Context.—

In advanced gastric, esophageal, and gastroesophageal junction adenocarcinomas (GE-GEJ-AC) that overexpress ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2), anti-HER2 monoclonal antibody therapy confers survival benefit. To select patients for treatment, HER2 expression and gene amplification are evaluated by immunohistochemistry (IHC) and in situ hybridization.

Objective.—

To determine whether GE-GEJ-AC tested for HER2 on biopsy specimens of a primary tumor show different IHC scores and/or HER2 amplification by in situ hybridization in matched resection specimens, potentially changing therapy eligibility.

Design.—

Immunohistochemistry and silver in situ hybridization were performed in biopsy and/or resection specimens from 100 patients. HER2 testing was performed in matched resection and biopsy specimens of 15 cases to determine whether GE-GEJ-AC with IHC scores of 0, 1+, and 2+ in biopsy and resection specimens had different IHC and silver in situ hybridization results.

Results.—

The IHC 3+ cases showed HER2 amplification in 4 of 5 cases (80%), and IHC scores of 0, 1+, and 2+ showed 3.5%, 14.3%, and 23.5% HER2 amplification by silver in situ hybridization. Among the 15 paired biopsy and resection specimens, 9 (60%) had at least pT2 stage GE-GEJ-AC with HER2 IHC scores of 0, 1+, or 2+ in the biopsy, and 2 of those 9 cases (22%) had IHC 3+ and HER2 amplification by silver in situ hybridization on the resection specimen.

Conclusions.—

Our data suggest that HER2 testing should be repeated on resection specimens of GE-GEJ-AC with HER2 IHC scores of negative (0 and 1+) or equivocal (2+) and in situ hybridization amplification negative biopsy specimen results to evaluate for HER2 heterogeneity when patients are being considered for anti-HER2 therapy.

Gastric adenocarcinoma is the most frequent malignancy arising in the stomach, and nearly 1 million new cases were estimated to have occurred in 2012, representing the fifth most common malignancy and the third leading cause of cancer-related deaths in both sexes worldwide.1,2  In the United States, about 26 370 cases of stomach cancer and 16 910 cases of esophageal cancer were anticipated to be diagnosed in 2016.3,4  About 61.7% of esophageal cancers are adenocarcinomas, which have increased more than 5-fold during the past 4 decades in the United States.5,6 

The Trastuzumab for Gastric Cancer trial demonstrated that the anti-HER2 monoclonal antibody trastuzumab, in combination with chemotherapy (capecitabine and cisplatin or fluorouracil and cisplatin), significantly prolonged survival for patients with locally advanced or metastatic disease compared with chemotherapy alone, without incremental toxicity.7  The maximum survival benefit was observed in tumors with either 3+ HER2 immunohistochemistry (IHC) or cases with an HER2 score of 2+ and amplification by in situ hybridization (ISH). Trastuzumab in combination with chemotherapy may be offered to patients with HER2+ gastric, esophageal, and gastroesophageal junction adenocarcinomas (GE-GEJ-ACs).8 

The HER2 protein (HER2/neu, ERBB2) is a transmembrane tyrosine kinase receptor, member of the epidermal growth factor receptor family, and is involved in tumor cell proliferation, apoptosis, adhesion, migration, and differentiation. This gene family is composed of 4 members: HER1 (also known as EGFR), HER2, HER3 (also termed ERBB3), and HER4 (also termed ERBB4). Initial studies detected HER2 overexpression in 9% to 38% of gastric cancers and reported its prognostic significance.9  Other studies, which used various assays (IHC, fluorescent, silver, and chromogen ISH), reported HER2 overexpression in 7% to 34% of gastric tumors10,11  and in 24% to 32% of esophageal and gastroesophageal junction adenocarcinomas.12  HER2 positivity was reported in at least 20% of Western patients with metastatic gastric adenocarcinoma.13  HER2 positivity is more frequently associated with intestinal than diffuse morphology (30% versus 3.8%), gastroesophageal junction and esophageal location as compared with gastric adenocarcinomas (38.9% versus 18.1%), and is more frequently positive in moderately differentiated than poorly differentiated adenocarcinomas.13,14 

The National Comprehensive Cancer Network guidelines recommend that assessment for HER2 status should be performed first using IHC following the modified scoring system used in the Trastuzumab for Gastric Cancer trial.1517  The guidelines recommend trastuzumab with chemotherapy only for patients with IHC 3+ or IHC 2+ with evidence of HER2 (ERBB2) amplification by ISH (HER2 [ERBB2] to CEP17 ratio ≥ 2). Trastuzumab is not recommended if the IHC score is 0 or 1+.

