Fibrolamellar Variant Of Hepatocellular Carcinoma Research Articles

Therapeutic, Clinicopathological, and Molecular Correlates of PRKACA Expression in Gastrointestinal Cancers.

PRKACA alterations have clear diagnostic and biological roles in the fibrolamellar variant of hepatocellular carcinoma and a potential predictive role in that cancer type. However, the roles of PRKACA have not been comprehensively examined in gastric and colorectal cancers (GC and CRC). This study, therefore, sought to investigate the roles of PRKACA expression in GC and CRC. The clinico-genomic data of 441 GC and 629 CRC cases were analyzed for therapeutic, clinicopathological, and biological correlates using appropriate bioinformatics and statistical tools. Furthermore, the deregulation of PRKACA expression in GC and CRC was investigated using correlative and regression analyses. The results showed that PRKACA expression subsets were enriched for gene targets of chemotherapeutics, tyrosine kinase, and β-adrenergic inhibitors. Moreover, high PRKACA expression was associated with adverse clinicopathological and genomic features of GC and CRC. Gene Ontology Enrichment Analysis also showed that PRKACA-high subsets of the GI cancers were enriched for the biological and molecular functions that are associated with cell motility, invasion, and metastasis but not cell proliferation. Finally, multiple regression analyses identified multiple methylation loci, transcription factors, miRNA species, and PRKACA copy number changes that deregulated PRKACA expression in GC and CRC. This study has identified potential predictive and clinicopathological roles for PRKACA expression in GI cancers and has added to the growing body of knowledge on the deregulation of PRKACA in cancer.

Desmoplastic small round cell tumor of the liver: diagnosing a rare case on liver biopsy

Desmoplastic small round-cell tumors (DSRCT) frequently develop in the retroperitoneum, pelvis, omentum, and mesentery. Here, we present an unusual case of primary DSRCT in the liver. The patient was an 11-year-old boy with multiple solid masses in the liver parenchyma. The tumor in the needle biopsy had a histology revealing a small round cell morphology and desmoplasia. It shows the immunohistochemical features of DSRCT and documentation of EWSR1-WT1 fusion.A potential diagnostic pitfall is exerted when evaluating liver biopsy, in which DSRCT is a great mimicker and may be easily confused with more common liver malignancies of childhood, such as hepatoblastoma, calcifying nested stromal-epithelial tumor, undifferentiated embryonal sarcoma, and other small round cell tumors, as well as the fibrolamellar variant of hepatocellular carcinoma. This distinction is critical because an accurate therapeutic approach requires a correct diagnosis.

Fibrolamellar hepatocellular carcinoma: An epidemiologic and 5-year cancer survival assessment based off SEER data

The fibrolamellar variant of hepatocellular carcinoma makes up a small percentage of liver tumors. Despite being a subset, it has been noted in the literature to have variations in terms of its epidemiology and intervention recommendations. Using the Surveillance, Epidemiology, and End Results database, 339 cases from 1988 to 2016 were studied. Favorable prognostic epidemiological factors included male sex, younger ages, and white race. Those who underwent any lymph node resection (combined with liver resection) did better than those without lymph node resection; chemotherapy proved beneficial for those where surgery was contraindicated. To our knowledge, this report is the largest conglomerate dataset analyzing prognostic profiles and treatment strategies for fibrolamellar hepatocellular carcinoma.

Giant hepatic capillary hemangioma, a diagnostic dilemma: case report

Hepatic Hemangiomas (HH) are benign tumors of the liver consisting of a blood-filled cavity supplied by the hepatic artery. Most of the HH are asymptomatic and are discovered incidentally during radiological imaging of various unrelated pathology. Typical capillary hemangiomas range from a few millimeters to three centimeters and are unlikely to generate any future symptomatology. However, giant liver hemangiomas (more than 10 cm) are a very rare entity and might become symptomatic, hence requiring prompt intervention. We are reporting this case to make the readers aware of the pitfalls and radiological uncertainties while interpreting vascular lesions of the liver. We reported a case of a 21-year-old female with complaint of awareness of a mass over the right upper abdomen since a period of one year which has been gradually increasing in size. On pre-operative Contrast-Enhanced Computed Tomography, features suggestive of Fibrolamellar variant of Hepatocellular Carcinoma was found which was substantiated by biochemical investigations. However, post-operative histopathological examination revealed a capillary hemangioma.

