A case report of insulinoma presenting with seizures and localized on endoscopic ultrasound

Abstract

Insulinomas are rare functioning neuroendocrine (NEN) tumors. Up to 10% of insulinomas are associated with multiple endocrine neoplasia 1 (MEN1). Most of the tumors present with symptomatic hypoglycemia. Several non‐invasive and invasive techniques are used to localize the lesion. We present a case of insulinoma presenting with seizure episodes with negative results on non‐invasive imaging diagnosed and localized with endoscopic ultrasound. A 36‐year‐old male was brought by ambulance to the emergency department with an episode of generalized tonic–clonic seizures. He had been previously healthy and did not have family history of neuro‐endocrine tumors. At the time of the attack, the patient's blood glucose checked via point‐of‐care testing was 28.8 (70–99 mg/dL). He was given IV dextrose. Physical examination after the patient regained consciousness was completely unremarkable. Hypoglycemia workup revealed a normal morning cortisol level of 281 (138–689 nmol/L). Insulin level was 62.4 mcunit/ml (2.36–24.9), and c‐peptide was 8.13 (1.1–4.4 ng/mL) consistent with hyperinsulinemia. Magnetic resonance cholangiopancreatography (MRCP), fluorine‐18‐l‐dihydroxyphenylalanine whole‐body positron emission tomography scan (NM 18F‐DOPA whole‐body PET scan), and gallium Ga 68 dodecanetetraacetic acid (Ga‐68 DOTATATE) scan were normal and did not reveal any pancreatic lesion consistent with insulinoma. Due to high suspicion of insulinoma and negative non‐invasive imaging, an endoscopic ultrasound (EUS) was performed, which showed a hypoechoic homogenous mass lesion sized 13 × 9 mm in the proximal body/neck of the pancreas. A fine needle biopsy (FNA) via EUS was performed. Histopathology showed a well‐differentiated neuroendocrine tumor, consistent with Grade 1 insulinoma (T1N0M0). The patient underwent a distal pancreatectomy and splenectomy. In cases of high clinical and biochemical suspicion of insulinoma but negative non‐invasive imaging, invasive modalities should be used to localize the culprit lesion.

The purpose of presentation of this case is to educate the readers about the challenges faced in the diagnosis of insulinoma. As well as to highlight the utility of EUS in a case of suspected insulinoma when the imaging studies are negative, despite the biochemical evidence of endogenous insulin production.

1. INTRODUCTION

Insulinomas are rare functioning neuroendocrine (NEN) tumors with an annual incidence of 1–4 cases per million. Up to 10% of insulinomas are associated with multiple endocrine neoplasia 1 (MEN1). Most of the tumors present with symptomatic hypoglycemia and the diagnosis is established by demonstrating endogenous hyperinsulinemia in the presence of hypoglycemia. ¹ Several non‐invasive techniques are used to localize the lesion and include an ultrasound (US) abdomen, computer tomography (CT scan), magnetic resonance imaging (MRI), and molecular imaging techniques like NM 18F‐DOPA whole‐body PET CT and Ga‐68 DOTATATE scan. ² , ³ , ⁴ Due to the low sensitivity of the non‐invasive methods, the localization of the tumor presents a diagnostic challenge, and invasive techniques like endoscopic ultrasound (EUS) and angiography and arterial stimulation venous sampling (ASVS) should be used if the suspicion is high. ⁵ , ⁶ We present a case of insulinoma presenting with seizure episodes. Laboratory testing revealed evidence of hyperglycemia, but all the non‐invasive testing, including molecular imaging, was negatispan>, and the diagnosis was established after localizing and fine‐needle aspiration (FNA) of the tumor with EUS.

2. CASE PRESENTATION

A 36‐year‐old male was brought by the ambulance to the emergency department with an episode of a generalized tonic–clonic seizure. As per the witness, the patient was sitting when he suddenly collapsed and had jerky movements of his arms and legs. The episode lasted for about 5 min. There was no bowel or bladder incontinence. After the episode, the patient remained confused for 15–20 min. At the time of the seizure, the patient's blood glucose checked via point‐of‐care testing was 28.8 (70–99 mg/dL). He was given IV dextrose after the patient regained consciousness, he reported feeling sweaty and palpitations before the seizure episode. He denied any headache, neck pain, fever, dizziness, weakness, cough, rhinorrhea, sore throat, dysuria, nausea, vomiting, or diarrhea.

The patient reported an off‐and‐on feeling of light‐headedness in the last 2–3 months that improved after drinking juice. He did not have any chronic illnesses or previous surgeries. He denied taking any medications, including multivitamins or herbal remedies. The patient was a non‐smoker and did not drink alcohol. There was no family history of insulinoma, parathyroid adenoma, adrenal tumors, or family history of multiple endocrine neoplasia. No family history of cardiovascular diseases or sudden death at early age was reported.

After the patient regained consciousness, physical examination revealed a temperature of 36.8°C, respiratory rate of 20 breaths per minute, blood pressure of 135/80 mmHg, heart rate of 76 beats per minute, and oxygen saturation of 99% on room air. Respiratory, abdominal, and neurologic examination was normal.

