A Review on Surgery of Gastro-Entero-Pancreatic Neuroendocrine Tumors

S Partelli and others A review on surgery of NETs 171:4 R153–R162 Review

GEP–NETS UPDATE A review on surgery of gastro-entero-pancreatic neuroendocrine tumors

1 Stefano Partelli, Angela Maurizi, Domenico Tamburrino , Andrea Baldoni, Correspondence Vanessa Polenta, Stefano Crippa and Massimo Falconi should be addressed to M Falconi Pancreatic Surgery Unit, Universita` Politecnica delle Marche, Via Conca, 71, 60126 Ancona, Italy and 1Department Email of Surgery, University of Verona, Verona, Italy [email protected]

Abstract

The incidence of neuroendocrine tumors (NETs) has increased in the last decades. Surgical treatment encompasses a panel of approaches ranging from conservative procedures to extended surgical resection. Tumor size and localization usually represent the main drivers in the choice of the most appropriate surgical resection. In the presence of small (!2 cm) and asymptomatic nonfunctioning NETs, a conservative treatment is usually recommended. For localized NETs measuring above 2 cm, surgical resection represents the cornerstone in the management of these tumors. As they are relatively biologically indolent, an extended resection is often justiﬁed also in the presence of advanced NETs. Surgical options for NET liver metastases range from limited resection up to liver transplantation. Surgical choices for metastatic NETs need to consider the extent of disease, the grade of tumor, and the presence of extra-abdominal disease. Any surgical procedures should always be balanced with the beneﬁt of survival or relieving symptoms and patients’ comorbidities.

European Journal of Endocrinology (2014) 171, R153–R162 European Journal of Endocrinology

Introduction

Neuroendocrine tumors (NETs) arise from the cells present classiﬁcations for NETs. The gastro-entero-pancreatic throughout the diffuse endocrine system. They comprise (GEP) NETs present as functioning or nonfunctioning a broad family of tumors, the most common of which tumors. Functioning tumors are commonly associated arise in the lungs and bronchi, small intestine, appendix, with a speciﬁc hormonal syndrome directly related to a rectum, and pancreas. These neoplasms were previously hormone secreted by the neoplasm, such as insulinomas, regarded as rare, but in fact are increasing in incidence gastrinomas with Zollinger–Ellison or carcinoid syndrome (3.65/100 000 individuals per year) (1) and occur as (3). Most of NETs share the characteristic of longer survival frequently as testicular tumors, Hodgkin’s disease, glio- than adenocarcinomas originating from the same organs. mas, and multiple myeloma (2).Therearemultiple As a consequence, surgery plays a key role not only for

Invited Author’s proﬁle Dr M Falconi is currently Associate Professor of Surgery and Chairman of the Pancreatic Unit, University Politecnica delle Marche (Ancona, Italy). He studied medicine at the University of Verona, specializing in general surgery, gastroenterology, and endoscopy. He has participated in international medical research projects in such diverse places as Germany, Spain, Ecuador, and Japan. A member of many medical societies, including IAP, EPC, and EHPBA, Prof. M Falconi is currently on the executive committees of ENETS and IAP.

