This is the most common primary malignant tumor arising within the liver, accounting for >90% of all primary liver cancers. Metastatic tumors to the liver are actually more common, usually from the colon or prostate or breast. It is sometimes erroneously referred to as a hepatoma which should be avoided since this name implies a benign neoplasm. About 350,000 cases per year are diagnosed around the world. It is a global problem with 2-4 annual cases/100,000 in North and South America but 20 annual cases/100,000 around the Mediterranean and 150 annual cases/100,000 in China, Korea, and Taiwan. Males are favored ranging from 2:1 to 8:1.
There is a well-established link with hepatitis B viral infection (HBV) which accounts for the high prevalence throughout the world. In the West, hepatitis C viral infection (HCV) and alcoholism are the main culprits. Several mechanisms have been hypothesized to account for the neoplastic transformation. Because of the association of HBV infection, vaccination programs for children have dramatically decreased the infection rates.
The tumor may present with upper abdominal pain, malaise, weight loss, and fatigue. Depending upon the degree of liver involvement as well as the presence of cirrhosis, there may be jaundice, gastrointestinal bleeding, and fever. Serum alpha-feto protein is elevated in 60-75% of cases. The disease is progressive and death usually occurs within 10 months of initial diagnosis from cachexia, gastrointestinal bleeding, liver failure, or rupture of the tumor with massive hemorrhage.
The tumor may present as a solitary, multiple, or diffusely infiltrative cancer. HCCs have a marked propensity for vascular invasion, especially the portal vein or inferior vena cava. Under the microscope, the tumor grows in seveal patterns ranging from trabecular to an acinar pseudoglandular pattern.
PATHOGENESIS CHARACTERIZATION Agent Pathogenesis FIBRONECTIN
Hepatocellular carcinomas show abnormal expression of fibronectin protein.
Torbenson M, Wang J, Choti M, Ashfaq R, Maitra A, Wilentz RE, Boitnott J.
Departments of Pathology (MT, AM, REW, JB) and Surgery (MC), The Johns Hopkins Hospital, Baltimore, Maryland.
Mod Pathol 2002 Aug;15(8):826-30 Abstract quote
Fibronectin plays an important role in cell-to-cell adhesion, cell migration, and cell signaling. In the liver, fibronectin expression has been studied primarily as a component of the extracellular matrix, but little information is available on the expression of fibronectin protein in the neoplastic cells of hepatocellular carcinomas (HCCs).
Twenty-four surgically resected HCCs were immunostained with fibronectin. Tumor and normal liver tissues were concurrently analyzed in all cases, and expression in the tumor was evaluated in comparison to the nonneoplastic liver. The average age at resection was 54 +/- 18 years for the 18 men and 6 women. Twenty-one of the cases were classic HCCs including 6 cases that were well differentiated, 12 cases moderately differentiated, and 3 cases poorly differentiated. The remaining 3 cases were moderately differentiated fibrolamellar carcinomas. In the normal liver, fibronectin labeled the sinusoids and weakly to moderately stained the cytoplasm of hepatocytes. In HCCs, 15/24 showed overexpression of fibronectin in the cytoplasm, 8/24 showed no change from the nonneoplastic liver, and one case showed decreased cytoplasmic staining. In addition, an abnormal membranous staining pattern was noted in 16/24 HCCs. In contrast to the HCCs, none of the three fibrolamellar carcinomas showed increased cytoplasmic or membranous staining. Excluding fibrolamellar carcinoma, increased cytoplasmic staining and/or an abnormal membranous staining was noted in 19/21 (90%) of HCCs.
Fibronectin shows abnormal cytoplasmic and/or membranous staining in the majority of HCCs. The implications of fibronectin overexpression are uncertain but may reflect a critical step in tumor genesis.
HBV INFECTION Viral DNA integrated into the host cell genome
Tumors are clonal with respect to these insertions
Viral integration induces genomic instability
HBV X protein acts as a transactivator of cellular and viral promoters and binds to tumor suppressor gene p53
Full-length genomic analysis of hepatitis B virus isolates in a patient progressing from hepatitis to hepatocellular carcinoma.
Lin X, Qian GS, Lu PX, Wu L, Wen YM.
Department of Molecular Virology, Shanghai Medical University, Shanghai, China
Med Virol 2001 Jul;64(3):299-304 Abstract quote
In hepatitis B virus (HBV)-endemic countries, the majority of hepatocellular carcinoma (HCC) arises in HBV carriers. High frequency of mutations at nucleotides 1762(A-->T) and 1764(G-->A) in the core promoter region have been described in HCC. Due to the differences in genetic backgrounds, environmental risk factors and random cellular insertion sites, it is difficult to analyze the possible roles of HBV variants detected in different HCC patients.
In a follow-up cohort study, an HBsAg-positive asymptomatic carrier was diagnosed HCC within 4 years. Eleven full-length HBV isolates, three from the first serum sample obtained 4 years pre-HCC, and eight from serum sample, peri-tumor and tumor tissue post-HCC of this individual were sequenced and used to transfect HepG2 cells. When sequences were compared between pre- and post-HCC isolates, no single mutation common to all post-HCC isolates that differed from pre-HCC isolates was found.
Among all 11 isolates, there were 20 predicted amino acid substitutions shared by two or more post-HCC isolates. These were located in the S(5), X(4), core(4), polymerase(4), pre-S1(2) and pre-S2(1) proteins. Possible roles of amino acid substitutions and enhanced replication efficiency in cells transfected by post-HCC isolates are discussed.
AFLATOXINS Produced by molds and activated by hepatocytes
Products are intercalated into DNA to form mutagenic adducts with guanosine of p53 gene
Microsomal enzymes responsible for detoxifying aflatoxins are mutated in high risk areas
Acts synergistically with HBV infection
Genomic instability in chronic viral hepatitis and hepatocellular carcinoma
Maria Pina Dore, MD Giuseppe Realdi, MD Daniela Mura, MD Angela Onida, MD Giovanni Massarelli, MD Giuseppe Dettori, MD David Yates Graham, MD Antonia Rogado Sepulveda, MD, PhD
Hum Pathol 2001;32:698-703. Abstract quote
Chronic hepatitis may progress to cirrhosis and hepatocellular carcinoma (HCC). Progressive accumulation of mutations and genomic instability in chronic viral hepatitis might flag an increased risk of HCC development.
