712454

research-article2017
IJSXXX10.1177/1066896917712454International Journal of Surgical PathologyMahansaria et al

Original Article
International Journal of Surgical Pathology

Ampullary Mixed Adenoneuroendocrine

2017, Vol. 25(7) 585­–591
© The Author(s) 2017
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DOI: 10.1177/1066896917712454
https://doi.org/10.1177/1066896917712454

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Shyam Sunder Mahansaria, MBBS, MS, MCh1, Nikhil Agrawal, MBBS, MS, MCh1,
Asit Arora, MBBS, MS, MCh1, Chhagan Bihari, MBBS, MD1,
Murali Appukuttan, MBBS, MS, DNB, MCh1, and
Tushar Kanti Chattopadhyay, MBBS, MS1

Abstract
Introduction. Mixed adenoneuroendocrine carcinoma (MANEC) has recently been defined by the World Health
Organization in 2010. These are rare tumors and MANECs of ampullary region are even rarer. Only 19 cases have been
reported in literature. We present 3 cases; the largest series, second case of amphicrine tumor and first case associated
with chronic pancreatitis. Methods. Retrospective review of 3 patients who were diagnosed to have ampullary MANEC.
Results. All 3 patients were diagnosed preoperatively as neuroendocrine carcinoma and underwent margin negative
pancreaticoduodenectomy. The histopathology revealed MANECs of small cell, mixed type in 2 patients and large cell,
amphicrine type in 1 patient. The neuroendocrine component was grade 3 in all, the tumor was T3 in 2 and T2 in 1
and all had nodal metastases. Two patients received adjuvant chemotherapy and 2 of them had recurrence at 13 and 16
months. The median survival was 15 months. Conclusion. Ampullary MANECs are rare tumors. They are diagnosed on
histopathologic examination of the resected specimen. Clinical presentation, management, and prognosis is similar to
ampullary adenocarcinoma in literature.

Keywords
ampullary MANEC, pancreaticoduodenectomy

Introduction Ampullary MANECs are rare tumors and only 19

The first description of a gastrointestinal tumor with both
exocrine and neuroendocrine components was published
by Cordier1 in 1924. Besides gastrointestinal segments, it
has also been reported in the pancreas, gallbladder, and
uterine cervix.2 These tumors have been reported with dif-
ferent names, including composite carcinoid, mucin-pro-
ducing carcinoid, argentaffin cell adenocarcinoma, goblet
cell carcinoid, adenocarcinoid, small cell undifferentiated
carcinoma, and so on.3 In the most recent 2010 World
Health Organization (WHO) classification of neoplasm of
the gastrointestinal tract, these neoplasms are called mixed
adenoneuroendocrine carcinoma (MANEC).4
Diagnosis is based mainly on the tumor cytomorphol-
ogy and architecture, being completed by the immunos-
tains with specific neuroendocrine markers such as
chromogranin, synaptophysin, and neuron-specific eno-
lase (NSE), and combined with the markers on nonendo-
crine differentiation such as periodic acid-Schiff (PAS)
alcian blue, MUC 1, MOC 31, and S-100.
cases have been reported in literature. The presentation,
management and prognosis of these tumors is not well
defined. We retrospectively reviewed our patients to
study these aspects.
Methods
Patients with the diagnosis of ampullary MANEC at our
institution on final histopathology from January 2010 to
December 2016 were identified and included retrospec-
tively in the study. The demography, presentation, imag-
ing, surgery, histopathology, and clinical outcome were
analyzed. The histopathological typing and grading of
1
Institute of Liver & Biliary Sciences, New Delhi, India
Corresponding Author:
Nikhil Agrawal, Department of HPB Surgery, Institute of Liver & Biliary
Sciences, D1, Vasant Kunj, New Delhi 110070, India.
Email: drnkhl@gmail.com
586 International Journal of Surgical Pathology 25(7)

Table 1.  Histopathology and Immunohistochemistry.

