Clinica I Features of Hepa tocellula r Carcinoma : Review of 211 Patients in Hong Kong

C. L. LAI, MB, MRCP,' K. C. LAM, MB, FRACP,t K. P. WONG, MB, DMRD, FRCR,$ , ~ D. TODD, MD, FRCP, FRACP" P. C. WU, MB, M R C P A T H AND

A retrospective study of 211 patients with proven hepatocellular carcinoma (HCC) was made. The commonest symptoms were anorexia and malaise (73%). Five patients (2.5%) had near-normal biochemical tests despite the presence of massive tumors. Diagnostic yield from angiography, percutaneous peritoneoscopic biopsy, or scintiscanning was 87-9896. Three percent of the patients had resectable tumors. Median survival for patients with untreated disease was 3 . 5 weeks. Apart from histology, the total serum bilirubin level was the only factor of prognostic value. Only 12 patients had preexisting symptomatic cirrhosis. When compared with 80 patients with symptomatic postnecrotic cirrhosis without malignancy, patients with HCC had higher SGOTSGPT ratio, higher serum albumin levels, and higher platelet counts. There was only minimal overlap of patients with symptomatic postnecrotic cirrhosis and those with HCC. The authors conclude that their patients with HCC appeared late for treatment. A probable difference in the development of symptomatic postnecrotic cirrhosis and of HCC with asymptomatic postnecrotic cirrhosis is suggested. Cancer 47:2746-2755, 1981.

recent interest in the clinical aspects of hepatocellular carcinoma (HCC).10J1J517.19.22 The incidence of HCC among Chinese is high.32 In Hong Kong, it is the second most common malignant t~mor. We ~ have examined our recent clinical experience with HCC and have found notable differences from other repqrts. We have also compared the HCC patients with cirrhotic patients who died without having HCC.
H E R E HAS BEEN

Materials

The study included 21 1 consecutive patients with histologically proven HCC, 159 by biopsy, and 52 by
From the University Departments of Medicine and Pathology and the Institute of Radiology and Oncology, Queen Mary Hospital, Hong Kong. * Lecturer, University Department of Medicine, Queen Mary Hospital, Hong Kong. t Reader, University Department of Medicine, Queen Mary Hospital, Hong Kong. $ Senior Medical Officer, Institute of Radiology and Oncology, Queen Mary Hospital, Hong Kong. P Senior Lecturer, University Department of Pathology, Queen Mary Hospital, Hong Kong. II Professor, University Department of Medicine, Queen Mary Hospital, Hong Kong. Address for reprints: C. L. Lai, University Department of Medicine, Queen Mary Hospital, Hong Kong. The authors thank Drs. K. W. Chan, C. Y. Cheng, K. S. Lai, H. M. Lam, N. W. Lee, and J. L. Taw for the peritoneoscopy examinations and Drs. S. F. Lok and K. W. Woo for their help in the preparation of the manuscript. Accepted for publication May 14, 1980.

necropsy (vide infra), admitted to the University Department of Medicine, Queen Mary Hospital, Hong Kong from January 1970 to June 1977. In addition, 19 patients in the biopsy-proven group also had necropsies, making a total of 71 necropsies in the whole series. Other than by histologic diagnosis, the patients in this study were unselected. For comparison, 80 patients with histologically proven postnecrotic cirrhosis of the liver were studied. These were all the postnecrotic cirrhosis patients admitted during the same period and shown by necropsy not to have HCC. All patients were Chinese; the majority were from Southern China.
Sex and Age Incidence

Of the 211 HCC patients, 177 were male and 34 female. Their ages ranged from 16 to 78 with a peak incidence of presentation during the sixthdecade (Fig. 1).
Clinical Features

With two exceptions, all patients had symptoms either directly related to their tumors or to hepatic decompensation (99%) (Table 1). One-hundred-ninetynine patients had no previous history of chronic liver disease, although most of them had evidence of liver cirrhosis on clinical examination, as described by Sherlock.26Although close association between HCC

0008-543X/81/0601/2746 $1.05 0 American Cancer Society

2746

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HEPATOCELLULAR CARCINOMA I N HONGKONG . Lai et al. 70

