Endocrine-Related Cancer 10.1530/ERC-17-0285 of differentNETs (forexample,pancreatico-duodenal 2013 neuroendocrine tumors(NETs) ( increase inmortalityfrommalignancy, particularlyfrom This decreaseinmortalityfrom hormoneexcessledtoan Lamers 1978 of thepatientsinsomeearlyseries( excess; thiswasthecauseofdeathformorethan75% to amajordecreaseinmortalitycausedbyhormone of theexcessproductiondifferenthormones,leading of patientswithMEN1isthepossibilitytocontrolmost over thelast20 years. Amajoradvanceinthemanagement The managementofMEN1-associatedNETs hasevolved Introduction duodenal NETs andthymic bronchial NETs. surgical managementofMEN1-associatedfunctionalandnon-functionalpancreatico- quality oflife.Herein,wereviewthechangesthatoccurredinlast20 years patient remainsdisease-andsymptom-freeforaslongpossiblemaintainsagood high riskofrecurrence.TheoverallaimmanagementinMEN1istoensurethatthe associated withminimalmorbidity. Thismustbeappliedtoahereditarydiseasewith therapy becauseoftheriskaggressivebehaviorandtoselectappropriate NETs. Themainchallengesareto localizethesetumors,toselectthosethatneed however, theyhavealsoledtoanincreaseinmortalityfrommalignancy, particularly the managementofMEN1haveledtoadecreaseinmortalitydueexcesshormones; disorder associatedwithnumerousneuroendocrinetumors(NETs). Recentadvancesin Multiple endocrineneoplasiatype1(MEN1)isahereditaryautosomaldominant Abstract Centre, ClinicalEpidemiology/ClinicalTrials Unit,Dijon,France Oncology Team, andINSERM,CIC1432,ClinicalEpidemiologyUnit,UniversityHospitalofDijon,Investigation 4 3 2 1 S M Sadowski management strategies therapeutic approaches and The future: surgical advances inMEN1 Endocrine Surgery, UniversityHospitalofDijon,andINSERM,U866,EpidemiologyClinicalResearchinDigestive Oncology, OscarLambretCancerCenter, UniversityofLille,France Gastroenterology andHepatology, UniversityHospitalofReims,France Thoracic andEndocrineSurgeryFacultyofMedicine,UniversityHospitalsGeneva,Switzerland http://erc.endocrinology-journals.org DOI: 10.1530/ERC-17-0285 Thematic Review ). Researchers recognized early the aggressive potential , Majewski & Wilson 1979 1 , G Cadiot 2 , E Dansin Goudet S MSadowski et al. © 2017SocietyforEndocrinology 3 Published byBioscientifica Ltd. , P Goudet Ballard , et al Vasen Printed inGreat Britain . 2010 t al et et al 4 , and Ito . 1989 . 1964 et al F Triponez ). . ,

functional orNFandsecrete manydifferenthormones, Duodeno-pancreatic NETs (pNETs) inMEN1areeither Duodeno-pancreatic NETs the surgicalmanagementofMEN1-associated NETs. in the mainchangesthathaveoccurredinlast20 years have beenperformedrecently. Inthisreview, wewilldescribe the recommendationsoverlasttwodecades. aggressive surgery, leadingto numerousmodificationsin however, they alsorecognizedthedeleteriouseffects of NETs, mainlynon-functional (NF),andthymicNETs); management ofMEN1 Advances insurgical The guesteditorsfor thissectionwereLoisMulliganandFrank Weber. This paperispartofa thematicreviewsectionon20Years of MEN1. Despite the rarity of MEN1, many high-quality studies Despite the rarity of MEN1, many high-quality studies 1 Downloaded fromBioscientifica.com at10/02/202102:21:49AM f f f f f f f f f f (2017) Endocrine-Related Cancer [email protected] Email to FTriponez should beaddressed Correspondence lung NET NET pancreatico-gastro-intestinal thymic NET (NET) neuro-endocrine tumors neoplasia type 1 (MEN1) multiple endocrine Key Words 24 10 24: 24 , T243–T260 10 T243

–T260

via freeaccess Thematic Review S M Sadowski et al. Advances in surgical 24:10 T244 management of MEN1

