Patterns of Intrahepatic Recurrence after Curative Resection of Hepatocellular Carcinoma

TAKASHI MATSUMATA, TAKASHI KANEMATSIJ, K E N ~ I TAKENAKA, YASUHIRO YOSHIDA, TAKASHI NISHIZAKI A N D KEIZO SL~GIMACHI

Secvnd Department of Surgen, Kvushu .nLiw,stt\. Faculty of Mt.dLcine, Fukuoka 812. Japan

Using selective angiograms of the liver, we analyzed the patterns of intrahepatic recurrence of hepatocellular carcinomas following curative surgery. In 33 patients with intraheptaic recurrences, seven patients (2 1 %) had a recurrence near the resected hepatic stump. The re- maining 26 had either a nodular recurrence in segments away from the resected margin or a widespread multi- nodular recurrence in the liver remnant. There was a recurrence within the first postoperative year in five of 16 patients with a nodular recurrence and in eight of 10 patients with a widespread multinodular recurrence. In these patients, particularly those with a widespread multinodular recurrence, tumor thrombi in the portal vein present before the operation and/or disseminated during operation from such an advanced main tumor seemed to be the most important and significant factor related to the early recurrence in the remnant liver. This evidence suggests that in cases of surgery for hep- atocellular carcinoma it is important to establish a tech- nique to prevent dissemination of cancer cells due to operative manipulation and also adequate adjuvant therapy rather than attempting to obtain an ample re- section margin.

At t h e t ime of curative resection for hepatocellular carcinoma, every effort has to be made to avoid over- looking other sites of t umor in the remnant liver. Here, preoperative imaging modalities a n d intraoperative ultrasonography a re of great use. However, there a re immediate recurrences in the hepatic remnant , and these are not always at the resected margin of the remnant liver. L in et al. (1) reported that in 119 of 209 hepatec- tomized patients, there was a local recurrence within 1 year after the surgery. Ong and Chan ( 2 ) reported tha t 20 of 67 patients died within 6 months after operation, a n d in all of these patients, there was a widespread recurrence in the liver remnant. Therefore, we considered i t necessary to analyze the pa t te rns of intrahepatic re- currence of hepatocellular carcinomas after curative sur- gery. We made use of selective arteriograms of t h e liver and our findings are reported herein

Received June 20, 1988; accepted August 23. 1988. Address reprint requests to: Takashi Matsumata, M.D., Second

Department of Surgery, Kyushu Liniversit!. Faculty of Medicine, 8-1 - 1 Maidashi, Higashi-ku, Fukuoka 81%. .Japan.

MATERIALS AND METHODS

From April, 1971, to March, 1988, curative hepatic resections were performed in the Second Depart,ment of Surgery, Kyushu University Hospital, on 147 consecutive Japanese patients with a single hepat,ocellular carcinoma. Single hepatocellular carci- noma is defined as one tumor nodule, without satellite cancer nodules evident on the preoperative hepatogram or in the resected specimen. “Curative hepatic resection” refers to no residual t,umors in the remnant liver, as seen on the intraoper- ative ultrasonography or on the hepatogram performed 1 month after the surgery. According to Lee et, al. ( 3 ) , the absolutely curative resection margin is defined as a margin of more than 1 cm of nontumorous liver tissue.

All our patients were seen regularly in the outpatient clinic. When recurrences were suspected, the patients were readmitted and selective hepatic angiography was carried out. Among the 147 patients, the 53 wit.h recurrences included inhahepatic in 47, pulmonary met.astases in eight and bone, brain and lymph nodes metastases in one each. In the 47 patient.s with intrahe- patic recurrences, t,he 33 confirmed by stereoscopic angio- graphic evaluation were included in the present study. In these 3:3 patients, lobular resections were performed in eight, seg- rnentectomies in five, subsegmentectomies in eight and subseg- mental wedge resections in 12. The maximum diameter of the tumors ranged from 1.1 to 16.0 cm with an average of 5.6 cm in the resected specimen. There were 26 men and seven women ranging in age from 36 to 74 years. Intrahepatic recurrences on the hepatograms in 33 patients were separated into three pat- terns:

Pat,tern I: Pattern 11:

Recurrence near the resected hepat.ic stump. Nodular recurrence; solitary or a few nodules in the other segments away from the resected mar- gin.

Pattern 111: Widespread multinodular recurrence in the liver remnant (Fig. 1).

A411 33 patients included in the present study were those operated on since 1976; hence, each pattern described above was also confirmed by computed tomography. Clinicopatholog- ical comparisons were made between patterns.

Statistical analyses were made using the x’ and Student’s t test,s, and values less than 0.05 were considered to be statisti- cally significant. The values are expressed as the mean +. S.D.

RESULTS

There were seven patients with a recurrence near the resected hepatic s tump (Pa t te rn I), a n d 10 had a wide- spread multinodular recurrence (Pa t te rn 111). Nodular

458 MATSUMATA E T AL. HEPATOLOGY

recurrence (Pattern 11) was present in 16; eight patients had a single nodule and the other eight had three or four recurrent nodules in the remnant liver. Preoperative laboratory data for each pattern are shown in Table 1. There was no significant difference in values of serum albumin and total bilirubin in all three patterns. Value of the indocyanine green test was significantly high in those with Pattern 11, compared to findings for Pattern I11 (p < 0.05), and the platelet count in those with Pattern I11 was double the count in those with Patterns I and 11.