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localized tumors but also for advanced NETs. Tumor imaging-based observation with a first control after grading and tumor stage represent the main prognostic 6 months from diagnosis seems to be reasonably safe. factors of NETs. Well- and moderately differentiated NETs Preliminary reports have demonstrated the safety of this defined by a value of Ki67 !20% have a significantly conservative approach (9, 12, 13). Lee et al. (12) retro- better survival compared with poorly differentiated spectively analyzed 134 patients with pancreatic NET neuroendocrine carcinomas. Similarly, a small tumor !2 cm. Of those, 57 underwent surgery with a risk of size, along with the absence of metastases, is associated complications of nearly 50%. The remaining 77 patients with a lower risk of recurrence after surgery (4). Sub- were conservatively managed and they were all free of sequently, surgical treatment of NETs is strictly related to progression disease. In addition, Gaujoux et al. (13) the localization of NETs, the grade of tumor, and the stage published a bi-institutional study where they observed of disease. Surgery can be a valid option in all stages of 46 patients with small, incidentally discovered pancreatic disease ranging from conservative approach to radical NETs. Overall, eight patients (17%) underwent surgery operations that include multiple organs resection and also after a median time of 41 months. All resected tumors were liver transplantation (LT). This article aims to elucidate the T stage 1 (nZ7) or 2 (nZ1), node negative with neither best surgical management of patients with GEP NET and to vascular or peripancreatic fat invasion. address the role of different surgical procedures. On the other hand, surgery still represents the treatment of choice for pancreatic NETs O2 cm and/or for symptomatic forms. Radical surgery for pancreatic Management of localized disease NETs includes both typical and atypical pancreatic The management of localized GEP NET depends mainly resections. Typical resections differ according to tumor on tumor size, tumor localization, and patients’ comor- site: lesions of the pancreatic head are treated with bidities. Surgical resection is often the best treatment for a pancreaticoduodenectomy, while lesions of the body the majority of localized NETs, although a conservative and tail with a distal pancreatectomy. Currently, when approach is currently advocated for small, incidentally performed in high-volume centers, pancreatic typical discovered tumors. Small, benign neoplasms are usually resections have an acceptable mortality rate (!5%), readily curable by surgical resection with a favorable although the percentage of complications is still signi- prognosis, although all these tumors should always be ficant ranging from 40 to 50% (14, 15). Typical pancreatic considered as potentially malignant (3).Themain resections are also associated with a high incidence of European and North American guidelines recommend exocrine and endocrine insufficiency (16). Risk of long-

European Journal of Endocrinology surgical resection for localized NETs irrespective of tumor term pancreatic impairment has increased the use of grading (5, 6, 7). parenchyma-sparing techniques or atypical resections such as enucleation and middle pancreatectomy that Pancreatic NETs " The incidence of small, incidentally consists of the resection of the central part of the gland. discovered pancreatic NETs has increased significantly in Currently, these procedures are limited only for small the last decade with the widespread use of high-quality functioning tumors (!2 cm) (17). In particular, surgery imaging techniques (8). Incidental diagnosis of pancreatic still plays an important role in the management of NETs is associated with a significantly better survival after insulinomas. Recurrence after surgery for insulinomas is curative resection compared with patients with symptoms exceptional and these neoplasms can be safely resected (9). Moreover, Bettini et al. (10) demonstrated that with enucleation that can be performed both with an patients with incidental diagnosis associated with a ‘open’ approach and laparoscopically (18, 19). The role of tumor size !2 cm had a 5-year overall survival of 100% lymphadenectomy for patients with pancreatic NET is still with a minimal risk of recurrence. On the basis of these unclear (20). Lymph node metastases occur only in the experiences, the European Neuroendocrine Tumor Society 30% of patients affected by these tumors (20), but the (ENETS) guidelines now recommend a ‘wait and see’ association between node metastases and poorer survival policy in selected patients with asymptomatic sporadic is still debated (4). pancreatic NETs (5). This management should be considered only in the presence of a low-grade (G1) NET. Gastric NETs " Borch et al. (21) studied a total of Consequently, tumor grading should always be assessed 65 patients with gastric NETs of different types from by fine-needle aspiration or biopsy (11). Although a 24 hospitals and managed with a differentiated treatment follow-up protocol has not been investigated, a yearly in relation to type. The conclusion of this study is that the

