4.1 Basic statistics 4.1.1 Causes of death of newly enrolled patients during the survey period

The mortality rate during the survey period for newly enrolled patients with HCC was 14.0% (2585 patients). The cause of death was cancer for 59.3%, liver failure for 15.8%, gastrointestinal hemorrhage for 1.4% and rupture of gastroesophageal varices for 2.0%. The surgical mortality was 0.9% (22 patients), giving a surgical mortality rate of 0.3% among the 7737 patients who underwent surgery. The mortality rate for newly enrolled patients with ICC was 30.2% (402 patients). The cause of death was cancer for 82.1% and liver failure for 5.2% (Table 2).

TABLE 2. Prognosis Hepatocellular carcinoma Intrahepatic cholangiocarcinoma Combined hepatocellular cholangiocarcinoma Surviving patients 13 236 759 128 Deaths from all causes, n (%) 2585 402 64 Liver cancer 1534 (59.3) 330 (82.1) 54 (84.4) Liver failure 409 (15.8) 21 (5.2) 3 (4.7) Gastrointestinal hemorrhage 36 (1.4) 2 (0.5) 0 (0.0) Rupture of esophageal/gastric varices 52 (2.0) 0 (0.0) 1 (1.6) Intraperitoneal hemorrhage due to tumor rupture 59 (2.3) 1 (0.2) 0 (0.0) Surgery 22 (0.9) 2 (0.5) 0 (0.0) Other 321 (12.4) 24 (6.0) 5 (7.8) Unknown 152 (5.9) 22 (5.5) 1 (1.6) Survival status unknown 2698 169 10 4.1.2 Past medical history

The proportions of patients with a history of transfusions and a history of excessive alcohol use were 22.0% and 26.9% for HCC, and 9.2% and 17.1% for ICC, respectively. The proportion with hypertension was 49.9% for HCC and 47.8% for ICC, and the proportion with diabetes was 32.5% for HCC and 20.3% for ICC. The proportion with a body mass index (BMI) of ≥25 kg/m2 was 30.1% for HCC and 21.5% for ICC. The proportion with severe obesity (BMI ≥ 30 kg/m2) was 5.2% for HCC and 4.0% for ICC.

4.1.3 Clinical and imaging diagnosis

The mean age of men and women at clinical diagnosis of primary liver cancer was 69.3 and 73.0 years for HCC, and 70.4 and 69.1 years for ICC, respectively. The ratio of male to female patients was 2.48:1 for HCC and 1.56:1 for ICC.

The liver damage grade at diagnosis of HCC was A in 63.7% of patients, B in 30.7% and C in 5.6%. The Child–Pugh grade was A in 75.2% of patients, B in 21.1% and C in 3.7%. Serum albumin was measured by the BCG method in 24.6% and the modified BCP method in 75.4% of patients (Tables 3 and 4).

