Abstract
Localized insulinoma is an uncommon entity that can result in substantial morbidity due to the associated hypoglycemia. Recent studies have suggested an increase in the incidence of insulinoma in recent decades that may possibly be secondary to increased awareness, incidental diagnoses, and better diagnostic methods. Diagnosing and localizing insulinoma within the pancreas can be challenging, but advances in nuclear imaging may improve diagnostic accuracy. Delays in diagnosis are common, but once a localized insulinoma is diagnosed and appropriately treated, the long-term prognosis is excellent. Surgical resection is considered the standard of care management option for localized insulinoma, but tumor ablation with endoscopic ultrasound guidance has also been shown to be an effective and safe method for therapy.
Introduction
In 1926, Dr William J Mayo operated on a patient with hypoglycemia induced by metastatic pancreatic neuroendocrine tumor (pNET) which led to the first description of insulinoma (Wilder et al. 1927). Although the first described case was malignant, these neoplasms are more likely benign with an estimated incidence of one to four cases per one million person-years and may possibly be rising (Service et al. 1991, Halfdanarson et al. 2008, Peltola et al. 2018, Sada et al. 2020, 2021a , Svensson et al. 2022). A recent study using data from the Surveillance, Epidemiology and End Results (SEER) program reported a threefold increase in the incidence of pNET but did not address insulinoma specifically (Sonbol et al. 2022). However, another study from Finland suggested a near doubling of the incidence over a 30-year period (Peltola et al. 2018). Even when benign, insulinoma can be associated with significant morbidity and quality of life debility, but following resection, both health-related quality of life and life expectancy are comparable with that of the general population (Peltola et al. 2021). Underdiagnosis, misdiagnosis, or diagnostic delay are common despite the debilitating symptoms of hypoglycemia (Service et al. 1991, Sakurai et al. 2012). In one study, the median diagnostic delay was 13 months (Peltola et al. 2018). Although most insulinomas are sporadic, a minority is secondary to multiple endocrine neoplasia, type 1 (MEN-1) and the presentation of hypoglycemia can occasionally be the first manifestation of MEN-1 (Placzkowski et al. 2009, Svensson et al. 2022). Routine genetic testing is usually not performed in patients with newly diagnosed insulinoma, but a thorough past medical history and family history should be obtained, and patients should be referred for appropriate testing if there is suspicion of the insulinoma being a part of the manifestation of MEN-1.
When the diagnosis of insulinoma is confirmed, the gold standard treatment is surgical resection as the role of medical management of hypoglycemic symptoms is modest at best (Finlayson & Clark 2004, Okabayashi et al. 2013). Non-surgical therapy can be considered in patients who either have comorbidities precluding resection or do not want to undergo resection after being appropriately counseled about therapeutic options.
There has been tremendous advancement in the surgical management of insulinoma with the widespread adoption of minimally invasive approaches including laparoscopic and robotic surgery which coincide with the rapid improvements in radiological localization which facilitates the adoption of more conservative resection like enucleation (Sweet et al. 2007, Sada et al. 2021b, 2022 ). Recently, there has been a shift in the management of pNET in general including insulinoma with the increased utilization of interventional and ablation techniques which are a potential alternative to surgical resection in selected patients who are poor surgical candidates (Levy et al. 2012). In this review, we discuss both surgical and other interventional (ablative) management of insulinoma while focusing on the outcomes of both modalities.
Localization and choosing the surgical approach
When feasible, a minimally invasive approach including laparoscopic or robotic is preferred over an open approach for insulinoma resection as minimally invasive approaches are associated with faster recovery and less complications (Ayav et al. 2005, Cunha et al. 2007, Belfiori et al. 2018, Howe et al. 2020). The role of preoperative localization is critical in the era of minimally invasive surgery which does not allow for manual palpation of the pancreas. The most common utilized methods to localize an insulinoma are cross-sectional imaging studies including computed tomography (CT), magnetic resonance imaging, and somatostatin receptor imaging such as gallium 68 (68Ga) or copper 64 (64Cu) DOTATATE positron emission tomography (PET) imaging (Rostambeigi & Thompson 2009, Sadowski et al. 2014, Nockel et al. 2017, Christ et al. 2020, Imperiale et al. 2022). More recently, PET imaging targeting the glucagon-like peptide-1 receptor (GLP-1R) which is expressed by benign insulinoma cells, has been explored but is not yet widely available (Christ et al. 2020, Luo & Chen 2021, Shah et al. 2021). As opposed to benign insulinoma cells, malignant insulinoma often lack GLP-1R and express somatostatin receptor subtype 2 (SST2) which suggests that utilizing SST2 targeted images is helpful when planning for peptide receptor radionuclide therapy (Wild et al. 2011).