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type of gastric NETs is helpful in the prediction of metastases are common also with small tumors (33). These malignant potential and long-term survival and it is a metastases will often grow conspicuously large and may be guide to management. Three types of gastric NETs are mistaken to represent the primary tumor. As tumor spread generally recognized: type 1 (associated with chronic to the lymph nodes and liver can occur also in patients atropic gastritis), type 2 (associated with Zollinger–Ellison with small primary tumors, surgery of the primary tumors syndrome), and type 3 (sporadic) (22). Types 1 and 2 should adhere to oncological principles. This involves gastric NETs are both associated with hypergastrinemia. clearance of lymph node metastases by dissection around Treatment options for types 1 and 2 gastric NETs !2cmor the mesentery (30). The surgical procedure should include smaller include: i) endoscopic mucosal resection, if careful examination of the entire bowel, because multiple feasible, with biopsy of the tumor and adjacent mucosa synchronous lesions may be present. Surgery at an early and ii) observation (23, 24, 25). Currently, there is no stage of the disease is favorable when growth is less evidence that endoscopic resection is superior to endo- extensive in the mesentery (32, 34). Colon NETs should be scopic surveillance. However, when tumor invades behind treated with an appropriate right or left-sided hemico- the submucosa, positive resection margins after endo- lectomy or sigmoidectomy (35). scopic mucosal resection, multiple tumors O1cm or regional lymph node metastasis, local resection, or Appendiceal NETs " Appendiceal NETs are often ident- gastrectomy should be performed (23). Gastric resection ified incidentally, during appendectomy performed for procedures include total gastrectomy and sparing appendicitis (36). Most NETs of the appendix have well- procedures such as partial gastrectomy or antrectomy. differentiated histology, and for most tumors !2 cm and Antrectomy plays a role in avoiding gastrin stimulation confined to the appendix, simple appendectomy is and is effective in nearly 80% of type 1 gastric NETs sufficient because metastases are uncommon (37). (26, 27). Surgery in type 2 tumors is focused on removing However, some controversy exists regarding the manage- the source of hypergastrinemia, either by excision of ment of appendiceal NETs measuring below 2 cm with mostly duodenal gastrinomas via duodenotomy or by more aggressive histologic features (38, 39). According pylorus-preserving pancreaticoduodenectomy. Patients to Moertel et al. (36), patients with larger tumors and with non-metastatic gastric NET and normal gastrin levels metastasis are younger than those with smaller and (type 3) present usually more aggressive tumors and they clinically benign tumors. As a result of a retrospective should be treated with radical resection of the tumor analysis of 1570 appendiceal NETs, performed by Sandor with meticulous regional lymphadenectomy (24, 28). et al. (39), it was highlighted that careful evaluation and

European Journal of Endocrinology postoperative follow-up are of paramount importance NETs of the duodenum, papilla of Vater, small because of the increased risk of coexisting neoplasms and intestine, and colon " For localized lesions arising in the uncommon presentation of metastatic disease. the duodenum, endoscopic resection is recommended, Patients with an incomplete resection or tumors larger when feasible. In particular, endoscopic resection is than 2 cm are at risk for locoregional or distant metastases recommended for duodenal NETs !1 cm, whereas the andtheyshouldundergore-explorationwithright optimal treatment for lesions measuring between 1 and colectomy (37). Right colectomy is also considered as the 2 cm is more controversial, with some recommending treatment of choice for appendix goblet cell tumors as the endoscopic removal and others recommending surgical risk of metastases is very high (40). treatment (29). Transduodenal local excision with or without lymph node sampling and pancreaticoduode- Rectal NETs " The treatment of rectal lesions is based on nectomy are other options for primary treatment of the size of the primary tumor. If the lesion is 2 cm or less, non-metastatic duodenal NETs O2 cm. Nevertheless, the endoscopic or transanal excision is recommended (41, 42). optimal approach remains unclear as the biological Given the higher risk of invasion with larger tumors, behavior of these NETs remains largely unknown (30, 31). examination under anesthesia and/or endoscopic ultra- Although ileum/jejunum NETs often present with sound (EUS) before the procedure should be considered metastases at diagnosis, surgical treatment has become for tumors 1–2 cm in size. Tumors larger than 2 cm, those increasingly important for their management (32). For with invasion of the muscularis propria, or those associated patients presenting with tumors in the jejunum/ileum, with lymph node metastases should be treated with low surgical resection of the bowel with regional lymphade- anterior resection or, in rare cases, an abdominoperineal nectomy is recommended (30). Mesenteric lymph node resection (42).

