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A detailed look at pseudomyxoma peritonei
What is it?
Pseudomyxoma peritonei (PMP) is often a slowly progressive disease that produces extensive mucus accumulation within the abdomen and pelvis.
There are two clinically distinct groups of peritoneal mucinous lesions. The first can be described as low-grade mucinous carcinoma peritonei (MCP-L), which would include mucin producing disease from an appendiceal adenoma to a well-differentiated mucinous carcinomatosis or well-differentiated variants of mucinous adenocarcinomas. The second group can be described as high-grade mucinous carcinoma peritonei (MCP-H) and would apply to either moderately or poorly differentiated adenocarcinomas.
In PMP, an adenoma arises within the appendix and as it grows it occludes the lumen of the appendix. This can be classified as a low-grade appendiceal mucinous neoplasm (LAMN). If the diagnosis is made before the appendix ruptures and the mucin created is contained within it, this is termed a LAMN 1 lesion. If the appendix ruptures leaking mucous containing epithelial cells into the abdominal cavity leading to low-grade mucinous carcinoma peritonei, this is termed a LAMN 2 lesion. After the appendix decompresses the perforation may reseal only to extrude more adenomatous epithelial cells at a later time.
Sometimes neither a primary appendiceal tumour nor a normal appendix is apparent. In these cases it may be that the appendix has ruptured and has been obliterated by the developing fibrosis. PMP is often referred to as being a 'borderline malignant' condition. The tumour is not biologically aggressive because it does not metastasise via the lymphatics or blood stream like gastrointestinal adenocarcinomas, however, it can still be a fatal process. The space required within the abdomen and pelvis for normal nutritional function eventually becomes replaced by mucinous tumour.
Most of these tumour cells are surrounded by fluid of varying consistency. Bulky cellular deposits are usually found within the omentum and beneath the right hemidiaphragm. Gravity creates a further accumulation of adenomucinous cells within the pelvis where the peritoneum reflects over the pelvic organs.
Common sites involved in tumour dispersion also include the stomach, the area around the terminal ileum and the recto-sigmoid colon within the pelvis. All three of these sites are fixed to the retroperitoneum and are not free to move as a result of peristaltic activity. The peristaltic activity of the small bowel may prevent mucinous tumour implantation on these surfaces resulting in relative sparing of the small bowel.
What causes PMP?
For the majority of people with true PMP, an adenoma is found in the appendix. Like many other tumours, PMP can occur in people who lead healthy lifestyles. There is no known inheritance pattern with PMP.
Signs and symptoms
For women and men the most predominant feature is a gradual increase in abdominal girth. This increases pressure on the gut and prevents the patient from eating normally. Despite this, the patient often notes an increase in body weight. The symptoms can be non-specific and are often misdiagnosed as irritable bowel and ovarian neoplasia in women.
How is it diagnosed?
The diagnosis of PMP can be difficult. It is often an unexpected finding during investigations of non-specific abdominal symptoms, either on USS/CT scan or when the patient has undergone an abdominal operation. The diagnosis of PMP can be confused with mucinous tumours that can arise in the gastrointestinal tract, gallbladder and in the ovaries.
Women with both low-grade mucinous carcinoma peritonei and high-grade mucinous carcinoma peritonei often have ovarian involvement by mucinous tumour. The ovarian tumour is often the presenting clinical symptom or sign and is often assumed to be the primary site, therefore no attempt is made to identify the appendix as a possible source of mucinous tumour.
In some cases the primary tumour in the appendix can be quite inconspicuous in the context of abundant mucinous peritoneal tumour and may only be diagnosed during the process of dealing with another abdominal condition. For instance it is not uncommon to identify the presence of mucin during a routine hernia repair operation. In addition, rupture and fibrosis can obliterate the appendix. Other problems are that ovarian tumours are often interpreted pathologically as primary mucinous borderline malignant tumours. This happens particularly when the appendix has not been removed, but even occurs when an appendiceal adenoma is identified.
This depends upon the level of disease present:
If there is just an abnormality contained within the appendix without any evidence of rupture this is classified as a LAMN 1 and we would normally just monitor the situation carefully over a number of years with episodic scans (CT scan) and blood tests.
The abnormality within the appendix has generated enough mucin to cause the appendix to rupture - although the amount of mucin outside the appendix is only visible microscopically. In this situation we offer to either keep the patient under regular review (Watch and Wait) or offer a "risk reducing" operation, which may be done using minimal access/laparoscopic techniques.
This procedure requires the removal of areas that are at risk from the disease:
- Removal of the gall bladder (cholecystectomy)
- Removal of both greater and lesser omentum
- Excision of the umbilicus (tummy button)
- Division of scars created by previous surgery (adhesions)
- Then standard hyperthermic intra-peritonel chemotherapy (90 minutes of Mitomycin C at 41 degrees Celsius) - "HIPEC" is used to reduce the risk of any potentially viable cells remaining.
This is where the appendix tumour has caused rupture of the appendix with widespread dissemination of mucin throughout the abdomen and pelvis. There are two potential approaches in the management of PMP:
1. Watch and Wait - Monitor the situation closely with a combination of repeated scans and blood tests over a number of years.
2. Cytoreductive surgery and HIPEC - Cytoreductive surgery refers to the aggressive removal or destruction of all visible tumours present throughout the peritoneal cavity. Peritonectomy procedures involve stripping the parietal peritoneum and resecting structures at fixed sites that contain adenomucinosis. This can be accomplished by removal or destruction of the tumour using a combination of surgical techniques that include organ resection and tumour destruction using electro-evaporation. The operation may comprise a number of different procedures including:
- Total or Segmental colectomy (right hemi-colectomy, sigmoid colectomy, anterior resection).
