Well-differentiated neuroendocrine tumors of the appendix

INTRODUCTION — Neoplasms of the appendix are rare. They are found in approximately 1 percent of appendectomy specimens [1,2] and account for only approximately 0.5 of 1 percent of intestinal neoplasms [3].

Appendiceal neoplasms comprise several histologic types:

●Epithelial neoplasms include invasive adenocarcinomas, low-grade appendiceal mucinous neoplasms, and goblet cell adenocarcinomas. Histologically, goblet cell adenocarcinomas (previously called goblet cell carcinoids or adenocarcinoids) have features of both adenocarcinomas and well-differentiated neuroendocrine tumors (NETs). They are more aggressive than well-differentiated NETs [4] and are classified and staged as appendiceal carcinomas [5]. (See "Epithelial tumors of the appendix" and "Appendiceal mucinous lesions".)

●Neuroendocrine neoplasms of the gastrointestinal tract include well-differentiated NETs (grades 1, 2, and 3), poorly differentiated neuroendocrine carcinomas (large cell and small cell types), and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) [6].

MiNEN typically show a combination of neuroendocrine carcinoma and adenocarcinoma, and these tumors are treated like high-grade neuroendocrine carcinomas. (See "High-grade gastroenteropancreatic neuroendocrine neoplasms".)

This topic will focus on the clinical presentation, staging workup, and treatment of well-differentiated NETs arising in the appendix. The evaluation and management of epithelial neoplasms (including goblet cell adenocarcinomas) and mucinous lesions arising in the appendix, the management of high-grade neuroendocrine carcinomas of the digestive tract, and the pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system are all addressed in detail elsewhere. (See "Epithelial tumors of the appendix" and "Appendiceal mucinous lesions" and "High-grade gastroenteropancreatic neuroendocrine neoplasms" and "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system".)

TERMINOLOGY AND CLASSIFICATION — NETs arising in the tubular gastrointestinal tract, lung, and genitourinary tract were initially referred to as "carcinoids" because they seemed morphologically different and clinically less aggressive than the more common gastrointestinal tract adenocarcinomas.

While most NETs are relatively slow-growing neoplasms, some behave aggressively. Histologic grade and differentiation correlate closely with clinical behavior. Grade refers to the proliferative activity of tumors, commonly measured by the mitotic rate (number of mitotic figures per 10 high-powered fields [HPF]) or the Ki-67 index. By contrast, differentiation refers to the extent to which neoplastic cells resemble their nonneoplastic counterparts.

The most recent nomenclature for NETs of the digestive system (which includes the appendix) from the World Health Organization (WHO) distinguishes two broad subgroups (table 1) [7]:

●Well-differentiated NETs, which are further subdivided into low grade, intermediate grade, and high grade according to proliferative rate. In general, the clinical behavior of the low- and intermediate-grade tumors is relatively indolent. The clinical behavior of well-differentiated, high-grade tumors is somewhat worse than that of well-differentiated, intermediate-grade NETs, but it is better than that of poorly differentiated neuroendocrine carcinomas. (See "High-grade gastroenteropancreatic neuroendocrine neoplasms", section on 'High-grade well-differentiated tumors'.)

●Poorly differentiated neuroendocrine carcinomas, which are high-grade carcinomas that resemble small cell or large cell neuroendocrine carcinomas of the lung (picture 1) [8]. They generally behave in a biologically aggressive fashion.

Within the appendix, 70 to 75 percent of neuroendocrine neoplasms are well-differentiated NETs; the remainder are high-grade neuroendocrine carcinomas [4,9]. A more detailed discussion of the pathology and classification of NETs arising in the digestive tract and of high-grade neuroendocrine carcinomas arising in the digestive tract is presented elsewhere. (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on 'Classification and terminology' and "High-grade gastroenteropancreatic neuroendocrine neoplasms".)

In addition, a separate category, mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN), typically shows a combination of neuroendocrine carcinoma and adenocarcinoma, and these tumors are treated like high-grade neuroendocrine carcinomas [6]. (See "High-grade gastroenteropancreatic neuroendocrine neoplasms".)

