Neuroendocrine Tumors Arising in Meckel’s Diverticula: Frequency of Advanced Disease Warrants Aggressive Management

Abstract

Background

Meckel’s diverticulum is a common anomaly of the GI tract, which occasionally gives rise to cancer. The most frequent tumor affecting these diverticula are neuroendocrine tumors (NETs), and whether these should be treated in similar fashion as small bowel NETs or appendiceal NETs is unclear.

Methods

A retrospective chart review was conducted at a single academic medical center between 1998–2012. Demographic, radiologic, biochemical, and clinicopathologic data were collected, as well as status at last follow-up.

Results

Seven patients were identified with NETs involving Meckel’s diverticula, including one with limited information other than the management of her late metastases. Of the 6 other patients, all had involvement of regional nodes, including 3 patients with tumors <2 cm in size, and 4 had liver metastases at presentation.

Conclusions

NETs in Meckel’s diverticula are rare tumors, but when they develop, are often associated with nodal metastases and liver metastases, even when the tumors are small. Therefore, the optimal management of these NETs is small bowel resection with regional lymphadenectomy, and debulking of liver metastases where feasible.

Introduction

A Meckel’s diverticulum results from the failed or incomplete closure of the vitelline duct during the 8^th week of embryologic development. Affecting approximately 2% of the population, it is the most common developmental abnormality of the gastrointestinal tract[1]. Diverticula average 3 cm in length and are generally located within 100 cm of the ileocecal valve[1,2]. Heterotopic mucosa may be found in Meckel’s diverticula, with gastric mucosa being the most common (present in 60%), although other heterotopic tissues such as pancreatic acini, pancreatic islets, Brunner’s glands, colonic mucosa, endometriosis, or hepatobiliary tissue can also be present[3]. Despite the presence of nests of ectopic tissue, the majority of Meckel’s diverticula are asymptomatic, with an estimated lifetime complication rate of around 4%[4]. Individuals most likely to develop complications are those aged 40 years or younger, those with diverticula two centimeters in length or greater, and those containing heterotopic tissue[5]. When complications do present, gastrointestinal bleeding is the most common clinical symptom, generally related to an ulcer caused by secretion from associated gastric mucosa[6].

Rarely, a Meckel’s diverticulum can serve as the site for tumor development; it is estimated that 0.5% to 3.2% of complications from a Meckel’s are related to malignancy[7,8]. In a review of 159 patients with cancer arising from a Meckel’s diverticulum taken from the Surveillance, Epidemiology, and End Results (SEER) database, Thirunavukarasu et al. found carcinoid to be the most common malignancy arising from a Meckel’s (76.5% of cases), followed by adenocarcinoma (11.4%), GIST/leiomyosarcoma and sarcoma (10.8%), and lymphoma (1.3%)[7]. Carcinoids, or more properly, neuroendocrine tumors (NETs) arising from Meckel’s diverticula are often found incidentally, with over half of patents showing no symptoms. Those with symptoms typically report abdominal pain, diarrhea, weight loss, nausea, and vomiting[9]. The most common presentation of NETs within a Meckel’s diverticulum is that of obstruction[10].

While the average size of NETs in Meckel’s diverticula is similar to appendiceal carcinoids, their natural history is thought to be more similar to those arising from the ileum, with at least 24% of patients having evidence of metastases at the time of diagnosis[6,9,11]. However, a recent series by Poncet et al. examining eight cases found the incidence of metastases to be 75%[12]. Some authors believe that the rate of metastases arising from NETs of Meckel’s diverticula is falsely elevated, due to a greater tendency to report more advanced cases arising from this rare site, than to publish cases discovered incidentally[6]. There have been fewer than 200 cases of NETs arising from Meckel’s diverticula published in the literature, with the majority of these cases described within larger series of GI NETs, and fewer as isolated case reports[9]. Here we report seven cases of NETs arising from Meckel’s diverticula managed at a single academic institution.

Materials and Methods

A review of all cases of NETs found in Meckel’s diverticula presenting to the University of Iowa Hospital and Clinics between 1998 and 2012 were identified from the Department of Pathology database under an IRB-approved protocol using the keywords “Meckel’s diverticulum” and “carcinoid tumor”. For each patient, clinical parameters such as sex, age at diagnosis, signs and symptoms, findings on pre-operative imaging, serum hormone levels, surgical and additional therapy, and status at follow-up were recorded. Pathological features such as tumor stage, number of primary tumors identified, maximum tumor diameter, grade, presence of perineural and vascular invasion, status of regional lymph nodes, and presence of distant metastases were also entered into our database. All patients were staged according to the American Joint Committee on Cancer guidelines and graded according to current WHO/ENETS guidelines[13,14]. Complete follow-up data was obtained for all patients, and a review of the relevant literature conducted. Approval of the University of Iowa Institutional Review Board was obtained prior to construction of the database.

Results

Patient Characteristics

Seven patients were identified as having the pathological diagnosis of NET within a Meckel’s diverticulum, with complete clinical and pathological data available in six cases. The other patient was initially worked-up and treated at an outside institution, and was only referred to our institution after developing metastatic disease; records regarding the treatment of her primary tumor could not be obtained.

There were two female and five male patients, with ages ranging from 43 to 83 years (mean 60.7 s.d. ±16.6 years). Follow-up ranged from 6 to 156 months (median 18 months, s.d. ± 53 months; Table 1). All patients were alive at the end of the follow-up period except one who died of metastatic disease. The presentation was variable among patients, which will be discussed for each patient individually.

Table 1.

Demographics, presentation, operative findings, and status at follow-up

Patient Number	Age (years)	Sex	Presentation	Initial Treatment of Primary	Liver Metastases	Regional Node Metastases	Other Treatments	Duration and status at follow-up
1	58	M	Carcinoid Syndrome	Small bowel resection	+	+	Somatostatin analogs, liver wedge resection, cholecystectomy, appendectomy	86 months, alive
2	43	M	Abdominal Pain	Small bowel resection	+	+	Somatostatin analogs, RFA & enucleation of liver lesions, cholecystectomy, appendectomy	22 months, alive
3	77	M	RUQ pain	Small bowel resection	+	+	Somatostatin, RFA & enucleation of liver lesions, cholecystectomy, appendectomy	18 months, alive
4	68	M	Incidental liver lesions	Small bowel resection	+	+	Somatostatin, RFA & enucleation of liver lesions, Cholecystectomy	6 month, alive
5	38	F	Incidental finding during appendectomy	Diverticulectomy	−	−	unknown	156 months, deceased
6	83	F	Abdominal Pain	Small bowel resection	−	+	Cholecystectomy Somatostatin analogs	6 month, alive
7	58	M	Incidental finding on colonoscopy	Small bowel resection	−	+	Right hemicolectomy, cholecystectomy	7 months, alive

Patient #1 presented with symptoms typical of carcinoid syndrome, with flushing and diarrhea for one year. A CT was performed, which revealed a metastatic lesion in the liver with no primary tumor seen. An FNA of the liver lesion revealed a metastatic neuroendocrine tumor. He was then explored, where small bowel resection of the primary tumor in a Meckel’s diverticulum, cholecystectomy, and wedge resection of the right liver lesion were performed. He was maintained on somatostatin analogs post-operatively and was free of tumor for a number of years. He was later found to have multiple new liver lesions on CT at 56 months follow-up, and went on to receive hepatic intra-arterial embolization with ⁹⁰Y microspheres. He is currently doing well at 86 months after his initial surgery with stable disease.

Three patients (#2, 3, 6) presented with abdominal pain. Patient #2 had sudden onset of abdominal pain with nausea and vomiting. A CT revealed a mesenteric mass, which was later found to be a neuroendocrine tumor on CT-guided biopsy. At exploration, he was found to have over 60 small bowel NETs, including one in a Meckel’s diverticulum. He underwent resection of 125 cm of small bowel, cholecystectomy, radiofrequency ablation of two liver lesions, and enucleation of two liver lesions. He has been maintained on Sandostatin LAR post-operatively, and has had no further progression of his liver lesions at 22 months follow-up.

Patient #3 presented with persistent right upper quadrant pain and was initially evaluated for gallbladder disease. Due to negative work-up and persistent pain, he underwent a CT scan, which revealed one large liver lesion and multiple smaller lesions. The larger lesion was biopsied and pathology was consistent with a metastatic NET. Subsequent imaging revealed a mass in the mesentery, and at exploration he underwent small bowel resection for his primary, which was found in a Meckel’s diverticulum, as well as cholecystectomy, radiofrequency ablation of seven liver lesions, and enucleation of one liver lesion. At 12 months follow-up, he was noted to have significantly increased tumor burden in the liver and was referred for evaluation for embolization. The patient elected to follow-up locally and went on to receive transarterial chemoembolization of the right liver lobe, followed by the left lobe eight weeks later. Follow-up CT at 18 months post-surgery indicated partial response to the chemoembolization with response in multiple hepatic metastases and no further progression of disease. However, he was found to have new micronodular disease in his mesentery and omentum and new ascites, as well as splenic metastases.

Three patients (#4, 5, and 7) were found to have incidental lesions during work-up for unrelated complaints. Patient #4 was found to have liver lesions on a CT scan done for evaluation of renal stones. He later underwent laparoscopic biopsy of the liver lesions, which confirmed the presence of metastatic NETs. During the biopsy a lesion was also noted at the tip of a Meckel’s diverticulum. The mass and diverticulum were removed by simple diverticulectomy, which revealed the primary NET. We later explored him, found a mesenteric mass adjacent to the diverticulectomy site, and performed small bowel resection with removal of regional nodes. A cholecystectomy, radiofrequency ablation of 7 and enucleation of 5 liver lesions were also performed. He remains on Sandostatin LAR, and at 6 months follow-up had improvement in serum biomarkers and no evidence of disease progression on CT.

Patient #5 was found to have a Meckel’s diverticulum with associated tumor incidentally during a routine appendectomy after presenting with fever and abdominal pain. The Meckel’s was removed by diverticulectomy and pathology revealed a NET. This procedure was done at an outside institution, and from the records it was unclear as to whether she received any further treatment or work-up at that time. Following her initial operation, her disease course remained steady and progressive. She was incidentally found to have numerous peritoneal metastases during a gynecologic procedure 2 years after initial resection and underwent 6 cycles of chemotherapy with 5-fluorouracil and Streptozocin. She was well until nine years later, when she experienced increased abdominal pain, weight loss and diarrhea. CT revealed multiple liver metastases and numerous bone metastases were seen on bone scan. A liver biopsy confirmed metastatic NET, and coincidentally she was diagnosed with a locally invasive ductal carcinoma of the breast for which she underwent excisional biopsy and axillary lymph node dissection. She underwent no further work-up to determine the etiology of her bone metastases. For her neuroendocrine disease she resumed chemotherapy with 5-fluorouracil and Streptozocin. She chose to discontinue treatment after 5 days due to side effects. She later went on to receive 3 chemoembolizations to the liver with Streptozocin and Adriamycin, only to experience continued progression. She was last seen at 156 months of follow-up, at which time she elected to receive hospice care and died shortly thereafter.

Patient #6 presented with a one-year history of vague abdominal pain with radiation to the back following meals. A CT revealed several enlarged mesenteric lymph nodes and a possibly thickened segment of small bowel. CT-guided biopsy of one of the enlarged nodes revealed a well-differentiated NET. Subsequently she underwent small bowel resection for a primary found in a Meckel’s diverticulum, with cholecystectomy; no liver lesions were seen on CT or at exploration. She was restarted on Sandostatin LAR 6 months post-surgery due to increased diarrhea and fatigue. Repeat imaging studies are scheduled for her 12 month follow-up.

Patient #7 was diagnosed with carcinoid following biopsy of an ileal polyp removed during a screening colonoscopy. Octreotide scan and CT were negative. Repeat colonoscopy one year later revealed a 3.1 cm ileocolic mass. He was asymptomatic. He underwent an exploratory laparotomy with right hemicolectomy and small bowel resection for an ileocolic tumor and two ileal tumors (one of which was located in a Meckel’s diverticulum), as well as a cholecystectomy. At 7 months post-surgery he remains asymptomatic with no evidence of metastases or recurrence on CT scan.

Preoperative Imaging

Five of the six patients who had preoperative CT scans had metastatic nodal or liver disease detected (Table 2). Three patients were found to have liver lesions on CT at the time of initial presentation, with a fourth (#2) having only a mesenteric mass on initial CT imaging, but later liver lesions and nodal disease on a second preoperative CT 3 months later. Patient #6 presented with nodal disease, and no evidence of primary tumor or liver lesions. Four of the five patients with preoperative Octreotide scans were found to have increased uptake in the liver, one had nodal uptake, and in two, the primary tumor was localized. Preoperative CT and Octreotide scans were negative for Patient #7.

Table 2.

Findings on pre-operative imaging

Patient Number	Primary Lesion	CT Imaging	Nodal Disease	Primary Lesion	Octreoscan	Nodal Disease
		Liver Lesions			Liver Lesions
1	−	+	−	−	+	−
2	+	+	+	+	+	−
3	+	+	+	+	+	−
4	−	+	_	−	+	+
5	*	*	*	*	*	*
6	−	−	+	*	*	*
7	−	−	−	−	−	−

^*No data available

Preoperative Labs

Preoperative labs were available for six patients (Table 3). Serum serotonin levels were increased in five patients (from 685 to 2396 ng/mL; normal 50–200 ng/ml). Three patients had elevations in Chromogranin A (from 197 to 9941 ng/mL; normal 0–95 ng/ml). Pancreastatin levels were elevated in four patients (from 284 to 891 pg/ml; normal 0–135 pg/ml). All 4 patients who had Neurokinin A and Substance P levels measured were within the normal range. Urinary 5-HIAA was elevated in both of the patients in whom it was checked.

Table 3.

Preoperative biochemical testing

Patient Number	Serotonin (50–200ng/ml)	Chromogranin A (0–95ng/ml)	Neurokinin A (<40pg/ml)	Pancreastatin (0–135pg/ml)	Substance P (40–270pg/ml)	Urinary 5-HIAA (3–15mg/24hr)
1	2396	9941	*	59	*	61
2	685	197	24	284	103	*
3	1079	2534	24	586	130	*
4	65	70	12	631	76	37
5	*	*	*	*	*	*
6	1124	62	14	891	87	*
7	348	46	*	84	*	*

^*No data available

Surgical Intervention

All seven patients underwent resection of the primary tumor, including patients with evidence of liver metastases. One patient (#5) only had diverticulectomy performed with no lymphadenectomy, years prior to presenting to us with metastatic disease. The remaining patients had exploratory laparotomy with small bowel resection including resection of the Meckel’s diverticulum, appendectomy (if not previously removed), regional lymphadenectomy, and cholecystectomy. Additionally, three patients had radiofrequency ablation and enucleation of a number of liver lesions, and one patient had a right liver wedge resection to remove a large focus of disease. Five patients were maintained on Sandostatin LAR post-surgery.

Pathological Features

Pathologic data were available for 6 patients. In 4 cases the tumor was found to be a solitary lesion arising from a Meckel’s diverticulum, with no other primaries identified (Table 4). In one patient (#2), >60 tumors were identified intraoperatively by palpation (47 found by the pathologists), including the one arising from a Meckel’s diverticulum. Patient #7 was found to have an ileocolic tumor and two additional ileal tumors, one of which was located in a Meckel’s diverticulum. The average tumor size for the 6 patients where pathology was available was 2.33± 0.78 cm. The surgical margins were negative in all resections. Two patients were found to have tumor invasion into the muscularis propria, one had tumor invasion through the muscularis without invasion into the overlying serosa, and three had evidence of further invasion into the serosa or underlying mesenteric adipose tissue. Lymphovascular invasion was present in five cases, and perineural invasion in two. Liver metastases and positive lymph nodes were present in four patients, and two patients had nodal metastases without liver involvement. One patient had tumor present in the appendix. Patients were staged according to American Joint Committee on Cancer guidelines[13], with three of the five patients being T4, one T3, and two were T2. Four of six patients had nodal and liver metastases (Stage IV), and two had nodal metastases only (Stage III). All pathology slides were also reviewed and assigned a grade according to WHO and ENETS guidelines[14]. Five patients were classified as having low grade tumors, and one patient was found to have an intermediate grade tumor.

Table 4.

Summary of pathologic findings

Patient Number	Stage	Tumor	Nodes	Mets	WHO- ENETS Grade	Ki-67 Index	Total # NETs	Size (cm)	Tumor in Appendix	Vascular Invasion	Perineural Invasion	Positive Nodes	Other Metastases	Clear Margins
1	IV	4	1	1	Low	<3%	1	1	−	+	+	3/17	liver	+
2	IV	4m	1	1	Low	<3%	47	3	+	+	+	20/25	liver	+
3	IV	2	1	1	Low	<3%	1	1.9	−	+	+	6/21	liver	+
4	IV	2	1	1	Intermed.	3–20%	1	2.5	−	*	*	2/11	liver	+
5	*	*	*	*	*	*	1	*	*	*	*	*	*	*
6	IIIb	3	1	0	Low	<3%	1	2.5	*	+	−	2/10	−	+
7	IIIb	4m	1	0	Low	<3%	3	0.7	*	+	*	4/15	−	+

^*No data available

DISCUSSION

This study examining a series of seven patients managed at a single institution highlights the various clinical presentations of NETs arising from a Meckel’s diverticulum. A number of reports in the literature describe NETs in a Meckel’s diverticulum that were discovered incidentally during an abdominal exploration for another indication or at autopsy[11,15,16,17]. A review of the literature by Nies et al.[6] found that 64% of patients with NETs in a Meckel’s diverticulum were asymptomatic at the time of diagnosis, and 26% were found incidentally at autopsy. The remainder of patients present with symptoms including abdominal pain, nausea, vomiting, and diarrhea[6,9]. Three patients in this series were asymptomatic with incidental discovery of their disease; one was found at appendectomy to have an abnormal Meckel’s diverticulum, another was identified during screening colonoscopy, and the other had liver lesions found during evaluation for kidney stones. Three patients in the series presented with symptoms of vague abdominal pain and underwent abdominal imaging for this. Two of these patients were found to have metastatic disease with no evidence of a primary lesion on CT imaging (one patient with liver metastases and one with nodal disease), while the primary tumor with nodal and liver metastases were found in the third. Less frequently, cases of patients with more florid symptoms of carcinoid syndrome resulting from a Meckel’s NET have been described[18,19,20]. The incidence of carcinoid syndrome in patients with ileal NETs is approximately 20–30%, which is similar to the 12–25% reported in patients with tumors arising from a Meckel’s diverticulum[10,12,21]. One of the patients (#1) in this series who had a large liver metastasis at the time of diagnosis presented with symptoms of carcinoid syndrome. Regardless of the circumstances, five of the six patients were found to have evidence of metastatic disease on CT imaging at the time of diagnosis. In only 2 of these 5 patients was the primary tumor identified on imaging. These findings emphasize the importance of considering a tumor arising in the small bowel (or a Meckel’s diverticulum) in patients presenting with metastatic NETs to the liver, particularly in cases where a primary tumor cannot be localized by pre-operative imaging.

The results for different serum biomarkers were variable in this study. Serotonin appeared to be the most useful, being elevated in 5 of 6 patients tested with Meckel’s NETs. The next most valuable was pancreastatin, which was elevated in 4 of 6, including 1 in whom the serotonin was normal. Chromogranin A (CgA) was only elevated in 3 of 6 patients. Pancreastatin is a fragment of CGA, and was found to be elevated in two patients with normal CgA levels. Pancreastatin has been reported to be 100-fold more sensitive than CgA, and combined with serotonin, may be a very useful biomarker to screen for midgut NETs[22]. Neurokinin A is another potentially useful biomarker for midgut NETs, and recent reports suggest it to be of value in predicting poor prognosis when the absolute value exceeds 50 pg/ml (which was not seen in any of our patients)[23].

All patients in the series had surgical resection of the primary lesion, with six patients undergoing surgical exploration with small bowel resection and lymphadenectomy, and one patient having simple diverticulectomy. Although there are guidelines for the management of ileal and appendiceal NETs[24,25], the literature offers no consensus for the management of NETs arising from Meckel’s diverticula. Many would agree that Meckel’s NETs >2 cm are more often associated with metastases to regional lymph nodes and would therefore warrant wide resections to include adjacent small bowel and the associated mesenteric nodes[12]. Management of smaller Meckel’s NETs is less clear. Some believe that in small, incidentally-found tumors, simple diverticulectomy or wedge resection is adequate, as such tumors are likely to be of a localized stage[11]. Such treatment decisions are based largely on experience with appendiceal NETs[6,12], as the appendix is also a small GI diverticulum that can serve as a primary site for NETs. Appendiceal NETs show little propensity for metastatic spread of tumors <2 cm[25]. However, the series by Poncet et al.[12] cautions that even small Meckel’s NETS should be managed aggressively, as evidenced by nodal or distant metastases in 6 of their 8 patients, 5 of whom had tumors ≤2 cm in diameter. One patient in the current series had a 7 mm tumor and nodal metastases, as 2 other patients with tumors <2 cm (10 and 17 mm) had both nodal and liver metastases. Given that 3 of the 6 patients in our series had primary tumors <2 cm and all had involvement of regional nodes, we agree with the recommendation that all primary NETs arising from Meckel’s diverticula should be excised with adequate small bowel margins and regional lymphadenectomy, as one would do for such tumors of small bowel origin[12,24,26].

Many tumors are found incidentally in Meckel’s diverticula after laparoscopic removal. However, if there is suspicion of a tumor within a Meckel’s intraoperatively, the tumor is likely to be larger, and therefore simple diverticulectomy should be considered inadequate treatment. In this situation, it is also important to palpate the small bowel to look for multricentric tumors (as seen in 2 of our 6 patients), as well as perform small bowel resection and lymphadenectomy. Nies et al.[6] found that at least 19% of patients had multiple tumor nodules in addition to the one arising from the Meckel’s diverticulum, and we previously reported a multicentricity rate of 25% in small bowel NETs[27]. The importance of abdominal exploration is highlighted by patient #5 in our series. A small tumor was identified incidentally in the tip of a Meckel’s diverticulum during a routine appendectomy and the tumor was completely excised by diverticulectomy. To our knowledge, she underwent no further work-up or surveillance following the procedure, and went on to develop metastatic disease and ultimately die of this 13 years later. Additionally, there were two patients in our series with multifocal tumors scattered throughout the ileum. Although these only represent a few examples, they bring to light some of the potential inadequacies of simple diverticulectomy, as well as laparoscopic exploration only without further palpation of the bowel and mesentery.

In addition to undergoing resection of the affected area of small bowel andregional lymphadenectomy, all four patients in this series with evidence of metastatic spread to the liver also underwent aggressive treatment of these metastases through surgical excision, radiofrequency ablation, or enucleation. Debulking of liver metastases has been shown to improve survival in patients with NETs[28,29]. Historically there is a 30% to 40% 5-year survival rate with untreated liver metastases[28,30]; series by Sarmiento et al.[28] and Mayo et al.[29] found that 5-year survival rates markedly improve with surgical intervention, to 61 and 74%, respectively. The same strategy should be applied to those with Meckel’s NETs. All 4 of our patients having debulking are still alive at follow-up, though two patients have had progression of their liver lesions necessitating embolization. Since all patients in our series with evidence of liver metastases underwent surgical intervention, it is difficult to draw conclusions regarding whether these interventions improved survival, although the series by Poncet[12], Sarmiento[28], and Mayo et al.[29] suggest that aggressive management of NET liver metastases results in improved long term survival. It is therefore recommended that liver metastases in patients with Meckel’s NETs should also be aggressively managed.

Following resection, six cases in this series underwent pathologic review and classification in accordance with the most recent TNM staging recommendations and according to the WHO and ENETs grading systems[13,14]. The primary tumors ranged in size from 7 mm to 3.1 cm, and all were found to be locally invasive. All tumors were classified as low grade, with the exception of 1 tumor that was intermediate grade. All patients had nodal disease and 4 of 6 also had liver metastases. Four patients were therefore AJCC Stage IV and two were Stage III, similar to what is seen in small bowel NETs, where size is not correlated with the presence of metastases[24].

There is currently debate surrounding the metastatic potential of NETs arising from Meckel’s diverticula. A recent review reports the incidence of metastatic disease present at the time of diagnosis to be around 24%[6]. However, much of this data is derived from case reports, and some believe this incidence may be inflated due to the reporting of more advanced cases. In a recent single institutional series by Poncet et al.[12] with 8 cases, the largest in the literature, metastases were found in 75% of patients (3 with nodal metastases only, 3 with nodal and liver metastases). In the current series, 100% of 6 patients had nodal metastases and 67% had liver metastases; the remaining patient’s initial records were unavailable, but she ultimately developed liver metastases. These findings emphasize the aggressive nature of NETs arising from Meckel’s diverticula and suggests that their propensity to metastasize equals, if not exceeds, that of small bowel NETs, in which non-localized disease is present in 64% of patients[30].

Clarifying the metastatic potential of NETs arising from Meckel’s diverticula is important, as it has prognostic significance and plays a role in management. The long-term prognosis for patients with Meckel’s NETs is unclear due to limited data, however the series by Poncet et al.[12] reported a 5-year survival of 80% for patients with regional disease and 75% for those with liver metastases. In our series, 6 of the 7 patients were alive at the end of the follow-up period (ranging from 6 to 156 months, median 18 months). From this data, though limited, it appears that survival may be comparable to five-year survival rates for those with small bowel NETs derived from the SEER database (54–60% for localized disease, 64–73% for regional metastases, and 36–50% distant metastases)[30]. Since NETs within Meckel’s diverticula are rare, it will be difficult to accurately define their natural history, and therefore, we believe they should be managed more like small bowel NETs than appendiceal NETs.