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Gastrointestinal Pathology
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Case 3 -
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Gastric Adenocarcinoma; Poorly Differentiated, Tubular (WHO Classification) with
HER-2 High Amplification and Heterogeneity
Priyanthi Kumarasinghe, PathWest, Queen Elizabeth II Medical Centre, Perth, Australia
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Clinical History
A 65 year old male underwent a total gastrectomy. A previous endoscopic biopsy showed a poorly differentiated adenocarcinoma. Her-2 status was assessed.
Case 3 - Figure 5
HER-2 protein expression of the area shown in figure 3 demonstrating marked heterogeneity
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Case 3 - Figure 6
HER2 immunohistochemical expression of the dysplastic epithelium and invasive carcinoma in contrast to the negative non-neoplastic tissue
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Case 3 - Figure 7
HER-2 protein expression in the area shown in figure 2 that includes dysplastic and invasive areas
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Case 3 - Figure 8
HER-2 protein expression, scored as 3+ according to Hoffman et al
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Case 3 - Figure 9
HER-2 protein expression in vascular emboli
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Case 3 - Figure 10
HER-2 gene amplification with Silver In- Situ Hybridisation (SISH); tumour cells show high amplification
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Introduction:
Over expression of HER-2 has been documented in 6.8 – 34% of gastric carcinomas including
gastro-oesophageal junctional (GOJ) tumours with most studies documenting values between 15-25%.
[1,
2,
3,
4,
5]
The
incidence of gastric cancer has declined in Western countries over the past 50 years, however it appears
that the incidence of GOJ cancer is increasing.
[6,
7].
HER2 over expression and/or gene amplification
has been shown to be a significant negative prognostic factor for GC.
[8,
9]
Furthermore, targeting HER2
with Herceptin® (trastuzumab), a monoclonal antibody directed against HER2 has been shown to inhibit
tumour cell growth in vitro and in vivo.
[9,
10,
11]
The first randomised clinical trial (ToGA) investigating
the role for trastuzumab in advanced gastric carcinoma reported a significant improvement in the median
overall survival with trastuzumab in combination with chemotherapy, compared to chemotherapy alone (13.8
vs 11.1 months; HR 0.74, 95% CI 0.60, 0.91; p=0.0046).
[12] Exploratory subgroup analysis suggested that
in patients with the highest levels of HER2 protein expression (IHC2+/FISH+ or IHC3+), the survival
benefit with trastuzumab was further increased compared to chemotherapy alone (16.0 vs 11.8 months).
[12]
This combination approach is the first to show an increase in median survival beyond one year. As a
result, trastuzumab has recently been formally approved in some countries (European Union and Australia)
for the treatment of metastatic HER-2 positive gastric carcinoma. Since HER-2
overexpression/amplification is key to determine the eligibility for treatment there is a need to
accurately identify HER-2 status of gastric cancer. Standard validated methodologies in formalin-fixed
paraffin-embedded tumour samples used globally are immunohistochemistry (IHC) to detect HER2 protein over
expression and in situ hybridisation (ISH) to identify HER2 gene amplification. Judging by the
experience of HER-2 testing for breast carcinoma it is clear that a valid testing algorithm needs to be
used for gastric HER-2 testing. This is even more important as there are significant differences in the
patho-biology, diagnosis and management of gastric carcinoma compared to breast carcinoma.
Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
Sections were of a
malignant ulcer in the antrum from a partial gastrectomy specimen. They showed a poorly differentiated
gastric adenocarcinoma (figures 1-4). The tumour consisted of a minor component of tubular/glandular
structures (figure 2) with a major component of poorly differentiated carcinoma featuring solid islands
of poorly differentiated malignant cells are (figure 4). There was no classic signet ring cell or poorly
cohesive components. Glandular structures were complex and lined by pleomorphic epithelial cells with
large irregular nuclei and contained scant to moderate amounts of eosinophilic cytoplasm. Immunoprofile
was as expected for gastric adenocarcinoma; neuroendocrine markers were negative. There were also areas
of high grade dysplasia (figure 2). Immunohistochemical stains for HER-2 protein expression (Cerb-B2,
polyclonal antibody) showed strong membranous positivity in a heterogeneous pattern in the invasive
component (figures 5-9). In addition the dysplastic areas (figure 7) and some but not all vascular
emboli (figure 9) showed strong 3+ positivity. Protein expression was scored as 3+ (figure 8) according
to criteria recommended by Hoffman et al, modified from those used for breast carcinoma.1 The degree of
heterogeneity varied from 30-80% (figures 5 & 6). HER-2 gene amplification by silver in-situ
hybridisation (SISH; Ventana INFORM HER 2) demonstrated high amplification (figure 10). The average
count of HER2 copy numbers was 25. Chromosome 17 analysis showed an average count of 2.5. HER-2/Cep 17
ratio was 10. This patient had a preoperative endoscopic biopsy that showed poorly differentiated
adenocarcinoma. The biopsy was negative for Her-2 over expression/amplification both by IHC and SISH.
