Challenging the Current Risk Factors of Appendiceal Neuroendocrine Neoplasms: Can They Accurately Predict Local Lymph Nodal Invasion? Results from a Large Case Series

Abstract

Background: Appendiceal neuroendocrine neoplasms (ANEN) are uncommon entities, which run mostly an indolent course. Appendicectomy alone is usually curative, except for in a selected group of patients that are deemed to be at risk of loco-regional metastases, in whom a completion right hemicolectomy (RHC) is recommended. The current “Guidelines” criteria for the latter have been controversial, and may result in overtreatment, which is concerning for a young patient population. Objective: The aim of this study is to evaluate the prognostic value of the current criteria in identifying more accurately those at-risk patients. Methods: This was a retrospective study of the 263 cases of ANEN referred for advice or management to a tertiary referral unit over a 10-year period. Seventy-two patients underwent RHC, based on criteria, suggested by International Guidelines. Each one of those was assessed to identify whether it correlated with lymph node invasion (LNI) at the RHC surgical specimen. Results: Tumour grade (p < 0.001), vascular (p = 0.044) and lymph vessel invasion (p < 0.001) were all found to be statistically significant independent risk factors for LNI identified following RHC, whilst tumour size (p = 0.375) and mesoappendiceal invasion (MAI) (p = 0.317) were not statistically significant. However, deep MAI and tumour size >2 cm showed a correlation with each other on LNI positive subgroup analysis. Location in appendiceal base made LNI more likely but again was not significant (p = 0.133). Conclusions: Higher tumour grade and lymphovascular invasion should be considered as the most important risk prognosticators. Surprisingly, tumour size was not found to be significant in our cohort. Further international multicentre studies with large numbers of patients are needed to fully validate those data.

The risk of lymph node metastases and their impact on survival in patients with appendiceal neuroendocrine neoplasms: a systematic review and meta-analysis of adult and paediatric patients

“…We identified seven studies reporting LN status at RHC for tumour size cutoffs of 10 and 20 mm [3,[11][12][13][14][15][16]. The rate of LN metastases for a cutoff size >10 mm was 48.6% (vs 12.1% for lesions <10 mm) among adult patients, with a random-effects OR of 4.8 (95% CI, 1.5-15.8; heterogeneity, P = 0.061; I 2 = 46.3%, Egger's p-value = 0.093, Fig.…”

The effect of prophylactic surgery in survival and HRQoL in appendiceal NEN

“…For tumor size 10–20 mm, various histopathological parameters have been applied to identify right candidates for completion pRHC although not fully validated. In particular, the location of the primary tumor in the base of the appendix, grade 2, mesoappendix, vascular, lymph vessel, and perineural invasion has been implied as a risk factors for synchronous LN metastases necessitating completion pRHC [ 7 , 8 , 13 , 27 , 28 ]. However, these factors were not confirmed in our study with respect to LN metastases prediction.…”

“…Contemporary guidelines suggest a rather aggressive surgical approach with completion pRHC as a treatment option for patients diagnosed with tumors ≥20 mm or tumors 10–20 mm in the presence of certain histopathological parameters [ 5 , 6 ]. However, recent cohort studies and meta-analyses have questioned the validity of currently applied criteria for completion pRHC in WD-ANENs [ 2 , 7 – 10 ]. Nevertheless, the association of indolent locoregional lymph node (LN) metastases with long-term patient outcomes has not been fully determined [ 10 , 11 ].…”

Neuroendocrine neoplasms of the appendix, colon and rectum

“…The prognostic impact of clinical and pathological parameters in NETs has been more extensively investigated, but a great variability of results is observed with special reference to the identification of independent factors when tested at multivariable analysis. In a recent study, size > 15 mm, presence of lympho-vascular invasion and G2 grade have been identified as independent indicators for the presence of lymph node metastases 6 , but only the latter two were identified in a similar study 7 and neither tumor grade nor tumor size were associated with disease-related survival in another study 8 . All these discrepancies reflect the high heterogeneity of study planning and case selection, which are the major biases of retrospective studies and are the cause of different indications to surgical treatment in different national and international guidelines.…”