Appendix cancer is a rare disease that originates in the appendix, a small, finger-shaped pouch extending from the large intestine in the lower right abdomen. It occurs when cells within the appendix multiply uncontrollably, forming a tumor. While its exact function remains uncertain, the appendix is sometimes thought to play a role in the immune system. Given its rarity, appendix cancer is often discovered incidentally during surgeries for other conditions, such as appendicitis, or during abdominal imaging. It accounts for less than one percent of all gastrointestinal cancers diagnosed annually.
Diverse Forms of Appendix Cancer
Appendix cancer encompasses several distinct types. Neuroendocrine tumors (carcinoid tumors) are the most frequently encountered type, representing approximately 32% to 57% of all appendiceal tumors. These tumors typically grow slowly and originate from hormone-producing cells, often found at the tip of the appendix.
Mucinous neoplasms can range from low-grade to more advanced forms. These tumors produce mucin, a jelly-like substance, and can lead to pseudomyxoma peritonei (PMP) if they rupture and spread into the abdominal cavity. Low-grade mucinous neoplasms (LAMNs) have the potential to progress into mucinous adenocarcinoma, a more aggressive cancer.
Adenocarcinomas arise from cells lining the inner surface of the appendix. This category includes colonic-type adenocarcinoma, which behaves similarly to colorectal cancer, and signet ring cell adenocarcinoma, an aggressive variant. Goblet cell carcinomas (adenocarcinoids) possess features of both adenocarcinomas and carcinoid tumors, often exhibiting more aggressive behavior than typical carcinoids.
Factors Increasing Risk
While the precise causes of appendix cancer are not fully understood, certain factors may increase an individual’s likelihood of developing appendix cancer. Most diagnoses occur in individuals between 40 and 60 years old, with a rising incidence of appendix cancer among younger adults.
Women are more prone to developing carcinoid tumors of the appendix than men. Smoking has been linked to an increased risk for appendix cancer.
A family history of certain conditions, such as multiple endocrine neoplasia type 1 (MEN1) syndrome, may elevate risk. A recent study suggests that about one in ten patients with appendiceal cancer carries an inherited genetic variant associated with cancer predisposition. Certain medical histories, including atrophic gastritis, pernicious anemia, and Zollinger-Ellison syndrome, have also been associated with an increased risk.
While lifestyle factors such as diet and alcohol consumption are not strongly established as direct causes of appendix cancer, adopting healthy lifestyle choices can contribute to overall cancer prevention. The exact combination of factors that initiate appendix cancer remains an area of ongoing research.
Cellular Origins of Appendix Cancer
Cancer development in the appendix involves alterations at the cellular level. This process begins when normal cells acquire genetic mutations, changes to their DNA. These mutations can be inherited from parents or occur during a person’s lifetime due to DNA damage.
These genetic changes often affect oncogenes and tumor suppressor genes. Oncogenes are typically involved in promoting cell growth and division; when mutated, they can become overactive, leading to uncontrolled cell proliferation. Examples of oncogenes frequently mutated in appendix cancer include KRAS, GNAS, and BRAF. For instance, KRAS mutations are common in appendiceal adenocarcinomas, while GNAS mutations are frequently observed in mucinous adenocarcinomas.
Tumor suppressor genes regulate cell division and initiate cell death if a cell becomes damaged. When these genes are mutated, they lose their protective function, allowing abnormal cells to continue growing and dividing without restraint. While genes like TP53 and SMAD4 act as tumor suppressors, they are less frequently mutated in appendix cancers compared to colorectal cancer. The accumulation of multiple genetic changes in both oncogenes and tumor suppressor genes is typically required for cancer to develop and progress. Distinct genetic profiles are often observed among the different types of appendix cancer, highlighting the varied biological pathways involved in their formation.