Challenges and controversies in management of pancreatic neuroendocrine tumours in patients with MEN1

Review

Challenges and controversies in management of pancreatic neuroendocrine tumours in patients with MEN1 Christopher J Yates, Paul J Newey, Rajesh V Thakker

Multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder, is characterised by the occurrence of pancreatic neuroendocrine tumours (P-NETs) in association with parathyroid and pituitary tumours. P-NETs, which include gastrinomas, insulinomas, and non-functioning tumours, occur in more than 80% of MEN1 patients and account for 50% of disease-specific deaths. However, there is no consensus about the optimal methods for detecting and treating P-NETs in MEN1 patients, and extrapolations from approaches used in patients with non-familial (sporadic) P-NETs require caution because of differences, such as the younger age of onset, multi-focality of P-NETs, and concomitant presence of other tumours in MEN1 patients. Thus, the early detection of P-NETs by circulating biomarkers and imaging modalities, and their appropriate treatments by surgical approaches and/or radionuclide therapy, chemotherapy, and biotherapy pose challenges and controversies. These challenges and controversies will be reviewed and possible approaches proposed. Multiple endocrine neoplasia type 1 (MEN1) is characterised by the combined occurrence of tumours involving the parathyroid glands, pancreatic islets, and anterior pituitary gland, which occur in approximately 95%, 80–100%, and 54–65% of patients, respectively.1,2 Some MEN1 patients may also develop adrenocortical tumours, carcinoid tumours, lipomas, facial angiofibromas, and collagenomas.3,4 MEN1 is an autosomal dominant inherited disorder, although approximately 10% of patients have de-novo mutations of the MEN1 tumour suppressor gene and therefore lack a family history.1 Pancreatic islet cell tumours, also referred to as pancreatic neuroendocrine tumours (P-NETs), may secrete gastrointestinal (GI) hormones (eg, gastrin, insulin, glucagon) and result in clinical syndromes of hormone excess, or they may not secrete hormones and are referred to as non-secreting or non-functioning (NF) P-NETs. In addition, such P-NETs may secrete pancreatic polypeptide (PP), which does not lead to clinical manifestations of hormone excess and PPomas are therefore often classified as NF P-NETs (table 1).2,5-11 Prior to 1980, P-NETs accounted for about 90% of all MEN1-related deaths, and over two-thirds of these were attributable to gastrinomas, which are associated with gastric acid hypersecretion that leads to multiple duodenal ulcers and life-threatening GI haemorrhage.12–14 The majority (>80%) of these gastrinomas in MEN1 patients are now known to be located within the duodenum,15 but it is important to note that duodenal and pancreatic gastrinomas may also occur together in about 13% of patients,16 and that isolated pancreatic gastrinoma may occur also in some patients.17 Mortality from gastrinomarelated GI bleeding has been markedly reduced following the advent of drugs inhibiting gastric-acid secretion—eg, histamine-2 receptor antagonists, proton pump inhibitors (PPIs), and somatostatin analogues (SSAs)—and the major cause of disease-specific mortality is now the malignant sequelae of P-NETs.18,19 Indeed, a recent study, which followed 106 patients with MEN1-associated P-NETs for 15 years, reported that the mean age of death was

55 years, which is lower than that expected for the general population and that approximately 40% of deaths were due to malignant P-NETs.18 This high contribution of P-NETs to earlier mortality in MEN1 patients, when compared with that in non-MEN1 patients (ie, the general population), may partially be attributable to the younger age of onset and multifocal occurrence of P-NETs in MEN1 patients (table 1).3,18,20,21 Thus, MEN1 P-NETs, which are usually diagnosed between 0 and 50 years of age, are frequently multiple, although small (ie, <1 cm), and occur on a background of diffuse pancreatic microadenomatosis (table 1).2 Moreover, P-NETs in MEN1 will occur concomitantly with other tumours and the associated comorbidities may also decrease survival rates. The most common P-NETs in MEN1 patients are NF P-NETs, which occur in almost all patients (approximately 95% on pathological examination), and fewer than 15% may be large or symptomatic (table 1).2 Gastrinomas and insulinomas occur in about 55% and 20%, respectively, while other functioning P-NETs occur in 3% or less of MEN1 patients (table 1).2,5–11 More than 80% of MEN1associated gastrinomas are located in the duodenum and between 34–85% will have metastasised to local lymph nodes at diagnosis. However, other P-NETs in MEN1 patients are invariably located within the pancreas with lower rates of lymph node metastases (10–33%).2 NonMEN1 P-NETs, by contrast, are usually solitary pancreatic lesions diagnosed between 50 and 80 years of age, with about 50% to more than 75% reported to have regional or distant metastases at diagnosis.22–24 These differences between MEN1 and non-MEN1 P-NETs make it difficult to extrapolate results of detection modalities and treatment outcomes from studies of non-MEN1 to MEN1 tumours.25 This increases reliance on consensus expert opinions, as noted by the MEN1 clinical practice guidelines published in 2012,25 which recognise the uncertainty across important aspects of care. This Review discusses contemporary challenges and controversies in the management of MEN1 P-NETs and in particular those related to screening, prognosis, surgery, and antitumour

