Romanian Biotechnological Letters Vol. 23, No. 6, 2018 [602897]

Romanian Biotechnological Letters Vol. 23, No. 6, 2018
Copyright © 2018 University of Buc harest Printed in Romania. All rights reser ved
ORIGINAL PAPER

Romanian Biotechnologi cal Letters, Vol. 23, No. 6, 2018 14193

Mixed adenoneuroendocrine carci noma of the gastrointestinal
tract-features, diagnosis, m anagement and prognostics

DOI: 10.26327/RBL2018.175

Received for publica tion, March, 10, 2018
Accepted, June, 6, 2018

ALEXANDRA BOLOCAN1,2, DAN NICOLAE PĂDURARU1,2, CORNELIA NIȚIPIR2,
RĂZVAN HAINĂROȘIE2, SILVIU M IREL PIȚURU2, CAMELIA DIACONU2,3,
ANDRA SUCEVEANU4, ANCA PANTEA STOIAN2
1- IIIrd Emergency General Surgery Department, Emergency University Hospital, Bucharest, Romania
2 – “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
3 – Clinical Emergency Hospital of Bucharest, Internal Medicine Clinic, 8 Calea Floreasca,
Bucharest, Romania
4 – “Ovidius” University, Faculty of Medicine, Universitatii street, 900470, Constanta, Romania
#All authors had equal contribution to this research.
*Address for correspondence to: [anonimizat], Anca Pantea Stoian MD, PhD

Abstract
Immunohistochemical studies of gastrointestinal tumours have identified a broad spectrum of
combinations between exocrine and neuroendocrine com ponents. The wide range of this type of neoplasia
varies from adenomas or adenocarcinomas with scat tering neuroendocrine cells to classic neuroendocrine
tumours with focally dispos ed of exocrine elements.
Both the exocrine and endocrine elements may have different morphopathological features. The
exocrine segment may be an adenoma or even adenocarcinoma with various degrees of differentiation, and the neuroendocrine fraction can be poorly or well differentiated.
The mixed adenoneuroendocrine carcinomas group (MANECs) include those carcinomas in which
both neuroendocrine and exocrine components represent at least 30% of the entire tumoral mass. The number of cases mentioned in the literature is small due to the low incidence of this type of pathology,
but it can affect any segment of the gastrointestinal tract and depend on the degree of malignancy of each
component and its localisation, patients were classified in different prognostic categories.
The current review presents a synthesis of morphopathological, immunohistochemical, molecular
and genetic characteristics, clinical-imaging diagno stic elements, management and prognosis specific to
this type of cancer.

Keywords : MANEC, gastrointestinal, histological, immunohistochemical, p rognosis

1. Introduction
Gastrointestinal exo-neuroendocri ne tumours were first describe d in 1924 by Cordier (LA
ROSA & al.[1];R.CORDIER[2]). The cases reported at that time ha d very different descriptions
such as composite carcinomas, m ucin-producing carcinoid, argent affin cell adenocarcinomas,
goblet cell carcinomas, undiffere ntiated small cell carcinomas, and the list can continue. Thus,
in 1987, Lewin classifies this t ype of mixed neoplasm in 3 broa d categories: collision, combined
and amphicrine tumours.
In 2010, the World Health Organiz ation (WHO) established the te rm "mixed
adenoneuroendocrine carcinoma" (M ANECs) (G.GRINDI & al.[3]) for neoplasia that exhibits
both components, exocrine and neuroendocrine, at least 30% each (LA ROSA & al.[1]; K.
CHING-MING[4]; R.CARMELO & al.[5]).