Abstract 4877: Transcriptome sequencing of pediatric hepatocellular carcinoma reveals genomic events involving APC and TERT

Abstract Background: The goal of this project is to molecularly characterize a cohort of pediatric HCCs in order to understand the spectrum of genetic drivers for this disease. Hepatocellular carcinoma (HCC) is a rare pediatric liver tumor with a poor prognosis. The fibrolamellar variant of HCC (FL-HCC) has a characteristic DNAJB1-PRKACA gene fusion. In non-FL-HCC a genetic cause has not been identified. We hypothesize that alterations in known cancer genes play a role in non-FL-HCC tumorigenesis. Methods: We have used RNA sequencing (RNA-seq) on fresh frozen tissue to survey a cohort of 8 FL-HCCs, 4 pediatric HCCs, and 6 normal liver samples for chimeric transcripts. Fusion transcripts in the tumor samples were detected using deFuse on FASTQ files followed by subtraction of fusions called in the normal liver dataset. Fusions were verified using BLAST and validated by RT-PCR. On average the deFuse algorithm predicted 150 fusion transcripts per tumor; filtering by normal liver reduced the number of calls in the tumors by ~60%. As expected, DNAJB1-PRKACA fusions were identified in the FL-HCC cohort with no additional fusions. Filtering by the COSMIC Cancer Gene Census list reduced the total number of fusion calls to 5 for the HCC dataset (3 unique events, 2 of which were confirmed by RT-PCR). Results: The first event is an inversion disrupting APC, resulting in two in-frame fusion transcripts between APC and AP3B1. This fusion was confirmed and the intronic breakpoints were mapped in tumor and germline DNA through WGS by 10X Genomics®. Variant calling by Platypus on tumor RNA-seq reads did not identify additional variants in APC. Reports of inversion of APC are rare, however we have identified an additional published case of APC inversion in a patient with pediatric HCC. We will perform WGS on germline DNA from this patient to determine if the APC inversion breakpoint is recurrent. The second event is a deletion encompassing the TERT promoter and results in an in-frame fusion between TERT and LPCAT1. An increase in TERT expression is seen in this tumor as compared to both normal liver and other pediatric HCCs. Conclusions: The detection of chimeric transcripts by RNA-seq has allowed us to identify two structural variants involving known cancer genes in two tumors, including an inversion of APC which have been historically difficult to detect. These events present a possible genetic cause for these tumors and provide genes for further analysis in the remaining cases with no identified fusions. These results will inform future studies as we expand this cohort to include 18 additional pediatric HCCs which we plan to characterize through NGS and targeted sequencing. Citation Format: Katherine Haines, Angshumoy Roy, Stephen Sarabia, Linghua Wang, Pavel Sumazin, Kyle Covington, Harsha Doddapaneni, Oliver Hampton, Donna M. Muzny, Dolores Lopez-Terrada, David A. Wheeler, Sharon E. Plon, D. Williams Parsons. Transcriptome sequencing of pediatric hepatocellular carcinoma reveals genomic events involving APC and TERT [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4877. doi:10.1158/1538-7445.AM2017-4877

Repeated metastasectomy in an adolescent with fibrolamellar hepatocellular carcinoma: A case report

Abstract The fibrolamellar variant of hepatocellular carcinoma (FL-HCC) is a primary malignancy of the liver classically identified in the non-cirrhotic liver. By virtue of the non-cirrhotic liver background, patients with FL-HCC are more likely to be selected for surgical resection as primary treatment than in classic HCC. Synchronous and metachranous metastasis of FL-HCC can be treated with either resection, chemotherapy, or both. We present here an adolescent who underwent resection of a large FL-HCC following neo-adjuvant chemotherapy. The patient went on to receive surveillance and resection of five serially identified metastasis. Despite repeated aggressive metastasectomy, we observed survival in this case surpassing the median reported survival for adolescents with FL-HCC. This case supports the hypothesis proposed previously that aggressive surgical resection, including metastasectomy in the thoracic and abdominal cavity, should be offered to patients with this rare tumor.

