Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma
Haematolymphoid Tumours (WHO Classification, 5th ed.)
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Primary Author(s)*
Ahmed Eladely, MBBCh. Andrew Siref, MD.
Creighton University, Omaha, NE.
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 CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma |
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. PCAETL 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, and 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) Disseminated to visceral sites (lungs, testes, CNS) Lymph nodes spared |
| Laboratory Findings | None |
Sites of Involvement
PCAETL can present with either localized or generalized skin lesions and may affect the 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 | 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 | EBER, CD1a, CD30, CD25, ALK1, EMA |
| Variable | CD45RA(+/-), CD15(-/+) [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. 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 fusion | KHDRBS1-JAK2
PCM1-JAK2 TFG-JAK2 |
Self-oligo/dimerization of JAK2 | 3 of 12 patients | No | Unknown | Yes | Potential therapeutic target with JAK inhibitors.[11] |
| MYC fusion | ACTB-MYC
NPM1-MYC |
Chimeric MYC proteins with altered cell cycle regulation. | 2 of 12 patients | No | Unknown | No | Both patients had JAK2 fusions.[11] |
| ABL1 fusion[9] | SELENO1-ABL1 | Retained its catalytic tyrosine kinase domain but lost its N-terminal SH2 and SH3 regulatory domains | 1 of 6 patients | No | Unknown | Yes | Potential therapeutic target with Imatinib.[12] |
| BAZ1A rearrangement[11] | None specified | None specified | 2 of 12 patients | No | Unknown | No | |
| PTPRC rearrangement[11] | None specified | None specified | 2 of 12 patients | No | Unknown | No | |
| RB1 rearrangement[11] | None specified | None specified | 2 of 12 patients | No | Unknown | No | |
| MTAP rearrangement[11] | None specified | None specified | 3 of 12 patients | No | Unknown | No | |
| SH2B3 rearrangement[11] | None specified | None specified | 2 of 12 patients | No | Unknown | No | |
| CLEC16A rearrangement[11] | None specified | None specified | 2 of 12 patients | No | Unknown | No | |
| PIP4K2A rearrangement[11] | None specified | None specified | 2 of 12 patients | No | Unknown | No | |
| DLEU1 rearrangement[11] | None specified | None specified | 2 of 12 patients | No | Unknown | No | |
| SLC24A2 rearrangement[11] | None specified | None specified | 2 of 12 patients | No | Unknown | No | |
| ABR rearrangement[11] | None specified | None specified | 2 of 12 patients | No | Unknown | No | |
| GNA14 rearrangement[11] | None specified | None specified | 2 of 12 patients | No | Unknown | No | |
| RHCE rearrangement[11] | None specified | None specified | 2 of 12 patients | No | Unknown | No | |
| RHD rearrangement[11] | None specified | None specified | 2 of 12 patients | No | Unknown | No | |
| DLG2 rearrangement[11] | None specified | None specified | 2 of 12 patients | No | Unknown | No | |
| FRMD4A rearrangement[11] | None specified | None specified | 2 of 12 patients | No | Unknown | No |
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 |
|---|---|---|---|---|---|---|
| 1 | Loss | p36.11[10][11] | No | No | No | |
| 1 | Loss | 1p36.22[11] | No | No | No | |
| 1 | Loss | 1p36.32-p36.33[10][11] | No | No | No | |
| 2 | Loss | q37.3[10] | No | No | No | |
| 4 | Loss | q13.2[11] | ||||
| 7 | Gain | q21.11-q22.3[10] | No | No | No | |
| 7 | Gain | q22.1[11] | No | No | No | |
| 7 | Gain | q32.1-q36.1[10] | No | No | No | |
| 7 | Gain | q35[11] | No | No | ||
| 7 | Gain | q36.1-q36.3[10][11] | No | No | No | |
| 7 | Loss | p14.1[11] | No | No | No | |
| 7 | Loss | q34[10][11] | No | No | No | |
| 8 | Loss | p12[10] | No | No | No | |
| 8 | Gain | q24.3[10] | No | No | No | |
| 9 | Loss | p21.3[10][11] | No | No | No | The most frequently affected locus, shows losses in the MTAP, CDKN2A, and CDKN2B regions (12/20 patients).[10] It was also the most common in another study (10/12 patients).[11] |
| 10 | Loss | p11.22[11] | No | No | No | |
| 11 | Loss | q23.2[11] | No | No | No | |
| 12 | Loss | q24.12 | No | No | No | |
| 13 | Loss | q14.11[10][11] | No | No | No | |
| 14 | Loss | q11.2[10][11] | No | No | No | |
| 16 | Loss | p13.13[11] | No | No | No | |
| 17 | Loss | p13.2[10] | No | No | No | |
| 17 | Loss | p13.3[11] | No | No | No | No cancer genes.[11] |
| 17 | Gain | q21.31[10] | No | No | No | |
| 17 | Gain | q21.33-q22[10][11] | No | No | No | |
| 17 | Gain | q22[11] | No | No | No | |
| 17 | Gain | q25.3[10] | No | No | No | |
| 19 | Loss | p13.3[11] | No | No | No | |
| 21 | Gain | q22.12[10] | No | No | No | |
| X | Gain | p11.23-p11.22[10] | No | No | No | |
| X | Gain | q28[10] | No | No | No |
All the genes found in these regions are implicated in several pathways associated with lymphoma and tumor development, including T-cell signaling, DNA damage response, the JAK-STAT pathway, and epigenetic modifications.[10]
Characteristic Chromosomal Patterns
