Version May 2024
INTRODUCTION — The term "neuroendocrine tumor (NET)" refers to well-differentiated neuroendocrine neoplasms, and "neuroendocrine carcinoma (NEC)" refers to poorly differentiated neuroendocrine cancers. The term "carcinoid" has been generally applied to well-differentiated neuroendocrine tumors (NETs) originating in the digestive tract, lungs, or rare primary sites such as the kidneys or ovaries. (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on 'Pathology, tumor classification, and nomenclature' and "High-grade gastroenteropancreatic neuroendocrine neoplasms".)
"Carcinoid syndrome" is the term applied to a constellation of symptoms mediated by various humoral factors that are elaborated by some NETs (table 1) [1]. Two of the most common manifestations are flushing and diarrhea (table 2). (See "Clinical features of carcinoid syndrome".)
Most NETs are associated with carcinoid syndrome only when they have metastasized to the liver (table 3).
In general, the basic principles of evaluation and management of patients with NETs include:
●Radiographic staging and tumor localization – Common imaging modalities include computed tomography (CT) or magnetic resonance imaging (MRI) scans as well as somatostatin receptor-based diagnostic imaging (Indium-111 pentetreotide imaging [OctreoScan] or gallium Ga-68 DOTATATE (or gallium Ga-68 DOTATOC or copper Cu-64 DOTATATE) integrated positron emission tomography [PET]/CT scanning). Where available, integrated PET/CT using one of the radiolabeled somatostatin analogs is preferred over OctreoScan because of greater sensitivity.
Upper and lower endoscopy (with attention to the terminal ileum) should be performed for the evaluation of metastatic NET with an unknown primary site. CT enterography can also be used for this purpose. While video capsule endoscopy allows for evaluation of the entire small intestine, routine use of capsule endoscopy cannot be recommended due to the risk of bowel obstruction from retention of the capsule at the site of an intestinal NET. (See "Neuroendocrine neoplasms of unknown primary site", section on 'Well-differentiated neuroendocrine tumor'.)
Mesenteric masses are usually indicative of a primary tumor located in the small intestine. Radiographic staging and tumor localization of NETs is addressed in detail elsewhere. (See "Diagnosis of carcinoid syndrome and tumor localization".)
●Pathologic assessment of tumor differentiation and/or grade (assessment of mitotic rate and/or Ki-67 index, presence/absence of necrosis and pleomorphism) – This subject is addressed in detail elsewhere. (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on 'Pathology, tumor classification, and nomenclature'.)
●Removal of the tumor if all disease is surgically resectable, even if liver metastases are present. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Surgical resection'.)
●Control of carcinoid symptoms, if present. (See "Treatment of the carcinoid syndrome".)
●Judicious use of antitumor therapy for unresectable metastatic disease – One of the key principles underlying selection of appropriate therapy for advanced disease is the indolent nature of most well-differentiated NETs and their prolonged natural history; this must be weighed against the toxicity of available antitumor regimens.
This topic review will provide an overview of treatment of localized NETs, focusing on treatment of digestive tract primary sites. Antitumor treatment, prognosis and biochemical monitoring of patients with advanced or metastatic disease, diagnosis and treatment of the carcinoid syndrome, radiologic staging, tumor localization and histologic assessment of gastroenteropancreatic NETs, management of bronchial and thymic NETs, and evaluation and management of high-grade neuroendocrine carcinomas are discussed in detail elsewhere.
●(See "Diagnosis of carcinoid syndrome and tumor localization".)
●(See "Treatment of the carcinoid syndrome".)
●(See "Diagnosis of carcinoid syndrome and tumor localization".)
●(See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system".)
●(See "Thymic neuroendocrine (carcinoid) tumors".)
●(See "High-grade gastroenteropancreatic neuroendocrine neoplasms".)
STAGING AND TREATMENT OF LOCALIZED TUMORS — The treatment of choice for a patient who has a localized well-differentiated neuroendocrine tumor (NET) is usually surgery. The extent of the surgical resection depends on the site of origin and size of the primary tumor. A detailed discussion of the clinical presentation of NETs arising in specific organs is available elsewhere. (See "Clinical characteristics of well-differentiated neuroendocrine (carcinoid) tumors arising in the gastrointestinal and genitourinary tracts".)
