Glypican-3 expression in hepatocellular tumors: diagnostic value for preneoplastic lesions and hepatocellular carcinomas

Glypican-3 (GPC3), a member of heparan sulfate proteoglycans, plays a role in cell growth, differentiation, and migration. The objectives of this study were to assess the diagnostic value of GPC3 immunostaining in hepatocellular carcinomas (HCCs) and to analyze its expression profile in preneoplastic lesions. Tissue microarrays were built by sampling 54 HCCs and adjacent liver tissues (21 developing from cirrhosis and 33 from normal liver) and 94 cirrhotic macronodules. Fourteen typical liver cell adenomas and 5 with malignant foci were also included. Sections were assessed for GPC3 expression by immunohistochemistry. GPC3 staining was observed in 19 (90%) of 21 HCC cases with cirrhosis and in 18 (64%) of 28 HCC cases with normal liver (P < .01). When staining was positive, it was both membranous and cytoplasmic. Positive staining was observed in 1 case of nonneoplastic adjacent liver. In cases of adenomas, only malignant foci were positive. Among the 94 macronodules, GPC3 immunostaining was noted in 48% (14/29) of high-grade dysplastic or early HCC and in 3% (2/65, P < .001) of benign or low-grade dysplastic macronodules. This study shows that GPC3 is an efficient diagnostic marker of HCC, potentially useful in the differential diagnosis of liver cell adenomas and well-differentiated HCC. Our results also suggest that GPC3 may be considered as an early marker of liver carcinogenesis because it is able to identify some cirrhotic macronodules with malignant potential.     

Utility of glypican-3 in differentiating hepatocellular carcinoma from other primary and metastatic lesions in FNA of the liver: an immunocytochemical study.

We evaluated the immunocytochemical expression of GPC3 in archival material obtained from fine needle aspiration of hepatic lesions to assess the sensitivity and specificity of this marker in cytological material and its potential diagnostic utility in differentiating hepatocellular carcinoma (HCC) from other primary benign or malignant hepatic tumors and from metastatic lesions in the liver. Forty-nine FNAs of the liver obtained between January 2000 and June 2006 were identified from our cytology files. Cytological diagnoses (confirmed by tissue diagnosis and/or clinical follow-up) included: 7 adenomas, 1 focal nodular hyperplasia (FNH), 24 HCCs, and 17 metastatic tumors. On the basis of the histological, clinical and/or radiological follow-up, 20 of 24 (83.3%) FNAs confirmed positive for HCC-expressed GPC3. All the seven adenomas and the only FNH were negative for GPC3. Sixteen out of seventeen metastatic malignancies were negative for GPC3. The only case expressing GPC3 was an anaplastic carcinoma with neuroendocrine features of unknown origin. In this study, the sensitivity of GPC3 in the diagnosis of HCC in the cytological material was 83.3%, the specificity 96%, the positive predictive value (PPV) 95% and negative predictive value (NPV) was 85.7%. Immunocytochemical staining for GPC3 in alcohol-fixed FNA material is a highly sensitive and specific method capable of distinguishing HCC from other benign and malignant hepatic lesions and from the great majority of metastatic lesions.     

Diagnostic utility of CD10 in differentiating hepatocellular carcinoma from metastatic carcinoma in fine-needle aspiration biopsy (FNAB) of the liver

The differential diagnosis between hepatocellular carcinoma (HCC) and metastatic carcinoma, especially in moderate-poorly differentiated (MPD) HCC and poorly differentiated carcinoma, can be challenging in fine-needle aspiration biopsy (FNAB) of the liver. Recent studies demonstrate that canalicular staining for CD10 appears to be a highly specific marker for hepatocytic differentiation. The objective of this study was to test the utility of CD10 in differentiating HCC from metastatic carcinoma in FNAB of the liver. Formalin-fixed, paraffin-embedded cell blocks of 55 cases (22 HCC, 23 metastases, and 10 benign hepatic lesions) of FNAB of the liver were immunostained using monoclonal antibody against CD10, with microwave oven antigen retrieval, followed by a standard ABC method. Nineteen (86%) of 22 HCC cases were positive for CD10 with a canalicular staining pattern. Among them, 9 (82%) of 11 well-differentiated (WD) HCC and 10 (91%) of 11 MPD HCC were positive for CD10. Three (13%) of 23 metastatic carcinomas were positive for CD10, demonstrating a contrasting cytoplasmic and membranous staining pattern. The three positive cases were metastatic renal cell carcinoma (RCC), choriocarcinoma, and adenocarcinoma of the lung. All 10 cases of benign hepatic lesions showed positivity for CD10 with a canalicular and focal membranous staining pattern. In conclusion, CD10 appears to be a useful marker in discriminating between HCC and metastatic carcinoma when applied to FNAB of the liver. CD10 does not provide discrimination between WD HCC and benign hepatocytes.     

