Postoperative Recurrence of Hepatocellular Carcinoma
TAKESHI NAGAO, M.D., SUMIO INOUE, M.D., FUYO YOSHIMI, M.D., MOTOHIDE SODEYAMA, M.D., YOSHIMICHI OMORI, M.D., TETSUAKI MIZUTA, M.D., NOBUHIRO KAWANO, M.D., and YASUHIKO MORIOKA, M.D.
Sixty-nine patients with hepatocellular carcinoma underwent curative hepatic resections as primary cases from 1981 to 1986. Seven patients died in the hospital after operation. The other 62 patients left the hospital and were closely followed for 25 to 78 months. Recurrence of carcinoma became obvious in 41 (66%) of 62 patients. The clinical and pathologic features of these 41 patients were not significantly different from those of the other patients. Recurrent tumors were found in the residual liver in 38 patients (93%), in the bone in 2 (5%), and in the lung in 1 (2%). Recurrence was diagnosed within 1 year, between 1 and 2 years, and more than 2 years after the operation in 22 (56%), 10 (26%), and 7 (18%) patients, respectively. It was difficult to determine the exact time of recurrence in two patients. There was a significant negative correlation between the size of primary tumor and time until recurrence; the larger the primary tumor, the shorter the time until recurrence. Among the 29 patients who underwent local excisions for their primary tumors, 19 recurrences were observed. Eighteen were found in the residual liver, in the same segment as the primary tumor, or in one near it. Larger hepatic resection for primary tumors is thus advocated to prevent recurrence.
From the First Surgical Department, University of Tokyo, Tokyo, Japan
rent study we investigated the postoperative recurrence of HCC to determine how to decrease the incidence of recurrence and improve the long-term results of hepatic resections for HCC. Patients and Methods
Seventy-three hepatic resections for HCC were performed from January 1981 to December 1986 at the First Surgical Department, Tokyo University Hospital. Three were resections for recurrent tumors in the residual liver, and one was a noncurative resection for diffuse HCC. The other 69 patients underwent curative resections, i.e., macroscopically complete removal of tumor tissue, as primary cases. Clinical records of these 69 patients were reviewed to clarify the details of recurrence. Patients who were discharged from the hospital had been closely followed at our outpatient clinic or affiliated institutions. Blood chemistry, measurement of alpha-fetoprotein (AFP) level, and ultrasonography were performed at least once a month for the early detection of recurrence. Computed tomography was also performed more than twice a year. When recurrence was suspected, angiography and needle biopsy under ultrasonic guidance were performed for confirmation. The follow-up period of the surviving patients ranged from 25 to 78 months (mean, 44.4 months). Student's t test, chi square test, Fisher's exact method, and simple regression analysis by the least squares method were used for statistical analysis. Survival curves of patients experiencing recurrence were obtained using the Kaplan-Meier method,7 and survival curves were compared by the generalized Wilcoxon test.8 A value of p < 0.05 was considered significant.
,H_ ' EPATOCELLULAR CARCINOMA (HCC), a highly malignant disease that carries a poor prognosis, is very common in Asian countries. The incidence of resection for HCC has increased greatly during the last decade because of the progress in diagnostic imaging tools. 1-3 Early detection of HCC has recently become possible and the number of hepatic resections, especially for small HCC, has increased. As a result short-term outcome has improved greatly, as have surgical techniques, and operative mortality rates have been reduced to a few per cent.4'5 The long-term results, however, are not yet satisfactory. We reviewed our previous hepatic resections for HCC, and found that postoperative recurrence was the main cause of the poor long-term results.6 In the curAddress correspondence and reprint requests to Takeshi Nagao, M.D., First Surgical Department, University of Tokyo, 7-3-1 Hongo, Bunkyoku, Tokyo 113, Japan. Accepted for publication: May 22, 1989.