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Lancet Diabetes Endocrinol 2015 Published Online July 10, 2015 http://dx.doi.org/10.1016/ S2213-8587(15)00043-1 Academic Endocrine Unit, Radcliffe Department of Clinical Medicine, University of Oxford, Oxford, UK (C J Yates PhD, P J Newey DPhil, Prof R V Thakker MD); Department of Diabetes and Endocrinology, Melbourne Health, Melbourne, VIC, Australia (C J Yates); Department of Diabetes and Endocrinology, Western Health, Melbourne, VIC, Australia (C J Yates); Department of Medicine, University of Melbourne, Melbourne, VIC, Australia (C J Yates); and Division of Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK (P J Newey) Correspondence to: Prof Rajesh V Thakker, May Professor of Medicine, Academic Endocrine Unit, University of Oxford, O.C.D.E.M, Churchill Hospital, Headington, Oxford, OX3 7LI, UK [email protected]

1

Review

Hormones produced

Clinical presentation

Non-functioning

May produce hormones that are not secreted; clinically inert; or inadequately concentrated to induce symptoms

Incidental finding on imaging and/or biopsy; direct tumour mass effects

Gastrinoma

Gastrin

Insulinoma

Mean size (cm)

Metastatic sites (%)

Mean prevalence (%)

Important differences versus non-MEN1-associated P-NETs

<1·0

Lymph node (14–33%)*; liver (9–19%)*

96% (range 80–100) (0–13% large/ symptomatic)

Small size, multiplicity, background of diffuse pancreatic microadenomatosis

Abdominal pain, heartburn, nausea, gastrointestinal bleeding, diarrhoea (steatorrhoea)

<1·0

Lymph node (34–85%); liver (2–14%)

54% (range 20–61)

Younger age of presentation, small size, more than 80% located in duodenum, multiplicity, background of diffuse pancreatic microadenomatosis, early occurrence of lymph node metastases and low likelihood of surgical cure

Insulin

Neuroglycopenia, hypoglycaemia, autonomic symptoms

<1·0

Lymph node (0–10%); liver (0–20%)

18% (range 7–31)

Younger age of presentation, background of diffuse pancreatic microadenomatosis

Rare functioning

Glucagon

··†

Median 3·3 (range 0·9–11·0)

Lymph node (25%); liver (40%)‡

3% (range 1–6)

Background of diffuse pancreatic microadenomatosis

Rare functioning

Vasoactive intestinal peptide

Severe watery diarrhoea, hypokalaemia, achlorhydria

Median 4·0 (range 0·3–6·0)

Lymph node (0–100%); liver (0–33%)‡

3% (range 1–12)

Background of diffuse pancreatic microadenomatosis

Rare functioning

Somatostatinoma

··§

··

Lymph node (50%); lung (50%)‡

<1%

Background of diffuse pancreatic microadenomatosis

Rare functioning

Other: growth-hormone-releasing hormone; adrenocorticotrophic hormone; parathyroid hormone related peptide; carcinoid

Variable

··

··

<1%

Background of diffuse pancreatic microadenomatosis

MEN1=multiple endocrine neoplasia type 1. P-NETs=pancreatic neuroendocrine tumours. *These data report metastasis rates from macroscopic tumours (ie >2 cm in size). There are limited data from tumours <1 cm and these suggest a low metastasis rate of about 4%.†The classical signs of the glucagonoma syndrome (necrolytic migratory erythema, thromboembolism, and weight loss) have not been observed in MEN1 patients. ‡Very low sample sizes for rare functioning P-NETs of between one and five cases. §Somatostatinomas are found in MEN1, but have not been reported to be associated with signs of the somatostatinoma syndrome (steatorrhoea, diarrhoea, cholelithasis, and weight loss) in MEN1 patients; somatostatinomas of 6·0 cm and 8·0 cm have been reported in two MEN1 patients.

Table 1: Characteristics of MEN1-associated P-NETs2,5–11

therapies for advanced disease. However, in our search of the published literature for this Review, it is important to recognise the potential risk of introducing bias, as publications on MEN1 P-NETs often report outcomes from selected patient groups that have been managed within expert centres.

Screening for MEN1 P-NETs Challenges The challenges in screening for MEN1 P-NETs are to establish methods that are affordable, safe, and standardised; sufficiently sensitive to detect tumours that require intervention; and can be performed with adequate frequency to detect the majority of rapidly growing tumours. The availability of genetic testing for MEN1 coding region mutations, which can be detected in more than 90% of patients, has facilitated the identification of individuals at risk of developing MEN1associated tumours.1,25 However, the absence of a genotype–phenotype correlation means that a MEN1 mutant carrier is at risk of developing any of the more than 12 associated endocrine tumour types of which 2

about 50% are P-NETs.1,25 Regular screening (eg, annually) for these P-NETs using plasma hormonal measurements and imaging modalities is useful but costly especially as screening will need to be performed lifelong and P-NETs may occur in young patients—eg, gastrinoma, insulinoma, and NF P-NET have been reported between 5 and 12 years of age and a study of 19 MEN1 mutation carriers identified a greater than 40% P-NET penetrance during the second decade.8,25–27 The goals of screening for MEN1 P-NETs are to identify tumours at a stage when therapy can reduce morbidity and mortality, and to provide reassurance for MEN1 mutation carriers who have not developed tumours.25,28 Indeed, this is achievable by using biochemical and radiological screening, as recommended by the current guidelines, for all MEN1 mutation carriers commencing from about 10 years of age,25 and a recent study has shown a shift towards less advanced clinical presentations in 73 patients who underwent screening, with lower rates of malignant P-NETs (0% vs 14%), metastases (0% vs 7%), and death (0% vs 7%)29 when compared with those who did not undergo screening.