Epithelioid angiomyolipoma of the liver with striking giant cell component: Fine‐needle aspiration biopsy findings of a rare neoplasm

Angiomyolipoma (AML) is a uncommon benign neoplasm of the liver with cyto‐ and histologic features similar to the more commonly encountered renal AML. Tumors composed predominantly of epithelioid cells have been referred to as epithelioid AML. Because most liver lesions are first evaluated by fine‐needle aspiration biopsy (FNAB), it is important to distinguish this variant of AML from more common hepatic neoplasms such as hepatocellular carcinoma (HCC) or metastatic tumors. Rare reports of epithelioid AML of the liver diagnosed by FNAB are in the literature. Here, we describe the cytologic findings of a unique case of epithelioid AML with numerous giant cells. Diagn. Cytopathol. 2009. © 2009 Wiley‐Liss, Inc.     

磷脂酰肌醇蛋白聚糖-3的表达在肝细胞癌诊断中的意义

目的 探讨磷脂酰肌醇蛋白聚糖-3( GPC3)免疫组织化学染色在肝细胞癌病理诊断的应用价值。方法 制作14个含731例肝肿瘤和肿瘤旁肝组织芯片,其中肝细胞癌357例、胆管癌26例、肝细胞癌癌旁肝组织包括肝硬化171例、血管瘤旁肝组织93例、肝转移癌84例。全部病例采用免疫组织化学检测GPC3（1G12克隆）蛋白表达,实验设阳性对照。结果 72.0％的肝细胞癌(257/357)GPC3呈阳性反应,其余374例非肝细胞癌病例均为阴性,包括胆管癌、肝转移癌、肝细胞癌癌旁肝组织（包括肝硬化和血管瘤旁肝组织）。GPC3阳性率在不同的肝细胞癌组织学分级的差异有统计学意义(P＜0.01),阳性率高低排列为Ⅲ级(77.1％,64/83)、Ⅱ级(73.3％,187/255)、Ⅰ级6/12和Ⅳ级(0)为阴性。结论 GPC3免疫组织化学检测是肝细胞癌诊断的良好指标,敏感性达72.0％;也是区别瘤旁肝组织和肝转移癌的鉴别诊断指标,其特异性达100％。     

Podocalyxin-like protein 1 expression in primary hepatic tumours and tumour-like lesions

AIMS: The differential diagnosis of benign hepatic lesions and well-differentiated hepatocellular carcinomas can be a challenge, especially in small biopsy specimens. Recently, novel proteins expressed by the neovasculature in hepatocellular carcinoma (HCC) have been identified. The aim of this study was to compare the expression of podocalyxin-like protein 1 (PODXL1), a CD34-related sialomucin, in HCC and benign liver tumours or tumour-like lesions. METHODS AND RESULTS: Vascular marker expression was examined using tissue microarrays as well as standard paraffin sections from formalin fixed paraffin-embedded liver tissue samples. Expression of PODXL1 was compared with anti-CD34, CD31 and von Willebrand factor VIII staining by immunohistochemistry. PODXL1 is expressed in tumour-associated microvasculature endothelial cells in HCC, as well as in capillarized sinusoidal endothelium of focal nodular hyperplasia (FNH) and hepatic adenoma. Expression in cirrhotic nodules correlates with CD34 and highlights endothelium in the inflow area. In dysplastic nodules CD34 and PODXL1 are not or only focally expressed. CONCLUSIONS: Expression patterns of CD34 and PODXL1 are almost identical in primary hepatic tumours and tumour-like lesions. The presence of CD34+ and PODXL1+ sinusoidal endothelial cells aids in the diagnosis of HCC. Sinusoidal expression of PODXL1 is also seen in a less diffuse pattern in FNH and adenoma.     

Diagnostic utility of immunohistochemistry in hepatocellular carcinoma, its variants and their mimics.

