Special IssueAn Update in Immunohistochemistry (Part II)
Application of Immunohistochemistry in Gastrointestinal
and Liver Neoplasms
New Markers and Evolving Practice
Zongming Eric Chen, MD, PhD; Fan Lin, MD, PhD
 Context.Diagnosis of primary gastrointestinal and liver
neoplasms is usually straightforward. Immunohistochem-
istry is most helpful to differentiate metastatic carcinomas
with morphologic similarity and to resolve tumors of
unknown origin. Recently, several new markers highly
sensitive and specific for primary liver and gastrointestinal
tumors have been discovered. Their potential diagnostic
application has not been widely appreciated by general
practicing pathologists. In addition, a new trend in
immunohistochemistry application has started, focusing
on assessing predictive markers (such as human epidermal
growth factor receptor 2) and mutation-specific markers
(v-raf murine sarcoma viral oncogene homolog B V600E)
to directly guide clinical management. Practicing pathol-
ogists need to be aware of and prepared for this evolving
trend.
Objectives.To summarize the usefulness of several
recently discovered immunohistochemical markers in the
study of gastrointestinal and liver tumors; to suggest the
most current and effective immunohistochemical panels
I mmunohistochemistry (IHC) is commonly used in the
diagnosis of gastrointestinal (GI) and liver neoplasms to
facilitate accurate tumor classification.14 There are two
practical goals: One is to confirm a tumor diagnosis by
excluding morphologic mimickers or to identify the most
reasonable tissue or organ of origin in cases of metastatic
carcinoma of unknown primary.5,6 The other is to provide
meaningful prognostic information and even predict re-
sponsiveness to standard chemotherapy or novel molecular
targeted therapy.710 In the last 5 to 6 years, several new
sensitive and specific markers with proven diagnostic value
have become available for pathologists to better address
these goals. The purpose of this review is to discuss practical
applications of these new markers in the context of common
problematic issues encountered in the routine diagnosis of
Accepted for publication May 29, 2014.
From the Department of Laboratory Medicine, Geisinger Medical
Center, Danville, Pennsylvania.
The authors have no relevant financial interest in the products or
companies described in this article.
Reprints: Zongming Eric Chen, MD, PhD, Department of Labora-
tory Medicine, MC 0131, Geisinger Medical Center, 100 N
Academy Ave, Danville, PA 17822 (e-mail: zechen@geisinger.edu).
14 Arch Pathol Lab MedVol 139, January 2015
addressing common diagnostic challenges for these tu-
mors; to share practical experience and useful tips for
human epidermal growth factor receptor 2 testing in
gastric and gastroesophageal junction adenocarcinoma
and v-raf murine sarcoma viral oncogene homolog B
V600E immunohistochemistry in colorectal carcinoma.
Data Sources.Sources include literature review, and
authors research data and practice experience. The cases
illustrated are selected from the pathology archives of the
Geisinger Medical Center (Danville, Pennsylvania).
Conclusions.Application of immunohistochemistry in
gastrointestinal and liver tumors continues to evolve. New
tumor-specific markers constantly emerge and help
pathologists to further improve diagnostic accuracy.
Assessment of predictive and prognostic markers by
immunohistochemistry in routine pathologic diagnosis is
a new trend and will greatly facilitate the advancement of
personalized cancer therapy.
(Arch Pathol Lab Med. 2015;139:1423; doi: 10.5858/
arpa.2014-0153-RA)
GI tract and liver tumors. We limited our scope to include
mainly tumors of epithelial cell origin and will not
emphasize mesenchymal tumors, with the exception of GI
stromal tumors (GISTs) and tumors of lymphoid origin.
It is noteworthy that assessment of prognostic and
predictive markers by IHC in GI tumors has become
increasingly popular.7 Microsatellite instability (MSI) in
colorectal carcinoma (CRC),11,12 human epithelial growth
factor receptor 2 (HER2) in gastric and gastroesophageal
junction (GEJ) adenocarcinoma,810 and even Ki-67 in
neuroendocrine tumors (NETs)13,14 are some familiar
examples. Currently, not only are pathologists depending
on IHC results for diagnosis, but our clinical colleagues have
also become interested in knowing the results before they
start to formulate the best management plan for individual
patients. In a sense, this has begun a new trend to transform
IHC from a traditional qualitative assay most useful in
distinguishing tumor types to a quantitative clinical test
whose result is essential for clinical decision making. With
rapid advances in our understanding of molecular and
genetic mechanisms of carcinogenesis and a continuous
push for personalized cancer therapy, it is highly likely that
this trend will rapidly progress. As practicing pathologists, it
GI and Liver ImmunohistochemistryChen & Lin
 Table 1. A Panel of Immunomarkers Helpful in
Confirming Hepatocellular Differentiation
Markers Staining Pattern Sensitivity, % Specificity, %
ARG1 Cytoplasmic 8095 95100
and nuclear
HepPar1 Cytoplasmic 7080 ~80
GPC3 Cytoplasmic 5080 ~95
pCEA Canalicular 90 100
CD10 Canalicular n/a n/a
CD34 Sinusoidal n/a n/a
Abbreviations: ARG1, arginase 1; GPC3, glypican 3; HepPar1,
hepatocyte paraffin 1; n/a, not available; pCEA, polyclonal carcinoem-
bryonic antigen.
is our clinical responsibility to be vigilant in overseeing all
aspects of IHC to ensure test precision and result accuracy.
