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Management and outcome of high-risk neuroendocrine tumors of the appendix in children; A systematic review

  • Paul van Amstel
    Correspondence
    Corresponding author. Emma Children's Hospital, Amsterdam UMC, University of Amsterdam & Vrije Universiteit Amsterdam, Department of Pediatric Surgery, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
    Affiliations
    Emma Children's Hospital, Amsterdam UMC location, University of Amsterdam, Pediatric Surgery, Meibergdreef 9, Amsterdam, the Netherlands

    Amsterdam Reproduction & Development, Amsterdam, the Netherlands

    Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
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  • Amber Mahieu
    Affiliations
    Emma Children's Hospital, Amsterdam UMC location, University of Amsterdam, Pediatric Surgery, Meibergdreef 9, Amsterdam, the Netherlands
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  • Roel Bakx
    Affiliations
    Emma Children's Hospital, Amsterdam UMC location, University of Amsterdam, Pediatric Surgery, Meibergdreef 9, Amsterdam, the Netherlands

    Amsterdam Reproduction & Development, Amsterdam, the Netherlands
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  • Ralph de Vries
    Affiliations
    Vrije Universiteit Amsterdam, University Library, Amsterdam, the Netherlands
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  • Martine F. Raphael
    Affiliations
    Emma Children's Hospital, Amsterdam UMC location, University of Amsterdam, Pediatric Oncology, Meibergdreef 9, Amsterdam, the Netherlands
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  • Joep P.M. Derikx
    Affiliations
    Emma Children's Hospital, Amsterdam UMC location, University of Amsterdam, Pediatric Surgery, Meibergdreef 9, Amsterdam, the Netherlands

    Amsterdam Reproduction & Development, Amsterdam, the Netherlands

    Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
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  • L.W. Ernest van Heurn
    Affiliations
    Emma Children's Hospital, Amsterdam UMC location, University of Amsterdam, Pediatric Surgery, Meibergdreef 9, Amsterdam, the Netherlands

    Amsterdam Reproduction & Development, Amsterdam, the Netherlands

    Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
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  • Ramon R. Gorter
    Affiliations
    Emma Children's Hospital, Amsterdam UMC location, University of Amsterdam, Pediatric Surgery, Meibergdreef 9, Amsterdam, the Netherlands

    Amsterdam Reproduction & Development, Amsterdam, the Netherlands

    Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
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Open AccessPublished:November 02, 2022DOI:https://doi.org/10.1016/j.ejso.2022.10.021

      Abstract

      This study systematically reviewed the literature to investigate the value of secondary surgery for children with a high-risk neuroendocrine tumor (NET) of appendix. A systematic search was performed in PubMed, Embase and Web of Science. All randomized controlled trials, cohort studies, and case series reporting on the management and outcomes of patients (<20 years) with a histopathologically proven NET of the appendix were eligible for inclusion. Two authors independently selected eligible articles, assessed risk of bias, and extracted data. The outcomes of patients with a high-risk NET treated with secondary surgery were compared to those treated without secondary surgery. Primary outcomes were recurrence rate and disease-free survival. The literature search yielded 667 articles, of which 29 were included. These studies reported on 1112 patients, of whom 145 (13%) had high-risk NET. Heterogeneity between studies was large and risk of bias was serious in 26 and moderate in three studies. Secondary surgery after primary appendectomy was performed in 64 of 145 patients (44%). Length of follow-up ranged between 0 and 612 months. In both treatment groups no recurrences were reported, and thus disease-free survival was 100%. Based on current literature, the value of secondary surgery for pediatric high-risk NET of the appendix may be questioned. However, evidence is scarce, of low-quality, and heterogeneity between studies is large. Large international studies with adequate follow-up are needed to generate high-quality evidence on this topic.

      Keywords

      Abbreviations:

      NEN (Neuroendocrine Neoplasm), NET (Neuroendocrine Tumor), NEC (Neuroendocrine Carcinoma), MiNEN (Mixed Neuroendocrine non-neuroendcrine neoplasm), ENETS (European Neuroendocrine Tumor Society), NANETS (North American Neuroendocrine Tumor Society), hrQoL (health related Quality of Life), IAA (Intra-abdominal abscess), ROBINS-I (Risk Of Bias In Non-randomised Studies of Interventions)

      1. Background

      Neuroendocrine neoplasms (NENs) of the appendix are very rare in children, but are still the most frequently found gastro-intestinal tract tumors after lymphomas [
      • Moertel C.G.
      • Weiland L.H.
      • Nagorney D.M.
      • Dockerty M.B.
      Carcinoid tumor of the appendix: treatment and prognosis.
      ]. As described by the recently updated World Health Organization classification, three different subgroups of NENs are distinguished; neuroendocrine tumors (NETs), neuroendocrine carcinomas (NECs), and mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs). Treatment strategies of these subgroups of NENs are different, as prognosis of NECs and MiNENs is significantly poorer compared to NETs [
      • Nagtegaal I.D.
      • Odze R.D.
      • Klimstra D.
      • et al.
      The 2019 WHO classification of tumours of the digestive system.
      ]. International societies have developed guidelines to provide guidance and uniformity in the management of NENs of the appendix [
      • Pape U.F.
      • Niederle B.
      • Costa F.
      • et al.
      ENETS consensus guidelines for neuroendocrine neoplasms of the appendix (excluding goblet cell carcinomas).
      ]. Cornerstone is surgery, reserving somatostatin analogues for sporadic patients with distant metastases and/or carcinoid syndrome. The guideline describes that NECs and MiNENs should be treated with oncological right-sided hemicolectomy, irrespective of tumor size. For NETs, however, surgical treatment depends on tumor size and various histopathological risk factors predicting potential aggressive behavior (i.e. incomplete resection, tumor at base of appendix, grade 2 NET, lymphovascular or >3 mm mesoappendiceal invasion of tumor cells). In these guidelines, patients with tumors <1 cm (pT1) or 1–2 cm (pT2) without risk factors for aggressive behavior are considered to be at low risk of lymphatic metastasis and/or recurrent disease (low-risk NET of the appendix) and an appendectomy is recommended. While patients with tumors >2 cm (pT3) or 1–2 cm (pT2) with risk factors for aggressive behavior are considered to be at high-risk of lymphatic metastasis and/or recurrent disease (high-risk NET of the appendix) [
      • Anderson J.R.
      • Wilson B.G.
      Carcinoid tumours of the appendix.
      ,
      • Bamboat Z.M.
      • Berger D.L.
      Is right hemicolectomy for 2.0-cm appendiceal carcinoids justified?.
      ,
      • Bowman G.A.
      • Rosenthal D.
      Carcinoid tumors of the appendix.
      ,
      • Boxberger N.
      • Redlich A.
      • Böger C.
      • et al.
      Neuroendocrine tumors of the appendix in children and adolescents.
      ,
      • de Lambert G.
      • Lardy H.
      • Martelli H.
      • Orbach D.
      • Gauthier F.
      • Guérin F.
      Surgical management of neuroendocrine tumors of the appendix in children and adolescents: a retrospective French multicenter study of 114 cases.
      ,
      • Moertel C.L.
      • Weiland L.H.
      • Telander R.L.
      Carcinoid tumor of the appendix in the first two decades of life.
      ,
      • Spunt S.L.
      • Pratt C.B.
      • Rao B.N.
      • et al.
      Childhood carcinoid tumors: the st jude children's research hospital experience.
      ,
      • Syracuse D.C.
      • Perzin K.H.
      • Price J.B.
      • Wiedel P.D.
      • Mesa-Tejada R.
      Carcinoid tumors of the appendix. Mesoappendiceal extension and nodal metastases.
      ]. Complementary right-sided hemicolectomy is recommended in these patients to completely ensure that no residual tumor is left behind and no tumor metastasis to lymph nodes has occurred [
      • Pape U.F.
      • Niederle B.
      • Costa F.
      • et al.
      ENETS consensus guidelines for neuroendocrine neoplasms of the appendix (excluding goblet cell carcinomas).
      ,
      • Yao J.C.
      • Hassan M.
      • Phan A.
      • et al.
      One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States.
      ].
      These recommendations, however, are predominantly based upon studies in the adult population. Questions are now raised whether or not these recommendations are also applicable in children. Especially the value of a complementary right-sided hemicolectomy is questioned for pediatric patients with a high-risk NET of the appendix, as it appears that residual tumor and positive lymph nodes are found in only very few patients and most importantly disease-free survival is reported to be excellent. Therefore this systematic review aimed to investigate the value of secondary surgery for children and adolescents <20 years old treated for a high-risk NET of the appendix in terms of recurrences and disease-free survival.

      2. Methods

      Before the start of the systematic review, the protocol was registered at PROSPERO: International prospective register of systematic reviews (identification number CRD42021281199). This study was reported according to the Preferred Reporting Items for Systematic reviews and Meta-analysis (PRISMA) guidelines [
      • Page M.J.
      • McKenzie J.E.
      • Bossuyt P.M.
      • et al.
      The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
      ]. Only previously published data was analysed and therefore ethical approval and written informed consent were not required.

      2.1 Participants and type of studies

      All studies reporting on the management of histopathologcally proven high-risk (pT2 with risk factors and pT3) NET of the appendix in children and adolescents <20 years old were considered for inclusion. All NETs were classified according to the European Neuroendocrine Tumor Society (ENETS) classification, based on the histopathological features that were described in the original studies and divided into low-risk and high-risk NETs of the appendix. pT2 NETs of the appendix were considered as a high-risk NET, if any of the following risk factors were reported: Incomplete resection, tumor at base of appendix, grade 2 NET, lymphovascular or >3 mm mesoappendiceal invasion of tumor cells. Studies that reported results of the treatment of goblet cell carcinoid, mixed adenoneuroendocrine carcinoma or grade 3 neuroendocrine carcinoma of the appendix were excluded. Randomized controlled trials, prospective or historical cohort studies, and case series were included in the review. Case reports, expert opinions and letters to the editor were excluded. Languages were restricted to English, German, French and Dutch. Lastly, only studies that reported on our primary outcomes were eligible for inclusion. Primary outcomes of this review were recurrence rate and disease-free survival.

      2.2 Types of interventions

      The intervention group was defined as those patients with a high-risk NET of the appendix that were treated with secondary surgery (such as right hemicolectomy, ileocaecal resection or caecectomy) after initial appendectomy. The control group consisted of patients that were not treated with secondary surgery after appendectomy.

      2.3 Search methods

      In order to identify all relevant publications we performed a comprehensive search in the bibliographic databases PubMed, Embase, and Web of Science from inception up to July 18, 2022, in collaboration with a medical information specialist. The following terms were used (including synonyms and closely related words) as index terms or free-text words: "Neuroendocrine Tumors", "Carcinoid", "Appendix", "Adolescent", "Child", "Infant". The references of the identified articles were searched for relevant publications. Duplicate articles were excluded. The full search strategies for all databases can be found in Appendix 1.

