Indian Journal of Pathology and Microbiology
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Year : 2021  |  Volume : 64  |  Issue : 5  |  Page : 2-3
Applicability and interpretation of HER2/Neu & PD-L1 stains in gastrointestinal tract tumours

Department of Pathology, All India Institute of Medical Sciences, New Delhi, India

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Date of Submission08-Mar-2021
Date of Acceptance28-Mar-2021
Date of Web Publication7-Jun-2021


The luminal gastrointestinal tract carcinomas are one of the major causes of cancer-related deaths. To improve overall survival, the current trend is to combine targeted therapeutic agents with conventional chemotherapies. Major trials have shown survival benefits with this approach and many more trials are being undertaken. However, pathologists often get perplexed by different methods of interpretation and reporting of these stains, vital for deciding therapeutic approaches.

Keywords: Colorectal carcinoma, esophageal carcinoma, gastric carcinoma, HER2/neu, immunohistochemistry, PD-L1

How to cite this article:
Das P, Mehra L. Applicability and interpretation of HER2/Neu & PD-L1 stains in gastrointestinal tract tumours. Indian J Pathol Microbiol 2021;64, Suppl S1:2-3

How to cite this URL:
Das P, Mehra L. Applicability and interpretation of HER2/Neu & PD-L1 stains in gastrointestinal tract tumours. Indian J Pathol Microbiol [serial online] 2021 [cited 2021 Oct 19];64, Suppl S1:2-3. Available from: https://www.ijpmonline.org/text.asp?2021/64/5/2/317908

The global burden of gastrointestinal tract (GIT) cancers is around 26% and they are responsible for 35% of all cancer-related deaths.[1] Only a small group of patients benefit from the traditional treatment due to late detection and neoadjuvant therapy combining traditional chemotherapy and targeted antagonists are increasingly being used to improve prognosis in GIT carcinomas. Trastuzumab targeting the extracellular domain of HER2/neu receptor, which is a well-established treatment modality in breast carcinoma is also currently being favoured in many GIT cancers, especially the upper GIT carcinomas. Similarly, Nivolumab targeting PD-L1 receptor, which is well accepted as neoadjuvant therapy in squamous cell carcinoma (SCC) of the lung, renal cell carcinoma, and Hodgkin's lymphomas, is being administered in GIT carcinomas as well.

Applicability of HER2/neu in GIT Tumours

HER2 is a ligand-independent tyrosine kinase growth factor receptor regulating the growth and survival of tumor cells by forming a heterodimer with other epidermal growth factor receptors as HER3. Advanced gastric (GC), gastro-esophageal carcinomas (GEJ), esophageal adenocarcinomas (EA), and colorectal carcinomas (CRC) are being favoured for HER2/neu directed targeted therapy. HER2/neu positive GCs also show intestinal histology, advanced stage, and lymph node metastasis, hence, associated with poor prognosis prognostic information. The prevalence of HER2/neu expression has been found in 26% in EAs,[2] 11- 22% of GCs,[3] and 5- 54% of CRCs.[4] However, the benefits of anti-HER2/neu therapy are less defined in GIT tumors other than in GCs.

Interpretation of HER2/Neu in GIT Tumours

A potential problem of analysing HER2 immunohistochemistry (IHC) stained slide in GIT cancers is that the scoring technique differs from that in breast cancers. HER2 3+ IHC score is considered when at least a cluster of 5 positive tumour cells show 'intense' circumferential, basolateral, or lateral membranous positivity in GC biopsies; or when at least >10% of the tumour tissue shows 'intense' positivity in the resected GIT carcinoma specimens.

As per the HERACLES (HER2/neu Amplification for CRC Enhanced Stratification) Trial, 2+ score with any membranous positivity in <50% tumour cells and 3+ intense membranous stain in <10% tumour cells are not benefitted with anti-HER2 therapy. It is to be noted that in contrast to breast carcinomas, in GCs the assessment is mainly 'intensity' based, rather than the pattern of positivity. An alternative 'magnification rule'- based interpretation described 3+ membranous (any pattern) positivity when the same is detected at low magnification (2-5x objective lens), and 2+ IHC positivity when unequivocal positivity detected at low magnification (10x–20x). Any staining visible only at the 40x objective lens represents 1+ IHC score. Equivocal IHC 2+ score with any of these methods should be retested using fluorescence in-situ hybridization (FISH) technique [HER2:CEP17 ratio of 2.0, or when using a single probe >6.0 copies).

Also, strict, and broad definitions of HER2 assessment have been described. As per the strict criteria, a consensus scoring system is considered by incorporating 3+/2+ IHC scores and FISH amplification results in combination. Whereas in the broad method, IHC scores 3+/2+ are considered positive irrespective of the FISH result or HER2/neu amplified with FISH without an IHC analysis. The strict method has a low discordance rate for HER2/neu analysis, especially when compared between primary tumours and corresponding metastasis.[5] Also, the strict criteria seem further valid as the survival benefit of Trastuzumab therapy was detected only in HER2/neu 3+ group in the TOGA trial.

