Insulinomas are the most common functional pancreatic neuroendocrine neoplasm; when treatment is delayed, they induce hyperinsulinemic hypoglycemia, which is life-threatening. As surgical resection is the only curative treatment for insulinoma, preoperative localization is crucial; however, localization based on conventional imaging modalities such as computed tomography (CT) and magnetic resonance imaging is often inconclusive. Somatostatin receptor-targeted imaging is another option for detecting pancreatic neuroendocrine neoplasms but has low sensitivity and is not specific for insulinoma. The clinical application of other localizing approaches such as selective arterial calcium stimulation and endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) is limited by their being invasive and/or technically complex. Moreover, an EUS-FNA specimen of an insulinoma may be negative on insulin immunostaining. Thus, a noninvasive and clinically practical insulinoma-specific diagnostic tool to discriminate insulinomas with high accuracy is anticipated. Glucagon-like peptide-1 receptor (GLP-1R)-targeted imaging has emerged in the effort to fulfill this need. We recently developed the novel fluorine-18-labeled exendin-4-based probe conjugated with polyethylene glycol, [¹⁸F]FB(ePEG12)12-exendin-4 (¹⁸F-exendin-4) for positron emission tomography (PET) imaging and reported its clinical benefit in a case of insulinoma in the pancreatic tail. We report here a case of insulinoma in the pancreatic head in which an EUS-FNA specimen was negative on insulin immunostaining while precise preoperative localization and conclusive evidence for curative enucleation was provided by ¹⁸F-exendin-4 PET/CT (Japan Registry of Clinical Trials; jRCTs051200156).

Insulinomas are the most common functional pancreatic neuroendocrine neoplasms, occurring in 1–4 cases per million population [1-5]. Insulinomas induce hypoglycemia due to excess insulin secretion and manifest variously; when diagnosis and treatment are delayed, they can lead to seizures, loss of consciousness, coma and death [4-6].

As surgical resection is the only curative treatment for insulinoma, precise preoperative localization of the responsible tumor is crucial for effective surgery. However, tumor localization based on conventional imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI) can be occasionally challenging partly because the majority of insulinomas are as small as less than 2 cm in diameter [7-9]. Somatostatin receptor (SSTR)-targeted imaging is an alternative approach to pancreatic neuroendocrine neoplasm (pNEN) detection, but it has low sensitivity for insulinomas due to their low expression of SSTR type 2 (SSTR2) in comparison with that of other pNENs [9, 10]. In addition, SSTR-targeted imaging does not confirm the insulin secretory capacity of the tumor. Selective arterial calcium stimulation test (SACST) and endoscopic ultrasonography (EUS)-guided fine needle aspiration (EUS-FNA), which reveal the endocrinological characteristics of insulinomas, are often used to localize insulinomas, but their invasiveness and dependence on the facility and experience of the operator limits their clinical relevance [7-9]. In addition, even if the responsible lesion is successfully detected by EUS, the specimen can be negative on insulin immunostaining [11, 12]. Thus, a noninvasive and insulinoma-specific diagnostic method that can detect the responsible tumor with high accuracy is needed [9, 13].

In recent years, glucagon-like peptide-1 receptor (GLP-1R)-targeted imaging, particularly positron emission tomography (PET) using radiolabeled exendin-4-based probes, has emerged as a novel noninvasive diagnostic tool for insulinomas [10, 13-17]. Indeed, we have developed a novel GLP-1R-targeted imaging method using the polyethylene glycol (PEG) conjugated fluorine-18 (¹⁸F)-labeled exendin-4-based probe, [¹⁸F]FB(ePEG12)12-exendin-4 (¹⁸F-exendin-4) PET/CT [18, 19]. The favorable sensitivity and specificity of this imaging method for detecting insulinoma in preclinical models [18] and the clinical safety in healthy human subjects [19] have been previously demonstrated. Moreover, we recently reported the first clinical case of an insulinoma in which ¹⁸F-exendin-4 PET/CT successfully detected the responsible tumor in the pancreatic tail and led to curative laparoscopic enucleation [20]. Here we report a case in which ¹⁸F-exendin-4 PET/CT noninvasively provided preoperative localization and critical evidence of the insulinoma located in the pancreatic head, despite a negative finding of insulin staining on a EUS-FNA biopsy specimen.