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Surgery of advanced NETs lower rate of progression in those with resection of the primary compared with the unresected cohort were Several treatment modalities are available in the manage- demonstrated (53). Published recommendations differ ment of advanced NETs. These treatments include for small intestine and pancreatic NETs. Indeed, while somatostatin analogs, peptide receptor radionuclide ENETS suggests the removal of the primary tumor to therapy, targeted therapies (everolimus and sunitinib), make the only persisting problem for intestinal NETs and chemotherapy (43). In this setting, surgery should (30), the resection of the primary tumor in metastatic always be included in a multimodal approach. pancreatic NETs is not recommended, except for selected Surgical management of advanced and/or metastatic low-risk patients with life-threatening symptoms due NETs is still controversial. While patients with hormonal to complications (5). Concerning intestinal NETs, a symptoms can be relieved with cytoreductive procedures, systematic review by Capurso et al. (54) demonstrated a the role of surgery for patients with non-functioning possible benefit of resection of the primary lesion in disease is more debated. In particular, it is still unclear patients affected by small intestinal NETs with unresect- about the role of primary tumor resection and the impact able LM. They demonstrated a clear trend toward longer of liver metastases (LM) resection on survival. As most of survival in patients who underwent surgical resection in NETs have a low aggressive behavior, a tendency to all studies, with a median overall survival ranging from promote aggressive surgery, even in the presence of LM, 75 to 139 months compared with 50–88 months in exists. Generally, when R0 resection is achievable, an patients who did not have resection (54). Regarding aggressive approach for well-differentiated NETs, possibly pancreatic NETs, another systematic review by Capurso ! with a Ki67 10%, is widely used (44, 45, 46). Some et al. (55) evaluated the potential benefits or harms of patients present with locally advanced tumors with local surgical resection of the primary lesion without con- infiltration of the portal vein or stomach. For these comitant resection of metastases. This systematic review patients, a pancreatic resection extended to nearby organs included three studies (56, 57, 58), one prospective study might be a valuable option (47). Nevertheless, the choice with a relatively small sample size and an other two of surgery is often influenced not only by the improve- retrospective studies. The overall survival data did not ment in survival but also by the risk–benefit balance differ significantly in the two studies (56, 58), whereas regarding morbidity and mortality. ENETS guidelines the third study (57) did not report data on overall identified some essential prerequisites before performing survival. Nevertheless, the 5-year survival rate seemed surgery in patients with LM from digestive NETs (48). generally higher in patients who had their primary

European Journal of Endocrinology These criteria include: i) the presence of well-differentiated tumor resected, with a difference of 30% in one study, lesions (Ki67 !5%); ii) the absence of right heart of 33% in a second (57), and no difference in a third insufﬁciency; iii) the absence of extra-abdominal disease; study (56). Given the absence of randomization in the and iv) the absence of diffuse peritoneal carcinomatosis examined studies, a bias toward a more aggressive (48). Under these circumstances, we recognize two approach in patients with a better overall performance different phases in the management of these patients, status, a less advanced disease, or possibly with location which are the primary tumor resection and the surgical of the tumor in the body or tail of the pancreas seems treatment of liver lesions. likely. When synchronous resectable LM is present, a combined surgical approach is a valid option. Surgery of primary tumor Surgery of LM At the time of diagnosis, more than 80% of LM are bilobar (49) and curative resection is not possible. Curative resection (R0/R1) is associated with a better Synchronous liver and pancreatic resection seem to be long-term survival in all series and survival rates of associated with a better survival, although the risk of 60–80% can be achieved (48). However, the overall recurrence remains high (50, 51, 52). The removal of survival after hepatic resection has been reported in primary tumor in the presence of unresectable LM is still 46–86% at 5 years and 35–79% at 10 years (49, 59, 60, debated. Potential advantages may be to relieve symp- 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72). This wide toms and to increase survival. In particular, in patients heterogeneity reﬂects the selection bias that is present in with symptomatic non-functioning pancreatic NET and the majority of series. In addition, Elias et al. (73) unresectable LM, a marked reduction of symptoms and a reported that fewer than 50% of the LM were detected

