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

Abstract

Neuroendocrine neoplasms (NEN) of the appendix are a relatively frequent subgroup of NEN with an approximate incidence rate of 0.15-0.6/100,000/year and with a slight female preponderance in Western series [1,2,3,4,5,6,7,8,9,10,11,12]. Although NEN are frequently reported [13], most cases are of an early stage [12,13,14]. The reported incidence has increased in more recent years [1,6]; however, the overall incidence rate is probably roughly within the same range between different races, although some differences have been reported [1,12,15,16,17,18]. Furthermore, common practice in performing appendicectomies may also influence the reported incidence of appendiceal NEN [19,20].Appendiceal NEN comprise the largest subgroup of appendiceal neoplasms with approximately 30-80% of all appendiceal neoplasms [1,13,14,21,22,23,24]. Mean age at diagnosis has been reported between 38 and 51 years [6,24,25,26]. However, appendiceal NEN have also been reported in pediatric patients between 4.5 and 19.5 years of age [2,4,17,27,28,29], but population-based data are not available for this special subgroup.The prognosis of the majority of appendiceal NEN is excellent in the series that report outcome on lower tumor stages with 5-year survival rates (YSR) of 100% or close to this [7,14,11,25,30,31,32]. However, the whole cohort including all tumor stages does not show such a favorable prognosis, with 5-YSR ranging between 70 and 85% [11,25,30,31,33]. Advanced stages with distant metastases have been reported with a much poorer prognosis and a 5-YSR of as low as 12-28% [1,11,14]. However, it is not clear to which extent more ‘malignant' histologies such as goblet cell carcinoids (GCC) or mixed adenoneuroendocrine carcinomas with a poorer prognosis per se were included in such series.Appendiceal NEN present with an incidence of 0.15-0.6/100,000/year. They are diagnosed slightly more often in female than in male patients at an average age of 40-50 years. Appendiceal NEN are, however, much more frequently diagnosed incidentally during appendicectomy with a rate of approximately 3-5/1,000 appendicectomies. Racial differences may occur but data are inconclusive. In contrast, malignant tumors seem to occur more often in Caucasians compared to other races. Appendiceal NEN may also rarely occur in children but apparently with an excellent long-term outcome. While at a lower stage, survival is extremely good (local disease: 5-YSR of 95-100%, regional disease: 5-YSR of 85-100%), on the other hand, the few cases with distant metastasis present with relatively poor survival figures (5-YSR: <25%).From the available data, it is concluded that an appendiceal NEN <1 cm, with invasion up to the subserosa or mesoappendiceal invasion up to 3 mm and clear surgical margins poses no further risk of recurrence after appendicectomy.Most tumors (70%) are located at the tip of the appendix. However, tumors at the base of the appendix, tumors of 1-2 cm in diameter and tumors with deep mesoappendiceal invasion or margin invasion confer a relevant risk of recurrence, and further surgical procedures are warranted, although no data have literally proven a survival benefit of more aggressive surgery.Most appendiceal NEN in adults as well as in children are incidental findings in postappendicectomy specimen and therefore no characteristic tumor-specific symptomatology has been established [5,17]. However, symptoms that lead to appendicectomy such as right lower abdominal pain are indirectly associated with appendiceal NEN, although due to their most frequent localization at the tip of the appendix (approx. 70%) these tumors are very likely not causative of acute appendicitis [34,35,36,37,38,39,40,41]. In the rare cases of distant metastases, these may cause symptoms related to the localization of the metastases.A carcinoid syndrome is an extreme exception in metastatic patients [35,36,38] and more likely associated with an intestinal primary tumor.Appendiceal NEN are rarely symptomatic in the large majority of cases due to the incidental nature of their diagnosis. However, tumors with extensive local disease or distant metastases may appear symptomatic with abdominal pain, a tumor mass effect or signs of bowel obstruction. An association with the carcinoid syndrome is extremely rare and indicates metastatic disease.Since most appendiceal NEN are incidentally diagnosed during postoperative histology, diagnostic procedures relate mostly to postoperative staging, follow-up and to the rare cases with suspected or evidenced distant metastasis.There are no specific diagnostic studies focusing on appendiceal NEN only, and therefore the considerations which apply to small intestinal NEN are considered to be also valid for appendiceal NEN and have not been changed since the previous version of the guidelines.Cross-sectional imaging using CT or MRI with modern protocols should be used to rule out locoregional or distant metastasis [42,43,44,45]. NEN limited to the app