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© 1999 American Society for Clinical Oncology Recurrence Patterns of Hepatocellular and Fibrolamellar Carcinoma After Liver Transplantation From the Klinik für Abdominal-und Transplantationschirurgie; Abteilung Hämatologie und Onkologie; Abteilung Gastroenterologie und Hepatologie; Institut für Pathologie; and Abteilung Biometrie, Medizinische Hochschule Hannover, Hannover, Germany. Address reprint requests to Priv.-Doz. Dr. Hans J. Schlitt, Klinik für Abdominal- und Transplantationschirurgie, Medizinische Hochschule Hannover, Carl-Neuberg-Str 1, D-30623 Hannover, Germany; Email schlitt{at}tx-amb.mh-hannover.de
PURPOSE: Tumor recurrence is the major limitation of long-term survival after liver transplantation for hepatocellular carcinoma (HCC) or fibrolamellar carcinoma (FLC). Understanding tumor-biologic characteristics is important for selection of patients and for development of adjuvant therapeutic strategies. PATIENTS AND METHODS: The study included 69 patients who underwent potentially curative liver transplantation for HCC/FLC and survived for more than 150 days; minimum follow-up was 33 months. Frequency, localization, and timing of recurrence were analyzed and compared with primary tumor and patient characteristics.
RESULTS: Tumor recurrence was observed in 39 patients at 67 locations. Hematogenous spread was the major route of tumor recurrence (87%), and the most frequent sites were the liver (62%), lung (56%), and bone (18%). Parameters associated with recurrence were absence of cirrhosis, tumor size greater than 5 cm, more than five nodules, vascular infiltration, and International Union Against Cancer (UICC) stage IVA. Selective intrahepatic recurrence was found in nine patients (23%); it was associated with highly differentiated tumors, lack of vascular infiltration, and male sex. Recurrence at multiple sites was found predominantly in young patients ( CONCLUSION: In transplant recipients, hepatocellular carcinomas vary considerably in their pattern and kinetics of metastases. Tumor cells may persist in a dormant state for long time periods before giving rise to clinical metastases. Surgical treatment of recurrence should be considered whenever possible.
HEPATOCELLULAR CARCINOMA IS ONE of the most frequent tumor entities world-wide, and tumor recurrence is a major limitation of long-term survival in liver transplant patients even after radical surgical treatment.1 Strategies for avoiding and treating tumor recurrence and for improving long-term results of liver transplantation for hepatocellular cancer must be based on a detailed knowledge of its tumor-biologic characteristics. After liver resection for hepatocellular carcinoma, tumors recur mainly in the liver.14 Recurrence can be caused by three mechanisms: inadequate resection, intrahepatic hematogenous tumor cell spread, and de novo (multicentric) tumor development in a cirrhotic liver. In such a heterogeneous setting, analysis of tumor-biologic aspects concerning HCC metastasis is difficult. In contrast to resection, the background for tumor recurrence after liver transplantation is basically different. In cases of radical local tumor removal, recurrence after transplantation can only be caused by preoperative or intraoperative spread of tumor cells (micrometastases). Therefore, the transplant situation represents a good model for studying biologic features of hepatocellular carcinoma metastasis in detail. We report on patterns of tumor recurrence in a large series of patients who received liver transplants for hepatocellular carcinoma (HCC) or fibrolamellar carcinoma (FLC) at a single center. In contrast to previous reports that have analyzed survival rates and potentially predictive parameters in the overall population,5-7 our study focused on tumor-biologic aspects, such as the routes of metastasis, risk factors, timing, and tissue distribution of tumor recurrence, and in this article, we report on the therapeutic strategies applied for recurrent hepatocellular carcinoma after transplantation. Because the indications for liver transplantation in our center have changed over time, the study included a broad variety of tumor stages. For this analysis, only patients who had undergone radical (R0) tumor resection were evaluated, excluding tumor-unrelated, perioperative, in-hospital deaths.
