Combined modality treatment of pseudomyxoma peritonei

Combined modality treatment of pseudomyxoma peritonei

Combined modality treatment of pseudomyxoma peritonei By Robert M. Smeenk This study has been performed in The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital Amsterdam, the Netherlands. 7KHSXEOLFDWLRQRIWKLVWKHVLVKDVEHHQPDGHSRVVLEOHE\ÀQDQFLDOVXSSRUWRI The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital Stichting Bevordering Kanker onderzoek Universiteit van Amsterdam Nutricia B.V. Dansac Nederland ThermoSolutions Novartis Oncology 3À]HU%9 AstraZeneca B.V. Johnson and Johnson Medical B.V. Tyco Healthcare B.V. ISBN-13: 978-90-9021441-2 Cover design: Lay-out: Printed by:

Dustin Remmé Chris Bor Printing Partners Ipskamp

Combined modality treatment of pseudomyxoma peritonei ACADEMISCH PROEFSCHRIFT

ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam RSJH]DJYDQGH5HFWRU0DJQLÀFXV prof. mr. P.F. van der Heijden ten overstaan van een door het college voor promoties ingestelde commissie, in het openbaar te verdedigen in de Aula der Universiteit op 2 februari 2007, te Amsterdam om 10.00 uur

door

Robert Matthijs Smeenk

geboren te Moshi (Tanzania)

Promotiecommissie: Promotor:

Prof. dr. B.B.R. Kroon

Co-promotores:

Dr. F.A.N. Zoetmulder Dr. V.J. Verwaal

Overige leden:

Prof. dr. J.J.B. van Lanschot Prof. drs. J.F.W.M. Bartelsman Prof. dr. D.J. Richel Prof. dr. T. Wiggers Dr. H. Boot Dr. M.J. van de Vijver

Faculteit der Geneeskunde

Contents Chapter 1 Introduction and outline of the thesis

7

Chapter 2 Pseudomyxoma peritonei and appendiceal neoplasms: a population based study Submitted

13

Chapter 3 Pseudomyxoma peritonei: three illustrating case histories Ned Tijdschr Geneesk, in press.

27

Chapter 4 Toxicity and mortality of cytoreduction and intraoperative hyperthermic intraperitoneal chemotherapy in pseudomyxoma peritonei - a report of 103 procedures Eur J Surg Oncol 2006; 32(2):186-90

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Chapter 5 Survival analysis of pseudomyxoma peritonei patients treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy Ann Surg, in press

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Chapter 6 Learning curve of combined modality treatment in patients with peritoneal surface disease Submitted

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Chapter 7 Progressive pseudomyxoma peritonei after combined modality treatment: management and outcome Ann Surg Oncol, in press Chapter 8 Pseudomyxoma peritonei and the urinary tract: involvement and treatment related complications J Surg Oncol 2006; 93(1):20-3

71

83

Chapter 9 Pseudomyxoma peritonei and pregnancy: a report of two cases Submitted

91

Chapter 10 Pseudomyxoma peritonei: a comprehensive review Canc Treat Rev, in press

97

Chapter 11 General discussion

113

Chapter 12 Summary, Nederlandse samenvatting

121

Dankwoord

131

Curriculum vitae

135

1

chapter

Introduction and outline of the thesis


Pseudomyxoma peritonei (PMP) is a rare disease with an incidence of approximately one per million, characterized by diffuse collections of gelatinous material in the abdomen and pelvis, and mucinous implants on the peritoneal surfaces. If literately translated, PMP implies a false mucinous tumour of the peritoneum as the tumour is GHSRVLWHGRQEXWQRWGHULYHGIURPWKHSHULWRQHXP303ZDVÀUVWGHVFULEHGE\:HUWK in 1884 as a peculiar reaction of the peritoneum to jelly like material, related to an ovarian neoplasm.1/DWHURQLQWKHÀUVWLQFLGHQFHRI303ZLWKDF\VWRIWKHDSSHQGL[ was reported.2 Since then, there has been a considerable number of reports about this disease. The term PMP was originally applied to intraperitoneal mucinous spread originating from a cystadenoma of the appendix. When this tumour grows and occludes the lumen, mucous accumulates and the appendix ruptures. The peritoneum is then seeded with mucous-producing cells, which continue to proliferate and produce progressive DPRXQWVRIPXFRXV6WXGLHVLQWKHLPPXQRKLVWRFKHPLFDODQGPROHFXODUJHQHWLFÀHOG have obtained evidence that PMP is a disease of intestinal goblet cells with mucinsecreting proteins that account for the high mucin/cell ratio which can exceed 10:1.3,4 7KHSURJUHVVLYHDFFXPXODWLRQRIPXFLQRXVDVFLWHVJUDGXDOO\ÀOOVWKHSHULWRQHDOFDYLW\ DFFRUGLQJ WR D W\SLFDO UHGLVWULEXWLRQ SDWWHUQ GRPLQDWHG E\ SHULWRQHDO ÁXLG ÁRZ DQG gravity.5 Finally, this results in the characteristic abdominal distension or so-called “jelly belly”.6 Inevitably, this condition progresses to intestinal obstruction, which without treatment is fatal. Although the site of the primary tumour is mainly reported as the appendix, also pancreas, urachus, colon and especially the ovaries have been described as primaries of PMP.7,8 There has been a huge controversy regarding the frequent ovarian involvement in women with PMP: the ovaries have been proposed as both the primary tumour and metastases from an appendiceal primary.6,9-16 In addition, there has been some debate regarding the histopathology of PMP. It has EHHQFODVVLÀHGPDLQO\DVDGLVHDVHZLWKEHQLJQFKDUDFWHULVWLFVEXWDOVRDVDPDOLJQDQW SURFHVVEHFDXVHRIWKHÁXLGWUDQVLWLRQIURPEHQLJQWRPDOLJQDQWKLVWRORJ\7RSURYLGH DSURSHUGHÀQLWLRQDQGFODVVLÀFDWLRQLQWKLVUHJDUG5RQQHWWDQGFROOHDJXHVSURSRVHG to apply the term PMP only to a pathologically and prognostic homogeneous group of cases. These cases are characterized by histological benign peritoneal tumours that are frequently associated with an appendiceal mucinous adenoma and have an indolent clinical course.17 Clinicopathological studies have supplied growing evidence that this mucinous cystadenoma of the appendix as the common primary of PMP.14,18 Important LQUHJDUGWRWKHGHÀQLWLRQRI303LVWKHGLIIHUHQWLDWLRQIURPPXFLQSURGXFLQJFDUFLQRmas of gastro-intestinal and ovarian origin. These tumours have a completely different biological and prognostic behaviour, and should be treated in a different way.6,9

9

7KHGLDJQRVLV303FDQEHGLIÀFXOWLIRQHLVQRWIDPLOLDUZLWKSDWKRJHQHVLVKLVWRSDthology, and diagnostic signs. PMP is still mistaken for mucinous carcinomatosis and ovarian involvement is regularly incorrectly diagnosed as an ovarian mucinous tumour RUF\VW,QWKHVHFDVHVWKHSURJQRVLVRI303SDWLHQWVVLJQLÀFDQWO\ZRUVHQVDVWKH\DUH treated by inappropriate regimens. Knowledge of disease characteristics will facilitate DQHDUO\GLDJQRVLVZKLFKKDVDVLJQLÀFDQWLPSDFWRQWUHDWPHQWUHVXOWVDQGVXUYLYDORI patients. Originally, treatment of PMP involved surgery but other modalities such as mucolytic agents, phototherapy and radiotherapy have been applied.19-21 Surgical debulking with appendectomy, ovariectomy and omentectomy has been the mainstay of treatment for a long period but survival after this treatment strategy is not satisfactory and disease recurrence or progression is imminent. 22-24 In the last 20 years PMP treatment has howHYHU XQGHUJRQH D VLJQLÀFDQW LPSURYHPHQW 7KH XVH RI LQWUDSHULWRQHDO FKHPRWKHUDS\ was introduced and combined modality treatment for peritoneal surface disease such as peritoneal carcinomatosis and PMP became available.25-31 This treatment scheme consists of a loco regional approach with cytoreductive surgery and intraperitoneal lavage with chemotherapy. The goal of this treatment strategy is two-fold: surgery for complete removal of macroscopic tumour and intraperitoneal chemotherapy to erase microscopic residue. Nowadays, the intraperitoneal chemotherapy is performed intraoperatively and optimized by hyperthermia to improve tissue penetration and cytotoxic properties of the chemotherapeutic agent.32 The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital (NKI-AvL) initiated this treatment scheme in 1995 and PMP patients are now treated standard with cytoreductive surgery and intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC). The HIPEC-procedure includes 90 minutes of peritoneal lavage with a heated & GH[WURVHSHULWRQHDOGLDO\VHÁXLGOLWUHV DGGHGZLWKVRPHSRWDVVLXP DQGKHSDULQWRSUHYHQWFORWWLQJ7KLVÁXLGFRQWDLQVPJPñRI0LWRP\FLQ&ZKLFK has proved to be an effective chemotherapeutic agent for PMP.28 In the NKI-AvL, this procedure is performed by the open coliseum technique with the aid of a homemade perfusion machine.27

Chapter 1 10

This thesis provides an overview of current understanding of and recent developments in PMP pathogenesis, diagnosis, and treatment. It contains a population based study (Chapter 2), three illustrative case histories (Chapter 3), the results on morbidity, mortality, survival and learning curve of this combined modality treatment at the NKI-AvL (Chapter 4 to 6) and a discussion of management and outcome of progressive disease (Chapter 7). In addition, the rare involvement of the retroperitoneal urinary tract by PMP (Chapter 8), two cases of PMP in pregnant women (Chapter 9), and a review of


recent literature (Chapter 10) is presented. This dissertation closes with a general discussion (Chapter 11) and a summary (Chapter 12).

References 1. Werth R. Klinische und anatomische untersuchungen zur lehre von den bauchgeschwuelsten und der laparotomie. Arch Gynaecol Obstet 1884; 24:100-118. 2. Frankel E. Uber das sogenannte pseudomyxoma peritonei. Med Wochenschr 1901;965-970. 3. O’Connell JT, Tomlinson JS, Roberts AA et al. Pseudomyxoma peritonei is a disease of MUC2expressing goblet cells. Am J Pathol 2002; 161:551-564. 4. Heiskala K, Giles-Komar J, Heiskala M et al. High expression of RELP (Reg IV) in neoplastic goblet cells of appendiceal mucinous cystadenoma and pseudomyxoma peritonei. Virchows Arch 2006; 448:295-300. 5. Sugarbaker PH. Pseudomyxoma peritonei. A cancer whose biology is characterized by a redistribution phenomenon. Ann Surg 1994; 219:109-111. 6. Sugarbaker PH, Ronnett BM, Archer A et al. Pseudomyxoma peritonei syndrome. Adv Surg 1996; 30:233-280. 7. de Bree E, Witkamp A, Van De Vijver M et al. Unusual origins of Pseudomyxoma peritonei. J Surg Oncol 2000; 75:270-274. 8. Smeenk RM, Bex A, Verwaal VJ et al. Pseudomyxoma peritonei and the urinary tract: involvement and treatment related complications. J Surg Oncol 2006; 93:20-23. 9. Young RH, Gilks CB, Scully RE. Mucinous tumors of the appendix associated with mucinous tumors of the ovary and pseudomyxoma peritonei. A clinicopathological analysis of 22 cases supporting an origin in the appendix. Am J Surg Pathol 1991; 15:415-429. 10. Prayson RA, Hart WR, Petras RE. Pseudomyxoma peritonei. A clinicopathologic study of 19 cases with emphasis on site of origin and nature of associated ovarian tumors. Am J Surg Pathol 1994; 18:591-603. 11. Seidman JD, Elsayed AM, Sobin LH et al. Association of mucinous tumors of the ovary and appendix. A clinicopathologic study of 25 cases. Am J Surg Pathol 1993; 17:22-34. 12. Cuatrecasas M, Matias-Guiu X, Prat J. Synchronous mucinous tumors of the appendix and the ovary associated with pseudomyxoma peritonei. A clinicopathologic study of six cases with comparative analysis of c-Ki-ras mutations. Am J Surg Pathol 1996; 20:739-746. 13. Guerrieri C, Franlund B, Fristedt S et al. Mucinous tumors of the vermiform appendix and ovary, and pseudomyxoma peritonei: histogenetic implications of cytokeratin 7 expression. Hum Pathol 1997; 28:1039-1045. 14. Ronnett BM, Shmookler BM, Diener-West M et al. Immunohistochemical evidence supporting the appendiceal origin of pseudomyxoma peritonei in women. Int J Gynecol Pathol 1997; 16:1-9. 15. Szych C, Staebler A, Connolly DC et al. Molecular genetic evidence supporting the clonality and appendiceal origin of Pseudomyxoma peritonei in women. Am J Pathol 1999; 154:1849-1855. 16. Ronnett BM, Kurman RJ, Zahn CM et al. Pseudomyxoma peritonei in women: a clinicopathologic analysis of 30 cases with emphasis on site of origin, prognosis, and relationship to ovarian mucinous tumors of low malignant potential. Hum Pathol 1995; 26:509-524. 17. Ronnett BM, Zahn CM, Kurman RJ et al. Disseminated peritoneal adenomucinosis and peritoneal mucinous carcinomatosis. A clinicopathologic analysis of 109 cases with emphasis on distinguishing pathologic features, site of origin, prognosis, and relationship to “pseudomyxoma peritonei”. Am J Surg Pathol 1995; 19:1390-1408. 18. Young RH. Pseudomyxoma peritonei and selected other aspects of the spread of appendiceal neoplasms. Semin Diagn Pathol 2004; 21:134-150.

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19. Green N, Gancedo H, Smith R et al. Pseudomyxoma peritonei-nonoperative management and ELRFKHPLFDOÀQGLQJV$FDVHUHSRUW&DQFHU 20. Piver MS, Lele SB, Patsner B. Pseudomyxoma peritonei: possible prevention of mucinous ascites by peritoneal lavage. Obstet Gynecol 1984; 64:95S-96S. 21. El Sayed S. Pseudomyxoma peritonei treated by radiotherapy. Clin Oncol (R Coll Radiol) 1990; 2:120122. 22. Gough DB, Donohue JH, Schutt AJ et al. Pseudomyxoma peritonei. Long-term patient survival with an aggressive regional approach. Ann Surg 1994; 219:112-119. 23. Smith JW, Kemeny N, Caldwell C et al. Pseudomyxoma peritonei of appendiceal origin. The Memorial Sloan-Kettering Cancer Center experience. Cancer 1992; 70:396-401. 24. Miner TJ, Shia J, Jaques DP et al. Long-term survival following treatment of pseudomyxoma peritonei: an analysis of surgical therapy. Ann Surg 2005; 241:300-308. 25. Sugarbaker PH, Gianola FJ, Speyer JC et al. Prospective, randomized trial of intravenous versus LQWUDSHULWRQHDOÁXRURXUDFLOLQSDWLHQWVZLWKDGYDQFHGSULPDU\FRORQRUUHFWDOFDQFHU6XUJHU\ 98:414-422. 26. Mann WJ, Jr., Wagner J, Chumas J et al. The management of pseudomyxoma peritonei. Cancer 1990; 66:1636-1640. 27. Zoetmulder FA, van der Vange N, Witkamp AJ et al. [Hyperthermic intra-peritoneal chemotherapy (HIPEC) in patients with peritoneal pseudomyxoma or peritoneal metastases of colorectal carcinoma; good preliminary results from the Netherlands Cancer Institute]. Ned Tijdschr Geneeskd 1999; 143:1863-1868. 28. Sugarbaker PH, Landy D, Jaffe G et al. Histologic changes induced by intraperitoneal chemotherapy ZLWKÁXRURXUDFLODQGPLWRP\FLQ&LQSDWLHQWVZLWKSHULWRQHDOFDUFLQRPDWRVLVIURPF\VWDGHQRFDUFLnoma of the colon or appendix. Cancer 1990; 65:1495-1501. 29. Sugarbaker PH. Cytoreductive surgery and peri-operative intraperitoneal chemotherapy as a curative approach to pseudomyxoma peritonei syndrome. Eur J Surg Oncol 2001; 27:239-243. 30. Sugarbaker PH. Cytoreductive surgery and intraperitoneal chemotherapy with peritoneal spread of cystadenocarcinoma. Eur J Surg Suppl 1991;75-82. 31. Sugarbaker PH, Zhu BW, Sese GB et al. Peritoneal carcinomatosis from appendiceal cancer: results in 69 patients treated by cytoreductive surgery and intraperitoneal chemotherapy. Dis Colon Rectum 1993; 36:323-329. 32. Witkamp AJ, de Bree E, Van Goethem R et al. Rationale and techniques of intra-operative hyperthermic intraperitoneal chemotherapy. Cancer Treat Rev 2001; 27:365-374.