Case 1 Case 2 Case 3

Tumor size (cm) 4 4 1.5
Tumor location Ampulla-NOS Ampulla-NOS Periampulla-duodenum
Resection margins R0 R0 R0
Lymph nodes (positive/resected) 4/24 4/39 4/17
Pathological tumor stage pT3, pN1 pT3, pN1 pT2, pN1
Type of MANEC Mixed Amphicrine Mixed
Adenocarcinoma tumor grade/type Grade 2, intestinal type Grade 3, Grade 3, intestinal type
pancreatobiliary type (signet ring cell differentiation 10%)
Neuroendocrine tumor grade Grade 3 Grade 3 Grade 3
Neuroendocrine tumor type Small cell type Large cell type Small cell type
Immunohistochemistry PAS+ MUC 1+, NSE+ MUC 1+
Synaptophysin+ S-100 and MOC31+ Synaptophysin+
Chromogranin+ Synaptophysin+ Chromogranin+
Chromogranin+
Ki-67 index >50% >50% 40%
Perineural invasion Present Absent Present
Lymphovascular invasion Present Present Present

Abbreviations: NOS, not otherwise specified; MANEC, mixed adenoneuroendocrine carcinoma.

glandular and neuroendocrine component was done as per
the current WHO classification of tumors of the digestive
system.
Results
In the study period, of the 153 patients diagnosed with
periampullary tumor who underwent pancreaticoduode-
nectomy, 3 patients were diagnosed to have ampullary
MANEC (Table 1). Two patients were male. Age of the
patients was 37, 39, and 64 years. The patients presented
with pain abdomen, jaundice, and/or weight loss.
Preoperative serum CA19-9 and chromogranin-A were
normal in all patients. Contrast-enhanced computed
tomography scan of the abdomen showed heterogeneous
hypodense periampullary tumor and it was associated with
chronic pancreatitis in case 1 (Figure 1A and B). The
lesions were biopsied endoscopically and reported as neu-
roendocrine carcinoma. All three underwent pancreatico-
duodenectomy. The pancreaticojejunostomy in patient
with chronic pancreatitis was done after opening the entire
length of the duct. The postoperative course was compli-
cated by surgical site infection (case 1) and pancreatic fis-
tula (cases 2 and 3).
On histopathology, all were R0 resections. Two patients
were T3N1 and 1 patient was T2N1 (Table 1). The tumor
location was ampulla–not otherwise specified (ampulla-
NOS) in cases 1 and 2, while it was periampulla-duode-
num in case 3. The type of MANEC was small cell; mixed
in cases 1 (Figure 1C-E) and 3 (Figure 3A-C) and large
cell; amphicrine in case 2 (Figure 2A-E). The neuroendo-
crine component was grade 3 in all the patients. The
adenocarcinoma component was grade 2; intestinal type in
case 1, grade 3; pancreatobiliary type in case 2 and grade
3; intestinal type in case 3. The Ki-67 index of the neuro-
endocrine component was ≥40% in all cases.
Cases 1 and 3 received 6 cycles of adjuvant gem-
citabine and oxaliplatin, while case 2 did not tolerate
adjuvant chemotherapy. Cases 2 and 3 had recurrence at
13 and 16 months, respectively. Case 1 presented 8
months later with pain abdomen, ascites, and hypoalbu-
minemia. CA-19.9 was 2347.8 U/mL (normal 0-37 U/
mL). Contrast-enhanced computed tomography revealed
liver parenchymal disease and portal hypertension; but
there was no evidence of recurrence. The ascitic fluid
cytology was also negative for malignant cells. He died
of liver failure 4 months later.
Discussion
Neuroendocrine tumors (NETs) of the digestive system are
classified as: NET G1 (mitotic count: <2 per 10 high-
power fields [HPF]; and/or ≤2% Ki-67 index); NET G2
(mitotic count: 2-20 per 10 HPF; and/or 2%-20% Ki-67
index); neuroendocrine carcinoma (mitotic count: >20 per
10 HPF; and/or >20% Ki-67 index; large- or small-cell
type); and MANECs. Routine immunohistochemical
staining will frequently identify few neuroendocrine cells
in adenocarcinomas. Similarly, the presence of an exocrine
component in high-grade gastrointestinal neuroendocrine
carcinomas is widely documented.3 However, according to
the 2010 WHO classification,4 MANECs by definition are
neoplasms in which exocrine and endocrine components
represent at least 30% of the lesion.
Mahansaria et al 587