2747

and liver cirrhosis is well recognized, only 12 patients in our series (6%) had previously been diagnosed to have cirrhosis of the liver. In these, the cirrhosis produced symptoms 1.3 to 15 years (median 2.8 years) before the diagnosis of HCC. All 12 patients had new symptoms (Table 1) that led to the diagnosis of HCC. The majority of patients had fever during some period of their observation. In most patients, the cause of the fever could not be conclusively attributed to the tumor, and in none was this a presenting complaint; so fever was not included in Table 1. Jaundice was usually of the mixed conjugated and unconjugated type. In one patient, it was predominantly of the conjugated type, and necropsy revealed tumor infiltration of the upper 4 cm of the common bile duct. The 27 patients with erythrocytosis were diagnosed according to the procedure previously outlined by this Department.18 The two patients who had unrelated features were admitted for attempted suicide and cerebral hemorrhage. Forty patients (19%) had no clinically detectable ascites. Fifteen patients (7%) had no detectable hepatomegaly. In seven of these patients, this was due to the tense ascites; in the remaining eight patients, the liver size was within normal limits.
Lobur Involvement

a
60

fema Ie

0 mare

......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ........ ........ ........ ........ ........

......... ......... .........

50
v)

m .........

s
6
Z

Z 2 40 +

......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... .........

0"
30

20

10

,........... .......... ........... ............ .......... ........... ..........

The predominant lobar involvement of the liver on presentation was determined by the following methods: clinical examination, scintiscanning, peritoneoscopy, laparotomy, and necropsy in those who died within one week of presentation. Thirty-eight percent had preTABLE 1. Features on Presentation in 21 1 Patients with Hepatocellular Carcinoma
As chief complaint
No.
%

0 .
AGE IN YEARS

1
I

FIG.1. Distribution of the age of presentation in 21 1 patients with hepatocellular carcinoma.

~No.
5 5 2
% %

As associated feature

Total

dominant right lobe involvement, and 10% had predominant left lobe involvement. In 52%, both lobes were involved to similar extents. Extrahepatic Metastases Extrahepatic metastases were sought by chest x-ray (all patients), at laparotomy (39 patients), at necropsy (71 patients), or by other special investigation as justified by the clinical features. Metastasis was present in 30 (12%) of our patients, and the sites involved are listed in Table 2. This incidence may be an underestimation, since only 71 patients had necropsy. Of the 15 patients found to have lung metastasis, only nine (60%) had detectable lesions on routine chest x-ray.

Abdominal paiddiscomfort Abdominal distension Abdominal mass Jaundice Haemetemesishnelena Anorexia and malaise Hypoglycemia Diarrhea Ankle edema Encephalopathy Rupture of carcinoma Dyspnoea 2 pleural effusion Unrelated features Vertebral metastases Weight loss with no anorexia Erythrocytosis

96

69 13 lo 9
9

46 33
6

5 4 4 3 3 2 2
1

5 4 4 2 2 2 1 1
1

13
69

2 2 1

48 35 7 5
17

27 145
10

40

19
11 6

1 0.5 -

24 13 40 21

13 7 21 2 3 12
6

19

2
0.5 19

2748

CANCER June 1 1981

Vol. 41

120

110
100 90
v ,
I -

r
55.6%

Resectability

The criteria for resectability of HCC were serum total bilirubin level of less than 85 pmol/l, localization of tumor to one anatomic lobe, absence of invasion of portal vein, and absence of extrahepatic metastases. Only seven patients (3%) had surgically resectable tumors. In all of these, resection was attempted.
Alcohol Iiitake

80

Z 2 70
I -

<
60
50

6 6
Z

A history of excessive alcohol intake was obtained by direct questioning of the patients. Where possible, cross-checking with patients relatives was tried, but this was often found to be of little help. Table 3 shows that significant alcohol intake was uncommon.
Hematology and Biochemistry

40

30
20

10

4
TOTAL BILIRUBIN LEVEL (urnol/l)
FIG.2. Distribution of the total serum bilirubin levels on presentation in 205 patients with hepatocellular carcinoma. Mean = 74.5 p,moVI; range = 5.1-560.9 pmoV1. TABLE 2.
Site and Frequency of Extrahepatic Metastases in 21 1 Patients with Hepatocellular Carcinoma No. of patients Lung Lymph nodes Brain Vertebrae Stomach
15 10 3
1

