Nesidioblastosis and Subsequent Diabetes Mellitus in a Dog with Hyperinsulinemic Hypoglycemia Treated with Partial Pancreatectomy.

A 6.5 yr old castrated male mixed-breed dog was presented for clinical signs associated with hypoglycemia. Hyperinsulinemic hypoglycemia was diagnosed as the cause of the persistent hypoglycemia. No obvious pancreatic mass was seen on abdominal computed tomography and exploratory laparotomy. A partial pancreatectomy was performed with the suspicion of an insulinoma-causing hyperinsulinemic hypoglycemia. Nesidioblastosis was diagnosed based clinical, biochemical, and histopathologic findings. There was beta cell hyperplasia and no evidence of neoplasia. The dog was euglycemic postoperatively after a partial pancreatectomy. Long-term follow-up after 2 yr revealed that the dog was diagnosed with diabetes mellitus.

Circularity of islets is a distinct marker for the pathological diagnosis of adult non-neoplastic hyperinsulinemic hypoglycemia using surgical specimens.

BACKGROUND: Adult non-neoplastic hyperinsulinemic hypoglycemia (ANHH), also known as adult-onset nesidioblastosis, is a rare cause of endogenous hyperinsulinemic hypoglycemia in adults. This disease is characterized by diffuse hyperplasia of pancreatic endocrine cells and is diagnosed by a pathological examination. While diagnostic criteria for this disease have already been proposed, we established more quantitative criteria for evaluating islet morphology. METHODS: We measured the number, maximum diameter, total area, and circularity (representing how closely islets resemble perfect spheres) of islets contained in representative sections of ANHH (n = 4) and control cases (n = 5) using the NIS-Elements software program. We also measured the average cell size, percentage of cells with enlarged nuclei, and percentage of cells with recognizable nucleoli for each of three representative islets. We also assessed the interobserver diagnostic concordance of ANHH between five experienced and seven less-experienced pathologists. RESULTS: There was no significant difference in the number, maximum diameter, or total area of islets between the two groups, even after correcting for these parameters per unit area. However, the number of islets with low circularity (< 0.71) per total area of the pancreatic parenchyma was significantly larger in ANHH specimens than in controls. We also found that the percentage of cells with recognizable nucleoli was significantly higher in the ANHH group than in the controls. There were no significant differences in the average cell size or the number of cells with enlarged nuclei between the groups. The correct diagnosis rate with the blind test was 47.5% ± 6.12% for experienced pathologists and 50.0% ± 8.63% for less-experienced pathologists, with no significant differences noted. CONCLUSIONS: Low circularity, which indicates an irregular islet shape, referred to as "irregular shape and occasional enlargement of islets" and "lobulated islet structure" in a previous report, is a useful marker for diagnosing ANHH. An increased percentage of recognizable nucleoli, corresponding to "macronucleoli in ß-cells," has potential diagnostic value.

Pathological features in non-neoplastic congenital and adult hyperinsulinism: from nesidioblastosis to current terminology and understanding.

Nesidioblastoma and nesidioblastosis were terms given to neoplastic and non-neoplastic lesions of the pancreas associated with pancreatogenous hyperinsulinaemic hypoglycaemia. While nesidioblastoma was rapidly replaced by islet cell tumour, nesidioblastosis, defined as the proliferation of islet cells budding off from pancreatic ducts, was the diagnostic term associated with congenital hyperinsulinism of infancy (CHI) and adult non-neoplastic hyperinsulinaemic hypoglycaemia (ANHH). When it was shown that nesidioblastosis was not specific for CHI or ANHH, it was no longer applied to CHI but kept for the morphological diagnosis of ANHH. In severe CHI cases, a diffuse form with hypertrophic ß-cells in all islets can be distinguished from a focal form with hyperactive ß-cells changes in a limited adenomatoid hyperplastic area. Genetically, mutations were identified in several ß-cell genes involved in insulin secretion. Most common are mutations in the ABCC8 or KCNJ11 genes, solely affected in the diffuse form and associated with a focal maternal allelic loss on 11p15.5 in the focal form. Focal CHI can be localized by 18F-DOPA-PET and is thus curable by targeted resection. Diffuse CHI that fails medical treatment requires subtotal pancreatectomy. In ANHH, an idiopathic form can be distinguished from a form associated with gastric bypass, in whom GLP1-induced stimulation of the ß-cells is discussed. While the ß-cells in idiopathic ANHH are diffusely affected and are either hypertrophic or show only little changes, it is controversial whether there is a ß-cell increase or ß-cell hyperactivity in patients with gastric bypass. Recognizing morphological signs of ß-cell hyperactivity needs a good knowledge of the non-neoplastic endocrine pancreas across all ages.

