Insulinoma


Article Author:
Fenghao Zhuo


Article Editor:
Catherine Anastasopoulou


Editors In Chief:
Ishwarlal Jialal


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
9/3/2019 5:38:17 PM

Introduction

Insulinoma is a type of functional neuroendocrine tumor (NET) which manifests with hypoglycemia caused by inappropriately high secretion of insulin. It more commonly presents as a solitary benign tumor, but it can sometimes be associated with multiple endocrine neoplasia type 1 (MEN1). Patients with insulinoma have hypoglycemic episodes, more characteristically as fasting hypoglycemia. Insulinoma is usually diagnosed by biochemical testing when there is high clinical suspicion. Surgical resection is the preferred treatment choice. Localization with imaging studies is fundamental to characterize the tumor better before surgical resection. There are also other treatment options available depending on the stage and grade of the tumor.

Etiology

The etiology of solitary insulinoma is not clearly understood. Normally high plasma glucose concentration would trigger the secretion of insulin from the pancreatic beta cells and vice versa. In patients with insulinoma, insulin still gets secreted, even when plasma glucose concentration is low. The hyperinsulinemia could result from an upregulated translation process due to a variant of insulin splice.[1] When the intracellular insulin store has been filled up, insulin gets secreted to the blood. Hyperinsulinemia causes increased glycogen synthesis, decreased gluconeogenesis, and glycogenolysis, all of which attribute to hypoglycemia.

MEN1 is a disorder characterized by a predisposition to the pituitary, parathyroid, and enteropancreatic tumors. When insulinomas are associated with MEN1, a mutation in the MEN1 gene at chromosome 11q13 is typically present in most cases.[2]

Epidemiology

The incidence of insulinoma is around 1 to 4 per million per year.[3][4] More commonly, insulinoma is a single benign tumor, and only in 5.8% of cases, it can be malignant.[3] It can coexist with other benign tumors in 7% of the cases, and in 6% to 7.6% of the cases, it is associated with MEN1 syndrome.[3][5] Surgical diagnosis happens at a median age of 47 to 50 years old.[3][5]

History and Physical

Fasting hypoglycemia is the most characteristic finding of insulinoma, reported in 73% of the population.[5] Around 20% of patients have both fasting and postprandial hypoglycemic symptoms.[5] There have been increasing numbers of patients reporting only postprandial hypoglycemic symptoms, and this is more prominent in men.[5] Weight gain occurs in most of these patients.

Hypoglycemia presents in different ways. Sympathoadrenal activation symptoms, including palpitations, tremulousness, and diaphoresis, can be seen. Severe hypoglycemia can cause neuroglycopenic symptoms, including blurry vision, confusion, seizures, or a change in behavior. Amnesia of the hypoglycemic event is common.

Insulinoma should be suspected when a patient presents with the Whipple’s triad which includes: symptoms of hypoglycemia, a documented low plasma glucose concentration, and subsequent improvement of the symptoms with the use of glucose treatment.

Evaluation

There are two crucial steps in evaluating an insulinoma. The first one is to establish the diagnosis with biochemical tests when there is high clinical suspicion, and the second one is to localize the tumor.

A 72-hour fast is the gold-standard test for diagnosing insulinoma.[4][6] It is useful when the Whipple triad is not observable and when there were no biochemical tests during spontaneous hypoglycemic episodes. [7] The combination of plasma glucose concentration under 55 mg/dL, insulin level greater than or equal to 3 microUnits/mL, C peptide level greater than or equal to 0.6 ng/mL, proinsulin level greater than or equal to 5 pmol/L, beta-hydroxybutyrate level less than or equal to 2.7 mmol/L and a simultaneous negative sulfonylurea level indicates that the hypoglycemia induction is by hyperinsulinemia.

A successful preoperative localization by noninvasive modalities remains around 75%.[5] Computed tomography (CT) with contrast is the most frequently used initial noninvasive testing.[6] CT detects 70 to 80% of the tumors where the insulinoma usually presents as a small solid mass, which enhances after contrast.[8][9] Abdominal ultrasound (US) focusing on the pancreas is sometimes preferred, given its convenience and low cost. Magnetic resonance image (MRI) detects about 85% of the insulinomas that seem to enhance homogeneously after gadolinium administration.[8][9] Glucagon-like peptide-1 receptor (GLP-1) imaging is a promising new modality test and has been studied to localize insulinoma with success detection rate of 66 to 97% in some small studies.[10][11]

