Lymph nodes & spleen, nonlymphoma
Lymph node & spleen-nonlymphoid neoplasms
Acute lymphoblastic leukemia / lymphoma


Topic Completed: 15 February 2021

Minor changes: 26 March 2021

Copyright: 2003-2021, PathologyOutlines.com, Inc.

PubMed Search: Acute lymphoblastic leukemia / lymphoblastic lymphoma [TI] free full text[sb]

Morgan Hrones, M.D.
Patricia Tsang, M.D., M.B.A.
Page views in 2020: 9,149
Page views in 2021 to date: 8,021
Cite this page: Hrones M, Tsang P. Acute lymphoblastic leukemia / lymphoma . PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphnodesALL.html. Accessed May 16th, 2021.
Definition / general
  • Highly aggressive neoplasm of precursor lymphoid (blast) cells
  • 2 main subtypes based on lymphoid lineage
    • B lymphoblastic leukemia / lymphoma (B-ALL / LBL)
    • T lymphoblastic leukemia / lymphoma (T-ALL / LBL)
Essential features
  • Characterized by neoplastic proliferation of clonal precursor B cells or T cells that typically have blastic cytomorphology
  • Lymphoblastic lymphoma generally refers to tissue mass lesion, while leukemia refers to bone marrow or blood involvement
  • B-ALL / LBL has a better prognosis in children than in adults
  • Childhood B lineage ALL / LBL has a better prognosis than childhood T lineage ALL / LBL
  • Immature cell markers, such as CD34 and TdT, can help to differentiate lymphoblasts from Burkitt lymphoma which, is considered a mature high grade B cell lymphoma that mimics lymphoblastic lymphoma / leukemia
Terminology
  • Lymphoblastic leukemia / lymphoma
  • Acute lymphoblastic leukemia (ALL)
  • Precursor B cell lymphoblastic leukemia / lymphoma or precursor T lymphoblastic leukemia / lymphoma
  • Separation of lymphoblastic leukemias and lymphomas based on a measure of disease burden / stage
    • Cases with tissue involvement + replacement of < 25% marrow involvement by lymphoid blasts = lymphoblastic lymphoma (LBL)
    • Cases with ≥ 25% marrow involvement = lymphoblastic leukemia
ICD coding
  • ICD-O:
    • 9811/3 - B lymphoblastic leukemia / lymphoma, NOS
    • 9837/3 - T lymphoblastic leukemia / lymphoma
  • ICD-10:
    • C83.5 - Lymphoblastic lymphoma, B cell or T cell
Epidemiology
Sites
  • Bone marrow, peripheral blood or nodal involvement
  • Anterior mediastinum
    • Particularly T-LBL
    • Compromised cardiac function and superior vena cava syndrome may result
  • Less frequent sites involved
    • Skin
    • Soft tissues
    • Central nervous system
Pathophysiology
  • Clonal proliferation of precursor B cells in the bone marrow
  • Clonal proliferation of precursor T cells in the thymus (thymocytes)
  • Specific sequential pathologic mechanisms that follow appear to be variable, based on the varying genetic aberrations identified
Etiology
  • Idiopathic and likely multifactorial
  • Chromosomal aberrations with gene mutations and rearrangements commonly cited
  • Specific risk factors seen in a minority of patients:
    • Prenatal radiation exposure (Xradiation)
    • Postnatal exposure to high doses of radiation (e.g. therapeutic radiation was previously used for tinea capitis and thymus enlargement)
    • Genetic conditions, such as Down syndrome, neurofibromatosis and ataxia telangiectasia
    • Inherited genetic polymorphisms
  • Reference: Swerdlow: WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues (Medicine), 4th Edition, 2017
Clinical features
  • B-ALL / LBL
    • Common presentation of fever, fatigue, bone or joint pain, bleeding or anorexia (signs of bone marrow infiltration)
    • May present with widespread lymphadenopathy, hepatosplenomegaly, involvement of skin, soft tissue and testes, with predilection for the central nervous system
    • Mediastinal mass uncommon
  • T-ALL / LBL
    • Most commonly presents with anterior mediastinal mass with or without superior vena cava syndrome
    • Lymph node involvement on Xray / CT / MRI showing thymic enlargement or pleural effusion, resulting in symptoms of respiratory distress
    • Generalized lymphadenopathy and hepatosplenomegaly also frequent
  • Reference: Swerdlow: WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues (Medicine), 4th Edition, 2017
Diagnosis
  • Multimodal pathologic evaluation with some combination of morphology, flow cytometry, immunohistochemistry, cytogenetics, FISH, PCR, NGS and basic clinical laboratory tests
  • Nodal excisional biopsy may be the initial diagnostic procedure, although marrow involvement is frequently present simultaneously
  • If marrow involvement suspected, initial approach may consist of complete blood count and peripheral blood smear, followed by bone marrow aspiration and biopsy
Laboratory
  • Complete blood count
    • Almost universally shows anemia and thrombocytopenia
      • ~25% have severely decreased platelet count (< 20,000/uL)
    • Total white blood cell (WBC) count variable but most commonly presents with neutropenia
      • 50% show WBC count < 10,000/uL
      • 30% show WBC count 5,000 - 50,000/uL
      • 20% show WBC count > 50,000/uL
      • 20% show preleukemic state with cytopenia < 1 year before overt leukemia
    • Rare reports of asymptomatic hypereosinophilia (Cancer 1984;54:1058), most commonly seen in the setting of t(5;14) (q31;q32) or relatively less common recurrent abnormalities, such as translocation t(7;12)(q22;p13); also reported in the setting of hyperdiploidy (Blood 2020;135:974, Swerdlow: WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues (Medicine), 4th Edition, 2017)
Radiology description
  • Lymphadenopathy
  • T-LBL may show an anterior mediastinal mass due to thymic enlargement or presence of pleural effusion on Xray
Radiology images

