Altered glycosaminoglycan composition in reactive and neoplastic human liver

We have investigated the glycosaminoglycan composition of normal human liver, focal nodular hyperplasia, hepatic adenoma, and hepatocellular carcinoma. Uronic acid increased about 4 fold in the benign and reactive lesions, and greater than 7 fold in the carcinoma. Whereas in focal nodular hyperplasia and adenoma dermatan sulfate was the predominant glycosaminoglycan, in hepatocellular carcinoma chondroitin sulfate was the predominant species; it increased 24 fold over normal liver and 3-5 fold over all the other tissues. HPLC analysis of chondroitinase ABC or AC digests showed a 58 fold increase in Delta-Di-OS disaccharides in hepatocellular carcinoma, indicating significant undersulfation of chondroitin sulfate. Surprisingly, the normal-appearing liver surrounding the carcinoma showed glycosaminoglycan changes similar to adenoma and nodular hyperplasia. These results thus indicate that specific glycosaminoglycan changes occur in hepatocellular carcinoma, and suggest for the first time that proteoglycan metabolism is also altered in the non-cirrhotic, hepatic parenchyma adjacent to liver carcinoma.     

超声随访在肝硬化结节恶变筛查及诊断中的价值研究

目的:研究超声随访在肝硬化结节恶变筛查及诊断中的价值。方法:选取我院收治的乙肝后肝硬化患者83例,均采取超声检查,观察超声随访在肝硬化结节恶变筛查及诊断中的应用价值。结果:本组83例随访发现,出现肝硬化伴增生性结节患者演变小肝癌21例。增生性结节患者的增生性结节直径与小肝癌患者肿块直径比较,差异无统计学意义(P0.05)。增生性结节患者的回声情况与小肝癌患者比较,差异有统计学意义(P0.05)。超声随访发现,结节由112个增加至126个,结节数量增加。肝硬化结节14例,在超声引导下行肝穿刺活检,成功13例,失败1例,病理诊断肝硬化结节患者9例,肝癌患者3例,与超声的检查结果相同。结论:超声随访在肝硬化结节恶变的筛查诊断中具有较高的临床价值,可在早期提供较为准确的检查结果,帮助医师做出诊断,及早治疗以改善预后。     

Expression of CD44 and cyclin D1 in fine needle aspiration cytology of papillary thyroid carcinoma

OBJECTIVE: To compare the expression pattern of CD44 and cyclin D1 immunostaining in fine needle aspiration specimens of papillary carcinoma of the thyroid and nonpapillary lesions. STUDY DESIGN: The study was performed on 80 fine needle aspiration cytologic smears of thyroid lesion retrospectively using monoclonal antibodies and on histologic material from a proportion of cases. RESULTS: Most papillary carcinomas expressed intense cell membrane or diffuse cytoplasmic staining for CD44 (97.8%). Focal immunoreactivity was observed in follicular neoplasms (28.5%) and nodular goiter (4.7%). There was no difference in CD44 immunostaining between follicular carcinoma and adenoma. Cyclin D1 was expressed in the nuclei of most papillary carcinomas (79.2%). Focal nuclear immunoreactivity was noted in nodular goiters (23.5%) and follicular neoplasms (10%). In resected specimens, all papillary carcinomas (19 cases) showed intense membranous or granular CD44 immunoreactivity. Focal cyclin D1 expression was noted in 52.6%. There was no difference in CD44 and cyclin D1 expression between the group of papillary carcinomas with regional lymph node metastasis as compared to those without metastasis. Positive staining for both CD44 and cyclin D1 would strongly favor papillary carcinoma, although further studies on cytologic material are necessary to verify this diagnostic approach. CONCLUSION: Most papillary carcinomas express CD44 and cyclin D1, whereas it is less common in follicular neoplasms and nodular goiter. This may be helpful in diagnostically difficult cases.     

Highly well differentiated hepatocellular carcinoma and benign hepatocellular lesions. Can they be distinguished on fine needle aspiration biopsy?

