MR with Gd-EOB-DTPA in assessment of liver nodules in cirrhotic patients

To date the imaging diagnosis of liver lesions is based mainly on the identification of vascular features, which are typical of overt hepatocellular carcinoma(HCC), but the hepatocarcinogenesis is a complex and multistep event during which, a spectrum of nodules develop within the liver parenchyma, including benign small and large regenerative nodule(RN), low-grade dysplastic nodule(LGDN), high-grade dysplastic nodule(HGDN), early HCC, and well differentiated HCC. These nodules may be characterised not only on the basis of their respective different blood supplies, but also on their different hepatocyte function. Recently, in liver imaging the introduction of hepatobiliary magnetic resonance imaging contrast agent offered the clinicians the possibility to obtain, at once, information not only related to the vascular changes of liver nodules but also information on hepatocyte function. For this reasons this new approach becomes the most relevant diagnostic clue for differentiating low-risk nodules(LGDN-RN) from highrisk nodules(HGDN/early HCC or overt HCC) and consequently new diagnostic algorithms for HCC have been proposed. The use of hepatobiliary contrast agents is constantly increasing and gradually changing the standard of diagnosis of HCC. The main purpose of this review is to underline the added value of Gd-EOB-DTPA in early-stage diagnoses of HCC. We also analyse the guidelines for the diagnosis and management of HCC, the key concepts of HCC development, growth and spread and the imaging appearance of precursor nodules that eventually may transform into overt HCC.     

Early diagnosis of primary liver cancer: imaging versus genetics

Early diagnosis of hepatocellular carcinoma (HCC) in nodules smaller than 2 cm detected by screening ultrasounds becomes essential given that, at that stage, no vascular invasion is usually detected and treatment is associated with a high rate of long-term survival. Improvements in imaging techniques in the last few years have allowed a conclusive diagnosis of HCC in these small nodules without invasive procedures. However, a conclusive diagnosis of HCC by imaging is not always possible and, in more than half of cases, biopsy is needed. On the other hand, histological confirmation of HCC in such tiny nodules is very complex, and in most cases impossible because of the limited sample obtained. In addition, serum tumor markers currently available show low accuracy and are useless for early diagnosis. Progress in the knowledge of molecular mechanisms associated with malignant transformation will allow the use of new techniques that will facilitate diagnosis for HCC in very early stages.     

1.5 Harmonic Imaging Sonography with microbubble contrast agent improves characterization of hepatocellular carcinoma

AIM: To investigate the usefulness of 1.5 Harmonic Imaging Sonography with the use of the contrast agent Levovist for the diagnosis of hepatocellular carcinoma (HCC) and for the evaluation of therapeutic response. METHODS: Phantom experiments were performed to compare the contrast effects of 2nd harmonic imaging and 1.5 Harmonic Imaging Sonography. 1.5 Harmonic Imaging Sonography was employed to examine 36 patients with HCC (42 nodules) before and after the treatment and to compare against the findings obtained using other diagnostic imaging modalities. RESULTS: In 1.5 Harmonic Imaging Sonography, the tumor vessels of HCCs were clearly identified during the early phase, and late-phase images clearly demonstrated the differences in contrast enhancement between the tumor and surrounding hepatic parenchyma. Blood flow within the tumor was detected in 36 nodules (85.7%) during the early phase and in all 42 nodules (100%) during the late phase using 1.5 Harmonic Imaging Sonography, in 38 nodules (90.5%) using contrast-enhanced CT, in 34 nodules (81.0%) using digital subtraction angiography (DSA), and in 42 nodules (100%) using US CO2angiography. Following transcatheter arterial embolization, 1.5 Harmonic Imaging Sonography detected blood flow and contrast enhancement within the tumors that were judged to contain viable tissue in 20 of 42 nodules (47.6%). However, 6 of these 20 cases were not judged in contrast-enhanced CT. 1.5 Harmonic Imaging Sonography was compared with the US CO2 angiography findings as the gold standard, and the sensitivity and specificity of these images for discerning viable and nonviable HCC after transcatheter arterial embolization were 100% and 100%, respectively. CONCLUSION: 1.5 Harmonic Imaging Sonography permits the vascular structures of HCCs to be identified and blood flow within the tumor to be clearly demonstrated. Furthermore, 1.5 Harmonic Imaging Sonography is potentially useful for evaluating the therapeutic effects of transcatheter arterial embolization on HCC.     