Percentage 7 5 1
0.5

0.5
14

TOTAL

30

Hematologic and biochemical findings on presentation are listed in Table 4. Anemia in the patients was usually multifactorial, and the actual level of hemoglobin was of little significance in assessing the degree of hypersplenism or hepatocellular dysfunction. The levels of serum total bilirubin, alkaline phosphatase, glutamic oxaloacetic transaminase (SGOT) and glutamic pyruvic transaminase (SGPT) showed a wide scatter with skewed distribution (Figs. 2, 3, and 4). The SGOT to SGPT ratio was calculated by linear regression by the least square fit method (Fig. 5). The slope of 1.44 confirmed the findings of OkudaZo and of Ellis et a1. for hepatic malignancies. The serum total bilirubin levels on presentation were normal in 56% of patients, and the alkaline phosphatase was below 200 pmol/minutes 1, i . e . , the range that indicates space-occupying lesions in the liver, in 38%. Two patients had normal and three patients had near-normal biochemical values; yet all five (2.5%) had gross hepatomegaly caused by tumor infiltration. Hepatitis B virus surface antigen (HBsAg) was tested for by radioimmunoassay (Austria 11, Abbott Laboratories, IL.) in the last 20 consecutive patients of the series, and it was detected in 19 (95%). Periodic acid Schiff-positive globules in hepatocytes as an indicator of al anti-trypsin deficiency was looked for in all liver specimens but was detected in only one.
Diagnostic Investigations

TABLE 3. Consumption of Alcohol in 21 1 Patients with Hepatocellular Carcinoma

No. of patients

Percentage

Amount of alcohol <80 glday 80- 160 glday > 160 glday

Scintiscanning
188
19

89
9 2

Rectilinear anterior liver scanning with colloidal radioactive Indium-113m was performed in 145 patients, the results are presented in Table 5.

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HEPATOCELLULAR CARCINOMA IN HONGKONG . Lai et a / .

30. 2%
60

2749

Angiography
In 41 patients, celiac arteriography, followed by portal vein visualization by splenoportography or by arterioportography , was performed according to the techniques described by Reuter and R e d ~ n a n . ~ ~ Radiographic features of HCC were seen in 40 (98%), and the types of changes are tabulated in Table 6 . Only one patient with HCC had a false negative result, and in him only features of liver cirrhosis were noted. At necropsy, this patient had a small cirrhotic liver with a solitary tumor, 3 cm in diameter, in the left lobe.

50

v)

5 c Q L

40

Histologic Diagnosis
Liver biopsy was attempted in all consenting patients whose platelet count and prothrombin time were within the safety margin. When clinical examination and radiologic investigations suggested that the tumor might be surgically resectable, peritoneoscopic examination with biopsy was carried out. Otherwise, percutaneous needle biopsy was done. Of 89 percutaneous liver biopsies, 86 (97%) were positive and 3 were negative for tumor. Of 71 peritoneoscopic biopsies, 68 (96%)were positive, and three were negative for tumor. In five others, liver biopsy was done during laparotomy, and all showed tumor tissue. [n the remaining 52 patients, histologic diagnosis of HCC was made following necropsy because clotting defects precluded biopsy.

'
0

30

13.4%

10.9%

20
7 .9%

?.4%

10

0 -

Survival
The outcome was known in 104 patients who had inoperable tumor and had received no antitumor treatment. Of the remaining 107 patients, 85 patients were lost to follow-up; one patient was still alive at the time of writing this report, four years after diagnosis of HCC; 11 patients had either hepatic artery ligation or resection; and ten patients received chemotherapy between March 1977 and June 1977 (this was the period when chemotherapy was instituted in our Department). The survival of the 104 patients who had no antitumor treatment and who died in this hospital ranged from one day to 70 weeks with a 50% survival of 3.5 weeks. The survival curve is shown in Figure 6 . The modes of death of these 104 patients are listed in Table 7. Patients were classified as dying from liver failure when they had deepening jaundice, progressive prolongation of prothrombin time, mental disorientation, and flapping tremor. A significant number of patients had progressive cachexia probably due to tumor progression. It was often difficult to separate liver failure from cachexia. We have therefore grouped the two causes together.

ALKALINE PHOSPHATASE LEVEL (urnol/rnin. I ) FIG.3 . Distribution of the serum alkaline phosphatase levels on presentation in 202 patients with hepatocellular carcinoma. Mean = 362.4 pmoVmin/l; range = 73- 1560.