Carcinoid syndrome — As with other intestinal well-differentiated NETs, those arising in the appendix can secrete serotonin and other vasoactive substances (table 2). These substances are responsible for carcinoid syndrome, which is characterized by episodic flushing, wheezing, diarrhea, and right-sided valvular heart disease. More than 90 percent of patients with carcinoid syndrome have metastatic disease, typically to the liver. Midgut NETs (ie, those arising in the appendix and small bowel) are more commonly associated with classic carcinoid syndrome than those that arise in the foregut or hindgut (table 3). However, the presence of carcinoid syndrome is relatively rare in patients with appendiceal NETs compared with those with small intestinal NETs [10-12], and it is generally indicative of metastatic disease. (See "Clinical characteristics of well-differentiated neuroendocrine (carcinoid) tumors arising in the gastrointestinal and genitourinary tracts" and "Clinical features of carcinoid syndrome".)

EPIDEMIOLOGY — Well-differentiated NETs are relatively rare tumors, but the incidence has been rising over time in the United States and elsewhere. As an example, in an analysis of 64,971 NETs reported to the Surveillance, Epidemiology, and End Results (SEER) registry, the age-adjusted incidence rate for all NETs rose from 1.09 to 6.98 per 100,000 between 1973 and 2012 [13]. The appendix accounts for between 16 and 38 percent of all NETs arising within the tubular intestinal tract; the majority arise in the small bowel [14,15]. (See "Clinical characteristics of well-differentiated neuroendocrine (carcinoid) tumors arising in the gastrointestinal and genitourinary tracts", section on 'Epidemiology'.)

The reported incidence of appendiceal NETs is 3 to 9 per 1000 appendectomies, accounting for approximately one NET in every 150 to 300 appendectomies [16-18]. However, the distribution of tumor types within the appendix might be changing over time:

●In some older reports, well-differentiated NETs accounted for over 50 percent of neoplasms arising in the appendix (table 4) [1,18].

●More recently, mucinous neoplasms seem to be more common:

•In a large series of appendiceal tumors derived from the SEER database of the National Cancer Institute (NCI) between 1973 and 2003, the most frequent histology was mucinous adenocarcinoma, followed by intestinal-type adenocarcinoma; NETs ("malignant carcinoids") comprised only 11 percent (table 5) [19].

•In another large contemporary surgical series, well-differentiated NETs accounted for 18 percent of the unexpected histopathologic findings in appendectomy specimens; low-grade mucinous neoplasms and simple mucoceles (also termed "retention cysts") accounted for nearly one-half of the cases [2].

Appendiceal NETs are detected most commonly in patients in their 40s, which is much younger than the average age for other primary malignant appendiceal neoplasms [16,20,21]. Epidemiologic studies show a slight but consistently higher incidence in women, although this association has in part been attributed to the greater frequency of incidental appendectomies in women who undergo pelvic surgery. (See "Clinical characteristics of well-differentiated neuroendocrine (carcinoid) tumors arising in the gastrointestinal and genitourinary tracts", section on 'Appendix'.)

CLINICAL PRESENTATION — The majority of appendiceal NETs are found incidentally at the time of appendectomy. Most are submucosal and located in the distal one-third of the appendix, where they are unlikely to cause obstruction (picture 2A-B) [1,22]. As a result, most patients are asymptomatic at presentation. Symptoms are more likely with large tumors and with metastases beyond the regional lymph nodes. Approximately 10 percent of appendiceal NETs are located at the base of the appendix, where they can cause obstruction leading to appendicitis [23].

The likelihood of regional and distant metastases at presentation is related to tumor size but is generally lower for appendiceal as compared with small intestinal NETs (table 6). In a more recent series of 902 well-differentiated NETs derived from the National Cancer Database (NCDB) that examined the relationship between tumor size and risk of metastases, nodal metastases were present at diagnosis in 12 percent of patients with tumors ≤2 cm and in 43 percent of those with larger tumors [4]. The corresponding rates for distant metastases were 0.8 and 4.1 percent for smaller and larger tumors, respectively. Higher rates of nodal involvement in patients with tumor size 1 to 2 cm are reported by others [17,24].

