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Appendiceal tumors and pseudomyxoma peritonei: French Intergroup Clinical Practice Guidelines for diagnosis, treatments and follow-up (RENAPE, RENAPATH, SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, ACHBT, SFR)

Published:November 20, 2021DOI:https://doi.org/10.1016/j.dld.2021.10.005

      Abstract

      Introduction

      This document is a summary of the French Intergroup guidelines regarding the management of appendicular epithelial tumors (AT) and pseudomyxoma peritonei (PMP) published in March 2020, available on the website of the French Society of Gastroenterology (SNFGE) (www.tncd.org).

      Methods

      All French medical societies specialized in the management of AT and PMP collaboratively established these recommendations based on literature until December 2019 and the results of a Delphi vote carried out by the Peritoneal Surface Oncology Group International experts, and graded into 4 categories (A, B, C, Expert Agreement) according to their level of evidence.

      Results

      AT and PMP are rare but represent a wide range of clinico-pathological entities with several pathological classification systems and different biological behaviors. Their treatment modalities may vary accordingly and range from simple surveillance or laparoscopic appendectomy to complete cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) and / or systemic chemotherapy. The prognosis of these neoplasms may also largely vary according to their pathological grade and spreading at diagnosis or during the follow-up. Given the rarity of certain situations, the therapeutic strategy adapted to each patient, must be discussed in a specialized multidisciplinary meeting after a specialized pathological and radiological pre-therapeutic assessment and a clinical examination by a surgeon specializing in the management of rare peritoneal malignancies.

      Conclusion

      These recommendations are proposed to achieve the most beneficial strategy in a daily practice as the wide range and the rareness of these entities renders their management challenging. These guidelines are permanently being reviewed.

      Keywords

      1. Introduction and methodology

      1.1 Introduction

      The present article is a summary of the French intergroup guidelines published in March 2020 on the website of the SNFGE society.
      These guidelines were written by a multidisciplinary committee originating from the main French medical societies (RENAPE, RENAPATH, SNFGE, GERCOR, FFCD, UNICANCER, SFCD, SFED, SFRO, ACHBT, SFR, SIAD, FRI) and including several experts from different specialties involved in the management of patients with epithelial appendiceal neoplasms and peritoneal malignancies.
      The initial document was reviewed and modified after further evaluation by a review committee and the last version was finally validated by the steering committee made up of members from the participating National Societies.

      1.2 Methodology

      The method for developing these recommendations was made by a working group from the RENAPE (Réseau National de prise en charge des Tumeurs Rares du Péritoine) network, in collaboration with international experts from the Peritoneal Surface Oncology Group International (PSOGI) who recently established a consensus on the management of appendicular tumors and pseodomyxoma peritonei [
      • Govaerts K.
      • Lurvink R.J.
      • De Hingh I.H.J.T.
      • Van der Speeten K.
      • Villeneuve L.
      • Kusamura S.
      • et al.
      Appendiceal tumours and pseudomyxoma peritonei: literature review with PSOGI/EURACAN clinical practice guidelines for diagnosis and treatment.
      ] and peritoneal mesothelioma [
      • Kusamura S.
      • Kepenekian V.
      • Villeneuve L.
      • Lurvink R.J.
      • Govaerts K.
      • De Hingh I.H.J.T.
      • et al.
      Peritoneal mesothelioma: PSOGI/EURACAN clinical practice guidelines for diagnosis, treatment and follow-up.
      ]. These recommendations come from questions assessed according to the Delphi method and the GRADE system was used for their grading [
      • Lurvink R.J.
      • Villeneuve L.
      • Govaerts K.
      • de Hingh I.H.J.T.
      • Moran B.J.
      • Deraco M.
      • et al.
      The Delphi and GRADE methodology used in the PSOGI 2018 consensus statement on Pseudomyxoma Peritonei and Peritoneal Mesothelioma.
      ]. This consensus involved 80 international experts (surgeons and oncologists) for appendicular tumors. A total of 35 questions on appendicular tumors and 69 questions on pseudomyxoma peritonei were submitted during the Delphi process.
      For each chapter, an exhaustive literature data research was also carried out.
      The Delphi technique is a reliable method for obtaining consensus on a specific topic that lacks scientific evidence and therefore relies on expert opinion. It consists of multiple voting rounds. Each participant can state their opinion independently of other participants. After each round, the results are summarized and returned to the participants in a subsequent round. These results are returned to create a debate, through which participants may reconsider their response in the next round [
      • Lurvink R.J.
      • Villeneuve L.
      • Govaerts K.
      • de Hingh I.H.J.T.
      • Moran B.J.
      • Deraco M.
      • et al.
      The Delphi and GRADE methodology used in the PSOGI 2018 consensus statement on Pseudomyxoma Peritonei and Peritoneal Mesothelioma.
      ].
      The working group met twice in February 2018 and February 2019.
      The gradation of these recommendations corresponds to the level of evidence available in the literature and / or to the results of the Delphi vote carried out by the PSOGI experts, on which the formulated conclusions are based. In the event of insufficient evidence, these recommendations have been graded according to expert opinion.
      The presentation method chosen for the TNCD according to 4 levels (A, B, C, agreement or expert opinion) is summarized as follow:
      • -
        Grade A: Strong recommendation based, for example, on high-powered randomized controlled trial (s), meta-analysis (s) of randomized controlled trial (s), or an analysis of decision based on well-conducted studies
      • -
        Grade B: Recommendation based on scientific presumption from low-powered randomized controlled trials, well-conducted non-randomized controlled studies, or cohort studies.
      • -
        Grade C Recommendation based on a low level of evidence from case-control studies, comparative studies with significant bias, retrospective studies, case series, descriptive epidemiological studies (cross-sectional, longitudinal).
      • -
        Expert agreement: Recommendation based on agreement or expert opinion in the absence of sufficient data from the literature.

      2. General considerations

      Appendicular epithelial tumors (AT) are rare, found in 2% of appendectomy specimen, but represent a wide range of clinico-pathological entities with several pathological classification systems and different biological behaviors.
      Thus, the treatment modalities may vary according to the histological subtype and the stage of the disease and can range from simple laparoscopic appendectomy to complete cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) and / or systemic chemotherapy.
      Given the rarity of certain situations, the decision on the therapeutic strategy, adapted to each patient, requires a specialized pre-therapeutic assessment, a clinical examination by a surgeon specializing in the management of rare peritoneal malignancies and a discussion in specialized multidisciplinary meeting.
      Appendicular epithelial tumors may be responsible for appendicular mucocele; defined as progressive distension of the appendix, of obstructive origin, by intraluminal accumulation of mucoid material. Appendicular epithelial tumors, including those with uncertain potential for malignancy and adenocarcinomas, are known for their ability to produce mucus and therefore belong to the group of appendicular mucinous tumors. Some of them, when perforated (spontaneously or iatrogenly), are the main cause of peritoneal pseudomyxoma (PMP), characterized by the accumulation of ascites and mucinous implants in the peritoneal cavity.