OBJECTIVE: To determine whether highly well differentiated hepatocellular carcinoma can be distinguished from benign hepatocellular lesions on fine needle aspiration biopsy (FNAB). STUDY DESIGN: Ninety-five FNABs from 88 patients with hepatic masses/diffuse conditions were reviewed according to new cytologic criteria established by Takenaka et al. They were classified into well-, moderately and poorly differentiated hepatocellular carcinomas (W-, M- and P-HCC) and benign aspirates and histologically verified. RESULTS: There were 21 W-HCC, 39 M-HCC, 10 P-HCC, 3 problematic and 22 benign aspirates. The most useful criteria for diagnosing highly W-HCC were architectural features on the smears/cell block sections, including hypercellularity; arborescent, cohesive clusters; broad trabeculae; transgressing and peripheral endothelium; and cytologic details of small, monotonous hepatocytes with nuclear crowding, decreased cytoplasm, increased nuclear/cytoplasmic ratio, atypical naked nuclei and tumor giant cells. Well-defined cytoplasmic borders, abundant thick and monotonous cytoplasm, eccentric nuclei, thick nuclear membranes, irregular nuclear contours, increased chromatin density, irregular chromatin distribution and macronucleoli were not always detectable in highly W-HCC. In fact, some of them were seen in dysplastic hepatocytes. Deficient reticulin patterns and diffuse sinusoidal CD34 reactivity were helpful. CONCLUSION: Experience, attention to architectural and cytologic details in smears/cell blocks and clinicopathologic correlation should reduce the number of indeterminate reports. However, there will always remain some cytohistologically challenging cases.     

Hepatocellular carcinoma and preneoplastic lesions of the liver: evaluation of argyrophilic nucleolar organizer regions (AgNORs).

The authors applied a silver colloid technique to identify Argyrophilic Organiser Region (AgNOR) to 8 groups of hepatic lesions: alcoholic hepatitis with dysplasia (3 cases); chronic active hepatitis with dysplasia (4 cases); cirrhosis with dysplasia (5 cases); focal nodular hyperplasia (4 cases) and hepatocellular carcinomas (3 cases of grade I, 3 cases of grade II and 5 cases of grade III of Edmondson). Four cases of non-specific reactive hepatitis were used as control. This work suggests the simplicity and utility of simultaneous application of clumps per cell, AgNORs per clump and total AgNORs counts in the evaluation of neoplastic and preneoplastic lesions of the liver. The results show, in hepatocellular carcinomas, a relationship between the number of clumps, the AgNORs per clump, the total number of AgNORs and the grading of Edmondson. The nodular lesions that can be considered in the differential diagnosis with carcinoma are sufficiently well discriminated using the two parameters AgNORs per clump and total number of AgNORs.     

Fine needle aspiration cytology of focal nodular hyperplasia of the liver

In five cases, the fine needle aspiration (FNA) cytologic study of ultrasonically detected solitary liver tumors yielded a diagnosis of focal nodular hyperplasia. Cytomorphologically, the lesions were characterized by the presence of both abundant normal hepatocytes and numerous epithelial cells in ductal formations, clusters or tightly packed groups in the FNA samples. In two of the five cases, the cytologic diagnosis was confirmed by subsequent histologic studies; in the remaining three cases, the clinical data were consistent with focal nodular hyperplasia of the liver. All five patients were women, four of whom had used oral contraceptives for long periods of time (5 to 15 years), which has previously been linked to the development of focal nodular hyperplasia of the liver. Based on the findings in this study, FNA cytology should be adequate for making the differential diagnosis of focal nodular hyperplasia versus liver-cell adenoma when solitary liver tumors are detected in such cases; it can yield a morphologic diagnosis and facilitate the decision as to whether surgical intervention is required.     

Fine needle aspiration biopsy of hepatocellular carcinoma and hepatocellular nodular lesions: role,controversies and approach to diagnosis