Distant metastases predominantly affect the liver [9]. Extrahepatic metastases are extremely uncommon [9,25,26]. Features of carcinoid syndrome may be present in patients with tumors that have metastasized to the liver.

STAGING AND PROGNOSIS — The 2010 American Joint Committee on Cancer (AJCC) staging manual contained a Tumor, Node, Metastasis (TNM) staging system for well-differentiated appendiceal NETs for the first time; the most recent version (eighth edition, 2017) is outlined in the table (table 7) [27]. Notably, goblet cell adenocarcinomas and high-grade neuroendocrine carcinomas are more aggressive than well-differentiated NETs and are classified and staged according to the criteria for appendiceal carcinomas. (See "Epithelial tumors of the appendix", section on 'Goblet cell adenocarcinoma'.)

Staging workup — A staging workup is advised for individuals with an appendiceal NET >2 cm, those with an incomplete resection (either a lack of nodes or a positive margin), and those with concern for distant metastases based on clinical symptoms. As noted above, the likelihood of regional and distant metastases is related to tumor size (table 6).

To assess possible liver involvement, consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) recommend a helical, contrast-enhanced, triple-phase computed tomography (CT) scan or magnetic resonance imaging (MRI) for individuals with an appendiceal NET >2 cm, those with an incomplete resection (nodes, margin), and those with concern for distant metastases [28]. Contrast-enhanced MRI is preferred by some physicians because of its greater sensitivity for liver metastases. (See "Diagnosis of carcinoid syndrome and tumor localization", section on 'Magnetic resonance imaging'.)

Somatostatin receptor-based diagnostic imaging (with indium-111 pentetreotide single-photon emission computed tomography [SPECT] imaging [OctreoScan] or gallium Ga-68 DOTATATE [or gallium Ga-68 DOTATOC or copper Cu-64 DOTATATE] integrated positron emission tomography [PET]/CT scanning) offers whole-body imaging and is the most sensitive imaging modality for diagnosis and staging of metastatic disease outside of the liver. Where available, PET/CT using one of the radiolabeled somatostatin analogs is preferred over OctreoScan because of greater sensitivity. (See "Diagnosis of carcinoid syndrome and tumor localization", section on 'Somatostatin receptor-based imaging' and "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring", section on 'Somatostatin receptor-based imaging techniques'.)

However, in general, somatostatin receptor-based diagnostic imaging is not necessary for most patients [12,29]. Consistent with guidelines from the European Neuroendocrine Tumor Society (ENETS), we restrict preoperative testing to patients with higher risk disease who have an increased likelihood of spread and to those with suspected metastatic disease and/or symptoms suggestive of carcinoid syndrome [12]. (See 'Carcinoid syndrome' above and "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring".)

Colonoscopy — A colonoscopy is reasonable, as approximately 20 percent of NETs are associated with a synchronous non-NET neoplasm [21,29], 25 to 50 percent of which are colorectal cancers [30,31]. Whether this is needed in very young patients with small well-differentiated appendiceal NETs is unclear.

Assay of tumor markers — Although some guidelines advocate baseline measurement of serum levels of chromogranin A (CgA) and measurement of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in a 24-hour urine collection [29], we do not routinely pursue this testing.

NETs have the capacity to produce and secrete a variety of bioactive amines and peptides. Elevated urinary levels of 5-HIAA are highly specific for serotonin-producing NETs (ie, those arising in the midgut), but they are not particularly sensitive, particularly for localized tumors. Twenty-four-hour urine 5-HIAA can be assessed if there is suspicion for carcinoid syndrome in the setting of advanced disease. (See "Overview of tumor biomarkers in gastroenteropancreatic neuroendocrine tumors", section on 'Serotonin and 5-hydroxyindoleacetic acid (5-HIAA)'.)

