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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:
[email protected] authors are co-contributing first
authors.Received 20 April 2016; revised 28 August 2016; accepted 31
August 2016; published online 14 October 2016
Modern Pathology (2017) 30, 255–266
© 2017 USCAP, Inc All rights reserved 0893-3952/17 $32.00
255
www.modernpathology.org
http://dx.doi.org/10.1038/modpathol.2016.174mailto:[email protected]://www.modernpathology.org
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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
Non-ampullary–duodenal carcinomas
256 Y Xue et al
Modern Pathology (2017) 30, 255–266
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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
Modern Pathology (2017) 30, 255–266
Non-ampullary–duodenal carcinomas
Y Xue et al 257
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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.
Modern Pathology (2017) 30, 255–266
Non-ampullary–duodenal carcinomas
258 Y Xue et al
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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.
Modern Pathology (2017) 30, 255–266
Non-ampullary–duodenal carcinomas
Y Xue et al 259
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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.
Modern Pathology (2017) 30, 255–266
Non-ampullary–duodenal carcinomas
260 Y Xue et al
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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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262 Y Xue et al
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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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264 Y Xue et al
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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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Y Xue et al 265
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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