Introduction
Appendiceal neuroendocrine neoplasms (ANENs) arise from the subepithelial neuroendocrine cells of the appendiceal wall and are generally discovered incidentally at appendectomy for acute appendicitis [
1,
2]. They commonly exhibit a benign clinical course with a minority developing locoregional lymph node (LN) metastases. Few cases have been reported with distant stage disease [
3]. The literature shows great diversity in terms of disease-specific mortality and its association with the presence of locoregional metastatic disease in LNs of the mesentery, as well as the type and extent of surgery undertaken. This diversity is mainly attributed to the fact that in the majority of series, not only well-differentiated (WD) ANENs were included [
4,
5].
Due to the indolent course of the disease and because there is currently no adjuvant therapy that is known to improve overall survival (OS) in ANENs, surgery is considered the mainstay of treatment. Appendectomy alone has traditionally been considered an adequate treatment for ANENs <10 mm, whereas a completion prophylactic right hemicolectomy (RHC) following appendectomy is generally advocated for lesions >20 mm. This approach to ANEN management is also in accordance with current European Neuroendocrine Tumour Society (ENETS) guidelines [
6]. However, histopathological parameters determining the risk of LN metastases and their associated mortality in adult and paediatric patients with an ANEN measuring between 10 and 20 mm have not been clearly defined and are still a matter of debate.
Earlier systematic reviews, including a recent appraisal from ENETS on unmet needs in ANEN management included only retrospective, observational, institutional and registry-based studies, as no randomized trial on ANENs is available to date [
7]. Importantly, several large studies on this topic were published during recent years contributing valuable new evidence in the field of ANENs. To date, predominant predictive factors associated with disease outcomes in terms of locoregional metastatic propensity are size and grade of the primary tumour as defined by the Ki-67 proliferation index. Some investigators also argue the clinical importance of serosal penetration, i.e. meso-appendix invasion and other histopathological parameters.
Although the various ANEN size cut‐offs for completion prophylactic RHC used in recent publications have potentially caused a loss of valuable information, light has been shed on the predictive value of other histopathological factors of the appendectomy specimen with respect to the risk for locoregional LN metastases. There remains a great need for summarized evidence to address the “grey zones” in ANEN management and in particular appropriateness, effectiveness and safety of completion prophylactic RHC in ANEN cases. Foremost, the risk of LN metastases as a function of tumour size and their morphological characteristics remains to be determined.
Our aim was to compare the rate of LN metastases and their impact on survival for adult and paediatric patients with ANENs undergoing RHC at different size cutoffs, with and without the presence of specific morphological parameters at histopathology, and also to assess the rate of complications following RHC in ANENs.
Discussion
The present meta-analysis confirms that tumour size, vascular invasion, lymph vessel invasion and perineural invasion are strong predictors for LN metastases in adult patients with ANEN. On the contrary, tumour location on the appendix as well as meso-appendix invasion were not unambiguously confirmed as affecting the risk for LN metastases. Regarding different tumour size cutoffs in adult patients, the rate of LN metastases at RHC for lesions <10 mm was 12.1% vs 38.5% for lesions 10–20 mm vs 61% for tumours >20 mm. A random-effects OR of 4.8 (95% CI, 1.5–15.8) was estimated for a 10 mm size cutoff, whereas for a 20 mm cutoff, random-effects OR was 3.2 (95% CI, 1.3–7.8). Thus, primary tumour size retains its value as a predictive marker of metastatic propensity to locoregional LN.
Disease-specific mortality rates at 10 years of follow-up reported in two studies of adults with ANEN were as low as 0.8% and 4.4% for patients with and without LN metastases undergoing RHC, respectively. Notably, the presence of LN metastases does not seem to clearly affect survival in patients who have undergone curative resection, i.e. either RHC or appendectomy alone. Thus, we were unable to provide evidence that the presence of LN metastases affects OS or that RHC exerts a prophylactic effect. The complication rate of prophylactic RHC in this meta-analysis was 11.4%, with lower complication rates demonstrated over time, implying a generally safer procedure nowadays. In paediatric patients, available data were limited and no clear relationships between the parameters we investigated and LN metastases were evident. However, regardless of the extent of surgery in children, favourable long-term survival rates were reported, implying an excellent prognosis for paediatric ANEN cases subjected to curative resection.
In the efforts to adopt a precision medicine surgical and post-treatment surveillance approach in the management of ANEN, one of the main challenges is related to the paucity of validated biomarkers to guide the extent of locoregional resective surgery, i.e. to select the best candidates for prophylactic RHC and monitor patient outcomes. Overall, the rate of LN metastases in our study prior to different strata division and analysis, in both adult and pediatric patients, was 34.6%, as compared with the corresponding figure of 24.5% in a recent meta-analysis in ANENs [
37]. The reasons for this discrepancy may be multifaceted and could potentially imply that the implementation of not validated risk factors, such as meso-appendiceal invasion in the grey zone of 10–20 mm tumour size to guide the extent of surgery may have led to unnecessary completion RHCs.
