HAEM5:ALK-positive anaplastic large cell lymphoma

Haematolymphoid Tumours (5th ed.)

editHAEM5 Conversion Notes

This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Anaplastic Large Cell Lymphoma, ALK-Positive.

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Primary Author(s)*

Miguel Gonzalez Mancera, MD, Cedars-Sinai, Los Angeles, CA

Sumire Kitahara, MD, Cedars-Sinai, Los Angeles, CA

Cancer Category / Type

• HAEM4:Mature T- and NK-cell Neoplasms

Cancer Sub-Classification / Subtype

• Systemic T-cell lymphoma

Definition / Description of Disease

Anaplastic Large Cell Lymphoma, ALK-Positive (ALK+ ALCL) is a T-cell lymphoma characterized by usually large lymphoma cells with abundant cytoplasm and pleomorphic nuclei, often horse-shoe shaped (see Morphologic Features below), with a chromosomal rearrangement involving the ALK gene resulting in expression of ALK protein and CD30

Synonyms / Terminology

• Ki-1 (CD30) lymphoma - obsolete

Epidemiology / Prevalence

• ALCL (ALK+, ALK-, and primary cutaneous) account for <5% of all cases of non-Hodgkin lymphoma (NHL)

• ALK+ ALCL
  • ~3% of adult NHL
  • 10-20% of childhood lymphomas
  • Most frequent in the first three decades of life
  • Male:female = 1.5:1

Clinical Features

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Signs and Symptoms	Most patients (70%) present with advanced (stage III-IV) disease and B-symptoms.
Laboratory Findings	Noncontributory

editv4:Clinical Features

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• Most patients (70%) present with advanced (stage III-IV) disease and B-symptoms.

Sites of Involvement

• Lymph nodes and extranodal sites (most commonly skin, bone, soft tissue, lungs and liver)
• Bone marrow involvement detected in 30% when using immunohistochemistry (CD30 and EMA). Can miss marrow involvement by H&E evaluation alone, which detects involvement with ~10% incidence.

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Morphologic Features

"Hallmark cells"

• Lymphoma cells characterized by eccentric, horseshoe-shaped or kidney-shaped nuclei, often with eosinophilic cytoplasm accentuated near the nucleus
• Usually large in size, but may also be smaller
• Present in varying proportions
• Seen in all morphological variants/patterns of ALK+ ALCL

Morphological variants/patterns

1. Common (60%): predominant population of large hallmark cells
2. Lymphohistiocytic (10%): lymphoma cells are admixed with numerous reactive histiocytes that may obscure the lymphoma cells; lymphoma cells often cluster around vessels and are often smaller than in the common pattern
3. Small cell (5-10%): predominant population of smaller lymphoma cells; hallmark cells are often concentrated around vessels; may also see "fried egg cells" (pale cytoplasm with central nucleus) or signet ring-like cells; can misdiagnose of peripheral T-cell lymphoma, NOS
4. Hodgkin-like (3%): mimics nodular sclerosis classic Hodgkin lymphoma
5. Composite (15%): more than one pattern in a single lymph node

When lymph node is only partially involved, lymphoma characteristically grows in the sinuses, which may mimic a metastatic tumor.

Immunophenotype

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Finding	Marker
Positive (universal) - Cell membrane and Golgi; large lymphoma cells show strongest staining; smaller cells may show weak, partial to negative staining	CD30
Positive (universal) - Cellular location of ALK staining varies depending on ALK translocation partner. In the most common t(2;5), most cases show both cytoplasmic and nuclear	ALK
Positive (subset)	EMA
Negative - >75% of cases are CD3-negative	CD3
Positive (70%)	CD4
Negative in majority of cases	CD8
Positive in majority of cases	CD2
Positive in majority of cases	CD5
Positive	TIA1
Positive	Granzyme B
Positive	Perforin
Variably positive	CD45
Positive (universal)	CD25
Negative (universal)	BCL2

editv4:Immunophenotype

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ALK+ ALCL show the following staining pattern:

• CD30+: Cell membrane and Golgi; large lymphoma cells show strongest staining; smaller cells may show weak, partial to negative staining
• ALK+: cellular location of ALK staining varies depending on ALK translocation partner. In the most common t(2;5), most cases show both cytoplasmic and nuclear ALK staining. In the small cell variant, staining is usually restricted to the nucleus
• EMA+: some cases show positivity in only a proportion of lymphoma cells
• CD3(-): >75% of cases are CD3-negative
• CD4>>>CD8
• CD2 and CD5: Majority positive
• Cytotoxic marker(s)+: TIA1, granzyme B and/or perforin
• CD45: variably positive
• CD25+
• BCL2-negative

Chromosomal Rearrangements (Gene Fusions)

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Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
t(2;5)(p23;q35)	3' ALK / 5' NPM1	NPM1::ALK fusion protein	84%	No	No	Yes	ALK inhibition (crizotinib) can be an effective 2nd-line therapeutic strategy as ALK is essential for the proliferation and survival of ALK+ ALCL cells Drug resistance may develop due to: Mutations of the ALK gene impairing binding of the inhibitor; other ALK inhibitors are not currently FDA-approved for use in ALK+ ALCL See also gene mutations section above Engagement of other cell signaling pathways
t(1;2)(q25;p23)	3' ALK / 5' TPM3	TPM3::ALK Fusion protein	13%	No	No	No
inv(2)(p23q35)	3' ALK / 5' ATIC	ATIC::ALK fusion protein	1%	No	No	No
t(2;3)(p23;q12.2)	3' ALK / 5' TFG	TFG::ALK fusion protein	<1%	No	No	No
t(2;17)(p23;q23)	3' ALK / 5' CLTC	CLTC::ALK fusion protein	<1%	No	No	No
t(X;2)(q11-22;p23)	3' ALK / 5' MSN	MSN::ALK fusion protein	<1%	No	No	No
t(2;19)(p23;p13.1)	3' ALK / 5' TPM4	TPM4::ALK fusion protein	<1%	No	No	No
t(2;22)(p23;q11.2)	3' ALK / 5' MYH9	MYH9::ALK fusion protein	<1%	No	No	No
t(2;17)(p23;q25)	3' ALK / 5' RNF213	RNF213::ALK fusion protein	<1%	No	No	No
t(2;9)(p23;q33)	3' ALK / 5' TRAF-1	TRAF-1::ALK fusion protein	<1%	No	No	No

editv4:Chromosomal Rearrangements (Gene Fusions)

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• ALK(+) ALCL is characterized by chromosomal translocations involving ALK gene, a receptor tyrosine kinase domain at 2p23.
• Approximately 80% of cases show a cytogenetic translocation t(2;5) (NPM1-ALK, t(2;5)(p23;q35)) which fuses the ALK gene to the nucleophosmine (NPM) gene at 5q35, resulting in the overexpression and constitutive activation of a chimeric ALK fusion protein, which plays an important role in ALK-mediated oncogenesis.
• ALK translocations may be seen in multiple malignancies including epithelial malignancies, inflammatory myofibroblastic tumor, non-Hodgkin's lymphoma, and ALK+ histiocytosis .

FISH break apart probe for ALK gene showing a split signal indicating ALK rearrangement in a case of ALK(+) ALCL.

Table below shows described ALK translocations with ALK staining pattern, and frequency of cases. Of note, identifying the ALK fusion partner is not considered necessary in routine clinical practice.

Chromosomal Anomaly	ALK partner	ALK staining pattern	Percentage of cases
t(2;5)(p23;q35)	NPM1	Nuclear, nucleolar, diffuse cytoplasmic	84%
t(1;2)(q25;p23)	TPM3	Diffuse cytoplasmic with peripheral intensification	13%
inv(2)(p23q35)	ATIC	Diffuse cytoplasmic	1%
t(2;3)(p23;q12.2)	TFG	Diffuse cytoplasmic	<1%
t(2;17)(p23;q23)	CLTC	Granular cytoplasmic	<1%
t(X;2)(q11-22;p23)	MSN	Membrane	<1%
t(2;19)(p23;p13.1)	TPM4	Diffuse cytoplasmic	<1%
t(2;22)(p23;q11.2)	MYH9	Diffuse cytoplasmic	<1%
t(2;17)(p23;q25)	RNF213	Diffuse cytoplasmic	<1%
t(2;9)(p23;q33)	TRAF-1	Diffuse cytoplasmic	<1%

editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).

