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Original Article |

Impact of Histological Grade of Hepatocellular Carcinoma on the Outcome of Liver Transplantation FREE

Sumihito Tamura, MD; Tomoaki Kato, MD; Mariana Berho, MD; Evangelos P. Misiakos, MD; Christopher O'Brien, MD; K. Rajender Reddy, MD; Jose R. Nery, MD; George W. Burke, MD; Eugene R. Schiff, MD; Joshua Miller, MD; Andreas G. Tzakis, MD
[+] Author Affiliations

From the Division of Transplantation, Department of Surgery (Drs Tamura, Kato, Misiakos, Nery, Burke, Miller, and Tzakis), the Division of Immunopathology, Department of Pathology (Dr Berho), and the Division of Hepatology, Department of Medicine (Drs O'Brien, Reddy, and Schiff), University of Miami School of Medicine, Miami, Fla.


Arch Surg. 2001;136(1):25-30. doi:10.1001/archsurg.136.1.25.
Text Size: A A A
Published online

Hypothesis  Histological grade of hepatocellular carcinoma (HCC) is an important prognostic factor affecting patient survival after orthotopic liver transplantation (OLT).

Design  Retrospective analysis.

Setting  University-based teaching hospital.

Patients  Of 952 OLTs performed between June 1991 and January 1999, 56 OLT recipients had histologically proven HCC in the explant liver. Of those, 53 patients with complete clinicopathologic data were analyzed. A single pathologist blinded to the outcome of each patient reviewed all histological specimens.

Results  Median follow-up was 709 days. Overall survival for patients with tumors sized 5 cm or less at 1, 3, and 5 years was 87%, 78%, and 71%, respectively (Kaplan-Meier). Univariate analysis revealed the size, number, and distribution of tumors; the presence of microscopic vascular invasion and lymph node metastasis; histological differentiation; and pTNM stage to be statistically significant factors affecting survival. Multivariate analysis revealed histological differentiation and pTNM stage to be the independent and statistically significant factors affecting survival (P = .002 and .03, respectively). When pTNM stage was excluded from multivariate analysis, histological differentiation and size remained the significant independent factors (P = .02 and .03, respectively). Three-year survival for patients with small (≤5 cm) tumor with well- to moderately differentiated and poorly differentiated HCC was 82% and 67%, respectively. Three-year survival for patients with large (>5 cm) tumor with well- to moderately differentiated and poorly differentiated HCC was 62.5% and 0%, respectively.

Conclusions  In our retrospective experience, histological differentiation had a statistically significant effect on the prognosis of HCC after OLT. However, before altering the current OLT selection criteria for patients with HCC, prospective studies are required to confirm the impact of histological grade on clinical outcome.

Figures in this Article

HEPATOCELLULAR carcinoma (HCC) is a major cause of death worldwide, with a high incidence in Asia and South Africa.1 More than 80% of patients with HCC have liver cirrhosis, particularly related to chronic viral hepatitis types B and C.2 Although surgical resection of the tumor is considered the best option,3 it is possible in only a minority of patients owing to impaired functional reserve of the liver and multicentricity. To overcome the limited application of resection, other treatment modalities have been investigated.4,5

Use of orthotopic liver transplantation (OLT) for the treatment of HCC has been controversial. Although the results to date are comparable to those for conventional partial hepatectomy,6,7 the application of transplantation for treating cancer remains a difficult decision given the shortage of donor organs. Earlier studies6,8 observed that patients with HCC did poorly compared with patients with benign disease. A recent experience,9 however, reported that patients with HCC, who were carefully selected on the basis of the size and number of lesions, did as well after OLT as patients without cancer.

In addition, data from a large international registry10 suggested that histological differentiation of the tumor was an important prognostic factor in the outcome of OLT for HCC. We describe our experience evaluating multiple factors, including clinicopathologic features, in the outcome of HCC after OLT.

Between June 1991 and January 1999, 952 liver transplantations were performed at Jackson Memorial Hospital/University of Miami Medical Center, Miami, Fla. A retrospective study revealed 56 OLT recipients with histologically proven HCC in the explant liver. Patients with so-called incidental tumor, ie, tumor not identified during pretransplant workup but found in explant liver, were also included in the study. Histological slides from 53 of the 56 patients were available for analysis, and these patients formed the study population. Data on demographics; pretransplant α-fetoprotein level; Child-Pugh class; presence of viral hepatitis types B and C; chemotherapy before and after OLT; size, number, and distribution of tumors; pTNM stage according to Union Internationale Contre le Cancer (UICC) criteria11; histological differentiation of the tumor; presence of microscopic vascular invasion and lymph node metastasis; and donor bone marrow infusions were collected and analyzed.