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by preoperative imaging modalities compared with a Liver transplantation final pathological count. These results suggest that NET NET metastases represent at this moment an indication of LM are frequently more extensive than identified, even LT. The review of the European Liver Transplant Registry intraoperatively, and that a real curative R0/R1 resection (ELTR) data reveals that the transplant experience in NET is difficult to achieve. Mayo et al. (74) reported one of patients is limited and ill defined (80). Moreover, all usable the largest series of patients who underwent surgical information about the value of LT in the treatment of management for neuroendocrine LM. Median survival in NETs comes from small, single-center series and from two this study was 125 months, but disease recurred in multicentric retrospective studies (81, 82). Considering nearly all the patients, confirming that a real curative their former experience with hepatocellular cancer, the resection is far from being achieved in metastatic NETs. Milan group improved the results of LT for NETs by In order to select patients who will really benefit from prospectively applying strict inclusion criteria. These surgery, an accurate preoperative imaging work-up is criteria include the following: i) well-differentiated NETs necessary. Indeed, the main criterion in the assessment (Ki67 !5%); ii) portosystemic tumor drainage; iii) patient of possible surgical resection for LM from NETs is age !55 years; iv) stable disease for at least 6 months; morphological and it regards the localization of lesions. v) pre-transplant R0 primary tumor resection; vi) hepatic Frilling et al. (75) defined the role of aggressive surgical tumor involvement !50% of the liver volume; and resection in relation to localization patterns of neuro- vii) absence of extra-hepatic disease (83). Recently, endocrine hepatic metastases. In this study, three Le Treut et al. (84) have described a large retrospective different patterns of metastatic spread were identified: cohort of 213 patients who underwent LT for NETs, which single metastasis of any size (type 1); isolated metastatic represents by far the largest cohort in the literature. At a bulk accompanied by smaller deposits, with both liver mean follow-up of 56 months, 17% of patients died from lobes always involved (type 2); and disseminated early or late complications of LT and the 5-year overall metastatic spread, with both liver lobes always involved, survival rate was 52% with a disease-specific survival rate single lesion of varying size, and virtually no normal of 30%. These results demonstrate that LT is a valid option liver parenchyma (type 3). All patients with type 1 in well-selected patients with neuroendocrine LM, metastases underwent R0 resection, none of patients although post-operative mortality is still high. with type 2 metastases were suitable for staged hepatic resection, and the 21% of type 3 patients underwent LT. Patients with type 1 LM had a significantly better Surgery of NETs in multiple endocrine neo- European Journal of Endocrinology survival than patients with types 2 and 3 metastases. plasia type 1 patients This advantage is mainly related to the higher prob- ability of performing a curative resection for unilobar Surgical management of NETs in affected patients is often metastases. On the other hand, the management of challenging, especially for the presence of multifocal bilobar LM is often challenging. In this setting, pancreatic neoplasms. Nearly 80% of patients with Kianmanesh et al. (76) evaluated the feasibility of a multiple endocrine neoplasia type 1 (MEN1) had multiple strategy based on a two-step surgical approach. This duodenal and/or pancreatic NETs. These tumors include technique includes a first step when primary tumor and non-functioning NETs (80–100%), gastrinomas (54%), all left-sided LM are resected while a portal vein ligation and insulinomas (18%) (85). Surgery is mandatory for is performed to induce hypertrophy in the left liver. Two i) functioning tumors, ii) tumors with resectable LM, months later, in the absence of tumor progression, a iii) tumors with size O2 cm, and iv) for symptomatic non- second step including a right or extended right functioning NETs (86). Atypical, parenchyma-preserving hepatectomy is planned. This surgical approach proved procedures are always preferred in respect of total to be safe with a 5-year disease-free survival of 50% pancreatectomy even in the case of multifocal NETs (87). and represents a valid option in the management of On the contrary, total pancreatectomy is highly rec- bilobar LM from NETs (76). As disease progression is ommended in the presence of a familial history of a common occurrence, a multimodality treatment disease-related mortality (85). Pancreatic NETs !2cm approach for progressive disease is necessary (77). For are associated with a very low risk of metastases and small NET LM, radiofrequency ablation has been proven mortality (88). For this reason, for patients with MEN1 as safe and effective in prolonging survival and relieving affected by pancreatic NETs !2 cm, a careful watching symptoms (78, 79). policy is recommended. In these patients, it seems