There were 4 biopsy fragments examined with all 4 featuring tumour occupying approximately 60% of the
biopsy volume.
Differential Diagnoses:
Gastric adenocarcinoma; poorly differentiated, tubular (WHO classification)
with HER-2 high amplification and heterogeneity
Final Diagnosis:
Gastric adenocarcinoma; poorly differentiated, tubular (WHO classification) with
HER-2 high amplification and heterogeneity
Case Discussion:
The location of the adenocarcinoma was in the antrum. The carcinoma showed
glandular/tubular structures with a poorly differentiated component. There was evidence of high grade
dysplasia and chronic gastritis with focal intestinal metaplasia in the non-neoplastic/non-dysplastic
gastric mucosa. The preoperative endoscopic biopsy showed an adenocarcinoma with poorly differentiated
solid areas together with glandular/tubular differentiation. There were no dysplastic areas.
Importantly both immunohistochemistry and gene amplification studies were negative for HER2 over-
expression/amplification. This case illustrates significant heterogeneity of HER-2 expression in gastric
carcinoma that could result in a negative test in biopsy. This was in spite of strong protein expression
and high amplification as demonstrated with IHC and ISH studies in the resection specimen. The focus of
this case is to highlight tissue of HER2 over expression/amplification in gastric carcinoma and the
issues related to interpretation of test results, heterogeneity and concomitant HER-2 expression in
dysplastic areas. The implications when the biopsies are tested to identify the patients who are
eligible for a Herceptin treatment are also discussed.
Review of the Literature/Treatment Options (if applicable):
HER2 over expression/amplification in
gastric carcinoma and implications: Over expression of HER-2 has been documented in 6.8 – 34% of gastric
and gastro-oesophageal junctional adenocarcinomas. Lower rates have been reported in tissue microarray
based studies
[3,
4].
Positivity rate is higher in "intestinal" than diffuse cancers and
gastro-oesophageal junctional than distal gastric cancers
[1,
5,
9,
12].
There is no clear-cut explanation
thus so far for these differences. It is known that in breast cancer HER2 gene amplification almost
invariably induces and occurs before HER2 protein over-expression on the tumor cell surface
[13,
14].
Interestingly a significant number of IHC 2+ cases were shown to be consistently HER 2 amplified;
(Hoffmann et al - 35.7% , ToGA - 54.6% and Lee et al 35.3%)
[1,
5,
12].
HER2-positive status in gastric
cancer also appears to be associated with poorer prognosis, more aggressive disease, and shorter
survival. Preclinical studies have indicated that trastuzumab exerts antitumor activity in HER2-
overexpressing human gastric cell lines and xenograft models
[9,
11].
Trastuzumab with chemotherapy
treatment combination is the first to show an increase in median survival beyond one year as shown in the
ToGA results. As such HER2 status is predictive of patients that are most likely to benefit from
trastuzumab therapy. The survival advantage was noted to be greater in patients with high expression of
HER-2 (IHC 2+ and FISH +, or IHC 3+) than in those with low expression (IHC 0 or 1+ and FISH +), 16.0
months vs 11.8 months respectively [12]. As such the case illustrated here is likely to benefit from
Herceptin treatment on the basis of available evidence. Testing for HER2 over-expression/amplification:
Standard validated methodologies in formalin-fixed paraffin- embedded tumour samples used worldwide are
immunohistochemistry (IHC) to detect HER2 protein over expression and in situ hybridisation (ISH) to
identify HER2 gene amplification. HER2 over expression and gene amplification in GC appears to differ
from that in breast cancer in many ways. This was demonstrated by Hoffmann et al in their study. They
showed when breast scoring criteria were applied 11 of 29 gastric carcinoma that were amplified with FISH
were equivocal or negative for immunohistochemistry. The reasons cited were <10%, incomplete and
moderate IHC expression being interpreted as IHC 0,1+, 2+ and 0 respectively. As such they recommended
that moderate and incomplete (basolateral) membranous staining pattern to be considered IHC3+ for gastric
cancers (Table 1). They also recommend that any number of tumour cells (not >10%) in biopsy material
to be considered positive (Table 1). A cluster may be defined as a collection of 3-5 cells. Others also
have shown similar experiences of under calling of truly amplified cases if breast scoring criteria are
used for gastric cancer
[15,
16]
Studies show excellent correlation between IHC 3+ and gene amplification
[1,
5,
12].