      3. Appendiceal tumors

      3.1 Pathological classification

      RECOMMENDATIONS
      • The entire appendix should be examined histologically. (expert agreement)
      • A review by the pathologists of the RENAPATH group (TENpath for neuroendocrine tumors) is proposed in case of doubt. (expert agreement)
      • The 2016 PSOGI classification must be adopted for appendicular tumors. (expert agreement)
      The consensus of the Peritoneal Surface Oncology Group International (PSOGI) [
      • Carr N.J.
      • Bibeau F.
      • Bradley R.F.
      • Dartigues P.
      • Feakins R.M.
      • Geisinger K.R.
      • et al.
      The histopathological classification, diagnosis and differential diagnosis of mucinous appendiceal neoplasms, appendiceal adenocarcinomas and pseudomyxoma peritonei.
      ] classifies appendicular tumors as:
      • Adenomas: epithelial proliferation of the columnar lining of the intestinal type similar to colorectal adenomas. with or without dysplasia. Precursors of colorectal-type adenocarcinomas.
      • Serrated polyps (serrated adenoma): epithelial proliferations of "serrated" appearance with or without dysplasias and correspond to potential precursors of mucinous adenocarcinomas.
      • Low grade mucinous appendicular tumors (LAMN): proliferation of very well differentiated mucosecreting columnar epithelium, of flat or villous architecture with low grade cyto-nuclear atypia, causing a distension and often an appendicular rupture without destructive infiltration but with expansive “pushing type” extension beyond the appendicular serosa with risk of peritoneal pseudomyxoma.
      • High-grade appendicular mucinous tumors (HAMN): HAMN could be considered as an intermediate group between LAMN and mucinous adenocarcinomas [
        • Legué L.M.
        • Creemers G.-.J.
        • de Hingh I.H.J.T.
        • Lemmens V.E.P.P.
        • Huysentruyt C.J.
        Review: pathology and its clinical relevance of mucinous appendiceal neoplasms and Pseudomyxoma Peritonei.
        ]. It is a proliferation of the very well differentiated mucosecreting columnar epithelium of planar or villous architecture with high grade cyto-nuclear atypia without destructive invasion or extension beyond the muscularis.
      • Mucinous adenocarcinoma (without or with signet ring cells): adenocarcinoma with at least 50% mucosecreting cells. An adenocarcinoma with a majority of signet ring cells (> 50%) is called signet ring cell adenocarcinoma.
      • Non-mucinous adenocarcinoma: colonic-type adenocarcinoma
      • Goblet cell adenocarcinoma (GCC): mixed tumor of epithelial and neuroendocrine elements with the presence of goblet cells of the intestinal type [
        • Clift A.K.
        • Kornasiewicz O.
        • Drymousis P.
        • Faiz O.
        • Wasan H.S.
        • Kinross J.M.
        • et al.
        Goblet cell carcinomas of the appendix: rare but aggressive neoplasms with challenging management.
        ]
      • Neuroendocrine Tumor (NET)
      • Other: Mesenchymal Tumor, sarcoma, lymphoma, metastasis.

      3.2 Epidemiology, associated cancers

      Appendicular epithelial tumors are identified in 0.9–1.4% of appendectomy specimens [
      • Hatch Q.M.
      • Gilbert E.W.
      Appendiceal neoplasms.
      ]. The most common are NETs (not covered in this chapter) [
      • Hatch Q.M.
      • Gilbert E.W.
      Appendiceal neoplasms.
      ]. AT is diagnosed on the surgical specimen in 0.2–0.3% of appendectomized patients [
      • Gillion J.-.F.
      • Franco D.
      • Chapuis O.
      • Serpeau D.
      • Convard J.-.P.
      • Jullès M.-.C.
      • et al.
      [Appendiceal mucoceles, pseudomyxoma peritonei and appendiceal mucinous neoplasms: update on the contribution of imaging to choice of surgical approach].
      ].
      To date, no familial form has been described.
      One should note that, for patients with appendicular epithelial tumor, regardless of its histologic subtype, there is a high incidence of colorectal polyps and neoplasia, either synchronous or metachronous [
      • Smeenk R.M.
      • van Velthuysen M.L.F.
      • Verwaal V.J.
      • Zoetmulder F.A.N.
      Appendiceal neoplasms and pseudomyxoma peritonei: a population based study.
      ,
      • Trivedi A.N.
      • Levine E.A.
      • Mishra G.
      Adenocarcinoma of the appendix is rarely detected by colonoscopy.
      ].

      3.3 Discovery modalities

      An appendicular tumor is responsible for unspecific symptoms and more than 50% of patients are asymptomatic. Otherwise, acute abdominal pain (which may mimic acute appendicitis) or chronic pain, abdominal mass or weight loss may be observed [
      • Legué L.M.
      • Creemers G.-.J.
      • de Hingh I.H.J.T.
      • Lemmens V.E.P.P.
      • Huysentruyt C.J.
      Review: pathology and its clinical relevance of mucinous appendiceal neoplasms and Pseudomyxoma Peritonei.
      ]. Clinical examination is not sufficient to confirm the diagnosis of appendicular epithelial tumor.
      The most frequent discovery modality is a fortuitous appendicular epithelial tumor on an appendectomy specimen, which corresponds to approximately 2/3 of cases [
      • Gillion J.-.F.
      • Franco D.
      • Chapuis O.
      • Serpeau D.
      • Convard J.-.P.
      • Jullès M.-.C.
      • et al.
      [Appendiceal mucoceles, pseudomyxoma peritonei and appendiceal mucinous neoplasms: update on the contribution of imaging to choice of surgical approach].
      ].
      Another clinical situation is the discovery of an appendicular epithelial tumor pre- and intraoperatively without apparent synchronous peritoneal involvement.
      Finally, the last clinical situation is the discovery of an appendicular epithelial tumor with peritoneal synchronous involvement. In case of a mucinous epithelial tumor, regardless of its grade, it is defined as PMP (see below).

      3.4 Pre therapeutic exploration

      RECOMMENDATIONS
      OPTIONS
      • Peritoneal MRI (garde C level of recommendation) in case of mucinous neoplasia or mucinous adenocarcinoma [
        • Low R.N.
        • Barone R.M.
        • Gurney J.M.
        • Muller W.D.
        Mucinous appendiceal neoplasms: preoperative MR staging and classification compared with surgical and histopathologic findings.
        ,
        • Low R.N.
        • Barone R.M.
        • Lucero J.
        Comparison of MRI and CT for predicting the Peritoneal Cancer Index (PCI) preoperatively in patients being considered for cytoreductive surgical procedures.
        ]
      • Tumor markers:
        • The literature concerning the assay of tumor markers only concerns appendicular epithelial tumors associated with peritoneal involvement (see PMP chapter).
        • In case of isolated appendicular epithelial tumor, tumor markers (ACE, Ca-125, Ca-15-3, Ca-19-9) lack diagnostic specificity but can be assayed in the follow-up. In current practice, the contribution of tumor markers remains very modest (expert agreement) [
          Les recommandations.
          ]. (2014).