HER2 heterogeneity in GE-GEJ-AC has been described to range from 4.8% to up to 50% of cases.14,15  Heterogeneity of HER2 expression and amplification in GE-GEJ-AC can create discordant results between biopsy and resection specimens leading to false-negative results and potential undertreatment. Previous studies reported the concordance rates of HER 2 positivity (IHC 2+ and amplification by ISH or IHC 3+) between initial biopsy of primary tumor and matched resection specimen, whereas limited data have been reported for cases with 0, 1, or 2+ by IHC.18,19  The purpose of our study was to evaluate for heterogeneity and HER2 positivity in resection specimens of cases with the initial biopsy of the primary tumor with scores of 0, 1+, or 2+ by IHC to determine whether HER2 heterogeneity and discordance between biopsy and resection specimens may result in missed therapeutic opportunities in GE-GEJ-AC.

Patient Samples

We retrospectively examined specimens from 100 patients with GE-GEJ-AC. The study was approved by the institutional review board. The specimens were collected from 2009 to 2015 and were stored in the archives of the Department of Pathology and Cell Biology at Columbia University Medical Center (New York, New York). All cases had HER2 IHC and ISH results available that were reported on the biopsy and or resection specimens. Patient's age and sex, pathologic tumor grade, stage, location of tumor, histologic subtype, and lymph node and distant metastases status were retrieved from the electronic medical records (Table 1).

Table 1

Clinicopathologic Parameters of Study Group

Clinicopathologic Parameters of Study Group
Clinicopathologic Parameters of Study Group

All patients had biopsies or resections (gastrectomy, esophagectomy, esophagogastrectomy, or endoscopic mucosal resection) of the primary adenocarcinoma (69 patients [69%] had a resection only, 12 [12%] had a biopsy only, and 19 cases [19%] had matched biopsy and resection specimens). Of those 19 cases, 15 (79%) had sufficient tissue to test for HER2 expression by IHC and amplification by ISH in both the biopsy and the corresponding, resection specimen. One slide from the resection specimen, containing the most differentiated areas of the adenocarcinoma, was used for IHC/ISH.

Tumor location was assigned based on the American Joint Committee on Cancer (AJCC) 7th edition20  criteria: cancers involving the gastroesophageal junction with their epicenter within the proximal 2 cm of the cardia were staged as esophageal cancer; cancers with their epicenter more than 2 cm distal to the gastroesophageal junction, even with gastroesophageal junction involvement, were staged as stomach cancer; and cancers with their epicenter located between those of esophageal and stomach were staged as gastroesophageal junction cancer.

Immunohistochemistry and In Situ Hybridization

The HER2 IHC was performed on formalin-fixed, paraffin-embedded tissue sections for 15 cases of paired biopsy and resection specimens. The formalin-fixation time for the biopsy and resection specimens varied from 3 to 72 hours. Tissue processing time was approximately 2 to 3 hours for biopsy specimens and approximately 8 hours for resection specimens. The cases for this study were selected before the recently published College of American Pathologists/American Society for Clinical Pathology/American Society of Clinical Oncology guidelines21  were released with a required 6- to 72-hour specimen-fixation time. Immunohistochemistry was performed with anti-HER-2/neu (4B5) rabbit monoclonal primary antibody (Pathway HER2 [4B5], Roche/Ventana Medical Systems, Tucson, Arizona) on an automated IHC slide-staining instrument (Roche/Ventana), following the manufacturer's instructions.

