Multicentric occurrence of hepatocellular carcinoma: In terms of pathology study

The remarkable advances in diagnostic techniques and in the pathomorphologic study of minute hepatocellular carcinomas (HCCs) in the early stage indicate that many HCCs are multicentric in origin. Morphologically, combinations of HCC nodules and other nodules, such as adenomatous hyperplasia containing cancerous foci, well-differentiated HCC, or well-differentiated HCC containing moderate or poorly differentiated cancerous tissue are considered to originate and proliferate in situ. These combinations are considered to be HCC of synchronous multicentric origin. We found that, in HCC associated with liver cirrhosis, 6 of 74 consecutively resected HCCs (8.3%) and 4 of 8 autopsy cases (50%) satisfied the above criteria for multicentric origin. This discrepancy between surgical and autopsy cases can be explained thus: In surgical cases, morphologic examination is limited to only the vicinity of the main tumor and patients with multiple minute tumors HCC tend not to be sent to the operation table. Thus, the frequency seen in autopsy cases may reflect the true figures for multicentric origin. In 94 HCCs associated with chronic hepatitis, we found none showing coexistence of the above nodules that are suggestive of synchronous multicentric origin.     

A case of hepatocellular carcinoma consisting of two solitary poorly differentiated polyclonal intrahepatic tumor nodules

Two intrahepatic solitary tumors consisting of poorly differentiated hepatocellular carcinoma (HCC) were identified as polyclonal HCC nodules by analysis of the pattern of integration of hepatitis B viral DNA into nuclear DNA. After the removal of each nodule by partial liver resection, recurrent multiple tumors appeared within 10 months postoperatively. The findings in this case suggest that the effectiveness of reduction surgery for intrahepatic multiple tumors is limited in solitary multicentric HCC that consists of poorly differentiated HCC.     

Determination of the clonal origin of multiple human hepatocellular carcinomas by cloning and polymerase chain reaction of the integrated hepatitis B virus DNA

The poor prognosis of hepatocellular carcinoma (HCC) is partly the result of the high rate of recurrence that is caused either by intrahepatic metastasis (IM) or independent multicentric occurrence (MO). For convenience, discrimination of IM and MO is based on pathological findings, but reliable parameters are not sufficiently established. In the case of hepatitis B virus (HBV)-associated HCC, molecular discrimination of IM from MO can be achieved by comparison of integrated HBV DNAs. However, Southern blotting cannot be used for this purpose when one tumor is saved in frozen form and the other is in paraffin-embedded form. To solve this problem, we employed polymerase chain reaction (PCR) assays to confirm the clonality of primary and recurrent tumors. From the frozen tissue, we determined the junction between the integrated HBV and flanking genomic DNA by molecular cloning, and checked the existence of an identical junction in the DNA of paraffin-embedded tissue by PCR. Using this method, as well as Southern blotting, we proved in 6 of 8 patients that two nodular HCC lesions resected metachronously or simultaneously were caused by MO, while the remaining 2 cases were caused by IM. In 1 IM case, band patterns between two HCCs detected by Southern blotting were not identical.     

Histopathologic differentiation of the main nodule determines outcome after hepatic resection for synchronous multicentric hepatocellular carcinomas

BACKGROUND/AIMS: Clinicopathological features and outcome after surgery in patients with synchronous multicentric hepatocellular carcinoma were examined in relation to the histopathological grade of differentiation of the main nodule. METHODOLOGY: Two hundred and sixty-five patients with synchronous multicentric hepatocellular carcinoma (total, 683 nodules) who had undergone curative hepatectomy from 1988 through 1999 were studied retrospectively. In multicentric occurrences of hepatocellular carcinoma, the tumor with the largest dimension was defined as the main nodule, and the others as accessory nodules. RESULTS: The histopathological grade of differentiation of the main nodule was assessed to be well differentiated in 72 patients (27.2%), moderately differentiated in 160 patients (60.4%), and poorly differentiated in 33 patients (12.4%). Tumor size of the main nodule was significantly smaller in patients with well differentiated hepatocellular carcinoma than in patients with moderately or poorly differentiated hepatocellular carcinoma. Alpha-fetoprotein levels were significantly lower in cases in which the main nodule was diagnosed to be well differentiated hepatocellular carcinoma than in other cases. The 5-year survival rate and recurrence-free survival rate were significantly greater in cases in which the main nodule showed well differentiated hepatocellular carcinoma (78.1% and 33.8%, respectively) than in other cases [moderately differentiated 49.0% (p<0.0001), 11.6% (P=0.0002); poorly differentiated 37.4% (p<0.0001), 8.3% (P=0.0002), respectively]. Multivariate analysis identified the histopathological grade of the main nodule as significant independent prognostic factors. CONCLUSIONS: There were differences in surgical outcome in relation to the histopathological grade of differentiation of the main nodule in patients with synchronous multicentric hepatocellular carcinoma.     

