Abstract
Fine needle aspiration (FNA) has become one of the most popular diagnostic approaches for focal liver lesions, not only for primary hepatocellular carcinoma (HCC) and cholangiocarcinoma but also for various metastatic tumors. For practicing cytopathologists, recognition of normal cellular components of liver, pigments, and FNA-carried contaminating cells is important for accurate diagnosis of different types of tumors. One particular diagnostic challenge of liver FNA is well-differentiated HCC, because the tumor cells are very similar to its normal counterparts. Identification of endothelium, either wrapping around tumor cell groups or traversing tumor cell sheets, is a highly specific and sensitive indicator for HCCs. Separation of more poorly differentiated HCCs from cholangiocarcinoma, metastatic carcinomas, angiosarcoma, and hepatoblastoma may require not only characteristic cytomorphological features but also immunohistochemical or even molecular markers. This chapter covers most of the common diagnostic dilemmas encountered in daily cytopathological practice.
Keywords
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Conrad R, Castelino-Prabhu S, Cobb C, Raza A. Cytopathologic diagnosis of liver mass lesions. J Gastrointest Oncol. 2013;4:53–61.
Butnor KJ. My approach to the diagnosis of mesothelial lesions. J Clin Pathol. 2006;59:564–74.
Niels T, Torben S, Kjeld W. Correlation between pathological and clinical findings in 195 consecutive liver biopsies showing brown pigment. Gut. 1965;6:194–200.
Bassett ML, Halliday JW, Powell LW. Value of hepatic iron measurements in early hemochromatosis and determination of the critical iron level associated with fibrosis. Hepatology. 1986;6:24–9.
Harman D. Lipofuscin and ceroid formation: the cellular recycling system. Adv Exp Med Biol. 1989;266:3–15.
Russack V1, Vass L, Gupta PK. Comparison of morphologic features of benign hepatocytes associated with nonmalignant and malignant liver lesions. Acta Cytol. 1993;37:153–7.
Swamy MC, Arathi C, Kodandaswamy C. Value of ultrasonography-guided fine needle aspiration cytology in the investigative sequence of hepatic lesions with an emphasis on hepatocellular carcinoma. J Cytol. 2011;28:178–84.
Wee A. Fine needle aspiration biopsy of the liver: algorithmic approach and current issues in the diagnosis of hepatocellular carcinoma. CytoJournal. 2005;2:7–12.
Zhu ZW, Friess H, Wang L, Abou-Shady M, Zimmermann A, Lander AD, Korc M, Kleeff J, Büchler MW. Enhanced glypican-3 expression differentiates the majority of hepatocellular carcinomas from benign hepatic disorders. Gut. 2001;48:558–64.
Yamauchi N, Watanabe A, Hishinuma M, Ohashi K, Midorikawa Y, Morishita Y, Niki T, Shibahara J, Mori M, Makuuchi M, Hippo Y, Kodama T, Iwanari H, Aburatani H, Fukayama M. Glypican 3 oncofetal protein is a promising diagnostic marker for hepatocellular carcinoma. Mod Pathol. 2005;18:1591–8.
Shafizadeh N, Ferrell LD, Kakar S. Utility and limitations of glypican-3 expression for the diagnosis of hepatocellular carcinoma at both ends of the differentiation spectrum. Mod Pathol. 2008;21:1011–8.
Libbrecht L, Severi T, Cassiman D, Vander Borght S, Pirenne J, Nevens F, Verslype C, van Pelt J, Roskams T. Glypican-3 expression distinguishes small hepatocellular carcinomas from cirrhosis, dysplastic nodules, and focal nodular hyperplasia-like nodules. Am J Surg Pathol. 2006;30:1405–11.
Coston WM, Loera S, Lau SK, Ishizawa S, Jiang Z, Wu CL, Yen Y, Weiss LM, Chu PG. Distinction of hepatocellular carcinoma from benign hepatic mimickers using Glypican-3 and CD34 immunohistochemistry. Am J Surg Pathol. 2008;32:433–44.
Huang H, Fujii H, Sankila A, Mahler-Araujo BM, Matsuda M, Cathomas G, Ohgaki H. Beta-catenin mutations are frequent in human hepatocellular carcinomas associated with hepatitis C virus infection. Am J Pathol. 1999;155:1795–801.
Nasarek A, Werner M, Nolte M, Klempnauer J, Georgii A. Trisomy 1 and 8 occur frequently in hepatocellular carcinoma but not in liver cell adenoma and focal nodular hyperplasia. A fluorescence in situ hybridization study. Virchows Arch. 1995;427:373–8.
Wilkens L, Bredt M, Flemming P, Schwarze Y, Becker T, Mengel M, von Wasielewski R, Klempnauer J, Kreipe H. Diagnostic impact of fluorescence in situ hybridization in the differentiation of hepatocellular adenoma and well-differentiated hepatocellular carcinoma. J Mol Diagn. 2001;3:68–73.
Saleh HA, Aulicino M, Zaidi SY, et al. Discriminating hepatocellular carcinoma from metastatic carcinoma on fine-needle aspiration biopsy of the liver: the utility of immunocytochemical panel. Diagn Cytopathol. 2009;37:184–90.
Canberk S, Onenerk M, Sayman E, Goret CC, Erkan M, Atasoy T, Kilicoglu GZ. Is DOG1 really useful in the diagnosis of salivary gland acinic cell carcinoma? A DOG1 (clone K9) analysis in fine needle aspiration cell blocks and the review of the literature. Cytojournal. 2015;12:18–24.
Gokce A, Vikram D, Olca B. Expression of markers of hepatocellular differentiation in pancreatic acinar cell neoplasms; a potential diagnostic pitfall. Am J Clin Pathol. 2016;146:163–9.
Pérez-Guillermo M, Masgrau NA, García-Solano J, Sola-Pérez J, de Agustín y de Agustín P. Cytologic aspect of fibrolamellar hepatocellular carcinoma in fine-needle aspirates. Diagn Cytopathol. 1999;21:180–7.
Rondell PG. Fibrolamellar carcinoma. Surg Pathol Clin. 2018;11(2):377–87.
Riehle KJ, Yeh MM, Yu JJ, Kenerson HL, Harris WP, Park JO, Yeung RS. mTORC1 and FGFR1 signaling in fibrolamellar hepatocellular carcinoma. Mod Pathol. 2015;28:103–10.
Singh HK, Silverman JF, Geisinger KR. Fine-needle aspiration cytomorphology of clear-cell hepatocellular carcinoma. Diagn Cytopathol. 1997;17:306–10.
de Gonzalez AKK, Salomao MA, Lagana SM. Current concepts in the immunohistochemical evaluation of liver tumors. World J Hepatol. 2015;7:1403–11.
Fu LY, Mitchell KA, Cai G. Clear cell hepatocellular carcinoma diagnosed by bile duct brushing cytology. Diagn Cytopathol. 2016;44:147–51.
Chen L, Huang K, Himmelfarb EA, Zhai J, Lai JP, Lin F, Wang HL. Diagnostic value of maspin in distinguishing adenocarcinoma from benign biliary epithelium on endoscopic bile duct biopsy. Hum Pathol. 2015;46:1647–54.
Kanzawa M, Sanuki T, Onodera M, Fujikura K, Itoh T, Zen Y. Double immunostaining for maspin and p53 on cell blocks increases the diagnostic value of biliary brushing cytology. Pathol Int. 2017;67:91–8.
Katabi N. Neoplasia of gallbladder and biliary epithelium. Arch Pathol Lab Med. 2010;134:1621–7.
Brooks C, Gausman V, Kokoy-Mondragon C, Munot K, Amin SP, Desai A, Kipp C, Poneros J, Sethi A, Gress FG, Kahaleh M, Murty VV, Sharaiha R, Gonda TA. Role of fluorescent in situ hybridization, cholangioscopic biopsies, and EUS-FNA in the evaluation of biliary strictures. Dig Dis Sci. 2018;63:636–44.
