Intestinal-Type Adenocarcinoma: Classification, Immunophenotype, Molecular Features and Differential Diagnosis

Abstract

Intestinal-type adenocarcinoma is the second most frequent sinonasal adenocarcinoma. High incidence of these tumors is seen among workers with occupational wood dust exposure, particularly of hardwood dusts. Intestinal-type adenocarcinoma has striking histomorphologic and immunophenotypic similarities with colorectal adenocarcinomas, but on the level of molecular pathologic mechanisms these tumors have their own specific features different from gastrointestinal tumors. This article provides an update on current histopathologic classification of intestinal-type adenocarcinomas, their immunophenotypic properties, recent advances in molecular pathologic features and differential diagnostic considerations.

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Head and Neck Pathol (2017) 11:295–300
DOI 10.1007/s12105-017-0800-7
PROCEEDINGS OF THE 2017 NORTH AMERICAN SOCIETY OF HEAD AND NECK PATHOLOGY
COMPANION MEETING (SAN ANTONIO, TX)
Intestinal-Type Adenocarcinoma: Classification,
Immunophenotype, Molecular Features andDifferential
Diagnosis
IlmoLeivo1 
Received: 11 January 2017 / Accepted: 6 February 2017 / Published online: 20 March 2017
© The Author(s) 2017. This article is published with open access at Springerlink.com
age range and a mean of 50–64 years. ITACs are most
frequently localized in the ethmoid sinus (40%), the nasal
cavity (25%) and the maxillary antrum (20%). Rare tumors
with intestinal-type differentiation may also occur in other
areas of the upper airways [3, 4], and in lung [5]. ITACs are
aggressive malignancies with frequent local spread to the
orbit, the skull base and the intracranial space, and with a
possibility of metastatic spread.
Occurrence of ITAC has a strong association with occu-
pational exposure to hardwood dusts [6–9]. In woodwork-
ing industries, workers with long-term exposure to hard-
wood dusts have an incidence approaching 1000 times that
in control populations. Occupational wood dust exposure
has been documented in ca. 20% of cases of ITAC, while
the rest are sporadic. The highest incidences are seen in
furniture industry using hardwoods, particularly beech
and oak [8, 9]. The incidence of ITAC is also high among
woodworkers who lay hardwood floors. Other occupational
dust exposures with risk for ITAC have been reported in
shoe and leather industry and in textile manufacture. Also
long-term exposure to chromium and nickel has been
incriminated [10]. The carcinogenic compounds in occupa-
tional dusts have not been identified, but etiologic roles for
tannins or chronic inflammation have been speculated [10].
Dr. Barnes reported that patients with ITAC had cumulative
exposure times for wood dusts of 40–43years [1]. Further-
more, ITACs associated with dust exposure were diagnosed
mostly in men (85–95%) and predominantly in the ethmoid
sinus [1]. This contrasts with sporadic ITACs that are more
frequent in women and often arise in the maxillary antrum.
Abstract Intestinal-type adenocarcinoma is the second
most frequent sinonasal adenocarcinoma. High incidence
of these tumors is seen among workers with occupational
wood dust exposure, particularly of hardwood dusts.
Intestinal-type adenocarcinoma has striking histomorpho-
logic and immunophenotypic similarities with colorectal
adenocarcinomas, but on the level of molecular pathologic
mechanisms these tumors have their own specific features
different from gastrointestinal tumors. This article provides
an update on current histopathologic classification of intes-
tinal-type adenocarcinomas, their immunophenotypic prop-
erties, recent advances in molecular pathologic features and
differential diagnostic considerations.
Keywords Intestinal-type adenocarcinoma·
Sinonasal adenocarcinoma· Sinonasal nonintestinal
adenocarcinoma· Head and neck adenocarcinoma·
Immunohistochemistry· Molecular pathology· Wood dust
exposure
Intestinal-type adenocarcinoma (ITAC) is the second most
common type of sinonasal adenocarcinoma after adenoid
cystic carcinoma. It is composed of subtypes described
by Dr. Barnes that resemble carcinomas or adenomas of
intestinal origin, and occasionally the normal intestinal
mucosa [1, 2]. ITACs occur mostly in males with a wide
Proceedings of the 2017 North American Society of Head and
Neck Pathology Companion Meeting (San Antonio, TX).