Multicentric occurrence of hepatocellular carcinoma with nonalcoholic steatohepatitis

AIM:To reveal the manner of hepatocellular carcinoma (HCC) development in patients with nonalcoholic steatohepatitis(NASH) focusing on multicentric occurrence (MO) of HCC.METHODS:We compared clinicopathological characteristics between patients with and without MO of HCC arising from NASH background.The clinical features were implicated with reference to the literature available.RESULTS:MO of HCC was identified with histological proof in 4 out of 12 patients with NASH-related HCC(2 males and 2 females).One patient had synchronous MO;an advanced HCC,two well-differentiated HCCs and a dysplastic nodule,followed by the development of metachronous MO of HCC.The other three patients had multiple advanced HCCs accompanied by a well-differentiated HCC or a dysplastic nodule.Of these three patients,one had synchronous MO,one had metachronous MO and the other had both synchronous and metachronous MO.There were no obvious differences between the patients with or without MO in terms of liver function tests,tumor markers and anatomical extent of HCC.On the other hand,all four patients with MO of HCC were older than 70 years old and had the comorbidities of obesity,type 2 diabetes mellitus(T2DM),hypertension and cirrhosis.Although these conditions were not limited to MO of HCC,all the conditions were met in only one of eight patients without MO of HCC.Thus,concurrence of these conditions may be a predisposing situation to synchronous MO of HCC.In particular,old age,T2DM and cirrhosis were suggested to be prerequisite for MO because these factors were depicted in common among two other cases with MO of HCC under NASH in the literature.CONCLUSION:The putative predisposing factors and necessary preconditions for synchronous MO of HCC in NASH were suggested in this study.Further investigations are required to clarify the accurate prevalence and predictors of MO to establish better strategies for treatment and prevention leading to the prognostic improvement in NASH.     

Early Stage Hepatocellular Carcinoma Detected during Intraoperative Ultrasonography

Objectives: Recently, it has been recognized that there are increasing incidences of hepatocellular carcinoma (HCC) multicentricity. Thus, intraoperatively detected hepatic lesions that were once thought to be metastatic lesions now need to be carefully reexamined to determine whether they are true metastatic lesions or the multicentric development of HCC. Methods: We investigated the histological characteristics of small nodular lesions detected during intraoperative ultrasonography in 33 consecutive patients with small HCC wbo underwent laparotomy at our institution. Results: Fourteen nodular lesions were found incidentally in 10 of 33 patients (30.3%), and were classified into tbe following three groups: 11 nodules in nine patients (27.3%) were HCC, two nodules in two patients (6.1%) were hemangioma, and one nodule in one patient (3.0%) was a large regenerative nodule. HCC therefore comprised 78.6% of tbe intraoperatively detected nodular lesions. Of the 11 HCCs, six were hyperechoic, four were hypoechoic, and one was isoechoic. Five (83.3%) of six small hyperechoic HCCs and two (50.0%) of four hypoechoic HCCs were well differentiated and retained their preexisting liver structure. Tbese findings closely coincide with the characteristics of early stage HCC. Thus, early stage HCC comprised 63.6% of tbe intraoperatively detected HCC cases. Conclusions: A certain proportion of small satellite HCCs detected during intraoperative ultrasonography in patients with small HCC, which were previously thought to be metastatic lesions from tbe main HCC, may instead he early stage HCCs. Such findings would also support the concept of the multicentric development of HCC. Approximately 60% of all small HCC cases detected intraoperatively may be early stage HCC. As a result, it is predicted that the emergence of HCC is either multicentric or unicentric, with early intrabepatic spread, altbough the former seems to be more common.     

