Giant 12 cm Pancreatic Insulinoma: Tumor Evolution, Management, and Pathologic Considerations

ABSTRACT

Insulinomas are characteristically small pancreatic neuroendocrine tumors, though giant variants have been reported. We describe a 63-year-old woman who presented with refractory hypoglycemia attributable to an exceptionally large 12 cm pancreatic mass that failed to respond to medical treatment. She was quickly taken for surgical resection, after which hypoglycemia quickly resolved. Histopathologic examination demonstrated a well-differentiated pT3N0 neuroendocrine tumor demonstrating negative staining for insulin and pancreatic and duodenal homeobox 1, with positive staining for insulinoma-associated protein 1, alpha-thalassemia/mental retardation X-linked, and alpha-1-antitrypsin. Repeat imaging showed no tumor recurrence. This case illustrates an uncommon presentation and highlights key immunostains in delineating different insulinoma phenotypes.

INTRODUCTION

Insulinomas are rare pancreatic neuroendocrine tumors with an incidence of approximately 1–4 cases per million annually and are typically small (<2 cm) and benign.¹ Giant insulinomas are extremely uncommon and often present with more severe symptoms and complex management strategies.

Diagnosis relies on clinical and biochemical evidence of inappropriate insulin secretion during hypoglycemia and is supported by imaging. Immunohistochemical (IHC) staining for insulin is used to support diagnosis but is not necessary as clinical function and hormone staining may be discordant. Advancements have improved understanding of how changes during insulinoma evolution contribute to varying clinical, biochemical, and IHC findings. Insulinoma-associated protein 1 (INSM1), first described as a IHC marker for neuroendocrine neoplasms in 2015, is now included in National Comprehensive Cancer Network guidelines as 1 of 3 core markers of neuroendocrine differentiation.^2,3

Research increasingly focuses on biomarkers that improve diagnostic yield and provide insight into tumor behavior.⁴ Loss of alpha-thalassemia/mental retardation X-linked protein and expression of pancreatic and duodenal homeobox 1 expression and alpha-1-antritrypsin are among the additional markers studied in aggressive insulinomas.⁵

We present a case of a 63-year-old woman with sudden onset medically refractory severe hypoglycemia attributed to a 12 cm pancreatic mass. Multidisciplinary evaluation established the diagnosis of this exceptionally rare presentation of a defeated insulinoma. The patient has provided informed consent for this publication.

CASE REPORT

A 63-year-old woman with a medical history of hypertension, osteoporosis, supraventricular tachycardia, and prior stroke was admitted from the emergency department for persistent hypoglycemia. Family history was notable for a mother with diabetes and family history of BRCA1 for which the patient's genetic testing was negative. The patient's symptoms began 6 months before when she presented to the emergency department for left-sided weakness and hypoglycemia. She then began to monitor sugars at home which revealed persistent fasting hypoglycemia for which she was seen by endocrinology 3 months later. Clinical picture was concerning for possible insulinoma at this time given normal cortisol levels. Patient subsequently had monitored in office fast during which the following laboratory test results were collected supporting the diagnosis of insulinoma: fasting proinsulin levels 591 pmol/L, c-peptide 6.9 ng/mL, insulin 18 mU/L, beta-hydroxybutyrate 0.09 mmol/L, and postglucagon increase in glucose >25 mg/dL. Cross-sectional outpatient imaging with computed tomography a month before her admission demonstrated a 12 cm mass involving the pancreatic tail and distal body.

During her hospitalization, she required escalation of hypoglycemic medications and drips including a dextrose infusion, diazoxide, and octreotide. Despite maximum medical management, hypoglycemia worsened and she was evaluated for urgent surgery. Additional workup including insulin antibody testing and hypoglycemic agent screening were negative, ruling out autoimmune and exogenous causes.

Repeat computed tomography demonstrated a large pancreatic tail tumor extending into the splenic hilum and abutting the left adrenal gland, without evidence of metastatic disease (Figure 1). Given refractory hypoglycemia and tumor burden, the patient was taken to the operating room for definitive management.

Figure 1.

Cross-sectional imaging with computed tomography demonstrating pancreatic tumor without evidence of metastatic disease to liver or lungs.

Intraoperatively, a large tumor was identified in the distal pancreas, abutting the transverse mesocolon and involving the anterior aspect of the left adrenal gland. The patient underwent uneventful en bloc distal pancreatectomy and splenectomy with resection of the transverse mesocolon and a portion of the left adrenal gland (Figure 2).