Chapter 1 12

2

chapter

Pseudomyxoma peritonei and appendiceal neoplasms: a population based study

R.M. Smeenk MD1; M.L.F. van Velthuysen MD PhD2; V.J. Verwaal MD PhD1; F.A.N. Zoetmulder MD PhD1

Department of Surgery1, Department of Pathology2 The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital Amsterdam, the Netherlands

Background: Pseudomyxoma peritonei (PMP) is a rare disease, which is thought to originate from an appendiceal mucinous epithelial neoplasm, but the primary tumour is RIWHQQRWLGHQWLÀHG7KHLQFLGHQFHLVHVWLPDWHGDWRQHSHUPLOOLRQSHU\HDUZLWKIHPDOH dominance. Aim of this study is to evaluate epidemiology of PMP in a nationwide database and substantiate the primary origin of this disease. Methods: The nationwide pathology database of the Netherlands was searched for both primary appendiceal lesions and PMP between 1995 and 2005 to determine incidence, patient characteristics, and histopathological features. In addition, the relation between appendiceal lesions and PMP was investigated. Results: Annually approximately 17.000 appendectomies are performed in the NethHUODQGV $ PXFLQRXV HSLWKHOLDO QHRSODVP ZDV LGHQWLÀHG LQ EHQLJQ malignant) and twenty percent (20%) of these patients developed PMP. Thirteen percent of patients with an appendiceal epithelial neoplasm had an additional epithelial lesion in the colon. From the nationwide database 267 patients (62 men and 205 women) ZLWK303ZHUHLGHQWLÀHGZKLFKGHPRQVWUDWHVDQLQFLGHQFHRI303LQWKH1HWKHUODQGV RI DSSUR[LPDWHO\ SHU PLOOLRQ SHU \HDU 7KH SULPDU\ VLWH ZDV LGHQWLÀHG LQ DQG dominated by the appendix (82%). Although mucinous epithelial neoplasms were more common in women (M:F=1:1.8), the development of PMP in these women was more common than in men with similar lesions (22 vs. 15%). For mucocele and non-mucinous neoplasm the association with PMP was only 2% and 3%, respectively. Conclusions: Patients with an epithelial neoplasm at appendectomy should undergo colonoscopy for additional colonic epithelial neoplasms. Patients with a mucinous epithelial neoplasm of the appendix, especially women, should be followed for development of PMP. Submitted

Population based study of PMP

Introduction .DUO5RNLWDQVN\ÀUVWUHSRUWHGRQDPXFRFHOHRIWKHDSSHQGL[ZLWKPXFLQRXVGHJHQeration.1 A few decennia later in 1884 Werth introduced the term pseudomyxoma peritonei (PMP), literally translated as an untrue mucinous tumour of the peritoneum.2 He described it as a peculiar reaction of the peritoneum to a jelly-like substance in the SHULWRQHDOFDYLW\UHODWHGWRDEHQLJQRYDULDQQHRSODVP,QWKHÀUVW\HDURIWKHIROORZLQJFHQWXU\LWZDV)UDQNHOZKRÀUVWGHVFULEHGWKHUHODWLRQRI303WRWKHUXSWXUHRIDQ appendiceal mucinous cyst.3 Since then there have been numerous reports on origin, histopathology, and epidemiology of PMP. Currently PMP is thought to be associated with appendiceal mucinous epithelial neoplasms.4-8 These tumours tend to form progressive amounts of mucous, which eventually results in the blow-out of the appendix and the release of mucous producing tumour cells in the peritoneal cavity. Free tumour cells are spread throughout the peritoneal FDYLW\ ZKHUH WKH GLVWULEXWLRQ SDWWHUQ VHHPV DVVRFLDWHG ZLWK WKH SHULWRQHDO ÁXLG ÁRZ and gravity.9 Ultimately, progressive peritoneal implants and mucinous ascites arise, the characteristic clinical features of PMP. PMP is often characterized as a benign peritoneal surface disease because tumour cells hardly show any invasive properties, lymphatic metastases are found in only few cases, and there is no hematogenic dissemination. Analysis of tumour specimen has howHYHUVKRZQWKDWWKHUHLVDÁXLGWUDQVLWLRQIURPEHQLJQWRPDOLJQDQWFKDUDFWHULVWLFVDQG LQ RUGHU WR SURYLGH D XVHIXO SDWKRORJLFDO FODVVLÀFDWLRQ 5RQQHWW DQG FROOHDJXHV ÀUVW described a categorization into three pathological subtypes with increasing malignancy grade.10 Disseminated peritoneal adenomucinosis (DPAM) is the subtype with benign characteristics. It is characterized by pools of mucous with only few well-differentiated epithelial tumour cells (high mucus/cell ratio) with no or hardly any atypia. Peritoneal mucinous carcinomatosis (PMCA), the other end of the spectrum, is characterized by larger amounts of moderately or poorly differentiated tumour cells with considerable atypia (and sometimes invasive properties). PMCA is the subtype with malignant features, histopathologically comparable with peritoneal mucinous carcinomatosis of colorectal origin, and a grim prognosis.6,10 Finally, an intermediate subtype PMCA-I is characterized predominantly by features of DPAM but focal characteristics of PMCA. Notwithstanding its convenience, especially regarding the assessment of prognosis, this FODVVLÀFDWLRQ LV QRW DFFHSWHG XQDQLPRXVO\ 2WKHUV FDWHJRUL]H 303 LQWR ORZ RU KLJK malignancy grade.11-13 Because ovarian involvement is seen in the majority of female patients, an ovarian primary has long been suggested the cause of PMP.14-18 However, results of several clinical, histopathological, immunohistochemical and molecular genetic studies strongly suggest

15

that in PMP ovarian tumour deposits are almost always metastases of an appendiceal primary.7,11,19-22 The main purpose of this study was to evaluate PMP epidemiology in the Netherlands and associated appendiceal neoplasms. Furthermore, patients treated at The Netherlands Cancer Institute were evaluated for their representation of the Dutch PMP population.

Methods Databases This study is based on a search in the nationwide pathology database of the Netherlands (Pathologic Anatomic National Automated Archive or PALGA). This database contains anonymous patient characteristics such as age, gender, and conclusions and coded summaries of all pathology reports in the Netherlands since 1992. To relate the number of primary appendiceal neoplasms resulting in PMP to the incidence of these neoplasms, three queries were performed. First the database was searched for all patients with a primary appendiceal epithelial neoplasm or mucocele mentioned in the coded summary. The second query was limited to pathology reports mentioning PMP either in the conclusion or in the coded summary. A third query was performed to search for all appendectomies performed in the Netherlands. All searches regarded the 10-year period from 1995 to 2005. The search on PMP included the entire pathological history of the patients. To investigate whether the patient group of the national cancer institute of the Netherlands is representative for the Dutch PMP patient population, the results of the queries in the nationwide database were compared with a prospective PMP database built at this institute. Both databases obviously display an overlap of patients.

Database analysis and inclusion criteria Primary appendiceal lesions

Chapter 2 16

The diagnosis appendiceal lesion was based on the conclusion of pathology reports from the PALGA database. Appendiceal lesions were categorized into 3 groups: mucoceles; mucinous epithelial neoplasms, consisting of mucinous cystadenoma (MCA) or mucinous adenocarcinoma (MAC); non-mucinous epithelial neoplasms, consisting of villous-, tubular-, serrated adenoma or adenocarcinoma. Metastases in the appendix and carcinoid tumours were excluded from analysis.

Population based study of PMP

PMP The diagnosis PMP was based on the descriptive conclusion of pathology reports from the PALGA database, which had to mention tumour specimen with abundant extra cellular mucus and/or peritoneal mucinous deposits containing no or few (well differentiated) epithelial cells with no or very little cytological atypia. Pathology reports concluding PMP but only mentioning extra cellular mucin were excluded from analysis as the other criteria were not met. Pathology reports concluding PMP but describing an overt mucinous adenocarcinoma were excluded as well. 7KHSULPDU\WXPRXUZDVLGHQWLÀHGDVDSSHQGLFHDOLQFDVHRIDSDWKRORJ\UHSRUWGHVFULEing PMP and a primary appendiceal epithelial neoplasm or a mucocele. In case of SDWKRORJ\UHSRUWVPHQWLRQLQJ303LQERWKWKHDSSHQGL[DQGWKHRYDULHVEXWQRGHÀnite primary origin, the site of origin was diagnosed as consistent with the appendix. This was based on previous criteria formulated after comparing ovarian and appendiceal origins of PMP.11,23303RULJLQZDVFODVVLÀHGDVRYDULDQLQFDVHRI303LQRQHRU two ovaries and a normal appendix in the pathologic history. The difference between the number of PMP patients with an appendiceal primary found in the PMP search (n=148), and the number of PMP patients found in the search for appendiceal neoplasms (n=138) is partly caused by the fact that, in cases of extensive surgery, the appendix is mentioned in the conclusion of the report but not in the coded summary, and partly due to metachronous presentation of the appendiceal lesion.

Statistics Statistical analysis of difference between variables was performed using the Pearson Chi-Square test. Patients with missing data were excluded from analysis. Statistical sigQLÀFDQFHZDVVHWDWDSYDOXHRIOHVVWKDQ'DWDZHUHDQDO\VHGXVLQJWKH6WDWLVWLFDO Package for Social Sciences (SPSS Inc., Chicago, IL), version 11.5, and SAS version 8.2.

Results Primary appendiceal lesions Approximately 170.000 appendectomies were performed in the Netherlands between DQG$QDSSHQGLFHDOPXFRFHOHRUHSLWKHOLDOQHRSODVPZDVLGHQWLÀHGLQ patients (608 men and 874 women), which translates to an incidence of 9 per million per year. The median age of these patients was 61 years (range 7-93) for men and 64 years (range 11-97) for women. A mucocele was found in approximately 1 out of every 300 appendices. One out of every 165 resected appendices contained an epithelial neoplasm, 50% mucinous and 50% non-mucinous. The mucinous epithelial neoplasms were benign in 73% and malig17

nant in 27%, while this distribution was 47% vs. 53% for the non-mucinous epithelial neoplasms. Approximately 1 out of 10 patients with an appendiceal epithelial lesion GHYHORSHG3037KHSUREDELOLW\RIGHYHORSLQJ303ZDVVLJQLÀFDQWO\KLJKHULQSDWLHQWV with a mucinous epithelial neoplasm (20%) than in patients with either a mucocele (2%) or a non-mucinous epithelial neoplasm (3%) (p 60%, depending on pathological subtype and completeness of CRS. Recognising PMP patients in an early stage, in which complete cytoreduction is still achievable, can result in a considerable survival improvement. Ned Tijdschr Geneesk, in press

Three illustrating case histories

Pseudomyxoma peritonei (PMP) is a disease that is characterized by the presence of mucinous tumour deposits on the peritoneal surface and omentum with a progressive quantity of mucinous ascites. PMP is a rare disease with an incidence of approximately 1 per million per year. Since 1995, the Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital (NKI – AVL) has developed into a treatment centre for patients with PMP in the Netherlands.1,2 We want to bring attention to this rare disease, which sometimes is not recognized as such, by presenting three case histories.

Case histories Patient A, a 47-year old man, was admitted elsewhere for appendectomy due to a susSHFWHGDFXWHDSSHQGLFLWLVZLWKDSSHQGLFHDOLQÀOWUDWLRQ3DWKRORJLFDOH[DPLQDWLRQRIWKH appendix revealed a cystadenoma. The patient was seen again 4 years later with vague XSSHUDEGRPLQDOFRPSODLQWVDQGDGLVWHQGHGDEGRPHQ&($ZDVUDLVHGƬJO 5). A computed tomography (CT) scan and a biopsy suggested PMP. Laparotomy was performed in our hospital, during which a massive amount of mucinous ascites was removed, the peritoneal surface was stripped and a distal gastrectomy, transverse colon resection, ileocoecum resection, partial small bowel resection, rectum resection, cholecystectomy, peritonectomy, and omentectomy were performed. Unfortunately, the entire tumour mass could not be removed: some small PMP deposits were left behind on the small bowel surface and in the sub hepatic region. Then the abdominal cavity ZDVZDVKHGSHURSHUDWLYHO\ZLWK0LWRP\FLQ&VROXWHLQDKHDWHGODYDJHÁXLGK\SHUWKHUmic intraperitoneal chemotherapy or HIPEC), after which necessary bowel anastomoses were made. The postoperative period was uncomplicated and the patient was released 18 days after operation. Pathological examination showed PMP specimen with few epithelial cells and very little atypia. Because of the latter, systemic chemotherapy (5Fluorouracil/Leucovorin) was given. In the next years, there was slow progression of disease and 69 months after the primary treatment a second procedure of CRS and HIPEC was performed. This time a macroscopic complete cytoreduction could be accomplished. The postoperative period was uncomplicated. At a recent follow-up, 19 months after the second procedure, there was no evidence of disease. Patient B, a 30-years old man from Portugal, was referred to our institute due to progressive abdominal distension and suspicion of PMP. A laparoscopy and intra-abdominal ELRSV\ FRQÀUPHG WKH GLDJQRVLV ,Q DGGLWLRQ WXPRXU PDUNHUV ZHUH UDLVHG &($ ƬJO&$N8O 6XUJHU\UHYHDOHGDSHUIRUDWHGWXPRXURIWKHDSSHQGL[ and extensive peritoneal tumour growth. Four litres of mucinous ascites were drained. The peritoneum was stripped and an ileocoecum resection, a rectosigmoid resection, a subtotal gastrectomy, a splenectomie, a cholecystectomy, an omentectomy, and peritonectomy were performed, by which a macroscopic complete cytoreduction was 29

accomplished. After this, the lavage with HIPEC was performed. The postoperative period was uncomplicated and the patient could be discharged 14 days after operation. Pathological examination showed a primary villous adenoma of the appendix and PMP with only few epithelial cells without atypia. Additional systemic chemotherapy was therefore withdrawn. Nine months after treatment there was mass recurrence with ascites. Histology showed a well-differentiated adenocarcinoma, demonstrating dedifferentiation of tumour cells. Despite treatment with 5-Fluorouracil, Leucovorin and Oxaliplatin, progressive disease developed and the patient died ten months after the diagnosis of recurrence. Patient C, a 48-year old woman, was admitted to a hospital elsewhere for the treatment of an ovarian neoplasm. At laparotomy the uterus, ovaries and omentum were resected. Pathological examination showed PMP originating from a mucinous cystadenoma of the appendix with ovarian metastases. Initially no treatment was started, but after a rise in tumour marker CA-125 systemic chemotherapy (Endoxan/Carboplatin) was given. Despite this, recurrence developed and she was referred to our institute. CEA ZDVDWWKDWPRPHQWƬJODQG&$ZDVN8O7KHSHULWRQHXPZDVVWULSSHG and a subtotal gastrectomy, a subtotal colectomy, a splenectomy, a cholecystectomy, and an omentectomy were performed. A complete cytoreduction could however not be achieved and tumour residues of less than 2.5mm thick remained around the liver and RQWKHVPDOOERZHO6XEVHTXHQWO\WKHSHULWRQHDOFDYLW\ZDVÁXVKHGZLWK+,3(&DQGD colostomy was constructed. Pathological examination revealed extra cellular mucus with few epithelial cells with no atypia. This resulted in abandoning systemic chemotherapy. The postoperative period was initially uncomplicated and the patient was released after GD\V+RZHYHUDIHZPRQWKVODWHUDYHVLFRYDJLQDOÀVWXODKDGGHYHORSHGIRUZKLFK surgery of the bladder was performed. The colostomy was removed 3 years after initial treatment. At last follow-up, 7 years and 5 months after initial treatment there was no evidence of disease.