A. Wee
Fine needle aspiration biopsy of hepatocellular carcinoma and hepatocellular nodular lesions: role, controversies and appr oach to diagnosis The role of fine needle aspiration (FNA) biopsy of the liver has evolved. Advances in imaging modalities have obviated the need for tissue confirmation in clinically classic hepatocellular carcinoma (HCC). The risks of needle tract seeding and haematogenous dissemination have been actively debated. Nowadays, cytopathologists are confronted by smaller and smaller nodules, detected due to increased surveillance of high‐risk cirrhotic patients. Tissue characterization of small well‐differentiated hepatocellular nodular lesions (size less than and equal to 2 cm) is extremely challenging and has therapeutic implications. Major issues in the cytodiagnosis of HCC include: (i) distinguishing benign hepatocellular nodular lesions, namely, large regenerative nodules, dysplastic nodules, focal nodular hyperplasia and hepatocellular adenoma from reactive hepatocytes; (ii) distinguishing well‐differentiated HCC from benign hepatocellular nodular lesions; (iii) distinguishing poorly differentiated HCC from intrahepatic cholangiocarcinoma and metastatic carcinomas; (iv) determining the histogenesis of a malignant tumour; and (v) determining the site of origin of a malignant tumour. An overview of the biological evolution and histopathological aspects of dysplastic nodules, small HCCs and ‘nodule‐in‐nodule’ lesions is presented in tandem with clinically relevant nomenclature. An algorithmic approach to FNA diagnosis of HCC and hepatocellular nodular lesions is outlined. Optimal results depend on (i) a dedicated radiologist‐cytopathologist team; (ii) an on‐site cytology service, (iii) a combined cytohistological approach, (iv) immunohistochemistry, and (v) clinicopathological correlation. As we move towards personalized medicine, it is envisaged that hepatic FNA is likely to become a point of care in the management protocol as it takes on the additional role of procurement of tumour and peritumoural tissues for genomic and proteomic profiling to enable targeted molecular therapy.     

Contrast-enhanced power doppler sonography in detection and differentiation of focal liver lesions

The aim of the study is to evaluate the contrast enhanced power doppler technique as a method to detect and differentiate vascular patterns of focal liver lesions. Fourty-nine patients with focal liver lesions were included in the study, twenty-nine of them with malignant liver lesions (9 HCC, 20 metastatic), twenty patients with benign lesions (12 haemangiomas, 5 focal nodular hyperplasia, 3 focal steatosis). In all patients classic B-mode and power doppler sonography was performed prior to administration of the contrast medium Levovist (300 mg/ml) and a power doppler examination subsequent to medium administration. Contrast administration led to lowering the number of "no-flow" lesions from 19 to 11. Postcontrast scan analysis revealed markedly enhanced flow in 15 cases in comparison to only 4 in pre-contrast examinations. The pre-contrast power doppler showed central flow in 7, and peripheral in 26 focal liver lesions. On the other hand, the postcontrast study revealed a central flow in 14, and peripheral in 34 focal liver lesions. Statistical significance between pre- and post-contrast power doppler detection of vascularization existed in malignant focal liver lesions and haemangiomas. The same pre- and post-contrast evaluation proved to be statistically non-significant in the focal nodular hyperplasia and focal steatosis groups. Administration of contrast medium enables a better visualization of intratumor blood vessels in focal liver lesions. This, in combination with the power doppler technique, brings such scans close to angiographic findings.     

Two-color immunostaining of liver fine needle aspiration biopsies with CD34 and carcinoembryonic antigen. Potential utilization in the diagnosis of primary hepatocellular carcinoma vs. metastatic tumor

OBJECTIVE: To examine immunohistochemical staining of cell block material with antibodies against vascular marker CD34 and polyclonal carcinoembryonic antigen (pCEA) for their clinical utility as part of a 2-color staining protocol in fine needle aspiration (FNA) biopsy of liver masses to distinguish metastases from primary hepatocellular carcinoma (HCC). STUDY DESIGN: The authors obtained cell block material from 96 liver FNAs and performed simultaneous (i.e., "dual-color") immunohistochemical staining utilizing antibodies against vascular marker CD34 and pCEA. Cases were blinded and evaluated by the authors for staining pattern and intensity. A consensus was obtained, the results were unblinded, and the diagnoses were correlated. RESULTS: After staining, 89 cases had sufficient tissue for evaluation. Of the 19 HCC cases, 16 (84%) showed peripheral staining with CD34, and 13 (68%) showed a canalicular or mixed canalicular-cytoplasmic staining pattern for pCEA. Thirteen cases (68%) showed staining for both antigens. All HCC exhibited immunostaining for at least 1 antibody in an appropriate staining pattern. Of the 67 cases of metastatic malignancy, 5 (7%) showed a predominantly transgressing pattern of CD34 staining, 43 (64%) showed a predominantly cytoplasmic or mixed cytoplasmic-canalicular pattern of pCEA staining, and 2 cases (3%) showed staining for both antigens in a transgressing CD34 pattern and cytoplasmic pCEA pattern. None of the 3 normal liver tissue blocks showed staining with either antigen. CONCLUSION: Two-color immunohistochemical staining of liver cell block material obtained by FNA with antibodies to CD34 and pCEA can be helpful in differentiating metastatic tumors vs. primary HCC.     

