Persistent or recurrent Barrett's neoplasia after an endoscopic therapy session is associated with DNA content abnormality and can be detected by DNA flow cytometric analysis of paraffin-embedded tissue.
Persistent or recurrent Barrett's neoplasia after an endoscopic therapy session is associated with DNA content abnormality and can be detected by DNA flow cytometric analysis of paraffin-embedded tissue.
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DOI：
10.1038/s41379-021-00832-8
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Choi WT
中科院分区：
文献类型：
--
作者：
Bowman CJ;Zhang R;Balitzer D;Wang D;Rabinovitch PS;Kővári BP;Mattis AN;Kakar S;Lauwers GY;Choi WT
内镜治疗目前是治疗Barrett食管（BE）患者高度异型增生（HGD）或粘膜内腺癌（IMC）的标准治疗。可见病变采用内镜下粘膜切除术（EMR）治疗，通常与射频消融术（RFA）结合使用。然而，内窥镜治疗可能需要多次治疗（每2-3个月一次），并不总能确保肿瘤完全根除。此外，尽管完全根除，复发并不罕见。本研究评估了哪些潜在的风险因素可以预测内镜治疗后的不良反应。分析了45例接受至少一次内镜治疗（单独EMR或消融伴或不伴既往EMR）以治疗HGD/IMC、低度异型增生（LGD）或不确定异型增生（IND）的BE患者。对45例患者的82份福尔马林固定石蜡包埋标本进行DNA流式细胞术检测，其中包括78份HGD/IMC，2份LGD和2份IND。从每个组织块切下3 - 4个60 μ m厚的切片，并手动解剖HGD/IMC、LGD或IND区域。使用单变量和多变量考克斯模型及脆弱性术语检查每次内镜检查后临床病理学风险因素与持续/复发HGD/IMC之间的潜在相关性。82例标本中有60例（73%）显示DNA含量异常（非整倍体或4 N分数升高）。这些均为HGD/IMC标本（占该组的77%）。在这60例DNA含量异常的HGD/IMC样本中，42例（70%）在平均16个月（范围：1个月至9.4年）的随访时间内与持续性/复发性HGD/IMC（n = 41）或食管腺癌（EAC; n = 1）的后续发展相关。相比之下，在剩余的22个样本（均具有正常DNA含量）中，仅6个（27%，均为HGD/IMC）与持续性/复发性HGD/IMC相关。对于每例患者的结局分析，45例患者中有11例（24%）发生了持续性/复发性HGD/IMC或EAC，尽管进行了多次内镜检查（平均值：3.6，范围：1-11）。在单变量考克斯模型中，异常DNA含量的存在（风险比[HR] = 3.8，p = 0.007），长BE段≥ 3 cm（HR = 3.4，p = 0.002），内镜结节性（HR = 2.5，p = 0.042）和单独EMR治疗（HR = 2.9，p = 0.006）与持续性/复发性HGD/IMC或EAC的风险增加显著相关。然而，在多变量分析中，只有异常DNA含量（HR = 6.0，p = 0.003）和单独EMR治疗（HR = 2.7，p = 0.047）仍然是显著的风险因素。年龄≥ 60岁、性别、种族、体重指数（BMI）≥ 30 kg/m2、存在食管裂孔疝和肿瘤形成的EMR外侧缘阳性不是持续/复发HGD/IMC或EAC的显著风险因素（p > 0.05）。在DNA含量异常的情况下，持续/复发HGD/IMC或EAC的3个月、6个月、1年、3年和6年校正概率分别为31%、56%、67%、79%和83%。在DNA含量正常的情况下，相应的概率分别为10%、21%、28%、38%和43%。总之，在基线HGD/IMC的BE患者中，DNA含量异常和单独EMR治疗与每次内镜检查后持续/复发HGD/IMC或EAC显著相关。通过DNA流式细胞术检测的DNA含量异常识别HGD/IMC患者中持续/复发HGD/IMC或EAC的风险最高，并且它也作为HGD/IMC的诊断标志物，估计灵敏度为77%。在DNA含量异常的情况下诊断HGD/IMC可能需要替代治疗策略以及更短监测间隔的长期随访。
Endoscopic therapy is currently the standard of care for the treatment of high-grade dysplasia (HGD) or intramucosal adenocarcinoma (IMC) in patients with Barrett’s esophagus (BE). Visible lesions are treated with endoscopic mucosal resection (EMR), which is often coupled with radiofrequency ablation (RFA). However, endoscopic therapy may require multiple sessions (one session every 2-3 months) and does not always assure complete eradication of neoplasia. Furthermore, despite complete eradication, recurrences are not uncommon. This study assesses which potential risk factors can predict a poor response after endoscopic sessions. Forty-five BE patients who underwent at least one endoscopic session (EMR alone or ablation with or without preceding EMR) for the treatment of HGD/IMC, low-grade dysplasia (LGD), or indefinite for dysplasia (IND) were analyzed. DNA flow cytometry was performed on 82 formalin-fixed