# Beyond Gastric Specificity: V-Set and Immunoglobulin Domain-Containing 1 (VSIG1) in Digestive Tract Tumors

## TL;DR

VSIG1 is a protein originally thought to be specific to the stomach but is now understood to reflect epithelial differentiation in various digestive tract tumors, not just gastric ones.

## Contribution

This review clarifies that VSIG1 reflects epithelial differentiation rather than tumor origin, impacting tumor classification and diagnostic interpretation.

## Key findings

- VSIG1 expression correlates with preserved glandular architecture and epithelial differentiation in gastric cancer.
- VSIG1 positivity is observed in non-gastric tumors with gastric-type features, indicating lineage engagement.
- VSIG1's role as a differentiation marker is more relevant than its use as a tumor origin or aggressiveness indicator.

## Abstract

VSIG1 is a protein that is normally expressed at higher levels in the stomach mucosa and is involved in maintaining epithelial differentiation. In recent years, VSIG1 has been increasingly studied in cancer, particularly in tumors of the gastrointestinal tract. While it was initially considered a stomach-specific marker, accumulating evidence shows that VSIG1 can also be expressed in other epithelial tumors, especially those showing gastric-type features. In this review, we summarize current knowledge on VSIG1 expression, with a focus on gastric and non-gastric digestive tract tumors. We discuss how VSIG1 expression relates to epithelial differentiation and tumor plasticity rather than tumor origin or aggressiveness. Understanding the biological context of VSIG1 expression may help pathologists and researchers interpret tumor phenotypes more accurately and avoid overestimating the specificity or clinical significance of this marker.

V-set and immunoglobulin domain-containing 1 (VSIG1) is a member of the immunoglobulin superfamily that has attracted increasing attention as a differentiation-associated protein in gastrointestinal neoplasia. Although initially described as a gastric-specific marker, accumulating evidence indicates that VSIG1 more accurately reflects gastric-enriched epithelial differentiation rather than strict anatomical origin. This conceptual shift has implications for phenotype-oriented tumor classification and diagnostic interpretation in the context of lineage plasticity. A structured and transparently reported literature search was conducted in PubMed/MEDLINE, Web of Science, and Scopus, covering studies published between 2000 and 2024. Eligible studies included original research and relevant reviews evaluating VSIG1 expression in normal tissues and digestive tract tumors, with emphasis on immunohistochemical patterns and clinicopathological correlations. In gastric cancer, VSIG1 expression consistently correlates with preserved glandular architecture and epithelial differentiation, whereas reduced or absent expression accompanies dedifferentiation and architectural disorganization. Outside the stomach, VSIG1 positivity is uncommon but reproducible in tumors exhibiting gastric-type or mixed differentiation, including settings of hepato-gastric phenotypic overlap. These patterns support interpretation of VSIG1 as a context-dependent indicator of lineage engagement and differentiation state rather than tumor origin or aggressiveness. Current data on independent prognostic value are limited and partially conflicting, and predictive roles remain unsupported, while functional data remain limited.