Histological data on the tumor lesions of all patients were retrieved and reviewed by a single expert pathologist (M.B.) masked to the data on the outcome of patients after undergoing OLT. Histological differentiation was defined by the criteria of Kondo12 and Sugihara et al,13 which classify HCC into 3 categories: well, moderately, and poorly differentiated. These classifications have overlapping and similar definitions to the Edmondson-Steiner classification.14

Overall survival and disease-free survival rates were calculated using the Kaplan-Meier method,15 and statistical significance was defined using the log-rank test.16 Factors related to survival were analyzed using the Cox proportional hazards regression model17 and SAS statistical software (SAS Institute Inc, Cary, NC). Statistical significance was defined as P<.05, corresponding to the test of null hypothesis that all coefficients associated with the risk factor in the regression are zero. Comparison of continuous ordinal data between 2 groups was performed using the Mann-Whitney U test.

DEMOGRAPHIC DATA

Of 53 patients in the study, 36 (68%) were men and 17 (32%) were women. Mean age was 57 years (range, 20-77 years). Most patients (n = 44 [83%]) had viral hepatitis, 37 (70%) of whom were hepatitis C virus antibody positive. Twenty patients (38%) had Child-Pugh class B and 20 (38%) had Child-Pugh class C cirrhosis. Mean tumor size was 4.4 cm (range, 0.5-18 cm). After OLT, HCC (incidental tumor) was found in the explant livers of 13 patients (25%). Mean tumor size in incidental cases was 2.5 cm (range, 0.5-6.0 cm). Twenty-four patients (45%) received donor bone marrow infusions for induction of immunologic tolerance after OLT. Other demographic features are summarized in Table 1.

Table Graphic Jump LocationTable 1. Overall Survival According to Clinicopathologic Features*
SURVIVAL AND RECURRENCE

Median follow-up was 709 days and mean follow-up was 887 days, with the longest survival exceeding 8 years (2976 days to date). Of 53 patients, 17 (32%) died and 36 (68%) are currently alive. Four patients died of systemic infection, 1 of chronic rejection, and 1 of an acute cardiac event. None died of recurrent hepatitis. Overall survival at 1, 3, and 5 years was 79%, 65%, and 61%, respectively, whereas survival for patients with tumor size of 5 cm or less was 87%, 77%, and 71%, respectively. One-, 3-, and 5-year disease-free survival was 77%, 60%, and 60%, respectively (Figure 1). As of January 1999, there was no evidence of recurrence of HCC in 15 patients who had survived longer than 3 years. Of 14 patients (26%) in whom HCC recurred, 11 died of metastatic disease. One patient with recurrence died of systemic infection. Two patients who experienced recurrence were alive and well as of January 1999. Liver (n = 4 [29%]), lung (n = 3 [21%]), and bone (n = 2 [14%]) were the common sites of recurrent or metastatic disease. At the end of the study period, 34 patients (64%) were alive and free of disease.

Place holder to copy figure label and caption
Figure 1.

Overall survival and recurrence in 53 patients. Median follow-up was 709 days and mean follow-up was 887 days, with the longest survival exceeding 8 years (2976 days). No recurrence was noted more than 3 years after orthotopic liver transplantation.

Graphic Jump Location
UNIVARIATE ANALYSIS FOR SURVIVAL

Univariate analysis regarding survival was performed with the following factors: age, sex, presence of viral hepatitis, incidental tumor, pre-OLT α-fetoprotein level, Child-Pugh class, size of the tumor, presence of multiple tumors, presence of bilobar tumor, microscopic vascular invasion, microscopic lymph node metastasis, histological differentiation, UICC pTNM stage based on microscopic findings, donor bone marrow infusion, and chemotherapy (transarterial chemoembolization and intravenous chemotherapy). Eight factors—incidental tumor, size, multiple tumor, bilobar tumor, vascular invasion, lymph node metastasis, histological differentiation, and pTNM stage—significantly affected survival (P<.05, log-rank test). Bone marrow infusion after OLT did not affect survival (Table 1).