LIVER
The most common primary tumors of epithelial origin in
liver are hepatocellular carcinoma (HCC)15 and cholangio-
carcinoma (CCA)16 in adults, and hepatoblastoma17 in
young children. Hepatocellular adenoma (HCA) is a
relatively rare benign tumor and must be distinguished
from HCC and other benign nonneoplastic hepatic lesions.18
Metastatic carcinomas are common in the liver. Differenti-
ating them from primary liver tumors can pose a real
diagnostic challenge for pathologists.
HEPATOCELLULAR CARCINOMA
Based on classic morphologic features, most HCCs can be
easily recognized on hematoxylin-eosin sections. However,
many types of benign or malignant tumors may share
morphologic similarities. Some of the most notorious
mimickers of HCC include adrenocortical carcinoma, renal
cell carcinoma, clear cell sarcoma, melanoma, large cell
neuroendocrine carcinoma, and angiomyolipoma.1921 In
addition, poorly differentiated HCC and some HCC variants
may be difficult to discern based on morphology alone.22 In
these circumstances, IHC is not only helpful but necessary
for accurate diagnosis. In our experience, the most effective
IHC approach to address these problematic issues is to
positively confirm hepatocellular differentiation in the
tumor cells in conjunction with various tumor-specific
markers (covered in other review articles in this 2-part
special IHC series of articles) to exclude possible mimickers.
Table 1 lists a recommended panel of IHC markers along
with their reported sensitivities and specificities for diag-
nosing HCC. The top three markers are preferable because
they show a cytoplasmic expression pattern that is easily
recognizable, even in small biopsies with disrupted archi-
tecture or in cytologic specimens. The other markers are
useful supplements to increase sensitivity and specificity.
Within the panel, arginase 1 (ARG1)19,2327 is a newly
described marker with promising performance.
ARG1
ARG1 is a binuclear manganese metalloenzyme involved
in the urea cycle. It catalyzes the hydrolysis of arginine to
ornithine and urea.28 Recent studies have clearly demon-
strated that it is a great marker for hepatocellular
differentiation.19 Compared with hepatocyte paraffin 1
(HepPar1) and glypican 3 (GPC3), it shows better sensitivity
and specificity.2327 It is also positive in hepatoblastoma. So
far, only rare cases of non-HCC carcinomas have been
Arch Pathol Lab MedVol 139, January 2015
reported to be immunoreactive to ARG1.19,26,27 To the best
of our knowledge, there has not been any report of ARG1
expression in hepatoid carcinoma, a rare tumor from
extrahepatic sites (mostly stomach, pancreas, and uterus)
that shows hepatocellular differentiation.2933 In our expe-
rience, ARG1 is best used together with either HepPar1 or
GPC3 to increase diagnostic sensitivity and specificity for
HCC. Figure 1, a and b, show staining patterns of HepPar1
and ARG1 in a needle biopsy specimen of HCC. When all 3
markers are used simultaneously, they can identify almost
all HCCs, including rare variants.22 However, caution is still
warranted when the combination of these markers is used
to differentiate metastatic carcinomas from HCC, particu-
larly hepatoid carcinoma. In difficult scenarios, a distinction
between primary HCC and metastasis has to be made on
clinical grounds based on a patients history and an imaging
survey of most suspicious sites.
HCC VARIANT WITH UNUSUAL IHC STAINING
PROFILE
Scirrhous HCC is a rare morphologic variant, composed of
less than 5% of HCCs.34 It is characterized by marked
stromal fibrosis, subcapsular location, multinodularity, and
changes in clear cells, with preserved intratumoral portal
tracts. It also shows an unusual IHC phenotype. Most of the
tumors are negative for HepPar1 and positive for cytokeratin
7 (CK7), CK19, and epithelial cell adhesion molecule
(EPCAM), making it difficult to distinguish from intrahe-
patic CCA (IHCCA) and metastatic adenocarcinoma. It is
supposed to have a better prognosis than IHCCA.35
Recently, Krings et al22 studied 20 such tumors and found
that 85% were positive for ARG1 and 79% were positive for
GPC3, whereas only 26% were positive for HepPar1; 53% of
the tumors were also positive for CK7, and 26% were
positive for CK19.
