Utility of Immunohistochemistry in the Pancreatobiliary Tract · Utility of Immunohistochemistry in...

Utility of Immunohistochemistryin the Pancreatobiliary Tract

Fan Lin, MD, PhD; Zongming Eric Chen, MD, PhD; Hanlin L. Wang, MD, PhD

� Context.—Immunohistochemistry has become a usefulancillary study in the identification and classification ofpancreatic neoplasms. The diagnostic accuracy has beensignificantly improved because of the continuous discov-eries of tumor-associated biomarkers and the developmentof effective immunohistochemical panels.

Objectives.—To identify and classify pancreatic neo-plasms by immunohistochemistry.

Data Sources.—Literature review and authors’ researchdata and personal practice experience were used.

Conclusions.—To better guide therapeutic decisions andpredict the prognostic outcome, it is crucial to make anaccurate diagnosis of a pancreatic neoplasm. Application

of appropriate immunohistochemical panels enables pa-thologists to differentiate pancreaticobiliary adenocarci-nomas from reactive conditions and to identify rare typesof pancreatic neoplasms. Knowing the utilities and pitfallsof each tumor-associated biomarker is essential to avoidinga potential diagnostic error because an absolutely cancer-specific biomarker does not exist. This article reviewsfrequently used tumor-associated biomarkers, provideslists of effective immunohistochemical panels, and recom-mends a diagnostic algorithm as a standard approach topancreatic neoplasms.

(Arch Pathol Lab Med. 2015;139:24–38; doi: 10.5858/arpa.2014-0072-RA)

Pancreatic epithelial neoplasms can be simply classifiedinto solid and cystic neoplasms based on their gross

appearances, as illustrated in Figure 1. Pancreatic ductaladenocarcinoma (DADC) and its variants, such as colloidcarcinoma and medullary carcinoma, account for approxi-mately 85% of neoplasms, followed by intraductal papillarymucinous neoplasms (IPMNs) at 3% to 5%, and pancreaticneuroendocrine tumors (P-NETs) at 3% to 4%.1,2 Mucinouscystic neoplasm (MCNs), acinar cell carcinomas (ACCs),solid pseudopapillary tumors (SPT), and serous cystadeno-mas (SCA) are uncommon neoplasms of the pancreas.1,2

Accurate diagnosis for each entity is crucial for makingtherapeutic decisions and predicting a prognostic outcome.Numerous immunohistochemical (IHC) markers to improvediagnostic accuracy have been described in the literature.1–49

The selected immunomarkers for differentiating theseneoplasms are summarized in Table 1. The applicationsand pitfalls of important markers will be reviewed through-out this article.

PANCREATIC DADC AND ITS VARIANTS

Distinguishing pancreatic DADC from nonneoplasticpancreatic tissues/diseases, including chronic pancreatitis

and autoimmune pancreatitis, can be challenging, especiallyin small biopsies and fine-needle aspiration biopsy (FNAB)specimens. Numerous immunomarkers have been reportedto be useful in solving that problem. Those markers includevon Hippel-Lindau tumor suppressor (pVHL), placentalS100 (S100P), mammary serine protease inhibitor (maspin),insulin-like growth factor II messenger RNA bindingprotein-3 (IMP3), mesothelin, prostate stem cell antigen(PSCA), annexin A8, fascin, claudin 4, claudin 18, p53,SMAD family member 4 (DPC4/SMAD4), carcinoem-bryonic antigen (CEA), cytokeratin (CK) 17, CK19, mucin(MUC) 1, MUC2, MUC5AC, cancer antigen 19-9 (CA19-9),and EPCAM.1–49 More recently, 3 additional biomarkers(annexin A10, plectin 1, and aldo-keto reductase family 1,member B10 [AKR1B10]) have been reported as usefulmarkers to differentiate pancreatic DADCs from benign/reactive pancreatic ducts.50–52 Specifically, annexin A10, acalcium and phospholipid-binding protein expressed innormal gastric mucosa, was found to be positive in 78% (57of 73) of primary pancreatic DADCs and 83% (19 of 23) ofmetastatic pancreatic DADCs, 46% (154 of 337) of primarygastric ADCs and 47% (36 of 77) of metastatic gastricadenocarcinomas (ADCs), and only 2% of metastatic ADCsfrom other organs.50 Plectin 1 was reported to be positive in100% of primary and metastatic pancreatic DADCs and60% of pancreatic intraepithelial neoplasia (PanIN) 3 cases,but it was negative in all chronic pancreatitis and normalpancreatic tissues.51 AKR1B10 was found to be expressed in70% (35 of 50) of pancreatic DADCs and most PanINs.52 Wedo not have experience with these 3 newly describedimmunomarkers. Additional studies are needed to furthervalidate the clinical utilities of those 3 markers.

In our previous study,48 we investigated the utility of 26IHC markers (CAM 5.2, CK7, CK20, CK17, CK19, MUC1,

Accepted for publication March 25, 2014.From the Department of Laboratory Medicine, Geisinger Medical

Center, Danville, Pennsylvania (Drs Lin and Chen); and theDepartment of Pathology, University of California, Los Angeles (DrWang).

The authors have no relevant financial interest in the products orcompanies described in this article.

Reprints: Fan Lin, MD, PhD, Department of Laboratory Medicine,MC 01-31, Geisinger Medical Center, 100 N Academy Ave,Danville, PA 17822 (e-mail: [email protected]).

24 Arch Pathol Lab Med—Vol 139, January 2015 Immunohistochemistry in the Pancreatobiliary Tract—Lin et al

MUC2, MUC4, MUC5AC, MUC6, p53, DPC4/SMAD4,caudal type homeobox 2 [CDX2], pVHL, S100P, IMP3,maspin, mesothelin, claudin 4, claudin 18, annexin A8,fascin, PSCA, EPCAM, CEA, and CA19-9) in 60 cases ofpancreatic DADC on tissue microarray and routine tissuesections. We also performed immunohistochemical stains

for maspin, S100P, IMP3, and pVHL on cell blocks of 67pancreatic FNAB specimens, including 44 cases of pancre-atic DADC and 27 benign/reactive cases. The resultsdemonstrated that (1) more than 90% of pancreatic DADCswere positive for maspin, S100P, and IMP3; (2) nearly allpancreatic DADCs were negative for pVHL, whereas

Figure 1. Summary of the immunohistochemical profile for each pancreatic neoplasm. Abbreviations: ACC, acinar cell carcinoma; ADC,adenocarcinoma; BCL, B cell/CLL lymphoma; CA, carcinoma; CD, cluster of differentiation; CDX2, caudal type homeobox 2; CK, cytokeratin; CLL,chronic lymphocytic leukemia; DPC4, SMAD family member 4; ER, estrogen receptor; IMP3, insulin-like growth factor II messenger RNA bindingprotein-3; IPMN, intraductal papillary mucinous neoplasm; maspin, mammary serine protease inhibitor; MCN, mucinous cystic neoplasm; MSI,microsatellite instability; MUC, mucin; N, nuclear; NSE, neuron-specific enolase; PAX8, paired box 8; PB, pancreatoblastoma; PDX1, pancreatic andduodenal homeobox 1; P-NET, pancreatic neuroendocrine tumor; pVHL, von Hippel-Lindau tumor suppressor; PR, progesterone receptor; S100P,placental S100; SCA, serous cystadenoma; SPT, solid pseudopapillary tumor.