When there is high suspicion for insulinoma with negative noninvasive studies, invasive tests such as endoscopic ultrasonography (EUS) or a selective arterial calcium stimulation test (SACST) with hepatic venous sampling could be an approach considered. EUS has a sensitivity of 70 to 95% and is superior to CT for localization. [8][12] This is the preferred test of choice if non-invasive studies are negative as it also allows tissue acquisition that can be very helpful, especially in cases that the tumor is small.[12] SACST has a sensitivity of 93% for detecting insulinoma and could be performed when other imaging studies are negative, or in patients with MEN1 syndrome.[5][13]

Histology examination and immunostaining for chromogranin A, synaptophysin, and insulin should be done to support the diagnosis of insulinoma.[4] A Ki67 index should also be obtained for grading, especially when a patient demonstrates an aggressive clinical course.[4]

Tumor size of greater than or equal to 2 cm, Ki67 more than 2% and molecular features including chromosomal alteration such as 3p and 6q loss and 12 q gain or chromosomal instability, are possible predictors for metastatic disease and poor progression-free survival (PFS).[14]

Malignant insulinomas have evidence of extrapancreatic regional lymph nodes or even remote extension. Certain factors including fasting time for the occurrence of hypoglycemia being under 8 hours, higher blood insulin level (greater than or equal to 28 microUnits/mL) and higher C-peptide level (greater than or equal 4.0 ng/mL) at the glycemic nadir. These factors, as well as larger tumor size (greater than or equal to 2.5 cm), all correlate with an increased risk of malignant disease.[15] The extent of liver metastases and the presence of lymph node metastases are important prognostic factors.[13]

The recommendation is that all young patients with insulinoma undergo genetic testing. MEN1 syndrome should be a consideration in patients with either family and/or personal history of other endocrinopathies.[16]

Treatment / Management

Surgical resection is recommended for local disease but it should also be considered for advanced disease.[14] Single sporadic insulinoma is curable by surgical intervention.[4] Surgeons have described several different surgical approaches. The most commonly used is enucleation of the insulinoma and partial distal pancreatectomy.[3] Nowadays laparoscopic resection of insulinoma is gaining in popularity with a shorter hospital stay and at least similar favorable outcomes.[17] Robotic enucleation of insulinoma is being reported in some cases with also good short and long-term outcomes compared to the laparoscopic approach.[18][19] Patients with MEN1 might need a different surgical approach, including subtotal pancreatectomy in addition to enucleation of the tumors. EUS-guided ethanol ablation has been attempted in poor surgical candidates and has been successful in some case series.[13][20]

Clinicians can attempt medical treatment before surgery in recurrent or malignant cases.[13] For initial insulinomas, dietary modification, diazoxide, everolimus, and MedicAlert bracelets are prudent steps.[16] Other strategies, including glucagon pen, somatostatin analogs, and steroids, are also considerations.[16]

If the tumor is unresectable, if the patient has metastatic disease, or if he is a poor surgical candidate, diazoxide is an option.[7] Diazoxide can decrease insulin release and enhance glycogenolysis. Around 60% of the patients become symptom-free.[21] The efficacy of octreotide in patients with refractory hypoglycemia is less predictable but remains an option for patients who do not respond to diazoxide. For patients with refractory symptoms and stable tumor volume, adjusting the dose of octreotide or getting surgical resection could be considered.[16]

For patients with refractory symptoms and increasing tumor volume, oncologic control with referral to specialty centers is the recommended course.[16] For patients with well-differentiated pancreatic neuroendocrine tumors (pNET), targeted therapy (everolimus or sunitinib) are pharmaceutical options.[22] Everolimus inhibits the mammalian target of rapamycin.[23] Everolimus was found to improve median PFS in patients with low or intermediate-grade, advanced progressive pNET and a subgroup of functional pNET including but not limited to insulinomas.[24][25] It can also help to control hypoglycemia in patients with malignant insulinoma.[13] Lastly, sunitinib is also recommended for progressive metastatic pNET, although a small volume of patients with insulinoma participated in these studies.[16][26]

For advanced disease, surgical resection could still be an option if most (90% or more) of the tumor is safely resectable, or if the liver metastases seem to be resectable.[16] There has not been sufficient research on the different regimens of therapies to determine established choices.[16] Cytotoxic therapies such as 5-FU or temozolomide could be possibilities in patients with advanced pNET as palliative therapy [16]

Some research suggests neoadjuvant therapy of peptide receptor radionuclide therapy (PRRT) in unresectable or borderline resectable pNET because of survival benefits.[27][28]  PRRT can also control hypoglycemia in malignant insulinomas, but its role in insulinoma treatment still needs more investigation.[13][27][29]

Differential Diagnosis

  • Persistent hyperinsulinemic hypoglycemia of infancy (PHHI)
  • Noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS)
  • Post-gastric bypass hypoglycemia
  • Factitious use of insulin
  • Sulfonylurea-induced hypoglycemia
  • Insulin autoimmune hypoglycemia
  • Non-islet-cell tumors that secrete insulin-like growth factors (IGF)