      3.5 Available treatments

      3.5.1 Surgical treatments

      RECOMMENDATIONS
      • Appendectomy
        • It is recommended (expert agreement) that, faced with an appendicular mucocele to per-operatively handle it with extreme precaution, in order to avoid any extravasation of mucus or rupture of the mucocele in the peritoneal cavity (expert agreement) and the performance of peritoneal cytology (expert agreement). Full quadrant by quadrant exploration (30° optic camera) of the abdominal cavity should be performed to look for peritoneal involvement not visible on preoperative imaging exams. The extraction of the operative specimen should be done in an extraction bag and on the midline. (expert agreement)
        • The excision of the appendix must be complete with its mesoappendix allowing lymph node dissection, and the section of the operative part must pass into a healthy area at its base (coecal stapling) (grade C level recommendation level)
        • The laparoscopic approach is feasible (grade C recommendation level) for trained teams. The trocars should preferably be placed on the midline (expert agreement). Otherwise, a midline infra-umbilical laparotomy should be proposed.
      • Right colectomy
        • Right colectomy with ileocolic anastomosis and lymph node dissection.
        • En bloc resection of the adjoining mesocolon with identification of the vascular pedicle, requiring at least 12 lymph nodes to be analyzed.
      • Cytoreduction surgery with HIPEC
        • In case of peritoneal involvement (grade B recommendation level)
        • In an expert center (expert agreement)
        • Indication to be discussed “as an adjuvant” in the event of tumor perforation (spontaneous or iatrogenic) after appendicular resection or after R2 resection associated or not with peritoneal lesions. (expert agreement)
        • The peritoneal carcinomatosis index (PCI) [
          • Jacquet P.
          • Sugarbaker P.H.
          Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis.
          ] (Jacquet and Sugarbaker, 1996) is established using the measurement of the size of the peritoneal lesions (expert agreement).
        • Cytoreduction surgery allows excision of all macroscopic lesions.
        • Quantification of any residual disease after cytoreduction (CC score) [
          • Jacquet P.
          • Sugarbaker P.H.
          Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis.
          ] (expert agreement) (Jacquet and Sugarbaker, 1996):
          • CC0: no residual disease
          • CC1: residual disease <2.5 mm
          • CC2: residual disease> 2.5 mm
          • CC3: residual disease> 25 mm (never used as a rule)
        • In case of complete cytoreduction: hyperthermic intraperitoneal chemotherapy (HIPEC) is associated to cytoreductive surgery
        • For HIPEC regimen see chapter 4.4.1.5
      OPTIONS
      • Debulking surgery: see PMP chapter
      • “Wait and see” strategy in an expert center: Patient operated on for appendectomy with minimal peritoneal invasion or resected acellular mucin, especially in young women of childbearing age. (expert agreement)

      3.5.2 Medical treatments

      To resume, among the most studied medical treatments in appendix tumors, 5FU-based chemotherapy dominates, with in particular the FOLFOX-4 combination allowing to observe response rates between 20% and 40% [
      • Lieu C.H.
      • Lambert L.A.
      • Wolff R.A.
      • Eng C.
      • Zhang N.
      • Wen S.
      • et al.
      Systemic chemotherapy and surgical cytoreduction for poorly differentiated and signet ring cell adenocarcinomas of the appendix.
      ,
      • Shapiro J.F.
      • Chase J.L.
      • Wolff R.A.
      • Lambert L.A.
      • Mansfield P.F.
      • Overman M.J.
      • et al.
      Modern systemic chemotherapy in surgically unresectable neoplasms of appendiceal origin: a single-institution experience.
      ,
      • Pietrantonio F.
      • Maggi C.
      • Fanetti G.
      • Iacovelli R.
      • Di Bartolomeo M.
      • Ricchini F.
      • et al.
      FOLFOX-4 chemotherapy for patients with unresectable or relapsed peritoneal pseudomyxoma.
      ,
      • Shaib W.L.
      • Martin L.K.
      • Choi M.
      • Chen Z.
      • Krishna K.
      • Kim S.
      • et al.
      Hyperthermic intraperitoneal chemotherapy following cytoreductive surgery improves outcome in patients with primary appendiceal mucinous adenocarcinoma: a pooled analysis from three tertiary care centers.
      ,
      • Milovanov V.
      • Sardi A.
      • Aydin N.
      • Nieroda C.
      • Sittig M.
      • Nunez M.
      • et al.
      Extensive surgical history prior to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy is associated with poor survival outcomes in patients with peritoneal mucinous carcinomatosis of appendiceal origin.
      ,
      • Bijelic L.
      • Kumar A.S.
      • Stuart O.A.
      • Sugarbaker P.H.
      Systemic chemotherapy prior to cytoreductive surgery and HIPEC for carcinomatosis from appendix cancer: impact on perioperative outcomes and short-term survival.
      ,
      • Sugarbaker P.H.
      • Bijelic L.
      • Chang D.
      • Yoo D.
      Neoadjuvant FOLFOX chemotherapy in 34 consecutive patients with mucinous peritoneal carcinomatosis of appendiceal origin.
      ]. No study has really demonstrated the advantage of combining targeted therapy, such as anti-angiogenic or anti-EGFR with systemic chemotherapy, even though this strategy is widely practiced [
      • Choe J.H.
      • Overman M.J.
      • Fournier K.F.
      • Royal R.E.
      • Ohinata A.
      • Rafeeq S.
      • et al.
      Improved survival with anti-VEGF therapy in the treatment of unresectable appendiceal epithelial neoplasms.
      ].
      There are preclinical data and some clinical data of low level of evidence (grade C recommendation level) suggesting a promising role of antiangiogenic agents in this disease. No randomized clinical trial validates a therapeutic strategy compared to another in terms of the medical treatment to be administered.
      Although low grade tumors are considered to have a poor response to chemotherapy, there is no data in the literature to support this hypothesis. However, it seems logical to reserve chemotherapy for adenocarcinomas and poorly differentiated tumors, as well as those with signet ring cells because of their worse prognosis.
      Concerning the role of medical treatments in the perioperative situation, the low level of evidence available data are discordant. Several retrospective studies with a low level of evidence suggest the deleterious effect of primary chemotherapy on progression-free survival and overall survival, or of distant relapses [
      • Shaib W.L.
      • Martin L.K.
      • Choi M.
      • Chen Z.
      • Krishna K.
      • Kim S.
      • et al.
      Hyperthermic intraperitoneal chemotherapy following cytoreductive surgery improves outcome in patients with primary appendiceal mucinous adenocarcinoma: a pooled analysis from three tertiary care centers.
      ,
      • Chua T.C.
      • Moran B.J.
      • Sugarbaker P.H.
      • Levine E.A.
      • Glehen O.
      • Gilly F.N.
      • et al.
      Early- and long-term outcome data of patients with pseudomyxoma peritonei from appendiceal origin treated by a strategy of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.
      ,
      • Baratti D.
      • Kusamura S.
      • Nonaka D.
      • Langer M.
      • Andreola S.
      • Favaro M.
      • et al.
      Pseudomyxoma peritonei: clinical pathological and biological prognostic factors in patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC).
      ]. Other studies suggest the absence of toxicities and the possibility of facilitating the surgical procedure [
      • Pietrantonio F.
      • Maggi C.
      • Fanetti G.
      • Iacovelli R.
      • Di Bartolomeo M.
      • Ricchini F.
      • et al.
      FOLFOX-4 chemotherapy for patients with unresectable or relapsed peritoneal pseudomyxoma.
      ,
      • Milovanov V.
      • Sardi A.
      • Aydin N.
      • Nieroda C.
      • Sittig M.
      • Nunez M.
      • et al.
      Extensive surgical history prior to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy is associated with poor survival outcomes in patients with peritoneal mucinous carcinomatosis of appendiceal origin.
      ,
      • Bijelic L.
      • Kumar A.S.
      • Stuart O.A.
      • Sugarbaker P.H.
      Systemic chemotherapy prior to cytoreductive surgery and HIPEC for carcinomatosis from appendix cancer: impact on perioperative outcomes and short-term survival.
      ,
      • Sugarbaker P.H.
      • Bijelic L.
      • Chang D.
      • Yoo D.
      Neoadjuvant FOLFOX chemotherapy in 34 consecutive patients with mucinous peritoneal carcinomatosis of appendiceal origin.
      ]. The low chemotherapy response rate in these diseases explains these conflicting opinions.
      The deleterious effect of chemotherapy on survival must, however, be analyzed with caution, as selection bias could explain these results. In fact, chemotherapy would preferably be administered to patients in poor general condition or with more aggressive disease. The absence of a randomized clinical trial exposes this risk.