such as gastrin, insulin, pancreatic polypeptide (PP) or at 8–9 years (Cadiot et al. 1999). The only predictive vaso-intestinal polypeptide (VIP), which are associated factor for developing liver metastases is the size of pNETs, with distinct clinical syndromes. The incidence of pNETs with a 2.5–3 cm threshold in older series (Cadiot et al. in patients with MEN1 varies between 30 and 80% 1999, Norton et al. 2001) and a 2 cm threshold in the (Brandi et al. 2001, Goudet et al. 2011). Usually pNETs more recent studies. However, it is unclear whether the have an earlier onset in patients with MEN1 than in metastases came from the gastrinomas or the NF-pNETs. those without (Triponez et al. 2006a, Machens et al. 2007) This threshold is currently used for the management of and their hallmark is multiplicity in contrast to solitary patients with MEN1 and NF-pNETs (Partelli et al. 2016, sporadic pNETs. The main challenge is to locate the Triponez et al. 2006b, 2017). In patients with non- functional tumor among the NF tumors. metastatic disease and ZES–MEN1, 6% of those without a large pNET (<3 cm) developed liver metastases compared with 40% of those with pNET 3 cm, although the Gastrinoma and Zollinger–Ellison syndrome ≥ resection of the largest tumors was performed in 9 out The management of patients with Zollinger–Ellison of 10 patients with large tumors (Cadiot et al. 1999). The Syndrome (ZES) and MEN1 (ZES/MEN1) is more specific long-term prognosis of patients without large pNET or than that of patients with other types of pNETs related liver metastases is very good, reaching 95% at 10 years to MEN1, especially NF tumors. ZES/MEN1 is a fairly (Gibril et al. 2001). In patients with ZES/MEN1 who had common condition, as 20–30% of patients with ZES have an unfavorable outcome, 14% had aggressive tumor MEN1 (Mignon & Cadiot 1998, Falconi et al. 2016). ZES is growth, more metastases (liver 100% vs 10% in patients the most frequent functioning pNET type in patients with with a favorable outcome, bone 38% vs 0%) and a shorter MEN1, with an incidence of up to 28.5% in the ‘Groupe survival (88% vs 100% during follow-up) (Gibril et al. d’études des tumeurs neuro-endocrines’ (GTE)-MEN1 2001). Clinically, the main question is how to identify cohort of a total of 758 patients (Goudet et al. 2010). Its patients at high risk of metastases or death when they do prevalence has proportionally decreased over time because not have large tumors. The role of histo-prognostic factors of the easier recognition of NF-pNETs resulting from such as tumor grading obtained by EUS-guided biopsy has improvement in imaging techniques, notably endoscopic not been studied in MEN1 patients. Fluorodeoxyglucose ultrasound (EUS) and magnetic resonance imaging (MRI) positron emission tomography (FDG-PET) positivity is (Triponez et al. 2006a). associated with higher grade pNETS in patients with Endocrine-Related Cancer Endocrine-Related Pathologically, almost all gastrinomas are found in the MEN1 (Kornaczewski Jackson et al. 2017). Studies are duodenal wall (Anlauf et al. 2007, Falconi et al. 2016) and required to determine whether this could be used to select are associated with hyperplastic gastrin cell lesions and patients with ZES–MEN1 at risk of metastases or death. very small gastrin-producing micro-tumors of less than Questions about the management of patients with ZES 0.5 mm in diameter. Furthermore, multiple pancreatic and MEN1 concern ZES diagnosis, the search for tumors, NETs are almost always associated with duodenal NETs. treatment of the consequences of gastric hypersecretion They less commonly produce gastrin and cause ZES and the treatment of these tumors. (<15%) (Anlauf et al. 2007, Falconi et al. 2016), as most are NF tumors. However, they can secrete glucagon and/or Diagnosis of ZES pancreatic polypeptide (Anlauf et al. 2007). These tumors are usually small; in a French series of 77 patients with Gastrin-immunoreactive NETs, i.e. gastrinomas, must be ZES–MEN1, only 10 had pNETs measuring 3 cm or more distinguished from NETs associated with a functioning (Cadiot et al. 1999). syndrome, i.e. ZES; this is determined by gastric acid Prognostically, specific survival is mainly determined hypersecretion because of unregulated tumor-related by liver metastases (Goudet et al. 2010, Ito et al. hypergastrinemia. Compared with sporadic NETs, 2013). Gastrinomas have a higher mortality rate than in MEN1, we can observe the early development of insulinomas, but not than other types of pNETS, notably functioning syndromes such as ZES, because patients NF-pNETs (Goudet et al. 2010). In the 2 largest series of with MEN1 are young. Patients with ZES and MEN1 are patients with ZES–MEN1, the prevalence of liver metastases on average 10 years younger than those with sporadic ZES was 6–16% at the time of diagnosis (Jensen et al. 2008) at the time of diagnosis (Jensen et al. 2008, Singh et al. and their risk of developing liver metastases was 9–10% 2012). Therefore, ZES should be considered in patients

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with MEN1 with new digestive symptoms, including loose surgically, the treatment of multiple duodenal tumors stools, especially when diarrhea promptly disappears when that secrete gastrin. using proton pump inhibitor (PPI) therapy, epigastric pain and signs of gastroesophageal reflux even without severe Anti-secretory treatment There is no difference in esophagitis or tiny duodenal erosions on gastroscopy. anti-secretory treatment depending on whether the ZES Even so, since ZES is relatively frequent in MEN1, when is sporadic or not (Mignon & Cadiot 1998). When ZES hypergastrinemia occurs in patients with MEN1 without is suspected, PPI therapy must be administered promptly typical or pathognomonic signs of ZES, other causes must because complications from peptic lesions can develop be considered, especially for PPI therapy and pernicious rapidly (Ito et al. 2012). If possible, serum gastrin should anemia. Diagnosis of ZES relies on both basal gastric acid be drawn and gastric juice pH should be determined outputs and serum gastrin measurements, sometimes before beginning PPI (Ito et al. 2012). Modalities of PPI with secretin or more rarely calcium stimulation (Mignon therapy have not changed recently. & Cadiot 1998, Ito et al. 2012). Biological criteria for the diagnosis of ZES are the same in patients with or without Anti-tumor therapy Management of the tumors MEN1 (Mignon & Cadiot 1998). One major drawback relies on the specific individualized therapeutic aims. is the necessity of measuring gastric acid secretion, as Theoretically, the main goal is to reduce mortality currently few departments are able to perform it (Ito et al. and the second goal is to cure ZES. However, this can 2012, Falconi et al. 2016). Finally, hyperparathyroidism- only be achieved if all gastrinomas are resected, which related hypercalcemia can increase gastric acid output, necessitates aggressive resection (Whipple procedure or and it is therefore usually recommended to treat partial pancreaticoduodenectomy) (Mignon & Cadiot hyperparathyroidism before the pNETs. 1998, Norton et al. 2001, Jensen et al. 2008, Imamura et al. 2011, Lopez et al. 2013). Some groups perform Tumor localization duodenectomy without pancreatectomy, associated with lymph node resection (Imamura et al. 2011). Such Compared with other pNETs linked to MEN1, the aggressive surgery allowed long-term eugastrinemia in peculiarities of ZES are the localization of gastrinomas in 92% of patients compared with 33% in a short series with the duodenal wall and their multiplicity. Furthermore, a median follow-up of 136 months (Lopez et al. 2013). In

Endocrine-Related Cancer Endocrine-Related they are usually small and difficult to find. The tumor a series from the NIH, studying non-aggressive surgery, a workup must also include a search for metastases. For ZES cure was never obtained; however, the survival rates duodenal gastrinomas, investigation includes gastroscopy were high at 100% and 86% at 5 and 10 years, respectively and EUS; however, their sensitivity is probably low and (Norton et al. 1999). The Whipple procedure and partial they have not been specifically studied in the setting of pancreaticoduodenectomy significantly reduces the risk ZES/MEN1. The gold standard modalities for pancreatic of recurrence of ZES and the risk related to re-operation, gland analysis in patients with MEN1 are EUS and MRI, but is probably associated with higher mortality and which are complementary (Barbe et al. 2012). Although morbidity than less extensive resection. Aggressive surgery the sensitivity of EUS is much higher than that of MRI for in MEN1 patients often showed low mortality rates the detection of pNETs (Thomas-Marques et al. 2006, Barbe and non-different morbidity rates compared with less et al. 2012, Kappelle et al. 2017), larger tumors (>2 cm) can aggressive surgery (Lopez et al. 2013), although the same be found using MRI, especially in the pancreatic tail (Barbe results were not reported in every series (You et al. 2007). et al. 2012). Liver MRI is the reference imaging modality However, these were small studies involving experts in for the detection of liver metastases (d’Assignies et al. the field, which does not reflect real clinical scenarios. 2013). Gallium-68 DOTATOC PET/CT may become the Rendering patients eugastrinemic is different to curing technique of choice in the future; however, this has not ZES, which is based on negative secretin tests in the long yet been evaluated correctly (Froeling et al. 2012). term; the former has not been evaluated in terms of tumor recurrence in the pancreas, metastasis development and survival. About 20–30% of patients with ZES/MEN1 have Peculiarities of ZES treatment in patients with MEN1 fundic carcinoids, usually multiple, and some of these Compared with NF-pNETs, the treatment of the ZES have malignant potential (Lehy et al. 1992, Berna et al. includes the control of gastric acid hypersecretion and, 2008). Some patients undergo total gastrectomy for that

