Pseudomyxoma peritonei (PMP) is a rare clinical entity, characterized by diffuse intra-abdominal gelatinous ascites, the so-called “jelly belly,” with mucinous implants on peritoneal surfaces. Werth first introduced the term pseudomyxoma peritonei in 1884. It was initially believed to arise from a perforated cystadenoma of the appendix. However, currently, it has been more widely used to describe peritoneal dissemination of mucus-producing neoplasm most frequently from the appendix, but also small and large bowel, stomach, pancreas, lung, breast, gallbladder, fallopian tubes, and ovaries. Due to its indolent behavior, pseudomyxoma peritonei is often discovered incidentally with a relatively advanced stage during laparoscopy, laparotomy or imaging studies for other medical concerns. Pseudomyxoma peritonei merits consideration as a ‘borderline malignancy’ with changing prognosis based on the site of origin.
Patients with familial adenomatous polyposis (FAP) demonstrate an increased risk of developing mucinous adenocarcinoma of the appendix. KRAS mutation has also been present in 70 % of appendiceal adenomas.
The estimated incidence of pseudomyxoma peritonei is approximately 1 to 4 out of a million annually. The primary site is identified predominantly as mucinous appendiceal adenocarcinoma. Patients have an average age of 53 years at the time of diagnosis. Females are affected more frequently than males.
There are several steps involved in the pathogenesis of pseudomyxoma peritonei. Initially, tumor cells originating from the mucinous epithelium of the appendix continuously produce mucus into the appendiceal lumen and form a mucocele, which eventually ruptures. Free-floating mucinous epithelial tumor cells then implant in various parts of peritoneal cavity following the intraperitoneal fluid current and gravity, thanks to their absence of adhesive properties. It is termed as the so-called ‘redistribution phenomenon.’ The intraperitoneal fluid is most frequently reabsorbed through the right paracolic gutter toward the right hemidiaphragm and the greater and lesser omentum, thus becoming the major sites of tumor deposits when cells get trapped in small lymphatic systems. Gravity is another important redistribution mechanism, which facilitates the accumulation of tumor cells in the pelvis, such as the rectovesical pouch or the pouch of Douglas.
Mobile organs such as the small bowel and its mesentery are usually less likely to be involved compared to more fixed parts such as antrum, duodenojejunal flexure, ligament of Treitz, ileocecal and rectosigmoid region, early in the disease process. But in the end-stage disease, the entire peritoneal cavity could be engulfed. The implanted tumor cells continue to proliferate and produce a large amount of mucus and eventually form mucinous ascites over months or even years. The excessive tumor burden and subsequent high intra-abdominal pressure can further limit bowel movement and even result in small bowel obstruction that requires surgical resection. The extra-peritoneal invasion has been reported mainly in the pleural cavity. Lymphatic or hematogenic metastasis are rare occurrences.
Macroscopic examination often reveals abundant gelatinous pelvic or abdominal mucin or mucinous ascites accompanied by cystic epithelial implants on peritoneal surfaces. These lesions vary in size from a few mm to a few centimeters. A large ‘omental cake’ is also frequently found.
Multiple histological grading systems have been proposed for pseudomyxoma peritonei. Ronnett et al. first divided pseudomyxoma peritonei into two groups: disseminated peritoneal adenomucinosis (DPAM) and peritoneal mucinous carcinomatosis (PMCA). DPAM is characterized by abundant mucus containing scanty mucinous epithelial cells with minimal cytological atypia and mitotic activity, while PMCA is featured by more abundant mucinous epithelial cells with high-grade cytological atypia and mitotic activity. In 2010, the World Health Organization (WHO) further refined the grading system.
Researchers have suggested MUC 2 over-expression as a molecular marker for PMP of intestinal origin. Appendiceal tumors also express CK20, CEA, and CDX2, and are usually negative for CK7 and CA 125. There are also reports of loss of protein expression of the repair genes MLH1 and PMS2.
At the initial stage, pseudomyxoma peritonei is often asymptomatic or presents with non-specific signs and symptoms sometimes misdiagnosed as irritable bowel syndrome. As the disease progresses, patients may present with appendicitis-like symptoms, increased abdominal girth, the presence of pelvic masses or new-onset hernia. More advanced disease may result in abdominal distension, ascites, bowel obstruction, and nutritional compromise. Reports also exist of superinfected pseudomyxoma peritonei and subsequent sepsis.
