Long-Term Survivors After Resection for Primary Liver Cancer

Clinical Analysis of 19 Patients Surviving More Than Ten Years

XIN-DA ZHOU, MD, ZHAO-YOU TANG, MD, YE-QIN YU, MD, BING-HUI YANG, MD, ZHI-YING LIN, MD, JI-ZHEN LU, MD, ZENG-CHEN MA, MD, AND CHEN-LONG TANG, MD

From July 1958 to June 1978, a total of 333 cases with pathologically proven primary liver cancer (PLC) were admitted to the Zhong Shan Hospital, Shanghai Medical University, Shanghai, the people’s Republic of China. Of these, 39.6% (132 of 333) were resected and 14.4% (19 of 132) survived over 10 years after resection for PLC. These 19 patients surviving over 10 years were investigated in this paper. All 19 patients underwent radical resection, including right hemihepatectomy in two cases, left hemihepatectomy in ten cases, left lateral segmentectomy in three cases, and local resection in four cases. By the end of June 1988, follow-up varied from 10 years and 1 month to 26 years and 7 months, with a mean follow- up of 15 years and 4 months. All 19 patients are still alive with free of disease. The longest survival patient had a tumor measuring 10 X 8 X 6 cm in size and underwent local resection. Upon follow-up after 26 years and 7 months, the patient was found to be still living and well. Two patients with intraperitoneal ruptured PLC have survived for 19 years and 4 months, and 16 years and 11 months, respectively, after resection of the tumors free of disease and have returned to work. Subclinical recurrence of PLC was discovered in one patient in whom reoperation with cryosurgery was carried out. The patient has been in good condition with negative alpha-fetoprotein (AFP) for 8 years and 10 months after cryosurgery. Sub- clinical solitary pulmonary metastasis was detected in two patients because of a secondary rise in AFP level. Reoperations were carried out and the metastatic tumors were removed. These two patients are still in good health with negative AFP 9 years and 6 months, and 10 years and 1 months, respectively, after reoperation. These results indicate that early and radical resection are the principal factors influencing long-term survival; reoperation for subclinical recurrence and solitary metastasis remains an important approach to prolong survival further; intraperitoneal rupture of PLC does not exclude the possibility of cure; new surgical techniques, such as cryosurgery and bloodless hepatectomy, have been shown to be effective in some patients.

Cancer 63:2201-2206, 1989.

RIMARY LIVER CANCER (PLC) is a relatively rare P malignancy in the Western world, but one of the most frequent fatal tumors in Asia and Africa. Every year PLC causes 250,000 deaths in the world,’ 100,000 deaths in China,’ and 3000 deaths in ShanghaL3 In 1974 3254 cases with PLC in China were analyzed, with the extremely high proportion of late stage patients with jaundice or ascites (52.6%), the extremely low series resection rate (5.3%), and the dismal ultimate outcome (1-year survival, 8.6%).4 During the past 15 years, however, rapid progress has been made in the clinical research of PLC. Based on the advances of early detection of subclinical PLC, the

From the Liver Cancer Institute, Shanghai Medical University, Shanghai, People’s Republic of China.

The authors thank Professor Zhou-guang Wu, Head of the Department of Surgery, Zhong Shan Hospital, for data on one patient (Case I ) .

Address for reprints: Xin-da Zhou, MD, Liver Cancer Institute, Zhong Shan Hospital, Shanghai Medical University, Shanghai 200032, People’s Republic of China.

Accepted for publication on December 13, 1988.

growing knowledge regarding the biologic basis of surgical oncology, and the introduction of new surgical techniques and development of new surgical modalities, the role of surgery for PLC has become more imp~r t an t .~ The only effective treatment for PLC is surgical resection. Nev- ertheless, long survival of patients with PLC has rarely been encountered in the past several decades.

From July 1958 to June 1978, a total of 333 cases with pathologically proven PLC were admitted to the Zhong Shan Hospital, Shanghai Medical University, Shanghai, the People’s Republic of China. Of these, 39.6% (1 32 of 3 3 3 ) were resected and 14.4% ( 19 of 132) survived over 10 years after resection for PLC. These 19 patients sur- viving over 10 years are considered as the basis for this analysis.