Fibrolamellar HCC is also a variant of HCC with a distinct
morphology and characteristic clinicopathologic features.36
Unlike most conventional HCCs, the tumor cells are often
positive for CK7 and embedded in the dense fibrosis of a
noncirrhotic liver.37,38 Sometimes it can be challenging to
distinguish fibrolamellar HCC from metastatic tumor,
epithelioid hemangioendothelioma, or IHCCA, particularly
in small-needle biopsy specimens.38 It is helpful to confirm
the diagnosis by demonstrating expression of hepatocellular
differential markers. Recently, it was found that most
tumors also show immunoreactivity to CD68 in an
antibody-dependent fashion.39 The positive rate is higher
when the KP-1 clone is used, compared with other clones.3
This unique finding is also useful in practice to differentiate
fibrolamellar HCC from conventional HCC, which is
important for prognostic indication.36
HEPATOBLASTOMA
Hepatoblastoma is the most common primary liver
neoplasm in children younger than 5 years.17 Morpholog-
ically, it is usually composed of embryonal and fetal
hepatocyte-like cells with or without a mesenchymal
component,40 although in rare cases a purely fetal-type
hepatoblastoma may be difficult to distinguish from HCC. A
recent study of immunophenotypes of the tumor revealed
that high-mortality group AT hook 2 (HMGA2) is usually
positive in hepatoblastoma cells, as are GPC3 and b-
catenin.41 Interestingly, although HMGA2 appears to be
positive in all components, GPC3 is more likely to be
GI and Liver ImmunohistochemistryChen & Lin 15
Figure 1. a and b, Hepatocellular carcinoma. a, Hepatocyte paraffin 1 (HepPar1) staining. b, Arginase 1 (ARG1) staining. c and d,
Hepatoblastoma. c, HepPar1 staining. d, ARG1 staining (original magnifications 3100 [a and b] and 3200 [c and d]).
positive in the fetal component, and b-catenin positivity is
mainly seen in the embryonal component.41 The same study
also showed that HMGA2 was positive in about 40% of
HCCs developed in patients younger than 30 years and was
seldom positive in HCCs from older patients.41,42 The
clinical significance of this finding is still elusive. In our
experience, ARG1 is also positive in hepatoblastoma cells,
particularly in the fetal component. Figure 1, c and d, show
examples of HepPar1 and ARG1 staining in a case of
hepatoblastoma.
HEPATOCELLULAR ADENOMA
Hepatocellular adenoma is a relatively rare benign tumor
of the liver.18 Recent studies have suggested a molecular
classification system that identifies 4 major subtypes43,44:
hepatocyte nuclear factor 1 alpha (HNF1a)mutated HCA
(30%35%); b-cateninmutated HCA (10%15%); inflam-
matory HCA (50%); and unclassified (roughly 10%). Within
inflammatory HCAs, 10% of tumors may also be b-catenin
mutated. Identification of b-cateninmutated HCA is
important because these tumors show a strong association
with risk of HCC. Although some unique morphologic
16 Arch Pathol Lab MedVol 139, January 2015
features may be found in certain subtypes, a set of 4 or 5
IHC markers is needed for accurate classification.18,44 A
summary of these markers and their staining patterns in
HCA subtypes is listed in Table 2.
Differentiating inflammatory HCA from focal nodular
hyperplasia, a nonneoplastic condition related to aberrant
vascular proliferation, sometimes can be challenging on a
small biopsy. It has been noted that focal nodular
hyperplasia usually shows a unique geographic pattern of
glutamine synthetase stain and is consistently negative for
serum amyloid A protein (SAA) and C-reactive protein
(CRP).17,44,45 On the contrary, inflammatory HCA is usually
negative for glutamine synthetase (diffuse positivity seen
in tumors with b-catenin activation) and positive for SAA
and CRP. A caveat is that the staining patterns may be
difficult to interpret when lesional tissue is small or when
not enough normal liver tissue is present to compare.
Another practical challenge in diagnosing HCA is to
differentiate it from well-differentiated HCC.46 A number of
studies have suggested panels of IHC markers to help in this
distinction.46,47 Table 3 lists some of the most commonly
used IHC markers for this purpose. In addition, reticulin
GI and Liver ImmunohistochemistryChen & Lin
 Table 2. Immunohistochemistry Markers and Staining Patterns in Different Types of Hepatocellular Adenoma
LFABP SAA/CRP GS b-Catenin
HNF1a inactivation Negative Negative Central vein Membranous
b-Catenin activated Positive Negative Diffusely positive Nuclear
Inflammatory Positive Positive Central vein Membranous or nuclear
Unclassified Positive Negative Central vein Membranous
FNH Positive Negative Irregular anastomosing Membranous
Normal liver Positive Negative Central vein Membranous
Abbreviations: CRP, C-reactive protein; FNH, focal nodular hyperplasia; GS, glutamine synthetase; HNF1a, hepatocyte nuclear factor 1a; LFABP,
liver fatty acid binding protein; SAA, serum amyloidassociated protein.

