HAEM4Backup:Adult T-cell Leukemia/Lymphoma
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Primary Author(s)*
Prasad R. Kopparapu, PhD and Ferrin C. Wheeler, PhD, FACMG
Vanderbilt University Medical Center
Cancer Category/Type
Mature T- and NK-Cell Neoplasms
Cancer Sub-Classification / Subtype
Adult T-Cell Leukemia/lymphoma (ATLL)
Definition / Description of Disease
Adult T-cell Leukemia/Lymphoma (ATLL) is a systemic, aggressive T-cell malignancy cause by chronic infection of human T lymphotropic virus 1 (HTLV-1) with poor prognosis[1].
Synonyms / Terminology
Adult T-cell leukemia, Adult T-cell lymphoma, HTLV-1 associated adult T-cell leukemia-lymphoma.
Epidemiology / Prevalence
ATLL is endemic in many parts of Southwestern Japan, the Caribbean basin, Sub-Saharan Africa, South America, Romania, Northern Iran, parts of the Middle East and Australo-Melanesia[2][3].
ATLL occurs only in adults between 30 to 90 years of age with an average age of 58 years. The male-to-female ratio is 1.5:1[4].
Transmission occurs through breast milk, sexual fluids, peripheral blood and blood products[2].
Clinical Features
ATLL is classified into four clinical subtypes: Acute, Lymphoma, Chronic and Smoldering[5].
Acute: Most common type (65% of patients) with elevated WBC count, skin rash and generalized lymphadenopathy, hypercalcemia, hepatosplenomegaly, elevated LDH and frequent opportunistic infections like pneumocystis jirovecii pneumonia and strongyloidiasis.
Lymphoma: The lymphomatous variant is characterized by lymphadenopathy, absence of lymphocytosis, possible extranodal lesions with minimal peripheral blood involvement and less frequent hypercalcemia.
Chronic: The chronic variant can progress to acute or lymphomatous subtype. This variant manifests with lymphocytosis and exfoliative skin lesions. Atypical lymphocytes are fewer in number in peripheral blood. There can be mild hepatosplenomegaly and lymphadenopathy. Hypercalcemia is not observed, and no involvement of CNS, bone and gastrointestinal tract, and neither ascites nor pleural effusion.
Smoldering: This variant may also progress to the acute subtype upon long duration. This variant may present with skin or lung lesions. More than 5% circulating abnormal T-cell lymphocytes can be found in the absence of leukocytosis. No manifestation of hypercalcemia, hepatosplenomegaly or lymphadenopathy.
Sites of Involvement
In addition to lymph node involvement, there is involvement in extranodal sites like spleen, skin, lung, liver, gastrointestinal tract and CNS, making this a systemic disease with peripheral blood involvement[6].
Morphologic Features
The morphological features of ATLL in skin include erythema, papules, and nodules based on macroscopic examination and perivascular infiltration of atypical lymphoid cells, diffuse infiltration of medium to large sized atypical lymphoid cells and infiltration of large atypical lymphoid cell as per histopathological observations.
Lymph node lesions present as pleomorphic small, medium and large cell types, anaplastic and an angioimmunoblastic T-cell lymphoma type.
Infiltration of atypical lymphoid cells with irregular or round nuclei is seen in the bone marrow cavity with detection of hypercalcemia.
In liver, infiltration of atypical medium to large sized lymphoid cells with irregular nuclei is seen.
Diffuse, pleomorphic and anaplastic type cells can infiltrate the stomach destroying the gastric glands.
In peripheral blood, “flower like” cells that have multilobed nucleus with basophilic cytoplasm can be observed by Giemsa staining[7].
Immunophenotype
In most patients, tumor cells exhibit phenotype of mature CD4+ T cells by expressing CD2, CD3, CD5, CD25, CD45RO, CD29, T-cell receptor αβ, FOXP3, CD52, and HLA-DR[8][9].
Most cases are CD4+CD8-, but rarely, cases can be CD4-CD8+ or CD4+CD8+. A typical immunophenotype for ATLL is: CD2+, CD3+, CD4+, CD7-, CD8-, CD25+, CD30+/-, TCR αβ+[10].