Hepatocellular carcinoma (HCC) is known for its histomorphologic heterogeneity. Immunohistochemistry (IHC) can help in the comparative morphologic evaluation of HCC, its variants and their mimics. Some of these diagnostic challenges can be attributed to (i) the variety of neoplasms that can arise from the hepatic stem cell lineage; (ii) the spectrum of well-differentiated hepatocellular nodular lesions; (iii) the liver being a target for metastases with some of these histologic entities mimicking variants of HCC or actually arising in the liver; and (iv) the limitations of serum alpha-fetoprotein (AFP). The role of IHC is in the distinction of benign hepatocellular nodules from reactive hepatocytes; WD-HCC from benign hepatocellular nodules; poorly differentiated HCC from cholangiocarcinoma and metastases; and determination of histogenesis of malignant tumor; and of primary site of origin of malignant tumor. A panel of antibodies has more discriminant value. AFP expression usually indicates malignancy in a hepatocellular nodule and hepatocytic histogenesis of a malignancy. Polyclonal carcinoembryonic antigen (pCEA) and CD10 stain bile canaliculi in better-differentiated HCC. HepPar1 is generally accepted as a hepatocytic marker. However, not all HCC stain uniformly and not all HepPar1-positive tumors are of hepatocytic origin or arise in the liver. Mature hepatocytes and hepatocellular nodules stain with CAM 5.2, CK 8, and 18 but not with CK 7, 19, 20, or AE1/AE3. Biliary epithelium expresses CK 7 and 19. CD 34 highlights sinusoidal capillarization. AFP, pCEA/CD10, and CD34 are useful for ascertainment of malignancy in hepatocellular nodules; HepPar1 and cytokeratins to be included if histogenesis is the issue. IHC results should be interpreted in the larger context of the case.     

Discriminating hepatocellular carcinoma from metastatic carcinoma on fine‐needle aspiration biopsy of the liver: The utility of immunocytochemical panel

The cytomorphologic features of hepatocellular carcinoma (HCC) in fine‐needle aspiration (FNA) biopsy are well described. However, correctly diagnosing HCC on cytologic features alone and differentiating it from metastatic adenocarcinoma (MAC) remains a challenge. Studies have recommended the use of various immunocytochemical (ICC) stains to aid in the diagnosis and distinction of these tumors with variable success rates. In this study, we evaluated a panel of seven ICC stains, HepPar1, glypican‐3, polyclonal and monoclonal carcinoembryonic antigen (pCEA, mCEA), MOC‐31, CK7, and CK20, in 42 FNA cases of HCC and 48 FNA cases of MAC. The aim was to identify the most sensitive and specific markers and the best panel for accurate diagnosis. Overall, 38 of 42 HCC and 44/48 MAC tumors were correctly identified by a panel of four markers, CK7, MOC‐31, HepPar1, and glypica‐3, with accuracy rate of 90.5 and 91.7%, respectively. In the HCC group, glypican‐3 was most sensitive and detected in 34/42 (81%), whereas HepPar1 and pCEA were less sensitive and detected in 30/42 (71.4%) and 21/42 (50%), respectively. In the MAC group, MOC‐31 was most sensitive and detected in 38/48 (79.2%), followed by CK7 in 20/48 (41.7%). Stepwise logistic regression analysis showed that a panel of glypican‐3, HepPar1, MOC‐31, and CK7 is most helpful in diagnosing and accurately differentiating HCC from MAC on FNA biopsies of the liver. We conclude that a panel of HepPar1, glypican‐3, MOC‐31, and CK7 accurately and statistically significantly differentiates these two malignancies (P < 0.05). Diagn. Cytopathol. 2009. © 2009 Wiley‐Liss, Inc.     

The overexpression of polycomb group proteins Bmi1 and EZH2 is associated with the progression and aggressive biological behavior of hepatocellular carcinoma

Polycomb-group proteins Bmi1 and EZH2 are involved in the malignant transformation and biological aggressiveness of several human carcinomas. We herein examined the significance of the Bmi1 and EZH2 expression in hepatocellular carcinoma (HCC) and its preneoplastic lesions, dysplastic nodules. The expression of Bmi1 and EZH2 were examined immunohistochemically in HCC (n=27) and dysplastic nodules (n=14), and combined hepatocellular and cholangiocarcinoma (HC-CC) (n=14). The effect of Bmi1 and EZH2 knockdown was examined in cultured HCC cells (HuH7 and HepG2) using siRNA. It was determined that Bmi1 was constantly expressed in cholangiocytes, but not in hepatocytes, and EZH2 was detected in neither cholangiocytes nor hepatocytes. Bmi1 and EZH2 were overexpressed in HCC and more extensively in HC-CC (P<0.01). Interestingly, Bmi1 and EZH2 were not overexpressed in the dysplastic nodules. The expression of Bmi1 and EZH2 was heterogeneous and associated with vascular infiltration, the histological grades, and the cell proliferation activity in HCC and HC-CC. In cultured carcinoma cells overexpressing Bmi1 and EZH2, knockdown of Bmi1 and EZH2 resulted in decreased cell proliferation activities. Therefore, the overexpression of polycomb-group proteins Bmi1 and EZH2 is associated with the malignant progression of HCC, thereby reflecting the aggressive biological behavior in HCC and HC-CC.     

Expression and clinicopathologic significance of glypican 3 in hepatocellular carcinoma

Glypican 3 (GPC3) is a glycosylphosphatidylinositol-anchored membrane protein and plays an important role in regulation of cell growth, differentiation, and migration. The aims of this study were to investigate the expression of GPC3 in human liver, biliary tract, and pancreatic tumors and to evaluate its diagnostic role in differentiating hepatocellular carcinoma (HCC) from other hepatic mimickers. Immunohistochemistry was performed on a large collection of surgically resected samples from 941 primary liver tumors, 50 metastatic adenocarcinomas, and 30 normal livers as well as primary adenocarcinomas of the pancreas (n = 17), gallbladder (n = 30), and extrahepatic bile duct (n = 20). The relationship of GPC3 expression and clinicopathologic features in patients with HCC was determined. We found that 516 (52%) of the 991 liver neoplastic tissue samples demonstrated positive staining for GPC3. A high incidence of GPC3 expression (492/757; 65%) was observed in HCC, whereas intrahepatic cholangiocarcinomas, adenocarcinomas, and benign liver lesions displayed rare positive cases. There were significant correlations between GPC3 expression and clinicopathologic characteristics, including histologic grade (P < .001), intrahepatic metastasis (P = .007), and positive serum hepatitis B surface antigen (P = .042), in patients with HCC. In conclusion, our results confirm the high expression of GPC3 in HCC and suggest its potential diagnostic value as a clinical marker for this disease.     

Immunocytochemical staining of fine-needle aspiration biopsies of the liver as a diagnostic tool for hepatocellular carcinoma.

Fine-needle aspiration biopsy (FNAB) under ultrasonographic or computerized tomographic guidance is a useful diagnostic procedure for hepatic neoplasms. However, cytologic criteria alone may not allow for the distinction of hepatocellular carcinomas (HCC) from cholangiocarcinomas (CC) and metastatic adenocarcinomas (MA). In an effort to refine the FNAB diagnosis of hepatic malignancies, a panel of immunocytochemical stains was applied to aspiration specimens from primary and metastatic carcinomas in the liver. Anticytokeratin antibodies with different specificities (Cam 5.2 and AE1) were used in conjunction with antibodies to carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), and alpha-1-antitrypsin (AAT). All HCC, CC, and MA were immunoreactive with the antikeratin antibody Cam 5.2. However, only three (15%) HCC were positive with AE1, in contrast to 100% of CC and MA. Antibodies to CEA and AFP were also helpful diagnostic aids, especially for the three HCC that were immunoreactive with AE1. Canalicular staining for CEA was present in 47% of HCC, but in none of the CC or MA. AFP positivity occurred in 45% of HCC, but only one CC and none of the MA. AAT was not a useful marker for HCC due to low sensitivity and specificity. Immunocytochemistry is an effective adjunct to the cytodiagnosis of malignant liver tumors sampled by FNAB.     

