Edmund Cheesman

Enhanced Islet Cell Nucleomegaly Defines Diffuse Congenital Hyperinsulinism in Infancy but Not Other Forms of the Disease.

Objectives: To quantify islet cell nucleomegaly in controls and tissues obtained from patients with congenital hyperinsulinism in infancy (CHI) and to examine the association of nucleomegaly with proliferation. Methods: High-content analysis of histologic sections and serial block-face scanning electron microscopy were used to quantify nucleomegaly. Results: Enlarged islet cell nuclear areas were 4.3-fold larger than unaffected nuclei, and the mean nuclear volume increased to approximately threefold. Nucleomegaly was a normal feature of pediatric islets and detected in the normal regions of the pancreas from patients with focal CHI. The incidence of nucleomegaly was highest in diffuse CHI (CHI-D), with more than 45% of islets containing two or more affected cells. While in CHI-D nucleomegaly was negatively correlated with cell proliferation, in all other cases, there was a positive correlation. Conclusions: Increased incidence of nucleomegaly is pathognomonic for CHI-D, but these cells are nonproliferative, suggesting a novel role in the pathobiology of this condition.

Atypical Forms of Congenital Hyperinsulinism in Infancy Are Associated With Mosaic Patterns of Immature Islet Cells

Objectives: We aimed to characterize mosaic populations of pancreatic islet cells from patients with atypical congenital hyperinsulinism in infancy (CHI‐A) and the expression profile of NKX2.2, a key transcription factor expressed in &bgr;‐cells but suppressed in &dgr;‐cells in the mature pancreas. Patients/Methods: Tissue was isolated from three patients with CHI‐A following subtotal pancreatectomy. CHI‐A was diagnosed on the basis of islet mosaicism and the absence of histopathological hallmarks of focal and diffuse CHI (CHI‐D). Immunohistochemistry was used to identify and quantify the proportions of insulin‐secreting &bgr;‐cells and somatostatin‐secreting &dgr;‐cells in atypical islets, and results were compared with CHI‐D (n = 3) and age‐matched control tissues (n = 3). Results: In CHI‐A tissue, islets had a heterogeneous profile. In resting/quiescent islets, identified by a condensed cytoplasm and nuclear crowding, &bgr;‐cells were reduced to <50% of the total cell numbers in n = 65/70 islets, whereas &dgr;‐cell numbers were increased with 85% of islets (n = 49/57) containing >20% &dgr;‐cells. In comparison, all islets in control tissue (n = 72) and 99% of CHI‐D islets (n = 72) were composed of >50% &bgr;‐cells, and >20% &dgr;‐cells were found only in 12% of CHI‐D (n = 8/66) and 5% of control islets (n = 3/60). Active islets in CHI‐A tissue contained proportions of &bgr;‐cells and &dgr;‐cells similar to those of control and CHI‐D islets. Finally, when compared with active islets, quiescent islets had a twofold higher prevalence of somatostatin/NKX2.2+ coexpressed cells. Conclusions: Marked increases in NKX2.2 expression combined with increased numbers of &dgr;‐cells strongly imply that an immature &dgr;‐cell profile contributed to the pathobiology of CHI‐A.

Clinical Diversity in Focal Congenital Hyperinsulinism in Infancy Correlates With Histological Heterogeneity of Islet Cell Lesions

Background: Congenital Hyperinsulinism (CHI) is an important cause of severe and persistent hypoglycaemia in infancy and childhood. The focal form (CHI-F) of CHI can be potentially cured by pancreatic lesionectomy. While diagnostic characteristics of CHI-F pancreatic histopathology are well-recognized, correlation with clinical phenotype has not been established. Aims: We aimed to correlate the diversity in clinical profiles of patients with islet cell organization in CHI-F pancreatic tissue. Methods: Clinical datasets were obtained from 25 patients with CHI-F due to ABCC8/KCNJ11 mutations. 18F-DOPA PET-CT was used to localize focal lesions prior to surgery. Immunohistochemistry was used to support protein expression studies. Results: In 28% (n = 7) of patient tissues focal lesions were amorphous and projected into adjoining normal pancreatic tissue without clear delineation from normal tissue. In these cases, severe hypoglycaemia was detected within, on average, 2.8 ± 0.8 (range 1–7) days following birth. By contrast, in 72% (n = 18) of tissues focal lesions were encapsulated within a defined matrix capsule. In this group, the onset of severe hypoglycaemia was generally delayed; on average 46.6 ± 14.3 (range 1–180) days following birth. For patients with encapsulated lesions and later-onset hypoglycaemia, we found that surgical procedures were curative and less complex. Conclusion: CHI-F is associated with heterogeneity in the organization of focal lesions, which correlates well with clinical presentation and surgical outcomes.

Successful Curative Therapy With Rituximab and Allogeneic Haematopoietic Stem Cell Transplantation for MALT Lymphoma Associated With STK4-Mutated CD4+ Lymphocytopenia

Idiopathic CD4+ lymphocytopenia and extranodal marginal zone lymphoma of mucosa‐associated lymphoid tissue (MALT lymphoma) are rare diseases in children. We report the first case of a child with STK4‐mutated CD4+ lymphocytopenia who developed Epstein–Barr virus associated MALT lymphoma arising in the salivary gland. The child achieved complete remission with rituximab, and her immunodeficiency was cured by haematopoietic stem cell transplantation. The child remained well 24 months post transplantation.

Primary pleural precursor B‐Cell lymphoblastic lymphoma

Intrathoracic lymphoblastic lymphoma (LBL) is classically of T‐cell lineage, but these cases of pleural B‐cell LBL suggest that this is not always the case. Despite the clinical challenges involved every attempt should be made to secure a biopsy and histological diagnosis, as we move into an era of lineage‐directed therapies.

Islet cell proliferation is inappropriately maintained in the pancreas of children with congenital hyperinsulinism in infancy

o s te r T e m p la te ro m w w w .m a n c h e s te .a c .u k /p h o to g ra p h ic s Age (months) Congenital Hyperinsulinism of Infancy (CHI) is a potentially lethal condition of profound hypoglycaemia caused by unregulated insulin release in the neonatal period and early infancy. CHI mainly arises due to mutations in ATPsensitive K-channel genes (ABCC8 and KCNJ11) which can manifest in all islets cells – diffuse CHI (CHI-D), or can be localised to a focal lesion, focal CHI (CHI-F). Increased rates of cell proliferation have been reported in the CHI-D and this may be liked to ABCC8 and KCNJ11 defects. Here, we examined the proliferative index (PI) of islet cells in CHI-D patients and compared this with focal CHI (CHI-F), which is caused by loss of cell cycle repression in β-cells specifically within the focal domain. We also examined islet PI in patient tissues with severe CHI unrelated to defects in ABCC8 and KCNJ11, atypical CHI (CHI-A). Background