The demographics of the 127 patients are summarized in Table 1. There were 64 men (50.4%) and 63 women (49.6%). The median patient age was 58 years old (range, 26-83 years old). Preoperative tumor markers examination was done in 125 cases, elevated CA-199 and CEA were detected in 82 (67.8%) and 36 (29.8%) cases, respectively. The mean tumor size was 4.5 cm (range 1.0-11.0 cm), of which 43 (33.9%) had a tumor ≥ 5 cm. The differentiation of the IHCC was as follows: poor, 42 cases (33.1%); moderate, 52 cases (40.9%); well, 15 cases (11.8%); unknown, 18 (14.2%). Distribution according to T stage was as follows: T1, 35 cases (27.6%); T2, 56 cases (44.1%); T3, 33 cases (26.0%); and T4, 3 cases (2.4%). Lymph nodes metastasis was found in 41 of the cases (32.3%). According to the TNM staging, patients with stage I, II, III, and IV disease were 28 (22.0%), 34 (26.8%), 21 (16.5%), and 44 (34.6%) cases, respectively. Twenty eight patients received adjuvant chemotherapy.
Initial Disease Recurrence
Seventy-three (73/127, 57.5%) IHCC patients developed tumor recurrence. Disease progression was mainly documented by serial imaging in 65 patients (65/73, 89.0%), while 8 patients (8/73, 11.0%) had biopsy confirmation. Table 2 and Figure 1 show the anatomic locations of all initial tumor progressions.
Initial recurrences occurring in the potential PORT volume, remnant liver and distant sits were 46 (46/73, 63.0%), 36 (36/73, 49.3%) and 22 (22/73, 30.1%) cases, respectively. Among them, 20 cases had multiple sites of initial disease recurrence. Fifty-four patients had no evidence of disease at the last follow-up.
Of the 46 patients whose initial recurrence were inside the potential PORT volume, 29 (29/73, 39.7%) developed recurrence only inside the potential PORT volume, including 13 tumor bed recurrences, 7 lymph node metastases, and 9 with both tumor bed recurrences and lymph node metastases. Three had synchronous recurrences at remnant liver. Another 3 had synchronous recurrences at distant sites, and 11 had synchronous recurrences at remnant liver and distant sites.
Thirty-six patients developed initial recurrence in the remnant liver. Among them, 19 had remnant liver lesions as the only recurrences, 3 had synchronous recurrences in the potential PORT volume, another 3 had synchronous recurrences at distant sites, and 11 had synchronous recurrences at distant sites and the potential PORT volume.
Twenty-two had distant metastases at initial recurrence, 5 of them were distant metastases only (4 lung, 1 peritoneum), 3 had synchronous recurrences in the potential PORT volume, another 3 had synchronous remnant liver recurrences, and 11 had synchronous recurrences in the potential PORT volume and remnant liver.
The common sites of nodal metastases were lymph nodes around the abdominal aorta (station No.16, n=18), lymph nodes along the celiac artery (No.9, n=13), lymph nodes along the common hepatic artery (No.8, n=11), lymph nodes in the hepatoduodenal ligament (No. 12, n=8), lymph nodes on the posterior aspect of the pancreatic head (No.13, n=4) and lymph nodes at the root of the mesentery (No.14, n=2). All patients with station No.16 recurrences had metastatic lesions at other lymph node stations or distant sites. Among them, 11 cases had lesions in No.16a2 with no metastases in No.16b1, 6 had lesions in No.16a2 and No.16b1. Only 1 case had lymph node metastases at station No.16b1 without lesion at No.16a2, but that patient had multiple metastatic nodes on the posterior aspect of the pancreatic head.
Follow-up and Survival
The median follow-up time was 23.5 months (range 2-85 months). At the last follow-up on February 8, 2018, 59 patients were alive. The median recurrence free survival (RFS) and overall survival (OS) were 12.1 months and 24.8 months, respectively. In the univariate analysis of the entire cohort, improved survival was associated with age ≥ 55 years (RFS, 18.5 vs 10.0 months, p=0.046; OS, 34.8 vs 18.6 months, p=0.002) (Fig. 2), tumor size < 5cm (RFS, 19.8 vs 6.7 months, p=0.001; OS, 28.8 vs 21.5 months, p=0.071) (Fig. 3), no lymph node metastasis (RFS, 21.2 vs 6.1 months, p<0.001; OS, 40.2 vs 11.5 months, p<0.001) (Fig. 4), no history of hepatitis (RFS, 17.6 vs 10.4 months, p=0.005; OS, 25.2 vs 19.0 months, p=0.079) (Fig. 5), early tumor stage (stages I and II vs stages III and IV, RFS, 30.2 vs 7.7 months, p<0.001; OS, 45.5 vs 15.7 months, p<0.001) (Fig. 6) and better tumor differentiation (poor vs moderate vs well, RFS, 6.7 vs 15.6 vs 51.7 months, p=0.027; OS, 19.4 vs 28.8 months, not reached for well differentiation patients, p=0.003) (Fig. 7). The results of the univariate analysis are summarized in Table 3. In the multivariate analysis, RFS of tumor size (RR 2.191; 95% confidence interval [CI] 1.257-3.817; p=0.003) and tumor differentiation (RR 0.621; 95% confidence interval [CI] 0.408-0.947; p=0.027) reached statistical significance. OS of age (RR 0.418; 95% confidence interval [CI] 0.236-0.740; p=0.003) also reached significance.