[Mature teratoma of the anterior mediastinum with a predominance of the pancreatic component and signs of focal nesidioblastosis]. / Zrelaya teratoma perednego sredosteniya s preobladaniem pankreaticheskogo komponenta i priznakami fokal'nogo nezidioblastoza.

A case of a mature anterior mediastinal teratoma with a predominance of the pancreatic component (80% of the tumor) and signs of nesidioblastosis in a 46-year-old woman is presented. During histological examination, all components of the pancreatic parenchyma were determined - acini with interlobular and intralobular ducts, endocrine cells and islets of Langerhans of various sizes and shapes, as well as islet-duct complexes scattered in the acinar tissue. In addition to pancreatic tissue, cartilage, bronchial respiratory epithelium, small intestine tissue, hair follicles, and sebaceous glands were found in the neoplasm. Immunohistochemical examination revealed signs of focal nesidioblastosis. In the islets, insulin-positive ß-cells (80.0% of the volume of the islets), as well as endocrine cells expressing glucagon and somatostatin (10.0% of the volume of the islets) were determined. By 2020, only 4 such cases have been published in the English-language literature.

Hyperinsulinemic hypoglycemia in adults. Nesidioblastosis case report and review of the literature.

Hypoglycemia due to endogenous hyperinsulinism usually occurs in 2 pathological situations: the most frequent is insulinoma and, secondly, nesidioblastosis or also known as non-insulinoma pancreatic hypoglycemic syndrome. Nesidioblastosis is a rare cause of hyperinsulinic hypoglycemia in adults. We present the clinical case of an adult patient with recurrent hypoglycemia secondary to nesidioblastosis.

La hipoglucemia por hiperinsulinismo endógeno suele presentarse en dos situaciones patológicas: la más frecuente es el insulinoma y, en segundo lugar, la nesidioblastosis o síndrome hipoglucémico pancreático no insulinoma. La nesidioblastosis es una causa poco frecuente de hipoglucemia por hiperinsulinismo en adultos. Presentamos el caso de un paciente adulto con cuadros recurrentes de hipoglucemia secundarios a nesidioblastosis.

Utility of 68 Ga-DOTA-Exendin-4 positron emission tomography-computed tomography imaging in distinguishing between insulinoma and nesidioblastosis in patients with confirmed endogenous hyperinsulinaemic hypoglycaemia.

BACKGROUND: Because management is very different, it is important to differentiate between small focal insulinomas and diffuse pancreatic dysplasia (nesidioblastosis) in patients with confirmed endogenous hyperinsulinaemic hypoglycaemia (EHH). Most insulinomas highly express glucagon-like peptide-1 receptors enabling positron emission tomography-computed tomography imaging with its radiolabelled analogue; 68 Ga-DOTA-Exendin-4 (Exendin). AIM: To determine: (i) the utility of Exendin in EHH patients in a clinical setting; and (ii) whether the degree of Exendin uptake differentiates non-insulinoma pancreatogenous hypoglycaemia syndrome (NIPHS) from post-gastric bypass hypoglycaemia (PGBH). METHODS: This retrospective study reviewed the clinical, biochemistry and prior imaging findings in confirmed EHH patients referred for Exendin. Accuracy of Exendin was based on surgical findings and treatment outcomes. Finally, average Exendin uptake (SUVmax) of five PGBH studies was compared with the SUVmax of a key NIPHS case report. RESULTS: Twenty of 25 consecutive patients had confirmed EHH. Exendin located insulinomas in eight of nine patients enabling successful surgical excision with rapid and durable cure. Exendin correctly identified diffuse nesidioblastosis in two of three cases requiring partial pancreatectomy for hypoglycaemia control. All three relapsed within 1.7 years with one needing completion pancreatectomy. Establishing the cause in the remainder relied on other investigations, clinical correlation and response to empirical treatment. Finally, Exendin SUVmax could not distinguish between NIPHS and PGBH. CONCLUSION: In EHH patients, Exendin accurately identifies the site of insulinoma and thereby differentiates it from nesidioblastosis but negative findings should not be ignored. Exendin is unlikely to differentiate between normal pancreatic uptake, NIPHS and PGBH.