MULTIVARIATE ANALYSIS FOR SURVIVAL

To elucidate the independent factors affecting survival, multivariate analysis using the Cox proportional hazards model was performed with the following factors: age, sex, presence of viral hepatitis, pre-OLT α-fetoprotein level, Child-Pugh class, size of the tumor, presence of multiple tumors, presence of bilobar tumor, microscopic vascular invasion, microscopic lymph node metastasis, histological differentiation, UICC pTNM stage based on microscopic findings, donor bone marrow infusion, and chemotherapy (transarterial chemoembolization and intravenous chemotherapy). Multivariate analysis revealed histological differentiation and UICC pTNM stage to be the independent factors affecting survival (Table 2). Further analysis without UICC pTNM stage revealed histological differentiation and tumor size to be the independent factors affecting survival (Table 2).

Table Graphic Jump LocationTable 2. Cox Regression Model for Histological Differentiation and pTNM Stage and for Histological Differentiation and Size*

The outcome of patients with tumors larger than 5 cm with poorly differentiated HCC (range, 7-18 cm; median, 9.25 cm) was extremely poor (0% survival within 1 year of OLT). Patients with well- to moderately differentiated HCC with tumors larger than 5 cm (range, 5.5-15 cm; median, 6.25 cm) presented with unexpectedly good 3-year survival of 62% (Figure 2). Six of 8 patients in this group (well- to moderately differentiated tumors >5 cm) are alive without recurrence of tumors at a median follow-up of 38 months (range, 8 months to 8 years). These 6 patients all had a single nodule measuring 5.5 to 8 cm (median, 6.25 cm).

Place holder to copy figure label and caption
Figure 2.

Effect of histological differentiation in large (>5-cm) tumors. Although survival for patients with tumors larger than 5 cm with poorly differentiated hepatocellular carcinoma (HCC) was extremely poor, patients with well- to moderately differentiated HCC with tumors larger than 5 cm had unexpectedly good survival rates.

Graphic Jump Location

Patients with small tumors did well, with 3-year survival of 82% among patients with well- to moderately differentiated HCC and 67% among patients with poorly differentiated HCC. This difference in survival within the small tumor group was not statistically significant (P = .26, log-rank test) (Figure 3).

Place holder to copy figure label and caption
Figure 3.

Effect of histological differentiation in small (≤5-cm) tumors. Patients with small tumors did well in general. Three-year survival was 82% for patients with well- to moderately differentiated hepatocellular carcinoma (HCC) and 67% in patients with poorly differentiated HCC.

Graphic Jump Location
HISTOLOGICAL DIFFERENTIATION AND RECURRENCE

Univariate analysis for disease-free survival was performed with the factors studied in the survival analysis. Seven factors—incidental tumor, size, bilobar tumor, vascular invasion, lymph node metastasis, histological differentiation, and pTNM stage—showed a statistically significant difference (P<.05, log-rank test). Bone marrow infusion did not affect disease-free survival (Table 3). To characterize the independent factors affecting disease-free survival, multivariate analysis with Cox proportional hazards model was performed similarly to the overall survival analysis. Histological differentiation and microscopic lymph node metastasis were noted as the independent factors (Table 4). Excluding lymph node metastasis, only histological differentiation remained a significant factor (Table 4). To further understand the effect of histological differentiation of HCC on prognosis, recurrence was studied according to differentiation of the tumor. Nine of 15 patients with poorly differentiated HCC died; 7 of these deaths were directly related to recurrent disease. On the other hand, 8 of 38 patients with well- to moderately differentiated HCC died; 4 of these deaths were directly related to recurrent disease (Table 5). When combined with size criteria (Table 5), 5 of 6 patients with large (>5 cm), poorly differentiated HCC died of recurrence, although only 2 of 8 patients with large but well- to moderately differentiated HCC died of recurrence. When disease-free interval was compared in patients with recurrence based on histological differentiation, it was significantly greater in patients with well- to moderately differentiated HCC. The median disease-free interval of patients with well- to moderately differentiated HCC was 430 days, whereas that of patients with poorly differentiated HCC was 175 days (P = .006, Mann-Whitney U test) (Figure 4).

Table Graphic Jump LocationTable 3. Disease-Free Survival According to Clinicopathologic Features*
Table Graphic Jump LocationTable 4. Cox Regression Model for Histological Differentiation and Lymph Node Metastasis and for Histological Differentiation*
Table Graphic Jump LocationTable 5. Histological Differentiation, Tumor Size, and Prognosis
Place holder to copy figure label and caption
Figure 4.