假基因HMGA1L2在甲状腺肿瘤中的表达

应用RT-PCR技术检测假基因HMGA1L2在50例良、恶性甲状腺病变中HMGA1L2 mRNA的表达。结果显示HMGA1L2 mRNA在12例结节性甲状腺肿、9例甲状腺腺瘤和15例甲状腺乳头状癌中的阳性表达率均为100%, 而在14例甲状腺滤泡癌中的阳性率为35.7%, 与前3者差异有显著性。该研究首次报告了假基因HMGA1L2 mRNA在良、恶性甲状腺病变中的表达, 并且提示其在甲状腺滤泡癌与腺瘤的鉴别诊断中具有潜在的价值。     

Histological evidence of carcinoma in a hepatic tumour associated with oral contraceptives.

A primary hepatic tumour occurred in a 21-year-old woman who had been taking oral contraceptives for two years; she was treated by partial hepatectomy. Part of the neoplasm showed features suggestive of focal nodular hyperplasia, while the remainder had the histological characteristics of a well-differentiated hepatocellular carcinoma. This is the first report of malignant transformation of a tumour in a patient taking oral contraceptives.     

Hepatocellular carcinoma and focal nodular hyperplasia associated with norethandrolone-therapy: a case report

A 33-year-old woman was treated for severe aplastic anemia with norethandrolone over a period of four years, with a cumulative dose of 25 g. In the fifth year of therapy two intrahepatic tumors were detected and were classified as hepatocellular carcinoma and as focal nodular hyperplasia, respectively.     

肝脏局灶性结节增生的超声诊断

目的探讨超声对肝脏局灶性结节增生的诊断价值。方法采用基波超声对37例肝脏局灶性结节增生（FNH）进行检查,并进行超声造影。结果基波超声37例呈稍低回声或稍高回声,其中4例（10．8％）病灶中心回声不均,可见不规则低回声,血供丰富。超声造影提示动脉期37例（100％）高增强,其中7例（18．9％）可见特征性轮辐状增强。门脉期30例（81．1％）呈高增强,7例（18．9％）呈稍高或等增强。实质期20例（54．1％）呈高增强,17例（45．9％）呈等增强。结论超声对肝脏局灶性结节增生的诊断具有一定特征性,超声造影能提高对FNH的诊断准确性。     

The use of morphometry in the study of nodular and vascular lesions of the liver

This paper summarizes the use of morphometry on human autopsy livers to investigate three conditions characterized by the presence of hepatocellular nodules: nodular regenerative hyperplasia (NRH), partial nodular transformation (PNT) and focal nodular hyperplasia (FNH). Vascular abnormalities were seen in all cases. The nodules can be explained in all three conditions as a response to a greater blood supply in the nodules as compared to the surrounding parenchyma. In NRH, there appears to be ischemia caused by arteritis and secondary oblitertion of small portal veins. In PNT, ischemia may be caused by portal vein thrombosis. In FNH, there appears to be hyperemia caused by a spiderlike arterial anomaly.     

Cytotoxic peripheral T cell lymphoma arising in a patient with nodular lymphocyte predominant Hodgkin lymphoma: a case report

In this paper, we describe a case of nodular lymphocyte predominant Hodgkin lymphoma with the subsequent development of a peripheral T cell lymphoma. This case is unusual in that the sheets of atypical and small to intermediate-sized T cells in the diffuse component were CD8 positive and expressed cytotoxic proteins. The diagnosis of peripheral T cell lymphoma was supported by the demonstration of a clonal T cell receptor beta chain gene rearrangement by Southern blot analysis. Peripheral T cell lymphoma with a cytotoxic phenotype is a rare entity with an aggressive clinical behavior. As such, this report emphasizes the need to consider a diagnosis of coexisting peripheral T cell lymphoma in cases of nodular lymphocyte predominant Hodgkin lymphoma with atypical features, such as few or poorly defined B cell macronodules and diffuse T cell areas. The examination of both T cell receptor gamma and beta chain gene rearrangements should be performed to confirm such cases.     