stain is also helpful in revealing the abnormal trabecular
pattern in HCC. Some pathologists like to use endothelial
markers, such as CD34, to illustrate thickened trabeculae. In
our experience, these markers generally have low sensitivity
or specificity for HCC, and one has to be cautious not to rely
solely on them for the diagnosis. It is noteworthy that the
term well-differentiated hepatocellular neoplasm of uncertain
malignant potential (HUMP) has been proposed by some
experts to describe HCA-like lesions with atypical fea-
tures.48,49 However, at present this is just an evolving
concept. There has been no consensus on any specific
diagnostic criteria.
CHOLANGIOCARCINOMA
The practical challenge in the diagnosis of IHCCA is to
distinguish it from metastatic adenocarcinomas from various
sites. In most cases this can be resolved quite effectively with
the help of IHC and a detailed clinical history. A list of
tumor-specific markers that are commonly used for this
distinction is summarized in Table 4. However, differenti-
ating IHCCA from metastatic pancreatic ductal adenocarci-
nomas or adenocarcinoma from the upper GI tract can be
extremely difficult, if not impossible. Even IHC can offer
little help because of the lack of tissue-specific markers due
to the close relationship of these anatomic sites in the
embryonic and fetal development process. Interestingly, a
recent study by Lok et al50 showed that a panel of
nonconventional markers (placental S100 [S100P], von
Hippel-Lindau tumor suppressor [pVHL], mucin 5AC
[MUC5AC], and CK17) may offer more help than anyone
would anticipate. They studied the staining patterns in 41
IHCCAs and 60 pancreatic ductal adenocarcinomas and
identified a specific pattern (S100P/pVHL/MUC5AC/
CK17) essentially indicative of IHCC, whereas two other
patterns (S100P/pVHL/MUC5AC/CK17 and S100P/
pVHL/MUC5AC/CK17) were more suggestive of pan-
creatic ductal adenocarcinoma. The IHCCA-specific pattern
picked up almost 60% (24 of 41) of tumors tested. These
Table 3. Immunohistochemistry Markers to
Differentiate Well-Differentiated Hepatocellular
Carcinoma From Hepatocellular Adenoma
Sensitivity, Specificity,
Markers Malignant Benign % %
GPC3 Positive Negative 4060 95100
HSP70 Positive Negative 4060 95100
GS Diffuse Patchy/focal ~80 ~50
positive
PCNA or High Low ~90 ~60
Ki-67
Abbreviations: GPC3, glypican 3; GS, glutamine synthetase; HSP70,
heat shock protein 70; PCNA, proliferative cell nuclear antigen.
Arch Pathol Lab MedVol 139, January 2015
results are quite intriguing. However, the number of cases
examined was still very small. A thorough validation in a
large number of cases is necessary to establish its diagnostic
utility.
GI TUMORS
The GI tract is a large organ system with complex tissue
composition. Histologically, the most common primary
tumors of epithelial origin are adenocarcinoma and NETs.51
Some tumors may show dual differentiation, particularly
when they exhibit poorly differentiated or undifferentiated
morphology. Immunohistochemistry is helpful and often
necessary to confirm the diagnosis. In addition, more and
more frequently, IHC detection of Ki-67 is routinely
performed in NETs to calculate proliferative index and to
predict the aggressiveness of these tumors.52 Other IHC
applications focusing on assessment of predictive or
prognostic markers in GI tumors have also been gaining
popularity.712 Currently, these tests include HER2 in gastric
and GEJ adenocarcinomas, and MSI in CRCs, with the most
recent development of the mutation-specific IHC marker v-
raf murine sarcoma viral oncogene homolog B (BRAF)
V600E.5355 Nevertheless, in daily practice a major applica-
tion of IHC remains to help resolve problematic diagnostic
issues, such as distinguishing a possible metastatic carcino-
ma from an adjacent organ system or, rarely, a carcinoma of
unknown primary involving the GI tract. In this regard, IHC
markers highly sensitive and specific for GI tumors are
potentially of help. A set of IHC markers is routinely used to
facilitate the distinction. These include CK7, CK20, villin,
caudal type homeobox 2 (CDX2), mucin core proteins
(MUCs), and others.56 Recently, two new markers were
added to the list, and their enhanced ability to further
improve diagnostic accuracy has been gradually appreciated.
CADHERIN 17
Cadherin 17 (CDH17) is also known as liver-intestine
cadherin because it was originally discovered as a novel
calcium-dependent cell adhesion molecule expressed in the
liver and intestine of rats.57,58 In humans its distribution is
actually limited to the duodenum, jejunum, ileum, colon,
and part of the pancreatic duct. It is believed to function as
an intestinal peptide transporter.58,59 Its clinical utility in
diagnosing GI tumors was only recognized recently.6062 The
combined data indicate that positive CDH17 immunoreac-
tivity is most commonly seen in colorectal adenocarcinomas
(up to 96%) and a significant portion of gastric, pancreatic,
and biliary adenocarcinomas (25%50%). It is rarely found
in adenocarcinomas from outside of GI tract (1%10%).
