Surgical treatment for gastrointestinal neuroendocrine tumors

Abstract Neuroendocrine tumors (NETs) are rare neoplasms, with an estimated annual incidence of 6.9/100 000. They arise from cells of the diffuse endocrine system, which are mainly dispersed throughout the gastrointestinal (GI), pancreatic, and respiratory tracts. The incidence of GI‐NETs has recently begun to show a steady increase. According to the Surveillance, Epidemiology, and End Results database, 53% of patients with NETs present with localized disease, 20% with locoregional disease, and 27% with distant metastases at the time of diagnosis. Surgery is the mainstay for the treatment of locoregional GI‐NETs. Endoscopic resection is an option for well‐differentiated early GI‐NETs, which are thought to very rarely metastasize to lymph nodes. A lesion that is technically difficult to resect via endoscopy is an indication for local resection (partial resection without lymph node dissection). GI‐NETs with possible lymph node metastasis is an indication for enterectomy with lymph node dissection. For NETs with metastatic lesions, cytoreduction surgery can control hormonal hypersecretion and alleviate symptoms; therefore, cytoreduction surgery is recommended. The indications for surgery vary and are based on the organ where the NET arose; therefore, an understanding of the patient's clinical state and individualized treatment that is based on the characteristics of the patient's GI‐NET is needed. This review summarizes surgical treatments of GI‐NETs in each organ.

systemic circulation leads to a variety of secretory syndromes, which can manifest as flushing, diarrhea, wheezing, rash, or even multiorgan failure.
Most NETs grow slowly over the years, and patients with NETs show signs and symptoms related to the mass of the tumor; however, about 30% of patients can have signs and symptoms associated with the hypersecretion of hormones from the tumor. Patients with nonresectable functional NETs who show signs and symptoms of hormonal hypersecretion can require systemic treatment for both control of the tumor and their signs and symptoms. 5 NETs often secrete serotonin and other vasoactive substances, which lead to the typical carcinoid syndrome, characterized by flushing, diarrhea, and right-sided valvular heart disease.

| Epidemiology
A study based on the Surveillance, Epidemiology, and End Results (SEER) database showed that the age-adjusted annual incidences of NETs arising from the appendix, cecum, duodenum, colon, stomach, jejunum/ileum, and rectum were 0.15, 0.16, 0.19, 0.20, 0.30, 0.67, and 0.86, respectively. 6 Whereas Caucasian patients develop mainly midgut NETs, African American, Asian, and Native American patients more frequently develop rectal NETs. Female patients appear to develop NRTs of the stomach, appendix, or cecum more frequently, whereas NETs in male patients appear to be more frequent in the jejunum/ileum, duodenum, and rectum. 6 Recent epidemiological inconsistencies have been reported for American and European countries vs Asian countries, where a higher incidence of rectal primaries has been noted. 7

| Diagnosis
The diagnosis of NETs is based on histopathology, imaging, and clinical presentation. Computed tomography (CT) and magnetic resonance imaging (MRI) play a key role in assessing the location and extent of GI-NETs. In a series of 64 patients with metastatic GI-NETs, MRI was found to be more sensitive than CT for the detection of small liver metastases. 13 Poorly differentiated NEC >20 >20 Abbreviations: NEC, neuroendocrine carcinoma; NET, neuroendocrine tumor.

| SURG I C AL TRE ATMENT FOR G I -NE TS
Surgery is the mainstay treatment of locoregional GI-NET, which may be curative in the case of R0 resection. Patients with operable disease have better prognosis than those with inoperable disease, even in advanced stages. 19,20 The indications for the surgical treatment of patients with GI-NETS are described in the European NET Society (ENETS) guidelines 21

| Surgical treatment for gastric NETs
Gastrointestinal NETs arise from subepithelial, histamine-secreting, enterochromaffin-like cells. Type A gastritis is strongly associated with GI-NETS. The recommendations for treatment suggest that the selected surgical procedure should be based on the Rindi classification (Table 2, Figure 2). 24 Type I GI-NETs occur in patients with chronic atrophic gastritis. They account for approximately 80% of gastric carcinoids. 25 The chronic absence of gastric acid stimulates antral G cells to secrete excess serum gastrin, which, in turn, causes gastric neuroendocrine cell hyperplasia and the development of multifocal polypoid NETs.
Type I NETs generally behave in a benign fashion, and aggressive treatment is rarely needed.

