A 41-year woman presented as an outpatient to our Hospital in November 2012 for her annual thyroid condition follow-up (simple goiter associated with autoimmune chronic thyroiditis), complaining of neurological symptoms such as poor cognitive abilities and decreased alertness over the previous two years, sometimes associated with sweating and sudden hunger. During one of these episodes, the laboratory workout revealed low capillary blood glucose levels (36 mg/dl). On the suspicion of hypoglycemic syndrome, the patient was admitted to the Endocrine Unit of Forlì Hospital. At the physical examination her weight was 70 Kg and BMI 24.5; blood pressure was 110/70 mmHg and no abnormalities were found at abdominal, cardiac, pulmonary and neurological examination. Other causes of hypoglycemia were also excluded upon admission, namely exogenous insulin and oral hypoglycemic agent administration, as well as insulin autoimmune syndrome (Hirata disease), as insulin autoantibodies were negative.
A supervised 72-hour fasting test was performed, showing low venous glucose values (43 mg/dl; Fig. 1) and increased levels of insulin (3.7 mU/L) and C-peptide (0.43 nmol/L). The test was interrupted at the sixth hour and sugar was administered orally.
An abdominal CT scan revealed 2 lesions located within the body-tail of the pancreas, measuring 16 mm and 8 mm, respectively, and presenting contrast enhancement features typical of insulinomas (Fig. 2).
Subsequently, a 68Ga-DOTATOC positron emission tomography was performed, showing high expression of somatostatin receptors on the surface of the two above-mentioned pancreatic lesions, confirming the presence of neuroendocrine tumors (Fig. 3).
An extensive review of both personal and family history of the patient did not suggest the presence of MEN1. Circulating levels of parathormone and serum calcium, as well as prolactin, adrenocorticotrophic hormone, thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, growth hormone, and insulin-like growth factor 1 were normal in two different determinations. Additional diagnostic evaluation for MEN1 syndrome, such as magnetic resonance imaging (MRI) of the sella turcica and parathyroid scintigraphy, were also negative.
In December 2012, subtotal pancreasectomy was performed, and detailed histopathological examination revealed 2 tumors measuring 16 and 10 mm in the pancreatic body-tail along with several other small tumors (< 0.5 cm; Fig. 4). The immunohistochemistry staining for insulin (Fig. 5), chromogranin A (clone LK2H-10, Ventana Roche Diagnostics, Fig. 6), somatostatin receptors (Fig. 7, panel A), and synaptophysin (Fig. 7, panel B) was strongly positive. The proliferation activity examined with a commercial monoclonal anti-Ki-67 antibody (MIB-1, DAKO, Denmark) was 1% (Fig. 8) The histology was therefore compatible with multiple well differentiated neuroendocrine neoplasms, according to the World Health Organization grade 1 .
Clinically, the patient presented no symptoms of hypoglycemia, and blood sugar levels measured after surgery were within the normal range. She was therefore discharged from the surgical ward and no pharmacological treatment was given.
In January 2013, germline mutation analysis of the MEN1 gene was conducted at the University Hospital of Ferrara, Italy. DNA preparation, amplification of exons 2 and 10 of the MEN1 gene, denaturing gradient gel electrophoresis, single-strand conformation polymorphism analysis, and sequencing analysis of the MEN1 gene were performed and showed no mutations.
After one year (November 2013), computed tomographic scanning demonstrated a 10 mm lesion within the body of the pancreas, showing the same enhancing features typical of neuroendocrine tumors. Hence, a 68Ga-DOTATOC positron emission tomography was performed, showing moderate uptake of the radioligand at the level of the above described lesion. An FDG positron emission tomography was also performed which showed no uptake in the pancreas or other abdominal and extra-abdominal sites. Pancreatic ultrasound endoscopy confirmed the presence of a 13 mm tumor located in the body of the pancreas.
In January 2014, another supervised 72-hour fasting test was performed at the Endocrine Unit of Forli Hospital, showing low venous glucose values (42 mg/dl; Fig. 1) and increased levels of insulin (8.7 mU/L; Fig. 9) and C-peptide (0.43 nmol/L). The test was interrupted at the sixty-eighth hour (Fig. 1), even though the patient presented no symptoms of hypoglycemia.
The case was repeatedly discussed by the Multidisciplinary Medical Team for Management and Treatment of Neuroendocrine Tumors of Romagna both in January and February 2014. Various medical strategies were suggested, including a second surgical approach, radiolabeled target therapy and diazoxide treatment. However, the patient refused to undergo further surgery and other specific treatments with possible side effects. In February 2014, after seeking internationally recognized professional expert opinion (Kjell Oberg, University Hospital of Uppsala, Sweden), medical treatment with the somatostatin analog octreotide (30 mg given intramuscularly every 28 days) was started and regularly administered during the subsequent follow-up.
In the following 6 months, the patient did not show any symptoms or signs of hypoglycemia and the treatment with octreotide was tolerated without particular side effects. The plasma levels of chromogranin A, glycemia and insulin were within the normal range. The abdominal MRI performed in July 2014 showed a 12 mm angioma of the liver and apparently no lesions of the pancreas.
In November 2015, a CT scan of the abdomen was performed, showing no lesions within the pancreas and confirmed the presence of a stable angioma of the liver.
A second opinion was given by the Oncological Centre of Milan, confirming the treatment with somatostatin analogs, which was eventually discontinued in September 2016, because the patient’s desire for pregnancy.
A 68Ga-DOTATOC positron emission tomography performed in September 2018 showed no uptake of the radioligand.
In October 2018, pancreatic ultrasound endoscopy confirmed the absence of lesions in the head-body of the pancreas.
In the following years until April 2021, the patient continued with regular 6-month clinical check-ups, including measurements of basal glycemia, insulin, C-peptide and chromogranin A, which were always unremarkable, and annual imaging techniques, both with CT scans of the abdomen (Fig. 10) and MRI of the abdomen. All the results were completely negative for recurrent disease.
In April 2021 the patient was admitted to Endocrine Unit of Forli Hospital in order to perform once again a supervised 72-hour fasting test, about 9 years after the first one: the venous glucose values were never below 45 mg/dl and the levels of insulin (4.5 mU/L) and C-peptide (0.26) measured at the lowest sugar levels were not consistent with recurrency (Fig. 1 and Fig. 9). The test was not interrupted and the patient showed no symptoms of hypoglycemia, indicating complete remission of the insulinoma syndrome.
The patient now continues with the regular follow-up, remaining asymptomatic and taking no specific medical treatment.