If non-invasive imaging studies fail to localize the lesion, an invasive method should be pursued including endoscopic ultrasound (EUS) for localization or the selective arterial calcium stimulation test (SACST) for regionalization (Rostambeigi & Thompson 2009, Wang et al. 2018, Howe et al. 2020). The North American Neuroendocrine Tumor Society (NANETS) consensus paper on the surgical management of pNETs recommends the routine use of EUS to identify multifocal disease in patients with MEN-1 and in selected cases given its capability of detecting small pNETs or insulinomas not identifiable on cross-sectional imaging (Howe et al. 2020). SACST can regionalize an insulinoma in about 92–98% which allows for segmental resection of the involved anatomical region (Placzkowski et al. 2009,Rostambeigi & Thompson 2009). Additionally, it is important to highlight the role of intraoperative ultrasound (IOUS) in challenging cases when preoperative imaging fails to localize an insulinoma as IOUS is the most sensitive test for localization (Hiramoto et al. 2001). Combining IOUS and palpation by an experienced surgeon successfully localizes insulinomas in up to 92–98% of cases (Rostambeigi & Thompson 2009). The newer technology and rapid improvements in diagnostic imaging modalities helped to overcome the limitations of palpation when a minimally invasive approach is undertaken as blind resection of the pancreas without identifying a targetable lesion or section should not be performed (Rostambeigi & Thompson 2009, Howe et al. 2020). Figure 1 shows our algorithm for the management of sporadic insulinoma.
Management algorithm of sporadic localized insulinoma. A full color version of this figure is available at https://doi.org/10.1530/ERC-22-0362.
Citation: Endocrine-Related Cancer 30, 6; 10.1530/ERC-22-0362
Surgical resection
The type of surgical resection of all pNETs including insulinomas is mainly determined by the tumor size and location. Insulinoma, including benign and malignant, tends to present with almost equal incidence in all parts of the pancreas (Service et al. 1991, Sada et al. 2020, 2021a,b ). It is very important to inquire about the presence of familial pNETs including MEN1 and Von Hippel-Lindau (VHL) when deciding the management plan of insulinoma as these syndromes increase the risk of multifocal disease and recurrence (Demeure et al. 1991, Howe et al. 2020,Sada et al. 2021b ). Historically, radical resection was performed for patients with MEN-1 associated pNETs including total pancreatectomy or subtotal pancreatectomy combined with enucleation of the pancreatic head lesions (Demeure et al. 1991, Tonelli et al. 2006). There has been a shift toward adopting a more conservative individualized approach to balance the risk of recurrence and malignancy of pNETs with the short- and long-term morbidity associated with aggressive pancreatic resection (Tonelli et al. 2006). In MEN-1 patients with confirmed endogenous hyperinsulinism and images consistent with multiple pNETs, a selective arterial calcium stimulation test or GLP-1R PET/CT scan using 68Ga-DOTA-exendin-4 (when available) can identify the lesion associated with hyperinsulinism and differentiate it from concurrent non-functional pNETs (Antwi et al. 2018, 2019, Sada et al. 2021b ). Additionally, the use of intra-operative intratumoral alcohol injection in MEN-1 patients with multiple pNETs in whom surgical resection is not feasible has been described with good outcomes and symptom control (Levy et al. 2012).
Most insulinomas are benign and sporadic, and in these cases both enucleation and formal segmental resection are appropriate (Howe et al. 2020). For lesions located in the head/neck of the pancreas where a pancreaticoduodenectomy would be required for segmental pancreatic resection, enucleation is preferred if the lesion is small and within a sufficient distance of the pancreatic and/or bile duct to avoid the morbidity of a pancreaticoduodenectomy (Park et al. 1998, Howe et al. 2020). As noted in the NANETS consensus paper, enucleation is associated with more preserved endocrine and exocrine function but a higher rate of pancreatic fistula occurring in 10–56% of cases (Sallinen et al. 2018). Therefore, enucleation is favored for small lesions <2 cm located >2–3 mm from the main pancreatic and/or bile duct (Howe et al. 2020). Although enucleation is associated with a high rate of pancreatic fistula, the rate of significant morbidity or mortality after enucleation is lower than segmental pancreatic resection (Heidsma et al. 2021). A study including 1034 patients who underwent surgery for pNETs found that the rate of severe complications defined by Clavien–Dindo score ≥3 was 32.2% for pancreaticoduodenectomy, 19.5% for distal pancreatectomy, and 24.5% for enucleation while the rate of pancreatic fistula grade B/C was 22.7, 28.7, and 32.9%, respectively (Heidsma et al. 2021). Another study found that the rate of mortality, overall morbidity, and severe morbidity was lower following enucleation compared to segmental resection in small pNETs (≤2 cm) (Beane et al. 2021).