Interestingly, although CDH17 is transcriptionally regulated
by CDX2, some authors found it to be slightly more
sensitive and specific than CDX2 in identifying colorectal
adenocarcinomas.60,62 Recently, we also studied CDH17
GI and Liver ImmunohistochemistryChen & Lin 17
 Table 4. Immunohistochemistry Markers to Differentiate Intrahepatic Cholangiocarcinoma (IHCCA) From Metastasesa
Markers IHCCA Lung-A PDA Upper GI Colon Breast Bladder
CK7 
CK20    or   /
GATA3   /  
ER      
TTF1      
Napsin A      
SATB2     or  
pVHL      
CDH17 /  /  /
DPC4  or  or
CK17 or   or     /
Abbreviations: Bladder, urothelial carcinoma; CDH17, cadherin 17; CK, cytokeratin; DPC4, SMAD family member 4; ER, estrogen receptor; GATA3,
GATA-binding protein 3; GI, gastrointestinal; Lung-A, lung adenocarcinoma; PDA, pancreatic ductal adenocarcinoma; pVHL, von Hippel-Lindau
tumor suppressor; SATB2, special AT-rich sequence binding protein 2; TTF1, thyroid transcription factor 1.
a
indicates that usually more than 75% of cases are positive; , less than 5% of cases are positive; or , usually more than 50% of cases are
positive; and  or , less than 50% of cases are positive.

immunoreactivity in a large number of tumors derived from
various organ systems.63 Not only did our data further
confirm the reported findings, they also demonstrated its
usefulness in diagnosing CRC variant with poorly differen-
tiated or undifferentiated morphology, such as medullary
carcinoma, which characteristically lacks expression of
conventional intestinal differential markers, such as CK20
and CDX2. CDH17 has also been reported as a sensitive
marker for intestinal metaplasia, and thus helpful for
histologic diagnosis of early Barrett esophagus.6466 Recent-
ly, CDH17 has also been studied as a potential prognostic
marker in GI and pancreatobiliary carcinomas; however, its
clinical implication has not been well established.67,68
SPECIAL AT-RICH SEQUENCE BINDING PROTEIN 2
Special AT-rich sequence binding protein 2 (SATB2)
belongs to a family of nuclear matrixassociated tran-
scription factors that function as epigenetic regulators of
gene expression in a tissue-specific manner.6972 Studies
have shown that SATB2 carries out a wide spectrum of
biologic functions. It is a transcriptional activator of
immunoglobulin l expression.70 It also regulates neuronal
and osteoblast differentiation.69 Haploinsufficiency of the
SATB2 gene is associated with cleft palate syndrome in
humans.71 However, the role of SATB2 in the GI tract is
still elusive. Recently, Magnusson et al73 found that SATB2
immunoreactivity was restricted to the glandular lining
cells of the human lower GI tract, including appendix,
colon, and rectum, and a subset of neuronal cells in the
cerebral cortex and hippocampus. Some lymphocytes and
cells lining the seminiferous ducts and epididymis also
showed weak to moderate immunoreactivity. All other
tissue types tested were negative. They also studied
SATB2 expression in a large number of human carcino-
mas. Positive nuclear stain was found in 1336 of 1558
primary colon adenocarcinomas (86%) and 205 of 252
metastatic carcinomas of the colon (81%).73 Within the
noncolonic carcinomas, weak positive immunoreactivity
was found in 6 of 147 breast adenocarcinomas, 3 of 53
lung adenocarcinomas, 5 of 153 ovarian carcinomas, 1 of
15 cholangiocarcinomas, and 5 of 9 sinonasal carcinomas.
Upper GI carcinomas and pancreatic adenocarcinomas
were usually negative for SATB2.73 We recently also
studied SATB2 expression in a large number of tumors
derived from various organs.63 Our results confirm that
18 Arch Pathol Lab MedVol 139, January 2015
SATB2 is a highly sensitive and specific marker for
adenocarcinomas of the colon and rectum, with a
diagnostic sensitivity of 97% (121 of 125 cases) in CRCs.
Interestingly, we also found that SATB2 immunoreactivity
was seen in a significant number of medullary carcinomas
of the colon.
In addition to diagnostic utility, recent reports also
indicate a prognostic value of SATB2 in CRCs.74,75 High
SATB2 expression was associated with good prognosis in
colon cancer and might modulate sensitivity to chemother-
apy and radiation, whereas reduced expression of SATB2 in
colorectal adenocarcinomas was found to be associated with
poor prognosis, including tumor invasion, lymph node
metastasis, and distant metastasis.
