Department of Radiology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
Department of Pathology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
Hepatol Int. 2020 Mar;14(2):239-248. doi: 10.1007/s12072-020-10012-6. Epub 2020 Jan 29.
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.
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 (αSMA), and hypoxia (CAIX) were evaluated with immunohistochemistry.
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.
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.
肝细胞癌 (HCC) 可细分为五种大体类型，即模糊结节型 (VN)、单发结节型 (SN)、单发结节伴外生生长型 (SNEG)、融合多结节型 (CM) 和浸润型 (INF) 。然而，不同 HCC 大体类型的生物学行为差异的病理基础仍不清楚。
在 266 例 HCC 中，评估了 HCC 大体类型的组织病理学特征、临床结局及其与干性相关标志物状态和纤维性/缺氧肿瘤微环境 (TME) 的关系。用免疫组化法评估了干性相关标志物（CD24、CD44、CD133、SALL4、YAP1、K19 和 EpCAM）、纤维性肿瘤基质 (αSMA) 和缺氧 (CAIX)。
VN-SN-SNEG-CM-INF 型的分化程度越低、包膜形成越少、微血管侵犯越严重、肿瘤越大、坏死面积越大（p=0.005 均）。累积干性相关标志物和缺氧/纤维性 TME 的表达也呈 VN-SN-SNEG-CM-INF 型递增趋势（p<0.005），且彼此之间的表达密切相关。INF 型仅见于缺氧/纤维性 TME 或干性相关标志物高表达的 HCC 中。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。早期无复发生存率根据大体类型存在显著差异，VN 型的结果最佳，而 INF 型的结果最差。
HCC 干性相关标志物和缺氧/纤维性 TME 的表达呈 VN-SN-SNEG-CM-INF 大体类型递增趋势，其相互作用可能参与了各种大体形态特征及其不同生物学行为的决定。
