Malignant Insulinoma Arising From Nonfunctioning Pancreatic Neuroendocrine Tumor : ACG Case Reports Journal

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Malignant Insulinoma Arising From Nonfunctioning Pancreatic Neuroendocrine Tumor

Chatterjee, Ritodhi MD1; Ali, Basim MD1; Nguyen, Son H. DO2; Chen, Rui MD2; Sada, Yvonne H. MD3

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ACG Case Reports Journal 10(1):p e00954, January 2023. | DOI: 10.14309/crj.0000000000000954
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Pancreatic neuroendocrine tumors (PNETs) are rare neoplasms comprising <3% of all pancreatic malignancies, with an annual incidence of ≤1 case per 100,000 individuals.1 They are classified into nonfunctioning (NF-PNET) and functioning (F-PNET) subtypes. A small body of literature reports transformation of NF-PNETs into hormonally active phenotypes later in the disease course. Insulinomas are the most common F-PNET and carry high morbidity and mortality because of associated hypoglycemia.2 We present a patient with biopsy-proven NF-PNET found to have malignant insulinoma 2 years after initial diagnosis.


A 39-year-old man with treatment-refractory nonfunctioning PNET (NF-PNET) and distant metastases presented with recurrent hypoglycemic symptoms.

Two years prior, a hepatic mass was discovered incidentally on abdominal ultrasound performed at the request of the patient because of recent diagnosis of gallstones in a family member. Computed tomography showed an ill-defined 4.2 × 3.8-cm mass of the pancreatic head with lymphadenopathy and a 1.9-cm lesion of the right hepatic lobe. Endoscopic ultrasound-guided fine-needle aspiration of a peripancreatic lymph node yielded pathologic confirmation of low-grade PNET (Ki-67 <1%). Liver biopsy demonstrated neuroendocrine metastasis with high-grade features (Ki-67 30%). Over 2 years, disease progressed on several lines of antineoplastic treatment, including (chronologically) octreotide, capecitabine/temozolomide, microwave ablation of liver lesions, everolimus, sunitinib, and cisplatin/etoposide. Pancreatic mass measured 7.8 × 7.7 × 7 cm with >40 liver metastases on imaging 2 months before presentation (Figure 1).

Figure 1.:
T2-weighted axial magnetic resonance images demonstrating greater than 40 diffuse hepatic metastases, the largest measuring 8.5 × 5.3 cm in segment 5/6 and 6.2 × 6.9 cm in the right hepatic dome. Porta hepatis nodal conglomerate measuring 3.9 cm is also noted.

In the emergency department, the patient reported episodic fatigue, night sweats, palpitations, and hunger pangs for 3 weeks that resolved with carbohydrate intake, culminating in loss of consciousness. A fingerstick test in the ambulance showed serum glucose of 45 mg/dL. His medical history was notable for pancreatic insufficiency, non–insulin-dependent diabetes mellitus, and obesity (body mass index 37 kg/m2). Vital signs were notable for sinus tachycardia of 125 beats per minute and temperature of 99.6°F. Physical examination revealed hepatomegaly. Initial laboratory studies were as follows with reference ranges: glucose 43 (65–110 mg/dL), hemoglobin 9.7 (12.0–18.0 g/dL), white blood cell count 1.7 (3.5–10.0 × 103 cells/μL), aspartate aminotransferase 49 (10–42 IU/L), alanine aminotransferase 18 (7–55 IU/L), and alkaline phosphatase 134 (38–127 IU/L). The last hemoglobin A1c was 7.3 (4.2%–5.8%) 6 months before presentation. Lactic acid and blood cultures were negative.

Despite intravenous fluids containing 10% dextrose (D10), the patient continued to have intermittent hypoglycemia. A hypoglycemic disorder was diagnosed through observation of Whipple's triad: low plasma glucose (35 mg/dL), symptoms of hypoglycemia (diaphoresis and weakness), and relief with glucose correction. The following laboratory abnormalities confirmed insulinoma: serum insulin 70.4 (2.6–24.9 μIU/mL), C-peptide 12.6 (1.1–4.4 ng/mL), and proinsulin 407.6 (0.0–10.0 pmol/L). Remaining hypoglycemia workup including cortisol, beta-hydroxybutyrate, growth hormone, growth hormone–releasing hormone, insulin autoantibody, and sulfonylurea screen was negative.

Recurrent hypoglycemia persisted after 2 weeks despite D10 infusion at 225 mL/hr, 60 mg of oral prednisone daily, lanreotide, and a trial of inpatient chemotherapy with FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan). By day 22, the patient was receiving concentrated 50% dextrose (D50) at 140 mL/hr through the central line, 200 mg of prednisone daily, with frequent pushes of additional D50.

