- Email: [email protected]
Significance of tumor vascularity as a predictor of long-term prognosis in patients with small hepatocellular carcinoma treated by percutaneous ethanol injection therapy
Journal of Hepatology 1997; 26: 1055-1062 Printed in Denmark . AN rights reserved Munksgaard . Copenhagen
Copyright 8 European Association for the Study 01 the Liver 1997
Journalof Hepatology ISSN 0168-8278
Significance of tumor vascularity as a predictor of long-term prognosis in patients with small hepatocellular carcinoma treated by percutanaus ethanol injection therapy Hidenori
Toyoda, Takashi Kumuda, Department
Satoshi Nakano, Isao Takeda, Keiichi Sugiyama, Yasuhiro Sone of Gastroenterology,
Ogaki Municipal
Hospital,
Seiki Kiriyama
and
Ogaki, Japan
BackgroundAims: We estimated the significance of the vascularity of small hepatocelhdar carcinoma (HCC) as a predictor of long-term prognosis in patients treated with percutaneous ethanol injection therapy (PEIT/PEI). Metk&: Fifty-four patients who have been followedup in our hospital and who had HCC less than 20 mm in diameter were observed for 199 to 2074 days. Hepatic angiography (digital subtraction angiography; DSA and ultrasound angiography with intraarterial CO* microbubbles; USAG) was performed before treatment in all cases, and the vascularity of the tumor was clinically evaluated. The survival rate was analyzed according to this vascular@ Results: Of the 54 tumors, 24 had tumor stain on
DSA, while 30 did not, and 38 showed enhancement on USAG, while 16 did not. The 3- and 5-year survival rates were 48.7 and 34.1% of patients with positive staining HCC on DSA, and 89.7 and 69.7% of patients with negative staining HCC (p=O.O723). The rates were 48.6 and 36.7%, respectively, of patients with positive enhancement HCC on USAG, and both rates were 85.7% of patients with negative enhancement HCC (p=O.O231). Con&&~ Tumor vascularity will play a role in the long-term prognosis of these patients with small HCC when they are treated with PEIT/PEI.
R
important prognostic factors in patients with advanced HCC, the characteristics of HCC itself are thought to be more important in the long-term prognosis of patients with small HCC. The importance of the characteristics of HCC as a prognostic factor will be increased in patients treated with PEIT/PEI, because this treatment usually does not accompany the rapid impairment of liver function. The size (8-10) and the differentiation of HCC (11,12) are reported to be important prognostic factors for HCC treated by surgery. However, we do not yet have enough information about the predictors of longterm prognosis of patients with small HCC, especially when they are treated by PEIT/PEI. HCC is usually found to be hypervascular on angiography (13-17), but some small HCCs do not reveal a hypervascular stain (1,18-22). This is considered to be one of the characteristics of early-stage HCC. Thus the vascularity varies in small HCC. In this retrospective study we estimated the importance of the radiologi-
PROGRESS in the development of various scanning techniques has made it possible to detect small hepatocellular carcinoma (HCC) (l-3). However, the surgical resectability of HCC remains low, even when the HCC is found at an early stage, because most patients with HCC have underlying cirrhosis, which often precludes hepatectomy. Percutaneous ethanol injection therapy (PEIT/PEI) has been shown to be effective as an option for treatment of HCC (4,5), and also for small HCC (6). The reported survival of patients with small HCC treated with this technique was comparable to that of patients treated with surgical resection (7). While the reserve liver function will be one of the ECENT
Received 13 August; revised 15 November; accepted 21 November 1996
Correspondence: Takashi Kumuda, Department of Gastroenterology, Ogaki Municipal Hospital, 4-86 Minaminokawa, Ogaki, Gifu, 503 Japan. Tel. 81-584-81-3341. Fax. 81-584-75-5715.
Key words: Percutaneous ethanol injection therapy; Prognosis; Small HCC; Vascularity.
1055
H. Toyoda et al.
tally evaluated vascularity of HCC as a predictor of long-term prognosis in patients with small hepatocellular carcinoma treated by PEIT/PEI.
Patients and Methods Patients studied Between 1989 and 1995, 143 patients with liver cirrhosis, who had been followed up regularly at our hospital, were diagnosed as having an HCC less than 20 mm in diameter. Of these 143 patients, we selected 54 patients who had been treated with PEIT/PEI for this retrospective study. They were selected on the following criteria: 1) they had solitary HCC; 2) they had had no history of HCC (not a recurrence); 3) hepatic angiography including digital subtraction angiography (DSA) and ultrasound angiography with intraarterial COZ microbubbles (USAG) (23,24) had been performed before treatment; 4) a tumor specimen had been obtained by fine-needle biopsy under ultrasonographic guidance prior to the treatment; and 5) they had been followed up for more than 100 days after treatment. The patients consisted of 33 men and 21 women, with a mean age of 62.3 (48-79) years. All patients had liver cirrhosis. According to the Child-Pugh classification (25) 18 were in class A, 27 were in class B, and nine were in class C. All HCC were initially detected by plain ultrasonography. Pretreatment angiographic evaluation The hepatic angiography was performed before any treatment or biopsy. Selective hepatic intra-arterial DSA was carried out using a DSA apparatus (2050; Toshiba, Tokyo, Japan) with a 0.8-mm focal spot, a 1Zinch diameter image intensifier and a 1024~ 1024 matrix. Between 15 and 20 ml of the contrast material, Omnipaque (Nycomed AS, Oslo, Norway) was injected from the tip of a catheter inserted into the hepatic artery (either the proper, right, or left hepatic artery), at an injection rate of 5 to 7 ml/s. We always examined each of the hepatic arteries, including the accessory or replaced hepatic arteries. USAG were performed by injecting CO2 microbubbles through a catheter placed in the hepatic artery. CO2 microbubbles were prepared by vigorously mixing 10 ml of CO2 and 5 ml of the patient’s own blood, and injected under ultrasound monitoring (SSD-650C, Aloka, Tokyo, Japan). The findings of DSA and USAG were evaluated by two of the authors independently. On DSA, the presence of tumor stain was evaluated and tumors were classified into positive and negative staining. Tumors where the size of tumor stain was smaller than the size of tumor estimated by ultrasonography, indicating
1056
heterogeneity of vascularity within the tumor, were defined as having positive staining. On USAG, stronger enhancement of the tumor than of the surrounding liver was defined as positive enhancement. The enhancement of part of a tumor was classified as positive enhancement. The enhancement of a tumor to the same degree as the surrounding liver or lack of enhancement was defined as negative enhancement. Liver biopsy and percutaneous ethanol injection therapy (PEIT/PEI) Fine-needle biopsies were performed using a 21G biopsy needle (Top, Tokyo, Japan) under ultrasonographic guidance (SSDdSOCL, Aloka, Tokyo, Japan), prior to the start of the therapy (before the initial treatment session), and the diagnosis of HCC was confirmed. The lesions were biopsied twice and two specimens were obtained from each tumor. These specimens were assessed blind to source by two of the authors independently, and classified according to differentiation. Well-differentiated HCC is composed of the components of the Edmondson-Steiner criteria 1 (EGl) (26) only or EGl with partial EG2 (less than 50%) and moderately differentiated HCC is composed mostly of components of EG2. If there was discrepancy in differentiation between the two biopsied specimens, indicating heterogeneity of differentiation within the tumor, the tumor was classified into the lower grade differentiation category. We had no cases with poorly differentiated tumor. PEIT/PEI were performed under ultrasonographic guidance (SSD-650CL, Aloka, Tokyo, Japan). In one treatment session, 2-5 ml of 99.5% absolute ethanol was injected into the tumor. This injection was repeated twice a week for up to 6-10 sessions. The total volume of injected ethanol ranged from 20 to 55 ml. The end point of treatment was determined according to the posttreatment dynamic-enhanced computed tomography (CT). Usually the standard for the completion of the treatment was the presence of a necrotic low-density area in the site of the enhanced tumor on pretreatment dynamic-enhanced CT and the undetectability of tumor enhancement on the early phase of dynamic-enhanced CT. If HCC had not been enhanced by pretreatment dynamic-enhanced CT, the presence of a necrotic low density area larger than the defect of portal perfusion which had been detected on the late phase of pretreatment dynamic-enhanced CT was defined as the endpoint of the therapy. Follow-up after treatment and treatment for recurrence The patients were followed up regularly for the detection of recurrence by ultrasonography every other