TABLE 3. Clinical diagnosis (1) Hepatocellular carcinoma Intrahepatic cholangiocarcinoma Combined hepatocellular cholangiocarcinoma Evidence for diagnosis (multiple choices allowed)a (N = 35 880) (N = 2780) (N = 410) CT 15 280 1201 177 MRI 7872 585 85 Ultrasound 6040 476 65 Contrast ultrasound 1436 62 17 Angiography 2089 64 18 Pathology 998 247 22 Angio-CT 1764 49 16 Other 401 96 10 Evidence for diagnosis (whether dynamic study was performed) when diagnostic modality was “CT” or “MRI,” n (%) (N = 15 927) (N = 1083) (N = 178) Performed 15 927 (100.0) 1083 (100.0) 178 (100.0) Performance status, n (%) (N = 17 581) (N = 1273) (N = 188) PS0 12 877 (73.2) 856 (67.2) 141 (75.0) PS1 3154 (17.9) 262 (20.6) 30 (16.0) PS2 928 (5.3) 88 (6.9) 16 (8.5) PS3 454 (2.6) 42 (3.3) 1 (0.5) PS4 168 (1.0) 25 (2.0) 0 (0.0) Encephalopathy, n (%) (N = 18 851) (N = 1322) (N = 204) None 18 411 (97.7%) 1313 (99.3%) 204 (100.0%) Mild 338 (1.8%) 7 (0.5%) 0 (0.0%) Moderate–severe 102 (0.5%) 2 (0.2%) 0 (0.0%) Ascites, n (%) (N = 18 866) (N = 1324) (N = 203) None 16 696 (88.5) 1194 (90.2) 189 (93.1) Responded to treatment 1262 (6.7) 39 (2.9) 9 (4.4) Refractory to treatment 908 (4.8) 91 (6.9) 5 (2.5) Serum bilirubin (mg/dl), n (%) (N = 19 095) (N = 1340) (N = 205) 0.0–0.9 11 858 (62.1) 909 (67.8) 140 (68.3) 1.0–1.9 5781 (30.3) 287 (21.4) 51 (24.9) 2.0–3.0 919 (4.8) 48 (3.6) 4 (2.0) ≥3.1 537 (2.8) 96 (7.2) 10 (4.9) Serum albumin (g/dl), n (%) (N = 19 046) (N = 1327) (N = 205) <2.8 1335 (7.0) 81 (6.1) 15 (7.3) 2.8–2.9 801 (4.2) 48 (3.6) 5 (2.4) 3.0–3.5 4624 (24.3) 212 (16.0) 34 (16.6) >3.5 12  286 (64.5) 986 (74.3) 151 (73.7) Method of albumin measurement, n (%) (N = 14 531) (N = 1 034) (N = 147) BCG 3570 (24.6) 263 (25.4) 38 (25.9) Modified BCP 10 961 (75.4) 771 (74.6) 109 (74.1) ICG R15, n (%) (N = 10 017) (N = 777) (N = 138) ≤14 4938 (49.3) 583 (75.0) 82 (59.4) 15–24 2700 (27.0) 132 (17.0) 43 (31.2) 25–40 1611 (16.1) 44 (5.7) 11 (8.0) >40 768 (7.7) 18 (2.3) 2 (1.4) For all parameters, N is the total number of patients, excluding those in the “unknown” category, and (%) is the percentage of n. TABLE 4. Clinical diagnosis (2) Hepatocellular carcinoma Intrahepatic cholangiocarcinoma Combined hepatocellular cholangiocarcinoma Prothrombin activity, n (%) (N = 18 364) (N = 1251) (N = 200) <40 546 (3.0) 44 (3.5) 1 (0.5) 40–49 358 (1.9) 13 (1.0) 3 (1.5) 50–70 3050 (16.6) 120 (9.6) 22 (11.0) 71–80 3657 (19.9) 163 (13.0) 38 (19.0) >80 10 753 (58.6) 911 (72.8) 136 (68.0) Prothrombin time (INR), n (%) (N = 18 432) (N = 1266) (N = 201) ≤1.20 15 026 (81.5) 1115 (88.1) 180 (89.6) 1.21–1.30 1760 (9.5) 79 (6.2) 13 (6.5) 1.31–1.50 1044 (5.7) 34 (2.7) 4 (2.0) 1.51–1.80 347 (1.9) 21 (1.7) 3 (1.5) ≥1.81 255 (1.4) 17 (1.3) 1 (0.5) Platelets (×104/mm3), n (%) (N = 19 073) (N = 1338) (N = 205) <3.0 112 (0.6) 1 (0.1) 0 (0.0) 3.0–4.9 629 (3.3) 4 (0.3) 0 (0.0) 5.0–9.9 4708 (24.7) 70 (5.2) 19 (9.3) 10.0–14.9 5752 (30.2) 209 (15.6) 62 (30.2) 15.0–19.9 3974 (20.8) 367 (27.4) 47 (22.9) 20.0–99.9 3725 (19.5) 672 (50.2) 76 (37.1) ≥100 173 (0.9) 15 (1.1) 1 (0.5) Serum creatinine (mg/dl), n (%) (N = 18 881) (N = 1333) (N = 204) <1.0 15 085 (79.9) 1104 (82.8) 167 (81.9) ≥1.0 to <2.0 3176 (16.8) 191 (14.3) 33 (16.2) ≥2.0 to <3.0 221 (1.2) 14 (1.1) 1 (0.5) ≥3.0 399 (2.1) 24 (1.8) 3 (1.5) Liver damage grade, n (%) (N = 19 121) (N = 1341) (N = 205) A 12 187 (63.7) 1029 (76.7) 145 (70.7) B 5864 (30.7) 225 (16.8) 55 (26.8) C 1070 (5.6) 87 (6.5) 5 (2.4) Child–Pugh grade, n (%) (N = 18 522) (N = 1279) (N = 201) A 13 923 (75.2) 1008 (78.8) 163 (81.1) B 3916 (21.1) 241 (18.8) 33 (16.4) C 683 (3.7) 30 (2.3) 5 (2.5) AFP (ng/ml), n (%) (N = 18 604) (N = 996) (N = 198) <10 7413 (39.8) 818 (82.1) 74 (37.4) ≤199 7047 (37.9) 129 (13.0) 57 (28.8) ≤399 813 (4.4) 16 (1.6) 13 (6.6) ≤999 814 (4.4) 14 (1.4) 17 (8.6) ≤9999 1407 (7.6) 13 (1.3) 22 (11.1) ≤99 999 799 (4.3) 4 (0.4) 14 (7.1) ≥100 000 311 (1.7) 2 (0.2) 1 (0.5) AFP-L3, n (%) (N = 9286) (N = 278) (N = 110) <5.0 4192 (45.1) 191 (68.7) 33 (30.0) ≤9.9 1728 (18.6) 19 (6.8) 9 (8.2) ≤14.9 679 (7.3) 6 (2.2) 4 (3.6) ≤19.9 319 (3.4) 4 (1.4) 2 (1.8) ≥20.0 2368 (25.5) 58 (20.9) 62 (56.4) For all parameters, N is the total number of patients, excluding those in the “unknown” category, and (%) is the percentage of n. Abbreviation: AFP, α-fetoprotein.

