Primary cutaneous CD30-positive T-cell lymphoproliferative disorder: Primary cutaneous anaplastic large cell lymphoma

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Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification
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Primary Author(s)*

Theresa Spivey, MD, Shashirekha Shetty, PhD

WHO Classification of Disease

Structure Disease
Book Haematolymphoid Tumours (5th ed.)
Category T-cell and NK-cell lymphoid proliferations and lymphomas
Family Mature T-cell and NK-cell neoplasms
Type Primary cutaneous T-cell lymphoid proliferations and lymphomas
Subtype(s) Primary cutaneous CD30-positive T-cell lymphoproliferative disorder: Primary cutaneous anaplastic large cell lymphoma

Definition / Description of Disease

  • Primary cutaneous anaplastic large cell lymphoma (C-ALCL) is a form of cutaneous T-cell lymphoma with majority (>75%) of tumor cells expressing CD30.
  • CD30+ LPDs are a part of a spectrum of diseases with overlapping features and are associated with an excellent prognosis. The group includes lymphomatoid papulosis (LyP) and C-ALCL, which are distinguished by clinical features and disease course.
  • C-ALCL is a distinct entity from systemic anaplastic large cell lymphoma (ALCL), which can have cutaneous involvement.
  • Diagnosis must exclude large cell transformation of mycosis fungoides, which can express CD30.


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[1][2][3]

Synonyms / Terminology

  • Primary Cutaneous CD30-positive T-cell lymphoproliferative disorder

Epidemiology / Prevalence

  • Second most common type of cutaneous T-cell lymphoma
  • Median age: 60 years. Cases have been reported in children.
  • Male:Female 2-3:1
  • Disease-specific 5-year survival rate 95%


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[1][3]

Clinical Features

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Signs and Symptoms EXAMPLE: Asymptomatic (incidental finding on complete blood counts)

EXAMPLE: B-symptoms (weight loss, fever, night sweats)

EXAMPLE: Fatigue

EXAMPLE: Lymphadenopathy (uncommon)

Laboratory Findings EXAMPLE: Cytopenias

EXAMPLE: Lymphocytosis (low level)


editv4:Clinical Features
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  • Solitary or localized nodules or tumors, with frequent ulceration. Multifocal lesions are seen in 20% of patients.
  • Lesions may regress, either partially or completely, but cutaneous relapse is common.
  • Extracutaneous dissemination is seen in 10-15% of cases, most cases involving regional lymph nodes.
  • Associated with excellent prognosis, even in those with regional lymph node involvement or multifocal skin lesions.
  • Anaplastic morphology does not impact disease course or prognosis.
  • Distinguishing from LyP is important for therapy, as surgical excision and radiotherapy are first-line treatments in patients with C-ALCL.


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[1][2][3]

Sites of Involvement

  • Limited to cutaneous sites, most frequently affecting the trunk, face, and extremities.


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[1]

Morphologic Features

  • Sheets or nodular dermal infiltrate of large pleomorphic, anaplastic, or immunoblastic cells
  • Irregularly shaped nuclei
  • Abundant, pale to eosinophilic, cytoplasm
  • Reactive lymphocytes in the periphery
  • Ulcerated lesions may resemble lymphomatoid papulosis with increased inflammatory infiltrate composed of T-cells, histiocytes, eosinophils, and neutrophils, with fewer CD30+ cells.
  • In cases harboring DUSP22-IRF4 translocations, CD30+ cells commonly display biphasic morphology - small, cerebriform lymphocytes within the epidermis and large transformed cells in dermis.


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[1][2][3]

Immunophenotype

Finding Marker
Positive (activated T-cell markers)* CD4, CD30 (diagnosis requires >75% expression of tumor cells)
Variable (pan T-cell markers) CD2, CD3, CD5
Positive Cytotoxic proteins†: Granzyme B, TIA1, perforin

CD15 (40%), IRF4/MUM1, CLA (cutaneous lymphocyte antigen)

Negative EMA‡, ALK‡, PAX5, EBV, CD56 (rare cases with coexpression)

*Some cases may have a T-cell phenotype of CD4-/CD8+ or CD4+/CD8+ or null-cell phenotype.

†Cases with DUSP22-IRF4 rearrangement tend to express

‡EMA and ALK are typically positive in systemic ALCL, however there are rare cases of ALK+ primary C-ALCL.


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[1][2]

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
EXAMPLE: t(9;22)(q34;q11.2) EXAMPLE: 3'ABL1 / 5'BCR EXAMPLE: der(22) EXAMPLE: 20% (COSMIC)

EXAMPLE: 30% (add reference)

Yes No Yes EXAMPLE:

The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).


editv4:Chromosomal Rearrangements (Gene Fusions)
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  • Rearrangements of DUSP22-IRF4 locus on chromosome 6p25.3 are found in 25% of primary C-ALCL and in rare cases of LyP and transformed mycosis fungoides. The rearrangements have not found in systemic ALCL or other T-cell LPDs.[4]
  • TYK2 (19p13) rearrangements in 15% of CD30+ lymphoproliferative disorders, with recurrent NPM1-TYK2 fusions reported in primary C-ALCL and LyP.[5]
  • TP63 rearrangements on 3q28 are rare in C-ALCL.[6]
  • Rare cases of primary C-ALCL contain ALK rearrangements and associated expression of ALK.[7]


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)
  • DUSP22-IRF4 rearrangement have not been shown to impact disease behavior prognosis.[8]
  • TP63 rearrangements are associated with refractoriness to chemotherapy and poor prognosis[6]

Individual Region Genomic Gain / Loss / LOH

Put your text here and fill in the table (Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable. Do not delete table.)