Hipoglucemia hiperinsulínica en un adulto con nesidioblastosis / Hyperinsulinic Hypoglycemia in an Adult with Nesidioblastosis

RESUMEN Introducción: La Nesidioblastosis es una rara afección pancreática que provoca hipoglucemia por hipersinsulinismo endógeno en la infancia. Es poco habitual en el adulto; solo se han publicado casos aislados desde su descripción. Objetivo: Caracterizar la presentación de una hipoglucemia hiperinsulínica en un paciente adulto con Nesidioblastosis. Caso clínico: Paciente adulto de 35 años, blanco, sexo masculino, sospecha de insulinoma, con episodios de hipoglucemia en ayunas o tras un ejercicio que revertía con la ingesta de alimentos o soluciones glucosadas. Se le realizó pancreatectomía de un 85 por ciento y en el estudio histológico se detectó una Nesidioblastosis. Conclusiones: Es infrecuente en el adulto, realizar su diagnóstico es difícil, se llega a la cirugía con el conocimiento de un estado hiperinsulínico endógeno, sin la certeza de su origen(AU)

ABSTRACT Introduction: Nesidioblastosis is a rare pancreatic condition that causes hypoglycemia due to endogenous hypersinsulinism in childhood. It is unusual in adults; only isolated cases have been published including its description. Objective: To characterize a case of hyperinsulinic hypoglycemia, in an adult patient with nesidioblastosis. Clinical case: A 35-year-old, white, male, adult patient with suspected insulinoma, with episodes of hypoglycemia in the fasting state or after exercise that was reversed with ingestion of food or glucose solutions. 85 percent pancreatectomy was performed and nesidioblastosis was detected in the histological study. Conclusions: It is rare in adults, making its diagnosis is difficult, and surgery is reached with the knowledge of an endogenous hyperinsulinic state, without the certainty of its origin(AU)

Nesidioblastosis Associated with Pancreatic Heterotopia as a Differential Diagnosis of Hypoglycemia: A Literature Review and Case Report.

BACKGROUND Nesidioblastosis is a rare disease that is part of the differential diagnosis of pancreatogenic hyperinsulinemic hypoglycemia (PHH) in patients whose imaging studies do not localize insulinoma. Pancreatic heterotopia is a rare congenital abnormality characterized by pancreatic tissue anatomically separated from the main gland and found in 0.5% of abdominal surgeries. The purpose of this article is to provide a systematic review of the literature on nesidioblastosis in pancreatic ectopic tissue and to describe a case of the co-occurrence of these 2 rare conditions. CASE REPORT A 32-year-old man presented with adrenergic and neuroglycopenic symptoms, with laboratory-confirmed hyperinsulinemic hypoglycemia. There was no evidence of tumors on abdominal CT scan and MRI. Celiac trunk sampling with a calcium stimulation test was done, which showed an insulin gradient in the gastroduodenal artery. However, the intraoperative ultrasound showed a small nodule located at the pancreatic tail, leading to distal pancreatectomy. The histologic examination showed nesidioblastosis associated with pancreatic heterotopia. The patient remained asymptomatic after distal pancreatectomy. CONCLUSIONS Nesidioblastosis accounts for 0.5%-5% of all cases of PHH, with a histology showing hypertrophy and hyperplasia of pancreatic islets. Pancreatic heterotopia is a rare congenital anomaly resulting from failure of pancreatic cell migration, and is found as an incidentaloma in imaging or surgeries. Although it is a rare disease, nesidioblastosis should be considered in the investigation of hypoglycemia, even in the rare presentation of nesidioblastosis in patients with pancreatic heterotopy.

Receptor-Targeted Photodynamic Therapy of Glucagon-Like Peptide 1 Receptor-Positive Lesions.

Treatment of hyperinsulinemic hypoglycemia is challenging. Surgical treatment of insulinomas and focal lesions in congenital hyperinsulinism is invasive and carries major risks of morbidity. Medication to treat nesidioblastosis and diffuse congenital hyperinsulinism has varying efficacy and causes significant side effects. Here, we describe a novel method for therapy of hyperinsulinemic hyperglycemia, highly selectively killing ß-cells by receptor-targeted photodynamic therapy (rtPDT) with exendin-4-IRDye700DX, targeting the glucagon-like peptide 1 receptor (GLP-1R). Methods: A competitive binding assay was performed using Chinese hamster lung (CHL) cells transfected with the GLP-1R. The efficacy and specificity of rtPDT with exendin-4-IRDye700DX were examined in vitro in cells with different levels of GLP-1R expression. Tracer biodistribution was determined in BALB/c nude mice bearing subcutaneous CHL-GLP-1R xenografts. Induction of cellular damage and the effect on tumor growth were analyzed to determine treatment efficacy. Results: Exendin-4-IRDye700DX has a high affinity for the GLP-1R, with a half-maximal inhibitory concentration of 6.3 nM. rtPDT caused significant specific phototoxicity in GLP-1R-positive cells (2.3% ± 0.8% and 2.7% ± 0.3% remaining cell viability in CHL-GLP-1R and INS-1 cells, respectively). The tracer accumulates dose-dependently in GLP-1R-positive tumors. In vivo, rtPDT induces cellular damage in tumors, shown by strong expression of cleaved caspase-3, and leads to a prolonged median survival of the mice (36.5 vs. 22.5 d, respectively; P < 0.05). Conclusion: These data show in vitro as well as in vivo evidence of the potency of rtPDT using exendin-4-IRDye700DX. This approach might in the future provide a new, minimally invasive, highly specific treatment method for hyperinsulinemic hypoglycemia.