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Review

Advantages

Disadvantages

0·3 cm

Fast; facilitates tumour staging; inexpensive

Radiation exposure

100%

1·2 cm

Better soft tissue contrast than CT; facilitates tumour staging

Limited availability

N/A

0·3 cm

Most sensitive modality; can detect lymph node metastases

Invasive; poor imaging of distal pancreas; operator dependent; limited availability

Facilitates tumour staging

Radiation exposure; time consuming; limited availability

Highly sensitive, facilitates tumour staging

Radiation exposure; limited availability

Smallest Positive predictive lesion value (%) detected

Sensitivity (%)

Specificity (%)

CT (n=43)

81%

97%

96%

MRI (n=8)*

88%

100%

EUS (n=35)

100%

N/A

Octreotide scan (n=32)

84%

96%

96%

0·3 cm

68Gallium (68Ga)somatostatin receptor PET or PET-CT†

··

··

··

<1·0 cm

n=number of patients. EUS=endoscopic ultrasound. PET=positron emission tomography. MEN1=multiple endocrine neoplasia type 1. P-NETs=pancreatic neuroendocrine tumours. N/A=not available. *There are limited data on the sensitivity and specificity of MRI compared with histologically confirmed MEN1 P-NET. †No data are available for 68Ga-somatostatin receptor PET or PET-CT in MEN1 patients with P-NETs.

Table 2: Performance of preoperative pancreatic imaging modalities in MEN1 patients with P-NETs33–35

However, long-term follow-up studies are required to exclude confounders such as lead-time and lag-time bias, and confirm a true survival benefit.29–31

Controversies Selection of the optimal biochemical and imaging methods to screen for MEN1 P-NETs can be contentious. Current clinical practice guidelines for MEN1 recommend annual screening for asymptomatic P-NETs with a fasting plasma GI hormone profile that includes gastrin, insulin (with paired glucose), glucagon, vasoactive intestinal peptide (VIP), chromogranin A (CgA), and PP.25 Fasting plasma gastrin and insulin (with paired glucose) measurements are reliable and useful for detecting development of gastrinomas and insulinomas, respectively, which may be due to small (<1 cm) tumours, but occur with high frequencies and are associated with severe morbidity in MEN1 patients.1,25 However, the reliability of glucagon, CgA, and PP for detecting NF P-NETs, which also occur with a high frequency in asymptomatic MEN1 patients is unsatisfactory as the diagnostic sensitivities of these was 43%, 33%, and 36%, respectively.32 More reliable biomarkers are therefore needed to detect NF P-NETs in asymptomatic MEN1 patients. Such potential novel biomarkers may emerge from standardised in-depth phenotyping of MEN1 patients with NF P-NETs, which includes proteomic and metabolomic approaches using plasma/serum, urine, and tumour samples. Annual radiological screening using pancreatic and duodenal MRI, CT, and/or endoscopic ultrasound (EUS; table 2)25,33–35 is recommended by the current guidelines to detect P-NETs in MEN1 patients. EUS is likely the most sensitive test for the detection of P-NETs smaller than 1 cm,36,37 and can detect growth and the development of new P-NETs. Thus, one study using EUS in 35 MEN1 patients demonstrated a mean growth of 13% (SD 28) per year (from baseline diameter 0·9 cm) and an incidence of

new P-NET development of 0·52 per year.38 However, EUS is more invasive and has poor sensitivity for detecting tumours of the left side of the pancreas, including those larger than 1 cm.37,39 Furthermore, screening by EUS will identify P-NETs smaller than 1 cm for which surgery (or other treatments) is unlikely to be undertaken, thereby resulting in anxiety and unwarranted invasive procedures together with their inherent risks for MEN1 patients. Although the widespread availability and affordability of CT makes it an appealing alternative to EUS, the lifetime cumulative exposure to ionising radiation with this modality significantly limits its safety, particularly in younger patients, and therefore many centres favour use of MRI where possible.25,26 The advent of newer imaging methods such as positron emission tomography (PET), which are likely to be sensitive, offer the possibility of detecting multiple P-NETs, which are smaller than 1 cm in diameter and at an earlier stage of development. For example, one study has evaluated ⁶⁸Gallium (⁶⁸Ga)-somatostatin receptor (SMSR) PET or PET-CT in MEN1 P-NETs and was able to reveal previously undetected lesions in five of eight patients.34 Again the benefits of detecting such small and early P-NETs remain to be established, and, at present, surgery for such P-NETs would typically not be undertaken and in addition there are no chemopreventative drugs available with proven efficacy for these P-NETs. Nevertheless, radiological screening for P-NETs smaller than 1 cm in size is important for some centres that undertake surgery for these. Thus, annual screening with a modality sensitive for tumours of 1·0 cm or greater (eg, MRI/PET/CT) should detect the vast majority of rapidly growing P-NETs. Standardising the method and timing of such radiological screening where possible will greatly facilitate studies of its long-term benefit and enable future optimisation, such as increasing the screening interval if adequate P-NET detection can be maintained.