Central pancreatectomy for small lesions in the neck or proximal body of the pancreas is associated with high overall morbidity and is reserved for very selected cases and should be avoided if feasible (Iacono et al. 2013, Howe et al. 2020). For lesions located in the body or tail of the pancreas, either enucleation or distal pancreatectomy can be performed depending on lesion size and proximity to the main pancreatic duct. While enucleation preserves pancreatic parenchyma, it is associated with a higher overall complication rate and specifically a higher rate of pancreatic leak and fistula compared to distal pancreatectomy (Sallinen et al. 2018). Distal pancreatectomy, when advisable, may be performed with or without splenectomy.
If malignant insulinoma is suspected, a formal resection with lymphadenectomy is preferred over pancreatic preserving resection such as enucleation to allow for complete oncological resection and appropriate staging (Howe et al. 2020,Sada et al. 2020). Cytoreduction is an option in patients with metastatic insulinoma on a case-by-case basis as it can provide control of hypoglycemic symptoms and improves overall survival (Matej et al. 2016, Halfdanarson et al. 2020, Howe et al. 2020).
Endoscopic ablation
EUS is a reliable method of identifying pNETs, including insulinomas, and given the usual solitary nature of insulinomas, EUS-guided ablation is an option for regional therapy of localized insulinoma. EUS-guided ablation is typically reserved for patients deemed unsuitable for more invasive procedures, but to date, no prospective comparative trials have been conducted. Earlier techniques included ethanol injections as ablative therapy and a small study of eight patients showed this method to be both safe and effective for controlling hypoglycemic symptoms (Levy et al. 2012). More recently, other ablation techniques have been evaluated in the management of patients with pNETs, including radiofrequency ablation (RFA) and microwave ablation (Barthet et al. 2019, Oleinikov et al. 2019). These technologies have been evaluated in small studies and case reports, with few data pertaining to NETs and even fewer specifically to insulinomas. A systematic review of the published literature evaluated the efficacy of EUS-RFA in 61 patients with pancreatic NETs where 30% had insulinoma (Imperatore et al. 2020). In this study, the tumors were controlled in 96% of cases with no difference in effectiveness among functional and nonfunctional tumors, but the efficacy was less in larger tumors. One study of seven patients with solitary insulinoma reported that all patients achieved euglycemia, and none had progression after a median follow-up time of 21 months (Marx et al. 2022). Similarly, a report of four patients treated with EUS-RFA showed that all patients remained euglycemic after a median follow-up time of 22 months (Furnica et al. 2020). Other studies have shown similar efficacy with tumor control in more than 90% of treated patients and with adverse event rates up to 30%. Severe adverse events are uncommon with pancreatitis reported in up to 7% (Zhang et al. 2020, Garg et al. 2022, Spadaccini et al. 2022). A pooled analysis of 14 studies on EUS-RFA for solid pancreatic tumors reported serious adverse events in 1% and no procedure-related deaths (Spadaccini et al. 2022). Several retrospective studies, case reports, and case series pertaining specifically to EUS-guided ablative therapy for insulinomas report high efficacy in regard to both tumor and syndrome control (Furnica et al. 2020, Marx et al. 2022). A recent systematic review of 75 patients with insulinoma treated with EUS-RFA (n = 27), EUS-ethanol ablation (n = 47), or both modalities in one patient, reported a clinical success rate of 98.5% and substantial biochemical improvement. Adverse events were reported in 11 patients, including procedure-related abdominal pain (n = 7), mild pancreatitis (n = 2), necrotizing pancreatitis (n = 1), hematoma (n = 1); with no procedure-related deaths (El Sayed et al. 2021). Based on the available data, EUS-guided ablation is an effective and safe method for treating localized insulinoma. Table 1 summarizes case series studies that explored the role of ablative treatments for insulinoma.
Case series studies evaluating ablative treatments for insulinoma.
| Ref. | Year | No. of patients | Treatment | Follow-up | Complications |
|---|---|---|---|---|---|
| Furnica et al. (2020) | 2020 | 4 | EUS-RFA | Mean 22 months | None |
| Lakhtakia et al. (2020) | 2020 | 10 | EUS-RFA | 6–12 months | None |
| Levy et al. (2012) | 2012 | 8 | IOUS-ETOH (n = 3) EUS-ETOH (n = 5) |
Median 13 months | Minor bleeding (n = 1) Pseudocyst (n = 1) Pancreatitis with pseudocyst (n = 1) |
| Marx et al. (2022) | 2022 | 7 | EUS-RFA | Median 21 months | Mild abdominal pain (n = 1) Mild pancreatitis (n = 1) Necrotic fluid collection (n = 1) Retrogastric collection (n = 1) |
| Mosquera-Klinger & Carvajal (2021) | 2020 | 2 | EUS-ETOH | 12 months | None |
| de Nucci et al. (2020) | 2020 | 5 | EUS-RFA | 12 months | None |
| Oleinikov et al. (2019) | 2019 | 7 | EUS-RFA | Mean 10 months | Mild pancreatitis (n = 2) |
| Paik et al. (2016) | 2016 | 3 | EUS-ETOH | Median 16.5 months | Abdominal pain |
| Park et al. (2015) | 2015 | 2 | EUS-ETOH | Median 370 days | None |
| Sharma et al. (2017) | 2017 | 2 | EUS-RFA | 3 months | None |
| Yang et al. (2015) | 2015 | 4 | EUS-ETOH | Median 17.3 months | None |
ETOH, ethanol ablation.