ALEXANDRA BOLOCAN, DAN NICOLAE PĂ DURARU, CORNELIA NIȚIPIR, RĂZV AN HAINĂROȘIE,
SILVIU MIREL PIȚURU, CAMELIA DIACONU, ANDRA SUCEVEANU, ANCA PAN TEA STOIAN

14194 Romanian Biotechnological Letters, Vol. 23, No. 6, 2018
Immunohistochemical tests have identified a large number of com binations of the
exocrine and neuroendocrine components, ranging from adenomas o r adenocarcinomas
containing several neuroendocrine cells spread to classical neu roendocrine tumours with
focally disposed of exocrine eleme nts (LA ROSA & al.[1]; K. CHI NG-MING[4]).
However, MANECs are a type of neoplasia rarely encountered in m edical-surgical
practice, although mixed gastrointestinal tract tumours are fou nd in practice. They are
considered carcinomas because both epithelial and neuroendocrin e components are malignant
tumours. The distal oesophagus and the anal canal were the most frequent sites identified to
have a squamous cell carcinoma as an exocrine component (LA ROS A & al.[1]).
Depending on the spatial pattern of its elements, MANECs can be classified into two
categories: composite or collisi on neoplasm. Amphicrine tumours will be distinguished by a
divergent immunophenotypic model in which the exocrine and neur oendocrine traits are
expressed in the same cell.
All gastrointestinal segment s may be affected, but there have a lso been reported cases of
MANEC tumours in the pancreas, b ladder and cervix uteri. MANECs are a challenge for the
surgeon because in most cases only one of the tumour components is identified, and in
incomplete diagnostic circumstances, therapeutic management is insufficient or incorrect.

2. Materials and Methods
The paper is a review of the spe cialised literature, made using MDPI Open Access
Journals, EPOS, NCBI and other international databases.
In particular, papers from 2005 to 2017 were studied, represent ing both original articles
and literature syntheses.

3. Results
Symptomatology of MANECs is non specific, silent, and often tumo urs are identified only
after exploratory laparotomy for other pathologies or as incide ntalomas. A tumour occurs in 5th
or 6th decade, and patients are more likely to have metastatic liver pathology. This is why they
come for a specific medical assessment.
CT is the first-intention method in identifying and staging MAN EC (R.CARMELO &
al.[5]). Its sensitivity is proportional to the size of a tumou r. Liver metastases were the most
commonly recognized elements, and their dimensions may well exc eed the size of a primary
tumour. Bone radiology and CT identify osteosclerotic or mixed osteolytic-osteosclerotic bone
metastases (R.CARMELO & al.[5]; E.K.PAULSON [6]) . A primary tum our is small in size; it
is difficult to detect by CT and does not show a specific patte rn. CT evaluation readily identifies
submucosal lesions and liver metastases which enhance the arter ial phase due to their high
blood supply (F.GIBRIL & al [7]).
A tumour may expand to the mesent ery as a tumoral mass containi ng calcifications or as
a stellate/ spiculated mass. The mesenteric vessels may also be affected by the desmoplastic
reaction. Tumours can be classifi ed separately depending on how each component develops
(Table 1).

Table 1. MANECs- Spatial patterns

Type Description
Composite The two types of compon ents develop in separate areas of the tumor
Collision The exocrine and neuroendocrine parts are mixed and i n touch with each other

Mixed adenoneuroendocrine carcin oma of the gastrointestinal
tract-features, diagnosis, management and prognostics

Romanian Biotechnologi cal Letters, Vol. 23, No. 6, 2018
14195At barium examination, the appearance of mixed ulcerative and u lcers-infiltrative
adenoneurocrine carcinomas is s imilar to advanced stage gastric cancers. Most of the analysed
cases presented regional lymphade nopathy (R.CARMELO & al.[5]).
Desmoplastic reaction at the intestinal level causes intestinal obstruction, vascular
thrombosis, infarction, and ische mia of the affected intestinal segment.
Even immunohistochemically adenocar cinomas show among their cel ls some
neuroendocrine elements or if ne uroendocrine cancer presents fo cal non-neuroendocrine
components, neither are consid ered to be MANECs (Table 2).