Figure 2.

Intraoperative tumor specimen.

On postoperative day 1, hypoglycemia resolved with a period of transient hyperglycemia. She no longer required dextrose, and glucose levels eventually stabilized. Her postoperative course was otherwise unremarkable, and she was discharged home on postoperative day 3.

Final surgical pathology revealed a well-differentiated pancreatic neuroendocrine tumor (KI-67 6.6%, World Health Organization Grade 2) measuring 12 cm in greatest dimension with positive lymphovascular invasion and 0/15 lymph nodes positive for tumor (pT3N0). Resection margins were negative and neither the spleen nor the resected portion of the adrenal gland contained tumor (Figure 3). Tumor markers were positive for synaptophysin and chromogranin, however negative for insulin immunostaining. Given the patient's rapid onset of symptoms in this unusually large mass, further tests were sent to better understand the disease trajectory. Overall, the tumor stained positive for synaptophysin, chromogranin, INSM1, alpha-1-antitrypsin, and alpha-thalassemia/mental retardation X-linked, and negative for insulin and pancreatic and duodenal homeobox 1 (Figure 4).

Figure 3.

Hematoxylin and eosin (H&E) slides. (A) Delineation between the tumor and surrounding organs. (B) Magnification revealing a nested and trabecular architecture with uniform round cells and salt-and-pepper chromatin classic for neuroendocrine differentiation.

Figure 4.

Immunostaining. (A) Synaptophysin 10×, (B) INSM1 10×, (C) AAT 20×, and (D) ATRX 20×. AAT, alpha-1 antitrypsin; INSM1, insulinoma-associated protein 1; ATRX, alpha thalassemia/mental retardation X-linked.

The patient has since been seen in clinic and is doing well. All symptoms of hypoglycemia (previously consistent with the Whipple three times a day) have resolved, and blood glucose measurements have reliably been between 120 and 130 mmol/L. Imaging has since demonstrated complete resection of the tumor (Figure 5).

Figure 5.

Postoperative computed tomography demonstrating complete resection of pancreatic body/tail and spleen with no evidence of residual tumor or recurrence.

DISCUSSION

In addition to its extremely large size and clinical severity, this case highlights an important diagnostic journey in larger neuroendocrine tumors. Although insulinomas are classically positive for insulin on immunohistochemistry, many cases stain negative suspected due to rapid hormone secretion with loss of intracellular storage, tumor heterogeneity, and dedifferentiation in larger or higher grade tumors.^6,7 In a cohort of 80 patients undergoing surgery for insulinoma, malignant tumors stained for insulin in only 3 out of 7 cases vs 66 out of 73 benign tumors.⁸ This discordance is important because the diagnosis of a functional insulinoma is made clinically and biochemically, not by IHC. In a single-institution series of 292 insulinoma patients by Zhao et al,⁹ up to 20% of patients had negative insulin IHC, yet 100% experienced resolution of hypoglycemia after resection.

This case is unique in that our patient had no nodal or distant metastasis with favorably benign tumor pathology. In Callacondo et al's reference series of 3 giant insulinomas (10–15 cm), all tumors were insulin-positive and every patient had liver metastases and recurrence.¹⁰ Of these 3 patients, 1 recurred and required a right hepatectomy, 1 died of metastasis, and another had local recurrence however remained asymptomatic. Furthermore, the overall profile of our patient's tumor has not previously been described in prior giant-insulinoma reports, demonstrating the broader biological spectrum that is unknown of these tumors.

This case highlights an uncommon presentation of a giant insulinoma and underscores key diagnostic markers in understanding more rare presentations of these tumors, emphasizing the importance of clinical correlation and the need for further research linking tumor behavior to biochemical and genetic changes.

DISCLOSURES

Author contributions: S. Hormozian, A. Ko, and Z. Song contributed to concept and design; S. Hormozian, A. Ko, M. Teherian, and Z. Song contributed to data collection; all authors contributed to analysis and interpretation, writing, and revision. All authors approved the final version to be submitted and agreed to be held accountable for the report. Z. Song is the article guarantor.

Financial disclosure: None to report.

Informed consent was obtained for this case report.

ABBREVIATIONS:

ATRX

alpha-thalassemia/mental retardation X-linked

IHC

immunohistochemical

INSM1

insulinoma-associated protein1

PDX1

pancreatic and duodenal homeobox 1