Sporadic Burkitt Lymphoma Involving the Orbit – A Report of Two Cases and Review of Literature

ABSTRACT Burkitt lymphoma (BL) is an aggressive, rapidly growing B-cell non-Hodgkin lymphoma found predominantly in children and has three clinical subtypes. The sporadic subtype, seen in non-endemic areas, typically presents as an abdominal mass. Primary orbital involvement is rarely reported. We report two cases of sporadic orbital BL manifesting as unilateral rapidly progressive proptosis with orbit being the initial site of presentation. Following an incision biopsy, BL was confirmed on histopathology and immunohistochemistry. Both patients demonstrated a remarkable improvement with systemic chemotherapy. Burkitt lymphomas grow rapidly with the potential for vision loss. Albeit rare, clinicians should be aware of this entity as timely diagnosis and initiation with chemotherapy display a dramatic response.

Burkitt Lymphoma (BL) is an aggressive, rapidly progressive B-cell non-Hodgkin lymphoma (NHL) that may affect multiple organs. It has three subtypes: endemic, sporadic (non-endemic), and immunodeficiency-associated. 1 Endemic BL is seen in equatorial Africa while sporadic BL is seen outside the African region. 2 Sporadic BL typically presents as an abdominal mass, rarely involving the orbit. 1,2 Common causes of unilateral rapidly progressive proptosis in children are rhabdomyosarcoma, leukemias, and orbital cellulitis. BL being rare is generally not considered as a differential. Herein we present two cases of sporadic orbital BL from the Indian subcontinent that highlights the importance of keeping this diagnosis in mind in children presenting with sudden onset proptosis. The study adhered to the tenets of the declaration of Helsinki and informed consent was obtained from the patients.

Case 1
A 17-year-old Asian-Indian male presented with rapidly progressive proptosis of the left eye for the past 2 months, with worsening for 2 days. He was diagnosed elsewhere as idiopathic orbital inflammatory disease and treated with systemic steroids with nil improvement. On examination, his best-corrected visual acuity (BCVA) was 20/20 and 20/600 in the right and left eyes, respectively. The left eye revealed an axial proptosis of 13 mm with inferior conjunctival chemosis, lagophthalmos, exposure keratopathy, relative afferent pupillary defect, and restricted ocular motility in all gazes (Figure 1a). The intraocular pressure (IOP) was 10 and 54 mmHg on Goldman applanation tonometer. Fundus examination showed mild disc edema and chorioretinal folds in the left eye ( Figure 1b). There was no regional lymphadenopathy and systemic examination was unremarkable. An urgent canthotomy and cantholysis lowered the IOP in the left eye to 32 mm Hg. Complete blood count, peripheral blood smear, and biochemical analysis were within normal limits.
Contrast-enhanced computed tomography (CT) scan done a month back showed a retrobulbar, intraconal lesion along the inferomedial aspect of the left orbit without bony erosion (Figure 1d). Magnetic resonance imaging (MRI) revealed an ill-defined, retrobulbar, intraconal lesion extending upto the orbital apex causing significant proptosis with deformation of the left globe and stretching of the optic nerve. Restricted diffusion was seen in diffusion-weighted imaging (DWI) (Figure 1e). He underwent an urgent incisional biopsy via an inferior fornicial transconjunctival approach under general anesthesia.
Histopathology showed diffuse infiltrate of immature lymphoblasts and tumor cells arranged in sheets having a "starry sky" pattern. Immunohistochemistry (IHC) was positive for CD-20, CD-10, CD-45, BCL 6, c-MYC, and Ki-67 index was 100% confirming the diagnosis of BL. A pediatric oncologist's opinion was sought. Bone marrow aspiration cytology was normal. Positron emission tomography (PET)-CT revealed abnormal fluorodeoxyglucose (FDG) uptake in the sacral spinal canal and sacral nerve roots suggesting central nervous system (CNS) involvement. Cerebrospinal fluid (CSF) analysis was normal.
The patient was categorized as Group C BL under French-American-British/mature lymphoma B (FAB/ LMB) staging system. A Rituximab-based LMB 96 Group C chemotherapy protocol was advised. The patient was started on reduction phase cyclophosphamide, vincristine, prednisolone (COP) along with triple intrathecal (IT) drugs (methotrexate, hydrocortisone, cytarabine). He showed complete resolution of proptosis after two cycles. BCVA improved to 20/20 in both eyes. The patient received a total of 9 cycles of systemic and intrathecal chemotherapy. He developed pneumonia and sepsis during the intensive chemotherapy that were adequately managed with antibiotics and supportive treatment.
At 8 months follow-up, there was complete resolution of proptosis with minimal residual restriction of movements on elevation and abduction ( Figure 1h). Fundus examination of the left eye showed mild left disc pallor ( Figure 1c). A repeat PET-CT for response assessment revealed complete resolution of the left orbital lesion and the sacral intraspinal lesion, suggesting a complete metabolic response to treatment (Figure 1g).

