Current understanding of pathogenetic mechanisms in neuroendocrine neoplasms

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Current understanding of pathogenetic
mechanisms in neuroendocrine neoplasms
Roberta Modica, Alessia Liccardi, Roberto Minotta, Giuseppe Cannavale, Elio
Benevento & Annamaria Colao
To cite this article: Roberta Modica, Alessia Liccardi, Roberto Minotta, Giuseppe Cannavale,
Elio Benevento & Annamaria Colao (03 Nov 2023): Current understanding of pathogenetic
mechanisms in neuroendocrine neoplasms, Expert Review of Endocrinology & Metabolism,
DOI: 10.1080/17446651.2023.2279540
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REVIEW
Current understanding of pathogenetic mechanisms in neuroendocrine neoplasms
Roberta Modica
a
, Alessia Liccardi
a
, Roberto Minotta
a
, Giuseppe Cannavale
a
, Elio Benevento
a
and Annamaria Colao
a,b
a
Endocrinology Unit, Department of Clinical Medicine and Surgery, Federico II University, Naples, Napoli, Italy;
b
UNESCO Chair “Education for
Health and Sustainable Development, ” Federico II University, Naples, Italy
ABSTRACT
Introduction: Despite the fact that important advances in research on neuroendocrine neoplasms
(NENs) have been made, consistent data about their pathogenetic mechanism are still lacking.
Furthermore, different primary sites may recognize different pathogenetic mechanisms.
Areas covered: This review analyzes the possible biological and molecular mechanisms that may lead
to NEN onset and progression in different organs. Through extensive research of the literature, risk
factors including hypercholesterolemia, inflammatory bowel disease, chronic atrophic gastritis are
evaluated as potential pathogenetic mechanisms. Consistent evidence is available regarding sporadic
gastric NENs and MEN1 related duodenopancreatic NENs precursor lesions, and genetic-epigenetic
mutations may play a pivotal role in tumor development and bone metastases onset. In lung neuroen-
docrine tumors (NETs), diffuse proliferation of neuroendocrine cells on the bronchial wall (DIPNECH) has
been proposed as a premalignant lesion, while in lung neuroendocrine carcinoma nicotine and smoke
could be responsible for carcinogenic processes. Also, rare primary NENs such as thymic (T-NENs) and
Merkel cell carcinoma (MCC) have been analyzed, finding different possible pathogenetic mechanisms.
Expert opinion: New technologies in genomics and epigenomics are bringing new light to the
pathogenetic landscape of NENs, but further studies are needed to improve both prevention and
treatment in these heterogeneous neoplasms.
ARTICLE HISTORY
Received 25 May 2023
Accepted 1 November 2023
KEYWORDS
Cancer;
gastroenteropancreatic;
medullary thyroid
carcinoma; Merkel cell
carcinoma; neuroendocrine
neoplasm; neuroendocrine
tumor; pathogenetic
mechanism
1. Introduction
Neuroendocrine neoplasms (NENs) are a heterogeneous group of
malignancies arising from cells with a neuroendocrine phenotype,
scattered throughout various organs and systems in the body
[1,2]. Well-differentiated neuroendocrine tumors are characterized
by their unique ability to produce and release bioactive sub-
stances, including hormones and neurotransmitters [2].
Importantly, according to the SEER database their incidence is
increasing, partly due to improved diagnostic techniques and
awareness [3]. The complex interplay between the nervous and
endocrine systems gives rise to the intricate biology of these
neoplasms, making their diagnosis, management, and treatment
challenging yet fascinating [4–6]. NENs are mostly sporadic and
localized in the gastroenteropancreatic (GEP) tract (70%) and
bronchopulmonary system (25–30%), with a small percentage,
about 10%, occurring in association with hereditary syndromes
such as multiple endocrine neoplasia type 1 (MEN1), neurofibro-
matosis type 1 (NF1, von Recklinghausen’s disease), and Von
Hippel-Lindau (VHL) disease [2]. Understanding the etiology, clin-
ical presentation, and molecular mechanisms underlying neuroen-
docrine neoplasms is crucial for health-care professionals involved
in their care [4]. NENs are mainly nonfunctional diseases with an
indolent course in absence of specific clinical presentation or
symptoms, which leads to a delayed diagnosis. In view of their
heterogeneity, the World Health Organization (WHO) classifies
GEP-NENs into three major categories: well-differentiated neu-
roendocrine tumors (NETs), poorly differentiated neuroendocrine
carcinomas (NECs), and mixed neuroendocrine-non-
neuroendocrine neoplasms (MiNENs) [7,8]. GEP-NETs are further
classified into three grades based on the proliferative rate, includ-
ing grade 1 (G1), grade 2 (G2), and grade 3 (G3) [7]. The prolifera-
tive rate is assessed by the mitotic index and the Ki-67 labeling
index, which is a marker of cell proliferation [7]. G1 tumors have
a low proliferative rate, with a mitotic index of less than 2 and a Ki-
67 labeling index of less than 3% [7]. G2 tumors have a moderate
proliferative rate, with a mitotic index of 2 to 20 and a Ki-67
labeling index of 3% to 20% [7]. G3 tumors have a high prolifera-
tive rate, with a mitotic index of more than 20 and a Ki-67 labeling
index of more than 20% [7]. NECs are poorly differentiated NET
with a high proliferative rate and a Ki-67 labeling index of more
than 20% [7]. MiNENs are tumors composed of both neuroendo-
crine and non-neuroendocrine components, with each compo-
nent comprising at least 30% of the tumor [7]. Thoracic NENs
comprise typical carcinoids (TCs), atypical carcinoids (ACs), large-
cell neuroendocrine carcinoma (LCNEC), and small-cell lung carci-
noma (SCLC) divided according to mitotic rate and presence or
absence of necrosis [7,8]. Localized disease has a five-year survival
rate ranging from 78% to 93%, while in metastatic disease it
decreases to 19–38% with lymph node, liver, and bone being
the main sites of metastases [9,10]. Thus, morphological and
CONTACT Roberta Modica robertamodica@libero.it Endocrinology Unit, Department of Clinical Medicine and Surgery, Federico II University, Naples,
Napoli, Italy
EXPERT REVIEW OF ENDOCRINOLOGY & METABOLISM
https://doi.org/10.1080/17446651.2023.2279540
© 2023 Informa UK Limited, trading as Taylor & Francis Group

functional examinations are requested to complete staging.
