Ectopic insulinoma in a dog with insulin-induced hypoglycemia: a case report

Abstract

A 7-year-old spayed female Shih Tzu dog was presented for evaluation of recurrent hypoglycemia. Serum insulin levels during hypoglycemia were 35.3 μIU/mL. Ultrasonography and computed tomography showed a mesenteric nodule between the kidney and the portal vein, but no pancreatic mass was observed. During surgery, the nodule had neither anatomical adhesions nor vascular connections to the pancreas. Pancreatic inspection and palpation revealed no abnormalities. Hypoglycemia improved after resection of the nodule. Histopathological examination confirmed the nodule to be an islet cell carcinoma. Although extremely rare, ectopic insulinoma should be considered as a possible cause of insulin-induced hypoglycemia in dogs.

INTRODUCTION

Insulinoma is a functional insulin-secreting pancreatic tumor that induces hypoglycemia [1]. Provisional diagnosis is based on elevated serum insulin concentration with simultaneous hypoglycemia, identification of pancreatic mass by preoperative imaging, and often surgical exploration if imaging does not identify pancreatic mass [1,2]. Insulinoma is highly metastatic in dogs [1]. Since surgical resection is the main treatment, localizing and staging of insulinoma are important for successful treatment [1,2]. Multi-phase computed tomography (CT) is the most frequently used technique for localizing and staging the tumor [2].

Ectopic insulinoma is derived from ectopic islet β-cells [3]. Since it is not located in the pancreas, its diagnosis and treatment may be delayed. Consequently, patients may suffer from persistent hypoglycemia. To our knowledge, there is only one report of ectopic islet cell carcinoma in a dog in which an intravenous methylene blue infusion was applied for diagnosis [4]. This report presents the diagnosis and treatment of a dog with ectopic insulinoma and describes its imaging features.

CASE PRESENTATION

A 7-year-old spayed female Shih Tzu dog weighing 4 kg was presented for evaluation of recurrent hypoglycemia. The patient had mild lethargy and bilateral hindlimb weakness. Physical and neurological examinations were unremarkable. Hematology, blood gas analysis and biochemistry test results showed marked hypoglycemia (18 mg/dL; reference range, 77–125 mg/dL) and mild hypokalemia (3.7 mmol/L; reference range, 3.8–5.0 mmol/L). Serum insulin concentrations during hypoglycemia were 35.3 μIU/mL (reference range, 5.2–41.5 μIU/mL). Serum cortisol concentrations were 10.2 mg/dL.

There were no remarkable findings on abdominal radiography. Abdominal ultrasonography (US) (Aplio 500; Canon Medical Systems Korea Co., Ltd., Korea) using a 4.5–18 MHz linear transducer had negative findings in the pancreas. However, a hypoechoic nodule which had no connectivity with specific organs was identified. It was located in the mesentery between the right kidney’s medial region and the portal vein’s distal end. The vascular response at the periphery of the nodule was detected by superb microvascular imaging (Fig. 1).

Fig. 1. Ultrasonographic image of ectopic insulinoma in a dog. The tumor (callipers) is located in the mesentery and has neither connectivity nor adhesion to the pancreas. The vascular response in the periphery of the nodule is detected by superb microvascular imaging.

Multi-phase CT using a 16-slice CT scanner (Brivo CT385; GE Healthcare, USA) was performed on the day of presentation after obtaining the owner’s consent. The imaging parameters were as follows: 120 kVp; 150 mAs; matrix size, 512 × 512; rotation time, 0.6 sec; and slice thickness, 1.25 mm. Under general anesthesia, the patient was positioned in sternal recumbency receiving a 10% dextrose intravenous infusion. After a pre-contrast scan, 800 mg iodine/kg iohexol (Omnipaque 300, 3 mL/sec; GE Healthcare, China) was injected into the cephalic vein using a power injector (CT9000 ADV; Mallinckrodt, UK). The arterial, pancreatic, portal venous, and equilibrium phases were sequentially performed at 15, 28, 40 and 90 sec after injecting the contrast medium.