Additionally it has been noted by some that there is excellent correlation between IHC 0 and
1+ (negative) and non-amplification with ISH but only moderate agreement for IHC 2+ cases
[1,
5].
ToGA
study used the previously validated modified IHC scoring criteria
[1,
12].
The results showed that 4.9%,
15.7%, 54.6% and 94.9% gastric carcinomas that showed IHC0, 1+, 2+ and 3+ respectively were amplified
with FISH. The possible reasons for the differences include inherent heterogeneity of gastric carcinoma
and issues related to sample selection and perhaps tissue fixation. ToGA trial included cases that were
tested both on biopsies and resections. Tissue fixation is well known affect protein expression in
tumours else where [17]. HER2 over expression/amplification in gastric carcinoma and implications: Over
expression of HER-2 has been documented in 6.8 – 34% of gastric and gastro-oesophageal junctional
adenocarcinomas. Lower rates have been reported in tissue microarray based studies
[3,
4]
Positivity rate
is higher in "intestinal" than diffuse cancers and gastro-oesophageal junctional than distal gastric
cancers
[1,
5,
9,
12].
There is no clear-cut explanation thus so far for these differences. It is known
that in breast cancer HER2 gene amplification almost invariably induces and occurs before HER2 protein
over-expression on the tumor cell surface
[13,
14].
Interestingly a significant number of IHC 2+ cases
were shown to be consistently HER 2 amplified; (Hoffmann et al - 35.7% , ToGA - 54.6% and Lee et al
35.3%)
[1,
5,
12].
HER2-positive status in gastric cancer also appears to be associated with poorer
prognosis, more aggressive disease, and shorter survival. Preclinical studies have indicated that
trastuzumab exerts antitumor activity in HER2- overexpressing human gastric cell lines and xenograft
models
[9,
11].
Trastuzumab with chemotherapy treatment combination is the first to show an increase in
median survival beyond one year as shown in the ToGA results. As such HER2 status is predictive of
patients that are most likely to benefit from trastuzumab therapy. The survival advantage was noted to
be greater in patients with high expression of HER-2 (IHC 2+ and FISH +, or IHC 3+) than in those with
low expression (IHC 0 or 1+ and FISH +), 16.0 months vs 11.8 months respectively
[12] As such the case
illustrated here is likely to benefit from Herceptin treatment on the basis of available evidence.
Testing for HER2 over-expression/amplification: Standard validated methodologies in formalin-fixed
paraffin- embedded tumour samples used worldwide are immunohistochemistry (IHC) to detect HER2 protein
over expression and in situ hybridisation (ISH) to identify HER2 gene amplification. HER2 over
expression and gene amplification in GC appears to differ from that in breast cancer in many ways. This
was demonstrated by Hoffmann et al in their study. They showed when breast scoring criteria were applied
11 of 29 gastric carcinoma that were amplified with FISH were equivocal or negative for
immunohistochemistry. The reasons cited were <10%, incomplete and moderate IHC expression being
interpreted as IHC 0,1+, 2+ and 0 respectively. As such they recommended that moderate and incomplete
(basolateral) membranous staining pattern to be considered IHC3+ for gastric cancers (Table 1). They
also recommend that any number of tumour cells (not >10%) in biopsy material to be considered positive
(Table 1). A cluster may be defined as a collection of 3-5 cells. Others also have shown similar
experiences of under calling of truly amplified cases if breast scoring criteria are used for gastric
cancer
[15,
16].
Studies show excellent correlation between IHC 3+ and gene amplification
[1,
5,
12].
Additionally it has been noted by some that there is excellent correlation between IHC 0 and 1+
(negative) and non-amplification with ISH but only moderate agreement for IHC 2+ cases
[1,
5].
ToGA study
used the previously validated modified IHC scoring criteria
[1,
12].