Table 2 shows that patients with Pattern I1 had an accompanying histologically proven cirrhosis, a t a high frequency, compared with findings in patients with Pat-

tern I11 (p < 0.05). Differences in the volume of blood loss or in the operation time were not statistically signif- icant, in each classification, respectively. Difference in the types of operation performed was also not statisti- cally significant, as related to each pattern.

Thirteen of 16 patients with Pattern I1 had a tumor of less than 5 cm in diameter, whereas four of 10 patients with Pattern I11 had a tumor exceeding 10 cm in diame- ter. The average size of the tumor was 6.3, 3.2 and 8.8 cm in Patterns I, I1 and 111, respectively. Differences in tumor size were statistically significant between Patterns I and I1 (p < 0.01), as well as between Patterns I1 and I11 (p < 0.001).

An absolutely curative resection margin was obtained

FIG. 1. Widespread multinodular recurrence (Pattern 111); hepatogram taken 8 months after hepatectomy for a tumor located in the posterior segment. Multiple, minute nodules were widespread throughout the remnant liver.

TABLE 1. Preoperative laboratory data

Pattern I Pattern I1 Pattern 111 (n = 7) (n = 16) (n = 10) Parameters

Serum albumin (3.5-5.0 gm/dl)" 3.63 f 0.46 3.61 + 0.41 3.72 f 0.38 Total bilirubin (0.2-1.2 mg/dl) 1.33 f 0.57 0.84 f 0.40 0.84 k 0.41 Indocyanine green test (0-10%) 18.2f 11.3 22.9 f 10.3h 15.3 k 6.4 Platelet count (12-35 X lO'/mm.') 11.6 f 3.5 10.5 f 4.5 19.8 k 7.6'."

" Normal range. Significantly different from Pattern 111, a t p < 0.05. Significantly different from Pattern I, a t p < 0.02. Significantly different from Pattern 11, a t p < 0.001.

Vol. 9. No. 1 % . 1989

P a t t e r n

I

P a t t e r n

I I

459

-~

0 0 0 0

~~

0

01 0 0 0 . 0 0

1' \ H I b, 2. Clinicopathological data

P a t t e r n

I l l

Pattern 1 Pattern I1 Pattern 111 ( n = 71 ( n = 16) (11 = 1 0 ) I'aremrters

0 0

0 0 00.0

Age (yeare) r,2.(; 2 8.J .i6.9 ? 4.8 37.7 * 10.5 Sex i ma1e:feniale 1 .i.? 13::i 8:2 Cirrhosis ("G 1 / I 88 40 Operative blood loss I 1111 1

7 ,

1 , : x l t l i 9lI(l l.li01) ? 1,:lIJO "700 5 1.10~1 Operation time (nun 1 171 + 180 i 89 22'7 t fix Operation

Lobectoiny i 1 Segmentectom? - 1 - 1

Subsegmentectoni:, 1 > )

Wedge resection ri >

Tumor size ( c m J ! ' i .2 t ?.!I' 8.S * 4.8 Resect.ion margin less t hair 1 .I] c ' t n I ''c I . > , : i 1 70 Tumor capsule 1 '; 1 SI; I :) Macroscopic portal thromliw ( ' c I 1 4 ii 50

I

_ _ (50 - -

' Significantly different from Pattern I l l . :ri p < ~1 . I~X Significantly different from Pattern 1. at 1) < 0.01. Significantlv different from I'attrrn [I!. ; i t 1) < O.Oi11

I I I I I I 0 12 24 <-? 6 48 60

E.1 , v : + , , / .

FIG. 2. Pattern I: recurrence near the rrsected hepatic stump. I'ai tern 11: nodular recurrence; solitarv o r a i'eis nodules i n the other segments away from the resected margin Pattern 111: widespread multinodular recurrence in the liver remnant . In :i:i patients w i t h intrahepatic recurrences of hepatocellular carcinoma, only seven pa tients (21%) had Pattern I . Recurrence was recognized within or aroutitl the first postoperative year in five r i l ' 16 pa1 ients with I'attern I1 and in eight of' 10 patients with Pattern 111

for the nodular recurrence pattern. but there was no significant difference in each pattern, respect,ively. Tu- mor capsule was recognized in 24 (73%) , and the differ- ence was not significant, in each pattern, respect,ivelv. Macroscopic tumor thrombi in the portal vein were pres- ent in five of 10 patients (50%) with Pat,t,ern 111. and in one of 16 (6%) with Patt,ern I1 (p < 0.05).

Recurrence was recognized within or around 1 year in five of 16 patients with Pattern I1 and in eight of 10 with Pattern 111. The recurrence, verified by hepatogram, was 18.3 & 12.4, 25.1 f 14.7 and 12.5 k 11.9 months after the hepatic resection in those with Patterns I , I1 and 111. respectively, with a significant difference between Pat - terns I1 and I11 (p < 0.05) (Fig. 2 ) .