28
RECURRENCE OF HEPATOCELLULAR CARCINOMA
Vol. 211 - No. I
29
Results
Profile of Operated Patients with HCC The mean age at operation of the 69 patients was 57.4 years, and their ages ranged from 26 to 77 years. Fiftynine patients (86%) were men and 10 (14%) were women. Liver cirrhosis was present in 52 patients (76%), and other chronic liver diseases, such as chronic hepatitis and liver fibrosis, were found in 14 patients (20%). HCC was diagnosed in an otherwise normal liver in only three patients (4%). Hepatitis B surface antigen was measured by reversed passive hemagglutination test in 67 patients and was positive in 14 (21 %). The preoperative serum level of AFP was measured by radioimmunoassay in 67 patients. While the normal value is lower than 20 ng/mL, it was higher than 20, 200, and 2000 ng/mL in 50 (75%), 23 (34%), and 11 (16%) patients, respectively. Table 1 presents the details of the operations performed on the 69 patients. Major hepatic rejections, i.e., bisegmentectomies (lobectomies), were carried out on 25 patients (36%). Minor hepatic resections, i.e., segmentectomies and local excisions, were performed on 44 patients (64%). The tumor was solitary in 58 patients (84%), and multiple in 11 (16%). Two tumor nodules were found in six patients, three in four patients, and more than three in one patient. Investigation of the resected specimens revealed that 79% of the main tumors were encapsulated by fibrous tissue. The maximal diameter of the main tumor varied from 0.5 cm to 16.3 cm. It was less than 2 cm in 12 (17%) patients, between 2 cm and 5 cm in 37 (54%), between 5 cm and 10 cm in 11 (16%), and more than 10 cm in 9 (13%) patients. Figure 1 shows the outcomes in the 69 patients. Seven patients died in the hospital after the operation, yielding a hospital mortality rate of 10%. Six patients died of liver failure and one patient died of postoperative intra-abdominal bleeding. The other 62 patients were discharged from the hospital. Thirty-five of the 62 patients have died. Recurrence of HCC was the cause of death in 26 patients. Five patients died of hepatic failure due to severe cirrhosis.
Left Hospital 62
Alive
21
-with Recurrence
Died 35 15 I-Recurrence of HCC 26
-without Recurrence 12 1-Hepatic Failure
5
- Esophageal Varices 1
- Other Causes
3
FIG. 1. Results in 69 patients with HCC who underwent operation between 1981 and 1986 (final compilation, January 1, 1989).
Rupture of esophageal varices was the cause of death in one patient. The other three patients died of diseases not related to the liver. Although 27 of the 62 patients were still alive at the time of this inquiry (January 1989), recurrence of HCC had become obvious in 15. The other 12 patients were living without any signs or symptoms of recurrence.
Patients with Recurrence Postoperative recurrence of HCC was observed in 41 (66%) of 62 patients during the follow-up period. Table 2 shows the details of these 41 patients with recurrence in comparison to the other 21 patients. The seven patients who died in the hospital after operation were excluded from this inquiry. There was no significant difference between these two groups of patients for any item in the table. That is the clinical and pathologic features of patients with recurrence were no different from those of the other patients. This indicates that patients with recurrence are in no way special; any patient is subject to the recurrence of HCC after hepatectomy.
TABLE 1. Operations Performed on 69 Patients with HCC
Operation
HCC with LC
HCC Without LC
Total
Right lobectomy Left lobectomy Central bisegmentectomy Segmentectomy Local excision
8 3 1 14 26
11 2
19 5
0 1 3
1 15 29
Total
52
17
69
HCC, hepatocellular carcinoma. LC, liver cirrhosis.
Sites and Times of Recurrence The first recurrent tumor was found in the residual liver in 38 patients (93%), in the bone in 2 (5%), and in the lung in 1 (2%). The recurrent tumor became obvious within 1 year, between 1 and 2 years, and more than 2 years after the operation in 22 (56%), 10 (26%), and 7 patients (18%), respectively. It was difficult to determine the exact time of recurrence in two patients. These results indicate that recurrence occurs most often in the residual liver and within a very short time after operation.
TABLE 2. Clinical and Pathologic Characteristics of 41 Patients With Recurrence in Comparison with 21 Patients Without Recurrence
Characteristic
Recurrence (+) (No. of Patients)
Recurrence (-) (No. of Patients)
Total
Number of patients Mean age (years) HB surface antigen
41 57.8
21 56.4
62 57.3
Positive Negative Alpha-fetoprotein 5200 ng/mL >200 ng/mL Liver cirrhosis Yes No Number of tumors Solitary Multiple Tumor size* !5 cm >5cm Fibrous capsule Yes No Operation Major resectiont Minor resectiont
8 31
4 17
12 48
27 12
13 8
40 20
29 12
16 5
45 17
34 7
18 3
52 10
29 .12
13 8
42 20
31 9
18 3
49 12
14 27
8 13
22 40
*
Ann. Surg
NAGAO AND OTHERS
30
Maximum diameter of the main tumor in each patient.
t Bisegmentectomies (lobectomies). t Segmentectomies and local excisions.
