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What are Appendiceal NENs
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. However, more recent studies are finding higher figures e.g. a period prevalence of 7 per 100,000 individuals. The authors suggested this difference may reflect a rising prevalence, but also partly due to the inclusion of only metastatic forms of aNETs in the SEER program (Ronny Allan note: potentially pre 2010 classification possibly omitted many aNETs due to the definition of “benign”).
The majority (80%) of cases found incidentally, such as after a surgery for acute appendicitis. Most commonly seen at the tip of the appendix (67% of adult patients, 73% of pediatric patients). Most appendiceal NETs are < 2 cm with only 8-19% greater than the 2cm threshold. Approx 52-52% are < 1 cm leaving 28 – 30% measuring 1 – 2 cm.
aNETs rarely cause Carcinoid Syndrome (see below).
All of the above figures may vary between countries. The biggest study, US SEER 2012, is now significantly out of date.
Syndromes and Appendiceal NENs
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.
Guideline Controversy – Right Hemicolectomy for aNETs size 1-2cm
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.
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).
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.
Ronny Allan note: Watching the commentary on twitter, this remains controversial amongst healthcare professionals. If you have a 1-2cm aNET, always ask your doctor to explain the benefits and risks of appendectomy vs right hemicolectomy.
- Surgical Management of Patients with Neuroendocrine Neoplasms of the Appendix: Appendectomy or More – PubMed (nih.gov)
- Pathology Outlines – Well differentiated appendix neuroendocrine tumor
- UKINETS Guidance Appendiceal NETs.
- Management of Appendix Neuroendocrine Neoplasms: Insights on the Current Guidelines
- Epidemiology of neuroendocrine tumors of the appendix in the USA: a population-based national study (2014-2019)
- NCCN Guidelines for Neuroendocrine Neoplasms (see page NET-3) – account login required.
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