Appendiceal Cancer: Epidemiology, Pathology, Risk Factors, Symptoms, Diagnosis, Staging and Treatment

Appendiceal Cancer

~Introduction

Appendiceal cancer is a rare malignancy originating from the vermiform appendix, a narrow, finger-like pouch attached to the cecum in the right lower abdomen. Although historically considered similar to colorectal cancers, appendiceal malignancies are now recognized as distinct tumors with unique biological behaviors, histological subtypes, and treatment pathways.

This cancer accounts for less than 1% of all gastrointestinal neoplasms, but incidence rates are slowly increasing, partly due to improved imaging and more frequent appendectomies. Because the appendix is small and symptoms are subtle, many tumors remain undiagnosed until they present as acute appendicitis, are found incidentally during surgery, or spread within the peritoneum.

~Epidemiology

• Incidence: ~1–2 cases per 1 million people annually

• Slight female predominance for mucinous tumors

• More common between ages 30–60 years, depending upon subtype

• Often discovered incidentally in appendectomy specimens or during imaging for abdominal pain

~Pathology and Classification

Appendiceal cancers are heterogeneous. The major categories include:

1. Appendiceal Adenocarcinoma

Arises from glandular epithelium, similar to colorectal adenocarcinoma.

Subtypes:

• Mucinous adenocarcinoma

• Non-mucinous (colonic-type) adenocarcinoma

• Signet-ring cell adenocarcinoma (aggressive)

2. Neuroendocrine Tumors (NETs)

Also called carcinoid tumors, arise from neuroendocrine cells.
These are the most common appendiceal tumors, usually low grade and found incidentally.

3. Goblet Cell Adenocarcinoma (GCA)

Hybrid tumor with both neuroendocrine and adenocarcinoma features.
Intermediate aggressiveness.

4. High-Grade and Low-Grade Appendiceal Mucinous Neoplasms (HAMN & LAMN)

Produce mucin and are associated with pseudomyxoma peritonei (PMP).

5. Pseudomyxoma Peritonei (PMP)

Though not a primary cancer itself, PMP results from mucin-producing appendiceal tumors rupturing and spreading mucus-producing cells throughout the abdomen.

~Risk Factors

Although the exact causes are unknown, certain factors increase risk:

• Genetic syndromes:

  • Lynch syndrome

  • Familial adenomatous polyposis (rare association)

• Chronic inflammation

• Smoking and alcohol use

• Prior pelvic radiation therapy

• Age: Higher risk in older adults

Unlike colorectal cancer, dietary factors play a less clear role.

~Clinical Presentation

Appendiceal cancer is challenging to diagnose because early-stage disease produces minimal symptoms.

Common Signs and Symptoms

1. Right lower abdominal pain

   • Often mimics appendicitis

2. Abdominal distension

   • Especially in mucinous tumors

3. New-onset hernia

   • Caused by mucin accumulation

4. Unexplained weight loss

5. Changes in bowel habits

6. Nausea or vomiting

Symptoms of Advanced Disease

• Ascites or mucinous fluid buildup

• Pseudomyxoma peritonei with “jelly belly”

• Obstruction of the intestines

Up to 50% of cases present as acute appendicitis, leading to incidental discovery during appendectomy.

~Diagnosis

1. Laboratory Tests

• CBC: may show anemia

• Tumor markers: CEA, CA 19-9, CA-125 (especially in mucinous tumors)

• Hormonal markers for NETs: serotonin, chromogranin A

2. Imaging

CT Scan

• Best initial modality

• Can detect masses, mucin deposits, or perforation

MRI

• Useful for evaluating mucinous disease

• Helps map peritoneal spread

Ultrasound

• Sometimes identifies mass during appendicitis evaluation

3. Colonoscopy

• Performed after diagnosis to rule out synchronous colorectal tumors

4. Histopathology

Tumor tissue confirms the diagnosis. Pathologist evaluates:

• Grade

• Lymphovascular invasion

• Margins

• Perforation

5. Diagnostic Laparoscopy

Sometimes needed to evaluate peritoneal metastases.

~Staging

Appendiceal cancers are staged using the TNM staging system, although specifics vary by subtype.

