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Pseudomyxoma peritonei (PMP) is a peritoneal surface disease, characterized by peritoneal tumor lesions that produce mucinous ascites. It is a rare disease with an incidence of approximately 2 per million per year and an unexplained female preponderance. It is now common consensus that PMP is the result of a ruptured appendiceal mucocele containing a low-grade mucinous epithelial neoplasm, mostly a (cyst) adenoma. Primary ovarian tumors have been described, but usually ovarian tumor deposits are metastases from the appendix, as released tumor cells will spread throughout the peritoneal cavity according to the peritoneal fluid current toward predefined regions. The diaphragms and omentum are absorption sites where tumor cells accumulate. Gravity in its turn pulls tumor cells into the pelvis, where they easily adhere on the “sticky” ovarian surface. In the end stage of disease, tumor cells will be spread in all abdominal regions with excessive production of mucus. Intestinal obstruction then becomes inevitable.

A true definition of PMP, however, remains subject to discussion since many different disease entities are used. The most appropriate definition of PMP is a clinical entity consisting of indolent progression of peritoneal tumor lesions, histopathologically characterized as disseminated peritoneal adenomucinosis (DPAM) or low-grade PMP, and mucinous ascites, without signs of invasion, and associated considerable long-term survival. Other histopathological subtypes have been described such as peritoneal mucinous carcinomatosis (PMCA) or high-grade PMP, but these lesions are comparable by both histopathology and prognosis with peritoneal carcinomatosis of colorectal cancer origin.

The clinical entity PMP can be recognized by several symptoms. The most frequently observed symptom is progressive abdominal distension due to the growing amount of mucus produced by the multiplying peritoneal tumor deposits. Other symptoms consist of appendicitis-like complaints (thought to be associated with the appendiceal rupture), mucus in a hernia sac, or an ovarian mass in women. Often PMP is encountered by coincidence on imaging or during laparotomy. In case of mucinous deposits in the peritoneal cavity during diagnostic laparoscopy or celiotomy, the appendix should always be removed and examined. Large surgical resections should be reserved for specialized oncology centers.

The diagnosis of PMP is not only made by the previously described symptoms. The presence of peritoneal tumor lesions and intraperitoneal mucus is obligate with adequate histopathological examination to rule out any other peritoneal diseases that should not be defined as PMP. The characteristic redistribution of peritoneal tumor and mucus is best displayed by abdominal computed tomography. A histopathological diagnosis on the contrary is usually difficult to ascertain preoperatively since adequate cellular samples are hard to obtain by needle biopsy. Laparoscopy might be used for taking biopsy samples in case of early stage disease and no extensive prior abdominal surgery. Serum tumor markers are useful to acquire preoperatively to predict complete resection and as baseline for postoperative monitoring. Immunohistochemical markers have been reported for aiding in the diagnosis. In particular, CK7, CK20, and MUC-2 might differentiate between appendiceal and ovarian origins.

Until now there has been no standard treatment for PMP. Traditional treatment consists of limited palliative surgical debulking with occasionally adjuvant (intraperitoneal) chemotherapy or radiotherapy, depending on the tumor histopathology. A more aggressive approach has been suggested as well, including serial debulking surgery, with or without intraperitoneal chemotherapy. The most applied strategy, however, contains combined modality treatment: peritonectomy with hyperthermic intraperitoneal chemotherapy (HIPEC). The thesis behind this approach is the aim of macroscopic complete surgical cytoreduction, completed by elimination of microscopic residue to possibly cure patients. Surgical cytoreduction is performed by removing all intraperitoneal tumor, mucus, and peritoneal tumor lesions. The HIPEC will consequently provide a high locoregional concentration of chemotherapy without the disadvantage of systemic toxicity since the peritoneum-plasma barrier prevents high systemic concentrations. The hyperthermia probably enhances the cytotoxic effect of chemotherapy. Mitomycin-C is most widely used because of its favorable pharmacokinetic characteristics and minimal toxicity.