Materials and Methods

Of the 19 patients, 16 were male and 3 female, with a sex ratio of 5.3: 1. The patients’ ages ranged from 20 to 60 years, with a median age of 40 years.

220 1

2202 CANCER June I 1989 Vol. 63

Criteria for clinical staging were defined as follows: Stage I (subclinical), without obvious PLC symptoms or signs; Stage I1 (moderate), with obvious PLC symptoms or signs, but without obvious jaundice, ascites, or distant metas- tases. In this series, subclinical stage amounted to 36.8% (seven of 19), moderate stage 63.2% (12 of 19). There were eight cases with small PLC (G5 cm).

The abnormal laboratory findings in the following measurements were as follows: alpha-fetoprotein (AFP) (3500 ng/ml, radioimmunoassay6) 9 1.7% (1 1 of 12), gamma glutamyl transpeptidase (yGT) (> 10 units, Or- lowski’s method6) 41.2% (seven of 17), and alkaline phos- phatase (ALP) (>13 units, King and Armstrong’s method6) 35.3% (six of 17).

Liver disease background was noted as follows: with hepatitis history of over 5 years 26.3% (five of 19); coex- istent with liver cirrhosis 73.7% ( 14 of 19). Serum hepatitis B surface antigen (HBsAg) by reverse passive hemagglu- tination (RPHA) was observed in 83.3% (ten of 12).

The positive findings in different measures for local- ization were as follows: radionuclide scan (RS) 62.5% (ten of 16), ultrasound (US) 68.8% (11 of 16), and hepatic angiography (HA) 100% (two of two). Tumor was located in the right lobe in 26.3% (five of 19) and in the left lobe in 73.7% (14 of 19).

Types of resection in 19 patients included right hemi- hepatectomy (RH) in two cases (10.5%), left hemihepa- tectomy (LH) in ten cases (52.6%), left lateral segmentec- tomy (LLS) in three cases (1 5.8%), and local resection (any subsegmentectomy) in four cases (2 1.1%). Radical resection includes complete removal of the tumor, without grossly identified tumor emboli in portal vein, and tumor residue in neither the remaining liver tissue nor cut sur- face. In this series, all 19 patients underwent radical re- section.

Reoperation was done in 3 1.6% of the patients (six of 19), including reoperation after an initial operation for hemostasis for ruptured PLC, which was carried out in two cases; reoperation for subclinical recurrence or solitary metastasis after an initial radical resection was performed in three cases; reoperation, using bloodless hepatectomy with organ isolation hypothermic perfusion, for the tumor located near the inferior vena cava was done in one case.

Routine preoperative medication was given for 2 days6 An uneventful postoperative course was observed in pa- tients undergoing local resection, LLS, LH, and a non- cirrhotic liver; however, intensive care with albumin or plasma, fresh blood, and coagulants was necessary in pa- tients receiving RH in cirrhotic liver. Postoperative ad- juvant therapy with Chinese traditional medicine in com- bination with chemotherapy and/or immunotherapy was given in 13 patients. No postoperative adjuvant therapy was used in six patients. Serum AFP level and US were

measured every 2 to 3 months after radical resection to discover subclinical recurrence or metastasis.

Results

By the end of June 1988, follow-up varied from 10 years and 1 month to 26 years and 7 months, with a mean follow-up of 15 years and 4 months. All 19 patients are still alive and free of disease (Table 1).

Two patients (Patients 4 and 6) undergoing operation for hemostasis for ruptured PLC at the district hospital were admitted to our hospital. LH and LLS were carried out, respectively. These two patients have survived for 19 years and 4 months, and 16 years and 1 1 months, re- spectively, after resection of the tumors, free of disease, and have returned to work.