CT showed a 1.0 cm intraperitoneal nodule in the mesentery, located between the right kidney and the portal vein. No anatomical adhesions or vascular connections to the pancreas were observed. The nodule showed mild hyperattenuation in the arterial phase compared with the pancreas, and became more heterogeneously hyperattenuated in the pancreatic and portal venous phase. The enhancement pattern was the most conspicuous in the pancreatic phase and became almost isoattenuated in the equilibrium phase, indicative of a short wash-out time (Fig. 2). There were negative findings on the liver and other lymph nodes.

Fig. 2. Multi-phase computed tomography images of ectopic insulinoma in a dog. Transverse pre-contrast image (A), arterial phase image (B), pancreatic phase image (C), portal venous phase image (D), equilibrium phase image (E), and dorsal portal venous phase image (F) of the tumor (arrows). There is no anatomical or vascular connection to the pancreas (arrowheads). The nodule becomes heterogeneously hyperattenuated in the arterial, pancreatic, and portal venous phase. It is the most conspicuous in the pancreatic phase, and becomes almost isoattenuated in the equilibrium phase.

A differential diagnosis of the nodule included metastasis of occult insulinoma to a lymph node or mesentery, and ectopic insulinoma. The patient underwent surgery 4 d after the CT scan. Cefazolin (Cefazolin Inj., 30 mg/kg; Chong Kun Dang, Korea) was administered intravenously for prophylactic antibiotic. Anesthesia was induced with IV propofol (Probive Inj., 8 mg/kg; Myungmoon Pharm, Korea) and maintained with isoflurane. A well-encapsulated 1.0 cm nodule was identified in the mesentery, located in the medial aspect of the right pancreatic lobe (Fig. 3). There were neither anatomical nor vascular connections to the pancreas. Furthermore, the entire pancreas was inspected and palpated without finding any nodules. The regional lymph nodes and liver were unremarkable. The nodule was resected with 1–4 mm margin left. Subsequently, the patient’s blood glucose (BG) levels increased to 135 mg/dL. After the surgery, the pain was managed with intravenous butorphanol (Butophan Inj., 0.2 mg/kg; Myungmoon Pharm).

Fig. 3. Macroscopic aspect (A) and microscopic aspect (B) of ectopic insulinoma in a dog. (A) The mesenteric nodule (arrows) is separated from the pancreas (dotted curve) without anatomical and vascular connection. (B) Histopathology shows polygonal cells with pale eosinophilic granular cytoplasms (circles) (hematoxylin & eosin staining; × 28.8 magnification).

The resected nodule was stained with hematoxylin and eosin for the histopathologic evaluation. The unencapsulated, multilobular, and moderately cellular nodule expanded the surrounding adipose tissue. It comprised polygonal cells with distinct cell borders and pale eosinophilic granular cytoplasm (Fig. 3). The mitotic index was 3 in 10 high-power fields. Neoplastic tissue focally extended to the margin without lymphovascular invasion. Based on the histopathologic results, the diagnosis was consistent with an islet-cell carcinoma. The owner didn’t consent to immunohistochemistry analysis.

The patient was discharged 2 d after surgery and remained clinically healthy throughout the following 6 months. The BG concentrations during the three visits were 99, 93 and 113 mg/dL while fasting.

DISCUSSION

Ectopic insulinoma is an extremely rare disease in humans [3]. Localizing the suspected mass, and confirming the relationship between the extra-pancreatic mass and recurrent hypoglycemia are important for successful diagnosis and treatment [3]. Even if CT or magnetic resonance imaging (MRI) find extra-pancreatic mass, determining whether the mass is ectopic insulinoma is still difficult without histopathology or postoperative glycemic response [3]. ⁶⁸Gallium-Exendin-4 positron emission tomography/CT are useful in the diagnosis of ectopic insulinoma since it can determine the types and function of the tumors preoperatively [3]. However, intraoperative exploration of the pancreas is necessary to avoid missing insulinoma [3].

Insulinoma usually appears as hyperattenuating during arterial phase, and then small amounts of enhancement appear during the venous phase [1]. Although the incidence of ectopic insulinoma is low, ectopic insulinoma also seems to have the tendency of early enhancement pattern during the arterial phase [3]. In this case, the nodule showed mild hyperattenuation during the arterial phase, and became almost isoattenuated in the equilibrium phase. The enhancement pattern of the nodule is similar to that of insulinoma and ectopic insulinoma.