European Neuroendocrine Tumor Society (ENETS) guidelines
mainly suggest performing CT scan or MRI depending on site of
primary lesion, and 68 Ga-PET/CT as functional exam for low-grade
NENs, while FDG-PET is pivotal for G3 NENs (ENETS consensus,
Perren, 2017). Unfortunately, nowadays reliable diagnostic bio-
chemical markers are lacking and the role of chromogranin
A (CgA) and neuron-specific enolase (NSE) are debated, and no
routinary use is suggested [11].
Despite a growing attention regarding NENs, still little is
known about their physiopathology and underlying pathoge-
netic mechanisms. The pathogenesis of NENs is complex and
multifactorial, involving a combination of genetic, epigenetic,
and environmental factors [12–15]. Molecular studies have
shed light on the genetic alterations and signaling pathways
involved in the development and progression of NENs
[9,10,16]. In particular, the genetic mutations underlying
familiar syndrome associated with NENs are well recognized.
On the contrary, little is known about biology and early devel-
opment of these diseases regarding the possible evolution of
preneoplastic lesions into cancer both in sporadic and familial
NENs.
For the detection of molecular alterations, the most used
methods are monoclonal antibodies and genetic sequencing
of tumor cells with diagnostic and therapeutic purposes, and
this field is under development [17].
In this paper, we will provide a comprehensive overview of
our understanding of pathogenetic mechanisms in NENs, ana-
lyzing the current state of knowledge regarding their physio-
pathology, highlighting the most important biologic and
morphologic aspects according to anatomical site and their
relationship with classification, epidemiology, pathology, and
clinical manifestations.
2. Search methodology
Deepened research on ‘‘Pubmed’’ using the following terms:
‘neuroendocrine neoplasm,’’ ‘‘gastroenteropancreatic neu-
roendocrine tumor,’ ‘‘thymic neuroendocrine tumor,’’ ‘‘carci-
noid tumor,’’ ‘‘Merkel cell carcinoma,’’ ‘‘chronic atrophic
gastritis,’’ ‘‘MEN1,’’ ‘‘VHL,’’ ‘‘NF1,’’ “DIPNECH”,“medullary thyroid
carcinoma,” pathophysiology,’’ ‘‘preneoplastic lesion,’’ ‘‘envir-
onmental factor,’’ ‘‘neuroendocrine epithelial bodies,’’ and ”
pathogenetic mechanism” was carried out. No start date was
set and the last update was in April 2023. Also, manual search
was conducted within the reference lists of the identified
papers to add relevant studies. Among the reports identified
by the search strategy, all papers containing data about the
selected topic were considered. Abstracts were excluded. All
the identified references were assessed by title and abstract to
determine possible eligibility and papers were included if they
reported data about pathogenetic mechanisms in NENs. Only
articles published in the English language were considered.
3. GEP-NETs
The main site of NETs onset is the gastrointestinal tract, and
the vast diversity of its cells conveys GEP-NENs heterogeneity
[16]. GEP-NETs represent 1–4% of all gastrointestinal neo-
plasms and over the years, a steadily rising incidence of GEP-
NETs has been observed [3,16]. Consequently, a better under-
standing of their pathogenetic mechanisms could help to
identify the reason of these epidemiological rise and provide
an integration other identified predisposing and risk factors,
including environmental factors, sex, metabolic syndrome, and
nutrition, low vitamin D levels, microbiota, thus preventing
them and allowing clinicians to predispose prevention and
treatment strategies [10,12,18,19]. Different pathogenic
mechanisms have been proposed according to different pri-
mary. Sequential changes from hyperplasia to neoplasia have
been described in NETs [20]. Indeed, enterochromaffin-like
(ECL) cell hyperplasia is defined by at least two linear chains
per millimeter (linear) or at least five cells per gland (multi-
cellular), or one micronodule smaller than 150 m/mm (micro-
nodular) on bioptic sample, and the fusion of these elements
or the invasion of lamina propria could lead to neoplasm
Article highlights
●Neuroendocrine neoplasms (NENs) may recognize different pathoge-
netic mechanisms according to different primaries and the onset of
precursor lesions, as well as genetic alterations seem to play a pivotal
role both in sporadic and familial neoplasms.
●Among gastroenteropancreatic NENs, in small intestinal neuroendo-
crine tumors (SI-NETs) a carcinogenic process has been hypothesized
considering small intestinal enteroendocrine cells as a source of stem
cells. Genomic stability with no recurrent mutation has been reported
but according to epigenetic mechanisms specific miRNAs may play
an important role in SI-NETs development and prognosis: downregu-
lation of miR-133a, miR-145, miR-146, miR-222, and miR-10b and the
upregulation of miR-183, miR-488, and miR-19aCb has been found in
metastatic SI-NETs.
●In Type 1 gastric NETs (G-NETs) associated with chronic atrophic
gastritis, a transition from atrophic gastritis to hyperplastic/dysplastic
neuroendocrine nodules and ultimately to neoplasia due to hyper-
gastrinemia stimulation has been proposed. In Type 2 G-NETs the
hypertrophic oxyntic mucosa seems to be stimulated by gastrinoma
in MEN1 patients and interestingly MEN1 mutation has been reported
in 30-40% of cases of Type 3 G-NETs, although not associated with
preneoplastic lesions. The chronic use of proton pump inhibitors (PPI)
causing hypergastrinemia and cell hyperplasia has been proposed in
the development of G-NENs, though genetic predisposition or envir-
onmental factors may also play a role.
●MEN1-related pancreatic neuroendocrine tumors (pNETs) seem to
originate from pancreatic microadenomas and from non-islet tissue.
Main driver mutations in sporadic pNETs derive from MEN1, DAXX,
and ATRX alterations.
●Increased prevalence of colorectal NETs has been observed in
patients with inflammatory bowel diseases, NETs did not originate
from areas with chronic inflammation leading to the hypothesis that
NETs development was not directly correlated to a proinflammatory
microenvironment and even the presence of precursor lesions is
debated.
●Nicotine and hypoxia could be crucial in the pathogenetic mechan-
ism of lung carcinoids and carcinomas development, in particular
influence directly the signaling cascades Pi3K/AKT/mTOR and MAPK
both pivotal for cell proliferation, while VEGF secretion mediated by
the inflow of Ca2+ could lead to an increase of angiogenesis.
