Original Paper Oncology 1992;49:347-353

C. L. Lai* Johnson Y.N. Lau* P.C. Wub W. M. HuiA Edward C. S. LaiQ S. T. Fanc H. Ngand H.J. Line

Subclinical Hepatocellular Carcinoma in Hong Kong Chinese

Departments of a Medicine. b Pathology, c Surgery, d Diagnostic Radiology and * Clinical Biochemistry Unit, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong

Abstract Of the 208 Chinese patients with histologically proven hepatocellular car­ cinoma (HCC) seen during a 5-year period, 191 patients presented with symptomatic HCC and 17 patients with asymptomatic HCC (subclinical HCC. SCHCC) being picked up by u-fetoprotein (AFP) screening. Compared with the patients with symptomatic HCC, patients with SCHCC had a better perfor­ mance status (p < 0.01), higher serum albumin levels (p < 0.05) and lower alka­ line phosphatase levels (p < 0.01). In those patients with symptomatic HCC, 4.7% were operable and only 2 patients had a tumour diameter of less than 5 cm. In contrast, patients with SCHCC had a higher operability rate (76.5%, p < 0.0001) and all had a tumour of less than 5 cm in diameter (p < 0.0001). Patients with SCHCC, most of whom had their tumour resected, had a better long-term survival (p < 0.0001). We conclude that patients with SCHCC picked up by AFP serosurveillance have a better performance status, higher operability and better prognosis.

Introduction Hepatocellular carcinoma ( HCC) is one of the ten com­ monest cancers in the world [1], with an estimated annual incidence of one million cases [2, 3], Patients with HCC are usually asymptomatic in the early phase. From the grow th characteristics of the tumour, it was estimated that an asymptomatic tumour of less than 5 cm in diameter takes a median of 6-9 months to become clinically symptomatic, usually with a diameter of over 8 cm [4, 5]. Over 50% of these patients with symptomatic HCC have bilobar in­

volvement [6], rendering resection impossible. This was further limited by the accompanying cirrhosis and the overall resectability was estimated to be around 5% only [5,6], Those symptomatic patients carry a grave prognosis with a median survival of only a few weeks to a few months [6- 10], Early detection of the tumour at an early stage when it is asymptomatic (subclinical HCC, SCHCC, usually less than 5 cm in diameter) offers the best hope [5, 11]. This was made possible by the introduction of serosurveillance of the tumour marker, a-fetoprotein (AFP), and in somecen-

D r.C .L . Lai University Department o f Medicine Queen M a ry Hospital Pokfulam (H ong Kong)

< 1992 S. Karger A G . Basel 0030 2414 92 0495 0347 S 2.75 0

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Keywords Hepatocellular carcinoma Hepatocellular carcinoma, subclinical Fetoprotein screening

Table 1. Clinical and laboratory data of the 208 patients with HCC

Number of patients Male:female Median age (range), years Karnofsky scale > 90. % Presenting Symptoms, % Upper abdominal pain Abdominal mass Acute abdomen Haemoperitoneum Volvulus of the tumour Others Positive for HBsAg. % Bilirubin (normal range 4 23), pmol/1 Albumin (normal range 45-57), g/1 Alkaline phosphatase (normal range 49-132). IU/1 Serum alanine transaminases (normal range 5-48), IU/1 Elevated AFP (normal < 20 ng/ml), % > 20 ng/ml > 200 ng/ml > 400 ng/ml

Patients present.ng with symptomatic HCC

Patients with SCHCC

191 168:23 57 (22-80) 66

17 12:5 52(25-70) 94

65.4 21.5

0 0

1.6 0.8 11.0 91.6 7(5-430) 32(17 48)

0 0 0 100 22 (5-45) 39 (28-46)*

311 (62-1,539)

108(44-227)**

71(20-610)

72(16 445)

92 65 58

100 65 24

Median A FP level, mg/ml

2,722(1->50,000)

262 (46-9,409)

Patients with cirrhosis1, % Child’s classification, n A B C

8 7 .0 (n = 161)

82.3 ( n = 14)

135 21 5

13 I 0

Patients with tum our < 5 cm (%), n Patients with operable tumours (%), n Patients with tum our resected (%), n

2(1) 9(4.7) 8(4.2)

17(100)*** 14(82.4)*** 13(78.2)***

* p < 0.05; ** p < 0.01 ; *** p < 0.001. 1 Histological evidence of cirrhosis.

