A 62-year-old Indian woman with a history of pernicious anemia (intrinsic factor antibodies positive) and chronic atrophic gastritis presents with a 3-month history of persistent epigastric pain and vomiting. Upper endoscopy reveals a 4 cm polypoid lesion in the gastric fundus with areas of ulceration. Histopathology shows well-differentiated adenocarcinoma with intact glandular structures and intestinal-type epithelium. There is no evidence of signet-ring cells. Staging CT shows no distant metastases but involvement of perigastric lymph nodes. Which of the following best describes the carcinogenic sequence in this patient?
A. Chronic atrophic gastritis → achlorhydria → H. pylori overgrowth → intestinal metaplasia → signet-ring cell carcinoma
B. Pernicious anemia → autoimmune destruction of parietal cells → intestinal metaplasia → neuroendocrine carcinoma of fundus
C. Pernicious anemia → loss of intrinsic factor → direct malignant transformation of fundic glands → diffuse-type adenocarcinoma
Carcinogenic Sequence in Pernicious Anemia–Associated Gastric Cancer
The Correa Cascade (Modified for Pernicious Anemia)
Key Point
The Correa cascade describes the stepwise progression from normal mucosa to gastric cancer. In pernicious anemia, the sequence is:
Loading diagram...
Histological Features in This Patient
Table
Feature
Finding
Significance
Histology
Well-differentiated adenocarcinoma
Intestinal type
Glandular structures
Intact, organized
Not signet-ring cell (diffuse)
Epithelium
Intestinal-type
Arises from metaplastic mucosa
Location
Fundus
Site of parietal cell loss
Precursor lesion
Atrophic gastritis + intestinal metaplasia
Correa cascade
High-YieldNEET PG
Pernicious anemia → atrophic gastritis → intestinal metaplasia → dysplasia → intestinal-type gastric cancer. This is the classic teaching sequence and accounts for ~10% of gastric cancers in high-risk populations.
Why Pernicious Anemia Increases Cancer Risk
1.
Vitamin B12 deficiency impairs DNA synthesis and repair → increased mutagenesis
2.
Autoimmune destruction of parietal cells → loss of HCl and intrinsic factor
3.
Achlorhydria allows bacterial overgrowth and nitrosamine production
4.
Intestinal metaplasia is a precancerous lesion with altered differentiation
5.
Dysplasia develops over years to decades
6.
Adenocarcinoma emerges, typically intestinal type (well-formed glands)
Clinical Pearl
Patients with pernicious anemia have a 2–3-fold increased risk of gastric cancer. Screening with endoscopy is recommended in some high-risk populations, especially those with extensive atrophic gastritis and intestinal metaplasia.
Distinction from H. pylori–Associated Gastric Cancer
Warning
Do NOT confuse pernicious anemia–associated cancer with H. pylori–associated cancer. While both involve atrophic gastritis and intestinal metaplasia, the initiating mechanism differs:
