J Pathol Transl Med.  2018 Mar;52(2):85-92. 10.4132/jptm.2017.11.13.

The Clinicopathological and Prognostic Significance of the Gross Classification of Hepatocellular Carcinoma

• Lee Y
• Park H
• Lee H
• Cho JY
• Yoon YS
• Choi YR
• Han HS
• Jang ES
• Kim JW
• Jeong SH
• Ahn S
• Kim H

• KMID: 2408508
• DOI: http://doi.org/10.4132/jptm.2017.11.13

Abstract

BACKGROUND
We aimed to determine the clinicopathological significance of the gross classification of hepatocellular carcinoma (HCC) according to the Korean Liver Cancer Association (KLCA) guidelines.
METHODS
A retrospective analysis was performed on 242 cases of consecutively resected solitary primary HCC between 2003 and 2012 at Seoul National University Bundang Hospital. The gross classification (vaguely nodular [VN], expanding nodular [EN], multinodular confluent [MC], nodular with perinodular extension [NP], and infiltrative [INF]) was reviewed for all cases, and were correlated with various clinicopathological features and the expression status of "stemness"-related (cytokeratin 19 [CK19], epithelial cell adhesion molecule [EpCAM]), and epithelial-mesenchymal transition (EMT)-related (urokinase plasminogen activator receptor [uPAR] and Ezrin) markers.
RESULTS
Significant differences were seen in overall survival (p=.015) and disease-free survival (p = .034) according to the gross classification; INF type showed the worst prognosis while VN and EN types were more favorable. When the gross types were simplified into two groups, type 2 HCCs (MC/NP/INF) were more frequently larger and poorly differentiated, and showed more frequent microvascular and portal venous invasion, intratumoral fibrous stroma and higher pT stages compared to type 1 HCCs (EN/VN) (p < .05, all). CK19, EpCAM, uPAR, and ezrin expression was more frequently seen in type 2 HCCs (p < .05, all). Gross classification was an independent predictor of both overall and disease-free survival by multivariate analysis (overall survival: p=.030; hazard ratio, 4.118; 95% confidence interval, 1.142 to 14.844; disease-free survival: p=.016; hazard ratio, 1.617; 95% confidence interval, 1.092 to 2.394).
CONCLUSIONS
The gross classification of HCC had significant prognostic value and type 2 HCCs were associated with clinicopathological features of aggressive behavior, increased expression of "stemness"- and EMT-related markers, and decreased survival.

Keyword

Carcinoma, hepatocellular; Gross classification; Prognosis

MeSH Terms

Carcinoma, Hepatocellular*
Classification*
Disease-Free Survival
Epithelial Cells
Epithelial-Mesenchymal Transition
Liver Neoplasms
Multivariate Analysis
Plasminogen Activators
Prognosis
Retrospective Studies
Seoul
Plasminogen Activators

Figure

• 

  Fig. 1. Examples of the different gross types of hepatocellular carcinoma. (A) Vaguely nodular type. (B) Expanding nodular type. (C) Multinodular confluent type. (D) Nodular with perinodular extension type. (E) Infiltrative type.

• 

  Fig. 2. Immunohistochemical stain results for stemness- and epithelial-mesenchymal transition-related markers: cytokeratin 19 (A), epithelial cell adhesion molecule (B), and ezrin (C).

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  Fig. 3. Kaplan-Meier curves demonstrating differences in disease-free survival and overall survival according to gross classification of hepatocellular carcinoma. (A, B) Disease-free survival. (C, D) Overall survival. VN, vaguely nodular; EN, expanding nodular; MC, multinodular confluent; NP, nodular with perinodular extension; INF, infiltrative.

Reference

1. Liver Cancer Study Group of Japan. General rules for the clinical and pathological study of primary liver cancer. 2nd ed. Tokyo: Kanehara & Co;2003.

2. Kanai T, Hirohashi S, Upton MP, et al. Pathology of small hepatocellular carcinoma: a proposal for a new gross classification. Cancer. 1987; 60:810–9.

3. Choi GH, Han DH, Kim DH, et al. Outcome after curative resection for a huge (>or=10 cm) hepatocellular carcinoma and prognostic significance of gross tumor classification. Am J Surg. 2009; 198:693–701.

4. Fu X, Mao L, Tang M, et al. Gross classification of solitary small hepatocellular carcinoma on preoperative computed tomography: prognostic significance after radiofrequency ablation. Hepatol Res. 2016; 46:298–305.

5. Gong SC, Cho MY, Lee SW, Kim SH, Kim MY, Baik SK. The meaning of gross tumor type in the aspects of cytokeratin 19 expression and resection margin in patients with hepatocellular carcinoma. J Gastroenterol Hepatol. 2016; 31:206–12.

6. Hui AM, Takayama T, Sano K, et al. Predictive value of gross classification of hepatocellular carcinoma on recurrence and survival after hepatectomy. J Hepatol. 2000; 33:975–9.

7. Inayoshi J, Ichida T, Sugitani S, et al. Gross appearance of hepatocellular carcinoma reflects E-cadherin expression and risk of early recurrence after surgical treatment. J Gastroenterol Hepatol. 2003; 18:673–7.

8. Murakata A, Tanaka S, Mogushi K, et al. Gene expression signature of the gross morphology in hepatocellular carcinoma. Ann Surg. 2011; 253:94–100.

9. Shimada M, Rikimaru T, Hamatsu T, et al. The role of macroscopic classification in nodular-type hepatocellular carcinoma. Am J Surg. 2001; 182:177–82.

10. Trevisani F, Caraceni P, Bernardi M, et al. Gross pathologic types of hepatocellular carcinoma in Italian patients: relationship with demographic, environmental, and clinical factors. Cancer. 1993; 72:1557–63.

11. Tsujita E, Yamashita Y, Takeishi K, et al. The clinicopathological impact of gross classification on solitary small hepatocellular carcinoma. Hepatogastroenterology. 2013; 60:1726–30.

12. A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators. Hepatology. 1998. 28:751–5.

13. Jang JY, Lee JS, Kim HJ, et al. The general rules for the study of primary liver cancer. J Liver Cancer. 2017; 17:19–44.

14. Kurogi M, Nakashima O, Miyaaki H, Fujimoto M, Kojiro M. Clinicopathological study of scirrhous hepatocellular carcinoma. J Gastroenterol Hepatol. 2006; 21:1470–7.

15. International Consensus Group for Hepatocellular Neoplasia. Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia. Hepatology. 2009; 49:658–64.

16. Kim H, Choi GH, Na DC, et al. Human hepatocellular carcinomas with "stemness"-related marker expression: keratin 19 expression and a poor prognosis. Hepatology. 2011; 54:1707–17.

17. Kim H, Park YN. Hepatocellular carcinomas expressing ‘stemness’-related markers: clinicopathological characteristics. Dig Dis. 2014; 32:778–85.

18. Lee JM, Dedhar S, Kalluri R, Thompson EW. The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol. 2006; 172:973–81.

19. Okamura D, Ohtsuka M, Kimura F, et al. Ezrin expression is associated with hepatocellular carcinoma possibly derived from progenitor cells and early recurrence after surgical resection. Mod Pathol. 2008; 21:847–55.

20. Zhou L, Hayashi Y, Itoh T, Wang W, Rui J, Itoh H. Expression of urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor, and plasminogen activator inhibitor-1 and -2 in hepatocellular carcinoma. Pathol Int. 2000; 50:392–7.