Primary Peritoneal Carcinoma

Primary peritoneal carcinoma is a malignancy of the peritoneum that is histologically indistinguishable from high grade serous ovarian carcinoma. It arises with normal sized or minimally involved ovaries. It occurs almost exclusively in women, with a median age of 60 to 65 years. It accounts for 10 to 15 percent of what was classified as ovarian cancer.

It arises from the peritoneal mesothelium and Müllerian remnants (secondary Müllerian system). It can also arise from the fimbrial end of the fallopian tube (serous tubal intraepithelial carcinoma) that exfoliates onto the peritoneum.

It is linked to BRCA1 and BRCA2 mutations (risk persists after prophylactic bilateral salpingo oophorectomy at about 1 to 4 percent) and to Lynch syndrome.

Pathological criteria:

• Ovaries are normal in size or enlarged by benign process.
• Ovarian involvement is absent or limited to surface (below 5 x 5 mm) or cortical involvement below 5 x 5 mm.
• The histology is serous.

Presentation is at an advanced stage (stage III to IV) in over 90 percent, with peritoneal carcinomatosis, ascites and omental cake.

• Abdominal distension, bloating, early satiety, abdominal pain, nausea, change in bowel habit.
• Ascites (over 70 percent), weight loss, fatigue, and rarely pleural effusion with dyspnoea.
• Bowel obstruction in advanced disease; umbilical (Sister Mary Joseph) nodule.
• Examination: ascites, omental mass, fixed pelvic nodularity; normal sized ovaries.
• Persistent symptoms for over 12 times a month in women above 50 years must prompt investigation.

• CT chest, abdomen and pelvis with contrast: ascites, peritoneal and omental thickening or caking, normal sized ovaries; MRI or PET-CT in uncertain cases.
• CA-125 markedly raised (often over 500 U/mL); CEA and CA 19-9 to exclude gastrointestinal primaries.
• Cytology of ascitic fluid shows adenocarcinoma cells (psammoma bodies); immunohistochemistry: PAX8, WT1, p53 (mutant pattern in about 95 percent), p16, oestrogen receptor positive, and CK7 positive CK20 negative, which separates it from gastrointestinal metastasis; calretinin and mesothelin help to distinguish from mesothelioma, which is calretinin and WT1 positive but PAX8 negative.
• Image guided or laparoscopic biopsy of the peritoneum or omentum to obtain tissue for histology, immunostaining and molecular testing, before neoadjuvant chemotherapy. Laparoscopic assessment of disease distribution using a scoring system for resectability (Fagotti score above 8 predicts incomplete cytoreduction).
• Germline BRCA1 and BRCA2 testing, tumour BRCA testing, and homologous recombination deficiency testing; mismatch repair testing.

Treatment follows the principles of advanced high grade serous ovarian cancer.

• Primary cytoreductive surgery (when resectable and the patient is fit): total hysterectomy, bilateral salpingo oophorectomy, omentectomy, peritonectomy, and resection of involved bowel and diaphragmatic disease. The aim is no residual macroscopic disease, which is the strongest prognostic factor.
• Neoadjuvant chemotherapy for patients with unresectable disease or poor performance status: carboplatin AUC 5 to 6 with paclitaxel 175 mg/m2 intravenously over 3 hours every 21 days for 3 to 4 cycles, interval cytoreduction surgery, then 3 more cycles. Give dexamethasone 20 mg, chlorphenamine 10 mg and ranitidine or famotidine before paclitaxel to prevent hypersensitivity.
• Adjuvant chemotherapy for 6 cycles total of carboplatin and paclitaxel (a weekly dose dense schedule with paclitaxel 80 mg/m2 on days 1, 8 and 15 may be used). Add bevacizumab 15 mg/kg every 3 weeks for high risk (stage IV or suboptimal debulking) disease, for 15 months in all.
• Intraperitoneal chemotherapy with hyperthermia (HIPEC) at interval surgery: cisplatin 100 mg/m2 for 90 minutes has shown survival benefit at specialised centres.
• Maintenance with PARP inhibitors after response to platinum:
  • Olaparib 300 mg twice daily for 2 years in BRCA-mutated tumours.
  • Niraparib 200 to 300 mg daily irrespective of BRCA status (dose according to weight and platelet count).
  • Combination of olaparib with bevacizumab in HRD-positive tumours.
  • Monitor blood counts for anaemia, thrombocytopenia and myelodysplasia.
• Relapse, platinum sensitive (more than 6 months from platinum): repeat platinum based doublets (carboplatin with gemcitabine, paclitaxel or pegylated liposomal doxorubicin), with bevacizumab. Consider secondary cytoreduction in selected patients.
• Relapse, platinum resistant: single agent weekly paclitaxel 80 mg/m2, pegylated liposomal doxorubicin 40 mg/m2 every 4 weeks, topotecan 1.25 mg/m2 on days 1 to 5 every 21 days, or gemcitabine. Add bevacizumab 10 mg/kg every 2 weeks to chemotherapy. Use mirvetuximab soravtansine for folate receptor alpha high disease.
• Palliation: paracentesis with drain for ascites, and management of bowel obstruction (decompression, venting gastrostomy, octreotide 100 to 300 micrograms subcutaneously twice daily, dexamethasone, and antiemetics). Involve palliative care early.
• Surveillance: clinical examination and CA-125 every 3 months for 2 years, then every 6 months; imaging for suspected relapse.
• Genetic counselling and cascade testing of relatives. Risk reducing salpingo oophorectomy for BRCA carriers (age 35 to 40 for BRCA1, 40 to 45 for BRCA2) does not entirely eliminate risk.
• Median survival is 24 to 40 months, and 5-year survival is about 20 to 30 percent, similar to stage III ovarian cancer. BRCA-mutated disease has a better response to platinum and PARP inhibitors.