From a technique standpoint, EUS-guided alcohol ablation has been described using a linear echoendoscope and a 22- or 25-gauge needle. The needle is advanced into but not through the tumor, and injections are performed until hyperechoic changes are seen expanding within the insulinoma (Levy et al. 2012). The injected alcohol amount is decided based on the hyperechoic changes within the tumor and typically ranges between 0.1 and 3.0 mL.
EUS-RFA is performed using an RFA system, a needle electrode, a radiofrequency generator, and an inner-cooling system. Once the tip of the needle electrode is confirmed to be within the tumor using EUS images, energy is applied which corresponds to echogenic bubbles around the needle tip (Oleinikov et al. 2019). The procedure time of insulinoma ablation is about 60 min or so for both alcohol and RFA ablation which both can be performed under conscious sedation.
Radiation therapy
Targeted external beam radiotherapy is increasingly used for pancreatic malignancies and stereotactic body radiotherapy (SBRT) can deliver ablative radiation doses to pancreatic tumors with limited collateral damage, but the published literature is almost entirely limited to the much more common pancreatic adenocarcinoma (Kim et al. 2016, Huguet et al. 2021). SBRT was recently shown to control tumor growth and hypoglycemia in two cases and is a promising noninvasive modality that deserves further study (Myrehaug et al. 2020).
Conclusion
Insulinoma remains a rare entity associated with substantial morbidity and impact on quality of life when inadequately treated and the incidence may be rising in recent decades. Misdiagnosis and diagnostic delays are common, but once diagnosed and appropriately treated, benign insulinomas have an excellent prognosis. Making the diagnosis of insulinoma is often challenging, but advances in imaging, especially nuclear imaging, are expected to improve diagnostic accuracy. Intraoperative palpation and ultrasound as well as the SACST may still be required for diagnosis and localization of insulinoma. Surgical resection remains the standard of care for the management of solitary benign insulinoma, but EUS-ultrasound guided ablation has increasingly been used and found to be both effective and safe. Focused external beam radiotherapy has been reported to be an effective modality, but more research is needed prior to recommending radiotherapy as an option in routine practice.
Declaration of interest
Dr Halfdanarson reports the following potential conflicts of interest: Research Support (to institution): Thermo Fisher Scientific, Advanced Accelerator Applications (a Novartis company), Camurus, Crinetics. Consulting/Advisory Board (paid to institution): Ipsen, Advanced Accelerator Applications (a Novartis company), ITM Isotopen Technologien Muenchen, Crinetics, Viewpoint Molecular Targeting. Consulting/Advisory Board (personal payment): TerSera. Other authors declare no conflicts of interest.
Funding
No external funding or assistance was received for preparation of this manuscript.