The 17 patients dying from gastrointestinal bleeding were verified by necropsy to be either bleeding from varices or from diffuse oozing of the gastrointestinal tract. The three patients who died of pulmonary edema had gross ascites; necropsy revealed acute left heart dilatation. There was no record of overtransfusion, and the cause of the heart failure remains unknown. In the patient with candida peritonitis, the organism was isolated from the ascitic fluid. The peritonitis
TABLE 4.
Hematologic and Biochemical Parameters on Presentation in Patients with HCC
~~

Mean (range)

WCC x 109/1 Platelet count x 109/1 Bilirubin pmoUl Albumin g/l Globulin g/l Alkaline phosphatase pnoUmidl SGOT prnoVmidl SGPT pmoVmidl Prothrombin ratio

8.1 (2.8-20.4) 145 (20-565) 74.5 (5.1-560.9) 28.5 (9-48) 40.0 (21-64) 362.4 (73- 1560) 81.1 (11-552) 44.3 (8-260) 1.3 (1-2.7)

180 180 205 211 21 I 202 174 174 196

2750
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CANCER June 1 1981

Vol. 47

*n

12.6%

Jj.&p/to

33.3% 13.2%

Lo50

5
if
0

40

L30
20
10

appeared to be primary; there was no evidence of gut perforation, of diabetes mellitus, and of known history of corticosteroid ingestion. No intraabdominal focus of candida infection was found at necropsy. The patient who died from cerebral hemorrhage had generalized atherosclerosis, and the cerebral hemorrhage was considered to be unrelated to the HCC.
Prognostic Indicators

0-

,
SGOT (umol/min.l)

60
v)

z
O.

e 50 c
4

40
30 20 10
0-

if
0

'

30

3150

51100

101150

151200

201-

300

SGPT (umol/min.l)

FIG.4. Distribution of serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvate transaminase (SGPT) levels on presentation in patients with hepatocellular carcinoma. T o p : mean = 81.1 pmoVmin. I ; range = 11-552. Botrom: mean = 44.3 pmoY rnin. 1; range = 8-260.

Among clinical features, survival was found to be unrelated to age, sex, duration of onset of symptoms to presentation, blood counts, albumin level, globulin level, alkaline phosphatase, SGOT, SGPT, and prothrombin time. The only biochemical value found to be of prognostic significance was the bilirubin level on presentation. The correlation between the total serum bilirubin level and survival was calculated by computer (least square fit regression for log y against x) (Fig. 7) and was found to be highly significant (P < 0.001). The only histologic factor found to have prognostic significance was the presence of clear cells in the tumor. This finding emerged from a previously published study of the first 80 of the present series of patients.13Patients with clear cells in their tumors had significantly better survival than those without clear cells, and those with the diffuse clear cell pattern ( i . e . ,more than 50% of their tumor cells being clear cells) survived better than those with the focal pattern (i.e., less than 30% of their tumor cells being clear cells) (P < 0.001 in both cases).13
Comparison with Postnecrotic Cirrhosis without Superimposed Hepatocellular Carcinoma

TABLE 5 . Results of Indium Scintiscanning in 145 Patients with HCC

Scan diagnosis Space-occupying lesion with or without cirrhosis Suspicious space-occupying lesion Cirrhosis of liver without spaceoccupying lesion Normal

No. of patients
126 10 8 1

Percentage 87 7 6 1

TABLE 6. Frequency of Angiographic Findings in 41 Patients with HCC

No. of patients Neovascularity Tumour staining/pooling of contrast Space-occupying lesion with vessel displacement Portal vein infiltration Arteriovenous shunting Encasement of vessels No evidence of tumor 37 31 24 16 11 2
1

Percentage
90 76
59

39 27
5

Between January 1970 and June 1977, 80 patients with histologically proven postnecrotic cirrhosis were admitted into our unit and shown at necropsy not to have HCC. All had symptoms related to cirrhosis, although 11 had unrelated symptoms as their chief complaints. In studying this group of patients and the 199 patients with HCC diagnosed on first presentation (66 had necropsies), we have chosen for comparison the factors that might indicate the severity of chronic hepatocellular dysfunction and of portal hypertension, as well as the morphologic evidence of the degree of advancement of cirrhosis (Table 8). The hematologic and biochemical values were those obtained on first admission. The comparison of the degree of advancement of cirrhosis was only carried out in patients with necropsies because accurate morphologic comparisons could only be made with large necropsy specimens. The activity and the stage of evolution of the cirrhotic process were assessed according to the criteria described by Anthony et al. The determination of the activity of the

No. I 1

HEPATOCELLULAR CARClNOMA

IN

HONG KONC
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'

Lai et al.