Although PCAETL exhibit multiple copy number alterations (CNAs), they lack a distinct signature or genomic profile, as their recurrent CNAs partially or entirely overlap with those found in other aggressive cutaneous T cell lymphomas.[10]
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 |
|---|---|---|---|---|---|---|---|
| JAK3; p.R657W, p.M511I | Oncogene | None specified | None specified | No | Unknown | No | Gain-of-function mutations |
| JAK2; p.L393V | Oncogene | None specified | None specified | No | Unknown | No | Germline SNV renders JAK2 hypersensitive to cytokine stimulation |
| STAT3; p.H19R, p.G604A | Oncogene | JAK2 fusions, SH2B3 deletions | None specified | No | Unknown | No | Gain-of-function mutations |
| STAT5B; p.N642H, p.P702S, p.Y665F, p.S434L | Oncogene | SH2B3 deletions | None specified | No | Unknown | No | Gain-of-function mutations |
| SH2B3; p.L201Sfs78, p.V35Afs154 | Tumor Suppressor Gene (TSG) | STAT5B mutations, JAK or STAT gene mutations | JAK2 fusions | No | Unknown | No | Frameshift mutations leading to loss of function |
| SOCS1; p.S71Rfs*14 | Tumor Suppressor Gene (TSG) | JAK or STAT gene mutations | None specified | No | Unknown | No | Frameshift mutation leading to a premature stop codon[11] |
Many SNVs and deletions in other genes are also detected and are predicted to be deleterious.[11]
Epigenomic Alterations
Alteration in LIN28, ARID1A, PARP10, MLL3, and MLL5 have been described and may play a role in the pathogenesis.[10]
Genes and Main Pathways Involved
| Gene; Genetic Alteration | Pathway | Pathophysiologic Outcome |
|---|---|---|
| JAK2; Fusion | JAK-STAT | Constitutive activation leading to cytokine-independent cell survival and proliferation. Overactivation of signaling pathways due to self-oligo/dimerization of the chimeric proteins. |
| SH2B3; Deletion | JAK-STAT | Loss of negative feedback regulation on JAK2 signaling, resulting in enhanced JAK2 pathway activation. |
| PTPRC; Deletion | JAK-STAT | Disruption of negative regulation of the JAK-STAT pathway, contributing to overactivation of JAK2 signaling. |
| STAT3; SNV | JAK-STAT | Gain-of-function mutations resulting in enhanced signaling and cell survival. |
| STAT5; SNV | JAK-STAT | Gain-of-function mutations leading to overactivation of the pathway, promoting cell proliferation. |
| MYC; Fusions | Cell Cycle Regulation | Dysregulation of cell cycle processes, contributing to uncontrolled cell proliferation. |
| CDKN2A/B; Deletions | Cell Cycle Regulation | Inactivation of tumor suppressor genes leading to disruptions in cell cycle control. |
| TP53; Truncating Mutations (nonsense, frameshift) | Cell Cycle Regulation | Loss of p53 function leading to impaired DNA repair and increased genomic instability. |
| ARID1A; Deletions | Chromatin Regulation | Loss of chromatin remodeling activity affecting gene expression and cell growth regulation. |
| KMT2D; Truncating Mutations | Chromatin Regulation | Disruption in histone methylation, affecting gene expression and cell differentiation. |
| NCOR1; Truncating Mutations | Chromatin Regulation | Loss of corepressor function, leading to altered gene expression and potentially contributing to oncogenesis.[11] |
Genetic Diagnostic Testing Methods
Fluorescence In Situ Hybridization (FISH): Detects chromosomal rearrangements and specific gene fusions, such as JAK2 fusions.
Polymerase Chain Reaction (PCR): Amplifies specific regions of DNA to identify genetic alterations, including gene fusions and specific mutations.
Next-Generation Sequencing (NGS): Identifies pathogenic small-scale mutations (SNVs and INDELs) and structural alterations. NGS can analyze multiple genes and pathways simultaneously, which is useful for comprehensive genetic profiling.[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
(use the "Cite" icon at the top of the page) (Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference.)
- ↑ 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) - ↑ 2.0 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) - ↑ 3.0 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) - ↑ 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) - ↑ 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) - ↑ 6.0 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) - ↑ 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) - ↑ 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.
- ↑ 9.0 9.1 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). - ↑ 10.00 10.01 10.02 10.03 10.04 10.05 10.06 10.07 10.08 10.09 10.10 10.11 10.12 10.13 10.14 10.15 10.16 10.17 10.18 10.19 10.20 10.21 10.22 10.23 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) - ↑ 11.00 11.01 11.02 11.03 11.04 11.05 11.06 11.07 11.08 11.09 11.10 11.11 11.12 11.13 11.14 11.15 11.16 11.17 11.18 11.19 11.20 11.21 11.22 11.23 11.24 11.25 11.26 11.27 11.28 11.29 11.30 11.31 11.32 11.33 11.34 11.35 11.36 11.37 11.38 11.39 11.40 11.41 11.42 11.43 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). - ↑ Buus, Terkild B.; et al. (2021-12-09). "Oncogenic fusions JAK up CD8+ cytotoxic CTCL". Blood. 138 (23): 2311–2312. doi:10.1182/blood.2021013619. ISSN 0006-4971.
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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