- Intestinal-type adenocarcinoma is a well-defined histologic subtype of gastric cancer, characterized by its resemblance to intestinal epithelium.
- It follows a stepwise progression known as Correa’s cascade, involving the sequential transformation of normal gastric mucosa into malignant tissue.
- This subtype of gastric carcinoma is strongly associated with Helicobacter pylori infection, particularly strains harboring the cytotoxin-associated gene A (CagA) pathogenicity island. Additional environmental and genetic factors, including dietary carcinogens, smoking, and host immune response, contribute to its pathogenesis.
Pathogenesis and Molecular Mechanisms
- The development of intestinal-type adenocarcinoma follows a well-characterized sequence of histopathological changes. Initially, chronic non-atrophic gastritis arises due to persistent H. pylori infection, leading to inflammation and increased gastric epithelial turnover. Over time, progressive loss of gastric glandular cells results in atrophic gastritis, impairing acid secretion and promoting bacterial overgrowth.
- Intestinal metaplasia follows, wherein the gastric mucosa is replaced by intestinal-type epithelium. This can be classified into complete (small intestinal-type with absorptive cells and goblet cells) or incomplete (colonic-type with poorly differentiated columnar cells producing acidic mucins). Dysplasia then emerges as genetic mutations and epigenetic alterations accumulate, resulting in architectural and cytologic abnormalities. Ultimately, adenocarcinoma develops through malignant transformation, characterized by invasive neoplastic growth with glandular differentiation.
- Molecular alterations in intestinal-type adenocarcinoma include mutations in TP53, APC, and KRAS, along with loss of heterozygosity in tumor suppressor loci. Epigenetic modifications, such as promoter hypermethylation of CDH1 and aberrant Wnt/β-catenin signaling, contribute to its carcinogenesis.
Histopathological Features
- Intestinal-type adenocarcinoma exhibits diverse histologic architectures. The glandular/tubular pattern is characterized by well-formed glandular structures lined by columnar epithelial cells with nuclear stratification. The trabecular pattern consists of tumor cells arranged in interconnecting cords and trabeculae.
- The colonic pattern, seen in approximately 40% of cases, resembles conventional colorectal adenocarcinoma and often exhibits extensive invasive growth.
- In the papillary subtype, tumor cells form finger-like projections with fibrovascular cores.
- The solid subtype is poorly differentiated, with minimal glandular structures and a high mitotic index.
- The mucinous variant contains extracellular mucin pools with floating tumor cell clusters, resembling mucinous colorectal adenocarcinoma.
- A mixed pattern can be observed, where multiple histologic features coexist within a single tumor.
- Cytologically, the neoplastic cells are typically columnar, demonstrating nuclear pleomorphism, hyperchromasia, and frequent mitotic figures. The presence of intra- and extracellular mucins, along with occasional goblet cells, is a distinguishing feature.
- A rare, very well-differentiated variant of intestinal-type adenocarcinoma is recognized, characterized by low-grade nuclear atypia, pit and glandular anastomosis, spiky glands, and glandular outgrowth. This variant closely resembles intestinal metaplasia, making diagnosis challenging, particularly in biopsy specimens.
Immunohistochemical Profile
- Immunohistochemistry plays a critical role in distinguishing intestinal-type adenocarcinoma from other gastric neoplasms.
- The characteristic markers include consistent positivity for CK20, CDX2, Villin, MUC2, and SATB2. Variable positivity is observed for CK7 and CEA.
- Additionally, neuroendocrine differentiation may be present, with scattered chromogranin-positive cells.
- This immunohistochemical profile helps differentiate intestinal-type adenocarcinoma from diffuse-type gastric carcinoma, which typically lacks CDX2 and exhibits aberrant E-cadherin expression.
Clinical Features and Prognostic Considerations
- Intestinal-type adenocarcinoma is more prevalent in older male patients and is influenced by dietary factors such as high salt intake and low vegetable consumption, as well as chronic H. pylori infection.
- Compared to diffuse-type gastric carcinoma, it generally exhibits a more favorable prognosis due to its well-differentiated histology and lower propensity for peritoneal dissemination.
- However, advanced-stage cases with extensive invasion, lymph node metastasis, or molecular alterations associated with poor differentiation, such as TP53 mutations and microsatellite instability, have a less favorable prognosis.
- Standard treatment approaches include surgical resection (gastrectomy with lymphadenectomy), chemotherapy (e.g., 5-fluorouracil, platinum-based regimens), and targeted therapies based on molecular profiling.