Genomic instability at dinucleotide microsatellite loci in chromosomes 2, 13, and 17 and at 2 mononucleotide repeat loci was examined in liver tissues from 41 patients, including 30 without HCC (18 patients with chronic hepatitis and 12 with cirrhosis) and 11 with HCC. Genomic instability was detected in 51% of the 41 cases. Allelic imbalance at informative dinucleotide loci occurred in 37% of the cases. In 14 cases (34%), allelic imbalance was detected in chronic hepatitis or cirrhosis without HCC. Allelic imbalance at the chromosome 13 locus was detected in 50% of the cases of chronic hepatitis C. Allelic imbalance at the TP53 chromosome locus and/or at the chromosome 13 locus was significantly more frequent than alterations at the chromosome 2 locus (P = .026). Low-level microsatellite instability was found in 20% of all cases examined and high-level microsatellite instability in 3 patients (7.5%), including 2 cases of chronic hepatitis and 1 case of cirrhosis.
Our results show that allelic imbalance occurs frequently in hepatitis-related HCC as well as in chronic hepatitis in patients without HCC. Allelic imbalance at the D13S170 chromosome 13 locus (13q31.2) occurs frequently in chronic hepatitis, suggesting that genomic alterations affecting the long arm of chromosome 13 might be used to monitor the natural progression of chronic hepatitis-associated liver carcinogenesis.
Detection of chromosomal aberrations in well-differentiated hepatocellular carcinoma by bright-field in situ hybridization.
Wilkens L, Bredt M, Flemming A, Mengel M, Klempnauer J, Kreipe H, Flemming P.
Department of Pathology, Medizinische Hochschule, Hannover, Germany.
Mod Pathol 2002 Apr;15(4):470-5 Abstract quote
Differentiation between well-differentiated hepatocellular carcinoma (HCC) and nonmalignant lesions with increased cellular proliferation may be difficult in needle biopsies. Based on recurrent chromosome aberrations known for HCC, we developed a nonfluorescent in situ hybridization technique that allows combination with morphological analysis in bright-field microscopy.
Fourteen biopsies of HCC and 31 samples of regenerative nodules (n = 10), chronic hepatitis (n = 10), fibrosis or cirrhosis of unknown origin (n = 5), focal nodular hyperplasia (n = 2), primary biliary cirrhosis (n = 2), steatosis (n = 1), and adenomatous hyperplasia (n = 1) were analyzed with probes specific for the centromeric regions of chromosomes 1, 6, 7, and 8. After microwave pretreatment and in situ hybridization, signals were detected using a tyramine-based system and AEC as substrate. Evaluation of signals was done by conventional bright-field microscopy. Using this approach, aberrant counts were seen for at least one chromosome in 12/14 cases of HCC. In contrast, none of the nonmalignant lesions revealed aberrant counts for any of the chromosomes analyzed.
In conclusion, this new combination of in situ hybridization and tyramine amplification allows fast and reliable evaluation of chromosome aberrations in a histomorphological context similar to paraffin immunohistochemistry. Registration of imbalances contributes to a reliable differentiation between malignant and nonmalignant lesions of the liver.
CIRRHOSIS Stimulation of hepatocellular division with ongoing necrosis and inflammaiton
Occurrence of hepatocellular carcinoma and decompensation in western European patients with cirrhosis type B. The EUROHEP Study Group on Hepatitis B Virus and Cirrhosis.
Fattovich G, Giustina G, Schalm SW, Hadziyannis S, Sanchez-Tapias J, Almasio P, Christensen E, Krogsgaard K, Degos F, Carneiro de Moura M, et al.
Istituto di Semeiotica e Nefrologia Medica, University of Verona, Italy.
Hepatology 1995 Jan;21(1):77-82 Abstract quote
To examine the morbidity of compensated cirrhosis type B, a cohort of 349 Western European, white patients (86% men; mean age, 44 years) with biopsy-proven cirrhosis was followed up for a mean period of 73 months and was studied for occurrence of hepatocellular carcinoma (HCC) and decompensation.
At entry into the study all patients were tested for hepatitis B e antigen (HBeAg; 34% of patients were HBeAg-positive) and antibody to hepatitis delta virus (anti-HDV; 20% of patients were anti-HDV-positive); 48% of 252 patients tested were hepatitis B virus (HBV)-DNA-positive. During follow-up HCC developed in 32 (9%) of the 349 patients and decompensation was observed in 88 (28%) of 317 tumor-free patients. Five years after diagnosis, the probability of HCC appearance was 6% and the probability of decompensation was 23%. After the first episode of decompensation the probability of survival was 35% at 5 years. Cox's regression analysis identified three variables that independently correlated with HCC: age, serum levels of platelets, and liver firmness on physical examination. HBV (HBeAg or HBV-DNA) and HDV (anti-HDV) markers at presentation had no prognostic value for the development of HCC. In conclusion, a high proportion of patients with HBsAg-positive compensated cirrhosis do not experience worsening of their condition for several years, but once decompensation occurs life expectancy is poor. European, white patients with compensated cirrhosis type B are at consistent risk for HCC.
Prognostic factors for HCC reflect an advanced stage of cirrhosis and support the hypothesis that development of a tumor could be the likely consequence of long-standing hepatic disease.
Expression of Fas and Fas-related molecules in human hepatocellular carcinoma
Sug Hyung Lee, etal.
Hum Pathol 2001;32:250-256.
Many tumor cells, including hepatocellular carcinoma (HCC), express both Fas and its ligand on their surfaces, and it has remained a mystery why such cells do not spontaneously become apoptotic.
In the current study, we analyzed the alterations of Fas structure and the expression of Fas and Fas ligand (FasL) and of Fas pathway inhibitors, including soluble Fas (sFas), Fas-associated phosphatase-1 (FAP-1), and bcl-2, in 50 cases of human HCC.
Monoallelic loss of the Fas gene, as determined by loss of heterozygosity with intragenic polymorphisms, was observed in 5 of the 34 informative cases (15%), but none of the 50 cases showed Fas gene mutation. Expression of Fas and FasL was detected in 44 (88%) and 50 (100%) cases, respectively. sFas messenger RNA, as analyzed by in situ reverse-transcription polymerase chain reaction was expressed in 42 of the 50 cases (84%), and FAP-1 expression was observed in 40 of the 50 cases (80%).