The Expression of DNA Methyltransferase DNMT3a in Classical and Fibrolamellar Hepatocellular Carcinoma

The epigenetic regulation of DNA-templated processes has been studied extensively during the last 15 years. As was revealed, DNA modification such as methylation possess great impact on cell fate and can result in abnormal protein expression patterns what can lead to the induction of carcinogenesis. DNA (cytosine-5)-methyltransferases are enzymes that catalyses the transfer of methyl groups to specific CpG structures in DNA. The methylation of these sequences can lead to inappropriate gene expression such as the silencing of tumor suppressor genes in cancer cells. DNA (cytosine-5)-methyltransferase 3A (DNMT3a) gene encodes a DNA methyltransferase that is thought to function mainly in de novo methylation. In the normal liver DNMT3a is usually expressed on the medium level, as was described in literature. Hepatocellular carcinoma (HCC) still remains one of the most common cause of death among patients with cancer. Fibrolamellar hepatocellular carcinoma (FL) represents rare subtype, which affects usually young people (an onset between 20-30 years) and its etiology is poorly understood. In our study we compared the presence of DNMT3a protein between two different types of HCC-common type and fibrolamellar one. We performed immunohistochemical staining of formalin fixed paraffin embedded tissue sections obtained from 30 patients (22 HCC and 8 FL). We found that DNMT3a immunoreactivity is significantly more pronounced in the non-fibrolamellar variant of HCC than in the fibrolamellar one. The DNMT3a immunoreactivity was predominantly localized in cancer cell nuclei in a form of separate large granules spotted in proximity to heterochromatin region. The reduced presence of DNMT3a in the fibrolamellar variant of HCC may suggest that different epigenetic mechanisms are involved in development of this particular type of liver cancer. Improving our understanding of the roles of DNMT proteins in hepatocarcinogenesis can benefit in the development of epigenetic –based therapy designed for specific HCC subtype.

Primary biliary tract malignancies: MRI spectrum and mimics with histopathological correlation.

Contrast-enhanced magnetic resonance imaging and magnetic resonance cholangiopancreatography (MRCP), due to their excellent soft tissue contrasts, have become first-line noninvasive tests in the characterization and detection of both hepatic and pancreaticobiliary pathologies. MRCP is also helpful in detecting the level and cause of obstruction in patients presenting with jaundice. Cholangiocarcinoma (CCA) is the most common primary malignant tumor arising from the bile duct epithelium, with extrahepatic tumors presenting more often than with intrahepatic ones. However, the diagnosis and management of CCA is made more complex by a variety of malignant and benign conditions that resemble CCA, including hepatocellular carcinoma variants such as the fibrolamellar variant of hepatocellular carcinoma, cholangiocellular carcinoma, biliary metastases, hepatic inflammatory pseudotumor, lymphoepithelioma-like carcinoma, confluent fibrosis, primary sclerosis cholangitis, and the secondary sclerosing cholangitis complex. Consequently, knowledge of the underlying risk factors and imaging characteristics of these conditions is important in differentiating between neoplastic and non-neoplastic conditions in order to reach a definite diagnosis. Endoscopic retrograde cholangiopancreatography should be reserved for those patients who require intervention or biopsy for histopathological diagnosis.

Successful Multimodal Treatment for Aggressive Metastatic and Recurrent Fibrolamellar Hepatocellular Carcinoma in a Child

Fibrolamellar variant of hepatocellular carcinoma (FLHCC) does not have a favorable prognosis than conventional HCC, and there is no difference regarding the response to chemotherapy and the degree of surgical resectability. FLHCC commonly recurs after complete surgical resection, and there is a high rate of lymph node metastases. Herein, we report a 12-year-old girl with metastatic FLHCC with multiple recurrences aggressively treated with surgery, chemotherapy, and antiangiogenic agents. She is in complete remission after 4 years and 2 months after the diagnosis of metastatic FLHCC. The standard treatment of FLHCC is excision of the primary tumor and its metastases. Chemotherapy for FLHCC is controversial, and it has been suggested that cytoreductive chemotherapy was ineffective and adjuvant chemotherapy did not improve survival. Our patient with multiple recurrences was successfully treated with surgery, first-line chemotherapy with cisplatin and doxorubicin, second-line chemotherapy with 5-fluorouracil/interferon-α combination, and adjuvant antiangiogenic agents like cyclophosphamide and thalidomide. As FLHCC patients have no underlying liver disease, they can tolerate higher doses of chemotherapy compared with conventional HCC patients. We support the use of repeated aggressive surgery with adjuvant chemotherapy and antiangiogenic therapy, which provided complete remission in our patient with metastatic and recurrent FLHCC.