Staging studies — Multiphasic contrast-enhanced CT is recommended for evaluation of all patients with NETs, with the exception of tumors with very low probability of spread, such as most type 1 gastric NETs, or small (<1 cm) superficial (T1) rectal NETs. (See "Diagnosis of carcinoid syndrome and tumor localization", section on 'Tumor localization and staging'.)
The utility of other studies, including MRI, somatostatin receptor-based diagnostic imaging with either indium-111 pentetreotide scanning (OctreoScan) or integrated positron emission tomography (PET)/CT using gallium Ga-68 DOTATATE or gallium Ga-68 DOTATOC or copper Cu-64 DOTATATE, and biochemical markers, such as chromogranin A and urinary 5-hydroxyindoleacetic acid (5-HIAA), are discussed in detail elsewhere. (See "Diagnosis of carcinoid syndrome and tumor localization" and "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring" and "Diagnosis and staging of small bowel neoplasms", section on 'Neuroendocrine tumors' and "Overview of tumor biomarkers in gastroenteropancreatic neuroendocrine tumors".)
Treatment
Appendix — The prognosis of appendiceal NETs is best predicted by tumor size. In many series, tumors less than 2 cm in diameter (found in approximately 95 percent of patients) have a low likelihood of metastases at diagnosis (table 4). In contrast, up to 30 percent of larger tumors have already metastasized at diagnosis, mostly to regional nodes. (See "Well-differentiated neuroendocrine tumors of the appendix", section on 'Clinical presentation'.)
The current Tumor, Node, Metastasis (TNM) staging system (eighth edition, 2017) for appendiceal NETs is distinct from the TNM staging system for NETs arising at other sites within the gastrointestinal tract and lung (table 5) [2]. (See "Well-differentiated neuroendocrine tumors of the appendix", section on 'Staging and prognosis'.)
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 colectomy. 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.
Because of the association of tumor size with prognosis, a right hemicolectomy has been traditionally recommended for tumors greater than 2 cm or those with mesoappendiceal invasion [3]. On the other hand, whether or not a colectomy should be performed in some patients with smaller tumors is unclear; there is limited evidence on which to base clear indications for hemicolectomy. Some clinicians pursue completion right colectomy for tumors <2 cm only if there is evidence of mesoappendiceal invasion or positive or unclear margins, while others disagree and consider that appendectomy alone is adequate for tumors <2 cm, even with mesoappendiceal invasion. There is general agreement that tumors less than 1 cm can usually be treated by simple appendectomy [3].
These issues are discussed in more detail elsewhere. (See "Well-differentiated neuroendocrine tumors of the appendix", section on 'Treatment of localized disease'.)
Small intestine — The current (eighth edition, 2017) TNM staging system from the combined American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) has separate TNM classifications and prognostic stage groupings for jejunoileal (table 6) [4] and duodenal/ampullary tumors (table 7) [5]. (See "Epidemiology, clinical features, and types of small bowel neoplasms", section on 'Well-differentiated gastrointestinal neuroendocrine tumors'.)
NETs of the small intestine are most commonly found in the ileum within 60 cm of the ileocecal valve. All small intestinal NETs have the potential to metastasize, irrespective of size (table 4).
Because of this, in our view, and that of others [3], patients with non-metastatic tumors of any size should be treated with wide local excision that includes resection of the involved segment and small bowel mesentery. (See "Treatment of small bowel neoplasms", section on 'Neuroendocrine tumors'.).
Because multiple NETs are present in approximately 25 to 55 percent of cases, the remainder of the small bowel should be examined at the time of surgery [6,7]. Although this is a controversial area, resection of the primary tumor may be advised even in patients with known distant metastases in order to reduce the potential for bowel obstruction or bleeding, or to palliate abdominal pain related to the primary tumor; some reports note a beneficial impact on overall survival as well. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Management of the primary tumor in patients with metastatic disease'.)
The prognosis depends upon disease stage [8]. (See 'Stage and site of origin' below.)