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reason (Lehy et al. 1992, Berna et al. 2008) and we can whether they be gastrinomas or NF tumors, we and most suppose that fundic carcinoid development is probably experts recommend limiting surgery to patients with reduced when eugastrinemia is obtained. large tumors (>2 cm) and to those with a growing tumor. Based on other pNETs data, we can anticipate Surveillance should be performed in other situations that tumor resection reduces metastases development. (Fig. 1). We define significant growth as a 25% increase in However, this has not been proven in patients with MEN1, >1 cm tumors (Triponez & Cadiot 2007). regardless of whether ZES was present. Even in sporadic The surgical approach that is most widely used is ZES, the demonstration of a reduction in liver metastases enucleation (EN) for tumors of the pancreatic head development relies on very few data obtained in non- with duodenotomy and resection of the duodenal comparative studies (Fraker et al. 1994). In patients with tumors, lymph node resection and, in some cases, distal ZES/MEN1, surgery was not associated with a decrease in pancreatectomy (Jensen et al. 2008, Thompson 1998a). The metastases (Cadiot et al. 1999, Jensen et al. 2008, Singh Whipple procedure or partial pancreaticoduodenectomy et al. 2012). This could be: 1- because the risk of metastases is indicated when tumors of the duodenum or pancreatic is late and low, requiring a very long follow-up to be able to head are large and not enucleable. Other pancreatic tumors show differences in the risk; 2- because patients underwent are therefore enucleated. Median pancreatectomy can be surgery too late to reduce metastases development. Indeed, performed for centrally located lesions that are unsuitable for most experts, surgery is confined to patients with large for surgery. Finally, total duodeno-pancreatectomy is very tumors (>2–2.5 cm) or to those with growing tumors and rarely performed because of the high risk of sequelae, 3- because the type of surgery is not appropriate. notably life-threatening diabetes. In practice, considering the mortality and morbidity For other groups, systematic surgery is indicated rates of aggressive surgery of the duodenum and pancreas, as soon as pNETs are demonstrated regardless of their the long-term functioning sequelae (including diabetes, size (Bartsch et al. 2005, Tonelli et al. 2006, Lopez et al. pancreatic insufficiency, dumping and bloating), the 2013). Surgery type can be determined by the source of risk of recurrence related to MEN1 and the low risk of hypergastrinemia, shown using a selective arterial secretin metastases in the long term for small tumors (<2 cm), injection angiography (SASI) test. A Whipple procedure

No tumour2 seen or PPI and follow up3 Follow up imaging4 Tumour <2cm2

Endocrine-Related Cancer Endocrine-Related Imaging ZES without liver (EUS+MRI (or CT), metastases gastroscopy, SRS scingraphy1 Duodenal exploraon5 Tumor >2cm or + lymphadenectomy Surgery < 2cm growing tumor2 + excision of pNETs

oncological therapy Not operable (metastases, locally invasive) (Consider debulking in exceponal cases)

ZES with liver metastases

Duodenal exploraon + lymphadenectomy Operable + excision of pNETs + resecon of metastases

1some teams may perform SASI test 2almost all gastrinomasin MEN1 paentsare small duodenal tumours and the idenfied pancreac tumours on imaging studies are o en NF- pNETs(see also Fig. 3) 3some teams favour a more aggressive surgery for ZES 4follow-up imaging similar than for NF-pNETs (see Fig. 3) 5some teams favour a duodenotomy+ excision of duodenal tumours whileother teams favour a complete excision of the duodenum (Whipple, paral pancreacoduodenectomy or pancreas-preserving total duodenectomy) for the management of ZES

Figure 1 Management of MEN1 patients with ZES.

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is performed when it is localized to the duodenum/ with MEN1 developed insulinoma (Goudet et al. 2015). pancreatic head (Imamura et al. 2011, Lopez et al. 2013). The gold standard for the diagnosis of insulinoma is The endpoint used to compare both types of a 48-h supervised fast with negative levels of beta- management (i.e. systematic intervention vs selective hydroxybutyrate and sulfonylurea with a threshold for intervention and also the Whipple procedure vs limited proinsulin of ≥22 pmol/L (Guettier et al. 2013). Because surgery) should be overall survival. In a previous study, of their small size (82% <2 cm, 47% <1 cm), insulinomas there was a tendency for better survival in the ‘aggressive’ are difficult to localize and are scattered throughout the group, but this was not significant (overall 10-year pancreas gland (Service et al. 1991). Ultrasound (US), survival rates were 100% for the «active» group (n = 13) CT and MRI are widely used for detection, with EUS and 78% for the other group (n = 9) (P = 0.155) (Lopez et al. showing positive results in up to 95% of cases (McLean 2013). Disease-specific mortality at 10 years was 100% & Fairclough 2005). If these studies are negative, more in the first group vs 89% in the other group P( = 0.409) invasive techniques, such as selective angiography with (Lopez et al. 2013). intra-arterial calcium stimulation and hepatic venous These different ways of treating patients have not sampling for insulin levels, localize >80% of insulinomas been compared prospectively and they are the subject of (Brown et al. 1997, Guettier et al. 2009). Additionally, new much debate. somatostatin receptor (SSTR)-targeting PET modalities, such as 68Gallium-DOTATATE, are adjunct modalities for localization (Sadowski et al. 2015, 2016, Nockel et al. Type of surveillance 2017). As insulinomas express glucagon-like peptide 1 Whether patients have undergone surgery or not, (GLP1) receptor more than SSTR, PET imaging with labeled surveillance of the duodeno-pancreas and the main GLP1 analogs might be a promising tool (Antwi et al. metastatic sites is mandatory. MRI with diffusion sequences 2015). Intraoperative US (IOUS) with bimanual palpation is the most sensitive conventional imaging technique for improves the success rate of surgery, and blind distal the detection of liver metastases of NETs (d’Assignies et al. pancreatic resections should be avoided (Hirshberg et al. 2013). Theoretically, this should be performed annually. 2002, Nikfarjam et al. 2008). Concerning the pancreas, we propose to perform both Functional glucagonomas occur in <3% of patients MRI and EUS and then to choose one of the techniques with MEN1 and their clinical manifestations are skin rash according to its ability to detect and measure tumors. (necrolytic migratory erythema), weight loss, stomatitis Endocrine-Related Cancer Endocrine-Related These recommendations are applicable for NF-pNETs and anemia, although all of these may be absent. The and ZES in the context of MEN1. However, a direct most frequent location is in the tail of the pancreas and comparison of both techniques to detect a significant glucagonomas are often metastatic at the time of diagnosis. increase in the size of the tumors has not been conducted. MEN1 tumors that secrete VIP are rare. Patients develop The rate of increase in size has been shown to be low with watery diarrhea, hypokalemia and achlorhydria. The EUS for <2 cm NF-pNETs (1.3 + 3.2%/month in our series) diagnosis is established when elevated plasma VIP levels (Thomas-Marques et al. 2006) and 0.44 mm/year for pNETs are associated with an excess stool volume of 0.5–1 L per >1 cm in another series with a mean of 0.10 mm/year for day during fasting. VIPomas are also frequently located in all tumors (Kappelle et al. 2017). Therefore, we suggest the pancreatic tail. that there is no significant risk in performing MRI instead The management aim is to ensure that these patients of EUS every 2–3 years in cases of stable disease, which remain disease- and symptom-free for as long as possible is defined as 2 consecutive studies not demonstrating and maintain a good quality of life. The main goal for significant progression. patients with symptomatic functioning pNETs is to cure the functioning syndrome. This is obtained using surgery with careful evaluation of the extent of the disease Other functional duodeno-pancreatic NETs prior to planning specific therapy Thakker( et al. 2012). Insulinomas are the most common cause of endogenous Contrary to the recommendations for surgical resection hyperinsulinemic hypoglycemia in non-diabetic in NF-pNETs based on tumor size (Sadowski & Triponez adult patients, and 4–6% are associated with MEN1; 2015), the timing and extent of resection for functional 85% are solitary and 6–13% are multiple. A recent pNETs are still debated, especially regarding the type of study showed that 10% of patients aged under 20 years resection for multiple tumors in patients with MEN1

