Pseudomyxoma peritonei

Cancer Treatment Reviews (2007) 33, 138– 145

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TUMOUR REVIEW

Pseudomyxoma peritonei R.M. Smeenk, V.J. Verwaal *, F.A.N. Zoetmulder Department of Surgery, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands Received 1 October 2006; accepted 3 November 2006

KEYWORDS

Summary Pseudomyxoma peritonei (PMP) is a rare condition, which is known for its high mortality when not treated properly. The first step to improve prognosis of these patients is to recognize this clinical syndrome preferably in an early stage. Knowledge of pathogenesis and common diagnostic tools is essential in this regard. Treatment strategy for PMP should pursue complete cytoreduction and prevention of recurrence or progression. Combined modality treatment, consisting of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy, seems very efficient in this regard. This approach is currently carried out in many centers throughout the world with promising results and seems to win ground as the standard treatment approach. c 2006 Elsevier Ltd. All rights reserved.

Pseudomyxoma peritonei; Pathogenesis; Diagnosis; Treatment; Outcome

 Introduction

Pathogenesis

Pseudomyxoma peritonei (PMP) is a rare clinical syndrome with an estimated incidence of approximately one per million per year or 2 per 10,000 laparotomies, and a preponderance of women (2–3 times men).1–4 Literately, PMP implies an untrue mucinous tumor of the peritoneum, which reflects the origin of the tumor as tumor cells are deposited on but not originating from the peritoneum. Werth first described PMP in 1884 as a peculiar reaction of the peritoneum to jelly like material, produced by an ovarian neoplasm.5 In 1901 Frankel reported on the association of PMP with an appendiceal mucocele.6 Since then, there has been a considerable number of reports on the pathogenesis, diagnosis, treatment and prognosis of PMP. This review is meant to provide a comprehensive outline of these facets of this intriguing disease.

Etiology

* Corresponding author. Tel.: +31 205122551; fax: +31 205122554. E-mail address: [email protected] (V.J. Verwaal).



PMP is a loco regional disease within the abdomen, characterized by mucinous tumor on peritoneal surfaces producing a progressive amount of mucinous ascites. The primary tumor is thought to be predominately a mucinous epithelial neoplasm of the appendix.7–9 The development of PMP from a small mucinous epithelial tumor of the appendix is explained as follows. Multiplying adenomucinous tumor cells produce a large amount of intraluminal mucus and, with progressive growth, eventually cause obstruction of the appendiceal lumen. Consequently, rising intraluminal pressure results in the blow-out of the appendiceal mucocele with the slow leak of mucus, containing mucinous epithelial cells, into the peritoneal cavity. This moment is defined as the first step in the development of PMP. The perforation of the appendix may reseal and become even invisible, while over the course

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Pseudomyxoma peritonei of months or, in case of indolent behavior, years free epithelial cells in the peritoneal cavity continue to proliferate and produce mucinous ascites. In contrast to tumor cells of colorectal cancer origin that implant in the vicinity of the primary tumor, tumor cells from the ruptured appendiceal neoplasm are spread throughout the peritoneal cavity by the intraperitoneal fluid current and gravity. The absence of adhesive characteristics on the cell surface probably explains such passive movement. The intraperitoneal fluid current takes tumor cells to reabsorption sites where tumor cells get entrapped in the small resorption channels. Gravity for its part draws tumor cells through the paracolic gutters towards the pelvis. Accumulation and reproduction of the free and implanted tumor cells leads to progressive peritoneal mucinous tumor and ascites, but invasion of the peritoneal surface usually remains absent. This process of characteristic spread of peritoneal masses and mucinous ascites is known as the redistribution phenomenon.10 In established PMP, tumor deposits are found especially in the omentum, in the sub hepatic region, under the right diaphragm, in Douglas, around the rectum and sigmoid, and in women on the ovaries. Mobile peritoneal surfaces, such as the bowel surface, are spared in this stage of disease (visceral sparing), as tumor cells are not able to adhere. An exception herein are the intestinal parts that are fixed to the retroperitoneum such as the ileocoecum, rectum and sigmoid. In late stage disease, when PMP becomes generalized and mucinous ascites and tumor engulf the entire peritoneal cavity, including the left diaphragm and the spleen, bowel movement becomes limited with eventually tumor involvement of all bowel surfaces. Patients with a history of previous abdominal surgery are prone to the invasion of surgical wound surfaces by PMP as well.