Vascularity of smaN HCC treated by PEIT
month and dynamic-enhanced CT every 6 months. Recurrences were diagnosed when detected by ultrasonography or CT and identified by biopsy and/or imaging findings. Recurrent HCC was classified as local recurrence or multicentric occurrences. Local recurrence was defined as recurrent tumor in the same subsegment, and multicentric occurrence was defined as recurrence in the other segment. Treatment for recurrent HCC was selected in considering the characteristics of the tumor, reserve liver function, and/or the general condition of the patient. Usually PEIT/PEI was performed for HCC less than 2 cm in diameter or for HCC without tumor stain. Transcatheter arterial embolization (TAE) was performed for HCC larger than 2 cm and with tumor stain. We analyzed the survival of these patients according to the tumor staining on DSA or the enhancement on USAG, and estimated the effects of these factors on their prognosis. The date of the last injection in PEIT/ PEI was the starting point for the calculations. Patients who survived and patients who died from diseases other than liver disease and/or liver failure which had not been caused by HCC were defined as censored cases. Patients who died from HCC, including liver failure caused by HCC and/or metastasis from HCC, were defined as non-censored cases. The Kaplan-Meier method (27) was used to calculate survival rate, and the generalized Wilcoxon test (28) was used for statistical analysis. Multivariate analysis using a Cox proportional hazard regression model was also performed for the factors affecting long-term prognosis. The ttest and the chi-square test were used for the analysis of patients’ clinical characteristics. A probability of pcO.05 was considered statistically significant. Written informed consent was obtained from all patients after each was adequately informed of the aims and methods of the study, before each procedure. Results Of 54 patients, 24 patients had HCC with positive staining on DSA and the other 30 patients had HCC with negative staining. Thirty-eight patients had HCC with positive enhancement on USAG, including all HCC with positive staining on DSA, and 16 patients had HCC with negative enhancement. Pathologically, 30 patients had well-differentiated HCC and 24 patients had moderately differentiated HCC. Table 1 shows some of the clinical characteristics of the patients with HCC with positive and negative staining on DSA. There were no significant differences between these two groups in terms of age, sex, etiology, and liver function. The positive/negative staining was significantly related to the degree of the differentiation of
TABLE 1 Backgrounds of patients and presence/absence of tumor staining on digital subtraction angiography (DSA) Backgrounds
HCC with positive staining
HCC with negative staining
Sex (M/F) Age (years; mean?SD) Viral infection (HBV/HCV/none)* Total bilirubin (mg/dl; meantSD) Albumin (g/d]; mea&SD) Prothrombin time (%; mean? SD) ICGRIs (%; mean?SD) Child-Pugh classification (A/B/C) Ascites (+/-) Esophageal varices (+/-) Alpha-fetoprotein (ngml; meantSD) Tumor size (mm; mean *SD) Differentiation (well/moderately)
15/9 60.927.6 411812
18112 63.427.1 5/25/o
NS NS NS
1.3621.11
0.98kO.54
NS
3.1320.54
3.2820.52
NS
70.72 18.3
78.32 14.4
NS
25.4% 16.4 6/l 315
27.05 17.4 12/14/4
NS NS
5119 14/10 147.22240.3
4126 12/18 40.5258.0
NS NS p=O.O225
14.423.9
12.9k3.0
NS
8/16
2218
p=o.o077
* HBV; Hepatitis B virus, HCV, Hepatitis C virus.
the tumor (p=O.O077) and the level of alpha fetoprotein (p=O.O225). Similarly there were no significant differences between groups of positive and negative enhancement on USAG, except for the differentiation. All HCC in the USAG negative enhancement group were well differentiated. Survival rate according to tumor staining on DSA The patients were observed for 199 to 2074 days. The survival rates, compared according to positive and negative staining on DSA, are shown in Fig. 1. The 3and .5-year survival rates were 48.7 and 34.1%, respectively, in patients with positive staining HCC, and 89.7 and 69.7%, respectively, in patients with negative staining HCC. The prognosis tended to be better in patients with negative staining HCC, though the difference was not statistically significant @=0.0723). Survival rate according to enhancement on USAG The survival rate was compared between HCC with positive enhancement on USAG and HCC with negative enhancement (Fig. 2). The 3- and 5-year survival rates were 48.6 and 36.7%, respectively, in patients with positive enhancement HCC, and both rates were 85.7% (maximum observation period 1946 days) in patients with negative enhancement HCC. The survival rate of patients with negative enhancement HCC was significantly superior to that of patients with positive en1057
H. Toyodu et al.
c :..1....._.........__-.________ I 10 0
0
I
I
I
I
1
2
3
4
1: 5
I
6
(year4
Survival Time in Years
Survival Time in Years
Fig. I. Survival rate in patients according to vascularity evaluated by digital subtraction angiography (DSA). The survival rate in patients with negative staining HCC was higher than that in patients with positive staining HCC (p= 0.0723). -: survival rate inpatients with negative staining HCC on DSA . . .. . . . survival rate in patients with positive staining HCC on DSA.
Fig. 3. Survival rate in patients with well-differentiated HCC (n=30), according to the vasctdarity evaluated by ultrasound angiography with intraarterial CO2 microbubbles (USAG). The survival rate in patients with HCC with negative enhancement on WAG was signtjicantly higher than that in patients with HCC with positive enhancement (p=O.O048). -: survival rate in patients with HCC with negative enhancement on USAG . . .. . . . survival rate in patients with HCC with positive enhancement on USAG.
(W 100 90
3
80
22
70
cz; E 8
40
f
30
a
20 IO
0
0
1
2
3
4
5
6
(ye=)
2 I?
Survival Time in Years
Fig. 2. Survival rate in patients according to the vascularity evaluated by ultrasound angiography with intraarterial CO2 microbubbles (USAG). The survival rate in patients with HCC with negative enhancement on WAG was sign@ cantly higher than that in patients with HCC with positive enhancement (p=O.O231). -: survival rate in patients with HCC with negative enhancement on WAG. . . . .. . . survival rate tn patients with HCC with positive enhancement on USAG.
L....L....L....l... 20.
L.1
20.
0
1
2
3
5
4
6
(Y=W
Survival Time in Years
Fig. 4. Survival rate in patients according to the dfferentiation. The survival rate were similar between patients with well-dtfferentiated HCC and patients with moderately-dtfferentiated HCC (p=O.9034). -: survival rate inpatients with well-dtfferentiated HCC . . . .. . . survival rate in patients with moderately-dtfferentiated HCC.
hancement HCC (p=O.O231). This difference in prognosis was emphasized when focusing on the patients with well-differentiated HCC (n= 30; 16 with negative enhancement HCC and 14 with positive enhancement HCC, p=O.O048; Fig. 3).
and 54.8%, respectively, in patients with well-differentiated HCC. The difference, between these two groups was not significant (p=O.9034).