The [¹⁸F]FB(ePEG12)12-exendin-4 (¹⁸F-exendin-4) probe was synthesized and PET/CT imaging was performed as described previously [18, 19]. Before PET imaging, 43.001 MBq of the probe was administered intravenously over 5 min. Whole-body PET scan images were captured at 2 min per frame for 6 frames at 1 h and 3 min per frame for 6 frames at 2 h after the probe administration using an integrated PET/CT scanner (Discovery IQ; GE Healthcare, Waukesha, WI). Accumulation of the probe in the organs was quantified using the mean and maximum standardized uptake values in Advantage Workstation server 3.2 (GE Healthcare, Chicago, IL) [18]. This clinical study was approved by the Kyoto University Certified Review Board (Y0074) and the procedures were conducted in accordance to the provisions of the Declaration of Helsinki. Written informed consent was obtained from the patient.

The serum proinsulin level was measured using an ELISA kit (Cat. No. ENZ-KIT149-0001, Enzo Life Sciences, Lausen, Switzerland). The immunostaining for insulin was performed using polyclonal guinea pig anti-insulin antibody (Cat. No. IR002, Dako-Agilent, Santa Clara, CA), anti-proinsulin antibody (Cat. No. ab243131, Abcam, Cambridge, England) and anti-GLP-1R antibody (Cat. No. Mab3F52, Developmental Studies Hybridoma Bank (DSHB), Iowa City, IA) were used for evaluation of proinsulin and GLP-1R expression, respectively.

A 63-year-old female was referred to our hospital for symptomatic hypoglycemia occurring during the previous 13 months. At the age of 62, she was admitted twice to another hospital due to coma. The second time of admission (8 months after the first admission), she presented with right-side hemiparesis and slurred speech; blood test revealed low random serum glucose level (30 mg/dL) and hemoglobin A1c (HbA1c) level of 4.6%. She was then referred to an endocrinologist for evaluation of hypoglycemia at the age of 63. Hyperinsulinemic hypoglycemia was confirmed by blood test after fasting for 3.5 hours (plasma glucose level 44 mg/dL; serum insulin level 4.55 μU/mL; serum C-peptide level 1.68 ng/mL; total ketone body 274 μmol/L; acetoacetic acid and 3-hydroxybutyric acid levels 72 μmol/L and 202 μmol/L, respectively) and a glucagon administration elevated her plasma glucose level (from 34 mg/dL to 79 mg/dL), suggesting insulinoma. Her anti-insulin antibody was negative. Her adrenocorticotropic hormone, cortisol, thyroid-stimulating hormone, free thyroxine, and insulin-like growth factor 1 levels were within normal range (46.4 pg/mL, 12.5 μg/dL, 1.47 μIU/mL, 0.87 ng/dL, and 96 ng/mL, respectively). Contrast-enhanced abdominal CT scan showed a low-density area up to 10 mm in diameter with early enhancement in the pancreatic head (Fig. 1A, 1B) while abdominal MRI showed no evidence of pancreatic tumor (Fig. 1C, 1D). EUS revealed a low-echoic mass of 7 mm in the pancreatic head (Fig. 1E); EUS-FNA was then performed (Fig. 2A). Positive immunostaining of the biopsy specimen for chromogranin A (Fig. 2B), synaptophysin (Fig. 2C), CD56 (Fig. 2D) and pan-cytokeratin AE1/AE3 (Fig. 2E) were consistent with well-differentiated pNEN. However, staining was negative for insulin (Fig. 2F). Thus, localization and diagnosis of insulinoma could not be established despite strong clinical suspicion; she was then referred to our hospital and admitted for further evaluation.

Fig. 1

Representative images of conventional modalities for insulinoma

Axial images of computed tomography (CT) scan (A; plain CT, B; early phase of contrast-enhanced CT), non-contrast magnetic resonance imaging (C; T1-weighted image, D; T2-weighted image) and an image of endoscopic ultrasonography (E) are shown. A low-density area with early enhancement in the head of the pancreas on CT scan is indicated by a red arrowhead. A low-echoic pancreatic mass on endoscopic ultrasonography is indicated by a blue arrowhead.

