Ocular adnexal diffuse large B-cell lymphoma: local disease correlates with better outcomes.

PURPOSE: To describe the clinical, immunohistochemical and prognostic features, as well as outcomes of a large series of patients with orbital and periorbital diffuse large B-cell lymphoma (DLBCL). DESIGN: This study is a multicentre, retrospective non-comparative consecutive case series. METHODS: The setting for this study was institutional. A total of 37 consecutive patients identified from the institutions' databases with periorbital and orbital DLBCL were enrolled in the study. A retrospective chart review was used for observation. The main outcome measures were patient demographics, clinical features, imaging, immunohistochemical and histopathological data, treatments administered, and survival. RESULTS: A total of 20 out of 37 cases (54.1%) represented localised periorbital disease (group L), 11 of 37 (29.7%) had systemic disease at presentation with periorbital disease (group S1), and 6 of 37 (16.2%) had previous history of systemic lymphoma (group S2). In all, 28 out of 30 (93.3%) patients were CD20+, 5 of 25 (20%) were CD3+, and 11 of 11 (100%) were CD79a+ (varying denominators reflect the different numbers of patients tested). A total of 25 out of 32 patients (78.1%) received chemotherapy, 14 (43.8%) received rituxmab plus chemotherapy, and 19 (59.3%) received radiotherapy. Nine deaths occurred, one in group L (not lymphoma related), six in group S1, and two in group S2. Five-year Kaplan-Meier survival estimates were 55.9% for all cases, 90.9% for group L, 36.0% for group S1, and 0% for group S2. One-year progression-free survival estimates in groups S1 and S2 combined were 58.3% for patients treated with rituximab and 28.6% for those who were not. CONCLUSIONS: To our knowledge, this report represents the largest series of patients with periorbital and orbital DLBCL in the literature. The difference in survival between groups L, S1 and S2 was striking, reflecting the grave prognosis of systemic DLBCL, but conversely the relatively optimistic outlook for patients with localised disease. Rituximab plus chemotherapy may be associated with increased survival.

Long-term follow-up of drusen-like lesions in patients with type II mesangiocapillary glomerulonephritis.

BACKGROUND: Drusen-like lesions beneath the retina in patients with partial lipodystrophy and type II mesangiocapillary glomerulonephritis (MCGN) were first reported in 1989. This study reports the long-term follow-up of this original cohort of patients more than 10 years later. METHODS: Three patients had undergone renal transplantation. Retinopathy was graded semiquantitatively using an international classification and grading system. Progression was assessed by comparing the visual acuities and the colour, red-free and fluorescein angiographic photographs at baseline and review. RESULTS: The visual acuity in all four patients was unchanged, as were the bilateral drusen-like lesions. The retinal pigment hypertrophy at the posterior pole of two of the patients was also unchanged. There were no signs of choroidal neovascularisation or central serous retinopathy in any patient. There was no progression of retinopathy over 10 years in any patient. CONCLUSION: This study suggests that in patients with type II MCGN, (a) factors other than drusen may contribute to choroidal neovascularisation and (b) renal transplantation does not appear to increase the risk of progression of retinopathy.

Abnormal prion protein in the retina of the most commonly occurring subtype of sporadic Creutzfeldt-Jakob disease.

BACKGROUND: Involvement of the eye has been reported in patients with variant Creutzfeldt-Jakob disease (vCJD), but there is disagreement on whether retinal involvement occurs in sporadic Creutzfeldt-Jakob disease (sCJD). METHODS: Western blotting, paraffin embedded tissue blotting, and immunohistochemistry were used to test whether the abnormal form of the prion protein (PrPSc) accumulates to detectable levels in the eye in a case of the most common subtype of sCJD (MM1). RESULTS: Low levels of PrPSc were detectable in the retina, localised to the plexiform layers of the central retina. PrPSc was not detectable in other ocular tissues. CONCLUSIONS: The abnormal form of the prion protein is present in the retina in the most common sCJD subtype (MM1), albeit at levels lower than those found previously in vCJD and in sCJD of the VV2 subtype.