Images hosted on other servers:

T-LBL mediastinal involvement

Prognostic factors
  • Prognosis generally determined by lineage (B cell or T cell phenotype), plus cytogenetic or molecular abnormalities detected
  • B-ALL / LBL
    • Unfavorable prognostic factors:
      • Infancy and adult age of diagnosis
      • High white blood cell count
      • Slow response to initial therapy
      • Central nervous system involvement at the time of diagnosis
      • Minimal residual disease after therapy
  • T-ALL / LBL
    • Worse prognosis than B-ALL / LBL among pediatric population
    • Better prognosis than B-ALL / LBL among adult population
  • Reference: Swerdlow: WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues (Medicine), 4th Edition, 2017
Case reports
Treatment
  • Multiagent chemotherapeutic regimen stratified based on epidemiology, presentation and other patient specific associated characteristics of the disease, as well as presence of specific cytogenetic abnormalities and therapeutic response to initial induction (Pediatr Int 2018;60:4)
  • Intrathecal prophylactic therapy and radiation for those presenting with central nervous system involvement (Biol Blood Marrow Transplant 2016;22:575)
  • Allogeneic stem cell / bone marrow transplantation in those demonstrating high risk findings (Am J Hematol 2017;92:18)
  • Targeted tyrosine kinase inhibitors or JAK inhibitors may be used in patients with Ph-like ALL (Best Pract Res Clin Haematol 2018;31:351)
  • CAR-T cell immunotherapy in relapsed patients (Curr Hematol Malig Rep 2018;13:396)
  • Supportive therapy for cytopenias
Microscopic (histologic) description
  • In tissue masses or marrow, effacement of architecture by round blue cells raises the differential diagnoses of ALL / LBL versus neuroblastoma, Ewing sarcoma and other mimickers
  • Proliferation of typically small to medium sized primitive cells but some tumor cells may appear as larger blasts containing cytoplasmic vacuoles
  • B and T cell precursors are morphologically indistinguishable
  • In nodal involvement, blasts usually display a diffuse growth pattern
    • Partial nodal involvement of T-LBL may have a predominantly interfollicular distribution
    • Lymphoblasts may be oval in shape and display an indented nucleus with finely dispersed chromatin and inconspicuous nucleoli
  • Revised criteria to the original French American British (FAB) classification of ALL cytologic subtypes
    • L1 and L2 subtype segregation not shown to correlate with clinical or biologic behavior; thus, most commonly used for descriptive purpose at this time
      • L1 subtype: most common, with intermediate size, uniform features, scant basophilic cytoplasm, slightly condensed chromatin with inconspicuous / absent nucleoli
      • L2 subtype: more heterogeneous appearance, with slightly more cytoplasm and more prominent nucleoli, resembling myeloblasts
      • L3 subtype: now corresponds to leukemic phase of Burkitt lymphoma, a high grade mature B cell lymphoma (Blood Cancer J 2017;7:e577)
Microscopic (histologic) images