* Ilmo Leivo
ilmo.leivo@utu.fi
1 Department ofPathology andForensic Medicine, University
ofTurku, Turku, Finland
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296 Head and Neck Pathol (2017) 11:295–300
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Classification
ITACs mimic the appearances of neoplastic large and
small intestinal mucosa, and occasionally normal intestinal
mucosa. Based on histopathologic parameters, Dr. Barnes
classified ITACs into five categories: papillary, colonic,
solid, mucinous, and mixed subtypes [1]. On the other
hand, the classification of Kleinsasser and Schroeder [11]
subdivided ITACs into papillary-tubular cylindrical cell
type (corresponding to papillary, colonic, and solid sub-
types), alveolar goblet cell type and signet-ring cell type
(both corresponding to mucinous subtype), and transitional
type (corresponding to mixed subtype). The histologic sub-
types have been reported to correlate with differences in
clinical behavior [1, 10, 11].
In the Barnes classification papillary subtype of ITAC
(ca. 18% of all) shows prominent papillary fronds with
minor amounts of tubular structures (Fig.1). ITACs of this
type usually contain columnar goblet cells and they often
resemble intestinal villous or tubular adenomas. Rarely,
papillary ITACs may recapitulate the morphology of the
normal intestinal mucosa with nearly normal-looking villi
including the specialized cell types (goblet, resorptive,
Paneth, and argentaffin cells) and the muscularis mucosae
[12].
Colonic subtype of ITAC is the most frequent (ca. 40%),
displaying a glandular, tubular and trabecular architecture
with few papillae. This tumor often mimics a conventional
colorectal adenocarcinoma (Fig.2). Columnar tumor cells
are crowded back-to-back and they display nuclear pleo-
morphism. Intra- and extracellular mucins and few goblet
cells may be seen. ITACs of the colonic subtype often show
extensive invasive growth. Solid subtype of ITAC is less
differentiated and features predominantly solid growth pat-
terns with minor amounts of glandular structures (Fig.3).
Mucinous subtype of ITAC displays distended glands or
cell clusters within pools of extracellular mucin (Fig.4).
Cells of signet-ring type may be seen. Mucinous ITACs
resemble the mucinous variant of colorectal adenocarci-
noma. Mixed subtype of ITAC contains different composi-
tions of the various growth patterns above.
Exceedingly rare primary non-sinonasal ITACs of the
head and neck have been reported in the base of the tongue,
the major salivary glands, the pharynx and the larynx [3, 4,
Fig. 1 a Intestinal-type adenocarcinoma, papillary subtype. The
tumor has ample papillary projections, and some glandular and
tubular areas. H–E stain ×250. b The cells are usually cylindrical
with elongated and pleomorphic hyperchromatic nuclei and nuclear
crowding. Several mitotic figures are seen. H–E stain ×400. c Intes-
tinal-type adenocarcinoma, highly differentiated papillary subtype
resembling normal intestinal mucosa. H–E stain ×150. d Note the
orderly arrangement of cylindrical cells in the papillae with only mild
nuclear atypia. Occasional mitotic figures are seen. H–E stain ×400
▸
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297Head and Neck Pathol (2017) 11:295–300
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13]. These malignancies with intestinal differentiation dis-
play heterogeneous microscopic appearances composed of
glands and tubules reminiscent of colorectal adenocarcino-
mas. Positive staining of tumor cells for CK20, villin and/
or CDX-2 attests for intestinal differentiation.
Immunophenotype andMolecular Features
Immunohistochemical staining indicates that ITACs are
positive for CK20 (Fig.5a), CDX-2 (Fig.5b), villin, and
MUC2, and variably positive for CK7 (Fig. 5c) [14–16].
