Abstract
Background/Aim: Appendiceal adenocarcinomas are rare tumours with aggressive traits, most often diagnosed incidentally after routine appendectomy. Survival rates vary greatly between the different subgroups, and adenocarcinoma has the worst prognosis. Surgery is the only curative treatment, however, the long-term benefit of extended surgical resections over appendectomy has not been established. This study aimed to investigate survival outcomes in patients with appendiceal adenocarcinoma that undergo appendectomy versus right hemicolectomy (RHC).
Materials and Methods: This study involved a systematic literature search in databases PubMed, Embase and Cochrane Library using the COVIDENCE software. Cohort studies reporting survival outcomes for patients with non-metastasised appendiceal adenocarcinoma undergoing appendectomy versus RHC were included. A random-effects model was used to pool hazard ratios (HRs) in the meta-analysis performed in Review Manager. The ROBINS-I V2 tool was used for risk of bias assessment.
Results: A total of nine retrospective registry-based cohort studies were identified. Seven studies, with a total of 17,802 patients, reported overall survival (OS) from multivariable Cox- regression analysis. The pooled effect of adjusted HRs demonstrated increased OS [random-effects HR=0.69, 95% confidence interval (CI)=0.58-0.83] for patients undergoing RHC, with similar results in the sensitivity analysis excluding potential overlapping data (random-effects HR=0.70, 95% CI=0.51-0.96). No significant difference in OS was found in studies reporting subgroup analysis for well-differentiated adenocarcinoma.
Conclusion: This systematic review highlights the complexity of surgical treatment guidelines in appendiceal adenocarcinoma. The findings suggest a survival advantage for RHC compared to appendectomy. In well differentiated early-stage adenocarcinoma, appendectomy may be sufficient, although this may not apply to all subgroups.
Introduction
Appendiceal neoplasms are rare, with an incidental detection rate of 0.9-1.4% in surgical specimens, following routine appendectomy (1, 2). Despite constituting a small fraction of gastrointestinal malignancies, recent epidemiological studies indicate a rising incidence of appendiceal adenocarcinoma over the past two decades, particularly in Western populations (3-5). This trend has been accompanied by a growing recognition of their biological heterogeneity and complex case management, reflected in recent updates to the WHO classification system and Swedish national treatment guidelines (6-8).
The prognosis for appendiceal adenocarcinoma is generally poor, with five-year survival rates ranging from 27% to 93%, largely depending on the histological subtype, disease stage at diagnosis and completeness of surgical resection (9-11). Adenocarcinoma of the appendix, in particular mucinous subtypes, frequently presents with peritoneal dissemination (12-14). Right hemicolectomy (RHC) is commonly recommended for adenocarcinoma due to potential regional lymphatic spread, but its prognostic advantage over simple appendectomy is unclear (12, 13). For patients with peritoneal carcinomatosis, cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has demonstrated benefits in selected patients, although survival gains vary by tumour subtypes and extent of peritoneal involvement (14-18).
While consensus exists regarding the need for oncological resection in advanced cases, standardised guidelines specified for localised appendiceal adenocarcinoma and the optimal surgical extent remain unclear (8). The potential survival advantage of RHC over appendectomy has not been established, and decisions are often based on institutional preference or surgeon experience. To date, no systematic review has evaluated survival outcomes stratified by surgical extent in appendiceal adenocarcinoma, and only a few reviews have addressed goblet cell adenocarcinoma (19-21). Given the rarity of these tumours and variability in clinical practice, there is a need for rigorous analysis of available survival data to optimize long-term outcomes and guide management. Thus, this study aimed to investigate survival outcomes in patients with appendiceal adenocarcinoma that undergo appendectomy versus RHC.
Materials and Methods
Study design. This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Supplementary Table I) (22) and was prospectively registered in the international Prospective Register of Ongoing Systematic Reviews (PROSPERO) with ID-number CRD42024540816.