The 'unified hypothesis' of Geddes et al. is not supported by the data.

Inflicted head injury to the developing brain frequently results in serious disability. The pathogenesis of the neuraxial and ocular findings in infants believed to have suffered inflicted head injury remains the subject of considerable debate. Recent neuropathology studies of fatal cases of inflicted head injury and of a foetal/perinatal non-traumatic model have led to the proposal that there is a 'unified hypothesis', the essential feature of which is hypoxic brain swelling secondary to cervicomedullary injury. It has been suggested that less than violent forces may be involved and even that some cases may not be due to trauma at all. The purpose of this paper is to provide a critical review of the data upon which these suppositions are based on a background of what is already known. It is submitted that there are serious flaws in the methodology; the conclusions reached cannot logically be drawn from the data; and the 'unified hypothesis' is not supported by the evidence. On the basis of the data presented, it is also difficult to sustain the secondary hypothesis purporting to describe a minority cohort with 'infantile encephalopathy with subdural and retinal bleeding' of non-traumatic causation.

Immunolocalisation of opticin in the human eye.

AIM: To localise the recently discovered glycoprotein opticin in the adult human eye. METHODS: Polyclonal rabbit antisera were raised against two different opticin peptides. Isolated human vitreous collagen fibrils were extracted with 8 M urea and the extract analysed by SDS-PAGE and western blotting. Paraffin embedded sections from two normal eyes were subjected to immunohistochemical analysis. RESULTS: Western blot analysis of the vitreous collagen fibril extract specifically identified opticin as a 45-50 kDa component that migrated as a doublet. Opticin was especially immunolocalised to the vitreous humour where labelling was most intense in the basal and cortical vitreous gel and less intense in the central vitreous. In addition, specific staining was observed along the surfaces of adjacent basement membranes including the internal limiting membrane (ILM) and posterior capsule of the lens. In one eye, labelling was also observed on the anterior lens capsule, but no other ocular tissues were specifically labelled. A type XVIII collagen/endostatin antibody labelled several ocular tissues including the ILM and basal vitreous gel. CONCLUSION: The immunolocalisation of opticin was confined to the vitreous humour, ILM, and lens capsule. In situ hybridisation studies have previously demonstrated opticin expression by the posterior non-pigmented ciliary epithelium. Thus, the immunolocalisation data support the proposition that the non-pigmented ciliary epithelium secretes opticin into the vitreous cavity where it associates with vitreous collagen and adjacent basement membranes. The staining along the ILM suggests a role for opticin in vitreoretinal adhesion and the co-localisation of opticin with type XVIII collagen/endostatin at the ILM raises the possibility that interactions between these two molecules might contribute to vitreoretinal adhesion.

Missense mutations in COL8A2, the gene encoding the alpha2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy.

Corneal clarity is maintained by its endothelium, which functions abnormally in the endothelial dystrophies, leading to corneal opacification. This group of conditions includes Fuchs' endothelial dystrophy of the cornea (FECD), one of the commonest indications for corneal transplantation performed in developed countries, posterior polymorphous dystrophy (PPCD) and the congenital hereditary endothelial dystrophies (CHED). A genome-wide search of a three-generation family with early-onset FECD demonstrated significant linkage with D1S2830 (Z(max) = 3.72, theta = 0.0). Refinement of the critical region defined a 6-7 cM interval of chromosome 1p34.3-p32 within which lies the COL8A2 gene. This encodes the 703 amino acid alpha2 chain of type VIII collagen, a short-chain collagen which is a component of endothelial basement membranes and which represented a strong candidate gene. Analysis of its coding sequence defined a missense mutation (gln455lys) within the triple helical domain of the protein in this family. Mutation analysis in patients with FECD and PPCD demonstrated further missense substitutions in familial and sporadic cases of FECD as well as in a single family with PPCD. This is the first description of the molecular basis of any of the corneal endothelial dystrophies or of mutations in type VIII collagen in association with human disease. This suggests that the underlying pathogenesis of FECD and PPCD may be related to disturbance of the role of type VIII collagen in influencing the terminal differentiation of the neural crest derived corneal endothelial cell.

