As some centers have developed expertise with the care of neuroendocrine tumors (NETs), standard approaches have developed for the care of these relatively rare and complex diseases. In addition to the rarity of these tumors in the practice of most physicians, the management is made more complicated by the systemic effects of hormone-release syndromes, the indolent nature of some of the tumors, and the limited systemic antineoplastic options.
There are several sets of recent guidelines that can help to support decision-making for these patients [1–8]. As each of the groups writing the guidelines are working from the same data, and often have overlapping committee members, the guidelines are mostly similar in their recommendations. The differences may be within the details of management where the data are inconclusive, and so management style or expert opinion has greater influence on the recommendations. However, more significant patient problems occur when guidelines are not followed .
Over the last year, there have been some important reports that will influence future management guidelines. The reports in this review will certainly be incorporated in the upcoming guidelines committee discussions. These selected reports cover a variety of topics in the field of NETs, including the surgical management of primary and metastatic tumors, and the outcomes of the surgical management of the two most common functional endocrine tumors.
PRIMARY OPERATIVE TREATMENT OF PANCREATIC NEUROENDOCRINE TUMORS
The only potential curative treatment for pancreatic neuroendocrine tumors (PNETs) is operative resection. However, the resections can be morbid, and as more small PNETs are identified on imaging performed for reasons other than the evaluation of the pancreas, important questions have been raised about the indications for operation. Very few data are available to reveal the likelihood that the tumor would progress if left untreated.
Investigators have attempted to shed light on these issues in recent reports. Both the morbidity of intervention with modern surgical approaches and the prognosis of these tumors are important to the decision-making.
Incidentally identified tumors
The implications of the identification of unsuspected PNET, which are usually small, have been recognized rather than studied over the last decade. Clinicians in the field have observed increasing numbers of patients with these lesions seeking consultation, and though the typical approach has been to remove the tumors, there is also a significant question of whether observation may be an appropriate course for some patients. Recommendations for observation are not as well developed or supported by the data for tumors of the pancreas as they are for tumors of the adrenal gland.
Cheema et al.[10▪] from Moffitt Cancer Center have added informative material to this discussion. They have collected a series of 143 patients treated there between 1999 and 2010 for nonmetastatic PNETs. Incidentally discovered tumors accounted for 56 patients (55%), while in 125 patients the tumor was nonfunctional. A total of 123 patients had tumor resection; 12 patients had unresectable tumors, three were borderline resectable and elected not to proceed, and five had unfavorable relative risk because of systemic diseases. Most of the patients had stage 1 tumors (stage 1: 84 patients, stage 2: 41 patients, and stage 3: 18 patients).
The 5-year overall survival for patients who had incidentally discovered tumors was not different than for others (92 vs. 86%, respectively, P = 0.68); however, the incidentally discovered tumors were less likely to progress by 5 years (86 vs. 59%, P < 0.01). The main risk factor predicting the progression was a tumor grade of intermediate or high, which showed a lower progression-free survival. Features that were not predictive of progression-free survival included age, tumor location, and stage.
These data are important because they reveal that though patients with incidentally identified tumors do better than others, they still have risk of progression even when treated, and the better predictor seems to be tumor grade.
Morbidity and efficacy of primary resection
Resection of PNETs can carry significant morbidity and possibly mortality. However, modern surgical approaches to the pancreas have decreased the morbidity of pancreatic surgery overall. There are limited reports of the morbidity of resection for these specific diseases, which may be quite different from the more common pancreatic resections for adenocarcinoma.
Inchauste et al.[11▪] from the National Cancer Institute reported the results of 122 PNET resections done between 1998 and 2010 at the US National Cancer Institute. Of these, 62 patients had enucleation of tumors, while 60 patients had anatomic pancreatic resections.
The operative results from this very experienced group highlight the morbidity of these procedures. Pancreatic fistula is the most common significant complication of these procedures. This can result in deep surgical site infection, long-term inpatient care, and can require reoperation. Pancreatic fistula developed in 24% of all patients, including 27% of those who had enucleation only and 20% of those who had anatomic resections. The risk factors for fistula development were tumor development based upon hereditary syndromes, high BMI (BMI >25), and larger tumor size.
Norton et al.[12▪] compiled a series of PNET patients from the National Cancer Institute and Stanford University from 1982 to present. Among the 293 patients with PNET, 46 had involvement of the major vessels around the pancreas, most commonly the portal or superior mesenteric veins, and 42 of those were resected. Nine patients required vascular reconstruction. There were no deaths and the overall morbidity was 29%. The 10-year overall survival was 60% and the 10-year disease-free survival was 30%. Though technically challenging, resection of PNET with involvement of adjacent vascular involvement appeared to have results comparable to patients without such involvement. This is in contrast to the experience with pancreatic adenocarcinoma and would support resection of PNET with vascular involvement if technically feasible.
Efficacy of modified staging systems
There are two staging systems currently in common use for NETs (AJCC and ENETS). Strosberg et al.[13▪] from Moffitt cancer center have assessed those staging systems’ ability to predict relapse-free survival in their series of 123 patients with resected, nonmetastatic PNET (the same patients as reported by Cheema). They showed that both systems work to delineate the risk of recurrence (5-year recurrence-free survival: AJCC stage 1 = 78%, stage 2 = 53%, and stage 3 = 33%; ENETS stage 1 = 100%, stage 2 = 70%, and stage 3 = 53%).
PRIMARY MANAGEMENT OF SMALL INTESTINE NEUROENDOCRINE TUMORS (MID-GUT CARCINOIDS)
Small intestine neuroendocrine tumors (SNETs), commonly called mid-gut carcinoid tumors, present some special challenges for the surgeon. First, the primary tumor is often small and can be difficult to identify on preoperative imaging. Second, the mesenteric node disease can be quite bulky, can be hard or impossible to remove, and can cause substantial morbidity. Finally, the hormonal function of the tumor can be dramatic and requires specific therapy.
Survival after resection
The survival after resection of SNET and selective systemic therapy was described by Norlen et al.[14▪] from the University of Uppsala. Their series on 603 patients treated between 1985 and 2010 includes 517 patients who had operation or reoperation at their institution (312 were operated 1–3 times for SNET prior to referral). The operation included a standard approach of distal small bowel resection, usually including right hemicolectomy to enable an extensive mesenteric lymph node dissection. Liver disease was addressed by various combinations of resection and radiofrequency ablation (the currently favored combination), or hepatic artery embolization with Gelfoam or chemoembolization or yttrium-90 microspheres. A total of 497 patients received systemic therapy with interferon (477 patients) with or without somatostatin analog therapy.
Survival analysis shows median survival of 8.4 years, with a 5-year survival rate of 67%. Patients in whom resection was undertaken had better survival than those who could not undergo resection. Poor survival was associated with more advanced mesenteric nodal metastases, distant abdominal node metastases, liver metastases, extra-abdominal metastases, and carcinomatosis.
This extensive and well documented series sets the current standard for achievable results with modern therapy.
Role of prophylactic cholecystectomy
Patients who have SNET are frequently treated with somatostatin analogs at some point in their course. Somatostatin analogs are known to cause biliary stasis, and many clinicians have advocated cholecystectomy during operations for resection of these tumors.
Norlen et al. from the University of Uppsala evaluated this issue in their large cohort of SNET patients. Of 235 patients resected, 48 had already had cholecystectomy. Of the remaining 187 patients, 18 had their gallbladders removed during the SNET resection. A total of 144 patients went on to have somatostatin therapy, and of these, 92 had documented imaging of the gallbladder during follow-up.
A total of 63% of imaged patients who had somatostatin analog therapy had gallstones in their gallbladder, without prior evidence that this was the case. Of the patients treated with somatostatin analog therapy with the gallbladder in situ, 22 out of 144 developed gallbladder-related complications requiring cholecystectomy or drainage, including acute cholecystitis, cholangitis, gallbladder empyema, acute pancreatitis, or biliary colic (11 patients). These data support the concept that cholecystectomy is a rational addition to the resection procedure for SNET because of the likelihood that somatostatin analog therapy will be indicated, and that this may be accompanied by gallstone formation and complications.
Endovascular management of mesenteric venous compression
Metastatic adenopathy in the mesentery adjacent to SNET can be unresectable and can cause severe consequences including occlusion of the mesenteric veins. Hellman et al. from the University of Uppsala reported results of a novel approach in a small cohort of seven patients. They used transhepatically deployed expandable portal venous or superior mesenteric vein stents for patients with severe symptomatic portal drainage obstruction. Four patients resolved their symptoms, two were unchanged, and one patient was worse after the intervention. In general, symptom improvement paralleled the ability to improve blood flow. This may be an option in a group of patients who are otherwise very difficult to help.
Insulinoma is one of the two common functional PNETs and is characterized as a usually (but not always) benign tumor that is usually (but not always) curable.
Crippa et al.[17▪] from Verona IT reported a large modern series of insulinoma resections that adds to the literature by demonstrating the current distribution and outcomes of patients. They report 198 patients treated between 1990 and 2009, of whom 5.5% were in MEN-1 kindreds. A total of 175 patients had low-grade tumors and seven presented with lymph node or liver metastases. The surgical resections included 106 pancreatic tumor enucleations and 92 anatomic pancreas resections.
The mortality of resection was 0, and the overall morbidity was 52%. There were clinically significant pancreatic fistulas in 18%, with similar rates between resection and enucleation. Reoperation was substantially more common after enucleation procedures (9%) than resections (1%). Six patients suffered recurrences, five of whom had higher grade tumors, and four patients died of disease. This series supports the prevailing concepts that insulinoma is usually solitary, benign, and curable, but draws attention to the exceptions as well.
Gastrinoma is the other relatively common functional PNET, causing gastric acid hypersecretion and Zollinger–Ellison Syndrome through gastrin production. In comparison to insulinoma, gastrinoma is more commonly associated with invasive tumors, spread to lymph nodes, and liver metastases. The syndrome management for gastrinoma is simplified by the availability of potent acid-suppression medications, such as proton-pump inhibitors, that can completely suppress the acid production and symptoms. This has led to some speculation that, in patients without imageable disease, nonoperative acid-suppression therapy might be a preferable alternative to operative management.
Norton et al.[18▪] reported a large series of patients from the US National Cancer Institute that provides data regarding this issue. They described 58 patients with sporadic (as opposed to familial) gastrinoma and negative preoperative imaging for tumor, who had operative exploration. Tumor was identified in 57 of 58 patients, and 60% of tumors were less than 1 cm in size.
At a mean follow-up of 9.4 years, 46% of patients were disease free; three patients died of disease, each of whom had liver metastases identified at initial operation. This survival was longer than a contemporaneous cohort of patients with imaging-positive disease prior to their operation. They conclude, reasonably, that operative exploration is indicated in the group of patients with gastrinoma and negative imaging, in order to delay treatment delay that may allow liver metastases to develop.
OPERATIVE MANAGEMENT OF LIVER METASTASES
Liver metastases are an important issue in the management of NET, both because of their frequency and because the relatively indolent nature of the diseases changes the dynamics of therapy compared to patients with adenocarcinoma. In general, this makes incomplete resections or ablations more helpful for NET patients than this strategy is in other tumor types.
Cusati et al.[19▪] from the Mayo Clinic evaluated patients who had liver resections for metastatic nonfunctional PNET between 1987 and 2008. Of the 72 patients, there was curative intent in 39 and palliative intent (by >90% resection of disease) in 32. The median number of tumors resected was eight, and the median tumor size was 4.5 cm. Operative mortality was 0, though morbidity was 50%.
The overall survival at 1, 5, and 10 years was 97, 60, and 45%, respectively. The progression-free survival for intended curative operations was no different than for known palliative operations (1 year: 54 vs. 58%; 5 year: 11 vs. 4%). It seems reasonable to envision all of these operations as palliative. This high rate of recurrence with good survival encourages the aggressive approach to palliating symptoms of disease progression.
Gaujoux et al.[20▪] from Memorial-Sloan Kettering Cancer Center evaluated their experience in 36 patients who had synchronous liver and primary tumor resection for NET. They reported that 1 patient died after a pancreaticoduodenectomy and hepatic trisegmentectomy; in the remaining patients, the morbidity was 44%. These very complicated operations were followed by a 5-year survival of 69% and 5-year symptom-free survival of 60%. The authors report that patients were highly selected for both medical fitness and resectability before following this strategy. One can surmise from this series that complex procedures may be followed by acceptable operative risk and reasonable survival outcomes, if patients are well selected.
NETs are uncommon and have important tumor-specific biology that dictates optimal surgical management strategies. As centers with expertise have developed, the promulgation of guidelines may help to improve the standard of care for these diseases. Incremental data culled mainly from the recent experiences in therapy will help to inform the guidelines.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 76).
1. Salazar R, Wiedenmann B, Rindi G, Ruszniewski P. ENETS 2011 Consensus Guidelines for the management of patients with digestive neuroendocrine tumors: an update. Neuroendocrinology 2012; 95:71–73.
2. Pavel M, Baudin E, Couvelard A, et al. ENETS Consensus Guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary. Neuroendocrinology 2012; 95:157–176.
3. Pape UF, Perren A, Niederle B, et al. ENETS Consensus Guidelines for the management of patients with neuroendocrine neoplasms from the jejuno-ileum and the appendix including goblet cell carcinomas. Neuroendocrinology 2012; 95:135–156.
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6. Delle Fave G, Kwekkeboom DJ, Van Cutsem E, et al. ENETS Consensus Guidelines for the management of patients with gastroduodenal neoplasms. Neuroendocrinology 2012; 95:74–87.
7. Caplin M, Sundin A, Nillson O, et al. ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms: colorectal neuroendocrine neoplasms. Neuroendocrinology 2012; 95:88–97.
8. Clark OH, Benson AB 3rd, Berlin JD, et al. NCCN Clinical Practice Guidelines in Oncology: neuroendocrine tumors. J Natl Compr Canc Netw 2009; 7:712–747.
9. Visser BC, Ma Y, Zak Y, et al. Failure to comply with NCCN guidelines for the management of pancreatic cancer compromises outcomes. HPB 2012; 14:539–547.
10▪. Cheema A, Weber J, Strosberg JR. Incidental detection of pancreatic neuroendocrine tumors: an analysis of incidence and outcomes. Ann Surg Oncol 2012; 19:2932–2936.
Comparison of outcomes of tumors based upon symptoms or incidental discovery.
11▪. Inchauste SM, Lanier BJ, Libutti SK, et al. Rate of clinically significant postoperative pancreatic fistula in pancreatic neuroendocrine tumors. World J Surg 2012; 36:1517–1526.
Description of the occurrence of pancreatic fistula after PNET surgery.
12▪. Norton JA, Harris EJ, Chen Y, et al. Pancreatic endocrine tumors with major vascular abutment, involvement, or encasement and indication for resection. Arch Surg 2011; 146:724–732.
Outcomes of surgery for PNET with vascular involvement.
13▪. Strosberg JR, Cheema A, Weber JM, et al. Relapse-free survival in patients with nonmetastatic, surgically resected pancreatic neuroendocrine tumors: an analysis of the AJCC and ENETS Staging Classifications. Ann Surg 2012; 256:321–325.
A comparative analysis of ENETS and AJCC staging systems for NET applied to PNET.
14▪. Norlen O, Stalberg P, Oberg K, et al. Long-term results of surgery for small intestinal neuroendocrine tumors at a tertiary referral center. World J Surg 2012; 36:1419–1431.
Outcomes from a very large series of SNET from a Swedish center.
15. Norlen O, Hessman O, Stalberg P, et al. Prophylactic cholecystectomy in midgut carcinoid patients. World J Surg 2010; 34:1361–1367.
16. Hellman P, Hessman O, Akerstrom G, et al. Stenting of the superior mesenteric vein in midgut carcinoid disease with large mesenteric masses. World J Surg 2010; 34:1373–1379.
17▪. Crippa S, Zerbi A, Boninsegna L, et al. Surgical management of insulinomas: short- and long-term outcomes after enucleations and pancreatic resections. Arch Surg 2012; 147:261–266.
A modern series of insulinoma that demonstrates the spectrum of disease and the outcome of therapy.
18▪. Norton JA, Fraker DL, Alexander HR, Jensen RT. Value of surgery in patients with negative imaging and sporadic Zollinger–Ellison syndrome. Ann Surg 2012; 256:509–517.
Outcomes of operation for gastrinoma showing benefit to exploration for imaging-negative disease in patients with sporadic tumors.
19▪. Cusati D, Zhang L, Harmsen WS, et al. Metastatic nonfunctioning pancreatic neuroendocrine carcinoma to liver: surgical treatment and outcomes. J Am Coll Surg 2012; 215:117–124.discussion 24–25.
Outcomes of liver resection for metastatic PNET showing benefit for selected patients.
20▪. Gaujoux S, Gonen M, Tang L, et al. Synchronous resection of primary and liver metastases for neuroendocrine tumors. Ann Surg Oncol 2012 [Epub ahead of print].
Outcomes of simultaneous primary and liver PNET showing benefit for selected patients.