Pathobiological features of small hepatocellular carcinoma: correlation between tumor size and biological behavior

Abstract

Purpose: Increasing evidence has suggested that tumor size is one of the independent prognostic factors of patients with hepatocellular carcinoma (HCC). However, the criteria used to determine when HCC should be classified as small remain controversial. Our objective was to evaluate the relationship between the size of HCC and its clinicopathological features.

Methods: A retrospective study on 618 patients who underwent partial hepatectomy for solitary HCC was performed. These patients were divided into Groups 1-5 according to the tumor diameter: ≤ 1, 1.1-2, 2.1-3, 3.1-5 and >5 cm, respectively. The clinicopathological variables of the patients in each group were compared statistically.

Results: Except for the microHCC (≤ 1 cm) which differed significantly from the other four groups in the clinicopathological variables, almost no differences existed among HCC ranging from 1 to 3 cm, or HCCs > 3 cm. If ≤ 3 cm was used as the cut-off point for small HCC (SHCC), and >3 cm for large HCC (LHCC), significant differences (P < 0.05-0.01) were observed between SHCC and LHCC in: histological grades I-II (48.0 vs. 19.4 %), capsular invasion (15.4 vs. 36.3%), tumor thrombi (6.9 vs. 23.5%), satellite nodules (12.3 vs. 35.5%), noninvasive growth patterns (69.6 vs. 25.4%), the overall survival (OS, 119.6 ± 34.7 vs. 68.5 ± 6.6 months), and the recurrence-free survival (RFS, 67.0 ± 16.7 vs. 29.5 ± 3.2 months). Multivariate Cox regression analyses show that tumor size >3 cm was one of the independent prognostic factors for both OS and RFS.

Conclusions: The 3 cm cutoff seems to best determine the biological behavior and clinical prognosis of patients undergoing partial hepatectomy for early stage HCC. Overall, HCC smaller than 3 cm in diameter was closely related with a better prognosis which reflected the relatively benign pathobiological features at an early developmental stage. As HCC > 3 cm exhibited a tendency towards more aggressive behavior, we suggest that HCC ≤ 3 cm in diameter should be used as a critical size of SHCC at which curative treatment achieves better long-term survivals.

Fig. 1

Representative growth-pattern classification of HCC. a Transitional growth pattern revealing a transformation between the thin tumor cell cords (left) and surrounding liver cell plates (right) as indicated by arrowheads (×400). b Encapsulated growth pattern, displaying a fine fibrous capsule between the well-differentiated HCC (left) and liver tissue (right) (×200). c Near-by invasive growth pattern, showing a nearby tumor focus outside the capsule (×100). d Multifoci growth pattern, exhibiting several tumor foci infiltrated in the surrounding liver (×100)

Fig. 2

Kaplan–Meier survival curves for patients with different sizes of HCC in the five groups. a The five OS curves were separated into three distinct clusters by Group 1, Groups 2–3, and Groups 4–5, with significant difference between each cluster (log-rank test P < 0.001), b The five RFS curves were separated into two clusters by Groups 1–3 and Groups 4–5 (log-rank test P < 0.05–0.01)

Fig. 3

Kaplan–Meier survival curves for patients between the SHCC group and the LHCC group after partial hepatectomy. a OS (mean ± SE, log-rank test P < 0.001), b RFS (mean ± SE, log-rank P < 0.001)

Fig. 4

Schematic representation of a multistep progression from the extremely early microHCC to advanced LHCC. Generally, SHCC ≤ 3 cm has a very low risk of infiltrative behavior which provides a pathobiological basis for curative treatment. However, as illustrated by the vertical and diagonal dotted lines, each of these consecutive stages is not distinct because of tumor heterogeneity. Even at the same tumor size ≤3 cm the majority of SHCC show relatively benign behavior (Patterns A and B), a few of them could exhibit obviously invasive growth patterns (Patterns C and D) indicative of their progression into the highly aggressive stage