Survival
Results of the multivariate analysis are shown in Table 2. When vascularity was evaluated by DSA, it was the only significant factor affecting the prognosis (p= 0.0091); differentiation of the tumor and progression of cirrhosis (Child-Pugh classification) were other im-
rate according
to dtyferentiation
of tumor
Fig. 4 shows the comparison of survival rate according to the differentiation of the tumor. The 3- and 5-year survival rates were 61.5 and 46.1%, respectively, in patients with moderately differentiated HCC, and 75.1 10558
Multivariate analysis for the factors term prognosis
affecting
the long-
Vascularity of small HCC treated by PEIT
portant factors, but they were not statistically significant. When vascularity was evaluated by USAG, vascularity was also the only significant factor affecting the prognosis (p=O.O286), and differentiation was the other important factor. Recurrence
after PEIT/PEI
In 31 of 54 patients (S7.4%), recurrences were observed. Recurrences were observed twice in 10 patients, three times in seven patients, and four times in three patients. Of 31 first recurrences, 20 were local recurrences and 11 were multicentric occurrences. Fig. 5 shows the comparison of the local recurrence rate between HCC with positive staining on DSA and HCC with negative staining, and between HCC with positive enhancement on USAG and HCC with negative enhancement. The local recurrence rate in patients with positive staining HCC on DSA tended to be higher than that in patients with negative staining HCC, though the difference was not statistically significant @=0.2218). The local recurrence rate in patients with positive enhancement HCC on USAG was significantly higher than that in patients with negative enhancement HCC (p=O.O438). On the other hand, rates of multicentric occurrence were similar between patients with positive staining HCC on DSA and patients with negative staining HCC @=0.5002), and between patients with positive enhancement HCC on USAG and patients with negative enhancement HCC @=0.3202) (Fig. 6). The local recurrence rate depended on the vascularity of the primary HCC, while the rate of multicentric occurrence did not. Retreatment for the recurrence was performed once in 11 patients, twice in ten patients, 3 times in seven patients and 4 times in three patients after the initial PEIT/PEI. Recurrences were treated with PEIT/PEI in 41 cases and TAE in 23 cases, TAE was performed 13
TABLE 2 Multivariate analysis for factors affecting prognosis portional hazard regression model) Factors
Age Viral infection IcG~ts
Child-Pugh classification Alpha-fetoprotein Tmor size Differentiation Vascularity of tumor
(Cox pro-
p value DSA*
USAG**
0.1176 0.8456 0.1947 0.0509 0.5113 0.5329 0.0732 0.0091
0.4643 0.8116 0.3181 0.1724 0.8655 0.9158 0.0573 0.0286
* Vascularity was evaluated by digital subtraction angiography, and ** by ultrasound angiography with CO2 microbubbles.
2
3
4
5
6
w=w
Survival Time in Years
0
1
2
3
4
5
6
(ye=)
Survival Time in Years Fig. 5. Local recurrence rate of the patients according to the vascularity: A) evaluated by digital subtraction angiography (DSA) and B) evaluated by ultrasound angiography with intraarterial CO, microbubbles (WAG). A) The local recurrence rate in patients with positive staining HCC tended to be higher than that ofpatients with negative staining HCC (p=O.2218). -: local recurrence rate of patients with negative staining HCC on DSA . .. . . . . local recurrence rate of patients with positive staining HCC; CC on DSA. The I- and 3-year local recurrence rates were 16.9 and 61.6%, respectively, in patients with positive staining HCC, and 10.2 and 33.4%, respectively, in patients with negative staining HCC. B) The local recurrence rate in patients with positive enhancement HCC was significantly higher than that of patients with negative enhancement HCC (p=O.O438). -: local recurrence rate of patients with negative enhancement HCC on USAG: . . . .. . . local recurrence rate of patients with positive enhancement HCC on WAG. The l- and 3 year local recurrence rates were 16.2 and .59.8%, respectively, in patients with positive enhancement HCC, and 6.3 and 13.0%, respectively, in patients with negative enhancement HCC.
times for recurrence in patients with positive staining HCC on DSA and 10 times in patients with negative staining HCC, including 5 times in patients with negative enhancement HCC on USAG. 1059
H. Tayodu et al.
1
2
3
4
5
6
W=l
5
6
ww
Survival Time in Years
“0
1
2
3
4
Survival Time in Years
Fig. 6. The rate of multicentric occurrence in patients according to vascularity: A) evaluated by digital subtraction angiography (DSA) and B) evaluated by ultrasound angiography with intraarterial CO, microbubbles (USAG). The rates were similar between patients with positive staining HCC on DSA and patients with negative staining HCC (p=O.5002), and between patients with positive enhancement HCC on USAG and patients with negative enhancement HCC (p=O.3202). A) -: the rate of multicentric occurrence in patients with negative staining HCC on DSA. ......: the rate of multicentric occurrence in patients with positive staining HCC on DSA. B) -: the rate of multicentric occurrence in patients with negative enhancement HCC on USAG. . . .. . . . the rate of multicentric occurrence in patients with positive enhancement HCC on USAG.
Discussion HCC is usually a hypervascular tumor; it is considered to be caused by angiogenesis. This characteristic is reflected in angiographic findings such as tumor staining on DSA or enhancement on USAG (2,19,20,29,30). However, the vascularity can vary even if tumors are the same size or have the same degree of differentiation (31), and small HCCs with a diameter of 5 cm or less do not always reveal a hypervascular stain (1,18-22). In HCCs with a diameter of 2 cm or less, about half have been reported to lack a tumor stain on DSA (32). In some small HCCs, the sinusoidal endothelial cells 1060
still do not have the morphology of capillaries (33). Well-differentiated HCCs (2 1,34), and sometimes moderately differentiated HCCs (33) may be non-hypervascular. We evaluated the importance of tumor vascularity in predicting the long-term prognosis of patients with small HCC treated by PEIT/PEI. When HCC is treated by surgery, tumor size is considered to be an important prognostic factor for HCC (g-lo), and the prognosis is reported to be good when the diameter is less than 2 cm (8). HCC differentiation is also considered to be a prognostic factor (11,12). However, we do not have enough information about the predictors of the prognosis of patients with small HCC treated by PEIT/PEI. In this study we also compared the significance of differentiation and vascularity as predictors of long-term prognosis. Tumor vascularity can be estimated clinically by imaging techniques such as angiography. Staining and/or enhancement of the tumor by angiography showed hypervascularity (2,19,20,29,30). We observed a better survival rate in patients with non-hypervascular HCC (negative-staining HCC on DSA or negative-enhancement HCC on USAG) than in patients with hypervascular HCC (positive-staining HCC on DSA or positive-enhancement HCC on USAG). This difference was more significant when the vascularity of HCC was evaluated by USAG. Though the stain on DSA reflects the hypervascularity of HCC, its resolution capability may not be sufficient to demonstrate hypervascularity. USAG can easily be performed with ultrasound apparatus and COz, and is useful for detecting very slight increases in arterial blood supply, which often cannot be detected by DSA (24). In our study USAG detected the hypervascularity of HCC in 38 patients, including all patients with HCC with positive staining on DSA, while DSA detected hypervascularity in 24 patients. Thus, USAG is more sensitive in detecting the progression of hypervascularity in HCC than conventional angiography or DSA, and can identify non-hypervascular HCC strictly. The survival rate in patients with negative enhancement HCC on USAG shows the survival rate in patients with truly non-hypervascular HCC. Although the vascularity of small HCCs was related to their differentiation (p=O.O077, Table 2), the survival rate in non-hypervascular HCC was observed to be superior even in comparisons confined to well-differentiated HCCs when evaluation was by USAG. Vascularity can predict prognosis, independent of differentiation, as also shown by multivariate analysis. In the evaluation of surgically treated HCC, the differentiation of the tumor (11,12) is reported to be one of the prognostic factors, and the prognosis is considered
Vascularity of small HCC treated by PEIT
be better when Edmondson’s classification of the HCC is lower (8). In the present study we did not observe a difference in survival rate between well-differentiated and moderately differentiated HCC. We think this is partly because the specimens were obtained by fine-needle biopsy, rather than by surgical resection. We evaluated the differentiation from biopsied specimens, which might represent the differentiation of only localized parts of the whole tumor. Therefore there could be over- or underestimation of the differentiation in some HCC specimens evaluated from fine-needle bito
opsy. With regard to recurrences, the local recurrence rate was higher in patients with positive staining HCC on DSA or with positive enhancement HCC on USAG than in patients with negative staining HCC on DSA or with negative enhancement HCC on USAG, while there was no difference in the rate of multicentric occurrence. The high rate of local recurrence may suggest the possible presence of “occult” (undetectable by imaging technique) intrahepatic metastasis at the time of initial treatment (PEIT/PEI), in patients with positive staining HCC on DSA or with positive enhancement HCC on USAG. In conclusion, clinically evaluated tumor vascularity is a significant predictor of long-term prognosis in patients with small HCC, especially evaluated by USAG. In the treatment with PEIT/PEI, it is difficult to obtain the whole HCC specimen and less pathological information is obtained than at surgical treatment. Vascularity can be considered as a marker of the biological grade .of malignancy Clinical evaluation of tumor vascularity prior to therapy will assist prediction of the prognosis in patients with HCC treated with PEI/PEIT Non-hypervascularity may indicate a better prognosis in patients with small HCCs.
