Recently we treated a patient with mild abdominal pain suspected of being a diverticulitis in a CT scan. However, after resorting to the emergency department, an ultrasound raised the diagnosis of a pseudomyxoma peritonei, which was supported by the findings of the reviewed previous CT scan. However, there was nothing we could do. This case made me review my knowledge about this rare and aggressive disease. Is there anything new to offer? Could the diagnosis have been made earlier? Probably not. Let’s see…
According to some authors, the pseudomyxoma peritonei (PMP) was first describe in 1842 by Rockitansky. Later, Werth described it in 1884 in association with an ovarian carcinoma, and in 1901 Frankel was the first to describe a pseudomyxoma peritonei in association with an appendiceal tumor. In fact, PMP originates from mucinous appendiceal tumors in the majority of cases (82% - ovary is often metastatic, and primary is the appendix), but it can also be associated with mucinous neoplasms of the ovarian, colon and pancreas. After a recent consensus PMP should be referred as a “clinical entity characterized by the presence of mucinous ascitis, omental cake, peritoneal implants and possibly ovarian involvement”.
The primary of a pseudomyxoma peritonei can be a mucinous tumor of the appendix, ovarian, colon or pancreas.
Tumors of the appendix are rare, and usually incidentally found following an appendectomy due to appendicitis. Mucinous neoplasia of the appendix is estimated to represent 35% of appendiceal abnormalities. Although PMP is uncommon, 20% of epithelial neoplasms of the appendix are estimated to progress to PMP, which has a suggested incidence of 2-4 cases per million. Diagnosis is hard to make because symptoms are often vague and non-specific. Abdominal pain can be present, but appendicitis, increased abdominal gird and new onset of hernia are the three most frequent presentations. That is why 50% of patients are diagnosed with PMP on a CT scan performed without previous suspicion. Even though, in the suspicion of a PMP, CT scan is the best imaging tool for diagnosis. Additionally, 5% of patients have their diagnosis because of mucin within the hernia sac. Imagine repairing a hernia and having the operative field full of mucin. Disaster!
Immunohistochemistry is of good help in the diagnosis, analyzing the expression of mucins (MUC2 and MUC5AC), the expression of CDX-2 and CK-20, and CK-7. Most cases of PMP are positive for CK-20, CDX-2 and MUC2, supporting the appendix as the primary site. Interesting to see is that there is frequently no metastatic disease outside the peritoneal cavity, which may be explained by the high expression of N-cadherin and low expression of E-cadherin promoting a reduced cell adhesion.
Symptoms are vague and non-specific. CT scan is the best tool.
How does PMP develops? A mucinous appendiceal tumor will produce mucin and eventually occlude the lumen. Distension of the appendix originates a sterile mucocele. It will grow until eventually perforates, disseminating mucin and tumor cells into the peritoneal cavity. Although this is usually an indolent and asymptomatic process, appendicitis can occur in cases of a fast occlusion. Once in the peritoneal cavity tumor cells will proliferate and originate the characteristic “jelly belly”. The “redistribution phenomenon” described by Sugarbaker in 1994 dictates where large volume of disease will be found within the abdomen (great omentum, left paracolic gutter, hepatorenal space (Morison’s), under right hemidiaphragm, Treitz ligament and retovesical pouch). The characteristic “scalloping” of the liver and “omental cake” occur due the fluid absorption leading to tumor masses formation. This distribution of PMP within the abdomen (sparing the bowel) is the reason why a cytoreductive surgery combined with heated/hyperthermic intraperitoneal chemotherapy (HIPEC) can be effective as a treatment of this aggressive and rare disease. Even though, the treatment must be offer in time or the disease will in some way involve all abdominal organs making surgery impossible and leading to death.
Different classifications were born from the rarity of this entity and the lack of data. In 2015 a consensus was conducted to help organizing a classification that could be helpful in terms of prognosis and treatment decision. Appendiceal mucinous tumors can be: Low grade appendiceal mucinous neoplasm (LAMN); High grade appendiceal mucinous neoplasm (HAMN); Mucinous adenocarcinoma (some can have signet ring cells). PMP was described as an “intraperitoneal accumulation of mucus due to mucinous neoplasia characterized by the redistribution phenomenon”, and the majority has its primary origin in the appendix. Three main grades were proposed and accepted: Low-grade mucinous carcinoma peritonei (G1); High-grade mucinous carcinoma peritonei (G2); High-grade mucinous carcinoma peritonei with signet ring cells (G3). Lymph node involvement should not be used to classify the PMP. Additionally, grading of both appendiceal neoplasm and PMP are independent.
CEA, CA 19,9 and CA 125 are usually elevated.
The aim of this classification (help in prognosis and treatment decision) is yet to be achieve. There are reports of low-grade tumors with an aggressive behavior sometimes invalidating a cytoreductive surgery and allowing only for a maximal tumor debulking. The justification for the aggressive behavior presented by some histological favorable tumors is still a research field. The mutation of TP53 in PMP patients is known to confer a worse prognosis, however the same mutation can be found in both low-grade and high-grade tumors. Interesting is the fact that PMP patients often present elevated CEA, CA 19,9 and CA 125, and these tumor markers rapidly normalize after a good cytoreductive surgery. Elevation of all three markers increases the risk of recurrence and shortens the survival after cytoreductive surgery and HIPEC. Even though, they should not contraindicate surgery. Will the tumor markers be the core to understand and predict behavior of PMP?
Cytoreductive surgery with HIPEC has better outcomes than bebulk surgery.
The authors could not present a valid and systematic guideline to help doctors decide which patients have better prognosis and could benefit the most from the treatment. Cytoreductive surgery (complex surgery - greater omentectomy-splenectomy, left upper quadrant peritonectomy, right upper quadrant peritonectomy, lesser omentectomy-cholecystectomy, pelvic peritonectomy with resection of the sigmoid colon, and antrectomy) and HIPEC using cytotoxic medication seem to be the present-day treatment for PMP, giving best outcomes than debulk surgery. But… Do all patients have indication for that treatment? Which patients have missed the time for cytoreductive surgery? Which patients should be offered only a maximal tumor debulking? How should HIPEC be performed? Which medication should be used? Authors report the use of mitomycin-C at 42 degrees for one hour and others for 90 min. Does this work for all? Prospective trials are needed since nowadays data comes essentially from case series and case reports.
Medicine is still raw when it comes to PMP. That is why no one can give you all the answers. Feel free to study and do research…
Advised reading:
Dr. Carlos Eduardo Costa Almeida
General Surgeon
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