Background:In malignant pleural mesothelioma, epithelioid histology is traditionally considered a favorable prognostic marker. However, it remains clinically undetermined whether the intensity of an oncogenic insult can disrupt this link. Radiation-induced cases serve as an unconfounded biological model to dissect such trajectories masked by asbestos confounding.Methods:We performed an Individual Patient Data (IPD) synthesis of 20 strictly asbestos-unexposed human cases, applying clinically established dose stratification (intermediate: 20–45 Gy vs. high: >45 Gy). To confirm the observed pattern, we examined data from 829 dogs in the Colorado State University (CSU) Beagle Study.Results:In the intermediate-dose group (n= 13), a significant positive correlation persisted between age at radiotherapy and the latent period (ρ = 0.567,p= 0.043). Conversely, high-dose exposure (>45 Gy) showed a disruption of this age-dependent pattern, with a trend toward inverse correlation (ρ = −0.754,p= 0.084). Interaction analysis confirmed a statistically significant divergence between these dose-dependent trends (p= 0.005). The CSU Beagle Study (n= 829) demonstrated the physical basis of this phenomenon: in the canine model, high-dose exposure (≥0.74 Gy) triggered a “Step-Jump” in cumulative incidence (30.4% at 0.5 years), indicating instantaneous carcinogenic onset distinct from cumulative biological aging.Conclusions:This kinetic divergence points to a “Diagnostic Trap.” We propose a ‘Single- to Double-Brake’ framework where intermediate doses preserve age-dependent progression, whereas high doses likely trigger catastrophic genomic failure (chromothripsis) that bypasses the time required for morphological dedifferentiation. Consequently, morphologically indolent epithelioid tumors in high-dose survivors may harbor aggressive molecular profiles not predicted by histology alone, necessitating risk-stratified precision surveillance.
背景： 在恶性胸膜间皮瘤中，上皮样组织学传统上被认为是良好的预后标志。然而，致癌损伤的强度是否会破坏这种关联，在临床上仍不明确。辐射诱发的病例作为一个不受混杂因素干扰的生物模型，可用于剖析被石棉混杂效应掩盖的这种发展轨迹。
方法： 我们对20例严格无石棉暴露的人类病例进行了个体患者数据（IPD）综合分析，并应用临床确立的剂量分层（中等剂量：20–45 Gy 对比 高剂量：>45 Gy）。为了验证观察到的模式，我们还分析了科罗拉多州立大学（CSU）小猎犬研究中829只狗的数据。
结果： 在中等剂量组（n=13），放疗年龄与潜伏期之间持续存在显著正相关（ρ = 0.567，p= 0.043）。相反，高剂量暴露（>45 Gy）则显示这种年龄依赖模式被破坏，并呈现负相关的趋势（ρ = -0.754，p= 0.084）。交互分析证实，这两种剂量依赖性趋势之间存在统计学上的显著差异（p= 0.005）。CSU小猎犬研究（n=829）证明了这一现象的物理基础：在犬类模型中，高剂量暴露（≥0.74 Gy）引发了累积发病率的"阶跃式跳变"（0.5年时达30.4%），表明致癌过程是即时启动的，与累积的生物衰老过程不同。
结论： 这种动力学差异指向一个"诊断陷阱"。我们提出了一个'单刹车到双刹车'框架，其中中等剂量保留了年龄依赖的进展过程，而高剂量则可能引发灾难性的基因组故障（染色体碎裂），从而绕过了形态学去分化所需的时间。因此，高剂量幸存者中形态学上呈惰性的上皮样肿瘤，可能隐藏着仅凭组织学无法预测的侵袭性分子特征，这需要基于风险分层的精准监测。
肿瘤(癌症)患者之家