Arch Pathol Lab Med—Vol 139, January 2015 Immunohistochemistry in the Pancreatobiliary Tract—Lin et al 25

nonneoplastic ducts and acini were positive for pVHL in allcases; (3) normal/reactive pancreatic ducts were frequentlypositive for CK7, CK19, MUC1, MUC6, CA19-9, EPCAM,PSCA, mesothelin, annexin A8, claudin 4, and claudin 18;(4) normal pancreatic ducts were usually negative for IMP3,maspin, S100P, CK17, MUC2, MUC4, and MUC5AC; (5)60% of pancreatic DADCs were negative for DPC4/SMAD4,and 50% of cases were strongly positive for p53; (6) loss ofpVHL expression and S100P overexpression were observedin all PanINs, regardless of grade; and (7) strong back-ground staining was frequently seen with fascin, PSCA, andannexin A8.48 Markers like tumor-associated glycoprotein72 (TAG 72/B72.3), EPCAM, and epithelial cell adhesionmolecule (Ber-EP4) were usually positive in pancreaticDADCs, but they were frequently positive or weakly positivein normal or reactive ducts as well. In contrast, monoclonalCEA (mCEA) was strongly positive in most pancreaticDADCs, and the adjacent stroma also showed positivitybecause of the leaking of mCEA into the adjacent tissue.Normal/reactive ducts tended to be negative or only weaklypositive for mCEA.48

Based on that study and review of the literature,48 weconcluded that pVHL, maspin, S100P, IMP3, CK17,MUC5AC, and DPC4/SMAD4 were the best diagnosticpanel of immunomarkers for confirming the diagnosis ofpancreatic DADCs in both surgical and FNAB specimens. Inan autoimmune pancreatitis, the infiltrating plasma cellswere predominately positive for immunoglobulin G4(IgG4). An immunostain for IgG4 may be helpful indiagnosing a difficult case.53–55 The presence of abundantIgG4-positive plasma cells does not, however, preclude thediagnosis of pancreatic DADC because, in a small subset ofpancreatic DADC cases, the cancer-adjacent tissue mayshow features of autoimmune pancreatitis. The usefulimmunomarkers for the distinction between a pancreaticDADC and reactive ducts are summarized in Table 2.Additional discussion of pVHL, S100P, maspin, IMP3,MUC5AC, and CK17 will follow in the section below. Anexample of pancreatic DADC showing expression of pVHL,maspin, pVHL/maspin double stain, S100P, IMP3, MU-

C5AC, and DPC4/SMAD4 is illustrated in Figure 2, Athrough H.

VHL (von Hippel-Lindau) is a tumor suppressor gene.Inactivation of the VHL gene on band 3p25-26 bymutation, deletion, or hypermethylation is a frequentevent in both hereditary and sporadic clear cell renal cellcarcinomas (RCCs).56,57 Genetic alteration of the VHL geneappears to be a crucial step in the initiation andprogression of clear cell RCC. Our previous studydemonstrated pVHL was expressed in most renal cellneoplasms, including clear cell RCCs, papillary RCCs,chromophobe RCCs, and oncocytomas47 and in more than90% of metastatic RCCs. In addition, 90% of clear cellcarcinomas of the ovary and uterus were positive forpVHL.47 In contrast, many tumors from various organs,including carcinomas of the lung, pancreas, gastrointesti-nal tract, adrenal gland, prostate, and bladder, were

Table 1. Summary of Useful Markers in Selected Pancreatic Epithelial Neoplasms

Antibodies DADC ACC P-NET SPT PB

CK7 þ � or þ þ or � � þ or �CK19 þ � or þ � or þ � þ or �Mesothelin þ � � � þ or �S100P þ � � � þ or �Maspin þ � � � þ or �Glypican 3 � þ or � � � NDb-catenin M M or N M N and M N and C, or MþE-cadherin þ þ þ � � or þChromogranin � � þ � � or þCD10 � � þ þ � or þIMP3 þ � þ or � � � or þTrypsin � þ � � þ

Abbreviations: þ, usually more than 75% of cases are positive; �, less than 5% of cases are positive; þ or �, usually more than 50% of cases arepositive;� orþ, less than 50% of cases are positive; ACC, acinar cell carcinoma; C, cytoplasmic staining; CD10, cluster of differentiation 10; CK,cytokeratin; DADC, ductal adenocarcinoma; IMP3, insulin-like growth factor II messenger RNA binding protein-3; M, membranous staining;maspin, mammary serine protease inhibitor; N, nuclear staining; ND, no data; PB, pancreatoblastoma; P-NET, pancreatic neuroendocrine tumor;S100P, placental S100; SPT, solid pseudopapillary tumor. Antibody order based on the application of the group of antibodies to a specific entity.

Table 2. Pancreatic Ductal Adenocarcinoma(DADC) Versus Chronic Pancreatitis

AntibodiesPancreatic

DADC Pancreatitis

pVHL � þMaspin þ �S100P þ � or C þ onlyIMP3 þ �CK17 þ or � Usually �MUC5AC þ or � �p53 þ or � � or very weakly þmCEA þ Usually � or focally þDPC4/SMAD4 Loss (60%) þMesothelin þ � or weakly þ

Abbreviations: þ, usually more than 75% of cases are positive; �, lessthan 5% of cases are positive;þ or�, usually more than 50% of casesare positive;� orþ, less than 50% of cases are positive; C, cytoplasmicstaining; CK17, cytokeratin 17; DPC4, SMAD family member 4; IMP3,insulin-like growth factor II messenger RNA binding protein-3; mCEA,monoclonal carcinoembryonic antigen; MUC5AC, mucin 5AC; pVHL,von Hippel-Lindau tumor suppressor; maspin, mammary serineprotease inhibitor; S100P, placental S100. Antibody order based onthe application of the group of antibodies to a specific entity.

�Figure 2. A through H, A representative case of pancreatic ductal adenocarcinoma on hematoxylin-eosin–stained section (A), and loss of expressionof von Hippel-Lindau tumor suppressor (pVHL) (B), positive for mammary serine protease inhibitor (maspin) (C), positive for maspin and negativefor pVHL (double staining, brown-maspin and red-pVHL; D), positive for placental S100 (E), insulin-like growth factor II messenger RNA bindingprotein-3 (F), mucin 5AC (G), and loss of SMAD family member 4 (H) (original magnifications3200 [A, D, and E],3400 [B and C and F through H]).


negative for pVHL.47 Interestingly, normal/reactive pan-creatic ducts and acinar cells were positive for pVHL.Expression of pVHL has been also tested in ADCs of thegallbladder, extrahepatic bile ducts and intrahepatic bileducts.58–61 The results demonstrated (1) only 6% ofgallbladder ADCs were positive for pVHL,60 (2) 7.5% ofextrahepatic bile duct ADCs were positive for pVHL,58 and(3) in contrast, 71% of intrahepatic cholangiocarcinomas(ICCs) were positive for pVHL.61 Therefore, pVHL mayhave a role in the distinction of pancreatic DADC,gallbladder adenocarcinoma (ADC), and extrahepaticADC from ICC.

S100P belongs to the family of S100 calcium bindingproteins. It is a 95 amino acid protein first purified from thehuman placenta. The level of S100P expression has beenfound to increase during the progression from PanIN toinvasive ADC.42–44,46 Expression of S100P has been reportedin more than 90% of pancreatic DADCs, gallbladder ADCs,and extrahepatic ADCs.46,48,58–60 In contrast, only 27%% ofICCs were positive for S100P.61 Similar observations havealso been reported by Aishima et al,62 who found positivenuclear S100P staining in 8 of 69 (12%) of the peripheral-type ICCs, in contrast to 28 of 41 (68%) of the perihilarcholangiocarcinomas. Tsai et al63 reported a higher frequen-cy of S100P expression in peripheral ICCs (53%), but inmost of their positive cases, the staining was heterogeneouswith mixed nuclear, cytoplasmic and extracellular patterns.It is unclear how many of those cases showed nuclear S100Pexpression. In addition, one-half of their positive casesexhibited only focal staining.63 Overexpression of S100P wasalso frequently observed in IPMNs and MCNs but not inACCs, P-NETs, and SCAs.64,65 Reactive ducts may showcytoplasmic staining for S100P. As a rule, only nuclearpositivity or both nuclear and cytoplasmic positivity wasregarded as positive staining for S100P.

Maspin, also known as serpin B5, is a tumor suppressorgene expressed in some human epithelial cells. Maspinoverexpression can be seen in carcinomas from variousorgans including most ADCs of the pancreas and gallblad-der and in ICCs;* however, maspin overexpression was alsoreported in nontumorous gallbladder epithelium in patientswith cholelithiasis and intestinal metaplasia.66,67 Therefore,maspin alone cannot be used as a reliable diagnostic markerto differentiate benign from malignant gallbladder glandularlesions. Normal and reactive pancreatic ducts are usuallynegative for maspin.48

IMP3 is an oncofetal RNA-binding protein, also known asK homology domain containing protein overexpressed incancer, IGF2BP3, and L523S. Immunohistochemical expres-sion of IMP3 has been reported in various cancers, includingADCs of the pancreas, endocervix, and neuroendocrinecarcinomas of the lung.20–23,48,58–60 Expression of IMP3 wasdemonstrated in 37 of 38 (97%),20 99 of 112 (88.4%),22 and54 of 60 (90%) of the ADCs of the pancreas.48 Similarfindings of IMP3 expression in FNABs of the pancreas werereported.23 Expression of IMP3 was reported in 81%, 64%,and 90% of ADCs of the gallbladder, extrahepatic bile ducts,and intrahepatic bile ducts, respectively.58–61

MUC5AC is a high–molecular-weight glycoprotein of themucin family, which has been shown to serve an importantrole in pancreatic tumorigenesis.68,69 Overexpression ofMUC5AC has been reported in 60% to 100% of pancreatic

DADCs in several studies.10,48,70,71 Similarly, a high frequen-cy of MUC5AC expression has been reported in cholangio-carcinoma10,72–75 and in gallbladder ADC.60,72,76 In thestudies in which ICCs and extrahepatic cholangiocarcino-mas were separately evaluated, it was apparent thatextrahepatic cholangiocarcinomas more frequently ex-pressed MUC5AC than ICCs.70,72 Another interestingobservation was that peripheral-type ICCs showed MU-C5AC expression less commonly than hilar cholangiocarci-nomas. In the study by Guedj et al,77 32 of 52 hilarcholangiocarcinomas (62%) showed positivity for MUC5AC,in contrast to 13 of 59 (22%) peripheral ICCs. Similarly,Aishima et al78 reported positive MUC5AC staining in 69%to 72% of hilar tumors but only 25% to 27% of peripheralICCs (2 different anti-MUC5AC antibodies were used inthat study). The study from our group showed a similarfinding of a higher frequency of MUC5AC expression inpancreatic DADCs (67%) than in ICCs (12%).61

CK17 is a low–molecular-weight keratin that is normallyexpressed in myoepithelial and basal cells and subsets ofhair shaft epithelia.10 A few studies have demonstrated it tobe of value in the distinction between pancreaticobiliary andnonpancreaticobiliary ADCs.7,10,79,80 Our data showed CK17expression in 60% of pancreatic DADCs but only 12% ofICCs.48,61 Our findings of CK17 expression in ICCs seem tobe different from those reported by Chu et al,10 whodetected CK17 expression in 17 of 24 ICCs (71%). However,it is unclear whether hilar or perihilar cholangiocarcinomaswere included in that study. To support our findings, Sarbiaet al79 showed positive CK17 staining in 10 of 17 ADCs(59%) of the extrahepatic bile ducts, a frequency similar toours.48,61

Two variants of pancreatic DADC should be mentionedhere. One is colloid carcinoma, and the other is medullarycarcinoma. Colloid carcinoma is usually positive for CDX2and MUC2, but negative for MUC1, which is the oppositeto the IHC profile of a conventional pancreaticDADC.1,2,81 Identification of colloid carcinoma is impor-tant because it carries a much better prognosis than doesa conventional pancreatic DADC. Medullary carcinoma ofthe pancreas is rare and frequently demonstrates loss ofDNA mismatch repair proteins, especially MutL homolog1 (MLH1) and postmeiotic segregation increased 2(PMS2).1,2,82–84 Our unpublished data demonstrated thatboth colloid carcinoma and medullary carcinoma show asimilar IHC profile for the expression of pVHL, S100P,maspin, and IMP3 when compared with pancreaticDADCs.

DIFFERENTIAL DIAGNOSIS OF P-NET, ACC, SPT,AND PANCREATOBLASTOMA

In addition to the distinction between pancreatic DADCsand chronic pancreatitis/reactive ducts, another frequentlyencountered diagnostic problem is to differentiate P-NETfrom its mimics, such as ACC, SPT and rarely pancreato-blastoma (PB). The frequently used immunomarkers inmaking that differential diagnosis are summarized in Table3. The applications and pitfalls for some of the markers arediscussed in detail below.

Acinar Cell Carcinoma

Acinar cell carcinoma of the pancreas is a very rare,nonductal carcinoma, which accounts for about 1% ofpancreatic neoplasms in adults and approximately 15% in* References 24, 25, 44, 48, 60, 61, 66, 67.


pediatric patients.1,2 The differential diagnosis from pancre-atic DADC is relatively straightforward based on itsmorphologic features and the IHC profile. The diagnosticchallenge is to differentiate ACC from a neuroendocrineneoplasm and an SPT. Perhaps the most difficult diagnosticproblem is how to distinguish ACC from PB; sometimes, itis nearly impossible because of the significant overlapping ofboth morphologic and IHC features, especially in a small-core biopsy or an FNAB specimen. The classic IHC profile ofan ACC is outlined in Table 4.

Our experience and that of others showed CK7 isfrequently negative or only focally positive in ACCs, whichprovides a useful clue for differentiating an ACC from apancreatic DADC, which is nearly always diffusely positivefor CK7. A histochemical stain of periodic acid–Schiffdiastase is usually positive in ACC. Trypsin is usuallypositive but may give strong background staining. Up to25% of ACCs may show both nuclear and cytoplasmicpositivity for b-catenin,85,86 which can create a problem inthe distinction of an ACC from an SPT or a PB.Chromogranin was usually negative or showed onlyscattered positivity in endocrine cells. When more than25% of tumor cells are positive for endocrine markers, thetumor is regarded as a mixed acinar and endocrinecarcinoma. Based on our experience, other markers,including mesothelin, pVHL, S100P, and maspin, areusually negative in ACCs.

Several recently described immunomarkers have beenreported to be useful in confirming a diagnosis of ACC. Theantibody against COOH-terminal BCL10 was shown to bepositive in normal acinar cells and in 82% (14 of 17) of ACCsby Hosoda et al87 and 85% (40 of 47) of ACCs by La Rosa etal.88 BCL10 expression was not seen in P-NETs, pancreaticDADCs, SPTs, SCAs, MCNs, or IPMNs.87 Two of 4adenosquamous carcinomas (50%) were positive forBCL10.87 Glypican-3, an established immunomarker forhepatocellular carcinoma and yolk sac tumor, was positivein 58% (7 of 12) of ACCs but negative in pancreatic DADCsand P-NETs.89 Carboxyl ester lipase has been found to beanother sensitive marker positive in 91% (29 of 32) ofACCs.88

Pancreatic Neuroendocrine Tumor

Pancreatic neuroendocrine tumors are uncommon, ac-counting for approximately 3% of all pancreatic neo-plasms.1,2 Diagnosis of P-NET can be challenging becauseof the limited experience a pathologist may have with it andthe variety of morphologic variants, including spindle cell,oncocytic cell, rhabdoid cell, pleomorphic cell, lipid-rich,

and clear cell. The current World Health Organizationclassification of P-NETs was based on counting mitoses ormindbomb homolog 1 (MIB1/Ki-67) proliferative index.1

Pancreatic neuroendocrine tumors are divided into (1) P-NET grade 1 (0–1 mitosis/10 high-power fields or ,2%MIB1 index), (2) P-NET grade 2 (2–20 mitoses/10 high-power fields or 3%–20% MIB1 index), and (3) pancreaticneuroendocrine carcinoma (large cell neuroendocrine car-cinoma or small cell carcinoma; .20 mitoses/10 high-powerfields or .20% MIB1 index). Neuroendocrine features canbe confirmed by immunoreactivity to synaptophysin,chromogranin, and CD56. Our experience and that ofothers showed nearly 100% of P-NETs were positive forboth synaptophysin and chromogranin. In contrast, ourexperience showed CD56 was expressed in only 44% (7 of16) of P-NETs. Pancreatic neuroendocrine tumors werefrequently negative for both CK7 and CK20. Otherinvestigators90 have reported approximately 10% of P-NETswere positive for CK7 or CK20. CK19 positivity in P-NETsmay be associated with a more-aggressive clinical behav-ior.91,92

Several relatively P-NET-specific immunomarkers havebeen reported, including progesterone receptor (PR), pairedbox gene 8 (PAX8), pancreatic and duodenal homeobox 1(PDX1) and islet-1.90,93–100 Progesterone receptor has beenreported in 55% to 58.5% of P-NETs,93 which was similar toour finding of PR immunoreactivity in 56% (9 of 16) of P-NETs. Progesterone receptor immunoreactivity showed asignificant correlation with the absence of metastasis and

Table 4. Immunomarkers for Acinar Cell Carcinoma

Antibodies Literature

Trypsin þBCL10 þCarboxyl ester lipase þGlypican-3 þ or �b-catenin M or rarely N þ CpVHL �Mesothelin �S100P �CK7 � or focal þChromogranin � or rare cell positiveVimentin þ or �

Abbreviations: þ, usually more than 75% of cases are positive; �, lessthan 5% of cases are positive;þ or�, usually more than 50% of casesare positive;� orþ, less than 50% of cases are positive; BCL10, B cellCLL/lymphoma 10; C, cytoplasmic staining; CK7, cytokeratin 7; CLL,chronic lymphocytic leukemia; M, membranous staining; N, nuclearstaining; pVHL, von Hippel-Lindau tumor suppressor; S100P, placentalS100. Antibody order based on the application of the group ofantibodies to a specific entity.

Table 3. Summary of Useful Markers for Acinar Cell Carcinoma (ACC), Pancreatic Neuroendocrine Tumor (P-NET),Solid Pseudopapillary Tumor (SPT), and Pancreatoblastoma (PB)

Antibodies ACC P-NET SPT PB

b-catenin M or rarely N þ C M N þ C N þ C or MþE-cadherin þ þ � � or þChromogranin � þ � � or þCD10 � þ þ � or þTrypsin þ � � þGlypican 3 þ or � � � NDBCL10 þ � � ND

Abbreviations: þ, usually more than 75% of cases are positive; �, less than 5% of cases are positive; þ or �, usually more than 50% of cases arepositive;� orþ, less than 50% of cases are positive; BCL10, B cell CLL/lymphoma 10; C, cytoplasmic staining; CD10, cluster of differentiation 10;CLL, chronic lymphocytic leukemia; M, membranous staining; N, nuclear staining; ND, no data. Antibody order based on the application of thegroup of antibodies to a specific entity.


lack of invasion into the adjacent organs and largevessels.93,94 Progesterone receptor expression in otherneuroendocrine tumors (NETs) was very rare, with theexception of rare cases reported in lung carcinoid andduodenal NETs.93,94 Estrogen receptor expression in P-NETswas generally absent.

PAX8 is a member of the paired box (PAX) family oftranscription factors involved in the development of thyroidfollicular cells and the expression of thyroid-specific genesand, together with PAX2, is involved in the regulation of theorganogenesis of the kidney and the Mullerian system.PAX8 has been demonstrated to be a highly sensitive andrelatively specific marker for thyroid follicular cell tumors,RCCs, ovarian carcinomas, endometrial ADCs, and thymictumors. Immunoreactivity to PAX8 was seen in 50% to 74%of P-NETs.95–97 One study95 showed PAX8 expression wasseen in a significant percentage of duodenal and rectal NETsand 27% of SPTs of the pancreas. The immunoreactivity toPAX8 has been proven a consistent staining artifact by thecross-reaction between the anti-PAX8 antibody and PAX6antigen.98

The human insulin gene enhancer-binding protein islet-1is a transcription factor involved in the differentiation ofpancreatic endocrine cells. Graham et al99 showed islet-1

expression in 90% of P-NETs, 89% of duodenal NETs, 100%of rectal NETS, 38% of colonic NETs, and a small percentageof NETs from other organs. Koo and coworkers100 reportedthat islet-1 was positive in 27 of 33 (82%) and in 19 of 28(68%) of primary and metastatic P-NETs, respectively.Additionally, Agaimy et al101 demonstrated that islet-1expression was seen in nearly all extrapancreatic, poorlydifferentiated neuroendocrine carcinomas, such as pulmo-nary small cell carcinoma, Merkel cell carcinoma, medullarythyroid carcinoma, and adrenal neuroblastoma, whereaspancreatic poorly differentiated neuroendocrine carcinomasusually lacked islet-1 expression. These findings argueagainst the diagnostic value of using islet-1 to identify apancreatic origin when dealing with a poorly differentiatedneuroendocrine carcinoma.

PDX1 is a Hox-type transcription factor that regulatesboth exocrine and endocrine pancreatic differentiation andmaintains b-cell function. Chan et al90 reported expressionof PDX1 in 72% (18 of 25) of P-NETs, 10% (3 of 29) ofpulmonary NETs, and 4% (1 of 26) of gastrointestinal NETs.The expression of PDX1 was also seen in 5 of 5 metastatic P-NETs (100%) in the liver and 2 of 2 metastatic duodenalNETs (100%) in the liver.90 They suggested PDX1 was ahighly sensitive and specific marker for P-NETs.90 Another

Figure 3. A through D, A pancreatic neuroendocrine neoplasm on hematoxylin-eosin–stained section (A), and positive for progesterone receptor(B), paired box gene 8 (C), and islet-1 (D) (original magnification 3400 [A through D]).


study demonstrated that PDX1 expression was frequentlyassociated with the type of hormone secreted by a NET,regardless of whether it was of pancreatic or duodenalorigin.102 Most insulin- and gastrin-secreted NETs werepositive for PDX1, whereas glucagon-, somatostatin-, orserotonin-positive NETs usually lacked PDX1 expression.102

Based on those data, PDX1 appears to be a specific markerfor identifying insulin-positive or gastrin-positive NETs thatoriginate from either the pancreas or duodenum.

An example of a pancreatic neuroendocrine neoplasmwith positive staining for PR, PAX8, and islet-1 is shown inFigure 3, A through D. The useful immunomarkers for P-NETs, including Geisinger Medical Center (Danville, Penn-sylvania) data, are summarized in Table 5. A panel ofimmunomarkers that includes CK7, CK20, thyroid tran-scription factor 1 (TTF1), CDX2, cadherin-17 (CDH17),special AT-rich sequence-binding protein 2 (SATB2), PR,PDX1, and PAX8 is useful in differentiating a P-NET from aNET of other organs, which was described in theImmunohistochemistry in Undifferentiated Neoplasm/Tumor ofUncertain Origin article by Lin and Liu.126

Solid Pseudopapillary Tumor of the Pancreas

Solid pseudopapillary tumor is rare and only accounts for1% to 2% of pancreatic exocrine neoplasms and 5% of cysticneoplasms.1,2 It is defined as a low-grade malignant neoplasmthat occurs predominately in adolescent girls or youngwomen. Numerous immunomarkers for SPT have beenreported in the literature, as listed in Table 6.103–110 b-catenin,E-cadherin, CD10, vimentin, and chromogranin are the mosteffective IHC panel for confirming the diagnosis of SPT.103–110

More than 90% of SPTs showed both nuclear and cytoplasmicstaining for b-catenin and loss of E-cadherin expression.104,105

Chromogranin was consistently negative in SPT, which was auseful feature in differentiating it from a P-NET. Both CD10and vimentin were positive in nearly all reported SPTs.

Approximately 50% of SPTs expressed CD117 (c-Kit);however, CD117 expression was not associated withunderlying mutations of the KIT gene.111 A representativeSPT case is shown in Figure 4, A through F.

Pancreatoblastoma

Pancreatoblastoma is a very rare pancreatic neoplasm inadults, accounting for less than 1% of all pancreatictumors. However, it is the most common neoplasm inchildhood, accounting for about 25% of all pancreaticneoplasms seen before age 10 years.1,112 Most PBs consistof both acinar and squamous components; some may alsocontain endocrine and ductal components.1,112 The immu-nostaining results are largely dependent on the compo-nents in the tumor. Nuclear staining of b-catenin has beenreported in a significant percentage of cases, which issimilar to the findings in SPTs and ACCs.85,113 The‘‘squamous component’’ usually lacks the typical squa-mous immunophenotype, that is, being positive for CK5/6,CK14, and CK17. Instead, that component is usuallypositive for epithelial membrane antigen, CK8, CK18,and CK19 but negative for CK7. Loss of DPC4 expressionhas been reported in up to 22% of cases, and p53expression was usually not seen.85 a-Fetoprotein may bepositive in some cases, which is in keeping with theprimitive nature of this neoplasm. The useful immuno-markers for PB are summarized in Table 7.

SEROUS CYSTADENOMA

Serous cystadenoma is an uncommon neoplasm of thepancreas, accounting for 1% to 2% of all pancreaticneoplasms.1,2 It more often occurs in a middle-aged orolder woman in the body or tail of the pancreas.1,2 Amalignant counterpart, serous cystadenocarcinoma, hasbeen reported, which has a similar IHC profile as a benign

Table 5. Markers for Pancreatic NeuroendocrineTumora

Antibodies Literature GML Data, No. (%)

Synaptophysin, n ¼ 16 þ 16 (100)Chromogranin, n ¼ 16 þ 16 (100)CD56, n ¼ 16 þ 7 (44)PR, n ¼ 16 þ or � 9 (56)PAX8, n ¼ 32 þ or � 15 (47)PDX1 þ NDIslet-1 þ NDb-catenin, n ¼ 16 � 0 (0)CAM 5.2, n ¼ 16 þ 16 (100)CK7, n ¼ 16 � or þ 0 (0)CK20, n ¼ 16 � 1 (6)Vimentin, n ¼ 16 � 6 (38)CDX2, n ¼ 16 V 1 (6)Insulin, n ¼ 16 V 2 (12)CK19, n ¼ 16 þ or � 4 (25)

Abbreviations:þ, usually more than 75% of cases are positive;�, less than5% of cases are positive; þ or �, usually more than 50% of cases arepositive; � or þ, less than 50% of cases are positive; CD56, cluster ofdifferentiation 56; CDX2, caudal type homeobox 2; CK, cytokeratin; GML,Geisinger Medical Laboratories; ND, no data; PAX8, paired box gene 8;PDX1, pancreatic and duodenal homeobox 1; PR, progesterone receptor;V, variable. Antibody order based on the application of the group ofantibodies to a specific entity.a Reprinted from 3Lin F, Prichard JW, Liu H, Wilkerson M, Schuerch C, eds.

Handbook of Practical Immunohistochemistry: Frequently Asked Ques-tions. New York, NY: Springer; 2011, with permission from SpringerScienceþBusiness Media.

Table 6. Markers for Solid-PseudopapillaryNeoplasm of the Pancreas

Antibodies Literature

b-catenin N þ C positiveE-cadherin �Chromogranin �CD10 þVimentin þAE1/AE3 � or focally þCK7 � or focally þTrypsin �a-1 antitrypsin þCD56 þNSE þ or �Synaptophysin � or þClaudin 5 M þClaudin 7 � or focally C þProgesterone receptors (PR) þ or �PAX8 � or þEstrogen receptors (ER) �CD99 þ (C dot stain)Galectin 3 þCD117 (c-Kit) þ or �

Abbreviations: þ, usually more than 75% of cases are positive; �, lessthan 5% of cases are positive;þ or�, usually more than 50% of casesare positive;� orþ, less than 50% of cases are positive; C, cytoplasmicstaining; CD, cluster of differentiation; CK, cytokeratin; M, membra-nous staining; N, nuclear staining; NSE, neuron-specific enolase; PAX8,paired box gene 8. Antibody order based on the application of thegroup of antibodies to a specific entity.


SCA. Periodic acid–Schiff for glycogen is usually positive,and mucicarmine for mucin is usually negative. Both pVHLand MUC6 tend to show diffuse and strong cytoplasmicand membranous staining64; in contrast, in our experienceboth neuron-specific enolase (NSE) and inhibin-a more

frequently show focal and weak staining. The reports of theexpression of neuroendocrine markers, such as CD56,synaptophysin, and chromogranin A, were inconsis-tent.114,115 Our experience and studies by others showedthat SCA was usually negative for those 3 markers.

Figure 4. A through E, A representative case of solid-pseudopapillary tumor on hematoxylin-eosin–stained section (A), and positive for b-catenin(B), cluster of differentiation 10 (C), vimentin (D), progesterone receptor (E), and loss of E-cadherin expression (F) (original magnification 3400 [Athrough E]).


However, a recent study115 of 12 cases of SCA demon-strated that CD56, synaptophysin, and chromogranin Awere expressed in 75%, 92%, and 0% of the cases,respectively. Those data suggested that only chromograninA was a useful marker in distinguishing SCA from P-NET.Many cases may be positive for EPCAM and CA19-9,which are also positive in a high percentage of pancreaticmucin–producing neoplasms and DADCs. The usefulimmunomarkers from the literature and from our dataare summarized in Table 8. An example of a solid variant ofSCA with diffuse and strong positivity for pVHL, MUC6,and inhibin-a is shown in Figure 5, A through D.

MUCINOUS CYSTIC NEOPLASM

Mucinous cystic neoplasms of the pancreas are rela-tively uncommon neoplasms, accounting for approxi-mately 8% of surgically resected pancreatic cysticlesions.1,2 They occur almost exclusively in women, witha female to male ratio of 20:1.1,2 Mucinous cysticneoplasms consist of 2 components, an epithelial lining,and a subepithelial ovarian-type stroma. The ovarian-typestroma is the key feature to differentiate MCN fromIPMN,1,2 which is usually positive for PR, ER, smoothmuscle actin, CD10, and inhibin-a.116 Expression ofdifferent types of mucin, such as MUC5AC, is not veryuseful in differentiating an MCN from an IPMN. MUC2 isfrequently expressed in goblet cells of MCN. MUC1 tendsto be negative in a noninvasive MCN. DPC4/SMAD4expression is retained. Mucinous cystic neoplasms with aninvasive component may show a loss of DPC4/SMAD4expression and express MUC1.1 Loss of expression ofpVHL and overexpression of S100P were the frequentfindings in MCNs, regardless of the grade of epithelialdysplasia.64 The review of the literature and our GeisingerMedical Center data are summarized in Table 9.

INTRADUCTAL PAPILLARY MUCINOUS NEOPLASM

Intraductal papillary mucinous neoplasms are relativelycommon cystic neoplasms of the pancreas, accounting forapproximately 20% of all cystic pancreatic lesions.1,2

Intestinal-type IPMN is usually positive for MUC2, CDX2,and CK20. Gastric foveolar-type IPMN is usually positive forMUC5AC and negative for both MUC1 and MUC2.Pancreatobiliary-type IPMN is usually positive for MUC1and MUC5AC and negative for MUC2 and CDX2.Oncocytic type IPMN is usually positive for MUC5AC andMUC6.

Studies showed S100P expression and loss of expression

of pVHL in all types of IPMN, regardless of the grade of

epithelial dysplasia.64,65 Expression of DPC4/SMAD4 was

present in all tested cases in our study. Expression of MUC1,

loss of expression of DPC4/SMAD4, and overexpression of

p53 in IPMNs were frequently associated with invasive

Table 7. Markers for Pancreatoblastoma

Antibodies Acinar Endocrine Ductal

CK7 þ � þCK19 þ � þCAM 5.2 þ þ þTrypsin þ � �NSE � þ �Synaptophysin � þ �Chromogranin � þ �CEA � � þTAG 72 (B72.3) � � þ

Abbreviations: þ, usually more than 75% of cases are positive; �, lessthan 5% of cases are positive; CEA, carcinoembryonic antigen; CK,cytokeratin; NSE, neuron-specific enolase; TAG72 (B72.3), tumor-associated glycoprotein 72. Antibody order based on the application ofthe group of antibodies to a specific entity.