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(Jensen & Norton 2017). Furthermore, unlike ZES/MEN1, which requires Whipple resections for cure, functional pNETs are generally curable without extensive resections; however, they may recur (Falconi et al. 2016). It is generally accepted that surgical intervention should be performed in patients with MEN1 who have hypoglycemia/hyperinsulinism (Jensen et al. 2012). In patients with MEN1, hyperinsulinism may be caused by one insulinoma surrounded by multiple other functioning or NF-pNETs (Mignon et al. 1993); thus, the surgical approach is debated. The risk of recurrence persists over the patient’s lifetime because of germline mutations. Experts concur that total pancreaticoduodenectomy (PD) as an initial procedure should only be used under exceptional circumstances given the long natural course of this disease. Furthermore, PD results in severe insulin- dependent diabetes mellitus and exocrine pancreatic insufficiency, with significant morbidity and reduction Figure 2 Hypoglycemia symptom-free survival in 73 patients who underwent in quality of life for these generally young patients. surgery for non-metastatic pancreatic MEN1–insulinoma as a function of Many authors have thus proposed distal pancreatic type of surgery. CDP, cephalic duodenopancreatectomy; TP, total resection (DPR) associated with EN of any additional pancreatectomy; DP, distal pancreatectomy; E, enucleation alone. Adapted, with permission, from Vezzosi et al. (2015). Copyright 2015 tumors in the pancreatic head as the treatment of choice European Society of Endocrinology. for hypoglycemic symptoms (Cougard et al. 2000, Hellman et al. 2000, Giudici et al. 2012). Furthermore, EN manipulation in order to have a good basal reference and is an attractive parenchyma-sparing strategy, especially for evaluate the insulin/glucose ratio (Giudici et al. 2012). single dominant pNETs (Lopez et al. 2011, Bartsch et al. A large retrospective French multicenter study of 73 2013). Some centers have reported a pancreatic fistula rate patients with MEN1-insulinoma revealed that DPR was after EN of 24%, with no recurrences at the site of EN associated with the highest symptom-free survival and Endocrine-Related Cancer Endocrine-Related on long-term follow-up (median 77 months) (Nikfarjam manageable morbidity (Fig. 2) (Vezzosi et al. 2015). No et al. 2008); however, other studies have reported rates of recurrences were reported after DPR combined with EN recurrence of up to 57% after EN. Nikfarjam and coworkers for additional tumors in the pancreatic head. However, advocate a re-operation policy for patients with MEN1 and there were more complications after DPR than after EN recurrent insulinoma as an alternative to initial subtotal procedures (short-term 30.4 vs 22.2%) and more long- pancreatectomy (Nikfarjam et al. 2008). Moreover, term complications, such as endocrine and exocrine additional pancreatic surgery in high-volume centers has insufficiency. Diabetes occurred in 90% of patients a low morbidity (Norton et al. 2003). An important point who underwent DPR and in none of the patients who in favor of limited resection is the guarantee of cure of underwent EN alone. The overall cure rate was 82.2% and hyperinsulinism with intraoperative confirmation of reached 91.3% with DPR after median follow-up of 9 years. complete resection of the hypersecreting tumor tissue. Thus, DPR is associated with a low risk of hypoglycemic This can be achieved using rapid intraoperative insulin symptom recurrence, but because of the low morbidity, EN immuno-chemoluminescent assays, measured before and alone might be considered an alternative in patients with after resection with results obtained within a short period MEN1 (Vezzosi et al. 2015). In EN, an open or laparoscopic of time and confirming completeness of resection, with or approach did not significantly alter the risk of recurrence without concomitant glucose measurements (Proye et al. of hypoglycemia symptoms. 1998, Carneiro et al. 2002, Jensen et al. 2012). However, Another recent study (Tonelli et al. 2017) compared 8 there are little data in patients with MEN1, and because DPRs and 4 PDs in 12 patients with MEN1 with a clinical basal insulin level can be normal or released into the diagnosis of insulinoma. Forty percent of patients had blood by surgical maneuvers, a recent study in MEN1 multiple insulinoma, which was associated with additional recommends to determine insulin levels during pancreatic NF-pNETs in all patients, and 4/12 patients (33%) had

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metastatic lymph nodes. Overall, 9 patients underwent size and localization of functional pNETs and associated additional EN during their surgery. The decision between syndromes (e.g. ZES) are important factors to determine the 2 types of resection was based on the distribution of the extent and type of surgical resection and increase the tumors within the pancreas. The study concluded that, if chance of a cure. Future knowledge about the mutational the head of the pancreas is the most affected site and ZES landscape of pNETs will allow a more personalized is concomitant, PD is preferable over DPR. approach (Scarpa et al. 2017). Minimally invasive surgery is advancing and allows the use of accurate pre- and intraoperative localization Non-functional pancreatic NETs modalities. These are mandatory to help localize a tumor during surgery and avoid making a simple procedure more The standardization of biochemical and imaging protocols extensive (Whipple/PD). There have been few studies in for the follow-up of patients with MEN1 has led to a large patients with pNETs and MEN1. Laparoscopic IOUS has increase in the detection of NF tumors of the pancreas in transformed the approach to pNETs. In particular, in these patients (Thomas-Marques et al. 2006, Thakker et al. laparoscopic surgery, in which there is no tactile sensation 2012, Pieterman et al. 2014). Moreover, histopathological for the surgeon, IOUS has gained results similar to open analysis of resected MEN1-pancreases has shown surgery. The lack of tactile sensation has been cited as an numerous micro-tumors that were not identified using important factor in the failure to identify lesions and the imaging studies (Anlauf et al. 2006), further emphasizing resulting conversion to open surgery (Iihara et al. 2001, the diffuse involvement of the pancreas in patients Aggeli et al. 2016). Laparoscopic pancreatic surgery started with MEN1. Historically, NF tumors were diagnosed late 20 years ago and has evolved to be safe in high-volume because of local symptoms and were associated with a high centers with results comparable with those of open PD lethality early in life (Wilkinson et al. 1993, Doherty et al. (Correa-Gallego et al. 2014). Although mostly performed 1998, Goudet et al. 2010, Ito et al. 2013). Indeed, the mean for solitary lesions, in patients with MEN1, minimally age of death for patients who died because of NF-pNET was invasive procedures can be performed with similar safety 43 in a previous registry-based study (comprising patients to that of open procedures. Furthermore, minimally diagnosed with MEN1 in France from 1956 to 2003) and invasive procedures are associated with a shorter hospital 46 in the study by Doherty and coworkers analyzing stay and similar rates of postoperative complications (e.g. patients registered in the Washington University database fistula) Lopez( et al. 2016). (Doherty et al. 1998). The high prevalence and lethality Endocrine-Related Cancer Endocrine-Related Management of malignant insulinoma requires of pancreatic tumors led some authors recommending an special attention. This is a rare condition that occurs in aggressive management of those tumors. The ‘Norman about 4–14% of cases and is defined as local recurrence, Thompson procedure’ was popularized in the 1980s. This local invasion into surrounding tissues or the presence approach includes left pancreatectomy and enucleation of lymph node or distant metastases. Tumors of grade 2 of tumors in the head of the pancreas (since 1978) and or higher according to the World Health Organization duodenotomy with lymph node dissection in patients 2010 classification and those with peri-neural or lympho- with concomitant ZES (duodenotomy was introduced vascular invasion are also included. General management systematically in patients with ZES in 1986). Thompson goals for malignant functioning pNETs are symptom was convinced about the superiority of this aggressive control and tumor volume reduction, with surgery recom­ management over more conservative approaches mended if the lesions are resectable (Pavel et al. 2012, (Thompson 1998a,b) and convinced other surgeons to use Baudin et al. 2014). To further control symptoms or in similar approaches (in particular Akerström in Uppsala, non-surgical unresectable situations, adjuvant treatment Sweden and Proye in Lille, France) (Skogseid et al. 1996, is available, ranging from diazoxide and somatostatin Bartsch et al. 2000, Dean et al. 2000, Akerstrom et al. analogs to everolimus and chemotherapy, local therapies 2002, Dralle et al. 2004, Proye 1998). At that time, a (RFA, chemo-embolization, or radiotherapy) or peptide correlation between primary tumor size and the presence radio-receptor therapy (PRRT). of metastases had already been described (Akerstrom et al. In conclusion, there is currently no consensus 1991), but the proponents of aggressive management available about the extent of resection in functional believed strongly that ‘earlier detection and excision of pNETs for patients with MEN1 and future studies are tumors favors the possibility of a curative rather than needed. Pre- and peri-operative evaluation of number, palliative procedure’ (Thompson 1998a). Very good

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long-term results with low surgical morbidity were NF-pNET. They reported that surgery for small NF-pNETs reported (Thompson 1998a,b). In fact, he describes ‘no ≤2 cm was not associated with a significantly lower risk of operative morbidity’ but he did not give details about liver metastases or death and concluded that the majority operative morbidity. These internationally recognized of patients with MEN1 and NF-pNETs ≤2 cm could be surgeons were so convinced about this aggressive safely managed by watchful waiting, thereby avoiding management that they carefully followed their patients major surgery without increasing the risk of metastasis or and re-operated on them as soon as new tumors were death (Nell et al. 2017). The effect of surgery for tumors evidenced biochemically or morphologically. 2–3 cm was uncertain and the authors suggested an Despite repeated surgeries performed by internatio­ international randomized study to evaluate the effect of nally recognized experts, there were some disease-specific surgery on patients with MEN1 and NF-pNETs of 2–3 cm. deaths and significant peri-operative mortality and­­ In their population, changing the surgical strategy from morbidity. The Ann Arbor group carefully analyzed their performing surgery for patients with NF-pNETs of 1 cm patients and reported a median of 2 additional surgeries to performing surgery for patients with NF-pNETs of among 49 patients with MEN1, including 8 who needed 2 cm would lead to a reduction of 59% in the number of completion pancreatectomy and duodenectomy (leading pancreatic procedures. to total PD) after a median follow-up of 12 years. There The least invasive procedure is usually considered were 7 complications related to surgery, including 1 the best option. Lymph node dissection should be death after enterocutaneous fistula and 3 patients who added to pancreatic resection and adapted to the type required insulin pumps to treat postoperative diabetes. (in particular ZES vs NF-pNET) and location of the tumors Despite the aggressive protocol, 2 patients died of (Falconi et al. 2016). metastatic pNETs (Hausman et al. 2004, Gauger et al. There are currently several different recommendations 2009). Nell and coworkers (Nell et al. 2016) also reported for the management of patients with MEN1 and small 33% of major early complications and 23% of endocrine NF-pNETs. The Clinical Practice Guidelines for MEN1 and/or exocrine insufficiency among 61 patients with (Thakker et al. 2012) suggest surgical resection for MEN1 who underwent pancreatic surgery in a Dutch NF-pNETs >1 cm in size; similar guidelines are proposed academic center. These patients were young (median by the Uppsala group (Akerstrom et al. 2012), the Marburg 41 years old) and in good general health (ASA score I group (Bartsch et al. 2005) and the MEN consortium in or II for 89% of the patients), further emphasizing the Japan (Hanazaki et al. 2013). The National Comprehensive Endocrine-Related Cancer Endocrine-Related negative impact of complications in this population. Cancer Center in the USA suggests a more conservative After re-operating on a significant number of approach for tumors of 1–2 cm (www.nccn.org, version patients with MEN1 and experiencing the deleterious 3.2017). The European Neuroendocrine Tumor Society effects of this aggressive approach, different teams tried (Falconi et al. 2016) and the GTE (Triponez et al. 2006b) to evaluate the risk-benefit ratio of extensive/repeated also suggest conservative management of NF-pNETs pancreatic procedures for these tumors. By analyzing <2 cm if there are no signs of aggressiveness, such as rapid the French registry data, we confirmed the correlation progression, on imaging studies. We believe that 2 very between tumor size and the risk of metastasis (Triponez recently published studies (Nell et al. 2017, Triponez et al. 2006a) and the low risk of disease-specific death et al. 2017) will lead to a more uniformly accepted in patients with NF-pNET ≤2 cm (Triponez et al. 2006b). recommendation to use a watchful waiting strategy for Furthermore, these favorable results were confirmed after NF-pNETs of ≤2 cm (Fig. 3). a mean follow-up time of 10.7 years; out of 46 patients with NF-pNETs ≤2 cm, only 1 patient died of the disease; 16 showed significant disease progression (indicated by an Thymic NETs increase in the size or number of tumors, development of Introduction a hypersecretion syndrome or need for surgery); however, these patients could be treated accordingly with none Thymic tumors are rare. They are the most frequent presenting with metastasis at the end of the follow-up etiology of anterior mediastinal tumors. Histological (Triponez et al. 2017). classification subdivides these tumors into thymoma Almost simultaneously, the DutchMEN1 Study (subtypes A, AB, B1, B2, B3), thymic carcinoma Group analyzed data from 152 patients with MEN1 and (primarily squamous cell carcinoma) and more rarely