References
Antwi K, Fani M, Heye T, Nicolas G, Rottenburger C, Kaul F, Merkle E, Zech CJ, Boll D, Vogt DR, et al.2018 Comparison of glucagon-like peptide-1 receptor (GLP-1R) PET/CT, SPECT/CT and 3T MRI for the localisation of occult insulinomas: evaluation of diagnostic accuracy in a prospective crossover imaging study. European Journal of Nuclear Medicine and Molecular Imaging 45 2318–2327. (https://doi.org/10.1007/s00259-018-4101-5)
Antwi K, Nicolas G, Fani M, Heye T, Pattou F, Grossman A, Chanson P, Reubi JC, Perren A, Gloor B, et al.2019 68ga-Exendin-4 PET/CT detects insulinomas in patients with endogenous hyperinsulinemic hypoglycemia in MEN-1. Journal of Clinical Endocrinology and Metabolism 104 5843–5852. (https://doi.org/10.1210/jc.2018-02754)
Ayav A, Bresler L, Brunaud L, Boissel P, SFCL (Société Française de Chirurgie Laparoscopique) & AFCE (Association Francophone de Chirurgie Endocrinienne) 2005 Laparoscopic approach for solitary insulinoma: a multicentre study. Langenbeck’s Archives of Surgery 390 134–140. (https://doi.org/10.1007/s00423-004-0526-3)
Barthet M, Giovannini M, Lesavre N, Boustiere C, Napoleon B, Koch S, Gasmi M, Vanbiervliet G & & Gonzalez JM 2019 Endoscopic ultrasound-guided radiofrequency ablation for pancreatic neuroendocrine tumors and pancreatic cystic neoplasms: a prospective multicenter study. Endoscopy 51 836–842. (https://doi.org/10.1055/a-0824-7067)
Beane JD, Borrebach JD, Billderback A, Onuma AE, Adam MA, Zureikat AH & & Pitt HA 2021 Small pancreatic neuroendocrine tumors: resect or enucleate? American Journal of Surgery 222 29–34. (https://doi.org/10.1016/j.amjsurg.2020.12.013)
Belfiori G, Wiese D, Partelli S, Wachter S, Maurer E, Crippa S, Falconi M & & Bartsch DK 2018 Minimally invasive versus open treatment for benign sporadic insulinoma comparison of short-term and long-term outcomes. World Journal of Surgery 42 3223–3230. (https://doi.org/10.1007/s00268-018-4628-4)
Christ E, Antwi K, Fani M & & Wild D 2020 Innovative imaging of insulinoma: the end of sampling? A review. Endocrine-Related Cancer 27 R79–R92. (https://doi.org/10.1530/ERC-19-0476)
Cunha AS, Beau C, Rault A, Catargi B, Collet D & & Masson B 2007 Laparoscopic versus open approach for solitary insulinoma. Surgical Endoscopy 21 103–108. (https://doi.org/10.1007/s00464-006-0021-8)
Demeure MJ, Klonoff DC, Karam JH, Duh QY & & Clark OH 1991 Insulinomas associated with multiple endocrine neoplasia type I: the need for a different surgical approach. Surgery 110 998–1005.(https://doi.org/10.5555/uri:pii:003960609190342J)
de Nucci G, Imperatore N, Mandelli ED, di Nuovo F, d'Urbano C & & Manes G 2020 Endoscopic ultrasound-guided radiofrequency ablation of pancreatic neuroendocrine tumors: a case series. Endoscopy International Open 8 E1754–E1758. (https://doi.org/10.1055%2Fa-1261-9359)
El Sayed G, Frim L, Franklin J, McCrudden R, Gordon C, Al-Shamma S, Kiss S, Hegyi P, Eross B & & Hegyi PJ 2021 Endoscopic ultrasound-guided ethanol and radiofrequency ablation of pancreatic insulinomas: a systematic literature review. Therapeutic Advances in Gastroenterology 14 17562848211042171. (https://doi.org/10.1177/17562848211042171)
Finlayson E & & Clark OH 2004 Surgical treatment of insulinomas. Surgical Clinics of North America 84 775–785. (https://doi.org/10.1016/j.suc.2004.02.004)
Furnica RM, Deprez P, Maiter D, Vandeleene B & & Borbath I 2020 Endoscopic ultrasound-guided radiofrequency ablation: an effective and safe alternative for the treatment of benign insulinoma. Annales d'Endocrinologie 81 567–571. (https://doi.org/10.1016/j.ando.2020.11.009)
Garg R, Mohammed A, Singh A, Harnegie MP, Rustagi T, Stevens T & & Chahal P 2022 EUS-guided radiofrequency and ethanol ablation for pancreatic neuroendocrine tumors: a systematic review and meta-analysis. Endoscopic Ultrasound 11 170–185. (https://doi.org/10.4103/EUS-D-21-00044)
Halfdanarson TR, Rubin J, Farnell MB, Grant CS & & Petersen GM 2008 Pancreatic endocrine neoplasms: epidemiology and prognosis of pancreatic endocrine tumors. Endocrine-Related Cancer 15 409–427. (https://doi.org/10.1677/ERC-07-0221)