Between 1972 and December 1994, 999 liver transplantations were performed in 835 patients at the Medizinische Hochschule Hannover. Of those patients, 114 (13.6%) had HCC or FLC. Forty-five patients who either died within the first 150 days after transplantation (n = 35) or had macroscopically detectable extrahepatic tumors (mainly positive lymph nodes) at the time of transplantation (n = 10) were excluded; 31 of the patients who were excluded had received a transplant before 1988. Of the 35 patients excluded because they died within 150 days after transplantation, one had died after intracerebral bleeding into a brain metastasis of the liver tumor that was probably present at the time of transplantation; all others had no evidence of tumor at the time of death. Thus, 69 patients who had survived the perioperative period and who had no evidence of remaining tumor were included in this analysis. Because the indication for liver transplantation for HCC has changed considerably over time, a broad variety of tumor stages are included. Patient and tumor characteristics are listed in Table 1. Only six of the most recent patients had received pretreatment by chemoembolization, and four of them had also received adjuvant chemotherapy with adriamycin. Lymphadenectomy during transplantation was not performed systematically. Histologic analysis was performed according to the tumor-node-metastasis system and by use of the International Union Against Cancer (UICC) classification system. Immunosuppressive treatment was cyclosporine-based in most patients and included induction treatment by antithymocyte globulin or anti-interleukin 2 receptor monoclonal antibodies initially and long-term, dual (cyclosporine/corticosteroids) treatment in most patients.
Minimum follow-up in surviving patients was 36 months; the final date of follow-up was December 1997. The date of tumor recurrence was defined in one of two ways, as follows: (1) by observation of newly increased alpha-fetoprotein (AFP) values in patients with initially AFP-positive tumors and subsequent detection of tumor recurrence by imaging techniques (computed tomographic scan, ultrasound, chest x-ray, etc.), or (2) by the date of positive imaging findings and histologic confirmation in patients with AFP-negative tumors. During the observation period, 43 of the patients died, 32 from tumor recurrence and 11 because of tumor-unrelated causes, including one patient who died after radical resection of tumor recurrence. Fourteen patients died within the first year (recurrence, n = 8; no recurrence, n = 6), 20 died in the second or third year (recurrence, n = 19; no recurrence, n = 1), and nine died more than 3 years after transplantation (recurrence, n = 6; no recurrence, n = 3).
Statistical Methods P values of less than .05 were considered statistically significant. Calculated P values are given whenever they were less than .10; for P values of .10 or higher, "not significant" (NS) is indicated.
Frequency and Tissue Distribution of Tumor Recurrence Tumor recurrence after transplantation was observed in 39 (56.5%) of 69 patients studied. In these 39 patients, tumor recurrence was detected at 67 sites. Metastases were hematogenous in 58 instances (86.6%), in local lymph nodes in four cases (6.0%), and intraperitoneal in five cases (7.5%). Among these 39 patients, the liver was the most common individual site of recurrence (24 patients [61.5%]), followed by the lung (22 patients [56.4%]), bone (seven patients [17.9%]), and other sites, such as the CNS and the adrenal glands (five patients). Nine patients (23.1%) had only intrahepatic recurrence, 15 (38.5%) had intra- and extrahepatic recurrence, and another 15 (38.5%) presented with only extrahepatic tumor recurrence. Recurrence was limited to one tissue type only in 20 patients (lung only, n = 10; liver only, n = 9; bone only, n = 1) and was found in multiple organs or tissues in 19 patients.
