Appendiceal Mucinous Neoplasm

Low grade appendiceal mucinous neoplasm (LAMN) is a mucin producing epithelial tumour of the appendix with low grade cytological atypia, pushing (non-destructive) invasion, a villiform or undulating architecture and loss of the muscularis mucosae. Perforation or leakage of cellular mucin can lead to pseudomyxoma peritonei (mucinous ascites and peritoneal deposits).

It is found in 0.2% to 0.3% of appendicectomy specimens, with an incidence of about 0.2 to 0.4 cases in 100,000 people each year. Median age at diagnosis is 55 to 60, with a slight female predominance.

KRAS (about 50% to 60%) and GNAS (about 30% to 70%) mutations are frequent. Synchronous colorectal neoplasms occur in 10% to 20%, and ovarian mucinous tumours occur in women with peritoneal disease.

Pathophysiology. Obstruction of the appendiceal lumen causes mucin accumulation and dilatation (mucocele). Wall rupture spills epithelial cells that implant on the peritoneum and produce mucin, causing pseudomyxoma peritonei, which progresses locally and rarely metastasises to lymph nodes or distant organs.

Prognosis. Tumours confined to the appendix without rupture have an excellent outcome (over 95% 5-year survival after complete resection). Pseudomyxoma peritonei from low grade disease has 10-year survival of about 60% to 80% after complete cytoreduction.

• Frequently asymptomatic and found incidentally on imaging, at appendicectomy or during gynaecological surgery.
• Right iliac fossa pain or an acute appendicitis picture, or a palpable mass.
• Abdominal distension (jelly belly), early satiety, hernia and ovarian masses in pseudomyxoma peritonei.
• Intussusception in rare cases.

Red flags.

• Perforation, mucin on the serosa, or abdominal distension from mucinous ascites.
• Bowel obstruction.

• CT (and MRI) of the abdomen and pelvis: a cystic, dilated appendix (often over 15 mm), mural calcification, and mucinous ascites, scalloping of liver and spleen surfaces and omental disease in pseudomyxoma peritonei.
• Histology of the appendicectomy specimen, with documentation of margins (base), perforation, acellular or cellular mucin outside the appendix, and grade. The whole appendix is submitted for examination.
• CEA, CA 19-9 and CA 125 (often raised in pseudomyxoma). Colonoscopy to exclude synchronous neoplasia.
• Diagnostic laparoscopy when imaging shows peritoneal disease, with peritoneal cancer index scoring.

Differential diagnosis.

• Appendiceal mucocele from obstruction (retention cyst) and mucosal hyperplasia
• High grade appendiceal mucinous neoplasm and mucinous adenocarcinoma
• Ovarian mucinous tumour and appendiceal diverticulum
• Acute appendicitis and Crohn disease of the ileocaecal region

Management depends on whether the tumour is confined and whether it has ruptured.

Confined tumour (no perforation, no mucin outside the appendix, clear margin).

• Appendicectomy alone is curative. Right hemicolectomy is not needed, and lymph node dissection is not required.
• Follow up imaging for 2 to 5 years.

Positive base margin. Further surgery (caecal resection or right hemicolectomy) is needed to achieve clear margins, followed by surveillance.

Acellular mucin on the serosa or in the peritoneum. Surveillance with CT or MRI and tumour markers, because the risk of progression is low. Some centres perform laparoscopic washout.

Cellular mucin outside the appendix or established pseudomyxoma peritonei. Referral to a peritoneal malignancy centre for cytoreductive surgery (peritonectomy and organ resections as needed) with heated intraperitoneal chemotherapy.

Mitomycin 30 mg/m2 in 3 to 5 L of heated carrier solution (41 to 43 C) by intraperitoneal perfusion for 90 minutes, once at the time of complete cytoreduction. Maximum 35 mg/m2 for the single perfusion.

Monitoring: FBC daily for the first week and again at 3 to 4 weeks (delayed nadir), creatinine, urine output, liver tests, signs of haemolytic uraemic syndrome.

Adjustment:

• reduce by 25% to 50% in frail patients, after extensive previous pelvic radiotherapy or when creatinine clearance is under 50 mL/min
• avoid when creatinine clearance is under 30 mL/min
• give intravenous hydration and keep urine output over 1 mL/kg/h

Systemic chemotherapy. Has limited effect in low grade disease and is not used routinely.

Regimens for colorectal cancer are used for disease that cannot be resected, with modest benefit.

Oxaliplatin 85 mg/m2 IV over 2 hours on day 1, levoleucovorin 200 mg/m2 (or leucovorin 400 mg/m2) IV over 2 hours on day 1 and fluorouracil 400 mg/m2 IV bolus on day 1 followed by 2400 mg/m2 by continuous infusion over 46 hours. This is given every 14 days for 12 cycles after resection or until progression in advanced disease. Maximum oxaliplatin cumulative 850 mg/m2 because of cumulative neuropathy.

Monitoring: FBC, creatinine, liver tests, neuropathy and cold sensitivity, mucositis, diarrhoea, DPYD genotype before starting.

Adjustment:

• reduce oxaliplatin to 65 mg/m2 for persistent grade 2 neuropathy and stop for grade 3
• reduce fluorouracil by 20% after grade 3 mucositis or diarrhoea
• use oxaliplatin 65 mg/m2 when creatinine clearance is 30 to 50 mL/min and avoid under 30 mL/min
• delay for neutrophils under 1.0 x 10^9/L or platelets under 75 x 10^9/L

Supportive care. Nutrition, bowel obstruction management and repeat surgery for recurrence.

Monitoring. Yearly CT or MRI and tumour markers for 5 years (and up to 10 years after cytoreduction). Colonoscopy at diagnosis and every 3 to 5 years.

Referral and escalation.

• Referral to a peritoneal malignancy centre for any rupture, cellular mucin or pseudomyxoma peritonei.
• Same day assessment for obstruction or perforation.

Special groups.

• Women: ovarian examination and imaging, with oophorectomy where ovarian involvement is found.
• Pregnancy: surgery in the second trimester if symptomatic.
• Older adults: appendicectomy and surveillance for confined disease.