In HCC, serum α-fetoprotein (AFP) was <15 ng/ml in 39.8% of patients, 15–199 ng/ml in 37.9% and ≥200 ng/ml in 22.3%. Lectin-reactive AFP was <10% in 63.7% of patients, 10%–14.9% in 7.3% and ≥15% in 28.9%. PIVKA-II (protein induced by vitamin K absence or antagonist-II) was <40 mAU/ml in 38.9% of patients, 40–99 mAU/ml in 14.2%, and ≥100 mAU/ml in 46.9%. In ICC, CEA was <5.0 ng/ml in 56.1% of patients, 5.0–9.9 ng/ml in 19.0% and ≥10 ng/ml in 24.8%. CA19-9 was <37 U/ml in 36.1% of patients, 37–99 U/ml in 13.2% and ≥100 U/ml in 50.7% (Tables 3 to 5).

TABLE 5. Clinical diagnosis (3) Hepatocellular carcinoma Intrahepatic cholangiocarcinoma Combined hepatocellular cholangiocarcinoma PIVKA-Ⅱ (mAU/ml), n (%) (N = 17 987) (N = 823) (N = 193) <40 6995 (38.9) 671 (81.5) 90 (46.6) ≤99 2547 (14.2) 47 (5.7) 25 (13.0) ≤299 2161 (12.0) 25 (3.0) 25 (13.0) ≤499 775 (4.3) 13 (1.6) 8 (4.1) ≤999 920 (5.1) 10 (1.2) 6 (3.1) ≤2999 1262 (7.0) 18 (2.2) 10 (5.2) ≤9999 1187 (6.6) 21 (2.6) 12 (6.2) ≥10 000 2140 (11.9) 18 (2.2) 17 (8.8) CEA (ng/ml), n (%) (N = 9392) (N = 1220) (N = 166) Below detectable levels 43 (0.5) 3 (0.2) 1 (0.6) <2.5 3054 (32.5) 341 (28.0) 54 (32.5) ≤4.9 3791 (40.4) 340 (27.9) 52 (31.3) ≤9.9 1978 (21.1) 232 (19.0) 34 (20.5) ≤19.9 408 (4.3) 92 (7.5) 14 (8.4) ≤49.9 68 (0.7) 76 (6.2) 4 (2.4) ≤99.9 24 (0.3) 44 (3.6) 1 (0.6) ≥100 26 (0.3) 92 (7.5) 6 (3.6) CA19-9 (U/mL), n (%) (N = 8886) (N = 1225) (N = 163) Below detectable levels 370 (4.2) 22 (1.8) 8 (4.9) <37 6478 (72.9) 420 (34.3) 84 (51.5) ≤99 1520 (17.1) 162 (13.2) 28 (17.2) ≤299 378 (4.3) 157 (12.8) 21 (12.9) ≤999 88 (1.0) 133 (10.9) 7 (4.3) ≤2999 29 (0.3) 122 (10.0) 7 (4.3) ≤9999 15 (0.2) 81 (6.6) 3 (1.8) ≥10 000 8 (0.1) 128 (10.4) 5 (3.1) For all parameters, N is the total number of patients, excluding those in the “unknown” category, and (%) is the percentage of n. Abbreviations: AFP, α-fetoprotein; AFP-L3, lectin-reactive α-fetoprotein; CA 19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; ICG R15, indocyanine green retention rate at 15 min; INR, international normalized ratio; LCSGJ, Liver Cancer Study Group of Japan; PIVKA-II, protein induced by vitamin K absence or antagonist-II.

The hepatitis B surface antigen-positive rate was 13.8% for HCC, 5.8% for ICC, and 16.4% for combined HCC and ICC. The hepatitis C virus antibody-positive rate was 49.2% for HCC, 12.8% for ICC, and 29.0% for combined HCC and ICC (Tables 6 and 7). The proportion of patients with hepatitis B who underwent nucleos(t)ide analogue therapy before developing HCC and achieved undetectable HBV DNA or biochemical response was 80.4%. The proportion of patients who underwent therapy for hepatitis C before developing HCC and achieved a sustained virologic response (with unknown response treated as no response) was 31.2% (Table 7). The tumor diameter on imaging at diagnosis was ≤2 cm in 33.4% and 2.1–5.0 cm in 42.6% of patients with HCC. For ICC, these figures were 13.1% and 46.9%. The proportion of patients with unifocal disease was 65.2% for HCC and 76.1% for ICC. Tumor staining was observed in 93.5% and washout in 91.2% of patients with HCC. Vascular invasion was observed in the portal vein in 13.4%, hepatic veins in 6.1%, and bile duct in 3.7% of patients with HCC. Tumor rupture was observed in 2.0%, and F2 and larger/red color sign (+) esophageal or gastric varices were observed in 27.3% of patients with HCC (Tables 8 and 9).

TABLE 6. Hepatitis B virus related markers and viral load