Gross type of hepatocellular carcinoma reflects the tumor hypoxia, fibrosis, and stemness-related marker expression
Gross type of hepatocellular carcinoma reflects the tumor hypoxia, fibrosis, and stemness-related marker expression
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DOI：
10.1007/s12072-020-10012-6
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发表时间：
2020-01-29
影响因子：
6.6
通讯作者：
Park, Young Nyun
中科院分区：
文献类型：
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作者：
Rhee, Hyungjin;Chung, Taek;Park, Young Nyun
背景肝细胞癌（Hepatocellular carcinoma，HCC）大体上可分为五种类型，即：模糊结节型（vessel nodular，VN）、单发结节型（single nodular，SN）、单发结节伴多结节生长型（single nodular with proximal nodular growth，SNEG）、融合型多结节型（confluent multicodular，CM）和浸润型（infiltrative，INF）。然而，不同大体类型HCC生物学行为差异的病理学背景仍不清楚。方法分析266例手术切除的HCC的组织病理学特征、大体类型的临床结局及其与干细胞相关标志物状态和纤维化/缺氧肿瘤微环境（TME）的关系。用免疫组织化学评价干细胞相关标志物（CD 24、CD 44、CD 133、SALL 4、YAP 1、K19和EpCAM）、纤维性肿瘤间质（α SMA）和缺氧（CAIX）。结果在VN-SN-SNEG-CM-INF型中，肿瘤分化程度越高，包膜形成越少，微血管浸润越多，肿瘤体积越大，坏死面积越大（p = 0.005）。总干细胞相关标志物和缺氧/纤维化TME的表达按VN-SN-SNEG-CM-INF型顺序呈递增趋势（p < 0.005），且两者表达具有良好的相关性。INF型仅见于缺氧/纤维化TME或干细胞相关标志物高表达的HCC。CAIX表达和肿瘤坏死>= 30%是疾病特异性生存的独立预后标志物。早期无复发生存率显示基于大体类型的显著差异，VN型结局最好，INF型结局最差。结论肝癌干细胞相关TME和缺氧/纤维化TME的标志物表达按VN-SN-SNEG-CM-INF大体分型顺序呈递增趋势，它们之间的相互作用可能参与决定肝癌的各种大体形态学特征及其独特的生物学行为。
Background Hepatocellular carcinoma (HCC) is subclassified into five gross types, namely, vaguely nodular (VN), single nodular (SN), single nodular with extranodular growth (SNEG), confluent multinodular (CM), and infiltrative (INF) type. However, the pathological background underlying differences in biological behavior of different gross types of HCC remains unclear. Methods The histopathological features, clinical outcomes of HCC gross types, and their relationships with stemness-related marker status and fibrotic/hypoxic tumor microenvironment (TME) were evaluated in 266 resected HCCs. The stemness-related markers (CD24, CD44, CD133, SALL4, YAP1, K19 and EpCAM), fibrous tumor stroma (alpha SMA), and hypoxia (CAIX) were evaluated with immunohistochemistry. Results Poorer differentiation, reduced capsule formation, higher microvascular invasion, larger tumor size and larger area of necrosis were observed in order of VN-SN-SNEG-CM-INF type (p = 0.005 for all, linear-by-linear association). The expression of summed stemness-related markers and hypoxic/fibrotic TME showed an increasing trend in order of VN-SN-SNEG-CM-INF type (p < 0.005), and their expression well correlated with each other. INF type was found only in HCCs with hypoxic/fibrotic TME or high expression of stemness-related markers. CAIX expression and tumor necrosis >= 30% were independent prognostic markers for disease-specific survival. Early recurrence-free survival showed a significant difference based on gross types, revealing best outcome with VN type and worst outcome with INF type. Conclusion The marker expression of stemness-related and hypoxic/fibrotic TME of HCC showed an increasing trend in order of VN-SN-SNEG-CM-INF gross types, and their cross-talk may be involved in the determination of various gross-morphological features and their distinct biological behavior.