Subclinical recurrence of PLC was discovered in one patient (no. 13) in whom LH was performed in August 1975. AFP declined to normal (G20 ng/ml) following re- section but reappeared at a level of 800 ng/ml 4 years later. Subclinical recurrence of PLC was considered, de- spite the excellent condition of the patient; reoperation was performed in August 1979 and a tumor of 2 X 1.5 X 1 cm was found in the right lobe. Aspiration study confirmed hepatocellular carcinoma (HCC). Cryosurgery was carried out because no more liver could be resected. The frozen area included the whole lesion and some sur- rounding normal liver. The AFP declined to normal again 2 weeks after cryosurgery. The patient has been in good condition with negative AFP for 8 years and 10 months after reoperation and for 12 years and 10 months following the first operation.

Subclinical solitary pulmonary metastasis was detected in two patients (nos. 9 and 14) because of secondary rise in AFP level after resection of PLC. Reoperations were carried out and the metastatic tumors were removed. These two patients are still in good health with negative AFP 9 years and 6 months, and 10 years and 1 month, respectively, after reoperation, and 13 years and 2 months, and 12 years and 10 months, respectively, after the first operation. Both of them are capable of working.

One patient (no. 18) was picked up by AFP mass screening with no symptoms or signs. A selective hepatic arteriogram showed two small tumors on the right lobe, the right lower tumor measuring 1.7 cm in diameter and the right upper tumor 4 cm in diameter, very close to the inferior vena cava. The first operation was performed to resect the right lower tumor. Because the right upper tu- mor could not be resected by means of routine hepatec- tomy, hepatic artery catheterization was performed and postoperative perfusion chemotherapy with 5-fluorouracil carried out. After the first operation, however, the patient’s AFP level failed to drop and the right upper tumor failed

No. 11 LONG-TERM SURVIVAL AFTER PLC RESECTION - Zhou et al. 2203

TABLE 1. Clinical Data on 19 Patients With PLC

AFP (ng/ml) Operation Patient Age (yr)/ Clinical Serum Postop Outcome

no. sex staging H X HB HBsAg y-GT ALP Preop Postop Date Resection therapy Reop (mo)

1 2 3 4 5 6 7 8 9

10 I 1 12 13 14 15 16 17 18 19

51/M 40/M 35/F 40/M 58/M 41/M 30/M 20/F 45/M 32/M 21/M 44/M 57/M 42/M 60/M 49/M 21/F 22/M 38/M

- I1 I1 I1 I1 11 11 I1 I1 I1 8 yr I 12 yr I

I1 9 Yr I I 5 Yr

I1 I1 I 15 yr I I

- - -

- - -

-

-

-

- -

- -

ND ND ND ND ND ND ND

+ + + + + + + + + +

-

-

ND ND ND ND ND ND ND + + + + + + + + + + +

-

November 196 1 September 1966 November 1967 February 1969 September 1970 July 1971 August 1971 March 1973 April 1975 June 1975 July 1975 July 1975 August 1975 August 1975 September 1975 September 1975 September 1975 February 1978 Mav 1978

Local ND LH ND LH ND LH 2 RH 2 LLS ND LH ND RH 3 LH 3 LLS 3 Local 3 LH 2 LH 3 LH 3 LH 3 LLS ND LH 3 Local 3 Local 3

ND ND ND +a ND +b ND ND +C ND ND ND +d +e ND ND ND +f

ND

319 AFD 261 AFD 247 AFD 232 AFD 213 AFD 203 AFD 202 AFD 183 AFD* 158 AFD 156 AFD 155 AFD 155 AFD 154 AFD 154 AFD 153 AFD 153 AFD 153 AFDt 124 AFD 121 AFD

