REVIEW ARTICLE

The grey zone between pure (neuro)endocrine

and non-(neuro)endocrine tumours: a comment on concepts
and classification of mixed exocrineendocrine neoplasms
Marco Volante & Guido Rindi & Mauro Papotti
Received: 12 June 2006 / Accepted: 28 August 2006 / Published online: 11 October 2006
# Springer-Verlag 2006
Abstract Terms such as mixed endocrineexocrine carci-
noma (MEEC) and adenocarcinoma with neuroendocrine
(NE) differentiation (ADC-NE) identify tumours belonging
to the spectrum of neoplasms with divergent exocrine and
(neuro)endocrine differentiation. These tumours display
variable quantitative extent of the two components, poten-
tially ranging from 1 to 99%, and variable structural patterns,
ranging from single scattered NE cells to a well-defined NE
tumour cell population organized in organoid, trabecular or
solid growth patterns. In the present report, the grey zone of
tumours/carcinomas with mixed NE and non-NE features is
explored for various organs. From a practical point of view,
MEECs differ from carcinomas with focal NE differentiation
by (1) the extension of each component (more than 30%) and
(2) the structural pattern of the NE component, either
organoid for well-differentiated or solid/diffuse for poorly
differentiated cases. In MEECs, the most aggressive cell
population drives the clinical behaviour. Conversely, ADC-
NE generally do not show a different clinical outcome,
compared to the corresponding conventional forms, except
for prostatic adenocarcinoma, in which NE cells are a
negative prognostic factor. The recognition of MEECs may
be of relevance for a targeted therapeutic strategy, foreseeing
the use of biotherapies similar to those proposed for pure NE
tumours.
Keywords Neuroendocrine differentiation
.
Adenocarcinoma
.
Mixed endocrineexocrine carcinoma
.
Diagnosis
Background
Human cancers displaying a combination of neuroendocrine
(NE) and conventional (glandular, squamous or urothelial)
features are a well-known occurrence in various organs.
The spectrum of (neuro)endocrine and exocrine differ-
entiation in tumours is schematically depicted in Fig. 1.
Between the two extremes occupied by pure NE and pure
non-NE neoplasms, the spectrum of tumours having mixed
divergent differentiation along NE and non-NE lineages
displays a variable extension of the two components
(potentially ranging from 1 to 99%), and also, variable
morphological patterns (ranging from the single NE cell
scattered in conventional (adeno)carcinoma cells, to a well-
identifiable NE tumour cell population organized in the
known organoid, trabecular or solid NE growth patterns).
The reverse condition (i.e., focal non-NE differentiation in
almost pure NE tumours) is less common, being restricted
to small-cell lung carcinomas with focal glandular or
squamous components.
Different terms have been employed to label such
tumours based on both the extent and the structural patterns
of the individual components (Table 1). Among these, the
World Health Organization (WHO) classification of endo-
crine tumours proposed the term mixed exocrineendo-
crine carcinoma (MEEC) for cases that originated in the
pancreas, stomach and appendix [53]. By converse,
adenocarcinoma with NE differentiation was the most
common labeling used in tumours of the breast, prostate
and colon [9, 10, 13, 16, 20, 25, 53, 54]. In the lung, both
Virchows Arch (2006) 449:499506
DOI 10.1007/s00428-006-0306-2
M. Volante
:
M. Papotti (*)
Department of Clinical and Biological Sciences,
University of Turin and San Luigi Hospital,
Regione Gonzole10,
10043 Orbassano-Torino, Italy
e-mail: mauro.papotti@unito.it
G. Rindi
Department of Pathology, University of Parma,
Parma, Italy
non-small-cell carcinomas with focal NE differentiation [1,
29] and combined (mixed) small-cell and non-small-cell
carcinomas (most frequently squamous or glandular com-
ponents) have been reported [56].