      2.4 Study selection and data extraction

      Eligible articles were screened by two independent reviewers (PA, AM) based on title and abstract and subsequently full text articles were assessed according to the predefined in- and exclusion criteria. Discrepancies were resolved by consensus and in case of disagreement a third reviewer was consulted (RG). After article selection, two reviewers (PA, AM) independently extracted data from the included studies, according to a predefined data extraction form. Collected variables were general information (author, year, methodology, patient characteristics), histopathological findings (localization of NET, NET size, criteria for secondary surgery, NET invasion, surgical resection margins, classification of NET according to ENETS classification), primary appendectomy findings (preoperative suspicion of NET, intraoperative suspicion of NET, surgical approach, appendiceal perforation), secondary interventions (type of resection, reason for secondary surgery, histopathological findings after secondary surgery (number of positive lymph nodes, residual tumor), and follow-up data (recurrences, survival, complications, imaging studies, outpatient check-ups and health-related Quality of Life (hr-QoL)).

      2.5 Outcomes and definitions

      The primary outcomes of this systematic review were recurrence rate and disease-free survival. Recurrence rate was defined as imaging and/or histopathologically proven NET of the appendix or metastasis after initial resolution of disease. Disease-free survival was defined as alive and without recurrence of disease at moment of follow-up of the original studies.
      Secondary outcomes were overall survival defined as alive at moment of follow-up of the original studies and postoperative complication rate, defined as the proportion of patients experiencing at least one complication after secondary surgery. Complications included, but were not limited to:
      • Intra-abdominal abscess (IAA), defined as a radiologically confirmed accumulation of purulent fluid in a walled-off space within the abdominal cavity.
      • (Adhesive) bowel obstruction requiring readmission (diagnosis based on clinical signs and symptoms such as a history of constipation, nausea, vomiting and distended abdomen)
      • Superficial and Deep Surgical Site Infection, as defined by the CDC criteria [
        • Horan T.C.
        • Andrus M.
        • Dudeck M.A.
        CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting.
        ].
      • Anastomotic leakage, as defined by the International Study Group of Rectal Cancer (ISREC) [
        • Rahbari N.N.
        • Weitz J.
        • Hohenberger W.
        • et al.
        Definition and grading of anastomotic leakage following anterior resection of the rectum: a proposal by the International Study Group of Rectal Cancer.
        ,
        • van Helsdingen C.P.
        • Jongen A.C.
        • de Jonge W.J.
        • Bouvy N.D.
        • Derikx J.P.
        Consensus on the definition of colorectal anastomotic leakage: a modified Delphi study.
        ].
      If possible, complications were listed according to the Clavien-Dindo classification [
      • Clavien P.A.
      • Barkun J.
      • de Oliveira M.L.
      • et al.
      The Clavien-Dindo classification of surgical complications: five-year experience.
      ].
      Other secondary outcomes were the number of additional imaging studies during follow-up (including ultrasound, (PET-) Computed Tomography, Magnetic Resonance Imaging, and octreotide scintigraphy), length of follow-up (days), number of outpatient check-ups (both regular outpatient visits and telephone check-ups), health-related Quality of Life as measured by hr-QoL specific questionnaires, and cost-effectiveness of the treatment strategies, including direct and indirect medical costs.

      2.6 Risk of bias and quality of evidence assessment

      The Risk Of Bias In Non-randomised Studies of Interventions (ROBINS-I) tool was independently applied by two reviewers (PA, AM) [
      • Sterne J.A.
      • Hernán M.A.
      • Reeves B.C.
      • et al.
      ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions.
      ]. Risk of bias domains were assessed according to predefined definitions. Of specific interest were the risk of bias domains regarding confounding and missing data. Risk of bias due to confounding was considered low in randomized controlled trials, moderate in prospective and retrospective cohort studies that described baseline characteristics of the intervention and control groups, and serious in those studies that did not describe baseline characteristics for the intervention and control groups. Bias due to missing data was assessed serious if more than 50% of patients were lost to follow-up, moderate if less than 50% but more than 5% of patients were lost to follow-up, and low if less than 5% of patients were lost to follow-up.

      2.7 Data analysis

      Patients were classified as low risk-NET and high-risk NET according to the ENETS classification [
      • Pape U.F.
      • Niederle B.
      • Costa F.
      • et al.
      ENETS consensus guidelines for neuroendocrine neoplasms of the appendix (excluding goblet cell carcinomas).
      ]. Analyses were performed on patients with a high-risk NET. The group of patients treated with secondary surgery after appendectomy (intervention group) were compared to the group of patients that did not undergo secondary surgery after appendectomy (control group). Review Manager version 5.3.5 was used to perform meta-analyses on the primary outcomes, recurrence rate and disease-free survival, if events were reported. The Mantel-Haenszel method was used to compute risk ratios and their corresponding 95%CI. Heterogeneity was assessed with the Higgins I2 inconsistency test, with an I2 of more than 50% considered as substantial. Meta-analyses were performed using a random effects model. For the secondary outcomes only descriptive statistics were performed.

      3. Results

      3.1 Search

      The literature search generated a total of 1097 references: 438 in PubMed, 487 in Embase and 172 in Web of Science. After removing duplicates of references that were selected from more than one database, 667 references remained. Of these, 498 references were excluded after screening for title and abstract. Full text of 169 references were assessed and subsequently 140 references were excluded due to various reasons. Therefore, 29 studies were included in this systematic review. The flowchart of the search and selection process is presented in Fig. 1.