Table 2. Neuroendocrine markers for each location[6]

Non-endocrine markers Location
Chromogranin A Keratin 7 Gastric
Synaptophysin Keratin 20
CD56 CDX2 Colorectal
NSE* CEA**

*NSE-Neuron-specific enolase, **CEA- Carcinoembryonic antigen

A particular situation is the g oblet cell carcinoma of the appe ndix, classified by WHO in
2010 both in adenocarcinoma and neuroendocrine tumours, but can not be classified as MANECs
because of the <30% of the neuroe ndocrine component (LA ROSA & al.[1];N.J.CARR& al [8]).
Considering the malignant nature o f i t s e l e m e n t s , M A N E C i s r e g a rded as a malignant
pathology, and depending on the degree of differentiation of ea ch component, several prognostic
categories have been established. However, there is a rare comb ination of adenomas with a well-
differentiated neuroendocrine tu mour, known as MANET, whose bio logical aggression is low.
Although the cells of this type of neoplasia have a moderate de gree of nuclear atypia and a
reduced number of mitotic cell di visions, MANET can metastasise (LA ROSA & al.[1]).
Depending on the potential for malignancy, MANECs are classifie d into three major
categories, listed in Table 3.
Table 3. Classification of gastrointestinal exocrine-neuroendocrine neo plasms according to their degree
of malignancy (LA ROSA & al.[1].

Neoplasia Type
Degree Of malignancy High degree of malignancy Intermediate degree of
malignancy Reduced degree of
malignancy
MANEC* Adenoma / mixed
adenocarcinoma-NEC*** Mixed-Adenocarcinoma
G1 / G2 NET
Amphicrine carcinoma
MANET** Adenoma-NET****

MANEC: mixed adenoneuroendocrine carcinoma; MANET: mixed adenon euroendocrine tumour; NEC:
poorly differentiated neuroendocrine carcinoma; NET: a neuroend ocrine tumour, G1 / G2: corresponding
to 2010 WHO classification

High-grade malignant MANEC (NEC with small or large cells) is m ore common in the
distal half of the oesophagus, has equal chances of developing in both vertical and horizontal

ALEXANDRA BOLOCAN, DAN NICOLAE PĂ DURARU, CORNELIA NIȚIPIR, RĂZV AN HAINĂROȘIE,
SILVIU MIREL PIȚURU, CAMELIA DIACONU, ANDRA SUCEVEANU, ANCA PAN TEA STOIAN

