Goblet Cell Adenocarcinoma of the Appendix

Goblet cell adenocarcinoma (formerly goblet cell carcinoid) is a distinct appendiceal tumour composed of tubular clusters of goblet like mucin rich cells with neuroendocrine features. It behaves as an adenocarcinoma, and treatment depends on grade (proportion of adenocarcinoma pattern) and stage, not on the carcinoid type terminology.

Appendiceal tumours have an incidence of about 1 case in 100,000 people each year, and goblet cell adenocarcinoma forms about 10% to 15% of them. Mean age at diagnosis is 50 to 60, with equal sex distribution (women are more likely to present with ovarian metastases).

Risk factors are unclear. It is not linked with carcinoid syndrome. Familial predisposition is rare.

Pathophysiology. Tumours lack the KRAS, GNAS and APC changes of typical appendiceal adenocarcinoma and have alterations in Wnt signalling and chromatin regulators (for example ARID1A, SMAD4, TP53, CDH1 in higher grade). Spread is by local invasion, lymphatic spread (10% to 30%) and, in particular, transcoelomic dissemination to the peritoneum and ovaries.

Grading. Grade 1 (typical: over 75% goblet cell pattern), grade 2 (50% to 75% goblet pattern with a minority of signet ring or adenocarcinoma) and grade 3 (under 50%, or sheets of signet ring or poorly differentiated cells). Grade is the key prognostic feature.

Prognosis. Five year survival is about 90% to 95% for grade 1, 70% to 80% for grade 2 and 30% to 50% for grade 3 disease.

• Acute appendicitis (the commonest presentation), or a right iliac fossa mass.
• Abdominal pain, bloating and change in bowel habit.
• Ovarian mass (women), ascites and peritoneal nodularity from peritoneal disease.
• Often found unexpectedly on histology of an appendicectomy specimen.

Red flags.

• Perforation at presentation with mucin or peritoneal deposits.
• Ovarian mass, ascites or bowel obstruction.

• Histology of the appendicectomy specimen: goblet cell morphology, grade, depth of invasion, perforation, margins, lymphovascular and perineural invasion. Immunohistochemistry: CK20, CDX2, chromogranin A and synaptophysin (variable), with MMR status.
• CT of the chest, abdomen and pelvis (peritoneal disease, ovaries, liver) and MRI when needed. PET is of limited value for low grade mucinous or goblet cell tumours.
• CEA, CA 19-9 and CA 125, FBC and liver tests. Colonoscopy.
• Laparoscopy for staging when imaging is equivocal. Peritoneal cancer index is scored at surgery.

Differential diagnosis.

• Appendiceal neuroendocrine tumour (carcinoid) and appendiceal adenocarcinoma
• Low grade or high grade appendiceal mucinous neoplasm
• Colorectal adenocarcinoma with signet ring cells and metastatic gastric or breast cancer
• Primary ovarian neoplasm

Management follows histologic grade and stage.

Surgery.

• Right hemicolectomy with regional lymph node dissection for all patients after appendicectomy, because nodal involvement is found in 10% to 30%, including grade 1 tumours with invasion beyond the appendix or tumours over 2 cm.
• Prophylactic bilateral salpingo oophorectomy is considered in women past childbearing, because ovarian metastases are frequent.
• Cytoreductive surgery with heated intraperitoneal chemotherapy for peritoneal disease that can be completely removed (peritoneal cancer index low enough for complete cytoreduction): 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.

• Adjuvant therapy for grade 2 or 3 tumours, node positive disease or high risk features: 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, 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
• Advanced or unresectable disease uses the same 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, 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. Nutritional support, management of ascites and bowel obstruction, stoma care, and pain control.

Monitoring. CT every 3 to 6 months for 2 years and then every 6 to 12 months to year 5 (and up to 10 years for grade 2 or 3). CEA and CA 19-9 at each visit, and colonoscopy at 1 year.

Referral and escalation.

• Referral to a peritoneal malignancy centre for all patients with grade 2 or 3 tumours or peritoneal disease.
• Same day assessment for bowel obstruction or perforation.

Special groups.

• Women of reproductive age: fertility counselling before oophorectomy, with surveillance imaging of the ovaries.
• Older adults and frail patients: laparoscopic hemicolectomy and reduced intensity chemotherapy.
• Pregnancy: individualised planning with deferral of chemotherapy.