Early hepatocellular carcinoma (HCC) has been defined as a well-differentiated cancer with no substantial destruction of the preexisting hepatic framework.1 This lesion resembles in situ or microinvasive carcinoma, because it seldom vasoinvades or metastasizes,1 originates from a precursor,2 lacks known genetic alterations,3 and represents an initial stage of hepatocarcinogenesis.4 However, it remains to be clarified whether patients with early HCC are more likely to benefit from treatment than are those with overt HCC. Recent imaging techniques have facilitated detection of early HCC in at-risk patients undergoing regular follow-up for chronic viral hepatitis or cirrhosis. We thus conducted a prospective study of surgical treatment for Stage I HCC, possibly containing early HCC.5 This review shows the clinical significance of early HCC by assessing how the surgery will impact patients' survival.
Early hepatocellular carcinoma (HCC) is defined as a well-differentiated cancer containing Glisson's triad, but it remains unknown whether this lesion is curable by surgery. We studied 70 patients who had a single HCC smaller than 2 cm in diameter (Stage T1) and who underwent curative hepatectomy and long-term follow-up. Based on our typing system, the tumors were assigned as early HCC (n = 15), overt HCC (n = 52), and non-HCC tumor (n = 3). The rate of microscopic regional spread was lower in early HCCs than in overt HCCs (7% vs. 42%; P = .01). After a median follow-up of 6.3 years, both overall survival and recurrence-free survival in the early HCC group were significantly better than those in the overt HCC group (P = .01; P = .001, respectively): the 5-year rates of overall survival were 93% and 54% and those of recurrence-free survival were 47% and 16%, respectively. The early HCC group was at a lower risk of recurrence (relative risk, 0.31; 95% confidence interval, 0.15–0.65; P = .002) and death (0.26; 0.09–0.73; P = .01) than was the overt HCC group. Early HCC is a distinct clinical entity with a high rate of surgical cure. (Liver Transpl 2004;10:S16–S19.)
Between 1982 and 1991, we sought patients with early HCC among 1,172 patients referred with a preliminary diagnosis of liver tumor. A total of 596 patients were excluded: 485 were given a diagnosis of far-advanced (n = 214), other malignant (n = 152), and benign (n = 119) liver tumors; 70 had hepatic function of Child-Turcotte-Pugh (CTP) class C; 32 had equivocal findings in the liver; and 9 refused surgery. The remaining 576 patients were judged as having resectable HCC. Among them, 80 patients with clinical evidence of a single HCC smaller than 2 cm in diameter, with no vascular invasion (T1), lymph node metastasis (N0), or distant metastasis (M0) (Stage I HCC) were eligible for this study.
In the 80 patients with Stage I tumors, HCC was diagnosed on the basis of 6 specific imaging findings:6, 7 1) mosaic nodular appearance on ultrasonography; 2) a low-high-low density profile during dynamic CT; 3) tumor staining on angiography; 4) hypoattenuation on transarterial portographic CT; 5) hyperattenuation on hepatic arteriographic CT; and 6) deposition of Lipiodol on follow-up unenhanced CT. The diagnostic criteria for HCC required unequivocally specific evidence of at least 2 of the first 3 imaging findings. In cases failing to satisfy this requirement, other imaging methods were then used until at least two techniques confirmed the specific finding.
All 80 patients underwent ultrasonography, dynamic CT, and angiography, which had detection rates of 99%, 89%, and 69%, respectively. There were 70 patients whose tumor met the diagnostic criteria for HCC. The diagnosis was established with these 3 imaging methods in 45 patients; 4 methods were required in 18 patients, and 5 or 6 methods in 7 patients. The addition, portographic CT permitted diagnosis in 13 patients, arteriographic CT in 5, both CTs in 2, and Lipiodol-CT in 5. The other 10 patients whose tumor did not meet the criteria were followed.