The HER2 IHC scoring was performed as described by the College of American Pathologists as follows: score 0, no reactivity or no membranous reactivity in any cancer cell in the biopsy specimen and no reactivity or membranous reactivity in less than 10% of cancer cells in surgical specimens; score 1, cancer cell cluster (consisting of ≥5 neoplastic cells) with a faint or barely perceptible membranous reactivity, irrespective of the percentage of cancer cells positive in the biopsy specimen, and faint or barely perceptible membranous reactivity in at least 10% of cancer cells, with cells being reactive in only part of their membrane in surgical specimens; score 2, cancer cell cluster with a weak to moderate complete basolateral or lateral membranous reactivity, irrespective of the percentage of cancer cells positive in biopsy specimen, and weak to moderate complete basolateral or lateral membranous reactivity in more than 10% of tumor cells in the surgical specimen; and score 3, cancer cell cluster (consisting of ≥5 neoplastic cells) with a strong, complete basolateral or lateral membranous reactivity, irrespective of the percentage of cancer cells positive in the biopsy specimen, and strong complete basolateral or lateral membranous reactivity in at least 10% of cancer cells in the surgical specimen.17,21  An IHC score of 0 or 1+ is considered a negative result for HER2 expression. A score of 2+ is considered an equivocal result that should be confirmed with fluorescence in situ hybridization or other ISH techniques. National Comprehensive Cancer Network guidelines recommend fluorescence in situ hybridization only for cases with a score of IHC 2+. Tumors with a score of 3+ by IHC or positive amplification by fluorescence in situ hybridization are considered a HER2+ result.

Silver in situ hybridization (SISH) was performed using the Inform HER2 Dual ISH DNA Probe Cocktail Assay (Roche/Ventana). In this assay, the HER2 and chromosome 17 probes were detected using 2-color chromogenic ISH on formalin-fixed, paraffin-embedded cancer tissue specimens after staining with a BenchMark XT (Roche/Ventana) automated slide stainer or the BenchMark Ultra automated slide stainer (Roche/Ventana.).

Twenty to 40 cancer cells were counted and scored for HER2 (black signal) and CEP17 (red signal) by light microscopy. The total copy-number count for HER2 was divided by the total copy-number count for CEP17, and a score of 2.0 or more was considered amplified.

We identified 100 cases with a diagnosis of GE-GEJ-AC. The clinicopathologic characteristics of the study cases are summarized in Table 1. The group of patients consisted of 21 women (21%) and 79 men (79%), with a mean age of 67.46 years (range, 24–92 years). The group included 46 cases (46%) of gastric adenocarcinoma, 44 cases (44%) of gastroesophageal junction adenocarcinoma, and 10 cases (10%) of esophageal adenocarcinoma. In most of the cases (69%), the histologic grade was 3, followed by grade 2 (30%). The predominant Lauren histologic type was intestinal in 60 cases (60%), followed by the diffuse type in 33 cases (33%), mixed type in 4 cases (4%), and other types, such as mucinous or unspecified, in 3 cases (3%). Seventeen cases (17%) were pathologic stage 4, 38 cases (38%) were stage 3, 16 cases (16%) were stage 2, and 29 cases (29%) were stage 1. Lymph node status was positive for metastatic adenocarcinoma in 59% of the cases.

The results for HER2 IHC and SISH on biopsy, resection, or both in the 100 cases are summarized in Tables 2 and 3. In cases with IHC score of 3+, 4 out of 5 cases (80%) showed HER2 amplification, whereas, in cases with IHC scores of 0, 1+, and 2+, 2 of 57 (3.5%), 3 of 21 (14.3%), and 4 of 17 (23.5%) showed HER2 amplification by SISH, respectively, assessed as the highest HER2 marker status in either the biopsy or resection specimen (Tables 2 and 3).