However, even among patients with distant metastasis, five-year overall survival rates range from 40 to 85 percent; 10-year survival rates of 40 to 60 percent are reported [8-12]. Ten-year disease-specific survival rates stratified according to the 2010 AJCC/UICC stage groupings from a series of 6792 patients with small intestine NETs diagnosed between 1988 and 2009 derived from the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) registry were as follows [12]:
●Stage I – 95 percent (95% CI 93-97 percent)
●Stage IIA – 95 percent (95% CI 90-96 percent)
●Stage IIB – 77 percent (95% CI 71-83 percent)
●Stage IIIA – 68 percent (95% CI 58-77 percent)
●Stage IIIB – 77 percent (95% CI 74-80 percent)
●Stage IV – 42 percent (95% CI 38-46 percent)
Limited data are available that stratify prognosis according to the most recent eighth edition classification, which separates jejunoileal and duodenal/ampullary tumors and condenses stages I to IV disease (eliminating the A and B substages) (figure 1) [2].
Prognosis among surgically treated patients also depends on margin status [11,13]. (See 'Residual disease' below.)
Ampulla of Vater — Ampullary NETs are rare. The most recent TNM classification (eighth edition, 2017) has a distinct staging system for duodenal and ampullary NETs that is separate from that used for jejunoileal primary sites (table 7) [5].
There is a high likelihood of nodal metastases with ampullary NETs, even with tumor size <2 cm [14-17]. Pancreaticoduodenectomy has been advocated for resectable cases regardless of size due to relatively high risk of occult nodal metastases. However, these recommendations are based on very small case series, and treatment decisions may need to be individualized based on precise location of tumors, histologic grade, depth of invasion, and patient suitability for aggressive surgery.
Rectum — Most rectal NETs are small, localized, and mucosal or submucosal in location [18,19]. As with rectal adenocarcinomas, transrectal endoscopic ultrasound (TEUS) is often useful for assessment of tumor size, depth of invasion, and lymph node involvement in rectal NETs [20,21]. (See "Clinical characteristics of well-differentiated neuroendocrine (carcinoid) tumors arising in the gastrointestinal and genitourinary tracts", section on 'Rectum' and "Endoscopic ultrasound for evaluating patients with rectal cancer".)
The current (eighth edition, 2017) TNM staging system used for NETs of the colon and rectum is outlined in the table (table 8) [22]. While many small rectal NETs exhibit indolent behavior, certain risk factors predict for metastases. Traditionally, tumor size and depth of invasion (T stage) have been the main determinants of prognosis:
●According to one report [23], metastases were found in 2 percent of patients with tumors <1 cm, 10 to 15 percent in patients with tumors measuring 1.0 to 1.9 cm, and 60 to 80 percent in tumors measuring >2 cm.
●Another report [24] indicated that in tumors <2 cm, the rate of metastasis was 2 percent of patients if the tumor was confined to the submucosa, but as high as 48 percent if the tumor invaded the muscularis propria.
●More recent reports [25,26] have identified additional prognostic factors, including mitotic index and lymphovascular invasion (LVI), which could portend a poorer prognosis even among patients with relatively small (<2 cm) and superficial tumors [27].
Observation alone results in inferior outcomes, even for small tumors <1 cm [28]. Treatment options for localized rectal NETs include conventional endoscopic resection (standard polypectomy or endoscopic mucosal resection [EMR]), advanced endoscopic resection (endoscopic submucosal dissection, transanal endoscopic microsurgery [TEM], cap-assisted EMR), transanal surgical resection, or radical resection (low anterior resection [LAR], abdominoperineal resection [APR]). Decisions about technique should be based on tumor size and other risk factors for nodal metastases:
●Tumors smaller than 1 cm and confined to the mucosa or submucosa (T1) can generally be treated by standard endoscopic resection [18,23,29-32], particularly if they lack other risk factors (ie, mitotic rate >2 per 10 high-power fields [HPF] or LVI). A greater likelihood of negative resection margins may be achievable with more advanced endoscopic techniques including endoscopic submucosal dissection [33,34] and cap-assisted EMR (in which the tumor is suctioned into a cap and then removed with a snare) [35]. However it is unclear whether negative margins are necessary given the excellent outcome of patients with low-grade T1 tumors, even with positive or indeterminant margins [32].
●Large tumors (>2 cm) or those that invade the muscularis propria (≥T2) are generally treated with radical surgical resection (LAR or APR) [36]. This approach is endorsed by consensus-based guidelines from the National Comprehensive Cancer Network and the European Neuroendocrine Tumor Society [37,38]. Although some data suggest that local excision may be a viable alternative for some subgroups of patients with lower-risk rectal neuroendocrine tumors >2 cm, the optimal way to select these patients is not established, and we do not endorse this approach unless patients refuse radical resection [39].
