Gastric adenocarcinoma represents a complex and challenging malignancy that continues to be a significant global health concern. The pathology of gastric adenocarcinoma represents a complex narrative of cellular transformation that begins deep within the intricate layers of the stomach’s mucosal landscape.

At its core, this malignancy emerges as a profound disruption of normal cellular organization, where the delicate balance of growth, differentiation, and programmed cell death becomes fundamentally altered.

Fundamentally, all types of gastric adenocarcinoma share a critical pathological foundation: the progressive breakdown of cellular control mechanisms. Normal stomach epithelial cells undergo a malignant metamorphosis, characterized by uncontrolled proliferation, loss of normal architectural structure, and an ability to invade surrounding tissues.

This transformation is not a sudden event, but a gradual process of accumulated genetic and molecular alterations that progressively erode the cell’s ability to maintain normal function and restraint.

The pathological journey begins at the cellular level, where genetic mutations progressively compromise the intricate regulatory systems that typically govern cell growth and division. These mutations can affect crucial genes responsible for cell cycle control, DNA repair mechanisms, and apoptosis (programmed cell death). As these protective mechanisms fail, cells begin to multiply unchecked, developing increasingly aberrant characteristics that distinguish them from healthy stomach tissue.

Regardless of whether the adenocarcinoma follows a diffuse or intestinal pattern, the fundamental pathological process involves a systematic breakdown of cellular integrity.

Cancer cells lose their typical organizational structure, become less differentiated, and gain the ability to infiltrate surrounding tissues. They develop abnormal nuclear characteristics—becoming larger, more irregular, and losing the uniform appearance of healthy cells.

The cellular architecture becomes increasingly chaotic, with cells losing their typical cohesive relationships and developing an autonomous, invasive nature.

The pathological progression is marked by several key transformations. Initially, precancerous changes occur in the stomach’s mucosal lining, often characterized by:

• chronic inflammation
• cellular metaplasia (abnormal cell changes),
• dysplasia (abnormal cell development).

These initial stages represent a critical window where the cellular environment becomes increasingly conducive to malignant transformation. Chronic conditions such as persistent Helicobacter pylori infection, prolonged inflammation, and genetic predispositions create a microenvironment that progressively supports abnormal cellular growth.

As the disease advances, the pathological changes become more pronounced. Cancer cells develop the ability to break through basement membranes, invade surrounding tissues, and ultimately metastasize to distant organs. They acquire capabilities that normal cells do not possess—the ability to stimulate new blood vessel formation (angiogenesis), evade immune system detection, and survive in environments that would typically destroy abnormal cells.

The remarkable complexity of gastric adenocarcinoma lies in its ability to manifest differently while maintaining core pathological principles. Whether presenting as a tightly organized intestinal-type carcinoma with recognizable glandular structures or as a diffuse type with scattered, infiltrative cells, the underlying pathological mechanism remains fundamentally consistent: uncontrolled cellular proliferation that progressively compromises normal tissue function.

Diffuse vs.intestinal gastric cancer

Gastric adenocarcinomas are primarily classified into two distinct histological subtypes, each with unique pathological characteristics:

1. Intestinal-type gastric cancer

Characteristics:

• More structured cellular organization
• Typically develops from precancerous lesions
• More common in older populations
• Strong association with environmental and dietary factors

Pathological Features:

• Glandular formations resembling intestinal epithelium
• More differentiated cellular structures
• Often shows clear progression from inflammatory changes to neoplasia

2. Diffuse-type gastric cancer

Characteristics:

• Poorly cohesive cellular pattern
• Less structured cellular arrangement
• Higher tendency for infiltrative growth
• More likely to occur in younger patients
• Often associated with genetic predispositions

Pathological Features:

• Scattered, individual cancer cells
• Minimal glandular formation
• Tendency to infiltrate stomach wall extensively
• Higher potential for early metastasis

Feature	Intestinal Type	Diffuse Type
Genetic Markers	Higher E-cadherin expression	Frequent E-cadherin mutations
Progression	More predictable stages	More aggressive progression
Cellular Patterns	Organized glandular structures	Infiltrative, scattered cells

Histology

Intestinal carcinoma

• Well-defined glandular structures
• Organized cellular arrangement
• Varied differentiation levels
• Clear demarcation from surrounding tissue

Diffuse carcinoma

• Poorly cohesive cellular patterns
• Signet ring cell predominance
• Minimal glandular formation
• Extensive infiltrative growth
• Challenging diagnostic differentiation

Pathological grading system

Gastric adenocarcinomas are typically graded based on:

1. Cellular differentiation
2. Glandular formation percentage
3. Nuclear characteristics
4. Infiltrative patterns

Grading scale:

1. Well-differentiated (Grade 1)
2. Moderately differentiated (Grade 2)
3. Poorly differentiated (Grade 3)
4. Undifferentiated (Grade 4)

Clinical implications and diagnostic considerations

Key diagnostic challenges

• Subtle morphological differences
• Potential overlapping cellular characteristics
• Need for advanced molecular testing
• Importance of comprehensive tissue evaluation

Recommended diagnostic approach

1. Comprehensive tissue biopsy
2. Immunohistochemical studies
3. Molecular genetic analysis
4. Comprehensive clinical correlation

Recommended further investigation

• Molecular genetic profiling
• Advanced imaging techniques
• Comprehensive clinical correlation
• Multidisciplinary tumor board discussions