Influence of Primary Tumor and Patient Characteristics on Recurrence
Another parameter associated with higher rates of tumor recurrence was absence of cirrhosis (P = .0050). Only 19 (43%) of 44 patients with tumors in cirrhosis experienced recurrence, compared with 20 (80%) of 25 patients without cirrhosis. A comparison of the effect of cirrhosis for different UICC stages showed a particularly low recurrence rate for UICC stage I/II with cirrhosis (only one of 11 tumors recurred) compared with stage I/II without cirrhosis (three of four tumors recurred) (P = .0269). It must be considered, however, that tumor size was smaller in the 12 patients with cirrhosis (median, 3 cm; all tumors were
No effect on tumor recurrence was observed for tumor grading, hepatitis B surface antigen state, favorable (tumor unilocular or
Influence of Primary Tumor and Patient Characteristics on Localization of Recurrence
Combined intra- and extrahepatic recurrence was predicted by the primary presence of more than five tumor nodules (P = .0244) and by patient age of 40 years or younger (P = .0069) (Table 4). Tumor recurrence in one tissue type only (ie, liver, lung, or bone), compared with recurrence in various tissue types, was strongly predicted by patient age; older age (> 40 years) was associated with more tissue-restricted recurrence, whereas young age predicted recurrence in multiple tissues or organs (P = .0225) (Table 5).
Peritoneal recurrence was associated with young age and with tumors without cirrhosis in four of five patients. No association with primary tumor characteristics was found for the four cases with lymph node recurrence; none of these patients had intrahepatic recurrence, but all had metastases at other sites. All three patients with fibrolamellar carcinoma had both intra- and extrahepatic recurrence.
Kinetics of Tumor Recurrence
For patients with lymph node metastases, median time to recurrence was 249 days (range, 213 to 865 days); for patients with peritoneal metastases, the median time was 575 days (range, 341 to 3,204 days). The median time to recurrence was significantly higher in patients with fibrolamellar carcinoma (Table 6). Although there was a tendency toward a longer time to recurrence for patients with grade 1 tumors (compared with grade 2/3), this difference did not reach statistical significance because of the wide time ranges observed, particularly for grade 1 tumors. Four of those 10 patients had late recurrence (> 1,000 days), whereas only two of 26 patients with grade 2/3 tumors had late recurrence.
Outcome and Treatment of Tumor Recurrence In 15 patients, 21 surgical interventions were performed at 27 sites, with or without additional chemotherapy. In eight patients, pulmonary metastases were resected; two patients had repeated operations for recurrent pulmonary metastases. Peritoneal metastases were removed in three patients, and an ovariectomy was performed in one patient. In one patient, a lymphadenectomy along the celiac axis was performed. In three cases, liver metastases were removed by resection, and in two cases, liver retransplantation was performed 6 and 10 years after initial transplantation. In 11 of those 15 patients, complete removal of the recurrent tumor could be achieved at a median period of 3.1 years after transplantation. Of these 11 patients, seven are currently alive and recurrence-free at a median period of 4.3 years (maximum, 19 years) after reoperation. Three patients died from further tumor recurrence at a median period of 1.6 years after surgical reintervention, and one patient died of a tumor-unrelated cause.
The aim of this study was not to evaluate the overall concept of liver transplantation as treatment for HCC, but to analyze tumor-biologic aspects of recurrent HCC after transplantation and their therapeutic implications. For this purpose, the study population was selected on the basis of two factors: (1) potentially curative surgery, thus patients who had histologic evidence of nonradical resection were excluded retrospectively; and (2) survival for at least 150 days after transplantation, ie, the early perioperative period with its complications, an approach that has also been used by another group to obtain more valid results on the predictive value of primary tumor and patient characteristics.8 The size of the primary tumor and the number of nodules were found to be strongly associated with the risk of recurrence after transplantation. The association of these parameters with recurrence or survival has also been suggested by others,4,810 although it could not be detected in all studies,11 including our own study of an unselected patient population.7 The most significant differences in the present study were observed when tumor size of 5 cm and five nodules were used as cutoff points for statistical analysis. This suggests that these parameters might also be used as a basis for clinical decisions about liver transplantation. Other