Chromogranin A (CgA) is a nonhormonal protein that is stored and released with peptides and amines in NETs. Because it does not rely on serotonin secretion, serum level of CgA may be a more sensitive marker than urinary 5-HIAA for gastroenteropancreatic NETs, including those arising in the appendix; however, it is less specific [32]. Elevated CgA levels are present in a number of other conditions (table 8), and specificity depends on the cutoff value. Despite a high volume of published studies evaluating CgA in NETs, guidelines have increasingly deemphasized the role of this biomarker in clinical care. (See "Overview of tumor biomarkers in gastroenteropancreatic neuroendocrine tumors", section on 'Role of nonhormonal tumor markers in clinical practice'.)

Prognosis — Clinical behavior and prognosis are best predicted by tumor size. Tumors <2 cm (found in approximately 95 percent of patients) are unlikely to have metastasized, while up to one-third of larger lesions are metastatic at diagnosis (but usually to regional nodes rather than the liver) (table 6) [23,33-35]. In one series of 150 patients with appendiceal NETs from the Mayo Clinic, none of the 127 patients with tumors <2 cm metastasized compared with 3 of 14 with tumors 2 to 3 cm and four of nine with tumors larger than 4 cm [33].

Outcome is stage dependent. (See 'Staging and prognosis' above.)

Prognosis was addressed in an analysis of 900 appendiceal NETs derived from the Surveillance, Epidemiology, and End Results (SEER) registry of the National Cancer Institute (NCI) [36]. Five-year appendiceal NET-specific survival rates were as follows:

●Tumor size <2 cm without regional nodal or distant metastases – 100 percent

●Tumor size ≥2 but <3 cm with regional nodal metastases, or tumor size ≥3 cm with or without regional nodal or distant metastases – 78 percent

●Distant metastatic spread – 32 percent

Impact of perforation — Appendiceal NETs are mostly found incidentally during surgery for appendicitis; perforation of the appendix occurs in 10 to 20 percent of such cases [19]. The best available evidence (which is limited) suggests that perforation has no influence on the prognosis of classical appendiceal NETs. In a literature review that identified 103 patients with a classical appendiceal NET and associated perforation, no peritoneal recurrence or death was described [37]. Thus, the presence of a perforation need not influence the treatment or posttreatment surveillance plan.

TREATMENT OF LOCALIZED DISEASE

Indications for hemicolectomy — The majority of patients will be diagnosed after a simple appendectomy. We suggest completion right hemicolectomy with lymph node retrieval along the ileocolic and right colic arteries for all patients with a tumor >2 cm and for smaller tumors between 1 and 2 cm in the presence of deep mesoappendiceal invasion (>3 mm), positive or unclear margins, a higher proliferative rate (grade ≥2 (table 1)), lymphovascular invasion, and mixed histology (goblet cell adenocarcinoma). For well-differentiated NETs less than 1 cm in size, and for those tumors between 1.0 and 1.9 cm in the absence of mesoappendiceal invasion, positive/unclear margins, a higher proliferative rate, angioinvasion, or mixed histology, simple appendectomy alone is adequate.

These recommendations are consistent with consensus-based guidelines from the North American Neuroendocrine Tumor Society (NANETS) and the European Neuroendocrine Tumor Society (ENETS) [12,38,39]. However, this is a controversial area, and others disagree, considering appendectomy alone to be adequate for all tumors <2 cm, even with mesoappendiceal invasion or other adverse histologic features [33,40,41]. A summary of recommendations from different expert groups for management of appendiceal neuroendocrine neoplasms according to size and other features is presented in the table (table 9). Links to additional society guidelines can be found elsewhere. (See 'Society guideline links' below.)

The optimal surgical management for appendiceal NETs is subject to some debate. Because most are discovered incidentally in an appendectomy specimen done for other reasons, a decision must be made whether or not to return the patient to the operating room for a right hemicolectomy. Unlike simple appendectomy, colectomy removes the draining lymph nodes of the appendix and any residual disease that might remain at the base of the appendix or in the mesoappendix.