●The management of intermediate-sized tumors (1 to 2 cm confined to mucosa or submucosa) is somewhat controversial. Transanal resection or advanced endoscopic resection techniques (such as TEM) may be appropriate for tumors lacking risk factors, whereas radical resection may be more appropriate for tumors with risk factors such as elevated mitotic rate (or Ki-67 index), LVI, or size >1.5 cm [25,40].
For well-differentiated NETs, prognosis is mainly dependent on tumor size and depth of invasion, as reflected by the T-stage classification [10]. Prognosis stratified according to disease stage is available from the following reports:
●In a SEER database series, the five-year survival rates for localized, regional, or distant disease involving the rectum or rectosigmoid junction over the last decade were 90, 49, and 26 percent, respectively [41].
●In another report of 258 well-differentiated rectal NETs reported to the National Cancer Database between 1998 and 2002 that were stratified according to stage, five-year overall survival rates were 92, 88, 59, and 15 percent for stage I, II, III, and IV disease, respectively [42].
●Similarly, in a series of 122 Korean patients treated for rectal NET between 1995 and 2010, and staged according to the seventh edition AJCC staging system, five-year survival rates were 100, 80, 51, and 0 percent for stage I, II, III, and IV disease, respectively [43].
Prognosis is significantly worse for high grade neuroendocrine carcinomas [27]. (See "High-grade gastroenteropancreatic neuroendocrine neoplasms".)
Colon — Colonic NETs are staged similarly to rectal NETs. (See 'Rectum' above.)
Colonic NETs tend to be more aggressive than those arising in the rectum. In one large series derived from the SEER database, five-year survival rates were only 62 percent across all stages (compared with 88 percent for rectal NETs) [41]. In a dataset of 5457 colorectal NETs reported to the National Cancer Database between 1998 and 2002, compared with rectal primaries, a colonic primary site was associated with significantly poorer overall survival (hazard ratio [HR] for death 1.85, 95% CI 1.61-2.13) [42].
Well-differentiated colonic NETs have the worst prognosis of any gastrointestinal tract well-differentiated NET [30,41,44,45]. One reason for more aggressive behavior may be that colonic NETs are frequently right sided and may be clinically occult until locally advanced; approximately two-thirds have evidence of nodal or distant metastases at the time of diagnosis [46,47]. (See "Clinical characteristics of well-differentiated neuroendocrine (carcinoid) tumors arising in the gastrointestinal and genitourinary tracts", section on 'Colon'.)
Given that most tumors are >2 cm and/or invasive through the muscularis propria, patients with non-metastatic well-differentiated NETs of the colon should be managed with formal partial colectomy and regional lymphadenectomy, similar to treatment of colonic adenocarcinomas [30]. (See "Overview of the management of primary colon cancer", section on 'Surgical resection' and "Surgical resection of primary colon cancer".)
Prognosis is dependent on stage (table 8) [10]. Five-year overall survival for a series of 882 well-differentiated colonic NETs reported to the National Cancer Database between 1998 and 2002 and stratified according to AJCC stage were 86, 79, 65, and 27 percent for stage I, II, III, and IV disease, respectively [42].
Prognosis is significantly worse for high-grade neuroendocrine carcinomas. (See "High-grade gastroenteropancreatic neuroendocrine neoplasms".)
Stomach — Gastric NETs are subdivided into three categories, with differing biologic behavior and prognoses:
●Type 1 gastric NETs, which represent 70 to 80 percent of all gastric NETs, are associated with chronic atrophic gastritis. In this condition, serum gastrin rises in response to gastric achlorhydria. The elevated gastrin, in turn, stimulates neuroendocrine cell hyperplasia in the stomach and development of multifocal polypoid NETs. The clinical behavior of these tumors is usually indolent. Most are grade 1 tumors with stage I (superficially invasive and/or <1 cm in diameter) disease and no mortality with prolonged follow-up [48-50].
●Type 2 gastric NETs, which represent approximately 5 percent of gastric NETs, also occur as a result of elevated serum gastrin levels stimulating multifocal gastric NETs. The underlying cause of type 2 gastric NETs is a pancreatic or duodenal gastrinoma (Zollinger-Ellison syndrome). The clinical behavior is usually indolent.