      3.6 Therapeutic indications

      3.6.1 Surgical treatment

      3.6.1.1 Epithelial appendicular tumor discovered on appendectomy specimen

      RECOMMENDATIONS Take into account (grade C recommendation level):
      • the histological subtype
      • the peritoneal cytology (if performed)
      • the notion of perforation (spontaneous or iatrogenic)
      • the completeness of the mesoappendix excision
      • the lymph node invasion
      • the completeness of the appendicular epithelial tumor resection.

      3.6.1.1.1 Low grade appendiceal mucinous neoplasm

      RECOMMENDATIONS
      • In the event of incomplete resection (R1 or R2 surgery), surgical revision in the form of a caecectomy is recommended to obtain complete carcinological resection (grade C recommendation level) [
        • Omohwo C.
        • Nieroda C.A.
        • Studeman K.D.
        • Thieme H.
        • Kostuik P.
        • Ross A.S.
        • et al.
        Complete cytoreduction offers longterm survival in patients with peritoneal carcinomatosis from appendiceal tumors of unfavorable histology.
        ,
        • Chua T.C.
        • Moran B.J.
        • Sugarbaker P.H.
        • Levine E.A.
        • Glehen O.
        • Gilly F.N.
        • et al.
        Early- and long-term outcome data of patients with pseudomyxoma peritonei from appendiceal origin treated by a strategy of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.
        ].
      • In the event of an invaded meso‑appendix, ileotyphlectomy without lymph node dissection is recommended, in order to perform an R0 resection (grade C recommendation level).
      • In the event of a perforated tumor (spontaneous or iatrogenic) or tumor of stage pM1a (with PCI> 3 and more than one affected area) or pM1b, “adjuvant” complete cytoreductive surgery and HIPEC can be performed in an expert center. (expert agreement).
      • In other cases (in particular stage pM1a tumor with PCI <3): follow-up in a RENAPE expert center (expert agreement)
      • Right colectomy is not indicated in patients with low-grade appendicular mucinous tumors and with acellular or low-grade peritoneal pseudomyxoma (PMP) [
        • Honoré C.
        • Caruso F.
        • Dartigues P.
        • Benhaim L.
        • Chirica M.
        • Goéré D.
        • et al.
        Strategies for preventing Pseudomyxoma Peritonei after resection of a mucinous neoplasm of the appendix.
        ] (expert agreement).
      OPTION
      • Exploratory laparoscopy: to confirm the low grade character in cases of peritoneal pseudomyxoma (PMP) with minimal peritoneal invasion or acellular mucin when a “wait and see” strategy may be appropriate, especially in women of childbearing age or if peritoneal reassessment, in RENAPE expert center (assessment for complete cytoreduction surgery (CCR) and HIPEC) (expert agreement).

      3.6.1.1.2 High grade appendiceal neoplasm and mucinous appendiceal adenocarcinoma

      RECOMMENDATIONS
      • It is recommended to perform a right colectomy with lymph node dissection (grade C recommendation level) except in cases of high grade appendicular mucinous neoplasia (HAMN) of stage pTis [
        • Sugarbaker P.H.
        When and when not to perform a right colon resection with mucinous appendiceal neoplasms.
        ,
        • González-Moreno S.
        • Brun E.
        • Sugarbaker P.H.
        Lymph node metastasis in epithelial malignancies of the appendix with peritoneal dissemination does not reduce survival in patients treated by cytoreductive surgery and perioperative intraperitoneal chemotherapy.
        ,
        • González-Moreno S.
        • Sugarbaker P.H.
        Right hemicolectomy does not confer a survival advantage in patients with mucinous carcinoma of the appendix and peritoneal seeding.
        ].
      • In the event of lymph node invasion in the appendicular meso, an additional right colectomy is necessary (grade C recommendation level).
      • In cases of high-grade mucinous appendicular neoplasia (HAMN) of the pTis stage, follow-up in a RENAPE center is recommended (expert agreement).
      • In the event of a perforated tumor (spontaneous or iatrogenic) or stage pM1b, complete cytoreduction surgery (CRC) and HIPEC with “adjuvant” right colectomy can be performed in an expert center (grade C recommendation level)

      3.6.1.1.3 Goblet cell carcinoma

      RECOMMENDATIONS
      • A right hemicolectomy must be performed (grade C recommendation level).
      • In the event of resectable peritoneal metastases and an operable patient: complete cytoreduction surgery (CRC) and HIPEC in an expert center (grade C recommendation level).
      OPTION
      • In the event of a perforated goblet cell carcinoma (GCC) tumor (spontaneous or iatrogenic) without peritoneal lesion detectable on preoperative examinations: complete cytoreduction surgery (CCR) and HIPEC with “adjuvant” right colectomy should be discussed in an expert center (grade C recommendation level).

      3.6.1.1.4 Adenoma, serrated adenoma, hyperplastic polyp

      RECOMMENDATIONS
      • In case of low or high grade mucinous appendicular neoplasia (LAMN or HAMN) at the unruptured pTis stage and complete resection, adenomas, scalloped polyps and hyperplastic polyps, treatment by appendectomy is sufficient if a complete resection is carried out (expert agreement).

      3.6.1.2 Epithelial appendicular tumor discovered before or during surgery without obvious synchronous peritoneal spread

      RECOMMENDATIONS
      • Intraoperative diagnosis:
        • Appendectomy according to the carcinological criteria in chapter 3.5.1 (expert agreement)
      • Pre-operative diagnosis:
        • Abdomino-pelvic CT scan performed and patient informed of the risks of the intervention and potential discovery
        • Appendectomy according to the carcinological criteria in the chapter "available treatments" (expert agreement)

      3.6.1.3 Epithelial appendicular tumor with obvious synchronous peritoneal spread

      RECOMMENDATIONS
      • Preoperative diagnosis: this is an authentic low or high grade appendicular pseudomyxoma (PMP).
        • Complete cytoreductive surgery and HIPEC (grade B recommendation level).
        • No consensus on the HIPEC protocol (see chapter 4.4.1.5)
      • Intraoperative diagnosis
        • It is advisable to explore the abdominal cavity, to describe as precisely as possible the peritoneal involvement, the presence of droplets or mucinous plaques and the presence or not of infiltrating nodules, at best to establish the PCI [
          • Jacquet P.
          • Sugarbaker P.H.
          Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis.
          ] (Jacquet and Sugarbaker, 1996) which should included in the operative report.
        • Surgery should be limited to a peritoneal biopsy to histologically confirm the diagnosis. (grade B recommendation level)
        • Some authors suggest that biopsies from diaphragmatic peritonuem should be avoided due to the risk of pleural perforation and the resulting tumor dissemination [
          • Iversen L.H.
          • Rasmussen P.C.
          • Laurberg S.
          Value of laparoscopy before cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis.
          ].
          The patient is referred to the RENAPE regional expert center for treatment (grade B recommendation level).
        • The frozen section examination is not recommended.