We conducted an NOS quality assessment on all the included studies (Table
2). All cohort studies scored at least five points, achieving moderate to high quality. Heterogeneity between studies was observed in the assessment of certain parameters, i.e. lesion size cutoff of 20 mm, grade and mortality rate. As statistically significant “positive” results are more likely to be published rapidly in English language and high impact journals, leading to reporting biases, we also assessed non-English studies, as well as unpublished data from conference papers [
21,
22]. Complementary testing did not reveal small study effects in the present meta-analysis. Further factors, such as confounding and the precision of measurements, e.g. ICD-coded data in registry-based studies, might have introduced bias [
38]. Importantly, although registry-based studies might differ regarding the strength of their evidence, they still constitute a valuable information source for evidence-based medicine [
9].
With regard to the tumour size cutoffs investigated in this meta-analysis, we should clarify that traditionally a tumour size >20 mm constitutes a general indication for more extensive surgery, commonly completion RHC, based on the seminal paper in the New England Journal of Medicine published by pioneers in the field, namely Moertel et al. in 1987 [
19]. To date, for ANENs between 10 and 20 mm, various morphological parameters at histopathology have been applied as per ENETS guidelines to identify patients who would potentially benefit from completion prophylactic RHC. Therefore, for lesions <20 mm subjected to RHC, one or more morphological parameter was presumably present at histopathology in order to qualify for completion surgery. However, few studies reported patient data at the individual level and in some there was ambiguity over criteria for completion prophylactic RHC. Thus, the rates and OR of LN metastases in ANEN < 20 mm must be interpreted in the light of this knowledge.
The prognostic significance of meso-appendix invasion was not confirmed in our study. In the current ENETS guidelines, a meso-appendix invasion depth of >3 mm is arbitrarily used to distinguish T2 from T3 tumours in the TNM classification. However, there is insufficient information in the literature to substantiate whether meso-appendix invasion and the 3 mm cutoff are validated prognostic factors to guide the extent of surgery. In addition, the location of the primary tumour in the appendix has been implied as a risk factor for non-radical resection at appendectomy, thus metastatic propensity necessitating completion RHC. However, this was not confirmed in our study, as no clear association with the presence of LN metastases was evident. Finally, Grade 2 was potentially linked to higher risk for LN metastases; however, due to high interstudy heterogeneity and potential effect modifiers evident in metagression analysis, no safe conclusions could be derived. On the contrary, vascular, lymph vessel and perineural invasion were substantiated as strong predictors for LN metastases in adult patients with ANEN.
ANEN’s clinical course in children may be completely benign, as paediatric studies report 5‐ and 10-year DSS of 100% in all patients who had undergone curative resection, i.e. appendectomy alone or completion RHC. However, due to insufficient data having been reported, our meta-analysis could not confirm predictive factors for LM metastases to guide the extent of surgery as in adult patients. For tumour size cutoff >20 mm, a single study was eligible and reported an OR as high as 6.1, (95% CI: 1.2–30.4) for LN metastases. However the clinical significance of this remains unclear and should be validated in more studies [
29].
Our study has some limitations. Importantly, it constitutes an unplanned subset analysis of multiple observational studies on the rare entity of ANEN. The eligible institutional studies were underpowered or not even designed to assess differences in the outcomes of our interest. Further limitations include a lack of centralized pathology review that not only concerns interstudy concordance for tumour size and other histopathological parameters, but also changes within the NEN grading system over time. Moreover, regarding the SEER data quality, it should be noted that complete pathological data were not routinely included in the SEER database prior to 1988. However, in the SEER report by Sarshekeh included in this meta-analysis study, participants were only eligible for inclusion after 1988. All these limitations concern the general applicability of older studies nowadays, yet robust effects (e.g. for vascular invasion and the 20 mm size cutoff) had already been observed in the seminal study by Moertel et al. 32 years ago, as well as in very recent reports. Another important limitation was the high interstudy heterogeneity encountered when assessing certain morphological parameters, i.e. grade. However, in the absence of prospective studies, we used the best available evidence and applied a comprehensive search strategy and advanced statistical methods, including meta-regression, demonstrating the risk of LN metastases in relation to histopathology and their prognostic significance in adult and paediatric patients with WD ANEN.
In the random-effects model we adopted for 10-year DSS, I2 was 53%, suggesting that substantial variability in effect estimates on LN status is due to real study differences (heterogeneity). This is also evident from the wide scatter of effect estimates with broad CI that depict the uncertainty around this pooled estimate. Therefore, there is no strong evidence to date that positive locoregional LN metastases are associated with higher mortality. Hence, the true impact of LN status in ANEN, and whether a prophylactic surgical approach is beneficial, both need to be elucidated in further studies with long-term (>10 years) follow-up.
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