PET/CT in congenital hyperinsulinism: transforming patient's lives by molecular hybrid imaging

Abstract

Congenital hyperinsulinism (HI) is a life-threatening condition characterized by severe and recurrent episodes of hypoglycaemia due to defects in key genes involved in regulating insulin secretion. The delay in diagnosis and inappropriate management of HI lead to high risk of permanent hypoglycemic brain injury. The management of HI is challenging as each form of HI (focal, diffuse, and atypical) requires its own therapeutic strategy. In HI diagnostic work-up, integrated PET/CT scan is currently the first-line imaging technique allowing to differentiate between diffuse and focal form and, in the latter case, to localize the focus within the pancreas with high precision. Only in focal HI partial pancreatectomy is the treatment of choice and a curative surgical treatment means a real chance of transforming patient's lives and HI patient's future. The aim of this review is to discuss the role of PET/CT imaging in HI scenario, its technical advantages and limitations and how successful surgery is strongly dependent on accurate preoperative assessment (genetic analysis and PET/CT scan). A multidisciplinary approach in HI diagnosis and treatment inside a single team (involving different expertise) allows to manage children safely and properly, supporting their families in an organized care network.

Keywords: Congenital hyperinsulinism; DOPA; PET/CT; molecular hybrid imaging; pediatric.

Figure 1

¹⁸F-DOPA PET/TC - diffuse (A) and focal (B-D) pattern. (A) Axial F-DOPA PET image shows a uniform ¹⁸F-DOPA uptake throughout the pancreas. (B-D) PET/CT scan clearly show a focal ¹⁸F-DOPA uptake in the pancreatic area (corresponding to head, body, and tail, respectively, as indicated by the red arrow). In all cases, after partial pancreatectomy, PET/CT findings were pathologically confirmed resulting in a complete remission of hypoglycemia. In (D), posterior exophytic lesion in pancreatic tail (localized near to left kidney) could represent a challenging position of focal lesion but hybrid imaging ruled out any interpretative doubts about a possible false positive result (as for urinary excretion pitfall). In all reported cases of focal HI, quantitative analysis confirmed visual interpretation (resulting in SUV ratio >1.2).

Figure 2

Contrast-enhanced CT imaging: unusual findings in focal HI pattern. Added value of abdominal contrast-enhanced CT scan in focal form of HI (confirmed by histology) detected by ¹⁸F-DOPA PET. A. HYPO pattern: PET/CT imaging shows a focal area of increased dopaminergic activity corresponding to isthmus with respect to the rest of the pancreas (SUV ratio was slightly higher than 1.2). Contrast-enhanced CT imaging reveals a small area of reduced enhancement (maximum axial diameter of 9 mm) located laterally to the proximal tract of hepatic artery, corresponding to the focal lesion detected by ¹⁸F-DOPA PET in the pancreatic isthmus. This finding isn’t detectable assessing basal low-dose CT imaging. B. HYPER pattern: PET/CT images show a “bright” area of intense ¹⁸F-DOPA uptake localized within the entire pancreatic head, with a SUV ratio indicative of focal lesion. Abdominal contrast-enhanced CT imaging shows an increased contrast enhancement in the head of pancreas considering arterial phase while this finding is not detectable in portal phase. Contrast-enhanced CT scan (as for other conventional radiological methods) is usually unable to identify the focal HI lesion due to the absence of structural alterations. An accurate analysis of hybrid imaging data helps to obtain a correct localization of focal lesion (detected by PET scan) guiding surgical resection. Looking further ahead, a careful assessment of all hybrid imaging data could lead to discover uncommon findings increasing diagnostic confidence (especially for small/large HI focal lesion) and improving the knowledge of a challenging disease with heterogeneous features.

Figure 3

¹⁸F-DOPA PET/TC pitfall: tracer stasis in bile duct. One of the pitfalls of interpretation is due to physiological bile excretion of tracer with possible ¹⁸F-DOPA stasis in common bile duct. PET scanning of abdomen before 45-60 minutes (from tracer injection) sometimes doesn’t avoid this technical aspect resulting in an area of increased uptake in the head of pancreas. Integrated PET/CT images are helpful in the evaluation of this physiologic uptake pattern locating the hot spot in correspondence to common bile duct (as clearly detectable by current PET-CT imaging equipped with high resolution system).

Figure 4

Factitious hyperinsulinism (Munchausen Syndrome by Proxy). Diagnosis of factitious hyperinsulinism could be a challenge with serious consequence related to repeated severe episodes of hypoglycemia (especially when misdiagnosed). Insulin/C-peptide ratio analysis is helpful in case of exogenous insulin injection, but it could not be discrepant in case of sulfonamide-induced factitious hypoglycemia. In this scenario, when antidiabetic agents are not identified by most common toxicological screening tests in urine and genetic test results are pending, PET-CT imaging could be used as prompt diagnostic tool integrating metabolic information provided by ¹⁸F-DOPA and ⁶⁸Ga-DOTA peptide. Figure 4 shows integrated dual-tracer PET/CT imaging performed in a case of severe hyperinsulinemic hypoglycemia, unresponsive to medical therapy with late age of onset (16 years), normal insulin/C-peptide ratio and no abnormal finding in urine drug testing. A. ¹⁸F-DOPA PET imaging shows a diffuse ¹⁸F-DOPA uptake throughout the pancreas without detection of ectopic focal lesion. B. ⁶⁸Ga-DOTATATE PET/CT imaging reveals a faint tracer uptake throughout the pancreas. PET-CT imaging ruled out the presence of pancreatic or ectopic lesions responsible for the hyperinsulinism (including focal HI or insulinoma). Due to the high clinical suspicious, other toxicological tests were performed detecting an antidiabetic drug in urine (glibenclamide).