Significance of endothelium in the fine-needle aspiration biopsy diagnosis of hepatocellular carcinoma

We reviewed fine-needle aspiration biopsies (FNAB) of hepatocellular carcinoma (HCC) (n = 35), benign hepatic processes (n = 35), cholangiocarcinoma (CC) (n = 6), and metastatic tumors (n = 100) to evaluate the significance of endothelium present either peripherally-wrapping around groups of cells, (peripheral endothelium (PE)), or transgressing sheets of cells (transgressing endothelium (TE)), in distinguishing these lesions. These patterns were assessed as absent, focal, or prominent. Thirty-three of 35 (94%) HCCs contained either focal or prominent PE or TE, compared to only 3 of 35 (9%) benign hepatocytic lesions. Only one benign lesion contained a prominent endothelial component (TE only). Two cases of HCC failed to contain endothelium, one fibrolamellar variant and one well-differentiated HCC. These differences were statistically significant (P < 10^–5, sensitivity 94%, specificity 91%, and positive predictive value [PPV] 92%). Neither pattern of endothelium was present in any CC or metastatic tumor. These differences were also statistically significant (P < 10^–5, sensitivity 94%, and specificity and PVP 100%). We conclude that the presence of endothelium, at least focally in either one or both distinctive patterns, is highly sensitive and specific for HCC and aides in distinguishing it from benign hepatocytic lesions, CC, and metastases. © Wiley-Liss, Inc.     

Differential diagnostic value of GPC3-CD34 combined staining in small liver nodules with diameter less than 3 cm

The diagnostic value of combining glypican-3 (GPC3) and CD34 staining for small nodules in liver biopsy specimens has not been evaluated. In this study, 201 thin-core biopsy specimens were assessed using GPC3 and CD34 immunochemical staining, including 33 cirrhotic regenerative nodules, 31 high-grade dysplastic nodules, 70 hepatocellular carcinomas (HCCs) with nodules 3 cm or smaller, and 67 HCCs with nodules larger than 3 cm. The results showed that the accuracy of GPC3 staining (90.3%) among liver nodules 3 cm or smaller was better than its use among all nodules (P = .045). Furthermore, the positive expression rate of costaining was significantly greater than that observed for GPC3 or CD34 single staining (P < .001 and P = .002, respectively). These data demonstrate that GPC3 staining is more accurate for the diagnosis of HCC on thin-core biopsy specimens in nodules 3 cm or smaller compared with its use in all nodules, while GPC3 and CD34 costaining has better diagnostic value than does single staining.     

Liver Metastases of Neuroendocrine Tumors Rarely Show Overlapping Immunoprofile with Hepatocellular Carcinomas

The distinction of hepatocellular carcinoma (HCC), neuroendocrine tumor (NET) metastatic to the liver, and cholangiocarcinoma (CC) can sometimes be challenging on small biopsies. Tissue microarrays were constructed from HCCs, NETs, and CCs. The immunoprofile was evaluated using HepPar1, glypican-3 (GPC3), synaptophysin (SYN), chromogranin A (CHR), CD56, MOC-31, and pCEA. One hundred thirteen HCCs, 48 NETs, and 44 CCs were included. Of HCCs, 107 (95 %) expressed HepPar1 and/or GPC3, 52 (46 %) both, and 97 (88 %) marked with pCEA (canalicular pattern). Seven (6 %) expressed CD56, of which 3 (3 %) expressed SYN. All 7 HCCs that expressed CD56 and/or SYN also expressed HepPar1 and/or GPC3, and none of the HCCs expressed CHR. Fourteen (13 %) expressed MOC-31. All 48 NETs expressed at least one neuroendocrine marker: 47 (98 %) positive for SYN, 40 (83 %) for CHR, 39 (81 %) for CD56, and 34 (71 %) for all three markers. None expressed HepPar1 or GPC3. All 44 CCs showed at least focal reactivity with MOC-31 and pCEA (membranous/cytoplasmic). One (2 %) was positive for HepPar1, 4 (9 %) for GPC3, 1 (2 %) for SYN and CHR, and 7 (16 %) for CD56. HCCs rarely express CD56 and SYN, while all express either HepPar1 or GPC3. NETs do not express HepPar1 or GPC3 and almost always express SYN, while CHR and CD56 are seen in most cases. Rare CCs focally express HepPar1 and GPC3. Utilizing a limited staining panel can efficiently distinguish HCCs, NETs, and CCs and help avoid diagnostic pitfalls on small biopsies.     

The glypican 3 oncofetal protein is a promising diagnostic marker for hepatocellular carcinoma.