348

compared them with patients presenting with symptomat­ ic HCC during this 5-year period. Patients and Methods Patients This comprised of all patients with histologically proven HCC who were admitted to the University Department of Medicine at Queen Mary Hospital in a 5-year period (January 1984 to December 1988). A total of 208 Chinese patients with HCC were studied, 21 were excluded because the diagnosis was not confirmed histologically (table 1). Seventeen patients had SCHCC, all were picked up by the A FP serosurveillance programme. The remaining 191 patients presented with symptomatic HCC.

Lai/Lau/Wu/Hui/Lai/Fan/Ngan/Lin

Subclinical Hepatoma

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tres, with regular ultrasonography in high risk patients [12-19], In an early analysis of our AFP serosurveillance programme in which only patients with chronic HBV in­ fection who had been followed for at least 12 months were considered, 6 out of 290 patients (2.07%) screened pros­ pectively developed HCC in a 4-year period [20]. Because of the short duration of follow-up, a detailed analysis of the clinical course of SCHCC was impossible. In addition, we encountered 3 patients with SCHCC picked up during the first visit in this period and a further 8 patients in the 5th year, after the previous analysis. We reported here the long-term follow-up of these patients with SCHCC and

All patients with operable HCC had their tumours resected. For those patients with inoperable HCC, they were entered into various treatment trials including chemotherapy (doxorubicin or epidoxorubicin; n = 40), immunomodulatory therapy [recombinant interferon-a-2a (rIFN a, Roche; n = 86) and recombinant interleukin 2 (IL2, Cetus; n = 4)], and those receiving no antitum our therapy (n = 61) [7, 21,22]. Since doxorubicin has no effect on survival [7] and the effect of interferon-a was modest [21,22], they were grouped to­ gether in the survival analysis.

and those who died outside our hospital, the progress and outcome were traced as far as possible.

Statistics Statistical analyses were done using yj test, Fisher’s exact test or Mann-Whitney non-parametric test. Survival of the two groups of patients (symptomatic HCC vs. SCHCC) was analyzed using Kaplan-Meier curves and the degree of significance was determined by the Mantel-Cox test using the computer program BMDP (Calif., USA).

AFP Serosurveillance Programme

Operability and Survival Time The operability was assessed in terms of lobar involvement and liver function reserve. Lobar involvement was determined using the most accurate method available for a given patients which included USG, HAG, CT and peritoneoscopy. The liver function reserve was assessed by indocyanine green clearance and aminopyrine breath test. The tumours were considered inoperable by the following criteria. (1) Imaging showed bilobar involvement. (2) There was evi­ dence of main portal vein infiltration and/or extensive arteriovenous shunting. (3) There was evidence of extrahepatic metastasis from Xray of the chest and/or CT scan of the abdomen. (4) The patient’s Karnofsky scale was less than 50%. (5) The serum liver biochemistry showed severe cirrhosis as defined by bilirubin level of higher than 50 pmol/1 (normal < 30 pmol/1), serum albumin of less than 25 g/1 and prolonged prothrom bin time of over 5 s to that of the control, and gross ascites uncontrolled by diuretic therapy. (6) The liver func­ tion reserve was poor with an indocyanine green clearance of less than 15% at 15 min and/or aminopyrine breath test o f less than 4.5% at 2 h. (7) There was contraindication for surgery due to involvement of other systems, e.g. creatinine level of over 0.2 mmol/1 (nor­ mal < 0.12 mmol/1) and/or severe cardiac or pulmonary dysfunction. Decisions about the type and extent of hepatic resection were left to the clinical decision of the surgeons. The survival time of the patients was defined as the time from his­ tological diagnosis to the time of death or till December 1990 (2 years after this 5-year study period). For patients who defaulted follow-up

