Appendiceal Adenocarcinoma

Appendiceal adenocarcinoma is a primary malignant epithelial tumor of the appendix. It is rare, with an incidence of about 1 per million a year, but rising in younger adults. The mean age at diagnosis is about 50 to 60 years.

Histological types

• Mucinous adenocarcinoma (the commonest): produces mucin and can cause pseudomyxoma peritonei
• Colonic-type adenocarcinoma: resembles colon cancer with a KRAS or BRAF mutation, and behaves in the same way
• Goblet cell adenocarcinoma: formerly goblet cell carcinoid, a mixed tumor with a distinct growth pattern
• Signet ring cell adenocarcinoma: the worst prognosis

Mechanisms: spread is by direct extension, through the peritoneum (the dominant pattern in mucinous disease) and by lymphatics (more common in colonic-type disease). Hematogenous liver metastases are less common. The disease is often found after appendectomy for appendicitis or an imaging mass.

Prognosis depends on histology and stage: 5-year survival is about 80% for localized well-differentiated disease, and under 20% for poorly differentiated or signet ring disease with peritoneal spread. Complications: perforation, peritoneal dissemination, bowel obstruction and fistula.

• Acute appendicitis (about half of cases), a right iliac fossa mass, or an incidental finding
• Abdominal distension, ascites and weight loss in advanced disease
• Ovarian mass in women, from metastasis
• Anemia, change in bowel habit and obstruction when the cecum is involved
• Red flags: perforation with a mass, ascites, gelatinous ascites, and a mass in the pelvis

1. Histopathology after appendectomy with grade, depth of invasion, margin status, lymphovascular invasion, nodal status and mucin extension.
2. CT of the chest, abdomen and pelvis with intravenous contrast for staging, to identify peritoneal disease, nodes and liver metastases.
3. MRI of the abdomen for peritoneal evaluation and liver lesions.
4. Colonoscopy to exclude synchronous colonic neoplasm.
5. Tumor markers: carcinoembryonic antigen, CA 19-9 and CA 125 for baseline and follow-up.
6. Molecular testing: KRAS, NRAS, BRAF and mismatch repair status.

Differentials: appendiceal neuroendocrine tumor, low grade mucinous neoplasm, cecal carcinoma, ovarian carcinoma, lymphoma, Crohn disease.

1. Localized disease: right hemicolectomy with removal of at least 12 lymph nodes, even after an appendectomy that showed adenocarcinoma, since nodal disease occurs in about 10 to 30%.
2. Peritoneal disease: cytoreductive surgery with heated intraperitoneal chemotherapy in selected patients, with mitomycin C 30 mg/m2 as a single perfusion at 41 to 42 degrees Celsius for 90 minutes.
3. Adjuvant chemotherapy for node-positive or high-risk colonic-type disease, over 3 to 6 months:
   • CAPOX: oxaliplatin 130 mg/m2 IV on day 1 with capecitabine 1000 mg/m2 orally twice daily on days 1 to 14, every 21 days for 8 cycles (24 weeks) or 4 cycles (12 weeks) in lower-risk stage III.
   • FOLFOX: oxaliplatin 85 mg/m2 IV, leucovorin 400 mg/m2 IV, fluorouracil 400 mg/m2 IV bolus then 2400 mg/m2 over 46 hours, every 14 days for 6 to 12 cycles.
   • Test for dihydropyrimidine dehydrogenase deficiency before fluoropyrimidines. Monitor neuropathy, blood count and renal function.
4. Metastatic disease: FOLFOX or FOLFIRI (irinotecan 180 mg/m2 IV on day 1 with leucovorin and fluorouracil) with bevacizumab 5 mg/kg IV every 14 days, or cetuximab 500 mg/m2 IV every 14 days for RAS and BRAF wild-type tumors. Immune checkpoint therapy for mismatch repair deficient tumors: pembrolizumab 200 mg IV every 21 days (or 400 mg every 6 weeks) for up to 2 years.
5. Prophylaxis: cefazolin 2 g IV with metronidazole 500 mg IV as single doses before incision, and enoxaparin 40 mg SC once daily for 28 days after cancer surgery.
6. Follow-up: CT and carcinoembryonic antigen every 3 to 6 months for 2 years, then every 6 months to 5 years, with colonoscopy at 1 year and then every 3 to 5 years.
7. Complications of surgery: anastomotic leak, wound infection, ileus, and for heated intraperitoneal chemotherapy, renal injury and marrow suppression.

Counsel on prognosis, and on genetic testing when the tumor is mismatch repair deficient.