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segments of the stomach and it can also occur in the ascending and descending colon (LA ROSA
& al.[1];LA ROSA & al [9]; M.J.GAFFEY& al [10]).
This particular type of neoplasia, either combined or composite , has a villous or tubule-
villous adenoma/adenocarcinoma, or squamous cell carcinoma, alo ng with a small, intermediate
or large cell neuroendocrine carcinoma. Macroscopically, regard less of the location of a tumour,
it has a polyploid or an ulcerative stenosis-like appearance, w ith a diameter varying between 0.5
and 14 cm. It often presents areas of diffuse necrosis. Large o r small neuroendocrine cells were
positive for synaptophysin and chromogranin A, and the Ki67 ind ex was usually increased (60-
90%) (T.TANABE & al. [11]). They were also positive for peptide hormones (somatostatin,
ACTH adrenocorticotropic hormone, VIP vasoactive peptide) and n uclear accumulation of p53
antigen. P53 tumour cell antigen was identified in 63% of the a nalysed cases of gastric cancer
and 100% of the ampullary and colorectal tumours (LA ROSA & al. [1];(LA ROSA & al.[12]).
The neuroendocrine large cell colorectal subtype showed positiv e nuclear immunoreactivity for
CDX2(LA ROSA & al.[1]).
MANEC CD117 positive colorectal cancers with vascular invasion have been associated
with low survival rates (LA ROSA & al.[1];(LA ROSA & al.[12]). Intracellular neurosecretory
granules are similar to intrauterine immature proto endocrine c ells (C.CAPELA& al.[13]).
The prognosis of patients depends on the type of a tumour and i ts staging. People with
localised disease had better prognosis regarding survival compa red to those with metastases. In
this way, gastrointestinal MAN ECs have a better overall prognos is than pure NEC.
Mixed adenocarcinoma-neuroendocrine tumours (MANET) and amphicr ine carcinomas
are intermediate-grade MANEC (m oderately differentiated cells). MANET is neoplasia made up
of well-differentiated neuroendocrine cells. Unlike high-grade MANECs, in this type of cancer,
the exocrine component is more aggressive than the neuroendocri ne part. MANET is a composite
tumour consisting of tubular, pa pillary or mucinous adenocarcin oma areas and NET G1 / G2
areas. The locations where the pathology has been described are the oesophagus, stomach,
Ampulla of Vater, ileum, and colo n. 60 cases have been reported in the all literature, with a
majority of males aged 65 (LA RO SA & al.[1]). Gastric tumours h ave the same incidence in the
body and gastric antrum. The typical macroscopic appearance is a polypoid mass, between 1,5-
10,5 cm in diameter (Y.FUJIYOSHI & al. [14]). The c olon can be affected at any level , from the
cecum to the rectum. The annular tumours are large (5-7 cm in d iameter), and they can cause
constriction of the intestinal lu men. The cells of this tumour are moderately differentiated in
tubular, papillary or mucous. The well-differentiated neuroendo crine cells are organised in nests,
trabeculae or layers. The differences between intestinal and ga stric exocrine components are
mucin production and the presence of exocrine tumour markers (C EA, epithelial membrane
antigen and specific mucins) (H.R.JR. BATES & al.[15]).
5 cases of gastric MANEC were reported to be associated with ch ronic autoimmune gastric
atrophy and microcarcinoma tumours with enterochromaffin-like i ntramucosal cells (LA ROSA
& al.[1]; M.L.CARUSO & al.[16] ; G.PASQUINELLI & al.[17]).
Moreover, MANECs have been iden tified in distal ileum and cecum in patients with long
history of the intestinal inflammatory disease (F.AUBER & al.[1 8]) and also in patients with
Barrett oesophagus (N.R.CARY & al.[9]). Tahara et al. report an average age of 53 years for
gastric tumours occurring in patients with chronic gastric atro phy, affecting the entire stomach,
following the pattern of lines plastic (Brinton's Disease)(E.TA HARA & al.[20]). Histologically,
the tumour contains CEA positive signet ring cells, diffusely a rranged and neuroendocrine cells
which were positive for chromogr anin A and synaptophysin. Isola ted forms had better outcomes
regarding survival than patients with lymph node metastases who died on average ten months

Mixed adenoneuroendocrine carcin oma of the gastrointestinal
tract-features, diagnosis, management and prognostics