      3.6.2 Medical treatment

      3.6.2.1 Neoadjuvant chemotherapy

      RECOMMENDATIONS
      • For disease of uncertain resectability (grade B recommendation level)
      • FOLFOX 4 + bevacizumab for 4 to 8 courses (grade B recommendation level)
      CLINICAL TRIALS
      • No

      3.6.2.2 Adjuvant chemotherapy

      RECOMMENDATIONS
      • None
      OPTIONS
      CLINICAL TRIALS
      • No

      3.6.2.3 Chemotherapy for unresecable disease

      RECOMMENDATIONS
      • None
      OPTIONS
      CLINICAL TRIALS
      • No

      3.7 Post therapeutic follow up

      RECOMMENDATIONS
      • Thoraco-abdominopelvic CT scan every 3–6 months for the first two years then annually for 5 years. (expert agreement)
      • In the event of a low-grade appendicular mucinous tumor, follow-up by peritoneal MRI only in an expert center may be offered. (expert agreement) [
        • Low R.N.
        • Barone R.M.
        • Gurney J.M.
        • Muller W.D.
        Mucinous appendiceal neoplasms: preoperative MR staging and classification compared with surgical and histopathologic findings.
        ].
      • In the event of high-grade peritoneal pseudomyxoma (PMP), a follow-up by peritoneal MRI at least annually (expert agreement) associated with a thoracic CT can be considered according to the same procedures.
      • No tumor markers dosage (except for peritoneal pseudomyxoma (see below). (expert agreement)
      • Colonoscopic monitoring only in the event of associated colonic polyps as recommended by HAS. (expert agreement)

      4. Pseudomyxoma peritonei

      4.1 Definition and grade determination

      Pseudomyxoma peritonei (PMP) corresponds to a clinico-radiological situation defined by the accumulation of mucin, localized or diffuse, in the abdominal and / or pelvic cavity, in relation to the presence of a mucinous neoplasia located in the vast majority of cases in the appendix, much more rarely in the uraque, the pancreas and the ovary (teratome). The grade and the stage of the disease are prognostic factors for PMP of appendicular origin, conditioning the therapeutic strategy. The grade is listed in different classifications developed from relatively similar histological criteria and using recently standardized terminologies [
      • Carr N.J.
      • Bibeau F.
      • Bradley R.F.
      • Dartigues P.
      • Feakins R.M.
      • Geisinger K.R.
      • et al.
      The histopathological classification, diagnosis and differential diagnosis of mucinous appendiceal neoplasms, appendiceal adenocarcinomas and pseudomyxoma peritonei.
      ,
      • Carr N.J.
      • Cecil T.D.
      • Mohamed F.
      • Sobin L.H.
      • Sugarbaker P.H.
      • González-Moreno S.
      • et al.
      A consensus for classification and pathologic reporting of pseudomyxoma peritonei and associated appendiceal neoplasia: the results of the Peritoneal Surface Oncology Group International (PSOGI) modified delphi process.
      ]. It is most often identical to that of the primary appendicular lesion. The TNM classification defines the stage and is also based on certain histological criteria.
      RECOMMENDATIONS
      • The recommended classification is the histological classification according to WHO 2019 (5th edition) which can be supplemented by the histological classification according to the PSOGI (2016) [
        • Carr N.J.
        • Bibeau F.
        • Bradley R.F.
        • Dartigues P.
        • Feakins R.M.
        • Geisinger K.R.
        • et al.
        The histopathological classification, diagnosis and differential diagnosis of mucinous appendiceal neoplasms, appendiceal adenocarcinomas and pseudomyxoma peritonei.
        ,
        • Carr N.J.
        • Cecil T.D.
        • Mohamed F.
        • Sobin L.H.
        • Sugarbaker P.H.
        • González-Moreno S.
        • et al.
        A consensus for classification and pathologic reporting of pseudomyxoma peritonei and associated appendiceal neoplasia: the results of the Peritoneal Surface Oncology Group International (PSOGI) modified delphi process.
        ].
      • For PMP of appendicular origin, the pathologist must specify the grade and classification used, as well as the pTNM stage according to the 8th edition (UICC 8th edition, AJCC 8th edition) (expert agreement).

      4.2 Epidemiology, screening of family forms and other related cancers

      PMP is a rare disease with an estimated incidence of 0.2 per 100,000 population per year [
      • Smeenk R.M.
      • van Velthuysen M.L.F.
      • Verwaal V.J.
      • Zoetmulder F.A.N.
      Appendiceal neoplasms and pseudomyxoma peritonei: a population based study.
      ]. The age at diagnosis ranges from 20 to 80 years old. Symptoms are not specific. The diagnosis is based on the presence of mucin in the peritoneal cavity and is confirmed by histological analysis of peritoneal samples. Three familial cases are described in the literature, and candidate predisposition genes have been identified, whose role in familial forms still needs to be clarified [
      • Lung M.S.
      • Mitchell C.A.
      • Doyle M.A.
      • Lynch A.C.
      • Gorringe K.L.
      • Bowtell D.D.L.
      • et al.
      Germline whole exome sequencing of a family with appendiceal mucinous tumours presenting with pseudomyxoma peritonei.
      ].
      REFCOMMENDATIONS
      • No genetic predisposition has been demonstrated.
      • There is no specific research or analysis to be done, other than a full colonoscopy which is usually done looking for a colon tumor, which may be associated with the mucinous tumor of the appendix (grade C recommendation level).

      4.3 Pre-therapeutic explorations (and resectability and operability criteria)

      The major prognostic factors for PMP are: completeness of cytoreductive surgery and the grade. Only the histological analysis of a complete cytoreduction, in an expert center, will allow concluding on the histological grade of the PMP. The pre-therapeutic assessment must be carried out in an expert center and answer three questions:
      • -
        Confirm the site of the primary tumor (PMP of appendicular origin or of another origin);
      • -
        Determine the level of resectability of peritoneal disease: find out whether we are moving towards extensive cytoreduction, long and with high risks of intra- and post-operative complications, towards limited cytoreduction or towards incomplete cytoreduction;
      • -
        Determine the patient's level of operability.