In contrast, none of the 50 cases showed bcl-2 expression.
Our results showed that the majority of the HCCs (88%) coexpressed a death receptor, Fas and its cognate ligand, FasL, but all HCCs showed one or more alterations of the Fas pathway molecules known to inhibit Fas-mediated apoptosis.
These findings suggest that the expression of sFas and FAP-1 and, in part, loss of Fas expression, rather than Fas gene alteration or bcl-2 expression, may be involved in the Fas resistance of HCC in vivo and that these mechanisms may play important roles in the pathogenesis of human HCC.
High expression of p21 is correlated with human hepatocellular carcinoma in patients with hepatitis C virus-associated chronic liver diseases.
Wagayama H, Shiraki K, Sugimoto K, Ito T, Fujikawa K, Yamanaka T, Takase K, Nakano T.
First Department of Internal Medicine, Mie University School of Medicine, Tsu 514-8507, Japan.
Hum Pathol 2002 Apr;33(4):429-34 Abstract quote
p21(WAF1/CIP1) (p21) protein is a universal inhibitor of cyclin-dependent kinases and is regulated transcriptionally by p53, which is activated by DNA stress. Hepatocytes in chronic hepatitis receive several DNA stresses by lymphocytes and Kupffer cells.
Therefore, we analyzed p21 expression of hepatocytes in hepatitis C virus (HCV)-associated chronic liver diseases and investigated the possible involvement of p21 in hepatocarcinogenesis. We examined p21 expression in 35 cases of HCV-associated chronic hepatitis and 25 cases of HCV-associated liver cirrhosis by immunohistochemical analysis. The p21 labeling index (LI) was calculated as the ratio of positive cells to total cells. p21-positive hepatocytes were more numerous in areas of intense inflammation and spotty necrosis and areas close to fibrosis, and were increased according to the degrees of grading and staging. The p21 LI with liver cirrhosis was significantly higher than that with chronic hepatitis (14.4 +/- 5.9 versus 11.1 +/- 4.2, P = 0.014). The cumulative incidence of hepatocellular carcinoma (HCC) was significantly higher in the p21 LI >/=14% group than in the p21 LI <14% group (P = 0.0079). Multivariate analysis demonstrated that p21 expression can be recognized as an independent significant factor for HCC development (relative risk 5.00, P = 0.039). p21 LI decreased significantly after interferon therapy.
These results suggested that p21 is up-regulated by the stress of inflammation and fibrosis in HCV-associated chronic liver diseases and that high p21 expression might be related to hepatocarcinogenesis in cirrhotic patients.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL
The pathologist has the additional difficult task of differentiating several precursor lesions from hepatocellular carcinoma (HCC). These dysplastic nodules were once referred to as adenomatous hyperplasia. The most important message is fully developed malignant change even in a focus of less than 1 mm is diagnostic for HCC in the setting of a cirrhotic liver
Mallory bodies present in 20% of tumors, indistinguishable from alcoholic hyaline
Non-Mallory cytoplasmic globules present in 20%, usually PAS positive and diastase resistant (globules of alpha-1-antitrypsin)
Primary Liver Carcinoma in Genetic Hemochromatosis Reveals a Broad Histologic Spectrum
Mohib Morcos, MD
Sylvie Dubois, MSc
Marie-Pierre Bralet, MD
Jacques Belghiti, MD
Claude Degott, MD
Benoît Terris, MD
Am J Clin Pathol 2001;116:738-743 Abstract quote
Hepatocellular carcinoma (HCC) is a well-known complication of genetic hemochromatosis (GH). However, the frequency of primary liver carcinoma (PLC) with biliary differentiation, such as cholangiocarcinoma (CC) and combined hepatocholangiocarcinoma (CHCC), in GH remains unclear.
We analyzed the histologic type of 20 PLCs occurring in the background of GH; all patients were homozygotic for the C282Y mutation. Ten were depleted of iron by successive phlebotomies, while the remaining 10 were untreated. Histologically, 13 cases were classified as HCC, 3 as CC, and 4 as CHCC. Immunohistochemical detection of Hep Par 1, cytokeratin 19 (CK19), and MUC1 supported this classification; PLC with biliary differentiation was immunoreactive for MUC1 in 86% (6/7) of cases and for CK19 in 100% (7/7) of cases. The nontumoral liver exhibited no cirrhosis or extensive fibrosis in 6 cases. Von Meyenburg complexes were present in 11 cases and intraparenchymal bile duct adenomas in 3.
These data suggest that PLCs in patients with GH present a wide histologic spectrum, with tumors showing frequent biliary differentiation; may arise on a nonfibrotic or a cirrhotic liver; and often are associated with Von Meyenburg complexes and to a lesser extent with bile duct adenomas.
VARIANTS Clear cell Must distinguish from metatastatic renal cell carcinoma Combined (HCC with cholangiocarcinoma)
Combined Hepatocellular-Cholangiocarcinoma: A Histopathologic, Immunohistochemical, and In Situ Hybridization Study
Satish K. Tickoo, M.D.; Sui Y. Zee, M.D.; Sam Obiekwe, M.D.; Hong Xiao, B.S.; Jonathan Koea, M.D.; Christian Robiou, M.D.; Leslie H. Blumgart, M.D., F.A.C.S.; William Jarnagin, M.D.; Marc Ladanyi, M.D.; David S. Klimstra, M.D.
Am J Surg Pathol 2002; 26(8):989-997 Abstract quote
Combined hepatocellular-cholangiocarcinoma (CHC) forms a small but significant proportion of primary liver carcinomas. However, its diagnostic features are not well established, and this has possibly contributed to the variability in its reported clinical outcome in the literature. Many such tumors with features intermediate between hepatocellular carcinoma and cholangiocarcinoma (CC) may have been considered CC in the past based on positivity for "biliary differentiation" cytokeratins and the lack of availability of highly sensitive and specific hepatocellular markers. The utility of in situ hybridization for albumin mRNA, a recently available sensitive and specific hepatocellular marker, has not been reported in CHC.