Romanian Biotechnologi cal Letters, Vol. 23, No. 6, 2018
14197post-gastrectomy)(E.TAHARA & al.[2 0]).The mean survival rate at five years was 36%
(L.H.TANG& al.[21]).
Appendix cancers have been repor ted more frequently in male pat ients with a mean age of
50.5 years as diffuse infiltrative solid masses that invade the adjacent caecum and
peritoneum.(T.N.MOYANA& al.[22])
A particular type of MANEC-NET a ppearing in the stomach and the ampulla of Vater is
the pancreatic glandular-endocrine composite tumour (acinar cel ls) where neuroendocrine cells
are disposed in substantial poly gonal nests surrounded by vesse ls. Another type of histological
pattern described is that with well-differentiated cells that f orm glands or ducts, surrounded by
foveolar gastric cells, positive for cytokeratin 7, CEA or MUC2 (LA ROSA & al.[1]).
The most common sites of MANEC-NET, unfortunately, diagnosed in advanced stages
with parietal invasion and ganglion metastases, were those of t he intestinal tract. Lymph node.
And hepatic metastases show a neuroendocrine component identica l to that in a primary tumour.
The adenocarcinomatous component can be represented by many cel l types: scirrhous
argyrophil cells, signet ring cells, goblet cells.
Amphicrine cells were first described by Feyrter, and subsequen tly by Ratzenhofer in the
gastric mucosa of the rabbit as cells with argentaffin subnucle ar granules and mucin vacuoles at
the apical pole of the cell. T hey are sporadic carcinomas (LA R OSA & al.[1]).
Tumours formed by an adenoma a nd a neuroendocrine component, al so known as
glandular-carcinoid tumours, have been reported in the terminal ileum, colon, and rectum.
Macroscopically, the tumour has a polyploid appearance, with a s i z e f r o m 1 . 5 t o 3 c m . T h e
adenomatous part is made of vill ous or tubular glands, with a l ow or high degree of dysplasia. In
the case of composite tumours, th e neuroendocrine component is described centrally in the polyp,
small sized, nest-disposed, while the adenomatous part is perip herally located. Neuroendocrine
cells are argyrophil and positive for chromogranin A, synaptoph ysin, and in some cases also for
somatostatin, serotonin, and gluc agon. A tumour invades intesti nal mucosa and submucosa,
which allows the endoscopic resection of the polyp or a transan al excision surgery. The prognosis
of this type of cancer is exce llent, with no recurrences record ed (F.MCKEOWN [23]).
McKeown described in 1952 for the first time small cell oesopha geal carcinoma derived
from APUD cells (F.MCKEOWN [23]). . Immunohistochemically, the cells were positive for
chromogranin A, synaptopodin, CD 56 and NSE (Y.ZHU & al.[24];J. P.YUN & al.[25]).
Oesophagus MANECs are rare cancers, extremely aggressive, with poor prognosis regarding
survival. There are two main cat egories: squamous cell carcinom a and adenocarcinoma. There is
no standard therapeutic management, and the treatment includes chemotherapy, radiotherapy, and
surgical resection J .P.YUN & al.[25]).
Patients with upper gastric tumours present epigastric pain, dy sphagia, belching after meals,
in addition to signs of neoplastic impregnation (rapid involunt ary weight loss, loss of appetite,
asthenia, and fatigue). The most significant study of such case s, identified in our literature, relates
to the evaluation of 100 cases o f gastric cancer (L.NIE[26]).
A survey made by the Department of Pathology of Nanjing Univers ity Hospital, China,
tracked 14 patients with MANEC in the upper stomach (L.NIE[26]) . All cases required
gastrectomy and lymph node dissection. One patient required par tial hepatectomy. In 11 of the
cases, the muscular propria was i nvaded, 9 of the patients had lymph node metastases, and one
patient presented liver dissemin ation. In all cases, the curati ve resection (R0) was obtained. Four
of the tracked patients died in the next 12 months. The study a imed to correlate the histological
and immunohistochemical characteristics of a tumour with the pr ognosis of the patient.
Histologically, all 14 cases contained a poorly differentiated neuroendocrine component with a
solid, trabecular, tubular or scirrhous aspect, and at least fo cal necrosis in all cases. The

ALEXANDRA BOLOCAN, DAN NICOLAE PĂ DURARU, CORNELIA NIȚIPIR, RĂZV AN HAINĂROȘIE,
SILVIU MIREL PIȚURU, CAMELIA DIACONU, ANDRA SUCEVEANU, ANCA PAN TEA STOIAN