Bland right hepatic artery embolization, injection of embolizing agents without delivery of chemotherapy, was performed on day 23 to reduce tumor burden, with a concurrent trial of antihypoglycemic agent diazoxide uptitrated to maximum daily dose of 900 mg. The patient developed mild tumor lysis syndrome managed with continued hydration and patiromer for hyperkalemia, but hypoglycemia completely resolved 3 days later (Figure 2). D50 infusion was discontinued, and steroids were weaned to physiologic levels. Diazoxide was reduced to 200 mg thrice daily at discharge.

Figure 2.:
Scatter plot of inpatient blood glucose measurements. The blue line marks 70 mg/dL, the lower bound of normal at our institution. D10 infusion was initiated on day 1, D20 on day 16, and D50 on day 18. Diazoxide was initiated, and the patient underwent hepatic artery embolization on day 22. Dextrose supplementation was discontinued on day 25.

Two months later, the patient was readmitted with congestive heart failure and anasarca, likely multifactorial in etiology from large-volume intravenous fluid administration during prior hospitalizations, decreased hepatic synthetic function from extensive liver metastasis, and newly decreased right ventricular systolic function on echocardiography, a well-reported adverse effect of diazoxide.3 Hypoglycemia recurred off diazoxide, and the patient was again placed on intravenous dextrose. Weary of another prolonged hospitalization, he elected for hospice and died soon after requesting discontinuation of dextrose infusions.


Transformation of NF-PNETs into hormonally active functioning subtypes is a rare occurrence. This biological switch occurs in just 3.4%–6.8% of PNETs, and insulinomas are the most commonly reported phenotype, likely because of overt clinical symptoms.4 Only 28 other cases of malignant insulinomas arising from prior NF-PNETs have been described previously (Table 1). The median age at presentation was 56.5 years (range: 31–74), and the median duration from initial NF-PNET diagnosis was 47 months (range: 4–240). Some patients presented with symptomatic hypoglycemia while actively undergoing treatment or with recurrent disease after complete resection of NF-PNET, sometimes years later. The phenotypic change often coincided with new or rapidly growing distant metastases. Heterogeneity of tumor differentiation in our patient between lymph nodes and the liver may have foreshadowed transformation to F-PNET. Transformation portended poor prognosis, with only 5 of 28 (17.9%) patients remaining alive at report publication. The median survival was 12 months (range: 1–29).

Table 1. - Characteristics and treatment of 28 patients with NFPNET transformed into insulinoma, reported across 16 unique publications
Name (year) Age (yr) Gender Duration between NF-PNET and insulinoma diagnoses Therapies for NF-PNET Therapies for metachronous insulinoma Survival after insulinoma diagnosis
Sugiyama et al (2010) 11 50 M 20 yr Octreotide, surgery
Vashi et al (2011) 12 43 F 1 yr 8 mo Carboplatin, etoposide, FuDR, topotecan, TACE, sunitinib Somatostatin, diazoxide, prednisone Alive
Koshy et al (2013) 13 56 F 4 yr 6 mo Surgery Dizoxide, TACE, octreotide, MWA Alive
Ohn et al (2013) 8 46 F 4 mo Sunitinib Steroids, TACE, streptozocin, adriamycin
Arslan et al (2015) 14 62 M 2 yr
Fountas et al (2015) 15 64 M 2 yr 6 mo Everolimus, octreotide, sunitinib Diazoxide, methylprednisone, IV glucagon infusion, streptozocin, adriamycin Alive
De Mestier et al (2015) 6 - - 3 yr 4 mo
3 yr 11 mo
18 yr 3 mo
2 yr 6 mo
Nahmias et al (2015) 2 45 F 5 mo Lanreotide, PRRT Everolimus, streptozocin, DDP, 5-FU, PRRT 1 yr 6 mo
63 M 4 yr Lanreotide, PRRT Everolimus, TACE, diazoxide, dexamethasone
Yoshioka et al (2015) 16 69 F 5 yr 3 mo Surgery
Crona et al (2016) 17 74 M 1 yr 6 mo Temozolomide 2 mo
74 M 3 yr 11 mo Streptozocin, 5-FU, platinum 6 mo
Lowette et al (2016) 18 53 M 2 yr 5 mo Cisplatin, etoposide, sunitinib Everolimus, octreotide, diazoxide, FOLFOX, TACE 1 yr 5 mo
31 F 1 yr 11 mo Carboplatin, etoposide, doxorubicin, cyclophosphamide, cisplatin, octreotide, sunitinib, PRRT Diazoxide, octreotide, everolimus, TACE 3 mo
53 M 3 yr 1 mo Octreotide, sunitinib, cisplatin, etoposide, PRRT Diazoxide, octreotide 1 mo
57 F 6 yr 5 mo Surgery, everolimus Octreotide, everolimus, diazoxide, TACE Alive
Yu et al (2017) 19 53 M 5 yr Surgery, liver-directed therapies (unspecified) Octreotide, surgery, FOLFOX 1 yr 6 mo
39 F 6 yr Surgery, chemotherapy (unspecified), PRRT, octreotide, everolimus, capecitabine, temozolomide, sunitinib, lanreotide Everolimus, FOLFOX Alive
Clover et al (2018) 4 55 M 1 yr Cisplatin, etoposide, lanreotide, capecitabine, temzolomide, radiation, sunitinib TACE, everolimus, surgery, TACE, cabozantinib 1 yr
Juhlin et al (2019) 20 51 F 2 yr Lanreotide, streptozocin, 5-FU, pasireotide, everolimus, temozolamide 2 yr 5 mo
61 M 6 yr SSA, cisplatin, etoposide, PRRT, capecitabine, temozolomide, everolimus, TACE PRRT, everolimus, TACE, pasireotide, diazoxide 1 yr
65 F 5 yr SSA, PRRT Surgery, everolimus, TARE, octreotide, diazoxide, prednisolone 1 yr 7 mo
68 F 5 yr SSA Everolimus, octreotide, prednisolone 6 mo
Keen et al (2020) 21 59 F 14 yr Surgery Diazoxide, octreotide, surgery Alive
Henker et al (2022) 22 59 M Diazoxide, SIRT
5-FU, 5-fluorouracil; DDP, cis-dichlorodiammineplatinum; F, Female; FOLFOX, folinic acid, 5-fluorouracil, and oxaliplatin; FuDR, floxuridine; M, male; IV, intraveous; MWA, microwave ablation; NFPNET, nonfunctioning pancreatic neuroendocrine tumor; PRRT, peptide receptor radionucleotide therapy; SIRT, selective internal radiation therapy; SSA, somatostatin analogue (unspecified); TACE, transarterial chemoembolization; TARE, transarterial radioembolization.