Table 2

Overall ERBB2 (erb-b2 Receptor Tyrosine Kinase 2 or HER2) Immunohistochemistry and Silver In Situ Hybridization (SISH) Scores

Overall ERBB2 (erb-b2 Receptor Tyrosine Kinase 2 or HER2) Immunohistochemistry and Silver In Situ Hybridization (SISH) Scores
Overall ERBB2 (erb-b2 Receptor Tyrosine Kinase 2 or HER2) Immunohistochemistry and Silver In Situ Hybridization (SISH) Scores
Table 3

HER2 Immunohistochemistry Scores of Silver In Situ Hybridization (SISH) Amplified Cases Based on Tumor Location

HER2 Immunohistochemistry Scores of Silver In Situ Hybridization (SISH) Amplified Cases Based on Tumor Location
HER2 Immunohistochemistry Scores of Silver In Situ Hybridization (SISH) Amplified Cases Based on Tumor Location

HER2 Testing in Paired Biopsy and Resection Specimens

Among the 100 cases, 19 (19%) were identified with available biopsy and resection material. In 2 of the 19 cases (10.5%), tumor was only present on the biopsy specimen and, therefore, those cases were excluded. In 2 additional cases (10.5%), the biopsy material showed a HER2 IHC score of 3+ and amplification by SISH. Therefore, we compared the HER2 status between the paired biopsy and resection specimen using IHC and SISH in the remaining 15 cases (79%) with initial HER2 IHC scores of 0, 1+, or 2+ reported on the biopsy specimen.

Four of the 15 cases (27%) with paired biopsy and resection specimen showed heterogeneous HER2 expression and amplification (Table 4); however, only 2 of the 15 matched cases (13%) showed different HER2 positivity status (IHC 2+ and amplification by ISH or IHC 3+). Those 2 cases (Figures 1, A through F; and 2, A through F), with higher HER2 IHC scores and evidence of amplification involving at least 10% of the tumor when testing was repeated on the resection specimen, represented 22% of the 9 cases staged as pT2 or greater. All 4 cases (27%) with HER2 amplification by SISH in the resection specimen, but not in the biopsy specimen, had IHC scores of 3, and amplification scores ranged from 5.3 to 10.3, with 2 cases demonstrating IHC 3+ and SISH amplification involving at least 10% of the tumor area (Table 4). Those 4 cases with discordant HER2 status, with positivity in the resection specimen and negative status in the biopsy, had at least 6 biopsy fragments in the initial biopsy specimen.

Table 4

Summary of Clinicopathologic and HER2 Results in 15 Paired Biopsy and Resection Specimens

Summary of Clinicopathologic and HER2 Results in 15 Paired Biopsy and Resection Specimens
Summary of Clinicopathologic and HER2 Results in 15 Paired Biopsy and Resection Specimens
Figure 1

A and D, Gastroesophageal junction adenocarcinoma, intestinal type, moderately differentiated, biopsy (A) and resection (D). B, ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2) immunohistochemistry, negative. C, HER2 in situ hybridization, not amplified E, HER2 immunohistochemistry, positive 3+. F, HER2 in situ hybridization, amplified (hematoxylin-eosin, original magnification ×200 [A and D]; original magnifications ×200 [B and E] and ×400 [C and F]).

Figure 1

A and D, Gastroesophageal junction adenocarcinoma, intestinal type, moderately differentiated, biopsy (A) and resection (D). B, ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2) immunohistochemistry, negative. C, HER2 in situ hybridization, not amplified E, HER2 immunohistochemistry, positive 3+. F, HER2 in situ hybridization, amplified (hematoxylin-eosin, original magnification ×200 [A and D]; original magnifications ×200 [B and E] and ×400 [C and F]).

Close modal
Figure 2

A and D, Gastric adenocarcinoma, mixed type, poorly differentiated, biopsy (A) and resection (D). B, HER2 immunohistochemistry, negative 1+. C, HER2 in situ hybridization, not amplified. E, HER2 immunohistochemistry, positive 3+. F, HER2 in situ hybridization, amplified (hematoxylin-eosin, original magnification ×200 [A and D]; original magnifications ×200 [B and E] and ×400 [C and F]).

Figure 2

A and D, Gastric adenocarcinoma, mixed type, poorly differentiated, biopsy (A) and resection (D). B, HER2 immunohistochemistry, negative 1+. C, HER2 in situ hybridization, not amplified. E, HER2 immunohistochemistry, positive 3+. F, HER2 in situ hybridization, amplified (hematoxylin-eosin, original magnification ×200 [A and D]; original magnifications ×200 [B and E] and ×400 [C and F]).