Origins The high incidence of simultaneous disease in the appendix and ovaries in female PMP patients has led to confusion about the true origin. In clinicopathological, molecular genetic and immunohistochemical studies the origin of PMP has been studied intensively.2,11–16 The prominent hypothesis indicates ovarian tumor as metastatic disease from an appendiceal primary. Tumor cells spread to the pelvis conforming to the distribution phenomenon tend to get entangled on the irregular surface of ovulating ovaries. It might be that the ovaries are acting as a stepping stone where free intraperitoneal epithelial cells find a foothold. A contrasting theory designates a primary ovarian mucinous cystadenoma or cystadenocarcinoma (with borderline or low malignant potential), which causes intraperitoneal tumor spread after rupture of the cystic tumor. These tumors present with distinctive features: their size is usually greater, their presentation unilaterally with multiloculated cysts and the tumor found in the stroma instead of at the surface.17,18 In these cases, an associated appendiceal tumor is not found. In rare cases two synchronous primary tumors (in the appendix and ovary) or a multifocal process might be associated with PMP.19,20 Despite this limited controversy, the appendix is still the alleged dominant origin associated with PMP.21 Origins other than appendix or ovary are rare and include pancreas, colon or urachus.22,23

139

Histopathology A proper histopathological definition of PMP is difficult as histopathological features are inhomogeneous. PMP shows a wide range in the mucus/cell ratio and the amount, differentiation and grade of atypia of epithelial cells. A widely accepted and used definition of PMP is proposed by Ronnett and colleagues. They describe PMP as a clinical–pathological entity characterized by mucinous ascites and non-invasive mucinous implants with a typical distribution, containing histological benign mucinous epithelium derived from an appendiceal mucinous adenoma and having a benign clinical course.24 Although they thus describe PMP as a benign disease, their categorization classifies PMP into three pathological subtypes with different pathological characteristics (including malignant features) and associated with a different prognosis: disseminated peritoneal adenomucinosis (DPAM), peritoneal mucinous carcinomatosis (PMCA), and an intermediate subtype (PMCA-I). Histopathologically, DPAM is characterized by an abundance of mucus with focally adenomucinous epithelium with hardly any atypia or mitotic activity. DPAM has non-invasive properties, an indolent behavior and a good prognosis. PMCA in contrast is the pathological subtype with malignant features. Histopathologically, PMCA is characterized by peritoneal tumor composed of more abundant mucinous tumor cells with the architecture and cytological features of carcinoma. PMCA occasionally shows invasive properties, comparable with peritoneal carcinomatosis of colorectal origin, and has a grim prognosis. Finally, the intermediate subtype PMCA-I is characterized by an abundance of DPAM lesions but focal areas with PMCA lesions. The behavior and prognosis of PMCA-I subtype lies somewhere in between DPAM and PMCA.25–27 Although Ronnett’s classification is applied broadly, another frequently used classification separates PMP into low-grade or high-grade tumor. Recently Bradley et al. reviewed the pathology in 101 PMP patients and concluded that the low-grade histology of PMP included those cases referred to as DPAM in the same category as PMCA-I. PMCA cases are classified as pseudomyxoma peritonei-high grade.25 These classifications into pathological subtypes is rather useful for the determination of prognosis and the evaluation of further treatment strategy. Histopathological and survival analysis of these different subtypes has shown that DPAM patients are most likely to benefit from loco regional treatment and represent the real PMP patient with a good prognosis. PMCA patients should be classified and treated as peritoneal carcinomatosis of colorectal origin, as they do not seem to benefit from (aggressive) treatment and have a comparable prognosis.3,26,27

Diagnosis Presenting symptoms Very characteristic and essential in the diagnosis of PMP are the presenting symptoms, which can be categorized roughly into three groups. The most important symptom is increasing abdominal girth (50%), which characterizes the progressive stage of disease with peritoneal dissemination. Patients