Discussion Pathogenesis

Chapter 3 30

In PMP the primary tumour is usually a mucinous (cyst)adenoma of the appendix.3 Progressive intraluminal mucous production and obstruction eventually results in a mucocele. When this mucocele perforates, mucous producing tumour cells are released in the abdominal cavity, where they do not grow in the vicinity of the perforation to multiply locally like as in a carcinoma, but are spread throughout the peritoneal cavity conforming to the redistribution phenomenon.4 This pattern of dissemination is FKDUDFWHUL]HGE\WKHSDVVLYHPRYHPHQWRIWXPRXUFHOOVDORQJZLWKWKHSHULWRQHDOÁXLG ÁRZ7KLVFXUUHQW PRYHVDZD\IURPWKHVPDOOERZHODQGPHVHQWHU\ZKHUHWKHÁXLG


is produced, and passes the paracolic gutters towards omentum and diaphragm, where WKHÁXLGLVUHDEVRUEHG$WWKHVHORFDWLRQVWXPRXUFHOOVJHWVWXFNLQWKHRSHQODFXQDV RIO\PSKYHVVHOVDQGPD\IRUPDODUJHWXPRXUPDVVOLNHWKHRPHQWDOFDNHÀJXUH ,Q addition, gravity transports tumour cells and mucous to the pelvis, where in women a large ovarian tumour mass can develop. Finally, tumour cells may accumulate at sticky surgical wound surfaces. Altogether, this explains the characteristic distribution of PMP with limited tumour at the primary appendix site and often massive tumour on the ovaries, omentum and sub diaphragmatic space.3 The small bowel is, because of its mobility in contrast to other intraperitoneal viscera, usually free from tumour until a late stage. Histopathologically, PMP is essentially a benign tumour. Histology shows adenomatous epithelial cells that are of GI tract origin on immunohistochemistry, show little mitosis, and show no tendency of invasive growth or systemic metastasis. There is however a gradual transition from pure benign PMP to PMP with more malignant features. Ronnett and colleagues divided PMP in 3 pathological subtypes with different pathological characteristics (grade of malignancy) and prognosis.57KHLPSRUWDQFHRIWKLVFODVVLÀFDtion is found in the determination of prognosis and evaluation of additional treatment. Dedifferentiation from low to high malignancy grade has been observed at time of UHFXUUHQWRUSURJUHVVLYHGLVHDVHDQGLQÁXHQFHVSURJQRVLVQHJDWLYHO\6

Presenting symptoms PMP is actually a clinical diagnosis. The median age of PMP patients is 57 years. The classic presentation sign (in 23% of patients) is increasing abdominal girth, the so-called -HOO\%HOO\FDXVHGE\SURJUHVVLYHPXFLQRXVDVFLWHV,QRIZRPHQWKHÀUVWV\PSWRPLV an ovarian mass. These patients are usually in a late stage of disease. In some cases (14%), PXFRXVLVIRXQGGXULQJWKHUHSDLURIDKHUQLDOVDFN,QRISDWLHQWVWKHÀUVWV\PSWRP is acute appendicitis. In contrast, these patients are in the early stage of the disease.

Figure 1. Omental cake of PMP.

31

Ultrasonography shows mucinous ascites and in many cases a pathologic omental cake or an ovarian mass. The common imaging technique consists of CT, which shows ascites of somewhat higher density than normal ascites, with typical thumb printing on the liver VXUIDFH DQG FRPSUHVVLRQ RI WKH LQWHVWLQHV ÀJXUH 7KH GLDJQRVLV LV FRPSOHWH ZKHQ aspiration obtains sticky mucous, with no or very few epithelial cells. Approximately 60% of PMP patients have an increased CEA and/or CA 19.9.7

Figure 2. CT scan with characteristic signs of PMP: thumbprints on the liver surface (1) and compression of the intestines (2) by the large amount of mucinous ascites.

Treatment

Chapter 3 32

Traditionally, treatment of PMP has consisted of serial surgical cytoreductions, without an effort to be complete.8 Usually this means evacuating all mucinous ascites and performing an appendectomy, ileocolectomy, omentectomy, and/or ovariectomy. The result of this approach is excellent in the short term. Morbidity is low and patients recover to lead a normal life. However, almost all will have a recurrence in a few years time. A VHFRQGF\WRUHGXFWLRQLVXVXDOO\PRUHGLIÀFXOWDQGOHVVVXFFHVVIXO7KHVHFRQGV\PSWRP free interval is shorter and followed by a third operation and a fourth until either the tumour becomes completely inoperable and the patient dies of cachexia as result of a lack of functional bowel, or the patient dies of treatment related complications. Gough et al. published a series of 26 patients treated this way with a median survival of almost 3 years and a 5-year survival of 10%.9 The surgeon Sugarbaker, introduced the so-called peritonectomy procedures. This surgical technique aims at the complete removal of PMP tissue through extra peritoneal dissection. These peritonectomy procedures can be very helpful, especially in the pelvis and sub diaphragmatic areas.10 Recently, the Memorial Sloan Kettering group published their experience with this aggressive form of cytoreductive surgery (CRS). In 97 cases, they were able to perform a complete cytoreduction in 55%. The 10-year survival rate


was 21%, but only 12% of patient was free of disease. Completeness of cytoreduction and histology were strong prognostic indicators.11 Sugarbaker is one of the advocates of combining CRS with HIPEC. The idea of the HIPEC is to expose residual microscopic or macroscopic tumour cells to very high doses of heated chemotherapy.12 The major advantage of HIPEC is the local effect that can never be reached by systemic exposure, due to general toxicity. In the NKI – AVL, CRS is combined with intraoperative HIPEC with Mitomycin C (35 mg/m2) at a temperature of 40-41 C for 90 minutes. Figure 3 shows a scheme of our HIPEC lavage V\VWHPDQGÀJXUHVKRZVWKHSHURSHUDWLYHVHWWLQJ7KH+,3(&SURFHGXUHLVGHVFULEHG in detail by Verwaal and colleagues.13 The NKI-AVL is the only treatment centre in the Netherlands for patients with PMP, but for more than a year there has been already a close collaboration with the Sint Antonius Hospital in Nieuwegein. Expansion of the number of Dutch treatment centres for PMP seems unnecessary because of the low incidence.

Figure 3. Scheme of HIPEC lavage system.

&56ZLWK+,3(&VHHPVDQHIÀFLHQWWUHDWPHQWVWUDWHJ\IRU303SDWLHQWVZLWKDFRQsiderable long term survival, despite the relatively high treatment related morbidity and mortality.2,14-21 In patients with a complete cytoreduction and low malignancy grade a 5year survival probability of more than 80% is realistic. Patients with a high malignancy grade however suffer the same poor prognosis as patients with peritoneal carcinomatosis of colorectal cancer with a 5-year survival probability of 20-25%. 33

Figure 4. Peroperative setting of the ´RSHQ DEGRPHQ WHFKQLTXHµ LQÁRZ drain; 2: temperature probe; 3: clamp for OLIWLQJRI WKHDEGRPHQRXWÁRZGUDLQ

The use of additional systemic chemotherapy for PMP with malignant features is based on the employment of systemic therapy in patients with peritoneal carcinomatosis of colorectal cancer origin. The value of systemic therapy in such a loco regional disease as PMP is however questionable, as the history of patient B and C illustrates.6,15 In our institute we have currently changed our regimen for PMP patients with high malignancy grade from 5-Fluorouracil and Leucovorin to Xeloda. The future must reveal the additional value of this treatment approach.

Conclusion Pseudomyxoma peritonei is a rare disease that originates in most cases from a mucinous adenoma of the appendix. With CT scan and a histological biopsy, one can usually ascertain the right diagnosis. As PMP is restricted to the peritoneal cavity, it is very suitable for a loco regional approach such as CRS plus HIPEC.

References

Chapter 3 34

1. Zoetmulder FA, van der Vange N, Witkamp AJ et al. [Hyperthermic intra-peritoneal chemotherapy (HIPEC) in patients with peritoneal pseudomyxoma or peritoneal metastases of colorectal carcinoma; good preliminary results from the Netherlands Cancer Institute]. Ned Tijdschr Geneeskd 1999; 143:1863-1868. 2. Smeenk RM, Verwaal VJ, Zoetmulder FA. Toxicity and mortality of cytoreduction and intraoperative hyperthermic intraperitoneal chemotherapy in pseudomyxoma peritonei-a report of 103 procedures. Eur J Surg Oncol 2005. 3. Sugarbaker PH, Ronnett BM, Archer A et al. Pseudomyxoma peritonei syndrome. Adv Surg 1996; 30:233-280. 4. Sugarbaker PH. Pseudomyxoma peritonei. A cancer whose biology is characterized by a redistribution phenomenon. Ann Surg 1994; 219:109-111.

Three illustrating case histories 5. Ronnett BM, Zahn CM, Kurman RJ et al. Disseminated peritoneal adenomucinosis and peritoneal mucinous carcinomatosis. A clinicopathologic analysis of 109 cases with emphasis on distinguishing pathologic features, site of origin, prognosis, and relationship to “pseudomyxoma peritonei”. Am J Surg Pathol 1995; 19:1390-1408. 6. Smeenk RM, Verwaal VJ, Antonini N, Zoetmulder FA. Progressive pseudomyxoma peritonei after combined modality treatment: management and outcome. Ann Surg Oncol . 2006. Ref Type: In Press 7. Carmignani CP, Hampton R, Sugarbaker CE et al. Utility of CEA and CA 19-9 tumor markers in diagnosis and prognostic assessment of mucinous epithelial cancers of the appendix. J Surg Oncol 2004; 87:162-166. 8. Dejong CH, Booster MH, Theunissen PH et al. [Pseudomyxoma peritonei]. Ned Tijdschr Geneeskd 1997; 141:1196-1198. 9. Gough DB, Donohue JH, Schutt AJ et al. Pseudomyxoma peritonei. Long-term patient survival with an aggressive regional approach. Ann Surg 1994; 219:112-119. 10. Sugarbaker PH. Peritonectomy procedures. Surg Oncol Clin N Am 2003; 12:703-27, xiii. 11. Miner TJ, Shia J, Jaques DP et al. Long-term survival following treatment of pseudomyxoma peritonei: an analysis of surgical therapy. Ann Surg 2005; 241:300-308. 12. Witkamp AJ, de Bree E, Van Goethem R et al. Rationale and techniques of intra-operative hyperthermic intraperitoneal chemotherapy. Cancer Treat Rev 2001; 27:365-374. 13. Verwaal VJ, van Ruth S, de Bree E et al. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol 2003; 21:3737-3743. 14. Sugarbaker PH. New standard of care for appendiceal epithelial neoplasms and pseudomyxoma peritonei syndrome? Lancet Oncol 2006; 7:69-76. 15. Smeenk RM, Verwaal VJ, Zoetmulder FA. Survival analysis of pseudomyxoma peritonei treated by cytoreductive surgery in combination with intraoperative hyperthermic intraperitoneal chemotherapy. Ann Surg . 2006. Ref Type: In Press 16. Guner Z, Schmidt U, Dahlke MH et al. Cytoreductive surgery and intraperitoneal chemotherapy for pseudomyxoma peritonei. Int J Colorectal Dis 2005; 20:155-160. 17. Deraco M, Baratti D, Inglese MG et al. Peritonectomy and intraperitoneal hyperthermic perfusion ,3+3 DVWUDWHJ\WKDWKDVFRQÀUPHGLWVHIÀFDF\LQSDWLHQWVZLWKSVHXGRP\[RPDSHULWRQHL$QQ6XUJ Oncol 2004; 11:393-398. 18. Elias D, Laurent S, Antoun S et al. [Pseudomyxoma peritonei treated with complete resection and immediate intraperitoneal chemotherapy]. Gastroenterol Clin Biol 2003; 27:407-412. 19. Loungnarath R, Causeret S, Bossard N et al. Cytoreductive surgery with intraperitoneal chemohyperthermia for the treatment of pseudomyxoma peritonei: a prospective study. Dis Colon Rectum 2005; 48:1372-1379. 20. Moran BJ. Establishment of a peritoneal malignancy treatment centre in the United Kingdom. Eur J Surg Oncol 2006; 32:614-618. 21. Bryant J, Clegg AJ, Sidhu MK et al. Systematic review of the Sugarbaker procedure for pseudomyxoma peritonei. Br J Surg 2005; 92:153-158.

35

4

chapter

Toxicity and mortality of cytoreduction and intra-operative hyperthermic intraperitoneal chemotherapy in pseudomyxoma peritonei - A report of 103 procedures -

R. M. Smeenk., V. J. Verwaal, F.A.N. Zoetmulder

Department of Surgery The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital Amsterdam, the Netherlands

Aims: To report on treatment related toxicity and mortality in patients with pseudomyxoma peritonei (PMP) treated by cytoreduction in combination with intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) and to identify prognostic factors. Methods: A review was performed of 103 procedures of cytoreduction and intraoperative HIPEC for PMP between 1996 and 2004. Toxicity was graded according to the 1DWLRQDO&DQFHU,QVWLWXWH&RPPRQ7R[LFLW\&ULWHULD1&,&7& FODVVLÀFDWLRQ$VXUJLFDOFRPSOLFDWLRQZDVGHÀQHGDVDQ\SRVWRSHUDWLYHHYHQWWKDWQHHGHGUHLQWHUYHQWLRQ Pre and peroperative factors were studied on their relationship to toxicity and mortality. Results: The median hospital stay was 21 days (4-149) with a treatment related toxicity of 54% and a 30 days mortality of 3%. In univariate analysis, toxicity was associated with abdominal tumour load (p 2.5mm in any region.

Treatment One hundred and fourteen procedures were performed in 103 patients. The ability to achieve complete cytoreduction was correlated with the tumor load (p0.05). Table 1 shows the locations of SURJUHVVLYHGLVHDVH3URJUHVVLYHGLVHDVHRQVXUJLFDOZRXQGVXUIDFHVQ ZDVFRQÀQHG to stomach/bowel (n=6), abdominal wall/scar (n=3), colostomy (n=1), and vagina-top (n=1). Extraperitoneal disease was observed in the pleural cavity (n=4) and retroperitoneal in the ureter (n=1). Pathology at progression was categorized as DPAM or PMCA-I in 25 and 14 patients, respectively. Dedifferentiation was observed in 8/39 patients (20%). In 4 patients dedifferentiation was diagnosed at biopsy or obduction. In another 4 patients early aggressive progression (n=3) or distant metastasis (n=1) strongly suggested dedifferentiation compared to the original DPAM histology. In 4 of these 8 patients progressive disease was located in multiple regions.

Management and outcome of progressive disease Table 2 shows the management and outcome of progressive disease and the association of the choice of treatment with pathological subtype, result of initial cytoreduction and 3)67KHPHGLDQLQWHUYDOEHWZHHQGLDJQRVLVRIÀUVWSURJUHVVLRQDQGVXUJLFDOWUHDWPHQW was 3.4 months (range 0.5-53.1). Figure 2 shows the impact of PFS (after initial CRS) on WKH26SUREDELOLW\DIWHUWKHÀUVWSURJUHVVLRQ LQSDWLHQWVZLWKSURJUHVVLYHGLVHDVH

Figure 2. Overall survival probability after progression related to the progression free survival (PFS) after initial treatment in patients with progressive PMP after primary CRS and HIPEC. PMP, pseudomyxoma peritonei; CRS, cytoreductive surgery; HIPEC, hyperthermic intraperitoneal chemotherapy.

77

The 3-year PFS probability and the 3-year OS probability after a second procedure of CRS and HIPEC (n=8) was 42.9% (95% CI 18.2%-100%) and 100%, respectively. In 2 of these patients systemic chemotherapy was given prior to the second procedure. In case of a surgical intervention only (n=10) 3-year PFS probability and 3-year OS probability was 22.2% (95% CI 6.5%-75.4%) and 53.3% (95% CI 28.2%-100%), respectively. In 2 of these patients, with DPAM subtype, a second procedure of CRS and +,3(&KDGEHHQSHUIRUPHGIRUDVHFRQGSURJUHVVLRQWKUHH\HDUVDIWHUWKHÀUVW%RWK patients had no evidence of disease at end of follow up. One patient, with local progression of DPAM in the abdominal scar, had been treated three times with a local resection. At end of follow up, 47.9 months after the primary treatment there was no evidence of disease. Fifteen patients with progression were observed and 42.9% of these patients (95% CI 18.2%-100%) showed no further progress during the 3 years after the diagnosis of proJUHVVLRQ,QRQHRIWKHVHSDWLHQWVZLWK'3$0VXEW\SHÀQDOO\VHFRQG&56SOXV+,3(& was performed because of slowly diffuse progression. This patient was alive with disease at end of follow up. Three-year OS probability of this treatment group was 66.0% (95% CI 43.4%-100%). All patients that had died of disease had the PMCA-I subtype. Six patients were treated for progressive disease with systemic chemotherapy. Three patients with initial DPAM subtype were treated this way as they had showed dedifferentiation into PMCA-I at progression. Table 2. Management and outcome of progressive PMP after primary CRS with HIPEC, associated with pathology at time of diagnosis, result of initial CRS and PFS after primary treatment. Extent Treatment for Initial Result of Median PFS after Median FU Outcome progression (n) pathology (n) initial initial CRS and after treatment for (n) CRS (n) HIPEC, progression, in months in months (95% CI) (range) Limited Surgery only (10) DPAM (4) R1 (1) 21.7 (14.4-33.6) 18.1 (2.3-49.6) NED (6) PMCA-I (6) R2a (8) AWD (1) R2b (1) DOD (3) Observation (15) DPAM (10) R1 (2) 64.4 (15.8,->) 16.8 (3.4-70.3) AWD (11) PMCA-I (5) R2a (8) DOD (4) R2b (5) Diffuse

Chapter 7 78

2nd HIPEC (8)

DPAM (8)

R1 (1) R2a (7)

34.1 (13.8-68.3)

19.3 (8.8-56.6)

NED (2) AWD (2) DOD (4) DOD (6)

Systemic chemo DPAM (3) R2a (5) 14.3 (12.8-17.3) 14.8 (9.8-33.6) only (6) PMCA-I (3) R2b (1) PMP, pseudomyxoma peritonei; CRS, cytoreductive surgery; HIPEC, hyperthermic intraperitoneal FKHPRWKHUDS\3)6SURJUHVVLRQIUHHVXUYLYDO&,FRQÀGHQFHLQWHUYDO)8IROORZXS'3$0GLVVHPLQDWHG peritoneal adenomucinosis; PMCA-I: intermediate pathological subtype; R1, no macroscopic tumor residue; 5DPDFURVFRSLFUHVLGXHPPLQDQ\UHJLRQ5EPDFURVFRSLFUHVLGXH!PPLQDQ\UHJLRQ1('QR evidence of disease; AWD, alive with disease; DOD, died of disease.