Almost 20 years ago, Lewin [34] proposed a nomencla-
ture for mixed exocrineendocrine tumours in which three
separate patterns were recognized: (a) the exocrine and
endocrine areas were admixed within the same tumour
mass comprising at least one third of the tumour; (b) the
phenotypic mixture was at the cellular level, i.e., amphi-
crine cells composed the whole tumour cell population and
(c) the exocrine and endocrine areas were juxtaposed
without mixture within the same tumour mass, thus,
defining the typical collision tumour; this study by Lewin
has the merit of introducing the criterion of the extent of the
NE cell component, which is, incidentally, the one still
currently used (i.e., 30%) and of keeping as a separate
entity the so-called collision tumours, which should be kept
clearly separate, from both a pathogenetic and a classifica-
tive point of view, from the former two entities (as, for
example, in the pancreas) [33].
The described morphological, immunophenotypical and
terminological heterogeneity in these tumours has, so far,
obtained limited clinical attention, mainly due to the low
prognostic impact of NE differentiation in conventional
(adeno)carcinomas. A possible exception is prostatic
adenocarcinoma, in which the NE cell component was
shown to be a negative prognostic factor [3, 5, 52].
Aim of the present report is to explore the grey zone of
tumours/carcinomas with mixed non-NE and NE features in
various organs and to discuss whether a unifying concept
for such heterogeneous group of tumours is possible.
Pure (neuro)endocrine tumours
Neuroendocrine tumours classically arise in the gastroin-
testinal tract, pancreas, lung and thymus. Endocrine glands
such as parathyroid, pituitary, thyroid and adrenal may also
host neuroendocrine tumours (which are labelled with
different terms, including adenoma, carcinoma, medullary
Table 1 Terms in use to define tumors with mixed exocrine
endocrine features
CURRENT TERMINOLOGY
Mixed exoendocrine tumor or carcinoma
Composite glandularendocrine tumor or carcinoma
Combined exocrineNE tumor or carcinoma
Collision tumor (adenocarcinoma+carcinoid/small cell carcinoma)
NE differentiated adenocarcinoma
Adenocarcinoma with (focal) NE differentiation
(adeno)Carcinoma with divergent differentiation
Multidirectionally differentiated carcinoma
Endocrine mucin-producing carcinoma
Amphicrine tumor
Adenocarcinoid
Goblet cell carcinoid
Mucinous carcinoid
Fig. 1 Schematic representation
of NE differentiation in human
tumors. NE Neuroendocrine,
WDET well differentiated endo-
crine tumor, TC typical (lung)
carcinoid, WDEC well-differen-
tiated endocrine carcinoma, AC
atypical (lung) carcinoid, PDEC
poorly differentiated endocrine
carcinoma, SCLC small cell
lung carcinoma, LCNEC large
cell neuroendocrine carcinoma,
GI gastrointestinal
500 Virchows Arch (2006) 449:499506
carcinoma, pheochromocytoma, etc). According to the
widely used terminology adopted for the lung, the spectrum
of NE tumours include typical and atypical (malignant)
carcinoids and poorly differentiated (small cell) NE
carcinomas [56]. The former two are referred to as well-
differentiated endocrine tumour or carcinoma, respectively,
according to the WHO classification of endocrine tumours
which specifically took into consideration gastroentero
pancreatic NE tumours [14, 25, 53].
The most recent entry of the list of pure NE tumours is
the large-cell NE carcinoma (LCNEC), described in 1991 in
the lung [55] and now recognized in several other non-NE
organs, including parotid, larynx, gallbladder, rectum,
kidney, ampulla, urinary bladder, uterus, prostate [12, 17,
18, 21, 24, 3638, 45]. Also, the other pure forms of NE
tumours (carcinoids and small-cell carcinomas) can excep-
tionally develop in non-NE organs, including the skin,
larynx, parotid, breast, gallbladder, uterine cervix, bladder
and prostate [9, 10, 16, 20, 26, 49, 54, 59]. Needless to say,
these NE tumours are, in all, similar to those developed in
other classical locations and differ in morphology and
phenotype from carcinomas with NE differentiation.
