Refining Diagnostic Subtypes of Peripheral T-Cell Lymphoma Using a Multiparameter Approach
Notice bibliographique
Résumé
Peripheral T-cell lymphoma (PTCL) encompasses a diverse group of post-thymic lymphomas, with ~40% of cases not further classifiable and designated as PTCL-not otherwise specified (PTCL-NOS). Two molecular prognostic subtypes of PTCL-NOS, PTCL-TBX21 and PTCL-GATA3, were identified through gene expression profiling (GEP). A subset of PTCL-NOS with T-follicular helper (TFH) differentiation was subsequently categorized as nodal PTCL with TFH phenotype (PTCL-TFH), also known in current classifications as nodal PTCL-TFH, NOS, or TFH lymphoma, NOS. However, the boundary between PTCL-NOS and PTCL-TFH remains poorly defined. To refine these subtypes, 101 PTCL-NOS with centralized pathology review and extensive immunophenotyping by immunohistochemistry (IHC) using 22 antibodies, digital GEP (nCounter, NanoString Inc) (n= 70), and RNA sequencing (n= 73) were included in this study. IHC was used to identify PTCL-TFH cases (those with strong expression of more than two TFH markers); the remaining patients were classified as PTCL-GATA3 and PTCL-TBX21 using pre-defined GEP signatures. Cases were reclassified into PTCL-NOS (n= 63) and PTCL-TFH (n= 38), with PTCL-NOS subclassified into PTCL-GATA3 (n= 22; 34%) and PTCL-TBX21 (n= 41; 66%) and showing significant differences in OS (p<0.001). PTCL-GATA3 was characterized by medium to large transformed cells (average= 90%, 70-100%) and had minimal tumor microenvironment (TME) (TME-poor: 100%). In contrast, PTCL-TBX21 was more heterogeneous, associated with pleomorphic cells in a polymorphous background (TME-rich: 78%), including Lennert lymphoma-like cases (22%). mRNA and CIBERSORT analysis substantiated the findings and identified a subset enriched in cytotoxic features in the PTCL-TBX21 subtype. IHC indicated that PTCL-GATA3 cases were CD4+/CD8- (83%) or CD4-/CD8- (17%) and lacked expression of CD8 or cytotoxic markers compared to PTCL-TBX21 (p<0.01). PTCL-GATA3 showed significantly higher expression of LEF1 (average= 80%), Ki67 (80%), and MYC (25%) than PTCL-TBX21 (25%, 30%, <5%, respectively, p<0.01). mRNA and protein expression of these biomarkers showed a significant positive correlation (r=0.5, p<0.001), and expectedly higher mRNA expression of LEF1 and MYC was observed in the PTCL-GATA3 versus PTCL-TBX21 (p<0.05). Strong expression of CD30 (>50% of cells) was only seen in PTCL-GATA3 cases. EBER positivity, found only in rare background cells, was not significantly different (18% of PTCL-GATA3 vs. 12% of PTCL-TBX21). Within PTCL-TBX21, we identified cytotoxic and non-cytotoxic subsets with divergent morphological, phenotypic, and clinical findings. The cytotoxic PTCL-TBX21 exhibited an activated cytotoxic phenotype (23/25, 96%), denoted by TIA1 and granzyme-B and/or perforin expression. Extranodal involvement and single-cell apoptosis were observed in 17% and 45% of the cytotoxic cases, respectively, but absent in non-cytotoxic PTCL-TBX21 cases. A trend towards higher Ki67 expression (average= 40% vs. 20%, p= 0.08) was seen in the cytotoxic subgroup. In contrast, the non-cytotoxic PTCL-TBX21 was associated with a CD4+/CD8- phenotype and higher ICOS expression (average= 30%) and CCR4 (60%) compared to the cytotoxic PTCL-TBX21 (p= 0.001). PTCL-TFH cases showed a CD4+/CD8- phenotype (90%) and rarely a CD4-/CD8- phenotype (10%). While a subset of PTCL-TFH cases had AITL-like features such as numerous clear cells and/or prominent vasculature (31% of cases), which were not seen in the other subgroups, the remaining cases exhibited morphology that was indistinguishable from other PTLC-NOS cases including sheets of transformed cells or pleomorphic cells in a polymorphous background. Morphologically, PTCL-TFH cases, like PTCL-TBX21 were associated with a rich TME (TME-rich: 75%). CIBERSORT analysis showed enrichment of plasma cells (p<0.01) in PTCL-TFH, compared to PTCL-TBX21, and validated by morphology (30% of cases vs. 5%). Expression of one TFH marker was frequent in some PTCL-NOS cases (PTCL-GATA3= 41% of cases, PTCL-TBX21-non cytotoxic= 47%, PTCL-TBX21-cytotoxic= 5%). Conclusion: Our comprehensive evaluation underscores the importance of integrating morphology, immunophenotyping, and GEP in achieving an accurate diagnosis, potentially leading to more tailored treatment strategies for PTCL. Correlation with pending whole-exome sequencing studies will be provided at the time of presentation.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,004 | 0,005 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,007 | 0,002 |
| Études des sciences et des technologies | 0,001 | 0,000 |
| Communication savante | 0,002 | 0,001 |
| Science ouverte | 0,002 | 0,002 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».