      3.2 General characteristics of the included studies

      Designs of the included studies were two prospective and 27 retrospective cohort studies [
      • Boxberger N.
      • Redlich A.
      • Böger C.
      • et al.
      Neuroendocrine tumors of the appendix in children and adolescents.
      ,
      • de Lambert G.
      • Lardy H.
      • Martelli H.
      • Orbach D.
      • Gauthier F.
      • Guérin F.
      Surgical management of neuroendocrine tumors of the appendix in children and adolescents: a retrospective French multicenter study of 114 cases.
      ,
      • Moertel C.L.
      • Weiland L.H.
      • Telander R.L.
      Carcinoid tumor of the appendix in the first two decades of life.
      ,
      • Spunt S.L.
      • Pratt C.B.
      • Rao B.N.
      • et al.
      Childhood carcinoid tumors: the st jude children's research hospital experience.
      ,
      • Abadía Barnó P.
      • Rivilla F.
      • Barquín Yagüez J.
      • Abadía Barnó M.
      • García Pérez J.C.
      Appendiceal carcinoid tumor in children: a conservative surgical approach.
      ,
      • Akova F.
      • Aydin E.
      • Nur Eray Y.
      • et al.
      Long-term outcomes in pediatric appendiceal carcinoids: Turkey experience.
      ,
      • Corpron C.A.
      • Black C.T.
      • Herzog C.E.
      • Sellin R.V.
      • Lally K.P.
      • Andrassy R.J.
      A half century of experience with carcinoid tumors in children.
      ,
      • Dall'Igna P.
      • Ferrari A.
      • Luzzatto C.
      • et al.
      Carcinoid tumor of the appendix in childhood: the experience of two Italian institutions.
      ,
      • Fernández K.S.
      • Aldrink J.H.
      • Ranalli M.
      • Ruymann F.B.
      • Caniano D.A.
      Carcinoid tumors in children and adolescents: risk for second malignancies.
      ,
      • Hatzipantelis E.
      • Panagopoulou P.
      • Sidi-Fragandrea V.
      • Fragandrea I.
      • Koliouskas D.E.
      Carcinoid tumors of the appendix in children: experience from a tertiary center in northern Greece.
      ,
      • Henderson L.
      • Fehily C.
      • Folaranmi S.
      • et al.
      Management and outcome of neuroendocrine tumours of the appendix-a two centre UK experience.
      ,
      • Jónsson T.
      • Jóhannsson J.H.
      • Hallgrimsson J.G.
      Carcinoid tumors of the appendix in children younger than 16 years. A retrospective clinical and pathologic study.
      ,
      • Kim S.S.
      • Kays D.W.
      • Larson S.D.
      • Islam S.
      Appendiceal carcinoids in children--management and outcomes.
      ,
      • Kulkarni K.P.
      • Sergi C.
      Appendix carcinoids in childhood: long-term experience at a single institution in Western Canada and systematic review.
      ,
      • Neves G.R.
      • Chapchap P.
      • Sredni S.T.
      • Viana C.R.
      • Mendes W.L.
      Childhood carcinoid tumors: description of a case series in a Brazilian cancer center.
      ,
      • Njere I.
      • Smith L.L.
      • Thurairasa D.
      • et al.
      Systematic review and meta-analysis of appendiceal carcinoid tumors in children.
      ,
      • Parikh P.P.
      • Perez E.A.
      • Neville H.L.
      • Hogan A.R.
      • Sola J.E.
      Nationwide overview of survival and management of appendiceal tumors in children.
      ,
      • Pelizzo G.
      • La Riccia A.
      • Bouvier R.
      • Chappuis J.P.
      • Franchella A.
      Carcinoid tumors of the appendix in children.
      ,
      • Pérez-Albert P.
      • de Rojas T.
      • Lendínez M.
      • et al.
      Management and outcome of children with neuroendocrine tumors of the appendix in Spain: is there room for improvement?.
      ,
      • Prommegger R.
      • Obrist P.
      • Ensinger C.
      • Profanter C.
      • Mittermair R.
      • Hager J.
      Retrospective evaluation of carcinoid tumors of the appendix in children.
      ,
      • Ranaweera C.
      • Brar A.
      • Somers G.R.
      • Sheikh F.
      • Pierro A.
      • Zani A.
      Management of pediatric appendiceal carcinoid: a single institution experience from 5000 appendectomies.
      ,
      • Ryden S.E.
      • Drake R.M.
      • Franciosi R.A.
      Carcinoid tumors of the appendix in children.
      ,
      • Scott A.
      • Upadhyay V.
      Carcinoid tumours of the appendix in children in Auckland, New Zealand: 1965-2008.
      ,
      • Sommer C.
      • Gumy Pause F.
      • Diezi M.
      • Rougemont A.L.
      • Wildhaber B.E.
      A national long-term study of neuroendocrine tumors of the appendix in children: are we too aggressive?.
      ,
      • Vandevelde A.
      • Gera P.
      Carcinoid tumours of the appendix in children having appendicectomies at Princess Margaret Hospital since 1995.
      ,
      • Virgone C.
      • Cecchetto G.
      • Alaggio R.
      • et al.
      Appendiceal neuroendocrine tumours in childhood: Italian TREP project.
      ,
      • Wu H.
      • Chintagumpala M.
      • Hicks J.
      • Nuchtern J.G.
      • Okcu M.F.
      • Venkatramani R.
      Neuroendocrine tumor of the appendix in children.
      ,
      • Kartal İ.
      Childhood neuroendocrine tumors of the digestive system: a single center experience.
      ,
      • Yalçın B.
      • Karnak İ.
      • Orhan D.
      • et al.
      Paediatric appendiceal neuroendocrine tumours: a review of 33 cases from a single center.
      ]. The general characteristics of the studies are presented in Table 1. A total of 1112 patients with a NET of the appendix (both low risk and high-risk NET) were included in these studies, of whom 254 were male and 593 were female. For 265 patients gender data was missing. Age of the patients ranged between 9 months and 19.5 years. Follow-up duration ranged between 0 months and 51 years.
      Table 1General characteristics.
      AuthorStudy designAge range (years)No. of patientspT1pT2pT3High-risk NETsIndications for secondary surgeryIntervention groupControl groupFollow-up period (months)
      Akova (2018)Retrospective cohort10–16104604G2: 3; G2 + MI: 1042–89
      Barno (2018)Retrospective cohort13–1883504Base: 2; MI: 2222–326
      Boxberger (2013)Prospective cohort4–20237165521021TS: 10910–153
      Corpron (1995)Retrospective cohort6–19228504MI: 41318–360
      Dall'Igna (2005)Retrospective cohort5–17146403MI + R1: 33024–214
      De Lambert (2016)Retrospective cohort5–17114??1029MI: 16; TS: 10 LVI: 2; G2: 110191–120
      Fernandez (2015)Retrospective cohort8–1728171015MI: 3; LVI: 1; TS: 15012–156
      Hatzipantelis (2010)Retrospective cohort4–131918101MI: 1016–118
      Henderson (2014)Retrospective cohort8–1527131007MI: 7071–193
      Jonsson (1989)Retrospective cohort4–151817101MI: 10126–351
      Kartal (2022)Retrospective cohort6–171541012TS: 1, MI: 1023–159
      Kim (2014)Retrospective cohort7–171310211TS: 1108–154
      Kulkarni (2013)Retrospective cohort10–1875201LVI: 11
      Primary surgery was a total colectomy for familial adenomatous polyposis (FAP).
      01–84
      Moertel (1990)Retrospective cohort6–202315336LVI: 3; TS: 3249–612
      Neves (2006)Retrospective cohort4–1785301MI: 11042
      Njere (2018)Retrospective cohort8–16116502missing111–72
      Parikh (2018)Retrospective cohort0–19109??1111TS: 1183120–312
      Pelizzo (2001)Retrospective cohort8–18108022TS: 22036
      Pérez-Albert (2017)Retrospective cohort8–161714201MI + base + R1: 1014–92
      Prommegger (2002)Retrospective cohort6–16364404Base or MI: 4042–360
      Ranaweera (2019)Retrospective cohort0–1832207512TS: 5; missing:71201–60
      Ryden (1975)Retrospective cohort7–143017111TS: 10124–288
      Scott (2011)Retrospective cohort7–1547211422TS: 211?
      Sommer (2019)Retrospective cohort5–164031512R1: 1; TS: 1110–158
      Spunt (2000)Retrospective cohort8–1551302R1 + MI: 2206–244
      Vandevelde (2015)Retrospective cohort9–152115504LVI: 2; MI + LVI: 1; MI: 1040–6
      Virgone (2014)Prospective cohort0.75–17113??55TS: 5141–151
      Wu (2017)Retrospective cohort6–174530505MI: 2; missing: 3141–150
      Yalcin (2022)Retrospective cohort7–163319522TS: 2025–227
      MI: Mesoappendiceal invasion; LVI: lymphovascular invasion; TS: Tumor size; R1: Positive resection margin.
      a Primary surgery was a total colectomy for familial adenomatous polyposis (FAP).
      Histopathological characteristics of all (both low-risk and high-risk) NETs are displayed in Table 2. Tumor location was reported in 19 studies [
      • Boxberger N.
      • Redlich A.
      • Böger C.
      • et al.
      Neuroendocrine tumors of the appendix in children and adolescents.
      ,
      • de Lambert G.
      • Lardy H.
      • Martelli H.
      • Orbach D.
      • Gauthier F.
      • Guérin F.
      Surgical management of neuroendocrine tumors of the appendix in children and adolescents: a retrospective French multicenter study of 114 cases.
      ,
      • Moertel C.L.
      • Weiland L.H.
      • Telander R.L.
      Carcinoid tumor of the appendix in the first two decades of life.
      ,
      • Abadía Barnó P.
      • Rivilla F.
      • Barquín Yagüez J.
      • Abadía Barnó M.
      • García Pérez J.C.
      Appendiceal carcinoid tumor in children: a conservative surgical approach.
      ,
      • Akova F.
      • Aydin E.
      • Nur Eray Y.
      • et al.
      Long-term outcomes in pediatric appendiceal carcinoids: Turkey experience.
      ,
      • Corpron C.A.
      • Black C.T.
      • Herzog C.E.
      • Sellin R.V.
      • Lally K.P.
      • Andrassy R.J.
      A half century of experience with carcinoid tumors in children.
      ,
      • Fernández K.S.
      • Aldrink J.H.
      • Ranalli M.
      • Ruymann F.B.
      • Caniano D.A.
      Carcinoid tumors in children and adolescents: risk for second malignancies.
      ,
      • Hatzipantelis E.
      • Panagopoulou P.
      • Sidi-Fragandrea V.
      • Fragandrea I.
      • Koliouskas D.E.
      Carcinoid tumors of the appendix in children: experience from a tertiary center in northern Greece.
      ,
      • Henderson L.
      • Fehily C.
      • Folaranmi S.
      • et al.
      Management and outcome of neuroendocrine tumours of the appendix-a two centre UK experience.
      ,
      • Jónsson T.
      • Jóhannsson J.H.
      • Hallgrimsson J.G.
      Carcinoid tumors of the appendix in children younger than 16 years. A retrospective clinical and pathologic study.
      ,
      • Njere I.
      • Smith L.L.
      • Thurairasa D.
      • et al.
      Systematic review and meta-analysis of appendiceal carcinoid tumors in children.
      ,
      • Parikh P.P.
      • Perez E.A.
      • Neville H.L.
      • Hogan A.R.
      • Sola J.E.
      Nationwide overview of survival and management of appendiceal tumors in children.
      ,
      • Pelizzo G.
      • La Riccia A.
      • Bouvier R.
      • Chappuis J.P.
      • Franchella A.
      Carcinoid tumors of the appendix in children.
      ,
      • Prommegger R.
      • Obrist P.
      • Ensinger C.
      • Profanter C.
      • Mittermair R.
      • Hager J.
      Retrospective evaluation of carcinoid tumors of the appendix in children.
      ,
      • Ranaweera C.
      • Brar A.
      • Somers G.R.
      • Sheikh F.
      • Pierro A.
      • Zani A.
      Management of pediatric appendiceal carcinoid: a single institution experience from 5000 appendectomies.
      ,
      • Scott A.
      • Upadhyay V.
      Carcinoid tumours of the appendix in children in Auckland, New Zealand: 1965-2008.
      ,
      • Sommer C.
      • Gumy Pause F.
      • Diezi M.
      • Rougemont A.L.
      • Wildhaber B.E.
      A national long-term study of neuroendocrine tumors of the appendix in children: are we too aggressive?.
      ,
      • Virgone C.
      • Cecchetto G.
      • Alaggio R.
      • et al.
      Appendiceal neuroendocrine tumours in childhood: Italian TREP project.
      ,
      • Wu H.
      • Chintagumpala M.
      • Hicks J.
      • Nuchtern J.G.
      • Okcu M.F.
      • Venkatramani R.
      Neuroendocrine tumor of the appendix in children.
      ,
      • Yalçın B.
      • Karnak İ.
      • Orhan D.
      • et al.
      Paediatric appendiceal neuroendocrine tumours: a review of 33 cases from a single center.
      ]. In 485 of 873 cases (55.6%) the NET was located at the tip of the appendix, 161 NETs (18.4%) were found at the body of the appendix, 55 (6.3%) at the base of the appendix, and location was not reported in 172 cases. The extent of invasion into the deepest layer of the appendix was described by 20 studies [
      • Boxberger N.
      • Redlich A.
      • Böger C.
      • et al.
      Neuroendocrine tumors of the appendix in children and adolescents.
      ,
      • Moertel C.L.
      • Weiland L.H.
      • Telander R.L.
      Carcinoid tumor of the appendix in the first two decades of life.
      ,
      • Abadía Barnó P.
      • Rivilla F.
      • Barquín Yagüez J.
      • Abadía Barnó M.
      • García Pérez J.C.
      Appendiceal carcinoid tumor in children: a conservative surgical approach.
      ,
      • Akova F.
      • Aydin E.
      • Nur Eray Y.
      • et al.
      Long-term outcomes in pediatric appendiceal carcinoids: Turkey experience.
      ,
      • Corpron C.A.
      • Black C.T.
      • Herzog C.E.
      • Sellin R.V.
      • Lally K.P.
      • Andrassy R.J.
      A half century of experience with carcinoid tumors in children.
      ,
      • Dall'Igna P.
      • Ferrari A.
      • Luzzatto C.
      • et al.
      Carcinoid tumor of the appendix in childhood: the experience of two Italian institutions.
      ,
      • Fernández K.S.
      • Aldrink J.H.
      • Ranalli M.
      • Ruymann F.B.
      • Caniano D.A.
      Carcinoid tumors in children and adolescents: risk for second malignancies.
      ,
      • Hatzipantelis E.
      • Panagopoulou P.
      • Sidi-Fragandrea V.
      • Fragandrea I.
      • Koliouskas D.E.
      Carcinoid tumors of the appendix in children: experience from a tertiary center in northern Greece.
      ,
      • Henderson L.
      • Fehily C.
      • Folaranmi S.
      • et al.
      Management and outcome of neuroendocrine tumours of the appendix-a two centre UK experience.
      ,
      • Jónsson T.
      • Jóhannsson J.H.
      • Hallgrimsson J.G.
      Carcinoid tumors of the appendix in children younger than 16 years. A retrospective clinical and pathologic study.
      ,
      • Kulkarni K.P.
      • Sergi C.
      Appendix carcinoids in childhood: long-term experience at a single institution in Western Canada and systematic review.
      ,
      • Neves G.R.
      • Chapchap P.
      • Sredni S.T.
      • Viana C.R.
      • Mendes W.L.
      Childhood carcinoid tumors: description of a case series in a Brazilian cancer center.
      ,
      • Pelizzo G.
      • La Riccia A.
      • Bouvier R.
      • Chappuis J.P.
      • Franchella A.
      Carcinoid tumors of the appendix in children.
      ,
      • Ryden S.E.
      • Drake R.M.
      • Franciosi R.A.
      Carcinoid tumors of the appendix in children.
      ,
      • Scott A.
      • Upadhyay V.
      Carcinoid tumours of the appendix in children in Auckland, New Zealand: 1965-2008.
      ,
      • Sommer C.
      • Gumy Pause F.
      • Diezi M.
      • Rougemont A.L.
      • Wildhaber B.E.
      A national long-term study of neuroendocrine tumors of the appendix in children: are we too aggressive?.
      ,
      • Vandevelde A.
      • Gera P.
      Carcinoid tumours of the appendix in children having appendicectomies at Princess Margaret Hospital since 1995.
      ,
      • Wu H.
      • Chintagumpala M.
      • Hicks J.
      • Nuchtern J.G.
      • Okcu M.F.
      • Venkatramani R.
      Neuroendocrine tumor of the appendix in children.
      ,
      • Kartal İ.
      Childhood neuroendocrine tumors of the digestive system: a single center experience.
      ,
      • Yalçın B.
      • Karnak İ.
      • Orhan D.
      • et al.
      Paediatric appendiceal neuroendocrine tumours: a review of 33 cases from a single center.
      ]. NET invasion into the subserosa was found most frequently (175/662 cases; 26.4%), followed by invasion into the muscularis (125/662 cases; 18.9%) and invasion into the serosa (118/662 cases; 17.8%). Invasion of the deepest layer of the appendix was not described for 164 cases. Mesoappendiceal invasion was reported in 26 studies and was found in 264 patients (27.8%) [
      • Boxberger N.
      • Redlich A.
      • Böger C.
      • et al.
      Neuroendocrine tumors of the appendix in children and adolescents.
      ,
      • de Lambert G.
      • Lardy H.
      • Martelli H.
      • Orbach D.
      • Gauthier F.
      • Guérin F.
      Surgical management of neuroendocrine tumors of the appendix in children and adolescents: a retrospective French multicenter study of 114 cases.
      ,
      • Moertel C.L.
      • Weiland L.H.
      • Telander R.L.
      Carcinoid tumor of the appendix in the first two decades of life.
      ,
      • Spunt S.L.
      • Pratt C.B.
      • Rao B.N.
      • et al.
      Childhood carcinoid tumors: the st jude children's research hospital experience.
      ,
      • Abadía Barnó P.
      • Rivilla F.
      • Barquín Yagüez J.
      • Abadía Barnó M.
      • García Pérez J.C.
      Appendiceal carcinoid tumor in children: a conservative surgical approach.
      ,
      • Akova F.
      • Aydin E.
      • Nur Eray Y.
      • et al.
      Long-term outcomes in pediatric appendiceal carcinoids: Turkey experience.
      ,
      • Corpron C.A.
      • Black C.T.
      • Herzog C.E.
      • Sellin R.V.
      • Lally K.P.
      • Andrassy R.J.
      A half century of experience with carcinoid tumors in children.
      ,
      • Dall'Igna P.
      • Ferrari A.
      • Luzzatto C.
      • et al.
      Carcinoid tumor of the appendix in childhood: the experience of two Italian institutions.
      ,
      • Fernández K.S.
      • Aldrink J.H.
      • Ranalli M.
      • Ruymann F.B.
      • Caniano D.A.
      Carcinoid tumors in children and adolescents: risk for second malignancies.
      ,
      • Hatzipantelis E.
      • Panagopoulou P.
      • Sidi-Fragandrea V.
      • Fragandrea I.
      • Koliouskas D.E.
      Carcinoid tumors of the appendix in children: experience from a tertiary center in northern Greece.
      ,
      • Henderson L.
      • Fehily C.
      • Folaranmi S.
      • et al.
      Management and outcome of neuroendocrine tumours of the appendix-a two centre UK experience.
      ,
      • Jónsson T.
      • Jóhannsson J.H.
      • Hallgrimsson J.G.
      Carcinoid tumors of the appendix in children younger than 16 years. A retrospective clinical and pathologic study.
      ,
      • Kim S.S.
      • Kays D.W.
      • Larson S.D.
      • Islam S.
      Appendiceal carcinoids in children--management and outcomes.
      ,
      • Kulkarni K.P.
      • Sergi C.
      Appendix carcinoids in childhood: long-term experience at a single institution in Western Canada and systematic review.
      ,
      • Neves G.R.
      • Chapchap P.
      • Sredni S.T.
      • Viana C.R.
      • Mendes W.L.
      Childhood carcinoid tumors: description of a case series in a Brazilian cancer center.
      ,
      • Pelizzo G.
      • La Riccia A.
      • Bouvier R.
      • Chappuis J.P.
      • Franchella A.
      Carcinoid tumors of the appendix in children.
      ,
      • Pérez-Albert P.
      • de Rojas T.
      • Lendínez M.
      • et al.
      Management and outcome of children with neuroendocrine tumors of the appendix in Spain: is there room for improvement?.
      ,
      • Prommegger R.
      • Obrist P.
      • Ensinger C.
      • Profanter C.
      • Mittermair R.
      • Hager J.
      Retrospective evaluation of carcinoid tumors of the appendix in children.
      ,
      • Ryden S.E.
      • Drake R.M.
      • Franciosi R.A.
      Carcinoid tumors of the appendix in children.
      ,
      • Scott A.
      • Upadhyay V.
      Carcinoid tumours of the appendix in children in Auckland, New Zealand: 1965-2008.
      ,
      • Sommer C.
      • Gumy Pause F.
      • Diezi M.
      • Rougemont A.L.
      • Wildhaber B.E.
      A national long-term study of neuroendocrine tumors of the appendix in children: are we too aggressive?.
      ,
      • Vandevelde A.
      • Gera P.
      Carcinoid tumours of the appendix in children having appendicectomies at Princess Margaret Hospital since 1995.
      ,
      • Virgone C.
      • Cecchetto G.
      • Alaggio R.
      • et al.
      Appendiceal neuroendocrine tumours in childhood: Italian TREP project.
      ,
      • Wu H.
      • Chintagumpala M.
      • Hicks J.
      • Nuchtern J.G.
      • Okcu M.F.
      • Venkatramani R.
      Neuroendocrine tumor of the appendix in children.
      ,
      • Kartal İ.
      Childhood neuroendocrine tumors of the digestive system: a single center experience.
      ,
      • Yalçın B.
      • Karnak İ.
      • Orhan D.
      • et al.
      Paediatric appendiceal neuroendocrine tumours: a review of 33 cases from a single center.
      ]. Lymphovascular invasion was reported in 11 studies and was found in 58 of 520 patients (11.2%) [
      • Boxberger N.
      • Redlich A.
      • Böger C.
      • et al.
      Neuroendocrine tumors of the appendix in children and adolescents.
      ,
      • de Lambert G.
      • Lardy H.
      • Martelli H.
      • Orbach D.
      • Gauthier F.
      • Guérin F.
      Surgical management of neuroendocrine tumors of the appendix in children and adolescents: a retrospective French multicenter study of 114 cases.
      ,
      • Moertel C.L.
      • Weiland L.H.
      • Telander R.L.
      Carcinoid tumor of the appendix in the first two decades of life.
      ,
      • Abadía Barnó P.
      • Rivilla F.
      • Barquín Yagüez J.
      • Abadía Barnó M.
      • García Pérez J.C.
      Appendiceal carcinoid tumor in children: a conservative surgical approach.
      ,
      • Akova F.
      • Aydin E.
      • Nur Eray Y.
      • et al.
      Long-term outcomes in pediatric appendiceal carcinoids: Turkey experience.
      ,
      • Dall'Igna P.
      • Ferrari A.
      • Luzzatto C.
      • et al.
      Carcinoid tumor of the appendix in childhood: the experience of two Italian institutions.
      ,
      • Fernández K.S.
      • Aldrink J.H.
      • Ranalli M.
      • Ruymann F.B.
      • Caniano D.A.
      Carcinoid tumors in children and adolescents: risk for second malignancies.
      ,
      • Kim S.S.
      • Kays D.W.
      • Larson S.D.
      • Islam S.
      Appendiceal carcinoids in children--management and outcomes.
      ,
      • Kulkarni K.P.
      • Sergi C.
      Appendix carcinoids in childhood: long-term experience at a single institution in Western Canada and systematic review.
      ,
      • Vandevelde A.
      • Gera P.
      Carcinoid tumours of the appendix in children having appendicectomies at Princess Margaret Hospital since 1995.
      ,
      • Wu H.
      • Chintagumpala M.
      • Hicks J.
      • Nuchtern J.G.
      • Okcu M.F.
      • Venkatramani R.
      Neuroendocrine tumor of the appendix in children.
      ]. Seven studies described perineural invasion in 40 of 141 patients (28.4%) [
      • Abadía Barnó P.
      • Rivilla F.
      • Barquín Yagüez J.
      • Abadía Barnó M.
      • García Pérez J.C.
      Appendiceal carcinoid tumor in children: a conservative surgical approach.
      ,
      • Akova F.
      • Aydin E.
      • Nur Eray Y.
      • et al.
      Long-term outcomes in pediatric appendiceal carcinoids: Turkey experience.
      ,
      • Dall'Igna P.
      • Ferrari A.
      • Luzzatto C.
      • et al.
      Carcinoid tumor of the appendix in childhood: the experience of two Italian institutions.
      ,
      • Kim S.S.
      • Kays D.W.
      • Larson S.D.
      • Islam S.
      Appendiceal carcinoids in children--management and outcomes.
      ,
      • Ryden S.E.
      • Drake R.M.
      • Franciosi R.A.
      Carcinoid tumors of the appendix in children.
      ,
      • Vandevelde A.
      • Gera P.
      Carcinoid tumours of the appendix in children having appendicectomies at Princess Margaret Hospital since 1995.
      ,
      • Wu H.
      • Chintagumpala M.
      • Hicks J.
      • Nuchtern J.G.
      • Okcu M.F.
      • Venkatramani R.
      Neuroendocrine tumor of the appendix in children.
      ]. Resection margins were positive in 31 of 823 patients (3.8%) [
      • Boxberger N.
      • Redlich A.
      • Böger C.
      • et al.
      Neuroendocrine tumors of the appendix in children and adolescents.
      ,
      • de Lambert G.
      • Lardy H.
      • Martelli H.
      • Orbach D.
      • Gauthier F.
      • Guérin F.
      Surgical management of neuroendocrine tumors of the appendix in children and adolescents: a retrospective French multicenter study of 114 cases.
      ,
      • Spunt S.L.
      • Pratt C.B.
      • Rao B.N.
      • et al.
      Childhood carcinoid tumors: the st jude children's research hospital experience.
      ,
      • Abadía Barnó P.
      • Rivilla F.
      • Barquín Yagüez J.
      • Abadía Barnó M.
      • García Pérez J.C.
      Appendiceal carcinoid tumor in children: a conservative surgical approach.
      ,
      • Akova F.
      • Aydin E.
      • Nur Eray Y.
      • et al.
      Long-term outcomes in pediatric appendiceal carcinoids: Turkey experience.
      ,
      • Dall'Igna P.
      • Ferrari A.
      • Luzzatto C.
      • et al.
      Carcinoid tumor of the appendix in childhood: the experience of two Italian institutions.
      ,
      • Fernández K.S.
      • Aldrink J.H.
      • Ranalli M.
      • Ruymann F.B.
      • Caniano D.A.
      Carcinoid tumors in children and adolescents: risk for second malignancies.
      ,
      • Kim S.S.
      • Kays D.W.
      • Larson S.D.
      • Islam S.
      Appendiceal carcinoids in children--management and outcomes.
      ,
      • Pelizzo G.
      • La Riccia A.
      • Bouvier R.
      • Chappuis J.P.
      • Franchella A.
      Carcinoid tumors of the appendix in children.
      ,
      • Pérez-Albert P.
      • de Rojas T.
      • Lendínez M.
      • et al.
      Management and outcome of children with neuroendocrine tumors of the appendix in Spain: is there room for improvement?.
      ,
      • Prommegger R.
      • Obrist P.
      • Ensinger C.
      • Profanter C.
      • Mittermair R.
      • Hager J.
      Retrospective evaluation of carcinoid tumors of the appendix in children.
      ,
      • Scott A.
      • Upadhyay V.
      Carcinoid tumours of the appendix in children in Auckland, New Zealand: 1965-2008.
      ,
      • Sommer C.
      • Gumy Pause F.
      • Diezi M.
      • Rougemont A.L.
      • Wildhaber B.E.
      A national long-term study of neuroendocrine tumors of the appendix in children: are we too aggressive?.
      ,
      • Vandevelde A.
      • Gera P.
      Carcinoid tumours of the appendix in children having appendicectomies at Princess Margaret Hospital since 1995.
      ,
      • Virgone C.
      • Cecchetto G.
      • Alaggio R.
      • et al.
      Appendiceal neuroendocrine tumours in childhood: Italian TREP project.
      ,
      • Wu H.
      • Chintagumpala M.
      • Hicks J.
      • Nuchtern J.G.
      • Okcu M.F.
      • Venkatramani R.
      Neuroendocrine tumor of the appendix in children.
      ,
      • Yalçın B.
      • Karnak İ.
      • Orhan D.
      • et al.
      Paediatric appendiceal neuroendocrine tumours: a review of 33 cases from a single center.
      ].
      Table 2Histopathological characteristics.