      4.3.1 Radiologic assessment

      CT scan underestimates the extent of peritoneal metastases, especially in diagnosing small lesions or lesions with low contrast with adjacent structures, such as the small intestine [
      • Low R.N.
      • Barone R.M.
      • Lucero J.
      Comparison of MRI and CT for predicting the Peritoneal Cancer Index (PCI) preoperatively in patients being considered for cytoreductive surgical procedures.
      ,
      • Chua T.C.
      • Yan T.D.
      • Deraco M.
      • Glehen O.
      • Moran B.J.
      • Sugarbaker P.H.
      • et al.
      Multi-institutional experience of diffuse intra-abdominal multicystic peritoneal mesothelioma.
      ,
      • Dohan A.
      • Hoeffel C.
      • Soyer P.
      • Jannot A.S.
      • Valette P.-.J.
      • Thivolet A.
      • et al.
      Evaluation of the peritoneal carcinomatosis index with CT and MRI.
      ,
      • Low R.N.
      • Barone R.M.
      • Rousset P.
      Peritoneal MRI in patients undergoing cytoreductive surgery and HIPEC: history, clinical applications, and implementation.
      ]. Despite this, CT scan with injection intra-venous of contrast is the most widely used in the preoperative work-up and follow-up of patients with PMP.
      Increasingly, MRI appears to be an essential complement for preoperative evaluation, for carrying out exhaustive lesion mapping and for monitoring patients with PMP [
      • Low R.N.
      • Barone R.M.
      • Lucero J.
      Comparison of MRI and CT for predicting the Peritoneal Cancer Index (PCI) preoperatively in patients being considered for cytoreductive surgical procedures.
      ,
      • Low R.N.
      • Barone R.M.
      • Rousset P.
      Peritoneal MRI in patients undergoing cytoreductive surgery and HIPEC: history, clinical applications, and implementation.
      ,
      • Low R.N.
      • Barone R.M.
      Combined diffusion-weighted and gadolinium-enhanced MRI can accurately predict the peritoneal cancer index preoperatively in patients being considered for cytoreductive surgical procedures.
      ,
      • Menassel B.
      • Duclos A.
      • Passot G.
      • Dohan A.
      • Payet C.
      • Isaac S.
      • et al.
      Preoperative CT and MRI prediction of non-resectability in patients treated for pseudomyxoma peritonei from mucinous appendiceal neoplasms.
      ]. The liquid character of peritoneal implants, linked to the presence of mucin, makes their detection easier on the T2-weighted and diffusion sequences. In a study of 22 patients (17 appendicular tumors and 5 ovarian carcinomas), comparing MRI with CT scan in the preoperative assessment, Low et al. showed that MRI allowed better categorization of tumor volume (in 91% of patients versus 50% for CT), compared to surgical PCI [
      • Low R.N.
      • Barone R.M.
      • Lucero J.
      Comparison of MRI and CT for predicting the Peritoneal Cancer Index (PCI) preoperatively in patients being considered for cytoreductive surgical procedures.
      ]. In the study by Menassel et al. performed in 82 patients with PMP, MRI was particularly useful and effective compared to CT scan, for the assessment of hepatic hilum invasion and that of the small intestine, these two elements being the main risk factors for resectability [
      • Low R.N.
      • Barone R.M.
      • Rousset P.
      Peritoneal MRI in patients undergoing cytoreductive surgery and HIPEC: history, clinical applications, and implementation.
      ,
      • Menassel B.
      • Duclos A.
      • Passot G.
      • Dohan A.
      • Payet C.
      • Isaac S.
      • et al.
      Preoperative CT and MRI prediction of non-resectability in patients treated for pseudomyxoma peritonei from mucinous appendiceal neoplasms.
      ]. Low et al. also showed in 22 patients with PMP, that MRI was effective in predicting suboptimal cytoreduction in the presence of a mesenteric mass of more than 5 cm or with an upper mesenteric sheath as well as in the event of impairment diffuse from the small intestine [
      • Low R.N.
      • Barone R.M.
      • Gurney J.M.
      • Muller W.D.
      Mucinous appendiceal neoplasms: preoperative MR staging and classification compared with surgical and histopathologic findings.
      ].
      Given the low tissue / weak cellular nature of mucinous lesions, and the high rates of false negatives, the PET scanner is not widely used in practice.

      4.3.2 Endoscopic assessment

      In patients with colorectal cancer, pre- and post-operative colonoscopy are recommended based on the risk of 3–5% of synchronous tumor or 2–3% metachronous tumor [
      • Bülow S.
      • Svendsen L.B.
      • Mellemgaard A.
      Metachronous colorectal carcinoma.
      ,
      • Heald R.J.
      • Bussey H.J.
      Clinical experiences at St. Mark's Hospital with multiple synchronous cancers of the colon and rectum.
      ]. A German multicenter observational study reports that the incidence of colonic neoplasm is 6,2% in cases of carcinoid tumor of the appendix, 10,1% in cases of adenocarcinoma of the appendix and 8,9% in cases of mucinous adenocarcinoma [
      • Benedix F.
      • Reimer A.
      • Gastinger I.
      • Mroczkowski P.
      • Lippert H.
      • Kube R.
      • et al.
      Primary appendiceal carcinoma–epidemiology, surgery and survival: results of a German multi-center study.
      ].
      RECOMMENDATIONS
      • The dosage of the serosal markers: CA19-9, ACE and CA125, is recommended in the pre-therapeutic assessment of patients with PMP (grade C recommendation level). Their increase is correlated with the spread of carcinoma and are prognostic factors.
      • An injected thoraco-abdomino-pelvic CT scan must be performed in the pre-treatment assessment (grade C recommendation level).
      • Peritoneal MRI performed in an expert center usefully supplements the CT-scan for the assessment of the level of resectability and must be performed in the pre-treatment assessment (grade C recommendation level).
      • Total colonoscopy is recommended in the pre-treatment assessment of patients with PMP, looking for a synchronous tumor (expert agreement).
      OPTIONS
      • In doubt about the site of the primary tumor after imaging workup, gastroscopy is indicated. As the synchronous association of gastric cancer - PMP of appendicular origin is particularly rare, gastroscopy is not essential if the appendicular origin is evident on imaging (expert agreement).
      • The performance of an exploratory laparoscopy in patients with PMP should be discussed on a case-by-case basis and performed, if necessary, in an expert center, placing the trocars on the midline (expert agreement).
      • In the event of a typical PMP appearance on imaging, histological confirmation by biopsy at an expert center is optional (expert agreement).
      • In case of diagnostic doubt, a biopsy is indicated, preferably performed during an exploratory laparoscopy in an expert center (expert agreement).