140 present with a typical ‘‘jelly belly’’ and complaints of intestinal obstruction, caused by the progressive amount of mucinous tumor and ascites. The second most common group is characterized by local symptoms, reflecting the location of the primary or metastatic tumor. Patients with symptoms mimicking an acute appendicitis (25%) will undergo an appendectomy, during which the surgeon identifies an infected and occasionally perforated appendiceal mucocele. In some cases, the perforated appendiceal surface is surrounded by deposits of mucus (Fig. 1) or spots of mucinous deposits are found on peritoneal surfaces, which proclaims the first step towards the development of PMP. Histopathological examination of the appendix usually reveals a mucinous epithelial neoplasm. In 30% of female patients, the first symptom is an ovarian mass. Often, these patients first consult the gynecologist with a pelvic mass. The correct diagnosis is then awaited for until after surgery, when examination of the mucinous ovarian tumor and the appendix reveals PMP metastases from an appendiceal primary or less frequently an ovarian primary. These patients are then referred to the surgeon. The last group of patients is diagnosed by coincidence (20%). During laparoscopy or laparotomy for whatever reason, or during hernia repair, the surgeon or gynecologist unexpectedly encounters mucus.28–31 Further analysis eventually discloses the true diagnosis. In most patients PMP is identified at first presentation. However, occasionally the first symptoms have not resulted in the correct diagnosis. These patients have had a vague right lower abdominal pain with no further treatment or a perforated appendix with initially an unidentified tumor and/or unnoticed peritoneal tumor deposits. When they present several months or even years later with abdominal distension, thorough analysis and/or revision of the original specimen from previous surgery reveals the correct diagnosis. The mean interval between the existence of a primary (appendiceal) tumor and established PMP is described to be approximately 21 months, but extremely long intervals have been reported before.32,33

Figure 1 Perforated appendiceal mucocele with mucinous deposit on the outer surface: (1) coecum, (2) normal appendiceal lumen and (3) dilated lumen.

R.M. Smeenk et al.

Imaging and laboratory Ultrasound is the first imaging technique to use for further establishment of the diagnosis. Usually, the radiologist visualizes free intraperitoneal fluid, which can be aspirated for cytology. Needle aspiration then reveals pools of mucus with no or very few (well-differentiated) epithelial cells, which provides a false relieve as this finding is actually the key-stone in PMP. The next step in the diagnostic process should then be a computed tomography (CT) scan, which is pathognomic for PMP. CT demonstrates the characteristic distribution of mucinous ascites, which can be differentiated from normal watery ascites by analyzing density properties (Hounsfield Units [H.U.]). Normal ascites is characterized by a low density image (+/ 0 H.U.), while the density of mucinous ascites is significantly higher (5– 20 H.U.). In addition, CT demonstrates the involvement of abdominal regions and the stage of disease. In early stage disease, omentum, sub hepatic region, ileocoecum region, sigmoid and ovaries may be involved, with visceral sparing. In late stage disease however, generally all regions are affected and abundant mucinous ascites causes compression of small bowel and impression of the liver surface (Fig. 2). Other imaging modalities have been used, such as magnetic resonance imaging (MRI), positron emission tomography (PET), radioimmunochemistry and radioimmunoscintigraphy, but do not seem to have any additional value.34–39 When PMP is confirmed by CT, there is a role for serum tumor markers CEA and CA 19.9 in the completion of the diagnostic workup, as these tumor markers are raised in most PMP patients and can be used as preoperative benchmark.40

Treatment Precursor of PMP In patients with an appendiceal mucocele, containing a mucinous epithelial neoplasm, perforation might have taken

Figure 2 CT scan illustrating ‘‘thumb printing’’ of the liver surface (1) and compression of small bowel (2) by the excessive amount of mucinous ascites (3).

Pseudomyxoma peritonei place, though not always macroscopically visible. Little deposits of mucus and tumor cells might be visible on the outer surface of the appendix, the possible precursors of PMP, but frequently there is no sign of intraperitoneal tumor or mucus. Although the clinical signs of PMP are not yet established, microscopic dissemination might have taken place. In these patients a wait and see policy after appendectomy can be justified, but close follow-up with tumor markers and ultrasound is essential to detect PMP in an early stage.