TA B L E 2 Rindi classification
that of type I and II tumors, and radical resection with lymphadenectomy is required.
The frequency of lymph node metastasis in GI-NETs with tumor diameters of 1-2 cm was reported to be 21%. 27 Therefore, the JNETS guidelines recommend D2 dissection for GI-NETs with tumors larger than 1 cm or invasion of the submucosal layer. 22

| Surgical treatment for duodenal NETs
Duodenal NETs often present as individual small, pale sessile lesions located mostly in the first or second part of the duodenum. 28,29 The recommended treatment for isolated NETs arising in the duodenum is endoscopic resection, if possible. 30 Subcentimeter G1 duodenal NETs in nonampullary locations can be treated by endoscopic resection. Periampullary NETs and duodenal NETs larger than 2 cm should be considered for surgical resection. The treatment for duodenal NETs of between 1 and 2 cm remains controversial. 21 Submucosal endoscopic dissection has a better rate of complete resection, but has a longer procedural time and higher complication rate (e.g., bleeding and perforation).
Surgical treatment options include local excision with locoregional lymph node sampling or pancreatoduodenectomy (PD). In patients with suspected lymph node metastases, PD is the first choice for curative intent.

| Surgical treatment for NETs of the small intestine
Most small bowel NETs originate in the distal ileum. 31 Approximately 25% of patients have multifocal tumors at the time of diagnosis, which are often clustered in close proximity to each other. 32 Although the malignant potential of intestinal NETs correlates with tumor size, even subcentimeter neoplasms can metastasize. 33 The liver, mesentery, and peritoneum are frequent metastatic sites.
Because the risk of metastasis to the lymph nodes is high, even when the tumor diameter is small, 34 small bowel resection with dissection of the mesenteric lymph nodes should be performed.

| Surgical treatment for NETs of the appendix
Neuroendocrine tumors of the appendix have been found in one of 300 appendectomy specimens, and most are found incidentally after surgery for appendicitis. The malignant potential of appendiceal NETs appears to be strictly related to tumor size. A study of a large series of patients did not find metastatic disease in 127 patients who had tumors smaller than 2 cm. 35 Consequently, a simple appendectomy has been considered adequate for tumors smaller than 2 cm, whereas right hemicolectomy has been recommended for tumors larger than 2 cm. However, locoregional or distant metastases in patients with tumors measuring 1

F I G U R E 2
Algorism of surgical treatment for gastric neuroendocrine tumors or 2 cm in diameter have recently been reported. 36 The negative prognostic factors for tumors of this size range include location at the base of the appendix, lymphovascular invasion, or extensive invasion of the mesoappendix (Figure 3). 36 Therefore, right hemicolectomy with lymph node dissection is recommended for patients with invasive tumors.
Rault-Petit et al 37 examined 403 patients with appendiceal NETs (26 patients with lymph node metastasis), but could not identify the predictors of lymph node metastasis, and the predictors remain unknown.

| Surgical treatment for NETs of the colon and rectum
Colonic NETs most frequently arise in the ascending colon. Colectomy with regional lymphadenectomy has been recommended for these tumors. 38 Colonic NETs distal to the cecum tend to be more aggressive than rectal NETs and are often poorly differentiated. 39 Rectal NETS with a tumor diameter greater than 2 cm show a very high frequency of lymph node metastasis (58%-76%), and therefore these tumors are indications for rectal resection plus lymph node dissection. 40,41 On the other hand, for tumors with a diameter of 1-2 cm, ENETS guidelines recommend local resection if neither MP invasion nor lymph node metastasis is suspected. 42 The reported predictors of lymph node metastasis for rectal NETs include the following characteristics: (a) tumor diameter >1 cm; (b) ulcerations; (c) presence of vascular invasion. 40,41 In Japan, the frequency of lymph node metastasis in NETs of the rectum ranges as high as 18.5%-30.4%, even for tumors of 1-2 cm. Therefore, according to the JNETS guidelines, patients with tumors (a) larger

| Chemotherapy and surgical treatment for NETs associated with metastases
In recent years, the therapeutic armamentarium for metastatic GI-NETs has expanded considerably. New systemic treatments for tumor and syndrome control have been shown to delay progression as well as diminish symptoms related to hormone secretion.
Everolimus is an inhibitor of the mammalian target of rapamycin (mTOR). The RADIANT-4 trial showed that everolimus significantly improved PFS over placebo in advanced well-differentiated, nonfunctional lung or GI-NETs. 43 Bevacizumab is a vascular endothelial growth factor (VEGF) inhibitor, which was shown in the BETTER trial to be safe and potentially efficacious in progressive, metastatic, well-differentiated GI-NETs. 44 Combined therapy yielded improved response rates and median survival rates. 45  OS rate of 51% in the transplantation arm vs 22% in the nontransplantation arm (P = .001). 58 Cytoreduction surgery for patients with lung metastases and peritoneal dissemination might also reduce the signs and symptoms associated with these types of metastases. 59,60 The resection of primary tumor has been recently reported to possibly lead to the prolonged survival of patients with GI-NETs associated with metastases. 61 Additional variables related to survival for each NET subtype were identified and might help select patients who benefit from removal of the primary tumor.

| CON CLUS IONS
In general, surgery is the first-line treatment for patients with localized GI-NETs, and it should also be considered for palliation in patients with metastatic or bulky disease. The indications for surgery vary, based on the organ where the NET arose; therefore, an understanding of the patient's clinical state and individualized treatment that is based on the characteristics of the patient's GI-NET are needed.

D I SCLOS U R E
Conflicts of Interest: The authors declare no conflicts of interest.