Involvement include Lymphadenopathy with enlarged cervical or peripheral lymph nodes presenting as painless, rapidly enlarged lymph nodes. Abdominal Symptoms may include constipation, vomiting, nausea, diarrhea, paroxysmal abdominal pain, or distension due to mesenteric or retroperitoneal involvement [ ]. B Symptoms include fever, night sweats, and weight loss may occur but are less common than in other lymphomas [ ]. Other commonly involved regions include the abdomen, cervical or peripheral lymph nodes, neck, mediastinum, and kidneys [ , ]. BL may affect head and neck bones, central nervous system, bowel, ovaries, or other organs Cancer cells in BL can spread to other parts of the body [ , ].
Clinicians often initially suspect common dental ailments when patients present with oral symptoms such as swelling, pain, trismus, leading to potential misdiagnosis [ ]. Diagnosing Burkitt’s lymphoma based solely on oral manifestations poses several challenges [ ] as symptoms can overlap with other conditions, including infections, other malignant or benign odontogenic or non-odontogenic tumours. Consideration of Burkitt’s Lymphoma is essential when assessing acute or persistent, chronic oral lesions, dental pain unresponsive to conventional treatment or increasing abnormal tooth mobility, especially in young and seemingly fit and healthy patients [ , ]. Dentists play a crucial role in identifying of these early signs and symptoms followed by urgent speciality and multidisciplinary team referral. This necessitates a comprehensive clinical evaluation, radiographic investigations, blood tests, biopsy for definitive diagnosis [ , ].
The diagnostic gold standards following thorough physical examination are ultrasounds and CT scans, which serves to narrow down the differential diagnosis [ ]. Diagnosis of BL is a multidisciplinary aspect involving multiple teams. Clinical assessment involving thorough History and physical examination is imperative focusing on lymphadenopathy and organomegaly. Supportive examinations that can be performed include chest X-ray, bone marrow aspiration, CT scan, analysis of cerebrospinal fluid, and lymph node biopsy. Imaging techniques such as ultrasound (particularly for visceral involvement such as spleen, abdomen, and CNS), CT scans or MRI are helpful in assessing the extent of disease. Tissue Biopsy for histological confirmation [ , ] confirms the type and stage of disease. Characteristic histology shows a high proliferation index with starry sky appearance due to macrophage infiltration [ , ]. A bone marrow biopsy may show dense blasts infiltration in the bone marrow consistent with acute leukemia [ ]. Immunophenotyping is another tool which confirms typically positive for CD19, CD20, and CD10, with negative staining for BCL2. Cytogenetics detect MYC translocation with t(8; 14) gene being the most common (18,26,30,31). The neoplasm exhibits aggressive behaviour and moderate prognosis [ ], with early detection and treatment resulting in higher survival rate [ ]. Central Nervous System (CNS) and Cerebrospinal Fluid (CSF) involvement and abnormal blood tests including more than twice the upper limit of Lactate dehydrogenase (LDH) levels in blood denotes poorer prognosis [ , , ].
The management of Burkitt’s lymphoma involves a multidisciplinary approach. Chemotherapy is the first choice in the treatment of BL using doxorubicin, methotrexate, vincristine, cytarabine, prednisone, and cyclophosphamide [ ]. Radiotherapy modalities are not widely used as a treatment option for BL. Chemotherapy can be used as a single therapy or a combination of various forms of therapy. Anticancer drugs generally affect cell division which occurs rapidly [ , , ]. Intensive chemotherapy regimens, often including cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or similar regimens, are standard [ ]. Intensive multi-agent chemotherapy regimens (systemic or intrathecal) are often used due to the aggressive nature of the disease [ ], designed to target the rapidly proliferating cells typical of Burkitt’s Lymphoma. A multi agent regime of the use of etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R) [ , ], a regimen of infused drugs based on in vitro studies showing enhanced tumour-cell killing with prolonged low-concentration drug exposure, as compared with brief, high-concentration exposure [ ]. The therapeutic application of the combination of Galiximab and cytotoxic drugs in the treatment of drug resistant B-cell malignancies [ ] causes cell lysis through antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and apoptosis (cell death). Rituximab has demonstrated efficacy in Burkitt’s disease and is widely used for BL treatment in both paediatric and adult patients (11,28,29]. Monoclonal antibodies and new immunotherapy approaches represent exciting advances for the treatment of this haematological disease. Revolutionary therapies are now possible, and clinical trials could hopefully determine how to best incorporate these new technologies into existing targeted treatment protocols [ , ].