Data from the large Mayo Clinic series cited above suggest that tumor size is an important determinant of the need for further surgery [33]. None of the 120 patients with tumors less than 2 cm developed disease recurrence after simple appendectomy compared with 1 of 12 with a larger tumor. Furthermore, in a compilation of reports from single centers and large population and literature surveys, the risk of nodal metastases at diagnosis was 0, 7.5, and 33 percent for patients with appendiceal NETs <1, 1 to 1.9, and >2 cm, respectively (table 6) [35].

In addition to tumor size, other studies suggest that lymphovascular and perineural invasion are also risk factors for nodal metastases [24,42].

These data, taken together with the fact that as many as 88 percent of those with regional nodal metastases survive for five years or longer, support the view that patients with tumors >2 cm in size should undergo right colectomy.

On the other hand, whether or not a colectomy should be performed in some patients with smaller (<2 cm) tumors is unclear; the available data are conflicting:

●Although the Mayo Clinic series suggested that appendectomy is sufficient in such cases [33], at least two older reports demonstrate a higher potential for metastatic spread with small tumors in the setting of mesoappendiceal invasion [43,44].

●A review of the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute (NCI) reported much higher rates of lymph node metastases than previously appreciated for tumors <2 cm [17]. Among patients reported to the database between 1988 and 2003, lymph node metastases were found in 15 percent (4 of 27) of patients with appendiceal NETs less than 1 cm and in 47 percent (16 of 34) of those with NETs between 1.0 and 1.9 cm. The 10-year survival rates in these two groups were 100 and 92 percent, respectively, while it was 91 percent in patients with NETs >2 cm, despite the fact that 86 percent of them had lymph node metastases. Whether these excellent outcomes reflected favorable biology or the impact of surgical removal of nodal metastases is unclear.

●A second SEER-based series of 573 patients with well-differentiated appendiceal NETs reported to the registry between 1988 and 2013 reported a 31 percent probability of nodal metastases in tumors 1.1 to 2 cm and a 64 percent probability in tumors >2 cm [45]. The analysis also indicated the prognostic importance of the number of nodes evaluated; among those with tumors >1 cm, five-year overall survival rates were worse when 12 or fewer lymph nodes were identified (five-year survival 88 versus 96 percent).

●On the other hand, benefit for completion right hemicolectomy could not be shown in a series from the National Cancer Database (NCDB) specifically addressing management of 1 to 2 cm appendiceal NETs [40]. Of the 916 patients reported to the database between 1998 and 2011 who had appendiceal NETs between 1 and 2 cm, 42 percent were managed with primary resection, and 58 percent were managed with a right hemicolectomy. Formal resection of the right colon did not appear to improve survival (five-year survival 88.7 versus 87.4 percent), even for higher grade and higher stage tumors. Among those undergoing a right hemicolectomy, 28 percent had positive nodes. Other observational studies have demonstrated similar results [41].

A nomogram has been developed to predict the risk of nodal metastases based on tumor size and depth of invasion; however, there is no agreement as to what level of risk would warrant a right hemicolectomy [46].

Evaluating for synchronous colorectal cancers — If a right hemicolectomy is pursued, prior to the procedure, a full colonoscopy could be undertaken to rule out a synchronous colon cancer. However, whether this is needed in a young person with a small well-differentiated appendiceal NET is unclear.

The surgeon should also perform a complete inspection of the bowel intraoperatively since up to 25 percent of midgut NETs (small bowel, proximal colon) may be multifocal and are sometimes associated with malignant gastrointestinal tumors of other histologic types [47,48].