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• Chromosomal Rearrangements (Gene Fusions)
• Individual Region Genomic Gain/Loss/LOH
• Characteristic Chromosomal Patterns
• Gene Mutations (SNV/INDEL)

Diagnosis

• As stated above, the diagnosis is based on histology and immunohistochemistry
• FISH is not required for diagnosis in routine practice

Prognosis

• ALK+ ALCL has a better survival rate compared to ALK-negative ALCL
  • However, differences in patient age (younger in ALK+) may account for this better survival
• Different ALK translocation partners do not have prognostic significance
• Survival is predicted by International Prognostic Index (IPI) with overall long term survival rate approaching 80%
• Detecting minimal residual disease by PCR for NPM1-ALK (not readily commercially available) in bone marrow and peripheral blood during treatment could identify patients at risk of relapse
• Small-cell or lymphohistiocytic patterns tend to present with disseminated disease and have a less favorable prognosis than the common pattern
• NOTCH1 may be a biomarker for risk of relapse

Therapy

• CD30 expression on ALCL (ALK+ or ALK-) allows for targeted therapy
  • First-line therapy: Brentuximab (anti-CD30) vedotin + CHP (cyclophosphamide, doxorubicin, and prednisone)
• ALK inhibition (crizotinib) can be an effective 2nd-line therapeutic strategy as ALK is essential for the proliferation and survival of ALK+ ALCL cells
  • Drug resistance may develop due to:
    1. Mutations of the ALK gene impairing binding of the inhibitor; other ALK inhibitors are not currently FDA-approved for use in ALK+ ALCL
    2. See also gene mutations section above
    3. Engagement of other cell signaling pathways
• Preclinical models suggest role of:
  • Combination therapy with hypomethylating agents (such as azacitidine) and epigenetic modifying drugs (such as romidepsin, a histone deacetylase inhibitor)
  • Inhibitors of HSP90 and mTOR inhibition
  • NOTCH1 inhibition by γ-secretase inhibitors (GSI) in combination with crizotinib may provide synergistic anti-tumor activity, or as a single agent in ALK-inhibitor resistant cell lines

Individual Region Genomic Gain / Loss / LOH

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Chr #	Gain / Loss / Amp / LOH	Minimal Region Genomic Coordinates [Genome Build]	Minimal Region Cytoband	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
2q	Gain	EXAMPLE chr7:1- 159,335,973 [hg38]	EXAMPLE chr7	Yes	Yes	No	EXAMPLE Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).
EXAMPLE 8	EXAMPLE Gain	EXAMPLE chr8:1-145,138,636 [hg38]	EXAMPLE chr8	No	No	No	EXAMPLE Common recurrent secondary finding for t(8;21) (add reference).

editv4:Genomic Gain/Loss/LOH

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Frequent secondary chromosomal imbalances are seen in ALK+ ALCL (58% of cases), as based on comparative genomic hybridization analysis.

Chromosome Number	Gain/Loss/Amp/LOH	Frequency	Comment
2q	Gain	12%
4q	Loss	28%
11q22 (ATM)	Loss, LOH	28%
13q	Loss	28%	Also see in ALK- cases
7p	Gain	12%	Also seen in ALK- cases
17p13 (TP53)	Gain	28%
17p13 (TP53)	Loss	9%	More common in ALK- cases (42%)
17q24-qter	Gain	28%

Characteristic Chromosomal Patterns

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Chromosomal Pattern	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE Co-deletion of 1p and 18q	Yes	No	No	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

editv4:Characteristic Chromosomal Aberrations / Patterns

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See other sections.

Gene Mutations (SNV / INDEL)

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Gene; Genetic Alteration	Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)	Prevalence (COSMIC / TCGA / Other)	Concomitant Mutations	Mutually Exclusive Mutations	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: TP53; Variable LOF mutations EXAMPLE: EGFR; Exon 20 mutations EXAMPLE: BRAF; Activating mutations	EXAMPLE: TSG	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add Reference)	EXAMPLE: IDH1 R123H	EXAMPLE: EGFR amplification				EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).

Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

editv4:Gene Mutations (SNV/INDEL)

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• Limited literature on somatic mutations in ALK+ ALCL

Gene	Function or Presumed Mechanism	Frequency
LRP1B	Tumor suppressor	19%
NOTCH1	Activating	9.3% (p.Thr349Pro) 10.2% (p.Thr311Pro)
TP53	Tumor suppressor	11%

• Epigenetic modifier genes: KMT2D, TET2, EP300, KMT2C
• Other mutations: EPHA5

Negative genes mutations:

• JAK1, STAT3: Mutations described in ALK(-) ALCL, and breast implant-associated anaplastic large cell lymphoma (BIA-ALCL)

• RHOA, DNMT3A, CD28: Mutations described in peripheral T cell-lymphoma (PTCL), NOS, and in angioimmunoblastic T-cell lymphoma (AITL)
• IDH2 mutations are relatively specific for AITL

A variety of mechanisms for the acquired resistance to ALK inhibitors, such as crizotinib, have been described:

• ALK kinase domain secondary mutations, including L1196 M, G1269A, L1152R, C1156Y, I1171T, F1174 L, G1202R, and S1206Y, have been identified as the key mechanism of resistance
• The G1269A mutation, in which the glycine at 1269 is substituted with an alanine, causes steric hindrance, resulting in decreased affinity for crizotinib.
• Gain in ALK copy number and loss of ALK gene rearrangement have also been implicated in the development of acquired resistance to crizotinib.
  

Epigenomic Alterations

• NPM-ALK via STAT3-activated DNA methyltransferases uses epigenetic silencing mechanisms to:
  • Downregulate tumor suppressor genes to maintain its own expression (i.e. to inhibit downregulation of NPM-ALK). Silenced tumor suppressors include:
    • STAT5A
    • SHP-1 phosphotyrosine phosphatase
    • IL-2Rγ
    • miR-150
    • DNMT1 mRNA inhibitor miR-21
  • Silence T-cell receptor complex and signaling pathway (CD3e, ZAP70, LAT, SLP76)
• Histone H3 lysine 27 (H3K27) trimethylation silences promoters of important T-cell transcription factor genes (GATA3, TCF1 and LEF1)
• Reader is directed to this review for more comprehensive review of epigenetics in peripheral T-cell lymphomas

Genes and Main Pathways Involved

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Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations	EXAMPLE: MAPK signaling	EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations	EXAMPLE: Cell cycle regulation	EXAMPLE: Unregulated cell division
EXAMPLE:  KMT2C and ARID1A; Inactivating mutations	EXAMPLE:  Histone modification, chromatin remodeling	EXAMPLE:  Abnormal gene expression program

editv4:Genes and Main Pathways Involved

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• Activation of the ALK catalytic domain leads to the oncogenic properties of the ALK protein, leading to activation of multiple signaling cascades including:
  • RAS-ERK
  • JAK/STAT
    • STAT3 is a pivotal transcription factor in most ALCL subtypes:
      • NPM1/ALK and variants lead to expression of ALK fusion proteins with constitutive ALK tyrosine kinase activity, which converges in the activation of the downstream oncogenic transcription factor STAT3.
      • In the absence of ALK fusions there are activation JAK1 and/or STAT3 mutations in ALK(-) ALCL , and some BIA-ALCL. .
  • PI3K/AKT/mTOR
• ALK-NPM-STAT3 induces:
  • See Epigenomics section above
  • TGF beta, IL-10, PD-L1/CD274 to create immunosuppressive microenvironment and evasion of immune system
  • ICOS expression (CD28 costimulatory receptor superfamily)
  • HIF1α expression induces expression of VEGF (tumor angiogenesis); allows lymphoma cells to adapt to hypoxic conditions
• Expression of embryonic genes (SOX2, SALL4) promoting stem cell-like program
• Deregulation of microRNAs (miR-155, miR-101, miR-17-92 cluster, miR-26a, miR-16)

Genetic Diagnostic Testing Methods

• Diagnosis is based on histologic evaluation and immunohistochemical positivity for CD30 and ALK on the T-lymphoma cells.
• FISH using an ALK breakapart probe or karyotype analysis can detect ALK translocations, but is not required for diagnosis as it can be established by morphology and immunohistochemistry.

Familial Forms

• None

Additional Information

• None

Links

• See References.

References

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Notes

*Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.

*Citation of this Page: “ALK-positive anaplastic large cell lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 06/21/2024, https://ccga.io/index.php/HAEM5:ALK-positive_anaplastic_large_cell_lymphoma.

Other Sections

Primary Authors*

Miguel Gonzalez Mancera, MD

Sumire Kitahara, MD

Cedars-Sinai, Los Angeles, CA