References 1. Shinagawa T, Ohto M, Kimura K, Tsunetomi S, Morita M, Saisho H, Tsuchiya Y, Saotome N, Karasawa E, Miki M, Ueno T, Okuda K. Diagnosis and clinical features of small hepatocellular carcinoma with emphasis on the utility of realtime ultrasonography. A study in 51 patients. Gastroenterology 1984,86: 495502. 2. Okuda K. Early detection of hepatocellular carcinoma. Hepatology 1986; 6: 729-38. 3. Ebara M, Ohto M, Shinagawa T, Sugiura N, Kimura K, Matsutani S, Morita M, Saisho H, Tsuchiya Y, Okuda K. Natural history of minute hepatoeellular carcinoma smaller than three centimeters complicating cirrhosis. A study in 22 patients. Gastroenterology 1986; 90: 289-98. 4. Livraghi T, Salmi A, Bolondi L, Martin G, Arienti V, Monti F, Vettori C. Small hepatocellular carcinoma: percutaneous alchohol injection - results in 23 patients. Radiology 1988; 168: 313. 5. Shiina S, Tagawa K, Unuma T, Fujino H, Uta Y, Niwa Y,
6.
7.
8.
9.
10.
11.
12.
13.
14. 15. 16. 17. 18.
19.
20.
21.
Hata Y, Komatsu Y, Yasushi S, Terano A, Sugimoto T. Percutaneous ethanol injection therapy of hepatocellular carcinoma: analysis of 77 patients. Am J Roentogenol 1990; 155: 1221-6. Ehara M, Ohto M, Sugiura N, Kita K, Yoshikawa M, Okuda K, Kondo E Kondo Y. Percutaneous ethanol injection for the treatment of small hepatocellular carcinoma: study of 95 patients. J Gastroenterol Hepatol 1990; 5: 616-26. Castells A, Bruix J, Bru C, Fuster J, Vilana R, Navasa M, Ayuso C, Boix L, Visa J, Rodes J. Treatment of small hepatocellular carcinoma in cirrhotic patients: a cohort study comparing surgical resection and percutaneous ethanol injection. Hepatology 1993; 18: 11216. Haratake J, Takeda S, Kasai T, Nakano S, Tokui N. Predictable factors for estimating prognosis of patients after resection of hepatocellular carcinoma. Cancer 1993; 72: 1178-83. Sugioka A, Tsuzuki T, Kanai T. Postresection prognosis of patients with hepatocellular carcinoma. Surgery 1993; 113: 612-8. Arii S, Tanaka J, Yamazoe Y, Minematsu S, Morino T, Fujita K, Maetani S, Tobe T. Predictive factors for intrahepatic recurrence of hepatocellular carcinoma after partial hepatectomy. Cancer 1992; 69: 913-9. Kitamoto M, Nakanishi T, Kira S, Kawaguchi M, Nakashio R, Suemori S, Kajiyama G, Asahara T, Dohi K. The assessment of proliferating cell nuclear antigen immunohistochemical staining in small hepatocellular carcinoma and its relationship to histologic characteristics and prognosis. Cancer 1993; 72: 1859965. Kanai T, Hirohashi S, Upton ME Noguchi M, Kishi K, Makuuchi M, Yamasaki S, Hasegawa H, Takayasu K, Moriyama N, Shimosato Y. Pathology of small hepatocellular carcinoma: a proposal for a new gross classification. Cancer 1987; 60: 810-9. Okuda K, Obata H, Jinnouchi S, Kubo Y, Nagasaki Y, Shimokawa Y, Motoike Y, Muto H, Nakajima Y, Musha H, Yamazaki T, Sakamoto K, Kojiro M, Nakashima T Angiographic assessment of gross anatomy of hepatocellular carcinoma: comparison of celiac angiograms and liver pathology in 100 cases. Radiology 1977; 123: 21-9. Cooper JN. Imaging and hepatocellular carcinoma. Gastroenter01 Clin North Am 1987; 16: 591-602. Boijsen E, Abrams HL. Roentgenographic diagnosis of primary carcinoma of liver. Acta Radio1 1965; 3: 257-77. Reuter SR, Redman HC, Siders DB. The spectrum of angiographic findings in hepatoma. Radiology 1970; 94: 89-94, Chuang VP Hepatic tumor angiography. A subject review. Radiology 1983; 148: 633-9. Chen DS, Sheu JC, Sung JL, Lai MY, Lee CS, Su CT, Tsang YM, How SW, Wang TH, Yu JY, Yang TH, Wang CY, Hsu CY. Small hepatocellular carcinoma - a clinicopathological study in thirteen patients. Gastroenterology 1982; 83: 110919. Takayasu K, Shima Y, Muramatsu Y, Goto H, Moriyama N, Yamada T, Makuuchi M, Yamasaki S, Hasegawa H, Okazaki N, Hirohashi S, Kishi K. Angiography of small hepatocellular carcinomas: analysis of 105 resected tumors. Am J Roentogenol 1986; 147: 525-9. Sumida M, Ohto M, Ebara M, Kimura K, Okuda K, Hirooka N. Accuracy of angiography in the diagnosis of small hepatocellular carcinoma. Am J Roentogenol1986; 147: 5316. Sonoda T, Shirabe K, Takenaka K, Kanematsu T, Yasumori
1061
H. Toyoda et al.
22.
23.
24.
25.
26.
27. 28.
K, Sugimachi K. Angiographically undetected small hepatocellular carcinoma: clinicopathological characteristics, follow-up and treatment. Hepatology 1989; 10: 1003-7. Ikeda K, Saitoh S, Koida I, Tsubota A, Arase Y, Chayama K, Kumada H. Diagnosis and follow-up of small hepatocellular carcinoma with selective intraarterial digital subtraction angiography. Hepatology 1993; 17: 1003-7. Matsuda Y, Yabuuchi I. Hepatic tumors: US contrast enhancement with CO2 microbubbles. Radiology 1986; 6: 72938. Kudo M, Tomita S, Tochio H, Mimura J, Okabe Y, Kashida H, Hirasa M, Ibuki Y, Todo A. Small hepatocellular carcinoma: diagnosis with US angiography with intraarterial CO2 microbubbles. Radiology 1992; 182: 155-60. Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973; 60: 646-9. Edmondson HA, Steiner PE. Primary carcinoma of the liver. A study of 100 cases among 48,900 necropsies. Cancer 1954; 7: 462-503. Kaplan EL, Meier I? Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457-81. Gehan E. A generalized Wilcoxon test for comparing arbitrarily singly-censored samples. Biometrika 1965; 52: 203-23.
IO62
29. Honda H, Ochiai K, Adachi E, Yasumori K, Hayashi T, Kawashima A, Fukuya T, Gibo M, Matsumata T, Tsuneyoshi M, Masuda K. Hepatocellular carcinoma: correlation of CT, angiographic, and histopathologic findings. Radiology 1993; 189: 857-62. 30. Takashima T, Matsui 0. Infusion hepatic angiography in the detection of small hepatocellular carcinomas. Radiology 1980; 136: 321-5. 31. Trevisani F, Caraceni P, Bernardi M, D’Intino PE, Arienti V, Amorati P Stefanini GE Grazi G, Mazziotti A, Fornale L, Gozzetti G, Gasbarrini G. Gross pathologic types of hepatocellular carcinoma in Italian patients: relationship with demographic, environmental, and clinical factors. Cancer 1993; 72: 1557-63. 32. Ikeda K, Saitoh S, Koida I, Tsubota A, Arase Y, Chayama K, Kumada H. Imaging diagnosis of small hepatocellular carcinoma. Hepatology 1994; 20: 82-7. 33. Kin M, Torimura T, Ueno T, Inuzuka S, Tanikawa K. Sinusoidal capillarization in small hepatocellular carcinoma. Path01 Int 1994; 44: 771-8. 34. Yoshimatsu S, Inoue Y, Ibukuro K, Suzuki S. Hypovascular hepatocellular carcinoma undetected at angiography and CT with iodized oil. Radiology 1989; 171: 343-7.