      Author
      CasesTumor locationExtent of invasion (deepest layer appendix)Mesoappendiceal invasionLymphovascular invasionPerineural invasionR1 resectionNET grade
      BaseMidTipMucosaSubmucosaMuscularisSubserosaSerosa
      Akova (2018)100370126113005 G1, 5 G2
      Barno (2018)8340130440108 G1
      Boxberger (2013)2371547151095710917122111140 G1, 21 G2
      Corpron (1995)2201130300115
      Dall'Igna (2005)14425500314 G1
      De Lambert (2016)114122561207348 G1, 1 G2
      Fernandez (2015)28118111331
      Hatzipantelis (2010)190019423082
      Henderson (2014)270020115311427 G1
      Jonsson (1989181311071733
      Kartal (2022)151112114 G1, 1 G2
      Kim (2014)137111
      Kulkarni (2013)711211137 G1
      Moertel (1990)235312710618
      Neves (2006)81131
      Njere (2018)1103
      Parikh (2018)109
      Pelizzo (2001)1020851221
      Pérez-Albert (2017)17223 G1, 1 G2
      Prommegger (2002)36272711
      Ranaweera (2019)32161
      Ryden (1975)30037016414
      Scott (2011)4781116041101581
      Sommer (2019)403430391674224 G1, 3 G2
      Spunt (2000)522
      Vandevelde (2015)2127424810
      Virgone (2014)11321162528284 G1, 4 G2
      Wu (2017)45019168981042308 G1
      Yalcin (2022)331611576640
      G1: Grade 1; G2: Grade 2.

