MET expression by immunohistochemistry as a biomarker in pancreatic neuroendocrine tumours

MET (c-MET) is a receptor tyrosine kinase implicated in numerous cancers, including pancreatic neuroendocrine tumours (pNETs), by promoting cell proliferation, survival, invasion and angiogenesis. Rec

Summary

A study from the Yale University School of Medicine (Departments of Pathology, Medicine, and Surgery; senior authors Samuel G. Katz, Po-Han Chen, David Klimstra, Pamela L. Kunz) evaluating the prognostic and biomarker utility of MET (c-MET) receptor tyrosine kinase expression by immunohistochemistry (IHC) in pancreatic neuroendocrine tumours (pNETs).

Evaluating 125 well-differentiated pNET tissue microarray cores across 112 patients using semi-quantitative H-scoring, the authors demonstrate that MET overexpression is common (83.5% positive) and strongly correlates with adverse histopathological features (lymphovascular invasion, perineural invasion, higher WHO tumour grade) as well as distant metastatic dissemination and dramatically reduced progression-free and overall survival.

The verbatim abstract is preserved in the description: frontmatter. The sections below provide a structured pathology digest and clinical appraisal of the reported findings. The article is published in Histopathology (Wiley; DOI: 10.1111/his.70273). Full text is paywalled at the publisher.

Background & Clinical Context

Pancreatic neuroendocrine tumours (pNETs) are clinically and biologically heterogeneous neoplasms. While many well-differentiated tumors follow an indolent course, a substantial subset develops local invasion, treatment resistance, or distant metastases (predominantly hepatic).

• The MET Pathway: MET (mesenchymal-epithelial transition factor / c-MET) encodes a receptor tyrosine kinase whose canonical ligand is hepatocyte growth factor (HGF). Activation triggers downstream MAPK, PI3K/Akt, and STAT signaling cascades driving tumor cell proliferation, motility, invasion, angiogenesis, and therapeutic resistance.

• Theranostic Interest: As targeted anti-MET agents (including multi-targeted kinase inhibitors such as cabozantinib, selective MET inhibitors, antibody-drug conjugates like telisotuzumab vedotin, and c-MET-directed CAR-T therapies) advance in clinical oncology, identifying practical tissue biomarkers to stratify patients at risk of aggressive progression or potential drug responsiveness is crucial.

• Role of IHC: While genomic testing (e.g. MET amplification or exon 14 skipping) identifies specific oncogenic subsets in non-small cell lung cancer, protein overexpression assessed by standardized IHC is an accessible, cost-effective, and direct phenotypic readout of receptor availability.

Cohort & Methodology

• Specimens: Tissue microarrays (TMAs) constructed from resected well-differentiated gastroenteropancreatic neuroendocrine tumours.

• Cohort Size: 125 pNET cores derived from 112 patients meeting strict inclusion criteria.

• IHC Scoring: Semi-quantitative H-score system: $\text{H-score} = [1 \times (\% \text{ 1+ cells})] + [2 \times (\% \text{ 2+ cells})] + [3 \times (\% \text{ 3+ cells})]$ yielding a dynamic range of 0 to 300 based on membrane/cytoplasmic staining intensity and proportion.

• Outcome Endpoints: Progression-free survival (PFS) and overall survival (OS), correlated with clinicopathological variables (tumour grade, stage, lymphovascular invasion, perineural invasion, metastasis, radiological progression).

Key Findings

1. Prevalence of MET Expression

• 83.5% of evaluated pNET cases exhibited positive MET immunoreactivity, confirming that MET pathway activation or protein expression is widespread across well-differentiated pNETs.

2. Clinicopathological Correlations

Higher continuous MET H-scores were significantly associated with adverse pathological determinants ($P < 0.05$):

• Higher WHO Tumour Grade: Elevated expression tracked with higher proliferation / histological grade.

• Lymphovascular Invasion (LVI): Markedly higher H-scores in LVI-positive tumors.

• Distant Metastases: Significantly elevated expression in patients with metastatic disease at presentation or follow-up.

3. Clinically Actionable Cut-off Thresholds

H-Score Cut-off	Primary Associations	Clinical & Pathological Significance
H-score $\ge$ 150	• Lymphovascular invasion (LVI) • Perineural invasion (PNI) • Radiological progression • Overall survival ($P < 0.05$)	Identifies an aggressive biological phenotype prone to microvascular infiltration and clinical progression.
H-score $\ge$ 200	• Progression-Free Survival: Mean 8.7 years vs. 13.4 years ($P < 0.05$) • Overall Survival: Mean 3.6 years vs. 7.7 years ($P < 0.05$)	Definitive high-expression threshold that stratifies patients into substantially shortened survival trajectories (>4-year deficit in overall survival).

Pathological & Clinical Implications

1. Adverse Prognostication in Well-Differentiated Disease: In well-differentiated pNETs, where histological distinction between indolent and aggressive behavior can be challenging on small biopsies or low-grade resections, an elevated MET H-score ($\ge$150 or $\ge$200) provides independent prognostic stratification.

2. Predictive Biomarker for Targeted Therapeutics: Provides empirical rationale for enrolling high-MET pNET patients into clinical trials assessing MET tyrosine kinase inhibitors, MET-directed ADCs, or combination regimens, especially following resistance to somatostatin analogues or PRRT.

3. Need for Assay Standardization: Harmonization of antibody clone selection (e.g., SP44 vs. other diagnostic clones), staining platforms, and automated image analysis or validated scoring thresholds will be necessary before routine clinical adoption.