Copyright 8 European Association for the Study 01 the Liver 1997
Journalof Hepatology ISSN 0168-8278
Significance of tumor vascularity as a predictor of long-term prognosis in patients with small hepatocellular carcinoma treated by percutanaus ethanol injection therapy Hidenori
Toyoda, Takashi Kumuda, Department
Satoshi Nakano, Isao Takeda, Keiichi Sugiyama, Yasuhiro Sone of Gastroenterology,
Ogaki Municipal
Hospital,
Seiki Kiriyama
and
Ogaki, Japan
BackgroundAims: We estimated the significance of the vascularity of small hepatocelhdar carcinoma (HCC) as a predictor of long-term prognosis in patients treated with percutaneous ethanol injection therapy (PEIT/PEI). Metk&: Fifty-four patients who have been followedup in our hospital and who had HCC less than 20 mm in diameter were observed for 199 to 2074 days. Hepatic angiography (digital subtraction angiography; DSA and ultrasound angiography with intraarterial CO* microbubbles; USAG) was performed before treatment in all cases, and the vascularity of the tumor was clinically evaluated. The survival rate was analyzed according to this vascular@ Results: Of the 54 tumors, 24 had tumor stain on
DSA, while 30 did not, and 38 showed enhancement on USAG, while 16 did not. The 3- and 5-year survival rates were 48.7 and 34.1% of patients with positive staining HCC on DSA, and 89.7 and 69.7% of patients with negative staining HCC (p=O.O723). The rates were 48.6 and 36.7%, respectively, of patients with positive enhancement HCC on USAG, and both rates were 85.7% of patients with negative enhancement HCC (p=O.O231). Con&&~ Tumor vascularity will play a role in the long-term prognosis of these patients with small HCC when they are treated with PEIT/PEI.
R
important prognostic factors in patients with advanced HCC, the characteristics of HCC itself are thought to be more important in the long-term prognosis of patients with small HCC. The importance of the characteristics of HCC as a prognostic factor will be increased in patients treated with PEIT/PEI, because this treatment usually does not accompany the rapid impairment of liver function. The size (8-10) and the differentiation of HCC (11,12) are reported to be important prognostic factors for HCC treated by surgery. However, we do not yet have enough information about the predictors of longterm prognosis of patients with small HCC, especially when they are treated by PEIT/PEI. HCC is usually found to be hypervascular on angiography (13-17), but some small HCCs do not reveal a hypervascular stain (1,18-22). This is considered to be one of the characteristics of early-stage HCC. Thus the vascularity varies in small HCC. In this retrospective study we estimated the importance of the radiologi-
PROGRESS in the development of various scanning techniques has made it possible to detect small hepatocellular carcinoma (HCC) (l-3). However, the surgical resectability of HCC remains low, even when the HCC is found at an early stage, because most patients with HCC have underlying cirrhosis, which often precludes hepatectomy. Percutaneous ethanol injection therapy (PEIT/PEI) has been shown to be effective as an option for treatment of HCC (4,5), and also for small HCC (6). The reported survival of patients with small HCC treated with this technique was comparable to that of patients treated with surgical resection (7). While the reserve liver function will be one of the ECENT
Received 13 August; revised 15 November; accepted 21 November 1996
Correspondence: Takashi Kumuda, Department of Gastroenterology, Ogaki Municipal Hospital, 4-86 Minaminokawa, Ogaki, Gifu, 503 Japan. Tel. 81-584-81-3341. Fax. 81-584-75-5715.
Key words: Percutaneous ethanol injection therapy; Prognosis; Small HCC; Vascularity.
1055
H. Toyoda et al.
tally evaluated vascularity of HCC as a predictor of long-term prognosis in patients with small hepatocellular carcinoma treated by PEIT/PEI.
Patients and Methods Patients studied Between 1989 and 1995, 143 patients with liver cirrhosis, who had been followed up regularly at our hospital, were diagnosed as having an HCC less than 20 mm in diameter. Of these 143 patients, we selected 54 patients who had been treated with PEIT/PEI for this retrospective study. They were selected on the following criteria: 1) they had solitary HCC; 2) they had had no history of HCC (not a recurrence); 3) hepatic angiography including digital subtraction angiography (DSA) and ultrasound angiography with intraarterial COZ microbubbles (USAG) (23,24) had been performed before treatment; 4) a tumor specimen had been obtained by fine-needle biopsy under ultrasonographic guidance prior to the treatment; and 5) they had been followed up for more than 100 days after treatment. The patients consisted of 33 men and 21 women, with a mean age of 62.3 (48-79) years. All patients had liver cirrhosis. According to the Child-Pugh classification (25) 18 were in class A, 27 were in class B, and nine were in class C. All HCC were initially detected by plain ultrasonography. Pretreatment angiographic evaluation The hepatic angiography was performed before any treatment or biopsy. Selective hepatic intra-arterial DSA was carried out using a DSA apparatus (2050; Toshiba, Tokyo, Japan) with a 0.8-mm focal spot, a 1Zinch diameter image intensifier and a 1024~ 1024 matrix. Between 15 and 20 ml of the contrast material, Omnipaque (Nycomed AS, Oslo, Norway) was injected from the tip of a catheter inserted into the hepatic artery (either the proper, right, or left hepatic artery), at an injection rate of 5 to 7 ml/s. We always examined each of the hepatic arteries, including the accessory or replaced hepatic arteries. USAG were performed by injecting CO2 microbubbles through a catheter placed in the hepatic artery. CO2 microbubbles were prepared by vigorously mixing 10 ml of CO2 and 5 ml of the patient’s own blood, and injected under ultrasound monitoring (SSD-650C, Aloka, Tokyo, Japan). The findings of DSA and USAG were evaluated by two of the authors independently. On DSA, the presence of tumor stain was evaluated and tumors were classified into positive and negative staining. Tumors where the size of tumor stain was smaller than the size of tumor estimated by ultrasonography, indicating
1056
heterogeneity of vascularity within the tumor, were defined as having positive staining. On USAG, stronger enhancement of the tumor than of the surrounding liver was defined as positive enhancement. The enhancement of part of a tumor was classified as positive enhancement. The enhancement of a tumor to the same degree as the surrounding liver or lack of enhancement was defined as negative enhancement. Liver biopsy and percutaneous ethanol injection therapy (PEIT/PEI) Fine-needle biopsies were performed using a 21G biopsy needle (Top, Tokyo, Japan) under ultrasonographic guidance (SSDdSOCL, Aloka, Tokyo, Japan), prior to the start of the therapy (before the initial treatment session), and the diagnosis of HCC was confirmed. The lesions were biopsied twice and two specimens were obtained from each tumor. These specimens were assessed blind to source by two of the authors independently, and classified according to differentiation. Well-differentiated HCC is composed of the components of the Edmondson-Steiner criteria 1 (EGl) (26) only or EGl with partial EG2 (less than 50%) and moderately differentiated HCC is composed mostly of components of EG2. If there was discrepancy in differentiation between the two biopsied specimens, indicating heterogeneity of differentiation within the tumor, the tumor was classified into the lower grade differentiation category. We had no cases with poorly differentiated tumor. PEIT/PEI were performed under ultrasonographic guidance (SSD-650CL, Aloka, Tokyo, Japan). In one treatment session, 2-5 ml of 99.5% absolute ethanol was injected into the tumor. This injection was repeated twice a week for up to 6-10 sessions. The total volume of injected ethanol ranged from 20 to 55 ml. The end point of treatment was determined according to the posttreatment dynamic-enhanced computed tomography (CT). Usually the standard for the completion of the treatment was the presence of a necrotic low-density area in the site of the enhanced tumor on pretreatment dynamic-enhanced CT and the undetectability of tumor enhancement on the early phase of dynamic-enhanced CT. If HCC had not been enhanced by pretreatment dynamic-enhanced CT, the presence of a necrotic low density area larger than the defect of portal perfusion which had been detected on the late phase of pretreatment dynamic-enhanced CT was defined as the endpoint of the therapy. Follow-up after treatment and treatment for recurrence The patients were followed up regularly for the detection of recurrence by ultrasonography every other