●Type 3 (sporadic) gastric NETs occur in the absence of atrophic gastritis or the Zollinger-Ellison syndrome. They account for 20 percent of gastric NETs and are the most aggressive; local or hepatic metastases are present in up to 65 percent of patients who come to resection.
Definitions and a more complete discussion of characteristics of the different types of gastric NETs are discussed elsewhere. (See "Clinical characteristics of well-differentiated neuroendocrine (carcinoid) tumors arising in the gastrointestinal and genitourinary tracts", section on 'Stomach'.)
The current (eighth edition, 2017) staging system is depicted in the table (table 9) [51].
Management depends on the type of gastric NET:
●Type 3 (sporadic) gastric NETs are generally treated by partial or total gastrectomy with local lymph node resection [52-54]. The risk of nodal metastases is dependent on tumor size and depth. Some have suggested that endoscopic resection alone may represent adequate therapy for tumors <1 cm invading the lamina propria or submucosa only [50,55], while others suggest wedge resection or endoscopic therapy alone only for those with a well-differentiated (grade 1) gastric NET no larger than 1.5 cm and without lymphovascular invasion [56]. However, this is not a standard approach, and we generally advocate gastrectomy/lymphadenectomy for all type 3 tumors, regardless of size and histologic differentiation.
For type 1 and 2 gastric NETs smaller than 1 to 2 cm, endoscopic resection represents adequate therapy [49,57,58]. Subsequent endoscopic surveillance is needed every 6 to 12 months since these patients continue to exhibit mucosal changes and hyperplasia of enterochromaffin-like cells (ECL) due to sustained hypergastrinemia. (See 'Post-treatment follow-up' below.)
Progression to a malignant phenotype or disease-related death is rare with small tumors [59]. Metastases occur in less than 10 percent of tumors ≤2 cm [60].
Antrectomy is a controversial option for type 1 gastric NETs if there are numerous progressive tumors. Antrectomy reduces hypergastrinemia by reducing the gastrin-producing cell mass in the antrum of the stomach; in most cases, this leads to tumor regression [57,61-64]. This approach was used in a series of 51 patients with type I gastric NETs, 10 of whom had antrectomy (eight in conjunction with endoscopic removal of the largest tumor) [57]. Seven of the eight with residual disease became endoscopically tumor-free, and one progressed and died of metastatic disease. In all, 9 of the 10 patients treated with antrectomy remained tumor free for an average of 65 months.
●More aggressive surgical therapy is rarely needed for type 1 gastric NETs unless there is extensive tumor involvement of the gastric wall (which increases the risk for a coexisting adenocarcinoma [65]), tumor size >2 cm (which increases the risk for metastases [60]), poorly differentiated histology, or emergent bleeding [66].
The role of medical rather than surgical therapy (anti-gastrin maneuvers such as acidification by diet or dilute oral hydrochloric acid, or somatostatin analog therapy) for type 1 tumors is debated [52,63,67,68]. Gastrin levels may or may not decrease, and continued endoscopic surveillance is necessary.
Lung — The preferred treatment for bronchial NETs is surgical resection. The clinical features, diagnosis, and treatment of bronchial NETs are discussed separately. (See "Lung neuroendocrine (carcinoid) tumors: Epidemiology, risk factors, classification, histology, diagnosis, and staging".)
POST-TREATMENT FOLLOW-UP — There is limited evidence from which to make recommendations for follow-up after resection of a well-differentiated neuroendocrine tumor (NET). For all resected well-differentiated small intestinal and colonic NETs and for rectal, gastric, and appendiceal NETs >2 cm, in our practice we focus on long-term (rather than frequent) surveillance given the fact that distant relapses can occur beyond five years after surgery, particularly with small bowel primary tumors. As an example, in one study of 129 midgut NETs, there was a fairly steady annual rate of recurrence for the first eight years after surgery, followed by a decline in risk of recurrence after eight years [69]. For patients with resected small intestinal NETs, we generally recommend surveillance with triple-phase CT scans or MRI of the abdomen and pelvis every six months for the first year after surgery, then roughly annually for approximately 10 years after surgery [70]. For surveillance of NETs at other sites, we generally follow a similar strategy; however, more frequent surveillance can be considered for more aggressive tumors, such as grade 2, lymph node positive, gastric or rectal NETs. We do not recommend post-treatment surveillance for low-grade appendiceal tumors <2 cm and superficial low-grade rectal tumors <1 cm in size given the exceptionally low risks of recurrence.