Comparison of disease-free intervals between well- to moderately differentiated hepatocellular carcinoma (HCC) and poorly differentiated HCC in patients with recurrence.

Graphic Jump Location

Previously, significant prognostic factors after OLT for HCC have included features such as size, number, and distribution of the tumor; nodal metastasis; vascular invasion; and TNM stage based on microscopic findings.7,9,1821 The role of histological differentiation of the tumor was not studied.7,9,1821 To date, to our knowledge, only one published study10 from an international registry has suggested that histological differentiation is a significant and independent prognostic factor after OLT for patients with HCC. This study10 was viewed critically by other investigators mainly because it was based on observations of different pathologists from multiple transplant centers. Our study is from the patient records of a single center where all the histological slides were collected and evaluated by a single pathologist, thereby excluding major intraobserver variability in histological differentiation.

The role of OLT in the management of HCC has been controversial. Orthotopic liver transplantation has an advantage over partial resection in that it can be applied regardless of the functional reserve of the liver. Also, it is now known that there is a group of patients with HCC that presents with multicentric, metachronous hepatocarcinogenesis.2224 Total hepatectomy performed at the time of OLT allows removal of a potentially carcinogenic liver. Long-term results from earlier studies6,8 were, nevertheless, disappointing. These series noted 20% to 30% overall 5-year survival, a high recurrence rate, and occasional long-term survival free of recurrent disease. Further studies7,1820,25 revealed that successful transplantation for HCC yielding results comparable to conventional partial hepatectomy can be achieved in patients with early-stage disease. These results were encouraging and suggested that OLT should be added to the therapeutic spectrum for HCC in selected patients. The most recent studies,9,26 based on strict criteria for the size and number of tumors, observed 4-year actual survival of 75% and recurrence-free survival of 83%9 or 5-year survival of 74%. Similarly, our overall survival of 78% and disease-free survival of 69% in 3 years for patients with tumor size of 5 cm or less reinforces the recommendation of OLT for such patients. Among patients with low-grade (well- to moderately differentiated) HCC, even better 3-year survival of 81% was observed. Furthermore, patients with large (>5 cm) but well-differentiated tumors demonstrated 3-year survival of 62%, suggesting that these patients might also be candidates for OLT in selected circumstances. On the contrary, patients with large (>5 cm) poorly differentiated tumors had a dismal prognosis. In our study, most of these patients presented with recurrence within a short period, and none survived more than a year.

Our single-center study reaffirms the findings of the multicenter study and suggests that, aside from size and multiplicity, histological differentiation of the tumor is a statistically significant factor affecting prognosis. In our multivariate analysis, histological differentiation of the tumor, an indicator of biological aggressiveness and progression,13,27 was an independent, statistically significant factor affecting survival. Histological differentiation of the tumor was also a statistically significant factor in multivariate analysis for disease-free survival. From these results, it seems that indication for OLT should not be defined solely by size of the tumor but also with consideration of biological aggressiveness of the tumor cells as indicated by histological differentiation.

Orthotopic liver transplantation for HCC has several problems that must be considered. Waiting time for a graft is often 1 year or longer, during which HCC might grow and progress. To circumvent this problem, adjunctive measures might be necessary. Effective adjuvant therapy to prevent further progression of the tumor could be applied. Because most OLT candidates have poor functional reserve of the liver, nonsurgical local ablation modalities such as thermal ablation28,29 or percutaneous ethanol injection therapy30 might be useful. In our series, a small number of patients received transarterial chemoembolization before OLT and chemotherapy after OLT. Although a previous study31 suggested the beneficial effect of chemotherapy or adjuvant therapy combined with OLT for HCC, this was not clearly demonstrated in our series, probably because of the small number of patients. Further prospective studies are required. More attractive options, such as living-related liver transplantation,32 split-liver transplantation,33 or domino transplantation,34,35 should be serious considerations because these measures can effectively reduce waiting time.