Fig. 2

Microscopic pathological images of the pancreatic tumor obtained from endoscopic ultrasonography-guided fine needle aspiration

Representative images of the biopsy specimen stained with hematoxylin and eosin (A), chromogranin A (B), synaptophysin (C), CD56 (D), pan-cytokeratin AE1/AE3 (E), insulin (F), proinsulin (G) and glucagon-like peptide-1 receptor (GLP-1R) (H) are shown. The tumor cells were positive for neuroendocrine differentiation markers (B–D) and an epithelial marker (E) strongly suggesting the diagnosis of well-differentiated pancreatic neuroendocrine neoplasm; the tumor cells were negative for insulin (F) despite positive findings for proinsulin (G) and GLP-1R (H). Original magnification; ×200, scale bar; 100 μm.

Her past medical history included depression. Her regular medications included trihexyphenidyl hydrochloride, brexpiprazole, blonanserin and flunitrazepam. She had no history of diabetes mellitus, other endocrinopathies, or previous gastric surgery. She had consumed no alcohol or taken any anti-diabetic agents.

On admission, she was alert; height, 158.4 cm; weight, 46.0 kg; body mass index, 18.3 kg/m²; pulse, 74 beats per minute; and blood pressure, 102/74 mmHg. There was no notable change in her body weight over the previous 2 years.

¹⁸F-exendin-4 PET/CT scans were then performed and no adverse events were observed during the scans. ¹⁸F-exendin-4 PET/CT demonstrated clear focal uptakes corresponding to the tumor in the pancreatic head at both 1 h and 2 h after administration of the probe (Fig. 3A–C). The maximum standardized uptake values (SUVmax) and the mean standardized uptake values (SUVmean) of the tumor were 13.8 and 10.0 at 1 h, 17.3 and 11.4 at 2 h, respectively. These values were clearly higher than those of the surrounding organs except for those in the gall bladder, the kidneys and the urinary bladder (Fig. 3A–C). No other focal uptakes were detected (Fig. 3A).

Fig. 3

[¹⁸F]FB(ePEG12)12-exendin-4 PET/CT images of the pancreatic tumor

Maximum intensity projection images of PET (A; frontal images, B; oblique image) and fusion images of PET/CT at 1 h and 2 h after the probe administration (C) are shown. The tumor in the head of the pancreas is clearly visualized (indicated by red arrowheads) at both time points. The gall bladder, the kidneys, and the urinary bladder are indicated by blue, green, yellow arrowheads, respectively.

Additionally, a fating blood test in the morning showed the remarkable elevations of serum proinsulin level (43.6 pmol/L) and serum proinsulin/insulin ratio (1.79) along with a low plasma glucose level (63 mg/dL). SACST demonstrated a marked elevation in insulin levels greater than 10-fold in the proximal and distal gastroduodenal arteries and the posterior superior pancreaticoduodenal artery; there was no comparable elevation in the right and left hepatic arteries, dorsal and transverse pancreatic arteries, or proximal and distal splenic arteries (Table 1). These results suggested the presence of a responsible tumor in the head of the pancreas, which was consistent with the findings of ¹⁸F-exendin-4 PET/CT.

Based on these results, the tumor was considered an insulinoma responsible for her severe hypoglycemia. She then underwent a laparoscopic tumor enucleation. Histopathological examination of the tumor revealed a small glandular and alveolar proliferation of uniform cubic cells with oval nuclei and eosinophilic cytoplasm (Fig. 4A), which is typical of a well-differentiated pNEN. In accord with the EUS-FNA findings, the immunostaining was positive for chromogranin A (Fig. 4B), synaptophysin (Fig. 4C), CD56 (Fig. 4D) and pan-cytokeratin AE1/AE3 (Fig. 4E). The Ki-67 labeling index was 2% (Fig. 4F). The tumor cells were also positive for insulin (Fig. 4G) as well as proinsulin (Fig. 4H) and GLP-1R (Fig. 4I). Notably, insulin and proinsulin were heterogeneously expressed among the tumor cells, whereas GLP-1R was expressed in almost all tumor cells (Fig. 4G–I). Additional immunohistochemical evaluation revealed that the EUS-FNA specimen was also positive for proinsulin (Fig. 2G) and GLP-1R (Fig. 2H) staining although it was negative for insulin (Fig. 2F). On the basis of these pathological findings, the tumor was diagnosed as a well-differentiated, benign insulinoma and classified as NET G1 under the 2019 WHO classification [21].

