The molecular genetics behind cancer is an ever-changing field with new pathways being elucidated on a daily basis. One pathway of particular interest involves the E-cadherin (CDH1) gene, which plays an intricate role in diffuse gastric cancer. Although this condition is relatively rare, there are certain “alarm” symptoms that are present in both the history and physical exam that can give health care professionals clues towards an accurate diagnosis.

E-cadherin is a cell adhesion molecule that is encoded on chromosome 16. It is responsible for cell-to-cell adhesion between epithelial cells, forming a barrier between adjacent cells. When this gene is mutated, it allows cancer cells to invade previously impenetrable borders and can contribute to metastases. The loss of E-cadherins has been implicated in gastric, colorectal, lobular breast, and ovarian cancers. 

Patients with a mutated CDH1 gene leading to an E-cadherin deficiency have a greater than 80% chance of acquiring diffuse gastric cancer in their lifetime. They can present with cancer any time from their teens to their 80s; however, they typically present around age 40 years. Families with this known mutation are usually advised to have a total gastrectomy sometime between 20 and 40 years of age.

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In patients with suspected diffuse gastric cancer, confirming the diagnosis using endoscopy can prove to be challenging. The cancerous cells are typically located below an intact mucosa and can be easily missed, even with extensive biopsies. Some endoscopy centers use stains such as methylene blue and congo red during endoscopy to aid in detecting the cancer cells. Diffuse gastric cancer is often referred to as linitis plastica due to its appearance on inspection that resembles a leather bottle. Upon microscopic inspection, signet-ring cells are present with their nuclei pushed to the periphery secondary to the mucin that they are producing.

Although rare, there are several key alarm signs and symptoms that could indicate a diagnosis of diffuse gastric cancer. Patients typically complain of relatively substantial, unintended weight loss secondary to decreased appetite, persistent nausea and vomiting, or early satiety. Patients may have a strong family history of cancer, especially involving gastric, colorectal, ovarian, and breast cancer. Physical exam and imaging findings of gastric cancer can include acanthosis nigricans, Virchow’s node (positive lymphadenopathy indicating metastasis to the left supraclavicular node), Sister Mary Joseph node (metastasis to a periumbilical lymph node), Krukenberg tumor (metastases to both ovaries), Leser-Trelat sign (sudden onset and appearance of pigmented seborrheic keratoses), and Blumer’s Shelf (metastatic prerectal mass).

Questions to Readers

  • What are your experiences in diagnosing diffuse gastric cancer?
  • How do you think gene therapy could play a role in treating diffuse gastric cancer?

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