Figure 1.  Case 1: (A) Coronal section of contrast-enhanced computed tomography scan of the abdomen venous phase showed
grossly dilated main pancreatic duct (black arrow) with calcification in head and tail of the pancreas (white arrow). (B) Axial
section of pancreatic parenchyma phase showed heterogeneous hypodense lesion (3.7 × 3.9 × 3.3 cm) in periampullary region
with peripheral calcification (black arrow). (C) Adenocarcinoma component is highlighted by presence of periodic acid–Schiff
(PAS)-positive intraluminal mucin (large arrow) and intracytoplasmic mucin vacuoles (small arrow) (200×). (D) Neuroendocrine
component is positive for synaptophysin. (E) High Ki-67 index in neuroendocrine tumor.

Ampullary carcinoma has been subclassified into 4 cat-
egories based on the exact location; intra-ampulla with
tumor limited only to the ampulla; ampulla-ductal with
thickening of bile/pancreatic duct resulting in elevation of
papilla into the duodenal lumen; periampulla-duodenum
with exophytic tumor growing into the duodenal lumen
and minimal intra-ampullary growth; and ampulla-NOS
indicating tumor located at the papilla of Vater with mixed
involvement of duodenum, intra-ampulla, and bile/pancre-
atic ducts.5 Of the total 22 ampullary MANECs (including
the present series), distribution of ampullary MANEC
were intra-ampulla in 18% (4/22), periampulla-duodenum
in 27% (6/22) and ampulla-NOS in 55% (12/22) (Table 2).
As with other ampullary carcinomas, ampulla-NOS is the
most common location for ampullary MANECs.5
Three types of MANECs have been described accord-
ing to the distribution of neuroendocrine and exocrine
component; amphicrine, mixed or combined and colli-
sion.3,22,23 The Amphicrine type arises from early stem
cells that proliferate into a neoplasm before differentiating
into endocrine and exocrine lineage cells (ie, one cell type
that has both exocrine and endocrine features). It is the rar-
est among all the 3 types of MANECs. This pattern was
found in one of our cases. Only 1 case of amphicrine
ampullary MANEC has been reported earlier (Table 2).21
Once the stem cells differentiate into primitive exocrine
588 International Journal of Surgical Pathology 25(7)

Figure 2.  Case 2: (A) Tumor section (200×, hematoxylin and eosin). (B) MUC-1 positivity (200×). (C) Chromogranin A positivity.
(D) Synaptophysin positivity. (E) Ki-67 >20%. All 3 stains are positive in the same cell as shown in (B), (C), and (D), suggesting
amphicrine tumor.

Figure 3.  Case 3: (A) Tumor section showing adenocarcinoma component (large arrow) (200×, hematoxylin and eosin). (B)
Tumor section showing neuroendocrine component (small arrow) (200×, hematoxylin and eosin). (C) Neuroendocrine component
is positive for synaptophysin (blue arrow) (200×).

and endocrine cells, 2 types of histological patterns may
occur; mixed and collision. In the mixed type, the exocrine
and endocrine cells are intimately intermixed together. In
the present series, 2 cases showed mixed differentiation.
Most reported cases of ampullary MANECs were of this
type (Table 2). The collision type shows the endocrine part
at one end and the exocrine part at the other end, with an
intermixed central zone. Of the total 22 ampullary
MANECs, 68% (15/22) were mixed type, 23% (5/22) col-
lision type, and 9% (2/22) amphicrine type (Table 2).
Chang et al23 also suggested adding solitary concomitant
and multiple concomitant types to the classification. The
solitary concomitant type shows a single tumor composed
of distinctly separate exocrine and endocrine components,
with a dividing fibrous band found between the 2 parts.
The multiple concomitant type contains isolated exocrine
 Table 2.  Summary of Ampullary Mixed Adenoneuroendocrine Tumor in the Literature.