Fig. 4

Microscopic pathological images of the resected tumor

Representative images of the resected tumor sample stained with hematoxylin and eosin (A), chromogranin A (B), synaptophysin (C), CD56 (D), pan-cytokeratin AE1/AE3 (E), Ki-67 (F), insulin (G), proinsulin (H) and GLP-1R (I) are shown. The hematoxylin and eosin staining revealed a small glandular proliferation of cells with oval nuclei and eosinophilic cytoplasm, typical findings in pancreatic neuroendocrine neoplasm (A), supported by positive findings for neuroendocrine differentiation and epithelial markers (B–E). The Ki-67 labeling index was 2% (F). The tumor cells were heterogeneously positive for insulin (G) and proinsulin (H), but diffusely positive for GLP-1R (I). Original magnification; ×200, scale bar; 100 μm.

After surgery, her hypoglycemic episodes were resolved. Four months after surgery, no recurrence of hypoglycemia was observed; blood test revealed HbA1c level 5.2% and fasting plasma glucose level 106 mg/dL.

There is a need in the field of insulinoma treatment for an in vivo pancreatic β-cell imaging method that can non-invasively localize the tumor and distinguish it from other pancreatic neoplasms [13, 22]; imaging probes targeting β-cell-specific molecules have been investigated for their use as clinical tools in PET and single-photon emission CT (SPECT). In this context, GLP-1R is considered an ideal target, as the receptor is substantially expressed in normal pancreatic β-cells in contrast to its low expression in other endocrine cells [23] and exocrine cells [24] and has a remarkably higher level of expression in insulinomas [10, 25, 26]. In addition, the GLP-1R agonist exendin-4 in our probe is a biologically stable peptide widely used in radiolabeling techniques. Indeed, some radiolabeled exendin-4-based probes have shown favorable performance in clinical studies and have been developed for PET and SPECT [15, 16, 27, 28]; improvements of tracers are under investigation [10]. The superiority of the spatial resolution of SPECT suggests that GLP-1R-targeted PET imaging holds particular clinical promise for precise localization of insulinoma.

In the present case, our PET/CT imaging method using the ¹⁸F-exendin-4 probe permitted clear visualization of an insulinoma located in the head of the pancreas. PET/CT using gallium-68 (⁶⁸Ga)-labeled exendin-4 probes has been reported to detect insulinoma with high sensitivity [15, 16]; our ¹⁸F-exendin-4 probe can be expected to exhibit the advantage, as previously described [18-20]; ¹⁸F is a broadly supplied radioisotope that enables high-resolution images owing to its low positron emission energy. In addition, PEGylation can improve the pharmacokinetics and probe delivery of ¹⁸F through increasing its molecular weight and stability in circulation [29]. We recently demonstrated the clinical usefulness of ¹⁸F-exendin-4 PET/CT for detecting insulinoma in a case study in which the responsible tumor was localized in the pancreatic tail [20]. The present case extends the usefulness of the technique to an insulinoma in the pancreatic head, in which the surrounding organs are more likely to impede identification of the tumor. The sensitivity and specificity for detecting insulinoma needs to be investigated further in a large-scale clinical trial that includes malignant insulinomas as well as those not identified by other modalities.

Interestingly, EUS-FNA in the present case revealed a hypoechoic lesion but failed to confirm the insulin-positive tumor. While EUS has reasonable diagnostic performance in identifying and localizing small lesions in comparison with CT and MRI [30-32] and the clinical relevance of EUS-FNA for the diagnosis of insulinoma has been established [31, 32], previous reports demonstrate the necessity of vigilance in cases of tumors in which the biopsy specimen on staining is negative for insulin [11, 12]. The utility of GLP-1R-targeted imaging has been suggested for such cases [12]. In the present case, the positive finding in the biopsy specimen for proinsulin staining suggests a possible abnormality in proinsulin to insulin conversion. It has been reported that abnormal proinsulin processing may be observed in insulinomas [33, 34] due to secretory granules containing proinsulin resulting from earlier occurrence of hypoglycemia during the fasting period [34]. Considering the heterogeneous positivity of insulin staining of the resected tumor in the present case, another possibility is that the sampling site of the biopsy happened to be within the proinsulin-dominant tumor tissue. Several previous reports demonstrated benign and malignant insulinomas with heterogenous (including negative) staining patterns for insulin [35-39] (Table 2). Notably, Werner et al. mentioned a case of hypoglycemia with pNEN predominantly secreting proinsulin which was revealed only by GLP-1R-targeted PET/CT [40]. Likewise, ¹⁸F-exendin-4 PET/CT in the present case provided functional evidence of insulinoma consistent with the diffuse expression of GLP-1R in the tumor cells, highlighting the clinical importance of the diagnostic value of our imaging method as a proof-of-concept case [12].