While interpreting, the possibility of sampling error and intra-tumoral heterogeneity should be considered, especially in GIT carcinomas. All HER2 0/1+ staining patterns should be considered negative without the need for further ISH analysis. Even after applying the strict criteria, 5% negative to positive conversion and 18% positive to negative conversion rates have been documented. At least 4-5 biopsy fragments yield better results for Her2 IHC analysis.

Applicability PDL1 Staining in GIT Tumors

The programmed death receptor 1 ligand 1 (PD-L1) binds to its receptor PD-1 on T, B, and Natural killer (NK) cells resulting in apoptosis of immune-activated T cells and immune escape of the tumour cells. A high rate of expression of PD-L1/PD-L2 has been identified in ECs with a high somatic mutation rate and associated with poor prognosis, especially in Eastern-Asians.[6] PD-L1 expressing GCs (50-80%) also show large tumour-size, lymph node metastasis, and poor prognosis, especially in stage II/III GCs. PD-L1 overexpression was independent of the Lauren's GC subtype, and associated with high-MSI and EBV subgroups of ACRG GC tumour types. PD-L1 expression is also a sought-after actionable target in esophageal SCC (14-63%), and CRCs, though the experience is limited.[7],[8] Though, not all patients treated with targeted immunotherapy are benefitted due to primary or acquired resistance; several trials are currently investigating the role of anti-PD-1/PD-L1 in GIT cancers.

Interpretation of PD-L1 in GIT Tumours

Interpretation of membranous and cytoplasmic PD-L1 IHC staining in tumour tissue is expressed as the 'Tumour-proportion score' and 'Tumour-infiltrating immune cell proportion score (TI-IPS)'. However, the problem in interpretation is the use of different counting methods and cut-offs for overexpression of PD-L1 in various studies in GIT tumours. Also, some authors used a combined intensity and area-positivity-based combined Immunoreactive Score (IRS) or 'H' scoring system. Moderate or strong staining of ≥5% to ≥25% of tumour cells while was considered as overexpression cut-offs in some studies, others considered a combined H-score cut-off ≥ score 1 (when added the intensity and area positivity for generating the H-score) or ≥ score 4 as PD-L1 overexpression (when multiplied the intensity and area positivity for generating the H-score).[5],[6],[7],[8] Some authors also used a Combined Positive Scoring system (CPS), defined by the number of PD-L1 positive tumour cells, lymphocytes, and macrophages together, divided by the total number of viable tumour cells, multiplied by 100, and taken as ≥1 CPS score as PD-L1 overexpression cut-off.

Hence, to avoid confusion in applying the overexpression cut-offs, it is better to evaluate the whole tumour section and report the overall tumour% score and TI-IPS% scores separately based on 'moderate to strong membranous and cytoplasmic staining'. Reporting in CPS format should be acceptable as well. The antibody clone used should also be mentioned in the report.

This issue highlights the importance of identifying actionable targets in GIT-tumours from the point of view of medical oncologists. A large cohort multicentre study for validating the tumour target reporting systems of the GIT tumours is the need of the hour.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Lengyel CG, Habeeb B, Khan SZ, El Bairi K, Altuna SC, Hussain S, et al. Role of Her-2 in gastrointestinal tumours beyond gastric cancer: A tool for precision medicine. Gastrointest Disord 2020;3:1-22.  Back to cited text no. 1
Gowryshankar A, Nagaraja V, Eslick GD. HER2 status in Barrett's esophagus & esophageal cancer: A meta analysis. J Gastrointest Oncol 2014;5:25-35.  Back to cited text no. 2
Lei Y-Y, Huang J-Y, Zhao Q-R, Jiang N, Xu H-M, Wang Z-N, et al. The clinicopathological parameters and prognostic significance of HER2 expression in gastric cancer patients: A meta-analysis of literature. World J Surg Oncol 2017;15:1-7.  Back to cited text no. 3
Pyo JS, Kang G, Park K. Clinicopathological significance and diagnostic accuracy of HER2 immunohistochemistry in colorectal cancer: A meta-analysis. Int J Biol Markers 2017;31:e389-94.  Back to cited text no. 4
Creemers A, Ter Veer E, De Waal L, Lodder P, Hooijer GKJ, Van Grieken NCT, et al. Discordance in HER2 status in gastro-esophageal adenocarcinomas: A systematic review and meta-analysis. Sci Rep 2017;7:1-10.  Back to cited text no. 5
Yu W, Guo Y. Prognostic significance of programmed death ligand-1 immunohistochemical expression in esophageal cancer: A meta-analysis of the literature. Medicine (United States) 2018;97:e11614.  Back to cited text no. 6
Zhang M, Dong Y, Liu H, Wang Y, Zhao S, Xuan Q, et al. The clinicopathological and prognostic significance of PD-L1 expression in gastric cancer: A meta-analysis of 10 studies with 1,901 patients. Sci Rep 2016;6:1-9.  Back to cited text no. 7
Yang L, Xue R, Pan C. Prognostic and clinicopathological value of PD-L1 in colorectal cancer: A systematic review and meta-analysis. Onco Targets Ther 2019;12:3671-82.  Back to cited text no. 8

Correspondence Address:
Prasenjit Das
Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110029
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpm.ijpm_260_21

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