The role of nonhormonal biomarkers such as chromogranin A (CgA) in surveillance is controversial as the contribution to detection of recurrent disease is limited [69,71]. Furthermore, specificity is limited as a number of conditions and medications (especially proton pump inhibitors) can falsely elevate the CgA (table 10). Consensus-based guidelines have increasingly deemphasized the role of CgA in clinical care. (See "Overview of tumor biomarkers in gastroenteropancreatic neuroendocrine tumors", section on 'Role of nonhormonal tumor markers in clinical practice'.)
In general, 24-hour measurements of urinary 5-hydroxyindoleacetic acid (5-HIAA) are not recommended for postoperative surveillance of tumors that are unlikely to produce serotonin (ie, well-differentiated NETs of the hindgut [distal colon and rectum], or foregut [lungs, stomach, duodenum]). If serial assay of 24-hour urinary 5-HIAA is performed for the rare localized midgut tumor that was initially associated with a significant elevation in 5-HIAA, measurement requires strict adherence to dietary restrictions before and during urine collection. (See "Overview of tumor biomarkers in gastroenteropancreatic neuroendocrine tumors", section on 'Serotonin and 5-hydroxyindoleacetic acid (5-HIAA)'.)
Recommendations from expert groups — Our recommendations are consistent with those of the National Comprehensive Cancer Network (NCCN) [72], which are relatively non-specific after treatment of all resected small intestinal and colonic NETs and for rectal, gastric, and appendiceal NETs >2 cm:
●3 to 12 months postresection: Abdominal or abdominopelvic multiphasic CT or MRI scan for gastrointestinal NETs, chest CT with or without contrast for lung/thymus NETs. Assay of biochemical markers as clinically indicated.
●>1 year postresection: Every 12 to 24 months abdominal or abdominopelvic multiphasic CT or MRI scan for gastrointestinal NETs, chest CT with or without contrast for lung/thymus NETs. Assay of biochemical markers as clinically indicated.
●>10 years postresection: Continue surveillance as clinically indicated.
These recommendations are particularly applicable for low and low-intermediate grade tumors (ie, ki-67 <10 percent). More frequent surveillance and scan intervals may be appropriate for higher-grade NETs and particularly grade 3 NETs, particularly during the first two to three years after surgery.
Post-treatment surveillance is not recommended by the NCCN [72] for appendiceal tumors <2 cm and rectal tumors <1 cm in size given the exceptionally low risks of recurrence. For T1 rectal tumors 1 to 2 cm in size, the only surveillance recommended is endorectal ultrasound or rectal MRI at 6 and 12 months. We agree with this position. (See "Well-differentiated neuroendocrine tumors of the appendix", section on 'Posttreatment follow-up'.)
The NCCN [72] guidelines for post-treatment surveillance of type I gastric NETs ≤2 cm include esophagogastroduodenoscopy (EGD) every one to two years. Routine imaging studies are not recommended. We agree with this position.
Consensus-based follow-up guidelines are also available from a number of other groups including the Commonwealth Neuroendocrine Tumour Collaboration (CommNETs) [73], European Society for Medical Oncology (ESMO) [74], European Neuroendocrine Tumor Society (ENETs) [75,76] and North American Neuroendocrine Tumor Society (NANETS) [70,77]. These recommendations, which are largely random and not based on analysis of any published data, are compared with those of the NCCN in the table (table 11).
PROGNOSIS AND PROGNOSTIC FACTORS — Prognosis depends primarily on tumor stage, margin status, histologic grade/differentiation, and site of origin.
Stage and site of origin — The prognostic validity of tumor stage for well-differentiated neuroendocrine tumors (NETs) of the gastrointestinal tract is supported by several studies [10,12,13,78,79]. However, at least some data suggest that there are no significant differences in outcomes between stage I and IIA midgut (jejunal and ileocecal) NETs (10-year overall survival 95 percent for both [12]), and heterogeneous outcomes in patients with stage IIIB (node positive) disease depending on whether disease was resected (five-year overall survival 95 percent) or unresectable (five-year overall survival 78 percent) [13]. (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on 'Staging system'.)