      4.4 Treatments

      4.4.1 Surgical treatment

      4.4.1.1 Complete cytoreductive surgery and HIPEC

      The combination of complete cytoreductive surgery (CRS) followed by HIPEC has improved patient survival compared to surgical treatment alone with iterative "debulking". Indeed, the survivals reported after incomplete iterative surgeries varied from 15 to 20% at 5 years and less than 10% at 10 years. However, no prospective randomized controlled study comparing treatment with repeated "debulking" surgery to treatment with complete cytoreductive surgery followed by HIPEC, is available. Currently, after cytoreductive surgery and HIPEC, the median overall survival ranges from 97 to 111 months, reaching 196 months (16,3 years) in the multicenter series published in 2012 and which included 2218 patients [
      • Chua T.C.
      • Moran B.J.
      • Sugarbaker P.H.
      • Levine E.A.
      • Glehen O.
      • Gilly F.N.
      • et al.
      Early- and long-term outcome data of patients with pseudomyxoma peritonei from appendiceal origin treated by a strategy of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.
      ]. Recurrence-free survival was also high, reaching 98 months (8,2 years) in the study by Chua et al. Recently, a PSOGI analysis carried out on 1924 patients operated on for PMP of appendicular origin between February 1993 and January 2018, demonstrated that the survival of patients having had cytoreduction followed by HIPEC had a higher survival than that of patients having CRS alone (overall survival 57,8% (95% CI, 50,8% −65,7%) vs. 46,2% (95% CI, 40,3% −52,8%; adjusted HR, 0,65; 95% CI, 0,50–0,83; p < 0,001) [
      • Kusamura S.
      • Barretta F.
      • Yonemura Y.
      • Sugarbaker P.H.
      • Moran B.J.
      • Levine E.A.
      • et al.
      The role of hyperthermic intraperitoneal chemotherapy in pseudomyxoma peritonei after cytoreductive surgery.
      ]. However, this is a retrospective analysis and the patients and types of surgery do were not comparable. Performing HIPEC was associated with better survival in the event of low-grade, high-grade lesions, CC0/1 and CC2/3 cytoreduction, intraperitoneal use of a protocol combining oxaliplatin IP to 5FU IV, or cisplatin and mitomycin C IP. In multivariate analysis, the factors significantly associated with decreased survival were: absence of HIPEC, age> 65 years, systemic chemotherapy preoperative emic, lymph node involvement, PCI at 29 vs 10, high histological grade. The results of the recent PSOGI series [
      • Kusamura S.
      • Barretta F.
      • Yonemura Y.
      • Sugarbaker P.H.
      • Moran B.J.
      • Levine E.A.
      • et al.
      The role of hyperthermic intraperitoneal chemotherapy in pseudomyxoma peritonei after cytoreductive surgery.
      ], once again validate the performance of a HIPEC after complete cytoreductive CC0/CC1 and after incomplete cytoreductive CC2/3 which is new data which will have to be confirmed. In addition, the association with a HIPEC was not associated with an increased risk of severe complications, reoperations, mortality at D30 and D90.

      4.4.1.2 Debulking surgery

      When complete cytoreductive surgery is not feasible either because of a contraindication related to the patient (general condition, anesthesia, etc.), or because of a major peritoneal extension not accessible to complete resection, surgery of "debulking", carried out in expert centers, can improve the symptoms related to the disease (expert agreement).
      The purpose of this surgery is to resect most of the disease, and / or the masses responsible for painful or compressive symptoms, and to improve the quality of life of patients, while being conservative enough to limit postoperative mortality and morbidity [
      • Dayal S.
      • Taflampas P.
      • Riss S.
      • Chandrakumaran K.
      • Cecil T.D.
      • Mohamed F.
      • et al.
      Complete cytoreduction for pseudomyxoma peritonei is optimal but maximal tumor debulking may be beneficial in patients in whom complete tumor removal cannot be achieved.
      ,
      • Delhorme J.-.B.
      • Elias D.
      • Varatharajah S.
      • Benhaim L.
      • Dumont F.
      • Honoré C.
      • et al.
      Can a benefit be expected from surgical debulking of unresectable pseudomyxoma peritonei?.
      ].

      4.4.1.3 Place of laparoscopy

      It is not currently recommended to treat a patient affected with PMP by laparoscopy (expert agreement), although there have been a few series of patients with low-grade and very limited PMP, in whom it has been performed [
      • Arjona-Sanchez A.
      • Esquivel J.
      • Glehen O.
      • Passot G.
      • Turaga K.K.
      • Labow D.
      • et al.
      A minimally invasive approach for peritonectomy procedures and hyperthermic intraperitoneal chemotherapy (HIPEC) in limited peritoneal carcinomatosis: the American Society of Peritoneal Surface Malignancies (ASPSM) multi-institution analysis.
      ,
      • Salti G.I.
      • Naffouje S.A.
      Feasibility of hand-assisted laparoscopic cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal surface malignancy.
      ].

      4.4.1.4 Place of iterative surgery

      A new complete cytoreductive surgery associated or not with HIPEC can be proposed to patients selected according to the extent of the recurrent peritoneal disease, the time to onset of recurrence, the histology of the PMP, the general condition of the patient (expert agreement) [
      • Delhorme J.-.B.
      • Honoré C.
      • Benhaim L.
      • Dumont F.
      • Dartigues P.
      • Dromain C.
      • et al.
      Long-term survival after aggressive treatment of relapsed serosal or distant pseudomyxoma peritonei.
      ,
      • Golse N.
      • Bakrin N.
      • Passot G.
      • Mohamed F.
      • Vaudoyer D.
      • Gilly F.-.N.
      • et al.
      Iterative procedures combining cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for peritoneal recurrence: postoperative and long-term results.
      ,
      • Vaira M.
      • Robella M.
      • Mellano A.
      • Sottile A.
      • De Simone M.
      Iterative procedures combining cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for isolated peritoneal recurrence.
      ,
      • Kirby R.
      • Liauw W.
      • Zhao J.
      • Morris D.
      Quality of life study following cytoreductive surgery and intraperitoneal chemotherapy for pseudomyxoma peritonei including redo procedures.
      ].

      4.4.1.5 Place of intraperitoneal chemotherapy

      Intra-peritoneal chemotherapy is performed after complete cytoreductive surgery, in the form of a heated bath (HIPEC). No randomized studies comparing cytoreductive surgery alone with cytoreductive surgery plus HIPEC have been performed. Some teams also perform immediate postoperative intraperitoneal chemotherapy over a period of 5 days, after cytoreductive surgery and HIPEC. The most widely used chemotherapy is mitomycin C [
      • Sørensen O.
      • Andersen A.M.
      • Larsen S.G.
      • Giercksky K.-.E.
      • Flatmark K.
      Intraperitoneal mitomycin C improves survival compared to cytoreductive surgery alone in an experimental model of high-grade pseudomyxoma peritonei.
      ]. Many other protocols of HIPEC are used, in monotherapy or bitherapy using cisplatin, oxaliplatin, etc. No study currently allows to recommend one protocol more than another.
      Pressurized intraperitoneal chemotherapy (PIPAC), without associated resection, has also been reported [
      • Sgarbura O.
      • Hübner M.
      • Alyami M.
      • Eveno C.
      • Gagnière J.
      • Pache B.
      • et al.
      Oxaliplatin use in pressurized intraperitoneal aerosol chemotherapy (PIPAC) is safe and effective: a multicenter study.
      ]. Its effectiveness is under evaluation.
      RECOMMENDATIONS
      • All patients with PMP must be discussed in a regional multidisciplinary meeting attached to the RENAPE network (expert agreement).
      • Complete cytoreductive surgery followed by HIPEC is the standard treatment. (Grade B recommendation level). This treatment must be carried out in an expert center (expert agreement).
      • Abdominal exploration by laparoscopy should be reserved in fraily patients, for whom a major resection will not be proposed, or in the event of aggressive histology (goblet cell carcinoma, poorly cohesive cells), in whom a major invasion or unresectable pathology could lead to proposing systemic chemotherapy (expert agreement).
      • HIPEC is performed with mitomycin C and cisplatin, over a period of 90 min and at a temperature of 41 °C (Grade C recommendation level) at a dose of 25 mg / m² (50% dose at T0.25% at 30 min and 25% at 60 min) (expert agreement), either open- or closed abdomen, depending on the centre's experience (expert agreement).
      • This treatment must be carried out in an expert center (expert agreement).
      • In the event of low-grade unresectable PMP, HIPEC may be discussed, this could delay the recurrence of ascites, and stabilize the course of the disease (expert agreement).
      • In the event of high-grade PMP with incomplete CC2 resection, performing HIPEC is not recommended (expert agreement).
      OPTION
      • HIPEC with oxaliplatin at a dose of 250 mg / m² in 3 fractions over a period of 90 min and intravenous bolus of 5 FU 400 mg / m2 (expert agreement).
      No clinical trial