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MRI 1x/3years Stable (or EUS or CT) No tumour Follow up imaging

Tumour <2cm EUS if not done, EUS if notdone Surgery (unique or Follow up imaging Progressive Consider Gallium DOTA PET mulple) for Staging

Imaging1 NF-pNET (MRI or EUS or CT) Tumour >2cm EUS if not done Consider Gallium DOTA Surgery PET for Staging Tumour + liver metastases

Surgery Opon 1: Opon 2: Most conservave as possible incuding enucleaon if Thompson procedure (spleen-preserving distal feasible, sparing as much pancreac ssue as possible pancreatectomy + enucleaon of tumours in the head of Depends on the number, size, posion of NF-pNETs and the pancreas, (+ duodenal exploraon in case of ZES)2 presence of lymphnode or liver metastases

1We favour MRI as the first imaging technique because it is not invasive (as compared to EUS) and non-ionizing (as compared to CT). Furthermore, EUS is more sensive to detect small tumours but as we favour a conservave management for NF-pNETs < 2 cm, it is not necessary to acvely search for very small tumours except for staging and /or in a pre-operave seng 2see also flowchart on ZES (Fig. 1)

Figure 3 Management of MEN1 patients with NF-pNET.

NETs. Thymic neuroendocrine tumors (TNETs) account Diagnosis and screening for 2–5% of all thymic tumors. TNETs are classified as Once a diagnosis of MEN1 is established, explorations for a

Endocrine-Related Cancer Endocrine-Related well-differentiated (typical and atypical) carcinoids or thymic tumor are required. Radiological screening should poorly differentiated (large-cell neuroendocrine and start at the age of 15 years and should be repeated every small-cell) carcinomas (Marx et al. 2015). Most TNETs 1–3 years (Thakker et al. 2012). To limit radiation exposure, are sporadic, but some are associated with MEN1 thoracic low-dose CT scan or MRI is recommended. There (TNETs-MEN1). This association was described for the first is no biochemical test for screening and/or diagnosis of time in 1972 by Rosai and coworkers based on three case TNETs-MEN1. Screening is required regardless of gender reports (Rosai et al. 1972). TNETs-MEN1 are characterized by and smoking status, since publications did not confirm genotype–phenotype correlations with MEN1 mutations, that TNETs-MEN1 occurred exclusively in males and strong heritability and a poor outcome with frequent smokers (Christakis et al. 2016). At diagnosis, most recurrences and a higher risk of death (Goudet et al. 2009, patients with TNETs-MEN1 are asymptomatic, without Thevenon et al. 2015, de Laat et al. 2016). carcinoid syndrome; however, liver, bone and lung metastasis (synchronous or metachronous) may be found. Incidence

The incidence of TNETs-MEN1 varies from 2 to 8%. Prognosis Goudet and coworkers reported 21 TNETs among 761 patients with MEN1 (2.8%) from the GTE series (Goudet In a Japanese study of 1320 patients with thymic tumors et al. 2009). In Dutch, North American and Italian (1093 thymomas, 186 thymic carcinomas, 40 sporadic series, the incidence of TNETs-MEN1 was 3.4, 2 and 3%, TNETs and 1 TNETs-MEN1), the 10-year survival rate respectively (Ferolla et al. 2005, de Laat et al. 2014, Singh for thymic carcinoids was 80%, while it was 90% for Ospina et al. 2015). In a prospective study of 85 patients thymomas and 50% for thymic carcinomas (Kondo & with MEN1, Gibril and coworkers identified 7 TNETs (8%) Monden 2003). In contrast, TNETs-MEN1 has a high (Gibril et al. 2003). mortality rate. In the GTE series, the median survival was

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Figure 4 (A) Overall survival with 95% CI for thymic neuroendocrine tumors associated with MEN1. Reproduced, with permission, from de Laat JM et al., Natural course and survival of neuroendocrine tumors of thymus and lung in MEN1 patients, Journal of Clinical Endocrinology and Metabolism, 2014, volume 99, pages 3325–3333, by permission of Oxford University Press. (B) Overall survival with 95% CI for thymic neuroendocrine tumors associated with MEN1. Reproduced, with permission, from Hormones and Cancer, Clinical features, treatments and outcomes of patients with thymic carcinoids and multiple endocrine neoplasia type 1 syndrome at MD Anderson Cancer Center, volume 7, 2016, pages 279–287, Christakis I, Qiu W, Silva Figueroa AM, Hyde S, Cote GJ, Busaidy NL, Williams M, Grubbs E, Lee JE & Perrier ND. With permission of Springer. (C) Scars of total thymectomy by robot-assisted thoracoscopy surgery (courtesy Prof. Porte, Dr Pintilie, Lille University Hospital, France). (D) Preoperative thoracic computed tomography (CT) scan.