Ne tumours with focal non-NE component (<30%)
Rare forms of well-differentiated NE tumours (carcinoids)
were found to contain a variable amount of exocrine
(mucinous) cells, admixed with the neuroendocrine cell
population. The tumour cell phenotype differed from that of
pure NE or exocrine cells only in the exceptional occurrence
of amphicrine elements, so defined by the co-existence of
exocrine and neuroendocrine differentiation within the same
cell [11, 47]. These tumours were referred to as goblet cell
carcinoids or signet ring cell carcinoids or adeno-carcinoids,
have been more commonly described in the appendix and
are de facto mixed exocrineendocrine tumours, although
the exocrine cell population may not reach the requested
threshold of 30% (see below) [53]. Other rare cases have
been described, mostly in the pancreas in which a pure NE
tumour, functioning or nonfunctioning, had focal areas of
acinar [41] or ductal differentiation, never exceeding 510%
of tumour area [15]. Although it has been suggested that
ductular structures may represent an intrinsic neoplastic
component of the tumour [15], more recent molecular
evidence claimed that the ductular component occasionally
found in pancreatic endocrine tumours is the result of
entrapment of preexisting nonneoplastic ductules and that
the tumours are otherwise not distinctive from conventional
pancreatic endocrine tumours [57].
Finally, small-cell carcinomas, mostly of the lung, can
grow in combined forms, being this latter sometimes
characterized by minimal glandular or squamous compo-
nent, and are again classified in the group of combined
(mixed endocrineexocrine) carcinomas [56]. Probably, the
phenomenon of non-NE-differentiated lineages in predom-
inantly NE tumours is more common than expected and
simply has never been thoroughly investigated, in spite of
the possible clinical relevance given the higher aggressive
potential of transformed exocrine cells. In this respect,
several data in breast cancer have indicated that NE-
differentiated carcinomas contain a spectrum of mixed
amphicrine cell types, including focal apocrine differentia-
tion in tumours with an organoid growth pattern and
extensive chromogranin immunoreactivity [50].
Mixed exocrineendocrine carcinomas (NE or non-NE
cells >30%)
The WHO classification of endocrine tumours has incorpo-
rated mixed endocrineexocrine carcinomas (MEEC) in the
section on endocrine tumours of the pancreas and briefly
commented of these forms in the paragraphs on stomach and
appendiceal endocrine tumours [53]. In the pancreas and
stomach, these were defined as epithelial malignant
tumours characterised by a combination of a predominant
exocrine component and a NE cell subpopulation repre-
sented by at least one-third of the tumour area [14, 25, 53].
MEEC can be encountered not only in the pancreas [40],
but virtually at all sites, being prostate and breast among the
most common locations [16, 54] and also in the organs
where pure carcinoid tumours are usually found (e.g.,
gastroenteric tract and lung) [26]. MEECs are distinguished
(at least from a morphological viewpoint) from adenocarci-
nomas with neuroendocrine differentiation by the more
limited NE cells component in these latter. In the lung,
combined forms are recognized as variants of small-cell
carcinoma (code # 8045/3), which contain areas of classical
small-cell cancer admixed with foci of squamous or
glandular differentiation [56].
In the literature, the definition of MEEC and the
distinguishing criteria from carcinomas with NE differenti-
ation are not uniform: some take into account the extension
of the NE component only, while others consider type and
extent of the observed morphological patterns [9, 10, 20,
34, 49, 59]. This lack of standardization created several
controversies in both fields of tumour recognition and
treatment of these lesions. In addition, especially in
pulmonary and gastroenteropancreatic sites, a relatively
wide spectrum (and possibly a continuum) of NE-differen-
tiated tumours does exist including tumours with well-
represented (>30% of tumour area) NE cell component and
tumours with scattered NE cells only [1, 32, 40, 42, 43, 49].