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3

Review

Tumour grading

TNM classification*

WHO 2010† Well differentiated Grade 1 Low grade Mitotic count <2‡ Ki67 index <3%

ENETS T—primary tumour T1—confined to pancreas <2 cm T2—confined to pancreas 2–4 cm T3—confined to pancreas >4 cm, or invading duodenum or bile duct T4—invasion of adjacent organs or major vessels for any T, add (m) for multiple tumours§

AJCC T—primary tumour T1—confined to pancreas <2 cm T2—confined to pancreas ≥2 cm T3—peripancreatic spread without major vessel invasion T4—invasion of adjacent organs or major vessels

N-RLNs N0—no regional lymph node metastasis present N1—regional lymph node metastasis

N-RLNs N0—no regional lymph node metastasis present N1—regional lymph node metastasis

Grade 2 Intermediate grade Mitotic count 2–20 Ki67 index 3–20%

Poorly differentiated small-cell or large-cell variant Grade 3 High grade Mitotic count >20 Ki67 index >20% Proposed further stratification Low risk CK19– C-KIT– Intermediate risk CK19+ C-KIT– High risk CK19+ C-KIT+

M—distant metastasis M0—no distant metastasis M1—distant metastasis present

M—distant metastasis M0—no distant metastasis M1—distant metastasis present

Stage IA (T1, N0, M0) IB (T2, N0, M0) IIA (T3, N0, M0) IIB (T1–3, N1, M1) III (T4, any N, M0) IV (any T, any N, M1)

Stage I (T1, N0, M0) IIA (T2, N0, M0) IIB (T3, N0, M0) IIIA (T4, N0, M0) IIIB (any T, N1, M0) IV (any T, any N, M1)

Figure 1: WHO classification system with ENETs and AJCC TNM staging systems for P-NETs41–43,52,53 *TNM classification: T describes the size or direct extent of the primary tumour; N describes the presence of regional lymph node (RLN) involvement; M describes the presence of distant metastasis. Ki67 index is a cellular marker for proliferation. †With proposed additional risk stratification based on cytokeratin 19 and C-KIT expression. ‡Mitotic count per 10 high power fields. §The addition of the letter m (eg, T1m) denotes the presence of multiple tumours. ENETS=European Neuroendocrine Tumors Society. AJCC=American Joint Committee on Cancer.

Sensitivity (%)

Specificity (%)

Transabdominal ultrasound

14–88%

CT

82–100%

92–100% 83–100%

MRI

55–79%

88–100%

Octreotide scan

81–96%

88–100%

⁶⁸Gallium-Somatostatin receptor PET or PET-CT

93%

96%

P-NET=pancreatic neuroendocrine tumours.

Table 3: Sensitivity and specificity of staging investigations for the detection of hepatic metastases in non-MEN1 P-NETs43,47,48

Predictors of outcomes and prognosis Challenges Establishing accurate predictors of outcomes that would guide the clinical management of MEN1 P-NETs represents a major challenge. Tumour grading and staging have been useful predictors for survival and treatment outcomes in oncology, but their use in MEN1 P-NETs remains to be established. Non-MEN1 P-NETs are graded (G) into one of three tiers as G1, G2, and G3 indicating well-differentiated, intermediate-differentiated, and poorly-differentiated tumours, respectively, using proliferation indices (nuclear Ki67 immunolabeling index) and/or mitotic count, and the grading of tumours is predictive of survival.23,40 Assessment of both indices (ie, 4

Ki67 immunolabelling and mitotic count) is advised as discordance is common, with Ki67 typically associated with higher grading (figure 1),41–43 such that it has been suggested that the prognostic value of Ki67 index could be improved by raising the threshold that demarcates tumours between grades 1 to 2 from 3% to 5%.44 However, the performance of this grading system has not been evaluated in MEN1 tumours and requires further investigation. Moreover, given the prognostic importance of grading P-NETs, it would seem important to develop further preoperative histological assessment techniques, such as Ki67 index evaluations of EUS-guided fine-needle aspirates that can obtain 2000 cells or more from nonMEN1 P-NETs, and have been reported to correlate with 5-year survival in non-MEN1 patients.44,45 Data from MEN1 patients is required, but this may be challenging, as the P-NETs may be multiple and small thereby requiring multiple biopsies and limiting the numbers of cells that can be obtained in each aspirate. Tumour-node-metastasis (TNM) staging was only developed for NETs in 2006 and recent studies in nonMEN1 patients with P-NETs have evaluated the utility of the original European Neuroendocrine Tumours Society (ENETs) TNM system, the 2010 American Joint Committee on Cancer (AJCC) system, and the WHO system (figure 1), in predicting outcomes and survival.23,42,43,46 One study of 75 non-MEN1 patients reported that the original ENETs TNM and the 2010 AJCC systems were not successful at predicting recurrence-free survival accurately.42 However, another study of 1072 non-MEN1 patients compared the ENETs TNM, and AJCC 2010 TNM systems and reported that curative surgery, TNM strategy, and grading were effective predictors of outcomes, and that grading was the second most effective independent predictor of survival in the absence of staging information.23 However, the AJCC 2010 TNM system was found to have very large 95% CIs, thereby indicating an inaccurate predictive ability.23 Thus, the ENETs TNM staging system was found to be superior to the AJCC 2010 TNM staging system and recommended for use in clinical practice.23 The performance of such TNM staging in MEN1 P-NETs has not been evaluated. The occurrence of malignant P-NETs that are associated with about 40% of deaths in MEN1 patients18 and the role of octreotide scanning, which has been reported to be the best widely available modality for detecting metastases in non-MEN1 P-NETs (sensitivity 81–96%, specificity 88–100%; table 3), has not been evaluated in MEN1 patients.47 Similarly, novel radiolabelled somatostatin analogues (SSAs; eg, ⁶⁸Ga-DOTATATE, ⁶⁸Ga-DOTANOC) with PET or PET-CT, which have been used to stage nonMEN1 NETs and shown to be faster (1–2 h vs 24–48 h), more sensitive (about 93%), than octreotide scans, and highly specific (about 96%; table 3),47,48 remain to be assessed in MEN1 patients with P-NETs. Interestingly, ¹⁸fluorodeoxyglucose (FDG) uptake is greater than