DISCUSSION

Lee et al. (3) asserted that, a minimum of 1 cni 0 1 adequate margin was required for ti curative operation of

a hepatocellular carcinoma; hence, an ample margin ob- tained in such cases would be expected to reduce the rate of' recurrence near t,he site of the resected hepatic stump. However, in our 33 patients with int,rahepatic recur- rences of hepatocellular carcinoma, seven (21 %) had a recurrence near t,he resected hepatic stump (Pattern I ) . The remaining 26 had either a nodular recurrence in the other segments away from the resected margin (Pattern 11) 01' a widespread multinodular recurrence in the liver remnant (Pattern 111). There was no significant differ- ence with regard to the ratio of a resection margin of less than 1.0 cm, in each pattern. These observations clearly showed the significance of limited hepatic resection (4, 5). 111 principle, excision of a malignant tumor should be wide; however. if this concept is applied in cases of a cirrhotic liver, t.he results are potentially jeopardized by complications which will ensue.

Hepatocellular carcinoma may be of. multicentric ori- gin in cirrhotic patients (61, so that a metachronous occurrence of a new primary tumor mav be related to the late recurrence in those with Pattern I1 and an associated cirrhosis. A careful, long-term follow-up after curative hepatic resection is necessary, even for those with small hepatocellular carcinoma. A second radical resection may have to be done to achieve good results (7) .

In those with the widespread multinodular recurrence pattern, there was a recurrence within or around the first powjperative year in eight of our 10 patients. Lipiodol computed tomography scan can detect tumors as small as 3 iiim (81, and intraoperative ultrasonography can be used to survey t.he liver for satellite lesions (9). However, further improvement of imaging modalities is necessary for a preoperative detection of all minute lesions. There was a statistically significant difference with respect to the presence of tumor thrombi in the portal vein between Patt.erns I1 and 111; therefore, in the widespread multi- nodular recurrence pattern in patients with a relatively large tumor, there may also be tumor thrombi not de- t.ectahle with the present imaging modalities.

I n addition, hepatocellular carcinoma tends to spread intrahepaticallj, from t.he portal vein system ( 2 , lo ) , and

460 MATSUMATA ET AL. HEPATOLOGY

at surgery, manipulation of the liver is inevitable to mobilize the cancer-bearing hepatic lobe. Particularly, operations on bulky tumor inevitably involve a longer operation time and a greater degree of manipulation. Therefore, portal vein invasion present before the oper- ation and/or disseminated during operation from such an advanced main tumor seemed to be the most impor- tant and significant factor related to early recurrence in the remnant liver. The large platelet count in those with a widespread multinodular recurrence pattern may play some part in arrest of the cancer cells released during surgery.

As the present surgical treatments for hepatocellular carcinoma have limitations, a non-touch resection tech- nique (11) and adjuvant therapy have to be designed for such patients.

Acknowledgment: We thank M. Ohara for pertinent comments.

REFERENCES

1. Lin TY, Lee CS, Chen KM, et al. Role of surgery in the treatment of primary carcinoma of the liver: a 31-year experience. Br J Surg 1987; 74~839-842.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

Ong GB, Chan PKW. Primary carcinoma of the liver. Surg Gynecol Obstet 1976; 143:31-38. Lee CS, Sung JL, Hwang LY, et al. Surgical treatment of 109 patients with symptomatic and asymptomatic hepatocellular car- cinoma. Surgery 1986; 99:481-490. Kanematsu T, Takenaka K, Matsumata T, et al. Limited hepatic resection effective for selected cirrhotic patients with primary liver cancer. Ann Surg 1984; 19951-56. Yoshida Y, Kanematsu T, Matsumata T, et al. Surgical margin and recurrence after resection of hepatocellular carcinoma in pa- tients with cirrhosis: further evaluation of limited hepatic resec- tion. Ann Surg 1989 (in press). Foster JH. Survival after liver resection for cancer. Cancer 1970;

Kanematsu T, Matsumata T, Takenaka K, e t al. Clinical manage- ment of recurrent hepatocellular carcinoma after primary resec- tion. Br J Surg 1988; 75203-206. Okuda K. Early recognition of hepatocellular carcinoma. Hepatol-

Sheu JC, Lee CS, Sung JL, et al. Intraoperative hepatic ultraso- nography-an indispensable procedure in resection of small hepa- tocellular carcinomas. Surgery 1985; 97:97-103. Nakashima T. Vascular changes and hemodynamics in hepatocel- lular carcinoma. In: Okuda K, Peters RL, eds. Hepatocellular carcinoma. New York: Wiley Medical, 1976 169-203. Matsumata T, Kanematsu T, Takenaka K, et al. Lack of intrahe- patic recurrence of hepatocellular carcinoma by temporary portal venous embolization with starch microspheres. Surgery 1989 (in press).

26:493-502.

O ~ Y 1986; 6~729-738.