POSTTREATMENT FOLLOW-UP — There are no randomized trial data or evidence-based guidelines for follow-up after resection of a gastrointestinal NET at any site. Recommendations are generally based on risk and anticipated patterns of recurrence based on the primary tumor characteristics. Various organizations have put forth recommendations for follow-up surveillance after resection:

●The consensus-based recommendations from the National Comprehensive Cancer Network (NCCN) are based on tumor size [28]. Patients with tumors <2 cm do not require routine surveillance, and tests should only be ordered as clinically indicated. For tumors >2 cm, a history and physical examination and abdominal/pelvic imaging are recommended between 3 and 12 months after resection, and consideration of tumor markers (5-hydroxyindoleacetic acid [5-HIAA], chromogranin) as clinically indicated; after the first year, a history and physical examination and abdominal/pelvic imaging are recommended every 12 to 24 months. Beyond 10 years, surveillance is recommended as clinically indicated.

●The North American Neuroendocrine Tumor Society (NANETS) has similar recommendations to the NCCN, with the exception that tumors <1 cm do not generally require further surveillance, but tumors between 1 and 2 cm with poor prognostic features (nodal metastases, lymphovascular invasion, mesoappendiceal invasion, intermediate- or high-grade or mixed histology) should trigger surveillance similar to that for tumors >2 cm, with a history and physical examination, consideration of tumor markers (5-HIAA and chromogranin), and consideration of CT or MRI within three to six months of surgery and subsequently every 6 to 12 months for at least seven years after surgery [38].

●The European Neuroendocrine Tumor Society (ENETS) recommends no specific follow-up strategy in cases of curative resection for appendiceal neuroendocrine neoplasms <1 and for those tumors >1 cm that are treated with right hemicolectomy without proof of lymph node involvement [12]. Long-term follow-up is recommended in cases with involvement of lymph nodes or resected distant metastases. Regular follow-up is also advised for patients who have not undergone hemicolectomy and have tumors >1 cm with risk factors (including location at the base of the appendix, deep mesoappendiceal invasion, intermediate-grade histology, and vascular invasion).

In our practice, we generally recommend the following:

●For appendiceal NETs ≤2 cm without high-risk features (nodal metastases, lymphovascular invasion, mesoappendiceal invasion, intermediate- or high-grade or mixed histology) that are confined to the appendix and treated with simple appendectomy, we do not recommend routine follow-up.

●For larger or node-positive tumors treated with right hemicolectomy, between 3 and 12 months postresection, we perform a history and physical examination and perform CT or MRI imaging. The value of tumor markers, including chromogranin A, to aid in early detection of recurrence has not been established, and we do not routinely obtain these biomarkers for surveillance.

Beyond one year postresection, we perform a history and physical examination every 6 to 12 months and cross-sectional imaging studies annually. We do not generally include somatostatin receptor-based imaging in the posttreatment follow-up strategy, but this could be considered as a baseline assessment in a patient with high-risk features if it was not done preoperatively [49].

The optimal duration of follow-up is not established. Most guidelines, including those of the NCCN and NANETS [28,50], suggest 10 years of follow-up.

TREATMENT OF METASTATIC DISEASE — For patients who have somatostatin receptor-positive disease (as determined by somatostatin receptor-based diagnostic imaging), symptoms of carcinoid syndrome can often be well controlled with long-acting somatostatin analogs. Although few patients have objective tumor regression, somatostatin analogs prolong the time to disease progression and overall survival in asymptomatic patients. (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Somatostatin analogs'.)

Liver resection for selected patients may be beneficial, particularly for symptom relief. If liver resection is not feasible, then hepatic artery embolization can be considered. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Surgical resection' and "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Hepatic arterial embolization'.)

The best systemic therapy option for patients with progressive metastatic gastrointestinal NETs that are not amenable to local ablative therapies or resection is not established.

For patients with somatostatin receptor-positive tumors (as determined by somatostatin receptor-based diagnostic imaging), treatment with peptide receptor radioligand therapy (PRRT) using radiolabeled somatostatin analogs (eg, lutetium Lu-177 dotatate [¹⁷⁷Lu-Dotatate]) is an option. Everolimus can also be considered for patients with progression following somatostatin analog therapy who are not candidates for PRRT. (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Radiolabeled somatostatin analogs' and "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Everolimus'.)