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Review

MEN1 patient with P-NET

• Assess for symptoms • GI hormones (gastrin, insulin, VIP, PP, CgA) • Consider endoscopic ultrasound-guided biopsy and grading* • Consider staging with 68Gallium-somatostatin receptor PET or PET-CT*

• Symptoms of hormone excess • Elevations in GI hormones consistent with hormone-secreting functioning P-NET

• Asymptomatic • GI hormones (except PP) not elevated, consistent with non-secreting non-functioning P-NET

Undertake appropriate biochemical and radiological investigations

Undertake appropriate biochemical and radiological investigations

Gastrinoma

Insulinoma

VIPoma

Glucagonoma

Non-metastatic P-NET

Metastatic P-NET

Treatment • Surgery—if isolated resectable tumour • Non-surgical—if multiple tumours or metastatic disease (mainly protonpump inhibitors)

Treatment • Surgery—if no metastases or isolated resectable metastasis • Non-surgical—if metastatic disease

Treatment • Surgery—if no metastases or isolated resectable metastasis • Non-surgical—if metastatic disease

Treatment • Surgery—if no metastases or isolated resectable metastasis • Non-surgical—if metastatic disease

Assess size

Further investigations and treatment as detailed in figure 3

<2 cm

Follow up with 6–12 monthly MRI. If increase in size to >2 cm proceed to surgery

>2 cm

Treatment • Surgery

Figure 2: Suggested clinical, investigative, and management approach to MEN1 patients with P-NETs All investigations and management plans should be discussed at a multidisciplinary team meeting. Consider the use of endoscopic ultrasound-guided biopsy and grading; and staging with ⁶⁸Gallium-somatostatin receptor PET or PET-CT, which represent recent developments that are after publication of the clinical guidelines in 2012.25 MEN1=multiple endocrine neoplasia type 1. P-NET=pancreatic neuroendocrine tumour. GI=gastrointestinal. VIP=vasoactive intestinal peptide. PP=pancreatic polypeptide. CgA= Chromogranin A. PET=positron emission tomography. *Should only be undertaken by experts in the procedure.

⁶⁸Ga-SMSR uptake in high-grade non-MEN1 NETs, and hence combination ¹⁸FDG and ⁶⁸Ga-SMSR PET-CT may facilitate tailored therapy for patients with high-grade metastases and vice versa (figure 2, figure 3).47 These modalities may decrease supplemental scanning and unnecessary surgery for patients with MEN1 P-NETs.49–51

Controversies The utility of novel markers in predicting treatment responses and survival remains controversial, and awaits further evaluation. Thus, current proliferation indices and peptide hormone/bioamine immunostaining are not accurate predictors for outcomes in non-metastatic MEN1 P-NETs, and alternative markers are therefore required, and markers used for non-MEN1 P-NETs need to be assessed in MEN1 P-NETs. For example, expression of cytokeratin K19 (CK19) and C-KIT have been reported to be independent prognostic markers for poor outcomes in non-MEN1 P-NETs, irrespective of tumour size, mitotic index, lymphatic invasion, and tumour necrosis.52,53 An

immunohistochemical classification based on these findings has been proposed52,53 in which P-NETs that are KIT–/CK19– are considered low risk, those KIT–/CK19+ are intermediate risk, and those KIT+/CK19+ are high risk for poor outcomes (figure 1). The loss of the tumoursuppressor genes ATRX and DAXX, which has been observed in MEN1 P-NETs size 3 cm or greater and is proposed to represent a late event in tumour development,54 requires further evaluation. In addition, altered expression of other markers may help to target treatment. These may include loss of expression of the DNA repair enzyme O-6-methylguanine-DNA-methyltransferase (MGMT), which is associated with better responses to the alkylating agent, temozolamide;55 overexpression of BCL2, a target for platinum-based chemotherapeutic agents; altered expression of mTOR pathways that can be targeted by everolimus; altered expression of tyrosine kinases which are targets of inhibitors such as sunitinib and sorafenib; and abnormal expression of vascular endothelial growth factors (VEGFs)

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5

Review

which are targets for humanised monoclonal antibodies (eg, bevacizumab).56–58 However, systematic analysis of altered expression of these is rarely undertaken in MEN1 P-NETs, and as yet their roles in responses to treatment and prognosis prediction remains unknown. Studies in MEN1 patients have identified some potential new molecular markers that may be associated with P-NET aggressiveness. Thus, MEN1 mutations involving Jun-D interacting domain have been reported to be associated with increased P-NET aggressiveness and decreased survival,59 and those involving the CHES1 interacting domain have been reported to be associated with a higher risk of malignant P-NETs.60 An association between the O blood group and increased risk of death from P-NETs has also been reported.61 These findings remain to be validated in larger studies and in different populations.