The impact of stage on 5-, 10-, and 15-year outcomes can be illustrated by the results of a Swedish series of 135 surgically managed small intestine NETs (table 12) [11].
Site also determines prognosis. As a general principle, well-differentiated NETs originating in the midgut (small intestine, proximal colon) are more prone to metastasize than are well-differentiated tumors of the foregut (lung, stomach) or hindgut (distal colon, rectum) (table 3). However, they also progress more slowly once they do metastasize, and as a result, median survival durations are longer among patients with metastatic (stage IV) NETs of the small intestine compared with metastatic tumors originating in other sites [9]. Prognosis is particularly poor for colonic NETs [30].
The differing prognosis according to stage and site of origin can be illustrated by an analysis of the Surveillance, Epidemiology, and End Results (SEER) database that evaluated the impact of primary tumor site and stage (localized, locally advanced, metastatic) in 35,618 patients with well-differentiated gastrointestinal tract NETs (table 13) [80].
Residual disease — Prognosis among surgically treated patients also depends on whether or not the resection was complete [11,13]. The impact of residual disease on outcomes can be illustrated by the results of a Swedish series of 135 surgically managed small intestine NETs (table 12) [11].
Tumor differentiation and grade — The World Health Organization (WHO) classification system for neuroendocrine neoplasms of the digestive system separates these tumors into two major categories (table 14) [81]:
●Well-differentiated NETs show a solid, trabecular, gyriform, or glandular pattern of cellular arrangement, with fairly uniform nuclei, salt-and-pepper chromatin, and finely granular cytoplasm.
●Poorly differentiated neuroendocrine carcinomas are high-grade carcinomas that resemble small cell or large cell neuroendocrine carcinoma of the lung (picture 1). (See "High-grade gastroenteropancreatic neuroendocrine neoplasms".)
All poorly differentiated gastroenteropancreatic NETs are high grade (grade 3), but it is now recognized that there is a subset of well- and moderately well-differentiated tumors that have a proliferative index that places them in the high-grade category; these are referred to as "NET, G3" tumors. Their clinical behavior is in between poorly differentiated neuroendocrine carcinomas and intermediate-grade well-differentiated NETs. (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on '2010 and 2019 World Health Organization classification' and "High-grade gastroenteropancreatic neuroendocrine neoplasms", section on 'High-grade well-differentiated tumors'.)
Multiple studies have evaluated the impact of tumor grade (defined primarily by mitotic rate per 10 high-power fields [HPF] and/or Ki-67 labeling) on prognosis of gastroenteropancreatic NETs. In one institutional study, five-year survival rates for metastatic gastrointestinal NETs of low-, intermediate-, or high-grade histologic differentiation were 87, 38, and 0 percent, respectively [82].
Issues related to grading of gastroenteropancreatic NETs are discussed in detail elsewhere. (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on 'Issues related to assessing grade'.)
Other prognostic factors
●Tumor burden – Among patients with liver metastases, tumor burden is an important prognostic factor. In one institutional study of 301 patients with metastatic NETs of the small intestine, five-year survival rates for those with <5 and ≥5 metastases were 79 and 47 percent, respectively [83].
●Carcinoid heart disease – Presence of clinically significant valvular damage represents an important adverse prognostic factor. In a report of 146 patients with metastatic midgut NETs, five-year survival rates were 75 percent for the entire cohort, while they were only 45 percent among the 23 patients (16 percent) with carcinoid heart disease [9]. (See "Carcinoid heart disease".)
●Hormone production – There is some evidence that, among patients with metastatic small bowel NETs, functioning tumors (ie, those associated with the carcinoid syndrome) have a worse prognosis than nonfunctioning tumors [84,85]. However, this is probably attributable to tumor burden.
●Metastatic site – There is some evidence that site of metastasis correlates with survival outcomes. A multivariate analysis of SEER data found that patients with liver metastasis had worse survival than did those with brain and bone metastasis [86].
Survival trends — Multiple studies, based upon population registries as well as institutional data, have documented a trend towards improved survival for well-differentiated NETs over the past three decades [45,87,88]. As an example, an analysis of the SEER database observed a dramatic increase in survival among patients diagnosed with a NET between 2009 and 2012 as compared with 2000 to 2004 (hazard ratio for death 0.79, 95% CI 0.74-0.85) [45]. These survival improvements have been attributed to treatment advances, including long-acting somatostatin analogs; however, earlier diagnosis may also be an explanatory factor.