Vascularity of smaN HCC treated by PEIT
month and dynamic-enhanced CT every 6 months. Recurrences were diagnosed when detected by ultrasonography or CT and identified by biopsy and/or imaging findings. Recurrent HCC was classified as local recurrence or multicentric occurrences. Local recurrence was defined as recurrent tumor in the same subsegment, and multicentric occurrence was defined as recurrence in the other segment. Treatment for recurrent HCC was selected in considering the characteristics of the tumor, reserve liver function, and/or the general condition of the patient. Usually PEIT/PEI was performed for HCC less than 2 cm in diameter or for HCC without tumor stain. Transcatheter arterial embolization (TAE) was performed for HCC larger than 2 cm and with tumor stain. We analyzed the survival of these patients according to the tumor staining on DSA or the enhancement on USAG, and estimated the effects of these factors on their prognosis. The date of the last injection in PEIT/ PEI was the starting point for the calculations. Patients who survived and patients who died from diseases other than liver disease and/or liver failure which had not been caused by HCC were defined as censored cases. Patients who died from HCC, including liver failure caused by HCC and/or metastasis from HCC, were defined as non-censored cases. The Kaplan-Meier method (27) was used to calculate survival rate, and the generalized Wilcoxon test (28) was used for statistical analysis. Multivariate analysis using a Cox proportional hazard regression model was also performed for the factors affecting long-term prognosis. The ttest and the chi-square test were used for the analysis of patients’ clinical characteristics. A probability of pcO.05 was considered statistically significant. Written informed consent was obtained from all patients after each was adequately informed of the aims and methods of the study, before each procedure. Results Of 54 patients, 24 patients had HCC with positive staining on DSA and the other 30 patients had HCC with negative staining. Thirty-eight patients had HCC with positive enhancement on USAG, including all HCC with positive staining on DSA, and 16 patients had HCC with negative enhancement. Pathologically, 30 patients had well-differentiated HCC and 24 patients had moderately differentiated HCC. Table 1 shows some of the clinical characteristics of the patients with HCC with positive and negative staining on DSA. There were no significant differences between these two groups in terms of age, sex, etiology, and liver function. The positive/negative staining was significantly related to the degree of the differentiation of
TABLE 1 Backgrounds of patients and presence/absence of tumor staining on digital subtraction angiography (DSA) Backgrounds
HCC with positive staining
HCC with negative staining
Sex (M/F) Age (years; mean?SD) Viral infection (HBV/HCV/none)* Total bilirubin (mg/dl; meantSD) Albumin (g/d]; mea&SD) Prothrombin time (%; mean? SD) ICGRIs (%; mean?SD) Child-Pugh classification (A/B/C) Ascites (+/-) Esophageal varices (+/-) Alpha-fetoprotein (ngml; meantSD) Tumor size (mm; mean *SD) Differentiation (well/moderately)
15/9 60.927.6 411812
18112 63.427.1 5/25/o
NS NS NS
1.3621.11
0.98kO.54
NS
3.1320.54
3.2820.52
NS
70.72 18.3
78.32 14.4
NS
25.4% 16.4 6/l 315
27.05 17.4 12/14/4
NS NS
5119 14/10 147.22240.3
4126 12/18 40.5258.0
NS NS p=O.O225
14.423.9
12.9k3.0
NS
8/16
2218
p=o.o077
* HBV; Hepatitis B virus, HCV, Hepatitis C virus.
the tumor (p=O.O077) and the level of alpha fetoprotein (p=O.O225). Similarly there were no significant differences between groups of positive and negative enhancement on USAG, except for the differentiation. All HCC in the USAG negative enhancement group were well differentiated. Survival rate according to tumor staining on DSA The patients were observed for 199 to 2074 days. The survival rates, compared according to positive and negative staining on DSA, are shown in Fig. 1. The 3and .5-year survival rates were 48.7 and 34.1%, respectively, in patients with positive staining HCC, and 89.7 and 69.7%, respectively, in patients with negative staining HCC. The prognosis tended to be better in patients with negative staining HCC, though the difference was not statistically significant @=0.0723). Survival rate according to enhancement on USAG The survival rate was compared between HCC with positive enhancement on USAG and HCC with negative enhancement (Fig. 2). The 3- and 5-year survival rates were 48.6 and 36.7%, respectively, in patients with positive enhancement HCC, and both rates were 85.7% (maximum observation period 1946 days) in patients with negative enhancement HCC. The survival rate of patients with negative enhancement HCC was significantly superior to that of patients with positive en1057
H. Toyodu et al.
c :..1....._.........__-.________ I 10 0
0
I
I
I
I
1
2
3
4
1: 5
I
6
(year4
Survival Time in Years
Survival Time in Years
Fig. I. Survival rate in patients according to vascularity evaluated by digital subtraction angiography (DSA). The survival rate in patients with negative staining HCC was higher than that in patients with positive staining HCC (p= 0.0723). -: survival rate inpatients with negative staining HCC on DSA . . .. . . . survival rate in patients with positive staining HCC on DSA.
Fig. 3. Survival rate in patients with well-differentiated HCC (n=30), according to the vasctdarity evaluated by ultrasound angiography with intraarterial CO2 microbubbles (USAG). The survival rate in patients with HCC with negative enhancement on WAG was signtjicantly higher than that in patients with HCC with positive enhancement (p=O.O048). -: survival rate in patients with HCC with negative enhancement on USAG . . .. . . . survival rate in patients with HCC with positive enhancement on USAG.
(W 100 90
3
80
22
70
cz; E 8
40
f
30
a
20 IO
0
0
1
2
3
4
5
6
(ye=)
2 I?
Survival Time in Years
Fig. 2. Survival rate in patients according to the vascularity evaluated by ultrasound angiography with intraarterial CO2 microbubbles (USAG). The survival rate in patients with HCC with negative enhancement on WAG was sign@ cantly higher than that in patients with HCC with positive enhancement (p=O.O231). -: survival rate in patients with HCC with negative enhancement on WAG. . . . .. . . survival rate tn patients with HCC with positive enhancement on USAG.
L....L....L....l... 20.
L.1
20.
0
1
2
3
5
4
6
(Y=W
Survival Time in Years
Fig. 4. Survival rate in patients according to the dfferentiation. The survival rate were similar between patients with well-dtfferentiated HCC and patients with moderately-dtfferentiated HCC (p=O.9034). -: survival rate inpatients with well-dtfferentiated HCC . . . .. . . survival rate in patients with moderately-dtfferentiated HCC.
hancement HCC (p=O.O231). This difference in prognosis was emphasized when focusing on the patients with well-differentiated HCC (n= 30; 16 with negative enhancement HCC and 14 with positive enhancement HCC, p=O.O048; Fig. 3).
and 54.8%, respectively, in patients with well-differentiated HCC. The difference, between these two groups was not significant (p=O.9034).