Tumor Size, Preoperative Type of Adenoca Tumor NET Lymph

Authors, reference Age, y Sex cm Diagnosis Tumor Location MANEC Grade/Type Grade Node Outcome
6
Jones et al 64 F 1.5 Adenoca Intra-ampulla Mixed G1, goblet cells G1 Negative Surgery; alive (35 months)
Misonou et al7 47 F 3 Adenoca Intra-ampulla Mixed G1, intestinal type G3 Positive Surgery; suspected recurrence
(9 months)
Alex et al8 63 F 1.5 Adenoca Intra-ampulla Mixed G1–2, goblet cells G1-2 Negative Surgery; alive (24 months)
Burke and Lee9 45 M NA Adenoca Periampulla-duodenum Mixed G1, goblet cells G1 Negative Surgery; alive (24 months)
Manzanares et al10 75 M 1.5 Adenoca Periampulla-duodenum Mixed G2, pancreatobiliary G1-2 Negative Surgery; dead (14 months)
Nassar et al11 89 M NA Adenoca Periampulla-duodenum Mixed G2, intestinal type; G3 Negative Surgery; alive (6 months)
adenoma
69 F NA Adenoca Periampulla-duodenum Mixed G2, intestinal type; G3 Negative Surgery; NA
adenoma
Zhang et al12 69 M 1.5 Adenoca Periampulla-duodenum Mixed G1-2, intestinal type; G3 Negative Surgery; alive (33 months)
adenoma
60 M 5 MANEC Ampulla-NOS Mixed G3, signet ring cells G3 Positive Palliative alive (9 months)
Mayol et al13 34 M 3 Adenoca Ampulla-NOS Collision NA NA Negative Surgery; dead (16 months)
Shaw et al14 27 F 2 Adenoca Ampulla-NOS Mixed G2-3, signet ring G1 Negative Surgery; dead
cells
Williams et al15 58 F 1.2 MANEC Ampulla-NOS Collision G2, intestinal type G1-2 Positive Surgery; alive (NA)
Moncur et al16 78 M 2.3 Adenoca Ampulla-NOS Mixed Acinar cell G3 Negative Autopsy; dead (2 months)
carcinoma of
pancreas
Marco et al17 64 M 4 NA Ampulla-NOS Collision G2-3, G1 Negative Surgery; dead (14 months)
pancreatobiliary
Deschamps et al18 49 F 5 Adenoca Ampulla NOS Collision G1, intestinal type; G1 Positive Surgery + chemotherapy; alive
adenoma (36 months)
Vilardell F et al19 81 M 2.7 Adenoca Ampulla-NOS Collision G-2, intestinal type G3 Positive Surgery; NA
Huang et al20 43 F 2 Adenoca Intra-ampulla Mixed G-3, intestinal type G3 Negative Surgery + chemotherapy; dead
(20 months; recurrence)
60 F 1.7 Adenoca Ampulla-NOS Mixed G-3, glandular G3 Negative Surgery + chemotherapy; dead
differentiation (15 months; recurrence)
Ginori et al21 69 M 2 NA Ampulla-NOS Amphicrine NA G2 Positive Surgery; alive (12 months with
no recurrence)

Abbreviations: adenoca, adenocarcinoma; NOS, not otherwise specified; NET, neuroendocrine tumor; G1, grade 1; G2. grade 2; G3, grade 3; NA, not available; MANEC, mixed adenoneuroendocrine
carcinoma.