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advisable to perform a yearly follow-up with a prompt recommended both for sporadic and inherited forms indication for surgery when tumor diameter growth because of the high risk of complications. For metastatic O5 mm/year (89). NETs, surgery plays a role when liver involvement is Surgical treatment of gastrinomas in MEN1 patients is limited, in the presence of low-grade tumors, and in the still debated (90). A conservative approach, with medical absence of extra-abdominal lesions. treatment of hypergastrinemia, is recommended (91).On the contrary, other authors suggest a surgical treatment for

tumors O3 cm in size or when a biochemical diagnosis Declaration of interest is unequivocal (92, 93). Nevertheless, patients who are The authors declare that there is no conflict of interest that could be conservatively treated have a risk of LM of 23–29% perceived as prejudicing the impartiality of the review. compared with 3–5% of those patients who undergo radical surgery (94, 95). The extension of surgery in these patients is also a matter of debate. Thompson (96) suggests Funding This review did not receive any specific grant from any funding agency in a procedure that includes duodenotomy, enucleation of the public, commercial, or not-for-profit sector. all pancreatic NETs, and locoregional lymphadenectomy. Other authors recommend a Whipple’s pancreaticoduodenectomy because this procedure is associated with a rate References of cure of 77% (97, 98, 99, 100). We recommend a Whipple’s pancreaticoduodenectomy for gastrinomas in 1 Lawrence B, Gustafsson BI, Chan A, Svejda B, Kidd M & Modlin IM. MEN1 patients. The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinology and Metabolism Clinics of North America 2011 40 1–18 Primary hyperparathyroidism (HPT) is associated with (vii). (doi:10.1016/j.ecl.2010.12.005) MEN1 syndrome in the 80–90% of cases (101). HPT in 2 Modlin IM, Oberg K, Chung DC, Jensen RT, de Herder WW, patients with MEN1 syndrome is usually more aggressive Thakker RV, Caplin M, Delle Fave G, Kaltsas GA, Krenning EP et al. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncology than sporadic HPT and often involves multiple glands 2008 9 61–72. (doi:10.1016/S1470-2045(07)70410-2) (102). Surgery is the treatment of choice for HPT in 3 Niederle MB, Hackl M, Kaserer K & Niederle B. Gastroenteropancreatic patients with MEN1 syndrome (103, 104). Many authors neuroendocrine tumours: the current incidence and staging based recommend a subtotal parathyroidectomy (including on the WHO and European Neuroendocrine Tumour Society classification: an analysis based on prospectively collected parameters. at least three glands) or, alternatively, a total para- Endocrine-Related Cancer 2010 17 909–918. (doi:10.1677/ERC-10-0152) thyroidectomy with autotransplantation (103, 105, 106). 4 Bilimoria KY, Talamonti MS, Tomlinson JS, Stewart AK,

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Received 28 February 2014 Revised version received 3 June 2014 Accepted 11 June 2014 European Journal of Endocrinology

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