Established PMP When mucinous tumor on the peritoneal surface or mucinous ascites is visualized on CT or during abdominal surgery, adequate treatment of established PMP should be pursued. The choice of treatment strategy in this case has varied much in the past. Advocators of a waiting policy felt that especially PMP with indolent behavior is not qualified for surgery.41 These patients could be spared from surgery and its concomitant complications. However, although no survival data is available from large studies, untreated PMP patients will eventually suffer death through intestinal obstruction by massive mucinous ascites and large tumor deposits.7 Flimsy data has been presented on alternative non-surgical treatment, such as periodic symptomatic drainage of mucinous ascites, mucolytic treatment, peritoneal washing with 5% dextrose and systemic chemotherapy.42–46 The major pitfall of these strategies is the limited number of only case-reports with limited follow-up. Traditional surgical treatment is a moreover accepted and applied strategy. Early literature on this approach consists mostly of reports from gynecologists, as in the past the assumed origin of PMP was ovarian.4,46–48 Traditional surgery consists of a first debulking with ovariectomy and omentectomy, but recurrence is imminent and a second debulking with mechanical rinsing necessary. The third recurrence is usually accompanied by intestinal obstruction, at which point the surgeon is consulted for bowel resection and a stomy. Finally, a fourth or fifth recurrence is untreatable and followed by death through obstruction or complications of the treatment. Repetitive surgical debulking as treatment for PMP has been described mostly in case studies. The only large study was presented by the Mayo Clinic. They published a series of 26 patients treated this way with an estimated 5-year survival of 53%.49 At end of follow-up only 3% of patients was free of disease. A more aggressive approach consists of aggressive cytoreductive surgery with the intent to obtain complete macroscopic cytoreduction in one or more operations. The Memorial Sloan Kettering Center reported on this treatment strategy in an analysis of 97 PMP patients.50 An average of 2.2 debulking operations was needed to reach complete cytoreduction in 55% of patients. Their treatment strategy resulted in a 10-years actuarial survival of 21%, and a disease free rate at end of follow-up of 12%. The major disadvantage of repetitive surgical debulking seems the imminent recurrent or progressive disease as result of microscopic tumor residue. A relatively new treatment approach, consisting of a surgical and chemotherapeutical modality, seems to win

141 ground as the standard treatment for peritoneal surface disease of all kinds of origin.51–56 For PMP patients this new treatment strategy was introduced in the early nineties by the surgeon Sugarbaker.57 The surgical modality, consisting of so-called peritonectomy procedures with resection of involved viscera (Fig. 3), aims at resection of peritoneal surfaces in a tumor-free plain, thus making it easier to accomplish a macroscopic complete cytoreduction.58 For the purpose of eradicating any macroscopic or microscopic tumor residue to prevent recurrence, surgery is combined with hyperthermic intraperitoneal chemotherapy (HIPEC). This combined modality treatment is a loco regional approach that can be justified as an approach with curative intent, especially in PMP patients because of the characteristic dissemination pattern and non-invasive character. At present cytoreductive surgery with HIPEC is increasingly employed as treatment for PMP patients all over the world with promising results.59–66 Although no randomized trials are available because of the low incidence and ethical problems, results of various studies performed in the last 7 years show that combined modality treatment seems favorable compared to serial debulking surgery with unstandardized intraperitoneal chemotherapy (Table 1). The observed inter-institutional variation is remarkable and is probably explained by the difference in patient selection, classifications, and follow-up. Although there is a variety of techniques for performing the HIPEC lavage (Table 1), it remains questionable whether these techniques differ in treatment outcome. The favorable outcome of combined modality treatment in comparison with traditional surgical treatment is probably related to the effort to accomplish not only macroscopic but also microscopic complete cytoreduction. HIPEC is thought to contribute to the prevention of recurrence or progression in patients with microscopic to minimal macroscopic tumor residue, as pharmacokinetic studies suggest a potential cytotoxic effect up to a tumor depth of 2.5 mm.67 Overall, the 5-year overall survival of combined modality treatment exceeds 75% for patients with benign disease (DPAM) and complete cytoreduction. The recurrence rate

Figure 3 Peritonectomy procedure: en bloc resection of PMP deposits including peritoneum (1) and colon (2).

142 Table 1

R.M. Smeenk et al. Results of comparable studies on treatment of PMP patients HIPEC technique

CC (%)

TOX (%)

MORT (%)

Traditional treatment Gough et al.15 (56) Miner et al.16 (97) Combined modality treatment Sugarbaker et al. (n = 385) (72) Elias et al. (n = 36) (66)

Deraco et al. (n = 33) (60) Guner et al. (n = 28) (61) Loungnarath et al. (n = 27) (62) Smeenk et al. (n = 103) (33;68)

MMC (+5-FU) closed abdomen peri-operative OXALI (MMC) closed abdomen intra/perioperative MMC/CISPL closed abdomen intra-operative MMC/CISPL open abdomen intra-operative MMC/CISPL closed abdomen intra-operative MMC open abdomen intraoperative