Tumor hemodynamics in hepatic nodules associated with liver cirrhosis: relationship between cancer progression and tumor hemodynamic change]

Tumor hemodynamics including arterial vascularity (AV) and portal perfusion (PP) were evaluated in histologically confirmed 55 hepatic nodules associated with cirrhosis using ultrasonographic (US) angiography during intraarterial carbon dioxide microbubbles injection and CT during arterial portography. Tumor hemodynamic patterns were classified into 6 types as follows: Type I (n = 10): PP (+), AV (hypo); Type I' (n = 2): PP (+), AV (iso); Type II (n = 5): PP (-), AV (hypo); Type III (n = 8): PP (-), AV (iso); Type IV (n = 25): PP (-), AV (hyper), Type V (n = 5): PP (partially +), AV (vascular spot in hypovascular). Eight nodules of Type I were diagnosed as benign nodules histologically including adenomatous hyperplasia (AH) (n = 6) and regenerative nodule (n = 2). Hundred percent (5/5) of Type II and 88% (7/8) of Type III nodules were well-differentiated HCC, in contrast to 8% (2/25) of Type IV nodules, typical HCCs. Fatty metamorphosis was observed in 75% (6/8) of Type III nodules, in contrast to 16% (4/25) of typical (classical) HCC nodules (Type IV). We concluded that at the malignant transformation from AH to HCC, reduction of portal blood flow in the nodule precedes the initiation of the increase of the arterial tumor vessel. Moreover, early stage HCC could exhibit hypovascular (Type I, II), isovascular (Type III), or vascular spot in hypovascular pattern (Type V) compared with a typical HCC (Type IV). It was also suggested that the more mature as a neoplasms the HCC becomes, the more the arterial tumor vessel in the nodule increases and fatty metamorphosis of well-differentiated HCC is highly related with tumor hemodynamic condition, i.e., hypoperfusion state from both arterial and portal vessel.     

肝细胞癌癌前结节影像学特征的研究进展

肝细胞癌(HCC)发生是一个多步骤过程,在其发展中检测出HCC癌前病变和进展期HCC,对预测肿瘤行为、判断病变程度、采用最佳治疗策略、改善患者生存至关重要。肝脏成像技术的快速进展和广泛应用,尤其是肝细胞特异性对比剂钆塞酸二钠MRI(Gd-EOB-DTPA MRI)可提供肝结节血管变化、肝细胞功能信息,能够精确区分肝硬化再生结节、低度异型增生结节、高度异型增生结节、早期HCC(early HCC)和HCC,从而进行恶性进展的风险度分层。现综述Gd-EOB-DTPA MRI在HCC早期诊断中的价值,分析HCC多步发展过程中的关键概念,以及癌前病变最终可能转化成典型HCC的影像学表现。     

Imaging diagnosis

The diagnosis of hepatocellular carcinoma (HCC) is based on imaging examinations in combination with clinical and laboratory findings. Despite technological advances, imaging cirrhotic patients remains a challenging issue because nonmalignant hepatocellular lesions, such as dysplastic nodules, mimic a small HCC. One of the key pathologic factors for differential diagnosis that is reflected in imaging appearances is the vascular supply to the lesion. It is accepted that imaging techniques may establish the diagnosis of HCC in nodules larger than 2 cm showing characteristic arterial hypervascularization. In lesions ranging from 1 to 2 cm, biopsy is still recommended, although a negative response can never be used to rule out malignancy completely. Although ultrasonography is widely accepted for HCC surveillance, spiral computed tomography (CT) or dynamic magnetic resonance imaging is required for diagnostic confirmation and intrahepatic tumor staging. These examinations have replaced invasive procedures, such as lipiodol CT, but remain relatively insensitive for the detection of tiny HCC lesions and tumor vascular invasion into peripheral portal vein branches.     