275 1

cirrhosis was based on following features: the amount of cellular infiltration, the definition of the borders of the regeneration nodules, the degree of bile duct proliferdtion, and the presence or absence of hepatitis. Twelve percent (8/66) of the HCC patient had no morphologic evidence of cirrhosis. Of the remaining 58 patients, a significantly higher proportion (38%) had less active cirrhosis when compared with the 80 patients with postnecrotic cirrhosis without HCC (15%). Since there was a difference in the SGOT and SGPT levels in HCC group (Fig. 5 ) , the SGOT and SGPT levels in the two groups were also compared. The distribution of the SGOT and SGPT values in the 80 patients with postnecrotic cirrhosis is shown in Figure 8. The difference in the ratio of SGOT to SGPT values in these patients and in the patients with HCC (linear regression by least square fit method) was statistically significant (Figs. 5 and 9) ( P < 0.0001). To examine this problem further, we also analyzed the hematologic and biochemical data in the 12 patients (five with necropsies) who had HCC after the diagnosis of symptomatic cirrhosis (Table 9). With the development of HCC, only the SGOT to SGPT ratio changed significantly in the direction shown in Figures 5 and 9: the platelet counts and albumin levels did not show any changes shown in Table 8. Discussion
Review of 21 1 Patients with Heputocellulur Carcinotna

500

400

.E
C

E, -

0' 0
v)

300

200

100

Compared with previous reports, several notable differences were found in our present series. Anorexia and malaise, being present in 73% of patients, were the most common symptoms in our patients but were not emphasized in other reports. These symptoms are known to reflect constitutional disturbance in hepatocellular disease.fi A high incidence of their occurrence underscores the general disturbance and hepatocellular dysfunction produced by the tumor. Diarrhea was common (21%). The 2% frequency of diarrhea as a chief complaint is comparable with the 3.7% frequency among early symptoms in Okuda's series.Iy In addition, 19% of our patients also had diarrhea as an accompanying feature. The diarrhea was usually mild and chronic. Stool cultures were almost invariably negative for pathogenic organisms. Although diarrhea in white persons with cirrhosis had been considered the sine qua non of alcoholism,6alcohol intake was insignificant in the present series (Table 2). The cause of diarrhea requires further study. The yield of positive results from Indium scintiscanning (87%), peritoneoscopic biopsy (96%), percutaneous needle biopsy (97%), and celiac angiography

100

200

300

SGPT (urnol/rnin. I )

FIG. 5 . Correlation between SGOT and SGPT levels on presentation in 174 patients with hepatocellular carcinoma. Y = 16.83 + 1.44 X; r = 0.647.

(98%) was higher than generally reported from HCC All of these methods patients in the are more sensitive diagnostically than tests for alphafetoprotein in our patients (65%) reported in a previous study.'" Such a high yield was at least partly the result
TABLE 7 . Cause of Death in 104 Patients with Untreated HCC
No. of patients
Liver failure/cachexia Rupture of carcinoma Gastrointestinal bleeding Hypoglycemia Pulmonary edema Bronchopneumonia Cerebral metastasis Candida peritonitis Cerebral hemorrhage
55 18 17 5 3 3
1 1

Percentage

53
17 16 5 3

3
1

I
1

2752

CANCER June I 1981

Vol. 47

FIG.6. Survival curve for 104 patients with untreated hepatocellular carcinoma. Range = 1 day70 weeks.

10
WEEKS

20

30

40

70

of advanced disease on presentation. However, we may have underestimated the false negative rates for these diagnostic methods, since small asymptomatic HCC not detectable by any of these methods would be missed unless necropsy was performed on every patient investigated. The true false negative rates are being studied in a continuing prospective study in our Department. There appears to be general agreement on the values of angiography in the detection, localization, and assessment of resectability of HCC.20.24 The pitfall with this technique seemed to be small tumors in the left lobe of cirrhotic livers. Recent data have shown that such pitfalls may be minimized by noting blockage or displacement of branches of the portal vein instead of arterial changes in the left lobe.31 Late presentation of the patients was likely to be the reason for the low resectability rate of the tumors (3%).

