The Positivity of Phosphorylated STAT3 Is a Novel Marker for Favorable Prognosis in Germinal Center B-Cell Type of Diffuse Large B-Cell Lymphoma

Am J Surg Pathol. 2021 Jun 1;45(6):832-840. doi: 10.1097/PAS.0000000000001691.


On the basis of immunohistochemistry, diffuse large B-cell lymphoma (DLBCL) is categorized as a germinal center B-cell (GCB) or non-GCB subtype. Recent integrated genomic analyses have highlighted the importance of the JAK-STAT3 pathway in the molecular pathogenesis of DLBCL. However, its relevance to clinical outcomes remains controversial. Therefore, we evaluated the extent of the nuclear expression of phosphorylated STAT3 (pSTAT3), a surrogate marker of signal transducer and activator of transcription 3 (STAT3) activation, by immunohistochemistry. We also analyzed the potential relationship between pSTAT3 positivity (defined as ≥40% positive neoplastic cells) and clinicopathologic characteristics in 294 patients with DLBCL. pSTAT3 was detected in 122 patients (42%), with a higher rate in the non-GCB subtype than in the GCB subtype (57% vs. 28%, P<0.001). Factors potentially activating STAT3, MYD88L265P, and Epstein-Barr virus-encoded small RNA were identified in the pSTAT3-positive non-GCB subtype, whereas the pSTAT3-positive GCB subtype often showed STAT3 mutations and lacked EZH2 mutations and the rearrangements of BCL2 and MYC. Multivariate analyses revealed that the pSTAT3-positive GCB subtype showed a favorable prognosis (HR: 0.17; 95% confidence interval, 0.04-0.7; P=0.014). These findings suggest that pSTAT3 positivity may have a unique impact on the clinicopathologic characteristics of DLBCL, making it a promising novel marker for the favorable prognosis of patients with the GCB subtype.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / analysis*
  • Biomarkers, Tumor / genetics
  • DNA Mutational Analysis
  • Enhancer of Zeste Homolog 2 Protein / genetics
  • Female
  • Gene Rearrangement
  • Herpesvirus 4, Human / genetics
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization, Fluorescence
  • Japan
  • Lymphoma, Large B-Cell, Diffuse / chemistry*
  • Lymphoma, Large B-Cell, Diffuse / drug therapy
  • Lymphoma, Large B-Cell, Diffuse / genetics
  • Lymphoma, Large B-Cell, Diffuse / virology
  • Male
  • Middle Aged
  • Mutation
  • Myeloid Differentiation Factor 88 / genetics
  • Phosphorylation
  • Prognosis
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-myc / genetics
  • RNA, Viral / genetics
  • STAT3 Transcription Factor / analysis*
  • STAT3 Transcription Factor / genetics
  • Suppressor of Cytokine Signaling 1 Protein / genetics


  • BCL2 protein, human
  • Biomarkers, Tumor
  • MYC protein, human
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins c-myc
  • RNA, Viral
  • SOCS1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Suppressor of Cytokine Signaling 1 Protein
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein