Non-ampullary–duodenal carcinomas:clinicopathologic analysis of 47 cases andcomparison with ampullary and pancreaticadenocarcinomasYue Xue1,9, Alessandro Vanoli2,9, Serdar Balci1, Michelle M Reid1, Burcu Saka1,Pelin Bagci1, Bahar Memis1, Hyejeong Choi3, Nobuyike Ohike4, Takuma Tajiri5,Takashi Muraki1, Brian Quigley1, Bassel F El-Rayes6, Walid Shaib6, David Kooby7,Juan Sarmiento7, Shishir K Maithel7, Jessica H Knight8, Michael Goodman8,Alyssa M Krasinskas1 and Volkan Adsay1

1Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA;2Department of Molecular Medicine, San Matteo Hospital, University of Pavia, Pavia, Italy; 3Departmentof Pathology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea;4Department of Pathology, Showa University Fujigaoka Hospital, Yokohama, Japan; 5Department ofPathology, Tokai University Hachioji Hospital, Tokyo, Japan; 6Department of Hematology and MedicalOncology, Emory University School of Medicine, Atlanta, GA, USA; 7Department of Surgery, Emory UniversitySchool of Medicine, Atlanta, GA, USA and 8Department of Epidemiology, Emory University Rollins School ofPublic Health, Atlanta, GA, USA

Literature on non-ampullary–duodenal carcinomas is limited. We analyzed 47 resected non-ampullary–duodenalcarcinomas. Histologically, 78% were tubular-type adenocarcinomas mostly gastro-pancreatobiliary type andonly 19% pure intestinal. Immunohistochemistry (n= 38) revealed commonness of ‘gastro-pancreatobiliarymarkers’ (CK7 55, MUC1 50, MUC5AC 50, and MUC6 34%), whereas ‘intestinal markers’ were relatively lesscommon (MUC2 36, CK20 42, and CDX2 44%). Squamous and mucinous differentiation were rare (in five each);previously, unrecognized adenocarcinoma patterns were noted (three microcystic/vacuolated, two cribriform,one of comedo-like, oncocytic papillary, and goblet-cell-carcinoid-like). An adenoma component common inampullary–duodenal cancers was noted in only about a third. Most had plaque-like or ulcerating growth.Mismatch repair protein alterations were detected in 13% (all with plaque-like growth and pushing-borderinfiltration). When compared with ampullary (n= 355) and pancreatic ductal (n= 227) carcinomas, non-ampullary–duodenal carcinomas had intermediary pathologic features with mean invasive size of 2.9 cm (vs1.9, and 3.3) and 59% nodal metastasis (vs 45, and 77%). Its survival (3-, 5-year rates of 57 and 57%) was similar tothat of ampullary–duodenal carcinomas (59 and 52%; P= 0.78), but was significantly better than the ampullaryductal (41 and 29%, Po0.001) and pancreatic (28 and 18%, Po0.001) carcinomas. In conclusion, non-ampullary–duodenal carcinomas are more histologically heterogeneous than previously appreciated. Their morphologicversatility (commonly showing gastro-pancreatobiliary lineage and hitherto unrecognized patterns), frequentplaque-like growth minus an adenoma component, and frequent expression of gastro-pancreatobiliary markerssuggest that many non-ampullary–duodenal carcinomas may arise from Brunner glands or gastric metaplasia orheterotopic pancreatobiliary epithelium. The clinical behavior of non-ampullary–duodenal carcinoma is closer tothat of ampullary–duodenal subset of ampullary carcinomas, but is significantly better than that of ampullaryductal and pancreatic cancers. The frequency of mismatch repair protein alterations suggest that routine testingshould be considered, especially in the non-ampullary-duodenal carcinomas with plaque-like growth andpushing-border infiltration.Modern Pathology (2017) 30, 255–266; doi:10.1038/modpathol.2016.174; published online 14 October 2016

Correspondence: Dr V Adsay, MD, Department of Pathology and Laboratory Medicine, Emory University Hospital, 1364 Clifton Road NE,Room H-180B, Atlanta, GA 30322, USA.E-mail: nadsay@emory.edu9These authors are co-contributing first authors.Received 20 April 2016; revised 28 August 2016; accepted 31 August 2016; published online 14 October 2016

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http://dx.doi.org/10.1038/modpathol.2016.174mailto:nadsay@emory.eduhttp://www.modernpathology.org

Tumors arising in the non-ampullary (extra-ampul-lary) segment of the duodenum are considered true‘duodenal cancers’. These primary ‘duodenal’ carci-nomas are rare and constitute 35–50% of all smallintestinal carcinomas.1 Their analysis is frequentlycombined with other small bowel, pancreatic, anddistal bile duct cancers (periampullary cancers) thathas caused marked confusion in the literature regard-ing their frequency and clinicopathologic charact-eristics.2 Through a more vigorous site-specificclassification, many tumors that were previouslydeemed ‘duodenal cancers’ have now been recentlyshown to comprise distinct specific types, such asthose arising from the ampulla of Vater (ampullarycarcinoma of not-otherwise-specified type), those thatgrow predominantly on the ampulla’s duodenal surface(ampullary–duodenal or ‘periampullary’–duodenal),3and those that arise from non/extra-ampullary–duodenum. It is also now being appreciated thatampullary carcinoma arising from the ampullaryducts, that is, ampullary ductal group, has distinctcharacteristics. Although ampullary–duodenal can-cers are typically large, ulcerated, or vegetatingintestinal-type adenocarcinomas that are often asso-ciated with an abundant intestinal-adenomatouscomponent and have a relatively good survival(3-year survival 59%, and 5-year 52%), ampullaryductal cancers typically form scirrhous circumferen-tial tumors on the wall of ampullary ducts (ampullaryportion of common bile duct and main pancreaticduct) with minimal mucosal changes in the duodenalsurface of the ampulla, and are typically pancreato-biliary type adenocarcinomas and show aggressivebehavior despite being small (mean size 1.8 cm, and 5year 29%).3 For non-ampullary–duodenal carcino-mas, the literature reveals conflicting results, largelybecause they have often been analyzed with ampul-lary or other intestinal cancers. Recent studies areindicating that they may in fact be fairly similar to‘ampullary cancers’,4,5 but many of their character-istics have not been fully elucidated.

To better characterize the clinicopathologic fea-tures, immunophenotype and clinical behavior ofnon-ampullary–duodenal carcinomas (duodenalcancers that clearly spare the ampulla), we per-formed an analysis of 47 resected examples, andcompared these with those of 355 ampullary and 227pancreatic ductal adenocarcinomas.

Materials and methods

The study was conducted in accordance with theInstitutional Review Board requirements. The studyincluded the resected duodenal carcinomas col-lected from 2000 to 2014 from Emory UniversityHospital and University of Pittsburg. Non-invasivetumors (adenoma-only cases) and tumors arising inthe setting of familial adenomatous polyposis andCrohn’s disease were carefully excluded. Using thesecriteria, 47 cases were qualified as non-ampullary–

duodenal carcinomas. For comparison, 355 ampul-lary (of which, 29 were ampullary–duodenal, 66ampullary ductal and the remaining 260 were eitherintra-ampullary papillary-tubular neoplasm—asso-ciated or not-otherwise-specified types) cancers and227 pancreatic ductal adenocarcinomas wereretrieved from the database during the same periodof time, and assessed for long-term follow-up.

Definitions

A tumor was designated as:

Non-ampullary–duodenal carcinoma, if it histologi-cally spared the ampulla, with no evidence ofpreinvasive or invasive lesions in the major ampulla.Ampullary carcinoma, if its epicenter was located inthe lumen or walls of the distal (intra-ampullarycomponent) common bile duct and/or pancreaticduct, or at the ‘papilla of Vater’ (junction of duodenaland ampullary mucosa as defined by the College ofAmerican Pathologists),6 or the duodenal surface ofthe papilla.3

a. Ampullary–duodenal carcinoma, (also knownas ‘periampullary–duodenal) were regarded asa subset of ampullary carcinomas arising fromthe duodenal surface of the ampulla itself,and showing an exophytic ulcero-fungatingtumor growing into the duodenal lumen andeccentrically engulfing the ampulla orificewith only minimal intra-ampullary luminalinvolvement.3

b. Ampullary ductal carcinoma, represented car-cinomas arising from nontumoral (flat) intrae-pithelial neoplasms of the ducts, and formingconstrictive, sclerotic, plaque-like thickening ofthe walls of the common bile duct and/pancreatic duct resulting in mucosa-covered,button-like elevations of the papilla into theduodenal lumen.3 These are now regardedunder the heading of ‘intra-ampullary’ categoryby the recent modification of the College ofAmerican Pathologists protocol.

Demographic and Clinical Data

Information on the patients’ gender, age, and clinicaloutcome was obtained from the medical records, bycontacting the primary treating physician, or throughthe Surveillance and Epidemiology and End Resultdatabase.

Pathologic Parameters

These 47 cases were analyzed for ‘overall tumor size’,the size of the invasive carcinoma, the growth pattern,the presence of perineural and lymphovascularinvasion, and the lymph node status, according tothe American Joint Committee on Cancer staging

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tumor classification,7 the presence of preinvasive(adenomatous) components of the tumor and thefeatures of the uninvolved mucosa at the tumor edges.

Histologically, cases were classified as tubulartype (if the predominant pattern was tubular/gland-ular differentiation) and non-tubular types. Thetubular group was subclassified into three categories:intestinal, gastro-pancreatobiliary, and mixed type(if the intestinal, pancreatobiliary, and/or gastricfeatures were present in the same case).8 Briefly,invasive carcinomas with more basophilic appear-ance and complex glands lined by pseudostratifiedcolumnar cells with cigar-shaped nuclei were classi-fied as intestinal type; those with widely separatedsmall tubular units lined by one or two layers ofcuboidal cells were classified as pancreatobiliarytype; and those with a tubular and papillaryproliferation with foveolar-type or pyloric-type(Brunner gland) differentiation were classified asgastric type.8 In this study, gastric and pancreato-biliary lineages were grouped together in accordancewith recent concepts in pancreatic histology thatfavor the combined classification of these twolineages because of their close association, sharedimmunophenotype, and frequent co-occurrence.8,9,10Non tubule-forming carcinoma types (such as muci-nous, medullary, poorly cohesive/poorly differen-tiated carcinoma, and adenosquamous carcinomas)were classified according to the World HealthOrganization 2010 Classification of DigestiveTumors.11 Histologic findings of the carcinomaswere noted for other patterns as well.

Immunohistochemical Analysis

Cell lineage markers. Immunohistochemical analy-sis was performed on 38 cases (with the tissue block orunstained slides available) with cell lineage markers,which are known to be differentially expressed indifferent components of the gastrointestinal tract:MUC1 (Clone Ma695, 1:160, Novocastra, New Castle,UK), marker typically present in pancreatobiliarydifferentiation; MUC2 (Ccp58, 1:100, Novocastra,New Castle, UK), intestinal (goblet cell) differentiation;CDX2 (CDX2-88, 1:200, Biogenex, San Ramon, CA,USA), intestinal transcription factor; MUC5AC (CLH2,1:200, Leica), foveolar mucin marker; MUC6 (CLH5,1:80, Leica), pyloric/Brunner gland marker; CK7 (OB-TL 12/30, 1: 40, DAKO, Carpenteria, CA, USA), typicalof gastro-pancreatobiliary tumors; and CK20 (Ks 20.8,1/40, Dako, Carpenteria, CA, USA) typically expressedin lower-intestinal neoplasms.

DNA mismatch repair protein markers. Immuno-histochemical analysis was performed with MLH1(G168-758, 1:20, BD Pharmiger, San Diego, CA,USA), PMS2 (A16-4, 1:50, BD Pharmiger, San Diego,CA, USA), MSH2 (FE11, 1:20, Calbiochem, SanDiego, CA, USA), and MSH6 (44/MSH6, 1:50, BDPharmiger, San Diego, CA, USA).

Methodology. Immunohistochemistry was per-formed using a polymer-based detection system(Envision+; Dako, Carpinteria, CA, USA) with mousemonoclonal antibodies according to the manufac-turer’s instructions. Sections were deparaffinizedand rehydrated with deionized water. Then, theywere heated in citrate buffer, pH 6.0, using anelectric pressure cooker for 3min at 12–15 poundsper square inch at ~ 120 °C and cooled for 10minbefore immunostaining. All slides were loaded ontoan automated system (Autostainer; Dako), in whichthey are exposed to 3% hydrogen peroxide for 5min,incubated with primary antibody for 30min, incu-bated with labeled polymer (Envision+ dual link) for30min, incubated in 3,30-diaminobenzidine as achromogen for 5min, and counterstained withhematoxylin for 5min. These incubations wereperformed at room temperature. Between incuba-tions, sections were performed using the Tissue-TekSCA cover slipper (Sakura Finetek USA, Torrance,CA, USA). Positive controls and negative controlswith primary antibody replaced by Tris-bufferedsaline were run with the patient/study slides.

Evaluation of immunohistochemical stains. Thepercentage of cells showing cytoplasmic (MUC2,MUC5AC, MUC6, CK7, and CK20), apical membra-nous or cytoplasmic (MUC1), and nuclear (CDX2)labeling was evaluated. Only the cases with 4 25%immunoreactive cells were regarded as positive.12 Formismatch repair protein status (MLH1, PMS2, MSH2andMSH6), the lack of nuclear staining in the invasivecarcinoma was interpreted as an abnormal result.

Statistical Analysis

Comparisons of patient and tumor characteristicswere made by means of an unpaired Student's t-testfor continuous variables and by χ2-analysis forcategorical variables. Comparisons among differentgroups were performed by using analysis of variancetest. Overall survival was analyzed using theKaplan–Meier method and differences among groupswere assessed by log-rank test. A Cox proportionalhazard regression was used to identify independentfactors associated with post-resection survival. Atwo-sided P-value of o0.05 was considered to bestatistically significant. All statistical analyses wereperformed with SAS version 9.2 (SAS Institute, Cary,NC, USA) statistical software package.

Results

General Characteristics of Non-Ampullary–DuodenalCarcinomas and Comparison with both AmpullaryCarcinomas and Pancreatic Ductal Adenocarcinomas

There were 29 men and 18 women with non-ampullary–duodenal carcinomas (Table 1). Themean age was 63 years. Common presenting

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symptoms were anemia (22%), duodenal obstruction(22%), right upper quadrant/epigastric pain (19%),nausea and vomiting (19%), and gastrointestinalbleeding (16%). One patient was incidentally diag-nosed when undergoing imaging studies for largegallbladder obstruction. Twenty-eight patientsunderwent pylorus-sparing pancreaticoduodenect-omy (67%), 12 underwent segmental duodenectomy(28%), and 2 underwent classic pancreaticoduode-nectomy (5%). The anatomic distribution of thetumor among 39 patients, in which the preciselocalization of the tumor was properly recorded,was as follows—first segment of duodenum: 3 cases(8%); second (descending) segment of duodenum: 24cases (62%); third (horizontal) segment of duode-num: 6 cases (15%); fourth (ascending) part of theduodenum: 4 cases (10%); and junction between thethird and fourth segments of the duodenum: 2 cases(5%). The mean overall size of tumor was 3.5 cm (vs2.6 cm for ampullary, Po0.01; and 3.3 cm forpancreatic ductal, P=0.36). The mean invasion sizewas 2.9 cm (vs 1.9 cm for ampullary, Po0.01; and3.3 cm for pancreatic ductal, P=0.13). The rate oflymph node positivity was 59% (vs 45 % forampullary, P=0.08; and 77% for pancreatic ductal,P=0.02). The positive margins were present in onlytwo cases (one with positive proximal margin; and

the other with positive duodenal radial margin).The rate of margin positivity was similar to that forampullary carcinomas (5%), but significantly lowerthan that of pancreatic ductal carcinomas (23%;Po0.01). Frequency of perineural invasion was 48%(vs 34% for ampullary, P=0.08 and 96% of pancrea-tic ductal, Po0.01). Frequency of vascular invasionwas 76% (vs 63% for ampullary, P=0.11 and 80%for pancreatic ductal, P=0.54). Among 38 patientswith adequate information available, only twopatients (5%) had documented neoadjuvant che-motherapy and/or radiation before surgicalresection.

Comparison of Non-Ampullary–Duodenal Carcinomaswith Ampullary–Duodenal Subset of AmpullaryCarcinomas

There was no statistically significant difference inage or gender between non-ampullary–duodenalcarcinomas and the ampullary–duodenal subset ofampullary carcinomas (Table 2). The mean overallsize of non-ampullary–duodenal carcinomas wassignificantly smaller than that of ampullary–duode-nal carcinomas (3.5 cm vs 4.8 cm, Po0.01); how-ever, due to the paucity of adenoma component innon-ampullary–duodenal carcinomas, the mean

Table 1 General characteristics of non-ampullary–duodenal carcinomas and comparison with both ampullary carcinomas and pancreaticductal adenocarcinomas

CharacteristicsNon-ampullary–duodenal

carcinoma Ampullary carcinomaPancreatic ductaladenocarcinoma P† P††

(n=47) (n=355) (n=227)

Mean age (years) 63 65 65 0.28 0.3

GenderF 18 (38%) 150 (43%) 129 (57%) 0.57 0.02M 29 (62%) 205 (57%) 98 (43%)

Overall size (cm) 3.5 (0.1–8.0) 2.6 (0.3–9.5) 3.3 (0.6–7.0) o0.01 0.36Invasive size (cm) 2.9 (0.1–6.5) 1.9 (0.1–9.5) 3.3 (0.6–7.0) o0.01 0.13

LN statusPositive 26 (59%) 146 (45%) 174 (77%) 0.08 0.02Negative 18 (41%) 177 (55%) 53 (23%)

Margin statusNegative 38 (95%) 336 (96%) 175 (77%)Positive 2 (5%) 15 (4%) 52 (23%) 0.83 o0.01

Perineural invasion 21 (48%) 122 (34%) 217 (96%) 0.08 o0.01Vascular invasion 34 (76%) 225 (63%) 180 (80%) 0.11 0.54

Survival rates1 year 86% 85% 65% 0.75 o0.0013 year 57% 62% 28%5 year 57% 49% 18%

Abbreviations: F, female; M, male.P† comparison between non-ampullary–duodenal carcinoma and ampullary carcinoma.P†† comparison between non-ampullary–duodenal carcinoma and pancreatic ductal adenocarcinoma.

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invasion size was very similar between the twogroups (2.9 cm for non-ampullary–duodenal carci-nomas vs 3.2 cm for ampullary–duodenal carcino-mas, P=0.48). The rate of lymph node positivity was59% in non-ampullary–duodenal carcinomas vs64% in ampullary–duodenal carcinoma (P=0.66).There was no significant difference in perineural andvascular invasion rates between the two groups (41%and 69% for ampullary–duodenal cancers vs 48%and 76% for non-ampullary–duodenal carcinomas,respectively; P-values of 0.59 and 0.53, respectively).

Gross Features of Non-Ampullary–DuodenalCarcinomas

Three growth patterns of non-ampullary–duodenalcarcinomas were noted: a well-defined plaque-likepattern in 16 cases (Figure 1a), an ulcero-plaquepattern in 16 cases (Figure 1b), and a polypoid-vegetating growth pattern in 6 cases. In contrast, thevast majority of ampullary–duodenal subset ofampullary carcinomas had polypoid-vegetatinggrowth (prominent adenoma component).

Histologic Patterns

By morphologic assessment using the conventionalhistopathologic criteria, 37 cases (78%) with pre-dominant tubular (glandular) pattern were classifiedas tubular type. Among these cases, pure intestinaltype was only seen in 7 (19%) (Figure 2a) with theremaining 30 (81%) categorized as non-intestinaltype. The non-intestinal-type group included gastro-pancreatobiliary pattern in 15 cases (50%) (Figure 2band c), and hybrid or mixed features in 15 cases(50%; Figure 2d). Atypical and uncharacterizedpatterns were also identified, that are seldom (if atall) seen elsewhere in the gastrointestinal tract. Inparticular, two cases (5%) showed a cribriformpattern (Figure 3a). Three cases (6%) focally showeda microcystic/vacuolated pattern (Figure 3b) similarto that recently described in pancreatic adenocarci-noma by Dursun et al.13 Another case (2%), with anoncocytic papillary pattern, was characterized bydistinctive papillary growth pattern, consisting ofarborizing papillae lined by cuboidal cells withnuclei having single prominent eccentric nucleoli(Figure 3C). One case (2%) showed an unusualcomedocarcinoma-like architecture (Figure 3d),mimicking comedo-type in situ carcinoma of thebreast. One case (2%) had a superficial ‘goblet-cell-carcinoid’-like component (Figure 3e), characterizedby tight clusters of tumor cells with goblet cell orsignet ring-like morphology, but was not immunor-eactive for neuroendocrine markers and the deeperpart of the tumor was mucinous type with signet ringcells floating within the abundant extracellularmucin.

Other rare carcinoma types also occurred, includ-ing adenosquamous carcinoma (one case), mucinous

(one case), medullary (two cases), and poorlycohesive cell type (two cases). A mucinous compo-nent was also identified in four additional cases, butfalling short of the criteria for mucinous carcinomas.Besides the adenosquamous case, focal squamoidfeatures were observed in four additional cases.

Only 17 (37%) of non-ampullary–duodenal carci-nomas showed an identifiable adenomatous compo-nent, and even these were often small or limited inamount.

Changes in the Background Mucosa

In 15 of non-ampullary–duodenal carcinoma cases,the background mucosa showed abnormalities ofgastric type or proliferation of Brunner glands. Mostof these occurred in those arising in proximalduodenum. Among the 27 cases of non-ampullary–duodenal carcinomas arising in first/second portionof duodenum, gastric heterotopia was found in onecase in the proximity with the tumor; foveolardysplasia, in two cases; surface foveolar metapla-sia/Brunner’s gland hyperplasia with/without cysticchanges in nine cases; and intestinal adenoma wasfound only in one case. Among the 12 cases of non-ampullary–duodenal carcinomas arising in third/fourth portion of duodenum, intestinal adenoma waspresent in nine cases; only one case had both

Table 2 Comparison between non-ampullary–duodenal carcino-mas and ampullary–duodenal subset of ampullary carcinomas

Characteristics

Non-ampullary–duodenalcarcinoma

Ampullary–duodenal P-value

(n=47) (n=29)

Mean age (years) 63 60 0.38

GenderF 18 (38%) 14 (48%) 0.39M 29 (62%) 15 (52%)

Overall size (cm) 3.5 (0.1–8.0) 4.8 (2.2–8.0) o0.01Invasive size (cm) 2.9 (0.1–6.5) 3.2 (0.2–6.0) 0.48

LN statusPositive 26 (59%) 18 (64%) 0.66Negative 18 (41%) 10 (36%)

Margin status 0.74Negative 38 (95%) 27 (93%)Positive 2 (5%) 2 (7%)

Perineural invasion 21 (48%) 12 (41%) 0.59Vascular invasion 34 (76%) 20 (69%) 0.53

Survival rates1 year 86% 80% 0.783 year 57% 59%5 year 57% 52%

Abbreviations: F, female; M, male.

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Figure 1 Gross features of non-ampullary–duodenal carcinomas: (a) plaque-like growth pattern; and (b) ulcero-plaque-like growth patternwith Crohn’s like features.

Figure 2 Histologic patterns of non-ampullary–duodenal carcinomas: (a) intestinal type; (b) gastro-pancreatobiliary type withpancreatobiliary component; (c) gastro-pancreatobiliary type with gastric component; and (d) mixed, both intestinal and pancreatobiliaryphenotypes.

Figure 3 Atypical and uncharacterized histologic patterns of non-ampullary–duodenal carcinomas: (a) cribriform pattern; (b) microcysticpattern; (c) oncocytic papillary pattern; (d) comedocarcinoma-like pattern; and (e) goblet-cell-carcinoid-like pattern.

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intestinal adenoma and pyloric gland adenoma. Nogastric heterotopia, foveolar dysplasia, or anyobvious foveolar metaplasia/Brunner’s gland hyper-plasia were identified in this group arising in distalduodenum.

Interestingly, in eight cases (17%), the uninvolvedmucosa away from carcinoma showed atrophicduodenitis (villous blunting and significantlyincreased intraepithelial lymphocytes—featurescharacteristic of celiac or similar diseases). In thisgroup, the overall mean age was 63 years with a maleto female ratio of 0.6. The mean overall tumor sizewas 3.5 cm and the mean invasion size was 3.5 cm.All margins were negative. Rates of perineural andlymphovascular invasion were 50% and 75%,respectively, and 50% of cases had positive lymphnodes. The plaque-like growth pattern was observedin four of these, ulcero-plaque growth pattern inthree, and polypoid inverted growth pattern in one.The histologic types were heterogeneous, withglandular pattern in five cases (gastro-pancreatobili-ary pattern in one case, pure intestinal pattern inone, and mixed pattern in three); medullary in onecase, adenosquamous carcinoma in one, and poorlycohesive adenocarcinoma in another. Four of eightpatients died at 4–81 months.

Immunoprofile of Non-Ampullary–DuodenalCarcinomas

Immunohistochemical markers that are typicallyexpressed consistently in intestinal neoplasms wererelatively low in frequency in non-ampullary–duo-denal carcinomas (MUC2 36, CK20 42, and CDX244%), whereas those of gastro-pancreatobiliaryappeared to be fairly common (CK7 55, MUC1 50,MUC5AC 50, and MUC6 34%). Intestinal-typecarcinomas (by morphology) expressed CK7 in 14%of cases and the pancreatobiliary marker MUC1 in29% (Figure 4a). Notably, gastro-pancreatobiliarytumors (by morphology) expressed MUC1, MUC5ACand MUC6 in 67%, 60% and 67% of the cases,respectively; however, 20% of these tumorsexpressed the intestinal marker CDX2 (Figure 4b).Most importantly, akin to the ampullary carcinoma,there was often a discrepancy between the pheno-type of the preinvasive (adenomatous) and invasivecomponents. In six cases, the adenomatous compo-nent showed an intestinal phenotype by morphologyand expressed intestinal markers MUC2 and CDX2,with focal, if any, immunoreactivity for either gastricor pancreatobiliary markers, although the invasiveadenocarcinoma of these cases was of gastro-pancreatobiliary type by histology and immunopro-file (Figure 5).

Recently Ang et al.12 proposed immunohistochem-ical criteria to subtype the ampullary adenocarci-noma into intestinal, pancreatobiliary, andambiguous subgroups. By extra-polating their cri-teria to non-ampullary–duodenal carcinoma, among

all 38 non-ampullary–duodenal carcinoma caseswith available tissue blocks or unstained slides,66% of carcinomas were classified as non-intestinaltype (18% qualifying as pancreatobiliary, 48% fall-ing into ambiguous type; Table 3). Seven morpholo-gically intestinal cases were all classified asintestinal by Ang’s immunohistochemical criteria.However, 15 morphologically pancreatobiliary caseswere subdivided into three categories using Ang’sIHC criteria: intestinal (one case), pancreatobiliary(seven cases), and ambiguous (seven cases). Seventy-seven percentage of the mixed morphologic patterntumors remained in the same group, whereas 23%were re-classified into intestinal subtype by Angcriteria. Table 4 documents the expression of thedifferent immunohistochemical markers in 38 non-ampullary–duodenal carcinomas, along with theirdistribution among the histologic subtypes.

DNA Mismatch Repair Protein Deficiency inNon-Ampullary–Duodenal Carcinomas

DNA mismatch repair protein deficiency wasdetected by immunohistochemistry in six non-ampullary–duodenal carcinomas (13%): two casesshowed the loss of MSH2/MSH6 proteins; twoshowed loss of MSH6 protein; one showed loss ofMLH1/PMS2; and one showed loss of MSH1, PMS2,and MSH6 proteins. Unfortunately, a revisit of theclinical histories of these patients from the charts didnot reveal any relevant information regarding Lynchsyndrome. Of the six cases with DNA mismatchrepair protein deficiency, three cases were of theintestinal type and moderately differentiated; theother three cases were of medullary histologicfeatures. Tumor-infiltrating lymphocytes were notedin all six cases, ranging from 2 to 77/HPF. All thecases showed pushing-border infiltration microsco-pically (Figure 6) and plaque-like growth pattern(Figure 1a), which accounted for 37.5% of theplaque-like growth pattern cases. Furthermore, ifplaque-like growth pattern was present, the fre-quency of mismatch repair protein deficiency washigher (37.5%) than if plaque-like growth was absent(9.1%). This difference was statistically significant(P=0.041). In univariate analysis, these DNA mis-match repair protein deficiency cases seemed todisplay a more favorable outcome, but the differencein survival did not reach statistical significance(P=0.109).

Transmural lymphoid hyperplasia (Crohn’s likeinfiltrates) was seen in six patients with one caseshowing loss of MLH1 and PMS2 protein expressionwith wild-type BRAF gene, suggesting microsatelliteinstability. Morphologically, this tumor showedmedullary type growth pattern with uninvolvedduodenal mucosa showing celiac disease-likefeatures.

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Figure 4 Unusual/mixed lineage patterns of non-ampullary–duodenal carcinomas: (a) hematoxylin and eosin (left): intestinal-appearingmorphology; and immunohistochemical stains: positive for CK7 (middle) and MUC1 (right) markers. (b) Hematoxylin and eosin (left):pancreatobiliary-appearing morphology; and immunohistochemical stains (right): positive for CDX2.

Figure 5 Discrepancy between the phenotype of the preinvasive (adenomatous) and invasive components in non-ampullary–duodenalcarcinomas: (a) positive for MUC2 in adenomatous component, (b) whereas positive for CK7 in invasive component.

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Prognosis of Non-Ampullary–Duodenal Carcinomas,and Comparison with Ampullary Carcinomas andPancreatic Ductal Adenocarcinomas

Of the 30 non-ampullary–duodenal carcinomas withfollow-up information available survival rangedfrom 1–106 months (mean, 18 months). The presenceof morphologic gastro-pancreatobiliary pattern,regardless of its extent, appeared to be associatedwith more aggressive behavior than those that didnot, but this did not reach statistical value (P=0.07;Figure 7). None of the other histologic parametersreached statistical significance.

The 3- and 5-year survival rates of resected non-ampullary–duodenal carcinomas were 57% and57%, respectively, which was similar to those ofpatients with ampullary carcinomas (62 and 49%;P=0.75), especially, the ampullary–duodenal subsetof ampullary carcinomas (59% and 52%, respec-tively) (P=0.78; Table 2); however, when comparedwith the ampullary ductal subset of ampullarycarcinomas (41% and 29%, respectively), they hadmuch better survival (Po0.001).3 Non-ampullary–duodenal tumors were also associated with incom-parably better outcome than pancreatic ductaladenocarcinoma patients (3- and 5-year survivalrates of 28% and 18%, respectively; Po0.001;Table 1).

The survival of non-ampullary–duodenal carcino-mas with pure or almost exclusively composed ofgastro-pancreatobiliary type seemed to have a prog-nosis similar to the ampullary ductal subtype ofampullary carcinomas and pancreatic ductal carci-nomas, at least during the early follow-up period (1-

year rate 76% vs 81% vs 65%, respectively).Although its 5-year survival (54%) appeared to bebetter than ampullary ductal ampullary carcinomasand pancreatic ductal adenocarcinomas (36% vs18%, respectively), this did not reach statisticalsignificance, perhaps due to the low number of cases(P-values of 0.82 and 0.1; Table 5).

Discussion

In this study, non-ampullary–duodenal carcinomaswere found to have several distinctive characteris-tics. First, unlike other intestinal carcinomas, non-ampullary–duodenal carcinomas less commonlyarise from overt adenomatous epithelial lesions.Only 37% of the cases in this study had anidentifiable adenoma component, and this wasprominent in only 14% of cases, as opposed tolower-intestinal cancers and the ampullary–duode-nal subset of ampullary carcinomas, where the vastmajority has a prominent adenoma component.Interestingly, the distal duodenal carcinomas weremore commonly associated with intestinal-typeadenomas (9/12) vs the proximal examples (firstand second portion of duodenum) more commonlyassociated with gastric/Brunner gland abnormalitiesin the background mucosa (12/27), but seldom withintestinal-type adenoma (only one case).

It is now being increasingly appreciated thatcarcinomas arising from adenomas are biologicallydifferent. Non-ampullary–duodenal carcinomasinstead often form plaque/ulcero-plaque-like lesions,which may be partly responsible for their more

Table 3 Correlation between histological and immunohistochemical typing of non-ampullary–duodenal carcinomas based on the criteriaproposed by Ang et al. for ampullary carcinoma

Histological typing

Intestinal Pancreatobiliary Mixed Mucinous Poorly differentiated Total(n=7) (n=15) (n=13) (n=1) (n=2) (n=38)

Immunohistochemical typingIntestinal 7 (100) 1 (6) 3 (23 ) 1 (100) 1 (50) 13Pancreatobiliary 0 (0) 7 (47) 0 (0) 0 (0) 0 (0) 7Ambiguous 0 (0) 7 (47) 10 (77) 0 (0) 1 (50) 18

Table 4 Expression of the immunohistochemical markers among the histotype of non-ampullary–duodenal carcinomas

Histotype (n)

Pancreatobiliarymarkers Gastric markers Intestinal markers

MUC1 CK7 MUC5AC MUC6 MUC2 CDX2 CK20

Intestinal (7) 2 (29) 1 (14) 3 (43) 1 (14) 5 (71) 6 (86) 6 (86)Pancreatobiliary (15) 10 (67) 11 (73) 9 (60) 10 (67) 0 (0) 3 (20) 2 (13)Mixed (13) 7 (54) 8 (62) 4 (31) 1 (8) 7 (54) 7 (54) 6 (46)Mucinous (1) 0 (0) 0 (0) 1 (100) 0 (0) 1 (100) 1 (100) 1 (100)Poorly differentiated (2) 0 (0) 1 (50) 2 (100) 1 (50) 1 (50) 0 (0) 1 (50)

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subtle appearance (and smaller overall size) atdiagnosis, compared with the ampullary–duodenalsubset of ampullary carcinomas although the size ofthe invasive components of these two groups iscomparable. Of note, this plaque-like growth had aclose association with DNA mismatch repair proteindeficiency, which we found in 13% of non-ampul-lary–duodenal carcinomas overall, with all of theseshowing plaque-like growth pattern, pushing-borderinfiltration, and tumor-infiltrating lymphocytesmicroscopically. Considering that DNA mismatchrepair protein testing is now performed routinely incolorectal cancer, where the frequency of mismatchrepair protein deficiency is also about the samerate,14 a DNA mismatch repair protein testing mayhave to be considered in at least the cases with thesefindings, if not all non-ampullary–duodenal carci-nomas. The lack of overt adenoma component inmost non-ampullary–duodenal carcinomas (alongwith other findings discussed below) also leads tothe impression that they may be arising fromBrunner glands (or non-intestinal cell types that arenot prone to form adenomas).

In addition, marked contrast with lower-intestinalcancers, most of which are pure intestinal type, non-ampullary–duodenal carcinomas exhibit a strikingdegree of morphologic versatility. In our study, thegastro-pancreatobiliary and mixed patterns werepredominant, with only 19 % of cases qualifying aspure intestinal by morphology and 34% immuno-histochemically by Ang criteria proposed for classi-fying ampullary carcinomas into pancreatobiliaryversus intestinal recently.12 Ushike et al.10 noted intheir recent study of 38 ‘extra-ampullary–duodenalcarcinomas’ that only about a third of their casesqualified as ‘intestinal’, and 50% as gastric, withadditional 5% as pancreatobiliary. It should be notedhere that our series is predominantly composed ofcases from the second segment of the duodenumwith only three cases (7%) from first segment,presumably due to our group’s interest in pancrea-tobiliary tract; whereas, in the study by Ushiku andLauwers, 40% of their cases were from the first

segment, possibly representing the gastric patholo-gists’ perspective. Nonetheless, both our studies arein accordance that non-ampullary–duodenal carci-nomas are more commonly of gastro-pancrea-tobiliary type.

Non-ampullary–duodenal carcinomas also differsignificantly from other intestinal cancers by theirimmunoprofile15,16 as well, in that o50% expressMUC2, CDX2, and CK20, markers that are consis-tently positive in lower-intestinal cancers. Instead,gastro-pancreatobiliary markers, which are seldomexpressed in intestinal cancers, are fairly common innon-ampullary–duodenal carcinoma (MUC1 50,MUC5AC 50, MUC6 34, and CK7 55%), highlightingthis tumor’s closer relationship to gastric/pancreato-biliary (foregut) carcinomas, rather than lower-intestinal ones.

It should also be noted that in a manner similar toampullary carcinomas, but different than otherintestinal carcinomas, non-ampullary–duodenal car-cinomas, often show mixed/hybrid phenotypes pre-sumably related to the fact that a variety of cell typesreside in this region (including Brunner glands, aswell as metaplastic/heterotopic epithelium of gastricand pancreatic origin) that can also occur frequentlyin the duodenum, and may be responsible for the notuncommon expression of gastro-pancreatobiliarylineage markers (MUC5AC/MUC6/CK7) even inintestinal-appearing cases. As a consequence, it isnot surprising that non-ampullary–duodenal carci-nomas can give rise to hitherto unrecognizedadenocarcinoma patterns (outside the realm ofconventional intestinal and pancreatobiliary adeno-carcinomas), including comedocarcinoma-like,papillary-oncocytoid, and cribriform, and partiallyalso microcystic although a version of the latter alsooccurs in pancreatobiliary adenocarcinomas.

Separately, the fact that celiac disease-like changes(atrophy and intraepithelial lymphocytosis) wereseen in the duodenal mucosa away from theadenocarcinoma in 17% of the non-ampullary–duodenal carcinomas in our cohort begs the question

Figure 6 Non-ampullary–duodenal carcinoma case with DNAmismatch repair protein deficiency: pushing-border infiltrationpattern with Crohn’s like features.

non-gastro-pancreatobiliary

gastro-pancreatobiliary

Surv

ival

Months after resection

Figure 7 Survival comparison of gastro-pancreatobiliary vs non-gastro-pancreatobiliary phenotypes.

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of whether tumor development may, at least in part,result from an injury mechanism specific to theduodenum. Whether the cases arising in this settingconnote different biology or not requires furtherstudies.

In our cohort the 5-year survival rate for non-ampullary–duodenal carcinomas was 57%. Thisfigure is similar to the studies that focused onwell-characterized cases of non-ampullary–duode-nal carcinomas, where it is ~ 55% with a range of54–60% in the largest institutional series on thistopic.5,10,17,18 We found that the presence ofgastric-pancreatobiliary histology may be associatedwith more aggressive behavior (although this did notreach statistical significance), which was alsoreported by others10,16 and thus it is important toattempt to recognize and report this lineage (nomatter the quantity) in any non-ampullary–duodenalcarcinoma case.

When compared with a well-characterized cohortof ampullary carcinomas, the prognosis of non-ampullary–duodenal carcinomas is fairly similar,when all ampullary carcinomas are consideredtogether. Not surprisingly, it is the ampullary–duodenal subset of ampullary carcinomas that non-ampullary–duodenal carcinomas are most similar to,whereas the ampullary ductal subset of ampullarycarcinoma has a worse outcome than non-ampul-lary–duodenal carcinoma (5 year, 29% vs 57%).More importantly, the prognosis of non-ampullary–duodenal carcinoma is incomparably better than thatof pancreatic ductal adenocarcinoma. Having saidthat, non-ampullary–duodenal carcinomas with pureor almost exclusively gastro-pancreatobiliary typeappear to have aggressiveness similar to the ampul-lary ductal subset of ampullary carcinomas andpancreatic ductal adenocarcinomas at least at theearly phase (1-year rate 76%, 81%, and 65%,respectively); although their long-term survival mayprove to be better (54% vs 36% vs 18%, respectively,in this study, which did not reach statisticalsignificance, probably due to low numbers). This isimportant, because, for non-ampullary–duodenalcarcinoma that occurs close to the pancreas, pan-creatic ductal adenocarcinoma with secondary inva-sion into duodenum becomes an important and

highly challenging differential. These findings alsohighlight the importance of accurate grossing inpancreatoduodenectomy specimens in identifyingthe site of origin of these tumors, as our study showsthat non-ampullary–duodenal carcinomas havemuch better outcomes than their pancreatic ductalcarcinoma and ampullary ductal ampullary carci-noma counterparts. These findings are in sharpcontrast to those of Westgaard et al.,19 who in theirstudies of all periampullary adenocarcinomas (non-ampullary–duodenal carcinomas included) sug-gested that it is histology (pancreatobiliary vsintestinal) and not location that played a criticalrole in the prognosis of these tumors. It should alsobe kept in mind that besides behavioral differencesthere may be various etiopathogenetic and molecularmechanistic differences between the cancers arisingfrom different areas of this relatively small region,and each may require different managementapproaches in the future accordingly.

In conclusion, this study elucidates that non-ampullary–duodenal cancers have clinicopathologiccharacteristics similar to ampullary–duodenal can-cers, but different from the other intestinal andpancreatobiliary tract cancers. Compared withlower-intestinal cancers non-ampullary–duodenalcarcinomas often exhibit gastro-pancreatobiliarylineage, and are seldom of pure intestinal type, afact that should be considered when devising site-specific treatment protocols for these tumors. Non-ampullary–duodenal carcinomas also appear to havedifferent carcinogenic mechanisms, often skippingthe adenoma-carcinoma sequence (only a third hasidentifiable adenoma component). This, combinedwith frequent plaque-like growth (which seems tohave an association with DNA mismatch repairprotein deficiency), warrants further analysis fordeveloping more specific therapies. It is also impor-tant for pathologists to recognize the morphologicversatility of these carcinomas for accurate diagnosisthat may in part be related to the epithelial diversityof this region. The paucity of adenomatous elements,common plaque-like growth, and tendency forgastro-pancreatobiliary lineage with hitherto unrec-ognized patterns discovered in this study suggestthat a subset of non-ampullary–duodenal carcinomas

Table 5 Survival comparison of non-ampullary–duodenal carcinomas of gastro-pancreatobiliary type (morphology) with both ampullaryductal subset of ampullary carcinomas and pancreatic ductal adenocarcinomas

Survival ratesNon-ampullary–duodenal carcinoma of gastro-

pancreatobiliary type* (n=13)Ampullary ductal

(n=66)Pancreatic ductal adenocarcinoma

(n=227) P† P††

1 year 76 81 65 0.82 0.13 year 54 52 285 year 54 36 18

*Non-ampullary–duodenal carcinoma with pure or almost exclusively gastro-pancreatobiliary type (morphology) with the follow-up informationavailable.P† comparison between non-ampullary–duodenal carcinoma of gastro-pancreatobiliary type* and ampullary ductal.P†† comparison between non-ampullary–duodenal carcinoma of gastro-pancreatobiliary type* and pancreatic ductal adenocarcinoma.

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may be arising from submucosal ductular/glandularelements (including Brunner glands) or heterotopictissue that distinguishes this region from othersegments of the gastrointestinal tract.

Disclosure/conflict of interest

The authors declare no conflict of interest.

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Non-ampullary–duodenal carcinomas: clinicopathologic analysis of 47 cases and comparison with ampullary and pancreatic adenocarcinomasMainMaterials and methodsDefinitionsDemographic and Clinical DataPathologic ParametersImmunohistochemical AnalysisCell lineage markersDNA mismatch repair protein markersMethodologyEvaluation of immunohistochemical stains

Statistical Analysis

ResultsGeneral Characteristics of Non-Ampullary–Duodenal Carcinomas and Comparison with both Ampullary Carcinomas and Pancreatic Ductal AdenocarcinomasComparison of Non-Ampullary–Duodenal Carcinomas with Ampullary–Duodenal Subset of Ampullary CarcinomasGross Features of Non-Ampullary–Duodenal CarcinomasHistologic PatternsChanges in the Background MucosaImmunoprofile of Non-Ampullary–Duodenal CarcinomasDNA Mismatch Repair Protein Deficiency in Non-Ampullary–Duodenal CarcinomasPrognosis of Non-Ampullary–Duodenal Carcinomas, and Comparison with Ampullary Carcinomas and Pancreatic Ductal Adenocarcinomas

DiscussionReferences