A study of Diagnosis and surgical management of pancreatic insulinoma

Introduction: Insulinomas are the most common functioning neuroendocrine tumors of the pancreas, occurring in almost 1-4 per 1 million persons each year. They pose a challenge for pre-operative localization. Many invasive and noninvasive methods exist for localization of an insulinoma. Intra-operative ultrasonography (IOUS) with palpation can be done for tumors not localized by conventional imaging modalities. Pancreas Preserving surgery is the treatment of choice. This article gives an overview on localization and surgical strategies for treatment of insulinoma. Materials and Methods: This is a retrospective data of the patients undergoing surgical treatment of insulinoma in the Osmania General Hospital, Hyderabad between 2007 to 2017. Demographic data, symptoms and diagnostic tests and type of resections were analyzed from medical records. All patients had a completeintraoperative exploration of the pancreas done by digital palpation and intra operative ultrasonography. Results: 10cases (6 males and 4 females) of insulinoma aged between 22 and 55 years, with a median age of 30 years were included in the analysis. The size of the insulinoma ranged between 1.2 to 3 cm with average size of 2.14cm. 8 patients presented with Neuro glycopenicsymptoms howeversympatho adrenergic symptoms were present in all cases. Different modalities were employed for pre-operative localization of these patients out of which 5 cases were localized with CT, 2 cases with MRI, 1 case with EUS, 2 of them could not be localized preoperatively were localized by IOUS. Tumor was in Head 2 cases, in the neck1 case and in the body/ Tail in 7 cases. 2 patients underwent Enucleation, 5 underwent distal pancreatectomy and splenectomy, 2 underwent distal pancreatectomy and 1 underwent central pancreatectomy. 4 had pancreatic leak. All are symptom free and no episode of hypoglycemia at the time of discharge. Conclusion: Insulinomas are the most common neuroendocrine tumors of the pancreas. Surgical resection is the treatment of choice for insulinomas. From a surgical standpoint, localization of the tumor is of critical importance. Intraoperative Ultrasonography with palpation gives good help in localizing the lesion.


Introduction
Insulinomas are the most common functioning neuroendocrine tumors of the pancreas, occurring in almost 1-4 per 1 million persons each year [1][2][3]. Insulinomas are insulin-secreting neoplasms that arise from pancreatic beta cells. Sporadic insulinomas are usually solitary, benign and encapsulated small lesions. Ninety percent of them measure <2 cm and with 30% being <1 cm in diameter. Ten percent are multiple, 10% are malignant and 10% are associated with multiple endocrine neoplasia type 1 (MEN-1) [2][3][4]. Insulinomas present with repeated episodes of hypoglycemia due to endogenous hyperinsulinemia, which occurs mostly in the fasting state but may sometimes occur in the postprandial period. Symptoms are categorized into the neuroglycopenic type, which result from dysfunction of the central nervous system due to a lack of glucose, its primary energy substrate, and the sympatho adrenal type which occur as part of the stress response and the subsequent release of catecholamines. Neuroglycopenic symptoms include diplopia, behavioral changes, confusion, fatigue, amnesia, seizures and even death if hypoglycemia persists for a long time. Due to stimulation of the autonomic nervous system, results in hunger, sweating, anxiety, paresthesia's, palpitations and other adrenergic symptoms [2,4]. Historically, Whipple's triad has summarized the clinical picture and diagnosis of insulinoma (induction of the symptoms after fasting or exercise, a plasma glucose <50mg/dl when symptomatic, relief of symptoms after administration of oral or intravenous glucose) and is still employed today to diagnose hypoglycemic disorders in non-diabetic patients [5]. Diagnosis of an insulinoma is dependent on documenting inappropriately elevated levels of insulin in the setting of low circulating levels of glucose [4]. Once a state of incongruent hyperinsulinemia has been diagnosed, localization studies are necessary to visualize the tumor. Surgical resection (conventional or laparoscopic) is the primary treatment modality for insulinomas, and so accurate localization of the tumor before or during surgery is important. Multiple studies have been performed in evaluating the sensitivity of both invasive and noninvasive preoperative localization techniques [4,[6][7][8][9][10]. Additional studies have assessed the role of intraoperative ultrasound and palpation in tumor localization [4][5][6].Following biological and biochemical confirmation of an insulinoma, preoperative localization is sought using computed tomography (CT) [11][12][13], magnetic resonance imaging (MRI) [13][14][15][16], endoscopic ultrasonography (EUS) [17][18][19], intra-arterial calcium stimulation test with hepatic venous sampling [20], and/or angiography and arterial stimulation venous sampling (ASVS) [21][22][23][24][25].
The present study aims to analyze the clinical, epidemiological, Radiological findings and surgical out comes of Insulinoma treated in our institute.