Figure 2 shows the relation between the maximal diameter of the primary tumor and the time of recurrence. There was a significant negative correlation between these two indices. The larger the primary tumor, the shorter the time until recurrence. As shown in Table 1, the incidence of minor hepatic resections for HCC has been very high recently. Advances in diagnostic techniques have enhanced the early detection of small HCC through the follow-up of patients with chronic liver diseases. Local excision, smaller than one segment of the liver, is the operation of choice in most instances for such patients because the poor functional reserve of the cirrhotic liver does not permit larger resection. Nineteen recurrences were observed after 29 local excisions. Eighteen (95%) of 19 recurrences were in the residual liver. Recurrent tumor in the liver was solitary in the early stage of recurrence in 17 patients but was multiple from the beginning of recurrence in one. Figure 3 shows the relation between the sites (segments) of primary tumors and recurrent tumors in these 17 patients. Ten recurrences occurred in the same segment as the primary tumor, and seven recurrences were seen in a neighboring segment. No recurrence was observed in a segment of the liver distant from the primary tumor. In the case of major hepatic resection, most recurrent tumors were diagnosed in the segment next to the surgical margin, not in a distant segment. Curative resection of the primary
-
January 1990
tumor, i.e., macroscopically complete removal of tumor was performed in every patient in this study. The recurrences that we encountered could be clinically discerned from those arising from remnant cancer tissue at the surgical margin because a cancer-free zone could be
tissue,
identified between the recurrent tumor and surgical margin by ultrasonography or computed tomography. Risk Factors for Recurrence
Table 3 compares the background factors between two groups of patients: a high-risk group in whom the recurrence became obvious within 1 year after operation, and a low-risk group who survived more than 1 year without recurrence. Patients in whom the recurrence occurred after 1 year of observation were included in the second group. Those who died within 1 year after operation without recurrence were excluded from this investigation. The incidence of tumors measuring more than 5 cm in diameter. was greater in the high-risk group than in the low-risk group (p < 0.05). However there were no other significant differences between these two groups of patients. Tumor size was the only factor that carried a high risk of early recurrence. Treatment of Recurrent Tumors
The therapy for recurrent HCC is usually more difficult than that for primary HCC because of the more severe circumstances. In some patients a combination of several therapies was used. Table 4 shows the main therapies performed in each patient. Surgical resection was the treat-
15
Y =6.76-0.lOx (r= -0.33, p
TAKESHI NAGAO, M.D., SUMIO INOUE, M.D., FUYO YOSHIMI, M.D., MOTOHIDE SODEYAMA, M.D., YOSHIMICHI OMORI, M.D., TETSUAKI MIZUTA, M.D., NOBUHIRO KAWANO, M.D., and YASUHIKO MORIOKA, M.D.
Sixty-nine patients with hepatocellular carcinoma underwent curative hepatic resections as primary cases from 1981 to 1986. Seven patients died in the hospital after operation. The other 62 patients left the hospital and were closely followed for 25 to 78 months. Recurrence of carcinoma became obvious in 41 (66%) of 62 patients. The clinical and pathologic features of these 41 patients were not significantly different from those of the other patients. Recurrent tumors were found in the residual liver in 38 patients (93%), in the bone in 2 (5%), and in the lung in 1 (2%). Recurrence was diagnosed within 1 year, between 1 and 2 years, and more than 2 years after the operation in 22 (56%), 10 (26%), and 7 (18%) patients, respectively. It was difficult to determine the exact time of recurrence in two patients. There was a significant negative correlation between the size of primary tumor and time until recurrence; the larger the primary tumor, the shorter the time until recurrence. Among the 29 patients who underwent local excisions for their primary tumors, 19 recurrences were observed. Eighteen were found in the residual liver, in the same segment as the primary tumor, or in one near it. Larger hepatic resection for primary tumors is thus advocated to prevent recurrence.
From the First Surgical Department, University of Tokyo, Tokyo, Japan
rent study we investigated the postoperative recurrence of HCC to determine how to decrease the incidence of recurrence and improve the long-term results of hepatic resections for HCC. Patients and Methods
Seventy-three hepatic resections for HCC were performed from January 1981 to December 1986 at the First Surgical Department, Tokyo University Hospital. Three were resections for recurrent tumors in the residual liver, and one was a noncurative resection for diffuse HCC. The other 69 patients underwent curative resections, i.e., macroscopically complete removal of tumor tissue, as primary cases. Clinical records of these 69 patients were reviewed to clarify the details of recurrence. Patients who were discharged from the hospital had been closely followed at our outpatient clinic or affiliated institutions. Blood chemistry, measurement of alpha-fetoprotein (AFP) level, and ultrasonography were performed at least once a month for the early detection of recurrence. Computed tomography was also performed more than twice a year. When recurrence was suspected, angiography and needle biopsy under ultrasonic guidance were performed for confirmation. The follow-up period of the surviving patients ranged from 25 to 78 months (mean, 44.4 months). Student's t test, chi square test, Fisher's exact method, and simple regression analysis by the least squares method were used for statistical analysis. Survival curves of patients experiencing recurrence were obtained using the Kaplan-Meier method,7 and survival curves were compared by the generalized Wilcoxon test.8 A value of p < 0.05 was considered significant.
