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