Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma

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Haematolymphoid Tumours (5th ed.)

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Primary Author(s)*

Ahmed Eladely, MBBCh. Andrew Siref, MD.

Creighton University, Omaha, NE.

Cancer Category / Type

Book WHO Classification of Disease - 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 Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma

Cancer Sub-Classification / Subtype

None

Definition / Description of Disease

Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma (PCAETL) is a rare and poorly characterized neoplastic proliferation of T lymphocytes with CD8 and cytotoxic molecule expression. PACETL is marked by epidermal necrosis, a high proliferation index, and aggressive clinical behavior. It should be distinguished from other rare epidermotropic subtypes of cutaneous gamma-delta T-cell lymphomas (such as gamma-delta mycosis fungoides), CD8+ mycosis fungoides, localized pagetoid reticulosis, type D lymphomatoid papulosis.[1][2][3]

Synonyms / Terminology

Berti lymphoma

Disseminated pagetoid reticulosis, Ketron–Goodman type (obsolete)

Epidemiology / Prevalence

PCAETL is rare, comprising less than 1% of all cutaneous T-cell lymphomas. It typically occurs in adults and shows a predilection for males.[1][3]

Clinical Features

Signs and Symptoms Diffusely distributed papules (common)

Localized papules (less common)

Ulcerated nodules, tumors, and plaques

Erosion or central necrosis

Preceded by chronic, poorly defined patches (subset)

Disseminate to visceral sites (lungs, testes, CNS)

Lymph nodes spared

No association with immunosuppression[1][2][3]

Laboratory Findings None

Sites of Involvement

PACETL can present with either localized or generalized skin lesions and may affect oral mucosa.[4]

Morphologic Features

Pagetoid epithelial involvement (epidermal and adnexal) is typically observed, however the infiltrate may involve the entire dermis. [3][5] Lymphocyte morphology ranges from monomorphic to pleomorphic. Rimming of subcutaneous fat spaces has been reported. Spongiosis can result in blister formation.[6]

The tumor cells typically consist of atypical small to large lymphocytes with indented nuclei, minimal cytoplasm, and occasional immunoblastic features. Histological signs of cytotoxicity are evident, including epidermal necrosis or ulceration, dermal necrosis, karyorrhexis, and rare angiocentric destruction.[2][3][6] Ulceration can resemble pyoderma gangrenosum.[7] There is often pronounced pagetoid epidermotropism, particularly in cases with widespread lesions.[1][8]

Immunophenotype

Finding Marker
Positive (universal) CD3, TIA1, granzyme B, perforin, CCR4
CD4/CD8 CD8+/CD4-; rare cases of double positivity or double negativity have been reported
CD2/CD5/CD7 CD2(+/-), CD5(-), CD7(-/+)
TCR TCR-βF1+, rarely TCRγδ+; rare cases of double positive and null type have been reported
Ki67 % >75%
Negative (universal) EBER, CD1a, CD30, CD25, ALK1, EMA
Variable CD45RA(+/-), CD15(-/+)

Immunohistochemistry for phosphorylated STAT3 and STAT5 can be utilized to identify activation of the JAK/STAT pathway.[9][10][11]

Chromosomal Rearrangements (Gene Fusions)

In PCAETL, recurrent genomic events affecting genes involved in the cell cycle, chromatin regulation, and the JAK/STAT pathway have been reported, including complex genomic rearrangements and diverse JAK2 fusions.[10]Upregulated JAK2 signaling is a consistent finding in nearly all cases, distinguishing PCAETL from other cytotoxic cutaneous T-cell lymphomas. Cases without JAK2 fusions often exhibit gain-of-function mutations in JAK2, STAT3, and STAT5B, alongside loss of negative regulators of the JAK/STAT pathway, particularly SH2B3.[11]

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
JAK2 fusions KHDRBS1-JAK2

PCM1-JAK2

TFG-JAK2

Self-oligo/dimerization of JAK2 Yes Unknown Yes Confers cytokine-independent survival

Potential therapeutic target with JAK inhibitors [9][10][11]

PTPRC fusion
SH2B3 fusion

Individual Region Genomic Gain / Loss / LOH

Chr # Gain / Loss / Amp / LOH Minimal Region Cytoband Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
1p Deletion 1p Yes Unknown No Associated with chromatin remodeling and tumor suppression.
7 Gain q21.11-q22.3
7 Gain q32.1-q36.1
7 Gain q36.1-q36.3
8 Gain q24.3
9 Loss p21.3
14 Loss q11.2
17 Gain q21.31
17 Gain q21.33-q22
17 Gain q25.3
8p Deletion 8p Yes Unknown No Common in fusion-negative cases.[9][10][11]

Characteristic Chromosomal Patterns

Chromosomal Pattern Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
Deletions within 1p, 8p, 9q, 10p, 11q and 13q

Gains within 7q, 8q, 17q and 21q

Yes Unknown Unknown Identified in fusion-negative cases.[9][10][11]

Gene Mutations (SNV / INDEL)

Gene; Genetic Alteration Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / 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
JAK2