How to characterize non-hypervascular hepatic nodules on contrast-enhanced computed tomography in chronic liver disease: feasibility of contrast-enhanced ultrasound with a microbubble contrast agent

Background and Aim: Although hypervascular appearance is characteristic in hepatocellular carcinoma (HCC), hepatic nodules without hypervascular appearance are sometimes found in patients with chronic liver disease (CLD). The aim of the present study was to clarify the efficacy of contrast‐enhanced ultrasound (CEUS) with Levovist to characterize small, non‐hypervascular hepatic nodules on contrast‐enhanced computed tomography (CECT) in patients with CLD. Methods: The subject was 41 hepatic nodules (<30 mm, 18.5 ± 5.6 mm) which showed non‐hypervascular appearance on CECT in 35 patients with CLD; their histological results were 31 HCC (15 well, 14 moderate, and two poor) and 10 regenerative nodules (RN). CEUS with Levovist was performed under intermittent scanning (1‐s interval) using APLIO at the early phase and the liver‐specific phase, and the contrast enhancement of the nodule was assessed in comparison to that of the surrounding liver parenchyma. The contrast‐enhanced findings with the time‐intensity analysis were compared with the histological results. Results: Twelve nodules with weak enhancement in the liver‐specific phase were HCC, regardless of their early‐phase appearances. The other 29 nodules with equivalent or weak enhancement in the early phase and equivalent enhancement in the liver‐specific phase were 19 HCC and 10 RN. Among them, the maximum‐intensity ratio of tumor to non‐tumor in the early phase was significantly higher in HCC than in RN (P < 0.01, n = 16), and the receiver‐operating characteristic analysis showed a sensitivity of 1.0 and a specificity of 0.83 for their characterization. Conclusion: CEUS with Levovist may be an alternative to biopsy to characterize small, non‐hypervascular hepatic nodules on CECT in patients with CLD.     

Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis

Selection of patients suffering from hepatocellular carcinoma (HCC) in cirrhosis for liver transplantation follows limits of number and diameter of tumor nodules. It has not been investigated whether there is a correlation of these parameters with vascular invasion. From 1989 to 2000, 1,188 liver transplantations were performed in 1,087 patients, including 120 patients (11%) with an HCC in cirrhosis. Selection criteria were a maximal diameter of up to 5 cm if the tumor appeared to be uninodular or of up to 3 cm in the case of 2 or 3 nodules. The postoperative mortality rate was 1.7%. One-, 5-, and 10-year survival was 90%, 71%, and 60%, respectively. In 940 transplantation patients without an HCC, these rates were 93%, 87%, and 83% (P < .0001). Vascular invasion and histopathologic grading were identified as prognostic parameters by multivariate analysis. In a logistic regression analysis, histopathologic grading and maximal diameter showed a significant correlation with a vascular invasion. Analyzing tumors larger than 5 cm, i.e., tumors not fulfilling the selection criteria as a result of diagnostic inaccuracy or progression thereafter, the rates of vascular invasion were significantly (P < .01) lower in patients suffering from well-differentiated tumors (25%) when compared with moderately and poorly differentiated tumors (100%). Liver transplantation is a safe and effective long-term treatment for small HCC in cirrhosis. Tumor diameter and number of nodules in correlation with the histopathologic grading were predictive of a vascular invasion only in HCC larger than 5 cm.     

Investigation of Resected Multinodular Hepatocellular Carcinoma: Assessment of Unicentric or Multicentric Genesis from Histological and Prognostic Viewpoint

Objectives : Multicentricity of hepatocellular carci-noma (HCC) is attracting a great deal of attention at present. However, few studies have focused on the prognostic comparison between unicentric and multicentric multinodular HCCs. The aim of this study is the reevaluation of histologic criteria of multicentric HCC and a prognostic comparison hetween the two groups mentioned ahove. Methods : Forty-nine cases with intra-hepatic multiple nodules of HCC, hy gross examination, among 184 consecutive resected HCCs were examined clinicopathologically. These cases were divided into three groups: group A, cases suggestive of multicentric genesis; group B, unicentric cases; and group C, inde-terminate cases. Histopathological characteristics and the cumulative survival rates were compared among these groups. Results : Five cases were categorized as group A, 36 cases as group B. and eight cases as group C. Nodules in group A were smaller than 2 cm in diameter, situated discretely and well differentiated, and with neither vascular nor capsular invasion. Most of the nodules lacked a tumor capsule and had an irregular horder. In the 36 cases of group B, all main tumors had vascular and/or capsular invasion. The cellularity index was almost the same in all groups. The cumulative survival rate of group A was hetter than that of group or group C. Conclusions: Small multiple nodules of well-differentiated hepatocellular carcinoma without vascular and capsular invasion might he multicentric, and these early detections and operations could result a fairly good prognosis, despite the multiple HCC nodules.     

