A 62-year-old woman with a history of chronic atrophic gastritis and pernicious anemia presents with persistent epigastric discomfort and loss of appetite for 3 months. Upper endoscopy shows a 4 cm polypoid lesion in the gastric fundus with central ulceration. Biopsy reveals well-differentiated adenocarcinoma arising from intestinal metaplasia. Immunohistochemistry shows CDX2 positivity. Staging CT reveals no distant metastases, but there is involvement of the gastric wall up to the serosa. Which of the following best describes the pathological sequence that led to this malignancy?

Explanation

## Intestinal-Type Gastric Carcinoma: The Correa Cascade **Key Point:** The Correa cascade describes the stepwise progression of intestinal-type gastric adenocarcinoma, beginning with chronic atrophic gastritis and proceeding through intestinal metaplasia, dysplasia, and finally invasive carcinoma [cite:Harrison 21e Ch 297]. ### The Correa Cascade (Multistep Carcinogenesis) ```mermaid flowchart TD A["Normal gastric mucosa"]:::outcome --> B["Chronic atrophic gastritis<br/>(H. pylori, autoimmune)"]:::outcome B --> C["Intestinal metaplasia<br/>(CDX2+ cells)"]:::outcome C --> D["Low-grade dysplasia<br/>(LGD)"]:::outcome D --> E["High-grade dysplasia<br/>(HGD)"]:::outcome E --> F["Invasive adenocarcinoma<br/>(Intestinal type)"]:::urgent B -.->|Risk factors| G["H. pylori infection<br/>Autoimmune atrophic gastritis<br/>Smoking, high salt diet"] C -.->|CDX2 activation| H["Intestinal differentiation<br/>Loss of gastric identity"] E -.->|Progression rate| I["HGD → Cancer<br/>~30% per year if untreated"] ``` **High-Yield:** The Correa cascade is the **intestinal pathway** for gastric cancer: 1. **Chronic atrophic gastritis** — Loss of gastric glands, hypochlorhydria 2. **Intestinal metaplasia** — Replacement of gastric mucosa with intestinal-type epithelium (CDX2+) 3. **Dysplasia** — Low-grade (LGD) → High-grade (HGD) 4. **Invasive adenocarcinoma** — Intestinal-type, typically well-differentiated ### Why This Patient Fits the Cascade | Feature | Patient Finding | Cascade Correlation | |---------|-----------------|---------------------| | **Chronic atrophic gastritis** | Pernicious anemia (autoimmune) | Starting point | | **Intestinal metaplasia** | CDX2+ on IHC | Intermediate step | | **Adenocarcinoma type** | Well-differentiated (intestinal) | End-stage | | **Location** | Fundus (atrophic area) | Site of metaplasia | | **Precursor lesion** | Dysplasia (presumed) | Confirmed by progression | **Clinical Pearl:** CDX2 (caudal-type homeobox 2) is a transcription factor that drives intestinal differentiation. Its presence on immunohistochemistry confirms that this carcinoma arose through the intestinal metaplasia pathway, not the diffuse pathway (which would show signet-ring cells and loss of E-cadherin). **Mnemonic:** **CAIDA** = **C**hronic atrophic gastritis, **A**trophic changes, **I**ntestinal metaplasia, **D**ysplasia, **A**denocarcinoma [cite:Robbins 10e Ch 17] ### Risk Factors Accelerating the Cascade - **H. pylori infection** — Chronic inflammation, atrophy - **Autoimmune atrophic gastritis** — Parietal cell antibodies (this patient's pernicious anemia) - **Smoking** — Carcinogenic compounds - **High-salt diet** — Gastric irritant - **Smoking + H. pylori** — Synergistic risk