Questions arise with respect to the diagnosis of early HCC. What patients are likely to have early HCC? The mean diameter of tumors incidentally resected prior to this study was 14 (SD 4) mm (n = 33),4 suggesting that patients with Stage I HCC are plausible candidates. Why are early HCC difficult to diagnose? The insufficient diagnostic specificity may be because the tumor itself contains Glisson's triad and because it lacks distinct neoangiogenesis.1, 4 What is the diagnostic approach to early HCC? To maximize chances for identification, we used up to 6 imaging methods, including angiographic CT and Lipiodol-CT.6 These additional methods resulted in fulfillment of the diagnostic criteria in 25 patients (of whom 10 had early HCC). The risk of overdiagnosis (3 of 70 cases, 4.3%), however, was almost similar to that (21 of 590 cases, 3.6%)8 reported in a study of patients in whom HCC was diagnosed on the basis of currently accepted standards. The clinical diagnosis of early HCC therefore requires refined imaging criteria, such as ours.
The 80 patients (55 men and 25 women; median age, 57 years; range, 30–74) had chronic hepatitis or cirrhosis caused by hepatitis B virus (surface antigen positive, n = 15; related antibody alone, n = 33), hepatitis C virus (n = 37, of 48 patients who survived beyond 1990, when the assay became available), or both (n = 2). Patients whose tumor met the diagnostic criteria for HCC were scheduled to undergo hepatectomy, while those whose tumor did not were observed. Ultrasound-guided local resection or segmentectomy by the clamp-crushing method was the routine procedure of choice.9, 10 The operation was defined as curative when all gross lesions were removed with a tumor-free margin.
The 70 patients (CTP class A, n = 59; class B, n = 11) underwent local resection (n = 53) or segmentectomy (n = 17). Intraoperative ultrasonography revealed that the tumor stage had been underestimated in 7 patients (10%): 5 had 2 tumors, 1 had 3 tumors, and 1 had a tumor measuring 3.0 cm. All 7 newly found tumors (size = 1.0 cm) were also resected, and the cases were reassigned to Stage II tumor. The mean blood loss was 766 (SD 539) ml and 11 patients (16%) required transfusions. All operations were curative, with a mean tumor-free surgical margin of 5 (SD 4) mm. One patient died of liver failure 3 months after operation (in-hospital mortality, 1.4%).
The definition for early HCC was as follows: macroscopically, the tumor was a distinctive nodule from the surrounding lobules by its size or color that did not substantially destroy the preexisting hepatic framework; microscopically, it had to contain Glisson's triad (the portal tracts), and to show hypercellularity (over 2-fold) with minimal cellular or nuclear atypia (Edmondson's grade 1), as well as definite structural atypia, as indicated by acinar formation, thin trabeculae, or remodeling of the cord architecture.1, 4
The resected tumors were typed according to our gross classification system for small HCC into “overt” types (type 1, single nodular; type 2, single nodular with extranodular growth; type 3, contiguous multinodular), “early” type, and others,1 by 3 liver pathologists who were unaware of clinical details. Tumor-cell differentiation was graded as 1, 2, or 3 according to Edmondson's system, and microscopic regional spread (vascular invasion and metastasis) of tumor was assessed. The final diagnosis was consistent with the histological criteria recommended by the International Working Party.11
Based on the typing system, the tumors were classified as early HCCs (n = 15), overt HCCs (n = 52), and other tumors (n = 3; 2 dysplastic nodules and 1 hemangioma, which were excluded from further analysis). Early HCCs were smaller than overt HCCs (14 vs. 17 mm, P = .02). All early HCCs contained Glisson's triad and were Edmondson's grade 1. The incidence of regional cancer spread was significantly lower in early HCCs (7%) than in overt HCCs (42%) (P = .01). Adenomatous hyperplasia2 coexisted in 47% of early HCC specimens and in 35% of overt HCC specimens (P = .55).
Postoperatively, all patients were screened by ultrasonography every 2 months and dynamic CT every 4 months. Recurrence was defined clinically as the appearance of a new lesion with radiological features typical of HCC, as confirmed by 2 imaging methods.12 Any tumor arising in the same segment as the initial tumor was considered a “local” recurrence. All patients were followed up for a minimum of 5 years or until death.
After a median follow-up of 6.3 years (range, 0.2–14.3), a total of 59 patients (88%) had recurrences in the remnant liver. Early (within 3 years) recurrence was significantly less frequent in the early HCC group (8%) than in the overt HCC group (74%) (P < .001). The median time to recurrence in the early HCC group was significantly longer than that in the overt HCC group (3.9 vs. 1.7 years, P < .001). The early groups had no local recurrence.