Surgery Challenges The selection criteria and choice of surgical procedures vary in different centres, making it difficult and challenging to provide definitive guidelines for surgical treatment of P-NETs in MEN1 patients. The ideal treatment for a non-metastatic, single, P-NET is surgical excision, as this offers the only potentially curative treatment.6 However, this situation rarely arises in patients with MEN1 who will have multiple P-NETs—eg, gastrinomas and insulinomas are multiple in more than 95% and more than 30% of MEN1 patients, respectively, with sizes varying from microadenomas to larger than 4 cm.2 The clinical behaviour of these P-NETs also varies and it is generally considered that all macroscopic P-NETs are potentially malignant, although the aggressiveness of an individual P-NET cannot be accurately predicted by tumour size, radiological features, or hormone production. However, studies have shown that most microadenomas are stable and infrequently increase in size; less than 20% of macroadenomas smaller than 2 cm will increase in size over 10 years; about 50–70% of P-NETs between 2–3 cm will be associated with lymph node metastases; and that 25–40% of P-NETs greater than 4 cm will be associated with hepatic metastases.62,63 Survival in patients with MEN1 correlates with non-metastatic disease—eg, survival at 15 years in MEN1 patients with gastrinomas smaller than 2·5 cm in size that were associated with non-metastatic or metastatic disease has been reported to be 100% and 50%, respectively.62–65 Thus, the occurrence of multiple P-NETs and their varied and unpredictable malignant potential in MEN1 patients pose major challenges for establishing selection criteria for surgery, as well as the timing and extent of surgery that would help in delivering the aims of surgery in MEN1 patients with P-NETs, which are to: alleviate symptoms and sequelae due to hormonal hypersecretion and tumour burden; achieve complete tumour and disease resection; preserve pancreatic function; and minimise morbidities such as 6

diabetes mellitus and malabsorption that are associated with pancreatic surgery. Currently there are no data available from controlled randomised studies that would help to make informed decisions regarding surgery. Instead these decisions rely on expert opinions, which agree that surgery, if feasible, should be undertaken in young MEN1 patients with P-NETs, for non-metastatic P-NETs that are greater than 2 cm in size, and for nonmetastatic insulinomas, glucagonomas, and VIPomas irrespective of size (figure 2).8,25

Controversies The role of surgery, and its timing and extent, for treatment of gastrinomas and non-functioning P-NETs remains controversial. Gastrinomas in MEN1 patients are predominantly located in the duodenum (>80% of gastrinomas) and also the pancreas, thereby necessitating surgical exploration in both organs if a cure is to be achieved.2 Several surgical approaches are used to treat gastrinomas in MEN1 patients. These include the Thompson procedure (ie, duodenotomy with excision of gastrinomas in the duodenal mucosa, enucleation [if feasible] or resection of tumours in the pancreatic head, peripancreatic lymph-node resection and corpora-caudal pancreatic resection); partial pancreaticoduodectomy (PD); pancreas preserving total duodenectomy (PPTD); and total pancreaticoduodenectomy (Whipple procedure). Total pancreaticoduodenectomy, which is associated with a substantially greater risk of diabetes mellitus and malabsorption when compared to other surgical approaches, is rarely undertaken and is reserved for patients who have gastrinomas with diffuse large pancreatic tumours. Reports of surgical outcomes, which are based on small numbers of patients and short duration of follow-up (3–5 years) indicate that the Thompson procedure, PD, and PPTD result in eugastrinaemia, with a negative secretin provocation test, in about 30%, more than 75%, and approximately 70% of MEN1 patients with gastrinomas, respectively.2,16 However, data regarding longer-term remission and survival are not known, and the benefits of such surgery over medical treatment with proton-pump inhibitors (eg, omeprazole and lansoprazole) that have dramatically reduced mortality due to GI bleeding and perforation, and achieved survival of about 90% at 5 years, about 85% at 10 years, and about 65% at 20 years in MEN1 patients,2 have resulted in many centres and guidelines recommending non-surgical management for gastrinomas in MEN1 patients, with surgery being reserved for patients in whom medical therapy has failed.25 Surgery is recommended for non-metastatic pancreatic gastrinomas larger than 2·0 cm, as it is reported to improve disease-specific survival over a mean of 12 years follow-up (99% vs 77% for combined nonMEN1/MEN1 P-NETs),25,66 although not all centres are agreed and some recommend surgical removal of nonmetastatic gastrinomas irrespective of size (figure 2).

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Non-functioning P-NETs, which are not associated with a clinical syndrome, are the commonest cause of death in MEN1 patients, with 5 and 10 years survival being about 75% and 50%, respectively.2 In addition, a significant correlation between increased size and the presence of liver metastases (4% if ≤1·0 cm, 10% if 1·1–2·0 cm, 18% if 2·1–3·0 cm, and 43% if >3·0 cm),5 which is associated with decreased survival has been reported. Most centres therefore recommend surgical resection for NF P-NETs that are 2·0 cm or greater in size, using procedures similar to those described above for gastrinomas, although other centres and the current guidelines25 recommend consideration of surgical resection for NF P-NETs that are 1·0 cm or greater in size. Surgical resection is recommended if there is significant growth (eg, doubling of tumour size over a 3–6 month interval). However, a study of 50 patients found no reduction in survival for P-NETs that were 2 cm or smaller managed without surgery over a 3-year follow-up period,20 and NF P-NETs in this size range typically have indolent growth.2 Expert opinions are therefore divided regarding the surgical management of P-NETS with the ENETs guidelines, recommending surgery for NF P-NETs larger than 2·0 cm, and the MEN1 clinical practice guidelines recommending surgical resection for NF P-NETs larger than 1·0 cm (figure 2).6,25 These controversies emphasise the need for welldesigned randomised control studies to clarify the roles of surgery; such studies in rare diseases are feasible as

illustrated by those establishing the value of prophylactic thyroidectomy for medullary thyroid cancer in patients with MEN2.67,68