螺旋CT三期扫描在肝癌诊断中的价值

目的：探讨肝癌螺旋CT多期扫描影像特征和临床应用价值.方法：对诊断为肝癌的83例患者先行全肝CT平扫,其中73例不论肿瘤大小（包括21例结节型）先作病灶动脉期扫描,再作全肝静脉期扫描,最后进行病灶平衡期扫描.10例仅行动脉期及静脉期扫描.结果：83例中57例为巨块型（68.67%）,16例为结节型（19.27%）,10例为弥漫型（12.04%）.73例中CT平扫、动脉期、静脉期及平衡期病灶的显示率分别为89%、98%、92%、98%.结论：螺旋多期扫描能获得肿瘤在各期增强征象,为肝癌的定性定量诊断提供更多的影像诊断信息;尤其在早期肝癌诊断,动脉期扫描可得到非常重要的诊断依据.     

分子生物学法分析青少年甲状腺肿物临床病理及特点

探讨青少年甲状腺肿物的临床病理学特点,甲状腺癌的复发、转移和结节性甲状腺肿复发的可能相关因素。按WHO病理分型标准和国际抗癌联盟(UICC)TNM分期标准回顾性分析青少年甲状腺肿物124例及其中部分甲状腺癌和结节性甲状腺肿的随访资料。124例甲状腺肿物患者男女比例约为1 3,甲状腺癌39例(31.5%),其中乳头状癌35例,滤泡癌3例,髓样癌1例;甲状腺腺瘤59例(47.6%),结节性甲状腺肿11例(8.9%),结节性甲状腺肿伴腺瘤7例(5.6%),甲状腺炎5例(4%),甲状舌管囊肿3例(2.4%)。本组资料显示,青少年甲状腺癌以乳头状癌为主,其复发、转移与组织学亚型为弥漫硬化型及甲状腺包膜和其外软组织受侵状态相关。虽然常见淋巴结转移、肺转移以及局部侵犯周围软组织,但患者总体预后较好。结节性甲状腺肿的复发与病变弥漫位于双叶有关,而与患者性别、年龄和是否伴有乳头样及腺瘤样增生关系不密切。     

A case report of hepatocellular carcinoma and focal nodular hyperplasia with a myelolipoma in two chimpanzees and a review of spontaneous hepatobiliary tumors in non-human primates

Spontaneous hepatobiliary tumors in non-human primates are uncommon. Here we report a case of hepatic carcinoma and a case of hepatic focal nodular hyperplasia (FNH) and myelolipoma in two captive chimpanzees. A 16-year-old male chimpanzee (4X0392) died after an 8-month history of hepatic amyloidosis and low-grade anemia. Necropsy findings included a hepatic neoplasm with highly pleomorphic hepatocytes arranged into irregular thickened trabeculae. The diagnosis was high-grade hepatocellular carcinoma. A second male chimpanzee (4X0080), 23 years of age, died suddenly of heart failure secondary to cardiomyopathy. An incidental finding at necropsy was a liver mass characterized by multinodularity, prominent fibrous septa, and biliary hyperplasia. These features were consistent with FNH. While 4X0392 had no history of experimental viral exposure, 4X0080 was vaccinated with inactivated hepatitis B virus, an attenuated hepatitis A virus, and was experimentally infected with hepatitis C virus and human immunodeficiency virus. A survey of the literature revealed 68 reported cases of hepatobiliary tumors in non-human primates, including 12 hepatocellular adenomas, eight cholangiocellular adenomas/cystadenomas, 22 hepatocellular carcinomas, seven cholangiocarcinomas, and seven gallbladder adenocarcinomas. The majority of reported cases have been in prosimians and Old World monkeys. Hepatic neoplasia is rare in chimpanzees. Only four hepatic neoplasms have been reported in chimpanzees, three of which were associated with viral hepatitis. FNH has not been previously described in any non-human primate.     