With regard to the criterion of extension of the NE
component within the tumour, the rule of at least 30% of
Virchows Arch (2006) 449:499506 501
NE-differentiated areas allows to consider as true MEECs
those tumours with a well-represented or significant NE cell
population, only. On the other hand, however, no reason-
able explanation is provided for this limit from both a
pathogenetic and histogenetic point of view. In addition, the
morphological criterion appears essential for the definition
of MEEC and intrinsic to the rule of 30%, as those cases
with a well-represented NE component are easily recog-
nized as such (Fig. 1). Indeed, MEECs are the result of
intermingling of frankly glandular areas with typical
organoid NE areas (in the case of a well-differentiated
tumour) or classical small-cell carcinoma areas. This latter
pattern is relatively common in lung cancer where it is
recognized as a variant (combined small-cell carcinoma,
ICD 8045/3) of small-cell carcinoma in the WHO classifi-
cation of lung tumours [56]. Rarely, this combination has
been described in gastrointestinal (Fig. 2a,b), breast and
prostatic adenocarcinomas. The criterion of the structural
Fig. 2 Different morphological
and immunohistochemical pat-
terns in non-NE tumours with
NE differentiation. a, b A case
of mixed adenocarcinoma
(top) and poorly differentiated
NE (bottom) carcinoma of the
gallbladder: chromogranin A
immunohistochemistry b stained
positive in the NE component.
c, d Goblet cell carcinoid of the
appendix, showing an intimate
coexistence of mucin-laden sig-
net ring cells (c) with chromo-
granin A-positive NE cells (d).
e, f Colonic adenocarcinoma
including basally located NE
cells (f, blue color), showing no
evidence of proliferation, as
revealed by double immunohis-
tochemical staining with Ki-67
(f, brown color). (a, c, e H&E;
b, d immunoperoxidase; f dou-
ble immunohistochemical reac-
tion by immunoperoxidase
brown color and immuno-alka-
line phosphataseblue color; a,
b 200, c, d 600, e, f 400)
502 Virchows Arch (2006) 449:499506
pattern in the definition of MEEC is relevant to allow
separation of conventional adenocarcinoma with a less
represented NE cell population randomly spread in the
exocrine tumour, in the absence of carcinoid-like or small-
cell areas (see below).
A separate comment is deserved for the so-called goblet
cell carcinoids (group B of Lewin) [34], which represent an
intimate mixture of mucin-laden signet ring cells and highly
granulated NE cells in a tumour with classical organoid
pattern (Fig. 2c,d). At least in the appendix, goblet cell
carcinoids were the first reported examples of mixed
exocrine and endocrine tumours and are classified as their
pure NE counterparts, according to the current WHO
classification of appendiceal carcinoids. Indeed, the relative
proportions of the two components are variable, and only in
some cases are they large enough to justify a diagnosis of
mixed exocrineendocrine carcinoma. Many other cases
have limited mucinous cell population (or more rarely,
scant NE cell among signet ring cells and would better fit in
the following definition (see below). A case of multiple
microscopic signet ring cell carcinoids was reported in the
gallbladder, in which many small organoid-patterned
carcinoid tumours infiltrated the gallbladder wall and had
focal exocrine cell differentiation, in the form of scattered
mucin-laden signet ring cells in the neoplastic nests [44].
Only scant amphicrine cells were found by double stain-
ings, and the proportion of signet ring cells did not exceed
20% of the whole tumour. Given the peculiar morphology
of goblet cell carcinoids, they should retain their original
descriptive terminology.
Non-NE carcinomas with focal NE component (<30%)
Conventional (adeno)carcinomas of various organs, includ-
ing breast, prostate, lung, colon, stomach and so on, may
display specialized differentiation in both exocrine and NE
cell lineages. Exocrine differentiation may include mucin-
ous or signet ring cell changes, apocrine differentiation in
breast carcinoma, Paneth cell differentiation in gastrointes-
tinal cancer, acinar differentiation in pancreatic cancer,
Clara cell features in pulmonary adenocarcinoma or even
basaloid features in pulmonary, prostatic or rectal carcino-
mas [16, 25, 48, 54, 56]. The interest in such rare exocrine
differentiation lines was very limited, either due to their
rarity andabove allthe lack of significant clinical
correlates, with the possible exception of basaloid carcino-
mas in the lung [8].