14198 Romanian Biotechnological Letters, Vol. 23, No. 6, 2018
neuroendocrine cells were round- oval, with eosinophilic granul es, vesicular or granular nucleus,
with or without visible nucleoli. The most sensitive immunohist ochemical marker for
neuroendocrine cells was synapt ophysin (100% of the NEC compone nts were positive), followed
by chromogranin A (64%) and CD56 (57%) (L.NIE[26]). Depending o n the degree of
differentiation of the neuroendocr ine component, the cases coul d be grouped into MANEC-AC /
NEC and AC / NET. The first group, in turn, comprises three sub groups: well -differentiated
adenocarcinoma (DA), mucin secretory carcinoma (MPC) and poorly differentiated
adenocarcinoma (PDA).
A particular subtype of cancer with poor prognosis was hepatoid -NEC adenocarcinoma,
found in one case.
The rate of invasion of the muscu lar propria was higher for AC / NEC than for AC / NET,
but lower than for pure NE carcinomas. No significant differenc e in survival was found,
c o m p a r i n g A C / N E C , A C / N E T , a n d NEC. Tumorous grade and the p roportion of the
neuroendocrine component in the mass have influenced the progno sis negatively. Patients with
PDA / NEC had lower survival rates compared to those with MPC / NEC and DA / NEC.
The case of a 30-year-old patient with a family history of colo rectal neoplasia, which has
been diagnosed with colon MANEC located in her right colon, wit h lymph node and hepatic
metastases, has led physicians in Leuven, Belgium, to study the genetic changes of a tumour. Six
somatic modifications of the gene sequences were found. Both co mponents of a tumour were
positive for APC gene mutations ( Adenomatous polyposis coli-R10 96X and L1382fs), KRAS
(Kirsten rat oncogene homologous viral sarcoma-G12D), BCL9 (B-c ell CLL / lymphoma 9), and
FOXP1 P1) (L. VANACKER & al. [27]). The mutation of the SMARCA4 gene (SWI / SNF
related, matrix associated, actin dependent regulator of chroma tin, subfamily a, member 4) was
identified only in neuroendocrine cells. Belgian researchers be lieved that there is a relationship
between the two components, and the neuroendocrine phenotype ma y come from the
adenocarcinoma component due to mutations of the SMARCA4 gene. Immediately the following
hemicolectomy, the patient recei ved adjuvant treatment with Cis platin and Etoposide, high doses
of Carboplatin, Mitoxantrone, Cyclophosphamide, followed by aut ologous stem cell
transplantation. There were no recurrences.( Y. WENQING & al.[28])
Analyzes of gene mutations were also performed in the case of o esophageal MANEC. TP53
gene mutations, deletions of the RB1 and LOH genes, and PIK3CA, PTEN, KRAS, SOX2, DVL3
and TP63 genes, were present in both tumoral components as well as in the lymph nodes ( Y.
WENQING & al.[28];B. BALACHANDRA& al.[29]; G. KLÖPPEL& al.[30]) .

4. Discussion
The incidence of MANECs is unknown due to the rarity of this ty pe of a neuroendocrine
tumour. A wide variety of combin ations of the two components ha ve been reported, from
exocrine carcinomas with focal neuroendocrine cells to neuroend ocrine neoplasms with
scattering exocrine cells. Only those tumours in which each of the two elements exceeds 30% of
the tumour volume are admitted as mixed carcinomas. Each part, in turn, may have different
morphopathological characteristic s, from adenoma to adenocarcin oma with varying degrees of
cellular differentiation, and well or poorly differentiated neu roendocrine components. These
features significantly influence the evolution of the case.
MANETs are secondary to the simultaneous proliferation of sever al cell lines or stem cells
that differentiate into cells of different categories. In the c ase of amphicrine tumours, their
formation is based on a stem cell capable of divergent differen tiation in the same neoplastic cell.
Genetically, gastric and color ectal MANEC formation is closely related to abnormalities
of chromosomes 5q, 11q, 17q and 18q (LA ROSA & al.[1]). High-gr ade NEC malignancies of

Mixed adenoneuroendocrine carcin oma of the gastrointestinal
tract-features, diagnosis, management and prognostics

