What is the pathophysiology of linitis plastica in a patient with stomach cancer?

Pathophysiology of Linitis Plastica

Linitis plastica is characterized by diffuse infiltration of the gastric wall by poorly cohesive adenocarcinoma cells (typically signet-ring cells) that trigger an intense desmoplastic stromal reaction, resulting in a rigid, non-distensible "leather bottle" stomach with transmural fibrosis predominantly affecting the submucosal and muscular layers. 1, 2

Cellular and Histological Mechanisms

Tumor Cell Characteristics:

• The malignant cells are poorly differentiated and non-cohesive, most commonly signet-ring cells or other diffuse-type adenocarcinoma cells that lack cell-to-cell adhesion 1, 3
• These cells infiltrate diffusely through the gastric wall in cords, small clusters, and individual cells rather than forming discrete masses 1
• The infiltration pattern includes both pagetoid spread (rows of signet-ring cells below preserved epithelium) and replacement of normal glandular cells within the basal membrane 1

Stromal Response:

• The hallmark pathophysiologic feature is an intense desmoplastic reaction—excessive fibrous tissue deposition in response to tumor infiltration 2
• This fibrosis creates a rigid, thickened gastric wall that loses normal distensibility and peristaltic function 1, 2
• The fibrous stroma is not merely reactive but represents a critical component of the disease process that contributes to the characteristic clinical presentation 2

Pattern of Gastric Wall Involvement

Layer-Specific Infiltration:

• Linitis plastica preferentially involves the submucosal and muscular layers of the stomach, often with minimal or absent mucosal changes 2, 4
• This submucosal predominance explains why endoscopic biopsies frequently miss the diagnosis—the mucosa may appear grossly normal while extensive disease exists beneath 2, 5
• The tumor must involve more than one-third of the gastric wall macroscopically to meet the definition of linitis plastica 6

Macroscopic Classification:

• Linitis plastica represents Borrmann Type IV gastric cancer: a poorly demarcated, infiltrative, and diffuse tumor 1
• The diffuse infiltration causes loss of normal gastric folds and creates the characteristic "leather bottle" appearance on imaging 1, 2

Vascular and Microenvironmental Changes

Abnormal Neovascularization:

• Recent evidence demonstrates that linitis plastica is associated with aberrant vascular networks characterized by vessel enlargement, tortuosity, and leakage 4
• These abnormal vessels are non-functional and similar to neoplastic vasculature seen in other malignancies 4
• The vascular changes occur even in areas where mucosal architecture appears preserved 4

Molecular and Histologic Subtype

Lauren Classification:

• Linitis plastica belongs to the diffuse histologic type in the Lauren classification system 1, 3
• The diffuse type is characterized by poorly differentiated tumor cells with signet-ring or non-signet ring morphology 3
• This subtype has a predilection for the proximal stomach in Western populations, though it can affect any gastric region 3

Patterns of Spread

Preferential Metastatic Routes:

• Unlike other gastric cancers, linitis plastica shows a marked propensity for peritoneal dissemination and lymphatic invasion 2, 6
• The disease frequently presents with advanced-stage disease, with 75.8% having stage IV disease at diagnosis, predominantly due to peritoneal involvement 6
• Extension to neighboring organs is common due to the transmural infiltrative nature 2

Clinical Pitfalls

Diagnostic Challenges:

• The submucosal location of disease means that standard endoscopic forceps biopsies often "slide on the infiltrated walls" without capturing diagnostic tissue 2
• Endoscopic ultrasound-guided biopsy may be necessary to obtain adequate tissue from the thickened submucosal layer 5
• The mucosa may appear endoscopically normal despite extensive underlying disease, leading to delayed diagnosis 2, 4