POTENTIAL ROLE OF SATB2 IN DIFFERENTIATING
ADENOCARCINOMA OF THE UPPER AND LOWER
GASTROINTESTINAL TRACT
Compared with CDH17 and CDX2, SATB2 immunoreac-
tivity is much more selective for CRC and is rarely seen in
carcinomas of the esophagus and stomach. Whether SATB2
can also help to differentiate a primary small intestinal
adenocarcinoma from metastatic CRC involving the small
intestine has not been formally tested. This may be a
practical diagnostic challenge, and currently no specific IHC
markers can offer resolution.56,76 We recently examined
SATB2 immunoreactivity in 5 primary small intestinal
adenocarcinomas and found that 3 were negative. The
other 2 tumors with positive immunoreactivity were from
the distal ileum, where the normal small intestinal mucosa
adjacent to tumors was also positive for SATB2. In contrast,
all 4 metastatic colonic carcinomas involving the small
intestine showed positive immunoreactivity to SATB2.
These preliminary results are intriguing and suggest that
SATB2 may be useful in distinguishing adenocarcinomas
from the small and large intestine. However, a couple of
caveats warrant caution. First, the differential capacity is
dependent on whether or not SATB2 immunoreactivity is
present in the normal small intestinal mucosa in the same
region where the tumor occurs. Second, SATB2 expression
may be down-regulated or completely lost in some colonic
adenocarcinomas with aggressive behavior; a comparison
with the expression profile of the original tumor may be
recommended.
GI and Liver ImmunohistochemistryChen & Lin
Figure 2. Medullary carcinoma of the colon. a, Special AT-rich sequence binding protein 2 staining. b, Cadherin 17 staining (original magnification
3200).
Figure 3. Metastatic, well-differentiated neuroendocrine tumor from rectum. a, Cadherin 17 staining. b, Special AT-rich sequence binding protein 2
staining (original magnification 3200).
SATB2 AND CDH17 IN DIAGNOSIS OF MEDULLARY
CARCINOMA OF THE COLON
Medullary carcinoma of the colon is a distinct variant of
colonic adenocarcinoma.77,78 It usually occurs in elderly
patients, more frequently in women than men (2:1 ratio),
and often presents as a large mass in the right colon,
especially in the cecum. Histologically, the tumor is
characteristic for a number of features, including poorly
differentiated or undifferentiated morphology, pushing
border invasion, markedly increased intratumoral lympho-
cytosis, and peritumoral Crohn-like lymphoid reaction.
Molecular pathogenically, almost all tumors are MSI with
deficiency in mismatch repair proteins, predominantly a lack
of MutL homolog 1 (MLH1)/postmeiotic segregation
increased 2 (PMS2) expression due to MLH1 promoter
hypermethylation.79,80 Like most MSI colon adenocarcino-
mas, despite high tumor stages and grades, the prognosis in
terms of lymph node and distant metastasis is more
favorable compared with microsatellite-stable poorly differ-
entiated adenocarcinomas or neuroendocrine carcinomas of
the large intestine. Immunohistochemically, the tumor is
also unique. Unlike conventional colorectal adenocarcino-
Arch Pathol Lab MedVol 139, January 2015
mas, medullary carcinoma of the colon frequently lacks
CDX2 and CK20 expression.8183 Instead, it may express
markers not commonly associated with CRCs, such as CK7
and calretinin.83 Given these unusual features, an accurate
diagnosis of this tumor can be quite challenging, particularly
in a metastatic setting.
Recently we studied the diagnostic utility of SATB2 and
CDH17 in a cohort of 18 medullary carcinomas of the
colon.63 We found that CDH17 was positive in 16 of 18 cases
(89%), and SATB2 was positive in 16 of 18 cases (89%).
Interestingly, the 2 CDH17-negative cases were positive for
SATB2, and the 2 SATB2-negative cases were positive for
CDH17. Nearly all positive cases showed a diffuse and
strong staining pattern (Figure 2). In stark contrast, only 5 of
18 cases (25%) were focally positive for CK20, and 5 of 18
cases (27%) were convincingly positive for CDX2. Our data
demonstrate the usefulness of CDH17 and SATB2 in
diagnosing medullary carcinoma of the colon. They also
suggest that the combined use of the two markers may
increase diagnostic sensitivity. Figure 2, a and b, demon-
strate staining patterns of SATB2 and CDH17 in a medullary
carcinoma of the colon, respectively.
