Elsevier

Journal of Hepatology

Volume 38, Issue 2, February 2003, Pages 200-207
Journal of Hepatology

Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy

https://doi.org/10.1016/S0168-8278(02)00360-4Get rights and content

Abstract

Background/Aims: We conducted a retrospective cohort study to investigate factors to early and late phase recurrence of hepatocellular carcinoma (HCC).

Methods: The study population consisted of 249 patients including 157 with cirrhosis who underwent hepatectomy for HCC. The endpoint was time-to-recurrence. Using a Cox regression model, factors to early and late phase recurrences were investigated censoring recurrence-free patients at the 2-year time point and in patients without recurrence at 2 years.

Results: Actuarial probability of overall recurrence at 1, 3, and 5 years were 0.301, 0.623, and 0.790, respectively, with a median follow-up of 624 days. Early recurrence was observed in 123 out of 249 patients; while late recurrence was found in 61 out of 113 patients. Factors to early recurrence were as follows: non-anatomical resection, presence of microscopic vascular invasion, and serum alpha-fetoprotein level ≥32 ng/ml. Those contributing to late phase recurrence were higher grade of hepatitis activity, multiple tumors, and gross tumor classification.

Conclusions: Variables associated with metastatic recurrence were factors to early phase recurrence; whereas those related with elevated carcinogenesis contributed to late phase recurrence, thus providing an epidemiological evidence that different mechanisms, i.e. metastasis and de novo, are involved in intrahepatic recurrence after hepatectomy for HCC.

Introduction

Although remarkable advances in surgical and imaging modalities have improved the prognosis of hepatocellular carcinoma (HCC) patients [1], the high incidence of intrahepatic recurrence remains a major challenge in HCC therapy [2], [3]. In HCC, macro or microscopic portal venous tumor extension and intrahepatic metastasis have been the factors most consistently reported to be indicative of a poor prognosis after surgery [4], [5], [6], [7], [8], [9]. On the other hand, development of new tumors in the remnant liver, i.e. de novo primary HCC, is also thought to take place [10], [11]. It is usually difficult to distinguish intrahepatic recurrences of different etiologies since clonal discrimination is not done in clinical practice. Thus, this assumption remains merely a hypothesis. However, in theory, recurrence by metastasis takes place in the early period after surgery, whereas that in the late phase largely represents a new primary lesion. Different risk factors are presumed to be involved in each type of recurrence. In particular, risk factors contributing to de novo primary lesion development after hepatectomy has not yet been investigated on a comprehensive basis, although increased hepatitis activity has been reported as a risk factor by several authors [12], [13].

In the present study, we epidemiologically tested the hypothesis that intrahepatic recurrence of HCC is attributable to two different mechanisms: metastasis and de novo primary HCC. To this end, we conducted a retrospective cohort study that investigated factors possibly contributing to early (<2 years) and late (≥2 years) phase intrahepatic recurrence, separately, in 249 patients who underwent hepatectomy for HCC.

Section snippets

Population

The base population consisted of 272 consecutive patients who had undergone initial and curative hepatic resection for HCCs, less than 5 cm in diameter, at Shinshu University Hospital (180 patients between 1990 and 1998) and Tokyo University Hospital (92 patients between 1995 and 1998). The same surgical strategy for HCC was employed in the two institutions in this study period [5]. In brief, the indication of surgical resection and operative procedure was determined according to the decision

Cumulative risk of recurrence and rate of recurrence

Mean and median follow-up times were 854 and 624 days, respectively. Eight patients were lost to follow-up with a median follow-up period of 449 days (range 24–899 days). Recurrence was observed in 184 patients. Median follow-up of 113 patients without early recurrence was 1400 days (range 730–3712 days). The liver was the first site of recurrence in all of them, although lung, brain, or bone metastasis had occurred later in some. Overall cumulative recurrence rate curves for all patients are

Discussion

Although the recurrence rate (hazard function) is statistically equivalent to survival and cumulative survival functions, it depicts the natural history of HCC recurrence after hepatectomy graphically in an intuitive way (Fig. 3). After the early peak of recurrence (at approximately 1 year postoperatively), the recurrence rate was decreased but persisted over a long period, resulting in a second peak after 4 postoperative years. This is most likely explained as follows: recurrence due to

Acknowledgements

This work was supported by the grant aid from Sato Memorial Cancer Research Foundation.

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