,H_ ' EPATOCELLULAR CARCINOMA (HCC), a highly malignant disease that carries a poor prognosis, is very common in Asian countries. The incidence of resection for HCC has increased greatly during the last decade because of the progress in diagnostic imaging tools. 1-3 Early detection of HCC has recently become possible and the number of hepatic resections, especially for small HCC, has increased. As a result short-term outcome has improved greatly, as have surgical techniques, and operative mortality rates have been reduced to a few per cent.4'5 The long-term results, however, are not yet satisfactory. We reviewed our previous hepatic resections for HCC, and found that postoperative recurrence was the main cause of the poor long-term results.6 In the curAddress correspondence and reprint requests to Takeshi Nagao, M.D., First Surgical Department, University of Tokyo, 7-3-1 Hongo, Bunkyoku, Tokyo 113, Japan. Accepted for publication: May 22, 1989.
28
RECURRENCE OF HEPATOCELLULAR CARCINOMA
Vol. 211 - No. I
29
Results
Profile of Operated Patients with HCC The mean age at operation of the 69 patients was 57.4 years, and their ages ranged from 26 to 77 years. Fiftynine patients (86%) were men and 10 (14%) were women. Liver cirrhosis was present in 52 patients (76%), and other chronic liver diseases, such as chronic hepatitis and liver fibrosis, were found in 14 patients (20%). HCC was diagnosed in an otherwise normal liver in only three patients (4%). Hepatitis B surface antigen was measured by reversed passive hemagglutination test in 67 patients and was positive in 14 (21 %). The preoperative serum level of AFP was measured by radioimmunoassay in 67 patients. While the normal value is lower than 20 ng/mL, it was higher than 20, 200, and 2000 ng/mL in 50 (75%), 23 (34%), and 11 (16%) patients, respectively. Table 1 presents the details of the operations performed on the 69 patients. Major hepatic rejections, i.e., bisegmentectomies (lobectomies), were carried out on 25 patients (36%). Minor hepatic resections, i.e., segmentectomies and local excisions, were performed on 44 patients (64%). The tumor was solitary in 58 patients (84%), and multiple in 11 (16%). Two tumor nodules were found in six patients, three in four patients, and more than three in one patient. Investigation of the resected specimens revealed that 79% of the main tumors were encapsulated by fibrous tissue. The maximal diameter of the main tumor varied from 0.5 cm to 16.3 cm. It was less than 2 cm in 12 (17%) patients, between 2 cm and 5 cm in 37 (54%), between 5 cm and 10 cm in 11 (16%), and more than 10 cm in 9 (13%) patients. Figure 1 shows the outcomes in the 69 patients. Seven patients died in the hospital after the operation, yielding a hospital mortality rate of 10%. Six patients died of liver failure and one patient died of postoperative intra-abdominal bleeding. The other 62 patients were discharged from the hospital. Thirty-five of the 62 patients have died. Recurrence of HCC was the cause of death in 26 patients. Five patients died of hepatic failure due to severe cirrhosis.
Left Hospital 62
Alive
21
-with Recurrence
Died 35 15 I-Recurrence of HCC 26
-without Recurrence 12 1-Hepatic Failure
5
- Esophageal Varices 1
- Other Causes
3
FIG. 1. Results in 69 patients with HCC who underwent operation between 1981 and 1986 (final compilation, January 1, 1989).
Rupture of esophageal varices was the cause of death in one patient. The other three patients died of diseases not related to the liver. Although 27 of the 62 patients were still alive at the time of this inquiry (January 1989), recurrence of HCC had become obvious in 15. The other 12 patients were living without any signs or symptoms of recurrence.