Recurrence of hepatocellular carcinoma: multicentric occurrence or intrahepatic metastasis? A viewpoint in terms of pathology

Recurrence after successful surgical or nonsurgical treatment of hepatocellular carcinoma (HCC) is caused either by intrahepatic metastasis or by metachronously multicentric occurrence. Intrahepatic metastasis is a major cause of recurrence of advanced HCCs with varying degrees of vascular invasion, and multicentric occurrence is a frequent cause of recurrence in small HCCs with no obvious vascular invasion. It is estimated that at least 20% of small HCCs have a high probability of recurrence due to multicentric occurrence, based on the finding that adenomatous hyperplasia (AH) and/or atypical adenomatous hyperplasia (AAH), which are considered premalignant lesions, are found in the vicinity of resected small HCCs with liver cirrhosis. However, because neither AH nor AAH occur in HCC cases without liver cirrhosis, most recurrence of HCC in noncirrhotic liver is considered to be due to intrahepatic metastasis or to de novo hepatocarcinogenesis. In a survey of autopsy cases of liver cirrhosis with small HCC, smaller HCC nodules were found in other liver slices in 50% of cases, and it is estimated that approximately 50% of HCC is already multicentric in the early stage.     

Small hepatocellular carcinoma with minute satellite nodules

BACKGROUND/AIMS: To investigate the clinicopathologic characteristics of small hepatocellular carcinoma with minute satellite nodules. METHODOLOGY: We investigated the clinicopathologic characteristics of 131 solitary small (< or = 2.0 cm in diameter) hepatocellular carcinomas including 105 hepatocellular carcinomas without minute satellite nodules and 17 hepatocellular carcinomas with minute satellite nodules smaller than 5 mm, and also discuss the clinical significance. RESULTS: None of the clinical backgrounds of the patients and pathologic features of the main tumor, except for the average of preoperative serum alpha-fetoprotein, were significantly different between the two groups. Firstly, minute satellite nodules demonstrated that the maximum diameter of all minute satellite nodules was 1.5-4.0 mm, secondly, the moderately to poorly differentiated hepatocellular carcinomas had 4 or more minute satellite nodules within 1 cm from the main tumor, while well differentiated hepatocellular carcinomas may have 1 or 2 minute satellite nodules 6 cm or more away, and thirdly, 4 or more minute satellite nodules may present within 1 cm in intrahepatic metastasis cases, while 1 or 2 minute satellite nodules may be present 6 cm or more away from the main tumor in multicentric occurrence cases. CONCLUSIONS: At least 13% of solitary small hepatocellular carcinomas had preoperatively undetectable minute satellite nodules. In case of moderately to poorly differentiated hepatocellular carcinomas, hepatic resection as well as percutaneous ethanol injection should be performed including the surrounding liver tissue at least 1.0 cm from the main nodule. On the other hand, in well-differentiated hepatocellular carcinomas, which may indicate multicentric occurrence, closer observation and careful follow-up after therapy are recommended.     

Multistep and multicentric development of hepatocellular carcinoma: histological analysis of 980 resected nodules

BACKGROUND/AIMS: Histological observations support the concept of multistep and multicentric development of hepatocellular carcinoma (HCC) in cases of chronic liver disease. However, the relationship between the incidence of such a modality of development of HCC and the type of background liver disease has not been fully investigated. METHODS: A total of 980 HCC nodules resected from 664 patients were analyzed. Multistep HCC was defined as well differentiated HCC containing the portal tracts (early HCC), or the presence of early HCC-like areas in the periphery of the nodule. In cases with multiple nodules, if the smaller nodule showed the features of multistep HCC, or if each nodule showed a distinct histology, the case was defined to have multicentric HCC. RESULTS: Of the 980 nodules, 369 (37.7%) met the criteria of multistep HCC. Of the 664 patients, 177 (26.7%) had multiple nodules that met the criteria of multicentric HCC. Both the incidences of multistep and multicentric HCC were significantly higher in HCV-Ab-positive cases than in HBs-Ag-positive cases (46.0 vs. 19.1%, P<0.001 and 34.1 vs. 16.5%, P=0.005, respectively). CONCLUSIONS: Multistep and multicentric HCC develops most frequently in patients with HCV infection.     

Expression of vascular endothelial growth factor-C in human hepatocellular carcinoma

