Discussion
Insulinomas are commonly encountered as solitary benign tumors,
typically measuring less than 2 cm in diameter, and they constitute 87%
of all pancreatic tumors.[4] On the other hand, the malignant ones
account for the remaining 13%. These malignant variants tend to be
larger, with an average size of 6.2 cm. The most frequent locations for
insulinomas are the tail, body, and head of the pancreas. Notably, they
often coincide with a significant elevation in insulin levels. The
five-year survival rates differ markedly between benign and malignant
tumors, standing at 95.4% and 66.8%, respectively. [5]
Approximately 4% to 7% of insulinomas are associated with multiple
endocrine neoplasia type-1 (MEN-1), a condition characterized by an
earlier age of onset and multifocality. [6] Despite extensive
research, the etiology and pathogenesis of insulinomas remain elusive.
Clinically, the patients with an insulinoma manifest primarily as
episodic hypoglycemia, primarily due to excessive insulin secretion from
the tumor tissue. The diagnostic criteria for insulinoma include the
Whipple’s triad sign: (1) spontaneous periodic episodes of hypoglycemic
symptoms, coma, and associated psychoneurological symptoms, often
occurring during fasting or after physical exertion; (2) blood glucose
levels below 50.4 mg/dL during these episodes; and (3) prompt resolution
of the symptoms following oral or intravenous glucose administration. In
cases with atypical clinical manifestations, a 72-hour starvation test
is essential for a definitive diagnosis. [7, 8] The symptoms and the
test results of the patient in our reported case meet the qualitative
diagnostic criteria for insulinoma.
Benign insulinomas commonly respond well to surgical resection, and we
now have a variety of alternative therapeutic options. These include
endoscopic ultrasound-guided radiofrequency ablation, percutaneous
alcohol ablation, and transarterial embolization of the insulinoma.[9,
10] The preoperative localization of insulinomas directly impacts the
clearance rate, reoperation rate, and prognosis of the lesion. Accurate
localization diagnosis remains a significant challenge in insulinoma
diagnosis and treatment. Advancements in imaging technology have ushered
in an era of simple and non-invasive preoperative localization and
diagnosis of insulinomas. Invasive techniques, such as digital
subtraction angiography, percutaneous hepatic portal vein blood
sampling, and selective arterial calcium-stimulated venous blood
collection, have fallen out of favor. Routine imaging modalities,
including ultrasound of the upper abdomen, Magnetic Resonance Imaging
(MRI), Contrast-Enhanced Computed Tomography (CECT) of the abdomen, and
pancreatic CT perfusion imaging, are widely employed for localization
and diagnosis. In a single-center study, 286 patients with functional
pancreatic neuroendocrine tumors (pNETs) were included, of whom 266 had
insulinomas. The study demonstrated that CT, DSA, ultrasonography, and
MRI achieved favorable localization and diagnostic rates of 76.2%,
83.8%, 87.1%, and 92.9%, respectively.[11] Computed tomography
(CT) and magnetic resonance imaging (MRI) serve as primary imaging
modalities for localization and diagnosis of insulinomas. However, their
sensitivity remains inadequate, particularly for small-volume lesions.
Improving the detection rate and addressing deficiencies in lesion
characterization are ongoing challenges. Emerging imaging techniques,
including 68Gallium-DOTA-Tyr3-Octreotate Positron Emission
Tomography-Computed Tomography (68Ga-DOTATATE-PET-CT) and
68Gallium-NOTA-exendin-4 Positron Emission Tomography-Computed
Tomography (68Ga-NOTAexendin-4PET-CT), and other radionuclide receptor
imaging tests, exploit receptor-binding based imaging for precise
localization. In a prospective study, 68Ga-DOTATATE-PET-CT demonstrated
superior sensitivity for lesion detection and tumor-staging guiding,
compared to whole-body diffusion-weighted MRI (WB DWI) and
99mTc-HYNIC-Octreotide SPECT/CT. Diagnostic performance metrics for
pancreatic neuroendocrine tumors were as follows: sensitivity 100%,
specificity 80%, accuracy 84%, positive predictive value 57%, and
negative predictive value 100%.[12] Despite their clinical
significance, wider adoption of these novel imaging tests remains
limited due to availability constraints in many hospitals. In this case,
abdominal enhancement CT failed to detect the lesion, and radionuclide
receptor imaging was not performed. Hence, alternative localization
methods are necessary for further clarification.
Given that surgical removal of the tumor remains the sole effective
treatment, to prevent undue harm to the patient resulting from
misdiagnosis, a preoperative “gold standard” diagnosis is imperative,
which necessitates the pathologic examination. Endoscopic ultrasound
(EUS) offers the advantages of high resolution, proximity, and minimal
interference from intestinal gas. During both preoperative and
intraoperative phases, it allows comprehensive observation of the lesion
from all angles, eliminating blind spots and facilitating precise tumor
localization. In comparison to alternative imaging modalities,
endoscopic ultrasound offers notable benefits, particularly in enhancing
the detection rate of small lesions. Additionally, it can be used in
conjunction with fine-needle aspiration biopsy to perform histologic and
cytologic examinations on the lesion. Furthermore, it enables
qualitative diagnosis of the lesion, informing treatment decisions. In
situations where conventional imaging results are inconclusive, it
serves as a crucial complementary tool.[13]
However, EUS as an invasive procedure has several drawbacks. The
diagnostic effectiveness of insulinomas via EUS is constrained by the
location and size of the tumors. Specifically, EUS is less effective in
detecting insulinomas situated in the tail or the leptomeningeal region
of the pancreas, both of which tend to be small. The reliability of EUS
depends on the subjective interpretation of the sonographer, introducing
limitations. Detecting isoechoic insulinomas poses challenges for EUS,
and it cannot identify extra-pancreatic lesions like lymph node or liver
metastases. In this case, the patient underwent the EUS examination, and
a small lesion in the pancreatic neck, a location prone to oversight,
was identified. The fine-needle aspiration biopsy was subsequently
conducted to ascertain the lesion’s nature, confirming it as a
neuroendocrine tumor. The precise diagnosis of the lesion’s location and
nature enabled the patient to proceed with the next stage of surgical
treatment.
After pancreaticoduodenectomy, the patient did not encounter
hypoglycemic episodes. Hyperglycemia was attributed to secondary
diabetes mellitus. Exogenous insulin treatment resulted in adequate
glycemic control. Postoperatively, the patient underwent follow-up, with
no evidence of recurrence or metastasis.
The EUS-guided fine-needle aspiration biopsy (EUS-FNAB) serves as a
critical adjunctive technique when conventional imaging fails to
precisely localize and diagnose occult insulinomas. Furthermore, novel
molecular imaging technologies, including 68Ga-DOTATATE-PET-CT and
68Ga-NOTAexendin-4PET-CT, also offer precise and reliable localization
of the tumors. These advancements enhance clinicians’ diagnostic and
therapeutic capabilities for occult insulinomas, minimizing misdiagnoses
and enabling early intervention.