Table 8. Markers for Serous Cystadenomaa

Antibodies Literature GML Data, No. (%)

pVHL, n ¼ 13 þ 13 (100)MUC6, n ¼ 13 þ or � 12 (92)Inhibin-a, n ¼ 13 þ 12 (92)NSE, n ¼ 13 þ 7 (54)CK7, n ¼ 13 þ 13 (100)CK20, n ¼ 13 � 0 (0)S100P, n ¼ 13 � 0 (0)Synaptophysin, n ¼ 13 � or þ 0 (0)Chromogranin, n ¼ 13 � 0 (0)TAG 72 (B72.3), n ¼ 13 � 0 (0)CEA, n ¼ 13 � 0 (0)CA19-9, n ¼ 13 � or þ 4 (31)EPCAM, n ¼ 13 � 9 (69)Mucicarmine, n ¼ 13 � 0 (0)

Abbreviations: þ, usually more than 75% of cases are positive; �, lessthan 5% of cases are positive;þ or�, usually more than 50% of casesare positive;�orþ, less than 50% of cases are positive; CA19-9, cancerantigen 19.9; CEA, carcinoembryonic antigen; CK, cytokeratin; GML,Geisinger Medical Laboratories; MUC6, mucin 6; NSE, neuron-specificenolase; pVHL, von Hippel-Lindau tumor suppressor; S100P, placentalS100; TAG72 (B72.3), tumor-associated glycoprotein 72. Antibodyorder based on the application of the group of antibodies to a specificentity.a Reprinted from 3Lin F, Prichard JW, Liu H, Wilkerson M, Schuerch C,

eds. Handbook of Practical Immunohistochemistry: Frequently AskedQuestions. New York, NY: Springer; 2011, with permission fromSpringer Scienceþ Business Media.

Table 9. Markers for Mucinous Cystic Neoplasma

Antibodies LiteratureGML Data,

No. (%)

CK7, n ¼ 12 þ 12 (100)S100P, n ¼ 12 þ 8 (67)pVHL, n ¼ 12 � 4 (33)CD10, n ¼ 12 þ 4 (33)Estrogen receptor, n ¼ 12 þ 3 (25)Inhibin-a, n ¼ 12 þ or � 8 (67)Progesterone receptor, n ¼ 12 þ or � 6 (50)CK20, n ¼ 12 � or þ 4 (33)CEA, n ¼ 12 þ 12 (100)CA19-9, n ¼ 12 þ 11 (92)CDX2, n ¼ 12 � 3 (25)MUC1, n ¼ 12 � 2 (17)MUC2, n ¼ 12 � or þ 0 (0)MUC5AC, n ¼ 12 þ 8 (67)MUC6, n ¼ 12 � 6 (50)DPC4/SMAD4, n ¼ 12 þ 12 (100)

Abbreviations: þ, usually more than 75% of cases are positive; �, lessthan 5% of cases are positive;þ or�, usually more than 50% of casesare positive;�orþ, less than 50% of cases are positive; CA19-9, cancerantigen; CD, cluster of differentiation; CDX2, caudal type homeobox 2;CEA, carcinoembryonic antigen; CK, cytokeratin 19-9; DPC4/SMAD4,SMAD family member 4; GML, Geisinger Medical Laboratories; MUC,mucin; pVHL, von Hippel-Lindau tumor suppressor; S100P, placentalS100. Antibody order based on the application of the group ofantibodies to a specific entity.a Reprinted from 3Lin F, Prichard JW, Liu H, Wilkerson M, Schuerch C,

eds. Handbook of Practical Immunohistochemistry: Frequently AskedQuestions. New York, NY: Springer; 2011, with permission fromSpringer Scienceþ Business Media.


carcinoma.117 MUC6 tended to be expressed in the basallayer of epithelial cells; the papillary structures projectinginto the cystic space were frequently negative for MUC6.Maspin expression increased with increasing grade ofdysplasia in noninvasive lesions from intraductal papillarymucinous adenomas to intraductal papillary mucinousborderline neoplasm to noninvasive intraductal papillarymucinous carcinoma but decreased significantly in invasiveintraductal papillary mucinous carcinomas.118 The literatureand our Geisinger Medical Center data are summarized inTable 10.

COMMON METASTASES IN THE PANCREAS

Metastatic neoplasms of the pancreas are rare, accountingfor approximately 2% of all pancreatic malignancies.1,2 Themost common malignancies metastasizing to the pancreasare RCC, melanoma, non–small cell carcinoma of the lung,colorectal ADC, and breast carcinoma.119 The commonmetastases to the pancreas and useful immunomarkers foridentifying them are summarized in Table 11. For a detaileddiscussion of how to work up a tumor of uncertain origin,please refer to the review article Immunohistochemistry inUndifferentiated Neoplasm/Tumor of Uncertain Origin by Linand Liu.126

Clear cell RCC is the most common metastasis; it isusually positive for PAX8, pVHL, renal cell carcinomamarker, CD10, and vimentin and is negative for CK7 andCK20. Pulmonary ADC is another frequent metastasis.Approximately 75% of cases are positive for TTF1 andnapsin A. Both TTF1 and napsin A are negative in pancreaticDADCs; however, mucinous ADCs of the lung arefrequently positive for CDX2 and CK20 and negative forTTF1 and napsin A.

S100 is a highly sensitive (98%), but not specific, markerfor screening of melanoma. If a desmoplastic melanoma issuspected, sex-determining region Y box 10 (SOX10) shouldalso be included. Other markers, including melanoma-associated antigen recognized by T cells 1 (MART1), humanmelanoma black 45 (HMB45) and microphthalmia-associ-ated transcription factor (MiTF), are helpful. Caution shouldbe taken if the sample is fixed in alcohol because the S100antigen is not preserved well after alcohol fixation;therefore, a false-negative result may occur.

Some metastatic small cell carcinomas of the lung can benegative for both synaptophysin and chromogranin andeven for broad-spectrum cytokeratin, but they are veryinfrequently negative for CD56. The MIB-1 (Ki-67) prolif-erative index tends to be very high (.50%). It would be

Figure 5. A through D, A representative case of serous cystadenoma on hematoxylin-eosin–stained section (A), and positive for von Hippel-Lindautumor suppressor (B), mucin 6 (C), and inhibin-a (D) (original magnification 3200 [A through D]).


extremely unusual to have a small cell carcinoma with only amoderately increased MIB-1 (Ki-67) proliferative index.

Nearly 100% of metastatic colonic ADCs are positive forSATB2, CDH17, and CDX2; however, medullary carcinomaof the large intestine frequently demonstrates loss ofexpression of both CDX2 and CK20. In this instance, thetumor cells would likely demonstrate loss of expression ofeither MLH1/PMS2 or mutS homolog 2 (MSH2)/MSH6,and are frequently positive for SATB2, CDH17, trefoil factor3 (TFF3), MUC4, and calretinin.120

Entirely tissue-specific markers for the distinction be-tween pancreatic ADC and upper gastrointestinal ADC arenot available now. However, loss of DPC4/SMAD4 expres-sion, negative CDH17 expression, and expression of CK17are suggestive of a pancreatic primary.