Meara RS, Jhala D, Eloubeidi MA, Eltoum I, Chhieng DC, Crowe DR, Varadarajulu S, Jhala N. Endoscopic ultrasound-guided FNA biopsy of bile duct and gallbladder: analysis of 53 cases. Cytopathology. 2006;17:42–9.
Balani S, Malik R, Malik R, Kapoor N. Cytomorphological variables of hepatic malignancies in fine needle aspiration smears with special reference to grading of hepatocellular carcinoma. J Cytol. 2013;30:116–20.
Chaudhary HB, Bhanot P, Logroño R. Phenotypic diversity of intrahepatic and extrahepatic cholangiocarcinoma on aspiration cytology and core needle biopsy: case series and review of the literature. Cancer. 2005;105:220–8.
Hertz G, Reddy VB, Green L, Spitz D, Massarani-Wafai R, Selvaggi SM, Kluskens L, Gattuso P. Fine-needle aspiration biopsy of the liver: a multicenter study of 602 radiologically guided FNA. Diagn Cytopathol. 2000;23:326–8.
Curcio G, Traina M, Mocciaro F, Liotta R, Gentile R, Tarantino I, Barresi L, Granata A, Tuzzolino F, Gridelli B. Intraductal aspiration: a promising new tissue-sampling technique for the diagnosis of suspected malignant biliary strictures. Gastrointest Endosc. 2012;75:798–804.
Pitman MB, Centeno BA, Ali SZ, Genevay M, Stelow E, Mino-Kenudson M, Castillo CF, Schmidt CM, Brugge WR, Layfield LJ. Standardized terminology and nomenclature for pancreatobiliary cytology: the Papanicolaou Society of Cytopathology Guidelines. Cytojournal. 2014;11(Suppl 1):3–16.
Kipp BR, Stadheim LM, Halling SA, Pochron NL, Harmsen S, Nagorney DM, et al. A comparison of routine cytology and fluorescence in situ hybridization for the detection of malignant bile duct strictures. Am J Gastroenterol. 2004;99:1675–81.
Bertram S, Padden J, Kälsch J, Ahrens M, Pott L, Canbay A, Weber F, Fingas C, Hoffmann AC, Vietor A, Schlaak JF, Eisenacher M, Reis H, Sitek B, Baba HA. Novel immunohistochemical markers differentiate intrahepatic cholangiocarcinoma from benign bile duct lesions. J Clin Pathol. 2016;69:619–26.
Liew ZH, Loh TJ, Lim TKH, Lim TH, Khor CJL, Mesenas SJ, Kong CSC, Ong WC, Tan DMY. Role of fluorescence in situ hybridization in diagnosing cholangiocarcinoma in indeterminate biliary strictures. J Gastroenterol Hepatol. 2018;33:315–9.
Lagana SM, Moreira RK, Remotti HE, Bao F. Immunohistochemical distinction between intrahepatic cholangiocarcinoma and pancreatic ductal adenocarcinoma. Hum Pathol. 2014;45:394–400.
Wee A. Fine needle aspiration biopsy of hepatocellular carcinoma and hepatocellular nodular lesions: role, controversies and approach to diagnosis. Cytopathology. 2011;22:287–305.
Onofre AS, Pomjanski N, Buckstegge B, Böcking A. Immunocytochemical diagnosis of hepatocellular carcinoma and identification of carcinomas of unknown primary metastatic to the liver on fine-needle aspiration cytologies. Cancer. 2007;111:259–68.
Sampatanukul P, Leong AS, Kosolbhand P, Tangkijvanich P. Proliferating ductules are a diagnostic discriminator for intrahepatic cholangiocarcinoma in FNA biopsies. Diagn Cytopathol. 2000;22:359–63.
Lok T, et al. Immunohistochemical distinction between intrahepatic cholangiocarcinoma and pancreatic ductal adenocarcinoma. Hum Pathol. 2014;45:394–400.
