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Leukemia - Acute

Acute lymphoblastic leukemia (ALL) - general

Reviewer: Daniela Mihova, M.D. (see Reviewers page)
Revised: 20 March 2013, last major update September 2012
Copyright: (c) 2001-2013, PathologyOutlines.com, Inc.


● 6050 cases/year in US in 2012 (National Cancer Institute), peaks at age 4; usually age 15 years or less
● 80% of childhood leukemia is ALL
● Higher incidence in whites, males and advanced (not developing) countries
● 85% are B cell, 15% are T cell, but both often express aberrant myeloid or lymphoid associated antigens
● Note that only 10-20% of lymphoblastic lymphoma is B cell lineage
Risk factors: in utero radiation, Down syndrome, ataxia telangiectasia, but most cases have no known cause
Symptoms: abrupt stormy onset, symptoms related to bone marrow depression (fatigue, fever, bleeding), bone pain and tenderness (due to marrow expansion), joint pain, generalized lymphadenopathy, hepatosplenomegaly, testicular involvement, CNS manifestations
Atypical presentation: hypercalcemia, bone lesions and no circulating blasts
Laboratory: anemia common, platelet count < 100K in 75% and < 10K in 15%; leukopenia (25%), WBC > 100K (10%)
Diagnosis: immunostains required for diagnosis
Relapse: blasts usually unchanged; may progress from L1 to L2, TdT positive to negative (25%), gain or lose an antigen (CD10, HLA-DR), evolve clonally (75%) or evolve to AML; CNS relapse common

Prognostic features

● Cytogenetics / FISH is single most important prognostic factor for adults (Blood 2008;111:2563)
Favorable prognosis: age 1-10 years, female, white; preB phenotype, hyperdiploidy > 50, t(12,21), normal WBC count at presentation, non-traumatic tap with no blasts, rapid response to chemotherapy, CD10+
Intermediate prognosis: hyperdiploidy 47-50, diploid, 6q- and rearrangements of 8q24
Unfavorable prognosis: under age 2 (usually have 11q23 translocations) or over age 10; t(9;22) (but not if age 59+ years, Am J Clin Pathol 2002;117:716); male, > 50x108/L, hypodiploidy, near tetraploidy, 17p-, MLL rearrangements and t(v;11q23); CD10- preB ALL; non-traumatic tap with > 5% blasts or traumatic tap with 7%+ blasts, also increased microvessel staining using CD105 in children (Leuk Res 2007;31:1741), MDR1 expression in children (Oncol Rep 2004;12:1201) or adults (Blood 2002;100:974)

Case reports

● Mature phenotype but non-L3 morphology (Mod Pathol 2004;17:832)


Children: multiagent chemotherapy plus CNS chemotherapy; 90% go into remission, 2/3 are cured; thrombopoietin may induce CML like changes (Am J Clin Pathol 2002;117:844)
Adults: choice of chemotherapy or stem cell transplantation is not clear (Hematology Am Soc Hematol Educ Program 2007:444)

Micro description

● Blasts have scant agranular cytoplasm, no Auer rods, coarse to fine chromatin, often indistinct nucleoli and no dysplastic myeloid cells
Peripheral smear: leukoerythroblastosis common with granulocyte precursors and nucleated RBCs, lymphoblasts, occasionally reactive lymphocytes and rarely marked eosinophilia
Bone marrow: hypercellular, high percentage of lymphoblasts
Children: 80% are L1, 10-20% L2 and < 5% L3
Adults: 35% are L1, 60% L2 and < 5% L3

Micro images

Peripheral smear images:

Blasts with scant cytoplasm and prominent nucleoli

L1 type (blood smears):
Blasts have minimal cytoplasm, variable nuclear   Blasts have moderate cytoplasm, round nuclei of variable size,
size and chromatin density, irregular nuclear    coarse chromatin and some resemble mature lymphocytes
contour, some small nucleoli

L1 type (bone marrow smears):