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
EXAMPLE:

7

EXAMPLE: Loss 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).

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Chromosome Number Gain/Loss/Amp/LOH Associated Genes
7q31 Gain MET
6q16-6q21 Loss PRDM1
13q34 Loss CDC16/CUL4A
  • The genomic gains and losses listed above are the most common and seen in 45% of cases.


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[9]

Characteristic Chromosomal Patterns

Put your text here (EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis. Do not delete table.)

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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  • Clonal T-cell receptor gene rearrangement is detected in majority of cases. [10]

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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N/A

Epigenomic Alterations

N/A

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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  • DUSP22 rearrangements associated with decreased production in the enzyme, dual-specificity phosphatase-22, which regulates MAPK signaling pathway.[6]
  • NPM1-TYK2 fusion is associated with constitutive STAT signaling.[5]

Genetic Diagnostic Testing Methods

  • Requires clinical and histopathologic correlation to diagnose and separate from lymphomatoid papulosis and large cell transformation of mycosis fungoides.
  • Must exclude systemic involvement by ALCL with cutaneous involvement or history of mycosis fungoides.


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[1]

Familial Forms

N/A

Additional Information

N/A

Links

References

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  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Arber DA, et al., (2017). Primary Cutaneous CD30-positive T-cell Lymphoproliferative Disorders, 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, p392-396.
  2. ↑ 2.0 2.1 2.2 2.3 Kempf, Werner; et al. (2011-10-13). "EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma*". Blood. 118 (15): 4024–4035. doi:10.1182/blood-2011-05-351346. ISSN 0006-4971. PMC 3204726. PMID 21841159.CS1 maint: PMC format (link)
  3. ↑ 3.0 3.1 3.2 3.3 Willemze, Rein; et al. (2019-04-18). "The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas". Blood. 133 (16): 1703–1714. doi:10.1182/blood-2018-11-881268. ISSN 0006-4971.
  4. ↑ Wada, David A.; et al. (2011-04). "Specificity of IRF4 translocations for primary cutaneous anaplastic large cell lymphoma: a multicenter study of 204 skin biopsies". Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 24 (4): 596–605. doi:10.1038/modpathol.2010.225. ISSN 1530-0285. PMC 3122134. PMID 21169992. Check date values in: |date= (help)
  5. ↑ 5.0 5.1 Velusamy, Thirunavukkarasu; et al. (2014-12-11). "A novel recurrent NPM1-TYK2 gene fusion in cutaneous CD30-positive lymphoproliferative disorders". Blood. 124 (25): 3768–3771. doi:10.1182/blood-2014-07-588434. ISSN 0006-4971.
  6. ↑ 6.0 6.1 6.2 Pedersen, Martin Bjerregård; et al. (2017-07-27). "DUSP22 and TP63 rearrangements predict outcome of ALK-negative anaplastic large cell lymphoma: a Danish cohort study". Blood. 130 (4): 554–557. doi:10.1182/blood-2016-12-755496. ISSN 0006-4971. PMC 5533203. PMID 28522440.CS1 maint: PMC format (link)
  7. ↑ Melchers, Rutger C.; et al. (2020-06). "Clinical, Histologic, and Molecular Characteristics of Anaplastic Lymphoma Kinase-positive Primary Cutaneous Anaplastic Large Cell Lymphoma". The American Journal of Surgical Pathology. 44 (6): 776–781. doi:10.1097/PAS.0000000000001449. ISSN 0147-5185. Check date values in: |date= (help)
  8. ↑ Willemze, Rein; et al. (2019-04-18). "The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas". Blood. 133 (16): 1703–1714. doi:10.1182/blood-2018-11-881268. ISSN 0006-4971. PMC 6473500. PMID 30635287.CS1 maint: PMC format (link)
  9. ↑ van Kester, Marloes S.; et al. (2010-02). "Cutaneous Anaplastic Large Cell Lymphoma and Peripheral T-Cell Lymphoma NOS Show Distinct Chromosomal Alterations and Differential Expression of Chemokine Receptors and Apoptosis Regulators". Journal of Investigative Dermatology. 130 (2): 563–575. doi:10.1038/jid.2009.270. ISSN 0022-202X. Check date values in: |date= (help)
  10. ↑ Greisser, Johannes; et al. (2006-11). "Detection of clonal rearrangement of T-cell receptor genes in the diagnosis of primary cutaneous CD30 lymphoproliferative disorders". Journal of Cutaneous Pathology. 33 (11): 711–715. doi:10.1111/j.1600-0560.2006.00560.x. ISSN 0303-6987. PMID 17083688. Check date values in: |date= (help)

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: “Primary cutaneous CD30-positive T-cell lymphoproliferative disorder: Primary cutaneous anaplastic large cell lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 09/6/2024, https://ccga.io/index.php/HAEM5:Primary_cutaneous_CD30-positive_T-cell_lymphoproliferative_disorder:_Primary_cutaneous_anaplastic_large_cell_lymphoma.

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