paraffin-embedded samples from the 45 patients, including 78 HGD/IMC, 2 LGD, and 2 IND. Eight non-dysplastic BE samples were used as controls. Three to four 60-micron thick sections were cut from each tissue block, and the area of HGD/IMC, LGD, or IND was manually dissected. Potential associations between clinicopathologic risk factors and persistent/recurrent HGD/IMC following each endoscopic session were examined using univariate and multivariate Cox models with frailty terms. Sixty (73%) of the 82 specimens showed abnormal DNA content (aneuploidy or elevated 4N fraction). These were all specimens with HGD/IMC (representing 77% of that group). Of these 60 HGD/IMC samples with abnormal DNA content, 42 (70%) were associated with subsequent development of persistent/recurrent HGD/IMC (n = 41) or esophageal adenocarcinoma (EAC; n = 1) within a mean follow-up time of 16 months (range: 1 month to 9.4 years). In contrast, only 6 (27%, all HGD/IMC) of the 22 remaining samples (all with normal DNA content) were associated with persistent/recurrent HGD/IMC. For outcome analysis per patient, 11 (24%) of the 45 patients developed persistent/recurrent HGD/IMC or EAC, despite multiple endoscopic sessions (mean: 3.6, range: 1–11). In a univariate Cox model, the presence of abnormal DNA content (hazard ratio [HR] = 3.8, p = 0.007), long BE segment ≥ 3 cm (HR = 3.4, p = 0.002), endoscopic nodularity (HR = 2.5, p = 0.042), and treatment with EMR alone (HR = 2.9, p = 0.006) were significantly associated with an increased risk for persistent/recurrent HGD/IMC or EAC. However, only abnormal DNA content (HR = 6.0, p = 0.003) and treatment with EMR alone (HR = 2.7, p = 0.047) remained as significant risk factors in a multivariate analysis. Age ≥ 60 years, gender, ethnicity, body mass index (BMI) ≥ 30 kg/m2, presence of hiatal hernia, and positive EMR lateral margin for neoplasia were not significant risk factors for persistent/recurrent HGD/IMC or EAC (p > 0.05). Three-month, 6-month, 1-year, 3-year, and 6-year adjusted probabilities of persistent/recurrent HGD/IMC or EAC in the setting of abnormal DNA content were 31%, 56%, 67%, 79%, and 83%, respectively. The corresponding probabilities in the setting of normal DNA content were 10%, 21%, 28%, 38%, and 43%, respectively. In conclusion, in BE patients with baseline HGD/IMC, both DNA content abnormality and treatment with EMR alone were significantly associated with persistent/recurrent HGD/IMC or EAC following each endoscopic session. DNA content abnormality as detected by DNA flow cytometry identifies HGD/IMC patients at highest risk for persistent/recurrent HGD/IMC or EAC, and it also serves as a diagnostic marker of HGD/IMC with an estimated sensitivity of 77%. The diagnosis of HGD/IMC in the setting of abnormal DNA content may warrant alternative treatment strategies as well as long-term follow-up with shorter surveillance intervals.
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