The prognosis of patients with carcinoid heart disease has also improved significantly over the past 20 years, possibly due to increasing valve replacement surgeries [89]. (See "Carcinoid heart disease", section on 'Prognosis'.)
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
●Localization and staging
•The treatment of choice for a patient who has a localized well-differentiated neuroendocrine tumor (NET) is usually surgery. The extent of the surgical resection depends on the site of origin and size of the primary tumor.
•Multiphasic contrast-enhanced CT is recommended for evaluation of all patients with NETs, with the exception of tumors with very low probability of spread, such as most type 1 gastric NETs, or small (<1 cm) superficial (T1) rectal NETs. The utility of other tests, including somatostatin receptor-based imaging, is discussed in detail elsewhere. (See 'Staging studies' above.)
●Management and prognosis
•For most patients with a localized NET, we recommend resection, the extent of which depends upon the site of origin and the size of the primary tumor (Grade 1B). Resection of the primary tumor may be advised even in patients with known distant metastases in order to reduce the potential for bowel obstruction or bleeding, or to palliate abdominal pain related to the primary tumor. This is a controversial area, and decision making must be individualized. (See 'Staging and treatment of localized tumors' above.)
Prognosis depends primarily on tumor stage, margin status, histologic grade/differentiation, and site of origin. (See 'Prognosis and prognostic factors' above.)
•The following represents our approach to specific sites:
-Simple appendectomy is usually sufficient for low-grade tumors <2 cm. A right hemicolectomy has been traditionally recommended for tumors >2 cm. It is unclear whether other potential risk factors, such as mesoappendiceal invasion, should lead to recommendation for right hemicolectomy in patients with a tumor size of 1 to 2 cm. In general, appendectomy alone is appropriate for tumors <1 cm. (See 'Appendix' above.)
-Patients with small bowel NETs require resection of the involved segment and small bowel mesentery. (See 'Small intestine' above.)
-Ampulla of Vater NETs may be more aggressive than other duodenal NETs. Pancreaticoduodenectomy has been advocated for resectable cases regardless of size. However, these recommendations are based on very small case series, and treatment decisions need to be individualized. (See 'Ampulla of Vater' above.)
-Rectal NETs that are smaller than 1 cm and confined to the mucosa or submucosa (T1) can be treated by local endoscopic excision. The management of tumors between 1 and 2 cm that are confined to the mucosa or submucosa is controversial, and treatment must be individualized based upon size and the presence of risk factors such as lymphovascular invasion and mitotic rate (or Ki-67 index). Tumors larger than 2 cm and those that invade into or beyond the muscularis propria or have regional lymph node metastases require low anterior resection (LAR) or abdominoperineal resection (APR). (See 'Rectum' above.)
-Most patients with non-metastatic colonic NETs should be managed with formal partial colectomy and regional lymphadenectomy. (See 'Colon' above.)
-Local management for gastric NETs depends on the type (see 'Stomach' above):
Type 3 (sporadic) gastric NETs are treated by partial or total gastrectomy with local lymph node resection.
For type 1 and 2 gastric NETs smaller than 1 to 2 cm, endoscopic resection is the treatment of choice. More aggressive surgical therapy is rarely needed for type 1 gastric NETs unless there is extensive tumor involvement of the gastric wall (which increases the risk for a coexisting adenocarcinoma), tumor size >2 cm, or emergent bleeding.
●Post-treatment follow-up
•Given the long natural history and the propensity for small bowel NETs to metastasize, we recommend surveillance with triple-phase CT scans or MRI of the abdomen or abdomen and pelvis 3 to 12 months after surgery, then roughly annually for approximately 10 years. A similar surveillance strategy can be pursued for rectal, gastric, and appendiceal NETs >2 cm, although more frequent surveillance should be considered for more aggressive tumors, such as grade 2 gastric or rectal NETs. (See 'Post-treatment follow-up' above.)
•Post-treatment surveillance generally is not recommended for appendiceal tumors <2 cm and T1 low-grade rectal tumors <1 cm in size.
•For type 1 gastric NETs ≤2 cm, we recommend esophagogastroduodenoscopy (EGD) roughly once a year, and imaging studies only as clinically indicated.
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Stephen Goldfinger, MD, who contributed to an earlier version of this topic review.
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