●In medullary thyroid cancer (MTC) RET mutations are drivers for
cancer development in familial forms, but also RAS gene mutations
and epigenetic alteration seem to be pivotal, in particular in sporadic
MTC.
●Data regarding pathogenetic mechanisms in NENs are currently
mainly available in gastro-entero-pancreatic (GEP) NENS, maybe due
to their relatively higher frequency, but better knowledge is still of
utmost importance in this field, to improve cancer prevention and
treatment strategies.
2R. MODICA ET AL.

development [20]. Molecular and genetic background that
may participate in the transition from naïve cell to hyperplastic
lesion and subsequently to malignancy is complex and not yet
completely recognized [21]. Apparently, these mechanisms are
different between pancreatic NEN (pNEN) and gastrointestinal
NET [21].
Small intestine NET s (SI-NET s) are the most common GEP-
NET s with an incidence of 1.05/100,000 per year [22]. No
precursor lesions have been observed for SI-NETs, on histolo-
gical exam of surgical specimen [23]. However, SI-NENs may
undergo a multiphase carcinogenic process due to the pre-
sence of small intestinal enteroendocrine cells, defined as an
active reserve of intestinal stem cells, taking part in the intest-
inal mucosa’s ongoing self-renewal and expressing a specific
molecular pattern (BMI1, HOPX, TERT, and Lrig1) [24]. Indeed it
has been proposed that these cells are able to dedifferentiate
leading to SI-NETs [24]. Moreover, SI-NETs seem to be less
associated with the specific molecular events seen in most
other NENs [25]. A genomic stability with no recurrent muta-
tions was observed in a study of 48 SI-NETs using a massively
parallel exome sequencing, on the other hand somatic copy
number alterations are common in with the loss of chromo-
some 18 found in over 60% SI-NETs [26,27]. Epigenetic
mechanisms are frequently involved in SI-NETs, indeed both
global hypomethylation and CpG island methylator pheno-
type have been described [28–30]. These DNA alterations
could lead to silent TCEB3C, implicated in tumor development,
and `to downregulate RASSF1A and CTNNB1 that are related
to a metastatic behavior [31,32]. Similarly, in metastatic SI-
NETs the downregulation of miR-133a, miR-145, miR-146,
miR-222, and miR-10b and the upregulation of miR-183, miR-
488, and miR-19aCb was observed and these alterations are
supposed to take part in pathogenetic mechanism [33]. Other
miRNA that could contribute to tumor dissemination are miR-
96, miR-182, miR-183, miR-196a, and miR-200a upregulated
and miR-31, miR-129-5p, miR-133a, and miR-215 downregu-
lated [34]. These data helped to classified SI-NETs in three
subgroups: one with chromosome 18 LOH-CDKN1B mutations,
found in older patients and with a better prognosis, another
with high degree of CpG island methylator phenotype but
lacking SCNAs with intermediate age at diagnosis and prog-
nosis and the last with a lot of copy number changes, in
younger patients and with a poor prognosis [35]. Lately, the
role of lipids has been evaluated as a risk factor in SI-NETs [13].
Indeed, lipids could support tumor development and progres-
sion, participating in the membrane phospholipids turnover.
Furthermore saturated fatty acids may protect the tumor cell
from the microenvironment oxidative stress [13]. Consistently,
a prospective study showed that meat and high fat intake are
associated with SI-NETs development [36]. Pancreatic NETs
(pNETs) have an incidence of 0.48/100.000 [22]. Several studies
investigated precursor lesions in pNETs, especially in heredi-
tary tumors, while in sporadic pNETs no precursor lesions have
yet been described [37]. In MEN1 patients pancreatic micro-
adenomas (<5 mm) are common findings and macroadenoma
(>5 mm) seem to originate from these lesions [38,39].
Furthermore, Vortmeyer et al. studied pancreas of MEN1
patients with no lesions and demonstrated a non-islet cell
origin of pNENs, in particular in the ductal/acinar system.
Indeed, these cells retain pluripotency and are able to form
islet-like structures and could be the real target of a ‘second
hit’ leading to pNENs [40]. The loss of heterozygosity has been
investigated as a marker for neoplastic growth in microadeno-
mas, macrotumors and monohormonal endocrine cells clus-
ters (MECCs) [41]. Loss of heterozygosity of MEN1 was
observed in 86% of macrotumors, in 100% of microadenomas
and, interestingly, in 95% of MECCs; these lesions could be
a microscopic form of microadenomas [41]. On the other
hand, morphologically normal islets and exocrine tissue
showed a retention of heterozygosity of MEN1 [41]. It is still
unclear if the mechanisms observed in MEN1 related pNENs
are similar to sporadic pNENs, because no precursor lesion has
been identified in these patients [41]. Molecular analysis of
pNENs has revealed several genetic alterations, such as inacti-
vating mutation of MEN1, DAXX (death-domain-associated
protein), and ATRX (α thalassemia/mental retardation syn-
drome X-linked) genes, involved in chromatin remodeling in
telomeric regions [42,43]. The MEN1 gene mutations can be
observed in hereditary tumors in patients with MEN1 syn-
drome, nevertheless in more than 35% of sporadic pNENs
this mutation occurs in a somatic way [42]. A mutation of
one of DAXX and ATRX is present in more than 45% of
sporadic pNETs, suggesting that they share the same pathway
[42]. DAXX/ATRX mutations lead to alternative lengthening of
the telomeres (ALT) phenotype and chromosomal instability
[44]. Less frequent mutations, observed in ∼15% of pNENs,
include PTEN, TSC2, TSC1, DEPDC5, and PIK3CA, all involved in
the mTOR pathway [45].
Gastric NETs (G-NETs) have an annual incidence of 0.4/
100,000 individuals [46]. These heterogeneous lesions have
been further divided into ECL cell NENs and antral NENs
based on the kind of neuroendocrine cell development [47].
Antral NENs represent the smaller part of G-NETs and are not
associated with precursor lesions, indeed neuroendocrine cell
dysplasia in the antrum has never been documented [47].
Three types of ECL NETs (Types 1, 2, and 3) are recognized
and precursor lesions have been correctly identified and
described in the context of Type 1 and Type 2 [20,46,48–50].