Several mechanisms have been proposed for this late-onset gain of function. Mirroring functional plasticity of multipotent progenitor cells in the pituitary, pancreatic stem cells may differentiate into insulin-secreting tumor cells de novo on metastasis to the liver.5 Studies have demonstrated the expression of hormones including insulin in NF-PNETs, and nearly all cases of transformation to malignant insulinoma were preceded by liver metastasis; these initially inactive neoplasms may thus harbor insulin-producing but clinically silent cells that potentiate in the milieu of the liver through an unknown pathophysiologic mechanism.6–8 The receptor tyrosine kinase inhibitor sunitinib may be implicated, as in vitro studies have demonstrated its ability to trigger epigenetic changes in cancer cells, and tyrosine kinase inhibitors can cause hypoglycemia.2,8 Sunitinib preceded symptoms in 8 of 28 cases (28.6%), although rarely as monotherapy; our patient received sunitinib 4 months before hospitalization. Recently, Yu et al have theorized that acquired functionality represents the natural history of malignant PNETs. Volume of insulin-secreting cells may gradually expand with increasing tumor bulk, that is, with liver metastasis, and eventually surpass the threshold necessary to trigger hypoglycemia.9 Therefore, perhaps all malignant insulinomas start off as NF-PNETs until clinically unmasked.

Although surgery is curative for benign insulinomas, malignant tumors are often metastatic at diagnosis. Alcohol or radiofrequency ablation, selective bland tumor embolization, or arterial chemoembolization has been successfully attempted in nonsurgical candidates. Options for medical management and palliation include somatostatin analogues, steroids, and diazoxide, which inhibit insulin secretion by inducing potassium channels in pancreatic beta cells.10 Compared with previous reports, the severity of hypoglycemia and refractory nature to medical treatment was somewhat unique in this case, likely in the setting of large tumor burden and rapid growth of the NET. At the peak of his illness, the patient was requiring a continuous D50 infusion at 140 mL/hr with frequent meals despite steroids: carbohydrate loads unprecedented at our institution. Although medical therapies are first line in patients with high hepatic tumor burden like ours, liver-targeted interventions such as ablation, embolization, and/or surgery may ultimately be necessary to address refractory hypoglycemia through reduction in malignant insulin-producing cells.

In summary, we describe a 39-year-old man with NF-PNET and liver metastases found to have malignant insulinoma manifesting as new-onset hypoglycemia, which resolved temporarily with diazoxide and bland hepatic artery embolization. All patients with distant spread of primary PNETs who develop hypoglycemia should undergo evaluation for insulinoma. In nonsurgical cases, hypoglycemia may be medically managed with steroids, somatostatin analogues, and diazoxide, along with therapies to reduce tumor burden.


Author contributions: R. Chatterjee conducted chart review and literature review to produce the initial manuscript draft and is the article guarantor. B. Ali and S.H. Nguyen led content design and manuscript revision. R. Chen and Y.H. Sada provided case report supervision and final revisions.

Financial disclosure: None to report.

Previous presentation: An abbreviated version of this case was presented as an e-Poster at ENDO 2022, June 11–14.

Informed consent was obtained for this case report.


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pancreatic neuroendocrine tumor; insulinoma; hepatic artery embolization; diazoxide; liver metastases

© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.