A basic laboratory workup revealed a normal complete blood count and metabolic and coagulation profile. Serum ethanol level was normal (Table 1). An MRI showed multiple calcified lesions in the brain concerning for neuro‐cysticercosis, which did not require any treatment. During the hospital stay, the patient had multiple episodes of hypoglycemia.

TABLE 1.

Baseline investigations.

Variables	Results	Reference range adults
Blood
Wbc (per μL)	8500	4000–11,000
Hgb (g/dL)	14.8	13–17
Hematocrit (%)	44.9	40–50
Absolute neutrophils count (per μL)	5800	2000–7000
Lymphocyte count (per μL)	2200	1000–3000
Platelets count (per μL)	186,000	150,000–400,000
PT (s)	10.1	9.7–11.8
APTT (s)	27.4	24.6–31.2
INR	0.9	N/A
Urea (mmol/L)	5.2	2.5–7.9
Creatinine (μmol/L)	61	62–106
Na (mmol/L)	142	135–145
K (mmol/L)	3.4	3.5–5.5
Cl (mmol/L)	105	95–105
HCO3 (mmol/L)	26	22–28
Adjusted calcium (mmol/L)	2.47	2.20–2.60
Mg (mmol/L)	0.94	0.75–1.0
Amylase (U/L)	20	25–125
Lipase (U/L)	73	13–60
Albumin (g/L)	41	35–55
Total protien (g/L)	77	60–78
ALT (U/L)	16	8–20
AST (U/L)	17	8–20
Alk phosphatase (U/L)	127	40–129
Bilirubin T (μmol/L)	7	2–17
Ethanol (mmol/L)	Negative	<2.2
CRP (mg/L)	2.1	0–5

Abbreviations: ALT, alanine transaminase; AST, aspartate aminotransferase; Cl, chloride; CRP, C‐reactive protein; HCO₃, bicarbonate; Hgb, hemoglobin; INR, International normalized ratio; K, potassium; Mg, magnesium; Na, sodium; PT, prothrombin time; PTT, partial thromboplastin time; WBC, white blood cells.

Hypoglycemia workup revealed a normal cortisol level, elevated insulin, and c‐peptide level consistent with hyperinsulinemia (Table 2). An MRCP, NM 18F‐DOPA whole‐body PET CT and Ga‐68 DOTATATE scan were normal and did not reveal any pancreatic lesion consistent with insulinoma. Due to high suspicion of insulinoma and negative non‐invasive imaging, an EUS was performed, showing hypoechoic homogenous mass lesion sized 13 × 9 mm in the proximal body/neck of the pancreas (Figure 1). A FNA via EUS was performed. Histopathology showed a well‐differentiated neuroendocrine tumor, consistent with Grade 1 insulinoma (T1N0M0). Patient underwent distal pancreatectomy and splenectomy. Postoperatively, the patient did not had any recurrence of hypoglycemia during hospital stay. A repeat insulin level 2 days after the procedure came to be 9.6 (2.6–24.9 micro‐Unit/mL), significantly improving from 103 at the time of presentation. After discharge from our hospital, the patient was followed up regularly up to 1 year. Luckily, he did not report any hypoglycemic episodes, no recurrence of seizures as well, has been completely asymptomatic, and resumed all his activities of daily living without any difficulty.

TABLE 2.

Endocrinology investigations.

Endocrinology results
Morning cortisol (nmol/L)	281	138–689
Point of care glucose (mg/dL)	43	70–99
Insulin (mcunit/mL)	62.4	2.36–24.9
C‐peptide (ng/mL)	8.13	1.1–4.4

FIGURE 1.

Hypoechoic homogenous mass lesion sized 13 × 9 mm in the proximal body/neck of pancreas.

3. DISCUSSION

Insulinomas are well‐differentiated NEN that most commonly present with hypoglycemia. Other presenting features include seizures, altered sensorium, unexplained weight gain, or abdominal pain. The median duration between symptoms onset and diagnosis may range from 18 to 35 months. ⁷ Although the majority of patients have fasting hypoglycemia, upto 21% patients report both fasting and postprandial hypoglycemia and 6% patients report exclusively postprandial hypoglycemia. ⁸ Nevertheless, the first step in evaluating hypoglycemia is to confirm the diagnosis by establishing Whipple's triad, which includes symptoms of hypoglycemia, plasma glucose concentration less than 55 mg/dL, and resolution of symptoms after correction of hypoglycemia. ⁹ If the etiology of hypoglycemia is not evident based on initial history and physical examination, the further diagnostic workup includes measurement of plasma glucose, plasma insulin level, pro‐insulin, C‐peptide, beta‐hydroxybutyrate (BHB), and screening for sulfonylureas during an episode of spontaneous hypoglycemia to assess for insulin‐mediated versus non‐insulin mediated hypoglycemia. In the absence of a spontaneous episode of hypoglycemia, a supervised 72‐h fast can be carried out to recreate a spontaneous hypoglycemia episode during which the above‐mentioned laboratory evaluation can be performed. The hypoglycemia episode is then corrected with the administration of 1 mcg glucagon injection, and the response of glucose to glucagon injection is measured by checking serum plasma glucose level. These laboratory investigations will differentiate insulin (exogenous or endogenous) mediated hypoglycemia from hypoglycemia caused by other mechanisms (e.g., noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS)). Anti‐insulin antibodies can be tested to evaluate for autoimmune insulin hypoglycemia. A plasma glucose level of less than 55 mg/dL, insulin level more than 3 uU/mL, C‐peptide more than 0.2 nmol/L, pro‐insulin more than 5 pmol/L, beta‐hydroxybutyrate less than 2.7 mmol/L with an increase in plasma glucose by more than 25 mg/dL, negative urine screen for sulfonylureas, serum insulin antibodies and negative history of previous bariatric surgery points toward insulinoma as the most probable etiology of endogenous hyperinsulinemic hypoglycemia (EHH). ¹⁰ A proposed approach to adult hypoglycemia evaluation based on endocrine society guidelines has been shown in Figure 2. ¹⁰ Hypoglycemia evaluation in our patient indicated insulinoma as the cause of hypoglycemia.