Immunophenotypic characterization of CD3, CD4, CD7 , CD8, and CD25 are the minimum requirement for an ATLL diagnosis.
| Finding | Marker |
|---|---|
| Positive (universal) | CD2, CD3, CD5, CD4, CCD4 |
| Positive (subset) | CD8, CD4, CD30, FOXP3 |
| Negative (universal) | CD7, CD8, TdT, TCL1, ALK1, B cell antigens, cytotoxic molecules |
| Negative (subset) | CD4,CD8, ALK |
Chromosomal Rearrangements (Gene Fusions)
Tandem duplications of 2q33.2 segments cause formation of CTLA4-CD28 and ICOS-CD28 fusion products that render prolonged co-stimulatory signals[11].
| Chromosomal Rearrangement | Genes in Fusion (5’ or 3’ Segments) | Pathogenic Derivative | Prevalence |
|---|---|---|---|
| 2q33.2 (Tandem Duplication) | 5’ CTLA/3’CD28 | der(2) | 7% |
| 2q33.2 (Tandem Duplication) | 5’ICOS/3’CD28 | der(2) | 7% |
Characteristic Chromosomal Aberrations / Patterns
Cytogenetic studies show that ATLL often has a complex abnormal karyotype without a single distinct abnormality. Observed recurrent abnormalities include trisomy for 3, 7 or 21 and monosomy for X as well as deletion of Y and abnormalities of chromosome 6 and 14. Chromosome 14 rearrangements involving TCRA and TCRD at 14q11 and TCL1 at 14q32 have been documented[12]. Frequent deletions in known fragile sites have been detected in over 500 patients[11].
Genomic Gain/Loss/LOH
ATLL with high number of chromosomal imbalances is associated with poor survival[13][14][15][16].
| Chromosome Number | Gain/Loss/Amp/LOH | Region |
|---|---|---|
| 1 | Gain | 1q |
| 2 | Gain | 2p |
| 3 | Gain | 3p |
| 4 | Gain | 4q |
| 6 | Loss | 6q |
| 7 | Gain | 7p, 7q |
| 9 | Amp | 9p |
| 10 | Loss | 10p |
| 13 | Loss | 13q |
| 14 | Gain | 14q |
| 16 | Loss | 16q |
| 18 | Loss | 18p |
Gene Mutations (SNV/INDEL)
Over 10% of ATLL cases harbor mostly gain of function mutations. ATLL harbors multiple recurrent mutations in genes involved in the TCR-NF-κB pathway, tumor suppressors, transcription factors involved in cell growth and proliferation, apoptosis, and immune surveillance[17][16][18].
| Gene | Mutation | Oncogene/Tumor Suppressor/Other | Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) | Prevalence (COSMIC/TCGA/Other) |
|---|---|---|---|---|
| PLCG1 | TCR – NF-κB Signaling | GOF | ||
| PKCB | TCR – NF-κB Signaling | GOF | ||
| CARD11 | TCR – NF-κB Signaling | GOF | ||
| VAV1 | TCR – NF-κB Signaling | GOF | ||
| CD237 | TCR – NF-κB Signaling | GOF | ||
| RHOA | RAS-RAF-ERK pathway | GOF | ||
| IRF4 | Transcription Factor | GOF | ||
| NOTCH1 | Transcription Factor | GOF | ||
| FBXW7 | Transcription Factor | GOF | ||
| STAT3 | Transcription Factor | GOF | ||
| TNFAIP3/A20 | TCR – NF-κB Signaling | LOF | ||
| NFKBIA/IκBα | TCR – NF-κB Signaling | LOF | ||
| TRAF3 | TCR – NF-κB Signaling | LOF | ||
| CBLB | TCR – NF-κB Signaling | LOF | ||
| TP53 | Tumor Suppressor | LOF | ||
| CDKN2 | Tumor Suppressor | LOF | ||
| GATA3 | Transcription Factor | LOF | ||
| EP300 | Transcription Factor | LOF | ||
| FAS | Apoptosis | LOF | ||
| WWOX | Apoptosis | LOF | ||
| HLA-B | Immune Surveillance | LOF | ||
| B2M | Immune Surveillance | LOF | ||
| PD-L1 | Immune Surveillance | Amplification |
Other Mutations
| Type | Gene/Region/Other |
|---|---|
| Concomitant Mutations | EXAMPLE IDH1 R123H |
| Secondary Mutations | EXAMPLE Trisomy 7 |
| Mutually Exclusive | EXAMPLE EGFR Amplification |
Epigenomics (Methylation)
Epigenetic alterations also result in dysregulated TCR/NF-κB signaling in ATLL. DNA hypermethylation of CpG islands is detected in 1/3rd of all ATLL patients. As a result, genes involved in Cys2-His2 (C2H2) zinc finger genes and those encoding MHC class I molecules are silenced[11].
ATLL patients have high expression of polycomb repressive complex (PRC) 2 components like EZH2, its homolog EZH1 and H3K27 methylase causing accumulation of trimethylation of H3K27 and altering the expression of over half of the genes. The severity of the disease is linked to continued down regulation of genes[19].