Recurrence of HCC is frequent shortly after curative hepatic resection, with the rates ranging from 75–100% at 5 years.13–16 However, recurrence in the early HCC group generally occurred 3 years after surgery and was detected as a single nodule in a different segment, suggesting multifocal development of HCC.12, 17 Multicentricity, however, is probably not the sole cause of recurrence, since the cumulative 5-year recurrence rate (53%) in this group was higher than the rate of newly developed HCC (35%) in an at-risk cohort with cirrhosis alone. This difference may be explained by a study showing that patients with a history of HCC are at greater risk of multicentric hepatocarcinogenesis than those without such a history.15 It is possible that multifocal tumors or precursors may have become detectable at various times during postoperative follow-up.
During follow-up, 42 patients (63%) died of recurrent HCC (n = 40), liver failure (n = 1), or sigmoid colon cancer (n = 1). The rates of both overall survival (Fig. 1) and recurrence-free survival were significantly higher in the early HCC group than in the overt HCC group (P = .01; P = .001). The 5-year rates of overall survival were 93% and 54%, and those of recurrence-free survival were 47% and 16% in the two groups, respectively. Significant differences in overall survival persisted throughout the follow-up period (at 10 years and later, 57% vs. 21%, P = .05). There were 8 long-term (over 10 years) survivors: 4 patients in the early HCC group (27%) and 4 in the overt HCC group (8%).
Of 16 variables evaluated, 3 were significantly related to recurrence on multivariate analyses: CTP class, type of HCC, and regional cancer spread. The first 2 variables were also significantly related to death. Early HCC was independently associated with reduced risks of recurrence (relative risk, 0.31; 95% confidence interval, 0.15–0.65; P = .002) and death (0.26; 0.09–0.73; P = .01) compared with overt HCC.
The 5-year survival after resection for early HCC (93%) contrasts sharply with reported results of Stage I HCC (46–53%),15, 18 and is comparable to that after transplantation for incidental or small HCC.19 Hence, a new subgrouping for this lesion, such as “Stage 0” HCC (not included in the current TNM classification), is of clinical value. Even when “local cure” of early HCC appears to have been achieved, over 90% survival seems unlikely to last in these patients with cirrhosis that is associated with “field cancerization.”17 In this respect, our outcome in the early HCC group shows a curability limit of local therapy which left the patients with diseased liver and, therefore, transplantation can be an only option for potentially “absolute cure.”20
In interpreting the treatment outcome, our surgical result is probably affected by potential sources of lead time bias and length bias.21, 22 We have already shown “less malignant” biological characteristics of early HCC1, 3 and a possible biological continuum from precursor via early to advanced HCC.2, 4 Although information on the natural history of early HCC is unavailable, the lesion itself may have a longer clinical course than overt HCC. The finding that recurrence occurred later and less often in the early HCC group suggests that biology of the disease rather than surgical intervention for any specific lesion plays an important role in the difference in outcome. Taken together, early HCC may represent an initial stage in the development of HCC, not just as concerns the index lesion but also with regard to the remaining liver. Ultimately, the only way to assess relevance of the biases would be to clarify whether disease-specific mortality from HCC can be reduced by screening or surveillance of at-risk subjects. Even so, the promise of surgery for small HCC suggests that early diagnosis and treatment for HCC seems justified, unless randomized controlled trials recommend an alternative policy.
We found that early HCC can be identified as a distinct clinical entity that has a high chance for surgical cure.5 In 15 patients with a single early HCC, the surgical outcome (5-year overall survival, 93%; recurrence-free survival, 47%) was encouraging as compared with that (54%; 16%) in 52 patients with overt HCC as well as with the results of reported studies.13–16 Minor hepatectomy with tumor clearance was well-tolerated (operative mortality, 1.4%) and ensured an optimal level of regional cure of early HCC (local recurrence, 0%). Moreover, multivariate analysis showed that the early HCC group had a lower risk of death than did the overt HCC group (relative risk, 0.26). These findings provide clinical evidence justifying the establishment of this new entity termed “early HCC.”