The most common G-NETs are Type 1 (80–90%), followed by
Type 3 (10–15%) and Type 2 (5–7%) [46]. Type 1 develops in
the presence of atrophic gastritis type A, a chronic inflamma-
tory gastric disease that selectively affects the fundus and
body of the stomach leading to hypo/achlorhydria that pro-
gresses to hypergastrinemia thanks to a compensatory hyper-
plasia of the antral gastrin cells [46,51–55]. Precursor lesions
that take place in a context of atrophic mucosa can be dys-
plastic (larger micronodules, joined micronodules, microno-
dules with new stroma, and microinfiltrative lesions) and
hyperplastic (diffuse, linear, micronodular, and adenomatoid
hyperplasia), this two conditions can evolve into a neoplasm,
this two conditions can evolve into a neoplasm [55,56]. TGF-α,
bFGF, or MEN1 gene alterations could represent the molecular
mechanisms underlying this transition [25]. Moreover,
a recently published whole-exome analysis on a familial clus-
ter has shown in 5 of 10 siblings with G-NETs Type 1 the
presence of a germline mutation in the ATP4A gene, which
codes for the subunit of the stomach proton pump [57]. On
the other hand, Type 2 originates from hypertrophic oxyntic
EXPERT REVIEW OF ENDOCRINOLOGY & METABOLISM 3

mucosa stimulated by gastrinoma, mostly duodenal, or pan-
creatic, in patients with MEN1 with Zollinger-Ellison syndrome
(ZES) [58–60]. Typically, there is a hypertrophic mucosa that
may cause a dysplastic ECL-cell proliferation observed only in
MEN1 patients. Hence, ECL cells appear to be more susceptible
to the mitogenic effect of hypergastrinemia due to menin
mutation [61]. Type 3 has no precursor lesion considering
that it originates from normal oxyntic mucosa [46]. These
aggressive G-NETs have demonstrated alterations of the
MEN1 locus in about 30–40% of cases [7]. Lately, other two
type of G-NETs have been hypothesized: Type 4, where hyper-
gastrinemia and hyperplasia of parietal cell lead to G-NET in
non MEN1 patient probably due to a defect in acid secretion;
Type 5 caused by the inappropriate chronic use of proton
pump inhibitor (PPI) [46,60,62]. Interestingly, a role of PPI has
been proposed in the pathogenetic mechanism of G-NETs.
A meta-analysis of six randomized controlled trials showed
that patients treated with PPI for more than 6 months were
significantly at risk of developing diffuse or linear/micronodu-
lar ECL cell hyperplasia than controls, although no NETs were
observed and only a mild hypergastrinemia was observed
(100–500 pg/mL) [63]. Several case reports have documented
the association between G-NETs and chronic PPI use with
a long follow-up time >10 years, speculating that much more
time is necessary to develop a G-NETs [64,65]. Alternatively,
since the majority of patients treated for a long time with PPI
have hypergastrinemia without developing G-NETs, it may be
suggested that hypergastrinemia alone is not sufficient and
another trigger is needed, such as genetic predisposition or
environmental factors [65–68]. Taken together, these data do
not clarify the role of PPI in the pathogenesis of G-NETs, which
remains still debated.
With regard to duodenal NETs (dNETs) representing up to
22% of NETs with an incidence of 0,34/100.000, different
entities have been recognized according to the cell pathology:
G-cell (>60%), D-cell (21%), gangliocytic paraganglioma (9%)
[23,69,70]. dNETs are mostly sporadic and nonfunctioning,
affecting patients of 50–70 years old and have a slight female
prevalence [71]. F Functioning dNENs are generally associated
with MEN1, showing a more aggressive manifestation in
younger patients with multiple primaries [72]. Interesting,
ampullary or periampullary NETs are more common in other
two genetic syndromes: NF1 and VHL [73]. Nevertheless, D-cell
dNENs have been associated more commonly with mutation
in NF1 gene than in MEN1 gene. In these tumors INFB1 muta-
tions and loss of chromosome 22 have been identified [25]. No
precursor lesion has been identified in sporadic dNENs and in
the context of NF1 or VHL. In case of MEN1, precursor lesion
has been linked to gastrin or somatostatin producing NETs
[74]. The causing mutation of the syndrome can influence the
type of lesion in the duodenum and allelic deletion of the
MEN1 gene is associated with microinvasive lesions, while
hyperplastic endocrine cells preserve heterozygosity [23,75].
Indeed, in case of MEN1 duodenal gastrinomas both diffuse
G-cell hyperplasia (simple, linear, micronodular or macronod-
ular neuroendocrine cell hyperplasia) and multicentric gastrin
producing microtumors (between 300 microns and 2 mm)
have been described, while no one of these lesions was
found in sporadic duodenal gastrinomas, thus suggesting dif-
ferent pathogenetic mechanisms [69]. In particular, in the
hyperplastic G-cell there was not loss of heterozygosity on
chromosome 11q13, even though they have germline MEN1
mutation, testifying that this event is crucial for neoplasm
development and maybe G-cell hyperplasia is secondary to
a greater susceptibility of MEN1 G-cell to an unknown growth
factor [69]. Moreover, a recent study focused on PPI showed
an association between G-cell hyperplasia in patients with
H. pylori gastritis treated with PPI and sporadic gastrinoma
[76]. However, data about duodenal precursor lesions are less
consistent and more studies about this topic should be
proposed.
The existence of preneoplastic lesions in esophageal NETs
(E-NETs) is debated, considering that E-NENs are extremely
rare. Only 0.04–1% of GEP-NETs are E-NETs, generally diag-
nosed during diagnostic examination when suspecting eso-
phageal adenocarcinomas or squamous-cell carcinomas,
developing in the lower third of the esophagus, as a single
lesion, but sometimes as an ulcerated or fungating mass [77].
Since E-NETs are typically a random finding on endoscopic
examination, early diagnosis is therefore difficult, but smoking
and alcohol abuse are acknowledged as major risk factors [78].
E-NENs can be found associated with adenocarcinoma and
Barrett mucosa or as a single large polypoid/nodular tumor
[79]. Mostly, E-NETs are carcinomas (90%) with focal or mild
expression of immunohistochemical markers, synaptophysin
and chromogranin A E-NETs and arise in the lower part of
the esophagus, probably because the bulk of neuroendocrine
cells is found in the lower esophageal submucosal [77,80]. To
date, no precursor lesions have been identified for E-NETs,
although the existence of endocrine cell hyperplasia also in
adenocarcinoma and Barrett mucosa supports the idea that
these lesions develop from a single stem cell who could
differentiate into goblet, Paneth, or endocrine cells [79].