Close modal

Of the paired 15 cases, 6 (40%) were pT1 stage, and of these, 1 case (17%) was upgraded from HER2 IHC 1+ and no amplification by SISH in the biopsy to IHC 3+ and positive amplification by SISH in the endoscopic resection specimen (Figure 3, A through F); another case (17%) had HER2 IHC 1+ and no amplification by SISH in the biopsy and IHC 2+ and focal (<10% area) positive amplification by SISH in the endoscopic resection specimen (Figure 4, A through F), and 1 case (17%) had an IHC score of 2+ and positive amplification in the biopsy, but was negative in the resection. Thus, 3 of the 6 pT1 cases (50%) showed evidence of HER2 heterogeneity (Table 4). Two separate pathologists reviewed the cases with discordant HER2 IHC and or SISH results to ensure validity of the results and to minimize interobserver variability.

Figure 3

A and D, Gastroesophageal adenocarcinoma, intestinal type, moderately differentiated, biopsy (A) and resection (D). B, HER2 immunohistochemistry, negative 1+. C, HER2 in situ hybridization, not amplified. E, HER2 immunohistochemistry, positive 3+. F, HER2 in situ hybridization, amplified (hematoxylin-eosin, original magnification ×200 [A and D]; original magnifications ×200 [B and E] and ×400 [C and F]).

Figure 3

A and D, Gastroesophageal adenocarcinoma, intestinal type, moderately differentiated, biopsy (A) and resection (D). B, HER2 immunohistochemistry, negative 1+. C, HER2 in situ hybridization, not amplified. E, HER2 immunohistochemistry, positive 3+. F, HER2 in situ hybridization, amplified (hematoxylin-eosin, original magnification ×200 [A and D]; original magnifications ×200 [B and E] and ×400 [C and F]).

Close modal
Figure 4

A and D, Gastric adenocarcinoma, intestinal type, moderately differentiated, biopsy (A) and resection (D). B, HER2 immunohistochemistry, negative 1+. C, HER2 in situ hybridization, not amplified. E, HER2 immunohistochemistry, focal positive 2+. F, HER2 in situ hybridization, focal amplified (hematoxylin-eosin, original magnification ×200 [A and D]; original magnifications ×200 [B and E] and ×400 [C and F]).

Figure 4

A and D, Gastric adenocarcinoma, intestinal type, moderately differentiated, biopsy (A) and resection (D). B, HER2 immunohistochemistry, negative 1+. C, HER2 in situ hybridization, not amplified. E, HER2 immunohistochemistry, focal positive 2+. F, HER2 in situ hybridization, focal amplified (hematoxylin-eosin, original magnification ×200 [A and D]; original magnifications ×200 [B and E] and ×400 [C and F]).

Close modal

Accurate assessment of HER2 status in gastric, gastroesophageal junction, and esophageal carcinomas is of great importance because anti-HER2 monoclonal antibody–targeted therapy, in combination with chemotherapy, has been shown to improve median overall survival of patients with HER2+ advanced GE-GEJ-AC.7 

In our study, the percentage of HER2+ cases (IHC 2+ and SISH amplification or IHC 3+) was slightly less than the percentage reported in other studies (4.3% [2 of 46] for gastric and 12.9% [7 of 54] for gastroesophageal junction and esophageal cancer). This may reflect a difference in our study population, namely a high frequency of poorly differentiated tumors (57%, 57 of 100) because HER2 positivity is less common in poorly differentiated gastroesophageal adenocarcinomas.10,13,14,22,23 