Materials and Methods
Place of study and type of study: This is a retrospective data of the medical records of patients undergoing surgical treatment of insulinoma in the Osmania General Hospital, Hyderabad between 2007 to 2017.
Demographic data, type and duration of symptoms, association or not with endocrine syndrome and diagnostic tests were obtained from registries of medical records. It was also analyzed, the surgical approach, intraoperative findings and complications.
The preoperative evaluation done with USG Abdomen, Contrast enhanced CT,Abdominal MRI and Endoscopic U/S (EUS). All patients had a complete intraoperative exploration of the pancreas done by digital palpation and intra operative ultrasonography.
Cure following surgical resection was defined as normal glucose levels in the setting of fasting without either pharmacologic assistance or the need for supplemental glucose at the time of discharge from the hospital.
Inclusion criteria: Biochemically detected, surgically resected and histopathological confirmed cases of Insulinoma of pancreas were included in this study.
Exclusion criteria: if Histopathology report doesn't show Insulinoma were excluded from the study.
Statistical methods: Continuous data were expressed as median/ range and analyzed by Kruskal-Wallis test, and categorical variables were expressed as number/ percentage and analyzed by chi-square test.

Results
Ten cases of insulinoma aged between 22 and 55 years, with a median age of 30 years were included in the analysis. There were 6 males and 4 females. Nine patients presented with pre-prandial hypoglycemia. One patient had hypoglycemia during the episode of seizure. Neuro glycopenic symptoms were present in 8 patients and sympatho adrenergic symptoms were present in allcases. Six cases were Obese. 3 patients were referred from psychiatry department due neuroglycopenic symptoms caused by Hypoglycemia. Different modalities were employed for pre-operative localization of these patients out of which 5 cases were localized with CT, 2 cases with MRI, 1 case with EUS, 2 of them could not be localized preoperatively were localized by IOUS. Tumor was in Head in 2 cases, in the neck1 case and in the body/ Tail in 7 cases [ Table 1].
All underwent surgery out of which 2 patients underwent Enucleation, 5 underwent distal pancreatectomy and splenectomy, 2 underwent distal pancreatectomy and 1 underwent central pancreatectomy. The size of the insulinoma ranged between 1.2 to 3 cm with average size of 2.14cm.
Three had grade A pancreatic leak and 1 had grade B pancreatic leak (following enucleation of the head lesion). All are symptom free and no episode of hypoglycemia at the time of discharge. During follow up 1 patient developed diabetes managed with oral hypoglycemic agents.    Insulinomas are insulin-secreting neoplasms that arise from pancreatic beta cells. Sporadic insulinomas are usually solitary, benign and encapsulated small lesions. Ninety percent of them measure <2 cm and with 30% being <1 cm in diameter. Ten percent are multiple, 10% are malignant and 10% are associated with multiple endocrine neoplasia type 1 (MEN-1) [2][3]. In a non-diabetic individual with fasting hypoglycemia, insulinoma should be considered in the differential diagnosis. Clinical presentation can vary, they may present with adrenergic symptoms like palpitations, tremor, anxiety, warmth and dry mouth, cholinergic symptoms comprising of hunger, sweating and paresthesia's [3][4].