PLC: primary liver cancer; H X HB: history of hepatitis and number of years; HBsAg: hepatitis B surface antigen; Serum HBsAg: detected by reverse passive hemagglutination test (RPHA); y-GT: gamma glutamyl transpeptidase, detected by Orlowski’s method, + = > 10 units, - = 5 10 units; ALP alkalind phosphatase, detected by King and Armstrong’s method, + = > 13 units, - = 5 13 units; AFP: alpha-fetoprotein, detected by radioimmunoassay, + = 2500 ng/ml, - = 520 ng/ml; Preop: pre- operative; Postop: postoperative; Clinical staging: 1 = subclinical, without obvious PLC symptoms or signs; 11 = moderate, with obvious PLC symptoms or signs, but without obvious cachexia, jaundice, ascites, or distant metastases; ND: not done; Resection: LH = left hemihepatectomy;

to regress. The second operation, using bloodless hepa- tectomy with organ isolation hypothermic perfusion, was camed out 6 months later, the right upper tumor with a 1.5 X 0.2 cm wall of the inferior vena cava being resected and the defect of the inferior vena cava repaired under a bloodless field. The liver was isolated from the systemic circulation for 76 minutes. The patient has survived for 9 years and 10 months after bloodless hepatectomy with negative AFP and has returned to work.

The longest survival patient (no. 1) had a tumor mea- suring 10 X 8 X 6 cm in size on the left lateral margin and underwent local resection. Pathologic study con- firmed HCC (well differentiation) with micronodular cir- rhosis. Upon follow-up after 26 years and 7 months, the patient was found to be still living and well. No adjuvant therapy was given postoperatively.

One patient (no. 8) underwent RH with removal of a tumor measuring 15 X 15 X 12 cm in size, the largest size of tumor in this series, in March 1973. Fifteen years and three months after operation, she is still a healthy woman with negative AFP. Another female patient (no. 17) was discovered at AFP mass screening as asymptom- atic and underwent LH in September 1975. The patient

RH = right hemihepatectomy; LLS = left lateral segmentectomy, Local = any subsegmentectomy; Reop: reoperation, +a and +b = initial he- mostasis operation for ruptured PLC was done at the district hospital, +c = lobectomy for subclinical pulmonary metastasis was done in De- cember 1978, +d = cryosurgery for subclinical recurrence was done in August 1979, +e = lobectomy for subclinical pulmonary metastasis was done in May 1978, +f = bloodless hepatectomy with organ isolation hypothermic perfusion was done in August 1978; AFD. alive, free of disease.

* Married in 1986, having a baby. t Married in 1985, having a baby.

has survived for 12 years and 9 months after operation, with negative AFP, and has returned to work.

On admission, serum AFP was detected in 12 patients. Of these, 1 1 patients (9 1.7%) had serum AFP levels > 500 ng/ml. The normalization rate (to c20 ng/ml) of AFP after radical resection of the tumor was 100% (1 1 of 1 1) in this series. The normalization time usually depends on the original AFP level. The time for normalization of AFP was within 2 months in subclinical PLC.

The sizes of tumor ranged from 1.5 X 1 X 1 cm to 15 X 15 X 12 cm. There were eight patients with small tumors ( ~ 5 cm), seven patients with large tumors (>5 cm to <10 cm), and four patients with very large tumors (2.10 cm). Single-nodule tumors amounted to 94.7% (18 of 19); grossly well-encapsulated tumors were found in 89.5% (1 7 of 19). Tumor emboli presented in the intrahepatic veins in 10.5% (two of 19). There was no tumor residue in the cut surface in this study. The sites of cancer were left lobe 73.7% (14 of 19), right lobe 26.3% (five of 19). Pathologic findings revealed that all 19 patients had HCC. The degree of cancer cell differentiation was as follows: well to moderate 5.6% (one of 18), moderate 72.2% (13 of 18), and poor 22.2% (four of 18). In the noncancerous

2204 CANCER June 1 1989 Vol. 63

TABLE 2. Pathologic Data and Diagnosis in 19 Patients With PLC

Tumor Diagnosis

Patient Site Tumor Cut Histology Cell no. N Size (cm) (lobe) Capsule embolus surface pattern grading Cirrhosis RS US HA

I 1 2 1 3 1 4 1 5 1 6 1 7 1 8 I 9 1

10 1 11 1 12 1 13 1 14 1 15 1 16 1 17 1 18 2

19 1

1 0 X 8 X 6 8 X 6 X 6

6.5 X 6.5 X 6.5 3.5 x 2 x 2

9 x 7 ?