Recently, the intestinal transcription and epigenetic fac-
tor SATB-2 has been identified as an additional marker
of intestinal differentiation in ITAC [17]. Occasional neu-
roendocrine cells in ITACs often express chromogranin
A (Fig. 5d) and/or synaptophysin. High levels of EGFR
protein expression has been found in a subset of ITACs,
Fig. 2 a Intestinal-type adenocarcinoma, colonic subtype. The tumor
has glandular and trabecular areas resembling appearances of colo-
rectal adenocarcinoma. H–E stain ×250. b The nuclei are crowded
and highly pleomorphic and show some hyperchromasia. There is
high mitotic activity. H–E stain ×400
Fig. 3 Intestinal-type adenocarcinoma, solid subtype. The tumor dis-
plays a diffuse growth pattern with minor amounts of poorly differ-
entiated glandular lumina. There is high mitotic activity. H–E stain
×250
Fig. 4 Intestinal-type adenocarcinoma, mucinous subtype. a Tumor
cells form clusters with glandular lumina, b and strips with goblet-
type cells, and are surrounded by ample pools of mucin. H–E stain
×400
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298 Head and Neck Pathol (2017) 11:295–300
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mostly in woodworkers [18, 19]. ITACs have shown a nor-
mal expression of mismatch repair proteins, β-catenin and
E-cadherin [20]. Although immunohistochemical studies
have indicated close similarities between ITACs and colo-
rectal adenocarcinomas, molecular pathological studies
have revealed important differences. In contrast to colorec-
tal carcinomas, activating mutations in KRAS and BRAF
oncogenes are rare in ITAC [19, 21–23]. Overexpression of
MET protein without MET gene amplification is frequent
in ITAC, but not in intestinal carcinomas, and may provide
opportunities for targeted therapies [24]. Loss of annexin
A1 expression and diminished A2 expression has been
reported in ITAC [25]. The frequency of TP53 mutations
in ITAC has ranged between 18–53% in different series
[21, 26, 27]. The risk of such mutations increases with the
duration and cumulative level of wood dust exposure [26,
27], but apparently not of smoking [27]. Nonsmokers have
almost exclusively single missense-type TP53 mutations
with G>A transition, while smokers have less frequent and
multiple frameshift mutations with G>T transition [27]. It
has been speculated that mutations occurring during wood
dust exposure might be related to reactive oxygen and/or
nitrogen species generated by chronic inflammation [26,
27].
Differential Diagnosis
The differential diagnosis of ITAC includes metastatic gas-
trointestinal carcinoma and sinonasal low-grade nonintesti-
nal adenocarcinoma [1, 28]. A colorectal adenocarcinoma
metastatic to the sinonasal tract cannot be distinguished
from a primary sinonasal ITAC by any of the above immu-
nohistochemical markers. Both ITACs and colorectal car-
cinomas express CK20, CDX-2, villin and MUC2, but the
expression of CK7 in a tumor may be suggestive of ITAC.
It is noteworthy that the expression of CK20 is more spe-
cific for ITAC than that of CDX-2. Additional specificity
for ITAC can be obtained by staining for SATB-2 [17].
While CDX-2 is helpful when diagnosing ITAC, it is not
fully specific as it can sometimes be expressed in sinonasal
undifferentiated carcinomas and in salivary-type sinonasal
adenocarcinomas [29]. Thus, if an intestinal-type tumor has
been detected in the sinonasal tract, colonoscopy or colo-
rectal radiographic studies should be performed to rule out
primary colorectal adenocarcinoma. However, sinonasal
metastases from gastrointestinal carcinomas are rare. In a
Fig. 5 Immunohistochemical staining of intestinal-type adenocar-
cinoma, papillary subtype. a CK20 is seen in most tumor cells, b
CDX-2 stains all tumor nuclei, c CK7 is variably positive in tumor
cells, d chromogranin A is seen in occasional neuroendocrine cells.
Peroxidase conjugated ABC Kit (Dako) ×400
▸
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299Head and Neck Pathol (2017) 11:295–300
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review of 82 metastatic sinonasal malignancies, only five
were derived from a primary tumor in the gastrointestinal
tract [12]. Finally, the differential diagnosis of ITAC from
sinonasal nonintestinal adenocarcinomas is supported
by immunohistochemistry for CK20, CDX-2, villin and
SATB-2 which only stain ITACs.
The treatment of ITAC is surgical resection varying
from lateral rhinotomy to partial maxillectomy and total
maxillectomy, with or without radiotherapy.
ITACs behave as high-grade malignancies. In 213
ITACs reviewed by Dr. Barnes, 50% of the patients devel-
oped local recurrences, 8% displayed cervical lymph node
metastases, and 13% had distant metastases. A total of
60% of patients died of disease. ITACs associated with
wood dust exposure had a somewhat better prognosis (with
50% survival rates at 5years) than sporadic ITACs (with
20–40% survival rates at 5years). Well-differentiated papil-
lary ITACs pursue an indolent course, but solid and muci-
nous subtypes have poorer outcomes [1, 10, 11].
Funding The funding was provided by Finnish Cancer Society, Fin-
ska Läkaresällskapet, and Maritza and Reino Salonen Foundation.
Compliance with Ethical Standards
Conflict of interest The author has no potential conflict of interest.
Human and Animal Participants The research has not involved
human participants and/or animals.
Informed Consent All patients whose samples have been illustrated
in figures have given their informed consent. The text component is a
review article with no primary patient data.
Open Access This article is distributed under the terms of the
Creative Commons Attribution 4.0 International License (http://
creativecommons.org/licenses/by/4.0/), which permits unrestricted
use, distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a
link to the Creative Commons license, and indicate if changes were
made.
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