The results showed that 4.9%,
15.7%, 54.6% and 94.9% gastric carcinomas that showed IHC0, 1+, 2+ and 3+ respectively were amplified
with FISH. The possible reasons for the differences include inherent heterogeneity of gastric carcinoma
and issues related to sample selection and perhaps tissue fixation. ToGA trial included cases that were
tested both on biopsies and resections. Tissue fixation is well known affect protein expression in
tumours else where [17] In this background when the European board, EMEA, approved trastuzumab for the
treatment of metastatic adenocarcinomas of the stomach and GOJ immunohistochemistry was determined to be
the method of choice to determine HER2 status [18]. ISH was restricted to those cases that have
equivocal (IHC2+) HER2 expression. In Australia, HER2 testing for eligibility for trastuzumab therapy in
breast cancer is done via a national diagnostic testing program based on either chromogenic ISH (CISH) or
silver ISH (SISH), with fluorescence ISH (FISH) in equivocal cases. This is due to false positive and
false negative rates documented with IHC. A similar national approach is underway for gastric HER-2
testing. Therapeutic Goods Administration (TGA) in Australia approved Trastuzumab for the treatment of
advanced gastric and GOJ cancers for those patients whose tumours are HER2 positive; positive HER-2
status is defined by IHC 3+ expression or SISH positivity for those who are IHC less than 3+ [19]. A
gastric cancer HER-2 testing study (GaTHER study) was conducted to evaluate the testing methods and to
determine the inter-laboratory reproducibility of HER2 scoring across 9 Australian reference
laboratories. Heterogeneity of gastric carcinoma: The issue of heterogeneity of HER-2 over-expression
is less well documented in gastric carcinoma compared to breast carcinoma
[1,
4,
5,
20,
21,
22,
23,
24].
Hoffman et al,
Grabsch et al, Bilious et al and Lee et al have demonstrated or noted significant tumour heterogeneity
ranging from 4.8%-50% strongly supporting modified scoring for gastric IHC interpretation
[1,
4,
5,
24].
However heterogeneity has not been formally defined except in the study by Lee et al in which the tumour
was determined to be heterogeneous if less than 2/3 of the tumour stained positive for IHC. In the same
study it was noted that there was excellent correlation between protein expression and amplification in
heterogeneous clones. Marx et al have reported conflicting results stating homogeneity of HER-2
amplification in gastric carcinoma; the major draw back in this study is that they based their
observations on a tissue microarray [23] As demonstrated in this case of highly amplified gastric
carcinoma with negative endoscopic biopsies, it is likely that tumour heterogeneity has significant
implications on HER-2 testing. It is anticipated that much of the testing be done on endoscopic biopsies
in clinically advanced gastric carcinoma. Extensive sampling should be specifically encouraged by the
endoscopist if HER2 testing is anticipated to be performed on biopsies. This is often the situation if
there's clinical concern of advanced gastric carcinoma and further surgery is unlikely. The endoscopic
biopsies of this case had 4 fragments with all showing carcinoma and the total tumour volume
approximating 60% of the biopsy volume. In the gastrectomy sections heterogeneity ranged from 30-80%
when tested in 3 blocks. Currently there are no formal recommendations with respect to the number of
biopsies be sampled at endoscopy or block selection in resected specimens for HER2 testing. In
gastrectomy specimens, it may be prudent to analyse more than one representative tumour block. Biopsies
on the other hand may be better preserved than the resections if the latter are not properly and timely
fixed. The clinical significance of heterogeneous HER-2 staining in gastric carcinoma with respect to
response to trastuzumab therapy is yet to be ascertained although one would speculate that only the HER-2
positive clones would be sensitive. HER2 over-expression/amplification in gastric epithelial dysplasia:
Interpretation problems associated with the distinction between intramucosal and invasive carcinoma and
the terminology issues between the "West" and the "East" have not reached agreement globally. In this
background it is important to evaluate and correlate HER-2 over expression/amplification in gastric
epithelial dysplasia. Lee et al recorded that in some cases HER2 positivity was noted in the dysplastic
epithelium while the carcinomatous/invasive component was negative [5]. This may have implications for
false-positive results in relation to invasive carcinoma. Further more the clinical significance and
therapeutic implications of positivity in dysplasia and not in the concomitant carcinoma is uncertain
currently. Practical difficulties may also be encountered in assigning HER-2 status in cases where areas
of high-grade dysplasia appear to be merging with invasive carcinoma, especially in biopsies. Currently
there are no other studies that document the issue of HER2 over expression in gastric epithelial
dysplasia. Over expression/amplification in gastric high-grade dysplasia is a novel finding suggesting a
role in pathogenesis and a possible role as a diagnostic biomarker for gastric dysplasia. Other issues:
Issues relating to testing on archival material, fixation, spurious protein expression in reactive
epithelium and intestinal metaplasia, and inherent problems of small biopsy artefacts have been mentioned
but not formally addressed. Lack of universal agreement for criteria of invasion and dysplasia and
concept of gastric adenomas together with the relative lack of experience of gastric cancer HER-2 testing
in these early stages are likely to have implications for comparing data worldwide. This also supports
the notion of many that central testing should be encouraged in the interim until the critical issues are
addressed. This is in the background of therapeutic and financial implications to correctly identify the
"intent to treat" group. Treatment options: Currently Herceptin treatment is formally approved for
advanced gastric and GOJ carcinoma in several countries based on the results shown in the landmark ToGA
trial. The efficacy in "non-advanced" carcinomas is currently unknown.
