Histologic findings in persistent hyperinsulinemic hypoglycemia of infancy: Australian experience

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is characterized by hyperinsulinism and profound hypoglycemia, with most children requiring pancreatic resection. The histological classification of PHHI is controver sial. Most authors acknowledge the existence of focal areas of islet cell p roliferation (adenomatosis) in 30%-50% of cases and a diffuse disorganisati on of islet architecture, termed "nesidiodysplasia,'' in others. De Lonlay et al. reported that cases with adenomatosis are focal with normal remainde r of pancreas and that focal and diffuse disease can be differentiated intr aoperatively, on the basis of increased beta-cell nuclear size found only i n the diffusely abnormal pancreas. We have examined pancreatic histology in a blinded controlled study of PHHI patients. Pancreatic tissue was obtaine d at autopsy from 60 normal subjects (age 17 weeks gestation to 76 years) a nd from surgical specimens of 31 PHHI patients. Sections from PHHI subjects (n = 294 blocks) and control sections were stained with hematoxylin and eo sin, insulin, glucagon, somatostatin, NSE, cytokeratin 19, and vimentin. Th ree sections from each PHHI patient were randomly chosen for further analys is. Age-matched control (n = 34) and PHHI sections (n = 66) were examined, with the identity of subjects concealed. A diagnosis of normal histology, a denomatosis, or diffuse nesidiodysplasia was recorded for each section. The presence of large beta-cell nuclei (>19 mu m), ductuloinsular complexes, a nd centroacinar cell proliferation was noted. Of a total of 65 subjects examined (34 control and 31 PHHI), 37 subjects we re identified as normal on both sections examined. All the control cases we re correctly identified as normal and none had large B-cell nuclei or centr oacinar cell proliferation. Of 31 PHHI patients, 28 were identified as abno rmal, either on the basis of abnormal architecture and/or abnormally large p-cell nuclei. Three patients were identified as normal in both sections. F ifteen of 31 patients had diffuse nesidiodysplasia only. Of 13 patients wit h areas of adenomatosis, 2 had resection of a nodule with adenomatosis pres ent in most of the tissue removed at surgery. Nine patients had a diagnosis of adenomatosis in one section and a diagnosis of diffuse nesidiodysplasia in the other sections from nonadjacent pancreas. Only 2 of 31 PHHI cases h ad adenomatosis on one section examined and normal pancreas on the other se ction examined. Large p-cell nuclei were variably found in PHHI sections. O nly 5 of 15 patients with diffuse nesidiodysplasia had large nuclei in both sections examined. Centroacinar cell proliferation was identified in 12 PH HI subjects, 6 with adenomatosis and diffuse nesidiodysplasia and 6 with di ffuse changes only. It was patchy in distribution within sections and prese nt in only one section in 7 of the 12 subjects. In summary, we have shown that a blinded observer could differentiate contr ol and PHHI pancreatic tissue. Only 2 of 31 patients (6%) had focal adenoma tosis with normal nonadjacent pancreas, the majority (24 of 31) had diffuse nesidiodysplasia affecting the remainder of their pancreas, with 38% (9 of 24) also having areas of adenomatosis. Large p-cell nuclei did not reliabl y identify those with diffuse disease in this study. There was evidence of significant ductal and centroacinar proliferation in 39% of PHHI cases, whi ch was not observed in any of the controls. We have shown that PHHI subject s have a spectrum of pancreatic histological abnormalities, from no abnorma lity to diffuse subtle changes to florid adenomatosis. Patients could not b e segregated into subtypes for different operative intervention despite the availability of full immunohistochemical staining.