High-grade Appendiceal Mucinous Neoplasm

High grade appendiceal mucinous neoplasm (HAMN) is a mucin producing appendiceal tumour with the architecture of a low grade appendiceal mucinous neoplasm (non-destructive, pushing invasion) but with high grade cytological atypia (nuclear enlargement, hyperchromasia, loss of polarity, mitoses). It has a higher risk of recurrence and peritoneal spread than the low grade type, and sits between a low grade neoplasm and invasive mucinous adenocarcinoma.

It is uncommon: it forms a small proportion of appendiceal mucinous neoplasms (about 5% to 20%), with an incidence of under 0.1 cases in 100,000 people each year. Median age at diagnosis is 55 to 65, with a slight female predominance.

KRAS and GNAS mutations are common, with TP53 mutation, SMAD4 loss and other changes in higher grade tumours. Synchronous colorectal neoplasms occur in 10% to 20%.

Pathophysiology. As with the low grade type, obstruction and mucin accumulation lead to wall rupture and peritoneal implantation, but the cells are more proliferative, so pseudomyxoma peritonei is more aggressive and nodal metastasis is more frequent.

Prognosis. Outcomes are good for confined tumours with clear margins. In pseudomyxoma peritonei from high grade disease, 5-year survival after complete cytoreduction and chemotherapy is about 30% to 60%, lower than for low grade disease.

• Often asymptomatic and found at appendicectomy or on imaging.
• Right iliac fossa pain, an appendicitis picture, or a mass.
• Abdominal distension, ascites, ovarian masses and bowel obstruction in pseudomyxoma peritonei.

Red flags.

• Perforation with mucin deposits, rapid distension, or obstruction.
• Weight loss and cachexia with peritoneal disease.

• CT and MRI of the abdomen and pelvis for a dilated, thick walled or irregular appendix, mucin, nodal and peritoneal disease.
• Histology of the whole appendix with documentation of high grade cytology, margins, perforation, mucin outside the appendix (acellular or cellular), nodal status and any invasive component (which would change the diagnosis to adenocarcinoma).
• CEA, CA 19-9 and CA 125, colonoscopy, and mismatch repair testing.
• Diagnostic laparoscopy with peritoneal cancer index when peritoneal disease is suspected.

Differential diagnosis.

• Low grade appendiceal mucinous neoplasm
• Mucinous adenocarcinoma of the appendix (destructive invasion) and goblet cell adenocarcinoma
• Ovarian mucinous tumour and colorectal mucinous adenocarcinoma

Management is individualised and more radical than for low grade tumours.

Confined tumour with clear margins. Appendicectomy with careful pathological review. Right hemicolectomy is considered by many centres because of nodal risk and the potential for high grade progression, particularly with any doubt about invasion.

Positive margin or perforation. Right hemicolectomy with lymph node dissection.

Peritoneal disease. Cytoreductive surgery with heated intraperitoneal chemotherapy at a peritoneal malignancy centre.

Mitomycin 30 mg/m2 in 3 to 5 L of heated carrier solution (41 to 43 C) is given by intraperitoneal perfusion for 90 minutes, once at the time of complete cytoreduction. The maximum is 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. Considered for high grade pseudomyxoma peritonei, nodal disease, or before and after cytoreduction in selected patients.

Regimen: 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. The maximum oxaliplatin cumulative dose is 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, stoma care and early palliative care for unresectable disease.

Monitoring. CT or MRI and tumour markers every 3 to 6 months for 2 years, then every 6 to 12 months for at least 5 years. Colonoscopy at diagnosis and then every 3 to 5 years.

Referral and escalation.

• Referral to a peritoneal malignancy centre for any suspicion of high grade disease, rupture or peritoneal involvement.
• Same day assessment for obstruction or perforation.

Special groups.

• Women: ovarian assessment and oophorectomy where involved.
• Older adults and frail patients: limited resection and surveillance, or systemic therapy alone.
• Pregnancy: individualised planning with the obstetric team.