Favorable Surgical Outcomes in Patients With Early Hepatocellular Carcinoma

Abstract

Background:

Early hepatocellular carcinoma (HCC) is defined as well-differentiated HCC with an obscure tumor margin in the classification of the Liver Cancer Study Group of Japan. However, the surgical outcomes in patients with early HCC have not yet been clarified.

Methods:

From 1985 to 1994, 186 patients with HCC 2 cm or less in greatest dimension underwent curative hepatectomy. Of the 186 cases, 37 were early HCC and 149 were small advanced HCC. The relationship between clinicopathological findings and surgical outcomes was examined.

Results:

The rate of hepatitis C antibody or number of tumors was significantly higher in patients with early HCC than in patients with small advanced HCC. Liver function test showed no differences between patients with early HCC and patients with small advanced HCC. The 5-and 10-year survival rates were 85% and 61%, respectively, in patients with early HCC, which was significantly better than in patients with small advanced HCC (P = 0.0137). Univariate and multivariate analysis showed Child-Pugh class, intrahepatic metastasis, and early HCC to be significant prognostic factors.

Conclusions:

Patients with early HCC had a different clinical background and good surgical outcomes; therefore, it should be recognized that early HCC is a distinct clinicopathological entity.

Patients with early hepatocellular carcinoma had a different clinical background and good surgical outcomes; therefore, it should be recognized that early hepatocellular carcinoma is a distinct clinicopathological entity.

Early hepatocellular carcinoma (HCC) is defined as well-differentiated HCC with an obscure tumor margin in the classification of the Liver Cancer Study Group of Japan.¹ Early HCC is often detected in cirrhotic liver and shows a hypovascular nodule in the arterial phase.^2,3 Most early HCCs are less than 2 cm in greatest dimension^1,4 and usually involves the interstitial tissue of the portal tract;^5,6 however, early HCC is recognized not to metastasize.¹ If this hypothesis is true, then the surgical outcomes of early HCC should be better than those of small advanced HCC even if the tumor is less than 2 cm in greatest dimension. The aim of this study is to clarify the characteristics and surgical outcomes of patients with early HCC.

METHODS

From 1985 to 1994, 787 patients with HCC underwent hepatectomy at the Institute of Gastroenterology, Tokyo Women's Medical University. Of these, 643 patients had curative resection. Curative resection is defined as resection in which the operative findings showed no tumor in the residual liver that was confirmed by intraoperative ultrasonography and in which no tumor was exposed at the surgical cut surface of the liver on macroscopic findings. Of those who underwent curative hepatectomy, 186 had HCC 2 cm or less in greatest dimension.

Patients with chronic hepatitis or liver cirrhosis were usually examined by ultrasonography every 3 months. When a small nodule was detected in the liver, patients underwent abdominal computed tomography. When a small nodular lesion larger than 1 cm in greatest dimension was not enhanced, we performed fine-needle biopsy of the lesion under ultrasonography and confirmed the diagnosis of the lesion.

Early HCC is well-differentiated HCC with an obscure tumor margin and with the same or lighter color than the surrounding liver parenchyma (Fig. 1a). Early HCC usually involves the portal tracts inside the tumor. Microscopic examination reveals that early HCC shows structural abnormalities, such as small acinar structures, an irregular thin trabecular pattern, or both. The cellular atypia of these tumors often are unremarkable, but the nuclear cytoplasmic ratio is increased due to the decrease in cell cytoplasm (Fig. 1c). The cytoplasm also shows increased eosinophilia or basophilia. The cell density can increase to approximately twice that of the surrounding normal tissue. Early HCC involves the interstitial tissue of the portal tract, which is a key point of differentiation from high-grade dysplastic nodules of the liver.^1,7 We sometimes encounter lesions with a nodule-in-nodule appearance such as moderately or poorly differentiated HCC in early HCC. We classified these nodules on the basis of nodule appearance as HCC to early HCC when the area of the inside nodule which shows more cellular atypia occupies less than half of the tumor.

FIGURE 1. Gross and microscopic photographs of early HCC and small advanced HCC. Early HCC (1.7 cm in diameter) has an obscure tumor margin and a lighter color than the surrounding liver parenchyma (a). Microscopic examination reveals that early HCC shows thin trabecular patterns with unremarkable cellular atypia and usually involves portal tracts inside the tumor (H&E staining; c). Small advanced HCC (1.1 cm in diameter) usually shows expansive growth and capsule formation (b). Microscopic examination of small advanced HCC reveals structural abnormalities and remarkable cellular atypia (H&E staining; d).

Small advanced HCC usually shows expansive growth and capsule formation with white, light tan, or green color in the gross findings (Fig. 1b). Microscopic examination of small advanced HCC reveals that structural abnormalities and the cellular atypia are remarkable (Fig. 1d). When the tumor was not solitary, most secondary tumors were detected on preoperative imaging; however, a few nodules were detected in the gross findings in the specimens. Of the 186 cases, 37 were early HCC and 149 were small advanced HCC. The relationship between clinicopathological findings and surgical outcomes was examined. Mortality (death within 1 month after surgery) in this series was 2.7% (5/186).

Gender, age, hepatitis B surface antigen, antihepatitis C, serum alpha-fetoprotein level (AFP), liver cirrhosis, indocyanine green retention at 15 minutes (ICGR15), Child-Pugh class, macroscopic number of tumors, gross appearance, histologic grading, microscopic portal vein invasion, microscopic satellite nodules, and the operative procedure were examined. Serum AFP levels were determined by logarithmic transformation.

Histologic grading was done according to the classification of the Liver Cancer Study Group of Japan.¹ Only 4 cases were poorly differentiated HCC. We therefore classified poorly and moderately differentiated HCC as nonwell differentiated HCC.