We investigated 27 CHCs with regard to their histomorphologic spectrum and association of these morphologies with immunohistochemical staining for different cytokeratins (CK7, CK19, and CK20; AE1; Cam 5.2), epithelial membrane antigen, polyclonal carcinoembryonic antigen and alpha-fetoprotein, and in situ hybridization for albumin mRNA. All 27 tumors contained areas morphologically intermediate between hepatocellular carcinoma and CC (transitional-type tumors), and in each case such areas formed at least 25% of the tumor. Nine (33%) tumors showed areas with "antler-like" morphology, a feature not previously described in CHC. Twenty-two of 23 tumors (96%) showed positive signals on in situ hybridization for albumin mRNA. Positivity for both hepatocellular (albumin mRNA) and biliary (keratin immunohistochemical profile) markers confirmed the light microscopic impression of biphenotypic differentiation in these tumors. Immunohistochemical positivity for all cytokeratins (except CK7) and epithelial membrane antigen, as well as the expression of albumin mRNA by in situ hybridization, did not show significant differences between hepatocellular carcinoma and CC-like areas.
Based on the cytokeratin profile and results on polyclonal carcinoembryonic antigen/alpha-fetoprotein alone, many such tumors would be classified as CC. However, the positivity for albumin mRNA by in situ hybridization proves that such an interpretation would not have been accurate. Clinically, CHCs showed many differences from pure hepatocellular carcinoma, including the absence of cirrhosis (0 of 27), rarity of serum hepatitis B or C marker positivity (4 of 27), and normal to only mildly elevated serum alpha-fetoprotein levels (median 187 ng/mL). The tumor followed an aggressive clinical course, with overall 3-and 5-year survival rates of 30% and 18%, and in the resected cases of 38% and 24%, respectively.
Compact Trabeculae grow together compressing sinusoids and forming sheets Fibrolammellar Young adults (20-40 yrs)
No association with HBV or cirrhosis risk factors
Large tumor with fibrous bands coursing throughout
Well differentiated polygonal cells rowing in nests and cords separated by parallel lamellae of dense collagen bundles
May have more favorabe outlook
Adult-type hepatocellular carcinoma in the center of a fibrolamellar hepatocellular carcinoma.
Seitz G, Zimmermann A, Friess H, Buchler MW.
Department of Visceral and Transplantation Surgery and the Institute of Pathology, University of Berne, Berne, Switzerland.
Hum Pathol 2002 Jul;33(7):765-9 Abstract quote
A large hepatic tumor was detected in the noncirrhotic liver of a 27-year-old female patient. The tumor was radiologically characterized by a peripheral mass encircling a central ovoid tumor, and was resected by an extended right hemihepatectomy.
Histologic examination revealed that the peripheral and major component of the tumor represented a fibrolamellar hepatocellular carcinoma, whereas the central, well-demarcated tumor was a less well-differentiated adult-type hepatocellular carcinoma completely encircled by the former. Cells of the peripheral tumor mass abundantly expressed cytokeratin-7, typically present in the fibrolamellar variant, whereas no cytokeratin-7 immunoreactivity was found in the central tumor.
To our knowledge, this is the first reported case of a not admixed but clearly separated evolution of these 2 histologic patterns within the same tumor, and suggests that the 2 types of hepatocellular carcinoma may share a common pathogenic pathway.
Mixed Pelioid Blood filled cystic spaces within the tumor Pseudoglandular Centers of trabeculae with dilated canaliculus Sarcomatoid (Carcinosarcoma) Scirrhous Occurs in cirrhotic liver with considerable fibrous tissue
Lacks lamellar fibrosis and pleomorphic cytology of fibrolamellar type
Sclerosing hepatic carcinoma Associated with hypercalcemia
Cirrhotic and non-cirrhotic livers
Trabecular Thickened trabeculae numbering up to 10-20 cells thick
SPECIAL STAINS/IMMUNOHISTOCHEMISTRY CHARACTERIZATION GENERAL Immunohistochemical Detection of Hepatocellular Carcinoma in the Setting of Ongoing Necrosis after Radiofrequency Ablation
Tomoo Itoh, M.D., Yasuko Orba, C.T., Hidehiro Takei, M.D., Yusuke Ishida, M.D., Makoto Saitoh, M.D., Hideaki Nakamura, M.D., Takashi Meguro, M.D., Shoichi Horita, M.D., Miri Fujita, M.D. and Kazuo Nagashima, M.D.
Laboratory of Molecular and Cellular Pathology (TI, YO, HT, YI, MS, KN), Hokkaido University School of Medicine, Hokkaido; Hokkaido Gastroenterology Hospital (HN, TM, SH), Hokkaido; Department of Pathology, Shin-Nittetsu Muroran General Hospital (MF), Muroran; and Core Research for Evolutional Science and Technology (KN), Tokyo, Japan
Mod Pathol 2002;15:110-115 Abstract quote
After radiofrequency ablation (RFA), hepatocellular carcinoma undergoes complete necrosis and an ongoing necrosis that is irreversible and characterized histologically by disrupted cell outlines, homogenous cytoplasmic eosinophilia, and preserved nuclear staining, with the cells appearing quite distinct from viable cancer cells.
Antibody to detect single-stranded DNA (ssDNA) specifically labeled nuclei in the setting of ongoing necrosis, but not viable tumor cells, whereas human mitochondrial antibody labeled the cytoplasm of viable cells but not cells of ongoing necrosis.
The results demonstrate that RFA causes denaturation of both DNA and proteins and that the immunohistochemistry of ssDNA and mitochondrial protein is useful in detection of ongoing necrosis after RFA and provides pathological information on the validity of this procedure.
Canalicular Immunostaining of Neprilysin (CD10) as a Diagnostic Marker for Hepatocellular Carcinomas
Nicole Borscheri, M.D.; Albert Roessner, M.D., Ph.D.; Christoph Röcken, M.D., Ph.D.
From the Department of Pathology, Otto-von-Guericke-University, Magdeburg, Germany.
Am J Surg Pathol 2001;25:1297-1303 Abstract quote
Neprilysin (CD10) is expressed in both normal and neoplastic liver tissue, where it exhibits a characteristic canalicular pattern (CD10 can ) similar to the one observed when antibodies cross-react with biliary glycoprotein I (p-CEA).