Physical examination may reveal a distended abdomen with a palpable omental cake. A rectal exam may reveal deposits in the pouch of Douglas or the rectovesical pouch. Ovarian masses may be palpable in females.
CT scan with contrast of the chest, abdomen, and pelvis is currently the imaging modality of choice for the diagnosis of pseudomyxoma peritonei. Typical CT appearance is ‘scalloping’ of the surface of the liver and spleen caused by loculated accumulations of mucin, which distinguishes mucin from fluid ascites. The mucinous material is similar in density to water. There are also islands of higher attenuation due to scattered solid elements and calcification within mucinous material. However, the primary appendiceal lesion might be absent or hard to identify on imaging. Compared to CT, gadolinium-enhanced MRI is more sensitive in localizing the tumor, and in assessing the small bowel as well as the hepatoduodenal ligament. PET/CT scan might be helpful in more aggressive variants by detecting extra-abdominal disease.
Circulating tumor markers:
Tumor markers are found to have prognostic value and are useful for follow up of patients after treatment. CEA and CA 19.9 are found to have a high level in PMP with an appendiceal origin. CA 125 is also found to be high but with ovarian involvement.
The final diagnosis relies on histopathological examination of the biopsy and surgical specimen through laparoscopy or laparotomy, especially when the clinical and radiological manifestations are not specific. Percutaneous image-guided biopsies are of limited value since the resultant material may be acellular mucin.
Traditional periodic surgical debulking has been less favored because of inevitable disease recurrence and a higher risk of repeated surgeries. Current recommended standard treatment for PMP consists of complete cytoreduction surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The goal of CRS is to remove all visible tumors. Resection is considered complete if no masses larger than 2.5 mm are left. HIPEC aims at eradicating any macroscopic or microscopic tumor residues. The most commonly used chemotherapeutic agent is mitomycin C (MMC), and the rationale for heating is to increase drug penetration. A baseline CT scan, as well as tumor markers, are recommended to be completed 3 months postoperatively and then every 6 months to monitor recurrence. Elective second look surgery when recurrence is considered for selected patients. However, since CRS/HIPEC is an aggressive treatment, medical comorbidities should be carefully assessed preoperatively. And patients with high-grade lesions or signet ring cell components with an ECOG (Eastern Co-operative Oncology Group) performance score of 2 to 3 have significantly poorer overall survival after the surgery. Those patients may benefit from a major palliative resection to improve quality of life. Postoperative systemic chemotherapy has been shown to benefit patients with high-grade neoplasm after CRS/HIPEC, but not those with low-grade neoplasm. However, there’s currently no widely accepted standardized plan. Preoperative systemic chemotherapy is generally not helpful.
Prognosis of pseudomyxoma peritonei correlates closely to histopathological classification. The ten-year survival rate of patients with low-grade tumors/DPAM is 63% compared to 40.1% in patients with high-grade tumors/PMCA and 0% in patients with high-grade tumors with signet ring cells following the treatment of CRS/HIPEC in one recent study.  However data varies between different studies.  Above all, patients who are undergoing CRS/HIPEC present with a better long-term outcome than those undergoing debulking surgery.
Patient with a newly diagnosed pseudomyxoma peritonei is recommended to undergo CRS/HIPEC if medically fit with the goal of achieving complete cytoreduction. Even though the long-term outcomes after treatment are impressive for patients with low-grade histology, there’s still a significant recurrence of the disease. Regular follow-up is essential to monitor disease progression.
Most cases of pseudomyxoma peritonei are discovered in an advanced stage due to its indolent behavior. Pathological diagnosis is crucial to determine the treatment plan. When suspicious lesions are encountered incidentally during laparoscopy or laparotomy, the best strategy is to take generous biopsies, remove appendix if accessible, and only proceed with further treatment after pathological confirmation of the diagnosis and clinical assessment of the patient. During follow-up, the primary care provider, nurse practitioner or internist should be aware of recurrence and consider imaging studies and referral to the oncologist. Pseudomyxoma peritonei treatment is best in an interprofessional team approach including specialists, oncology trained specialty nursing, and when necessary, pharmacists, collaborating for optimal patient care and outcomes. [Level V]
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