Case 2
A 4-year-old Asian-Indian female child presented to us with rapidly progressive painless proptosis of the left eye and swelling over the left cheek for the past 2.5 months. On examination, the vision was 20/25 at 10 feet (measured with Lea's symbols) in both eyes. There was gross proptosis of 16 mm in the left eye with inferomedial dystopia, restricted ocular motility in all gazes, and firm swelling over the entire left cheek (Figure 2a). Fundus examination showed mild disc edema in the left eye. There was no regional lymphadenopathy and systemic examination was unremarkable. Complete blood count, peripheral blood smear, and biochemical analysis were within normal limits.
MRI orbit revealed a large, lobulated lesion in the lateral and superolateral aspect of the left orbit, extending into the left maxilla, causing erosion of the alveolus, floor of maxillary sinus, and greater wing of sphenoid with intracranial extension in the temporal region ( Figure 2c). An incisional biopsy was done via a lid crease approach under general anesthesia. Biopsy was taken from the superolateral extraconal space and the lesion was friable and pinkish in color.
Histopathology and IHC were confirmatory of BL ( Figure 3). The patient was referred to a pediatric oncologist. Bone marrow aspiration cytology showed no infiltration. PET-CT revealed abnormal FDG uptake in the left orbit and cheek along with FDG avid lesions in the subhepatic region, retroperitoneum, and left iliac vessels (Figure 2d). The patient was started on COP regimen of LMB 96 chemotherapy protocol, with a substantial improvement within 48 hours (Figure 2b). Currently, at 2 months follow-up, the patient has completed 2 cycles of chemotherapy at her hometown and is doing well.

Discussion
Burkitt lymphoma (BL) was first described by Dr. Denis Burkitt. 3 It can arise from any location in the body and demonstrates a characteristic "starry sky" pattern on histology. 1 There is c-MYC overexpression in BL, most commonly due to translocation of the c-MYC gene on chromosome 8 with chromosome 14 which leads to rapid B cell proliferation. 1,4,5 c-MYC overexpression was seen in our first case. The endemic form (eBL) accounts for approximately 50% of all childhood cancers and commonly involves facial bones like mandible, maxilla, and orbit. 1,2 Nearly all these cases are associated with Epstein-Barr virus (EBV). 1,6 CNS involvement is common in eBL. 6 Sporadic BL (sBL) accounts for 30% of pediatric lymphomas. 5 Both cases in our series presented in the pediatric age group. As per literature, the peak incidence of sBL is around 10 years of age. 5 EBV is positive in 20-30% of sBL. 1 Our cases presented with orbital and CNS involvement. The most common site of involvement in  sBL is the abdomen. 1,5 Facial bones and other extranodal sites in the head and neck are involved in around 10% of cases, commonly as cervical lymphadenopathy. 6 Orbital and ocular involvement in sBL is rare. 1,2 CNS involvement is also uncommon in sBL and indicates a poor prognosis. 1,6 Our patients presented with a rapidly progressing proptosis and stretch optic neuropathy. Rapid growth of BL within the orbit can lead to optic nerve compression and thus vision loss. 5 Immunodeficiency-associated BL (iBL) is seen in HIV-positive patients, allograft recipients, and patients with congenital immunodeficiency, where it commonly involves lymph nodes, bone marrow, and CNS. 5 HIV test was negative for both our cases, thus indicating the cases were sporadic BL.
Sporadic BL primarily involving the orbit is universally rare. A review of literature revealed 27 cases of sBL with primary orbital involvement with only three cases reported so far from the Indian subcontinent (see table, Supplemental Digital Content 1, which summarizes the previously reported cases). Both our cases presented with proptosis that is similar to the cases reported in the literature. One of our cases had bone erosion involving the greater wing of sphenoid while bone erosion was observed in 10 of the 27 reported cases.
In our cases, the diagnosis was confirmed based on histopathology and IHC. Of the 27 cases reported in the literature, 18 had IHC confirmation. The remaining nine cases were diagnosed solely on histopathology findings. Gupta et al. reported three cases of sBL based on CD 20 positivity, histopathology, and clinical presentation. 2 However, CD20 positivity is seen in almost all B-cell lymphomas. Hence, a definitive diagnosis of sBL is debatable in all those cases. 7 Molecular analysis is highly confirmatory for the diagnosis of BL. 7 Chemotherapy is the mainstay of treatment in BL. Current treatment regimens involve various chemotherapy protocols consisting of intensive, multi-agent therapy of which the LMB 96 protocol is commonly used. 5,8 It includes treatment with cyclophosphamide, vincristine, prednisolone, doxorubicin, etoposide, cytarabine, and methotrexate given in reduction, induction, consolidation, and maintenance phases. 8 Rituximab is added to minimize adverse effects and to improve event-free survival time. 5 CNS prophylaxis with intrathecal methotrexate and/or cytarabine is the first-line therapy for CNS involvement. 5 Based on the extent of systemic involvement, the chemotherapy regimens vary from 2, 6, and 9 cycles for groups A, B, and C, respectively, as per the FAB/LMB classification. 8 Both our cases were treated according to group C LMB 96 chemotherapy protocol with intrathecal chemotherapy due to the presence of CNS involvement. Previously, a combination of chemotherapy and radiotherapy was used. However, there is no role for radiotherapy in BL, as it is not radiosensitive. 5,9 Chemotherapy alone is highly effective due to the rapid doubling time and high mitotic index. 5 Treatment-related complications are to be expected because of the intensive therapy and can be managed appropriately, as in our first patient who developed mucositis and cytopenia.
Due to the advancement in the treatment regimes, the overall 5-year survival rate is as high as 87% in patients younger than 19 years. 5 Of the 27 cases reported in the literature, 4 cases were alive without disease at last follow-up, the longest follow-up being 54 and 60 months in two cases, while 9 cases died of disease (Supplemental Digital Content 1). Both the patients in our study are still under follow-up and are currently alive without disease; however, long-term follow-up will be needed to determine the disease prognosis. Our first patient regained 20/20 vision, along with complete regression of proptosis, which was maintained at 8 months follow-up. Vision in the second patient could not be assessed objectively due to the patient's age, but she maintained a central, steady fixation. A good visual outcome in cases of orbital BL is rare. 4 Sporadic BL, though rare, should be considered a differential for rapidly progressive proptosis in the pediatric age group. The threshold for an incisional biopsy should be low in such cases. Despite the aggressive nature of these tumors, we can reduce the morbidity and improve prognosis by precise management of these rare orbital tumors.