Progressive PMP

Discussion PMP has been traditionally treated by limited CRS consisting of removal of the free mucus and resection of both the appendiceal primary and dominant metastatic sites such as the ovaries and omentum. In the short run this approach has been safe and successful in improving the patient’s well being. Recurrence or progression is however inevitable and leads to further surgery that is usually less successful. Intervals get shorter and eventually all surgical options are exhausted or patients die as consequence of surgical complications13. More aggressive surgery, which aims at complete removal of tumor in all affected areas, seems to prolong survival. Still in a recent series only 12% of patients remained free of disease at end of follow-up.14 The combination of complete CRS by the use of peritonectomy procedures and hyperthermic intraperitoneal chemotherapy (HIPEC) aims to further reduce the percentage of recurrence and progression. A number of series using this approach has now been published, showing indeed that long-term disease free and progression free survival can be improved.3-6,15,16 Still, even after this combined modality treatment progression was observed in our series in 41% of cases. In other published series recurrence or progression rates of 40-70% have been reported.6,7,15 As in other series, we observed that pathological subtype and result of initial cytoreduction were the dominant factors related to progression.3,10,17 The diagnosis of progressive disease is not always easy. After extensive surgery CT VFDQVDUHXVXDOO\GLIÀFXOWWRLQWHUSUHWGXHWRSRVWVXUJLFDOFKDQJHV:HIRXQGLWXVHIXO to make a baseline CT scan 3 months after primary CRS plus HIPEC and compare IXUWKHU&7VFDQVZLWKWKDW3URJUHVVLYHGLVHDVHZDVGHÀQHGDVDPDUNHGUDLVHRIVHUXP tumor markers and/or progressive masses on CT scan. A dominant site of progressive disease has been the sub hepatic region. This is the DUHD LQ ZKLFK LW LV WHFKQLFDOO\ YHU\ GLIÀFXOW WR UHDFK D FRPSOHWH F\WRUHGXFWLRQ 7KLV strongly suggests that incomplete resection is the dominant factor causing progression. Apparently HIPEC is not effective when large tumor residue is left behind. This is in accordance with our understanding of the action of HIPEC, which is probably only UHDFKLQJDQHIIHFWLYHGUXJKHDWGRVHVDWDVXSHUÀFLDOOHYHO7KXVSURJUHVVLYHGLVHDVHLQ one or two regions probably represents surgical failure, not HIPEC failure. In contrast, 36% of progressive disease was spread more diffuse in the abdomen, including areas that were left macroscopically free of disease. These patients seem to represent the failure of HIPEC to sterilize microscopic disease. Although this did not UHDFKVWDWLVWLFDOVLJQLÀFDQFH303ZLWKPRUHPDOLJQDQWIHDWXUHV30&$,GHGLIIHUHQtiated DPAM) was overrepresented in this pattern of failure. It seems that these cases represent the pattern of failure caused by the biology of PMP itself. Laparotomy scar, top of the vagina and bowel suture lines were incidentally observed WRKDUERUSURJUHVVLYHGLVHDVH,QWKHVHFDVHVLQFRPSOHWHH[SRVXUHWRWKHSHUIXVLRQÁXLG 79

was probably the cause of progression. In 5 patients progressive disease was found outside the abdominal cavity, especially in the thoracic cavity (n=4). Opening of routes to extra peritoneal spaces during CRS is probably the cause of this way of dissemination.8,18 Since we leave the diaphragm open during perfusion after CRS in this area, so effectively including the involved pleural cavity in the perfusion, this has not been observed anymore. In one patient metastasis to the bones was observed. As PMP is a non-invasive neoplasm, this true metastatic disease is probably the result of dedifferentiation into PMCA.

Chapter 7 80

7KHPDQDJHPHQWRISURJUHVVLYH303GXULQJWKLV\HDUVWXG\SHULRGKDVEHHQLQÁXenced by our increasing experience. Consequently not always the same treatment choices KDYHEHHQPDGH7KLVPDNHVLVGLIÀFXOWWRGUDZÀUPFRQFOXVLRQVRXWRIWKLVH[SHULence. The progression free survival after initial CRS and HIPEC is the only statistically VLJQLÀFDQWIDFWRUSUHGLFWLQJORQJWHUPVXUYLYDODIWHUWUHDWPHQWIRUSURJUHVVLYHGLVHDVH This seems closely related to tumor biology. In patients with PMCA-I and in patients presenting with dedifferentiated progressive disease the progression free survival tended to be short and the outcome of treatment of progressive disease poor. Based on our experience we now use the following algorithm. Patients with early progressive disease (short PFS) diffusely spread throughout the abdomen, usually PMCA-I subtype, are treated with (palliative) systemic chemotherapy, as prognosis in these patients is already very poor. However, the effect of chemotherapy is questionable as all patients in our series treated this way died within 3 years. Patients with early progressive disease limited to one or two regions are treated with simple resection. Such limited (residual) disease can easily be resected one more time. It seems obvious though, that patients with PMCA-I subtype have less chance of improved survival than DPAM patients as result of tumor biology. Patients with late progressive disease (long PFS) diffusely spread throughout the abdomen or diffuse progression after simple resection, and in good general health, are WUHDWHGZLWKDVHFRQGSURFHGXUHRI&56DQG+,3(&7KHVHSDWLHQWVPLJKWEHQHÀWIURP another curative attempt. Besides there is a group of patients with very indolent tumor behavior, with limited disease and hardly any progression over a long period of time, who are simply followed. In these cases it is probably worthwhile to observe before deciding to perform surgery with all its disadvantages. Because of the inherent differences in prognosis in these different patient groups it is impossible to judge the relative effectiveness of these different approaches. The exception is the group that received systemic chemotherapy. We did not observe any objective response on 5 FU based chemotherapy in these patients. It is questionable whether modern schedules including Capecitabin, Oxaliplatin and Bevacuzimab will do any better.

Progressive PMP

Notwithstanding the limitations of this study it is clear that management of progressive PMP after primary aggressive CRS and HIPEC is worthwhile and can result in longterm survival in a considerable percentage of patients. A second HIPEC is probably best restricted to patients with benign disease and progression free survival exceeding 1 year.

References 1. Sugarbaker PH. Pseudomyxoma peritonei. A cancer whose biology is characterized by a redistribution phenomenon. Ann Surg 1994; 219:109-111. 2. Deraco M, Gronchi A, Mazzaferro V et al. Feasibility of peritonectomy associated with intraperitoneal hyperthermic perfusion in patients with Pseudomyxoma peritonei. Tumori 2002; 88:370-375. 3. Elias D, Laurent S, Antoun S et al. [Pseudomyxoma peritonei treated with complete resection and immediate intraperitoneal chemotherapy]. Gastroenterol Clin Biol 2003; 27:407-412. 4. Sugarbaker PH. Cytoreductive surgery and peri-operative intraperitoneal chemotherapy as a curative approach to pseudomyxoma peritonei syndrome. Eur J Surg Oncol 2001; 27:239-243. 5. Guner Z, Schmidt U, Dahlke MH et al. Cytoreductive surgery and intraperitoneal chemotherapy for pseudomyxoma peritonei. Int J Colorectal Dis 2005; 20:155-160. 6. Deraco M, Baratti D, Inglese MG et al. Peritonectomy and intraperitoneal hyperthermic perfusion ,3+3 DVWUDWHJ\WKDWKDVFRQÀUPHGLWVHIÀFDF\LQSDWLHQWVZLWKSVHXGRP\[RPDSHULWRQHL$QQ6XUJ Oncol 2004; 11:393-398. 7. Bryant J, Clegg AJ, Sidhu MK et al. Systematic review of the Sugarbaker procedure for pseudomyxoma peritonei. Br J Surg 2005; 92:153-158. 8. Zoetmulder FA, Sugarbaker PH. Patterns of failure following treatment of pseudomyxoma peritonei of appendiceal origin. Eur J Cancer 1996; 32A:1727-1733. 9. Gough DB, Donohue JH, Schutt AJ et al. Pseudomyxoma peritonei. Long-term patient survival with an aggressive regional approach. Ann Surg 1994; 219:112-119. 10. Sugarbaker PH, Fernandez-Trigo V, Shamsa F. Clinical determinants of treatment failure in patients with pseudomyxoma peritonei. Cancer Treat Res 1996; 81:121-132. 11. Verwaal VJ, van Tinteren H, Ruth SV et al. Toxicity of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. J Surg Oncol 2004; 85:61-67. 12. Ronnett BM, Zahn CM, Kurman RJ et al. Disseminated peritoneal adenomucinosis and peritoneal mucinous carcinomatosis. A clinicopathologic analysis of 109 cases with emphasis on distinguishing pathologic features, site of origin, prognosis, and relationship to “pseudomyxoma peritonei”. Am J Surg Pathol 1995; 19:1390-1408. 13. Lang H, Jahne J, Flemming P et al. Pseudomyxoma peritonei of appendiceal origin--a report of seven cases and a review of published reports. Eur J Surg 1995; 161:355-360. 14. Miner TJ, Shia J, Jaques DP et al. Long-term survival following treatment of pseudomyxoma peritonei: an analysis of surgical therapy. Ann Surg 2005; 241:300-308. 15. Moran BJ, Mukherjee A, Sexton R. Operability and early outcome in 100 consecutive laparotomies for peritoneal malignancy. Br J Surg 2005. 16. Loungnarath R, Causeret S, Bossard N et al. Cytoreductive surgery with intraperitoneal chemohyperthermia for the treatment of pseudomyxoma peritonei: a prospective study. Dis Colon Rectum 2005; 48:1372-1379. 17. Yan H, Pestieau SR, Shmookler BM et al. Histopathologic analysis in 46 patients with pseudomyxoma peritonei syndrome: failure versus success with a second-look operation. Mod Pathol 2001; 14:164171. 18. Smeenk RM, Bex A, Verwaal VJ et al. Pseudomyxoma peritonei and the urinary tract: involvement and treatment related complications. J Surg Oncol 2006; 93:20-23.

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8

chapter

Pseudomyxoma peritonei and the urinary tract: Involvement and treatment related complications

R.M. Smeenk1, A. Bex2 , V.J. Verwaal1,S. Horenblas2 , F.A.N. Zoetmulder1

Department of Surgery1, Department of Urology2 The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital Amsterdam, the Netherlands

Background: Pseudomyxoma peritonei (PMP) is a rare clinical syndrome characterized by intraperitoneal accumulation of mucus produced by neoplastic cells of mostly appendiceal origin. The aim of this study was to analyze primary and secondary involvement and treatment related complications of the urinary tract in pseudomyxoma peritonei. Methods: A retrospective study of 92 patients with PMP, treated by cytoreduction and intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) at the Netherlands Cancer Institute between 1996 and 2004. Results: Seven patients presented with involvement of the urinary tract. Major urologic FRPSOLFDWLRQVRFFXUUHGLQÀYHSDWLHQWVRIZKLFKWZRKDGVHFRQGDU\LQYROYHPHQWRIWKH urinary tract. Major urologic complications consisted predominantly of surgical complications related to the bladder. All patients with secondary involvement and/or urologic complications had undergone previous pelvic surgery. Conclusions: The urinary tract is rarely involved in patients with PMP. Secondary involvement is mostly observed and may be a result of seeding of PMP of pelvic origin after prior pelvic surgery. There is a low urologic complication risk of treatment with cytoreduction and HIPEC. The combination of secondary involvement and previous pelvic surgery is an omen of treatment related urologic complications, necessitating (surgical) re-interventions and further management in close collaboration with urologists. J Surg Oncol 2006 Jan 1;93(1):20-3

PMP and the urinary tract

Introduction Pseudomyxoma peritonei (PMP) is a rare syndrome characterized by an extensive spread of intraperitoneal mucus and therefore patients mostly present with abdominal distension. Adenomucinous epithelial cells along peritoneal surfaces and omentum, derived from a ruptured intra-abdominal neoplasm are responsible for the mucus production. Most commonly the pathological origin is an adenoma or well-differentiated adenocarcinoma of the appendix (or the ovaries)1-4. Other primary tumor sites are rare and include pancreas4-6, stomach4, colon4,7, small bowel4. In unusual cases the urinary tract may be the primary source of PMP and few cases of mucinous adenocarcinomas originating from the urachus4,8-12 have been described. Contrary to these exceptional primary urologic sites, little is known about the secondary involvement of the urinary tract related to PMP growth13-15. Due to intraperitoneal seeding and its most common primary site of origin, PMP occurs at predictable abdominal sites such as the vesicorectal space, right colic fossa, right hemi diaphragmatic space and omentum. As most parts of the urinary tract are anatomically either retroperitoneal or extraperitoneal, secondary involvement is not very likely. The cornerstone of treatment of PMP is extensive cytoreductive surgery in combination with intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC). Complications of the urinary tract as a consequence of this aggressive management are not known. The aim of this study was to assess primary and secondary involvement of the urinary tract in PMP, and to analyze treatment related urologic complications.

Materials and methods Patients were diagnosed with PMP based on excessive abdominal mucus with characteristic distribution and on histology consistent with DPAM (disseminated peritoneal adenomucinosis), PMCA (peritoneal mucinous carcinomatosis) or PMCA-I (intermediate group), according to the criteria of Ronnett et al.16. There was no evidence of liver- or lung metastases on abdominal and chest computed tomography scans. Between 1996 and 2004, 92 patients were included. Eight patients underwent a second procedure because of recurrence. Each procedure was recorded as a single case. Patients were treated at the Netherlands Cancer Institute. The principles of cytoreduction and HIPEC are described in detail by Verwaal et al.17. %ULHÁ\WUHDWPHQWRI303FRQVLVWVRIVXUJLFDOUHVHFWLRQRIPDFURVFRSLFWXPRULQFOXGLQJ peritonectomy and resection of tumor-involved viscera. This is followed by intraoperative hyperthermic intraperitoneal chemotherapy with mitomycin C to erase microscopic residual tumor.

85

To assess involvement of the urinary tract, medical records were analyzed for clinical, radiological and pathological evidence. Complications were registered as toxicity according to the NCI-CTC. Data from the medical history were collected with regard WRSUHYLRXVVXUJLFDOLQWHUYHQWLRQVWKDWZHUHSHUIRUPHGIURPÀUVWVLJQVRI303WRWUHDWment with cytoreduction and HIPEC. Urologic complications were analyzed, divided in minor and major complications. Treatment of these complications was recorded. Each recorded complication was matched to evidence of primary or secondary PMP involvement, histological subtypes of PMP and previous surgery. Involvement of the urinary WUDFWZDVGHÀQHGDVSULPDU\LIWKHVRXUFHRI303ZDVLQWKHXULQDU\WUDFW,QFDVHRI 303LQÀOWUDWLQJLQWRWKHXULQDU\WUDFWWKHWHUPVHFRQGDU\LQYROYHPHQWZDVXVHG

Results Patients Seven patients (6 females, 1 male) with a median age of 54 years (30-71), presented with PMP involvement of the urinary tract. Two patients presented with the urachus as primary source. One of these patients had also secondary involvement of the urinary tract E\303$GGLWLRQDOÀYHSDWLHQWVSUHVHQWHGZLWKVHFRQGDU\LQYROYHPHQW7KHRULJLQRI PMP in patients with urinary tract involvement included appendix (n=3), ovary (n=2) and urachus (n=2). In the entire patient population of this study PMP originated in 90% in the appendix, in 3% in the ovary, in 2% in the urachus and in 2% in the colon. The histopathological diagnosis in patients with involvement of the urinary tract consisted of DPAM, PMCA-I or PMCA in respectively 3, 2 and 2 patients. The pelvis was seriously affected in 6 of the 7 patients with urinary tract involvement. PMP was located mainly at the bladder (dome) and was mostly diagnosed by preoperative computed tomography (n=5). However, preoperative clinical presentation of urinary tract involvement by PMP was seen in 2 patients. Both patients presented with hydronephrosis due to ureter obstruction by massive PMP deposits. One of these patients presented with a combination of stress- and urge incontinence, and two-sided hydronephrosis due to massive PMP deposits on ureters and bladder. In the last patient, resection of the bladder with urinary deviation was assessed by urologists preoperatively.