Patients with Recurrence Postoperative recurrence of HCC was observed in 41 (66%) of 62 patients during the follow-up period. Table 2 shows the details of these 41 patients with recurrence in comparison to the other 21 patients. The seven patients who died in the hospital after operation were excluded from this inquiry. There was no significant difference between these two groups of patients for any item in the table. That is the clinical and pathologic features of patients with recurrence were no different from those of the other patients. This indicates that patients with recurrence are in no way special; any patient is subject to the recurrence of HCC after hepatectomy.
TABLE 1. Operations Performed on 69 Patients with HCC
Operation
HCC with LC
HCC Without LC
Total
Right lobectomy Left lobectomy Central bisegmentectomy Segmentectomy Local excision
8 3 1 14 26
11 2
19 5
0 1 3
1 15 29
Total
52
17
69
HCC, hepatocellular carcinoma. LC, liver cirrhosis.
Sites and Times of Recurrence The first recurrent tumor was found in the residual liver in 38 patients (93%), in the bone in 2 (5%), and in the lung in 1 (2%). The recurrent tumor became obvious within 1 year, between 1 and 2 years, and more than 2 years after the operation in 22 (56%), 10 (26%), and 7 patients (18%), respectively. It was difficult to determine the exact time of recurrence in two patients. These results indicate that recurrence occurs most often in the residual liver and within a very short time after operation.
TABLE 2. Clinical and Pathologic Characteristics of 41 Patients With Recurrence in Comparison with 21 Patients Without Recurrence
Characteristic
Recurrence (+) (No. of Patients)
Recurrence (-) (No. of Patients)
Total
Number of patients Mean age (years) HB surface antigen
41 57.8
21 56.4
62 57.3
Positive Negative Alpha-fetoprotein 5200 ng/mL >200 ng/mL Liver cirrhosis Yes No Number of tumors Solitary Multiple Tumor size* !5 cm >5cm Fibrous capsule Yes No Operation Major resectiont Minor resectiont
8 31
4 17
12 48
27 12
13 8
40 20
29 12
16 5
45 17
34 7
18 3
52 10
29 .12
13 8
42 20
31 9
18 3
49 12
14 27
8 13
22 40
*
Ann. Surg
NAGAO AND OTHERS
30
Maximum diameter of the main tumor in each patient.
t Bisegmentectomies (lobectomies). t Segmentectomies and local excisions.
Figure 2 shows the relation between the maximal diameter of the primary tumor and the time of recurrence. There was a significant negative correlation between these two indices. The larger the primary tumor, the shorter the time until recurrence. As shown in Table 1, the incidence of minor hepatic resections for HCC has been very high recently. Advances in diagnostic techniques have enhanced the early detection of small HCC through the follow-up of patients with chronic liver diseases. Local excision, smaller than one segment of the liver, is the operation of choice in most instances for such patients because the poor functional reserve of the cirrhotic liver does not permit larger resection. Nineteen recurrences were observed after 29 local excisions. Eighteen (95%) of 19 recurrences were in the residual liver. Recurrent tumor in the liver was solitary in the early stage of recurrence in 17 patients but was multiple from the beginning of recurrence in one. Figure 3 shows the relation between the sites (segments) of primary tumors and recurrent tumors in these 17 patients. Ten recurrences occurred in the same segment as the primary tumor, and seven recurrences were seen in a neighboring segment. No recurrence was observed in a segment of the liver distant from the primary tumor. In the case of major hepatic resection, most recurrent tumors were diagnosed in the segment next to the surgical margin, not in a distant segment. Curative resection of the primary
-
January 1990
tumor, i.e., macroscopically complete removal of tumor was performed in every patient in this study. The recurrences that we encountered could be clinically discerned from those arising from remnant cancer tissue at the surgical margin because a cancer-free zone could be
tissue,
identified between the recurrent tumor and surgical margin by ultrasonography or computed tomography. Risk Factors for Recurrence
Table 3 compares the background factors between two groups of patients: a high-risk group in whom the recurrence became obvious within 1 year after operation, and a low-risk group who survived more than 1 year without recurrence. Patients in whom the recurrence occurred after 1 year of observation were included in the second group. Those who died within 1 year after operation without recurrence were excluded from this investigation. The incidence of tumors measuring more than 5 cm in diameter. was greater in the high-risk group than in the low-risk group (p < 0.05). However there were no other significant differences between these two groups of patients. Tumor size was the only factor that carried a high risk of early recurrence. Treatment of Recurrent Tumors
The therapy for recurrent HCC is usually more difficult than that for primary HCC because of the more severe circumstances. In some patients a combination of several therapies was used. Table 4 shows the main therapies performed in each patient. Surgical resection was the treat-
15
Y =6.76-0.lOx (r= -0.33, p