FIGURE 2.

Evaluation of hypoglycemia. ¹⁰ BG, blood glucose; BHB, betahydroxybutyrate; IGF, insulin‐like growth factor; NIPHS, non‐insulinoma pancreatogenous hypoglycemia syndrome; PGBH, post‐gastric bypass hypoglycemia.

A number of non‐invasive imaging modalities can be used to localize an insulinoma after the biochemical workup. These US abdomen, CT scan and MRI of the abdomen. The sensitivity of the US abdomen in localization of an insulinoma is reported to be 9%–64%, CT scan 33%–64%, and MRI 40%–90%. ¹¹ Up to 35% of patients with evidence of EHH have negative US, CT, and MRI during the evaluation of insulinoma. ² Neuroendocrine tumors are rich in somatostatin receptors (SSR), especially SSR subtype 2. Hence, somatostatin receptor scintigraphy using octreotide is a vital imaging modality in localizing gastric neuroendocrine tumors. SSR, however, has low expression in insulinomas compared to other gastric neuroendocrine tumors and hence, octreotide scans have a high false‐negative rate in cases of insulinoma. ² 68Ga‐DOTATATE positron emission tomography/computed tomography (68Ga‐DOTATATE PET) has shown a sensitivity of 95.1% in the detection of gastric neuroendocrine tumors. ³ 18F‐DOPA PET is another imaging modality with a higher sensitivity rate of 90% in localizing the lesions in case of insulin‐mediated hypoglycemia. ⁴

EUS and ASVS are invasive techniques to localize insulinoma when the non‐invasive techniques fail, and the suspicion remains high. EUS has a sensitivity of up to 89%, whereas the sensitivity of ASVS has been reported to be up to 93%. ⁵ , ⁶ Patel et al. reported 2 cases of insulinomas with negative imaging (including negative octreotide scan in one case). Both patients were diagnosed with FNA via EUS. ¹² Siddharth et al. also reported a case of insulinoma diagnosed with EUS who initially had a negative CT abdomen, MRI abdomen, and octreotide scan. ¹³ Our patient also had a negative US abdomen, CT abdomen, and MRI abdomen/MRCP. Given the high suspicion of a neuroendocrine tumor as the etiology of hypoglycemia, 18F‐DOPA PET/CT, and 68Ga‐DOTATATE PET/CT were performed, which, despite being highly sensitive modalities, were negative making it extremely challenging to localize the tumor. Hence, the diagnosis was established with EUS followed by FNA of the lesion.

4. CONCLUSION

Insulinoma can be the underlying etiology of unexplained recurrent seizures in an otherwise healthy patient. Due to the variable sensitivity of non‐invasive imaging modalities, the localization of insulinoma frequently presents a diagnostic challenge. In cases of high clinical and biochemical suspicion of insulinoma but negative non‐invasive imaging, invasive modalities should be used to localize the culprit lesion.

AUTHOR CONTRIBUTIONS

Waseem Umer: Conceptualization; data curation; writing – original draft; writing – review and editing. Ahmed Salah Mohammed: Conceptualization; data curation; writing – original draft; writing – review and editing. Adeel Ahmad Khan: Data curation; writing – original draft; writing – review and editing. Muhammad Umar Saddique: Data curation. Muhammad Zahid: Conceptualization; writing – review and editing.

FUNDING INFORMATION

No fund was obtained.

CONFLICT OF INTEREST STATEMENT

All authors have no conflict of interest.

ETHICS STATEMENT

The case was approved by the medical research center of Hamad Medical Corporation (HMC) with MRC‐04‐22‐284.

CONSENT

Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy.

Umer W, Mohammed AS, Khan AA, Saddique MU, Zahid M. A case report of insulinoma presenting with seizures and localized on endoscopic ultrasound. Clin Case Rep. 2023;11:e6967. doi: 10.1002/ccr3.6967

DATA AVAILABILITY STATEMENT

Not applicable.