Colon and rectal NETs account only for the 0.4% of all
malignancies of this district, their incidence is 1,04/100.000
individuals [22]. Areas of neuroendocrine differentiation of
less than 30% are often found in adenocarcinomas [81].
An increased colo-rectal NETs prevalence has been
described in patients with a chronic inflammatory bowel dis-
ease (IBD) undergoing surgery because of disease complica-
tion [82]. Albeit a standardized incidence ratio of colo-rectal
NETs of 2,5 for Crohn disease and 2,0 ulcerative colitis has
been identified, NETs did not originate from areas with chronic
inflammation leading to the hypothesis that NETs develop-
ment was not directly correlated to a proinflammatory micro-
environment and even the presence of precursor lesions is
debated [83,84]. Mucosal enterochromaffin cell (EC) hyperpla-
sia has been reported in the tissue surrounding NETs in these
patients, while EC dysplasia has never been described in these
districts [23,85]. Nevertheless, chronic inflammation could play
a role in the development of colon-rectal NENs, stimulating
endocrine cells proliferation [86].
NENs represent 50% to 70% of all appendiceal malignan-
cies, with an incidence of 0,15–06/100.000 people [87,88].
Appendiceal NENs (a-NENs) are generally single and mainly
on the tip of the organ (75% of cases) [89]. The age of onset is
4R. MODICA ET AL.

reduced compared to other sporadic NENs (30–40 years) [89].
Compared to colo-rectal NENs, there is no association with IBD
and mucosal EC hyperplasia [90]. In a-NENs an association with
Schwann cells has been observed. In particular, a subepithelial
aggregate composed of neurons, Schwann cells and neuroen-
docrine cells (subepithelial neuroendocrine complex, SNC) has
been recognized in the mucosa surrounding lesion [85,91].
The SNCs may sometimes be symptomatic by themselves,
representing the pathophysiologic substrate for the neuro-
genic appendicopathy, that leads to an increased release of
neuropeptides with the consequent onset of acute abdominal
pain mimicking acute appendicitis [92].
Several studies have observed that GI-NECs originate from
the same multipotent stem cells that may give rise to non-
NECs. NECs are very rare tumors with an incidence of 4,5/
1.000.000 people [22]. This suggestion derives from the fact
that often has been observed the presence of a well-
differentiated adenocarcinoma/adenoma overlying the
aggressive neuroendocrine component of MiNENs [93].
Moreover, GI-NECs share molecular alteration with non-NECs
lesions, such as the presence of a KRAS/BRAF, RB1, TP53,
CDKN2A, and ERBB2 mutation [94]. In gastric NEC, the RB1
mutation was the most distinctive, and these mutations have
not been observed in gastric neuroendocrine tumors [95]. In
a recent study, authors found that in tumor samples of colonic
NECs the most frequent mutations were TP53, BRAF, APC, and
KRAS, while in rectal tumors were TP53, APC, FBXW7, and
KRAS [96]. Some authors observed a BRAF mutation rate of
20% in a series of colorectal NECs while Idrees et al. reported
that all BRAF-mutated NECs were microsatellite stable [93,97].
Probably, NETs and NECs present different pathogenetic path-
ways and originate from different precursor cells, but because
of the rarity of these malignancies a clear pathway has not
been elucidated [98,99]. For example, RB1 mutations and
chromosomal abnormalities (extensive deletions and translo-
cations) were common in GI-NECs; TP53 and RB1 alteration are
prevalent in these neoplasms, and they contribute to neuroen-
docrine tumorigenesis, in which loss of TP53 and RB1 leads to
NECs, as confirmed by a murine model [100]. In precursor
lesions of GEP-NETs, such as pNETs, there are no mutations
or alterations of TP53, RB1, or other driver mutations common
in adenocarcinomas; instead, mutations of DAXX, MEN1, and
ATRX are observed [99]. Furthermore, NECs are anecdotally
associated with IBD thanks to some case series [101,102]. In
a case series of 14 patients with IBD and NENs, only in three
cases NEC was diagnosed [103].
3.1. LUNG-NENs
Pathological classification of lung NENs (L-NENs) has
evolved over years, reflecting the need of a better charac-
terization and recently a new histological diagnosis of car-
cinoid not-otherwise-specified (NOS) has been added to
TCs, ACs, SCLCs, and LCNECs (Figure 1) [104]. DIPNECH has
been classified as a premalignant lesion by the World
Health Organization, characterized as a histological entity
on incidental findings of lung nodule biopsies, more com-
mon in female rather than in male [105,106]. The preva-
lence of DIPNECH in female may support a role of gender
predisposition due to hormone profiling, but unfortunately
data are still lacking [97]. DIPNECH is characterized by
superficial and isolated lesions, or with basement mem-
brane invasion forming tumorlets (cell aggregates <5 mm)
or carcinoid tumors (if >5 mm) [105]. Clinically prognosis of
carcinoid is better than the one of carcinoma and patients
with TCs have got the best survival outcomes, but just few
data on pre-clinical differences between these two groups
are present in literature [107,108]. Patients with carcinoid
are usually younger than patients with carcinomas, as med-
ium age of onset in TCs is 45 years, while in SCLCs is 70
years [109,110]. This may imply that carcinoid’s cells may
have less time to accumulate genetic mutations in compar-
ison with that of carcinoma, as confirmed by microsatellite
marker analyses, and SCLCs have the highest mutational
rate [109]. There is not only a quantitative difference, but
also a qualitative one: loss of heterozygosity (LOH) for
Figure 1. Lung NEN. NEB: neuroendocrine body. α7nAChR: alpha-7 nicotinic acetylcholine receptors.
EXPERT REVIEW OF ENDOCRINOLOGY & METABOLISM 5

carcinoid often regards locus 11q, that includes MEN 1,
a tumor suppressor gene, while for carcinoma it often
regards locus 13q, that includes Rb gene, a proto-
oncogenic tumor suppressor gene (Table 1) [108,111].
