Appendix not only can become inflamed but can also undergo cancerous changes! It can pose a life-threatening risk similar to colorectal cancer.

Appendix not only can become inflamed but can also undergo cancerous changes! It can pose a life-threatening risk similar to colorectal cancer.

01

Anatomy and Function of the Appendix

The appendix is an intraperitoneal organ, and the peritoneum enveloping it forms a double-layered triangular mesentery along one side of its wall, known as the appendiceal mesentery. Therefore, the appendix is a freely movable organ within the abdominal cavity. Due to the mesentery often being shorter than the appendix, the appendix tends to be in a coiled state.

The appendix has an appearance similar to an earthworm, with a length of approximately 5 to 10 cm and a diameter of around 0.5 cm. Its tissue structure is similar to the large intestine, consisting of four layers from the inside out: mucosal layer, submucosal layer, muscular layer, and serosal layer. The mucosal and submucosal layers of the appendix contain rich lymphoid tissue, making the appendix a lymphoid organ with certain immune functions.

Research indicates that the appendix is involved in the production and maturation of B lymphocytes. The lymphoid tissue in the appendix begins to appear after birth, peaks in the teenage years, gradually decreases, and disappears completely after the age of 60. Therefore, removing the appendix in adults does not have a significant impact on the body's immune function.

02

Appendiceal Tumors

Appendicitis is a common appendiceal disease, characterized by inflammatory changes due to various factors. It is a common surgical condition, most prevalent in young individuals, with a higher incidence in males than females. Acute appendicitis is more common clinically, affecting individuals of all ages, including pregnant women. Chronic appendicitis is less common.

Appendiceal Tumors/Cancer: Although the incidence of appendiceal tumors is low, there is a rising trend within the population of digestive system cancers[1]. As a member of the tumor family, despite the seemingly insignificant size of appendiceal tumors, they pose a life-threatening risk similar to colorectal cancer.

Broadly, appendiceal tumors can be classified into epithelial-origin tumors (such as adenomas or adenocarcinomas) and non-epithelial-origin tumors (such as neuroendocrine tumors or lymphomas). Epithelial-origin appendiceal tumors are further categorized based on the production of mucus, with two distinct classes exhibiting significant differences in biological behavior and tumor prognosis. The World Health Organization (WHO) names most non-invasive epithelial-origin tumors as low-grade appendiceal mucinous neoplasms (LAMNs), which are well-differentiated adenomas capable of growing outside the appendix in a malignant manner, leading to extracellular mucin accumulation. These mucins can exist in cellular or non-cellular structural forms, and these tumors have potential malignant biological behaviors, such as causing appendiceal perforation, fibrosis of the appendiceal wall, mucin formation in the appendiceal wall, and extracellular mucin accumulation in the surrounding soft tissues. High-grade appendiceal mucinous neoplasms (HAMNs), in comparison to LAMNs, exhibit more aggressive cellular atypia.

The most common type of non-epithelial origin tumor in the appendix is neuroendocrine tumors (NETs). Histologically, they are similar to NETs in other parts of the digestive system and are often asymptomatic, typically discovered incidentally after an appendectomy. Other rare non-epithelial origin tumors in the appendix include gastrointestinal stromal tumors and lymphomas. Most appendix NETs have a lower tumor stage, leading to a relatively good prognosis. The 5-year survival rate for patients with localized lesions is approximately 95% to 100%. Although tumor size is correlated with survival, research indicates that the 5-year overall survival rate does not significantly differ between tumors smaller than 1 cm and those between 1 cm and 2 cm. The 5-year survival rate for tumors larger than 2 cm is around 70.5%. Patients with distant metastasis have a 5-year survival rate of less than 25%, with a median survival time of about 31 months.

03

Markers for Appendix Tumors

Appendiceal Adenocarcinoma: This can be classified into mucinous and non-mucinous types, with mucinous adenocarcinoma exhibiting high-grade cellular atypia and over 50% of lesions having extracellular mucin[2]. Appendiceal adenocarcinoma typically expresses p53, CD44, and CDX2.

Mucinous Tumors of the Appendix: Serum tumor markers CEA, CA19-9, and CA125 can be used for the diagnosis and disease status assessment of mucinous tumors of the appendix. Mutations in the KRAS, TP53, and SMAD4 genes can differentiate between HAMNs and LAMNs, although experts believe they have no significance in diagnosis or treatment.

04

Treatment of Appendix Tumors

Currently, there is no unified consensus on the treatment of appendix tumors. Experts suggest that the treatment of appendix tumors should be based on the patient's overall condition, tumor histopathological type, extent of involvement, and developmental trends, with surgery being the primary treatment method.[3]

05

Genetic Susceptibility of Appendix Tumors[4]

This study included patients with appendiceal cancer who underwent germline mutation testing of 14 cancer susceptibility genes in a clinical testing laboratory from March 1, 2012, to December 31, 2016. Clinical history, personal history, and family history of patients were obtained from the examination request forms filled out by clinical doctors. Multi-gene testing was performed using targeted custom capture, sequencing, and chromosomal rearrangement analysis. The primary endpoints were germline mutations, incidence, and spectrum in appendiceal cancer patients. Germline mutations in APC, BMPR1A, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, and TP53 genes were associated with susceptibility to gastrointestinal cancers.

In the cohort of 131 appendiceal cancer patients (90 females [68.7%]), 16 patients (15.11%) were found to have 5 deleterious sequence variants. Similarly, when limited to 74 patients with appendiceal cancer as the first and only primary tumor, 8 patients (10.8%) had at least 1 deleterious sequence variant in cancer susceptibility genes. Overall, harmful sequence variants were observed in 6 patients (4.6%) in MUTYH (5 cases with a single allele MUTYH, 1 case with a double allele MUTYH). Four patients with Lynch syndrome (3.1%) all had MLH1 gene sequence variants, with 3 cases diagnosed at the age of 50 or above. Three patients (8.1%) had deleterious sequence variants in other cancer susceptibility genes (3920 cases in APC [c.1307T>A, p.I2K], 2 cases in CHEK470 [c.157T>C, p.I1T], 4 cases in SMAD263 [c.287 98dup, p.L14IFS*1], 53 cases in TP524 [c.175G>A, p.R<>H]).

Conclusion: Among every 10 appendiceal cancer patients undergoing hereditary cancer susceptibility testing, one individual carries genetic mutations associated with cancer susceptibility. Given the high frequency and broad spectrum of germline genetic variations, these data suggest that genetic assessment may be necessary for all patients diagnosed with this rare malignancy.

References:

[1] Journal of Gastrointestinal Surgery, 2015, 19(4): 743-750.

[2] 4th ed. Lyon, France: IARC Press, 2010.

[3] Chinese Expert Consensus on Multidisciplinary Comprehensive Treatment of Appendiceal Tumors (2021 Edition).

[4] JAMA Oncol. 2022 Nov 11;9(1):95-101.

Statement: This article is for sharing only. If there are any copyright issues, please contact us as soon as possible and we will correct it as soon as possible. Thank you!