The aim of this retrospective study was to investigate the use of CD10 can in differentiating between hepatocellular carcinomas (HCCs; 63 specimens) and nonhepatocellular carcinomas (non-HCCs) metastatic to the liver (non-HCC; 25 specimens). Immunostaining was performed with antibodies directed against CD10, p-CEA, and -fetoprotein (AFP). Albumin mRNA was detected by nonradioactive in situ hybridization (ISH albumin ). In the HCC group a canalicular staining pattern for CD10 was found in 43 (68.3%) specimens, AFP was found in 15 (23.8%) specimens, and a canalicular staining pattern for p-CEA was present in 60 (95.2%) specimens. ISH albumin was performed in 35 HCC specimens and showed labeling of tumor cells in 30 (85.7%) specimens. In the non-HCC group, CD10 can , and p-CEA, immunostaining for AFP and labeling for ISH albumin were confined to non-neoplastic liver tissue. Sensitivity and specificity were, respectively, 68.3% and 100% for CD10 can , 23.8% and 100% for AFP, 95.2% and 100% for canalicular p-CEA, and 86.4% and 100% for ISH albumin .
Our results demonstrate that canalicular staining for CD10 is a highly specific marker of hepatocytic differentiation. Although it does not differentiate between benign and malignant lesions, CD10 can is clearly useful in differentiating between HCC and non-HCC.
Hepatocyte Antigen as a Marker of Hepatocellular Carcinoma: An Immunohistochemical Comparison to Carcinoembryonic Antigen, CD10, and Alpha-Fetoprotein
Peiguo G. Chu, M.D., Ph.D.; Shin Ishizawa, M.D.; Emerald Wu, B.S., HT (ASCP); Lawrence M. Weiss, M.D.
Am J Surg Pathol 2002; 26(8):978-988 Abstract quote
Hepatocyte monoclonal antibody (Hep) (alternatively Hep Par 1 for Hep paraffin 1) has been reported to stain normal hepatic tissue and hepatocellular carcinoma (HCC) with high specificity.
We have studied the Hepatocyte expression in 96 cases of HCC and 311 cases of nonhepatic epithelial tumors. All cases of HCC were also stained with CEA-Gold 5, CD10, and alpha-fetoprotein. Hep, CEA-Gold 5, CD10, and alpha-fetoprotein immunostains were performed on formalin-fixed, paraffin-embedded tissue sections. Hep immunoreactivity was detected in 88 of 96 cases of HCC (92%), with a cytoplasmic and granular pattern of staining. The level of Hep expression in HCC corresponded to the nuclear grade and growth pattern. All 50 cases of nuclear grade 1 and nuclear grade 2 HCC were positive (100%), whereas 37 of 44 nuclear grade 3 (84%) and 1 of 2 nuclear grade 4 (50%) were positive. Sixty-seven of 68 cases of HCC with a trabecular, pseudoglandular, or scirrhous growth pattern were positive (98%), whereas 22 of 27 cases of HCC with a compact growth pattern were positive (81%). CEA-Gold 5, CD10, and alpha-fetoprotein immunoreactivity was detected in 76% (73 of 96), 52% (50 of 96), and 31% (30 of 96) cases of HCC, respectively. The positive predictive value of the combination of all four antibodies was 97%. Three cases of HCC were negative for all four antibodies; these cases had a high nuclear grade or a sarcomatoid or compact growth pattern. Twenty of 311 cases of nonhepatic tumors were positive for Hep (6%): 15 were adenocarcinomas and five were neuroendocrine tumors. The negative predictive value of Hep in HCC was 94%. The Hep-positive nonhepatic epithelial tumors were easily distinguished from HCC by the expression of keratin 7 or keratin 20 for adenocarcinoma and chromogranin and synaptophysin for neuroendocrine tumors because HCC does usually not express these markers.
With the exception of two cases of hepatoid gastric carcinoma, all Hep-positive nonhepatic epithelial tumors were negative for alpha-fetoprotein, CEA-Gold 5, and CD10. Our study demonstrates that Hep is a relatively specific marker for HCC. It is useful in differentiating HCC from primary hepatic cholangiocarcinoma and metastatic tumors when combined with other immunomarkers.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES Distinguishing Nodules in a Cirrhotic Liver
Morphology Low-grade dysplastic nodule High-grade
HCC Large cell change Can be present Can be present Common Nuclear density>2x normal (small cell change) No small cell change Occasional small foci in borderline lesions Common, large foci Cell plates, zone >/= 3 cell thick (trabecular) None Rare in borderline lesions, no zones of trabeculae Common pattern Decrease or loss of reticulin Reticulin intact May see focal decrease or loss Common extensive Fibrous septa separating thick plates None None Occasional pattern Irregular, infiltrative edges Not present Sometimes present Occasional Pseudoglands Not present Rare Occasional pattern Presence of portal zones Usually present Usually present None Increased iron stores Occasional Occasional Almost always absent Fatty change Can be present Can be present Can be present Bile production Can be present Can be present Can be present Mallory Hyaline Can be present Can be present Can be present in clusters
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS
Ability to completely resect tumor is associated with best prognosis
In general, dismal prognosis, regardless of other factors
Improved postsurgical survival in patients with:
Lack of vascular invasion
Lack of underlying cirrhosis
Prognostic factors after hepatic resection for hepatocellular carcinoma with hepatitis C viral infection: univariate and multivariate analysis.
Hanazaki K, Kajikawa S, Koide N, Adachi W, Amano J.
Second Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan.
Am J Gastroenterol 2001 Apr;96(4):1243-50 Abstract quote
OBJECTIVES: Although the incidence of hepatocellular carcinoma (HCC) with hepatitis C virus (HCV) infection is higher than in patients with hepatitis B virus (HBV)-related HCC in Japan, the long-term prognosis and prognostic factors of HCV-related HCC after hepatic resection are poorly understood.
METHODS: The surgical outcome of HCV-related HCC in 172 consecutive patients who underwent hepatic resection between 1989 and 1997 was retrospectively clarified. Postresection prognostic factors were evaluated by univariate and multivariate analysis using Cox's proportional hazards model.