Key Factors Considered

• Tumor invasion into appendix wall

• Lymph node involvement

• Peritoneal dissemination

• Distant metastasis

Pseudomyxoma peritonei is staged separately due to its unique behavior.

~Treatment

Treatment varies significantly by tumor type, grade, and extent of disease.

1. Surgery (Primary Treatment)

Appendectomy

• Suitable for small, localized tumors

• Often adequate for NETs <2 cm

Right Hemicolectomy

Recommended for:

• Adenocarcinoma

• Goblet cell adenocarcinoma

• NETs >2 cm or involving mesoappendix

• Tumors with positive margins

Cytoreductive Surgery (CRS) + HIPEC

Used for pseudomyxoma peritonei and peritoneal metastasis.

CRS: removes all visible tumors
HIPEC: heated intraperitoneal chemotherapy, typically mitomycin C or oxaliplatin

This approach is one of the major advances in appendiceal tumor treatment and can significantly improve survival.

2. Systemic Chemotherapy

For Non-Mucinous Adenocarcinoma

Regimens similar to colorectal cancer:

• FOLFOX

• CAPOX

• FOLFIRI

For High-Grade or Metastatic Tumors

• Combination chemotherapy

• Targeted therapy in select cases

For Goblet Cell Adenocarcinoma

• Often treated like colorectal cancer

• Responds better to systemic chemotherapy compared to pure NETs

For Neuroendocrine Tumors

• Somatostatin analogs

• Targeted therapy (everolimus, sunitinib for advanced disease)

3. Radiation Therapy

Rarely used due to limited benefit
May help with:

• Pain control

• Local treatment of metastatic lesions

~Complications

Patients with appendiceal cancer may experience:

1. Perforation

Tumor rupture leading to mucin spread

2. Pseudomyxoma Peritonei

Causes:

• Massive abdominal distension

• Bowel dysfunction

• Recurrent fluid accumulation

3. Intestinal Obstruction

From tumor mass or mucin deposits

4. Metastasis

Common sites:

• Peritoneum

• Liver

• Ovaries

• Lymph nodes

~Prognosis

Prognosis varies widely by tumor subtype and stage.

Survival Rates by Subtype

Neuroendocrine Tumors

• Excellent prognosis

• 5-year survival: 80–90%

Low-Grade Mucinous Tumors

• Good long-term survival with CRS + HIPEC

• 5-year survival: 60–90%

High-Grade Mucinous Adenocarcinoma

• More aggressive

• 5-year survival: 40–60%

Non-Mucinous Adenocarcinoma

• Similar to colon cancer

• 5-year survival: 50–70% (localized)

Signet-Ring Cell Carcinoma

• Very poor prognosis

• High metastatic potential

• 5-year survival: <20%

~Follow-Up and Surveillance

Survivors require long-term monitoring.

Surveillance Includes:

• CT scan every 6–12 months

• Tumor markers (CEA, CA 19-9)

• Physical examination

• Colonoscopy at regular intervals

• Monitoring for recurrence or progression of PMP

~Recent Advances and Research

1. Genomic Profiling

Identification of biomarkers such as:

• KRAS

• GNAS

• TP53

• BRAF

Helps tailor targeted therapy.

2. Advancements in HIPEC

Improved techniques and drug combinations have enhanced outcomes in PMP.

3. Immunotherapy

Still under investigation
Potential benefit in MSI-high tumors

4. Personalized Treatment Approaches

Multidisciplinary tumor boards guide individualized patient care.

~Conclusion

Appendiceal cancer, though rare, encompasses a wide spectrum of tumors with diverse clinical and pathological behavior. Early diagnosis remains challenging because symptoms are often nonspecific or mimic appendicitis. Surgical resection is the cornerstone of treatment, with appendectomy, right hemicolectomy, or cytoreductive surgery plus HIPEC depending on tumor type and stage. Systemic therapies, including chemotherapy and targeted treatments, offer benefits in advanced or aggressive disease.

Ongoing research in molecular genetics, immunotherapy, and advanced surgical techniques continues to improve survival and quality of life. Because appendiceal cancers are unique entities, timely evaluation by specialists and individualized treatment plans play critical roles in achieving the best outcomes.