GI and Liver ImmunohistochemistryChen & Lin 19
 SATB2 AND CDH17 IN THE DIAGNOSIS OF GI NETS
The GI tract is a common site for NETs to develop. Most
GI NETs are well differentiated, and their biologic behavior
is primarily dependent on anatomic location, tumor size,
and mitotic counts or Ki-67 proliferative index.13 Clinically,
it is not uncommon to encounter metastases to lymph nodes
and liver even before the primary NET is big enough to be
recognized by conventional imaging studies. It is therefore
highly desirable to have GI-specific markers to help
diagnose and differentiate other NETs, such as those from
pancreas or lung. On the other hand, primary high-grade
neuroendocrine carcinomas of the GI tract are relatively
rare.84 When such a tumor is encountered, it is important to
exclude the possibility of metastasis from a small cell
carcinoma of the lung, where these tumors most commonly
occur. The diagnostic utility of IHC in distinguishing NETs
from various organ systems has been extensively stud-
ied.85,86 However, very little is known about the usefulness
of SATB2 and CDH17 in this setting. One report demon-
strated that CDH17 immunoreactivity was present in 100%
of well-differentiated NETs of the small intestine and
appendix, whereas CDX2 immunoreactivity was present
only in 74% and 90% of cases, respectively. A minority of
pancreatic endocrine tumors (3 of 26 cases; 12%) and
bronchial carcinoid tumors (12 of 50 cases; 24%) were also
immunoreactive to CDH17 but were all negative for
CDX2.62 These findings suggest that CDH17, compared
with CDX2, is more sensitive but less specific in well-
differentiated GI NETs. There has not been any published
study on SATB2 expression in NETs. However, data
presented in a poster from the 2013 United States and
Canadian Academy of Pathology meeting showed that
SATB2 immunoreactivity was seen in most well-differenti-
ated NETs of hindgut origin.87
We recently examined CDH17 and SATB2 immunoreac-
tivity in 158 well-differentiated NETs from various anatomic
sites (data not shown) and found that both markers are
highly selective for GI NETs. Figure 3 shows examples of
CDH17 and SATB2 immunostaining patterns in a well-
differentiated NET of the rectum metastasizing to liver.
Although our preliminary data on CDH17 immunoreactivity
are similar to the published results, the data on SATB2
immunoreactivity are more interesting. We found that
positive SATB2 immunoreactivity is seen in most NETs
from the appendix, colon, and rectum but is rarely seen in
NETs from the stomach, duodenum, pancreas, or lung.
Taken together, in our experience both CDH17 and SATB2
are potentially useful markers for diagnosing GI NETs, and
SATB2 seems more specific for NETs from the lower GI
tract. In practice, one should consider using these new
markers together with CDX2 to maximize sensitivity and
specificity for GI NETs.
SUCCINATE DEHYDROGENASEDEFICIENT GIST
Succinate dehydrogenase (SDH)deficient GIST has been
recognized as a unique variant with characteristic clinico-
pathologic features.8890 It tends to occur in young female
patients, with an exclusively gastric location. In fact, a great
majority of pediatric GISTs and all GISTs that occur in
Carney triad and Carney-Stratakis syndrome are found to
be in this category. Histologically, they show a predomi-
nantly epithelioid morphology and often a plexiform growth
pattern. They have a tendency to be associated with
multifocal or metachronous disease. They usually show an
20 Arch Pathol Lab MedVol 139, January 2015
indolent biologic behavior and may not follow the risk
stratification rule (based on size and mitosis) for conven-
tional GISTs. From a clinical perspective, it is important to
recognize this variant because of its absence of KIT (CD117)
or platelet-derived growth factor receptor mutations and its
primary resistance to imatinib therapy. The genetic patho-
genesis of these tumors is complex because of the fact that
multiple subtypes of SDH may be affected.88 However, from
a diagnostic perspective only one specific IHC assay for
succinate dehydrogenase B (SDHB) is necessary and
sufficient to identify all SDH-deficient GISTs.88,89 The
complete absence or a significant reduction of SDHB
immunoreactivity in tumor cells essentially confirms the
diagnosis.91
HER2 TESTING IN GASTRIC AND GEJ
ADENOCARCINOMA
HER2 is an important driver of tumorigenesis in several
solid tumors.92 For many years, anti-HER2 targeted therapy
has been effective in the treatment of breast carcinomas
with HER2 gene amplification.93 A recent clinical trial also
demonstrated that trastuzumab, an anti-HER2 agent, could
prolong survival in patients with HER2-positive gastric or
GEJ adenocarcinoma.94 This has started a new era of HER2
testing in these GI tumors. A number of excellent review
articles were published in the last 2 years to provide
comprehensive background knowledge and up-to-date
practical guidance on HER2 testing and scoring in gastric
and GEJ carcinomas.810 To avoid repetition here, we simply
point out a couple of the most important practical issues that
may help to ensure accurate and consistent HER2 testing
results. First, specific training is required before a pathol-
ogist can embark on HER2 testing in gastric and GEJ
cancer.8 This should be required regardless of his or her
previous experience with HER2 testing in breast cancer,
