Lymphoma, Malignant Small Noncleaved
Small noncleaved cell (SNCC) lymphomas are high-grade B-cell lymphoma. It is a historical term used to describe Burkitt lymphoma (BL). The World Health Organization Classification of lymphoid neoplasms identifies Burkitt lymphoma/leukemia as a highly aggressive mature B-cell neoplasm. It is further subdivided into endemic, sporadic, and immunodeficiency-associated variants. Some patients can also present with leukemia (L3 ALL).
Dennis Burkitt, a surgeon working in Kampala, Central Africa, first described BL in 1958. He noted children with lesions involving the face and jaw. Some children also had huge abdominal masses but no lymph node involvement. This condition was shown to be a lymphoma and named after him. It is a type of highly aggressive non-Hodgkin lymphoma (NHL), and it often presents in extranodal sites or as acute leukemia.
A few years later, Dr Burkitt met Dr Epstein, who was a pathologist. Dr Epstein and his colleagues identified Epstein-Barr virus (EBV) from the lymphoma samples Dr Burkitt provided establishing a role for EBV in the pathogenesis of Burkitt lymphoma.
The characteristic feature of this entity is the dysregulation and mutation of the c-MYC oncogene. It often resulted from translocation of chromosome 8 and 14 t(8:14). Other translocations are also reported causing c-MYC overexpression.
Burkittlike lymphoma (BLL) is morphologically different from BL. The Southwest Oncology Group (SWOG) published their experience with BLL. BLL is similar to BL with a high mitotic rate, prominent cytoplasmic basophilia, cytoplasmic vacuolation, and a starry sky pattern. Treatment is identical to protocols used to manage BL.
Epidemiologically BL is classified into sporadic, endemic, and HIV-associated varieties. The sporadic variant is present in North America and Europe, and the endemic variant is observed in equatorial Africa. HIV-associated BL accounts for about 30% of lymphoma patients with HIV. These lymphomas have a rapid and aggressive clinical course, commonly presenting in children and young adults, with frequent bone marrow and peripheral blood involvement. It is considered to be a medical emergency and requires immediate diagnostic and therapeutic intervention.
Burkitt lymphoma is a mature B-cell lymphoma. All the symptoms are caused by rapid turnover of the mature B lymphocytes and the involvement of extranodal sites and invasion of contiguous organs. C-MYC dysregulation is the basis for all the pathophysiology of Burkitt lymphoma. C-MYC is activated via its juxtaposition with immunoglobulin enhancers. The C-MYC is also mutated. Molecular epidemiology mapped the C-MYC mutation to several hotspots, which occurred in about 20% cases. The activation of C-MYC resulted in increased cell cycle progression, decreased apoptosis, increased cell growth and arrest of cell differentiation, increased cellular metabolism, and decreased cell adhesions.
Western Europe and United States
The incidence of sporadic BL is 2-3 cases per million individuals in the United States. It accounts for 1-2% of adult lymphoma cases, and up to 40% of lymphoma cases in children. The incidence of BLL is less frequent. The diagnosis has been problematic because of confusion regarding diagnostic criteria and changes in classification schemes. Thirty to forty percent of HIV-related non-Hodgkin lymphoma (NHL) cases are Burkitt lymphoma.
Incidence of endemic BL in African children is much higher than in the United States. The children are usually 4-7 years. It was estimated to be 50 times higher. EBV infection is found in nearly all cases.
Approximately 90% of pediatric patients and up to 89% of adults with BL/BLL treated with current intensive chemotherapy regimens have long-term disease-free survival. For those experience relapse, as many as 25% of patients may be able to achieve a long-term disease-free survival through high-dose therapy with autologous hematopoietic stem-cell transplantation. The addition of rituximab to this therapeutic regimen may further increase the response rate.
No racial predilection is reported, although the endemic BL observed primarily in equatorial Africa has primary jaw involvement (70% in children aged 4-7 years versus 15-20% in the sporadic US variety).
The male-to-female ratio is 2-3:1.
Endemic BL is common in children (30% of non-African pediatric lymphomas), but it is rare in adults (1-2% of all cases of NHL). Twenty to thirty percent of NHL in HIV patients are BL. It can present as an AIDS-defining illness and does not correlate with the CD4 counts.
Three different clinical variants of Burkitt lymphoma (BL) are described: endemic, sporadic, and immunodeficiency related. Their presentations may vary.
The endemic form is most commonly seen in patients in equatorial Africa, with face and jaw involvement. Other clinical presentations include abdominal masses, and ileal, cecal, ovarian, and breast involvement have also been documented. The geographic distribution of the tumor corresponds to the epidemiologic distribution of malarial infections.
The sporadic forms most often present with abdominal tumors with bone marrow involvement.
Patients usually present with extranodal disease. It can also present as a leukemic type such as L3 lymphocytic leukemia.
Generalized lymphadenopathy is rare. Approximately 90% of patients with sporadic BL and 50% of patients with endemic BL have abdominal masses upon presentation.
Patients with BLL may have variable presentation compared with those with BL. Patients with BLL usually present in their fourth or fifth decade of life. Braziel et al (2001) have reported on the clinical features of BLL after review of SWOG data. Median age was reported as 67 years (range, 28-69 y), and 70% of the patients presented with bulky advance disease (II, III, or IV), with 60% of patients having 2 or more extranodal sites of lymphoma involvement.
Patients with BL may have the following common findings and symptoms:
Face and jaw involvement in endemic BL
Abdominal masses can cause abdominal pain and distention, and ascites.
Nausea and vomiting
Loss of appetite and/or change in bowel habits
Signs and symptoms of acute abdomen
Right iliac fossa mass (40% of cases in the US National Cancer Institute [NCI] series)
Renal failure as a result of retroperitoneal disease and renal involvement
Mandibular or maxillary mass
Most common presentation in the endemic variety
Jaw involvement much less frequently (It only occurs in 15-20% of sporadic cases.)
Maxillary tumors – More common, may involve the orbit
Bone marrow involvement is common in BL.
CNS involvement is common, which includes the following:
Meningeal infiltration with or without cranial nerve (frequently third and seventh nerve) involvement – Most common mode of presentation with CNS disease
Headaches, visual impairment, and paraplegia from spinal involvement – May be initial presenting features in some cases
“B” systemic symptoms
Fever, weight loss, night sweats, fatigue
Although uncommon, may be associated with other presenting symptoms
The physical examination findings depend on the sites of extranodal involvement by BL.
Palpable tumor of the mandibulomaxillary region
Ecchymosis and/or petechiae (as a result of thrombocytopenia)
Meningeal signs (from CNS disease)
The following are considered etiologic factors that are implicated in the pathogenesis of BL:
Viral: EBV is associated with 95% of endemic SNCC lymphomas and 20-30% of sporadic BL cases.
c-MYC oncogene activation: The classic t(8;14)(q24;q32) reciprocal translocation (85%) results in the transposition of the c-MYC proto-oncogene on chromosome 8 with one of the immunoglobulin genes on chromosome 14, which results in activation of the c-MYC gene and is considered responsible for tumor proliferation. The variant translocations involving c-MYC transposition to the other immunoglobulin genes, t(2;8) and t(8;22), are also found in BL. C-MYC mutations are also presented.
P53 gene: Abnormalities in P53 genes have also been reported and are thought to be associated with the pathogenesis of BL.