University of Virginia Health System

Acute Lymphoblastic Leukemia (ALL)
L2 subtype

ALL L2- Bone marrow aspirate smear, Wright-Giemsa stain, 1000x

Definition:

In the L2 subtype of ALL the cell size is more variable, but is usually larger by 1 1/2 to 2 times than that of the L1 subtype. The cytoplasm is more abundant and grey to blue in color. Cytoplasmic vacuoles and granules usually  are not present. The nuclear contour is more variable with more indentations, and the nuclear chromatin is more clumped and one or more prominent nucleoli are usually visible. From a morphologic standpoint alone L2 ALL, and M0 and M1 AMLs cannot be distinguished unless Auer rods are seen (M1).

Pathobiology:

Like the L1 subtype, L2 ALLs of both B and T cell lineage represent proliferation of cells at the antigen-independent stage of lymphocyte development. In T cell ALL and T cell lymphoblastic lymphoma, the L2 subtype is more frequently seen, and often with the characteristic convoluted nuclear appearance. Most lymphoblastic lymphomas are of T cell lineage, and often present in the thymus.

Cytochemistry:

Like the L1 subtype the PAS stain may be positive, but the myeloperoxidase and Sudan black-B stains are negative.

Immunophenotype:

In both the B and T cell subtypes the phenotyping is similar to the L1 subtype. sIg expression is more frequent in the B cell L2 subtype.

Cytogenetics:

Similar to the L1 subtype in both the B and T cell subsets.

Note: The prognostic significance of L1 versus L2 morphology remains unclear. Most studies show no difference with all other factors being equal. Nevertheless, the L2 subtype represents the majority of adult ALLs in which the prognosis is much worse.

Differential Diagnosis:

In addition to those listed for L1 ALL, other differential diagnoses include:

• Blastic variant of mantle cell lymphoma
  • In this variant the mantle cell immunophenotype (CD19+, CD5+, FMC7+, Cyclin D1+, and CD 23-) along with TdT negativity and the cytogenetic signature finding of the t(11;14) are needed to make the distinction.
• Blastic variant of NK cell leukemia
  • The immunophenotypic profile (CD56+, CD16+, CD2+, cCD3 epsilon +, sCD3-, and presence of cytotoxic proteins, (e.g. perforin, granzyme B) identifies this subtype.
• Blastic variant of NK/T cell leukemia
  • Immunophenotype essentially same as with the NK cell subtype. The TCR is not expressed, although the normal NK/T cells express the NK cell marker CD56, and a restricted TCR that recognizes lipids presented by an MHC class I-like CD1d; they are derived from a subset of double positive (CD4+ and CD8+) thymic T cells.  
• Small cell lung cancer and other small blue cell tumors of nonhematologic origin with bone marrow involvement
  • These malignancies, especially small cell lung cancer, may be very difficult to distinguish from acute lymphoblastic and some subtypes of myeloblastic leukemias by morphology alone. The tendency of nonhematologic malignant cells to form syncytia and appear as clumps in bone marrow specimens is an important finding. This pattern of infiltration is best demonstrated on a paraffin-fixed bone marrow specimen. Immunohistiochemistry is often necessary (e.g. neuron-specific enolase positivity in small cell lung cancer).

Prognosis:

Similar to the L1 subtype. In the T cell subsets versus the B cell subsets, the prognosis is considerably worse in children, but better in adults.

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
• Kensey JH. Fifty years of studies of the biology and therapy of childhood leukemia. Blood 90: 4243, 1997
• Albritton K, Douer D, Gaynon PS, et al. eds. Treatment of acute lymphoblastic leukemia in the adolescent and young adult population. Am J Hematol/Oncol vol 6, No 4, Suppl 5, 2007
• 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
• Benlagha K, Kyin T, Beavis A, et al. A thymic precursor to the NK T cell lineage. Science 296:553, 2002

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