Selection criteria. The primary aim of this study was to compare survival outcomes in patients with appendiceal adenocarcinoma that underwent appendectomy versus RHC. The PICO-S framework was used for defining the selection criteria: Population − patients with histopathologically confirmed appendiceal adenocarcinoma; Intervention − appendectomy as the primary surgical resection; Comparison − RHC as an alternative surgical resection; Outcome − overall survival and cancer-specific survival; Study design − published peer-reviewed randomised controlled trials (RCTs), non-RCTs and cohort studies. Eligible studies included patients aged ≥18 years at the time of diagnosis with histopathological verification and a minimum follow-up of one year. The article language was limited to English. Studies including patients that underwent completion hemicolectomy, HIPEC, multivisceral resections of the lower gastrointestinal, gynaecological and urological organs, as well as patients with distant metastases or peritoneal carcinomatosis were excluded, unless outcomes were reported separately. Other exclusion criteria were articles that did not stratify outcome effect by surgical method, publication date before 01 January 2000, abstracts with preliminary results and inaccessible articles.
Literature search strategy. An electronic literature search was performed in the online databases PubMed (National Library of Medicine), Embase and The Cochrane Central Register of Controlled Trials (CENTRAL, via Cochrane Library), as well as the clinical trial registries ClinicalTrials. gov and International Clinical Trial Registries Platform Search Portal (ICTRP). Controlled vocabulary terms for “appendiceal neoplasm”, “carcinoid tumour”, “appendiceal adenocarcinoma”, “right hemicolectomy” and “appendectomy” was used in the literature search (Supplementary Table II). The literature search was re-run before publication. The final search date was 05 May 2025. The reference lists of all included publications were also manually screened. Grey literature was not sought for.
Study selection. Two independent reviewers (SR and FH) screened titles and abstracts using the COVIDENCE systematic review software (Veritas Health Innovation, Melbourne, Australia) applying the pre-determined selection criteria. Duplicate studies were automatically removed by the software. Subsequently, articles identified as potentially eligible underwent full-text review. Records were excluded if both reviewers independently agreed on exclusion at either the title/abstract or the full-text article. Disagreements were resolved by a third reviewer, with the final verdict determined by the senior author (PB).
Data extraction and outcomes. After final study selection, data were extracted using a standardized form including general study information (author name, year of publication, country, study design and number of participants), participant characteristics (age, sex, histopathological diagnosis, grade, subtypes, lymph node involvement and tumour staging), extent of surgical resection (appendectomy and RHC), overall survival (OS), cancer-specific survival and time of follow-up. When necessary, the authors of the original studies were contacted to obtain additional information.
Quality assessment. Risk of bias assessment was independently performed by two reviewers using Cochrane risk of bias in non-randomized studies - of interventions (ROBINS-I) version 2 assessment tool (23). This tool evaluates specific variables across seven different domains. Each domain is graded as low, moderate, serious or critical risk of bias.
Statistical analysis. Hazard ratios (HRs) from multivariable Cox-regression analyses reporting long-term overall survival were extracted. A primary meta-analysis including all eligible studies and a sensitivity analysis excluding studies with overlapping registry data were conducted using random-effects models in Review Manager (RevMan, version 8.1.1., The Cochrane Collaboration, Oxford, UK). Between-study variance (τ2) was estimated using the restricted maximum likelihood (REML) method. Confidence intervals (CI) and p-Values were based on normal (z) inference. For studies reporting subgroup HRs (e.g., by histology or stage) without an overall cohort estimate, a combined HR was derived by inverse-variance pooling of log-HRs from non-overlapping subgroups, ensuring one effect estimate per study, using Stata (StataCorp, Release 18, College Station, TX, USA). HRs with opposite reference groups were inverted to standardise comparisons across studies.
Ethical considerations. This study utilized only published and publicly accessible data; therefore, ethical approval was not required.