Even p53, another important tumor suppressor gene, is
mutated in carcinomas, while it is normally expressed in
carcinoid [112]. Despite these differences, it has been
proved that for all lung NEN the activation of mammalian
target of rapamycin (mTOR) pathway is pivotal, something
of interest for therapeutic strategies [112]. Patients with
carcinomas are predominantly smokers, while smoking sta-
tus seems to be not relevant for carcinoid development
[109]. Lung NENs arise from pulmonary neuroendocrine
cells that are mostly organized in bodies (NEBs), well inner-
vated [113]. It has been proved that NEBs have got specific
receptors to both hypoxia and nicotine that cause not only
a secretion of serotonin, that could lead to pulmonary
fibrosis and to pulmonary hypertension, but also
a proliferative response [114,115]. Nicotine, inhaled through
cigarette and e-cigarette smoking, has a direct signaling
cascades that promote cancer development [116]. When
the homomeric ionic alpha-7 nicotinic acetylcholine recep-
tors (α7nAChR) are activated, different pathways start, in
particular Pi3K/AKT/mTOR and MAPK both pivotal for cell
proliferation, while VEGF secretion mediated by the inflow
of Ca2+ could lead to an increase of angiogenesis [116].
Moreover, a study on primate models proved that prenatal
nicotine exposure increases NEBs formation [114]. Thus,
nicotine could have a role in causing hyperplasia, while
dysplasia and carcinogenesis could occur after prolonged
exposition to smoke. Only 3% of SCLC is reported in not-
smoker population [117]. Interesting 25% of them have got
EGFR mutations, suggesting different mutation drivers lead-
ing to these cancers development and different therapeutic
strategies [118]. Usually, this pathway is not involved in
SCLC [119]. In fact, targeted therapies for EGFR-mutated
lung adenocarcinomas could lead to transformation to
SCLC or occasionally LCNEC [119]. This has been documen-
ted in 5–14% of patients receiving first (erlotinib), second
(afatinib), and third (osimertinib) generation EGFR inhibitors.
Lastly, SCLC in a not-smoker patient may represent an
unsuspected metastasis, such as from HPV-related sites
like cervix or oropharynx [120]. Recently, different sub-
types of both SCLC and LCNEC have been described, but
their physiopathology is still not clear [121]. Interestingly, it
has also been considered immuno-receptor expression in
these tumors that, even if not prognostic for immunother-
apy response, is the pathological landmark of an immune
cells involvement during cancer development [4,122].
3.2. RARE NENs
3.2.1. Thymic NENs
Thymic neuroendocrine neoplasms (T-NENs) are rare neo-
plasms representing approximately 5% of thymic and med-
iastinal neoplasms and 0.4% of all neuroendocrine neoplasms
(NENs) [123].
T-NENs, as well as L-NENs, are traditionally classified using
the same criteria into TCs and AC, LCNECs and SCCs. T-NENs
TCs and ACs are more frequent in males, whereas there is
a female preponderance in L-NENs [123]. This sex difference
has not been described for LCNEC and SCC however, it has not
yet been possible to find a pathophysiological mechanism
underlying this gender difference [123]. AC and LCNEC are
by far the most frequent subtypes in the thymus, while SCCs
and TCs prevail in the lung. Interestingly, unlike lung LCNECs
and SCCs, T-NENs are not associated with cigarette smoking
[124]. T-NENs also have a worse prognosis than L-NENs with
5-year survival rates varying between the sundry subtypes,
decreasing from 50–70% in TC and AC to 30–66% in LCNEC
and to 0% (median survival 13–26 months) in SCCs [125]. Only
a few data are available about pathogenic mechanisms in
T-NENs. A study using comparative whole-genome hybridiza-
tion (CGH) showed an increasing mutational profile among
the various subtypes of T-NENs [126]. In particular, three clus-
ters based on chromosomal instability were highlighted.
Cluster 1 characterized by a low instability index consisted
mainly of TC and AC but also some LCNECs, which sometimes
showed a profile overlapping with TC and AC [126].
Furthermore, sequencing of tissue from the primary and
metastases showed heterogeneity of the neoplasm with the
possibility of evolution from one subtype to another [125,126].
In addition, in thymic LCNEC this study showed amplification
of the myc oncogene, myc contributes to tumor development
is its ability to promote cell proliferation [125]. Myc regulates
the expression of genes involved in cell cycle progression and
DNA replication, leading to uncontrolled cell division [127].
Additionally, myc influences cellular metabolism, angiogen-
esis, and genomic instability [125,127]. Another frequently
encountered mutation is that of MEN 1, indeed approximately
25% of patients with thymic carcinoid tumors harbor a MEN1
germline mutation and 8% of MEN1 patients develop T-NENs
[128,129]. The molecular evaluation of T-NENs lead to identify
pathways involved in differentiated and poorly differentiated
forms [130]. The methyltransferase EZH2, part of PRC2 (poly-
comb repressive complex 2) one of the two classes of poly-
comb-group proteins, is positive in LCNECs and poorly
differentiated forms [130]. EZH2 through methylation is
involved in silencing genes involved in the regulation of cell
cycle. In particular, EZH2 is associated with over expression of
TP53 and is associated with increased proliferation and
decreased survival [124]. A gene that is overexpressed in well-
differentiated forms is ATRX, a transcriptional regulator
required for deposition of histone H3.3 at telomeres that
influence DNA tridimensional structure [131]. T-NENs over-
express PAK3 (p21-activated kinase 3) and its upstream
Table 1. Molecular features of lung neuroendocrine neoplasms (L-NEN).
L-NEN
Loss of
heterozygosity
Gene involved
Typical carcinoid 11q MEN-1
Atypical carcinoid
Large cell neuroendocrine
carcinoma
3p, 5q and 13q Rb
Small cell carcinoma 3p, 4q, 5q, 13q and
15q
Rb. Possible mutation
of p53
6R. MODICA ET AL.

regulator RAC, both of which are involved in the regulation of
cell migration, angiogenesis and invasion [132]. Particularly in
T-NENs ACTH-secreting PAK3 has an important action on
fibroblasts and epithelial cells. Indeed, its activation leads to
increased angiogenesis and invasion activity. In one study, the
presence of this mutation was associated with aggressive and
metastatic disease [132]. Approximately 40% of T-NENs exhibit
ACTH hypersecretion, elevated β-catenin, pro-
opiomelanocortin (POMC) and carboxypeptidase E (CPE) and
decreased NOTCH2 levels [133]. The Notch signaling pathway
plays a critical role in tumorigenesis, and its dysregulation has
been implicated in various cancers. Notch promotes tumori-
genesis through multiple mechanisms, including the regula-
tion of cell proliferation, survival, angiogenesis, and metastasis
[134]. Levels of POMC and CPE have been found increased by
3- and 4-fold respectively in ACTH-secreting TNRNs, however
their role is not yet well known [133]. It is important to note
that the exact mechanisms underlying T-NENs may vary
depending on the specific tumor subtype and individual
cases. Further research is needed to elucidate the precise
pathogenetic mechanisms involved in these tumors and to
identify potential therapeutic targets.