589
590 International Journal of Surgical Pathology 25(7)
and endocrine tumors simultaneously.23 La Rosa et al3 sug-
gested grouping these tumors in different prognostic cate-
gories according to the grade of malignancy of each
component. They classified them into high-grade malig-
nant MANEC (formed by an adenomatous or carcinoma-
tous component and neuroendocrine carcinoma) and
intermediate grade malignant MANEC. The intermediate
grade malignant MANEC includes mixed adenocarci-
noma-neuroendocrine tumor (formed by carcinomatous
component and NET G1 or G2) and amphicrine carci-
noma. They also proposed a provisional category of mixed
adenoneuroendocrine tumor (low-grade malignant, formed
by adenoma and NET G1 or G2).3
Several studies have investigated the origin of these
tumors at molecular and genetic level. Kim et al24 ana-
lyzed the genome-wide loss of heterozygosity and sug-
gested that most have sequentially evolved from a
glandular precursor to a genetically heterogeneous adeno-
carcinoma and then to neuroendocrine differentiation,
while, occasionally dual differentiation concurrently arises
from a single precursor, possibly as a result of nondisjunc-
tional cell division.24 Furlan et al25 performed microallelo-
typing and showed close genetic relationship between both
components of mixed type and clonal divergence in colli-
sion tumors.
The ampullary MANEC in case 1 was associated with
chronic pancreatitis. To the best of our knowledge, it is the
first case of MANEC associated with chronic pancreatitis.
Preoperative diagnosis of MANEC is difficult due to
lack of specific clinical symptoms and radiological fea-
tures along with limitations of sampling and quantification
of each component on preoperative biopsy. They present
like periampullary tumors. Only 2 out of 22 cases had pre-
operative diagnosis of MANEC (Table 2). Most of the
cases were diagnosed as adenocarcinoma (Table 2). In the
present series, all 3 patients were diagnosed as neuroendo-
crine carcinoma on preoperative biopsy. A biopsy samples
a small area of tumor and may miss one component.
Moreover, exact quantification of each component is pos-
sible only in the resected specimen.
They should be treated surgically like periampullary
tumors. Pancreaticoduodenectomy should be done in
resectable tumors. Of the 22 cases of periampullary
MANECs, pancreaticoduodenectomy was done in 86%
(19/22) of patients (Table 2).
The largest published series of 2564 resected periam-
pullary adenocarcinoma have shown estimated median
survival of 22 months for the entire cohort.26 Positive
lymph nodes, positive surgical margins, higher tumor
stage, histologically proven pancreatobiliary origin, and
poorly differentiated tumor were associated with signifi-
cantly lower survival in patients of ampullary adenocarci-
noma after surgical resection.27,28 Another series of 346
patients studied predictors of survival in periampullary
cancers following pancreaticoduodenectomy. Only nodal
metastasis and neural invasion significantly predicted out-
come on multivariate analysis.29 In addition, 4 clinicopath-
ological subtypes of ampullary carcinoma are also
prognostically distinct with best prognosis of intra-ampulla
subtype and worst prognosis is of ampulla-NOS.5
Patients with intra-ampulla location of MANEC, low
grade adenocarcinoma and neuroendocrine component
with no lymph node metastasis have the best prognosis.
Whereas ampulla-NOS location, higher grades of adeno-
carcinoma, or neuroendocrine component with lymph
node metastasis seem to have poor outcome (Table 2). Few
authors have suggested that the prognosis depends mainly
on the stage of adenocarcinoma,12 whereas others have
suggested that the neuroendocrine tumor has higher inva-
siveness with poor prognosis than adenocarcinoma.30 It is
reasonable to treat based on more aggressive component
of the tumor.
In the present series, median survival after curative sur-
gical resection was 15 months. Though this is less than that
reported for periampullary carcinomas following pancre-
aticoduodenectomy, our patients had tumors that were
high grade and large in size with high Ki-67 index, neural
invasion, and lymph node metastasis.
Use of gemcitabine as adjuvant chemotherapy improves
survival in patients with periampullary malignancies; par-
ticularly in patients with poor prognostic factors.31 It is dif-
ficult to assess the impact of adjuvant chemotherapy and
suggest the best chemotherapeutic agent in ampullary
MANECs due to rarity of the disease. It may be adminis-
tered in patients with poor prognostic factors.
In conclusion, ampullary MANECs are rare tumors.
They are diagnosed after resection aided by immunohisto-
chemistry. Their presentation and surgical management is
similar to ampullary adenocarcinoma. With curative surgi-
cal resection, survival possibly similar to ampullary ade-
nocarcinoma can be obtained.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
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