Spasmolytic Polypeptide-Expressing Metaplasia (SPEM): the hidden linchpin in gastric carcinogenesis beyond the correa cascade

Gastric cancer remains a leading cause of cancer-related mortality worldwide, necessitating improved understanding of its precancerous stages. While Professor Correa’s cascade—which describes progression from atrophy to intestinal metaplasia to cancer—has long been held as the paradigm for gastric carcinogenesis, emerging evidence suggests a more complex pathway. The identification of compound glands containing basal proliferative intestinalized spasmolytic polypeptide-expressing metaplasia (SPEM) cells with luminal intestinal elements provides compelling morphological evidence for SPEM-driven carcinogenesis pathways. This review positions SPEM as an earlier and potentially more critical intervention point than previously recognized intestinal metaplasia. SPEM is characterized by trefoil factor 2-expressing cells that replace normal gastric lineages following parietal cell loss, representing a distinct metaplastic entity arising through either chief cell transdifferentiation or stem cell differentiation. Importantly, this metaplastic change occurs earlier in the carcinogenic sequence than traditional models suggest. SPEM exhibits remarkable biological duality determined by inflammatory context: canonical SPEM arising in acute injury serves beneficial reparative functions through mucus secretion, growth factor production, and reactive oxygen species defense, whereas proliferative intestinalized SPEM developing under chronic inflammation represents a high-risk precancerous state characterized by sustained proliferation, mixed gastric-intestinal lineage features, and autonomous cell cycle programming. Under chronic inflammatory conditions driven primarily by Helicobacter pylori infection, canonical SPEM may advance through a defined progression pathway: canonical SPEM → proliferative intestinalized SPEM → incomplete intestinal metaplasia. Molecularly, this transition is characterized by fundamental changes in cellular behavior and gene expression. Proliferative intestinalized SPEM, which constitutes a key component of incomplete intestinal metaplastic glands, exhibits sustained Ki-67-positive proliferation, progressive expression of intestinal transcripts including cystic fibrosis transmembrane conductance regulator ( CFTR), glutathione peroxidase 2 ( GPX2), deleted in malignant brain tumors 1 ( DMBT1), polymeric immunoglobulin receptor ( PIGR ), and villin 1 ( VIL1 ), and autonomous cell cycle programming that persists even after removal of the initial inflammatory stimulus. This progression is orchestrated largely by the interleukin-33/interleukin-13 signaling axis through type 2 immune responses, a self-perpetuating inflammatory microenvironment that continuously drives metaplastic transformation toward increasingly proliferative and intestinalized phenotypes. A critical distinction exists between canonical SPEM (protective, transient, fully reversible following Helicobacter pylori eradication) and proliferative intestinalized SPEM (pathological, persistent, therapeutically irreversible). Canonical SPEM demonstrates complete reversibility following Helicobacter pylori eradication, defining a valuable therapeutic window for intervention. In contrast, proliferative intestinalized SPEM—which manifests histologically as incomplete intestinal metaplasia—represents an irreversible “histological point of no return” with persistent proliferative dysfunction and autonomous cell cycle programming. Recent molecular characterization has enabled differentiation between these reversible canonical SPEM and high-risk proliferative forms, with clinical validation showing that proliferative intestinalized SPEM persists despite bacterial eradication. The significance of SPEM in gastric carcinogenesis is underscored by its near-universal presence in resected gastric cancers (approximately 90%) and its temporal precedence to intestinal metaplasia. These findings strongly support SPEM’s role as a critical precancerous lesion that may have been underappreciated in traditional models. This review synthesizes current understanding of SPEM’s pathogenesis, molecular mechanisms, and clinical implications. Furthermore, it proposes integration of SPEM assessment into gastric cancer risk stratification protocols to enable earlier intervention strategies that interrupt carcinogenesis at its most vulnerable and potentially reversible stage.