3.3. Merkel cell carcinoma
Merkel cell carcinoma (MCC) is a rare and aggressive neuroen-
docrine neoplasm [135]. MCC represents less than 1% of all
cutaneous carcinomas in Europe, but a 5.4-fold increase from
1986 to 2003 has been observed [136,137]. MCC can be
defined as immunogenic tumor, indeed the introduction of
immunotherapy improved its prognosis [138]. The pathoge-
netic mechanisms of MCC have been in depth analyzed. Two
forms of MCC characterized by two different pathogenetic
mechanisms have been identified: the first, which is found in
80% of cases, is due to the genetic integration of the poly-
omavirus; the second, less frequent, is due to exposure to
ultraviolet rays (UV) (Figure 2) [139–141]. Indeed, the two
main risk factors are immunosuppression (chronic lymphocytic
leukemia, HIV/AIDS, drugs, etc.) and chronic exposure to the
sun, respectively. Although the community has a significant
polyomavirus seropositivity, the incidence of MCC is very low
[139]. Indeed, two crucial events must occur at the same time
to determinate the MCC development: the clonal integration
of the viral small T antigen (ST) and large T antigen (LT) genes
in the cell genome and a mutation that lead to the loss of the
LT protein’s C-terminal expression [139,142]. These events
block viral replication, thereby LT and ST protein synthesis is
boosted, which encourages cell cycle advancement and survi-
val because mutated LT interacts with tumor suppressor pro-
tein retinoblastoma (pRB) involved in the cell cycle
progression. Concurrently, ST protein interacts with tumor
suppressor protein phosphatase 2A and mammalian target
of rapamycin (mTOR) pathway in mammalian cells [139]. UV-
induced MCC expresses a high tumor mutational burden char-
acterized by the ‘UV mutational signature’ that is the presence
of C-to-T pyrimidine dimers. Among these several mutations,
the ones involving RB and p53 are predominant [139].
3.4. Medullary thyroid cancer (MTC)
MTC is a distinct subtype of thyroid carcinoma originating
from the parafollicular C cells o, accounting for 3–5% of all
thyroid malignancies [143]. The development of MTC is pri-
marily driven by specific genetic mutations that lead to the
activation of critical signaling pathways and the dysregulation
of cellular processes [143]. Approximately 75–80% of MTCs are
Figure 2. Physiopathology of Merkel cell carcinoma. UV: ultraviolet radiation. DNA: desoxy-ribonucleic acid.
EXPERT REVIEW OF ENDOCRINOLOGY & METABOLISM 7

sporadic neoplasms, while a smaller proportion are hereditary
and associated with multiple endocrine neoplasia type 2
(MEN2) syndromes and familial medullary thyroid cancer
(FMTC) [144]. In both sporadic and hereditary MTC, activating
mutations in the RET proto-oncogene located on chromosome
10q11.21 play a central role in MTC pathogenesis [145,146].
The most common RET mutation in hereditary MTC is
a germline mutation in codon 634, while in sporadic MTC
cases various regions of the gene are involved [145,146].
These lead to activation of downstream signaling cascades,
primarily the mitogen-activated protein kinase (MAPK) and
phosphoinositide 3-kinase (PI3K)/Akt pathways, pivotal in pro-
liferation, survival, differentiation, and angiogenesis [147,148].
Moreover, it could have a role in increasing cell mobility.
Mutated RET can disrupt cell-cell and cell-matrix interactions
by altering the expression of adhesion molecules, such as
E-cadherin, and by inducing the secretion of matrix metallo-
proteinases (MMPs) [149]. These changes promote the invasive
behavior of MTC cells, facilitating their dissemination to regio-
nal lymph nodes and distant organs. In addition to the genetic
mutations driving MTC development, there is evidence to
suggest the presence of pre-neoplastic lesions that precede
the formation of fully malignant tumors [143]. These lesions,
known as C-cell hyperplasia, represent a precursor stage char-
acterized by the expansion and altered function of C cells in
the thyroid gland [143]. Genetic and molecular alterations
found in pre-neoplastic lesions, specifically C-cell hyperplasia,
provide insights into the molecular events leading to MTC.
Several genetic and molecular changes have been identified in
pre-neoplastic lesions, shedding light on the early stages of
MTC development [147]. For instance, mutations in the TP53
tumor suppressor gene have been observed in both pre-
neoplastic lesions and MTC, suggesting its involvement in
disease progression [147]. Activation of the RAS oncogene
pathway has also been implicated in the transformation of
pre-neoplastic lesions to MTC, with mutations in HRAS (17%)
and KRAS (7%) genes detected in these lesions [150]. Not only
genetic mutation could lead to the ‘second-hit,’ crucial to
carcinoma development but also epigenetic alteration.
Indeed, even if telomerase reverse transcriptase (TERT) promo-
ter is not mutated, his methylation has been reported in MTC,
increasing TERT expression and ending in telomerase activa-
tion [151]. This data has been associated with decreasing
disease-free and overall survival in MTC [151]. Moreover,
some microRNA (miRNA) could have a role in carcinogenesis.
In particular, miRNA-183 and 375 are overexpressed in spora-
dic versus hereditary MTC and were associated in lateral
lymph node metastases, residual disease, and distant metas-
tases, influencing mortality [152]. Interestingly, even without
clinical difference, global DNA methylation level has been
found to be higher in sporadic MTC rather than in hereditary
MTC [153].