Our study shows an overall high concordance of HER2 positivity (IHC 2+ and amplification by ISH or IHC 3+) between biopsy and paired resection specimens, similar to other reports.13  However, limited data reporting heterogeneity and rate of discordance between the primary biopsy and resection specimens have been reported for GE-GEJ-AC cases with HER2 0, 1+, or 2+ IHC scores, and previous studies performed ISH for HER2 IHC 2+ only, whereas we performed SISH for HER2 IHC 0, 1+, or 2+ scores.18,19  Our data demonstrate that both biopsy and resection specimens with HER2 IHC 0 and 1+ are not associated with HER2 amplification, and tumors with 2+ scores may or not be amplified, warranting reflex ISH in cases with HER2 IHC 2+. Intratumoral HER2 heterogeneity is the major cause of discordant HER2 status between biopsy and resection specimens,14,18,24,25  and a minimum of 5 biopsy fragments were shown to accurately predict HER2 status (sensitivity, 92%; specificity, 97%).26  In our study, 4 of the 15 cases (27%) showed heterogeneous expression in the biopsy versus resection specimen; however, only 2 cases (13%) showed different HER2 positivity status (IHC 2+ and amplification by ISH or IHC 3+). Of possible clinical relevance, 2 of 9 cases (22%) staged as pT2 or greater showed higher HER2 IHC scores and evidence of amplification involving at least 10% of the tumor when testing was performed on the resection specimen.

Our study also offers additional insight into the presence of HER2 heterogeneity in early GE-GEJ-AC (pT1), whereas other studies19,27  have mainly reported HER2 status of advanced gastroesophageal carcinoma. Three of the 6 pT1 cases (50%) showed evidence of HER2 heterogeneity, suggesting HER2 is frequently heterogeneous in the early stages of GE-GEJ-AC progression.

In conclusion, our data suggest that HER2 testing should be performed on resection specimens when the initial biopsy has a negative HER2 IHC (scores 0, 1+) or equivocal 2+ and amplification-negative results if patients are being considered for anti-HER2 monoclonal antibody–targeted therapies because biopsy testing alone may miss potential cases with HER2 positivity because of tumor heterogeneity.