Management of advanced disease Challenges The choice of optimal anti-tumour therapies for advanced P-NETs in MEN1 patients remains a challenge as such therapies have not formally been evaluated in MEN1 patients. Thus, over ten different treatments for advanced, metastatic P-NETs in MEN1 patients are available (figure 3), and the challenge is in selecting the most appropriate one for an individual patient, as none of the treatments is wholly effective and data for efficacy are generally only available from studies in non-MEN1 patients. These treatments comprise locoregional and systemic therapies and are indicated for hormonal hypersecretion, symptoms directly related to metastases, and tumour progression. Locoregional therapies consist of cytoreductive surgery, radiofrequency ablation (RFA), and transarterial embolisation/chemoembolisation (TAE/TACE), which have all demonstrated efficacy for between 15–24 months in advanced non-MEN1 NETs with isolated liver metastases, but careful selection is required to target the most appropriate therapy for each patient.69–71 Thus, for localised hepatic metastases or when more than 90% of tumour load is resectable, cytoreductive surgery, including resection of the primary,

Advanced metastatic P-NET

Locoregional therapy

Localised resectable hepatic disease

Cytoreductive (or curative) surgery

Systemic therapy

Unresectable hepatic disease

Low-grade diffuse disease

Low-volume disease with few lesions

High-volume disease

Refractory disease

Low volume disease

High-volume disease/rapid progression

RFA

TAE/TACE

SIRT

SSA

Streptozocin/ temozolomidebased chemotherapy

High-grade carcinomas

Refractory disease/ alternatives to chemotherapy

Everolimus +/– SSA

Sunitinib +/– SSA

PRRT

Cisplatin + etoposide/ irinotecan

Figure 3: Therapeutic options for advanced metastatic P-NETs Therapeutic choices (within dotted boxes) are dependent on disease phenotype. Locoregional therapies are effective for metastatic disease isolated to the liver and systemic therapy is more appropriate for those who are poor surgical candidates or when diffuse metastatic disease is present. However, it is important to note that there is a paucity of evidence for the utility of these therapeutic options in MEN1 patients. RFA=radiofrequency ablation. TAE/TACE=transarterial embolisation/chemoembolisation. SIRT=selective internal radiation therapy. SSA=somatostatin analogue. PRRT=peptide receptor radionuclide therapy.

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Search strategy and selection criteria We searched PubMed on Jan 21, 2014 (reviewed Nov 14, 2014), using the search terms “MEN1” OR “Multiple Endocrine Neoplasia 1” AND “neuroendocrine tumour” OR “NET”, and limited to full-text human clinical trials or reviews/meta-analyses that were written in English in the past 5 years. Highly regarded prior publications and relevant references from the articles identified by the literature search were also reviewed.

has been associated with symptomatic improvement in up to 95%;6,72,73 however, fewer than 15% of MEN1associated P-NETs meet these criteria and cure will rarely be achieved.74,75 Similarly, outcomes of other treatments in non-MEN1 patients which need to be evaluated in MEN1 patients are as follows: RFA for less bulky disease (eg, <5 cm) with fewer than ten liver lesions that has been shown to relieve symptoms in more than 95% of patients;6,70 selective hepatic TAE or TACE (typically using doxorubicin or streptozotocin) that have achieved 65–95% symptomatic responses, but seems more appropriate for unresectable multinodular disease with a higher tumour load, due to significant potential morbidity, which includes postembolisation syndrome, portal vein thrombosis, and hepatic insufficiency;69,71,76 and salvage selective internal radiation therapy with Yttrium (⁹⁰Y)-microspheres that has been associated with objective responses in 50–60%, but is associated with hepatic failure and remains an investigational therapy.69,77–79 Systemic therapies include SSAs, chemotherapy, tyrosine-kinase inhibitors (TKIs), mTOR pathway inhibitors, and peptide receptor radionuclide therapy (PRRT; figure 3). However, trials of systemic antitumour therapies have predominantly not included MEN1 patients with P-NETs. SSAs (octreotide and lanreotide) in non-MEN1 patients with treatment-naive welldifferentiated advanced gastroenteropancreatic NETs have resulted in a significantly increased median progression-free survival (PFS).80,81 To date, one retrospective non-controlled study of octreotide LAR therapy involving 20 patients with MEN1 P-NETs larger than 2 cm in size has demonstrated an objective tumour response in 10%, stable disease in 80%, and disease progression in 10% over 12–75 months of treatment;82 however, a prospective placebo-controlled trial of SSA therapy for P-NETs in MEN1 tumours is necessary to confirm an antiproliferative role. Studies of PRRT have demonstrated partial remission rates between 0–37% in somatostatin receptor scan-positive metastastic nonMEN1 P-NETs, using ⁹⁰Y and ¹⁷⁷Lu labelled SSAs (eg, ⁹⁰Y-DOTATOC or ¹⁷⁷Lu-DOTATATE).83,84 Cytotoxic chemotherapy has been used (figure 3) in non-MEN1 P-NETs patients with large tumour burdens and/or rapidly progressive metastatic disease, and streptozotocin 8