Operative procedures were classified into liver segmentectomy or larger resection, and subsegmentectomy. Liver segmentectomy refers to resection of a Couinaud segment.^8–10 Subsegmentectomy refers to resection of less than one Couinaud segment. When the tumor was located at the borderline of the segment, bisegmentectomy or hepatic lobectomy was performed. The selection between liver segmentectomy or larger resection and subsegmentectomy was made on the basis of liver function and tumor location. There was a tendency to select subsegmentectomy in cases with severe liver cirrhosis or tumors located at the surface of the liver. The surgical margin was considered positive when tumor was present less than 5 mm from the surgical cut surface of the liver on microscopic examination.

Cumulative survival rates were calculated with the Kaplan–Meier method; survival rates were compared using the log-rank test or Cox's proportional hazard model. The duration of survival was defined as the time from liver surgery to the date of death or last contact. The median follow up of the patients was 86 months (ranging from 12 days to 170 months). Several clinicopathological factors, including those found to be associated (P < 0.10) with patient survival by univariate analysis were subjected to multivariate analysis using Cox's proportional hazards model. Differences were considered significant when P < 0.05.

RESULTS

Patient Characteristics in Early HCC and Small Advanced HCC

The rate of hepatitis C virus antibody was significantly higher in patients with early HCC than in those with small advanced HCC; however, there were no differences in Child-Pugh class or the rate of liver cirrhosis. The 2-tumor rate was greater in patients with early HCC than in those with small advanced HCC, on the contrary the single-tumor rate was greater in patients with small advanced HCC than in those with early HCC. Fewer patients with early HCC underwent extended hepatectomy than those with small advanced HCC (Table 1).

TABLE 1. Patient Characteristics in Early HCC and Small Advanced HCC

Survival Rates

The 5- and 10-year survival rates in all patients were 68% and 47%, respectively. The 5- and 10-year survival rates were 85% and 61% in patients with early HCC, respectively, which is significantly better than in patients with small advanced HCC (P = 0.0137; Fig. 2).

FIGURE 2. Cumulative survival curve after surgery in patients with early HCC and small advanced HCC. The cumulative survival rate of patients with early HCC was significantly better than that of patients with small advanced HCC (P = 0.0137).

Univariate and Multivariate Analysis

In univariate analysis, Child-Pugh class (P = 0.0064), serum AFP level (P = 0.0263), liver cirrhosis (P = 0.0060), intrahepatic metastasis (P = 0.0010), and early HCC (P = 0.0137) were significant prognostic factors (Table 2). In multivariate analysis, Child-Pugh class (P = 0.005), microscopic intrahepatic metastasis (P = 0.002) and early HCC (P = 0.030) were significant prognostic factors (Table 3).

TABLE 2. Characteristics of Patients and 5- and 10-Year Survival Rates

TABLE 3. Multivariate Analysis of Prognostic Factors

DISCUSSION

This study showed that early HCC had a more favorable survival than small advanced HCC even if the tumor was less than 2 cm in greatest dimension. Stage I HCC is defined as a solitary tumor less than 2 cm in greatest dimension without vessel invasion, lymph node metastasis, or distant metastasis in the classification of the International Union Against Cancer (UICC)¹¹ or Liver Cancer Study Group of Japan.¹ We calculated the 5- and 10-year survival rates (66%, 37%) in patients (n = 84) with Stage I small advanced HCC in this series. The 5- and 10-year survival rates (85%, 61%) in patients with early HCC which included multiple tumors were better than those in patients with Stage I small advanced HCC. Takayama et al already mentioned that early HCC should be named Stage 0 HCC because of its good surgical outcomes.⁴ The favorable survival of patients with early HCC is considered to be related to a low potential of metastasis and multiple lesions were considered to be multicentric occurrence. Early HCC could not be managed with the usual stage classification.

The obscure tumor features of early HCC can be explained by the fact that early HCC had more expressed matrix metalloproteinase-1 (MMP-1) in the tumor cells.⁶ MMP-1 destroys type I collagen, and therefore tumor cells could invade into the interstitial tissue around early HCC. However, small advanced HCC had not expressed MMP-1 in the tumor cells. These findings may explain the presence of portal tracts inside the tumor in early HCC and the gross appearance of obscure tumor margins.^1,5,6

The number of tumors was larger in patients with early HCC than in those with small advanced HCC. The rate of hepatitis C virus antibody was significantly higher in patients with early HCC than in those with small advanced HCC. These findings show differences in background between early HCC and small advanced HCC. HCC is considered to involve multistep carcinogenesis. Advanced HCC has been considered to originate from moderately or poorly differentiated HCC in early HCC.^12–15 We sometimes encounter lesions with a nodule-in-nodule appearance such as moderately or poorly differentiated HCC in well differentiated HCC. However, the differences in background between early and small advanced HCC cannot explain the multistep nature of HCC. Early HCC may be considered a multicentric type of HCC, which occurs in the liver with hepatitis C virus infection.¹⁶ Some advanced HCC including small advanced HCC may not originate from early HCC.

The survival rate of patients with early HCC decreases 5 years after surgery (Fig. 2). This phenomenon is explained by the occurrence of second primary HCC or liver dysfunction. Therefore, second primary HCC should be prevented and the noncancerous liver after curative surgery for early HCC should be treated to improve the prognosis. Muto et al¹⁷ showed an acyclic retinoid polyprenoic acid to prevent second primary HCC. Ikeda et al¹⁸ demonstrated that interferon therapy for patients with HCC and hepatitis C virus antibody prevented hepatic recurrence after curative surgery or ablation therapy. Interferon therapy also can cure hepatitis C virus infection and improve liver function. These treatments are expected to improve surgical outcomes after curative local therapy for early HCC. Early detection and suitable treatment of early HCC may result in a more favorable survival.