The morbidity and mortality rates of combined modality treatment have been considerably higher than for traditional management, which is mainly attributable to the aggressive surgical arm. Especially patients with extensive disease and/or prior abdominal surgery were prone to complications. Multiple bowel resections, extensive adhesiolysis, and the desire to remove all macroscopic tumors from every peritoneal surface, including small bowel, contributed to significant complications: anastomotic leakage or leakage of serosal damage with consequent enteric fistulae, aggravated by the HIPEC, intra-abdominal abscesses, and thrombo-embolic events. The adverse events solely attributable to the HIPEC are much less common and the most important is leucopenia, which further compromises surgical complications.

Fortunately, the high morbidity and mortality rates in the first years of application decreased considerably with time. An evident learning curve has been witnessed for patient selection, surgical expertise, and postoperative patient management. Treatment-related morbidity and mortality, operation duration, blood loss, intensive care unit stay, and inpatient stay decreased and the rate of complete cytoreduction and overall survival increased. For patients with extensive disease, a 2-stage procedure has been introduced with most of the straightforward cytoreduction (eg, ovariectomy, ileocecal resection, omentectomy) at first instance, followed by a completing cytoreduction with HIPEC during a second laparotomy when the patient has recovered.

Other treatment modalities for PMP have been reported but are not that popular and evidence consists of scarce case reports. Mucolysis, photodynamic therapy, and intraperitoneal radiotherapy have not proven any benefit. The role of systemic chemotherapy has been questioned as well due to the failure to achieve objective responses. This is thought to be related to low-grade histopathology, the hypovascularity, and the frequent bulk of residual disease.

The results of surgical debulking alone are reasonable, with considerable long-term (10-year) survival of 32% to 60% in contrast to long-term survival after no standardized treatment (18%). Disease-free or progression-free survival, however, is disappointing with no more than 21% to 40% of patients disease-free at the end of follow-up (60-144 months).

Combined modality treatment is believed to provide better disease-free results and equal or improved overall survival, but follow-up has not been equal in all reported studies in comparison with traditional studies. With an estimated 10-year survival of 60% to 80%, and a disease-free state of up to 80%, combined modality seems, however, convincingly effective. Another comment on these results must be made, as these favorable rates are associated with favorable pathology. Survival studies have demonstrated that the benefit of an aggressive treatment approach for patients with high-grade tumor with extensive disease spread do not outweigh the risks.

For patients with low-grade disease, showing an indolent behavior, combined modality treatment might be preferable over traditional treatment, especially in prolonging disease-free survival. However, a high level of evidence is not available since randomized studies in the field of PMP are absent. It remains unknown which arm of combined modality treatment provides the survival benefit. The fair results of surgery alone suggest the important contribution of surgical cytoreduction to survival, and the HIPEC will probably play the most important role by preventing reseeding of free tumor cells. Also, available studies on combined modality treatment have shown a high population bias and treatment bias due to inclusion of heterogenous patient populations, histopathological subtypes, treatment techniques, and endpoints.

Follow-up of PMP patients is very important because the natural behavior of PMP creates the potential risk of recurrence after complete macroscopic resection and progression after incomplete resection. The optimal procedure for follow-up of PMP patients includes physical examination, abdominal computed tomography, and serum tumor markers. Even after combined modality treatment with complete cytoreduction, recurrences are described in up to 40%. This is probably due to ineffective distribution of perfusion fluid or due to biological insensitivity or tumor aggressiveness. Patients with low-grade disease still benefit from another attempt at cure, although the risk for morbidity lies in wait. In case of limited disease local surgical resection might be attempted, while a second procedure of cytoreduction and HIPEC can be offered when PMP has recurred diffusely. Patients with high-grade disease, defined from the surgical specimen after the procedure or due to dedifferentiation, should be treated with palliative intent.

In conclusion, the proper treatment for PMP remains uncertain because data with a high level of evidence are lacking, but the combination of (aggressive) surgical debulking with peritonectomy and hyperthermic intraperitoneal chemotherapy seems to improve the outcome. Since this treatment strategy is associated with considerable morbidity and mortality, patients should be compiled in specialized oncology centers.