Pathology of early hepatocellular carcinoma

As is observed in many types of human cancers, hepatocellular carcinoma (HCC) is characterized by an obvious multistage process of tumor progression. Histopathological and molecular biological studies have revealed that HCC associated with chronic liver disease evolves from precancerous lesions called adenomatous hyperplasia (also called dysplastic nodules) and early HCC to a progressed form. Early HCC corresponds to in situ or microinvasive carcinoma, and develops to progressed HCC through the stage of "nodule-in-nodule" type HCC (progressed HCC within early HCC), which indicates a transition from early to progressed HCC. It is consideredthat early HCC is a key step in the process of HCC development and progression. However, the molecular mechanisms of early hepatocarcinogenesis are far from clear. Specific mutations of classical oncogenes or tumor suppressor genes have not been identified in early HCC so far. Recent progress in comprehensive analysis of gene expression is shedding some light on this issue.     

Pathomorphologic study on the mechanism of fatty change in small hepatocellular carcinoma of humans

BACKGROUND/AIMS: Fatty change is frequently observed in small hepatocellular carcinoma (HCC) of the early stage. However, the mechanism of fatty change and its pathomorphological features in small HCC are not yet fully understood. These issues are addressed here. METHODS: Histological examinations were conducted on 260 HCC nodules (< or =3 cm in diameter) which were surgically obtained from 249 patients. According to the distribution pattern, fatty changes were classified into two types: 'diffuse type' when the change was found throughout the cancerous nodule; and 'focal type' when the change was localized in part of the nodule. To study the pathogenesis of fatty change in HCC in relation to angioarchitecture, the number of arterial tumor vessels and intratumoral portal tracts in 104 of the 260 nodules was counted. RESULTS: Fatty change was found in 51 of the 260 nodules (19.6%), the frequency was highest (36.4%) in the nodules whose diameter was 1.1 to approximately 1.5 cm, and the frequency decreased with the increase in tumor diameter. Small well-differentiated HCCs were often associated with a diffuse type fatty change. With the increase in tumor diameter, moderately differentiated cancerous tissues without associated fatty change appeared, and the focal type was found more frequently. According to the angioarchitecture, in HCCs < or =1.5 cm, the number of intratumoral arteries was significantly smaller in HCCs with fatty change (p<0.05), though the number of intratumoral portal tracts was not significantly different compared with HCCs without fatty change. CONCLUSION: These findings suggest that fatty change of small HCC is closely related to the tumor size, the histological grade and insufficient development of the arterial tumor vessels.     

Four-dimensional ultrasonography for therapeutic radiofrequency ablation for hepatocellular carcinoma

BACKGROUND/AIMS: We examined whether four-dimensional real-time flow imaging on ultrasonography (US) is valuable to display the accurate position of percutaneous radiofrequency ablation (RFA) needle in the nodule of hepatocellular carcinoma (HCC). METHODOLOGY: Ten patients with 12 HCC nodules were studied; nine were infected with hepatitis C virus (HCV) and one was diagnosed as non-B non-C. Diagnosis was done by helical dynamic CT and/or celiac angiography. Tumor vascularities in the early arterial and post-vascular phases after injection of a microbubble contrast agent were assessed by real-time US scanning of coded harmonic imaging and intermittent interval-delay scanning with a wide-band power Doppler technology. Percutaneous RFA was performed with four-dimensional real-time flow imaging under US to display the accurate position of cool-tip needle. RESULTS: It was possible to obtain accurate position of the needle during RFA procedure in all 12 nodules. The needle was confirmed to be inserted into the center of the tumor nodule by various angles. The simultaneous study before RFA therapy showed the inflow of arterial blood and tumor staining in all nodules at early arterial phase of coded harmonic angio on contrast-enhanced US scan. Posttreatment study to evaluate the therapeutic efficacy showed no blood flow at both early vascular and post-vascular phases. No residual blood flow was noted on early phase of CT scan with adequate safety margin. There was no discrepancy in the finding at early phase between contrast-enhanced US and dynamic CT. CONCLUSIONS: It appeared that four-dimensional real-time US provided more perceptible information on the spatial relationship between RFA needle and the target lesion, and resulted in accurate therapeutic efficacy for percutaneous RFA procedure.     

