Peritoneal Mesothelioma

Peritoneal mesothelioma is a malignant tumour of the peritoneal mesothelium that spreads across the peritoneal surfaces with ascites and little invasion of organs. Without treatment survival is about 12 months, but selected patients with epithelioid disease treated by complete cytoreduction and heated intraperitoneal chemotherapy can survive for years.

It forms 10% to 20% of mesotheliomas, with about 1 to 2 cases in 1,000,000 people each year in some countries. The male to female ratio is lower than for the pleural disease (about 1 to 1.5). Median age is about 50 to 60, and it also occurs in young women.

Asbestos exposure is found in about 30% to 50% of cases, less than in pleural mesothelioma. Other associations are prior abdominal radiotherapy, germline BAP1 variants, chronic peritoneal inflammation (for example recurrent serositis in familial Mediterranean fever) and erionite exposure. Many women have no exposure.

Pathophysiology. Fibres reach the peritoneum through the lymphatics and cause chronic inflammation, as with the pleura. BAP1 inactivation, CDKN2A loss and NF2 variants are frequent. Tumour cells seed the peritoneum and spread along its surface.

Histological subtypes. Epithelioid (75% to 90%) is commonest. Biphasic and sarcomatoid subtypes are aggressive. Well differentiated papillary mesothelioma and multicystic mesothelioma are low grade and rarely invasive but recur.

Prognosis. After complete cytoreduction with heated intraperitoneal chemotherapy, 5-year survival is about 40% to 60% in selected epithelioid patients. Sarcomatoid histology, high Ki-67, nodal involvement, extensive peritoneal disease and incomplete cytoreduction worsen survival.

• Abdominal distension, pain, early satiety and weight loss over weeks to months.
• Ascites (dry type with nodular masses in some), fever, night sweats and fatigue.
• Umbilical or inguinal hernia containing tumour, bowel obstruction, thrombocytosis and a palpable abdominal mass.
• Tumour may be found incidentally during surgery for hernia or appendicitis.

Red flags.

• Bowel obstruction or perforation.
• Venous thromboembolism, which is frequent.
• Rapidly recurrent ascites causing respiratory compromise.

• CT of the abdomen and pelvis with oral and intravenous contrast: ascites, omental caking, nodular peritoneal thickening and small bowel serosal disease, often without a primary mass. MRI helps assess the small bowel and mesentery. CT of the chest for staging.
• Ascitic fluid cytology has low sensitivity. Laparoscopic biopsy of several peritoneal sites gives the diagnosis and the peritoneal cancer index, which measures disease extent (0 to 39).
• Immunohistochemistry: calretinin, WT1, cytokeratin 5/6 and D2-40 positive, with negative adenocarcinoma markers (Ber-EP4, MOC31, claudin-4, CEA, PAX8 negative). BAP1 and MTAP loss support malignancy.
• Serum CA-125 may be raised and is not specific. Platelet count, albumin, creatinine and liver tests.
• Staging laparoscopy in surgical candidates, echocardiography and performance assessment.
• Germline BAP1 testing in younger patients and those with a family history.

Differential diagnosis.

• Primary peritoneal and ovarian serous carcinoma
• Peritoneal metastases from gastrointestinal, appendiceal or pancreatic cancer
• Pseudomyxoma peritonei
• Tuberculous peritonitis
• Desmoplastic small round cell tumour and peritoneal sarcomatosis
• Lymphomatosis and cirrhotic ascites

Cytoreductive surgery with heated intraperitoneal chemotherapy. Complete cytoreduction (peritonectomy with resection of involved organs) followed by intraperitoneal perfusion, in specialised centres, for epithelioid or biphasic disease with a peritoneal cancer index below 28, good performance status and no extra-abdominal disease.

• Intraperitoneal perfusion: cisplatin 50 mg/m2 with doxorubicin 15 mg/m2 in 2 to 3 L of heated carrier solution (41 to 43 C) by intraperitoneal perfusion for 90 minutes, once at the time of complete cytoreduction; maximum cisplatin 50 mg/m2 and doxorubicin 15 mg/m2 for the single perfusion; monitoring: creatinine, urine output, potassium, magnesium, sodium and FBC daily after surgery, audiometry, left ventricular ejection fraction when anthracycline exposure is prior; adjustment: omit or reduce cisplatin by 25% to 50% when creatinine clearance is under 60 mL/min, omit doxorubicin when cumulative anthracycline exposure is over 300 mg/m2 or ejection fraction is reduced, give intravenous hydration before and after

Systemic chemotherapy. Preoperative or postoperative chemotherapy for responders, or first line treatment for unresectable disease.

• Cisplatin with pemetrexed: cisplatin 75 mg/m2 IV over 1 to 2 hours with pre-hydration and post-hydration, and pemetrexed 500 mg/m2 IV over 10 minutes, both on day 1 of a 21-day cycle for up to 6 cycles; supplementation: folic acid 400 micrograms orally once daily starting 7 days before the first dose and continuing until 21 days after the last, vitamin B12 1000 micrograms IM starting 1 week before the first dose and repeated every 9 weeks, dexamethasone 4 mg orally twice daily on the day before, the day of and the day after each pemetrexed dose; maximum cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 each cycle; monitoring: FBC, creatinine and electrolytes before each cycle, audiometry, neuropathy symptoms; adjustment: give cisplatin only when creatinine clearance is 60 mL/min or more (substitute carboplatin AUC 5 IV on day 1 when it is lower), give pemetrexed only when clearance is 45 mL/min or more, stop NSAIDs from 2 days before to 2 days after each pemetrexed dose, hold for neutrophils under 1.0 x 10^9/L or platelets under 75 x 10^9/L and resume at 75% of the dose
• Nivolumab with ipilimumab (non-epithelioid disease, and an option for epithelioid disease): nivolumab 360 mg IV every 3 weeks with ipilimumab 1 mg/kg IV every 6 weeks, for up to 24 months or until progression or unacceptable toxicity; maximum nivolumab 360 mg each 3-week dose and ipilimumab 1 mg/kg each 6-week dose; monitoring: thyroid function, liver tests, creatinine, glucose and morning cortisol before each dose, symptoms of colitis, pneumonitis and hypophysitis; adjustment: no renal or mild hepatic dose adjustment, withhold for grade 2 immune toxicity and give prednisolone 0.5 to 1 mg/kg daily, stop permanently for grade 3 to 4 toxicity and give prednisolone 1 to 2 mg/kg daily tapered over at least 4 to 6 weeks

Palliation. Paracentesis for tense ascites, or a tunnelled peritoneal catheter for recurrent ascites. Nutrition support, bowel obstruction management and early palliative care.

Low grade variants. Well differentiated papillary mesothelioma and multicystic mesothelioma are managed by complete excision, with follow up for recurrence.

Monitoring. CT of the abdomen and pelvis every 3 months for 2 years, then every 6 months to year 5. Albumin, platelets and creatinine at each visit.

Referral and escalation.

• Referral to a mesothelioma or peritoneal malignancy centre on suspicion, before any operation.
• Urgent admission for bowel obstruction, perforation or sepsis.
• Notification of asbestos exposure where required.

Special groups.

• Women of childbearing age: discuss fertility and avoidance of pregnancy during treatment.
• Older adults: palliative systemic therapy or supportive care when surgery is not tolerable.
• Renal impairment: carboplatin replaces cisplatin, and pemetrexed is avoided under 45 mL/min.
• Known BAP1 carriers: surveillance for uveal melanoma, cutaneous melanoma and renal cancer.