不同肝病变组织中CD34、CD31、Ki-67的表达及意义

目的比较正常肝组织、慢性肝炎、肝硬化、肝细胞肝癌组织及肝转移腺癌中CD34、CD31、Ki-67不同表达,寻找有助于鉴别不同性质病变的生物学标记物.方法正常肝及病变肝组织标本共104例;其中,正常肝组织10例;慢生C型肝炎组织73例;肝硬化组织7例;肝细胞肝癌7例;结肠癌肝转移5例;乳腺癌肝转移2例.73例慢性C型肝炎组织全部为肝穿活检标本,其余组织均为手术切除标本.所有病例标本分别行CD34、CD31、Ki-67免疫组织化学染色,半定量评分系统评价染色结果.统计学分析结果数据.结果在非肿瘤组织,抗CD34阳性染色主要存在于汇管区,亦可见于汇管区周围的肝实质内血窦.阳性染色内皮细胞呈点状、线状、半环状及环状,散在或簇状分布.肿瘤组织内抗CD34阳性染色特征与非肿瘤组织相似,阳性染色血管在肿瘤组织内散布分布.CD34指数在各病变组中的表达排列顺序依次为:肝细胞肝癌>乳腺癌肝转移>结肠癌肝转移>肝硬化>慢性C型肝炎>正常肝组织,从正常肝组织至慢性肝炎至肝细胞肝癌,CD34表达明显增强.组织中,抗CD31阳性染色分布、定位、形态特征与CD34相似.CD31在慢性肝炎、肝硬化、肝细胞肝癌、结肠癌肝转移及乳腺癌肝转移组织中阳性表达率分别为:6.8%(5/73)、100%(7/7)、100%(7/7)、100%(5/5)、100%(2/2);肝癌组织中CD31染色强度明显大于非癌组织中,组间比较具有显著差异(P<0.05).Ki-67阳性染色细胞呈棕黄色核着色,散在分布于肝实质内.阳性染色细胞无形态特殊性,亦无分布上的特殊性.Ki-67在各病变组间的阳性表达率分别为:64.4%(47/73)、28.6%(2/7)、100%(7/7)、100%(5/5)、100%(2/2),其中以在结肠癌肝转移组织中表达最明显;组间比较具有非常显著差异(P<0.05).在正常肝脏、慢性C型肝炎、肝硬化、肝细胞肝癌CD34、CD31、Ki-67三种生物学标记物在同一标本同时表达的阳性率分别为:0%(0/0)、4.1%(3/73)、28.6%(2/7)、100%(7/7),CD34、CD31、Ki-67其中任两种同时表达的阳性率分别为0%(0/10)、63.0%(46/73)、100%(7/7)、100%(7/7).结论 CD34是慢性肝病、肝癌临床病理评价的指标之一,CD34与CD31、Ki-67同时分析有助于建立可靠的诊断.     

In situ hybridization of albumin mRNA in normal liver and liver tumors: Identification of hepatocellular origin

In situ hybridization was performed to detect albumin mRNA in normal liver, liver cirrhosis, primary liver tumors and secondary liver neoplasms. In areas of normal liver, and liver cirrhosis, signals for albumin mRNA were present in hepatocytes, whereas no signals were seen in other cells such as endothelial and Küpffer cells, bile duct epithelium and smooth muscle cells. In 53 of 56 hepatocellular carcinomas signals were present in tumor cells but in eight cholangiocarcinomas and 14 metastatic adenocarcinomas from large bowel or pancreas, carcinoma cells were negative for albumin mRNA. In three metastatic tumors (from two neuroendocrine carcinomas and one gastric leiomyosarcoma), tumor cells contained no signals, while the surrounding hepatocytes showed diffuse grains. In 15 of the 84 specimens examined in situ hybridization was applied to routine formalin-fixed and paraffin-embedded blocks and strong signals were obtained for albumin mRNA. We conclude that in situ hybridization of human albumin is a valid tool in the differential diagnosis of hepatocellular carcinoma from cholangiocarcinomas and tumors metastatic to the liver.