strongly predictive parameters were vascular invasion of the tumor and tumor UICC stage. However, these classifications were only known after the surgical procedure and histologic work-up, so they are not prospectively available for clinical decision making. The rate of HCC recurrence after transplantation, particularly for low UICC tumor stages I and II, was clearly associated with the concomitant presence or absence of cirrhosis. The recurrence rate was very low for patients with UICC stage I/II tumors in cirrhosis, whereas it was high for patients with stage I/II tumors without cirrhosis. It has to be considered, however, that the cirrhosis group also included tumors detected incidentally after transplantation, so that it is difficult to directly convert these observations into clinical practice. Nevertheless, the finding of a low recurrence rate of stage I/II tumors in cirrhosis clearly supports the data of others,12,13 suggesting that low tumor stages in cirrhosis represent a particularly favorable indication for transplantation. Whether the inferior prognosis of stage I/II tumors in the absence of cirrhosis is due to the considerably larger tumor size in these patients or whether it represents different biologic features remains speculative. The long time interval to recurrence in patients with large stage I/II tumors without cirrhosis has also been observed by others11 and may indicate that these tumors do not grow aggressively. Recurrent tumors were treated surgically in all three of these patients; one of them is alive almost 20 years after resection of the recurrent tumor, and another died with no tumor. Tumor recurrence after transplantation can be associated with three different routes of metastasis: lymphogenic, peritoneal, and hematogenous. Lymphatic spread leading to recurrence in lymph nodes in the celiac and para-aortal regions was observed in only 6% of the patients, although lymphadenectomy was not performed systematically. Since these patients had no evidence of tumor recurrence in the transplanted liver, these metastases must have occurred before transplantation. However, all patients with lymph node recurrence also had metastases at other localizations. Therefore, the prognostic relevance of lymphatic spread of HCC, and thus the importance of a more extensive lymphadenectomy during operation, remains speculative. Peritoneal tumor cell dissemination can occur by intraoperative spilling of tumor cells either from accidental opening of the tumor during hepatectomy or by lymphatic fluid leakage during dissection of the liver hilum. In the study group, peritoneal metastases were observed in 7.5% of the patients, particularly in young patients with no cirrhosis. Early intraperitoneal recurrence was usually associated with diffuse tumor infiltration, whereas the late recurrence in two patients was localized and was associated with highly differentiated tumors. This demonstrates that well-differentiated tumor cells can survive in the peritoneal cavity for several years before growing into detectable tumor nodules. Overall, peritoneal spread is also not a major pathway for tumor recurrence after liver transplantation for HCC, particularly not for tumors in cirrhosis. Hematogenous spread was the predominant route of metastasis in liver-transplanted patients. Remarkably, the major target for tumor recurrence by the hematogenous route was the transplanted liver itself, a feature that has also been suggested by others.4,5,10,11,14 This seems to be similar to the pattern after liver resection for HCC, in which the liver is also the most frequent site of recurrence. For intrahepatic recurrence, it has been suggested by molecular biologic analysis that both intrahepatic metastases of the primary tumor and de novo tumor development may play a similarly important role.1517 The biologic basis in the transplant setting, however, is markedly different because the carcinogenic potential is eliminated by complete removal of the organ. Although there may be a certain risk of de novo tumorigenesis after recurrent hepatitis and cirrhosis in the graft, this seems to be extremely rare.18 Therefore, intrahepatic recurrence after transplantation must be due to hematogenous metastasis of the original tumor. In one case in which the tumor reappeared in the transplanted liver after de novo hepatitis B cirrhosis had developed, it could be shown that this was due to recurrence.19 The various patterns of tumor recurrence after transplantation were clearly associated with different tumor and patient characteristics. Multifocal intra- and extrahepatic recurrence was frequently observed in young patients and in cases of vascular infiltration of the primary tumor. In contrast, selective intrahepatic metastases were observed mainly for well-differentiated and noninfiltrating tumors—an association that has already been suggested by an earlier report11—and for tumors originating from cirrhotic livers and