Background/Aims: Vascular endothelial growth factor‐C (VEGF‐C) is thought to be an important factor in tumor angiogenesis/lymphangiogenesis, but its role in hepatocellular carcinoma (HCC) has not yet been fully investigated. Methods: We immunohistochemically examined VEGF‐C expression in surgically resected tissues of 90 HCC. Results: In the 78 HCC with a single histological grade, VEGF‐C expression was significantly stronger in poorly differentiated HCC than in well‐ (P = 0.003) or moderately differentiated HCC (P = 0.0002). A ‘nodule‐in‐nodule’ case presented VEGF‐A expression in the well‐differentiated component and VEGF‐C expression in the moderately–poorly differentiated component. According to nodular diameter, VEGF‐C expression was significantly higher in nodules of 3.0 cm or larger (P = 0.0263). Extrahepatic metastases seen in seven cases expressed VEGF‐C. In 20 of the 28 cases who were able to be followed up, the frequency of intrahepatic recurrence tended to be higher and extrahepatic metastasis was significantly higher in the cases who had VEGF‐C expression in the tumor casts of the intrahepatic portal/hepatic vein branches than other cases without the expression (P = 0.0139). Disease‐free survival time tended to be shorter in cases with VEGF‐C expression in tumor casts of the portal/hepatic vein than in those without VEGF‐C expression (P = 0.053; log–rank test). Conclusions: VEGF‐C expression is related to the progression of HCC, and VEGF‐C expression in tumor casts of the intrahepatic portal/hepatic vein is considered to be a factor indicating recurrence/metastasis sites.     

Eight multicentric hepatocellular carcinomas occurring in the same segment of the liver

We present a rare case of eight multicentric hepatocellular carcinomas (HCCs) occurring in the same segment of the liver. In a 66‐year‐old Japanese man, multiple liver tumors were detected during follow‐up of chronic hepatitis C infection, and he was admitted to our hospital in 1995. Ultrasonography (US) showed eight tumors, each measuring between 10 and 15 mm in diameter, in the right lobe, and a 10‐mm tumor in the left lobe. Angio‐ultrasonography (US) showed no enhancement of the tumors, and multicentric occurrence was suspected. Portal angio‐US showed eight tumors in the right lobe located in the anterior segment. Accordingly, anterior segmentectomy and partial resection of the S3 subsegment were performed, in December, 1995. On histological examination, all eight tumors in the anterior segment and the tumor in the S3 subsegment were well differentiated HCC. The liver parenchyma showed cirrhosis. The grade and stage of hepatitis did not differ between the anterior segment and the S3 subsegment, but irregular regeneration of hepatocytes was more prominent in the anterior segment. The multicentric occurrence of HCCs in the anterior segment may be related to the more severe damage caused by chronic hepatitis in the anterior segment than in the left lobe of the liver.     

DNA ploidy pattern in synchronous and metachronous hepatocellular carcinomas.

DNA ploidy of hepatocellular carcinoma (HCC) was studied in 28 patients using a flow cytometric method. Fourteen patients had two HCCs synchronously, and the remaining 14 had tumor recurrence in the remnant liver 3-41 months after curative resection of primary HCCs. DNA ploidy pattern and histopathologic parameters were compared between the synchronous and metachronous HCCs. Among those with synchronous HCCs, both tumors were diploid in 7 cases and aneuploid in 2 instances. Five patients had HCCs of different DNA ploidy pattern. On the other hand, 5 of 14 patients with metachronous HCCs had a consistent DNA ploidy between primary and recurrent tumors. In 4 cases, the first tumor was diploid whereas the recurrent HCC was aneuploid or tetraploid. In the remaining 5 cases, the primary HCC was aneuploid, but the recurrent tumor was diploid. Assuming that the difference in DNA ploidy pattern indicates a different clonal origin, the current results indicate that at least 36% of synchronous HCCs and 64% of recurrent HCCs develop in a multicentric fashion.     

Multicentric hepatocellular carcinomas tend to grow in more damaged segments of the liver

In 115 patients (68 with liver cirrhosis and 47 without) who underwent curative resection of hepatocellular carcinoma (HCC) caused by hepatitis C virus (HCV)-related chronic liver diseases, we separated the liver into three segments (right, middle, and left) according to the three secondary branches of the Glissonean pedicle. We examined the weight of each resected segment. We also examined the histological findings of the segments in the same liver in 24 other patients with HCV-related chronic liver diseases. The average weight of the segments did not vary significantly in patients without liver cirrhosis. However, the average weight of the segments was significantly different in patients with liver cirrhosis (P = 0.0414) and the weight of the middle segment was lower than that of the other segments. In another group, of 246 patients with curative resection of HCC, of the 90 patients with single nodular HCCs, 45 nodules (50%) were located in the middle segment (P = 0.0004); in the 156 pa-tients with synchronous multicentric HCCs (total, 401 nodules), 220 nodules (54.9%) were located in the middle segment. In 74 of the 156 patients with synchronous multicentric HCCs (47.4%), the HCCs were located in the same segment. The grade, stage of hepatitis, and number of sites of irregular regeneration were significantly different in each segment (P < 0.05), and the middle segment had more advanced hepatitis than the other segments. The rate of occurrence of HCC in the middle segment was higher than that in the other segments. The difference among the segments of the liver in regard to the degree of damage done by hepatitis may be related to the differences in HCC occurrence among the liver segments. Received: June 7, 1999 / Accepted: December 17, 1999     