Metastatic Fibrolamellar Hepatocellular Carcinoma in Ascitic Fluid: A Report of a Case With Cytologic and Histologic Findings

The fibrolamellar variant of hepatocellular carcinoma (FL-HCC) is distinguished from other hepatocellular carcinomas (HCC) by its unique clinical and pathologic features. Cytologic features of this tumor by fine-needle aspiration (FNA) have been described earlier. We present here a unique case of metastatic FL-HCC to the omentum diagnosed by omental biopsy …

Fibrolamellar variant of hepatocellular carcinoma does not have a better survival than conventional hepatocellular carcinoma – Results and treatment recommendations from the Childhood Liver Tumour Strategy Group (SIOPEL) experience

PurposeFibrolamellar hepatocellular carcinoma (FL-HCC) and conventional hepatocellular carcinoma (HCC) cases in two consecutive paediatric HCC trials were analysed to compare outcome and derive treatment implications. Patients and methodsData of 24 FL-HCC (24% PRETEXT IV) and 38 HCC (42% PRETEXT IV) cases from SIOPEL-2 and -3 (1995–1998, 1998–2006) were analysed. Patients were treated according to SIOPEL-2 and -3 high-risk protocol (carboplatin+doxorubicin alternating with cisplatin; seven preoperative, three postoperative cycles) or with primary surgery followed by chemotherapy as indicated. ResultsThirteen of 24 FL-HCC (54%) and 32/38 HCC (84%) were initially treated with chemotherapy. Eight FL-HCC (33%) and five HCC patients (13%) had primary surgery. Partial response was observed in 31% of FL-HCC versus 53% of HCC patients (p=0.17). Complete resection was achieved in ten FL-HCC and seven HCC patients (p=0.08). Three-year event free survival (EFS) was 22% for FL-HCC versus 28% for HCC. Overall survival (OS) was not significantly different at 3 years follow up (42% for FL-HCC versus 33% for HCC, p=0.24). EFS/OS Kaplan–Meier curves did not differ significantly, with median follow up of 43 (FL-HCC) and 60 (HCC) months. No significant correlation was found between potential prognostic factors and OS. In the entire cohort nine out of 23 (39%) patients with complete resection or orthotopic liver transplantation versus 34/39 (87%) without successful surgical treatment, died. ConclusionsLong-term OS in FL-HCC and HCC is similar. With low response rates, complete resection remains the treatment of choice.

Fibrolamellar hepatocellular carcinoma presenting with budd-chiari syndrome, right atrial thrombus, and pulmonary emboli