with 5-fluorouracil (5-FU) and/or doxorubicin resulted in objective response rates of 36–40%, with a median PFS of 13–18 months;85–87 temozolomide plus capecitabine resulted in objective response rates of 70%, and median PFS of 18 months.88 For high-grade carcinomas, cisplatin plus etoposide resulted in response rates of 67%, median PFS of 8 months, and median overall survival of 19 months,89 and cisplatin plus irinotecan resulted in response rates of 57%, median PFS of 5·5 months, and median overall survival of 10·6 months.90 The effectiveness of these chemotherapies has not been evaluated in MEN1 patients. P-NETs may express tyrosine kinase receptors (TKRs), vascular endothelial growth factor receptors, and platelet-derived growth factor receptors. In addition, some P-NETs have activation of the mammalian target of rapamcycin (mTOR) signalling pathway that may be mediated by autocrine actions of insulin-like growth factor and result in stimulation of cell growth and proliferation, and angiogenesis. This has prompted use of inhibitors of TKRs and of the mTOR signalling pathway, which have been reported to be effective in treating non-MEN1 P-NETs.91,92 Thus, treatment of patients with advanced, well differentiated P-NETs with sunitinib malate, which inhibits TKRs, led to increased overall survival and a doubling in PFS when compared to patients receiving placebo (11·4 months vs 5·5 months, p<0·001).92 Treatment of patients with advanced, low-grade, or intermediate-grade P-NETs with everolimus, an mTOR inhibitor, also led to a doubling of median PFS when compared to patients receiving placebo (11·0 months vs 4·6 months, p<0·001).91 These two studies mainly included non-MEN1 patients; for example in the sunitinib study, which comprised 171 patients, there were only two MEN1 patients and none were in the treatment arm92 and in the everolimus study, which had 410 patients, details of MEN1 status were not provided.91

Controversies Appropriate use of therapies for advanced P-NETs in MEN1 patients can be controversial. For example, the availability of many different treatments for P-NETs without definite clinical trials showing their efficacy in MEN1 patients has led to treatments being offered on the basis of availability, cost, and expert opinions, although current guidelines25 recommended that these decisions should be made by multidisciplinary teams within centres of excellence. Nevertheless, it is imperative that systematic, multicentre, controlled trials are undertaken to determine the best possible treatment for MEN1 patients, as well as their cost-effectiveness. Such studies will require international collaborations and well-defined inclusion and exclusion criteria.93

Conclusion P-NETs are the major cause of disease-specific mortality in patients with MEN1; however, very few MEN1-specific

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studies have been undertaken to guide the management of these tumours. Thus, in the absence of robust data, clinicians rely on expert consensus guidelines and extrapolations from studies involving non-MEN1 P-NETs to determine management in MEN1 patients. The latter is particularly concerning because MEN1 P-NETs exhibit distinct characteristics from non-MEN1 P-NETs, such as smaller size, multiplicity, background diffuse microadenomatosis, and the presence of comorbidities (eg, parathyroid, pituitary, and carcinoid tumours). Sensitive screening for P-NETs, accurate pretreatment prognostic assessment of identified tumours, and prudent selection of available medical and surgical therapies appear critical in order to reduce premature morbidity and mortality due to MEN1 P-NETs. Systematic multicentre trials addressing these challenges are therefore vital. Contributors RVT conceived of the Review. CJY performed the literature search, prepared the figures, and wrote the first draft of the manuscript. PJN contributed to the writing and revision of the manuscript. RVT contributed to the writing and revision of each draft of the manuscript and approved the final version. Declaration of interests CJY reports grants from Royal Australasian College of Physicians, Australia Awards Endeavor Postgraduate Research Fellowship, Novartis, Ipsen, and The Unicorn Foundation, during the conduct of the study; and other grants from Novo Nordisk, outside the submitted work. PJN reports a grant from National Institute for Health Research (NIHR), during the conduct of the study; and personal fees from Ipsen pharmaceuticals, outside the submitted work. RVT reports grants from Medical Research Council (MRC) UK, NIHR Translation Research Collaboration, and NIHR Oxford Biomedical Research Centre during the conduct of the study; grants from Wellcome Trust; non-financial support from ENETS Advisory Board, advisory fees from Novartis, consultancy fees from AstraZeneca, remuneration for work undertaken as Chairman of NIHR/MRC Efficacy Mechanisms and Evaluations (EME) Board, grants from Kidney Research UK, Novartis, GlaxoSmithKline, EU FR7 TREAT-OA, EU FP7 Marie Curie, advisory and lecture fees from Ipsen, lecture fees from Novo Nordisk, author royalties from Elsevier, lecture fees from Lilly, outside the submitted work. Acknowledgments The UK Medical Research Council and National Institute for Health Research support RVT. RVT has an NIHR Senior Investigator Award. References 1 Thakker RV. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol Cell Endocrinol 2014; 386: 2–15. 2 Jensen RT, Berna MJ, Bingham DB, Norton JA. Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management, and controversies. Cancer 2008; 113 (suppl): 1807–43. 3 Trump D, Farren B, Wooding C, et al. Clinical studies of multiple endocrine neoplasia type 1 (MEN1). Q JM 1996; 89: 653–69. 4 Darling TN, Skarulis MC, Steinberg SM, Marx SJ, Spiegel AM, Turner M. Multiple facial angiofibromas and collagenomas in patients with multiple endocrine neoplasia type 1. Arch Dermatol 1997; 133: 853–57. 5 Triponez F, Dosseh D, Goudet P, et al. Epidemiology data on 108 MEN 1 patients from the GTE with isolated nonfunctioning tumors of the pancreas. Ann Surg 2006; 243: 265–72. 6 Jensen RT, Cadiot G, Brandi ML, et al, and the Barcelona Consensus Conference participants. ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms: functional pancreatic endocrine tumor syndromes. Neuroendocrinology 2012; 95: 98–119.

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