older patients. The presence of cirrhosis or active hepatitis has also been described as a risk factor for intrahepatic recurrence after resection, although in these patients it was considered to be due to multicentric carcinogenesis.20 The strong relationship between intrahepatic tumor recurrence after transplantation and male sex may point to a role of hormonal factors for this pathway of metastasis.21 Interestingly, in a recent study, the Pittsburgh group8 found a strong influence of male sex on the risk of HCC recurrence, and their patient population shows a particularly high rate of tumor recurrence in the liver.14 Because both intra- and extrahepatic recurrence are caused by the same route of tumor cell distribution, ie, the blood circulation, the tumor cells must differ in either their homing patterns (eg, by differential expression of adhesion molecules)22 or their microenvironmental requirements for cell growth (eg, certain cytokines, as also suggested for colon carcinoma).23 Such organ specificities in the pattern of tumor cell metastasis has been studied extensively in animal models2426 and are described in this article for hepatocellular carcinomas in the clinical situation. Our observations could be explained by the fact that highly differentiated tumor cells may require the specific cytokine microenvironment of the liver for proliferation, whereas less differentiated tumor cells may have less stringent growth requirements. The fact that aggressiveness and highly organ-specific recurrence patterns are not mutually exclusive, however, is demonstrated by cases of selective fulminant tumor recurrence in the liver graft very early after transplantation. In 20% of our patients, the tumor recurred more than 3 years after transplantation, a finding that is different from the low rate of late recurrence (1.4%) observed in a large series by Marsh et al.8 Long intervals to recurrence were mainly observed in patients with well-differentiated HCC or FLC and in patients with low UICC stages without cirrhosis. Cells from these tumors can obviously persist for many years. Micrometastases have been described in bone marrow of patients with various tumors27,28 and recently also in the blood of patients with HCC (Funaki et al29 and our own unpublished observations). The biologic relevance of these cells is still not completely clear, but their presence may be associated with a higher rate of tumor recurrence.27,28 What keeps these cells dormant for long periods and what later reactivates them to migration and recurrent tumor formation remains speculative.30 The predominance of young female patients among those with very late recurrence, although only at the borderline of statistical significance, again may suggest some contribution of hormonal factors. Adjuvant therapeutic strategies for prevention of HCC recurrence must take into account that probably most of the peripheral tumor cells are in a low proliferative state and, therefore, have only low susceptibility to standard chemotherapy. Although the protocols currently being used for adjuvant chemotherapy after transplantation suggest some positive effects,31 most studies have also included preoperative chemoembolization, so that the direct contribution of chemotherapy cannot be evaluated.32,33 Considering the low division rate of the potential target cells, immunologic approaches by monoclonal antibodies34,35 or gene therapeutic strategies36 may be more attractive tools for adjuvant treatment in these patients. The prognosis of tumor recurrence in transplant recipients is generally bad, and survival times after radiotherapy or chemotherapy for recurrence did not differ from the survival times when there was no tumor-specific treatment. The only patients who survived long term were some of the patients in whom tumor recurrence was approached surgically. Clearly, these patients represent a highly selected subgroup in which the recurrent tumor is usually well localized so that resection can be considered. Surgical treatment was particularly successful in patients in whom recurrence developed late after transplantation, ie, patients with well-differentiated primary tumors; some of these patients have then survived for longer periods. This success demonstrates that surgical treatment of recurrent tumor should be considered whenever possible, as is done for patients with intra- or extrahepatic recurrence after resection,37,38 and underlines the need for close monitoring (AFP levels, abdominothoracic computed tomographic scans, bone scans) of the patients in the early as well as the long-term postoperative phase. In individual cases, even retransplantation for late intrahepatic recurrence may be indicated. It must be kept in mind, however, that the risk for further tumor recurrence in these patients persists because micrometastastic cells in the periphery may survive. Targeting of these cells must be a major focus of future research.
 Deceased. 