CT, computed tomography; FLHCC, fibrolamellar hepatocellular carcinoma; HCC, hepatocellular carcinoma; IVC, inferior vena cava. A 24-year-old man was evaluated for 3 months of abdominal pain and new onset of shortness of breath, increased abdominal girth, and leg swelling. On physical examination, he was tachypneic, had dullness in flanks, and bilateral lower extremity edema. Liver biochemical tests were notable for marginal derangement and a normal alpha-fetoprotein. An abdominal computed tomography (CT) scan showed an 11.5-cm hepatic mass with satellite lesions, ascites, tumor extension into the inferior vena cava (IVC) causing obstruction, and bland thrombus extending from the lower IVC to the femoral veins bilaterally (Fig. 1A). A chest CT showed bilateral pulmonary emboli and bilateral pleural effusions. A 2D echocardiogram showed a presumed right atrial tumor thrombus (Fig. 1B). A liver biopsy showed large polygonal tumor cells with eosinophilic granular cytoplasm (positive stain for Heppar-1) surrounded by abundant fibrous stroma in parallel lamellae, consistent with a well-differentiated fibrolamellar variant of hepatocellular carcinoma (Fig. 1C,D). Given his advanced disease, he was not a candidate for hepatectomy, systemic chemotherapy, vascular intervention, or liver transplantation and was discharged to hospice care with symptomatic palliation. (A) Abdominal CT shows the presence of a large hepatic mass invading the inferior vena cava with ascites and bland thrombus in the lower inferior vena cava extending to the iliac veins. (B) 2D echocardiogram showing the presence of a right atrial thrombus. (C) Liver biopsy showing large polygonal tumor cells with eosinophilic granular cytoplasm surrounded by abundant fibrous stroma in parallel lamellae. (D) Liver biopsy showing cytologic features that include large nuclei with a single prominent nucleolus and pale pink globules in the cytoplasm. Fibrolamellar hepatocellular carcinoma (FLHCC) differs from traditional hepatocellular carcinoma (HCC) in patient demographics (mean age 25 years, equal sex distribution), and absence of underlying cirrhosis or usual risk factors. 1 Our patient presented with rare manifestations that included secondary Budd-Chiari syndrome and significant clot burden causing lower extremity edema and ascites, bilateral pulmonary emboli causing shortness of breath, and a right atrial thrombus. 2 He had both tumor thrombus and bland thrombus, with the latter likely related to a hypercoagulable state. Alpha-fetoprotein levels are usually normal. On imaging a heterogeneous mass characterized by hypervascularity and a central scar in the background of normal liver parenchyma is appreciated. Metastatic tumor burden, hepatic adenoma, focal nodular hyperplasia, traditional HCC, and hemangioma are in the differential diagnosis. In contrast to the central scar of focal nodular hyperplasia (FNH), the central scar has low attenuation on T2 images. 3 On biopsy, the presence of large polygonal tumor cells with vesicular nuclei and large nucleoli, eosinophilic granular cytoplasm, and abundant fibrous stroma in thin parallel lamellae around tumor cells support the diagnosis. 1, 4 Immunohistochemistry shows staining for both hepatocellular (Heppar-1) and biliary differentiation (cytokeratin-7 and epithelial membrane antigen), with the latter contrasting FLHCC and HCC. 4 There are limited data on survival stratified by treatment modalities or by disease stage for FLHCC as compared to HCC arising in noncirrhosis livers. In a multicenter study of patients without metastatic disease undergoing resection, the 5-year survival of patients with FLHCC was similar to those patients with HCC without underlying cirrhosis but higher than patients with HCC and concomitant cirrhosis (62% versus 58% versus 27%). 5 Chemotherapeutic options are limited. Given its increased expression in FLHCC, selective targeting of epidermal growth factor receptor may play a role. Modest 5-year survival rates (35%-50% survival rates) after transplantation have been reported. 6

Diagnosis of metastatic fibrolamellar hepatocellular carcinoma by endoscopic ultrasound-guided fine needle aspiration

The fibrolamellar variant of hepatocellular carcinoma (FL-HCC) is distinguished from other hepatocellular carcinomas (HCC) by its unique clinical and pathologic features. Cytological features for this tumor on fine needle aspiration (FNA) of primary tumors have been described earlier. We present here a unique case of metastatic FL-HCC diagnosed by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) of mediastinal adenopathy. A 32-year-old woman with a history of oral contraceptive use presented with nausea and severe abdominal pain but no ascites or stigmata of cirrhosis. She had a past history of resection of a liver lesion. Serial computed tomography scans revealed mediastinal lymphadenopathy and the patient was referred for endoscopic ultrasound (EUS). A transesophageal EUS-FNA was performed and tissue was collected for cytological evaluation by an on-site pathologist with no knowledge of prior history. Based on morphology correlated with prior history received later, a final diagnosis of metastatic FL-HCC in the retrocardiac lymph node was rendered on the EUS-FNA samples. There are very few reports in the literature where a diagnosis of FL-HCC is rendered at unusual sites. This case highlights that EUS-FNA is a relatively non-invasive, rapid, accurate and effective modality in obtaining tissue from otherwise hard-to-reach areas. It also suggests that metastasis of FL-HCC can be observed in mediastinal nodes and that diagnosis based on cytological features can be rendered even when the tumor is identified at unusual locations.