Fusion genes: KHDRBS1-JAK2, PCM1-JAK2, TFG-JAK2

Self-oligo/dimerization MYC fusions PTPRC, SH2B3 Yes Unknown Yes Potential therapeutic target with JAK inhibitors.[9][10][11]

Epigenomic Alterations

Unknown

Genes and Main Pathways Involved

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
JAK2; Fusion with KHDRBS1, PCM1, or TFG JAK-STAT signaling Upregulation leads to cytokine-independent activation.
SH2B3; Deletion JAK-STAT negative regulation Loss leads to hyperactivation of JAK2 signaling.[11]

Genetic Diagnostic Testing Methods

JAK2 by Next-generation sequencing (NGS). SH2B3 deletion by PCR or FISH.[11]

Familial Forms

Unknown

Additional Information

PCAETL has an aggressive clinical course, with a median survival time of 12 months. The prognosis is similar regardless of whether the morphology is small or large cell, or whether the lesions are localized or diffuse.[2]

Links

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References

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  1. 1.0 1.1 1.2 1.3 Berti, E.; et al. (1999-08). "Primary cutaneous CD8-positive epidermotropic cytotoxic T cell lymphomas. A distinct clinicopathological entity with an aggressive clinical behavior". The American Journal of Pathology. 155 (2): 483–492. doi:10.1016/S0002-9440(10)65144-9. ISSN 0002-9440. PMC 1866866. PMID 10433941. Check date values in: |date= (help)
  2. 2.0 2.1 2.2 2.3 Guitart, Joan; et al. (2017-05). "Primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphomas: reappraisal of a provisional entity in the 2016 WHO classification of cutaneous lymphomas". Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 30 (5): 761–772. doi:10.1038/modpathol.2016.240. ISSN 1530-0285. PMC 5413429. PMID 28128277. Check date values in: |date= (help)
  3. 3.0 3.1 3.2 3.3 3.4 Robson, Alistair; et al. (2015-10). "Aggressive epidermotropic cutaneous CD8+ lymphoma: a cutaneous lymphoma with distinct clinical and pathological features. Report of an EORTC Cutaneous Lymphoma Task Force Workshop". Histopathology. 67 (4): 425–441. doi:10.1111/his.12371. ISSN 1365-2559. PMID 24438036. Check date values in: |date= (help)
  4. Travassos, Daphine Caxias; et al. (2022-06). "Primary cutaneous CD8+ cytotoxic T-cell lymphoma of the face with intraoral involvement, resulting in facial nerve palsy after chemotherapy". Journal of Cutaneous Pathology. 49 (6): 560–564. doi:10.1111/cup.14199. ISSN 1600-0560. PMID 35001425 Check |pmid= value (help). Check date values in: |date= (help)
  5. Saruta, Hiroshi; et al. (2017-09). "Hematopoietic stem cell transplantation in advanced cutaneous T-cell lymphoma". The Journal of Dermatology. 44 (9): 1038–1042. doi:10.1111/1346-8138.13848. ISSN 1346-8138. PMID 28391645. Check date values in: |date= (help)
  6. 6.0 6.1 Nofal, Ahmad; et al. (2012-10). "Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma: proposed diagnostic criteria and therapeutic evaluation". Journal of the American Academy of Dermatology. 67 (4): 748–759. doi:10.1016/j.jaad.2011.07.043. ISSN 1097-6787. PMID 22226429. Check date values in: |date= (help)
  7. Deenen, N. J.; et al. (2019-02). "Pitfalls in diagnosing primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma". The British Journal of Dermatology. 180 (2): 411–412. doi:10.1111/bjd.17252. ISSN 1365-2133. PMID 30259963. Check date values in: |date= (help)
  8. Willemze, Rein; et al. (2005-05-15). "WHO-EORTC classification for cutaneous lymphomas". Blood. 105 (10): 3768–3785. doi:10.1182/blood-2004-09-3502. ISSN 0006-4971. PMID 15692063.
  9. 9.0 9.1 9.2 9.3 9.4 Lee, Katie; et al. (2021-12-09). "Primary cytotoxic T-cell lymphomas harbor recurrent targetable alterations in the JAK-STAT pathway". Blood. 138 (23): 2435–2440. doi:10.1182/blood.2021012536. ISSN 1528-0020. PMC 8662071 Check |pmc= value (help). PMID 34432866 Check |pmid= value (help).
  10. 10.0 10.1 10.2 10.3 10.4 10.5 Fanoni, Daniele; et al. (2018-12). "Array-based CGH of primary cutaneous CD8+ aggressive EPIDERMO-tropic cytotoxic T-cell lymphoma". Genes, Chromosomes & Cancer. 57 (12): 622–629. doi:10.1002/gcc.22673. ISSN 1098-2264. PMID 30307677. Check date values in: |date= (help)
  11. 11.0 11.1 11.2 11.3 11.4 11.5 11.6 11.7 Bastidas Torres, Armando N.; et al. (2022-03-01). "Deregulation of JAK2 signaling underlies primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma". Haematologica. 107 (3): 702–714. doi:10.3324/haematol.2020.274506. ISSN 1592-8721. PMC 8883537 Check |pmc= value (help). PMID 33792220 Check |pmid= value (help).

EXAMPLE Book

  1. 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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