Romanian Biotechnologi cal Letters, Vol. 23, No. 6, 2018
14199MANEC have been reported in the oesophagus, stomach, ampulla of Vater, colon and anorectal
region (LA ROSA & al.[1]); K. CHING-MING [31]). The average diameter of these carcinomas
is 5 cm. The non-neuroendocrine component of the squamous type was found more frequently in
oesophageal and anorectal cancers, and adenoma/adenocarcinoma w as predominantly found in
gastric and colorectal for ms (LA ROSA & al.[1]).
Histologically, the poorly differentiated neuroendocrine compon ent resembles small or
large cell NEC tumours. The small cell subtype has the cells di sposed of in nests or a diffuse
manner. The cells have a small am ount of cytoplasm, fusiform nu clei with granular chromatin
and insensible nucleoli. The mitosis rate is between 20-80 mito tic figures / ten high-power fields
(LA ROSA & al.[1]). High-grade non-small cell tumours are made up of cells with abundant
cytoplasm, vesicular nuclei , and prominent nucleoli.
The neuroendocrine component should be immunohistochemically po sitive for at least 2 of
3 markers used (synaptophysin, ch romogranin A, CD56) for making the diagnosis of high-grade
MANEC. (LA ROSA & al.[1]); G.GRI N D I & a l . [ 3 ] ) . T h e p r e s e n c e o f transcription factors
(TTF1, ASH1) is not correlated with the patient’s prognosis and is not specific for gastrointestinal
carcinomas; they are identifie d in lung, vesicular and urogenit al NECs.
No significant differences in survival rate were found between patients with high colorectal
grade MANEC and classical NEC pati ents (LA ROSA & al.[1]); A.PA TTA & al. [32])
As the neuroendocrine component i s less differentiated and repr esents a more significant
proportion than the exocrine ele ment for a tumour, the evolutio n and prognosis of the patient are
worse. Cases of gastric MANEC in the literature reported a five years survival chance with more
prolonged treatment in DA / NEC vs PDA / NEC and MPC / NEC. P53 gene mutation was the
most common mutation identified in gastric cancers (Y. WENQING & al. [28]). Some authors
claim the origin of a common prec ursor for the two components o f a tumour, but they state their
evolution in different cell lines . A similar theory is that of stem cells capable o f differentiation in
different cell lines. Arguments supporting this assertion are a mphicrine cells, expression of at least
one exocrine marker in neuroendoc rine cells, and expression of neuroendocrine mar kers in gastric
cells (Y. WENQING & al. [28]). Elective treatment for ga stric carcinomas is total or pa rtial
gastrectomy followed by Roux en Y oesophageal anastomosis. Chem otherapy with Cisplatin and
Etoposide are recommended in case of metastases. Gastrectomy is useful at early stages and for
obstruction of the oesophagus or pyloric junction. In advanced stages, platinum-based
chemotherapeutic agents are indi cated as the fir st line of trea tment (A.C.NICOLAE al.[33]).
To predict the evolution of a patient as accurate as possible, the two components of a tumour
are analysed and evaluated indiv idually regarding neoplastic gr ading. Jiang et al. consider that a
20% proportion of the neuroendocrine part amplifies the unfavou rable evolution, but Park et al.
suggests that already 10% represents a potentially fatal percen tage (Y. WENQING & al. [28]).
The degree of component differen tiation influences the prognosi s more than the volume occupied
by each component.
Poorly differentiated neuroendoc rine colon carcinomas are rare entities, which, if
metastasised, have a terrible outcome due to the lack of treatm ent. The presence of distant
metastases contraindicates resection in oncological limits. Thi s type of aggressive carcinoma
responds well to chemotherapy w ith Cisplatin and Etoposide, but the chance of survival remains
less than 12 months (B. BALACHAND RA & al. [29]; P.J.STEPHENS [ 34]). There have been
no reports of patients with stage IV MANEC who survived. A retr ospective study regarding the
efficacy of Cisplatin-Etoposide in the treatment of NEC with li ver metastases yielded the
following results: 12.5% of cases responded entirely to therapy , and 50% of patients had a partial
response (B. BALACHANDRA & al. [29 ]). The mean survival rate in this study was 4.5 months,
and no patient survived for more than 17 months (P.J.STEPHENS [ 34]) . The Belgian patient