Staging

Researchers have developed several classification and grading systems (WHO2010, ENETs, AJCC) for pNET. Most of them provide essential prognostic values.[13]

Newer classification systems include WHO2017 and AJCC 8 edition. AJCC (8th edition, 2017) includes ENETs definitions for T stage and prognostic stage grouping. There is further modification of this staging system available which might provide better prognostic information.[30]

TNM staging

TX - Tumor cannot be assessed

T1 - Tumor limited to the pancreas, less than 2 cm

T2 - Tumor limited to the pancreas, 2 to 4 cm

T3 - Tumor limited to the pancreas, greater than 4 cm; or tumor invading the duodenum or common bile duct

T4 - Tumor invasion of adjacent organs (e.g., stomach, spleen, colon, adrenal gland), or the walls of large vessels (celiac axis or the superior mesenteric artery)

NX - Regional lymph nodes cannot be assessed

N0 - No regional lymph node involvement

N1 - Regional lymph node involvement

M0 - No distant metastasis 

M1 - Distant metastasis 

M1a - Metastasis confined to the liver

M1b - Metastasis in at least one extrahepatic site (e.g., lung, ovary, nonregional lymph node, peritoneum, bone)

M1c - Both hepatic and extrahepatic metastases

Prognosis

In insulinoma patients, the 10-year survival rate is 88% after successful surgical removal, and 87.5% of patients get cured (being free of symptoms for at least six months) after surgery.[3] The 10-year survival in malignant insulinomas was 29% after successful surgical removal in one study, and the 5-year survival was 24% in another.[3][5] Patients with MEN1 syndrome or malignant insulinomas have a higher rate of failing initial surgery or having a recurrence of the disease.[3] The rate of recurrence among patients with MEN1 is around 21% at 10 and 20 years, while in those without MEN 1 is reported at 5% at 10 years and 7% at 20 years.[3]

Complications

The complications associated with insulinoma include persistent hypoglycemia causing interference with daily activities, irreversible neurocognitive impairment, and even death.

Postoperative and Rehabilitation Care

Insulinoma patients without MEN1 should have a follow-up at 3 to 6 months post resection.[4] Biochemical testing and imaging studies should be repeated at the follow-up visit. If cured, patients can be followed as needed if they experience recurrence of symptoms. Patients with persistent symptoms after surgery might have multiple tumors or MEN1 syndrome, and they should get repeat imaging studies.[16] Patients with multiple insulinomas, or with MEN1, should be followed yearly, even if they continued to be cured post resection.[4]

Deterrence and Patient Education

Patients and family members should receive education about recognizing symptoms associated with hypoglycemia and also be trained to use convenient ways to correct hypoglycemia quickly. Patients should follow up with endocrinology specialists for evaluation and treatment of insulinoma. Genetic testing is sometimes necessary.

Pearls and Other Issues

 

 

Enhancing Healthcare Team Outcomes

The evaluation of insulinoma includes biochemical testing and localization with imaging studies. An interprofessional team, including primary care physicians, pharmacists, radiologists, endocrinologists, surgeons, oncologists, specialty-trained nurses, and sometimes genetic specialists, could facilitate better management of insulinomas. [LEVEL V] Patient education is paramount. Length of follow up required post resection varies, and a timely adjustment of the treatment plan is more accessible if patients follow up as instructed. 


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Insulinoma - Questions

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A patient had several syncopes preceded by blurred vision and profuse diaphoresis. Work up revealed hypoglycemia and discovery of a pancreatic mass. What is the most likely diagnosis?



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What can be measured to differentiate between endogenous and exogenous insulin?



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A patient has had several episodes of syncope preceded by blurred vision, profuse sweating, and lethargy. Blood tests reveal hypoglycemia and ultrasound shows a mass in the mid-epigastrium. What is the most likely diagnosis?



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In a patient with an insulinoma, which of the following is an unlikely associated disorder?



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A 65-year-old male presents with numerous fainting episodes and headaches. The work-up reveals elevated levels of insulin. A CT scan reveals an isolated mass in the pancreas. Which of the following drugs is best for the treatment of this pancreatic mass?



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An otherwise healthy 40-year-old patient is seen in the clinic complaining of lethargy and confusion. She is found to have low levels of glucose, and she suffers three seizures while in observation. A CT scan reveals a 2 cm mass in the tail of the pancreas. Which of the following is the best treatment for this patient?



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Which of the following is not part of the Whipple triad?



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A patient is seen with complaints of recurrent episodes of syncope and diaphoresis. Blood work reveals that he has blood glucose of 40 mg. What is the most likely diagnosis?