3.5. Bone metastases
Bone metastases in NENs represent an advanced stage of
the disease and are associated with significant morbidity,
thus the understanding of their pathogenetic mechanism is
of great relevance [154]. The development of bone
metastases involves a complex interplay of cellular and
molecular mechanisms, which contribute to the infiltration,
growth, and survival of tumor cells within the bone micro-
environment [155]. The process of bone metastasis begins
with the invasion of tumor cells into the bloodstream or
lymphatic system. Once in circulation, tumor cells interact
with bone marrow-derived cells, such as osteoclasts, osteo-
blasts, and immune cells, through adhesion molecules and
chemotactic factors. This interaction facilitates the homing
of tumor cells to the bone microenvironment [155]. One of
the key factors contributing to bone metastases in NENs is
the secretion of various bioactive substances by tumor cells,
including growth factors, cytokines, and chemokines contri-
buting to the creation of a specific niche [156]. The creation
of this niche is crucial for the development of bone metas-
tasis, as neoplastic cells do not possess the characteristics
for the degradation of the extracellular matrix (ECM) and
require the activation of osteoclasts [155]. Cytokines pro-
duced by the tumor receptor led to increased expression of
nuclear factor-kappa B ligand (RANKL) and decreased osteo-
protegerin (OPG) values [10]. RANKL is a protein expressed
by osteoblasts and other stromal cells in the bone micro-
environment. It plays a central role in regulating bone
remodeling and osteoclast differentiation [157]. The
increased action of osteoclasts due to overexpression of
RANKL leads to increased resorption of bone ECM resulting
in the release of a number of growth factors that stimulate
homing, tumor cell proliferation, and bone destruction,
creating a vicious circle [10]. In addition, the ECM environ-
ment is characterized by hypoxia, acidic pH, and high levels
of extracellular calcium, all of which create a favorable
environment for tumor growth [10]. However, independent
of RANKL activation, tumor cytokines including cathepsin K,
IL 8, and VEGF alone are capable of stimulating bone
resorption through osteoclasts [158,159]. Studies have
shown the importance in the development of bone metas-
tases in NENs of the overexpression of CXCL12, together
with its C-X-C motif receptor 4 (CXCR4), which causes cell
hyperproliferation and angiogenesis [160]. Studies in other
neoplasms suggest a possible role of microRNAs as well,
however no evidence is currently available in NENs [10].
3.6. Conclusions
The heterogeneity of NENs biology and clinical course mir-
rors the heterogeneity in their pathogenetic mechanisms.
The identification of preneoplastic lesions as well as the
underlying mechanism leading to tumor onset may allow
to identify effective prevention strategies. Similar genetic
alterations seem to play a pivotal role both in sporadic
and familial neoplasms. Data regarding pathogenetic
mechanisms in NENs are currently mainly available in GEP
NENs, maybe due to their relatively higher frequency.
Enteroendocrine cells have been considered as a source of
stem cells in SI-NETs, while hypergastrinemia and chronic
use of PPI have been proposed as possible pathogenetic
mechanisms in G-NETs. The role of inflammation remains
debated mainly in colorectal NETs, while in lung carcinoids
nicotine and hypoxia could be crucial in tumor
8R. MODICA ET AL.

development. Available data remain heterogeneous and
better knowledge is still an unmet need in this field, though
essential to improve cancer prevention and treatment
strategies.
3.7. Expert opinion
Improved understanding of pathological mechanisms in NENs
remains a crucial issue, considering the steadily increasing
incidence and prevalence of these neoplasms. Furthermore,
the identification of the best treatment at the right time for
any individual patient is a compelling issue in NENs and
a deep knowledge of pathogenetic mechanisms will be essen-
tial to improve treatment strategies, as well as to identify new
therapeutic targets [4,161–163].
Genetic alterations both in familial and sporadic NENs, as
well as epigenetic modifications play a pivotal role in NEN
development [15]. Familial NENs, as pNENs in MEN1 genetic
syndrome, could represent a model to study early tumor
development, but these observations seem to be different in
the sporadic counterpart.
Other evidence, including the possible neoplastic suscept-
ibility suggested by a not negligible prevalence of second
primary malignancies in patients with NENs could find an
explanation with the identification of pathogenetic mechan-
isms [164]. Importantly, NENs and NECs may recognize dif-
ferent pathways of development rather than just
a progression from NEN to NEC, due to the different biolo-
gical characteristics reflecting different prognosis. Similarly,
the development of bone metastases could show peculiar
pathogenetic mechanisms, which differ from primary devel-
opment and consequently different treatment could be
required.
The role of inflammation in NENs is highly debated, despite
inflammation processes known to be involved in cancer onset
and progression. The tumor microenvironment including
growth factors, cytokines, and chemokines and other factors
including endocrine disrupting chemicals, as well as genetic
and epigenetic modification are known to create an interplay
with inflammation [12,15,164,165]. Environmental factors, gen-
der differences, metabolic syndrome and nutrition, lipid
homeostasis, low vitamin D levels, and microbiota have been
analyzed as risk factors in NENs, but their role in pathogenetic
mechanisms could not be negligible. One of the major chal-
lenges ahead is to integrate the available data because the
slight difference between risk factors and pathogenetic factors
may be due to difficulty in indentifying the underlying
mechanisms. The higher prevalence of DIPNECH in the female
sex, as well as other gender differences, should draw the
attention of clinicians to better evaluate the role of hormonal
status in NENs.
Substantial data have been currently obtained in MCC,
where the role of polyomavirus and UV ray exposure is clearly
involved in the pathogenetic mechanism. Nevertheless, MCC is
completely different from the majority of NENs in its biological
features, being extremely aggressive with high metastatic
potential, and treatment options, including immunotherapy
are not included in the therapeutic algorithm of other NENs.
Consequently, the effort to identify pathogenic mechanisms in
NENs may be even more difficult than in other cancer types.
The complex interplay among patient characteristics, environ-
ment, and tumor biology does not currently allow to depict
a reliable model of pathogenesis in NENs. This significant
clinical challenge warrants further investigation, mainly to
allow early diagnosis but also for the identification of potential
therapeutic targets and more effective and tailored treatment
options, leading to better survival outcomes and improved
quality of life [166].
Funding
This paper was not funded.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
Author contribution statement
Conception/Design: RoMo, AC.
Collection and/or assembly of data: RoMo, AL, RoMi, GC, EB.
Data analysis and interpretation: Ro Mo, AL, RoMi, GC, EB, AC.
Manuscript writing: Ro Mo, AL, RoMi, GC, EB.
Final approval of manuscript: RoMo, AL, RoMi, GC, EB, AC.
ORCID
Roberta Modica http://orcid.org/0000-0002-3768-5803
Alessia Liccardi http://orcid.org/0000-0003-1784-5491
Roberto Minotta http://orcid.org/0000-0002-8823-0702
Giuseppe Cannavale http://orcid.org/0000-0002-8524-1131
Elio Benevento http://orcid.org/0000-0002-4489-3651
Annamaria Colao http://orcid.org/0000-0003-4049-2559
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