HER2 scoring criteria in gastric cancer
| Surgical specimen - staining pattern | Biopsy specimen - staining pattern | Score | HER2 over expression assessment |
| No reactivity or membranous reactivity in <10% of tumour cells | No reactivity or no membranous reactivity in any tumour cell | 0 | Negative |
| Faint/barely perceptible membranous reactivity in ? 10% of tumour cells; cells are reactive only in part of their membrane | Tumour cell cluster with a faint/barely perceptible membranous reactivity irrespective of percentage of tumour cells stained | 1+ | Negative |
| Weak to moderate complete, basolateral or lateral membranous reactivity in ? 10% of tumour cells | Tumour cell cluster with a weak to moderate complete, basolateral or lateral membranous reactivity irrespective of percentage of tumour cells stained | 2+ | Equivocal |
| Strong complete, basolateral or lateral membranous reactivity in ? 10% of tumour cells | Tumour cell cluster with a strong complete, basolateral or lateral membranous reactivity irrespective of percentage of tumour cells stained | 3+ | Positive |
Conclusion(s):
- Tratuzumab is the first biological to show survival benefit in patients with
advanced, recurrent and metastatic gastric and gastro-oesophageal junctional adenocarcinoma.
- HER2 status of the tumour is a predictor of response to chemotherapy that combines Tratuzumab.
- Accurate testing is possible with appropriate use of test methods that include immunohistochemistry
and in-situ hybridisation techniques. Strong 3+ protein expression correlates well with gene
amplification while less than 3+ protein expression needs a second test with ISH.
- Heterogeneity, amplification in dysplastic epithelium, lack of experience in testing are confounding
factors that may result in false-positive and false negative results. Hence in the interim
central/reference lab testing for HER 2 status is encouraged.
- Whether heterogeneity and high versus low amplification would have an impact on response to therapy
needs further evaluation.
- Over expression/amplification of HER2 in gastric dysplasia may have a possible role in the
pathogenesis and diagnosis.
References:
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- Gravalos C, Jimeno A. Her2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol 2008; 19:523-9.
- Yan B, Ee XY, Omar SSB, Salto-Tellez M. HER2 gene amplification and protein expression in gastric cancer. J Clin Pathol 2010; 63: 839- 842
- Grabsch H, Sivakumar S, Gray S, Gabbert HE, Muller W. HER2 expression in gastric cancer: rare, heterogeneous and of no prognostic value – conclusions from 924 cases of two independent series. Cell Oncol 2010; 32 (1-2): 57-65
- Lee S, de Boer WB, Fermoyle S, Platten M, Kumarasinghe MP. HER-2 testing in gastric carcinoma: issues related to heterogeneity in biopsies and resections. Histopathology (accepted for publication)
- Gaca JG, Petersen RP, Peterson BL et al. Pathologic nodal status predicts disease-free survival after neoadjuvant chemoradiation for gastroesophageal junction carcinoma. Ann Surg Oncol 2006 Mar; 13(3):340-6.
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- Tanner M ET AL. Amplification of HER-2 in gastric carcinoma: association with topoisomerase IIalpha gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab. Ann Oncol 2005; 16:273–278
- Matsui Y et al. Suppression of tumor growth in human gastric cancer with HER2 over expression by an anti-HER2 antibody in a murine model. Int J Oncol 2005; 27:681–685
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