Fibrolamellar Hepatocellular Carcinoma: An Immunohistochemical Comparison With Conventional Hepatocellular Carcinoma

The fibrolamellar variant of hepatocellular carcinoma (FLC) differs from conventional hepatocellular carcinoma (HCC) in some clinical and pathological features. The authors investigated possible differences in reactivity between FLCs and HCCs using glypican-3 (GPC3), an oncofetal protein, and survivin, an antiapoptotic protein. They also compared staining of FLC and HCC with antibodies to cytokeratins 7 (CK7) and 19 (CK19) and CD34. GPC3 was significantly more often and more strongly expressed in HCCs (72%) than in FLCs (17%). Survivin nuclear translocation in tumor cells did not differ between HCCs (10%) and FLCs (9%). There was more abundant expression of CK7 in FLCs (92%) than in HCCs (33%), whereas CK19 was more often found in HCCs (20%) than in FLCs (5%). All tumors had CD34-positive sinusoids. This study shows that FLCs and HCCs differ in the expression of GPC3, CK7, and CK19 and that there is a lack of difference as regards survivin and CD34.

Utility and limitations of glypican-3 expression for the diagnosis of hepatocellular carcinoma at both ends of the differentiation spectrum

Glypican-3 is a heparin sulfate proteoglycan normally expressed in fetal liver and placenta, but not in normal adult liver. Preliminary studies have shown that glypican-3 can be useful for the diagnosis of hepatocellular carcinoma. We performed immunohistochemistry for glypican-3 on 80 resection cases of hepatocellular lesions to examine the utility of glypican-3 immunohistochemistry in hepatocellular carcinoma at two ends of the differentiation spectrum. Staining was compared to Hep Par 1 in poorly differentiated cases. Glypican-3 was expressed in 46 (79%) hepatocellular carcinomas (56, 83 and 89% of well, moderately and poorly differentiated respectively) and seven (64%) fibrolamellar carcinomas. Of the 16 well differentiated cases, 10 closely resembled adenoma and were diagnosed due to focal abnormalities and/or loss of reticulin. Glypican-3 expression was seen in 50% in this group. Hepatocellular carcinomas arising in cirrhotic liver were more likely to be glypican-3 positive (91 vs 57%, P=0.004). All hepatic adenomas and macroregenerative nodules were negative, and three (43%) high grade dysplastic nodules were positive. Focal staining was seen in regenerative nodules in four (11%) cirrhosis cases. Glypican-3 was significantly more sensitive than Hep Par 1 for diagnosis of poorly differentiated hepatocellular carcinomas (89 vs 63%, P=0.02). The difference was more significant when only cases with diffuse positive staining were considered (83 vs 21%, P<0.001). In conclusion, glypican-3 has high sensitivity for the diagnosis of hepatocellular carcinoma, but is less sensitive in the extremely well differentiated hepatocellular carcinoma and fibrolamellar variant of hepatocellular carcinoma. Caution should be exercised in using glypican-3 in biopsy specimens as cirrhotic nodules can show strong expression. Glypican-3 can be especially useful in the identification of poorly differentiated hepatocellular carcinoma as it has higher sensitivity compared to Hep Par 1.

Advances in the surgical management of liver malignancies.

Primary malignancies of the liver include tumors arising from the hepatocytes (hepatocellular carcinoma and the fibrolamellar variant) and the intrahepatic bile ducts (intrahepatic cholangiocarcinoma). Hepatocellular carcinoma is the most common primary cancer of the liver and is a leading cause of death from cancer worldwide. Although it is uncommon in the United States, the incidence of hepatocellular carcinoma is rising. Hepatitis, ethanol use, and cirrhosis often dominate the clinical picture and may dictate prognosis. New clinical and pathological staging systems have allowed for the more accurate stratification of patients to more appropriately identify patients for resection, transplantation, and percutaneous ablation therapies. A correlation between liver volume and surgical outcome has recently been demonstrated, with small liver remnant size being associated with increased morbidity. Portal vein embolization has therefore been proposed as one way to induce hypertrophy of the anticipated liver remnant before resection. Initial reports have shown that portal vein embolization decreases the incidence of postoperative complications. More recently, systemic chemotherapy and chemoembolization have been investigated as both primary and neoadjuvant therapy. Chemoimmunotherapy with 5-fluorouracil and interferon may be associated with a superior response rate in the fibrolamellar variant of hepatocellular carcinoma. Two recent randomized studies have also indicated improved survival after hepatic artery embolization in selected patients.

