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# 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** | <p>• Lymphovascular invasion (LVI)<br>• Perineural invasion (PNI)<br>• Radiological progression<br>• Overall survival ($P < 0.05$)</p>                                                                                                                | Identifies an aggressive biological phenotype prone to microvascular infiltration and clinical progression.                                             |
| **H-score $\ge$ 200** | <p>• <strong>Progression-Free Survival:</strong> Mean <strong>8.7 years</strong> vs. <strong>13.4 years</strong> ($P < 0.05$)<br>• <strong>Overall Survival:</strong> Mean <strong>3.6 years</strong> vs. <strong>7.7 years</strong> ($P < 0.05$)</p> | 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.