Survival
Results of the multivariate analysis are shown in Table 2. When vascularity was evaluated by DSA, it was the only significant factor affecting the prognosis (p= 0.0091); differentiation of the tumor and progression of cirrhosis (Child-Pugh classification) were other im-
rate according
to dtyferentiation
of tumor
Fig. 4 shows the comparison of survival rate according to the differentiation of the tumor. The 3- and 5-year survival rates were 61.5 and 46.1%, respectively, in patients with moderately differentiated HCC, and 75.1 10558
Multivariate analysis for the factors term prognosis
affecting
the long-
Vascularity of small HCC treated by PEIT
portant factors, but they were not statistically significant. When vascularity was evaluated by USAG, vascularity was also the only significant factor affecting the prognosis (p=O.O286), and differentiation was the other important factor. Recurrence
after PEIT/PEI
In 31 of 54 patients (S7.4%), recurrences were observed. Recurrences were observed twice in 10 patients, three times in seven patients, and four times in three patients. Of 31 first recurrences, 20 were local recurrences and 11 were multicentric occurrences. Fig. 5 shows the comparison of the local recurrence rate between HCC with positive staining on DSA and HCC with negative staining, and between HCC with positive enhancement on USAG and HCC with negative enhancement. The local recurrence rate in patients with positive staining HCC on DSA tended to be higher than that in patients with negative staining HCC, though the difference was not statistically significant @=0.2218). The local recurrence rate in patients with positive enhancement HCC on USAG was significantly higher than that in patients with negative enhancement HCC (p=O.O438). On the other hand, rates of multicentric occurrence were similar between patients with positive staining HCC on DSA and patients with negative staining HCC @=0.5002), and between patients with positive enhancement HCC on USAG and patients with negative enhancement HCC @=0.3202) (Fig. 6). The local recurrence rate depended on the vascularity of the primary HCC, while the rate of multicentric occurrence did not. Retreatment for the recurrence was performed once in 11 patients, twice in ten patients, 3 times in seven patients and 4 times in three patients after the initial PEIT/PEI. Recurrences were treated with PEIT/PEI in 41 cases and TAE in 23 cases, TAE was performed 13
TABLE 2 Multivariate analysis for factors affecting prognosis portional hazard regression model) Factors
Age Viral infection IcG~ts
Child-Pugh classification Alpha-fetoprotein Tmor size Differentiation Vascularity of tumor
(Cox pro-
p value DSA*
USAG**
0.1176 0.8456 0.1947 0.0509 0.5113 0.5329 0.0732 0.0091
0.4643 0.8116 0.3181 0.1724 0.8655 0.9158 0.0573 0.0286
* Vascularity was evaluated by digital subtraction angiography, and ** by ultrasound angiography with CO2 microbubbles.
2
3
4
5
6
w=w
Survival Time in Years
0
1
2
3
4
5
6
(ye=)
Survival Time in Years Fig. 5. Local recurrence rate of the patients according to the vascularity: A) evaluated by digital subtraction angiography (DSA) and B) evaluated by ultrasound angiography with intraarterial CO, microbubbles (WAG). A) The local recurrence rate in patients with positive staining HCC tended to be higher than that ofpatients with negative staining HCC (p=O.2218). -: local recurrence rate of patients with negative staining HCC on DSA . .. . . . . local recurrence rate of patients with positive staining HCC; CC on DSA. The I- and 3-year local recurrence rates were 16.9 and 61.6%, respectively, in patients with positive staining HCC, and 10.2 and 33.4%, respectively, in patients with negative staining HCC. B) The local recurrence rate in patients with positive enhancement HCC was significantly higher than that of patients with negative enhancement HCC (p=O.O438). -: local recurrence rate of patients with negative enhancement HCC on USAG: . . . .. . . local recurrence rate of patients with positive enhancement HCC on WAG. The l- and 3 year local recurrence rates were 16.2 and .59.8%, respectively, in patients with positive enhancement HCC, and 6.3 and 13.0%, respectively, in patients with negative enhancement HCC.
times for recurrence in patients with positive staining HCC on DSA and 10 times in patients with negative staining HCC, including 5 times in patients with negative enhancement HCC on USAG. 1059
H. Tayodu et al.
1
2
3
4
5
6
W=l
5
6
ww
Survival Time in Years
“0
1
2
3
4
Survival Time in Years
Fig. 6. The rate of multicentric occurrence in patients according to vascularity: A) evaluated by digital subtraction angiography (DSA) and B) evaluated by ultrasound angiography with intraarterial CO, microbubbles (USAG). The rates were similar between patients with positive staining HCC on DSA and patients with negative staining HCC (p=O.5002), and between patients with positive enhancement HCC on USAG and patients with negative enhancement HCC (p=O.3202). A) -: the rate of multicentric occurrence in patients with negative staining HCC on DSA. ......: the rate of multicentric occurrence in patients with positive staining HCC on DSA. B) -: the rate of multicentric occurrence in patients with negative enhancement HCC on USAG. . . .. . . . the rate of multicentric occurrence in patients with positive enhancement HCC on USAG.
Discussion HCC is usually a hypervascular tumor; it is considered to be caused by angiogenesis. This characteristic is reflected in angiographic findings such as tumor staining on DSA or enhancement on USAG (2,19,20,29,30). However, the vascularity can vary even if tumors are the same size or have the same degree of differentiation (31), and small HCCs with a diameter of 5 cm or less do not always reveal a hypervascular stain (1,18-22). In HCCs with a diameter of 2 cm or less, about half have been reported to lack a tumor stain on DSA (32). In some small HCCs, the sinusoidal endothelial cells 1060
still do not have the morphology of capillaries (33). Well-differentiated HCCs (2 1,34), and sometimes moderately differentiated HCCs (33) may be non-hypervascular. We evaluated the importance of tumor vascularity in predicting the long-term prognosis of patients with small HCC treated by PEIT/PEI. When HCC is treated by surgery, tumor size is considered to be an important prognostic factor for HCC (g-lo), and the prognosis is reported to be good when the diameter is less than 2 cm (8). HCC differentiation is also considered to be a prognostic factor (11,12). However, we do not have enough information about the predictors of the prognosis of patients with small HCC treated by PEIT/PEI. In this study we also compared the significance of differentiation and vascularity as predictors of long-term prognosis. Tumor vascularity can be estimated clinically by imaging techniques such as angiography. Staining and/or enhancement of the tumor by angiography showed hypervascularity (2,19,20,29,30). We observed a better survival rate in patients with non-hypervascular HCC (negative-staining HCC on DSA or negative-enhancement HCC on USAG) than in patients with hypervascular HCC (positive-staining HCC on DSA or positive-enhancement HCC on USAG). This difference was more significant when the vascularity of HCC was evaluated by USAG. Though the stain on DSA reflects the hypervascularity of HCC, its resolution capability may not be sufficient to demonstrate hypervascularity. USAG can easily be performed with ultrasound apparatus and COz, and is useful for detecting very slight increases in arterial blood supply, which often cannot be detected by DSA (24). In our study USAG detected the hypervascularity of HCC in 38 patients, including all patients with HCC with positive staining on DSA, while DSA detected hypervascularity in 24 patients. Thus, USAG is more sensitive in detecting the progression of hypervascularity in HCC than conventional angiography or DSA, and can identify non-hypervascular HCC strictly. The survival rate in patients with negative enhancement HCC on USAG shows the survival rate in patients with truly non-hypervascular HCC. Although the vascularity of small HCCs was related to their differentiation (p=O.O077, Table 2), the survival rate in non-hypervascular HCC was observed to be superior even in comparisons confined to well-differentiated HCCs when evaluation was by USAG. Vascularity can predict prognosis, independent of differentiation, as also shown by multivariate analysis. In the evaluation of surgically treated HCC, the differentiation of the tumor (11,12) is reported to be one of the prognostic factors, and the prognosis is considered
Vascularity of small HCC treated by PEIT
be better when Edmondson’s classification of the HCC is lower (8). In the present study we did not observe a difference in survival rate between well-differentiated and moderately differentiated HCC. We think this is partly because the specimens were obtained by fine-needle biopsy, rather than by surgical resection. We evaluated the differentiation from biopsied specimens, which might represent the differentiation of only localized parts of the whole tumor. Therefore there could be over- or underestimation of the differentiation in some HCC specimens evaluated from fine-needle bito
opsy. With regard to recurrences, the local recurrence rate was higher in patients with positive staining HCC on DSA or with positive enhancement HCC on USAG than in patients with negative staining HCC on DSA or with negative enhancement HCC on USAG, while there was no difference in the rate of multicentric occurrence. The high rate of local recurrence may suggest the possible presence of “occult” (undetectable by imaging technique) intrahepatic metastasis at the time of initial treatment (PEIT/PEI), in patients with positive staining HCC on DSA or with positive enhancement HCC on USAG. In conclusion, clinically evaluated tumor vascularity is a significant predictor of long-term prognosis in patients with small HCC, especially evaluated by USAG. In the treatment with PEIT/PEI, it is difficult to obtain the whole HCC specimen and less pathological information is obtained than at surgical treatment. Vascularity can be considered as a marker of the biological grade .of malignancy Clinical evaluation of tumor vascularity prior to therapy will assist prediction of the prognosis in patients with HCC treated with PEI/PEIT Non-hypervascularity may indicate a better prognosis in patients with small HCCs.