- greater omentectomy
- lesser omentectomy
- pelvic peritonectomy, which sometimes includes the rectum by anterior resection and removal of the ovaries and uterus
- stripping of the peritoneum from the left hemidiaphragm
- stripping of the peritoneum from the right hemidiaphragm
- stripping of disease from the surface of the liver
- partial or complete gastrectomy (rarely)
Patients are always warned and counselled about the potential need for stoma formation.
The long-term results depend on the extent to which the tumour can be surgically removed. The smaller the residual tumour deposits, the greater the chance it will respond to chemotherapy. Cytoreductive surgery is an extensive procedure that lasts, on average, more than 10 hours. If complete tumour removal has been possible, intraperitoneal chemotherapy has been given and the tumour is at the benign end of the spectrum, 50-80% will have 10-year disease free survival.
After cytoreduction, HIPEC is administered directly into the peritoneal cavity. The peritoneum-plasma barrier allows for a high concentration of drugs directly to the abdominal and pelvic surfaces where the tumour is located. The chemotherapy used is based on the drug's ability to produce a cytotoxic effect over a short time period (90 minutes in theatre) and to have an increased response with heat. The use of HIPEC after complete dissection of adhesions and before anastomoses are completed, allows optimal perfusion of the chemotherapy to the peritoneal surfaces and organs. Mitomycin C has a slow clearance from the peritoneal cavity. Pharmacokinetic studies of intra-operative intraperitoneal chemotherapy report an absorption of 75-90% of Mitomycin C within the first hour. Heating chemotherapy not only improves drug distribution but also improves the drug cytotoxicity penetration into tissue compared to chemotherapy administration at room temperature.
Evidence for the use of systemic chemotherapy in the management of PMP has yet to be established. However, intestinal type chemotherapy sometimes has beneficial effects if the tumour has features of mucinous adenocarcinoma.
A chemotherapy trial undertaken by The Christie team evaluated drugs for patients unsuitable for cytoreduction. The drugs used were mitomycin C and capcytobine and were relatively well tolerated. One third of patients benefited from the treatment with improved symptoms and stabilisation of mucin production.
Post-operative mortality and morbidity
Risk of death
In the worldwide literature, complete cytoreduction carries a mortality risk of 3%-5%. Our own prospectively collected data (collected since 2002) indicates that we have a mortality risk of less than 1%. The main complications are cardio-respiratory (lung infections and heart failure). There is also a risk of clots in the main leg veins, which can result in pulmonary embolus.
Risk of complication
In the worldwide literature, surgery also has significant morbidity (risk of complication) of around 30%. Our own figures show a risk of significant complication rate of 13.5% (year 2013-2014 data). Approximately 20% of patients require a stoma. A permanent stoma is required if all or most of the colon has to be removed. Our permanent stoma rate is approximately 4%. A temporary stoma is usually used when the rectum has to be removed and anastomosis (re-join) performed. This is because, although appearing intact at the time of surgery, it has a very high risk of leakage due to the particular position of the anastomosis, and the fact that intraperitoneal chemotherapy is used. The temporary stoma is usually closed between 3 and 6 months after the primary operation.
The Colorectal and Peritoneal Oncology Centre
Peritoneal tumours are treated at The Christie by a team that has specialist knowledge and skills in treating patients with these tumours of the abdomen.
Our team of 6 consultants and supporting staff have been treating patients since 2002, and in the last 7 years have seen 465 patients with PMP and operated on 312 (up to April 2014). 264 have had full cytoreduction with HIPEC. In addition to this, we have treated a number of patients with peritoneal metastases from colorectal cancer and in the past year we have been instrumental in establishing this treatment throughout the NHS in England. Last year we operated on 20 patients with this condition and anticipate that over the next 3 years this number will exceed an additional 50 cases per year
Fish R;Selvasekar C;Crichton P;Wilson MS;Fulford PE;Renehan AG;O'Dwyer ST. (2014). Risk-reducing laparoscopic cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for low-grade appendiceal mucinous neoplasm: early outcomes and technique. Surgical Endoscopy.28(1). 341-5.
McDonald, J., O'Dwyer, S., Rout, S., Chakrabarty, B., Sikand, K., Fulford, P., Wilson, M. & Renehan, A (2012). Classification of and cytoreductive surgery for low-grade appendiceal mucinous neoplasms. Br J Surg, 99(7), 987-92. eScholarID:177758 | DOI:10.1002/bjs.8739 [doi]
Farquharson, A, Pranesh, N, Witham, G, Swindell, R, Taylor, M, Renehan, A, Rout, S, Wilson, M, O'Dwyer, S, Saunders, M. (2008). A phase II study evaluating the use of concurrent mitomycin C and capecitabine in patients with advanced unresectable pseudomyxoma peritonei. Br J Cancer, 99( 4), 591-6. eScholarID:1d32623 | DOI:10.1038/sj.bjc.6604522
Bibi R, Pranesh N, Saunders M, Wilson M, O'dwyer S, Stern PL, Renehan A. (2006). A specific cadherin phenotype may characterise the disseminating yet non-metastatic behaviour of pseudomyxoma peritonei. Br J Cancer, 95( 9), 1258-64. eScholarID:1d30911