Genes and Main Pathways Involved
The most important genes involved in the development and progress of ATLL are the Tax and HBZ contributed by the HTLV-1 virus and genes listed in gene mutations table (above) from the host. The main pathways involved are TCR-NF-κB signaling by gain of function and amplifications in PLCG1, VAV1 and FYN, CD28, PRKCB, CARD11, IRF4 and RHOA; and loss of function mutations or deletions in CBLB, TRAF, TNFAIP3 and CSNK1A1[11].
Genes involving the immune surveillance program are also heavy altered to evade the immune response either by deletions in MHC class1 molecules, CD58, FAS or constitutive activation of PD-L1.
Genes involved in the Lymphocyte activation and differentiation(IRF4, GATA3, IKZF2) are also altered.
Chemokine receptors including CCR4 and CCR7 are responsible for the infiltration of neoplastic cells into other organs along with activation of PI3K/AKT signaling.
The epigenetic mechanism is also exploited to alter gene expression and promote ATLL progression as explained above.
Diagnostic Testing Methods
Initial diagnosis of ATLL should include a comprehensive physical exam with skin evaluation and CT scans of the chest, abdomen and pelvis. The laboratory evaluation should include: a complete blood count (CBC), metabolic panel (serum electrolyte levels, calcium, creatinine and blood urea nitrogen) and serum LDH levels. Testing methods including PCR, Flow Cytometry, ELISA, serology, and immunohistochemistry in addition to morphologic studies may be employed to diagnose ATLL[10].
Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)
ATLL diagnosis can be made based on seropositivity for HTLV-1 and histologically and/or cytologically proven peripheral T cell lymphoma (PTCL). Diagnosis can also be made by quantifying proviral DNA loads (PVLs) in peripheral blood mononuclear cells using real time PCR. PVL of an infected person can range from 0.01 to 50% or higher. Other diagnostic criteria includes appropriate patient demographic information, hypercalcemia, skin lesions and a leukemic phase.
The prognosis of ATLL is largely dependent on the subtype. The acute and lymphomatous subtypes are aggressive, with a median survival of 6.2 months and 10.2 months, respectively. The less-aggressive chronic and smoldering subtypes have a median survival of approximately 4.5 years[5]. Prognostic factors include clinical variant, age, serum calcium and LDH levels as well as detection of opportunistic infections of parasitic or viral types and p16 gene deletion and p53 mutation.
As ATLL is resistant to most chemotherapy, there is no standard chemotherapy regimen. High dose combination chemotherapy and bone marrow transplantation have been tried previously[20]. Monoclonal antibody-based therapies against IL-2R (anti-Tac), CCR4 (mogamulizumab) and CD52 (alemtuzumab) have also been attempted along with arsenic trioxide, interferon α and zidovudine[21].
Familial Forms
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Other Information
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References
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- ↑ Thiele, J. et al., (2017). Adult T-cell leukemia/lymphoma, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p363-367
- ↑ 2.0 2.1 Gessain, Antoine; et al. (2012). "Epidemiological Aspects and World Distribution of HTLV-1 Infection". Frontiers in Microbiology. 3: 388. doi:10.3389/fmicb.2012.00388. ISSN 1664-302X. PMC 3498738. PMID 23162541.
- ↑ Mehta-Shah, Neha; et al. (08 2017). "Adult T-Cell Leukemia/Lymphoma". Journal of Oncology Practice. 13 (8): 487–492. doi:10.1200/JOP.2017.021907. ISSN 1935-469X. PMC 6366298. PMID 28796966. Check date values in:
|date=(help) - ↑ Rocquain, Julien; et al. (2010-08-02). "Combined mutations of ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 and WT1 genes in myelodysplastic syndromes and acute myeloid leukemias". BMC cancer. 10: 401. doi:10.1186/1471-2407-10-401. ISSN 1471-2407. PMC 2923633. PMID 20678218.
- ↑ 5.0 5.1 Shimoyama, M. (1991-11). "Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87)". British Journal of Haematology. 79 (3): 428–437. doi:10.1111/j.1365-2141.1991.tb08051.x. ISSN 0007-1048. PMID 1751370. Check date values in:
|date=(help) - ↑ Bunn, P. A.; et al. (1983-08-04). "Clinical course of retrovirus-associated adult T-cell lymphoma in the United States". The New England Journal of Medicine. 309 (5): 257–264. doi:10.1056/NEJM198308043090501. ISSN 0028-4793. PMID 6602943.
