Burkitt lymphoma

ICD-10:C83.7

UCD-9:200.2

ICD0:M9687/3

MIM. 113970

DiseaseDB:1784

eMedicine:202677

MeSH:D002051

Definition: Burkitt lymphoma (BL) comprises the majority of childhood B cell lymphomas, but only up to 5% of adult B cell lymphomas. The cell of origin is a peripheral IgM+ memory B-cell (presence of somatic hypermutation of the Ig gene)

Images

 Burkitt lymphoma. Starry sky (lots of apoptosis = no anti-apoptosis protein = BCL2 neg), 100% Ki-67

• https://twitter.com/KyleBradleyMD/status/733661552948187136

Endemic Burkitt lymphoma

Burkitt lymphoma is a high grade non-Hodgkin lymphoma which in the endemic form is uniformly associated with EBV. The endemic form primarily affects children in East Africa. Although titers of IgG antibodies against the structural protein viral capsid antigen (VCA) are uniformly seen in all of the East African children, it was significantly higher in those developing Burkitt lymphoma. The endemic form refers to those cases occurring in Africa, peaks at ages 4-7, is increased incidence in males, and usually involving the jaw and other facial bones. Endemic Burkitt lymphoma also involves other extranodal sites.

Sporadic Burkitt lymphoma

Sporadic Burkitt is found throughout the world. It is also most common in children with a higher incidence in males. Sporadic forms are located mostly in the abdomen but may be diagnosed in other nodal and extranodal locations. Waldeyer ring involvement is reported but is considered rare.

Although EBV is associated with Burkitt lymphoma, it is not required as a causal agent.

Sporadic Burkitt lymphoma occurs in Western countries and only 10-12% are associated with EBV.

BL in patients with HIV is associated with a higher EBV association in 40-50% of the cases.

All types of BL regardless of geographic location or immunocompetence of the individual contain the MYC oncogene translocation juxtaposed on either the immunoglobulin heavy chain or light chain gene.

BL of the tonsil accounts for 5% of all primary extranodal non-Hodgkin lymphoma of the tonsil. Most of the oral cases of BL are endemic and occur in children. The true frequency of primary Burkitt lymphoma in adults is unknown. Burkitt lymphoma can also rarely occur as a late post-transplant lymphoproliferative disorder (PTLD).

Microscopy

At low magnification the histologic features of BL include the presence of a diffuse infiltrate of monotonous cells. The cells in classic BL are intermediate in size approximately the size of admixed histiocyte nuclei. The nuclei are round in shape and contain several or multiple basophilic nucleoli. The cytoplasm is moderately abundant and formalin causes retraction creating a squared off appearance. Numerous mitotic figures are usually seen.

Tingible body macrophages are present with phagocytized debris giving the tissue a “starry-sky” appearance.

In peripheral blood or bone marrow aspirates, the Wright-Giemsa stain shows multiple cytoplasmic vacuoles.

Immunochemistry

B cell immunohistochemical markers are uniformly positive (CD19, CD20, CD22, CD79a). The cells have a germinal center immunophenotype expressing CD10, bcl-6 and CD38. Unlike follicular lymphomas, CD43 is often positive.

Bcl-2 should be negative or only weakly positive and TdT is uniformly negative; positive TdT should prompt reevaluation for B lymphoblastic leukemia/lymphoma. Ki67 (MIB-1) is 100%.

CD5, CD23 and CD138 are negative.

EBV is usually negative in the sporadic type.

Synopsis

 Diffuse infiltrate of monotonous cells.
 Burkitt cells are intermediate in size and show a high mitotic rate. They are interspersed with tingible body macrophages.
 Burkitt lymphoma in the peripheral smear appears blastic with dark blue cytoplasm and multiple nucleoli. Cytoplasmic vacuoles are characteristic.
 Cells are strongly CD20 positive. CD10 is positive.The cells were also positive for bcl-6 and negative for BCL2.
 Ki67 is near or at 100%. (not shown).

Digital slides

 HPC:191 - Burkitt lymphoma
 HPC:135 - Burkitt lymphoma of the nasopharynx
 HPC:342 - Burkitt lymphoma (Mesentere)
 UI:1193 - Colonic Burkitt

Epidemiologic forms

Burkitt lymphoma takes three .

 Endemic Burkitt lymphoma most commonly affects children and exhibits a male predominance. It is common in equato-rial Africa and New Guinea and is strongly associated with EBV infection.
 Sporadic Burkitt lymphoma is less com-monly related to EBV infection and affects both children and adults, with a bimodal age distribution.
 Immunodeficiency-related Burkitt lymphoma is seen in the setting of congenital immunodeficiency, HIV infection, and posttransplant.

Burkitt lymphoma is one of the most rapidly replicating of all human tumors, and patients frequently present with the sudden development of large tumor masses.

In endemic Burkitt lymphoma, the tumor shows an unexplained predilection for areas of growth, including the sockets around deciduous teeth of young (2- to 4-year-old) children, and hormonally responsive locations, such as the breasts of pubertal and pregnant women, ovaries, testes, and thyroid.

In sporadic and immunodeficiency-associated Burkitt lymphoma, visceral involvement, particularly of the small bowel, is common, with initial symptoms related to obstruction or perforation.

Burkitt lymphoma diffusely effaces the nodal architecture.

A monomorphic proliferation of intermediate-sized cells is seen (nuclear size similar to that of histiocytes or endothelial cells); the round or oval nuclei have a thick nuclear membrane and two to four nucleoli, and the cytoplasm is moderately amphophilic.

Many Burkitt lymphomas have a somewhat cohesive appearance, and the cell borders maintain a molded contour, particularly at the periphery.