Contributed by Patricia Tsang, M.D.
B-LBL retroperitoneal fibroadipose

B-LBL retroperitoneal fibroadipose

B-LBL tongue, 20x

B-LBL tongue

B-LBL tongue, 60x

B-LBL tongue

B-LBL tongue TdT

B-LBL tongue TdT

B-LBL tongue PAX5

B-LBL tongue PAX5

B-LBL tongue CD20, 40x

B-LBL tongue CD20


T-LBL starry sky, 20x

T-LBL starry sky

T-LBL LN, 60x

T-LBL lymph node

T-LBL CD1a, 40x

T-LBL CD1a

Virtual slides

Images hosted on other servers:
ALL: lymphoblasts infiltrating skin

ALL, skin: lymphoblasts infiltrating skin

Cytology description
Peripheral smear description
  • Predominance of lymphoblasts
Peripheral smear images

Contributed by Patricia Tsang, M.D.
T-lymphoblast on blood smear T-lymphoblast on blood smear

T lymphoblast on blood smear

Positive stains
Negative stains
Flow cytometry images

Contributed by Patricia Tsang, M.D.
Flow cytometry of B-lymphoblastic lymphoma

B lymphoblastic lymphoma

Molecular / cytogenetics description
  • Most B-ALL show clonal IgH (immunoglobulin heavy locus) gene rearrangement; simultaneous T cell receptor (TCR) gene rearrangement present in up to 70%
  • Recurrent genetic abnormalities in B-ALL often have prognostic significance:
    • t(12;21) TEL-AML: very favorable prognosis; most common rearrangement in childhood B-ALL / LBL (25%), with cures of > 90%
    • Hyperdiploidy: favorable prognosis; trisomies 4, 10 and 17 have the best prognosis
    • t(9;22) BCR-ABL1 (Philadelphia chromosome): very poor prognosis; incidence increases with age, 3% of childhood cases and 25% of adult
    • t(v;11q23) MLL gene rearrangement: poor prognosis
    • Hypodiploidy: poor prognosis
    • BCR-ABL1-like IGH-CRLF2 translocation (and less commonly EPOR): CRLF2 translocation frequent in Down syndrome; standard risk in children and high risk in adolescents and adults; more frequent in Hispanics and Native Americans
    • t(5;14) IL3-IGH: uncertain prognostic significance; reactive eosinophilia is characteristic
  • Most T-ALL / LBL harbor T cell receptor gene rearrangement; simultaneous IGH gene rearrangement present in about 20%
  • In T-ALL / LBL, recurrent cytogenetic abnormalities can also be seen:
    • TCR loci at 14q11.2, 7p35 and 7p14-15, with various partner genes
    • Del (9p) with loss of tumor suppressor gene CDKN2A occurs in at least 30%
    • NOTCH1 gene mutations can lead to shorter survival in adult T-ALL / LBL
  • Reference: Swerdlow: WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues (Medicine), 4th Edition, 2017
Sample pathology report
  • Base of tongue, biopsy:
    • B lymphoblastic lymphoma, not otherwise specified (see microscopic description and FISH)
    • Microscopic description: Biopsy of the tongue shows benign squamous mucosa with an extensive and diffuse subepithelial infiltrate of medium sized to large neoplastic cells, some containing a prominent nucleolus. Mitoses and apoptotic bodies are readily observed. Immunohistochemistry demonstrates that the neoplastic cells are of precursor B cell origin (CD45+, PAX5+, CD79a+, TdT+, CD10+, CD43+, CD34 subset +, CD20 few scattered cells +). Not expressed are CD117, CD3, CD30, myeloperoxidase, lysozyme, EBV (EBER) and MYC. Proliferative fraction is > 95% based on Ki67.