Expression profiling of hepatocellular carcinoma has demonstrated that glypican 3 (GPC3), a heparan sulfate proteoglycan anchored to the membrane, is expressed at a markedly elevated level in hepatocellular carcinoma. In this paper, two monoclonal antibodies against GPC3, GPC3-C02 and A1836A, were confirmed to specifically recognize GPC3 molecule in cells from hepatocellular carcinoma and hepatoblastoma cell lines by immunoblotting, and both were confirmed to recognize different epitopes of the GPC3 molecule by epitope mapping. Then, we evaluated the feasibility of GPC3-immunohistochemistry in the pathological diagnosis of benign and malignant hepatocellular lesions by applying these monoclonal antibodies to formalin-fixed and paraffin-embedded specimens. The immunoreactivity turned out to be identical in the two monoclonal antibodies and was thus confirmed to represent the actual expression of the GPC3 molecule. The expression was observed in the fetal liver, but not in normal adult liver, liver cirrhosis or hepatitis except for a tiny focus of a regenerative nodule of fulminant hepatitis. Diffusely positive staining of GPC3 was observed in malignant hepatocytes in hepatoblastomas and in hepatocellular carcinomas (47/56, 84%). GPC3 expression was independent of the differentiation and size of the hepatocellular carcinoma. On the other hand, there was only weak and focal staining in low-grade (2/8) and high-grade dysplastic nodules (6/8). GPC3 immunoreactivity was detected in only one of 23 metastatic lesions of colorectal carcinoma, and its expression was entirely absent in the liver cell adenoma (0/7), carcinoid tumor (0/1), and cholangiocellular carcinoma (0/16). When compared with immunohistochemistry of hepatocyte antigen and alpha-fetoprotein, GPC3-immunohistochemistry was significantly much more specific and sensitive for hepatocellular carcinomas. Thus, GPC3 was confirmed to be one of the oncofetal proteins now attracting attention for their promise both as markers of hepatocellular carcinoma in routine histological examination and as targets in monoclonal antibody-based hepatocellular carcinoma therapy.     

Glypican 3 expression in human nonneoplastic, preneoplastic, and neoplastic tissues: a tissue microarray analysis of 4,387 tissue samples

Several studies have shown that glypican 3 (GPC3) could be a useful diagnostic marker for hepatocellular carcinoma (HCC) and for differentiating HCC from nonneoplastic and preneoplastic liver disease. To systematically investigate the epidemiology of GPC3 expression in the liver and in other organs and tissues, we used tissue microarray technology comprising 4,387 tissue samples from 139 tumor categories and 36 nonneoplastic and preneoplastic tissue types. The immunohistochemical expression of GPC3 was assessed semiquantitatively using a 10% cutoff score and was detected in 9.2% of nonneoplastic liver samples (11/119), 16% of preneoplastic nodular liver lesions (6/38), and 63.6% of HCCs (140/220), underlining the role of GPC3 in hepatocarcinogenesis. Furthermore, several other tumors revealed consistent expression of GPC3, including squamous cell carcinoma of the lung (27/50 [54%]), testicular nonseminomatous germ cell tumors (32/62 [52%]), and liposarcoma (15/29 [52%]).     

Hepatocarcinogenesis in liver cirrhosis: imaging diagnosis.

Hepatocellular carcinoma (HCC) frequently occurs in association with liver cirrhosis, as chronic liver disease is one of the most important factors in carcinogenesis. In addition to HCCs, recent reports of pathologic studies of resected specimens from cirrhotic liver describe associated small nodular lesions such as regenerative nodule, dysplastic nodule (adenomatous hyperplasia), and dysplastic nodule with subfocus of HCC (early HCC). In hepatocarcinogenesis of the cirrhotic liver, a regenerative nodule might be the first step in the development of HCC, going through phases of dysplastic nodule, early HCC and early advanced HCC in a multistep fashion. Fortunately, recent advances in various imaging techniques have facilitated the verification of these nodules. In this review, new nomenclature of small hepatocellular nodules, and detection and characterization of hepatic nodules in carcinogenesis with various imaging techniques are described with focus on the premalignant lesions and early stage of HCC. In addition, the efficacy of various imaging techniques for diagnosing them is discussed. Although the terms and definitions of these nodules are still variable and controversial, familiarity with the concept of these borderline lesions is important.     