Side effects associated with Chemotherapy treatment include B symptoms (fever, unintentional weight loss, night sweats), along with nausea, vomiting, prolonged bleeding or bruising, generalised fatigue, tiredness, aches, lethargy, flu-like symptoms, headaches, brittle nails, and hair loss [ ]. Ocular involvement may cause conjunctivitis, blurred vision, or photosensitivity. Supportive care, including pain management, oral hygiene maintenance, is vital, particularly in patients experiencing mucositis, oral ulcerations, xerostomia, or mucositis as a side effect of chemotherapy [ ]. Chemotherapy may result in altered kidney and liver function tests along with raised blood uric acid levels. Cardiorespiratory issues may also be faced as a side effect with symptoms of breathlessness, and pneumonia due to immunosuppression [ ]. Effective chemotherapy leads to over 80% event free survival for limited-stage disease. Radiotherapy and immunotherapy have been attempted with varying success [ ].
Regular follow-up is crucial to monitor for disease recurrence or secondary complications, especially involving the oral cavity. Burkitt lymphoma is often very responsive to the currently recommended intensive chemotherapy regimens, and cure rates for this disease remain high [ , , ]. Studies show people who receive prompt medical treatment have higher rates of remission [ , ]. Omoregie et al. [ ], describe the prevalence and differential diagnosis of benign and malignant tumours of the jaw with characteristic radiographic presentations that may mimic BL. These include Ameloblastoma, Odontogenic fibromyoma, Peripheral odontogenic fibroma, Fibrous dysplasia, Granular cell tumour, Central giant cell granuloma, Squamous cell carcinoma, Chondrosarcoma, Malignant fibrous histiocytoma, Langerhans Cell Histiocytosis [ , , ].
2
Case presentation
A 5 year old female was referred to the Paediatric Dental Unit at Chelsea and Westminster Hospital NHS Trust, for assessment of pain from newly erupted permanent lower central incisors and mobility of all deciduous mandibular teeth, in November 2022. Patient was an irregular attendee, and this was her first dental visit since age 1 year old. There was a history of severe hydronephrosis, and General Anaesthetic was undertaken for pyeloplasty at age 6 months old. Patient was otherwise medically fit and healthy currently.
Parents gave a history of pain from the lower incisors and second episode of swelling in the eye. They reported weight loss of 4 kg in 2 weeks. Parents stated that patient was taken to the General Practitioner (GP) 2 weeks prior to presentation in our department, for eye swelling and antibiotic eye drops were prescribed. This was a second episode of swollen eye and previously a similar presentation occurred with swelling and purulent exudate from the right eye, approximately 2 months ago. Patient was also seen at the Community Dental Services, who prescribed antibiotics (Metronidazole) due to possible periodontal involvement.
Physical examination revealed skin pallor without evidence of dry scaly patches, redness, no exophytic nodules and no brittleness of hair or nails. Patient had a high temperature on the day of presentation without evidence of hyperhidrosis. Extra-orally, there was a painless right eye swelling with proptosis, periorbital swelling, and oedema. Intraoral examination revealed mobile upper E’s and all lower deciduous teeth, with extensively swollen, erythematous gingivae in the lower anterior region, as shown in Fig. 1 . Lower permanent incisors were partially erupted, displaced and grade 3 mobile.
A lower standard occlusal radiograph and Dentopantomogram (DPT) revealed generalised severe bone loss, lack of trabecular bone pattern and appearance of displaced ‘floating teeth’ in the mandible, as shown in Fig. 2 .