Halfdanarson TR, Strosberg JR, Tang L, Bellizzi AM, Bergsland EK, O'Dorisio TM, Halperin DM, Fishbein L, Eads J, Hope TA, et al.2020 The North American neuroendocrine tumor society consensus guidelines for surveillance and medical management of pancreatic neuroendocrine tumors. Pancreas 49 863–881. (https://doi.org/10.1097/MPA.0000000000001597)
Heidsma CM, Tsilimigras DI, Van Dieren S, Rocha F, Abbott DE, Fields R, Smith PM, Poultsides GA, Cho C, Dillhoff M, et al.2021 Indications and outcomes of enucleation versus formal pancreatectomy for pancreatic neuroendocrine tumors. HPB 23 413–421. (https://doi.org/10.1016/j.hpb.2020.06.015)
Hiramoto JS, Feldstein VA, LaBerg JM & & Norton JA 2001 Intraoperative ultrasound and preoperative localization detects all occult insulinomas; discussion 1025–6. Archives of Surgery 136 1020–1025. (https://doi.org/10.1001/archsurg.136.9.1020)
Howe JR, Merchant NB, Conrad C, Keutgen XM, Hallet J, Drebin JA, Minter RM, Lairmore TC, Tseng JF, Zeh HJ, et al.2020 The North American Neuroendocrine Tumor Society consensus paper on the surgical management of pancreatic neuroendocrine tumors. Pancreas 49 1–33. (https://doi.org/10.1097/MPA.0000000000001454)
Huguet F, Dabout V, Rivin Del Campo E, Gaujoux S & & Bachet JB 2021 The role of radiotherapy in locally advanced pancreatic cancer. British Journal of Radiology 94 20210044. (https://doi.org/10.1259/bjr.20210044)
Iacono C, Verlato G, Ruzzenente A, Campagnaro T, Bacchelli C, Valdegamberi A, Bortolasi L & & Guglielmi A 2013 Systematic review of central pancreatectomy and meta-analysis of central versus distal pancreatectomy. British Journal of Surgery 100 873–885. (https://doi.org/10.1002/bjs.9136)
Imperatore N, de Nucci G, Mandelli ED, de Leone A, Zito FP, Lombardi G & & Manes G 2020 Endoscopic ultrasound-guided radiofrequency ablation of pancreatic neuroendocrine tumors: a systematic review of the literature. Endoscopy International Open 8 E1759–E1764. (https://doi.org/10.1055/a-1261-9605)
Imperiale A, Boursier C, Sahakian N, Ouvrard E, Chevalier E, Sebag F, Addeo P & & Taieb D 2022 Value of (68)Ga-DOTATOC and Carbidopa-Assisted (18)F-DOPA PET/CT for insulinoma localization. Journal of Nuclear Medicine 63 384–388. (https://doi.org/10.2967/jnumed.121.262401)
Kim SK, Wu CC & & Horowitz DP 2016 Stereotactic body radiotherapy for the pancreas: a critical review for the medical oncologist. Journal of Gastrointestinal Oncology 7 479–486. (https://doi.org/10.21037/jgo.2015.10.01)
Lakhtakia S, Memon SFF, Medarapalem JB, Chavan R, Nabi Z, Ramchandani MK, Gupta R & & Duvvur NR 2020 99 sustained clinical response with EUS guided RFA of pancreatic insulinoma. Oral Abstracts 61 (Supplement AB14)). (https://doi.org/10.1016/j.gie.2020.03.045)
Levy MJ, Thompson GB, Topazian MD, Callstrom MR, Grant CS & & Vella A 2012 US-guided ethanol ablation of insulinomas: a new treatment option. Gastrointestinal Endoscopy 75 200–206. (https://doi.org/10.1016/j.gie.2011.09.019)
Luo Y & & Chen X 2021 Imaging of insulinoma by targeting glucagonlike Peptide-1 receptor. PET Clinics 16 205–217. (https://doi.org/10.1016/j.cpet.2020.12.008)
Marx M, Trosic-Ivanisevic T, Caillol F, Demartines N, Schoepfer A, Pesenti C, Ratone JP, Robert M, Giovannini M & & Godat S 2022 EUS-guided radiofrequency ablation for pancreatic insulinoma: experience in 2 tertiary centers. Gastrointestinal Endoscopy 95 1256–1263. (https://doi.org/10.1016/j.gie.2021.11.045)
Matej A, Bujwid H & & Wroński J 2016 Glycemic control in patients with insulinoma. Hormones 15 489–499. (https://doi.org/10.14310/horm.2002.1706)
Mosquera-Klinger G & & Carvajal JJ 2021 Endoscopic ultrasound-guided ethanol ablation for the management of a symptomatic pancreatic insulinoma. Revista Espanola de Enfermedades Digestivas 113 48–51. (https://doi.org/10.17235/reed.2020.7109/2020)
Myrehaug S, Hallet J, Chu W, Yong E, Law C, Assal A, Koshkina O, Louie AV & & Singh S 2020 Proof of concept for stereotactic body radiation therapy in the treatment of functional neuroendocrine neoplasms. Journal of Radiosurgery and SBRT 6 321–324.