RESULTS: The overall incidence of postoperative complications was 23.2%, and 11 patients among that group had hospital deaths (6.4%) including 9 (5.2%) operative deaths. The mean and median overall survivals including hospital death after surgery were 41 months and 33 months, respectively. The 3-, 5-, and 7-yr overall survival rates after hepatic resection were 63%, 52%, and 47%, respectively. The 3-, 5-, and 7-yr disease-free survival rates after hepatic resection were 33%, 20%, and 15%, respectively. Multivariate analysis revealed that serum alpha-fetoprotein (AFP) of > or = 1000 ng/ml and the presence of vascular invasion were independent unfavorable prognostic factors affecting overall survival and that AFP of > or = 1000 ng/ml was an independently significant factor of poor disease-free survival.
CONCLUSIONS: We found the postresection survival of patients with HCV-related HCC should be stratified by the high value of AFP and the presence of vascular invasion. AFP may be the most powerful predictor of the long-term prognosis and recurrence in such patients.
Prognostic Histologic Indicators of Curatively Resected Hepatocellular Carcinomas A Multi-institutional Analysis of 425 Patients With Definition of a Histologic Prognostic Index
Gregory Y. Lauwers, M.D. ; Benoit Terris, M.D. , Ph.D. ; Ulysses J. Balis, M.D. ; Kenneth P. Batts, M.D. ; Jean-Marc Regimbeau, M.D. ; Yuchiao Chang, Ph.D. ; Fiona Graeme-Cook, M.B , B.Ch. ; Hirohiko Yamabe, M.D. ; Iwao Ikai, M.D. ; Karen R. Cleary, M.D. ; Shiro Fujita, M.D. ; Jean-Francois Flejou, M.D. ; Lawrence R. Zukerberg, M.D. ; David M. Nagorney, M.D. ; Jacques Belghiti, M.D. ; Yoshio Yamaoka, M.D. ; Jean-Nicolas Vauthey, M.D.
For the International Cooperative Study Group on Hepatocellular Carcinoma: Departments of: Pathology (G.Y.L., U.J.B., F.G.-C., L.R.Z.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, U.S.A.; Anatomopathologie (B.T., J.-F.F.), Hôpital Beaujon, Paris, France; Pathology (K.P.B.), Mayo Clinic, Rochester, Minnesota, U.S.A.; Surgery (J.-M.R., J.B.), Hôpital Beaujon, Paris, France; Clinical Research Program (Y.C.), Massachusetts General Hospital, Boston, Massachusetts, U.S.A.; Pathology (H.Y.), Kyoto University Graduate School of Medicine, Kyoto, Japan; Surgery (I.I., S.F., Y.Y.), Kyoto University Graduate School of Medicine, Kyoto, Japan; Pathology (K.R.C.), University of Texas M.D. Anderson Cancer Center, Houston, Texas, U.S.A.; Surgery (D.M.N.), Mayo Clinic, Rochester, Minnesota, U.S.A.; and Surgical Oncology (J.-N.V.), University of Texas M.D. Anderson Cancer Center, Houston, Texas, U.S.A.
Am J Surg Pathol 2002;26:25-34 Abstract quote
Despite growing information on the clinical behavior of hepatocellular carcinoma, the histologic features associated with survival are not well characterized. Clinical and pathologic data on 425 patients who underwent complete resection for hepatocellular carcinoma were reviewed.
Six microscopic features, namely, microvascular invasion, nuclear pleomorphism, mitosis, tumor architecture, growth interface, and tumor necrosis, were examined. Independent predictors of survival were identified and combined into a simple prognostic index. By univariate analysis, microvascular invasion, seen in 51.3% of patients (p <0.001), nuclear grade 3, present in 42% of the cases (p <0.001), and mitosis (p <0.008) were significant predictors of poor survival. Hepatocellular carcinoma with a compact growth pattern had a better prognosis as compared with macrotrabecular (p = 0.014) and acinar (p = 0.051) patterns.
By multiple regression analysis, only microvascular invasion (p <0.001) and nuclear grade 3 (p = 0.008) were independent predictors of poor survival. The predictive values of microvascular invasion and nuclear grade allowed the construction of a hepatocellular prognostic index (HPI) whereby HPI = (microvascular invasion status × 0.459) + (nuclear grade × 0.287), with microvascular invasion either absent (0) or present (1) and nuclear grade scored as 1, 2, or 3.
Using a cut-off of 0.746 (corresponding to at least nuclear grade 2 with microvascular invasion), two groups could be segregated: fair prognosis (HPI 0.746), with a 50% survival of 5.06 years, and poor prognosis (HPI >0.746) with a 50% survival of 2.71 years (p <0.001). HPI was more discriminating than Edmondson grade, with Edmondson II hepatocellular carcinomas dispersed in both fair and poor prognosis groups. Microvascular invasion and nuclear grade 3 emerge as strong prognostic indicators, and their combination provides adequate prognostic stratification.
Practically, hepatocellular carcinoma can be stratified in two groups with regard to prognosis: 1) fair prognosis group (nuclear grade 1 with or without microvascular invasion and nuclear grade 2 without microvascular invasion), and 2) poor prognosis (nuclear grade 2 with microvascular invasion and nuclear grade 3 with or without microvascular invasion). The combination of these histologic parameters provides adequate prognostic stratification.
Simple tumor profile chart based on cell kinetic parameters and histologic grade is useful for estimating the natural growth rate of hepatocellular carcinoma
Tomoki Nakajima, MD, PhD
Michihisa Moriguchi, MD
Yasuhide Mitsumoto, MD, PhD, etal
Hum Pathol 2002;33:92-99. Abstract quote
Thirty-four untreated hepatocellular carcinomas (HCCs) with known growth rates were classified into 5 groups on a tumor profile chart based on their doubling time (DT), Ki-67–positive index (Ki-67-PI), apoptotic index (Apo-I), and histologic grade.
