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Background <p>Current screening practices for esophageal squamous cell carcinoma (ESCC) subject to both over- and under-surveillance of precancerous lesions. This study aims to evaluate potential immunohistochemical (IHC) markers associated with the incidence of ESCC and to establish an IHC-based panel for surveillance.</p> Methods <p>Tissue microarrays were constructed using 946 formalin-fixed, paraffin-embedded (FFPE) samples from 883 participants with baseline Lugol-unstained lesions (LULs) enrolled in a population-based screening trial. Candidate IHC markers were identified from literature and our previous findings. IHC results (H-scores) were quantified via HALO software, and optimal cut-offs were set by X-tile. Incident esophageal malignancy identified during a median follow-up of 11.76 years served as the outcome. Cox regression models were applied to identify predictive markers.</p> Results <p>Eight candidate markers were evaluated. After multivariable adjustment and backward elimination, γH2AX and p53 were identified as significant predictors [HR (95% CI) <sub>γH2AX</sub> =2.91 (1.94–4.34), HR (95% CI) <sub>p53</sub> =3.57 (2.40–5.30)]. The IHC score, combining the expression of γH2AX and p53, demonstrated strong predictive accuracy (C-index = 0.705) with AUCs of 0.894 (3-year), 0.909 (5-year), and 0.733 (10-year). Compared with the current surveillance strategy, 5.06% of the previous low-risk group with non-dysplastic LULs changed to the high-risk group (both γH2AX and p53 positive) with a cumulative incidence of HGIN and above (HGINA) of 44.7% (17/38). while 29.17% of individuals in the previous high-risk group with low-grade intraepithelial neoplasia &gt; 1&#xa0;cm changed to the low-risk group (neither γH2AX nor p53 positive) with no incident of HGINA (0/7).</p> Conclusions <p>γH2AX, a novel incidence-warning IHC marker for esophageal squamous precancerous lesions, combined with p53, showed robust and durable predictive performance for incident malignancy after one-time screening. Integrating IHC testing could help refine risk stratification and mitigate over- and under-surveillance within current ESCC screening protocol.</p>

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γH2AX and p53 Immunohistochemistry predict the incidence risk of esophageal squamous precancerous lesions

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月21日

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  • Xiangwen Cheng,
  • Ying Liu,
  • Huanyu Chen,
  • Yaqi Pan,
  • Zhe Hu,
  • Zhen Liu,
  • Fangfang Liu,
  • Wenlei Yang,
  • Chuanhai Guo,
  • Lixin Zhang,
  • Liheng Zhang,
  • Fenglei Li,
  • Jiangang Li,
  • Xinna Liu,
  • Haijun Yang,
  • Muyan Cai,
  • Mengfei Liu,
  • Zhonghu He,
  • Yang Ke

摘要

Background

Current screening practices for esophageal squamous cell carcinoma (ESCC) subject to both over- and under-surveillance of precancerous lesions. This study aims to evaluate potential immunohistochemical (IHC) markers associated with the incidence of ESCC and to establish an IHC-based panel for surveillance.

Methods

Tissue microarrays were constructed using 946 formalin-fixed, paraffin-embedded (FFPE) samples from 883 participants with baseline Lugol-unstained lesions (LULs) enrolled in a population-based screening trial. Candidate IHC markers were identified from literature and our previous findings. IHC results (H-scores) were quantified via HALO software, and optimal cut-offs were set by X-tile. Incident esophageal malignancy identified during a median follow-up of 11.76 years served as the outcome. Cox regression models were applied to identify predictive markers.

Results

Eight candidate markers were evaluated. After multivariable adjustment and backward elimination, γH2AX and p53 were identified as significant predictors [HR (95% CI) γH2AX =2.91 (1.94–4.34), HR (95% CI) p53 =3.57 (2.40–5.30)]. The IHC score, combining the expression of γH2AX and p53, demonstrated strong predictive accuracy (C-index = 0.705) with AUCs of 0.894 (3-year), 0.909 (5-year), and 0.733 (10-year). Compared with the current surveillance strategy, 5.06% of the previous low-risk group with non-dysplastic LULs changed to the high-risk group (both γH2AX and p53 positive) with a cumulative incidence of HGIN and above (HGINA) of 44.7% (17/38). while 29.17% of individuals in the previous high-risk group with low-grade intraepithelial neoplasia > 1 cm changed to the low-risk group (neither γH2AX nor p53 positive) with no incident of HGINA (0/7).

Conclusions

γH2AX, a novel incidence-warning IHC marker for esophageal squamous precancerous lesions, combined with p53, showed robust and durable predictive performance for incident malignancy after one-time screening. Integrating IHC testing could help refine risk stratification and mitigate over- and under-surveillance within current ESCC screening protocol.