GALLBLADDER, EXTRAHEPATIC BILE DUCTS,AND INTRAHEPATIC BILE DUCTS

Following an extensive study and review of literature, webelieve the 4-marker panel of pVHL, maspin, IMP3, andS100P is the most sensitive and specific diagnostic panel todifferentiate ADC of the gallbladder and extrahepatic bileducts from reactive gallbladder/bile duct mucosa58–60;findings are summarized in Table 12. Other immuno-markers from recent publications are briefly reviewed here.Glucose transporter 1 (GLUT1) has been reported121 to beexpressed in 51.8% (N ¼ 115) of ADCs of the gallbladderand not expressed in normal/benign gallbladder mucosa.Riener and coworkers122 studied the expression of P-cadherin, CD24, and p53 in 39 cases of gallbladder ADCand demonstrated their expression in 64%, 42%, and 45% ofcases, respectively; in contrast, all 52 cases of normal/reactive gallbladder mucosa were negative for all 3 proteins.Tamura et al123 reported expression of regenerating islet-derived family, member 4 (REG4) was seen in 56% ofgallbladder carcinomas (N ¼ 34) and was negative in allnormal/reactive cases (N ¼ 28). Li et al124 reported theexpression frequencies for CDX2 and hepatocyte paraffin-1were 45.4% and 41.7% in gallbladder carcinomas (N¼ 108)and 14.3% and 5.7% in chronic cholecystitis (N ¼ 35),respectively; p16 was shown to be expressed in 45% of high-grade dysplasias and in 27.6% of gallbladder ADCs (N¼ 20)but was negative in 20 normal/reactive cases.125

Table 10. Markers for Intraductal PapillaryMucinous Neoplasma

Antibodies LiteratureGML Data,

No. (%)

CK7, n ¼ 18 þ 18 (100)S100P, n ¼ 18 þ 18 (100)pVHL, n ¼ 18 � 0 (0)CK19, n ¼ 16 þ 12 (75)CK20, n ¼ 16 � or þ 10 (62)CDX2, n ¼ 16 þ or � 6 (38)CEA, n ¼ 18 þ 18 (100)CA19-9, n ¼ 16 þ 10 (62)MUC1, n ¼ 18 V 9 (50)MUC2, n ¼ 18 V 8 (44)MUC5AC, n ¼ 18 þ 18 (100)MUC6, n ¼ 18 ND 14 (78)DPC4/SMAD4, n ¼ 18 þ 18 (100)

Abbreviations: þ, usually more than 75% of cases are positive; �, lessthan 5% of cases are positive;þ or�, usually more than 50% of casesare positive;�orþ, less than 50% of cases are positive; ND, no data; V,variable; CK, cytokeratin; S100P, placental S100; pVHL, von Hippel-Lindau tumor suppressor; CDX2, caudal type homeobox 2; CEA,carcinoembryonic antigen; CA19-9, cancer antigen 19-9; GML, Gei-singer Medical Laboratories; MUC, mucin; DPC4/SMAD4, SMADfamily member 4. Antibody order based on the application of the groupof antibodies to a specific entity.a Reprinted from 3Lin F, Prichard JW, Liu H, Wilkerson M, Schuerch C,

eds. Handbook of Practical Immunohistochemistry: Frequently AskedQuestions. New York, NY: Springer; 2011, with permission of SpringerScienceþ Business Media.

Table 11. Metastases in the Pancreas

Markers PDADC Kidney Lung-A Melanoma Upper GI Lung-S Colon Breast

CK7 þ � þ � þ þ or � � þCK20 � � � � þ or � � þ �S100 � � þ or � þ � � � � or þGATA3 � � � � � � � þER � � � � � � � þTTF1 � � þ � � þ � �Napsin A � � or þ þ � � � � �SATB2 � � � � � or þ � þ �pVHL � þ � � � � � �PAX8 � þ � � � � � �Synap � � � � � þ � �DPC4 � or þ þ þ þ þ þ þ þCK17 þ or � � � � � � � �

Abbreviations: þ, usually more than 75% of cases are positive; �, less than 5% of cases are positive; þ or �, usually more than 50% of cases arepositive;� orþ, less than 50% of cases are positive; CK, cytokeratin; DPC4, SMAD family member 4; ER, estrogen receptors; GATA3, GATA bindingprotein 3; GI, gastrointestinal; lung-A, lung adenocarcinoma; lung-S, lung small cell carcinoma; PAX8, paired box gene 8; PDADC, pancreaticductal adenocarcinoma; pVHL, von Hippel-Lindau tumor suppressor; SATB2, special AT-rich sequence-binding protein 2; synap, synaptophysin;TTF1, thyroid transcription factor 1.

Table 12. Gallbladder and Extrahepatic Bile DuctAdenocarcinoma (ADC) Versus Reactive Condition

MarkerGallbladder

ADCExtrahepatic

Bile Duct ADCReactive

Condition

pVHL � � þMaspin þ ND � or þS100P þ þ �IMP3 þ � �mCEA þ þ �

Abbreviations: þ, usually more than 75% of cases are positive; �, lessthan 5% of cases are positive; � or þ, less than 50% of cases arepositive; IMP3, insulin-like growth factor II messenger RNA bindingprotein-3; maspin, mammary serine protease inhibitor; mCEA, mono-clonal carcinoembryonic antigen; ND, no data; pVHL, von Hippel-Lindau tumor suppressor; S100P, placental S100.


In contrast to ADCs of the pancreas, gallbladder, andextrahepatic bile ducts, ICC has a unique IHC profile, assummarized in Table 13, in which, 71% of ICCs werepositive for pVHL, and the expression of S100P, MUC5AC,and CK17 was seen in only 27%, 12%, and 12% of cases,respectively.61

In summary, application of IHC in the diagnosis andclassification of a pancreatic solid or cystic tumor hasbecome a useful ancillary study and plays a crucial role inreaching a definitive diagnosis. An accurate diagnosis of apancreatic tumor is essential in understanding tumorpathobiology, in making an appropriate therapeutic deci-sion, and in predicting a prognostic outcome. This reviewarticle (1) recommends a simple working algorithm forworkup of a solid or cystic pancreatic tumor, (2) discussesthe emerging biomarkers for common pancreatic tumorswith a focus on their application and pitfalls, and (3)identifies the most effective IHC panels for solvingfrequently encountered diagnostic challenges and minimiz-ing overuse or underuse of the currently available andrapidly growing list of biomarkers. With advances inmolecular methodologies, additional tissue-specific bio-markers for ADCs of the pancreas, gallbladder, andextrahepatic and intrahepatic bile ducts will be discoveredin the future.

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Table 13. Intrahepatic Cholangiocarcinomas (ICCs)Versus Pancreatic Ductal Adenocarcinomas (DADC)

Marker Pancreatic DADC ICC

pVHL � þS100P þ � or þCK17 þ or � �MUC5AC þ or � �

Abbreviations: þ, usually more than 75% of cases are positive; �, lessthan 5% of cases are positive;þ or�, usually more than 50% of casesare positive; � or þ, less than 50% of cases are positive; CK17,cytokeratin 17; MUC5AC, mucin 5AC; pVHL, von Hippel-Lindautumor suppressor; S100P, placental S100.


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