In our experience, histological differentiation had a statistically significant effect on prognosis. Patients with small-sized HCC, regardless of histological grading, should be acceptable candidates for OLT. For relatively large tumors (slightly greater than 5 cm in diameter), OLT should not be denied solely on the basis of the size of the tumor. Because ultrasound-guided biopsy is a reliable and relatively safe method for obtaining histological information,36 we suggest a preoperative biopsy to determine the histological differentiation should the HCC be large. Nonetheless, such an approach might have inherent, albeit small, risks of bleeding and tumor seeding. The reported rates of tumor implantation attributable to needle biopsies have varied from 0.005% to 5.1%,37,38 with most of the implanted tumors occurring in the chest or the abdominal wall. Furthermore, tumor differentiation obtained through needle biopsy may not be well appreciated because of the small sample size. An alternative, therefore, may be an open or laparoscopic biopsy that can only be applied for superficial lesions. For deeper intraparenchymal lesions, an intraoperative ultrasound-guided approach seems appropriate.

In conclusion, treatment protocols for HCC with OLT with or without nonsurgical modalities should consider histological grade of the tumor as a possible factor affecting survival. In addition, before we alter patient selection criteria, prospective trials are needed to confirm the impact of histological grade on the outcome of OLT for HCC.

Corresponding author and reprints: Tomoaki Kato, MD, Division of Transplantation, Department of Surgery, University of Miami School of Medicine, 1801 NW Ninth Ave, Highland Professional Building, Suite 511, Miami, FL 33136.