References 1. Shinagawa T, Ohto M, Kimura K, Tsunetomi S, Morita M, Saisho H, Tsuchiya Y, Saotome N, Karasawa E, Miki M, Ueno T, Okuda K. Diagnosis and clinical features of small hepatocellular carcinoma with emphasis on the utility of realtime ultrasonography. A study in 51 patients. Gastroenterology 1984,86: 495502. 2. Okuda K. Early detection of hepatocellular carcinoma. Hepatology 1986; 6: 729-38. 3. Ebara M, Ohto M, Shinagawa T, Sugiura N, Kimura K, Matsutani S, Morita M, Saisho H, Tsuchiya Y, Okuda K. Natural history of minute hepatoeellular carcinoma smaller than three centimeters complicating cirrhosis. A study in 22 patients. Gastroenterology 1986; 90: 289-98. 4. Livraghi T, Salmi A, Bolondi L, Martin G, Arienti V, Monti F, Vettori C. Small hepatocellular carcinoma: percutaneous alchohol injection - results in 23 patients. Radiology 1988; 168: 313. 5. Shiina S, Tagawa K, Unuma T, Fujino H, Uta Y, Niwa Y,
6.
7.
8.
9.
10.
11.
12.
13.
14. 15. 16. 17. 18.
19.
20.
21.
Hata Y, Komatsu Y, Yasushi S, Terano A, Sugimoto T. Percutaneous ethanol injection therapy of hepatocellular carcinoma: analysis of 77 patients. Am J Roentogenol 1990; 155: 1221-6. Ehara M, Ohto M, Sugiura N, Kita K, Yoshikawa M, Okuda K, Kondo E Kondo Y. Percutaneous ethanol injection for the treatment of small hepatocellular carcinoma: study of 95 patients. J Gastroenterol Hepatol 1990; 5: 616-26. Castells A, Bruix J, Bru C, Fuster J, Vilana R, Navasa M, Ayuso C, Boix L, Visa J, Rodes J. Treatment of small hepatocellular carcinoma in cirrhotic patients: a cohort study comparing surgical resection and percutaneous ethanol injection. Hepatology 1993; 18: 11216. Haratake J, Takeda S, Kasai T, Nakano S, Tokui N. Predictable factors for estimating prognosis of patients after resection of hepatocellular carcinoma. Cancer 1993; 72: 1178-83. Sugioka A, Tsuzuki T, Kanai T. Postresection prognosis of patients with hepatocellular carcinoma. Surgery 1993; 113: 612-8. Arii S, Tanaka J, Yamazoe Y, Minematsu S, Morino T, Fujita K, Maetani S, Tobe T. Predictive factors for intrahepatic recurrence of hepatocellular carcinoma after partial hepatectomy. Cancer 1992; 69: 913-9. Kitamoto M, Nakanishi T, Kira S, Kawaguchi M, Nakashio R, Suemori S, Kajiyama G, Asahara T, Dohi K. The assessment of proliferating cell nuclear antigen immunohistochemical staining in small hepatocellular carcinoma and its relationship to histologic characteristics and prognosis. Cancer 1993; 72: 1859965. Kanai T, Hirohashi S, Upton ME Noguchi M, Kishi K, Makuuchi M, Yamasaki S, Hasegawa H, Takayasu K, Moriyama N, Shimosato Y. Pathology of small hepatocellular carcinoma: a proposal for a new gross classification. Cancer 1987; 60: 810-9. Okuda K, Obata H, Jinnouchi S, Kubo Y, Nagasaki Y, Shimokawa Y, Motoike Y, Muto H, Nakajima Y, Musha H, Yamazaki T, Sakamoto K, Kojiro M, Nakashima T Angiographic assessment of gross anatomy of hepatocellular carcinoma: comparison of celiac angiograms and liver pathology in 100 cases. Radiology 1977; 123: 21-9. Cooper JN. Imaging and hepatocellular carcinoma. Gastroenter01 Clin North Am 1987; 16: 591-602. Boijsen E, Abrams HL. Roentgenographic diagnosis of primary carcinoma of liver. Acta Radio1 1965; 3: 257-77. Reuter SR, Redman HC, Siders DB. The spectrum of angiographic findings in hepatoma. Radiology 1970; 94: 89-94, Chuang VP Hepatic tumor angiography. A subject review. Radiology 1983; 148: 633-9. Chen DS, Sheu JC, Sung JL, Lai MY, Lee CS, Su CT, Tsang YM, How SW, Wang TH, Yu JY, Yang TH, Wang CY, Hsu CY. Small hepatocellular carcinoma - a clinicopathological study in thirteen patients. Gastroenterology 1982; 83: 110919. Takayasu K, Shima Y, Muramatsu Y, Goto H, Moriyama N, Yamada T, Makuuchi M, Yamasaki S, Hasegawa H, Okazaki N, Hirohashi S, Kishi K. Angiography of small hepatocellular carcinomas: analysis of 105 resected tumors. Am J Roentogenol 1986; 147: 525-9. Sumida M, Ohto M, Ebara M, Kimura K, Okuda K, Hirooka N. Accuracy of angiography in the diagnosis of small hepatocellular carcinoma. Am J Roentogenol1986; 147: 5316. Sonoda T, Shirabe K, Takenaka K, Kanematsu T, Yasumori
1061
H. Toyoda et al.
22.
23.
24.
25.
26.
27. 28.
K, Sugimachi K. Angiographically undetected small hepatocellular carcinoma: clinicopathological characteristics, follow-up and treatment. Hepatology 1989; 10: 1003-7. Ikeda K, Saitoh S, Koida I, Tsubota A, Arase Y, Chayama K, Kumada H. Diagnosis and follow-up of small hepatocellular carcinoma with selective intraarterial digital subtraction angiography. Hepatology 1993; 17: 1003-7. Matsuda Y, Yabuuchi I. Hepatic tumors: US contrast enhancement with CO2 microbubbles. Radiology 1986; 6: 72938. Kudo M, Tomita S, Tochio H, Mimura J, Okabe Y, Kashida H, Hirasa M, Ibuki Y, Todo A. Small hepatocellular carcinoma: diagnosis with US angiography with intraarterial CO2 microbubbles. Radiology 1992; 182: 155-60. Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973; 60: 646-9. Edmondson HA, Steiner PE. Primary carcinoma of the liver. A study of 100 cases among 48,900 necropsies. Cancer 1954; 7: 462-503. Kaplan EL, Meier I? Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457-81. Gehan E. A generalized Wilcoxon test for comparing arbitrarily singly-censored samples. Biometrika 1965; 52: 203-23.
IO62
29. Honda H, Ochiai K, Adachi E, Yasumori K, Hayashi T, Kawashima A, Fukuya T, Gibo M, Matsumata T, Tsuneyoshi M, Masuda K. Hepatocellular carcinoma: correlation of CT, angiographic, and histopathologic findings. Radiology 1993; 189: 857-62. 30. Takashima T, Matsui 0. Infusion hepatic angiography in the detection of small hepatocellular carcinomas. Radiology 1980; 136: 321-5. 31. Trevisani F, Caraceni P, Bernardi M, D’Intino PE, Arienti V, Amorati P Stefanini GE Grazi G, Mazziotti A, Fornale L, Gozzetti G, Gasbarrini G. Gross pathologic types of hepatocellular carcinoma in Italian patients: relationship with demographic, environmental, and clinical factors. Cancer 1993; 72: 1557-63. 32. Ikeda K, Saitoh S, Koida I, Tsubota A, Arase Y, Chayama K, Kumada H. Imaging diagnosis of small hepatocellular carcinoma. Hepatology 1994; 20: 82-7. 33. Kin M, Torimura T, Ueno T, Inuzuka S, Tanikawa K. Sinusoidal capillarization in small hepatocellular carcinoma. Path01 Int 1994; 44: 771-8. 34. Yoshimatsu S, Inoue Y, Ibukuro K, Suzuki S. Hypovascular hepatocellular carcinoma undetected at angiography and CT with iodized oil. Radiology 1989; 171: 343-7.