1
Power
DG.
Kelsen
DP.
Shah
MA.
Advanced gastric cancer—slow but steady progress
.
Cancer Treat Rev
.
2010
;
36
(
5
):
384
392
. doi:.
2
[GLOBOCAN] Web Portal for International Cancer Research
.
Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012
.
International Agency for Research on Cancer
.
2012
. .
3
National Cancer Institute
.
Surveillance, Epidemiology, and End Results Program (SEER)
.
Cancer Stat Facts: Stomach Cancer 2016
. .
4
National Cancer Institute
.
Surveillance, Epidemiology, and End Results Program (SEER)
.
Cancer Stat Facts: Esophageal Cancer 2016
. .
5
Pohl
H.
Sirovich
B.
Welch
HG.
Esophageal adenocarcinoma incidence: are we reaching the peak? [published correction appears in Cancer Epidemiol Biomarkers Prev
.
2010
;
19(9):2416
].
Cancer Epidemiol Biomarkers Prev. 2010;
19
(
6
):
1468
1470
. doi:.
6
Rubenstein
JH.
Shaheen
NJ.
Epidemiology, diagnosis, and management of esophageal adenocarcinoma
.
Gastroenterology
.
2015
;
149
(
2
):
302
317.e1
. doi:.
7
Bang
YJ.
Van Cutsem
E.
Feyereislova
A.
et al
ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial [published correction appears in Lancet
.
2010
;
376(9749):1302].
Lancet
.
2010;
376
(
9742
):
687
697
. doi:.
8
Shah
MA.
Update on metastatic gastric and esophageal cancers
.
J Clin Oncol
.
2015
;
33
(
16
):
1760
1769
. doi:.
9
Jorgensen
JT.
Hersom
M.
HER2 as a prognostic marker in gastric cancer—a systematic analysis of data from the literature
.
J Cancer
.
2012
;
3
:
137
144
. doi:.
10
Gravalos
C.
Jimeno
A.
HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target
.
Ann Oncol
.
2008
;
19
(
9
):
1523
1529
. doi:.
11
Park
DI.
Yun
JW.
Park
JH.
et al.
HER-2/neu amplification is an independent prognostic factor in gastric cancer
.
Dig Dis Sci
.
2006
;
51
(
8
):
1371
1379
. doi:.
12
Hechtman
JF.
Polydorides
AD.
HER2/neu gene amplification and protein overexpression in gastric and gastroesophageal junction adenocarcinoma: a review of histopathology, diagnostic testing, and clinical implications
.
Arch Pathol Lab Med
.
2012
;
136
(
6
):
691
697
. doi:.
13
Janjigian
YY.
Werner
D.
Pauligk
C.
et al.
Prognosis of metastatic gastric and gastroesophageal junction cancer by HER2 status: a European and USA International collaborative analysis
.
Ann Oncol
.
2012
;
23
(
10
):
2656
2662
. doi:.
14
Lee
S.
de Boer
WB.
Fermoyle
S.
Platten
M.
Kumarasinghe
MP.
Human epidermal growth factor receptor 2 testing in gastric carcinoma: issues related to heterogeneity in biopsies and resections
.
Histopathology
.
2011
;
59
(
5
):
832
840
. doi:.
15
Hofmann
M.
Stoss
O.
Shi
D.
et al.
Assessment of a HER2 scoring system for gastric cancer: results from a validation study
.
Histopathology
.
2008
;
52
(
7
):
797
805
. doi:.
16
Ruschoff
J.
Hanna
W.
Bilous
M.
et al.
HER2 testing in gastric cancer: a practical approach
.
Mod Pathol
.
2012
;
25
(
5
):
637
650
. doi:.
17
[NCCN] National Comprehensive Cancer Network
.
NCCN Guidelines
.
2016
. .
18
Watson
S.
Validire
P.
Cervera
P.
et al.
Combined HER2 analysis of biopsies and surgical specimens to optimize detection of trastuzumab-eligible patients in eso-gastric adenocarcinoma: a GERCOR study
.
Ann Oncol
.
2013
;
24
(
12
):
3035
3039
. doi:.
19
Wang
T.
Hsieh
ET.
Henry
P.
Hanna
W.
Streutker
CJ.
Grin
A.
Matched biopsy and resection specimens of gastric and gastroesophageal adenocarcinoma show high concordance in HER2 status
.
Hum Pathol
.
2014
;
45
(
5
):
970
975
. doi:.
20
Edge
SB.
Byrd
DR.
Compton
CC.
Fritz
AG.
Greene
FL.
Trotti
AI.
eds
.
AJCC Cancer Staging Manual. 7th ed
.
New York, NY
:
Springer;
2010
.
21
Bartley
AN.
Washington
MK.
Ventura
CB.
et al.
HER2 testing and clinical decision making in gastroesophageal adenocarcinoma: guideline from the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology
.
Am J Clin Pathol
.
2016
;
146
(
6
):
647
669
. doi:.
22
Gardiman
MP.
Fassan
M.
Orvieto
E.
et al.
A 14-year-old girl with multiple tumors
.
Brain Pathol
.
2012
;
22
(
6
):
865
868
. doi:.
23
Alessandrini
L.
Fassan
M.
Gardiman
MP.
et al.
Thyroid-like follicular carcinoma of the kidney: report of two cases with detailed immunohistochemical profile and literature review
.
Virchows Arch
.
2012
;
461
(
3
):
345
350
. doi:.
24
Fusco
N.
Rocco
EG.
Del Conte
C.
et al.
HER2 in gastric cancer: a digital image analysis in pre-neoplastic, primary and metastatic lesions
.
Mod Pathol
.
2013
;
26
(
6
):
816
824
. doi:.
25
Pirrelli
M.
Caruso
ML.
Di Maggio
M.
Armentano
R.
Valentini
AM.
Are biopsy specimens predictive of HER2 status in gastric cancer patients?
Dig Dis Sci
.
2013
;
58
(
2
):
397
404
. doi:.
26
Gullo
I.
Grillo
F.
Molinaro
L.
et al.
Minimum biopsy set for HER2 evaluation in gastric and gastro-esophageal junction cancer
.
Endosc Int Open
.
2015
;
3
(
2
):
E165
170
. doi:.
27
Huang
SC.
Ng
KF.
Lee
SE.
Chen
KH.
Yeh
TS.
Chen
TC.
HER2 testing in paired biopsy and excision specimens of gastric cancer: the reliability of the scoring system and the clinicopathological factors relevant to discordance
.
Gastric Cancer
.
2016
;
19
(
1
):
176
182
. doi: .

Author notes

The authors have no relevant financial interest in the products or companies described in this article.

Competing Interests

Presented as an abstract at the annual meeting of the College of American Pathologists; September 26, 2016; Las Vegas, Nevada.