because significant differences in staining pattern and
scoring criteria exist between the two tumors. Secondly,
due to HER2 heterogeneity in gastric and GEJ adenocarci-
nomas, it is preferred to perform the test on resection
specimens whenever possible; when an in situ hybridization
test is performed to examine gene amplification in IHC 2
samples, it is most helpful to use IHC-stained sections as a
guide to locate the same area of interest for counting the in
situ hybridization signals. The overall HER2-positive rate in
diffuse-type gastric or GEJ adenocarcinoma is lower (5%)
compared with intestinal type (up to 30%).810,95 It may be
worth the effort to perform in situ hybridization to confirm
an IHC 3 result, particularly if a signet ring cell carcinoma
is involved. We have noticed a peculiar false-positive
circumferential membranous staining pattern in some of
the signet ring cell carcinomas tested. With regard to in situ
hybridization interpretation, HER2 copy number equal to or
greater than 6 should be considered as positive for
amplification regardless of HER2/chromosome enumeration
probe 17 ratio.8
BRAF V600E IHC IN CRC
BRAF represents one of the most frequently mutated
protein kinase genes in human tumors.96 It is found in
melanoma, papillary thyroid carcinoma, ovarian serous
tumors, CRCs, gliomas, hepatobiliary carcinomas, and hairy
cell leukemias.97101 In CRC, the most common mutation is
BRAF V600E. Currently, the mutation is tested in CRC
mainly for two purposes. BRAF V600E mutation in MSI
GI and Liver ImmunohistochemistryChen & Lin
CRCs can virtually exclude Lynch syndrome, and mutation-
positive tumors are resistant to antiepithelial growth factor
receptor therapy.53,54 Although it has been shown that BRAF
V600E mutation predicts a poor prognosis in right-sided
microsatellite-stable CRC, this prognostic indication has not
been widely explored clinically.102
Traditionally, BRAF mutation is detected by DNA
sequencing or polymerase chain reactionbased mutation
detection methods. Recently, antibodies specific to BRAF
V600E have been developed, and their use in IHC on
formalin-fixed, paraffin-embedded tumor tissue has become
popular.5355,97,98,100103 Currently, 2 antibodies are commer-
cially available. VE1 is the most commonly used antibody
clone and is recommended because of its high sensitivity
and specificity.104
At present, BRAF V600E IHC has not been widely used in
diagnostic laboratories. However, several recent publica-
tions have shown promising results using clinical sam-
ples.5355,97,98,100104 It seems that a new trend of using IHC as
screening test for BRAF V600E mutation in CRC has
evolved. In fact, some authors have proposed incorporating
BRAF V600E IHC into the current algorithm for universal
screening of CRC for Lynch syndrome.5355,100103
However, from a technical perspective, BRAF V600E IHC
still has some issues to be ironed out before it can be
deployed to routine clinical labs. Since its debut there have
been some negative comments in the literature regarding
the sensitivity and specificity of the assay for clinical use.105
This concern no longer exists in the most recently published
data, which indicate that BRAF V600E IHC is a sensitive and
reliable assay, generating results that correlated well with
those from molecular detection methods.53,54,101103 It is most
likely that optimizing the staining protocol has contributed
to the recent improvement of the assays performance.
Nevertheless, it is our experience that even with an ideal
staining protocol, the cytoplasmic staining intensity in BRAF
V600Emutated tumor samples may still vary significantly,
ranging from weak to strong. Background nonspecific stain,
particularly a peculiar nuclear staining, is common in
normal mucosa as well as nonmutated tumor cells. These
variables may cause significant problems in accurately
interpreting the staining results. Therefore, specific training
for pathologists and an appropriate quality assurance
program with prospective validation are absolutely needed
before the assay can be widely used.
CONCLUDING REMARKS
As the new era of genomic medicine unfolds, personalized
cancer therapy will become a reality. This will require a new
standard of diagnostic accuracy and precision. Immunohis-
tochemistry as an integral component of the practice of
diagnostic pathology will continuously evolve to help us
meet the new challenge. As practicing pathologists, it is our
responsibility to lead this evolution and to ensure the best
practice of IHC for patient care.
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surrogate for genotyping in colorectal adenocarcinoma. Histopathology. 2013;
63(2):187193.

Prepare Now for the CAP 15 Abstract Program

Dont Wait! Plan now to submit abstracts and case studies for the College of American
Pathologists (CAP) 2015 meeting, which will be held October 4th through the 7th in
Nashville, Tenn. Submissions for the CAP 15 Abstract Program will be accepted from:

Monday, February 9, 2015 through 6 p.m. Central time

Friday, April 10, 2015

Accepted submissions will appear on the Archives of Pathology & Laboratory Medicine
Web site as a supplement to the October 2015 issue. Visit the CAP 15 Web site at
www.cap.org/cap15 for additional abstract program information as it becomes
available.

Arch Pathol Lab MedVol 139, January 2015 GI and Liver ImmunohistochemistryChen & Lin 23