      3.3 Quality of the studies

      Risk of bias on the primary outcomes (recurrence rate and disease-free survival) was assessed as serious for 26 studies [
      • Moertel C.L.
      • Weiland L.H.
      • Telander R.L.
      Carcinoid tumor of the appendix in the first two decades of life.
      ,
      • Spunt S.L.
      • Pratt C.B.
      • Rao B.N.
      • et al.
      Childhood carcinoid tumors: the st jude children's research hospital experience.
      ,
      • Abadía Barnó P.
      • Rivilla F.
      • Barquín Yagüez J.
      • Abadía Barnó M.
      • García Pérez J.C.
      Appendiceal carcinoid tumor in children: a conservative surgical approach.
      ,
      • Akova F.
      • Aydin E.
      • Nur Eray Y.
      • et al.
      Long-term outcomes in pediatric appendiceal carcinoids: Turkey experience.
      ,
      • Corpron C.A.
      • Black C.T.
      • Herzog C.E.
      • Sellin R.V.
      • Lally K.P.
      • Andrassy R.J.
      A half century of experience with carcinoid tumors in children.
      ,
      • Dall'Igna P.
      • Ferrari A.
      • Luzzatto C.
      • et al.
      Carcinoid tumor of the appendix in childhood: the experience of two Italian institutions.
      ,
      • Fernández K.S.
      • Aldrink J.H.
      • Ranalli M.
      • Ruymann F.B.
      • Caniano D.A.
      Carcinoid tumors in children and adolescents: risk for second malignancies.
      ,
      • Hatzipantelis E.
      • Panagopoulou P.
      • Sidi-Fragandrea V.
      • Fragandrea I.
      • Koliouskas D.E.
      Carcinoid tumors of the appendix in children: experience from a tertiary center in northern Greece.
      ,
      • Henderson L.
      • Fehily C.
      • Folaranmi S.
      • et al.
      Management and outcome of neuroendocrine tumours of the appendix-a two centre UK experience.
      ,
      • Jónsson T.
      • Jóhannsson J.H.
      • Hallgrimsson J.G.
      Carcinoid tumors of the appendix in children younger than 16 years. A retrospective clinical and pathologic study.
      ,
      • Kim S.S.
      • Kays D.W.
      • Larson S.D.
      • Islam S.
      Appendiceal carcinoids in children--management and outcomes.
      ,
      • Kulkarni K.P.
      • Sergi C.
      Appendix carcinoids in childhood: long-term experience at a single institution in Western Canada and systematic review.
      ,
      • Neves G.R.
      • Chapchap P.
      • Sredni S.T.
      • Viana C.R.
      • Mendes W.L.
      Childhood carcinoid tumors: description of a case series in a Brazilian cancer center.
      ,
      • Njere I.
      • Smith L.L.
      • Thurairasa D.
      • et al.
      Systematic review and meta-analysis of appendiceal carcinoid tumors in children.
      ,
      • Parikh P.P.
      • Perez E.A.
      • Neville H.L.
      • Hogan A.R.
      • Sola J.E.
      Nationwide overview of survival and management of appendiceal tumors in children.
      ,
      • Pelizzo G.
      • La Riccia A.
      • Bouvier R.
      • Chappuis J.P.
      • Franchella A.
      Carcinoid tumors of the appendix in children.
      ,
      • Pérez-Albert P.
      • de Rojas T.
      • Lendínez M.
      • et al.
      Management and outcome of children with neuroendocrine tumors of the appendix in Spain: is there room for improvement?.
      ,
      • Prommegger R.
      • Obrist P.
      • Ensinger C.
      • Profanter C.
      • Mittermair R.
      • Hager J.
      Retrospective evaluation of carcinoid tumors of the appendix in children.
      ,
      • Ranaweera C.
      • Brar A.
      • Somers G.R.
      • Sheikh F.
      • Pierro A.
      • Zani A.
      Management of pediatric appendiceal carcinoid: a single institution experience from 5000 appendectomies.
      ,
      • Ryden S.E.
      • Drake R.M.
      • Franciosi R.A.
      Carcinoid tumors of the appendix in children.
      ,
      • Scott A.
      • Upadhyay V.
      Carcinoid tumours of the appendix in children in Auckland, New Zealand: 1965-2008.
      ,
      • Sommer C.
      • Gumy Pause F.
      • Diezi M.
      • Rougemont A.L.
      • Wildhaber B.E.
      A national long-term study of neuroendocrine tumors of the appendix in children: are we too aggressive?.
      ,
      • Vandevelde A.
      • Gera P.
      Carcinoid tumours of the appendix in children having appendicectomies at Princess Margaret Hospital since 1995.
      ,
      • Wu H.
      • Chintagumpala M.
      • Hicks J.
      • Nuchtern J.G.
      • Okcu M.F.
      • Venkatramani R.
      Neuroendocrine tumor of the appendix in children.
      ,
      • Kartal İ.
      Childhood neuroendocrine tumors of the digestive system: a single center experience.
      ,
      • Yalçın B.
      • Karnak İ.
      • Orhan D.
      • et al.
      Paediatric appendiceal neuroendocrine tumours: a review of 33 cases from a single center.
      ] and moderate for three studies [
      • Boxberger N.
      • Redlich A.
      • Böger C.
      • et al.
      Neuroendocrine tumors of the appendix in children and adolescents.
      ,
      • de Lambert G.
      • Lardy H.
      • Martelli H.
      • Orbach D.
      • Gauthier F.
      • Guérin F.
      Surgical management of neuroendocrine tumors of the appendix in children and adolescents: a retrospective French multicenter study of 114 cases.
      ,
      • Virgone C.
      • Cecchetto G.
      • Alaggio R.
      • et al.
      Appendiceal neuroendocrine tumours in childhood: Italian TREP project.
      ] (Table 3). The interrater reliability for overall judgement of risk of bias according to the ROBINS-I was almost perfect (96% agreement). Bias due to confounding was serious in 26 studies and moderate in only three. These three studies reported that the baseline characteristics of the intervention and control groups were comparable. Bias due to missing data was low in 7 studies (less than 5% of patients lost to follow-up), moderate in 17 studies (less than 50%, but more than 5% of patients lost to follow-up), and serious in 5 studies (more than 50% of patients lost to follow-up).
      Table 3Risk of bias on the primary outcomes.
      AuthorBias due to confoundingBias in selection of participants into the studyBias in classification of interventionsBias due to deviations from intended interventionsBias due to missing dataBias in measurement of outcomesBias in selection of the reported resultOverall Risk of Bias
      Akova (2018)SeriousLowLowLowLowModerateNo informationSerious
      Barno (2018)SeriousLowLowLowModerateModerateNo informationSerious
      Boxberger (2013)ModerateLowLowLowModerateModerateNo informationModerate
      Corpron (1995)SeriousLowLowLowLowModerateNo informationSerious
      Dall'Igna (2005)SeriousLowLowLowLowModerateNo informationSerious
      De Lambert (2016)ModerateLowLowLowModerateModerateNo informationModerate
      Fernandez (2015)SeriousLowLowLowModerateModerateNo informationSerious
      Hatzipantelis (2010)SeriousLowLowLowModerateModerateNo informationSerious
      Henderson (2014)SeriousLowLowLowModerateModerateNo informationSerious
      Jonsson (1989)SeriousLowLowLowModerateModerateNo informationSerious
      Kartal (2022)SeriousLowLowLowLowModerateNo informationSerious
      Kim (2014)SeriousLowLowLowLowModerateNo informationSerious
      Kulkarni (2013)SeriousLowLowLowLowModerateNo informationSerious
      Moertel (1990)SeriousLowLowLowModerateModerateNo informationSerious
      Neves (2006)SeriousLowLowLowSeriousModerateNo informationSerious
      Njere (2018)SeriousLowLowLowSeriousModerateNo informationSerious
      Parikh (2018)SeriousLowLowLowModerateModerateNo informationSerious
      Pelizzo (2001)SeriousLowLowLowModerateModerateNo informationSerious
      Pérez-Albert (2017)SeriousLowLowLowModerateModerateNo informationSerious
      Prommegger (2002)SeriousLowLowLowModerateModerateNo informationSerious
      Ranaweera (2019)SeriousLowLowLowModerateModerateNo informationSerious
      Ryden (1975)SeriousLowLowLowModerateModerateNo informationSerious
      Scott (2011)SeriousLowLowLowSeriousModerateNo informationSerious
      Sommer (2019)SeriousLowLowLowSeriousModerateNo informationSerious
      Spunt (2000)SeriousLowLowLowModerateModerateNo informationSerious
      Vandevelde (2015)SeriousLowLowLowSeriousModerateNo informationSerious
      Virgone (2014)ModerateLowLowLowLowModerateNo informationModerate
      Wu (2017)SeriousLowLowLowModerateModerateNo informationSerious
      Yalcin (2022)SeriousLowLowLowModerateModerateNo informationSerious

      3.4 High-risk NETs

      A high-risk NET was found at histopathological examination in 145 patients, 90 with a pT2 NET with risk factors and 55 with a pT3 NET. Secondary surgery was performed in 64 patients (intervention group), while 81 patients were observed without secondary surgery (control group). Indications for secondary surgery are displayed in Table 1. Most frequent indication for secondary surgery was mesoappendiceal invasion, which was found in 51 patients with a high-risk pT2 NET (57%). In the intervention group right hemicolectomy was performed in 43 patients (68%), ileocecal resection in 9 patients (14%), caecectomy in 2 patients (3%), and data regarding type of resection was missing in 10 patients (16%).

      3.5 Primary outcomes: recurrence rate and disease-free survival

      No recurrence was reported and thus disease-free survival was 100% for both intervention and control group. Because no events were reported in both the intervention and control group, it was not possible to perform a meta-analysis for comparison of secondary surgery and observation for patients with a high-risk NET. The number of positive lymph nodes at histopathological examination after secondary surgery was described in 13 studies [
      • Boxberger N.
      • Redlich A.
      • Böger C.
      • et al.
      Neuroendocrine tumors of the appendix in children and adolescents.
      ,
      • de Lambert G.
      • Lardy H.
      • Martelli H.
      • Orbach D.
      • Gauthier F.
      • Guérin F.
      Surgical management of neuroendocrine tumors of the appendix in children and adolescents: a retrospective French multicenter study of 114 cases.
      ,
      • Moertel C.L.
      • Weiland L.H.
      • Telander R.L.
      Carcinoid tumor of the appendix in the first two decades of life.
      ,
      • Abadía Barnó P.
      • Rivilla F.
      • Barquín Yagüez J.
      • Abadía Barnó M.
      • García Pérez J.C.
      Appendiceal carcinoid tumor in children: a conservative surgical approach.
      ,
      • Corpron C.A.
      • Black C.T.
      • Herzog C.E.
      • Sellin R.V.
      • Lally K.P.
      • Andrassy R.J.
      A half century of experience with carcinoid tumors in children.
      ,
      • Dall'Igna P.
      • Ferrari A.
      • Luzzatto C.
      • et al.
      Carcinoid tumor of the appendix in childhood: the experience of two Italian institutions.
      ,
      • Kim S.S.
      • Kays D.W.
      • Larson S.D.
      • Islam S.
      Appendiceal carcinoids in children--management and outcomes.
      ,
      • Kulkarni K.P.
      • Sergi C.
      Appendix carcinoids in childhood: long-term experience at a single institution in Western Canada and systematic review.
      ,
      • Neves G.R.
      • Chapchap P.
      • Sredni S.T.
      • Viana C.R.
      • Mendes W.L.
      Childhood carcinoid tumors: description of a case series in a Brazilian cancer center.
      ,
      • Scott A.
      • Upadhyay V.
      Carcinoid tumours of the appendix in children in Auckland, New Zealand: 1965-2008.
      ,
      • Sommer C.
      • Gumy Pause F.
      • Diezi M.
      • Rougemont A.L.
      • Wildhaber B.E.
      A national long-term study of neuroendocrine tumors of the appendix in children: are we too aggressive?.
      ,
      • Virgone C.
      • Cecchetto G.
      • Alaggio R.
      • et al.
      Appendiceal neuroendocrine tumours in childhood: Italian TREP project.
      ,
      • Wu H.
      • Chintagumpala M.
      • Hicks J.
      • Nuchtern J.G.
      • Okcu M.F.
      • Venkatramani R.
      Neuroendocrine tumor of the appendix in children.
      ]. In ten out of 30 patients (33%) one to three positive lymph nodes were found. Residual tumor at histopathological examination was described in ten studies and was found in two out of 33 patients (6%) [
      • Boxberger N.
      • Redlich A.
      • Böger C.
      • et al.
      Neuroendocrine tumors of the appendix in children and adolescents.
      ,
      • de Lambert G.
      • Lardy H.
      • Martelli H.
      • Orbach D.
      • Gauthier F.
      • Guérin F.
      Surgical management of neuroendocrine tumors of the appendix in children and adolescents: a retrospective French multicenter study of 114 cases.
      ,
      • Moertel C.L.
      • Weiland L.H.
      • Telander R.L.
      Carcinoid tumor of the appendix in the first two decades of life.
      ,
      • Spunt S.L.
      • Pratt C.B.
      • Rao B.N.
      • et al.
      Childhood carcinoid tumors: the st jude children's research hospital experience.
      ,
      • Abadía Barnó P.
      • Rivilla F.
      • Barquín Yagüez J.
      • Abadía Barnó M.
      • García Pérez J.C.
      Appendiceal carcinoid tumor in children: a conservative surgical approach.
      ,
      • Dall'Igna P.
      • Ferrari A.
      • Luzzatto C.
      • et al.
      Carcinoid tumor of the appendix in childhood: the experience of two Italian institutions.
      ,
      • Neves G.R.
      • Chapchap P.
      • Sredni S.T.
      • Viana C.R.
      • Mendes W.L.
      Childhood carcinoid tumors: description of a case series in a Brazilian cancer center.
      ,
      • Scott A.
      • Upadhyay V.
      Carcinoid tumours of the appendix in children in Auckland, New Zealand: 1965-2008.
      ,
      • Virgone C.
      • Cecchetto G.
      • Alaggio R.
      • et al.
      Appendiceal neuroendocrine tumours in childhood: Italian TREP project.
      ,
      • Wu H.
      • Chintagumpala M.
      • Hicks J.
      • Nuchtern J.G.
      • Okcu M.F.
      • Venkatramani R.
      Neuroendocrine tumor of the appendix in children.
      ].

      3.6 Secondary outcomes

      3.6.1 Overall survival

      Overall survival was reported in 23 studies, but was not described for patients with a high-risk NET specifically [
      • Boxberger N.
      • Redlich A.
      • Böger C.
      • et al.
      Neuroendocrine tumors of the appendix in children and adolescents.
      ,
      • de Lambert G.
      • Lardy H.
      • Martelli H.
      • Orbach D.
      • Gauthier F.
      • Guérin F.
      Surgical management of neuroendocrine tumors of the appendix in children and adolescents: a retrospective French multicenter study of 114 cases.
      ,
      • Moertel C.L.
      • Weiland L.H.
      • Telander R.L.
      Carcinoid tumor of the appendix in the first two decades of life.
      ,
      • Spunt S.L.
      • Pratt C.B.
      • Rao B.N.
      • et al.
      Childhood carcinoid tumors: the st jude children's research hospital experience.
      ,
      • Abadía Barnó P.
      • Rivilla F.
      • Barquín Yagüez J.
      • Abadía Barnó M.
      • García Pérez J.C.
      Appendiceal carcinoid tumor in children: a conservative surgical approach.
      ,
      • Akova F.
      • Aydin E.
      • Nur Eray Y.
      • et al.
      Long-term outcomes in pediatric appendiceal carcinoids: Turkey experience.
      ,
      • Corpron C.A.
      • Black C.T.
      • Herzog C.E.
      • Sellin R.V.
      • Lally K.P.
      • Andrassy R.J.
      A half century of experience with carcinoid tumors in children.
      ,
      • Dall'Igna P.
      • Ferrari A.
      • Luzzatto C.
      • et al.
      Carcinoid tumor of the appendix in childhood: the experience of two Italian institutions.
      ,
      • Fernández K.S.
      • Aldrink J.H.
      • Ranalli M.
      • Ruymann F.B.
      • Caniano D.A.
      Carcinoid tumors in children and adolescents: risk for second malignancies.
      ,
      • Hatzipantelis E.
      • Panagopoulou P.
      • Sidi-Fragandrea V.
      • Fragandrea I.
      • Koliouskas D.E.
      Carcinoid tumors of the appendix in children: experience from a tertiary center in northern Greece.
      ,
      • Henderson L.
      • Fehily C.
      • Folaranmi S.
      • et al.
      Management and outcome of neuroendocrine tumours of the appendix-a two centre UK experience.
      ,
      • Jónsson T.
      • Jóhannsson J.H.
      • Hallgrimsson J.G.
      Carcinoid tumors of the appendix in children younger than 16 years. A retrospective clinical and pathologic study.
      ,
      • Kulkarni K.P.
      • Sergi C.
      Appendix carcinoids in childhood: long-term experience at a single institution in Western Canada and systematic review.
      ,
      • Neves G.R.
      • Chapchap P.
      • Sredni S.T.
      • Viana C.R.
      • Mendes W.L.
      Childhood carcinoid tumors: description of a case series in a Brazilian cancer center.
      ,
      • Parikh P.P.
      • Perez E.A.
      • Neville H.L.
      • Hogan A.R.
      • Sola J.E.
      Nationwide overview of survival and management of appendiceal tumors in children.
      ,
      • Pelizzo G.
      • La Riccia A.
      • Bouvier R.
      • Chappuis J.P.
      • Franchella A.
      Carcinoid tumors of the appendix in children.
      ,
      • Prommegger R.
      • Obrist P.
      • Ensinger C.
      • Profanter C.
      • Mittermair R.
      • Hager J.
      Retrospective evaluation of carcinoid tumors of the appendix in children.
      ,
      • Ryden S.E.
      • Drake R.M.
      • Franciosi R.A.
      Carcinoid tumors of the appendix in children.
      ,
      • Sommer C.
      • Gumy Pause F.
      • Diezi M.
      • Rougemont A.L.
      • Wildhaber B.E.
      A national long-term study of neuroendocrine tumors of the appendix in children: are we too aggressive?.
      ,
      • Virgone C.
      • Cecchetto G.
      • Alaggio R.
      • et al.
      Appendiceal neuroendocrine tumours in childhood: Italian TREP project.
      ,
      • Wu H.
      • Chintagumpala M.
      • Hicks J.
      • Nuchtern J.G.
      • Okcu M.F.
      • Venkatramani R.
      Neuroendocrine tumor of the appendix in children.
      ,
      • Kartal İ.
      Childhood neuroendocrine tumors of the digestive system: a single center experience.
      ,
      • Yalçın B.
      • Karnak İ.
      • Orhan D.
      • et al.
      Paediatric appendiceal neuroendocrine tumours: a review of 33 cases from a single center.
      ]. Therefore the intervention and control group could not be compared with regard to overall survival. Three studies described four deaths, all unrelated to the NET of the appendix, resulting in an overall survival of 99.6% in the total population of all children with a NET (including low-risk and high-risk NETs) [
      • Moertel C.L.
      • Weiland L.H.
      • Telander R.L.
      Carcinoid tumor of the appendix in the first two decades of life.
      ,
      • Spunt S.L.
      • Pratt C.B.
      • Rao B.N.
      • et al.
      Childhood carcinoid tumors: the st jude children's research hospital experience.
      ,
      • Corpron C.A.
      • Black C.T.
      • Herzog C.E.
      • Sellin R.V.
      • Lally K.P.
      • Andrassy R.J.
      A half century of experience with carcinoid tumors in children.
      ].