Genetic evaluation of the dysplasia-carcinoma sequence in chronic viral liver disease: a detailed analysis of two cases and a review of the literature

Hepatocellular carcinoma (HCC) is one of the most frequent human malignancies, especially in Asia and Africa, but also in the Western world its incidence is increasing. HCC is a complication of chronic liver disease with cirrhosis as the most important risk factor. Viral co-pathogenesis due to hepatitis B virus (HBV) and hepatitis C virus (HCV) infection seems to be an important factor in the development of HCC. Curative therapy is often not possible due to the late detection of HCC. Thus, it is attractive to find parameters which predict malignant transformation in HBV- and HCV-infected livers. In the past decade, preneoplastic lesions, i.e. dysplastic foci or nodules, have gained interest as possible markers for imminent malignancy. Noteworthy, dysplastic liver lesions are increasingly detected by imaging techniques. We describe here two cases of chronic viral liver disease, one HBV-and one HCV-related, in which dysplastic lesions were present adjacent to HCC. In the HBV case, a (smaller) satellite of HCC was present as well. The neoplastic specimens were investigated by comparative genomic hybridization (CGH) and in situ hybridization (ISH). Both methods revealed multiple genetic alterations in the HCCs. The genetic patterns of the HBV-related HCC and the satellite tumor showed many shared alterations suggesting a clonal relationship. A subset of genetic changes were already present in dysplasias illustrating their preneoplastic nature. Surrounding liver cirrhosis samples did not display chromosomal aberrations. A literature survey illustrates the relative paucity of information concerning genetic alterations in preneoplastic liver lesions. However, all the data strongly suggests a role for liver cell dysplasia as a precursor condition of liver cell cancer.     

Expression profile and prognostic value of glypican‐3 in post‐operative South Korean hepatocellular carcinoma patients

Hepatocellular carcinoma (HCC) patients commonly experience poor overall survival (OS) and disease‐free survival (DFS) after curative surgical resection. Glypican‐3 (GPC3) has been suggested as a prognostic biomarker for post‐operative survival. However, few to none of these studies have included South Korean patients. This study aimed to determine GPC3 expression rate, clinical correlation, and post‐operative prognostic value in South Korean HCC patients who underwent curative surgical resection. Surgically resected tissues from 185 HCC patients were collected and assembled into tissue microarrays (TMAs), which were stained for GPC3 by immunohistochemistry. GPC3 expression rates were correlated with clinicopathological information, and survival analyses were performed to assess the prognostic value of GPC3. GPC3 expression was present in 153 patients (82.7%). GPC3‐positive patients were younger with higher frequencies of microvascular invasion and higher AFP levels than GPC3‐negative patients. There was no significant difference in survival between GPC3‐negative and GPC3‐positive patients. Based on multivariate analysis, GPC3 expression was not a prognostic marker for post‐operative survival. In South Korean HCC patients, GPC3 expression was more frequent in HCCs with aggressive features, but it was not an independent prognostic biomarker.     

Fine needle aspiration biopsy of thyroid nodules: cytologic and histopathologic correlation of 1096 patients

Via routinely used thyroid function tests, scintigraphy and ultrasonography (USG), important information is obtained in the clinical and diagnostic practice for thyroid nodules. However, the distinction between benign and malignant lesions cannot precisely be performed with these tests. Thyroid fine needle aspiration biopsy (FNAB) is considered the most reliable diagnostic method in the differentiation between benign and malignant thyroid nodules. It has recently been likely to perform aspiration from deeper nodules via the implemention of FNAB along with USG. Today, in cytopathological examination of thyroid FNAB, standardized Bethesda System for Reporting Thyroid Cytopathology (BSRTC) system is used. Here, FNAB was performed in 1096 patients with thyroid nodules in the Medical School of Selcuk University between January 2009 and July 2014. Patients consisted of 919 women and 177 men between 12 and 87 years of age. Evaluated via BSRTC, the results were classified as unsatisfactory, benign, atypia (or follicular lesions) of undetermined significance (AUS), follicular neoplasm or lesions suspicious for follicular neoplasm (FN), suspected malignant and malignant. After FNAB, 183 patients were operated and evaluated histopathologically. Histological malignancy rates of the categories were as follows: 16% (5), 15% (6) 14% (1) 60% (9), 72% (18) and 97% (63), respectively. In our study, we aimed to compare FNAB results of thyroid nodules with histopathology results after thyroidectomy and to show the sensitivity and specificity of FNAB technique to be higher in the follow-up and diagnosis of thyroid lesions. Given the malignancy detection rate in the follow-up of patients whose cytology was reported as inadequate, we also consider follow-ups are important in these patients.