Surgery

Chapter 8 86

Fifty-three patients had undergone previous surgery in the pelvis. This was due to V\PSWRPVRISHOYLFSDWKRORJ\SULRUWRWKHGHÀQLWHGLDJQRVLVRI303$OOSDWLHQWVZLWK secondary involvement of the urinary tract by PMP had undergone prior pelvic surgery. Resection of a part of the urinary tract was performed in 7 patients. In 5 patients resection and re-implantation of a part of the ureter was performed during cytoreduction. Three of these patients were diagnosed with secondary involvement of DPAM (n=2) or PMCA-I (n=1). In the other 2 patients, with preoperative hydronephro-


sis based on massive DPAM deposits, the distal ureter was resected (and re-implanted) due to surgical perforation at cytoreduction. In 2 patients with secondary involvement of DPAM, (part of) the bladder was resected at cytoreduction. Resection of the bladder dome with primary closure was performed in 1 patient. The other patient underwent cystectomy with a continent reservoir (Indiana pouch). Both patients with PMCA had undergone resection of both urachal tumor and bladder dome prior to treatment with cytoreduction and HIPEC.

Urologic complications The median follow-up after treatment was 45 months (1-95). The median hospital stay was 22 days (range 12-149). Patients with no complications had a median hospital stay of 19 days (12-35). A total of 13 procedures were complicated by minor or major urologic complications (table 1). Median hospital stay of these patients was 25.5 days (range 15-72), in contrast to 33 days (range 15-149) for patients with complications other than urologic. All patients had undergone previous pelvic surgery. Secondary involvement of the urinary tract was observed in 3 of these 13 procedures. Two of these 3 procedures caused 4/7 of the major urologic complications: these patients, diagnosed with DPAM, develRSHG EODGGHU OHDNDJH ZLWK ÀVWXOD IRUPDWLRQ YHVLFRYDJLQDO DQG YHVLFRHQWHUDO 7KUHH procedures without involvement of the urinary tract were responsible for the remaining major urologic complications: these patients developed a suture leak of the bladder, a YHVLFRHQWHUDOÀVWXODDIWHUVPDOOERZHOSHUIRUDWLRQ DQGDYHVLFRYDJLQDOÀVWXOD3DWLHQWV with PMCA-I or PMCA did not develop urologic complications. Treatment of major urologic complications is shown in table 2. Surgical treatment was QHFHVVDU\LQRXWRISURFHGXUHVZLWKDPDMRUXURORJLFFRPSOLFDWLRQ,QÀUVWLQVWDQFH Table 1. Distribution of minor and major urologic complications Complication Suture leak of bladder %ODGGHUÀVWXOD Urinary retention Urinary tract infection Incontinence, stress Incontinence, urge Number of procedures1 1 in some procedures more than one kind of complication was scored Table 2. Treatment of major urologic complications Patient Complication 1 Suture leak 2 6XWXUHOHDNDQGYHVLFRHQWHUDOÀVWXOD 3 6XWXUHOHDNDQGYHVLFRYDJLQDOÀVWXOD 4 9HVLFRHQWHUDOÀVWXOD 5 9HVLFRYDJLQDOÀVWXOD 1 two relaparatomies were needed

Minor 2 2 5 1 8

Major 3 4 5

Treatment Relaparotomy Relaparotomy1 Transvaginal closure Relaparotomy Indwelling catheter

87

VXWXUHOHDNVDQGÀVWXODVZHUHDSSURDFKHGFRQVHUYDWLYHO\E\QHIURVWRP\DQGRFFOXVLRQ balloons. However, due to the severity of complications, in 1 patient a relaparotomy ZDV SHUIRUPHG LQ ÀUVW LQVWDQFH (YHQWXDOO\ WKLV SDWLHQW QHHGHG UHODSDUDWRPLHV WR FORVHDEODGGHUVXWXUHOHDNUHVROYHDYHVLFRHQWHUDOÀVWXODDQGUHLPSODQWWKHXUHWHU,Q 2 patients a relaparotomy was eventually needed because of development of co-incident complications, such as an abscess or sepsis. Suture leaks of the bladder were repaired with a running suture of 3.0 Vicryl for the seromuscular layer, to be strengthened by a second suture line of single tied knots for the adventitia. A cystogram was performed routinely on day 7. In case of no extravasations the transurethral catheter was removed. Ureter repairs were followed by urinary VWHQWVZKLFKZHUHOHIWLQVLWXIRUZHHNVDIWHUUHSDLUIROORZHGE\URXWLQHFRQWUDVWÁXLG imaging. Minor urologic complications were treated according to hospital protocols.

Discussion

Chapter 8 88

The urinary tract is rarely involved in patients with PMP. This explains the minimal description of urinary tract involvement in literature. In this series of 92 patients with PMP, only 7 patients showed involvement of the urinary tract. Over the entire patient population, PMP found its origin mostly in the appendix. PMP rarely originated from the urinary tract. This resembles results described in literature4,18. It was therefore remarkable that 4 out of 7 patients with involvement of the urinary tract were diagnosed with PMP originating from an intrapelvic structure (urachus or ovary). The pelvis was seriously affected by PMP in all patients with secondary involvement of the urinary tract. Massive deposits of PMP were located at the vesicorectal space, the bladder dome or distal ureters. In addition, all patients with secondary involvement of the urinary tract had undergone prior surgery in the pelvis. It may be that prior pelvic surgery potentially compromises the integrity of the pelvic peritoneal lining. This may in turn explain the observed secondary involvement of the intrapelvic (but anatomically extraperitoneal) urinary structures as the bladder dome or distal ureter by a non invasive peritoneal surface tumor like DPAM. Secondary involvement of the urinary tract would thus be either due to direct seeding on deperitonealized surfaces or due to extraperitoneal spread through peritoneal defects. Though the numbers are small, it is intriguing to argue that secondary involvement of the urinary tract may be a consequence of a combination of PMP of pelvic origin and an earlier surgical intervention in the pelvis. Assuming that developing a secondary involvement is indeed associated with an earlier surgical intervention, the risk of developing it is not high. In this retrospective series, 53 patients had undergone pelvic surgery prior to cytoreduction and HIPEC. Among them were 6 patients with secondary urinary tract involvement (14%). In contrast, we did not observe any secondary involvement in patients without previous surgery.


As the urinary tract is rarely involved, major urologic complications occur infrequently. Minimal surgical manipulation or resection of (parts of) the urinary tract at cytoreduction logically results in minimal urologic complications. In this study, an association between urologic complications and tumor involvement of the urinary tract was seen in 4 out of 7 patients with major urologic complications. All patients with urologic complications had a history of (multiple) previous pelvic surgery. It can therefore be argued that urologic complications in patients with secondary involvement of the urinary tract are simply the consequence of repeated surgery in the pelvic area. Major complications can be treated well, mostly surgically and in collaboration with urologists. Due to the low incidence of urinary tract involvement, we do not recommend preoperative evaluation of patients by urologists but in those cases that have actual involvement shown on CT scan. In those cases, urinary stents can in our opinion be introduced pre or peroperatively. As there are many different views on this, so we can not make a recommendation here.

Conclusions The urinary tract is rarely involved in patients with PMP and secondary tumor involvement is most frequently observed. This may be a result of seeding of PMP (of pelvic origin) after prior pelvic surgery. The urologic complication risk of current standard treatment for PMP is low and complications can be treated well. The combination of secondary involvement at cytoreduction and HIPEC, and previous pelvic surgery is an omen of treatment related urologic complications, necessitating (surgical) re-interventions and further management in close collaboration with urologists.

References 1. Prayson RA, Hart WR, Petras RE. Pseudomyxoma peritonei. A clinicopathologic study of 19 cases with emphasis on site of origin and nature of associated ovarian tumors. Am J Surg Pathol 1994; 18:591-603. 2. Ronnett BM, Zahn CM, Kurman RJ et al. Disseminated peritoneal adenomucinosis and peritoneal mucinous carcinomatosis. A clinicopathologic analysis of 109 cases with emphasis on distinguishing pathologic features, site of origin, prognosis, and relationship to “pseudomyxoma peritonei”. Am J Surg Pathol 1995; 19:1390-1408. 3. de Bree E, Witkamp A, Van D, V et al. Unusual origins of Pseudomyxoma peritonei. J Surg Oncol 2000; 75:270-274. 4. Costa MJ. Pseudomyxoma peritonei. Histologic predictors of patient survival. Arch Pathol Lab Med 1994; 118:1215-1219. 5. de Bree E, Witkamp A, Van D, V et al. Unusual origins of Pseudomyxoma peritonei. J Surg Oncol 2000; 75:270-274.

89

6. Chejfec G, Rieker WJ, Jablokow VR et al. Pseudomyxoma peritonei associated with colloid carcinoma of the pancreas. Gastroenterology 1986; 90:202-205. 7. de Bree E, Witkamp A, Van D, V et al. Unusual origins of Pseudomyxoma peritonei. J Surg Oncol 2000; 75:270-274. 8. Stenhouse G, McRae D, Pollock AM. Urachal adenocarcinoma in situ with pseudomyxoma peritonei: a case report. J Clin Pathol 2003; 56:152-153. 9. Sasano H, Shizawa S, Nagura H et al. Mucinous adenocarcinoma arising in a giant urachal cyst associated with pseudomyxoma peritonei and stromal osseous metaplasia. Pathol Int 1997; 47:502-505. 10. Mendeloff J, McSwain NE, Jr. Pseudomyxoma peritonei due to mucinous adenocarcinoma of the urachus. South Med J 1971; 64:497-498. 11. de Bree E, Witkamp A, Van D, V et al. Unusual origins of Pseudomyxoma peritonei. J Surg Oncol 2000; 75:270-274. 12. Carr NJ, McLean AD. A mucinous tumour of the urachus: adenoma or low grade mucinous cystic tumour of uncertain malignant potential? Adv Clin Path 2001; 5:93-97. 13. Arly KS, Stephenson DV, Jr., Davis WC. Giant retroperitoneal mucocele simulating pseudomyxoma peritonei and mucinous adenocarcinoma. Am J Surg 1968; 116:439-443. 14. Moran CG, Morgan RH. Pseudomyxoma extraperitonei. J R Soc Med 1988; 81:668-669. 15. Brady MB, Ewing RH, Robinson AE et al. Flank mass and pain in a 72-year-old man. Invest Radiol 1986; 21:419-423. 16. Ronnett BM, Zahn CM, Kurman RJ et al. Disseminated peritoneal adenomucinosis and peritoneal mucinous carcinomatosis. A clinicopathologic analysis of 109 cases with emphasis on distinguishing pathologic features, site of origin, prognosis, and relationship to “pseudomyxoma peritonei”. Am J Surg Pathol 1995; 19:1390-1408. 17. Verwaal VJ, Van Tinteren H, Ruth SV et al. Toxicity of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. J Surg Oncol 2004; 85:61-67. 18. de Bree E, Witkamp A, Van D, V et al. Unusual origins of Pseudomyxoma peritonei. J Surg Oncol 2000; 75:270-274.

Chapter 8 90

9

chapter

Pseudomyxoma peritonei and pregnancy - Report of two cases -

A. Koops1, R.M. Smeenk 2 , F.A.N. Zoetmulder2 , A. Hoek1

1

Department of Obstetrics and Gynaecology, University Medical Centre Groningen, Groningen, the Netherlands 2 Department of Surgery, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.

Background: Pseudomyxoma peritonei (PMP) is a rare disease that requires surgical debulking and hyperthermic intraperitoneal chemotherapy (HIPEC). A dilemma rises when young women with a child wish are diagnosed with PMP. Cases: Two young women with a child wish were diagnosed with PMP of benign pathology. Because of the infertility caused by chemotherapy and the assumed indolent benign character of their disease, both women had been treated by surgery only. Both patients had spontaneous pregnancies. One patient remained disease-free but the other patient had extensive progression with dedifferentiation of disease resulting in no further treatment options. Conclusion: Reserved surgical treatment instead of cytoreductive surgery with HIPEC in young women with PMP and a child wish can be founded when the disease shows signs of indolence and benign pathology. Any suspicion of progression strongly favours adequate combined modality treatment to improve survival. Submitted

PMP and pregnancy

Introduction Pseudomyxoma peritonei (PMP) is a rare disease characterised by mucinous ascites and peritoneal implants. Werth introduced the term pseudomyxoma peritonei in 1884.1 Surgical debulking with hyperthermic intraperitoneal chemotherapy (HIPEC) is the recommended treatment, which seems to improve survival.2-4 Pregnancy in women with PMP is rare. Only two case reports have been described previously.5,6 In these cases, a dilemma rises when a choice between early treatment and a wait and see policy has to be made.

Cases Patient A, a 32-year-old woman was referred to the infertility clinic because of primary infertility since 15 months. Her medical history revealed an appendicitis acuta leading to appendectomy at the age of fourteen. The menstrual cycle was regular, there was an ovulatory cycle, and her partner’s semen analysis and the postcoitum test were QRUPDO8OWUDVRXQGVKRZHGDSHUVLVWHQWVPDOOOLTXLGSRFNHWEHKLQGWKHXWHUXVÀJXUH 1). Laparoscopy was performed to exclude pseudo cysts or adhesions and to detect the origin of this liquid pocket. All pelvic structures (uterus, ovaries and tubes) as well as

Figure 1. Transvaginal ultrasound image of the uterus of patient A showing a PMP deposit next to the uterus.

93

the cavum Douglasi were covered with a thick gelatinous liquid. A mucous-producing 4 cm long perforated appendix-stump was found and removed. The abdomen was rinsed thoroughly. Pathology showed a mucinous cystadenoma without evident atypia. Thus the diagnosis '3$0GLVVHPLQDWHGSHULWRQHDODGHQRPXFLQRVLV FRQIRUP5RQQHWW·VFODVVLÀFDWLRQZDV made.7 A therapeutic dilemma arose since aggressive surgical therapy with HIPEC was indicated but would affect fertility. The decision was postponed because of patient’s concern about this. After 12 months observation and screening there was no tumour activity. A spontaneous pregnancy with a dichorial twin appeared, which was complicated by growth discordance. A caesarean section was performed at 37 weeks’ gestation and two dysmature boys of 2260 and 1050 grams were born and admitted at the children’s ward. During the caesarean section the abdomen showed no signs of recurrence. There has been no evidence of recurrence until 40 months postoperative follow-up. Patient B, a 36-year-old woman underwent a caesarean section and delivered a healthy son. During operation, a mucinous tumour of 5 x 7 cm behind the uterus was found and resected. Pathology revealed PMP of uncertain origin. After revalidation, an explorative laparotomy was performed, which showed no intra-abdominal pathology. The resected appendix showed no pathological abnormalities. After four years, when she became pregnant for the second time, she was in a good condition without evidence of recurUHQFH+RZHYHUGXULQJWKHSUHJQDQF\DWXPRXUGHYHORSHGLQWKHULJKWRYDU\ÀJXUH 2). By 28 weeks gestation the tumour was increased in size to 17 x 13 cm. The child was GHOLYHUHGE\DFDHVDUHDQVHFWLRQDWZHHNVDQGÀYHGD\VDIWHUEHWDPHWKDVRQHDGPLQistration to enhance fetal lung maturation. A healthy boy of 2400 grams was born. The tumour was resected and exploration showed a PMP focus in the urachus. No other PMP deposits were found. A biopsy of the contra lateral ovary was normal. Therefore, the urachus as primary seemed most likely. Pathology was indifferent, but most suspicious for DPAM. At follow-up, 13 months after the second operation, there was a raise LQ&($ƬJO &RPSXWHGWRPRJUDSK\&7 VKRZHGHYLGHQFHRIWXPRXUDFWLYLW\LQ the left ovary and omentum. During explorative laparotomy widespread involvement of all abdominal structures was observed. Histology revealed mucinous carcinomatosis (PMCA).7 Cytoreductive surgery and HIPEC was therefore not performed.