The slow-growing HCCs (DT > 100 days) consisted of well-differentiated tumors with slight cell kinetic imbalance and were divided into groups A and B. Group A had Apo-I values <3%, and most tumors had Ki-67-PI values <10%, whereas group B had Apo-I values of 3‰ to 10‰ and Ki-67-PI values of 10% to 20%. The HCCs with intermediate growth rates, which had Ki-67-PI values similar to those of the tumors in group B, were divided into groups C and D based on differences in cell kinetics: group C consisted of well-differentiated tumors, most of which had Apo-I values <3‰, and group D consisted of moderately or poorly differentiated tumors with Apo-I values between 10‰ and 20‰. The rapidly growing tumors (DT < 50 days, group E) had higher Ki-67-PI values than other groups and a wide range of Apo-I values. Rapidly growing tumors were mostly moderately or poorly differentiated, with a large cell kinetic imbalance in favor of cell production.
This grouping system is useful for approximating the growth rate of HCCs in a clinical setting, even when only histologic parameters are available.
HEPATITIS B ASSOCIATION
Clinicopathologic and prognostic significance of the histologic activity of noncancerous liver tissue in hepatitis B virus-associated hepatocellular carcinoma.
Ng IO, Poon RT, Shek TW, Fan ST.
Department of Pathology, University of Hong Kong, Queen Mary Hospital, People's Republic of China.
Am J Clin Pathol 2002 Mar;117(3):411-8 Abstract quote
We prospectively studied 66 patients infected with the hepatitis B virus who underwent liver resection for hepatocellular carcinoma (HCC) to evaluate the influence of the histologic activity of noncancerous liver tissue on clinicopathologic features and prognosis.
Based on the histologic activity index (HAI) score of nontumorous liver tissue, patients were classified into 3 groups: mild, moderate, or severe hepatitis. Overall, higher HAI scores were more frequent in patients with poorer liver function: lower serum albumin levels and higher indocyanine green retention at 15 minutes. Moreover, patients with moderate hepatitis had more frequent venous invasion, and the tumor size decreased with increasing HAI scores. Similar results were observed when the fibrosis category was excluded in the calculation of HAI scores.
The overall or disease-free survival rates did not differ significantly among the 3 groups of patients. However, higher fibrosis scores were associated significantly with shorter disease-free survival rates. HAI scores correlated significantly with certain clinicopathologic features.
In patients with hepatitis B-related HCC, a higher fibrosis score in the nontumorous liver tissue, but not histologic hepatitic activity, seems to be a significant factor predisposing to shorter survival.
Intrahepatic metastases commonly found in 60% of tumors <5 cm in diameter and >95% of tumors >5 cm
Vascular invasion with portal vein thrombosis in 65-75% and hepatic vein thrombosis in 20-25%
May extend into inferior vena cava and right atrium and right ventricle
Bile duct invasion in 5%
Invasion in advanced disease to the diaphragm, gallbladder, and peritoneal dissemination
Extrahepatic metastases foundin 50% of cases at autopsy:
Lung in 50%
Regional lymph nodes
Adrenal glands 15%
Recurrence Underlying cirrhosis is risk factor for development of new tumors Survival
Most patients die of liver failure secondary to replacement of the liver by tumor
If surgically resectable, median survival of 20-45 months
5YRS of up to 75% for tumors <5 cm
Complete resection if possible
Orthotopic liver transplantation
Chemotherapy, hormonal therapy, and radiotherapy have little effect
CHEMOEMBOLIZATION Angiographic embolization of hepatic artery Chemoembolization combined with Lipiodol may produce tumor necrosis PERCUTANEOUS ETHANOL Percutaneous ethanol injection into tumor Has resulted in necrosis and palliation of tumors, usually <3cm TRANSPLANTATION
Orthotopic liver transplantation for hepatocellular carcinoma. Factors affecting long-term patient survival.
Ojogho ON, So SK, Keeffe EB, Berquist W, Concepcion W, Garcia-Kennedy R, Imperial J, Esquivel CO.
Department of Surgery, Stanford University Medical Center, Calif., USA.
Arch Surg 1996 Sep;131(9):935-9 Abstract quote
OBJECTIVE: To determine the influence of several clinicopathologic factors on the 3-year actuarial survival of patients with nonfibrolamellar hepatocellular carcinoma (HCC) following orthotopic liver transplantation (OLT).
DESIGN: A case series of 26 consecutive patients with HCC treated with OLT, with a maximum follow-up of 90 months.
SETTING: A tertiary care center.
PATIENTS: Between March 1988 and December 1993, 521 OLTs were performed in 480 patients, 27 of whom had HCC. One patient was excluded because of donor-transmitted melanoma. Of the remaining 26 patients, there were 18 adults and 8 children, with a mean age of 41 years (range, 0.2-67.4 years). Fourteen patients (54%) had either hepatitis B (n = 6) or hepatitis C (n = 8), while 15 (58%) had coincidental tumor.
INTERVENTION: OLT was performed using standard techniques.
MAIN OUTCOME MEASURES: The effect of several clinicopathologic factors on 3-year actuarial patient survival.
RESULTS: The overall actuarial survival rates for the 26 patients with HCC were 73%, 65.4%, and 65.4%, at 1, 2, and 3 years, respectively. Sixteen patients (62%) were alive at the time of this report, with 14 (54%) free of disease. None of the clinicopathologic factors significantly affected the 3-year patient survival rate. However, the rate of recurrent HCC was significantly higher in nonincidental vs coincidental tumors and in solitary vs multiple tumors.
CONCLUSION: Our results suggest that HCC should not contraindicate OLT, as long-term patient survival and cure can be achieved. While patient selection is important, survival in patients with HCC after OLT is not always predictable using the usual clinicopathologic prognostic factors.
Liver transplantation for hepatocellular carcinoma: a registry report of the impact of tumor characteristics on outcome.
Department of Surgery, Baylor University Medical Center, Dallas, Texas 75246, USA.
Ann Surg 1998 Oct;228(4):479-90 Abstract quote
OBJECTIVE: The objective of this study from the International Registry of Hepatic Tumors in Liver Transplantation is to analyze the impact of tumor characteristics on tumor recurrence and patient survival.
SUMMARY BACKGROUND DATA: Many attempts have been made to identify patients with hepatocellular carcinoma who can be treated successfully with liver transplantation. Studies presented to date lack enough patients to make reported findings universally accepted. In lieu of a prospective, randomized multicenter trial, in 1992 an International Registry of Hepatic Tumors in Liver Transplantation was established to collect data on these patients, their tumors, and their treatment.