Left: blasts contain large cytoplasmic azurophilic granules (uncommon), but were B cells by IHC and cytochemistry
Right: classic morphology and stains

L1 type (bone marrow biopsy):
Markedly hypercellular marrow with   Lymphoblasts occupy marrow, have    Lymphoblasts are small with more
lymphoblasts replacing normal      minimal cytoplasm and indistinct cell  condensed chromatin
marrow elements           borders, convoluted nuclei, angulated

Marrow contains lymphoblasts, one megakaryocyte,
normoblasts in upper half and occasional eosinophils
and eosinophil precursors

L1 type (stains):

Lymphoblasts have block and coarse granular PAS staining

L2 type (blood smears):
Three large lymphoblasts have    Lymphoblasts have variable size, moderate Most lymphoblasts have variable size,
moderate cytoplasm, large nuclei   cytoplasm, markedly irregular nuclei with  reticular chromatin with prominent
with coarsely reticular chromatin   coarse chromatin and distinct nucleoli     nucleoli and some have L1 features
and 1-3 prominent nucleoli

Classic morphology

Blasts have cytoplasmic azurophilic granules (uncommon)

L2 type (bone marrow smears):

Large lymphoblasts with cytoplasm that has numerous,
sharply defined clear vacuoles similar to L3, non-L3
features are reticular chromatin, prominent nucleoli, TdT+ and CD10+

L2 type (bone marrow biopsy):

Relatively large lymphoblasts with variable nuclear shape, dispersed chromatin and prominent nucleoli

L3 type (bone marrow smears):

Classic morphology

No prominent vacuoles, dispersed chromatin and
more obvious nucleoli than usually observed in L3,
diagnosed as ALL-L3 and non-Burkitt’s type

L3 type (stains):

Strong cytoplasmic staining by methyl green pyronine (left),
vacuoles are Oil Red O positive (right)

Unusual case with high myeloperoxidase activity


Relapsed ALL

Enzyme cytochemistry

● Negative for myeloperoxidase, chloroacetate esterase, non-specific esterase (usually) and only rarely positive for Sudan Black B (Mod Pathol 1992;5:68)
● Positive for PAS (75%, coarse clumping corresponds to glycogen), acid phosphatase (T-ALL has focal paranuclear staining)
● Only L3 stains for glycogen with Sudan Black B and PAS

Positive stains

● CD99 (MIC2), TdT, bcl2 and CD34

Negative stains

● Myeloperoxidase (usually, but positive in 23% of adults using a polyclonal antibody, Am J Clin Pathol 2001;116:25)
Note: TdT negative cases may demonstrate early T-cell lineage by flow cytometry (Arch Pathol Lab Med 2000;124:92)

Molecular description

● 90% have cytogenetic abnormalities, usually hyperdiploidy (> 50 chromosomes), also pseudodiploidy (46 chromosomes but structural anomalies), t(12,21); t(9,22) [Philadelphia chromosome] and t(4,11)

Electron microscopy images

L1 type:

Cytoplasm has small mitochondria, small Golgi region, scattered polyribosomes and
occasional strands of round endoplasmic reticulum, nucleus is indented with a small
nucleolus, chromatin is condensed and concentrated at nuclear periphery

L2 type:

Large lymphoblast with moderate cytoplasm, dispersed chromatin
with peripheral condensation and large prominent nucleolus

L3 type:

Abundant cytoplasm with numerous polyribosomes and large lipid vacuoles (arrow)
nuclei have peripherally condensed chromatin and 1+ prominent nucleoli

Differential diagnosis

Adult T cell leukemia
Hematogones - normal B lymphoid precursors (Am J Clin Pathol 2000;114:66)
● Hypoplastic anemia
Merkel cell carcinoma - may be TdT+ (Mod Pathol 2007;20:1113)
Non-Hodgkin’s lymphoma
● Reactive lymphocytosis

End of Leukemia - Acute > ALL > Acute lymphoblastic leukemia (ALL) - general

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