Clinicopathologic features and prognostic factors of resected solitary small-sized hepatocellular carcinoma

BACKGROUND/AIMS: Solitary small-sized HCCs tend to be considered as less aggressive cancer, and non-surgical treatments have recently been preferred. The aim of this study was to clarify the clinicopathological features and the prognostic factors of small-sized HCCs and to evaluate the significance of hepatic resection for them. METHODOLOGY: Eighty patients with HCC up to 2cm in diameter who had undergone hepatic resection were enrolled in this study. We investigated the clinicopathological features and evaluated the prognostic factors by univariate and multivariate analyses. RESULTS: The overall survival rates at 3, 5 and 10 years were 83%, 69% and 36%, respectively, and the corresponding disease-free survival rates were 63%, 41% and 10%. Well-differentiated, moderately differentiated and poorly differentiated HCC were detected in 29%, 65% and 6% of the patients, respectively. Furthermore, microscopic portal vein invasion (vp), hepatic vein invasion (vv) and intrahepatic metastasis (im) were positive in 15%, 4% and 10% of the patients, respectively. Multivariate analysis revealed that Child-Pugh classification (p=0.005) and vp (p=0.0008) were independent prognostic factors for survival rate and that platelet count (p=0.002) and tumor differentiation (p=0.0016) were independent prognostic factors for disease-free survival rate. CONCLUSIONS: Even solitary small-sized (up to 2cm in diameter) HCC already have the characteristics of advanced HCC. When hepatic function is well preserved, hepatic resection should be the first choice for local control, especially in cases of moderately to poorly differentiated HCC, because the frequency of microscopic vascular invasion is high.     

Differential diagnosis of nodular lesions in cirrhotic liver by post-vascular phase contrast-enhanced US with Levovist: comparison with superparamagnetic iron oxide magnetic resonance images

Background We investigated the diagnostic utility of post-vascular phase contrast-enhanced ultrasonography (US) and superparamagnetic iron oxide (SPIO)-enhanced magnetic resonance imaging (MRI) as compared to the histological diagnosis of differential grades of hepatocellular carcinomas (HCCs). Methods Forty-nine patients with histologically characterized liver nodules (well-differentiated HCC, n = 20; moderately differentiated HCC, n = 19; poorly differentiated HCC, n = 1; dysplastic nodule, n = 9) received contrast-enhanced US and SPIO-MRI. Subsequently, we quantitatively evaluated the relationships between the images of the nodules and their histological diagnosis and differential grades. Results The ratio of the echogenicity of the tumorous area to that of the nontumorous area with post-vascular phase contrast-enhanced US (post-vascular phase ratio) decreased as nodules became less differentiated (P < 0.05; Kruskal-Wallis test). The ratio of the intensity of the nontumorous area to that of the tumorous area on SPIO-enhanced MR images (SPIO intensity index) also decreased as nodules became less differentiated (P < 0.01). The post-vascular phase ratio correlated with the SPIO intensity index for HCCs and dysplastic nodules (r = 0.76). The conformity of the result from the post-vascular phase contrast-enhanced US and SPIO-MRI was 96%. Conclusions Contrast-enhanced US is a valuable method for predicting the histological grade of HCCs in cirrhotic patients, and may be a good alternative to SPIO-enhanced MRI.     

Clinicopathologic comparison between resected hepatocellular carcinomas (HCC) and recurrent tumors A special reference to multicentric carcinogenesis of HCC

Postoperative metachronous multicentric carcinogenesis of hepatocellular carcinoma (HCC) was studied by comparison of the histologic grade of resected and recurrent tumors in 31 cases which underwent ultrasound-guided fine-needle biopsies for the initial recurrent tumors with diameter of less than 20 mm. The criteria that the cases in which recurrent tumors show well-differentiated HCC without regard to the differentiation of resected tumors should be multicentric carcinogenesis, and that the cases in which recurrent tumors show moderate or poorly differentiated HCC with the same or lower degree of differentiation compared with the differentiation of resected tumor was consistent with metastasis, were applied. In 16 (51.6%) out of the 31 cases, multicentric carcinogenesis was thought to occur (multicentric group). In 14 cases, recurrence was thought to be metastasis (metastatic group). The multicentric group tended to have smaller diameters in resected tumors and a high incidence of the association of liver cirrhosis and adenomatous hyperplasia. In gross classification of resected tumors, six cases of all single nodular with perinodular tumor growth type and infiltrative type had metastatic recurrences, and multicentric carcinogenesis was often seen in cases of single nodular type, multinodular type and confluent multinodular type. In the multicentric group, recurrence occurred at every postoperative period as long as 65 months including four cases of early recurrence within 6 months and six cases of late recurrence later than 24 months. On the contrary, in 12 cases in the metastatic group the recurrent interval ranged from 6 to 19 months.     