      3.7 Complications after secondary surgery

      Three studies reported on postoperative complications after secondary surgery for a high-risk NET [
      • de Lambert G.
      • Lardy H.
      • Martelli H.
      • Orbach D.
      • Gauthier F.
      • Guérin F.
      Surgical management of neuroendocrine tumors of the appendix in children and adolescents: a retrospective French multicenter study of 114 cases.
      ,
      • Kim S.S.
      • Kays D.W.
      • Larson S.D.
      • Islam S.
      Appendiceal carcinoids in children--management and outcomes.
      ,
      • Wu H.
      • Chintagumpala M.
      • Hicks J.
      • Nuchtern J.G.
      • Okcu M.F.
      • Venkatramani R.
      Neuroendocrine tumor of the appendix in children.
      ]. All 20 patients in these studies underwent right hemicolectomy and only one (5%) developed an intra-abdominal abscess. Treatment for this complication was not described and therefore the Clavien-Dindo classification could not be applied.

      3.8 Additional imaging studies after appendectomy

      Data regarding additional imaging studies for diagnostic work-up after appendectomy for the intervention and control group could be extracted from 11 studies [
      • de Lambert G.
      • Lardy H.
      • Martelli H.
      • Orbach D.
      • Gauthier F.
      • Guérin F.
      Surgical management of neuroendocrine tumors of the appendix in children and adolescents: a retrospective French multicenter study of 114 cases.
      ,
      • Akova F.
      • Aydin E.
      • Nur Eray Y.
      • et al.
      Long-term outcomes in pediatric appendiceal carcinoids: Turkey experience.
      ,
      • Dall'Igna P.
      • Ferrari A.
      • Luzzatto C.
      • et al.
      Carcinoid tumor of the appendix in childhood: the experience of two Italian institutions.
      ,
      • Hatzipantelis E.
      • Panagopoulou P.
      • Sidi-Fragandrea V.
      • Fragandrea I.
      • Koliouskas D.E.
      Carcinoid tumors of the appendix in children: experience from a tertiary center in northern Greece.
      ,
      • Henderson L.
      • Fehily C.
      • Folaranmi S.
      • et al.
      Management and outcome of neuroendocrine tumours of the appendix-a two centre UK experience.
      ,
      • Kulkarni K.P.
      • Sergi C.
      Appendix carcinoids in childhood: long-term experience at a single institution in Western Canada and systematic review.
      ,
      • Pelizzo G.
      • La Riccia A.
      • Bouvier R.
      • Chappuis J.P.
      • Franchella A.
      Carcinoid tumors of the appendix in children.
      ,
      • Pérez-Albert P.
      • de Rojas T.
      • Lendínez M.
      • et al.
      Management and outcome of children with neuroendocrine tumors of the appendix in Spain: is there room for improvement?.
      ,
      • Prommegger R.
      • Obrist P.
      • Ensinger C.
      • Profanter C.
      • Mittermair R.
      • Hager J.
      Retrospective evaluation of carcinoid tumors of the appendix in children.
      ,
      • Vandevelde A.
      • Gera P.
      Carcinoid tumours of the appendix in children having appendicectomies at Princess Margaret Hospital since 1995.
      ,
      • Virgone C.
      • Cecchetto G.
      • Alaggio R.
      • et al.
      Appendiceal neuroendocrine tumours in childhood: Italian TREP project.
      ]. In these studies, 45 patients with a high-risk NET were observed after primary appendectomy. Imaging studies were performed in 26 of 45 patients (58%) and consisted of MRI, CT, chest X-ray, and octreotide scintigraphy. In the group of patients that underwent secondary surgery, 15 of 16 patients (94%) underwent imaging studies consisting of ultrasound, CT, and octreotide scintigraphy. Only two studies compared the intervention and control group with regard to the number of additional imaging studies during follow-up after diagnostic work-up and secondary surgery or appendectomy only [
      • de Lambert G.
      • Lardy H.
      • Martelli H.
      • Orbach D.
      • Gauthier F.
      • Guérin F.
      Surgical management of neuroendocrine tumors of the appendix in children and adolescents: a retrospective French multicenter study of 114 cases.
      ,
      • Pelizzo G.
      • La Riccia A.
      • Bouvier R.
      • Chappuis J.P.
      • Franchella A.
      Carcinoid tumors of the appendix in children.
      ]. In these studies, five of 11 patients (45%) that underwent secondary surgery were assessed clinically during follow-up, of whom three with both clinical examination and imaging, and four had urinary levels of 5-HIAA tested. In the group of patients that were observed after appendectomy, ten of 20 patients were (50%) were assessed clinically during follow-up, of whom nine with both clinical examination and imaging [
      • de Lambert G.
      • Lardy H.
      • Martelli H.
      • Orbach D.
      • Gauthier F.
      • Guérin F.
      Surgical management of neuroendocrine tumors of the appendix in children and adolescents: a retrospective French multicenter study of 114 cases.
      ,
      • Pelizzo G.
      • La Riccia A.
      • Bouvier R.
      • Chappuis J.P.
      • Franchella A.
      Carcinoid tumors of the appendix in children.
      ].

      3.9 Number of outpatient visits and surveillance strategies

      In none of the studies, the number of outpatient visits and telephone check-ups were compared between the patients with a high-risk NET that underwent secondary surgery and those that were observed after appendectomy. Standardized surveillance strategies for all patients (without differentiation between low-risk and high-risk NET) have been reported in six studies [
      • Akova F.
      • Aydin E.
      • Nur Eray Y.
      • et al.
      Long-term outcomes in pediatric appendiceal carcinoids: Turkey experience.
      ,
      • Dall'Igna P.
      • Ferrari A.
      • Luzzatto C.
      • et al.
      Carcinoid tumor of the appendix in childhood: the experience of two Italian institutions.
      ,
      • Kim S.S.
      • Kays D.W.
      • Larson S.D.
      • Islam S.
      Appendiceal carcinoids in children--management and outcomes.
      ,
      • Kulkarni K.P.
      • Sergi C.
      Appendix carcinoids in childhood: long-term experience at a single institution in Western Canada and systematic review.
      ,
      • Virgone C.
      • Cecchetto G.
      • Alaggio R.
      • et al.
      Appendiceal neuroendocrine tumours in childhood: Italian TREP project.
      ,
      • Kartal İ.
      Childhood neuroendocrine tumors of the digestive system: a single center experience.
      ]. Surveillance strategies consisted of serial ultrasounds, CT-scans or MRI at different intervals of every 3–6 months, gradually reduced to once a year after disease-free survival of one or two years. Additionally, in some studies urine 5-hydroxyindoleaceticacid (5-HIAA) and chromogranin A levels were determined as well. Octreotide scintigraphy was performed in cases of abnormal 5-HIAA or abnormal findings at imaging studies [
      • Virgone C.
      • Cecchetto G.
      • Alaggio R.
      • et al.
      Appendiceal neuroendocrine tumours in childhood: Italian TREP project.
      ].

      3.10 Quality of Life

      None of the studies reported on Quality of Life of patients.

      3.11 Cost-effectiveness

      None of the studies reported direct or indirect costs of the treatment strategies.