Results
Literature search. A total of 1,195 studies were identified from the electronic literature search. After removing duplicates (n=79), 1,116 titles and abstracts were screened for relevance. 43 remaining studies underwent full-text review, and nine studies (24-32) met the predetermined inclusion criteria (Figure 1). One multicentre cohort study was excluded solely for inclusion of completion-hemicolectomy in the RHC group; as no HRs were reported in the study, this did not influence the meta-analysis. Manual screening of reference lists from the included studies yielded 124 records, none of which were eligible.
PRISMA flow-chart over study selection process.
Study characteristics. All included studies were retrospective registry-based cohort studies. Five (28-32) were derived from the National Cancer Database (NCDB), a hospital-based cancer registry, and four (24-27) from Surveillance, Epidemiology and End Results (SEER), a population-based registry in the United States. The studies were published between 2016 and 2024. Overall, they included 24,226 patients with non-metastasised primary appendiceal adenocarcinoma. Eight studies (24-31) recorded a total of 12,348 RHC and 5464 appendectomies. One study (32) did not specify the distribution of surgical procedures (Table I).
Key characteristics of included studies.
Patient demographics. In total, 49.9% of patients were female and 50.1% male. Four (26, 27, 30, 32) studies reported a mean age (SD), ranging from 57.9 (14.7) to 62.5 (14.6) years. The remaining studies (24, 25, 28, 29, 31) reported categorical age, and despite differing category definitions, most patients were aged approximately 50-65 years (data not shown).
Patient cohorts comprised of mainly mucinous and non-mucinous adenocarcinoma, except for two studies also reporting conventional adenocarcinoma not otherwise specified. Only one study (25) included an additional subgroup, signet-ring cell carcinoma. Histological grade was reported for entire study populations. Moderately differentiated tumours constituted the largest subgroup (34.6-50.3%), followed by well differentiated tumours (16.8-43%) and poorly differentiated/undifferentiated tumours (4-24.4%). In three studies (29, 30, 32), discrepancies in cohort size between the total study populations and analytic cohorts rendered these distributions indicative rather than exact. Two studies (27, 28) were confined to well differentiated tumours (Table II).
Patient demographics.
All studies included patients with American Joint Committee on Cancer (AJCC) stage I-III disease, although one study (30) was restricted to T1 tumours (stage I and III). Rates of overall lymph node positivity were available in five studies (25, 27, 28, 30, 31), and varied considerably between cohorts, ranging from 8% to 32% (Table II). Among lymph node-positive patients, 80.1% underwent RHC in Straker et al. (31) and 71% in Waheed et al. (28).
Survival outcomes. Seven studies (25, 27-32), with a total of 17,802 patients, assessed OS in multivariable Cox-regression models, of which five (25, 29-32) reported a significant survival benefit for patients undergoing RHC. The pooled effect of adjusted HRs demonstrated increased OS (random-effects HR=0.69, 95% CI=0.58-0.83, p<0.0001; I2=78%) after RHC, with similar results in the sensitivity analysis excluding overlapping data (random-effects HR=0.70, 95% CI=0.51-0.96, p=0.03; I2=89%) (Figure 2). Findings were consistent when using subgroup HRs as originally reported, both in the main analysis (random-effects HR=0.72, 95% CI=0.62-0.82, p<0.00001; I2=70%) and in the sensitivity analysis excluding overlapping data (random-effects HR=0.72, 95% CI=0.57-0.90, p=0.004; I2=86%) (Supplementary Figure 1).
Forest plot illustrating meta-analysis of overall survival in patients with appendiceal adenocarcinoma, comparing appendectomy versus right hemicolectomy. (A) Main meta-analysis including all eligible studies; (B) Sensitivity analysis excluding studies with overlapping cohorts.
The subgroup meta-analysis of mucinous adenocarcinoma demonstrated increased OS after RHC (random-effects HR=0.76, 95% CI=0.68-0.85, p<0.00001; I2=0%) (Figure 3). These results were not consistent when using subgroup HRs as originally reported (random-effects HR=0.79, 95% CI=0.63-1.00, p=0.05; I2=67%) (Supplementary Figure 2). A subgroup meta-analysis for non-mucinous adenocarcinoma or stage-stratified survival outcomes was not feasible due to the limited number of studies available after accounting for overlapping data.