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Which of the following is a treatment for insulinomas?



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C peptide is invariably elevated in which of the following conditions?



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Which drug is used for insulinomas?



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What is the most common functional endocrine tumor of the pancreas?



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Which of the following tumors is the most common cause of hypoglycemia?



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What documented findings are not included in the Whipple triad?



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Patients with an insulinoma normally have insulin concentration over what level?



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A 39 year old man was brought to the emergency room by colleagues at work. He suddenly became sweaty and lost consciousness. Blood work up on admission reveals blood glucose of 42mg/dl (Normal blood glucose is between 70-100 mg/dl). A diagnosis of hypoglycemia was made and he was started on 50% glucose infusion. A C-peptide assay ordered shows markedly elevated values. Which of the following diagnosis is most likely responsible for his disease and clinical presentation?



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A 35-year-old previously healthy female was admitted to the hospital with symptomatic fasting hypoglycemia, which is her 4th episode in the last six months. She is not on any home medications. She works as a bank accountant and lives with her elderly mother, who has diabetes and takes insulin and metformin. Her vital signs were within normal limits, and the physical exam was unremarkable. Lab work reveals markedly elevated Insulin and C peptide levels, with undetectable sulfonylurea and meglitinides in the blood. Anti-insulin antibodies were also negative. Which of the following is the most likely cause of her recurrent hypoglycemia?



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A 25-year-old female presents to the hospital for evaluation of her recurrent diaphoresis, palpitations, and confusion. Her plasma glucose concentration is 45 mg/dl, and it responds to IV glucose. Which of the following sets of blood tests should is most appropriate to help diagnose the cause of her recurrent symptoms?



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A 28-year-old female presents to the hospital with diaphoresis and is found to be hypoglycemic on finger stick. She is given IV dextrose, and her symptoms improve. She undergoes biochemical testing, which is suggestive of hyperinsulinemia. She has a CT abdomen with contrast done for localization of the tumor, but it comes back negative. Which of the following is the best next step for diagnosing insulinoma in this case?



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A 30-year-old man with no past medical history presents to the emergency department with multiple episodes of a generalized tonic-clonic seizure. His seizure stopped upon arrival. His vital signs are stable. Blood work shows a plasma glucose concentration of 50 mg/dL. His CT head is negative for acute disease. EEG is negative for seizure activity. He has no family history of endocrinopathies. Further bloodwork shows insulin level 7 microU/mL, C peptide level 1 ng/mL, proinsulin level 8 pmol/L, beta-hydroxybutyrate level 0.3 mmol/L, and a negative sulfonylurea. CT abdomen shows a 1 cm solid mass in the pancreas, which enhanced after contrast. He undergoes surgical resection of the mass and follows up with endocrinology six months post resection. He has had no recurrence of the tumor on repeat imaging. He denies any recurrent symptoms. Which of the following is the next best step in the management of this patient?



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A 45-year-old male was diagnosed with insulinoma and underwent surgical resection. At 6-month post resection follow up, he was found to have the recurrence of the tumor on imaging studies. He was started on diazoxide but remained symptomatic with hypoglycemic episodes. Diazoxide was then switched to octreotide by his endocrinologist. He now presents again with recurrent symptoms of diaphoresis, palpitations, and blurry vision. His insulinoma size is also growing on repeat imaging. Which of the following is the next best step in the management of this patient?



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A 35-year-old female with multiple insulinomas followed up with endocrinology after surgical resection and was found to be cured (free of disease on repeat imaging and no recurrence of symptoms). When should this patient return to the endocrinology office?



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Insulinoma - References

References

Minn AH,Kayton M,Lorang D,Hoffmann SC,Harlan DM,Libutti SK,Shalev A, Insulinomas and expression of an insulin splice variant. Lancet (London, England). 2004 Jan 31;     [PubMed]
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Salazar R,Wiedenmann B,Rindi G,Ruszniewski P, ENETS 2011 Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Tumors: an update. Neuroendocrinology. 2012;     [PubMed]
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Christ E,Wild D,Forrer F,Brändle M,Sahli R,Clerici T,Gloor B,Martius F,Maecke H,Reubi JC, Glucagon-like peptide-1 receptor imaging for localization of insulinomas. The Journal of clinical endocrinology and metabolism. 2009 Nov;     [PubMed]
Luo Y,Pan Q,Yao S,Yu M,Wu W,Xue H,Kiesewetter DO,Zhu Z,Li F,Zhao Y,Chen X, Glucagon-Like Peptide-1 Receptor PET/CT with 68Ga-NOTA-Exendin-4 for Detecting Localized Insulinoma: A Prospective Cohort Study. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2016 May;     [PubMed]
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