The comparatively high resec ability rate of 20-30% in surgical series16, may be attributable to selective referral of patients with potentially resectable tumors to surgical units and those with advanced tumors to medical units. In the literature, serum biochemical measurements of bilirubin, alkaline phosphatase, SGOT, and SGPT are generally presented as means and standard deviations. This would imply normal distribution of these values. However, in the present study, distribution of such values was skewed. Hence, scattergrams, histograms, or medians and ranges would appear to be more appropriate methods of presentation of these values. In a high percentage of patients, the bikrubin level was normal (56%), and the alkaline phosphatase activity, despite massive tumors, was below the diagnostic range for space-occupying lesions in the liver (38%). In fact, even normal and near-normal biochemical

TABLE 8. Comparison between 199 Patients with HCC (66 with Necropsies) and 80 Patients with Symptomatic Postnecrotic Cirrhosis without HCC on Necropsy HCC All 199 patients Peak age incidence Diagnosis Death Incidence of HBsAg positivity (%) Platelet count x 10y/l Albumin gll Globulin g/l Morphology of cirrhosis No cirrhosis Cirrhosis with little activity Early stage cirrhosis with incomplete septae 6th decade 6th decade 95 147 2 77 28.4 -c 7.4 40.0 f 8.4 66 Patients* with necropsies* 6th decade* 6th decade* Symptomatic postnecrotic cirrhosis without HCC 80 Patients 5th decade 6th decade 87.5 68 5 77 24 t 6.2 42.4 rt 9.1

143 r 84* 27.7 5 6.9* 42.1 2 7.1* 8/66 (12%)* 22/58 (38%)* 10158 (17%)*

P < 0.0001 P < o.oO01

NS

NS

P < O.o001* P < 0.005*

NS

0 12/80 ( 15%)
16/80 (20%)

P < 0.005*
NS

* Represents those of the 66 HCC patients with necropsies.

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HEPATOCELLULAR CARCINOMA I N HONGKONG . Lai et a l .

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FIG.7. Correlation between total serum bilirubin level on presentation and survival in 104 patients with untreated hepatocellular carcinoma. Y = 6.83X '',3s: r = ; 0.39; P < 0.001.

$
I

300

2
I -

200

s?
100

0 0
SURVIVAL (WEEKS)

findings are encountered in the presence of HCC of considerable size. The prognostic usefulness of the total serum bilirubin level confirms Bengmark's observation." From the curve (Fig. 7), the significance of the correlation between total serum bilirubin level and patients' survival as a group was high ( P < 0.001). However an r-factor of 0.39 indicates that approximately 85% of the variation in survival is due to determinants other than bilirubin. The other clinicobiochemical features, i . e . , age, sex, incidence, and pattern of presentation, did not differ materially from previous r e p o r t ~ . ' " * ~ ~ ~ ' ~ ~ ' '
Comparison M i t h 80 Patients with Postnecrotic Cirrhosis ~ i t h o i r t Superimposed Heputocellitlar Carcin o mu

(95%) and in those with symptomatic postnecrotic cirrhosis (87.5%) (Table 8). The high incidence in the 20 patients with HCC in this series corresponds to the results of a larger study in progress in our Department
30Ln c

-3 I .6% 20.3%
I

Z
c Q:
0

20

if
0 10
Z

5.1%
O A

5.1%

SGOT (umol/min.l)

The processes of liver cirrhogenesis and carcinogenesis may be separate, although a common factor initiating both processes is p o s ~ i b l e . On ~ , ~the ~ other hand, liver cirrhosis has been considered a major predisposing factor to the development of HCC.' Recently, Kuboet ul.l 2 detected 3 1 HCC in patients with an initial clinical diagnosis of cirrhosis or chronic hepatitis. They concluded that HCC occurred when cirrhosis was not advanced or in a precirrhotic stage of chronic hepatitis. An association incidence of 92% between HCC and postnecrotic cirrhosis has been reported from this hospital," but failure to find an earlier age incidence for cirrhosis compared with HCC was considered to be evidence against cirrhosis being an important predisposing cause of HCC. In the present study, we found a comparable incidence of HBsAg positivity in patients with HCC

0 Z
1 0

SGPT (umol/min.l)

FIG. 8. Distribution of SGOT and SGPT levels in 79 patients with symptomatic postnecrotic cirrhosis. 7 0 p : Mean = 70.7 pmoVmin/l range = 5-883. Bottom: mean = 75.6 fimoUmini1: range = 3- 1908.