    • FISH: Interphase FISH analysis performed on formalin fixed paraffin embedded tissue shows the following results
      • Positive for tetraploidy, consistent with a favorable prognostic implication in B-ALL / LBL.
      • Negative for MYC-IGH t(8;14), BCR-ABL t(9;22), BCL2 rearrangement and BCL6 rearrangement.
      • No specific genetic abnormalities were identified in the FISH ALL panel to fulfill the diagnostic criteria of B-ALL/LBL with recurrent genetic abnormalities.
Differential diagnosis
  • Burkitt lymphoma, a high grade B cell lymphoma:
    • In BL, there is typically monotypic surface immunoglobulin light chain expression
    • Starry sky histologic pattern and cytoplasmic vacuoles on smear or touch preparation
    • Unlike B-ALL / LBL, its phenotype is mature showing consistent CD20 but without CD34 or TdT expression
  • Hematogones, non-clonal B cell precursors in bone marrow, can be confused with B-ALL, especially in minimal residual disease:
    • Typically smaller than lymphoblasts
    • Have characteristic immunophenotypic expression pattern by flow cytometry
  • Thymoma with reactive thymic T cells exhibiting CD4+ CD8+ immature T cell phenotype, resembling T-LBL in anterior mediastinal mass:
    • Immunohistochemistry highlights the neoplastic epithelial cell component
    • Lobulated architecture
    • May be associated with myasthenia gravis in adults
  • Incidental indolent T lymphoproliferative proliferations (Cytometry B Clin Cytom 2020;98:282)
Board review style question #1

A 4 year old boy is brought to the physician by his mother due to a 5 week history of lethargy, a progressively enlarging left sided neck mass and a 5 day onset of unexplainable bilateral diffuse lower leg petechial hemorrhage. On exam, the left posterior cervical lymph node is enlarged and nontender to palpation. A lymph node biopsy shows a predominance of interfollicular infiltrate containing numerous blast cells and focal necrosis. Immunohistochemistry is positive for PAX5, CD10 and TdT. Upon further workup, which of the following translocations would be associated with a good prognosis?

  1. t(12;21)
  2. t(14;18)
  3. t(8;14)
  4. t(9;22)
Board review style answer #1
Board review style question #2
A 58 year old Hispanic woman comes to the physician because of a 2 month history of bilateral axillary lymphadenopathy and a new onset right breast mass at 12 o'clock. The patient has a previous history significant for Down syndrome and a diagnosis of acute lymphoblastic leukemia 20 years ago for which she received treatment and has since been free of disease. Needle core biopsy of the breast mass reveals extensive involvement by monotonous medium sized lymphoid cells with a high N/C ratio and scant cytoplasm, consistent with a diagnosis of B lymphoblastic lymphoma. Which of the following genetic mutations is most likely detected in blast cells?

  1. BCR-ABL1
  2. CRLF2
  3. ETV6-RUNX1
  4. FLT3
Board review style answer #2
Back to top
Image 01 Image 02