8 X 8 X 8 15 x 15 x 15 10 X 10 X 8

1.5 x 1 x 1 3 X 3 X 3 5 X 4 X 4 4 X 3 X 3 3 X 3 X 3

12 X 7.5 X 6 6 X 6 X 6 4 X 3 X 3

1.7 x 1.7 x 1.7 4 X 4 X 4

1.5 X 1.2 X 1

Left Left Left Left Right Left Left Right Left Left Right Left Left Left Left Left Left Right Right Right

Well Well Well Ruptured Well Ruptured Well Well Well Well Well Well Well Well Well Well Well Well Well Well

HCC HCC HCC HCC HCC HCC HCC HCC HCC HCC HCC HCC HCC HCC HCC HCC HCC HCC HCC HCC

1-11 I1 I1 I1 11

ND I1

111 I1

111 I1 I1

I11 I1

111 I1 I1 11 11 I1

+ ND + +

++ + + + + +

++ + ++

-

- + ND

ND -

- - - + + +

++ + + + ++ + ++ ++

+

-

- - - -

-

ND + +

ND +

ND + + + -

- + + + + +

-

- -

-

ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND + + +

PLC primary liver cancer; Tumor embolus: + = tumor embolus in the intrahepatic veins, but resected; Cut surface: - = no tumor residue in the cut surface; HCC: hepatocellular carcinoma; Cell grading: I = well differentiation, 11 = moderate differentiation, I11 = poor differentiation;

portion, cirrhosis was present in 73.7% (14 of 19), micro- nodular cirrhosis amounted to 57.1% (eight of 14), and mixed micronodular and macronodular 42.9% (six of 14) of the patients with cirrhosis (Table 2).

Discussion

Early detection and radical resection are recognized as the most important factors influencing long-term survival after resection of PLC.7 Our previous data demonstrated that patients with subclinical PLC, a single tumor nodule, a tumor size of <5 cm, and normalization of AFP levels after resection had a much better prognosis than patients with clinical PLC, multiple nodules, a tumor size of >5 cm, without normalization of AFP after resection.8 In this series, subclinical stage amounted to 36.8% (seven of 19), single tumor nodule 94.7% (18 of 19), tumor size of <5 cm 42.1% (eight of 19), and normalization of AFP levels 100% ( 1 1 of 11). In contrast, in the 113 patients who did not survive 10 years after resection of PLC in the same period, subclinical stage amounted to 8.8% (10 of 1 13) (P < 0.0 I ) , single tumor nodule 6 1.9% (70 of 1 13) (P < O.Ol), tumor size of <5 cm 15.9% (18 of 113) (P < 0.0 l), and normalization of AFP level 38.1% (16 of 42) (P < 0.001). Subclinical PLC is detected principally by AFP survey or serial AFP monitoring in subjects with a background of liver disease. Based on a long-term follow- up study, a resection margin of approximately 2 cm from

Cirrhosis: - = without cirrhosis, + = micronodular cirrhosis, ++ = mixed micronodular and macronodular cirrhosis; Diagnosis: RS = ra- dionuclide scan, US = ultrasonography, HA = hepatic arteriography; ?: initial size of tumor did not record.

the tumor capsule was accepted as providing curative re- section of small PLC.' In this study radical resection amounted to 100% (1 9 of 19); in contrast, it was 54.0% (61 of 113) in the patients who did not survive 10 years after resection (P < 0.00 1). AFT normalization is achieved only after radical resection. Generally, serum AFP will be eliminated according to its half-life (3.5 to 4 days)." The failure of AFP to decline according to half-life, and to return to normal, always reveals a palliative resection. Thus, it is possible to predict the survival of the patients 2 months after surgery by using a microcomputer with high accuracy." We believe that by means of AFT sero- survey and US screening, one can obtain a higher pro- portion of resectable cases, higher percentage of radical resection, and higher survival rate after resection because of the much higher incidence of small PLC.12

Tumor biologic characteristics are another important factor influencing prognosis after resection. Our previous study showed that tumor capsule, tumor emboli, differ- entiation, tumor size, and metastasis are important factors influencing PLC prognosis. I 3 Our present data demon- strated that grossly well-encapsulated tumor was found in 89.5% of the patients (17 of 19), and it was 47.6% (49 of 103) in the patients who did not survive 10 years after resection (P < 0.01). It is considered that at an earlier stage, the higher the percentage of well encapsulated tu- mor, the lower the incidence of tumor emboli, and better the differentiation.'

