Appendiceal neuroendocrine tumours (aNET) (i.e. well differentiated) account for 75% of all aNENs, are mostly indolent tumours treated effectively with simple appendectomy. In fact, most are incidentally found upon presentation of right lower quadrant (RLQ) pain in keeping with appendicitis. They are typically (but not exclusively) diagnosed in younger patients.
Poorly differentiated appendiceal Neuroendocrine Carcinomas (aNEC) resemble small-cell or large-cell neuroendocrine carcinomas of the lung, have aggressive behaviour, and usually present with metastatic disease at diagnosis.
Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) are possible, particularly with Goblet Cell Adenocarcinoma. T0 qualify as a MiNEN, there should be at least 30% cellular positivity in both cancers.
The appendix is a thin tube that is joined to the large intestine close to the junction (the cecum) of the large and small intestine. It sits in the lower right part of your abdomen. Scientists aren’t sure what the appendix does as a job, but the most common hypothesis is that it was once a store of good bacteria, and another is that is a remnant of human evolution.
The location of the Appendix is shown below, worth nothing the base of the appendix is at the joint of the cecum and the tip is the end furthest away from the cecum (this is important for understanding radiology/pathology reports).
The appendix is the third most common place for NETs along the digestive tract and aNETs are the most common neoplasms of the appendix. aNETs are the fifth most common well differentiated NET behind lung, small intestine, rectum and stomach.
The 20-year prevalence of aNETs between 1993-2012, based on the US SEER database, was 2 per 100,000 persons. In the folow on study cover 20 years up to 2021, the summary stated “The appendix site specifically showed a notable increase in incidence over the past two decades.”
It follows on to say most aNETs are diagnosed at an early, localized stage, often incidentally during an appendectomy for appendicitis or other abdominal issues. In a study of 4,870 patients, 86.0% had T1 stage disease (least risk on the TNM scale). Appendiceal NETs generally have a favorable prognosis, especially when localised. The majority of cases (89.4%) were low-grade (Grade 1 (86.2%) or G2 (3.2%)) tumours, which exhibit slow growth. In guidelines, removal of small low grade tumours with R0 margins is considered curative.
Most commonly seen at the tip of the appendix (67% of adult patients, 73% of pediatric patients). Most appendiceal NETs are < 2 cm. 52 – 62% are < 1 cm, 28 – 30% are 1 – 2 cm. 8 – 19% are > 2 cm.
aNETs rarely cause Carcinoid Syndrome (see below).
All of the above figures may vary between countries. The biggest study, US SEER 2025 indicates diagnoses of Appendiceal NETs has increased by almost 13% over a period of 20 years.
So called ‘carcinoid syndrome‘ is rare in aNENs, mostly due to the low stage and curative surgery approach. But any manifestation of carcinoid syndrome would be similar to small intestine NETs, e.g. almost always in metastatic cases.
Most Multiple Endocrine Neoplasia (MEN) cases are related to foregut NETs but having a family history of multiple endocrine neoplasia type 1 (MEN1) syndrome can be a risk factor for appendiceal NET. For most, a family history of MEN1 will already be known.
There are numerous clinical practice guidelines on management of aNETs where management of these tumours is stratified according to risk of locoregional and distant metastasis. Most aNETs are less than 1cm and will be removed with curative intent and no further surveillance would be necessary. Tumours of 2cm plus would necessitate a right hemicolectomy.
However, there remains a lack of consensus regarding tumours that measure 1-2 cm. In these cases, some histopathological features such as size, tumour grade, presence of lymphovascular invasion, or mesoappendix infiltration must also be considered. Computed tomography or magnetic resonance imaging scans are recommended for evaluating the presence of additional disease, except in the case of tumours smaller than 1 cm without additional risk factors. Somatostatin receptor imaging should be considered in cases with suspected residual or distant disease. In general, controversy exists regarding the necessity of oncologic right hemicolectomy (RH) in aNET patients with histologic features suggestive of more aggressive disease.
This comparison of the main Appendiceal NET guidelines summaries the controversary. Consequently, staging definitions are different between Europe and North America.
Guidelines for aNEC and MiNEN will be similar to other NEC and MiNEN.
This is a very useful summary for those interested in the detail. Click here to read. 
One of the issues faced by guideline writers is a lack of data assessing the risks of doing something or not doing something. With aNETs, and as mentioned above, there has been controversy over the requirement for a right hemicolectomy to ensure margins in case of aNETs with a tumour size between 1 and 2cm.
As I was writing this blog post, the following study came out of the annual European NET Society conference, a timely addition to this blog post.
Findings
282 patients with suspected appendiceal tumours were identified, of whom 278 with an appendiceal NET of 1–2 cm in size were included. 163 (59%) had an appendectomy and 115 (41%) had a right-sided hemicolectomy, 110 (40%) were men, 168 (60%) were women, and mean age at initial surgery was 36·0 years (SD 18·2). Median follow-up was 13·0 years (IQR 11·0–15·6). After centralised histopathological review, appendiceal NETs were classified as a possible or probable primary tumour in two (1%) of 278 patients with distant peritoneal metastases and in two (1%) 278 patients with distant metastases in the liver. All metastases were diagnosed synchronously with no tumour-related deaths during follow-up. Regional lymph node metastases were found in 22 (20%) of 112 patients with right-sided hemicolectomy with available data. On the basis of histopathological risk factors, we estimated that 12·8% (95% CI 6·5 –21·1) of patients undergoing appendectomy probably had residual regional lymph node metastases. Overall survival was similar between patients with appendectomy and right-sided hemicolectomy (adjusted hazard ratio 0·88 [95% CI 0·36–2·17]; p=0·71).
Interpretation
This study provides evidence that right-sided hemicolectomy is not indicated after complete resection of an appendiceal NET of 1–2 cm in size by appendectomy, that regional lymph node metastases of appendiceal NETs are clinically irrelevant, and that an additional postoperative exclusion of metastases and histopathological evaluation of risk factors is not supported by the presented results. These findings should inform consensus best practice guidelines for this patient cohort.
This 2024 study from USA indicates support for conservative approach (see discussion document 4 below). The question is “Do Appendiceal Neuroendocrine Tumors Metastasize Post Appendectomy or Right Hemicolectomy?”. Their conclusion was “Stage IV appendiceal NETs are exceptionally rare, and distant metastases are synchronous in nearly all cases. The risk of metastatic spread after resection of local appendiceal NETs is negligible. Patients with tumors <2 cm should not be managed with completion right hemicolectomy, and the role of this operation for larger tumors is questionable. Postoperative surveillance is unlikely to be of benefit.”
To aid your discussion with the doctor, these 4 documents might help – the conclusions are useful for those to which this is relevant:
1. ENETS Guidelines (as linked above – click here
2. This study from Switzerland – click here
3. This study from France – click here
4. This study from USA (Moffit in Tampa) – click here
The pediatric patient in NETs is mainly in the locations covered by the Multiple Endocrine Neoplasia (MEN) hereditary syndromes. While there can be an overlap between MEN and appendiceal NETs, most are not hereditary cases. Other than that connection, the appendix appears to have a larger quota of pediatric patients than most other primary locations. Read more here.
Pediatric appendiceal neuroendocrine neoplasms: SEER registry analysis
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