case_images: PMC10803616_01
case_images: Representative histopathological images: neuroendocrine microtumor measuring 3.561 mm with several smaller clusters of neuroendocrine cells scattered within the macroscopically normal pancreas (yellow circles) (hematoxylin and eosin, x200 magnification) (A); immunohistochemistry for insulin showing positivity in neuroendocrine microtumor (blue arrow) and in the diverse smaller clusters of neuroendocrine cells (red arrow) (x100 magnification) (B); immunohistochemistry for glucagon showing positivity in normal islets (green arrow) and negativity in the microtumor (delimited area) as in the clusters of neuroendocrine cells previously tested positive to insulin (x200 magnification) (C).
case_images: fendo-14-1308662-g001.jpg
case_images: PMC10803616_01_fendo-14-1308662-g001.jpg
case_images: f1
case_images: Distal pancreatectomy was performed, and histopathological examination revealed two tumors measuring 0.6 and 1.1 cm with several smaller ones (<0.5 cm) along the pancreatic body; all of them were well-differentiated tumors (Ki67 < 3%) with positive immunohistochemistry staining for insulin, chromogranin A, and synaptophysin and negative staining for glucagon, confirming the diagnosis of insulinomatosis ( Figure 1 ).
case_images: PMC10803616_02
case_images: Patient with sporadic insulinomatosis (case 2) clinically presenting postprandial hyperinsulinemic hypoglycemia diagnosed for mixed meal test after normal response to prolonged fasting test. The same pattern of postprandial hypoglycemia was documented at the recurrence. Localization radiological exams and pathology documenting insulinomatosis after the first and second surgery are shown. (A) Biochemical and hormonal tests, radiological features, and pathological findings of the first surgery (enucleation). (B) Biochemical and hormonal tests, radiological features, and pathological findings of hypoglycemia recurrence 8 months after when distal pancreatectomy was provided. A1/B1. Prolonged fasting test was interrupted by the presence of ketonemia and the absence of hypoglycemia after 65 and 55 h with negative response at the glucagon test (increment <25 mg/dL); A2/B2. Mixed meal test was positive for hyperinsulinemic hypoglycemia 60 min on the first and second surgery; A3/B3. Pancreatic nodules were localized by computed tomography (A3/B3, arrow) and confirmed by endoscopic ultrasound (hypoechoic nodule measuring 1.5 cm in the pancreas tail (A3) and nodule in the distal extremity (1 cm) and hypervascularized nodule in the proximal segment of the pancreatic tail (0.6cm, arrow) (B3) whose biopsy was compatible with neuroendocrine neoplasia (IHC: insulin-positive); A4. Histology of the pancreatic nodule smaller (a) and larger in size (b) (hematoxylin and eosin); IHC documenting KI67 < 2 (c), positivity to chromogranin (d), and insulin (e); B4. Histology documenting three smaller pancreatic microtumors (f) and one larger tumor (g) stained by hematoxylin and eosin; transition between normal pancreatic tissue and neoplasia (h) (hematoxylin and eosin); IHQ revealing insulin-positive (i) well-differentiated neuroendocrine tumor (KI67 < 2%) (j), confirmed by positive IHC for synaptophysin (k).
case_images: fendo-14-1308662-g002.jpg
case_images: PMC10803616_02_fendo-14-1308662-g002.jpg
case_images: f2
case_images: An MMT showed HH at 60 min (glucose = 38 mg/dL and insulin = 284.5 microUI/mL) ( Figure 2A ;  Table 1 ). An abdominal MRI detected a 1.5-cm tumor in the tail of the pancreas, and a pancreatic EUS showed a 1.4-cm hypoechoic nodule in the same location ( Figure 2A ). The patient underwent enucleation of the pancreatic tumor, and the histological diagnosis was a pancreatic neuroendocrine tumor with positive immunohistochemistry for insulin, chromogranin, and synaptophysin and a Ki67 labeling index <3% (grade 1 tumor) ( Figure 2A ). Eight months after the surgery, hypoglycemia recurred, and a second prolonged fasting test was performed; the test was interrupted after 55 h when hyperketonemia was detected (1.1 mmol/L) concomitantly with a glucose of 68 mg/dL, insulin of <2.5 microUI/mL, and C-peptide of 1 ng/dL ( Figure 2B ). An MMT showed reactive hypoglycemia at 60 min (glucose = 55 mg/dL and insulin = 54 microUI/mL) ( Figure 2B ). An abdominal CT revealed two hypervascularized nodules in the pancreas, one of them measuring 1 cm at the extremity of the pancreatic tail and another measuring 0.6 cm between the tail and the body; the same lesions were identified in the EUS ( Figure 2B ). The patient underwent distal pancreatectomy that allowed the diagnosis of five neuroendocrine tumors measuring up to 0.6 cm (Ki67 < 3%) compatible with insulinomatosis ( Figure 2B ).
case_images: PMC10803616_03
case_images: PMC10803616_04
case_images: Long-term outcome (25 years) of a patient (case 4) diagnosed with malignant insulinomatosis 7 years after multiple surgical treatments by recurrent/persistent hypoglycemia. *, basal biochemical/hormonal values documenting hyperinsulinemic hypoglycemia before surgical procedures: 1999, enucleation; 2004, enucleation; 2005; subtotal duodenopancreatectomy; 2008, liver transplant after biopsy confirming hepatic metastasis and unsuccessful multiple treatments (diazoxide, somatostatin analogs, chemotherapy, and hepatic embolization); 2019/2021, basal biochemical/hormonal values documenting hyperinsulinemic hypoglycemia before radiofrequency ablation (red arrow: needle of ablation) of retroperitoneal tumoral mass (blue arrow) detected by magnetic resonance imaging in 2021.
case_images: fendo-14-1308662-g003.jpg
case_images: PMC10803616_04_fendo-14-1308662-g003.jpg
case_images: f3
case_images: The pre- and postprandial plasma glucose values are approximately 90 and 160 mg/dL, respectively ( Figure 3 ).