Liver transplantation and hepatocellular carcinoma.

Liver transplantation for advanced hepatocellular carcinoma (HCC) continues to be a subject of debate mostly due to a uniformly high failure rate secondary to recurrence. However, accumulating experiences have enabled detailed analysis of the prognostic factors affecting patient outcome. Clinicopathological factors affecting survival have been reported to include tumor size, number, lobar distribution, vascular invasion, lymphnode metastasis, and histologic type such as fibrolamellar variant of HCC. Poor prognosis has been associated with advanced stage of the tumor, particularly pTNM stage IV. Many transplant centers now use a protocol of adjuvant chemotherapy with reasonable success, although experiences are limited. Better understanding in tumor biology, particularly of the role of immunosuppression affecting tumor growth, will provide further success in the treatment of HCC by liver transplantation.

LIVER TRANSPLANTATION FOR MALIGNANT DISEASE

Recent progress has been made in identifying patients with malignant primary liver tumors who have the best chance of long-term survival after orthotopic liver transplantation. Patients with UICC stages I or II hepatocellular carcinoma, the fibrolamellar variant of hepatocellular carcinoma, or epithelioid hepatic hemangioendothelioma are acceptable candidates for orthotopic liver transplantation. Carefully selected patients with neuroendocrine tumors metastatic to the liver may also have long-term palliation with liver transplantation. Therapeutic strategies are currently being developed to minimize disease recurrence after liver transplantation for patients with advanced-stage hepatocellular carcinoma confined to the liver or with cholangiocarcinoma. However, published survival rates for most patients with malignant primary liver tumors remain suboptimal, and significant progress in preventing disease recurrence is required before liver transplantation can be widely applied to most patients with primary malignant liver tumors.

HBV-DNA sequences in tumor and nontumor tissue in a patient with the fibrolamellar variant of hepatocellular carcinoma

One patient with the fibrolamellar variant of hepatocellular carcinoma was found to be seropositive for HBsAg and anti-HBe. DNA from tumor and nontumor areas of the liver was examined by molecular hybridization for hepatitis B virus DNA sequences. Undigested DNA from the tumor gave a high-molecular-weight smear, and restriction-enzyme analysis indicated a single instance of integration. Nontumor liver tissue was analyzed from three separate areas. Hepatitis B virus DNA was detected in two of these; restriction-enzyme digestion suggested they contained different sites of viral integration. As with the typical hepatitis B virus-related hepatocellular carcinoma, analysis of hepatitis B virus DNA from nontumorous liver yielded a different pattern of high-molecular-weight bands, indicating that the virus genome had integrated at different chromosomal locations than that seen in the tumor. The finding of integrated hepatitis B virus DNA, especially in tumorous but also in nontumorous liver, would be consistent with an oncogenic role for hepatitis B virus in certain instances of fibrolamellar tumors and in the more typical hepatitis B virus-related hepatocellular carcinoma.

Primary malignant hepatic tumours in childhood

Twenty-four cases of hepatoblastoma, 14 cases of hepatocellular carcinoma and three cases of malignant mesenchymoma out of a total of 54 primary liver tumours were studied by light microscopy and immunohistochemistry. A remarkable finding in one case of hepatoblastoma and one case of hepatocellular carcinoma was a sarcoid-like reaction in the tumour tissue. Three cases of hepatoblastoma presented a macrotrabecular pattern. Among hepatocellular carcinomas, three cases corresponded to the fibrolamellar variant. By immunohistochemistry, the proportion of cases with positive staining for alpha 1-fetoprotein was higher in hepatoblastoma than in hepatocellular carcinoma. HBs-antigen could be demonstrated in non-neoplastic liver cells in two cases of hepatocellular carcinoma, but not in the tumour cells. No strong correlation between histological pattern and prognosis could be established in hepatoblastoma. However, there was a tendency to more aggressive biological behavior in cases with pronounced mitotic activity. The number of mitoses in hepatoblastoma varied widely. As in previous studies, patients with the fibrolamellar variant of hepatocellular carcinoma fared better than those with the classical type of this tumour. Prognosis in malignant mesenchymoma was not as poor as suggested from previous studies.