University of Virginia Health System

Acute Lymphoblastic Leukemia (ALL)/Lymphoma
L3 subtype (Burkitt's)

ALL L3 (Burkitt's Leukemia/Lymphoma)- Bone marrow aspirate Smear, Wright Giemsa stain, 1000x

Description:

The morphologic appearance of the malignant cells in L3 ALL/lymphoma (Burkitt's leukemia/lymphoma) on a Wright-Giemsa stain is essentially diagnostic, especially in the classic subtype. The cells are of medium size, about 1 1/2 to 2 times larger than L1 ALL cells, and they are rather uniform in size. The cytoplasm is very basophilic (blue) and contains a variable number of lipid-laden vacuoles that stain positive with oil red 0 (neutral fat). The vacuoles frequently cluster in a Golgi distribution. The nucleus is round to slightly oval, and the nuclear chromatin is coarse but evenly dispersed with some clumping. Nucleoli are prominant and usually multiple in number. On fixed paraffin sections of bone marrow and lymph node specimens the pattern of infiltration is diffuse with a "starry sky" appearance due to histiocytic engulfment of apoptotic Burkitt tumor cells. Mitotic figures are frequent reflecting the very high proliferative rate. Resting cells are essentially non-existent.

Pathobiology:

Unlike L1 and L2 ALLs, Burkitt's ALL/lymphoma represents a malignant proliferation of peripheral B cells in the germinal center. Most present as lymphomas, but some as acute leukemias (30-40%). CNS involvement at diagnosis occurs in 10% or more. When they present as lymphomas, leukemic transformation is a frequent occurrence during the course of the disease. Three morphologic variants are recognized:

• Classic Burkitt's
  • The malignant cells are monomorphic similar to those shown above.
• Atypical Burkitt's
  • In this subtype the malignant cells are more pleomorphic in size and shape, and nucleoli may be even more prominent. To meet the criteria for Burkitt's lymphoma/leukemia, one of the c-myc oncogene translocations must be present and essentially 100% of the cells must be in cycle. The finding of a c-myc translocation alone does not establish a diagnosis of Burkitt's. This translocation is found in some cases of large cell B cell lymphoma. Gene expression profiling by microarray analysis is needed to further characterize these subtypes.
• Burkitt's with plasmacytoid differentiation
  • This subtype also demonstrates a pleomorphism in the size and shape of the malignant cells, and in addition is characterized by the presence of a population of plasmablastic cells. Again, demonstration of c-myc oncogene translocations are necessary for definitive diagnosis.

Clinical Variants:  

• Endemic subtype 
  • This subtype is endemic to equatorial Africa, and characteristically presents as a tumor of facial bones in children. It is Epstein-Barr virus (EBV) positive in essentially all cases; the EBV genome is found in almost all of the malignant cells. The morphology of the malignant lymphocytes is that of classic Burkitt's variant.
• Sporadic subtype
  • This variant is seen world wide in children and young adults and most present with intra-abdominal tumors, frequently in extranodal sites (e.g. kidney, ovary). The morphologic features may be that of classic Burkitt's or the atypical variant.
• Immunodeficiency-associated subtype
  • Seen predominantly in patients with AIDS, but may be seen in other immunodeficient patients (e.g. organ transplant patients on immunosuppressive therapy). The association with the EBV varies but is less frequent. Most show a plasmacytoid differentiation.

Cytochemistry:

The vacuoles are oil red O positive (indicating neutral fat). Myeloperoxidase and Sudan black-B stains are negative.

Immunophenotype:

Unlike ALL of the L1 and L2 subtypes, Burkitt cells are strongly sIg+, usually with IgM. They are CD19+, CD20+, CD10+, and BCL6+, but are TdT- and CD34-, a profile that is important to separate this subtype from other B cell lymphoblastic neoplasms.

Cytogenetics:

In essentially 100% of cases, translocations involving the c-myc oncogene are found. Most involve the Ig heavy chain gene locus on chromosome 14, t(8;14), but may involve the kappa light chain gene locus on chromosome 2, t(2;8) or the lambda light chain gene locus on chromosome 22, t(8;22).

Differential Diagnosis:

Even though the morphologic features of classic Burkitt's lymphoma/leukemia are essentially diagnostic, immunophenotype, cytogenetics and mitotic rate should be determined.

• Pleomorphic large cell lymphomas of B or T cell lineage
  • Can be distinguished by immunophenotype and cytogenetics.
• L2 ALL, and M0 and M1 AMLs:
  • Morphology is quite different in these subtypes. The chromatin is more clumped and nucleoli are less numerous, the cytoplasm is much less basophilic, and cytoplasmic vacuoles usually are not visible.  Immunophenotypic and cytogenetic studies required for diagnosis in some cases.
• Blastic variant of mantle cell, NK, and TNK cell leukemia/lymphoma 
  • Immunophenotyping and cytogenetic studies may be required to establish diagnosis.
• Nonhematologic small blue cell tumors
  • The morphology alone, especially on fixed bone marrow biopsy specimens is usually sufficient for diagnosis. Immunophenotyping and cytogenetic studies may be necessary.

Prognosis:

Burkitt's lymphoma/leukemia has a high cure rate even in the presence of disseminated disease. With a short course of intensive chemotherapy, the cure rate in localized disease is >90%. In advanced stage, the cure rate is ~70%, and in those presenting with leukemia the cure rate is approximately 65%.

General References:

• Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. Pathology and genetics of tumors of hematopoietic and lymphoid tissues. Vol. 3 of World Health Organization classification of tumors. Lyon, France: IARC Press, 2001
• Bennett JM, Catovsky D, Daniel MT, et al: French-American-British (FAB) Cooperative Group: The morphological classification of acute lymphoblastic leukemia- concordance among observers and clinical correlations. Br J Haematol 47:553, 1981
• Ferry JA. Burkitt's lymphoma: Clinopathologic features and differential diagnosis. The Oncologist 11: 375, 2006
• Magrath I, Adde M, Shad A, et al: Adults and children with small noncleaved-cell lymphoma have similar excellent outcome when treated with the same chemotherapy regimen. J Clin Oncol 14:925, 1996
• Hummel M, Stefan B, Berger H et al. A biologic definition of Burkitt's lymphoma from transcriptional and generic profiling. N Eng J Med 354:2419, 2006
• Dave SS, Kai F, Wright GW, et al. Molecular diagnosis of Burkitt's lymphoma. N Engl J Med 354:2431, 2006

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