Nockel P, Babic B, Millo C, Herscovitch P, Patel D, Nilubol N, Sadowski SM, Cochran C, Gorden P & & Kebebew E 2017 Localization of insulinoma using 68ga-DOTATATE PET/CT scan. Journal of Clinical Endocrinology and Metabolism 102 195–199. (https://doi.org/10.1210/jc.2016-3445)
Okabayashi T, Shima Y, Sumiyoshi T, Kozuki A, Ito S, Ogawa Y, Kobayashi M & & Hanazaki K 2013 Diagnosis and management of insulinoma. World Journal of Gastroenterology 19 829–837. (https://doi.org/10.3748/wjg.v19.i6.829)
Oleinikov K, Dancour A, Epshtein J, Benson A, Mazeh H, Tal I, Matalon S, Benbassat CA, Livovsky DM, Goldin E, et al.2019 Endoscopic ultrasound-guided radiofrequency ablation: a new therapeutic approach for pancreatic neuroendocrine tumors. Journal of Clinical Endocrinology and Metabolism 104 2637–2647. (https://doi.org/10.1210/jc.2019-00282)
Paik WH, Seo DW, Dhir V & & Wang H-P 2016 Safety and efficacy of EUS-guided ethanol ablation for treating small solid pancreatic neoplasm. Medicine (Baltimore)95 e2538. (https://doi.org/10.1097%2FMD.0000000000002538)
Park BJ, Alexander HR, Libutti SK, Huang J, Royalty D, Skarulis MC, Jensen RT, Gorden P, Doppman JL, Shawker TH, et al.1998 Operative management of islet-cell tumors arising in the head of the pancreas. Surgery 124 1056–61. (https://doi.org/10.1067/msy.1998.92171)
Park DH, Choi J-H, Oh D, Lee SS, Seo D-W, Lee SK & & Kim M-H 2015 Endoscopic ultrasonography-guided ethanol ablation for small pancreatic neuroendocrine tumors: results of a pilot study. Clinical Endoscopy 48 158–164. (https://doi.org/10.5946%2Fce.2015.48.2.158)
Peltola E, Hannula P, Huhtala H, Metso S, Kiviniemi U, Vornanen M, Sand J, Laukkarinen J, Tiikkainen M, Schalin-Jantti C, et al.2018 Characteristics and outcomes of 79 patients with an insulinoma: a nationwide retrospective study in Finland. International Journal of Endocrinology 2018 2059481. (https://doi.org/10.1155/2018/2059481)
Peltola E, Hannula P, Huhtala H, Metso S, Sand J, Laukkarinen J, Tiikkainen M, Siren J, Soinio M, Nuutila P, et al.2021 Long-term morbidity and mortality in patients diagnosed with an insulinoma. European Journal of Endocrinology 185 577–586. (https://doi.org/10.1530/EJE-21-0230)
Placzkowski KA, Vella A, Thompson GB, Grant CS, Reading CC, Charboneau JW, Andrews JC, Lloyd RV & & Service FJ 2009 Secular trends in the presentation and management of functioning insulinoma at the Mayo Clinic, 1987–2007. Journal of Clinical Endocrinology and Metabolism 94 1069–1073. (https://doi.org/10.1210/jc.2008-2031)
Rostambeigi N & & Thompson GB 2009 What should be done in an operating room when an insulinoma cannot be found? Clinical Endocrinology 70 512–515. (https://doi.org/10.1111/j.1365-2265.2009.03527.x)
Sada A, Glasgow AE, Vella A, Thompson GB, McKenzie TJ & & Habermann EB 2020 Malignant insulinoma: A rare form of neuroendocrine tumor. World Journal of Surgery 44 2288–2294. (https://doi.org/10.1007/s00268-020-05445-x)
Sada A, Habermann EB, Szabo Yamashita T, Thompson GB, Lyden ML, Foster TR, Dy BM, Halfdanarson TR, Vella A & & McKenzie TJ 2022 Comparison between sporadic and multiple endocrine neoplasia type 1-associated insulinoma. Journal of the American College of Surgeons 235 756–763. (https://doi.org/10.1097/XCS.0000000000000307)
Sada A, Habermann EB, Yamashita TS, Thompson GB, Lyden ML, Foster TR, Dy BM, Halfdanarsond TR, Vella A & & McKenzie TJ 2021b Comparison between sporadic and multiple endocrine neoplasia type 1-associated insulinoma. Journal of the American College of Surgeons 235 756–763.(https://doi.org/10.1097/XCS.0000000000000307)
Sada A, Yamashita TS, Glasgow AE, Habermann EB, Thompson GB, Lyden ML, Dy BM, Halfdanarson TR, Vella A & & McKenzie TJ 2021a Comparison of benign and malignant insulinoma. American Journal of Surgery 221 437–447. (https://doi.org/10.1016/j.amjsurg.2020.08.003)
Sadowski SM, Neychev V, Cottle-Delisle C, Merkel R, Yang LA, Quezado MM, Chang R & & Kebebew E 2014 Detection of insulinoma using (68)gallium-DOTATATE PET/CT: a case report. Gland Surgery 3 E1–E5. (https://doi.org/10.3978/j.issn.2227-684X.2014.10.02)
