In a groundbreaking advancement for the characterization and treatment of lymphoma, researchers have identified a powerful predictive approach for molecular typing of CD5-positive diffuse large B-cell lymphoma (DLBCL) using immunohistochemical markers CD5 and p53. This innovative study sheds new light on how these markers can serve as reliable indicators for underlying genetic subtypes, promising to vastly enhance diagnostic precision and therapeutic decision-making in one of the most aggressive forms of lymphoma.
CD5-positive DLBCL represents a distinct and aggressive subset of diffuse large B-cell lymphoma, marked by unique clinical and pathological features that have puzzled oncologists and pathologists for years. Unlike other DLBCL subtypes, CD5-positive variants often present with extensive disease involvement, frequently demonstrating extranodal dissemination and advanced stage at diagnosis. These characteristics underscore the pressing need for accurate molecular subtyping to tailor personalized treatment strategies effectively.
The study meticulously examined 25 cases of CD5-positive DLBCL, integrating comprehensive clinical assessments with detailed immunohistochemical and genetic analyses. The cohort included a nearly equal gender distribution with thirteen females and twelve males, with a significant proportion of patients being older than 60 years—a demographic recognized for more challenging disease prognosis. Notably, the majority of cases presented at stage IV, highlighting the aggressive nature of the disease and its propensity for systemic involvement.
Immunophenotyping revealed a consistent expression of hallmark B-cell markers. All examined cases were positive for CD20 and MUM1, reinforcing their B-cell lineage and activated B-cell phenotype, respectively. The expression of other markers such as BCL6 and CD10 varied, signifying the heterogeneity within this lymphoma subtype. A striking finding was the high incidence of MYC and BCL2 co-expression—21 out of 24 evaluated cases—a known indicator of aggressive disease biology often associated with poor clinical outcomes.
Central to this investigation was the evaluation of p53 protein status through immunohistochemistry, which demonstrated an impressive 95.65% accuracy in predicting TP53 gene mutations—a critical oncogenic alteration driving tumor behavior. This correlation between protein expression pattern and genomic mutation allows for practical, cost-effective screening in routine pathology settings without immediate need for expensive molecular testing. By leveraging p53 immunostaining, clinicians can infer mutation status and thus approximate molecular subtype in a more accessible manner.
The genetic classification of the tumors into recognized molecular subtypes revealed that over half of the cases fell into the MCD subtype, characterized by concurrent mutations in MYD88 and CD79B. This subtype is linked to distinct pathogenic mechanisms and therapeutic vulnerabilities. A significant fraction exhibited TP53 mutations, grouped accordingly under a TP53^Mut category, aligning with their mutant p53 protein profile. The EZB subtype, associated with germinal center B-cell origin genetics, accounted for a minor proportion, underscoring the predominance of non-germinal center derived phenotypes in CD5-positive DLBCL.
The integration of CD5 expression intensity with p53 status brought forth a robust model for initial molecular stratification. Among patients with strong CD5 expression, a wild-type p53 immunophenotype reliably predicted the MCD molecular subtype, while a mutant p53 pattern strongly correlated with TP53 mutant subtype tumors. Conversely, in those with weaker or moderate CD5 expression, the alignment between p53 patterns and molecular subtypes was less pronounced but still informative, suggesting gradations in lymphoma biology that reflect underlying genetic diversity.
These revelations carry substantial clinical implications. Incorporating CD5 and p53 immunohistochemistry into routine diagnostic workflows could streamline initial molecular subtyping, enabling pathologists and oncologists to quickly classify this aggressive lymphoma into actionable categories. Such stratification paves the way for tailored therapeutic approaches, including targeted agents directed at specific molecular pathways aberrant in different subtypes, potentially improving patient outcomes while minimizing unnecessary toxicities.
Moreover, this study emphasizes the paradigm shift in lymphoma diagnostics from purely morphological assessment to integrated molecular pathology, blending traditional histology with state-of-the-art immunogenetic techniques. The deployment of accessible immunohistochemical markers as surrogates for complex genetic profiling democratizes precision oncology, making advanced stratification feasible even in resource-limited settings.
The detailed clinicopathological characterization within this cohort further enhances understanding of CD5-positive DLBCL, contextualizing molecular findings within patient demographics and disease burden. The preponderance of elderly patients presenting with advanced extranodal disease reiterates the aggressive clinical course and the urgent need for expedient and precise diagnostic tools.
Importantly, the high frequency of MYC/BCL2 double expression within these cases correlates with a notorious "double-expressor" phenotype, known to confer therapeutic resistance and poorer prognosis. Recognizing the interplay between immunophenotypic markers and genetic aberrations like TP53 mutations may help identify patients who require more aggressive or novel treatment regimens, including the use of emerging targeted therapies.
This study also signals the potential for future research avenues, where validating these findings in larger cohorts may solidify CD5 and p53 immunostaining as standard predictive biomarkers. Furthermore, integrating these markers with next-generation sequencing and emerging multi-omic technologies could refine classification even further and unravel the molecular complexity of CD5-positive DLBCL.
In summary, the research presents compelling evidence that CD5 and p53 immunohistochemical evaluation constitutes a valuable, practical, and accurate method for predicting molecular subtypes in CD5-positive diffuse large B-cell lymphoma. This innovative approach exemplifies the advancement of personalized medicine in hematologic malignancies, promising improved diagnostic accuracy and informing clinical management with tailored therapeutic considerations.
As the landscape of lymphoma classification evolves, studies like this underline the critical importance of incorporating molecular insights into everyday pathology practice. By bridging the gap between immunohistochemistry and genomics, the findings herald a new era where rapid, reliable, and affordable tumor profiling directly translates into better patient care and outcomes.
Subject of Research: Predictive value of CD5 and p53 immunohistochemistry in molecular subtyping of CD5-positive diffuse large B-cell lymphoma
Article Title: CD5 and p53 immunohistochemistry: valuable prediction method in molecular typing of CD5-positive diffuse large B-cell lymphoma
Article References:
Wang, H., Pan, H., Zhang, L. et al. CD5 and p53 immunohistochemistry: valuable prediction method in molecular typing of CD5-positive diffuse large B-cell lymphoma. BMC Cancer 25, 726 (2025). https://doi.org/10.1186/s12885-025-13990-8
Image Credits: Scienmag.com