ALEXANDRA BOLOCAN, DAN NICOLAE PĂ DURARU, CORNELIA NIȚIPIR, RĂZV AN HAINĂROȘIE,
SILVIU MIREL PIȚURU, CAMELIA DIACONU, ANDRA SUCEVEANU, ANCA PAN TEA STOIAN

14200 Romanian Biotechnological Letters, Vol. 23, No. 6, 2018
referenced in the Results section survived 20 years without rel apse due to the association of
Cisplatin-Etoposide initial therapy with high-dose chemotherapy regimens with Carboplatin,
Mitoxantrone and Cyclophosphamide, followed by autologous stem cell transplantation. The
researchers demonstrated the monoclonal link between exocrine a nd neuroendocrine components
by identifying KRAS mutations in both elements (G.ROBINSON [35] ).
The cause of the adenocarcinom a phenotype changing into the ne uroendocrine phenotype
was the phenomenon of rearrangin g up to 1000 chromosomal cluste rs into one or more
chromosomes at the same time, known in the Angl o-Saxon literatu re as "chromothripsis."
Practically, in the adenocarcinoma cell DNA, there is a catastr ophic mutation that allows the
development of aggressive clones of neuroendocrine cells (H.L. WALDUM [36]). The exon
sequences of adenocarcinoma and neuroendocrine carcinoma were c ompared, and the only event
produced in their behaviour was the hepatic domain of the SMARC A4 gene (B.
BALACHANDRA & al. [29]). The sam e type of mutation occurs in th e case of a
medulloblastoma subtype when some Wnt-responsive chromatin remo delling genes are altered
(B.G. WILSON & al. [37]). There a r e s e v e r a l s i m i l a r i t i e s b e t w e e n the neuron and the
neuroendocrine cell, which has a llowed comparative analysis of their morphology, functionality,
and gene profiles (C.POIANA& al. [38] C.POIANA & al. [39]).
It has been established that inactivation of the SMARC4A gene i s responsible for the
transformation of the exocrine cell into the neuroendocrine car c i n o m a c e l l , a s i n t h e c a s e o f
tumours of neuroectodermal origin , including the medulloblastom a .
Other histopathological subtypes can coexist with neuroendocrin e carcinoma. The literature
describes the association with i mmature teratoma, for example. Tumours with this type of
association carry adverse prognosis. Other factors associated w i t h b a d o u t c o m e a r e l a c k o f
staining for chromogranin in immunohistochemistry studies. This is usually related to G2 NET.
On the other hand, intense stain ing for somatostatin is associa ted with adverse outcome. By far,
the most important prognostic fact or is ki67 proliferation inde x (D.L. PĂUN & al. [40]).
History of NETs in the same fam ily carries bad prognosis as wel l.

5. Conclusion
Gastrointestinal MANEC is a heterogeneous group of tumours with different
morphopathological, clinical a nd prognostic elements depending on the type and degree of
differentiation of each component. Diagnostic suspicion is due to secondary symptoms such as
obstruction and liver metastases. The most useful imaging metho d remains CT (MDCT), but
evidence and precise diagnosis mad e on the histopathologic exam ination.
The central metastasis stations are regional lymph nodes and th e liver. The prognosis of
mixed adenoneuroendocrine carcinomas is weak, given the maligna nt nature of both
components of a tumour. Both parts of mixed carcinomas can infl uence the patient's prognosis
through their characteristics (s ize, histology, the degree of d ifferentiation).

Conflict of interest
The authors declare that they have no competing interests. All data can be accessed by e-mailing
the correspondence author.

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