In conclusion, we report the first clinical case of insulinoma in the pancreatic head in which ¹⁸F-labeled PEGylated exendin-4 PET/CT was effectively implemented. Although a negative finding for insulin staining of the EUS-FNA specimen rendered the preoperative diagnosis challenging, ¹⁸F-exendin-4 PET/CT greatly facilitated diagnosis and precise localization of the insulinoma without any complications, enabling curative and minimally invasive surgical resection. This case demonstrates that ¹⁸F-exendin-4 PET/CT may well be a useful diagnostic tool in insulinoma cases when findings obtained from EUS-FNA are inconclusive.

This study was funded by Suzuki Manpei Diabetes Foundation and Suzuken Memorial Foundation, Terumo Life Science Foundation, Kyoto Health Management Research Foundation, Japan Health Promotion Foundation, Japan Foundation of Applied Enzymology, Advanced Science, Technology & Management Research Institute of KYOTO (ASTEM RI/KYOTO).

NI has patents registered with UHA Mikakuto Co., Ltd., asken Inc., and Shiratori Pharmaceutical Co., Ltd.; has received royalties from Drawbridge Health, Inc.; has received speaker honoraria from Kowa Co., Ltd., MSD K.K., Astellas Pharma Inc., Kissei Pharmaceutical Co., Ltd., Sanofi K.K., Novartis Pharma K.K., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Sumitomo Pharma Co., Ltd., Daiichi-Sankyo Co., Ltd., Eli Lilly Japan K.K., Nippon Boehringer Ingelheim Co., Ltd., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corp., Taisho Pharmaceutical Holdings Co., Ltd., Terumo Corp., AstraZeneca K.K., Sanwa Kagaku Kenkyusho Co., Ltd., Abbott Japan LLC, Ajinomoto Co., Inc., Teijin Healthcare Ltd., Bayer Yakuhin, Ltd., Arkray Marketing, Inc., Johnson & Johnson K.K., Roche DC Japan K.K., Scohia Pharma, Inc., and Life Scan Japan K.K.; has served on advisory boards for Bayer Yakuhin, Ltd., Terumo Corp., Mitsubishi Tanabe Pharma Corp., Sanofi K.K., Novartis Pharma K.K., Kowa Co., Ltd., Abbott Japan LLC, Novo Nordisk Pharma Ltd., Scohia Pharma, Inc., Sumitomo Pharma Co., Ltd., Kissei Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., and Eli Lilly Japan K.K.; received consulting fees from Sumitomo Pharma Co., Ltd.; has received research grants from Terumo Corp., Drawbridge Health, Inc., asken Inc., and Japan Diabetes Foundation Inc.; and has received scholarship donations from Kissei Pharmaceutical Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Sanofi K.K., Daiichi-Sankyo Co., Ltd., Mitsubishi Tanabe Pharma Corp., Takeda Pharmaceutical Co., Ltd., Japan Tobacco Inc., Kyowa Kirin Co., Ltd., Sumitomo Pharma Co., Ltd., MSD K.K., Ono Pharmaceutical Co., Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Eli Lilly Japan K.K., Novo Nordisk Pharma Ltd., Teijin Pharma Ltd., Tsumura & Co., Roche DC Japan K.K., Life Scan Japan K.K., and Kowa Co., Ltd; and is a recipient of endowed chairs from MSD K.K., Ono Pharmaceutical Co., Ltd., and Mitsubishi Tanabe Pharma Corp. DY is a member of Endocrine Journal’s Editorial Board. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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