- ↑ Ohshima, Koichi (2007-06). "Pathological features of diseases associated with human T-cell leukemia virus type I". Cancer Science. 98 (6): 772–778. doi:10.1111/j.1349-7006.2007.00456.x. ISSN 1347-9032. PMID 17388788. Check date values in:
|date=(help) - ↑ Roncador, G.; et al. (2005-12). "FOXP3, a selective marker for a subset of adult T-cell leukaemia/lymphoma". Leukemia. 19 (12): 2247–2253. doi:10.1038/sj.leu.2403965. ISSN 0887-6924. PMID 16193085. Check date values in:
|date=(help) - ↑ Ishida, Takashi; et al. (2003-09-01). "Clinical significance of CCR4 expression in adult T-cell leukemia/lymphoma: its close association with skin involvement and unfavorable outcome". Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 9 (10 Pt 1): 3625–3634. ISSN 1078-0432. PMID 14506150.
- ↑ 10.0 10.1 NCCN Clinical Practice Guidelines in Oncology, T-Cell Lymphomas, Version 1.2021. Available at NCCN.org.
- ↑ 11.0 11.1 11.2 11.3 Kataoka, Keisuke; et al. (2015-11). "Integrated molecular analysis of adult T cell leukemia/lymphoma". Nature Genetics. 47 (11): 1304–1315. doi:10.1038/ng.3415. ISSN 1546-1718. PMID 26437031. Check date values in:
|date=(help) - ↑ "Correlation of chromosome abnormalities with histologic and immunologic characteristics in non-Hodgkin's lymphoma and adult T cell leukemia-lymphoma. Fifth International Workshop on Chromosomes in Leukemia-Lymphoma". Blood. 70 (5): 1554–1564. 1987-11. ISSN 0006-4971. PMID 2889485. Check date values in:
|date=(help) - ↑ Itoyama, T.; et al. (2001-06-01). "Cytogenetic analysis and clinical significance in adult T-cell leukemia/lymphoma: a study of 50 cases from the human T-cell leukemia virus type-1 endemic area, Nagasaki". Blood. 97 (11): 3612–3620. doi:10.1182/blood.v97.11.3612. ISSN 0006-4971. PMID 11369658.
- ↑ Tsukasaki, K.; et al. (2001-06-15). "Comparative genomic hybridization analysis in adult T-cell leukemia/lymphoma: correlation with clinical course". Blood. 97 (12): 3875–3881. doi:10.1182/blood.v97.12.3875. ISSN 0006-4971. PMID 11389029.
- ↑ Oshiro, Aya; et al. (2006-06-01). "Identification of subtype-specific genomic alterations in aggressive adult T-cell leukemia/lymphoma". Blood. 107 (11): 4500–4507. doi:10.1182/blood-2005-09-3801. ISSN 0006-4971. PMID 16484591.
- ↑ 16.0 16.1 Kataoka, Keisuke; et al. (01 11, 2018). "Prognostic relevance of integrated genetic profiling in adult T-cell leukemia/lymphoma". Blood. 131 (2): 215–225. doi:10.1182/blood-2017-01-761874. ISSN 1528-0020. PMC 5757690. PMID 29084771. Check date values in:
|date=(help) - ↑ Kogure, Yasunori; et al. (2017-09). "Genetic alterations in adult T-cell leukemia/lymphoma". Cancer Science. 108 (9): 1719–1725. doi:10.1111/cas.13303. ISSN 1349-7006. PMC 5581529. PMID 28627735. Check date values in:
|date=(help) - ↑ Kataoka, Keisuke; et al. (2015-11). "Integrated molecular analysis of adult T cell leukemia/lymphoma". Nature Genetics. 47 (11): 1304–1315. doi:10.1038/ng.3415. ISSN 1546-1718. PMID 26437031. Check date values in:
|date=(help) - ↑ Fujikawa, Dai; et al. (2016-04-07). "Polycomb-dependent epigenetic landscape in adult T-cell leukemia". Blood. 127 (14): 1790–1802. doi:10.1182/blood-2015-08-662593. ISSN 1528-0020. PMID 26773042.
- ↑ Hishizawa, Masakatsu; et al. (2010-08-26). "Transplantation of allogeneic hematopoietic stem cells for adult T-cell leukemia: a nationwide retrospective study". Blood. 116 (8): 1369–1376. doi:10.1182/blood-2009-10-247510. ISSN 1528-0020. PMID 20479287.
- ↑ Hermine, Olivier; et al. (02 2018). "A Review of New Findings in Adult T-cell Leukemia-Lymphoma: A Focus on Current and Emerging Treatment Strategies". Advances in Therapy. 35 (2): 135–152. doi:10.1007/s12325-018-0658-4. ISSN 1865-8652. PMC 5818559. PMID 29411267. Check date values in:
|date=(help)
EXAMPLE Book
- Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p129-171.
Notes
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