Discussion Chapter 9 94

Pseudomyxoma peritonei is a rare and unpredictable disease. It follows a ruptured mucinous epithelial neoplasm usually of the appendix but in rare cases also of ovary, pancreas or urachus.8,9 Mucous producing cells may implant on the peritoneal or omental surface resulting in PMP. Treatment by surgery alone results in long-term disease-free survival around 12%.10 Radical cytoreductive surgery in combination with heated intraperito-

PMP and pregnancy

Figure 2. Transvaginal ultrasound image of patient B showing a PMP deposit with a diameter of 5 cm on the right side of the uterus.

neal chemotherapy results in 10-year survival up to 80%.2 However, HIPEC in young women will most likely result in permanent infertility due to tuba adhesions. Two cases of pseudomyxoma peritonei in combination with sub fertility have been UHSRUWHGSUHYLRXVO\,QWKHÀUVW303ZDVWUHDWHGZLWKVXUJHU\DIWHUZKLFKVSRQWDQHRXV conceiving followed.5 The second patient had an ovarian mucinous cystadenocarcinoma accompanied with PMP. She was treated with intraperitoneal administration of cisplaWLQÀYHWLPHVIROORZLQJOHIWRRSKRUHFWRP\$IWHUZDUGVVKHFRQFHLYHGDQGGHOLYHUHGWZR times a healthy child without evidence of recurrence until 60 months postoperative.6 The choice for surgery and a wait and see policy in young female PMP patients can be based on good pathology, the absence of residual disease after surgery and a strong child wish on part of the mother. In case one this has resulted in a very satisfying situation up till now. However, in case two this choice has resulted in early progression and dedifferentiation into malignancy with a very poor prognosis. The simultaneous growth of tumour and child in this case suggests an important role of growth factors but this was not analysed for this report. Our cases illustrate the unpredictable nature of PMP and the danger to postpone effective therapy. In retrospect it seems clear that our decision to continue the wait and see policy in patient B has been disastrous. The conclusion therefore must be that a 95

wait and see policy in young women with PMP and a child wish can be founded if benign disease without recurrence after surgery is present. Any suspicion of PMP with malignant features or progressive disease strongly favours adequate combined modality treatment to improve survival.

References 1. Werth R. Klinische und anatomische untersuchungen zur lehre von den bauchgeschwuelsten und der laparotomie. Arch Gynaecol Obstet 1884; 24:100-118. 2. Sugarbaker PH. Cytoreductive surgery and peri-operative intraperitoneal chemotherapy as a curative approach to pseudomyxoma peritonei syndrome. Eur J Surg Oncol 2001; 27:239-243. 3. Deraco M, Baratti D, Inglese MG et al. Peritonectomy and intraperitoneal hyperthermic perfusion ,3+3 DVWUDWHJ\WKDWKDVFRQÀUPHGLWVHIÀFDF\LQSDWLHQWVZLWKSVHXGRP\[RPDSHULWRQHL$QQ6XUJ Oncol 2004; 11:393-398. 4. Elias D, Laurent S, Antoun S et al. [Pseudomyxoma peritonei treated with complete resection and immediate intraperitoneal chemotherapy]. Gastroenterol Clin Biol 2003; 27:407-412. 5. Hales HA, Peterson CM, Jolles CJ et al. Pseudomyxoma peritonei associated with secondary infertility. Fertil Steril 1992; 58:425-426. 6. Niwa K, Morishita S, Murase T et al. Successful pregnancy in a patient with pseudomyxoma peritonei arising from ovarian mucinous cystadenocarcinoma treated with cisplatin. Gynecol Oncol 1995; 59:398-400. 7. Ronnett BM, Zahn CM, Kurman RJ et al. Disseminated peritoneal adenomucinosis and peritoneal mucinous carcinomatosis. A clinicopathologic analysis of 109 cases with emphasis on distinguishing pathologic features, site of origin, prognosis, and relationship to “pseudomyxoma peritonei”. Am J Surg Pathol 1995; 19:1390-1408. 8. van Ruth S, Acherman YI, van de Vijver MJ et al. Pseudomyxoma peritonei: a review of 62 cases. Eur J Surg Oncol 2003; 29:682-688. 9. Smeenk RM, Bex A, Verwaal VJ et al. Pseudomyxoma peritonei and the urinary tract: involvement and treatment related complications. J Surg Oncol 2006; 93:20-23. 10. Miner TJ, Shia J, Jaques DP et al. Long-term survival following treatment of pseudomyxoma peritonei: an analysis of surgical therapy. Ann Surg 2005; 241:300-308.

Chapter 9 96

10

chapter

Pseudomyxoma peritonei: a comprehensive review

R.M. Smeenk; V.J. Verwaal; F.A.N. Zoetmulder

Department of Surgery The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital Amsterdam, the Netherlands

Abstract Pseudomyxoma peritonei (PMP) is a rare condition, which is known for its high mortalLW\ZKHQQRWWUHDWHGSURSHUO\7KHÀUVWVWHSWRLPSURYHSURJQRVLVRIWKHVHSDWLHQWVLVWR 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 LQWUDSHULWRQHDOFKHPRWKHUDS\VHHPVYHU\HIÀFLHQWLQWKLVUHJDUG7KLVDSSURDFKLVFXUrently carried out in many centers throughout the world with promising results and seems to win ground as the standard treatment approach. Canc Treat Rev, in press

A comprehensive review

Introduction 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 muciQRXVWXPRURIWKHSHULWRQHXPZKLFKUHÁHFWVWKHRULJLQRIWKHWXPRUDVWXPRUFHOOVDUH GHSRVLWHGRQEXWQRWRULJLQDWLQJIURPWKHSHULWRQHXP:HUWKÀUVWGHVFULEHG303LQ 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 amount 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.

Pathogenesis Etiology 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.79 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 epiWKHOLDOFHOOVLQWRWKHSHULWRQHDOFDYLW\7KLVPRPHQWLVGHÀQHGDVWKHÀUVWVWHSLQWKH development of PMP. The perforation of the appendix may reseal and become even invisible, while over the course 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 VSUHDGWKURXJKRXWWKHSHULWRQHDOFDYLW\E\WKHLQWUDSHULWRQHDOÁXLGFXUUHQWDQGJUDYity. The absence of adhesive characteristics on the cell surface probably explains such SDVVLYHPRYHPHQW7KHLQWUDSHULWRQHDOÁXLGFXUUHQWWDNHVWXPRUFHOOVWRUHDEVRUSWLRQ 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 99

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. $QH[FHSWLRQKHUHLQDUHWKHLQWHVWLQDOSDUWVWKDWDUHÀ[HGWRWKHUHWURSHULWRQHXPVXFK 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 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 conform 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 HSLWKHOLDOFHOOVÀQGDIRRWKROG 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

Histopathology

Chapter 10 100

$ SURSHU KLVWRSDWKRORJLFDO GHÀQLWLRQ RI 303 LV GLIÀFXOW DV KLVWRSDWKRORJLFDO IHDtures 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 XVHG GHÀQLWLRQ RI 303 LV SURSRVHG E\ 5RQQHWW DQG FROOHDJXHV 7KH\ GHVFULEH 303 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 catego-


UL]DWLRQ FODVVLÀHV 303 LQWR WKUHH SDWKRORJLFDO VXEW\SHV ZLWK GLIIHUHQW SDWKRORJLFDO 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 $OWKRXJK5RQQHWW·VFODVVLÀFDWLRQLVDSSOLHGEURDGO\DQRWKHUIUHTXHQWO\XVHGFODVVLÀFDtion 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 FDVHVDUHFODVVLÀHGDVSVHXGRP\[RPDSHULWRQHLKLJKJUDGH 25 7KHVHFODVVLÀFDWLRQVLQWRSDWKRORJLFDOVXEW\SHVLVUDWKHUXVHIXOIRUWKHGHWHUPLQDWLRQRI prognosis and the evaluation of further treatment strategy. Histopathological and survival analysis of these different subtypes has shown that DPAM patients are most likely WREHQHÀWIURPORFRUHJLRQDOWUHDWPHQWDQGUHSUHVHQWWKHUHDO303SDWLHQWZLWKDJRRG SURJQRVLV30&$SDWLHQWVVKRXOGEHFODVVLÀHGDQGWUHDWHGDVSHULWRQHDOFDUFLQRPDWRVLV RIFRORUHFWDORULJLQDVWKH\GRQRWVHHPWREHQHÀWIURPDJJUHVVLYH WUHDWPHQWDQGKDYH 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 present with a typical “jelly belly” and complaints of intestinal obstruction, caused by the progressive amount of mucinous tumor and ascites. 7KH VHFRQG PRVW FRPPRQ JURXS LV FKDUDFWHUL]HG E\ ORFDO V\PSWRPV UHÁHFWLQJ WKH location of the primary or metastatic tumor. Patients with symptoms mimicking an acute appendicitis (25%) will undergo an appendectomy, during which the surgeon LGHQWLÀHVDQLQIHFWHGDQGRFFDVLRQDOO\SHUIRUDWHGDSSHQGLFHDOPXFRFHOH,QVRPHFDVHV 101

WKH SHUIRUDWHG DSSHQGLFHDO VXUIDFH LV VXUURXQGHG E\ GHSRVLWV RI PXFXV ÀJXUH RU VSRWVRIPXFLQRXVGHSRVLWVDUHIRXQGRQSHULWRQHDOVXUIDFHVZKLFKSURFODLPVWKHÀUVW step towards the development of PMP. Histopathological examination of the appendix XVXDOO\ UHYHDOV D PXFLQRXV HSLWKHOLDO QHRSODVP ,Q RI IHPDOH SDWLHQWV WKH ÀUVW V\PSWRPLVDQRYDULDQPDVV2IWHQWKHVHSDWLHQWVÀUVWFRQVXOWWKHJ\QHFRORJLVWZLWKD 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. ,QPRVWSDWLHQWV303LVLGHQWLÀHGDWÀUVWSUHVHQWDWLRQ+RZHYHURFFDVLRQDOO\WKHÀUVW 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 LQLWLDOO\DQXQLGHQWLÀHGWXPRUDQGRUXQQRWLFHGSHULWRQHDOWXPRUGHSRVLWV:KHQWKH\

Chapter 10 102

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


present several months or even years later with abdominal distension, thorough analysis and/or revising 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

Imaging and laboratory 8OWUDVRXQGLVWKHÀUVWLPDJLQJWHFKQLTXHWRXVHIRUIXUWKHUHVWDEOLVKPHQWRIWKHGLDJQRVLV8VXDOO\WKHUDGLRORJLVWYLVXDOL]HVIUHHLQWUDSHULWRQHDOÁXLGZKLFKFDQEHDVSLUDWHG for cytology. Needle aspiration then reveals pools of mucus with no or very few (wellGLIIHUHQWLDWHG HSLWKHOLDOFHOOVZKLFKSURYLGHVDIDOVHUHOLHYHDVWKLVÀQGLQJLVDFWXDOO\WKH 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 mucinous ascites, which can be differentiated from normal watery ascites by DQDO\]LQJGHQVLW\SURSHUWLHV+RXQVÀHOG8QLWV>+8@ 1RUPDODVFLWHVLVFKDUDFWHUL]HG E\DORZGHQVLW\LPDJH+8 ZKLOHWKHGHQVLW\RIPXFLQRXVDVFLWHVLVVLJQLÀFDQWO\

Figure 2. Computed tomography scan illustrating the redistribution phenomenon with mucinous tumor in the pelvis (a), the right sub diaphragmatic space (b), the sub pyloric space (c), and sparing of the small bowel (d).

103

higher (5-20 H.U.). In addition, CT demonstrates the involvement of abdominal regions FRQIRUPWKHUHGLVWULEXWLRQSKHQRPHQRQÀJXUHDG WRJHWKHUZLWKWKHVWDJHRIGLVease. 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 ERZHODQGLPSUHVVLRQRIWKHOLYHUVXUIDFHÀJXUH 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:KHQ303LVFRQÀUPHGE\ CT, there is a role for serum tumor markers CEA and CA 19.9 in the completion of the diagnostic work-up as these tumor markers are raised in most PMP patients and can be used as preoperative benchmark.40 Figure 3. Computed tomography scan illustrating “thumb printing” of the liver surface (1) and compression of small bowel (2) by the excessive amount of mucinous ascites (3).

Treatment Precursor of PMP

Chapter 10 104

In patients with an appendiceal mucocele, containing a mucinous epithelial neoplasm, perforation might have taken 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 DSSHQGHFWRP\FDQEHMXVWLÀHGEXWFORVHIROORZXSZLWKWXPRUPDUNHUVDQGXOWUDVRXQG is essential to detect PMP in an early stage.


Established PMP When mucinous tumor on peritoneal surface or mucinous ascites is visualized on CT or during abdominal surgery, adequate treatment of the 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 TXDOLÀHGIRUVXUJHU\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 7UDGLWLRQDO VXUJHU\ FRQVLVWV RI D ÀUVW 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 UHVHFWLRQDQGDVWRP\)LQDOO\DIRXUWKRUÀIWKUHFXUUHQFHLVXQWUHDWDEOHDQGIROORZHG 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 ground as 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 P. Sugarbaker.57 The surgical modality, consist105

Figure 4. Peritonectomy procedure: en bloc resection of pseudomyxoma peritonei deposits including colon (1) and peritoneum (2).

LQJRIVRFDOOHGSHULWRQHFWRP\SURFHGXUHVZLWKUHVHFWLRQRILQYROYHGYLVFHUDÀJXUH 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 WUHDWPHQWLVDORFRUHJLRQDODSSURDFKWKDWFDQEHMXVWLÀHGDVDQDSSURDFKZLWKFXUDWLYH intent especially in PMP patients, because of the characteristic dissemination pattern and non-invasive character.

Chapter 10 106

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 SUREDEO\H[SODLQHGE\WKHGLIIHUHQFHLQSDWLHQWVHOHFWLRQFODVVLÀFDWLRQVDQGIROORZXS 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 2.5mm.67

A comprehensive review Table 1. Results of comparable studies on CRS and HIPEC in PMP patients. HIPEC technique CC TOX MORT 5-yr OS* FU NED (%) (%) ( %) (%) (months) (%) Traditional treatment Gough et al.15 53 144 3 Miner et al.16 80* 57 12 Combined modality treatment Sugarbaker et al. MMC (+5-FU) 65 27 3 86 38 62 (n=385) Closed abdomen Peri-operative Elias et al. OXALI (MMC) 92 44 8 >75 48 55 (n=36) Closed abdomen Intra/peri-operative Deraco et al. MMC/CISPL 92 18 3 97 29 74 (n=33) Closed abdomen Intra-operative Guner et al. MMC/CISPL 40 36 7 >75 51 NA (n=28) Open abdomen Intra-operative Loungnarath et al. MMC/CISPL 41 44 0 75e 23 NA (n=27) Closed abdomen Intra-operative Smeenk et al. MMC 90 54 3 >80 51 56 (n=103) Open abdomen Intra-operative Total 70 37 4 >80 40 62 CRS: cytoreductive surgery; HIPEC, hyperthermic intraperitoneal chemotherapy; PMP, pseudomyxoma peritonei; CC, complete cytoreduction, < 2.5mm residue; TOX, major toxicity; MORT, 30-days mortality; OS, overall surYLYDO)8IROORZXS1('QRHYLGHQFHRI GLVHDVH00&0LWRP\FLQ&)8ÁXRURXUDFLO2;$/,2[DOLSODWLQ CISPL, Cisplatin; NA, not available; * complete cytoreduction and DPAM; e estimation.

Overall, the 5-year overall survival of combined modality treatment exceeds 75% for patients with benign disease (DPAM) and complete cytoreduction. The recurrence rate is considerable as well: approximately 60% is free of disease after a median follow-up RI PRQWKV (VSHFLDOO\ SDWLHQWV ZLWK '3$0 VHHP WR EHQHÀW IURP WKLV DSSURDFK ,Q30&$SDWLHQWVLQFRQWUDVWLWUHPDLQVTXHVWLRQDEOHZKHWKHUWKH\EHQHÀWIURPWKLV 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 107

D ÀYH\HDU VXUYLYDO UDWH RI DIWHU VXUJHU\ ZLWK DGMXQFWLYH UDGLRWKHUDS\ FRPSDUHG 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 7KH\ IRXQG D VLJQLÀFDQW VKRUWHU GLVHDVH IUHH VXUvival 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 HIÀFDF\DQGSRVVLEOHEHQHÀWRIV\VWHPLFWKHUDS\-RQHVDQGFROOHJXHVDUHRQHRIWKHIHZ 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 disease3,27,51

Late stage disease ,QODWHVWDJHGLVHDVHZKHQWKHHQWLUHDEGRPHQLVÀOOHGZLWKPXFLQRXVWXPRUDQGDVFLWHV FRPELQHGPRGDOLW\WUHDWPHQWVHHPVWRORRVHLWVEHQHÀWPRUELGLW\LVKLJKDQGLQFRPplete cytoreduction more common.27,64 Incomplete cytoreduction reduces the effect of HIPEC and inevitably results in progressive disease with an expected limited survival.70 However, it seems that further management of progressive disease is worthwhile in a considerable percentage of patients.71 To reduce morbidity and perhaps to increase the probability of complete cytoreduction, a two step procedure might be worthwhile in patients with extensive disease. 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

Chapter 10 108

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 follow-up.57,71,72 After that a CT VFDQ VKRXOG EH SHUIRUPHG HYHU\ PRQWKV LQ WKH ÀUVW \HDU DQG RQFH D \HDU RU ZKHQ progression is suspected in the next years. Other useful servants in detecting disease in the post-surgical period are the tumor markers CEA and CA 19.9, which also act as prognostic factors for survival.73,74 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.71 The choice of treatment for progressive disease should primarily depend on the disease free interval, but also on pathological subtype and extent of disease.

