Appendix Cancer on the Rise: Implications for Diagnosis and Patient Care

By Vijay Kumar MalesuReviewed by Benedette Cuffari, M.Sc.

Introduction
What is appendix cancer?
How common is it?
Diagnosis and symptoms
Treatment options
Prognosis and survivorship
Ongoing research and clinical trials
Prognosis and survivorship
Future outlook
References
Further reading

Once considered an outlier in gastrointestinal oncology, appendix cancer is now at the forefront of precision medicine, driven by genomic insights, personalized therapies, and a surge in scientific and clinical interest.

Image Credit: sasirin pamai / Shutterstock.com

Introduction

Appendix cancer, once considered an exception within gastrointestinal oncology, remains rare, yet clinicians and researchers now view it with heightened urgency. Improved imaging, genomic profiling, and increased colonoscopy rates have revealed a steady rise in the incidence of appendix cancer, which has increased scientific scrutiny and public interest.¹

What is appendix cancer?

Appendix cancer originates in the epithelial or neuroendocrine cells lining the vermiform appendix, a slender intestinal outpouching whose exact physiological role remains unclear. Although it represents less than 1% of gastrointestinal malignancies and appears in only 0.5-1% of appendectomy specimens, improved imaging and routine histology have revealed a slow but steady increase in its incidence, with approximately one to two diagnoses reported for every one million people each year.^1,2

Appendiceal adenocarcinomas resemble colorectal cancers and may be conventional or mucinous. The mucinous subtype of appendix cancer frequently secretes gelatinous material that can seed the peritoneum. Goblet cell carcinoma (GCC) exhibits mixed glandular-neuroendocrine features and behaves more aggressively than typical adenocarcinoma.^1,2

Neuroendocrine tumors (NETs), which are also called carcinoids, originate near the appendiceal tip and account for about 65% of appendiceal neoplasms, usually following an indolent course. Pseudomyxoma peritonei (PMP), technically a clinicopathologic syndrome rather than an actual tumor, arises most commonly from low-grade mucinous lesions and produces diffuse mucinous ascites that can distort abdominal organs.^1,2

Early-stage appendix cancer frequently mimics uncomplicated appendicitis or causes no symptoms. As a result, many cases emerge only after routine appendectomy.

Recognition of the diverse histologic subtypes guides personalized management strategies ranging from simple appendectomy for small NETs to cytoreductive surgery (CRS) combined with heated intraperitoneal chemotherapy (HIPEC) for disseminated mucinous disease.^1,2

How common is it?

Appendix cancer remains exceptionally uncommon, as it represents only 0.4% of all gastrointestinal tumors. Population-based estimates suggest an annual incidence of between one and two cases for every million individuals; however, registry data have indicated a gradual rise in appendix cancer diagnoses over the past two decades.

Most tumors are discovered incidentally during surgery for presumed acute appendicitis, which demonstrates how easily this cancer can evade pre-operative detection. Adenocarcinoma typically appears in men aged 55-65 years, whereas malignant carcinoid is diagnosed earlier, around the late thirties.³

Why the resurgence in interest?

Recent data suggest rising rates of appendiceal cancer diagnoses, largely because modern imaging, pathology, and surveillance are able to identify previously unknown lesions. Pathologists have also improved classification criteria, which has led to re-reviews of archival specimens and re-labeling ambiguous tumors.

High-profile celebrity stories, energetic patient groups, and viral social media posts have also kept the disease in public view, leading to earlier medical consultations. Furthermore, genomic profiling routinely screens for Kirsten rat sarcoma viral oncogene homolog (KRAS) and guanine nucleotide-binding protein subunit alpha (GNAS) mutations, which have enabled precision oncology trials.¹

Diagnosis and symptoms

Most appendiceal malignancies remain undiagnosed for nearly a decade, with over 50% of all tumors discovered only after elective or emergency appendectomy. When symptoms emerge, they usually mimic classic acute appendicitis, like sudden right-lower-quadrant pain, fever, and leukocytosis, as tumor growth or superinfection blocks the narrow lumen. Mucinous lesions may stretch the appendix, rupture, and seed the peritoneum with mucus-secreting cells, which leads to the production of a slowly enlarging, distended “jelly-belly” abdomen typical of PMP.^1,3

Contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) can elucidate whether an appendix is wider than usual, exhibits mural irregularity, coarse or lamellated calcification, or a cystic mucocele with peritoneal scalloping, which strongly suggests neoplasia.

Ultrasonography may also help confirm the presence of a cystic mass. In the event that these studies are inconclusive or when diffuse peritoneal disease is suspected, image-guided biopsies are used to obtain tissue samples for definitive pathology.