Treatment of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third cause of cancer-related death. Despite therapeutic advances, the overall survival of patients with HCC has not significantly improved in the last two decades. In the majority of the cases there is underlying cirrhosis, so the prognosis of HCC depends on not only tumor stage but also liver function. There is not a widely accepted HCC staging system. In our group we have developed a new staging classification that stratifies HCC patients into four major categories and simultaneously links staging with treatment. Patients at an early stage are those who present with an asymptomatic single HCC with a maximum diameter of 5cm or up to three nodules each less than 3cm. They will benefit from curative therapies, including resection, liver transplantation (LT), and percutaneous ablation. Patients exceeding these limits, but who are free of cancer-related symptoms and vascular invasion or extrahepatic spread fit into the intermediate stage and may benefit from palliation with chemoembolization. The patients with mild cancer-related symptoms and/or vascular invasion or extrahepatic spread are included in the advanced stage. In this stage there is not effective therapy, and these patients may profit from new therapies in the setting of randomized controlled trials (RCTs). Finally, the patients with severe cancer-related symptoms or great tumor burden belong to the terminal stage and only benefit from symptomatic treatment.     

Hepatocellular carcinoma with cutaneous metastases

Two cases of cutaneous metastases from hepatocellular carcinoma (HCC) are reported. Both patients had been diagnosed with HCC at least one year before the appearance of skin lesions. The lesions presented as small reddish nodules in both patients, with a large additional vascular lesion in one of the patients. Cutaneous metastases from HCC are very rare. However, these two cases suggest that patients with HCC and presenting with skin nodules should have biopsies performed to confirm the diagnosis.     

Classification tool for the systematic histological assessment of hepatocellular carcinoma, macroregenerative nodules, and dysplastic nodules in cirrhotic liver

AIM: To design a classification tool for the histological assessment of hepatocellular carcinoma (HCC), dysplastic nodules (DN), and macroregenerative nodules (MRN) in cirrhotic liver. METHODS: Two hundred and twelve hepatocellular nodules (106 HCC; 74 MRN; 32 DN) were assessed systematically, quantitatively, and semiquantitatively as appropriate for 10 histological features that have been described as helpful in distinguishing small HCC, DN, and MRN in cirrhotic livers. The data were analyzed by multiple correspondence analysis (MCA). RESULTS: MCA distributed HCC, DN, and MRN as defined by traditional histological evaluation as well as the individual histological variables, in a "malignancy scale". Based on the MCA data representation, we created a classification tool, which categorizes an individual nodular lesion as MRN, DN, or HCC based on the balance of all histological features (i.e., vascular invasion, capsular invasion, tumor necrosis, tumor heterogeneity, reticulin loss, capillarization of sinusoids, trabecular thickness, nuclear atypia, and mitotic activity). The classification tool classified most (83%) of a validation set of 47 nodules in the same way as the routine histological assessment. No discrepancies were present for DN and MRN between the routine histological assignment and the classification tod. Of 25 HCC assigned by routine assessment in the validation set, 8 were assigned to the DN category by the classification tool. CONCLUSION: We have designed a classification tool for the histological assessment of HCC and its putative precursors in cirrhotic liver. Application of this tool systematically records histological features of diagnostic importance in the evaluation of small HCC.     

Classification tool for the systematic histological assessment of hepatocellular carcinoma, macroregenerative nodules, and dysplastic nodules in cirrhotic liver

AIM: To design a classification tool for the histological assessment of hepatocellular carcinoma (HCC), dysplastic nodules (DN), and macroregenerative nodules (MRN) in cirrhotic liver.METHODS: Two hundred and twelve hepatocellular nodules (106 HCC;74 MRN;32 DN) were assessed systematically, quantitatively, and semiquantitatively as appropriate for 10 histological features that have been described as helpful in distinguishing small HCC, DN, and MRN in cirrhotic livers. The data were analyzed by multiple correspondence analysis (MCA).RESULTS: MCA distributed HCC, DN, and MRN as defined by traditional histological evaluation as well as the individual histological variables, in a "malignancy scale".Based on the MCA data representation, we created a classification tool, which categorizes an individual nodular lesion as MRN, DN, or HCC based on the balance of all histological features (i.e., vascular invasion, capsular invasion, tumor necrosis, tumor heterogeneity, reticulin loss,capillarization of sinusoids, trabecular thickness, nuclear atypia, and mitotic activity). The classification tool dassified most (83%) of a validation set of 47 nodules in the same way as the routine histological assessment. No discrepandes were present for DN and MRN between the routine histological assignment and the classification tool. Of 25 HCC assigned by routine assessment in the validation set, 8were assigned to the DN category by the classification tool.CONCLUSION: We have designed a classification tool for the histological assessment of HCC and its putative precursors in cirrhotic liver. Application of this tool systematically records histological features of diagnostic importance in the evaluation of small HCC.     