      4.4.2 Systemic chemotherapy

      To date, no randomized trials, (only rare studies, most often retrospective and with small cohorts) have evaluated the benefit of systemic chemotherapy in patients with PMP. Furthermore, the radiological response according to the usual RECIST 1.1 criteria is difficult to assess (ascites and cystic lesions not target according to this classification). Therefore, the level of evidence on the benefit of systemic chemotherapy is very low.

      4.4.2.1 Low grade mucinous carcinomatosis

      4.4.2.1.1 Resectable disease

      The indication for adjuvant chemotherapy is of no carcinological interest if the histological analysis of the surgical specimen shows only low-grade lesions.

      4.4.2.1.2 Unresectable disease

      A recent American registry with an imprecise description of a cohort of 639 patients with low-grade mucinous carcinoma does not report any benefit on overall survival for the subgroup of 431 patients who received systemic chemotherapy [
      • Lu P.
      • Fields A.C.
      • Meyerhardt J.A.
      • Davids J.S.
      • Shabat G.
      • Bleday R.
      • et al.
      Systemic chemotherapy and survival in patients with metastatic low-grade appendiceal mucinous adenocarcinoma.
      ].

      4.4.2.2.2 High grade mucinous carcinomatosis

      High-grade lesions is correlated with a decrease in overall survival, even after complete cytoreductive with HIPEC [
      • Chua T.C.
      • Moran B.J.
      • Sugarbaker P.H.
      • Levine E.A.
      • Glehen O.
      • Gilly F.N.
      • et al.
      Early- and long-term outcome data of patients with pseudomyxoma peritonei from appendiceal origin treated by a strategy of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.
      ].

      4.4.2.2.2.1 Resectable disease

      In a prospective study carried out in 34 resectable patients immediately treated with preoperative systemic chemotherapy with 5 FU, oxaliplatin +/- bevacizumab, the tumor control rate was 65% and the rate of partial or complete histological response was 29% [
      • Sugarbaker P.H.
      • Bijelic L.
      • Chang D.
      • Yoo D.
      Neoadjuvant FOLFOX chemotherapy in 34 consecutive patients with mucinous peritoneal carcinomatosis of appendiceal origin.
      ]. A significant decrease in PCI and of the heaviness of the operative procedures (peritonectomies, organ resection) and an absence of increased postoperative morbidity and mortality, were also reported after preoperative chemotherapy [
      • Bijelic L.
      • Kumar A.S.
      • Stuart O.A.
      • Sugarbaker P.H.
      Systemic chemotherapy prior to cytoreductive surgery and HIPEC for carcinomatosis from appendix cancer: impact on perioperative outcomes and short-term survival.
      ].

      4.4.2.2.2.2 Unresectable disease

      In the study reported by Lieu et al., about 78 patients who received systemic chemotherapy for unresectable high grade mucinous carcinomatosis, the response rate was 44%, the second-line administration 57%, the subsequent complete resection 33%, and progression-free survival, 7,8 months and overall survival of 1,7 years [
      • Lieu C.H.
      • Lambert L.A.
      • Wolff R.A.
      • Eng C.
      • Zhang N.
      • Wen S.
      • et al.
      Systemic chemotherapy and surgical cytoreduction for poorly differentiated and signet ring cell adenocarcinomas of the appendix.
      ].
      RECOMMENDATIONS
      • Low grade peritoneal mucinous carcinoma (G1, well differentiated):
      • There is no indication for systemic chemotherapy if the disease is resectable (Grade C recommendation level).
      • No data demonstrates the benefit of a systemic chemotherapy in relation to best supportive care in the event of unresectable disease (Grade C recommendation level).
      • High grade peritoneal mucinous carcinoma (moderately differentiated G2 or poorly differentiated G3):
        • In case of complete cytoreductive surgery, a perioperative or postoperative systemic chemotherapy may be discussed on a case-by-case basis (expert agreement).
        • In case of high-grade mucinous peritoneal carcinomatosis appearing resectable, there is a potential indication for a neoadjuvant systemic chemotherapy with FOLFOX 3 months or CAPOX + / - bevacizumab, especially in case of major involvement (expert agreement).
        • In case of high-grade unresectable mucinous peritoneal carcinomatosis, systemic chemotherapy may be of benefit (Grade C recommendation level). The optimal protocol is not defined.
      No clinical trial

      4.5 Surveillance

      RECOMMENDATIONS (expert agreement)
      • For low grade lesions:
        • Peritoneal MRI + assay of CAE, CA19–9 and CA125 markers;
        • Every 6 months for 3 years then every year for 3 years then every 2 years until 15 years after initial care.
      • For high grade tumors:
        • Injected thoraco-abdomino-pelvic CT scan (without digestive opacification) + dosage of markers, and peritoneal MRI in case of doubt about the CT scan or increase in serum markers without anomaly on the CT scan;
        • Every 4 months for 3 years then every 6 months for 2 years then every year until 15 years after initial care.

      Declaration of Competing Interest

      No potential competing interest was reported by the authors.

      Acknowledgements

      The authors thank the review committee: Thomas Aparicio (Paris), Catherine Arvieux (Grenoble), Valérie Boige (Villejuif), Clarisse Dromain (Lausanne), Frédéric Dumont (Nantes), Sébastien Gaujoux (Paris), Thierry Lecomte (Tours), Christophe Louvet (Paris), Pierre Michel (Rouen), Emmanuelle Samalin (Montpellier), Philippe Soyer (Paris), Jean-Jacques Tuech (Rouen), Thomas Walter (Lyon), Karine Abboud (Saint Etienne), Koceila Amroun (Reims), Bogdan Badic (Brest), Bachir Elias (Thionville), Cécilia Frasconi (Marseille), Pierre Guillet (Toulon), Marine Jarry (Besançon), Dine Koriche (Béthune/Lens), Jean-Pierre Machayekh (Guilherand-Granges), Frédéric Marchal (Nancy), Pierre Meeus (Lyon), Nicolas Mocellin (Saint-Avold), Yann Mottaz (La Chaussée Saint Victor), Jean-François Paitel (Fréjus/Saint-Raphaël), Brice Paquette (Besançon), Guillaume Passot (Pierre- Bénite), Pierre-Guillaume Poureau (Brest), Charles Sabbagh (Amiens), Alexis Vinet (Châteauroux).

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