Colombo  M Hepatocellular carcinoma. J Hepatol. 1992;15225- 236
Link to Article
Schafer  DFSorrell  MF Hepatocellular carcinoma. Lancet. 1999;3531253- 1257
Link to Article
Okuda  KOhtsuki  TObata  H  et al.  Natural history of hepatocellular carcinoma and prognosis in relation to treatment: study of 850 patients. Cancer. 1985;56918- 928
Link to Article
Venook  AP Treatment of hepatocellular carcinoma: too many options? J Clin Oncol. 1994;121323- 1334
Farmer  DGRosove  MHShaked  ABusuttil  RW Current treatment modalities for hepatocellular carcinoma. Ann Surg. 1994;219236- 247
Link to Article
Penn  I Hepatic transplantation for primary and metastatic cancer of the liver. Surgery. 1991;110726- 735
Bismuth  HChiche  LAdam  RCastaing  DDiamond  TDennison  A Liver resection versus transplantation for hepatocellular carcinoma in cirrhotic patients. Ann Surg. 1993;218145- 151
Link to Article
Iwatsuki  SGordon  RDShaw  BW  JrStarzl  TE Role of liver transplantation in cancer therapy. Ann Surg. 1985;202401- 407
Link to Article
Mazzaferro  VRegalia  EDoci  R  et al.  Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334693- 699
Link to Article
Klintmalm  GB Liver transplantation for hepatocellular carcinoma: a registry report of the impact of tumor characteristics on outcome. Ann Surg. 1998;228479- 490
Link to Article
Hermanek  PedSobin  LHed(International Union Against Cancer), TNM Classification of Malignant Tumors. 4th ed, 2nd rev. Berlin, Germany Springer1992;
Kondo  Y Histologic features of hepatocellular carcinoma and allied disorders. Pathol Annu. 1985;20405- 430
Sugihara  SNakashima  OKojiro  MMajima  YTanaka  MTanikawa  K The morphologic transition in hepatocellular carcinoma: a comparison of the individual histologic features disclosed by ultrasound-guided fine-needle biopsy with those of autopsy. Cancer. 1992;701488- 1492
Link to Article
Edmondson  HASteiner  PE Primary carcinoma of the liver: a study of 100 cases among 48,900 necropsies. Cancer. 1954;7462- 503
Link to Article
Kaplan  EMeier  P Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53457- 481
Link to Article
Mantel  NHaenszel  W Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22719- 748
Cox  D Regression models and life tables. J R Stat Soc (B). 1972;34187- 220
McPeake  JRO'Grady  JGZaman  S  et al.  Liver transplantation for primary hepatocellular carcinoma: tumor size and number determine outcome. J Hepatol. 1993;18226- 234
Link to Article
Ringe  BPichimayr  RWittekind  CTusch  G Surgical treatment of hepatocellular carcinoma: experience with liver resection and transplantation in 198 patients. World J Surg. 1991;15270- 285
Link to Article
Selby  RKadry  ZCarr  BTzakis  AMadariaga  JRIwatsuki  S Liver transplantation for hepatocellular carcinoma. World J Surg. 1995;1953- 58
Link to Article
Iwatsuki  SStarzl  TESheahan  DG  et al.  Hepatic resection versus transplantation for hepatocellular carcinoma. Ann Surg. 1991;214221- 229
Link to Article
Yamamoto  TKajinao  KKudo  MSasaki  YArakawa  YHino  O Determination of the clonal origin of multiple human hepatocellular carcinomas by cloning and polymerase chain reaction of the integrated hepatitis B virus DNA. Hepatology. 1999;291446- 1452
Link to Article
Kumada  TNakano  STakeda  I  et al.  Patterns of recurrence after initial treatment in patients with small hepatocellular carcinoma. Hepatology. 1997;2587- 92
Link to Article
Eguchi  AFuruta  THaraguchi  MSugimachi  K A valid new approach in treating solitary new lesions after resection of hepatocellular carcinoma. J Surg Oncol. 1994;56263- 268
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Otto  GHeuschen  UHofmann  WJKrumm  GHinz  UHerfarth  C Survival and recurrence after liver transplantation versus liver resection for hepatocellular carcinoma: a retrospective analysis. Ann Surg. 1998;227424- 432
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Llovet  JMBruix  JFuster  J  et al.  Liver transplantation for small hepatocellular carcinoma: the tumor-node-metastasis classification does not have prognostic power. Hepatology. 1998;271572- 1577
Link to Article
Mise  KTashiro  SYogita  S  et al.  Assessment of the biological malignancy of hepatocellular carcinoma: relationship to clinicopathological factors and prognosis. Clin Cancer Res. 1998;41475- 1482
Seki  TWakabayashi  MNakagawa  T  et al.  Ultrasonically guided percutaneous microwave coagulation therapy for small hepatocellular carcinoma. Cancer. 1994;74817- 825
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Curley  SAIzzo  FDelrio  P  et al.  Radiofrequency ablation of unresectable primary and metastatic hepatic malignancies: results in 123 patients. Ann Surg. 1999;2301- 8
Link to Article
Shiina  STagawa  KNiwa  Y  et al.  Percutaneous ethanol injection therapy for hepatocellular carcinoma: results in 146 patients. AJR Am J Roentgenol. 1993;1601023- 1028
Link to Article
Olthoff  KMRosove  MHShackleton  CR  et al.  Adjuvant chemotherapy improves survival after liver transplantation for hepatocellular carcinoma. Ann Surg. 1995;221734- 743
Link to Article
Tanaka  KUemoto  STokunaga  Y  et al.  Surgical techniques and innovations in living-related liver transplantation. Ann Surg. 1993;21782- 91
Link to Article
Busuttil  RWGoss  JA Split liver transplantation. Ann Surg. 1999;229313- 321
Link to Article
Tzakis  AGNery  JRRaskin  JB  et al.  ‘Domino' liver transplantation combined with multivisceral transplantation. Arch Surg. 1997;1321145- 1147
Link to Article
Stangou  AJHeaton  NDRela  MPepys  MBHawkins  PNWilliams  R Domino hepatic transplantation using the liver from a patient with familial amyloid polyneuropathy. Transplantation. 1998;651496- 1498
Link to Article
Chapel  FGuettier  CChastang  C  et al.  Needle biopsy of hepatocellular carcinoma: assessment of prognostic contribution of histologic parameters including proliferating cell nuclear antigen labeling and correlations with clinical outcomes. Cancer. 1996;77864- 871
Link to Article
Takamori  RWong  LLDang  CWong  L Needle-tract implantation from hepatocellular cancer: is needle biopsy of the liver always necessary? Liver Transpl. 2000;667- 72
Smith  EH The hazards of fine-needle aspiration biopsy. Ultrasound Med Biol. 1984;10629- 634
Link to Article

Figures

Place holder to copy figure label and caption
Figure 2.

Effect of histological differentiation in large (>5-cm) tumors. Although survival for patients with tumors larger than 5 cm with poorly differentiated hepatocellular carcinoma (HCC) was extremely poor, patients with well- to moderately differentiated HCC with tumors larger than 5 cm had unexpectedly good survival rates.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Effect of histological differentiation in small (≤5-cm) tumors. Patients with small tumors did well in general. Three-year survival was 82% for patients with well- to moderately differentiated hepatocellular carcinoma (HCC) and 67% in patients with poorly differentiated HCC.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Comparison of disease-free intervals between well- to moderately differentiated hepatocellular carcinoma (HCC) and poorly differentiated HCC in patients with recurrence.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 1.