Results Of the 208 histologically proven HCC, the male:female ratio was 6.4:1 and only 18 patients (8.7%) had a previous history of symptomatic hepatitis and/or cirrhosis. His­ tologically, the biopsy specimens of 14 patients consisted mainly of tumour tissue, and the presence or absence of cirrhosis could not be determined from the specimens. A similar proportion of patients with symptomatic and SCHCC had histological evidence of cirrhosis (87.0 vs. 82.3%, respectively). Patients with Symptomatic HCC Most patients (n = 191.91.8%) presented with clinical symptoms. Only 9 patients with symptomatic HCC were operable (4.7%) (fig. 1). Majority of patients with sympto­ matic HCC had a tumour size of more than 8 cm in diame­ ter (93.7%). Two patients had a tumour of less than 5 cm but had multicentric disease and were deemed inoperable. All 9 patients with operable symptomatic HCC had tu­ mour diameter of over 5 cm (table 2). Three of them presented with acute abdomen, 2 with haemoperitoneum and 1 with volvulus of a pedunculated 8-cm tumour. Two of them died after 1.5 and 2 years of liver failure and recur­ rence of HCC, respectively. The 3rd patient who presented with volvulus of the tumour was well and had no evidence of tumour recurrence after 4.5 years of follow-up. Of the other 6 patients with operable symptomatic HCC, 1 patient was found to have another small deepseated tumour on the left lobe in addition to the tumour in the right lobe during laparotomy and he died 8 weeks later. Of the other 5 patients who had their tumour resected, 2 died of early liver failure at 3 and 10 weeks postoperatively, the other 3 died of tumour recurrence at 16, 24 and 28 months (table 2). Patients with SCHCC The pattern of AFP changes in Chinese patients with chronic HBV infection has been detailed previously [20], Seventeen patients with SCHCC were picked up (fig. 1), 3

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During the same period, all Chinese patients with chronic HBV infection attending the Liver Clinics at the University Department of Medicine were screened for serum AFP. A total of 1,264 patients (992 men, 272 women) were seen during this 5-year period. They had been followed for 1 88 months (mean 27 months). The scheme of the serosurveillance programme as well as the investigations in those pa­ tients with elevated A FP levels have been detailed previously [20], Briefly, patients were seen 3-6 monthly or more often when clinically indicated. At each visit, patients were clinically assessed and blood was taken for liver biochemistry, AFP and HBV serology. When ele­ vation in A FP level was observed (normal: < 20 mg/ml), the patients were called back except for female patients who were pregnant at that time. Blood tests were repeated and if AFP remained elevated, an ultrasonographic (USG) examination was performed. If the eleva­ tion in A FP persisted beyond 4 weeks in the absence of a hepatitic event, or if there was progressive increase in A FP levels, the patients were subjected to hepatic arteriography (HAG) and/or com­ puterized tomography (CT) with or without lipoidal examinations. HBV serology and serum AFP levels were determined by enzymelinked immunosorbent assays (ELISA, Abbott Laboratories, North Chicago, 111.).

Table 2. Outcome of the patients with operable HCC

Patient No.

Sex/ age years

Operative findings tum our diameter cm

Outcome/Survival

lobe of involvement R/L

other findings

8 12.5 5 7.5 8 7.5 5

R R R R R R R

volvulus of the tumour pedunculated haemoperitoneum a 1-cm satellite tumour nearby

8

R

Inoperable at laporatomy 9 M/48 10

R

Patients presented with symptomatic HCC With resection done 1 M/48 2 M/77 3 F/38 4 M/49 5 M/43 6 M/68 7 M/58 8

M/69

haemoperitoneum

a small tumour in the left lobe

well, 54 months died of tumour recurrence, 28 months died of tumour recurrence, 24 months died of tumour recurrence, 16 months died of tumour recurrence, 18 months died of early liver failure, 3 weeks died of liver failure. 18 months died of liver failure, 10 weeks died of the disease, 8 weeks

Patients with SCHCC

Inoperable at 12 13 14

1.7 1.4 2.5 3 4 4.5 3 2 2.5 3 two 2-cm nodules

L R L R R R R R R R R

well, 43 months well. 35 months well, 36 months well, 30 months well, 30 months tum our recurrence 32 months, alive 36 months tum our recurrence 26 months, alive 30 months tum our recurrence 36 months, died 42 months died of early liver failure, 1 week died of early liver failure. 3 weeks died of liver failure, 5 months

laparotomy and defaulters (with no surgery) 4 F/68 R cardiac arrest during surgery M 47 R 3 (HAG) F/58 3 (HAG) R

of whom were detected at their first visit. They were re­ ferred to us because of deranged liver biochemistry checked for some non-specific symptoms. The other 14 patients were picked up by the AFP serosurveillance programme. Compared to the symptomatic HCC pa­ tients, they had better performance status on presentation (p < 0.01), higher serum albumin levels (p

Subclinical hepatocellular carcinoma in Hong Kong Chinese.

Of the 208 Chinese patients with histologically proven hepatocellular carcinoma (HCC) seen during a 5-year period, 191 patients presented with symptom...
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