Nesidioblastosis and Insulinoma: A Rare Coexistence and a Therapeutic Challenge.

Background: Nesidioblastosis and insulinoma are disorders of the endocrine pancreas causing endogenous hyperinsulinemic hypoglycemia. Their coexistence is very unusual and treatment represents a still unresolved dilemma. Case Description: The patient was a 43-year-old Caucasian woman, with a 2-year history of repeated severe hypoglycemic events. The diagnostic work-up was strongly suggestive of insulinoma and the patient was submitted to surgical treatment carried out laparoscopically under robotic assistance. However, surgical exploration and intraoperative ultrasonography failed to detect a pancreatic tumor. Resection was therefore carried out based on the results of selective intra-arterial calcium stimulation test, following a step-up approach, eventually leading to a pancreatoduodenectomy at the splenic artery. The histopathology examination and the immunohistochemical staining were consistent with adult-onset nesidioblastosis. After surgery, the patient continued to experience hypoglycemia with futile response to medical treatments (octreotide, calcium antagonists, diazoxide, and prednisone). Following multidisciplinary evaluation and critical review of a repeat abdominal computed tomography scan, a small nodular lesion was identified in the tail of the pancreas. The nodule was enucleated laparoscopically and the pathological examination revealed an insulinoma. In spite of the insulinoma resection, glycemic values were only partially restored, with residual nocturnal hypoglycemia. Administration of uncooked cornstarch (1.25 g/kg body weight) at bedtime was associated with significant improvement of interstitial glucose levels (p < 0.0001) and reduction of nocturnal hypoglycemia episodes (p = 0.0002). Conclusions: This report describes a rare coexistence of adult-onset nesidioblastosis and insulinoma, suggesting the existence of a wide and continuous spectrum of proliferative ß-cell changes. Moreover, we propose that uncooked cornstarch may offer an additional approach to alleviate the hypoglycemic episodes when surgery is impracticable/unaccepted.

Nationwide survey of endogenous hyperinsulinemic hypoglycemia in Japan (2017-2018): Congenital hyperinsulinism, insulinoma, non-insulinoma pancreatogenous hypoglycemia syndrome and insulin autoimmune syndrome (Hirata's disease).

AIMS/INTRODUCTION: We aimed to investigate the nationwide incidence, treatment details and outcomes of patients with endogenous hyperinsulinemic hypoglycemia (EHH), including those with transient/persistent congenital hyperinsulinism (CHI), insulinoma, non-insulinoma pancreatogenous hypoglycemia syndrome and insulin autoimmune syndrome (Hirata's disease) in Japan. MATERIALS AND METHODS: A nationwide, questionnaire-based survey was carried out to determine the number of patients with EHH who were treated for hypoglycemia or hypoglycemia-related complications in 2017-2018. The questionnaires were sent to all hospitals in Japan with >300 beds, and with pediatric and/or adult clinics likely managing EHH patients. The secondary questionnaires were sent to obtain the patients' date of birth, sex, age at onset, treatment details and post-treatment outcomes. RESULTS: A total of 447 patients with CHI (197 transient CHI, 225 persistent CHI and 25, unknown histology), 205 with insulinoma (118 benign, 18 malignant and 69 unknown subtype), 111 with non-insulinoma pancreatogenous hypoglycemia syndrome (33 post-gastric surgery HH, 57 postprandial HH, 10 nesidioblastosis and 11 unknown subtype) and 22 with insulin autoimmune syndrome were identified. Novel findings included: (i) marked improvement in the prognosis of persistent CHI over the past 10 years; (ii) male dominance in the incidence of transient CHI; (iii) non-insulinoma pancreatogenous hypoglycemia syndrome emerging as the second most common form of EHH in adults; (iv) frequent association of diabetes mellitus with insulin autoimmune syndrome; and (v) frequent post-treatment residual hypoglycemia and impaired quality of life. CONCLUSIONS: The first nationwide, all age group survey of EHH showed the current status of each type of EHH disorder and the unmet needs of the patients.