Conclusion Pseudomyxoma peritonei (PMP) is a rare disease, with a grim prognosis when not WUHDWHG SURSHUO\ 7KH ÀUVW VWHS WR LPSURYH WKH SURJQRVLV LV WR UHFRJQL]H WKLV FOLQLFDO 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 of aggressive peritonectomy with (intraoperative) HIPEC seems to win ground as new standard approach. Centralization of patients in centers that treat these patients on a regular basis is fundamental to prevent high morbidity and mortality.

References 1. Mann WJ, Jr., Wagner J, Chumas J et al. The management of pseudomyxoma peritonei. Cancer 1990; 66:1636-1640. 2. Mukherjee A, Parvaiz A, Cecil TD et al. Pseudomyxoma peritonei usually originates from the appendix: a review of the evidence. Eur J Gynaecol Oncol 2004; 25:411-414. 3. Smith JW, Kemeny N, Caldwell C et al. Pseudomyxoma peritonei of appendiceal origin. The Memorial Sloan-Kettering Cancer Center experience. Cancer 1992; 70:396-401. 6KHUHU'0$EXODÀD2(OLDNLP53VHXGRP\[RPDSHULWRQHLDUHYLHZRI FXUUHQWOLWHUDWXUH*\QHFRO Obstet Invest 2001; 51:73-80. 5. Werth R. Klinische und anatomische untersuchungen zur lehre von den bauchgeschwuelsten und der laparotomie. Arch Gynaecol Obstet 1884; 24:100-118. 6. Frankel E. Uber das sogenannte pseudomyxoma peritonei. Med Wochenschr 1901;965-970. 7. Sugarbaker PH. Pseudomyxoma peritonei. Cancer Treat Res 1996; 81:105-119. 8. Young RH. Pseudomyxoma peritonei and selected other aspects of the spread of appendiceal neoplasms. Semin Diagn Pathol 2004; 21:134-150. 9. Hinson FL, Ambrose NS. Pseudomyxoma peritonei. Br J Surg 1998; 85:1332-1339. 10. Sugarbaker PH. Pseudomyxoma peritonei. A cancer whose biology is characterized by a redistribution phenomenon. Ann Surg 1994; 219:109-111. 11. Prayson RA, Hart WR, Petras RE. Pseudomyxoma peritonei. A clinicopathologic study of 19 cases with emphasis on site of origin and nature of associated ovarian tumors. Am J Surg Pathol 1994; 18:591-603. 12. Young RH, Gilks CB, Scully RE. Mucinous tumors of the appendix associated with mucinous tumors of the ovary and pseudomyxoma peritonei. A clinicopathological analysis of 22 cases supporting an origin in the appendix. Am J Surg Pathol 1991; 15:415-429. 13. Lamps LW, Gray GF, Jr., Dilday BR et al. The coexistence of low-grade mucinous neoplasms of the appendix and appendiceal diverticula: a possible role in the pathogenesis of pseudomyxoma peritonei. Mod Pathol 2000; 13:495-501.

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14. Guerrieri C, Franlund B, Fristedt S et al. Mucinous tumors of the vermiform appendix and ovary, and pseudomyxoma peritonei: histogenetic implications of cytokeratin 7 expression. Hum Pathol 1997; 28:1039-1045. 15. Szych C, Staebler A, Connolly DC et al. Molecular genetic evidence supporting the clonality and appendiceal origin of Pseudomyxoma peritonei in women. Am J Pathol 1999; 154:1849-1855. 16. Ronnett BM, Shmookler BM, Diener-West M et al. Immunohistochemical evidence supporting the appendiceal origin of pseudomyxoma peritonei in women. Int J Gynecol Pathol 1997; 16:1-9. 17. Ronnett BM, Kurman RJ, Zahn CM et al. Pseudomyxoma peritonei in women: a clinicopathologic analysis of 30 cases with emphasis on site of origin, prognosis, and relationship to ovarian mucinous tumors of low malignant potential. Hum Pathol 1995; 26:509-524. 18. Ronnett BM, Shmookler BM, Sugarbaker PH et al. Pseudomyxoma peritonei: new concepts in diagnosis, origin, nomenclature, and relationship to mucinous borderline (low malignant potential) tumors of the ovary. Anat Pathol 1997; 2:197-226. 19. Seidman JD, Elsayed AM, Sobin LH et al. Association of mucinous tumors of the ovary and appendix. A clinicopathologic study of 25 cases. Am J Surg Pathol 1993; 17:22-34. 20. Chuaqui RF, Zhuang Z, Emmert-Buck MR et al. Genetic analysis of synchronous mucinous tumors of the ovary and appendix. Hum Pathol 1996; 27:165-171. 21. Jacquemin G, Laloux P. Pseudomyxoma peritonei: review on a cluster of peritoneal mucinous diseases. Acta Chir Belg 2005; 105:127-133. 22. de Bree E, Witkamp A, Van De Vijver M et al. Unusual origins of Pseudomyxoma peritonei. J Surg Oncol 2000; 75:270-274. 23. Smeenk RM, Bex A, Verwaal VJ et al. Pseudomyxoma peritonei and the urinary tract: involvement and treatment related complications. J Surg Oncol 2006; 93:20-23. 24. Ronnett BM, Zahn CM, Kurman RJ et al. Disseminated peritoneal adenomucinosis and peritoneal mucinous carcinomatosis. A clinicopathologic analysis of 109 cases with emphasis on distinguishing pathologic features, site of origin, prognosis, and relationship to “pseudomyxoma peritonei”. Am J Surg Pathol 1995; 19:1390-1408. 25. Bradley RF, Stewart JH, Russell GB et al. Pseudomyxoma peritonei of appendiceal origin: a clinicopathologic analysis of 101 patients uniformly treated at a single institution, with literature review. Am J Surg Pathol 2006; 30:551-559. 26. Ronnett BM, Yan H, Kurman RJ et al. Patients with pseudomyxoma peritonei associated with dissemLQDWHG SHULWRQHDO DGHQRPXFLQRVLV KDYH D VLJQLÀFDQWO\ PRUH IDYRUDEOH SURJQRVLV WKDQ SDWLHQWV ZLWK peritoneal mucinous carcinomatosis. Cancer 2001; 92:85-91. 27. Smeenk RM, Verwaal VJ, Zoetmulder FA. Survival analysis of pseudomyxoma peritonei treated by cytoreductive surgery in combination with intraoperative hyperthermic intraperitoneal chemotherapy. Ann Surg . 2006. Ref Type: In Press 28. Baker WC, Goldman LB, deVere White RW. Pseudomyxoma peritonei presenting as a scrotal mass. J Urol 1988; 139:821-822. 29. Young RH, Rosenberg AE, Clement PB. Mucin deposits within inguinal hernia sacs: a presenting ÀQGLQJRI ORZJUDGHPXFLQRXVF\VWLFWXPRUVRI WKHDSSHQGL[$UHSRUWRI WZRFDVHVDQGDUHYLHZRI the literature. Mod Pathol 1997; 10:1228-1232. 30. Kalu E, Croucher C. Appendiceal mucocele: a rare differential diagnosis of a cystic right adnexal mass. Arch Gynecol Obstet 2005; 271:86-88. 31. Khan S, Patel AG, Jurkovic D. Incidental ultrasound diagnosis of pseudomyxoma peritonei in an asymptomatic woman. Ultrasound Obstet Gynecol 2002; 19:410-412. 32. Darnis E, Ronceray J, Grosieux P et al. [Pseudomyxoma peritonei in females. 13 personal cases. Practical deductions from a review of 420 cases in the literature]. J Gynecol Obstet Biol Reprod (Paris) 1987; 16:343-353. 33. Solkar MH, Akhtar NM, Khan Z et al. Pseudomyxoma extraperitonei occurring 35 years after appendicectomy: a case report and review of literature. World J Surg Oncol 2004; 2:19.

A comprehensive review 34. Bechtold RE, Chen MY, Loggie BW et al. CT appearance of disseminated peritoneal adenomucinosis. Abdom Imaging 2001; 26:406-410. 35. Hanbidge AE, Lynch D, Wilson SR. US of the peritoneum. Radiographics 2003; 23:663-684. 36. Tsai CJ. Ultrasound features of disseminated adenomucinosis (pseudomyxoma). Br J Radiol 1998; 71:564-566. 37. Kairemo KJ, Jekunen AP, Bondestam S et al. Detection of pseudomyxoma peritonei by radioimmunohistochemistry and radioimmunoscintigraphy. Cancer Biother Radiopharm 1996; 11:325-334. 38. Buy JN, Malbec L, Ghossain MA et al. Magnetic resonance imaging of pseudomyxoma peritonei. Eur J Radiol 1989; 9:115-118. 39. Sulkin TV, O’Neill H, Amin AI et al. CT in pseudomyxoma peritonei: a review of 17 cases. Clin Radiol 2002; 57:608-613. 40. Carmignani CP, Hampton R, Sugarbaker CE et al. Utility of CEA and CA 19-9 tumor markers in diagnosis and prognostic assessment of mucinous epithelial cancers of the appendix. J Surg Oncol 2004; 87:162-166. 41. Friedland JS, Allardice JT, Wyatt AP. Pseudomyxoma peritonei. J R Soc Med 1986; 79:480-482. 42. Haid M, Bowie L, Kim D et al. Peritoneal washing therapy for pseudomyxoma peritonei. South Med J 1981; 74:913-915. 43. Green N, Gancedo H, Smith R et al. Pseudomyxoma peritonei-nonoperative management and ELRFKHPLFDOÀQGLQJV$FDVHUHSRUW&DQFHU 44. Jones CM, III, Homesley HD. Successful treatment of pseudomyxoma peritonei of ovarian origin with cis-platinum, doxorubicin, and cyclophosphamide. Gynecol Oncol 1985; 22:257-259. 45. Piver MS, Lele SB, Patsner B. Pseudomyxoma peritonei: possible prevention of mucinous ascites by peritoneal lavage. Obstet Gynecol 1984; 64:95S-96S. 46. Carter J, Moradi MM, Elg S et al. Pseudomyxoma peritonei--experience from a tertiary referral centre. Aust N Z J Obstet Gynaecol 1991; 31:177-178. 47. Wertheim I, Fleischhacker D, McLachlin CM et al. Pseudomyxoma peritonei: a review of 23 cases. Obstet Gynecol 1994; 84:17-21. 48. Galani E, Marx GM, Steer CB et al. Pseudomyxoma peritonei: the ‘controversial’ disease. Int J Gynecol Cancer 2003; 13:413-418. 49. Gough DB, Donohue JH, Schutt AJ et al. Pseudomyxoma peritonei. Long-term patient survival with an aggressive regional approach. Ann Surg 1994; 219:112-119. 50. Miner TJ, Shia J, Jaques DP et al. Long-term survival following treatment of pseudomyxoma peritonei: an analysis of surgical therapy. Ann Surg 2005; 241:300-308. 51. Sugarbaker PH. New standard of care for appendiceal epithelial neoplasms and pseudomyxoma peritonei syndrome? Lancet Oncol 2006; 7:69-76. 52. Kusamura S, Younan R, Baratti D et al. Cytoreductive surgery followed by intraperitoneal hyperthermic perfusion: analysis of morbidity and mortality in 209 peritoneal surface malignancies treated with closed abdomen technique. Cancer 2006; 106:1144-1153. 53. Raspagliesi F, Kusamura S, Campos Torres JC et al. Cytoreduction combined with intraperitoneal hyperthermic perfusion chemotherapy in advanced/recurrent ovarian cancer patients: The experience of National Cancer Institute of Milan. Eur J Surg Oncol 2006. 54. Glehen O, Kwiatkowski F, Sugarbaker PH et al. Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for the management of peritoneal carcinomatosis from colorectal cancer: a multi-institutional study. J Clin Oncol 2004; 22:3284-3292. 55. Brigand C, Monneuse O, Mohamed F et al. Peritoneal mesothelioma treated by cytoreductive surgery and intraperitoneal hyperthermic chemotherapy: results of a prospective study. Ann Surg Oncol 2006; 13:405-412. 56. Verwaal VJ, van Ruth S, de Bree E et al. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol 2003; 21:3737-3743.

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57. Sugarbaker PH, Ronnett BM, Archer A et al. Pseudomyxoma peritonei syndrome. Adv Surg 1996; 30:233-280. 58. Sugarbaker PH. Peritonectomy procedures. Surg Oncol Clin N Am 2003; 12:703-27, xiii. 59. Sugarbaker PH. Cytoreductive surgery and peri-operative intraperitoneal chemotherapy as a curative approach to pseudomyxoma peritonei syndrome. Eur J Surg Oncol 2001; 27:239-243. 60. Butterworth SA, Panton ON, Klaassen DJ et al. Morbidity and mortality associated with intraperitoneal chemotherapy for Pseudomyxoma peritonei. Am J Surg 2002; 183:529-532. 61. Elias D, Laurent S, Antoun S et al. [Pseudomyxoma peritonei treated with complete resection and immediate intraperitoneal chemotherapy]. Gastroenterol Clin Biol 2003; 27:407-412. 62. Guner Z, Schmidt U, Dahlke MH et al. Cytoreductive surgery and intraperitoneal chemotherapy for pseudomyxoma peritonei. Int J Colorectal Dis 2005; 20:155-160. 63. Loungnarath R, Causeret S, Bossard N et al. Cytoreductive surgery with intraperitoneal chemohyperthermia for the treatment of pseudomyxoma peritonei: a prospective study. Dis Colon Rectum 2005; 48:1372-1379. 64. Smeenk RM, Verwaal VJ, Zoetmulder FA. Toxicity and mortality of cytoreduction and intraoperative hyperthermic intraperitoneal chemotherapy in pseudomyxoma peritonei-a report of 103 procedures. Eur J Surg Oncol 2005. 65. Scuderi S, Costamagna D, Vaira M et al. [Treatment of pseudomyxoma peritonei using cytoreduction and intraperitoneal hyperthermic chemotherapy]. Tumori 2003; 89:43-45. 66. Deraco M, Baratti D, Inglese MG et al. Peritonectomy and intraperitoneal hyperthermic perfusion ,3+3 DVWUDWHJ\WKDWKDVFRQÀUPHGLWVHIÀFDF\LQSDWLHQWVZLWKSVHXGRP\[RPDSHULWRQHL$QQ6XUJ Oncol 2004; 11:393-398. 67. Witkamp AJ, de Bree E, Van Goethem R et al. Rationale and techniques of intra-operative hyperthermic intraperitoneal chemotherapy. Cancer Treat Rev 2001; 27:365-374. 68. Moran BJ. Establishment of a peritoneal malignancy treatment centre in the United Kingdom. Eur J Surg Oncol 2006; 32:614-618. 69. Sindelar WF, DeLaney TF, Tochner Z et al. Technique of photodynamic therapy for disseminated intraperitoneal malignant neoplasms. Phase I study. Arch Surg 1991; 126:318-324. 70. Glehen O, Mohamed F, Sugarbaker PH. Incomplete cytoreduction in 174 patients with peritoneal carcinomatosis from appendiceal malignancy. Ann Surg 2004; 240:278-285. 71. Smeenk RM, Verwaal VJ, Antonini N, Zoetmulder FA. Progressive pseudomyxoma peritonei after combined modality treatment: management and outcome. Ann Surg Oncol . 2006. Ref Type: In Press 72. Zoetmulder FA, Sugarbaker PH. Patterns of failure following treatment of pseudomyxoma peritonei of appendiceal origin. Eur J Cancer 1996; 32A:1727-1733. 73. van Ruth S, Hart AA, Bonfrer JM et al. Prognostic value of baseline and serial carcinoembryonic antigen and carbohydrate antigen 19.9 measurements in patients with pseudomyxoma peritonei treated with cytoreduction and hyperthermic intraperitoneal chemotherapy. Ann Surg Oncol 2002; 9:961967. 74. Alexander-Sefre F, Chandrakumaran K, Banerjee S et al. Elevated tumour markers prior to complete tumour removal in patients with pseudomyxoma peritonei predict early recurrence. Colorectal Dis 2005; 7:382-386.

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chapter

General discussion

General discussion

Pseudomyxoma peritonei (PMP) is an intriguing but sometimes confusing disease. )DPLOLDULW\ZLWKDQGXQGHUVWDQGLQJRI303KDVJURZQFRQVLGHUDEO\LQWKHÀQDOGHFDGHV of the last century. Simultaneously, a new standard of care for PMP patients, consisting of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy +,3(& KDV HPHUJHG 7KH ÀUVW UHVXOWV RI WKLV FRPELQHG PRGDOLW\ WUHDWPHQW ZHUH very promising with a 3-year survival probability of 90%.1 These results have motivated many international oncology centres to apply this treatment strategy.2-6 This thesis provides an outline of various aspects of this rare but fascinating disease, but focuses on combined modality treatment.