9 years and 7 months, and the 10-year survival rate was Surgical treatment Complete resection is the 36% (Goudet et al. 2009). Patients with MEN1 had an standard of care for thymic tumors. The histological increased risk of death when they had TNETs (HR = 4.64); classification, stage and completeness of resection (R0) are

Endocrine-Related Cancer Endocrine-Related however, this was not the case if they had bronchial NETs major prognostic factors. Centers with expertise in thoracic (br-NETs) (Goudet et al. 2010). In cohorts with MEN1 and cardiovascular surgery are recommended. Thoracic from Utrecht (n = 323) and MD Anderson (n = 291), the MRI could be useful to evaluate the resectability. Surgical 10-year survival rates for the 11 and 9 cases of TNETs- guidelines recommend total thymectomy, which involves MEN1 were 25% and 45%, respectively (Fig. 4A,B) (de removing the thymoma and the entire thymus, as well Laat et al. 2014, Christakis et al. 2016), confirming the as all perithymic fat without opening the tumor capsule. increased aggressiveness of these tumors in patients with Median sternotomy is an elective approach. Depending MEN1 compared with sporadic tumors. on the tumor volume or pleuro-pulmonary extension, specific and/or complementary surgical approaches can be used (for example, antero-bilateral thoracotomy Treatment with transverse sternotomy (Clamshell) and partial Multidisciplinary management of thymic tumors is longitudinal sternotomy with anterolateral extension recommended. In France, the RENATEN (endocrine with thoracotomy (hemi-clamshell)). Complete resection tumors) and RYTHMIC (thymic tumors) networks may require resection of surrounding involved structures, were developed to improve the management of these including the pericardium, pleura, lung and even major rare tumors according to national and international vascular structures. Resection of suspected adenopathy guidelines (Caplin et al. 2015, http://www.nccn.org/, is also mandatory. Minimally invasive procedures, http://www.reseau-gte.org, http://www.rythymic.org/). such as video or robot-assisted thoracoscopy surgery Masaoka-Koga and ITMIG-IASLC (International Thymic (V- or RATS), can be used for small and/or well-encapsulated Malignancy Interest Group – International Association thymic tumors. In selected patients, minimally invasive for the Study of Lung Cancer) classifications are used techniques for thymectomy are used more frequently (Detterbeck et al. 2014). because they have demonstrated significant advantages in

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terms of peri-operative and esthetic outcomes (Fig. 4C,D) Bronchial NETs (Hess et al. 2016, Marulli et al. 2016). Most MEN1-associated lesions are either frequent Given the frequency of ectopic parathyroid glands (hyperparathyroidism, duodeno-pancreatic-NETs, in the thymus, prophylactic transcervical thymectomy pituitary lesions, adrenal lesions) or rare, with a bad is generally performed at the time of parathyroid prognosis, such as TNETs. Br-NETs do not belong to surgery for primary hyperparathyroidism in patients either of these categories and very little is known about with MEN1; however, its efficacy in preventing TNETs them. Indeed, the frequency of br-NETs in patients with and/or improving survival has not been demonstrated MEN1 ranges from 3% to 13% and may be up to 31% (Powell et al. 2008, Welch & McHenry 2012); this (Sachithanandan et al. 2005, Goudet et al. 2011, de Laat is probably because the thymectomy is only partial et al. 2014, Singh Ospina et al. 2015, Bartsch et al. 2016). in most patients, leaving a significant amount of This large range is the result of the use of imaging findings thymic tissue behind. There is currently debate over and/or pathology as the basis for diagnosis. Two recent whether total thymectomy (using minimally invasive and large series are dedicated to the natural history of techniques like VATS, RATS or subxyphoid approach) MEN1-related br-NETs (de Laat et al. 2014, Lecomte et al. should be added to parathyroidectomy at the time of 2017). In a Dutch study, br-NETs were diagnosed using the latter. Long-term follow-up of patients with MEN1 either imaging alone or using pathology when available. who have undergone preventive thymectomy during Nevertheless, the complete diagnosis of br-NET relies on parathyroidectomy is recommended. A prospective the basis of suggestive morphology and confirmatory evaluation of a RATS/VATS/subxyphoid approach for immunophenotyping, including the expression of complete prophylactic thymectomy in combination chromogranin A, synaptophysin and/or N-CAM by with cervical parathyroidectomy in patients with MEN1 neoplastic cells. Such criteria were recently used in the is required. French GTE registry (Lecomte et al. 2017). Fifty-one Radiotherapy and medical therapy Adjuvant patients had developed br-NETs (4.8%; 95% confidence radiotherapy for incomplete resection and/or positive interval, CI = 3.6%–6.2%). The female-to-male sex ratio margins or systemic treatments for metastatic disease was 1.2 (23 men, 28 women) and several cases belonged must be discussed by a multidisciplinary board and/or to the same families. The median age at br-NET diagnosis a dedicated network (for example, RENATEN in was 49 ± 11 years (range = 24–66 years). Considering the Endocrine-Related Cancer Endocrine-Related France). Medical treatments for unresectable/metastatic frequencies of histologically proven br-NETs, very similar sporadic TNETs are based primarily on somatostatin results were found worldwide: 4.6, 4.8, 4.9, 5.0 and 6.6% analogs, chemotherapy (temozolomide/5-fluorouracil/ in Dutch (n = 16) (de Laat et al. 2014), French (n = 51) oxaliplatin), mTOR inhibitors (everolimus) and PRRT. (Lecomte et al. 2017), US (n = 17) (Singh Ospina et al. 2015), Tasmanian (n = 6) (Sachithanandan et al. 2005) and German (n = 5) (Bartsch et al. 2016) cohorts, respectively. Conclusion Penetrance is another important clinical aspect of In patients with MEN1, investigations for a thymic br-NETs. No case has been described during the first 2 tumor need to be conducted and, in the case of TNETs, decades of life. The youngest patient described in the a potential diagnosis of MEN1 should be considered. literature was aged 20 years. The probability of developing Significant changes have occurred in the management of a br-NET increases slowly with age and reaches 8.1% TNETS in the last 20 years (Table 1). The main treatment (95% CI = 5.9–11.0%) at 60 years (Lecomte et al. 2017). of MEN1 associated TNETs is surgery. There was no evidence of the predominance of either

Table 1 Major changes in the management of Thymic neuroendocrine tumors (TNETs) associated with MEN1 (TNETs-MEN1) that occurred in the last 20 years.