Concurrent Adult-Onset Diffuse ß-Cell Nesidioblastosis and Pancreatic Neuroendocrine Tumor: A Case Report and Review of the Literature.

Nesidioblastosis is an uncommon cause of organic persistent hyperinsulinemic hypoglycemia in adults. We report a case of adult-onset diffuse ß-cell nesidioblastosis in a 49-year-old woman who was status-post Roux-en-Y gastric bypass and distal pancreatectomy for a well-differentiated pancreatic neuroendocrine tumor. While the neuroendocrine tumor was suspected to be an insulinoma, persistent hypoglycemia postoperatively suggested either incomplete resection or a second pancreatic neoplasm. Completion pancreatectomy revealed islet ß-cell hyperplasia and nuclear pleomorphism consistent with ß-cell nesidioblastosis. The patient's blood glucose levels normalized after completion pancreatectomy. While ß-cell nesidioblastosis and insulinomas can coexist in the same patient, pathologists should be aware of ß-cell nesidioblastosis as a potential cause for hyperinsulinemic hypoglycemia and should exclude it in patients who have not shown definitive clinical response after surgical excision of a pancreatic neuroendocrine tumor.

Nesidioblastosis de páncreas: presentación de un caso / Pancreatic nesidioblastosis: Case report

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A Case Report of Insulinoma Relapse on Background Nesidioblastosis: A Rare Cause of Adult Hypoglycemia.

Context: Nesidioblastosis is a rare cause of adult hypoglycemia. Current medical therapy can mitigate disease symptoms. However, side effects and limited efficacy may prevent long-term disease management. Case Description: A 63-year-old white woman presented at our institution on April 2017 with a history of distal spleno-pancreatectomy for well-differentiated insulinoma in 2013. Hypoglycemic events did not resolve after surgery, and residual nesidioblastosis near the pancreatic resection margins was identified. Hypoglycemic episodes increased in frequency and severity despite high-dose diazoxide (DZX) therapy. On April 2016, octreotide was introduced but soon discontinued for inefficacy. When the patient arrived at our attention, add-on pasireotide was started and glucose levels monitored by subcutaneous sensor. Compared with DZX, 225 mg/d alone, sensor glucose during pasireotide + DZX 75 mg/d showed occurrence of severe hypoglycemia. Pasireotide was discontinued, and the instrumental workup (68Ga-DOTATOC CT/positron emission tomography, 99mTc-nanocolloid scintigraphy and echo-endoscopy + fine-needle aspiration biopsy) identified an insulinoma relapse. Subtotal pancreatectomy was performed without further recurrence of hypoglycemia over 9 months of follow-up. Conclusions: Although insulinoma relapses on background nesidioblastosis rarely occur, they should be considered as an alternate diagnosis when medical therapy fails to prevent hypoglycemia. Further studies are warranted to test whether the immunophenotypic signature of nesidioblastosis/insulinoma may provide insights for a tailored use of pasireotide.

Resolution of hyperinsulinemic hypoglycemia following partial pancreatectomy in a dog with nesidioblastosis.

CASE DESCRIPTION A 6-year-old castrated male Australian Shepherd was evaluated because of a recent onset of persistent hypoglycemia. CLINICAL FINDINGS Physical examination results were generally unremarkable. No abnormalities were detected on thoracic radiographs, and abdominal ultrasonography revealed no obvious pancreatic lesion. Hematologic analysis revealed hypoglycemia with a high serum insulin-to-glucose concentration ratio. TREATMENT AND OUTCOME Insulinoma was suspected; medical treatment with prednisone was initiated, and exploratory laparotomy was performed. No pancreatic lesions or masses were observed. Partial left pancreatectomy and hepatic and local lymph node biopsies were performed. Histologic examination revealed islet cell hypertrophy and hyperplasia, with no evidence of neoplasia. Results of a PCR assay of the pancreatic tissue for Bartonella infection were negative. Clinical, biochemical, and histopathologic findings were compatible with nesidioblastosis. The clinical signs, including hypoglycemia, resolved after surgery. On follow-up examination 8 months later, the dog was apparently healthy and results of a CBC and serum biochemical analysis, including blood glucose concentration, were within respective reference ranges. CLINICAL RELEVANCE To our knowledge, this is the first report of nesidioblastosis in a dog for which clinical signs and clinicopathologic abnormalities resolved after partial pancreatectomy. Although extremely rare, nesidioblastosis should be considered a differential diagnosis in dogs with signs suggestive of insulinoma.