No. I I LONG-TERM SURVIVAL AFTER PLC RESECTION - Zhou et al. 2205

Furthermore, reoperation for subclinical recurrence and solitary metastasis remains an important approach to prolonging survival after radical resection of PLC.5,14,15 It has been demonstrated that PLC recurrence and solitary pulmonary metastasis could be detected in a subclinical stage by serial AFP determinations and US, and reoper- ation in these patients has resulted in a 19.1% (from 47.7% to 66.8%) increase of 5-year survival after radical resection of PLC.I4 In this study three patients (nos. 9, 13, and 14) were explored because of secondary rise in AFP levels after operation. Two of them (nos. 9 and 14) underwent resection of solitary pulmonary metastatic tumor and have survived for 9 years and 6 months, and 10 years and 1 month, respectively, after reoperation, and 13 years and 2 months, and 12 years and 10 months, respectively, after the first operation. Both of them are still in good condition with negative AFP and have returned to work. Recently, Nagasue et al. I 6 , l 7 have reported that serial determination of serum AFP and routine angiography after resection of liver cancer may be of value in detection of recurrence. One patient (no. 13) with subclinical recurrence under- went cryosurgery with liquid nitrogen because no more liver could be resected, and has survived for 8 years and 10 months after cryosurgery, and 12 years and 10 months after the first resection, with excellent condition and neg- ative AFP. Our previous report demonstrated that hepatic cryosurgery is a promising, safe, and simple treatment for neoplastic disease of liver. Cryosurgery with liquid nitro- gen (- 196OC) can be considered the surgery of choice for nonresectable PLC in patients without jaundice, ascites, and noncompensated liver function, and the whole tumor mass can be involved in the frozen

Bloodless hepatectomy, using organ isolation with hy- pothermic perfusion, has further increased the resection rate and was successful in one patient (no. 18), surviving 9 years and 10 months after bloodless hepatectomy. However, it is indicated only for patients with tumors located near the porta hepatis and the inferior vena cava and without severe cirrhosis.2',22 Routine employment of such a technique does not seem justified because it ne- cessitates a prolonged operative procedure and postop- erative h o s p i t a l i z a t i ~ n . ~ ~ ~ ~ ~

To improve the long-term survival after radical resec- tion for PLC, prevention of tumor recurrence and me- tastasis is most important and realistic. To our knowledge,

t i e n t ~ . ~ ~ It was reported that only 20.5% of patients un- dergoing PLC resection were accompanied with cirrhosis in the United States,26 but this was 73.7% (14 of 19) in this current series. Microscopically, over 90% of the pa- tients with PLC in the current study have underlying cir-

Although the tumor was solitary in 94.7% (1 8 of 19) in this study, based upon the higher incidence of dys- plasia in patients with cirrhosis, it may be possible that there is multicentric development of the cancer.28 Re- cently, however, comparison between subclinical PLC and clinical PLC clearly showed that with progression of the disease, multiple tumor nodules and bilateral involvement increased, the incidence of well-encapsulated tumors de- creased, and the incidence of tumor emboli in the intra- hepatic veins increa~ed.~ These findings suggested that spread of tumor to the blood vessels and through the cap- sule might play a more important role rather than mul- ticentric tumor emergence as the cause of the multinod- ular tumor pattern.

In conclusion, early detection and radical resection are the principal factors influencing long-term survival after resection; reoperation for subclinical recurrence and sol- itary metastasis remains an important approach to prolong survival further; new surgical techniques, such as cryo- surgery and bloodless hepatectomy, have been shown to be effective in some patients; intraperitoneal rupture of PLC does not exclude the possibility of cure. The devel- opment of a more aggressive approach to preventing re- currence and distant metastasis after radical resection is an important goal for the near future.

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