METHODS: The registry mails out new patient registration forms and patient follow-up forms twice yearly to all known liver transplant programs. Fifty-three programs in 21 countries have supplied information on 553 patients with tumors. Four hundred ten patients had hepatocellular carcinoma (HCC), and 12 had the fibrolamellar variant of HCC (FLL-HCC). These 422 patients were investigated for this study. One hundred sixty-nine of these (40.0%) were classified as "incidental tumors." For the remaining patients, the tumor was known before the transplant. Twenty-six and eight tenths percent of the patients had a history of hepatitis B and 32.7% had a history of hepatitis C.
RESULTS: One hundred ninety patients (46.7%) have died, 99 free of tumor and 91 with tumor. Death was tumor related in 90 patients. Of the 232 patients now living, 215 are free of tumor and 17 have tumor. The most common sites for recurrence are the transplanted liver (41.7%) and the lungs (28.7%). The overall patient survival was 72.2% at 1 year, 63.4% at 2 years, 47.4% at 4 years, and 44.4% at 5 years. Using univariate analysis, incidental tumors (p = 0.3107), FLL-HCC (p = 0.0704), multifocal tumor (p = 0.5464), and bilobar tumor (p = 0.1024) were not found to have an influence on patient survival. Four factors, tumor size greater than 5 cm (p = 0.0221), vascular invasion (p = 0.0005), positive nodes (p = 0.0014), and histologic grade (p = 0.0001) had a profound impact on patient survival. Using Cox multiple regression analysis, only histologic grade had a negative impact on overall patient survival (p = 0.0009) and for patients with known tumors (p = 0.0003). For incidental tumors, patient survival was negatively influenced by multifocality (p = 0.0021) and an age older than 60 years (p = 0.0008). Tumor histologic grade (p = 0.0134) and size (>5 cm) (p = 0.0133) were significantly linked to recurrence-free patient survival.
CONCLUSIONS: This analysis has documented three tumor characteristics that strongly impact patient survival after transplantation for HCC. In addition to tumor size greater than 5 cm and the presence of vascular invasion (which confirm several, single-center studies), this registry notes that a poorly differentiated HCC may be a contraindication for transplantation. A liver tumor's histologic grade may be important information to have when these patients are considered for liver transplantation.
Resection or transplantation for hepatocellular carcinoma in cirrhotic patients: outcomes based on indicated treatment strategy.
Figueras J, Jaurrieta E, Valls C, Ramos E, Serrano T, Rafecas A, Fabregat J, Torras J.
Liver Transplant Unit, Ciutat Sanitaria Universitaria Bellvitge, University of Barcelona, Spain.
J Am Coll Surg 2000 May;190(5):580-7 Abstract quote
BACKGROUND: Surgical resection has been the treatment of choice for hepatocellular carcinoma (HCC), but the resection rate remains low in cirrhotic patients and recurrence is common. Unfavorable results compared with benign disease and the shortage of organ donors have led to a restricted indication for orthotopic liver transplantation (OLT) for HCC.
STUDY DESIGN: The aim of this study was to analyze the results of our surgical approach to HCC in patients with cirrhosis. The first treatment strategy indicated in these patients was OLT. From January 1990 to May 1999, 85 patients underwent OLT and the remaining 35 had surgical resection.
RESULTS: One-, 3-, and 5-year survival rates were 84%, 74%, and 60% versus 83%, 57%, and 51%, respectively, in the OLT and resection groups (p = 0.34). Hepatic tumor recurrence was much less frequent in the OLT group than in the resection group. The 1-, 3-, and 5-year disease-free survival rates were 83%, 72%, and 60% versus 70%, 44%, and 31%, respectively (p = 0.027). In the multivariate Cox regression analysis, macroscopic vascular invasion was the only factor independently associated with death or recurrence after OLT (p = 0.006). After partial liver resection, the tumors significantly associated with mortality and recurrence in the multivariate analysis were solitary or multiple tumors greater than 2cm with microscopic vascular invasion (pathologic pT3) (p = 0.01).
CONCLUSIONS: Our results confirm that in cirrhotic patients, OLT may provide better outcomes than liver resection in carefully selected HCC and that longterm survival is similar to the results of OLT in cirrhotic patients without tumors.
Origin of adenocarcinoma in a transplanted liver determined by microsatellite analysis.
Kakar S, Burgart LJ, Charlton MR, Saito Y, Halling K, Thibodeau SN.
Divisions of Pathology, Gastroenterology/Hepatology, and Molecular Pathology, Mayo Clinic, Rochester, MN.
Hum Pathol 2002 Apr;33(4):435-6 Abstract quote
Inadvertent transmission of neoplastic cells from an organ donor can occur at the time of transplantation. Determination of recipient versus donor origin of a tumor is crucial for patient management.
This report illustrates the use of microsatellite (MS) analysis to determine the origin of adenocarcinoma arising in a liver transplant. The study patient was a 42-year-old male who had received a liver transplant for hepatitis C and alcohol-related cirrhosis. At the 1-year follow-up visit, a 1.5-cm liver mass was identified during routine ultrasound of the vascular anastamoses. A liver biopsy showed a moderately differentiated adenocarcinoma. Tumor, donor, and recipient DNA were isolated from the paraffin-embedded liver biopsy, pretransplant donor liver biopsy, and the explant liver tissue, respectively. MS analysis was performed by polymerase chain reaction using 5 markers: D5S346, ACTC, D2S123, D18S34, and TP53.
The allelic patterns of tumor DNA were identical to those of donor DNA and were distinct from the DNA profile of the recipient. The use of MS analysis clearly established that the adenocarcinoma was of donor origin.
Mod Pathol 2000;13:679-704
Tumors of the Liver and Intrahepatic Bile Ducts. Atlas of Tumor Pathology Third Series Fascicle 31. AFIP 2001
Large cell change-Term used in place of large cell dysplasia. Scattered foci within a cirrhotic liver consisting of enlarged hepatocytes with large, often irregularly shaped nuclei and nucleoli but with a normal nuclear:cytoplasmic ratio.
Small cell change-Term used in place of small cell dysplasia. Hepatocytes are smaller than normal liver cells and appear as a zone of nuclear crowding or increased nuclear density. Cytoplasm usually more basophilic than normal hepatocytes but lacking nuclear atypia or enlargement. Present as clusters.
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