Pathogenesis The growing evidence that supports a dominant role of an appendiceal neoplasm as the origin of PMP is strengthened by this thesis. A population-based study demonstrates the obvious association between PMP and mucinous epithelial neoplasms of the appendix, and discusses the pathogenesis of the frequent ovarian involvement in female PMP patients. These ovarian tumour masses are probably the result of the intraperitoneal dissemination process of (appendiceal) tumour cells, but may in some cases consist of a true primary ovarian tumour. In addition, in this thesis we demonstrate the female dominance in PMP patients. An airtight explanation is however not at hand, but one might think of a pure mechanical factor, with the irregular surface of ovulating ovaries as stepping stone for tumour deposits, or hormonal environmental factors. 1RW RQO\ 303 RULJLQ UHPDLQV D ÀHOG RI UHVHDUFK 303 KLVWRSDWKRORJ\ FDQ DOVR EH VWUHVVHGDVUHPDLQLQJGLIÀFXOWDQGQRWFRPSOHWHO\XQGHUVWRRG7KHJUDGXDOWUDQVLWLRQ from benign to malignant properties of PMP tumour cells still contributes to confuVLRQDQGPLVGLDJQRVHV$SURSHUDQGXQLIRUPO\DSSOLHGGHÀQLWLRQDQGFODVVLÀFDWLRQLV presented by Ronnett and colleagues and seems useful in this regard.7 It can be used for preoperative patient selection, evaluation and adjustment of treatment strategy, DQG DVVHVVLQJ SURJQRVLV ,Q WKLV WKHVLV ZH IUHTXHQWO\ DGUHVV WKLV FODVVLÀFDWLRQ ZKLFK includes disseminated peritoneal adenomucinosis (DPAM), peritoneal mucinous carcinomatosis (PMCA) and an intermediate subtype (PMCA-I). This thesis shows that PMCA resembles peritoneal carcinomatosis of colorectal origin in both histopathological features and prognosis, and should not be categorized as PMP.

Diagnosis Very important in recognizing PMP as such is knowledge of the presenting symptoms. 7KH ÀUVW V\PSWRP PLJKW EH WKDW RI DFXWH DSSHQGLFLWLV :KHQ SDWKRORJLFDO H[DPLQDtion of the appendix reveals an appendiceal mucinous neoplasm, patients should be 115

monitored for the development of PMP. Patients also present with symptoms like an ovarian mucinous mass, mucinous deposits on the peritoneal surface, mucous found during hernia repair, or progressive abdominal distension. In these cases further analysis is necessary. The most important diagnostic tools in this analysis are ultrasound with needle biopsy (revealing mucous with no or very few epithelial cells), computed tomography (CT), and tumour markers CEA and CA 19.9. PMP is diagnosed properly by recognizing the clinical presentation, the typical intraperitoneal distribution of mucous and peritoneal tumour on a CT scan, and the characteristic outcome of needle biopsy. The next step for patients with established PMP is treatment conforming to the current standard.

Combined modality treatment

Chapter 11 116

Traditionally, treatment of PMP consists of surgical debulking, repetitive when necessary. Recurrence after this approach is however imminent and eventually patients die of progressive insensitive disease or treatment related complications. CRS with HIPEC is a relatively new treatment strategy for PMP, based on the loco regional behaviour of the disease.8 As PMP is a peritoneal surface disease with, in principle, no lymphatic or haematogenous dissemination, it is a suitable treatment strategy with curative intent. This combined modality treatment is based on two elements that complement each other. 7KHÀUVWPRGDOLW\H[WHQVLYHVXUJLFDOF\WRUHGXFWLRQLQFOXGLQJWKHVRFDOOHGSHULWRQHFtomy procedures, is an attempt at complete resection of macroscopic tumour mass.9 These peritonectomy procedures consist of one or more of the following resections: 1) Greater omentectomy with if necessary splenectomy; 2) Stripping of the left diaphragm; 3) Stripping of the right diaphragm; 4) Cholecystectomy and lesser omentectomy; 5) Distal gastrectomy (antrectomy); 6) Pelvic peritonectomy with resection of the rectosigmoid by anterior resection. The number of procedures depends on the localization of tumour involvement. Other involved viscera such as ovaries or colon are resected along when necessary. Over the years, several institutions throughout the world have gained considerable experience in this surgical technique. The second modality, hyperthermic intraperitoneal chemotherapy or HIPEC, is meant to eradicate any tumour residue. This follows the surgery in the same procedure, before anastomoses are made and peritoneal defects (e.g. diaphragm) are closed. Because of the peritoneal plasma barrier, chemotherapy (usually Mitomycin-C, sometimes cisplatinum) can be applied locally in a high concentration with relatively few systemic side effects: the so-called regional dose intensity.10,11 Chemotherapy enters tumour cells by simple diffusion and thereby probably has a limited penetration depth up to 2mm, so RQO\PLFURVFRSLFRUVPDOOPDFURVFRSLFWXPRXUUHVLGXHLVH[SRVHGVXIÀFLHQWO\+RZHYer, hyperthermia seems to enhance tumour penetration and to synergize the cytotoxic effect.8,12 Finally, intraoperative management with the open abdomen technique pro-

General discussion

vides the opportunity to optimize exposure by manual distribution and rinsing the bowel surface and surgical wound surfaces. Altogether, the main goal of HIPEC is the prevention of recurrent or, in case of irradical resection, progressive disease. Essential in the realisation of this goal is (near) complete cytoreduction. At this moment, we assume that (completeness of) the surgical cytoreduction plays a dominant role in the treatment effect of this combined modality treatment. It might HYHQEHVRWKDWWKHUHLVDQHTXDOEHQHÀWZKHQSHUIRUPLQJDJJUHVVLYHVXUJLFDOF\WRUHduction only. However, randomized clinical trials that prove the superiority of CRS or DGGLWLRQDOEHQHÀWRI+,3(&DUHQRWDYDLODEOHEHFDXVHRIWKHORZLQFLGHQFHRI303DQG the subsequent ethical questions posed by such research. Many studies, including those in this thesis, have shown that results of this combined modality treatment are promising.2-5,13,14 Long-term overall survival is achieved in a FRQVLGHUDEOHDPRXQWRISDWLHQWVDQGLQDVLJQLÀFDQWSHUFHQWDJHRISDWLHQWVUHFXUUHQFH is not seen within the 10 year follow-up. Those patients that sooner or later develop recurrent or (slow) progressive disease are not given up on. Instead, as demonstrated in this thesis, even for these patients treatment possibilities that prolong survival are at hand.15 Furthermore, this dissertation illustrates that the growing experience with combined modality treatment, as it has evolved to the standard treatment of PMP in many oncology centres, improves treatment results and long-term survival considerably. The counter side of combined modality treatment is the somewhat high morbidity, mainly related to the (aggressive) surgical modality.2-5,16,17 Especially PMP patients with extensive disease and a long surgical history, necessitating widespread adhesiolysis, do QRWVHHPWREHQHÀWIURPVXUJHU\DVWKH\DUHSURQHWRFRPSOLFDWLRQVZLWKDKLJKULVNRI PRUWDOLW\$QRSWLRQIRUWKHVHSDWLHQWVPLJKWEHDWZRVWHSSURFHGXUHÀUVWWKHORZHU abdomen is cytoreduced; after 4-6 months, when the patient is recovered, the cytoreduction is completed and the HIPEC is performed. This approach is applied at this moment in The Netherlands Cancer Institute, but results will not be available until a reasonable follow-up has been achieved. Perioperative additional nutrition to optimize the patient’s condition might result in a shortened and less complicated recovery.18,19 Preoperative nutrition is therefore recomPHQGHG LQ WKH IRUP RI ORZÀEUH QXWULWLRQDO GULQNV 3RVWRSHUDWLYHO\ SDWLHQWV FDQ EH aided in their recovery by enteral nutrition through a feeding tube in the jejunum or by total parenterale nutrition when enteral nutrition is impossible or contraindicated. The most important prognostic factors for morbidity and survival are pathology and completeness of cytoreduction.2-5,14,16,17 Patients with extensive tumour load and unfaYRXUDEOHSDWKRORJ\30&$ DUHXQOLNHO\WREHQHÀWIURPWUHDWPHQWVXUYLYDOSUREDELOLW\ is minimal, while there is a high chance of treatment related morbidity and mortality. These patients are probably better off when treated palliatively. Knowledge of these prognostic indicators has resulted in a change in patient selection, which is now based 117

on pathological subtype and the probability of complete cytoreduction. Furthermore, the observed value of both adequate patient selection and surgical experience in diminishing complications and improving survival has taught us the importance of patient centralization.

Future prospects Although all facets of PMP have been analysed extensively, there is much research still to be done. A very important topic might be how to prevent the development of PMP. Of course, early resection of the primary tumour prevents tumour cell dissemination and thus the development of PMP. But can we develop measures (other than surgery) WKDWPLJKWLQWHUIHUHZLWKWKHÀUVWVWDJHRIWKHGLVHDVHSURFHVVZKHQPXFLQRXVWXPRXU cells are already released in the peritoneal cavity? Interference at this stage might prevent progressive production of mucinous ascites and tumour mass, with the consequent impact on survival. $WSUHVHQWDJURXSRIUHVHDUFKHUVLVVWXG\LQJWKHLQÁXHQFHRI+HOLFREDFWHUS\ORULRQ the development of PMP. They suggest a correlation between this bacterium and the pathogenesis of PMP. The results of these analyses might further explore antibacterial treatment in PMP in addition to the known antibacterial effect of Mitomycin C. Studies on the pathogenesis of PMP on a molecular level are now undertaken and might provide treatment techniques at a totally different level. In conclusion, knowledge of pathogenesis and diagnosis might result in early detection of PMP and affects the prognosis. PMP patients should always be referred to oncology centres that have gained considerable experience in treating these patients. It seems that HVSHFLDOO\SDWLHQWVZLWKFRPSOHWHO\UHVHFWDEOHGLVHDVHDQGIDYRXUDEOHSDWKRORJ\EHQHÀW from combined modality treatment.

References

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1. Sugarbaker PH, Zhu BW, Sese GB et al. Peritoneal carcinomatosis from appendiceal cancer: results in 69 patients treated by cytoreductive surgery and intraperitoneal chemotherapy. Dis Colon Rectum 1993; 36:323-329. 2. Elias D, Laurent S, Antoun S et al. [Pseudomyxoma peritonei treated with complete resection and immediate intraperitoneal chemotherapy]. Gastroenterol Clin Biol 2003; 27:407-412. 3. Loungnarath R, Causeret S, Bossard N et al. Cytoreductive surgery with intraperitoneal chemohyperthermia for the treatment of pseudomyxoma peritonei: a prospective study. Dis Colon Rectum 2005; 48:1372-1379. 4. Guner Z, Schmidt U, Dahlke MH et al. Cytoreductive surgery and intraperitoneal chemotherapy for pseudomyxoma peritonei. Int J Colorectal Dis 2005; 20:155-160.

General discussion 5. Deraco M, Baratti D, Inglese MG et al. Peritonectomy and intraperitoneal hyperthermic perfusion ,3+3 DVWUDWHJ\WKDWKDVFRQÀUPHGLWVHIÀFDF\LQSDWLHQWVZLWKSVHXGRP\[RPDSHULWRQHL$QQ6XUJ Oncol 2004; 11:393-398. 6. Moran BJ, Mukherjee A, Sexton R. Operability and early outcome in 100 consecutive laparotomies for peritoneal malignancy. Br J Surg 2005. 7. Ronnett BM, Zahn CM, Kurman RJ et al. Disseminated peritoneal adenomucinosis and peritoneal mucinous carcinomatosis. A clinicopathologic analysis of 109 cases with emphasis on distinguishing pathologic features, site of origin, prognosis, and relationship to “pseudomyxoma peritonei”. Am J Surg Pathol 1995; 19:1390-1408. 8. Sugarbaker PH, Ronnett BM, Archer A et al. Pseudomyxoma peritonei syndrome. Adv Surg 1996; 30:233-280. 9. Sugarbaker PH. Peritonectomy procedures. Surg Oncol Clin N Am 2003; 12:703-27, xiii. 10. van Ruth S, Verwaal VJ, Zoetmulder FA. Pharmacokinetics of intraperitoneal mitomycin C. Surg Oncol Clin N Am 2003; 12:771-780. 11. Jacquet P, Sugarbaker PH. Peritoneal-plasma barrier. Cancer Treat Res 1996; 82:53-63. 12. Witkamp AJ, de Bree E, Van Goethem R et al. Rationale and techniques of intra-operative hyperthermic intraperitoneal chemotherapy. Cancer Treat Rev 2001; 27:365-374. 13. Sugarbaker PH. Cytoreductive surgery and peri-operative intraperitoneal chemotherapy as a curative approach to pseudomyxoma peritonei syndrome. Eur J Surg Oncol 2001; 27:239-243. 14. Smeenk RM, Verwaal VJ, Zoetmulder FA. Survival analysis of pseudomyxoma peritonei treated by cytoreductive surgery in combination with intraoperative hyperthermic intraperitoneal chemotherapy. Ann Surg . 2006. Ref Type: In Press 15. Smeenk RM, Verwaal VJ, Antonini N, Zoetmulder FA. Progressive pseudomyxoma peritonei after combined modality treatment: management and outcome. Ann Surg Oncol . 2006. Ref Type: In Press 16. Smeenk RM, Verwaal VJ, Zoetmulder FA. Toxicity and mortality of cytoreduction and intraoperative hyperthermic intraperitoneal chemotherapy in pseudomyxoma peritonei-a report of 103 procedures. Eur J Surg Oncol 2005. 17. Sugarbaker PH, Chang D. Results of treatment of 385 patients with peritoneal surface spread of appendiceal malignancy. Ann Surg Oncol 1999; 6:727-731. 18. Hensrud DD. Nutrition screening and assessment. Med Clin North Am 1999; 83:1525-1546. 19. Hall JC. Nutritional assessment of surgery patients. J Am Coll Surg 2006; 202:837-843.

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Summary Including Dutch summary Nederlandse samenvatting

Summary

Since 1995, pseudomyxoma peritonei (PMP) patients have been treated at The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital (NKI – AVL) with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). This thesis focuses on aspects related to this combined modality treatment of PMP. In addition, pathogenesis and clinical features of this rare disease are discussed. Chapter 1 introduces PMP as a clinical entity and describes the current standard treatment approach for PMP. The end of this chapter contains the outline of the thesis. Chapter 2 provides a population based study of PMP in the Netherlands between 1995 and 2005. The main aim of this study was to evaluate PMP epidemiology in the Netherlands and associated appendiceal neoplasms. A mucinous epithelial neoplasm ZDVLGHQWLÀHGLQEHQLJQPDOLJQDQW RIDSSHQGHFWRP\VSHFLPHQDQG 20% of these patients developed PMP. Thirteen percent of patients had an additional epithelial lesion in the colon. From the nationwide database 267 patients (62 men and ZRPHQ ZLWK303ZHUHLGHQWLÀHGZKLFKWUDQVODWHVWRDQLQFLGHQFHWKDWDSSURDFKHV WKHSHUPLOOLRQSHU\HDU7KHSULPDU\VLWHZDVLGHQWLÀHGLQDQGGRPLQDWHGE\WKH appendix (82%). Especially mucinous epithelial neoplasms of the appendix were associated with PMP (20%). For mucocele and non-mucinous neoplasms the association with PMP was only 2% and 3%, respectively. In patients with an epithelial neoplasm at appendectomy colonoscopy is indicated and patients with a mucinous epithelial neoplasm of the appendix should be followed for development of PMP. Chapter 3 illustrates clinical implications of PMP diagnosis and treatment. Symptoms, pathology, diagnosis, treatment, and follow up of three patients with PMP are discussed. This chapter demonstrates how PMP is diagnosed with CT scan, biopsy, and serum tumour markers. The goal of these case histories is to contribute to the physicians’ familiarity with the disease as early recognition of PMP and referal of patients to a specialized institute improves the probability of long-term survival. In Chapter 4 toxicity and mortality of CRS and HIPEC was studied in 103 consecutive procedures performed between 1996 and 2004. Treatment related toxicity was observed in 54% of procedures with a 30 days mortality of 3%. Small bowel perforations and suture leaks were the main cause of toxicity. In univariate analysis, toxicity was associated with abdominal tumour load and completeness of cytoreduction. A favourable pathology was associated with a lower mortality. These data suggest that CRS and HIPEC is a treatment with considerable toxicity but acceptable mortality, both mainly surgery related. Survival of PMP patients treated by CRS and HIPEC is discussed in Chapter 5. In total, 103 PMP patients (34 men and 69 women) treated at The NKI – AVL were identiÀHGDQGVWXGLHGIRUVXUYLYDOGDWDDQGIDFWRUVZLWKSURJQRVWLFYDOXH7KHGLVHDVHVSHFLÀF 3-year and 5-year survival probability was 70.9% and 59.5%, respectively. Factors associated with survival were pathological subtype, completeness of cytoreduction, and degree 123

and location of tumor load (p