1990s 2017 Clinical features Male (non-smoker) Male/Female (smoker or not) Screening Chest CT MRI and/or low dose CT scan (Thakker et al. 2012) Classification Masaoka-Koga ITMIG-IASLC (Detterbeck et al. 2014) Surgical techniques Sternotomy and variants Video or robot assisted thoracic surgery (Hess et al. 2016)

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sex. These results were obtained when the 3 largest series MEN1 spectrum are associated with br-NET occurrence were pooled (female-to-male sex ratio: 1:16) (de Laat et al. (Lecomte et al. 2017). 2014, Singh Ospina et al. 2015, Lecomte et al. 2017). This Although precise histology is a major issue in conclusion was also true in the atypical carcinoid (AC) br-NETs, there are well-demonstrated inconsistencies subgroup, while a recent Surveillance, Epidemiology, in distinguishing between typical carcinoids (TC) and End Results (SEER) program population-based study and AC, between AC and large-cell neuroendocrine that considered all cases of sporadic and non-sporadic carcinomas (LCNEC) or between LCNEC and small-cell AC together described a predominance of women (69%) neuroendocrine carcinomas (SCLC). It may be difficult (N = 441) (Steuer et al. 2015). to assess cell size and cytological features in SCLC and The occurrence of br-NET-related clinical symptoms is LCNEC and also to recognize mitoses and necrosis among rather exceptional in the GTE cohort (14%), and a similar TC and AC (den Bakker et al. 2010, Volante et al. 2011, figure was also reported in the Mayo Clinic series (23%) Swarts et al. 2014). Ki67 immunohistochemistry may be (Singh Ospina et al. 2015, Lecomte et al. 2017). Thus, helpful in the differential diagnosis between the subtypes br-NETs are mostly diagnosed using screening during the of lung NETs (Travis et al. 2004). Most br-NETs were follow-up of patients with MEN1. Dyspnea, hemoptysis, classified as TC and AC in the GTE series; however, 5 cases cough and flushing, which are well-known br-NET-related of SCLC and LCNEC were also found (10%) (Lecomte symptoms, are useful for diagnosis if they are present et al. 2017). Until now, there have been no reports of (Fink et al. 2001). Several cases of br-NETs were found SCLC and LCNEC in MEN1, which is probably because in the same families (Lecomte et al. 2017). Therefore, of the small size of the published series and the rarity of the issue of possible clusters, such as those observed these high-grade neoplasms. It was generally regarded for TNETs, has to be raised. It is therefore important that MEN1-related br-NETs behave indolently, albeit to pay particular attention to families in which 1 or 2 with the potential for local mass effect, metastasis and cases have been already encountered. Recommendations recurrence after resection (Sachithanandan et al. 2005). for br-NET detection must be meticulously followed in The high frequency of smokers in this subset of patients these families. In other cases, br-NET detection is very is noteworthy and in-keeping with the epidemiology of challenging. There is no direct genotype–phenotype these neoplasms in the general population (Yeh & Chou correlation and no other more frequent lesions from the 2014). Loss of heterozygosity (LOH) at 11q13, in the Endocrine-Related Cancer Endocrine-Related

> 2 cm, and / or Staging4 Resecon central3 (lung sparing procedure, Low risk of Br-NET probable consider endobronchial NSCLC resecon if feasible) < 2 cm and not central3 Lung Opon 1: nodule Esmaon of risk Resecon (cf above) on chest CT of NSCLC1, 2 NSCLC excluded Opon 2: Follow-up with chest CT and resect if progressive High risk of follow guidelines NSCLC for NSCLC

NSCLC proven or Staging and suspected management of NSCLC

1NSCLC: non-smallcell lung cancer 2nodule size + morphology, clinical risk factors including age and smoking (MacMahon et al. 2017) 3tumours that are localized close to vital structures and that would need an extensive resecon if they grow 4for staging, mulphasic chest and abdominal CT is mandatory; consider Gallium DOTA PET for non-aggressive tumours and FDG PET-CT for aggressive tumours. Bronchoscopy (+ biopsy) is mandatory for centrally located lesions. See also (Caplin et al. 2015)

Figure 5 Management of MEN1 patients with br-NET.

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region containing the MEN1 gene, has been reported to The management of br-NETs in patients with MEN1 be frequent in sporadic cases of both SCLC and LCNEC classically follows that of sporadic br-NETs (Fig. 5). (Onuki et al. 1999). Nevertheless, subsequent studies have Resection is usually recommended but small non-central identified the presence of silencing MEN1 mutations in lesions (tumors that are not close to vital structures only very exceptional cases of sporadic high-grade NETs and that would not need an extensive resection if they (Debelenko et al. 2000). Although poorly differentiated slightly grow) can probably be followed without affecting br-NETS occur in MEN1, their cause is unknown. They mortality. The type of resection depends on the location must be considered because they represent 10% of of the tumor and should be as lung-sparing as possible, MEN1-related br-NETs. The most aggressive histological including the use of endobronchial resections when tumors were clearly responsible for br-NET-related deaths feasible (Brokx et al. 2015, Caplin et al. 2015). (SCLC, LNEC and several cases of AC) (Lecomte et al. 2017). In conclusion, br-NETs can be fatal. MEN1-related Several other distinctive features need to be highlighted br-NETs must be detected during a well-designed follow-up in MEN1-related br-NETs. TC was more common than and histological characterization must be performed. AC with a ratio of 2:1. In cases of sporadic br-NETs, this ratio ranges from 8:1 to 12:1. SCLCs account for only 5% of all MEN1-related lung tumors while SCLC is the third Declaration of interest most frequent type of primary lung malignancy after The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review. squamous cell carcinoma and adenocarcinoma in the general population (Swarts et al. 2014). Thus, clinicians must be aware of this particular histological spectrum of Funding lung tumors in MEN1 in order to diagnose and treat them This work did not receive any specific grant from any funding agency in properly knowing that when surgery was carried out, the public, commercial, or not-for-profit sector. large resections were not usually required and no surgery- related deaths occurred (Lecomte et al. 2017). Finally, these results highlight the importance of Author contribution statement detecting br-NETs in MEN1, since 37 (72%) patients Conception: S M S and F T. Manuscript writing and final approval of manuscript: all authors. required surgery and 7 (14%) died from br-NET (Lecomte et al. 2017). Moreover, systematic screening detected Endocrine-Related Cancer Endocrine-Related br-NETs in 27% of patients with MEN1 (de Laat et al. References

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Received in final form 7 August 2017 Accepted 15 August 2017 Accepted Preprint published online 15 August 2017 Endocrine-Related Cancer Endocrine-Related

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