Lagana SM, Moreira RK, Remotti HE, Bao F. Glutamine synthetase, heat shock protein-70, and glypican-3 in intrahepatic cholangiocarcinoma and tumors metastatic to liver. Appl Immunohistochem Mol Morphol. 2013;21:254–7.
Ma CK, Zarbo RJ, Frierson HF Jr, Lee MW. Comparative immunohistochemical study of primary and metastatic carcinomas of the liver. Am J Clin Pathol. 1993;99(5):551–7.
Vlajnic T, Brisse HJ, Aerts I, Fréneaux P, Cellier C, Fabre M, Klijanienko J. Fine needle aspiration in the diagnosis and classification of hepatoblastoma: analysis of 21 new cases. Diagn Cytopathol. 2017;45:91–100.
Shin E, Lee KB, Park SY, Kim SH, Ryu HS, Park YN, Yu E, Jang JJ. Gene expression profiling of human hepatoblastoma using archived formalin-fixed and paraffin-embedded tissues. Virchows Arch. 2011;458:453–65.
Gupta R, Mathur SR, Gupta SD, Durgapal P, Iyer VK, Das CJ, Shalimar, Acharya SK. Hepatic epithelioid hemangioendothelioma: a diagnostic pitfall in aspiration cytology. Cytojournal. 2009;6:25–30.
den Bakker MA, Marx A, Mukai K, Ströbel P. Mesenchymal tumours of the mediastinum–part II. Virchows Arch. 2015;467:501–17.
Jung MJ, Kim YO. A case of metastatic angiosarcoma diagnosed by liquid-based preparation: peculiar cytoplasmic changes. Korean J Pathol. 2014;48:241–7.
Dusenbery D. Combined hepatocellular-cholangiocarcinoma. Cytologic findings in four cases. Acta Cytol. 1997;41:903–9.
Gibbons D, de las Morenas A. Fine needle aspiration diagnosis of combined hepatocellular carcinoma and cholangiocarcinoma. A case report. Acta Cytol. 1997;4:1269–72.
Wee A, Nilsson B. Combined hepatocellular-cholangiocarcinoma. Diagnostic challenge in hepatic fine needle aspiration biopsy. Acta Cytol. 1999;43:131–8.
Gu Q, Yu X, Chen H, Chen G. Clinicopathological features of combined hepatocellular-cholangiocarcinoma with sarcomatous change: case report and literature review. Medicine (Baltimore). 2018;97:e9640. https://doi.org/10.1097/MD.9640.
Brunt E, Aishima S, Clavien PA, Fowler K, Goodman Z, Gores G, Gouw A, Kagen A, Klimstra D, Komuta M, Kondo F, Miksad R, Nakano M, Nakanuma Y, Ng I, Paradis V, Nyun Park Y, Quaglia A, Roncalli M, Roskams T, Sakamoto M, Saxena R, Sempoux C, Sirlin C, Stueck A, Thung S, Tsui WMS, Wang XW, Wee A, Yano H, Yeh M, Zen Y, Zucman-Rossi J, Theise N. cHCC-CCA: consensus terminology for primary liver carcinomas with both hepatocytic and cholangiocytic differentation. Hepatology. 2018;68:113–26.
Gera S, Ettel M, Acosta-Gonzalez G, Xu R. Clinical features, histology, and histogenesis of combined hepatocellular-cholangiocarcinoma. World J Hepatol. 2017;9:300–9.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2020 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Zhou, J., Wang, H., Jhala, N. (2020). Liver Cytopathology. In: Xu, H., Qian, X., Wang, H. (eds) Practical Cytopathology . Practical Anatomic Pathology. Springer, Cham. https://doi.org/10.1007/978-3-030-24059-2_16
Download citation
DOI: https://doi.org/10.1007/978-3-030-24059-2_16
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-24058-5
Online ISBN: 978-3-030-24059-2
eBook Packages: MedicineMedicine (R0)