On the other hand, foci of NE differentiation have been
recognized in non-neuroendocrine carcinomas for many
years, employing various methods and markers. Among
these, the immunohistochemical detection of chromogranin
A is the most popular and reliable test to identify NE cells
(Table 2). The interest for NE differentiation in non-NE
tumours embraces histogenetic, diagnostic and clinical
issues, mostly related to the correct morpho/functional
(hormonal) typing of different neoplastic components in
both primary and metastatic tumours. Additionally, signif-
icant clinical and prognostic correlates were proven in
prostatic adenocarcinoma, only, while remaining mostly
controversial for cancers at other sites.
Excluding MEEC cases described in the previous
paragraph, various patterns of focal NE differentiation (in
the range of 1 to 30% of the tumour area) were described.
In non-small-cell lung carcinoma, NE differentiation has
been reported in up to 36% of cases, depending on the
method used to identify NE cells [1, 29], although
controversial significant impact on prognosis was reported
[29, 46]. Focal NE differentiation is not mentioned in the
WHO classification of tumours of the digestive system
[25], although there are reports in the literature on the
occurrence of NE differentiation in esophageal [26], gastric
[42], colorectal [2, 4, 19, 22, 23, 30, 43] and extrahepatic
duct carcinomas [28]. The amount of NE cells is variable in
Table 2 Practical algorithm proposed for the identification of NE differentiation in non-NE carcinomas
Search for neuroendocrine differentiation
When? Upon request by the clinician (e.g., prostatic adenocarcinoma with high chromogranin blood levels and/or in hormonal escape)
Recognized organoid, solid, trabecular or small cell areas present in an otherwise conventional (adeno)carcinoma
Clinical history of previously resected NE tumor
Where? Organs classically hosting NE tumors (e.g., digestive tract, lung)
Non-NE organs in which NE differentiation has been described
Commonly: prostate, breast, colon, stomach, lung (NSCLC)
Occasionally: uterus, skin, kidney, gallbladder, parotid, larynx, etc.
How? Immunostainings first choice Chromogranin A
Second choice Synaptophysin, CD56, others
Additional Ki67 (cell proliferation) somatostatin receptors (targeted therapy)
What has to be reported [based on extent + architecture of NE component]
1 Mixed exocrineendocrine carcinoma (MEEC)
2 (adeno)Carcinoma with (focal) NE differentiation
Virchows Arch (2006) 449:499506 503
these tumours and is related to the method used to identify
such NE differentiation [43].
Immunoreactivity for chromogranin A is generally the
easiest and commonest procedure, which allows to detect NE
differentiation in up to 25% of cases. In the breast, more or
less extensive NE differentiation foci were described in
conventional lobular or ductal carcinomas [49, 54, 59] and
are kept separate from the exceptional carcinoid tumours
of the breast and the NE carcinoma subtype, both of which
display NE features in more than 50% of tumour cells [54].
In the prostate and bladder, NE differentiation has been
described in a fraction of prostatic and bladder adenocarci-
nomas [6, 27]. In the former tumour, the prognostic
implications of increased chromogranin blood levels (pro-
duced by the NE cell population) have been reported, being
a remarkable unfavourable prognostic indicator in both
surgically treated and hormonally treated patients [3, 5].
The extent of NE-differentiated cells in prostatic adeno-
carcinoma is highly heterogeneous. Generally, it is limited
to scant chromogranin A reactive cells located in a basal
position of neoplastic acini. The amount of NE cells
increases with increasing Gleasons grade being maximal
in solid or trabecular areas, also in association with a small
tumour cell size. Histological material obtained after
hormonal treatment of a prostatic carcinoma, sometimes
shows extensive areas of NE differentiation (occasionally
exceeding the threshold of 30%, although a diagnosis of
MEEC has never been considered in this context),
especially in the case of hormone refractory tumours [5,
16, 27]. It is interesting to note that increased NE cells were
reported in rectal adenocarcinomas after chemotherapy or
radiotherapy likely reflecting the relative resistance of low
proliferating NE cells to conventional antiblastic therapy
[51].