In our case, although no pancreatic mass was identified by multi-phase CT, suspicion of insulinoma was reasonable enough to perform surgical exploration. However, the absence of pancreatic lesions was confirmed by pancreatic inspection and palpation. In addition, the mesenteric nodule was completely separated from the pancreas without anatomical and vascular connections on surgical exploration, and was surrounded by adipose tissue on histopathologic evaluation. The postoperative hyperglycemia was identified immediately after resecting the nodule. These findings suggest that the tumor is inconsistent with insulinoma, and parallels ectopic insulinoma in people [3].

Successful insulinoma localization in humans relies on various preoperative and intraoperative methods. The preoperative methods include US, CT, MRI, endoscopic US and nuclear medicine examinations [5]. The intraoperative methods include pancreatic inspection, palpation, intraoperative US, and intraoperative glucose monitoring [5]. For preoperative localization, CT or MRI is accepted as the first choice with advantages of identifying small tumors and metastasis [5]. However, even with successful preoperative methods, intraoperative localization is also important for reconfirmation [5]. Intraoperative inspection, palpation, and US have been applied with a high success rate [5,6,7]. In cases with multiple tumors, intraoperative glucose monitoring is a useful diagnosis method [5,8]. If the BG levels do not increase after removing a tumor, it means that there are still other undetected tumors [5]. In our case, abdominal US and CT were applied for preoperative localization. Since small insulinomas may be missed by CT, pancreatic inspection and palpation was also performed. In addition, the postoperative hyperglycemia was identified indicating that no other insulin-secreting tumors remained [5]. Thus, occult insulinoma could be excluded by using multiple localizing techniques.

Extra-pancreatic paraneoplastic syndromes, hypoadrenocorticism, hepatic insufficiency, sepsis, and infectious diseases such as bartonellosis and babesiosis can also cause hypoglycemia in dogs [1,2,9,10]. In our case, the patient had no other mass except the mesenteric nodule, so extra-pancreatic paraneoplastic syndrome was excluded. The basal cortisol concentration was 10.2 mg/dL, so hypoadrenocorticism was excluded [11]. Hepatic insufficiency, sepsis, and other infectious diseases were also excluded based on the patient’s systemic stability and laboratory findings.

There are two limitations in our study. First, the other localization techniques including MRI, intraoperative US, and nuclear medicine examinations were not available. In people, MRI and intraoperative US have a high sensitivity in localizing small insulinomas, and nuclear medicine examinations are useful in demonstrating ectopic insulinomas preoperatively [3,5,12]. Therefore, we suggest that future studies should aim to use these methods to localize ectopic insulinoma in dogs.

Second, insufficient evidence was available to confirm an origin of the tumor in our study. Instead, the origin was suspected by the tumor location. The definition of ectopic insulinoma includes several categories based on its location and function. The first category is insulinoma originated from ectopic pancreas, which is commonly located in the stomach, duodenum, jejunum and rarely mesentery [3,13]. Second, nonfunctional gastrointestinal neuroendocrine tumors may secrete insulin as the tumors progress [3]. Third, ovarian tumors, cervical carcinoids, kidney carcinoids, paragangliomas, and liver neuroendocrine tumors have also been reported to secrete insulin [3]. In our case, the tumor was in the mesentery, and it was somewhat consistent with the first category. In addition, the patient had no other neuroendocrine tumors and no history of tumor resection; thus, the second and the third categories could be excluded except the paraganglioma. Paraganglioma can arise from any location, and in few cases, paragangliomas have been reported to secrete insulin in people [14]. However, it was excluded based on the absence of the zellballen pattern, a characteristic histopathological finding in paraganglioma [15].

In closing, although extremely rare, ectopic insulinoma is a differential diagnosis for insulin-induced hypoglycemic dogs with no pancreatic mass, but extra-pancreatic mass. Furthermore, to diagnose ectopic insulinoma successfully, our study emphasizes the importance of preoperative localization, intraoperative exploration, and postoperative glycemic response. Surgical excision of the ectopic insulinoma is the recommended treatment.