1. Okuda K, Ohtsuki T, Obata H, et al: Natural history of hepatocellular carcinoma and prognosis in relation to treatment: Study of 850 patients. Cancer 56:918-928, 1985[Medline] 2. Nagasue N, Uchida M, Makino Y, et al: Incidence and factors associated with intrahepatic recurrence following resection of hepatocellular carcinoma. Gastroenterology 105:488-494, 1993[Medline] 3. Belghiti J, Panis Y, Farges O, et al: Intrahepatic recurrence after resection of hepatocellular carcinoma complicating cirrhosis. Ann Surg 214:114-117, 1991[Medline] 4. Michel J, Suc B, Montpeyroux F, et al: Liver resection or transplantation for hepatocellular carcinoma? Retrospective analysis of 215 patients with cirrhosis. J Hepatol 26:1274-1280, 1997[Medline] 5. Ringe B, Wittekind C, Bechstein WO, et al: The role of liver transplantation in hepatobiliary malignancy: A retrospective analysis of 95 patients with particular regard to tumor stage and recurrence. Ann Surg 209:88-98, 1989[Medline] 6. Pichlmayr R, Weimann A, Ringe B: Indications for liver transplantation in hepatobiliary malignancy. Hepatology 20:33S-40S, 1994
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Pichlmayr R, Weimann A, Tusch G, et al: Indications and role of liver transplantation for malignant tumors. Oncologist 2:164-170, 1997 8. Marsh JW, Dvorchik I, Subotin M, et al: The prediction of risk of recurrence and time to recurrence of hepatocellular carcinoma after orthotopic liver transplantation: A pilot study. Hepatology 26:444-450, 1997[Medline] 9. Iwatsuki S, Starzl TE, Sheahan DG, et al: Hepatic resection versus transplantation for hepatocellular carcinoma. Ann Surg 214:221-229, 1991[Medline] 10. Bismuth H, Adam R, Raccuia J, et al: Liver transplantation for hepatocellular carcinoma in cirrhosis. Transplant Rev 10:12-23, 1996 11. O'Grady J Polson RJ, Rolles K, et al: Liver transplantation for malignant disease: Results in 93 consecutive patients. Ann Surg 207:373-379, 1988[Medline] 12. Bismuth H, Chiche L, Adam R, et al: Liver resection versus transplantation for hepatocellular carcinoma in cirrhotic patients. Ann Surg 218:145-151, 1993[Medline]
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Mazzaferro V, Regalia E, Doci R, et al: Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 334:693-699, 1996 14. Yokoyama I, Todo S, Iwatsuki S, et al: Liver transplantation in the treatment of primary liver cancer. Hepatogastroenterology 37:188-193, 1990[Medline] 15. Kumada T, Nakano S, Takeda I, et al: Patterns of recurrence after initial treatment in patients with small hepatocellular carcinoma. Hepatology 25:87-92, 1997[Medline] 16. Chen PJ, Chen DS, Lai MY, et al: Clonal origin of recurrent hepatocellular carcinomas. Gastroenterology 96:527-529, 1989[Medline] 17. Sheu JC, Huang GT, Chou HC, et al: Multiple hepatocellular carcinomas at the early stage have different clonality. Gastroenterology 105:1471-1476, 1993[Medline] 18. Böker K, Dalley G, Bahr MJ, et al: Long-term outcome of hepatitis C virus infection after liver transplantation. Hepatology 25:203-210, 1997[Medline] 19. Ringe B, Böker K Schlitt HJ, et al: Recurrence of hepatitis B virus cirrhosis and hepatocellular carcinoma: An indication for retransplantation? Clin Transplant 9:190-196, 1995[Medline] 20. Ko S, Nakajima Y, Kanehiro H, et al: Significant influence of accompanying chronic hepatitis status on recurrence of hepatocellular carcinoma after hepatectomy: Results of a multivariate analysis. Ann Surg 5:591-595, 1996 21. Naguse N, Yu L, Yukaya H, et al: Androgen and oestrogen receptors in hepatocellular carcinoma and surrounding liver parenchyma: Impact on intrahepatic recurrence after hepatic resection. Br J Surg 