The role of cytotoxic chemotherapy for midgut NET continues to be debated. The management of metastatic gastrointestinal NETs is discussed in detail elsewhere. (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Well-differentiated gastroenteropancreatic neuroendocrine tumors".)

SUMMARY AND RECOMMENDATIONS

●Terminology and classification

•Neoplasms arising in the appendix are divided into epithelial neoplasms (which include invasive adenocarcinomas, low-grade appendiceal mucinous neoplasms, and goblet cell adenocarcinomas) and neuroendocrine neoplasms (which include well-differentiated neuroendocrine tumors [NETs], neuroendocrine carcinomas [large cell and small cell types], and mixed neuroendocrine-non-neuroendocrine neoplasms [MiNEN]). MiNEN typically show a combination of neuroendocrine carcinoma and adenocarcinoma, and these tumors are treated like high-grade neuroendocrine carcinomas.

Among neuroendocrine neoplasms, histologic grade and differentiation correlate closely with clinical behavior (table 1). The majority (70 to 75 percent) of neuroendocrine neoplasms arising in the appendix are well-differentiated, grade 1 or 2 NETs. (See 'Terminology and classification' above.)

●Epidemiology and clinical presentation

•The majority of appendiceal NETs are asymptomatic and found incidentally at the time of appendectomy. The reported incidence of appendiceal NETs is 3 to 9 per 1000 appendectomies, accounting for approximately one NET in every 150 to 300 appendectomies. (See 'Epidemiology' above.)

•NETs arising in the appendix can secrete serotonin and other vasoactive substances, which cause carcinoid syndrome, characterized by episodic flushing, wheezing, and diarrhea. Carcinoid syndrome is relatively rare in patients with appendiceal NETs, and it generally indicates the presence of metastatic disease, typically to the liver. (See 'Carcinoid syndrome' above.)

●Staging and prognosis

•A preoperative staging workup is advised for individuals with tumor size >2 cm, those with an incomplete resection at the time of simple appendectomy (either a lack of nodes or a positive margin), and those with concern for distant metastases based on clinical symptoms. To assess for liver involvement, the staging workup should include a helical, contrast-enhanced, triple-phase CT scan or MRI. Contrast-enhanced MRI is preferred by some physicians because of its greater sensitivity for liver metastases. (See 'Staging workup' above.)

•Somatostatin receptor-based diagnostic imaging is not necessary for most patients. We obtain testing in the preoperative situation for individuals with higher-risk disease and for those with suspected metastatic disease or symptoms suggestive of carcinoid syndrome.

●Treatment of localized disease and prognosis

•For well-differentiated NETs discovered at the time of simple appendectomy, we suggest reoperation with a right hemicolectomy with lymph node retrieval along the ileocolic and right colic arteries for tumors larger than 2 cm, and for tumors between 1 and 1.9 cm with deep mesoappendiceal (>3 mm) or lymphovascular invasion, positive or uncertain margins, or mixed histology (eg, goblet cell adenocarcinoma) (Grade 2C).

Simple appendectomy alone is sufficient for tumors <1.0 cm in the absence of mesoappendiceal invasion, and for tumors 1 to 1.9 cm that lack mesoappendiceal invasion and other adverse histologic features. (See 'Terminology and classification' above.)

•Most patients have localized disease, and the prognosis is excellent. (See 'Prognosis' above.)

•Following treatment, we follow the National Comprehensive Cancer Network (NCCN) guidelines for posttreatment surveillance (see 'Posttreatment follow-up' above):

-For appendiceal NETs ≤2 cm confined to the appendix and treated with simple appendectomy, no follow-up is required.

-For larger or node-positive tumors treated with right hemicolectomy, between 3 and 12 months postresection, we perform a history and physical examination and CT imaging of the abdomen/pelvis. Tumor markers, including chromogranin A, are not routinely obtained because their value in early detection of recurrence has not been established.

-Between 1 to 10 years post resection, we perform a history and physical examination and radiographic imaging studies every one to two years.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Jeffrey A Meyerhardt, MD, MPH, and Richard Swanson, MD, who contributed to earlier versions of this topic review.