Sakurai A, Yamazaki M, Suzuki S, Fukushima T, Imai T, Kikumori T, Okamoto T, Horiuchi K, Uchino S, Kosugi S, et al.2012 Clinical features of insulinoma in patients with multiple endocrine neoplasia type 1: analysis of the database of the MEN Consortium of Japan. Endocrine Journal 59 859–866. (https://doi.org/10.1507/endocrj.ej12-0173)
Sallinen VJ, Le Large TYS, Tieftrunk E, Galeev S, Kovalenko Z, Haugvik SP, Antila A, Franklin O, Martinez-Moneo E, Robinson SM, et al.2018 Prognosis of sporadic resected small (<= 2 cm) nonfunctional pancreatic neuroendocrine tumors - a multi-institutional study. HPB 20 251–259. (https://doi.org/10.1016/j.hpb.2017.08.034)
Service FJ, McMahon MM, O'Brien PC & & Ballard DJ 1991 Functioning insulinoma--incidence, recurrence, and long-term survival of patients: a 60-year study. Mayo Clinic Proceedings 66 711–719. (https://doi.org/10.1016/s0025-6196(1262083-7)
Shah R, Garg R, Majmundar M, Purandare N, Malhotra G, Patil V, Ramteke-Jadhav S, Lila A, Shah N & & Bandgar T 2021 Exendin-4-based imaging in insulinoma localization: systematic review and meta-analysis. Clinical Endocrinology 95 354–364. (https://doi.org/10.1111/cen.14406)
Sharma NR, Sharma A, Perelman A & & Zelt C 2017 Spare the whipple: novel endoscopic radiofrequency ablation treatment for insulin secreting tumors: 2017 presidential poster award, abstract 2060. American Journal of Gastroenterology 112 S1133–S1134.
Sonbol MB, Mazza GL, Mi L, Oliver T, Starr J, Gudmundsdottir H, Cleary SP, Hobday T & & Halfdanarson TR 2022 Survival and incidence patterns of pancreatic neuroendocrine tumors over the last 2 decades: a SEER database analysis. Oncologist 27 573–578. (https://doi.org/10.1093/oncolo/oyac049)
Spadaccini M, Di Leo M, Iannone A, von den Hoff D, Fugazza A, Galtieri PA, Pellegatta G, Maselli R, Anderloni A, Colombo M, et al.2022 Endoscopic ultrasound-guided ablation of solid pancreatic lesions: a systematic review of early outcomes with pooled analysis. World Journal of Gastrointestinal Oncology 14 533–542. (https://doi.org/10.4251/wjgo.v14.i2.533)
Svensson E, Muth A, Hedenstrom P & & Ragnarsson O 2022 The incidence of insulinoma in Western Sweden between 2002 and 2019. Annals of Gastroenterology 35 434–440. (https://doi.org/10.20524/aog.2022.0707)
Sweet MP, Izumisato Y, Way LW, Clark OH, Masharani U & & Duh QY 2007 Laparoscopic enucleation of insulinomas. Archives of Surgery 142 1202–120 5. (https://doi.org/10.1001/archsurg.142.12.1202)
Tonelli F, Fratini G, Nesi G, Tommasi MS, Batignani G, Falchetti A & & Brandi ML 2006 Pancreatectomy in multiple endocrine neoplasia type 1-related gastrinomas and pancreatic endocrine neoplasias. Annals of Surgery 244 61–70. (https://doi.org/10.1097/01.sla.0000218073.77254.62)
Wang H, Ba Y, Xing Q & & Du JL 2018 Diagnostic value of endoscopic ultrasound for insulinoma localization: a systematic review and meta-analysis. PLoS One 13 e0206099. (https://doi.org/10.1371/journal.pone.0206099)
Wild D, Christ E, Caplin ME, Kurzawinski TR, Forrer F, Brändle M, Seufert J, Weber WA, Bomanji J, Perren A, et al.2011 Glucagon-like peptide-1 versus somatostatin receptor targeting reveals 2 distinct forms of malignant insulinomas. Journal of Nuclear Medicine 52 1073–1078. (https://doi.org/10.2967/jnumed.110.085142)
Wilder RM, Allan FN, Power MH & & Robertson HE 1927 Carcinoma of the islands of the pancreas. JAMA 89 348–355. (https://doi.org/10.1001/jama.1927.02690050014007)
Yang D, Inabnet 3rd WB, Sarpel U & & DiMaio CJ 2015 EUS-guided ethanol ablation of symptomatic pancreatic insulinomas. Gatrointestinal Endoscopy 82 1127. (https://doi.org/10.1016/j.gie.2015.06.030)
Zhang L, Tan S, Huang S, Zhong C, Lu M, Peng Y & & Tang X 2020 The safety and efficacy of endoscopic ultrasound-guided ablation therapy for solid pancreatic tumors: a systematic review. Scandinavian Journal of Gastroenterology 55 1121–1131. (https://doi.org/10.1080/00365521.2020.1797870)
