Histologically, there are two major subtypes of CHI, diffuse and focal [4] (Fig. 12.1). However, patients have been described with atypical histological forms of CHI which do not fit into the classification of diffuse or focal [16, 17]. The diffuse form of CHI affects all the ß-cells within the islets of Langerhans (Fig. 12.2). The histological subtype of CHI can be a guide as to the mode of inheritance. Diffuse disease can be familial or sporadic and can result from recessively inherited or dominantly acting mutations in the genes previously described whilst focal disease is always sporadic [18]. The diffuse and focal forms of CHI are histologically unrelated to nesidioblastosis [19] (which describes the proliferation of islets cells budding off from pancreatic ducts).

Focal pancreatic lesions appear as small regions of islet adenomatosis (nodular hyperplasia of islet-like cell clusters, including ductuloinsular complexes) measuring 2–10 mm which are characterised by ß-cells with enlarged nuclei surrounded by normal tissue [18, 20] (Fig. 12.2). Focal disease results from paternal uniparental disomy (UPD) encompassing chromosome11p15.5-11p15.1 within a single pancreatic ß-cell which unmasks a paternally inherited K_ATP channel mutation at 11p15.1 [21, 22]. Paternal UPD at 11p15.5 causes altered expression of a number of imprinted genes, including the maternally expressed tumour suppressor genes H19 and CDKN1C, and the paternally expressed growth factor IGF2, likely leading to clonal expansion of the single cell and dysregulated insulin secretion from the resulting focal lesion [21, 22].

In patients that are unresponsive to medical therapy with diazoxide it is essential to differentiate focal from diffuse disease as the surgical approaches are radically different [23]. Infants with diffuse and focal disease are clinically and biochemically undistinguishable, thus there is no biochemical marker which will help in the differentiation. The precise preoperative localisation and limited surgical removal of the focal domain “cures” the patient from the hypoglycaemia and minimizes the risk of pancreatic exocrine insufficiency. Focal lesions are typically invisible to the naked eye at the time of the operation (size can vary from 2 to 10 mm in diameter) and in most cases buried deep within the pancreas [4]. In contrast, patients with diffuse disease will require a near total pancreatectomy which will have life-long implications (with a high risk of developing diabetes mellitus and pancreatic exocrine insufficiency). Patients with diffuse CHI that are medically managed also have a high risk of developing diabetes mellitus [16].

In the past methods for identifying children with a focal CHI included intrahepatic pancreatic portal venous sampling (PVS), arterial calcium stimulation/venous sampling, acute insulin response testing to intravenous glucose, calcium and tolbutamide and biopsy of the tail of the pancreas. However, these investigations are not only technically difficult and challenging but also have poor sensitivity and specificity. Focal lesions cannot be visualized with magnetic resonance imaging (MRI) or computerized tomography (CT) scans.

However, recent advances in ¹⁸F-DOPA-PET (Fluorine-18-l-3,4-dihydroxyphenylalanine positron emission tomography) imaging have completely changed the diagnostic approach to these patients [24–30]. The principle of this radiological technique is based on the fact that pancreatic islets take up l–DOPA and convert it into dopamine by the aromatic amino acid decarboxylase [28]. The uptake of the positron emitting tracer ¹⁸F-DOPA is increased in ß-cells with a high rate of insulin synthesis and secretion (increased metabolism) compared to unaffected areas. Dopamine receptors are expressed in pancreatic ß-cells suggesting a possible role in regulating insulin secretion. However, the precise role of dopamine in the pancreatic ß-cells is still unclear.

The detection limit of PET imaging using ¹⁸F-DOPA-PET is equivalent to 10⁵–10⁶ cells and a diameter of approximately 1 mm [6]. The recent introduction of the integrated ¹⁸F-DOPA-PET/CT technique allows more precise preoperative localization of the focal lesion [31]. The new ¹⁸F-DOPA-PET/CT technique allows visualization of the splenic artery, portal vein, superior mesenteric and inferior mesenteric arteries as well as the duodenum and enables exact anatomical and functional description of the pancreatic focus [31]. Ectopic focal lesions (in the wall of the jejunum and the ileum) can also be detected by ¹⁸F-DOPA-PET [32, 33]. ¹⁸F-DOPA-PET/CT scan is indicated in those patients who have the genotype of a focal lesion (namely a paternally inherited mutation in ABCC8 or KCNJ11) or have no mutations in the ABCC8/KCNJ11 genes. If the patient has a homozygous or compound heterozygote mutation in ABCC8 or KCNJ11 then this is likely to be associated with diffuse disease and an ¹⁸F-DOPA-PET/CT is not required these cases. The aim of the ¹⁸F-DOPA-PET/CT is to allow pre-operative localisation of the focal domain [25, 26]. We recently reviewed our experience in the PET-CT localization of focal CHI and this suggests that in focal lesions, ¹⁸F-DOPA-PET scan is useful in defining the site and dimension of the focal lesion in 2/3 of patients [34].

Surgery is indicated for cases of diffuse CHI which are medically unresponsive (diazoxide and octreotide) and in all cases of focal disease provided that the focal lesion is accurately localised pre-operatively. A multidisciplinary team (involving the endocrinologist, histopathologist and surgeon) approach to patients with CHI can help in distinguishing focal from diffuse disease, locate focal lesions, and permit partial pancreatectomy with cure in most patients [5, 35]. It is recommended that surgery for CHI patients should be done in centers of expertise where all the facilities and resources are available. The surgeon has to work very closely with the histopathologist as intra-operative examination of pancreatic specimens will guide the surgeon on the extent of resection required [36]. Surgeons need to be aware about the limitations of ¹⁸F-DOPA-PET in identifying the exact location and the dimension of the focal lesion and should always rely on the intra-operative histological confirmation of complete excision of the focal lesion [34].