The mitotic rate is high (MIB-1/KI-67 is positive in >95% of cells), and necrosis is often present, particularly at the periphery.

Evenly distributed macrophages containing cellular debris give a mottled (“starry sky”) appearance to Burkitt lymphoma at low power.

Some classification systems make a distinction between “Burkitt” and “non-Burkitt” mor-phology of small noncleaved cell lymphomas; however, the criteria are subjective, and because of the lack of reproducibility, this histologic point is of limited clinical relevance.

The immunophenotype is that of a mature surface Ig+ B-cell, and both CD19 and CD20 are expressed.

CD10 is positive. BCL-2 expression is not present. TdT expression is lacking.

Differential diagnostic

 lymphoblastic lymphoma
 rapidly replicating large cell lymphomas

Epidemiology

 Most common in children (1/3 of lymphomas).
 3-4% of all lymphomas in adults in western countries
 frequently associated with immunodeficiency in adults

Synopsis

 endemic variant affecting africans, which primarily involves the jaws and other facial bones.
 non-endemic variant may be associated with immunodeficiency and usually presents with abdominal involvement (distal ileum, ciecum, mesentery).

Microscopy

 monomorphic infiltrate of the lymph node by medium-sized cells showing round nuclei with several nucleoli and basophilic cytoplasm.
 numerous benign macrophages confer a histologic pattern referred to as ’starry sky’ apparance.
 Involvement of the peripheral blood and bone marrow may occur.

Immunochemistry

 Pan-B antigens positive (CD19+, CD20+, CD22+)
 CD10+
 BCL6+
 CD38+, CD77+, CD43+
 Ki67: 100%
 BCL2- or BCL2+/- (20%)
 TdT-
 CD5-
 sIgM+ (membrane IgM)

Cytology

 blast cells in the peripheral blood and bone marrow display a basophilic cytoplasm with characteristic vacuolization.

• This aspect is indisinguishable from acute lymphoblastic leukemia (ALL) L3 of the FAB classification, which represents the leukemic counterpart of BL.

Differential diagnosis

 B lymphoblastic lymphoma
 DLBCL

Localization

 nodal Burkitt lymphoma
 intestinal Burkitt lymphoma

• ileal Burkitt lymphoma

 bilateral mammary Burkitt lymphoma (7761167)

Associations

 organ transplantation

• PTLD monotypic Burkitt lymphoma type (12766587)

Differential diagnosis

 The related form Burkitt-like lymphoma shows intermediate features between diffuse large cell lymphoma and Burkitt lymphoma and probably includes different disease entities.

• It was suggested by the WHO panel that only those cases with c-MYC rearrangeme+nt and/or a >99% proliferation fraction as demonstrated by Ki-67 positivity should be classified as Burkitt-like lymphoma.

Variant

 granulomatous reaction in Burkitt lymphoma (correlation with EBV) (16006809, 15104301)

Cytogenetics

The defining characteristic of Burkitt lymphoma is the presence of the translocation of the cMYC gene and the IgH gene [t8;14] which is found in 80% of the cases. The remaining 20% have a translocation of cMYC gene to either kappa or lambda light chain gene [2;8 kappa or 8;22 lambda)].

Fluorescence in situ hybridization (FISH) is used most commonly to detect the translocation, because it may not be detected by routine cytogenetics.

The breakpoint for endemic Burkitt is different than that of sporadic and HIV associated Burkitt lymphoma suggesting that the mechanism of onogenesis is different.

FISH studies are very helpful in demonstrating translocations that deregulate expression of the protooncogene c-myc (chromosome 8) paired with either the heavy-chain loci (chromosome 14) or light-chain locus (chromosome 2 and 22).

 8q24 rearrangements (MYC locus)

• translocation t(8;14)(q24;q32) (MYC/IGH) (60-70%)
• translocation t(8;22)(q24;q11) (MYC/) (10-15%)
• translocation t(2;8)(p11;q24) (MYC/) (2-5%)

Most chromosomal t(8;14) translocations in sporadic Burkitt lymphomas (BL) are mediated by immunoglobulin class switch recombination (CSR), yet all tumors express IgM, suggesting an incomplete or exclusively monoallelic CSR event. (16736499)

 additional anomalies

• duplication of chromosome 1, involving the 1q21-25 segment as the only detectable chromosome lesion
• 6q11-14 deletion
• 17p deletions (TP53 inactivation)
• trisomy 12, trisomy 7, trisomy 8 and trisomy 18

EBV

The role of EBV in endemic Burkitt lymphoma is not completely clear. In one study, although EBV titers against structural proteins were much higher in children developing Burkitt, EBV titres against non-structural proteins were the same as controls. Studies are lacking to elucidate the exact etiologic mechanisms involved.

Reviews

 http://www.semdiagpath.com/article/S0740-2570(14)00108-7/fulltext

References

 Duensing S, Lee BH, Dal Cin P, Munger K. Excessive centrosome abnormalities without ongoing numerical chromosome instability in a Burkitt’s lymphoma. Mol Cancer. 2003 Sep 8;2:30. PMID: 14498992

 Gong JZ, Stenzel TT, Bennett ER, Lagoo AS, Dunphy CH, Moore JO, Rizzieri DA, Tepperberg JH, Papenhausen P, Buckley PJ. Burkitt lymphoma arising in organ transplant recipients: a clinicopathologic study of five cases. Am J Surg Pathol. 2003 Jun;27(6):818-27. PMID: 12766587

 Hammerschmidt W, Sugden B. Epstein-Barr virus sustains Burkitt’s lymphomas and Hodgkin’s disease. Trends Mol Med. 2004 Jul;10(7):331-6. PMID: 15242681