Serum and urinary tumor markers may also provide insights into the type of appendix cancer. For example, carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9) are used to monitor mucinous tumors, while 24-hour 5-hydroxyindoleacetic acid (5-HIAA) and serum chromogranin A can be used to confirm neuroendocrine disease or carcinoid syndrome.^1,3

Treatment options

The treatment of appendix cancer depends on histologic subtype and extent of metastasis. For low-grade, in situ, or submucosal lesions, an appendectomy typically suffices and yields almost complete survival. High-grade tumors, vascular invasion, positive margins, or tumors with a diameter exceeding two centimeters (cm) warrant right hemicolectomy with regional lymphadenectomy to ensure accurate staging and clear margins.^4,5

When mucin or tumor cells seed the peritoneum, the preferred approach is complete CRS followed immediately by HIPEC. The closed-abdomen technique circulates mitomycin C in three liters of perfusate at 42 °C for 90 minutes and can be complemented by early postoperative instillations. This combined strategy significantly extends disease-free and overall survival in specific low-grade cases.

Patients who cannot undergo full cytoreduction or relapse after HIPEC may receive systemic therapy. Fluorouracil- or oxaliplatin-based regimens benefit moderate-to-high-grade tumors, whereas low-grade mucinous neoplasms respond poorly. Adjuvant chemotherapy shows no clear advantage after complete resection of low-grade disease.^4,5

Targeted and biologic options remain investigational. Current clinical trials are evaluating everolimus, somatostatin analogues, peptide receptor radionuclide therapy, and agents directed at phosphatidylinositol-3-kinase or Ak strain transformin (AKT) pathways, particularly for neuroendocrine or molecularly defined subsets. All decisions should arise from a multidisciplinary discussion at experienced, accredited centers.^4,5

Prognosis and survivorship

Localized NETs generally have excellent outcomes, with five-year survival rates nearing 93%. In contrast, high-grade mucinous or signet ring cell tumors are associated with a much poorer prognosis, with survival rates of about 27%.

Patients with mucinous tumors that spread into the peritoneum, such as PMP, are at a greater risk of frequent recurrences, which require long-term surveillance and repeat interventions. Early diagnosis is critical, as late-stage detection significantly worsens outcomes. Personalized treatment strategies based on histology and spread are essential for improving survivorship in this rare and complex malignancy.^1,2

Ongoing research and clinical trials

Ongoing research in appendiceal cancer is focused on better characterizing molecular subtypes to refine treatment strategies and improve outcomes. Investigators are actively working to distinguish between low-grade and high-grade tumors at the molecular level, including studies on specific mutations such as KRAS and GNAS. These insights aim to enable more accurate prognosis and patient stratification.

Multiple clinical trials are also evaluating the efficacy of targeted therapies, including agents that target specific genetic alterations. Immunotherapy, though still in its early stages for this cancer type, is being explored as a potential treatment approach, particularly in tumors exhibiting immune-responsive features.⁶

Researchers are also evaluating optimized protocols for HIPEC that include drug combinations, temperature settings, and perfusion durations. These trials aim to strike a balance between effectiveness and safety, as well as long-term benefits. Overall, the research reflects a substantial shift toward personalized and multimodal treatment approaches.⁶

Future outlook

For individuals diagnosed with or at risk for appendix cancer, being informed is essential. Advocacy for timely diagnosis, accurate classification, and access to specialized care at high-volume centers can greatly improve outcomes.

With continued research and awareness, patients have more opportunities for personalized, effective treatment and improved long-term survival.

References

1. Osueni, A., & Chowdhury, Y. S. (2023). Appendix cancer. In StatPearls [Internet]. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK555943/
2. Shaib, W.L., Assi, R., Shamseddine, A., Alese, O.B., Staley III, C., Memis, B., Adsay, V., Bekaii‐Saab, T. and El‐Rayes, B.F. (2017). Appendiceal mucinous neoplasms: diagnosis and management. The oncologist, 22(9), 1107-1116. DOI: 10.1634/theoncologist.2017-0081, https://academic.oup.com/oncolo/article/22/9/1107/6444557
3. Ruoff, C., Hanna, L., Zhi, W., Shahzad, G., Gotlieb, V., & Saif, M. W. (2011). Cancers of the appendix: review of the literatures. International Scholarly Research Notices, 2011(1), 728579. DOI: 10.5402/2011/728579
4. Kelly, K. J. (2015). Management of appendix cancer. Clinics in colon and rectal surgery, 28(04), 247-255. DOI: 10.1055/s-0035-1564433, https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0035-1564433
5. Zambrano-Lechuga, M. R., Galicia-Torres, J. L., & Alvarado-Rueda, Y. D. (2025). Mucinous appendiceal neoplasms. Surgery Open Digestive Advance, 19, 100201. DOI: 10.1016/j.soda.2025.100201, https://www.sciencedirect.com/science/article/pii/S2667008925000138
6. Strach, M. C., Sutherland, S., Horvath, L. G., & Mahon, K. (2022). The role of chemotherapy in the treatment of advanced appendiceal cancers: summary of the literature and future directions. Therapeutic Advances in Medical Oncology, 14, 17588359221112478. DOI: 10.1177/17588359221112478, https://journals.sagepub.com/doi/10.1177/17588359221112478

Further Reading

• All Appendix Content
• What is the Appendix?
• Why do Humans Have an Appendix?
• Appendix Cancer - Pseudomyxoma Peritonei (PMP)
• Appendicitis in Children