Tumor Staging But Not Grading Is Associated With Adverse Clinical Outcome in Neuroendocrine Tumors of the Appendix

Abstract

Appendiceal neuroendocrine neoplasms (NENs) are rare and usually incidentally discovered. Most cases are clinically indolent, although the rare aggressive ones are poorly predictable. The aim of this study was to test the applicability and prognostic significance of the new World Health Organization (WHO) classification and to test the several pathologic features and TNM staging systems (American Joint Committee on Cancer and European Neuroendocrine Tumor Society) in these tumors. A multi-institutional retrospective series of 138 appendiceal NENs was selected on the basis of the availability of both pathologic material and clinical information, including follow-up data. All cases were reviewed to record pathologic features and to apply year 2000 and 2010 WHO classifications, as well as European Neuroendocrine Tumor Society and American Joint Committee on Cancer TNM stages. Clinical and pathologic characteristics were compared with disease outcome by contingency, univariate, and multivariate survival analyses. Although up to one third of cases presented several malignancy-associated pathologic features, only 4 patients died of the disease. Adverse outcome was significantly associated with extramural extension (including mesoappendix), well-differentiated carcinoma diagnosis (2000 WHO classification), pT3-4 stage, older age, and presence of positive resection margins, but not with tumor size, mitotic or proliferative indexes, and, consequently, 2010 WHO grading. In the appendix, at variance with midgut/hindgut NENs, the 2000 WHO classification performs better than the grading-based 2010 WHO scheme and, together with tumor stage, is the most relevant parameter associated with clinical aggressiveness.

GEP–NETS UPDATE: A review on surgery of gastro-entero-pancreatic neuroendocrine tumors

“…Most NETs of the appendix have welldifferentiated histology, and for most tumors !2 cm and confined to the appendix, simple appendectomy is sufficient because metastases are uncommon (37). However, some controversy exists regarding the management of appendiceal NETs measuring below 2 cm with more aggressive histologic features (38,39). According to Moertel et al (36), patients with larger tumors and metastasis are younger than those with smaller and clinically benign tumors.…”

ENETS Consensus Guidelines for Neuroendocrine Neoplasms of the Appendix (Excluding Goblet Cell Carcinomas)

“…However, a risk of metastasis seems to exist, particularly in cases >1.5 cm [5,7,14,19,41,54,57,58,59]. …”

“…The only exception could be the extremely rare situation when the NEN is located at the base of the appendix or when a mesoappendiceal invasion >3 mm is discovered histopathologically. Under these circumstances, a completion of the resection seems advisable, although a worse prognosis has not been proven and a higher complication rate than with simple appendicectomy has to be considered [5,7,14,19,41,54,57,59]. …”

“…NEN of the appendix are usually G1 or G2 (Ki-67 index <20%) and thus should be considered NET [53]. Appendiceal G2 NET are considered to comprise a higher risk of recurrence and/or metastasis; however, direct proof of this is still pending and has in fact been challenged [54]. Besides WHO grading TNM staging according to either the UICC/AJCC classification or ENETS guidelines (or best according to both; table 2) is recommended [52,53,55,56].…”

Nowotwory neuroendokrynne jelita cienkiego i wyrostka robaczkowego — zasady postępowania (rekomendowane przez Polską Sieć Guzów Neuroendokrynnych)

“…Diameter of more than 2 cm, aNEN G1/G2 (NET classified as at least T3 (ENETS) or T2 (UICC/AJCC) [5,13,[78][79][80][81][82]; 2. Location at the base of the appendix (although there is no evidence for a poorer prognosis, and in such cases a higher incidence of complications should always be considered, compared to simple appendectomy) [79,[83][84][85][86]; 3. Mesoappendiceal invasion, MAI (there is no evidence of a correlation between the tumour size and MAI, which questions the ENETS arbitrary infiltration depth of 3 mm as a border between T2 < 3 mm and T3 > 3 mm) [5]; …”