A case of progressing focal nodular hyperplasia and its molecular expression pattern

We report the case of an adult male with progressing focal nodular hyperplasia (FNH). Although imaging studies suggested that the tumor was a classical FNH, the tumor biopsy showed glutamine synthetase expression and heat shock protein 70 in part of the tumor. As we could not definitely distinguish this case of FNH from early hepatocellular carcinoma (HCC), we performed laparoscopic partial hepatectomy. The surgical resected specimen showed that the tumor had a central scar with vascular and cholangiolar proliferation, which is compatible with FNH. Immunohistochemical analysis showed that the molecular expression pattern was compatible with FNH in the center of the tumor, whereas it partly resembled early HCC in the periphery of the tumor. FNH progression is occasionally found, and the molecular pattern of the progressing area in FNH might resemble that of early HCC due to morphologic and phenotypic changes induced by the regenerative mechanism and the alteration of blood flow. We should carefully observe progressing FNH.     

Latest developments in precancerous lesions of hepatocellular carcinoma

Hepatocarcinogenesis in human chronic liver diseases is a multi-step process in which hepatic precancerous lesions progress into early hepatocellular carcinoma(HCC) and progressed HCC, and the close surveillance and treatment of these lesions will help improve the survival rates of patients with HCC. The rapid development and extensive application of imaging technology have facilitated the discovery of nodular lesions of ambiguous significance, such as dysplastic nodules. Further investigations showed that these nodules may be hepatic precancerous lesions, and they often appear in patients with liver cirrhosis. Although the morphology of these nodules is not sufficient to support a diagnosis of malignant tumor, these nodules are closely correlated with the occurrence of HCC, as indicated by long-term follow-up studies. In recent years, the rapid development and wide application of pathology, molecular genetics and imaging technology have elucidated the characteristics of precancerous lesions. Based on our extensive review of the relevant literature, this article focuses on evidence indicating that high-grade dysplastic nodules are more likely to transform into HCC than low-grade dysplastic nodules based on clinical, pathological, molecular genetic and radiological assessments. In addition, evidence supporting the precancerous nature of large cell change in hepatitis B virus-related HCC is discussed.     

Revisiting the role of pathological analysis in transarterial chemoembolization-treated hepatocellular carcinoma after transplantation

AIM: To define the histopathological features predictive of post-transplant hepatocellular carcinoma (HCC) recurrence after transarterial chemoembolization, applicable for recipient risk stratification.METHODS: We retrospectively reviewed the specimens of all suspicious nodules (total 275) from 101 consecutive liver transplant recipients which came to our Pathology Unit over a 6-year period. All nodules were sampled and analyzed, and follow-up data were collected. We finally considered 11 histological variables for each patient: total number of nodules, number of viable nodules, size of the major nodule, size of the major viable nodule, occurrence of microscopic vascular invasion, maximum Edmondson''s grade, clear cell/sarcomatous changes, and the residual neoplastic volume. Survival data were computed by means of the Kaplan-Meier procedure and analyzed by means of the Cox proportional hazards model. The multivariate linear regression and a k-means cluster analysis were also used in order to compute the standardized histological score.RESULTS: The total number of nodules, the residual neoplastic volume (the total volume of all evaluated nodules minus the necrotic portion) and the microvascular invasion entered the Cox multivariate hazard model with HCC recurrence as dependent variable. The histological score was therefore computed and a cluster analysis sorted recipients into 3 risk groups, with 3.3%, 18.5% and 53.8% respectively of tumor recurrence rates and 1.6%, 11.1% and 38.5% of tumor-related mortality respectively at the end of follow-up.CONCLUSION: The histological score allows a reliable stratification of HCC recurrence risk, especially in those recipients found out to be beyond the Milan criteria after orthotopic liver transplantation (OLT).