Muscular Metastasis of Hepatocellular Carcinoma: Case Report and Literature Review

There are few case reports of hepatocellular carcinoma (HCC) metastasis to the skeletal muscle. A 78-year-old man developed a mass in the right shoulder. Washout of contrast medium during contrast-enhanced ultrasonography (CEUS) in both the primary HCC and the metastatic site was detected. Several nodules were scattered throughout the liver on an autopsy. In addition, the moderately differentiated HCC had metastasized to the right teres major muscle. Rare muscular metastasis should be considered if a hepatic tumor is moderately or poorly differentiated HCC. Early washout during CEUS is consistent with a pathological diagnosis of moderately or poorly differentiated HCC.     

Recent developments in imaging diagnostics for HCC: CT arteriography and CT arterioportography evaluation of vascular changes in premalignant and malignant hepatic nodules

We analyzed the hemodynamic properties and vascular supply changes in relation to the carcinogenesis of hepatocellular carcinoma (HCC), selecting 18 premalignant and malignant nodules less than 3 cm diameter (from 14 patients) for our study. The computed tomographic (CT) arteriography and CT arterioportography (CTAP) findings for these nodules were correlated with the histopathologic findings. The ratios of all microscopically counted arteries (normal hepatic and abnormal arteries), normal hepatic arteries, and portal veins in each nodule to those in the surrounding liver were calculated. Well differentiated lesions had low attenuation on CT arteriography and isoattenuation on CTAP. Moderately‐to‐poorly differentiated lesions had high attenuation on CT arteriography and low attenuation on CTAP. In well differentiated lesions, the ratios of all arteries, normal hepatic arteries, and portal veins were 1.17 ± 0.10, 0.66 ± 0.12, and 0.80 ± 0.10, respectively. In moderately‐to‐poorly differentiated lesions, the ratios were 2.64 ± 0.23, 0.09 ± 0.03, and 0.07 ± 0.03, respectively. We concluded that blood flow does not parallel the actual number of arteries seen on the histological examination of tumors. In well differentiated lesions, the combination of normal hepatic arterial degeneration and preserved portal veins results in low attenuation on CT arteriography and isoattenuation on CTAP. In advanced HCC, the combination of neoplastic (abnormal) arterial development by angiogenesis and obliteration of portal veins results in high attenuation on CTA and low attenuation on CTAP. These findings are characteristic of early and advanced stage HCC, and may reflect a combination of sequential changes in their hemodynamic states.     

Hepatic resection for hepatocellular carcinoma based on tumor hemodynamics

Survival or disease‐free survival is not considered an appropriate surrogate outcome for the locoregional curability (i.e. surgical margin) of hepatectomy for hepatocellular carcinoma because these are greatly influenced by non‐metastatic factors like multicentric carcinogenesis (MC) or liver function. Hepatocellular carcinoma metastasizes by hematogenous seeding; therefore, the tumor blood flow (TBF) drainage area is a high‐risk area for intrahepatic metastasis, and can be identified by computed tomography under hepatic arteriography and completely resected as part of the surgical margin. The TBF pattern is classified into marginal, portal vein or hypovascular types. Partial hepatectomies were mostly performed in patients with marginal or hypovascular type, whereas anatomical surgery was frequently performed in those with portal vein type. Pathologically, nodules inside the TBF drainage area were moderately or poorly differentiated carcinomas, suggesting intrahepatic metastasis. In contrast, those outside the drainage area were frequently solitary and contained well‐differentiated carcinoma, which is consistent with MC. The pattern of tumor recurrences after TBF‐based hepatectomy is divided into two distinct groups – “a few nodules” and “many nodules in multiple segments or extrahepatic” – indicating that intrahepatic recurrences develop from MC and from circulating tumor cells in peripheral blood, respectively. Anatomical resection has not shown a survival benefit over that of TBF‐based partial hepatectomy. TBF‐based hepatectomy enables us to preserve liver function without compromising locoregional curability.