      4. Discussion

      This systematic review included 29 studies reporting on 145 patients (<20 years old) with a high-risk NET of the appendix, of whom 81 were solely monitored after appendectomy and 64 underwent secondary surgery consisting of right hemicolectomy, ileocecal resection or caecectomy. Disease-free survival was 100% in both the group of patients that were observed after appendectomy (control group) and the group of patients that underwent secondary surgery (intervention group). During the follow-up period, ranging from no follow-up to 51 years, no recurrences were reported. The number of additional imaging studies for diagnostic work-up and during follow-up were comparable between the intervention and control group. Only one complication was reported, but this outcome might have been underreported in the included studies, as complication rates up to 50% after right hemicolectomy have been reported in the adult population [
      • Hanna M.H.
      • Hwang G.S.
      • Phelan M.J.
      • et al.
      Laparoscopic right hemicolectomy: short- and long-term outcomes of intracorporeal versus extracorporeal anastomosis.
      ]. Thus far, no studies have reported hr-QoL or cost-effectiveness of both treatment strategies. As disease-free survival seems to be 100% after appendectomy only and other secondary outcomes are reported to be comparable between groups, the value of secondary surgery for children with a high-risk NET of the appendix might be questioned. Although risk of bias of the included studies was moderate to severe and high quality data with adequate follow-up is lacking, appendectomy without secondary surgery seems to be sufficient for children with a high-risk NET of the appendix.
      Guidelines have been developed by the European Neuroendocrine Tumor Society (ENETS) and North American Neuroendocrine Tumor Society (NANETS) in order to aid in the management of patients with a NET of the appendix. The ENETS guideline was published in 2016 and recommends right hemicolectomy for patients with a pT2 NET with risk factors for aggressive behavior (i.e. tumor at the base of the appendix, lymphovascular invasion, grade 2 tumor, and >3 mm infiltration of the mesoappendix) or a pT3 NET. For these high-risk NETs an increased risk of lymphatic and distant metastasis has been reported and therefore right hemicolectomy is advised as a definitive long-term cure. The NANETS guideline recommends right hemicolectomy in patients with a NET at the base of the appendix, in patients with tumors greater than 2 cm, in those with tumor where size cannot be determined, those with incompletely resected tumors, those with lymphovascular invasion, those with invasion of the mesoappendix, and in patients with intermediate to high grade tumors. These recommendations are based on studies in adult populations, that found a 5-year survival rate of 70–85% for the whole cohort including all tumor stages. In case of advanced disease with distant metastases an even poorer prognosis with a 5-year survival rate of 12–28% has been reported [
      • Yao J.C.
      • Hassan M.
      • Phan A.
      • et al.
      One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States.
      ,
      • Hsu C.
      • Rashid A.
      • Xing Y.
      • et al.
      Varying malignant potential of appendiceal neuroendocrine tumors: importance of histologic subtype.
      ,
      • Landry C.S.
      • Woodall C.
      • Scoggins C.R.
      • McMasters K.M.
      • Martin 2nd, R.C.
      Analysis of 900 appendiceal carcinoid tumors for a proposed predictive staging system.
      ,
      • Quaedvlieg P.F.
      • Visser O.
      • Lamers C.B.
      • Janssen-Heijen M.L.
      • Taal B.G.
      Epidemiology and survival in patients with carcinoid disease in The Netherlands. An epidemiological study with 2391 patients.
      ].
      In contrast to the adult population, distant metastases and advanced disease at presentation have not been described in children. It might be possible that some goblet cell carcinomas or neuroendocrine carcinomas have been included in these studies on adult populations, leading to worse outcomes. Nonetheless, in current literature no recurrences have been reported and disease-free survival seems to be 100% in the pediatric population. Therefore the clinical course of NETs of the appendix seems to be more benign in children compared to the adult population, although large studies with adequate follow-up are needed to confirm this hypothesis. This raises the question whether or not secondary surgery is necessary in patients younger than 20 years diagnosed with a high-risk NET of the appendix. Since right hemicolectomy might be of no benefit for (disease-free) survival, the harm of potential complications should be taken into consideration. Data regarding complications after right hemicolectomy for any indication are scarce for the pediatric population, but in adults complication rates of 31–53% have been described [
      • Hanna M.H.
      • Hwang G.S.
      • Phelan M.J.
      • et al.
      Laparoscopic right hemicolectomy: short- and long-term outcomes of intracorporeal versus extracorporeal anastomosis.
      ,
      • Milone M.
      • Elmore U.
      • Vignali A.
      • et al.
      Recovery after intracorporeal anastomosis in laparoscopic right hemicolectomy: a systematic review and meta-analysis.
      ]. Although right hemicolectomy in case of treatment of NET of the appendix is an elective procedure and thus a lower complication rate is expected, the study of Bamboat et al. found a complication rate of 50% after right hemicolectomy for NET of the appendix [
      • Bamboat Z.M.
      • Berger D.L.
      Is right hemicolectomy for 2.0-cm appendiceal carcinoids justified?.
      ]. In our systematic review, only three studies reported complications after secondary surgery and a complication rate of 5% was found. It can be questioned whether or not this is an underestimation of the complication rate, as the majority of the studies did not mention complication rates after secondary surgery and large heterogeneity existed in the follow-up of patients.
      The heterogeneity in follow-up of patients is a major limitation to the current evidence and the results of our systematic review. Follow-up duration ranged between no follow-up and 51 years in the studies that were included in this review [
      • Boxberger N.
      • Redlich A.
      • Böger C.
      • et al.
      Neuroendocrine tumors of the appendix in children and adolescents.
      ,
      • Moertel C.L.
      • Weiland L.H.
      • Telander R.L.
      Carcinoid tumor of the appendix in the first two decades of life.
      ]. Furthermore, large heterogeneity in the method of follow-up existed between studies. Some authors contacted general practitioners for follow-up data or contacted all national pediatric surgeons and oncologists, whereas others only used medical records from the hospital in which the patient was initially treated [
      • de Lambert G.
      • Lardy H.
      • Martelli H.
      • Orbach D.
      • Gauthier F.
      • Guérin F.
      Surgical management of neuroendocrine tumors of the appendix in children and adolescents: a retrospective French multicenter study of 114 cases.
      ,
      • Moertel C.L.
      • Weiland L.H.
      • Telander R.L.
      Carcinoid tumor of the appendix in the first two decades of life.
      ,
      • Scott A.
      • Upadhyay V.
      Carcinoid tumours of the appendix in children in Auckland, New Zealand: 1965-2008.
      ]. It can be questioned if these methods of follow-up are completely accurate to determine disease-free survival of patients. It might therefore be possible that the 100% disease-free survival that was found in our systematic review is an overestimation of the actual disease-free survival rate. High quality data with adequate and extensive follow-up is needed in order to draw evidence-based conclusions on disease-free survival and recurrence rates.
      For patients with a low-risk NET of the appendix, no specific follow-up strategy seems to be necessary according to the current guidelines [
      • Pape U.F.
      • Niederle B.
      • Costa F.
      • et al.
      ENETS consensus guidelines for neuroendocrine neoplasms of the appendix (excluding goblet cell carcinomas).
      ,
      • Boudreaux J.P.
      • Klimstra D.S.
      • Hassan M.M.
      • et al.
      The NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-differentiated neuroendocrine tumors of the Jejunum, Ileum, Appendix, and Cecum.
      ]. Similarly, for patients that underwent right hemicolectomy for a high-risk NET of the appendix but without proof of lymph node involvement or residual disease, no follow-up strategy is advised. It could be a significant benefit of right hemicolectomy compared to observation after appendectomy only, if no (or only limited) follow-up is necessary after secondary surgery. However, in the studies included in our systematic review, differences between those patients that underwent secondary surgery and those that were observed after appendectomy with regard to surveillance strategies and follow-up were not clearly described. In the two studies that described the number of additional imaging studies during follow-up, no difference was found for patients that underwent secondary surgery compared to those that were observed after primary appendectomy [
      • de Lambert G.
      • Lardy H.
      • Martelli H.
      • Orbach D.
      • Gauthier F.
      • Guérin F.
      Surgical management of neuroendocrine tumors of the appendix in children and adolescents: a retrospective French multicenter study of 114 cases.
      ,
      • Pelizzo G.
      • La Riccia A.
      • Bouvier R.
      • Chappuis J.P.
      • Franchella A.
      Carcinoid tumors of the appendix in children.
      ].
      For patients with lymph node involvement or residual disease after right hemicolectomy and for patients with a high-risk NET that were observed after primary appendectomy, long-term follow-up is advised due to the presumed risk of lymph node metastasis but any benefit for the prevention of recurrence or influence on long-term outcomes is unproven [
      • Pape U.F.
      • Niederle B.
      • Costa F.
      • et al.
      ENETS consensus guidelines for neuroendocrine neoplasms of the appendix (excluding goblet cell carcinomas).
      ,
      • Boudreaux J.P.
      • Klimstra D.S.
      • Hassan M.M.
      • et al.
      The NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-differentiated neuroendocrine tumors of the Jejunum, Ileum, Appendix, and Cecum.
      ]. No consensus has been reached on the type of imaging studies or laboratory markers that are needed during follow-up of patients with a high-risk NET of the appendix. This systematic review revealed several surveillance and follow-up strategies, consisting of serial abdominal ultrasounds or CT-scans at different intervals for the detection of potential recurrence of disease. It can be questioned if imaging studies are an adequate follow-up method for these slowly growing tumors, especially in the early postoperative period. Sensitivity of imaging modalities for detecting metastasis or local recurrence have not been investigated and meanwhile patients are repetitively exposed to irradiation in case of CT-scan. Although laboratory markers such as urine 5-HIAA and serum CgA have been used for follow-up of patients with NET of the appendix as well, several studies concluded that these markers were not sensitive to detect metastasis [
      • Boxberger N.
      • Redlich A.
      • Böger C.
      • et al.
      Neuroendocrine tumors of the appendix in children and adolescents.
      ,
      • de Lambert G.
      • Lardy H.
      • Martelli H.
      • Orbach D.
      • Gauthier F.
      • Guérin F.
      Surgical management of neuroendocrine tumors of the appendix in children and adolescents: a retrospective French multicenter study of 114 cases.
      ].
      High quality data is also needed in order to determine the optimal follow-up strategy for patients with a high-risk NET of the appendix, as extensive follow-up might not be necessary. This may be of major influence on the quality of life of both patients and parents. It is well known that the diagnosis of cancer itself (and not only its treatment and complications) has a significant negative impact on quality of life of both the child and parents [
      • Landolt M.A.
      • Vollrath M.
      • Niggli F.K.
      • Gnehm H.E.
      • Sennhauser F.H.
      Health-related quality of life in children with newly diagnosed cancer: a one year follow-up study.
      ,
      • Roddenberry A.
      • Renk K.
      Quality of life in pediatric cancer patients: the relationships among parents' characteristics, children's characteristics, and informant concordance.
      ,
      • Wakefield C.E.
      • Sansom-Daly U.M.
      • McGill B.C.
      • et al.
      Providing psychological support to parents of childhood cancer survivors: 'cascade' intervention trial results and lessons for the future.
      ,
      • Yariş N.
      • Yavuz M.N.
      • Yavuz A.A.
      • Ökten A.
      Assessment of quality of life in pediatric cancer patients at diagnosis and during therapy.
      ]. Furthermore, it has been reported that worse parents’ quality of life is due to worse child quality of life, low parent resilience and especially higher fear of recurrence [
      • Wakefield C.E.
      • Sansom-Daly U.M.
      • McGill B.C.
      • et al.
      Providing psychological support to parents of childhood cancer survivors: 'cascade' intervention trial results and lessons for the future.
      ]. Reducing this fear of recurrence and limiting follow-up duration, if feasible, can therefore significantly improve quality of life.
      This systematic review is limited by the heterogeneity between the included studies, which is one of the reasons that no meta-analysis could be performed. As discussed, method and duration of follow-up differed significantly between studies. Furthermore, due to the retrospective design, the included studies were prone to bias by indication. The reason to choose for secondary surgery in some patients with a high-risk NET and for appendectomy with subsequent observation in others, was not described in the majority of studies. Besides, we chose to classify and analyze all NETs according to the ENETS guidelines, which limits extrapolation of results to the UICC/AJCC classification. Lastly, all studies in this review were assessed as moderate to severe risk of bias, indicating that high-quality data is lacking.
      In conclusion, this systematic review found a 100% disease-free survival of children and young adults (<20 years old) with a high-risk NET of the appendix, both in the group of patients that underwent secondary surgery and in those patients that were treated with appendectomy without secondary surgery. Therefore, secondary surgery does not seem to improve the risk of recurrence, indicating that appendectomy might be sufficient treatment. However, risk of bias was moderate to serious for the included studies and adequate follow-up was lacking. Large (international) prospective studies with adequate follow-up are needed to generate high-quality evidence regarding the necessity of secondary surgery in children with high-risk NET of the appendix.

      CRediT authorship contribution statement

      Paul van Amstel: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Data curation, Writing – original draft, Visualization. Amber Mahieu: Formal analysis, Investigation, Data curation. Roel Bakx: Conceptualization, Methodology, Writing – review & editing, Supervision. Ralph de Vries: Methodology, Investigation, Writing – review & editing. Martine F. Raphael: Conceptualization, Methodology, Writing – review & editing, Supervision. Joep P.M. Derikx: Conceptualization, Methodology, Writing – review & editing, Supervision. LW Ernest van Heurn: Conceptualization, Methodology, Writing – review & editing, Supervision. Ramon R. Gorter: Conceptualization, Methodology, Validation, Formal analysis, Writing – review & editing, Supervision.

      Declaration of competing interest

      The authors have no conflicts of interest to disclose for the submitted work. Outside the submitted work Dr. Ramon R. Gorter and Dr. R. Bakx received a (governmental) ZonMw grant for research in the field of complex appendicitis in the pediatric population. Grant Number: 80-85009-98-2007 .

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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