Overall survival and recurrence in 53 patients. Median follow-up was 709 days and mean follow-up was 887 days, with the longest survival exceeding 8 years (2976 days). No recurrence was noted more than 3 years after orthotopic liver transplantation.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 2. Cox Regression Model for Histological Differentiation and pTNM Stage and for Histological Differentiation and Size*
Table Graphic Jump LocationTable 3. Disease-Free Survival According to Clinicopathologic Features*
Table Graphic Jump LocationTable 4. Cox Regression Model for Histological Differentiation and Lymph Node Metastasis and for Histological Differentiation*
Table Graphic Jump LocationTable 5. Histological Differentiation, Tumor Size, and Prognosis
Table Graphic Jump LocationTable 1. Overall Survival According to Clinicopathologic Features*

References

Colombo  M Hepatocellular carcinoma. J Hepatol. 1992;15225- 236
Link to Article
Schafer  DFSorrell  MF Hepatocellular carcinoma. Lancet. 1999;3531253- 1257
Link to Article
Okuda  KOhtsuki  TObata  H  et al.  Natural history of hepatocellular carcinoma and prognosis in relation to treatment: study of 850 patients. Cancer. 1985;56918- 928
Link to Article
Venook  AP Treatment of hepatocellular carcinoma: too many options? J Clin Oncol. 1994;121323- 1334
Farmer  DGRosove  MHShaked  ABusuttil  RW Current treatment modalities for hepatocellular carcinoma. Ann Surg. 1994;219236- 247
Link to Article
Penn  I Hepatic transplantation for primary and metastatic cancer of the liver. Surgery. 1991;110726- 735
Bismuth  HChiche  LAdam  RCastaing  DDiamond  TDennison  A Liver resection versus transplantation for hepatocellular carcinoma in cirrhotic patients. Ann Surg. 1993;218145- 151
Link to Article
Iwatsuki  SGordon  RDShaw  BW  JrStarzl  TE Role of liver transplantation in cancer therapy. Ann Surg. 1985;202401- 407
Link to Article
Mazzaferro  VRegalia  EDoci  R  et al.  Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334693- 699
Link to Article
Klintmalm  GB Liver transplantation for hepatocellular carcinoma: a registry report of the impact of tumor characteristics on outcome. Ann Surg. 1998;228479- 490
Link to Article
Hermanek  PedSobin  LHed(International Union Against Cancer), TNM Classification of Malignant Tumors. 4th ed, 2nd rev. Berlin, Germany Springer1992;
Kondo  Y Histologic features of hepatocellular carcinoma and allied disorders. Pathol Annu. 1985;20405- 430
Sugihara  SNakashima  OKojiro  MMajima  YTanaka  MTanikawa  K The morphologic transition in hepatocellular carcinoma: a comparison of the individual histologic features disclosed by ultrasound-guided fine-needle biopsy with those of autopsy. Cancer. 1992;701488- 1492
Link to Article
Edmondson  HASteiner  PE Primary carcinoma of the liver: a study of 100 cases among 48,900 necropsies. Cancer. 1954;7462- 503
Link to Article
Kaplan  EMeier  P Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53457- 481
Link to Article
Mantel  NHaenszel  W Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22719- 748
Cox  D Regression models and life tables. J R Stat Soc (B). 1972;34187- 220
McPeake  JRO'Grady  JGZaman  S  et al.  Liver transplantation for primary hepatocellular carcinoma: tumor size and number determine outcome. J Hepatol. 1993;18226- 234
Link to Article
Ringe  BPichimayr  RWittekind  CTusch  G Surgical treatment of hepatocellular carcinoma: experience with liver resection and transplantation in 198 patients. World J Surg. 1991;15270- 285
Link to Article
Selby  RKadry  ZCarr  BTzakis  AMadariaga  JRIwatsuki  S Liver transplantation for hepatocellular carcinoma. World J Surg. 1995;1953- 58
Link to Article
Iwatsuki  SStarzl  TESheahan  DG  et al.  Hepatic resection versus transplantation for hepatocellular carcinoma. Ann Surg. 1991;214221- 229
Link to Article
Yamamoto  TKajinao  KKudo  MSasaki  YArakawa  YHino  O Determination of the clonal origin of multiple human hepatocellular carcinomas by cloning and polymerase chain reaction of the integrated hepatitis B virus DNA. Hepatology. 1999;291446- 1452
Link to Article
Kumada  TNakano  STakeda  I  et al.  Patterns of recurrence after initial treatment in patients with small hepatocellular carcinoma. Hepatology. 1997;2587- 92
Link to Article
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