82:542-547, 1995[Medline] 22. Osada T, Sakamoto M, Ino Y, et al: E-cadherin is involved in the intrahepatic metastasis of hepatocellular carcinoma. Hepatology 24:1460-1467, 1996[Medline] 23. Radinsky R: Molecular mechanisms for organ-specific colon carcinoma metastasis. Eur J Cancer 31A:1091-1095, 1995 24. Yeatman TJ, Nicolson GL: Molecular basis of tumor progression: Mechanisms of organ-specific metastasis. Semin Surg Oncol 9:256-263, 1993[Medline] 25. Rofstad EK: Metastatic behavior of human tumors in congenitally athymic nude mice: Intrinsic properties of the tumor cells and host immune reactivity. Int J Cancer 63:744-749, 1995[Medline] 26. Fidler IJ: Critical determinants of melanoma metastasis. J Invest Dermatol Symp Proc 1:203-208, 1996 27. Schlimok G, Funke I, Bock B, et al: Epithelial tumor cells in the bone marrow of patients with colorectal cancer: Immunocytochemical detection, phenotypic characterization and prognostic significance. J Clin Oncol 8:831-837, 1990[Abstract] 28. Pantel K, Izbicki J, Passlick B, et al: Frequency and prognostic significance of isolated tumor cells in bone marrow of patients with non-small-cell lung cancer without overt metastases. Lancet 347:649-635, 1996[Medline] 29. Funaki NO, Tanaka J, Seto SI, et al: Hematogenous spreading of hepatocellular carcinoma cells: Possible participation in recurrence in the liver. Hepatology 25:564-568, 1997[Medline] 30. Uhr JW, Scheuermann RH, Street NE, et al: Cancer dormancy: opportunities for new therapeutic approaches. Nat Med 3:505-509, 1997[Medline] 31. Stone MJ, Klintmalm GBG, Polter D, et al: Neoadjuvant chemotherapy and liver transplantation for hepatocellular carcinoma: A pilot study in 20 patients. Gastroenterology 104:196-202, 1993[Medline] 32. Schwartz ME, Sung M, Mor E, et al: A multidisciplinary approach to hepatocellular carcinoma in patients with cirrhosis. J Am Coll Surg 180:596-603, 1995[Medline] 33. Olthoff KM, Rosove MH, Shackleton CR, et al: Adjuvant chemotherapy improves survival after liver transplantation for hepatocellular carcinoma. Ann Surg 221:734-741, 1995[Medline] 34. Riethmüller G, Schneider-Gadicke E, Schlimok G, et al: Randomised trial of monoclonal antibody for adjuvant therapy of resected Dukes' C colorectal carcinoma. German Cancer Aid 17-1A study group. Lancet 343:1177-1183, 1994[Medline] 35. Adler R, Hurwitz E, Wands JR, et al: Specific targeting of adriamycin conjugates with monoclonal antibodies to hepatoma associated antigens to intrahepatic tumor in athymic mice. Hepatology 22:1482-1487, 1995[Medline]
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Kanai F, Lan KH, Shiratori Y, et al: In vivo gene therapy for alpha-fetoprotein-producing hepatocellular carcinoma by adenovirus-mediated transfer of cytosine desaminase gene. Cancer Res 57:461-465, 1997 37. Lo CM, Lai ECS, Fan ST, et al: Resection for extrahepatic recurrence of hepatocellular carcinoma. Br J Surg 81:1019-1021, 1994[Medline] 38. Nagasue N, Kohno H, Hayashi T, et al: Repeat hepatectomy for recurrent hepatocellular carcinoma. Br J Surg 83:127-131, 1996[Medline] Submitted June 10, 1998; accepted September 11, 1998.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
40 years) and for multicentric (> 5) primary tumors. Recurrences were observed within a wide time range after transplantation (43 to 3,204 days; median, 441 days); late recurrences (> 1,000 days, n = 8) were associated with highly differentiated or fibrolamellar tumors and low UICC stages. Surgical treatment was the only therapeutic option associated with prolonged survival after recurrence. 
7 cm). No influence of cirrhosis state on recurrence could be found for stage III and stage IVA tumors 