Total

5-yr OSa (%)

FU (months) NED (%)

53b 80

144 57

3 12

65

27

3

86

38

62

92

44

8

>75

48

55

92

18

3

97

29

74

40

36

7

>75

51

NA

41

44

0

75c

23

NA

90

54

3

>80

51

56

70

37

4

>80

40

62

HIPEC, hyperthermic intraperitoneal chemotherapy; PMP, pseudomyxoma peritonei; CC, complete cytoreduction, <2.5 mm residue; TOX, major toxicity; MORT, 30-days mortality; OS, overall survival; FU, follow-up; NED, no evidence of disease; MMC, Mitomycin C; 5-FU, 5fluorouracil; OXALI, Oxaliplatin; CISPL, Cisplatin; NA, not available. a Complete cytoreduction and DPAM. b Not all patients complete cytoreduction and DPAM. c Estimation.

is considerable as well: approximately 60% is free of disease after a median follow-up of 40 months. Especially patients with DPAM seem to benefit from this approach. In PMCA patients it remains questionable whether they benefit from this aggressive treatment at all.24,27 Although combined modality treatment is now gaining popularity as the mainstay of treatment, intraperitoneal chemotherapy is not universally accepted as the optimum treatment for these patients. The aggressiveness of this treatment strategy and concomitant high morbidity and mortality are probably the main reasons for skepticisms, but recent studies have demonstrated a decreasing trend when the necessary experience in treating these patients is gained.64,68 The combination of surgery and other modalities than intraperitoneal chemotherapy is uncommon and has shown various degrees of success. Fernandez and Daley described a five-year survival rate of 75% after surgery with adjunctive radiotherapy compared with 44% for chemotherapy, but follow up was short and the number of treated patients was small. Gough et al. performed surgery in combination with intra cavitary isotope and external beam radiotherapy.49 They found a significant shorter disease free survival in case of adjuvant radiotherapy, but numbers were small (n = 16) and there was no observed effect on overall survival. Photodynamic therapy combined with surgery has been applied widely in peritoneal surface disease other than PMP.69 It seems technically feasible, but the adjuvant effect for PMP has still to be evaluated. The effect of systemic chemotherapy in PMP seems questionable. The loco regional spread of well-differentiated tumor with a poor blood supply greatly diminishes the efficacy

and possible benefit of systemic therapy. Jones and collegues are one of the few that describe a possibly cured case of PMP, secondary to an ovarian primary.44 Most studies question an objective response of PMP to systemic chemotherapy and consider systemic therapy to be reserved for a palliative setting in patients with recurrent or progressive disease.3,27,51

Late stage disease In late stage disease, when the entire abdomen is filled with mucinous tumor and ascites, immediate combined modality treatment seems to loose its benefit.27,64 In these cases a two step procedure might be worthwhile. First the most feasible resections (the ileocoecum, the omentum and if necessary the ovaries) are performed. In a second stage, when the patient has recovered, the cytoreduction can be completed with intraoperative HIPEC.

Follow-up After treatment, patients should be monitored for (recurrent or) progressive disease. A CT scan is a very important tool for detecting progressive disease and can be performed 3 months after treatment as basis for further followup.57,70,71 After that, a CT scan should be performed every 6 months in the first year and once a year or when progression is suspected in the next years. Other useful servants in detecting disease in the postsurgical period are the tumor markers CEA and CA 19.9, which also act as prognostic factors for survival.72,73

Pseudomyxoma peritonei Together, CT and tumor markers form a powerful combination for postoperative disease monitoring. Although progression occurs even after aggressive treatment, thorough management of progressive disease seems worthwhile and can result in long-term survival.70 The choice of treatment for progressive disease should primarily depend on the progression free interval, but also on the pathological subtype and extent of disease.

Conclusion Pseudomyxoma peritonei (PMP) is a rare disease, with a grim prognosis when not treated properly. The first step to improve the prognosis is to recognize this clinical syndrome preferably in an early stage. Knowledge of pathogenesis and common diagnostic tools is essential in this regard. CT imaging should be the choice of radiological assistance in the diagnostic process. Surgical debulking is the standard treatment for PMP, but combined modality treatment, consisting of aggressive peritonectomy with (intraoperative) HIPEC, seems to win ground as the new standard approach. Centralization of patients in centers that treat these patients on a regular basis is fundamental to prevent high morbidity and mortality.

Conflicts of interest statement None declared.

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