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Immunohistochemical Approach to Genetic Subtyping of Anaplastic Large Cell Lymphoma.

ABSTRACT: Anaplastic large cell lymphoma (ALCL) can be classified genetically based on rearrangements (R) of the ALK , TP63 , and/or DUSP22 genes. ALK- R defines a specific entity, ALK-positive ALCL, while DUSP22- R and TP63- R define subgroups of ALK-negative ALCLs with distinct clinicopathologic features. ALK -R and TP63 -R produce oncogenic fusion proteins that can be detected by immunohistochemistry. ALK immunohistochemistry is an excellent surrogate for ALK- R and screening with p63 immunohistochemistry excludes TP63- R in two third of ALCLs. In contrast, DUSP22 -R does not produce a fusion protein and its identification requires fluorescence in situ hybridization. However, DUSP22- R ALCL has a characteristic phenotype including negativity for cytotoxic markers and phospho-STAT3 Y705 . Recently, we also identified overexpression of the LEF1 transcription factor in DUSP22- R ALCL. Here, we sought to validate this finding and examine models for predicting DUSP22- R using immunohistochemistry for LEF1 and TIA1 or phospho-STAT3 Y705 . We evaluated these 3 markers in our original discovery cohort (n=45) and in an independent validation cohort (n=46) of ALCLs. The correlation between DUSP22- R and LEF1 expression replicated strongly in the validation cohort ( P <0.0001). In addition, we identified and validated a strategy using LEF1 and TIA1 immunohistochemistry that predicted DUSP22- R with positive and negative predictive values of 100% after exclusion of indeterminate cases and would eliminate the need for fluorescence in situ hybridization in 65% of ALK-negative ALCLs. This approach had similar results in identifying DUSP22- R in the related condition, lymphomatoid papulosis. Together with previous data, these findings support a 4-marker immunohistochemistry algorithm using ALK, LEF1, TIA1, and p63 for genetic subtyping of ALCL.

SUBMITTER: Feldman AL

PROVIDER: S-EPMC9588576 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Immunohistochemical Approach to Genetic Subtyping of Anaplastic Large Cell Lymphoma.

Feldman Andrew L AL Oishi Naoki N Ketterling Rhett P RP Ansell Stephen M SM Shi Min M Dasari Surendra S

The American journal of surgical pathology 20220808 11

Anaplastic large cell lymphoma (ALCL) can be classified genetically based on rearrangements (R) of the ALK , TP63 , and/or DUSP22 genes. ALK- R defines a specific entity, ALK-positive ALCL, while DUSP22- R and TP63- R define subgroups of ALK-negative ALCLs with distinct clinicopathologic features. ALK -R and TP63 -R produce oncogenic fusion proteins that can be detected by immunohistochemistry. ALK immunohistochemistry is an excellent surrogate for ALK- R and screening with p63 immunohistochemis ...[more]

PMID: 35941721

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Project description:Genetic classification helps to disclose molecular heterogeneity and therapeutic implications in diffuse large B-cell lymphoma (DLBCL). Using whole exome/genome sequencing, RNA-sequencing, and fluorescence in situ hybridization in 337 newly diagnosed DLBCL patients, we established a simplified 38-gene algorithm (termed 'LymphPlex') based on the information on mutations of 35 genes and rearrangements of three genes (BCL2, BCL6, and MYC), identifying seven distinct genetic subtypes: TP53Mut (TP53 mutations), MCD-like (MYD88, CD79B, PIM1, MPEG1, BTG1, TBL1XR1, PRDM1, IRF4 mutations), BN2-like (BCL6 fusion, NOTCH2, CD70, DTX1, BTG2, TNFAIP3, CCND3 mutations), N1-like (NOTCH1 mutations), EZB-like (BCL2 fusion, EZH2, TNFRSF14, KMT2D, B2M, FAS, CREBBP, ARID1A, EP300, CIITA, STAT6, GNA13 mutations, with or without MYC rearrangement), and ST2-like (SGK1, TET2, SOCS1, DDX3X, ZFP36L1, DUSP2, STAT3, IRF8 mutations). Extended validation of 1001 DLBCL patients revealed clinical relevance and biological signature of each genetic subtype. TP53Mut subtype showed poor prognosis, characterized by p53 signaling dysregulation, immune deficiency, and PI3K activation. MCD-like subtype was associated with poor prognosis, activated B-cell (ABC) origin, BCL2/MYC double-expression, and NF-κB activation. BN2-like subtype showed favorable outcome within ABC-DLBCL and featured with NF-κB activation. N1-like and EZB-like subtypes were predominated by ABC-DLBCL and germinal center B-cell (GCB)-DLBCL, respectively. EZB-like-MYC+ subtype was characterized by an immunosuppressive tumor microenvironment, while EZB-like-MYC- subtype by NOTCH activation. ST2-like subtype showed favorable outcome within GCB-DLBCL and featured with stromal-1 modulation. Genetic subtype-guided targeted agents achieved encouraging clinical response when combined with immunochemotherapy. Collectively, LymphPlex provided high efficacy and feasibility, representing a step forward to the mechanism-based targeted therapy in DLBCL.

Dataset Information

Immunohistochemical Approach to Genetic Subtyping of Anaplastic Large Cell Lymphoma.

Publications

Immunohistochemical Approach to Genetic Subtyping of Anaplastic Large Cell Lymphoma.

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