HepPar1, MOC-31, pcea, mcea and CD10 for Distinguishing Hepatocellular Carcinoma vs. Metastatic Adenocarcinoma in Liver Fine Needle Aspirates

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1 HepPar1, MOC-31, pcea, mcea and CD10 for Distinguishing Hepatocellular Carcinoma vs. Metastatic Adenocarcinoma in Liver Fine Needle Aspirates Luoquan Wang, M.D., Magalis Vuolo, M.D., Mark J. Suhrland, M.D., and Kathie Schlesinger, M.D. Objective To investigate immunohistochemical staining of hepatocyte paraffin-1 (HepPar1), α-fetoprotein (AFP), polyclonal carcinoembryonic antigen (pcea), monoclonal CEA (mcea), MOC-31 and CD10 for differential diagnosis of hepatocellular carcinoma (HCC) from metastatic adenocarcinoma (MA) on fine needle aspiration biopsy (FNAB). Study Design Fifty-one archival, paraffinembedded FNAB cell blocks, representing 18 HCCs and 33 MAs, were immunostained with antibodies for AFP, CD10, pcea, mcea, HepPar1 and MOC-31. Results HepPar1, AFP, canalicular pcea and CD10 were positive in 78% (14 of 18), 28% (5 of 18), 72% (13 of 18) and 35% (6 of 17) of cases of HCC, respectively. The 33 MAs were negative for immunostaining of the above antibodies except for one AFP-positive MA. Ninety-seven percent (31 of 32) of the MAs and 6% (1 of 17) of the HCCs were positive for MOC-31. Monoclonal CEA was immunoreactive on 82% (27 of 33) of the MAs and negative on all the HCCs. We suggest using HepPar1, pcea, CD10, MOC-31 and mcea as a panel for distinguishing HCC from MA in liver FNABs. Fine Needle Aspiration Conclusion HepPar1 was the most sensitive marker for HCC, followed by canalicular staining for pcea. For MA, MOC-31 was the most sensitive marker; mcea was slightly less sensitive but more specific. We suggest using HepPar1, pcea, CD10, MOC-31 and mcea as a panel for distinguishing HCC from MA in liver FNAB. (Acta Cytol 2006; 50: ) Keywords: hepatocellular carcinoma, adenocarcinoma, immunohistochemistry, liver cancer. Fine needle aspiration biopsy (FNAB) has gained widespread use in the diagnosis of liver lesions. However, as in core needle biopsy, the differentiation of hepatocellular carcinoma (HCC) from metastatic adenocarcinoma (MA) on FNAB is sometimes a challenge. Although the cellular features of the specimen are still essential in the differential diagnosis between HCC and MA, application of immunomarkers has improved the diagnostic accuracy and is especially helpful in challenging cases. 1-3 In past decades, numerous antibodies have been suggested as useful in the distinction of HCC from From the Department of Pathology, Montefiore Medical Center, Bronx, New York, U.S.A. Drs. Wang, Vuolo, Suhrland and Schlesinger are Attending Pathologists. Presented at the 93rd annual meeting of the United States and Canadian Academy of Pathology, Vancouver, British Columbia, Canada, March 6 12, Address correspondence to: Luoquan Wang, M.D., Department of Pathology, Montefiore Medical Center, 111 E. 210th Street, Bronx, New York (luowang@yahoo.com). Financial Disclosure: The authors have no connection to any companies or products mentioned in this article. Received for publication July 7, Accepted for publication August 31, /06/ /$19.00/0 The International Academy of Cytology ACTA CYTOLOGICA 257

2 Wang et al MA. These have included α-fetoprotein (AFP), subtypes of cytokeratin, Ber-EP4, CD10, polyclonal carcinoembryonic antigen (pcea) and monoclonal CEA (mcea), among others. 2,4-11 For the most part, the sensitivity and specificity of these antibodies have not been satisfactory. Recent studies on surgical biopsy specimens have suggested that the monoclonal antibodies MOC-31 and HepPar1 are better markers for differentiating HCC from MA MOC-31, as a positive marker for MA, showed % specificity and sensitivity in several studies. 13,15-17 HepPar1, a marker for HCC, also showed high specificity and sensitivity. 12,18,19 The application of these antibodies to FNAB cell block material, which is fixed and processed differently from tissue biopsies, has been less thoroughly tested. 1,3,13,20 In this study, we examined the utility of AFP, CD10, mcea, pcea, MOC 31 and HepPar1 in diagnosing HCC vs. MA on liver FNAB cell blocks. Previous studies on cytokeratin subtypes reported conflicting results, 7,9,10,21,22 and studies of B72.3 and factor XIIIa have failed to demonstrate their usefulness, 4,23 so these antibodies were not included in this study. Table I Antibodies, Dilutions and Pretreatment Pretreat Antibodies Sources Dilutions buffer AFP Dako Corp. 1:2500 Hier ph 6 CD10 Cell Marque Corp. 1:20 HipH TRS (Hot Springs, Arkansas, U.S.A.) pcea Dako Corp. 1:8000 Hier ph 6 mcea Dako Corp. 1:200 Hier ph 6 HepPar1 Dako Corp. 1:100 Hier ph 6 MOC-31 Dako Corp. 1:50 Hier ph 6 Table II Immunohistochemical Staining Results Antibodies HCC (+) MA (+) AFP 5/18 (28%) 1/33 (3%) CD10 6/17 (35%) 0/32 (0%) pcea 13/18 (72%) 0/33 (0%) mcea 0/18 (0%) 27/33 (82%) HepPar1 14/18 (78%) 0/33 (0%) MOC-31 1/17 (6%) 31/32 (97%) Materials and Methods Fifty-one liver FNABs, representing 18 HCCs and 33 MAs diagnosed by the Department of Pathology, Montefiore Medical Center from 1997 to 2003, were selected for study. Only cases with adequate cellular material on original hematoxylin-eosin stained cell block sections and with unequivocal diagnoses, based on morphology, clinical findings or histologic confirmation, were used. The primary sites of the MAs included colon (n = 8), pancreas (n = 7), stomach (n = 2), breast (n = 2), small bowel (n = 1), urothelium (n = 1), lung (n = 1) and unknown origin (n = 11). The cell block material had been fixed initially in a 50% ethanol/2% carbowax solution. Histochoice fixative (Amresco Inc., Solon, Ohio, U.S.A.) was subsequently added, the specimens were centrifuged, and the resulting pellets were embedded in paraffin. Fourmicron-thick, deparaffinized sections were immunostained with antibodies against AFP, CD10, mcea, pcea, MOC 31 and HepPar1 using the Dako Envision System (Carpinteria, California, U.S.A.). The pretreatment buffer for antigen retrieval, working dilution and sources for each antibody are listed in Table I. Appropriate positive and negative controls were stained in parallel with the slides. In evaluating the stains, MOC-31 was considered positive when it showed a membranous staining pattern. CD10 and pcea were considered positive when a canalicular staining pattern was present. The staining pattern in the other stains was cytoplasmic. Only slides with adequate tissue and unequivocal staining were entered into the final results. Results The immunohistochemical results are summarized in Table II, and representative slides are illustrated in Figure 1. Two cases, 1 HCC and 1 MA, were excluded from the CD10 and MOC-31 results due to inadequate material remaining in the immunostained slides. AFP staining had limited sensitivity for HCC (28%) and was positive in 1 MA (3%). Canalicular staining for CD10 was somewhat more sensitive for HCC (35%). Two HCCs showed both membranous and cytoplasmic staining for CD10; that was interpreted as negative staining. Seven of 32 MAs showed cytoplasmic staining for CD10; they were also counted as negative. Canalicular staining for pcea was present in 72% of HCCs. Three HCCs and 26 MAs showed predominantly cytoplasmic pcea reactivity, which was counted as negative. HepPar1 was both the most sensitive and specific marker for HCC: sensitivity 78%, specificity 100%, positive predictive value (PPV) 100% and negative predictive value (NPV) 89%. For MA, mcea staining was highly specific but somewhat less sensitive: sensitivity 82%, specificity 100%, PPV 100% and NPV 75%. MOC-31was the most sensitive antibody for MA but also stained 1 HCC: sensitivity 97%, specificity 94%, PPV 97% and NPV 94%. Discussion The differential diagnosis of HCC vs. MA is clinically important because the prognosis and treatment ap- 258 ACTA CYTOLOGICA Volume 50 Number 3 May June 2006

3 Distinguishing HCC vs. Adenocarcinoma B C D U l ht rig C op y T N O O ed D E proach are different for these 2 entities. Often the cellular features of the FNAB, in conjunction with the clinical history, permit an accurate diagnosis. HCC typically appears as polygonal cells with round, centrally placed nuclei, prominent nucleoli, and eosinophilic, granular cytoplasm. Intranuclear cytoplasmic inclusions may be present. Naked nuclei are common. The tumor cells may be arranged in clusters surrounded by endothelial cells or in large sheets traversed by sinusoidal capillaries. In a stepwise logistic regression analysis of HCC, Bottles et al24 found the presence of polygonal cells with centrally D te ria P L M a I C A TE A Figure 1 (A) Cytoplasmic staining of HepPar1 in HCC. (B) Membranous staining of MOC-31 in MA. (C) Canalicular staining of pcea in HCC. (D) Canalicular staining of CD10 in HCC. (E) Cytoplasmic staining of mcea in MA. placed nuclei, malignant cells traversed by sinusoidal capillaries and bile pigment to be the key cytologic criteria. However, these key features may be absent from FNAB specimens in poorly differentiated HCC. Features of MA include columnar cells with polar nuclei, acinar formation and mucin production. As in HCC, these characteristic cellular features may not be evident, particularly in poorly differentiated MA. Even in less poorly differentiated tumors, the pathologic diagnosis on FNAB may be especially challenging because of limited material for evaluation and lack of clear-cut histologic architecture. Application of adjunct diag- Volume 50 Number 3 May June 2006 ACTA CYTOLOGICA 259

4 Wang et al nostic tools, such as immunohistochemical staining, is therefore sometimes essential for a definitive diagnosis. In past decades, a number of immunomarkers have been developed and used in the differential diagnosis of HCC from MA. AFP is one of the earliest of these markers. 2,4,8 In this study, 5 of 18 HCC cell blocks (28%) were positive for AFP, consistent with the 25 40% sensitivity reported in previous studies of surgical specimens. 4,6,25 The 5 AFP-positive HCCs were also positive for 1 or more of the other HCC markers studied. Regarding the 1 AFP-positive MA, positive AFP staining has been reported in adenocarcinoma with hepatoid differentiation. 26,27 The AFP-positive MA was a poorly differentiated carcinoma of unknown origin and did not show hepatoid differentiation on a small biopsy specimen. However, it also showed positive immunoreactivity with MOC-31 and mcea antibodies. Canalicular staining of HCC with pcea, attributed to cross-reactivity of antibody with biliary glycoprotein I, has been found to be highly specific for HCC in tissue. 5,28-31 By contrast, MA and cholangiocarcinoma show only cytoplasmic staining. 16,29,32 In this study, 13 of 18 HCC cell blocks (72%) showed canalicular pcea staining, while all 26 pcea-reactive MAs presented with cytoplasmic reactivity. Our data are similar to those from previous studies on surgical specimens, most of which found canalicular staining with pcea in 60 70% of HCCs. 17,18 However, it has been noted that the staining pattern of pcea on HCCs from our liver aspirates was not as sharp and clear-cut as reported for surgical specimens. We have not had difficulty in any case distinguishing it from the pattern of cytoplasmic staining seen on MA. We think that the atypical pcea staining pattern on FNAB materials is attributable to the fixation and process of the cell blocks. Three of our HCCs showed cytoplasmic staining similar to MA. Mainly used as a marker for hematopoietic neoplasia, CD10 stain has also been reported in variety of other neoplasms. 33 Its highly specific canalicular staining pattern in normal liver and in HCC makes it a potential marker for HCC. 11 Six of seventeen HCC cell blocks (35%) but none of the 32 MAs showed a canalicular staining pattern. One previous study of CD10 on tissue found that it was not contributory for diagnosing HCC in combined use with other antibodies because of its low sensitivity (32%). 17 However, another study, performed on formalin-fixed FNAB cell blocks, showed canalicular staining of CD10 in 82% of 22 well- to moderately differentiated HCCs. 3 The sensitivity in our cases, most of which were also well to moderately differentiated, was far lower. In addition, CD10 staining pattern was cytoplasmic and membranous in 2 HCC cases; the problem has been reported in surgical specimens as well. 17 However, CD10 was the only positive marker in 1 of our HCC cases, indicating that it may be useful for confirming suspected HCC when other antibodies are negative. mcea has served as a marker for adenocarcinoma In this study it was positive in 27 of 33 MAs (82%). All 18 HCCs were negative. Positive staining for mcea therefore supports a diagnosis of MA, although negative staining does not rule it out. Two new antibodies have emerged as more useful markers for the differential diagnosis of HCC vs. MA: HepPar1 as a positive marker for HCC and MOC-31 as a marker for MA. The monoclonal antibody HepPar1, developed by immunizing mice with failed liver allograft, reacts with the mitochondrial fraction of hepatocytes. 38 Chu et al recently reported on the immunoreactivity spectrum of HepPar1 in formalin-fixed tissue from a variety of neoplasms. In their study HepPar1 was positive in 88 of 96 HCCs (92%), but it also was positive in 20 of 311 nonhepatic neoplasms (6%). 18 In our study, 14 of 18 HCC cell blocks (78%) were positive for Hep- Par1, and none of the 33 MAs was immunoreactive. Although this sensitivity is lower than that reported for formalin-fixed tissue, HepPar1 was still the most sensitive marker for HCC. The lower sensitivity as compared with Chu s study may relate to the different fixatives used. Another study performed on formalinfixed FNAB cell blocks reported HepPar1 positivity in 100% of 50 HCC cases. 1 In Chu s study most Hep- Par1-negative HCCs were high grade. In the 4 Hep- Par1 negative HCCs we studied, 2 were poorly differentiated and 2 moderately differentiated. Thus, the lower sensitivity in our study is not entirely attributable to a greater proportion of poorly differentiated HCCs. None of the MAs in our study stained for HepPar1. However, the non-hccs that stained for HepPar1 in Chu s study included, in order of frequency, gastric, neuroendocrine, lung and ovarian carcinomas. 18 That our study included only 1 lung, 2 gastric and no neuroendocrine or ovarian carcinomas may explain why none of the MAs stained. Among the 4 HepPar1-negative HCCs in our study, 1 was positive for both AFP and pcea, 1 positive for pcea alone and 1 positive for CD10; the remaining 1 showed only cytoplasmic immunoreactivity for pcea. The combined immunohistochemical staining results of HepPar1, pcea and CD10 successfully recognized 94% (1 of 18) of HCC. MOC-31, a monoclonal antibody raised against a small cell carcinoma cell line, reacts with a 41-kd, membrane-based glycoprotein of unknown function. 39 Initially, MOC-31 was found to be useful for differentiating MA from mesothelioma, having very 260 ACTA CYTOLOGICA Volume 50 Number 3 May June 2006

5 Distinguishing HCC vs. Adenocarcinoma high sensitivity and specificity for MA. 39,40 Later, several studies showed it to be similarly useful for separating MA from HCC on formalin-fixed tissue. 13,15,16 Niemann et al, who studied MOC-31 expression in alcohol-fixed, paraffin-embedded liver FNAB cell blocks, found positive staining in 10 of 12 MAs (83%) and 2 of 16 HCCs (13%). 13 Our study supports these previous findings. Only 1 of 17 HCC cell blocks (6%) presented positive reactivity for MOC-31, and 1 of 32 MAs failed to show MOC-31 staining. The 1 MOC- 31 positive HCC showed characteristic cellular morphology and was also positive for HepPar1 and canalicular pcea. MOC-31 negative MA is a poorly differentiated carcinoma of unknown origin and was also negative for all other antibodies. Compared to mcea, MOC-31 had higher sensitivity but lower specificity for MA. Application of MOC-31 and mcea did not increase the sensitivity but improved the specificity in the diagnosis of MA. In summary, MOC-31, HepPar1, pcea, mcea and CD10 are useful markers for the differential diagnosis of HCC vs. MA on FNAB materials. HepPar1 is the most sensitive marker for HCC, followed by canalicular staining for pcea. MOC-31 is the most sensitive marker for MA, while mcea is the most specific one. We suggest using HepPar1, pcea, CD10, MOC-31 and mcea as a panel for distinguishing HCC from MA in liver FNABs. References 1. Siddiqui M, Saboorian M, Gokaslan S, Ashfaq R: Diagnostic utility of the HepPar1 antibody to differentiate hepatocellular carcinoma from metastatic carcinoma in fine needle aspiration samples. Cancer Cytopathology 2001;30: Bedrossian CW, Davila RM, Merenda G: Immunocytochemical evaluation of liver fine-needle aspirations. Arch Pathol Lab Med 1989;113: Lin F, Meschter S: Diagnostic utility of CD10 in differentiating hepatocellular carcinoma from metastatic carcinoma in fine needle aspiration biopsy (FNAB) of the liver. 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6 Wang et al Cancer 1988;62: Wu PC, Fang JW, Lau VK, Lai CL, Lo CK, Lau JY: Classification of hepatocellular carcinoma according to hepatocellular and biliary differentiation markers: Clinical and biological implications. Am J Pathol 1996;149: Hayashi Y, Takanashi Y, Ohsawa H, Ishii H, Nakatani Y: Hepatoid adenocarcinoma in the lung. Lung Cancer 2002;38: Kishimoto T, Nagai Y, Kato K, Ozaki D, Ishikura H: Hepatoid adenocarcinoma: A new clinicopathological entity and the hypotheses on carcinogenesis. Med Electron Microsc 2000;33: Foschini MP, Macchia S, Baccarini P, Milandri GL, Losi L, Spongano P, Panarelli M, Dal Monte PR, Eusebi V: Albumin mrna and pcea in the histopathologic diagnosis of hepatocellular carcinoma. Pathologica 1999;91: Tsutsumi Y, Onoda N, Misawa M, Kuroki M, Matsuoka Y: Immunohistochemical demonstration of nonspecific cross-reacting antigen in normal and neoplastic human tissues using a monoclonal antibody: Comparison with carcinoembryonic antigen localization. Acta Pathol Jpn 1990;40: Wee A, Nilsson B: pcea canalicular immunostaining in fine needle aspiration biopsy diagnosis of hepatocellular carcinoma. Acta Cytol 1997;41: Rishi M, Kovatich A, Ehya H: Utility of polyclonal and monoclonal antibodies against carcinoembryonic antigen in hepatic fine-needle aspirates. Diagn Cytopathol 1994;11:358 61; discussion Kim JC, Gong G, Roh SA, Park KC: Carcinoembryonic antigen gene and carcinoembryonic antigen expression in the liver metastasis of colorectal carcinoma. Mol Cells 1999;9: Chu PG, Aber DA: Paraffin-section detection of CD10 in 505 nonhematopoietic neoplasms: Frequent expression in renal cell carcinoma and endometrial stromal sarcoma. Am J Clin Pathol 2000;113: Guiot MC, Sawka R, Meakins JL, Jothy S: Immunohistologic diagnosis of multiple carcinomas: The role of monoclonal antibodies against carcinoembryonic antigen. Can J Surg 1989;32: Sheahan K, O Brien MJ, Burke B, Dervan PA, O Keane JC, Gottlieb LS, Zamcheck N: Differential reactivities of carcinoembryonic antigen (CEA) and CEA-related monoclonal and polyclonal antibodies in common epithelial malignancies. Am J Clin Pathol 1990;94: Jantscheff P, Bottger V, Price M, Micheel B, Kaiser G, Zotter S, Kotzsch M, Grossmann H, Karsten U: Production and characterization of monoclonal antibodies against carcinoembryonic antigen (CEA). Biomed Biochim Acta 1991;50: Nitzan DW, Livni N, Marmary Y, Ben-Baruch N, Sela J, Catane R: The use of monoclonal anti-cea antibody immunohistochemistry in detecting the origin of oral cavity metastasis. Int J Oral Maxillofac Surg 1990;19: Wennerberg A, Ma N, Coleman W: Hepatocyte paraffin 1: A monoclonal antibody that reacts with hepatocytes and can be used for differential diagnosis of hepatic tumors. Am J Pathol 1993;143: Sosolik R, McGaughy VR, De Young BR. Anti-MOC-31: A potential addition to the pulmonary adenocarcinoma versus mesothelioma immunohistochemistry panel. Mod Pathol 1997; 10: Morgan RL, De Young BR, McGaughy VR, Niemann TH: MOC-31 aids in the differentiation between adenocarcinoma and reactive mesothelial cells. Cancer 1999;87: ACTA CYTOLOGICA Volume 50 Number 3 May June 2006