It has to be mentioned that none of the studies reported
so far in the literature on NE differentiation in prostate or
other types of cancer took into consideration the extent of
the sampling as a potential source of discrepancy. In fact, in
most instances, the focal NE-differentiated component is
not equally distributed within a tumour but may be
considerably heterogeneous in different areas, therefore,
making equivocal the rule of the 30% cutoff. From a
practical point of view, adequate sampling (i.e., one paraffin
block for each centimeter of tumour size) is, therefore,
necessary to rule out the presence or quantify the extent of a
NE component and a panel of pan-NE markers may have a
higher sensitivity than a single antibody. Moreover, a totally
different approach consists in counting NE single scattered
cells positive by immunohistochemistry (i.e., at low power
field) as compared to estimating the extent of a morpho-
logically NE-patterned area within a lesion. All these
aspects have not been considered, to date, in any classifi-
cation scheme, but would deserve major consideration.
The nature of NE cells in non-NE carcinomas is
controversial. In some cases, they were considered termi-
nally differentiated cells, with no proliferative potential, and
therefore, although associated to the neoplastic growth,
probably not of neoplastic nature [42] (Fig. 2e,f). In other
cases, a consistent NE cell population is observed,
representing true neoplastic cells of divergent differentia-
tion outgrowing the adenocarcinoma cell component, often
after hormonal therapy in the case of prostatic adenocarci-
noma [5, 27]. In the pancreas, it has been well documented
that the morphological features and the proliferative activity
may segregate non-neoplastic from neoplastic NE cells in
the context of a non-NE carcinoma, thus, defining different
types of ductal adenocarcinomas with scattered endocrine
cells [40].
Summary and conclusion
We have summarized the spectrum of currently known NE-
differentiated tumours, including pure forms (well-differen-
tiated tumour/carcinoma-carcinoid/malignant carcinoid,
poorly differentiated small- and large-cell NE carcinoma)
and mixed tumours. In this latter group, the label proposed
by the WHO [53] of mixed exocrineendocrine carcino-
mas is of practical efficacy taking into consideration at
least two major diagnostic parameters: (1) extension of each
component (at least 30%), and (2) structural features of the
NE components as well-differentiated organoid or solid/
diffuse growth patterns.
All other carcinomas containing a variable amount of NE
cells below one-third of the entire tumour cell population,
and more frequently, when scattered in an otherwise
glandular growth pattern, are referred to as (adeno)
carcinomas with focal NE differentiation. In MEECs, the
most aggressive cell population drives the clinical behav-
iour, in general, of the well-differentiated NE component of
MEECs following the natural history of the exocrine
carcinoma while MEEC cases with small-cell carcinoma
component follow the disease progression of this latter.
Conversely, adenocarcinoma with focal NE differentiation
generally does not show any difference in the clinical
outcome, as shown in studies in the breast, lung and
gastrointestinal tract [10, 29, 35, 46, 49, 58]. A notable
exception is prostatic adenocarcinoma, in which the
presence of chromogranin A-positive NE cells is an
unfavourable prognostic factor [3, 5, 52]. The recognition
of such tumours may be of relevance for better addressing
the therapeutic strategy, and possibly, for evaluating also in
mixed endocrineexocrine tumours the same biotherapies
proposed for pure NE tumours [39].
New insights may come from the analysis of the
mechanisms leading to the development of both MEEC
504 Virchows Arch (2006) 449:499506
and divergent NE differentiation in conventional carcino-
mas. Several studies defined the role of specific transcription
factors (i.e., the family of basic helixloophelixbHLH
factors, including the human achaetescute homologue
1-hASH1) playing a pivotal role in the development and
differentiation of neuronal and endocrine cells of foregut and
midgut derivation [7, 31] and that have been found, by
means of alternative techniques, to be expressed in NE
carcinomas from various sites. Indeed, such transcriptional
molecules appear as a promising tool for the identification
of functional NE differentiation in MEECs.
Acknowledgement This work is supported by grants from the
Italian Ministry of University (ex 60% to MP, GR and MV).
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