VOl. 47

F I G .9 . Correlation between SGOT and SGPT levels on presentation in 79 patients with symptomatic postnecrotic cirrhosis. Y = 16.84 + 0.74 X; r = 0.889.

SGPT (urnol/rnin.)

(Lam and Lai, unpublished data) and is also similar to that reported in Chinese patients in TaiwanzsThe high association rate of hepatitis B virus with both HCC and symptomatic postnecrotic cirrhosis suggests that hepatitis B virus infection may be one of the possible initiating factors for both disease processes. However, several other factors, including platelet counts, serum albumin levels, and SGOT to SGPT ratio as well as the activity of the cirrhosis were significantly different in patients with HCC and in those with symptomatic postnecrotic cirrhosis (Table 8). The rise of the SGOT to SGPT ratio could be attributed to progkession of the tumor, as may be concluded from the 12 patients who were observed to have detectable HCC from preexisting cirrhosis (Table 9). To explain the higher albumin levels and platelet counts in the HCC group when compared with the symptomatic postnecrotic cirrhosis group (Table 81, we considered three possibilities. First, the 12% of HCC patients without cirrhosis could have contributed to the higher values of albumin concentration and platelet count. However,
TABLE 9. Comparison of Hematologic and Biochemical Findings in 12 Patients with Symptomatic Cirrhosis Before and After Diagnosis of Hepatocellular Carcinoma
On presentation with cirrhosis Platelet count x 10Yl Albumin g/l Globulin g/l Slope of SG0T:SGlT ratio
84.2 29.6 31.1
% %

On first diagnosis of HCC

83.5 -c 46 24.2 ? 8.6 44.8 ? 8.0
NS NS NS

38 6.8 13.0

0.549

2.152

P < O.OOO1

recalculation of the mean albumin levels and platelet counts after exclusion of the highest 12% of values in the HCC group still revealed significantly higher values in those with HCC. Second, paraneoplastic manifestations of HCC may be associated with abnormally high albumin levels or platelet This was not encountered in any individual patient in this series, but this mechanism cannot be excluded. Last, those higher values may simply be the result of less severe liver cirrhosis. This corroborates with the rarity of preexisting symptomatic cirrhosis in our patients with HCC (6%). Further evidence for this is the morphologic finding of significantly less active cirrhosis in the HCC patients when compared with the patients having symptomatic cirrhosis without HCC (Table 8). Possibly, the sequence of events runs as follows. Some common factor, possibly hepatitis B virus infection (vide supra), initiates the development of both cirrhosis and HCC. Additional factors, perhaps the status of nutrition or immunologic response, may promote severe hepatocellular destruction, so that cirrhosis subsequently becomes symptomatic. On the other hand, differences in the status of the same additional factors may have promoted carcinogenesis with the cirrhosis progressing more slowly and remaining asymptomatic. Thus overlap between the two groups is minimal, as was found in this study. With less severe chronic hepatocellular dysfunction and less active cirrhosis, the albumin levels were higher, and a lesser degree of portal hypertension with milder hypersplenism could explain the higher platelet counts. In Figure 10, we have introduced a modification into the last two steps in the scheme of Larouzeer a1.I4to include our current findings. Cirrhogenesis following

No. 11

HEPATOCELLULAR CARCINOMA I N HONG KONG . Lai et al.

2755

CIRRHOGENESIS

OF :HBV / - ; . . . Hc HEPATITIS CHRONIC CARRIER

FIG. 10. Proposed sequelae of chronic hepatitis B virus (HBV) infection.

CARCINOGENESIS

>
SET

0= CIRRHOSIS POOL
chronic hepatitis will lead to a pool of cirrhosis patients (continuous circle), some of whom become symptomatic (hatched square). Carcinogenesis occurring in parallel to cirrhogenesis will lead to a set of patients with HCC (rectangle) largely within the pool of cirrhotic patients. This HCC set overlaps the symptomatic cirrhosis set minimally. A small group of patients affected by carcinogenesis is uninvolved by cirrhogenesis and lies outside the continuous circle. To complete the picture, a fourth group of patients with cirrhosis who do not complain may be accidentally found to have cirrhosis or HCC (dotted circle); these patients may later become symptomatic.
REFERENCES
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