Original Research Article
Neuroglycopenic symptoms start as a blood glucose falls to approximately 50-55 mg/dL (2.8-3.1 mmol/L), which include slurred speech, blurred vision, confusion, drowsiness and difficulty in concentrating [2][3][4]. A strong clinical suspicion to diagnose an insulinoma with varied clinical presentation is needed. These patients tend to eat more to avoid symptoms of hypoglycemia and thus they become overweight and obese. Historically, Whipple's triad has summarized the clinical picture and diagnosis of insulinoma (induction of the symptoms after fasting or exercise, a plasma glucose <50mg/dl when symptomatic, relief of symptoms after administration of oral or intravenous glucose) and is still employed today to diagnose hypoglycemic disorders in non-diabetic patients [5].
Diagnosis of an insulinoma is dependent on documenting inappropriately elevated levels of insulin in the setting of low circulating levels of glucose. The measurement of serum insulin has proven useful for the diagnosis, and it is important the demonstration of elevated insulin (> 5 microU / mL) during an episode of symptomatic hypoglycemia. The relationship between insulin (microU / ml) and glucose (mg / dL)> 0.4 is highly suggestive, as well as increased levels of Cpeptide (> 2 nmol / L) [3,8]. Increased levels of Cpeptide are also valuable diagnostic, excluding the possibility of fictional disease [26].
Thus, more percentage of cases were localized preoperatively in our series as compared to the data by Jyotsna et al., where preoperative localization of insulinoma was successful in 71% with various imaging modalities, with CT angiography, 83%, intraarterial digital subtraction angiography, 65%, dual-phase CT, 57%, and conventional MRI in 31% and intraoperative palpation and ultrasonography localized 76% and 92%, respectively [33]. In Kaczirek et al. series, insulinoma was localized by conventional CT in 33%, single-slice helical CT in 58%, multi-detector CT in 100%, MRI in 85% and invasive angiography in 65% and with a combination of different modalities, the sensitivity rate was up to 88% [34].
When conventional imaging modalities cannot localize, intra operative ultrasonography with bimanual palpation willhelp.
Surgical excision of insulinoma remains the treatment of choice [35,36]. Traditional resections and parenchyma-sparing resections or a combination of both can be employed depending on indications. Factors that dictate the choice of procedure and should be addressed preoperatively are a diagnosis or not of MEN1, the number of insulinomas, the tumor's size, location in the pancreas and anatomical proximity to the major pancreatic duct and major blood vessels, and the likelihood of malignancy. As previously stated, the majority of insulinomas are sporadic and in turn most sporadic insulinomas are solitary and benign.
Therefore, parenchyma-sparing procedures such as enucleation and central pancreatectomy are frequently performed in the management of sporadic insulinoma.In this study, the tumor was slightly more prevalent in the body and tail (70%), and the literature shows equal distribution in the pancreatic parenchyma [2,3].
Although no patients required a pancreatic coduodenectomy in our series, it has been required in 5.5% to 16% of cases involving pancreatic head tumors in which main pancreatic duct injury is a concern [1,37].
Enucleation is safe if the lesion is located 2-3mm away from the main pancreatic duct. All pancreatic head lesions (N=2) in our study were removed via enucleation. Following enucleation inspection of the resection site under 3.5× loupe magnification for evidence of a pancreatic duct leak was performed. An alternative technique to pancreatic coduodenectomy or pancreatic head resection with Roux-en-Y pancreatojejunostomy to spare the duodenum and the normal pancreatic body and tail [38].
In this study, 5 patients underwent distal pancreatectomy and splenectomy due to tumor was proximity to splenic vessels and larger size. 2 patients underwent spleen preserving distal pancreatectomy and 1 underwent central pancreatectomy. The spleen can be preserved in patients undergoing a distal pancreatectomy as advised by reports suggesting patients undergoing spleen-preserving procedures have less postoperative complications including infection [4,39].
All procedures in the current study were performed via a laparotomy. Advances in laparoscopic techniques have resulted in recent studies proposing the use of laparoscopic enucleation or pancreatectomy with or without intraoperative ultrasound for the management of insulinomas in adults [40][41][42][43]. Although these studies are encouraging, we prefer laparotomy for the management of insulinomas mainly due to the critical role of intraoperative palpation and intraoperative ultrasound in identifying the lesions. We believe it is important to explore and palpate the entire pancreas and use intraoperative ultrasound to avoid missing lesions.
Recently, successful EUS-guided alcohol ablation and CT-guided RFA of pancreatic insulinomas have been reported in humans with poor general condition and were experiencing recurrent symptomatic episodes of hypoglycemia [44,45]. Both patients were discharged without any complications and reported no further hypoglycemic episodes.
Embolization of an insulinoma of the pancreas is another non-surgical alternative [46,47]. Medical treatment to normalize blood glucose is useful during the preoperative period, as well as for patients who cannot be cured by surgery, such as those with diffuse β-cell disease, multiple insulinomas, unresectable malignant insulinoma, those in whom surgery is contraindicated, or patients who refuse surgery [48].
Octreotide is a somatostatin analog that inhibits insulin secretion and the peripheral action of many gastrointestinal hormones, primarily via activation of

Conclusion
Insulinomas are the most common neuroendocrine tumors of the pancreas and cause hypoglycemia related to endogenous hyperinsulinism. More than 90% of insulinomas are benign and usually small, wellencapsulated, solitary tumors. Surgical resection is the treatment of choice for insulinomas and offers the only chance for cure. From a surgical standpoint, localization of the tumor is of critical importance. Successful identification eliminates the need for blind resections of pancreatic tissue. However, no consensus has been attained for the preoperative localization of these tumors.
Local availability and skill in specific invasive and noninvasive tests seem to determine the preoperative algorithm. Intraoperative Ultrasonography with palpation gives good help in localizing the lesion.
Advances in minimally invasive surgical techniques have for the last two decades permitted the introduction of laparoscopic surgery in the treatment of this condition. Results have been encouraging and comparable to those of open surgical techniques. However, there is an absence of randomized control studies that would conclusively verify the conclusions of these studies.
Message of this study: From a surgical standpoint, localization of the tumor is of critical importance. Successful identification eliminates the need for blind resections of pancreatic tissue.
Intraoperative Ultrasonography with bimanual palpation gives good help in localizing the lesion.

Authors Contribution
Author 1. Prepared the manuscript and performed all surgeries.
Author 2. Helped in data collection and involved in patient care.
Author 3. Helped in data analysis and statistical analysis. Assisted majority of surgeries.
Author 4. Supervised the paper and involved in patient care of these patients.