Forest plot illustrating meta-analysis of overall survival in patients with mucinous appendiceal adenocarcinoma, comparing appendectomy versus right hemicolectomy.
In Almasri et al. (30), subgroup analysis stratified by histological grade reported significantly improved 1-, 3- and 5-year OS rates in moderately/poorly differentiated patients who underwent RHC compared to appendectomy; 97%, 92% and 87% vs. 85%, 60% and 60%, respectively (p <0.001). Similarly, Aloysius et al. (26), assessing OS in mean months, demonstrated increased survival with RHC compared to appendectomy in poorly (160 months vs. 136 months, p=0.045) and moderately (163 months vs. 149 months, p=0.005) differentiated adenocarcinoma. In well differentiated adenocarcinoma, no significant difference was observed between the surgical procedures, as also shown in the two studies (27, 28) confined to well differentiated cohorts (Table II).
Subgroup analyses of stage-specific survival outcomes in Zhao et al. (25) reported that 5-year OS rate of patients who underwent RHC was superior to appendectomy for stage I (83.5% vs. 68.9%, p=0.002) and stage II (74.2% vs. 53.23%, p<0.001) disease, but not for stage III. Likewise, Marks et al. (29) found that RHC conferred significantly longer OS in stage I-II non-mucinous and stage II mucinous adenocarcinoma (Table II). In one study (24) assessing cancer-specific survival, RHC was associated with improved survival in T3 (stage II/III) non-mucinous tumours (p=0.018), whereas no survival advantage was observed for mucinous tumours across all T categories. In contrast, Straker et al. (31), analysing stage I/II and stage III subgroups, demonstrated no significant difference in survival for non-mucinous tumours.
Quality assessment. The risk of bias was assessed using the ROBINS-I version 2 tool (Figure 4). Seven studies (24, 27-29, 31, 32) were classified as being at moderate risk of bias, one study (25, 30) was at serious risk of bias and one study (26) was at critical risk of bias.
Risk of bias assessment of included studies using ROBINS-I version 2, demonstrating domain-specific and overall risk.
Discussion
To our knowledge, this is the first systematic review assessing survival outcomes in appendiceal adenocarcinoma stratified by surgical procedure. This question has long been debated, as the rarity of appendiceal malignancy has hindered prospective studies and RCTs. Studies included in this review are retrospective registry-based cohort analyses, limiting the ability to draw firm conclusions. Nevertheless, this is the most comprehensive evidence currently available to guide management in this rare malignancy.
Currently, Swedish (8) and international treatment guidelines (33) for patients with appendiceal adenocarcinoma follow those for right-sided colon adenocarcinoma, recommending RHC. This systematic review includes studies reporting data that span several decades, during which treatment strategies likely varied. Our findings suggest a survival advantage for RHC compared to appendectomy in non-metastasised appendiceal adenocarcinoma. RHC enables formal oncologic resection with lymphadenectomy, potentially improving outcomes by removing nodal metastases and informing the need for adjuvant systemic chemotherapy (33). It also removes adjacent colonic tissue along with potential microscopic tumour spread, thereby improving local disease control. Moreover, the choice of surgical procedure may affect staging accuracy since appendectomy alone rarely yields enough lymph nodes, increasing the risk of understaging. These factors combined may contribute to the survival benefit of RHC and may also account for the few studies demonstrating survival benefit in earlier stages (I and II).
Given the evidence provided in this review, the implementation of RHC for all patients with appendiceal adenocarcinoma, regardless of subtype, may be considered standard practise. However, implementing surgical guidelines with prospective RHC selection is challenging as appendiceal adenocarcinoma is often detected incidentally on histopathology, imaging or during surgery. Establishing guidelines that define time-specific recommendations for RHC in acute and elective cases is currently not feasible.
A survival benefit of RHC was not consistently observed in mucinous adenocarcinoma. However, subgroup meta-analysis for mucinous subtype retained some residual overlapping data, limiting the ability to draw definitive conclusions. Studies suggest that the mucinous subgroup, when well differentiated and confined to the appendix (stage I), may demonstrate a lower incidence of nodal involvement and primarily spread via peritoneal seeding rather than the lymphatics (24, 34-37). Thus, appendectomy alone may provide adequate local control in well differentiated early-stage mucinous adenocarcinoma (26, 27). Nonetheless, there is a lack of high-quality evidence, and current data remain insufficient to safely adapt this approach in clinical practice. The morbidity, higher risk of perioperative complications and prolonged recovery associated with RHC may outweigh the oncologic benefit in older and comorbid individuals within this subgroup.
Goblet cell adenocarcinoma, as well as non-invasive low- and high-grade appendiceal mucinous neoplasms, were not included in this review. Both possess histopathological characteristics that differentiate them from conventional adenocarcinomas. Nonetheless, they are typically considered within the same clinical decision-making process and could potentially benefit from similar recommendations.
Resection margin status is an additional important but often underreported factor in studies comparing appendectomy and RHC. Although higher rates of positive margins after appendectomy have been reported, this appears mainly related to tumour T-stage (29, 38). As RHC is more likely to achieve complete microscopic resection of advanced T-stage tumours, observed advantages of RHC may reflect differences in resection margins rather than lymphadenectomy alone.
The heterogeneity observed across studies partly reflects evolving histopathological classification and grading criteria over time, complicating comparisons between earlier and more contemporary cohorts. Further limitations of the registry studies include potential data overlap, suboptimal classification of surgery type, as well as the lack of reporting on completion hemicolectomies and proportional hazard assumptions. Patient selection may also introduce bias since higher-stage disease or more aggressive histopathological features are more likely to undergo RHC, while appendectomy may have been reserved for older patients with early-stage or significant comorbidities. Such confounding by indication is difficult to account for in retrospective studies and remains a major limitation of the current literature.
Assessing survival outcomes in appendiceal adenocarcinoma is complex. OS is robust and widely available but can be influenced by competing risks, whereas cancer-specific survival offers higher specificity for tumour-related effects, but may be affected by potential misclassification. Reporting both outcomes would provide a more balanced and reliable assessment of survival. Furthermore, the lack of a standardised reporting framework between studies suggests the need of adopting a core outcome set, thereby strengthening future meta-analyses and evidence for clinical decision-making.
Conclusion
This systematic review highlights the complexity of surgical treatment guidelines in appendiceal adenocarcinoma. The findings suggest a survival advantage for RHC compared to appendectomy. In well differentiated early-stage adenocarcinoma, appendectomy may be sufficient, although this may not apply to all subgroups. Interpretation of existing studies is complicated by heterogeneity, biases inherent to retrospective designs, and lack of standardised outcome reporting.
Acknowledgements
The Authors acknowledge the support of Matthias Bank (Library and ICT, Faculty of Medicine, Lund University) for designing and running the search strategy, and Valentinus Valdimarsson (Department of Surgery, Colorectal Unit, Skåne University Hospital) for providing valuable insights on the clinical management of appendiceal malignancies.
Footnotes
Authors’ Contributions
Conceptualization: SR, PB, ÅO; Investigation/Methodology/Software/Data curation: SR, FH; Formal analysis: SR, FH, PB, ÅS; Supervision: PB, ÅO; Writing – original draft: SR; Writing – review & editing: SR, FH, PB, ÅO.
Supplementary Material
Supplementary data can be found at: https://figshare.com/s/ab60f8a9c75a2d62cdde
Conflicts of Interest
The Authors declare that there are no conflicts of interest to declare.
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Artificial Intelligence (AI) Disclosure
No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.
- Received October 21, 2025.
- Revision received November 9, 2025.
- Accepted November 13, 2025.
- Copyright © 2026 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
References
Jump to section
Related Articles
Cited By...
- No citing articles found.