Ultrastructural morphology and expression of proteoglycans, betaig-h3, tenascin-C, fibrillin-1, and fibronectin in bullous keratopathy.

AIMS: To investigate the ultrastructural localisation of proteoglycans (PG), betaig-h3 (keratoepithelin), tenascin-C (TN-C)), fibrillin, and fibronectin in bullous keratopathy (BK) corneas. METHODS: Five corneas from cases of pseudophakic bullous keratopathy (BK) were examined by electron microscopy. PG were demonstrated using cuprolinic blue, and the proteins betaig-h3, TN-C, fibrillin, and fibronectin were immunolocalised with rabbit anti-betaig-h3, mouse anti-TN-C (BC10 and TN2), mouse anti-fibrillin-1 (MAB2502), mouse anti-fibrillin (MAB1919), and rabbit anti-fibronectin by using a standard immunogold technique. RESULTS: Epithelial cells contained numerous vacuoles. Epithelial folds and large, electron lucent subepithelial bullae were present. Basal lamina was thickened and traversed by disrupted anchoring filaments. In the stroma, interfibrillar collagen spacing was increased and abnormally large PG were present. Descemet's membrane (DM) contained lucent spaces in which there were small filaments. Keratocyte and endothelial cells contained melanin granules. A posterior collagenous layer (PCL) contained numerous microfilaments and wide spacing collagen fibres with a periodicity of 100 nm. Large quantities of abnormal PG were observed at the endothelial face of the PCL. Very strong labelling with betaig-h3 antibody was observed in the basement membrane, Bowman's layer, stroma, DM, and PCL, but not in keratocytes and endothelial cells. Strong labelling with BC10 and TN2 was seen below the epithelium, in electron lucent spaces where the hemidesmosomes were absent, in the fibrotic pannus, in parts of Bowman's layer, the stroma, and Descemet's membrane. Labelling with BC10 was stronger and more evenly distributed than with TN2. Fibrillin-1 (MAB2502) and fibrillin (MAB1919) labelling was similar to TN-C labelling. Fibrillin (MAB1919) labelling was stronger than fibrillin-1 (MAB2502) labelling. CONCLUSIONS: Immunoelectron microscopy showed precise labelling of proteins at both the cellular and the subcellular level. Expression of proteins betaig-h3, TN-C, fibrillin, and fibronectin was highly increased compared with normal cornea. In the oedematous stroma, increased collagen fibril separation may facilitate a wider distribution of some soluble proteins, such as betaig-h3, throughout stroma. The modified expression of the proteins studied in these cases of BK may be regarded as part of an injury response.

Developmental changes in patterns of expression of tenascin-C variants in the human cornea.

PURPOSE: To study patterns of expression of alternatively spliced tenascin-C (TN-C) variants believed to mediate cellular activities in human corneal development. METHODS: Serial sections of preterm, neonatal, child, and adult globes with normal anterior segments were labeled with monoclonal antibodies to TN-C. The antibodies included BC-4 and BC-8, which recognize epitopes in conserved domains of TN-C and can thus detect all TN-C variants, and BC-2, alpha-A2, alpha-A3, alpha-IIIB, TN11, and alpha-D, which bind to epitopes in alternatively spliced fibronectin type III repeats of TN-C. Bound antibodies were localized and visualized using an avidin-biotin complex-alkaline phosphatase technique. RESULTS: BC-4 and BC-8 showed similar patterns of staining, widely observed in preterm corneas, less so in neonatal corneas, and restricted to the limbus in the child and adult. BC-2, alpha-A2, alpha-A3, alpha-IIIB, TN11, and alpha-D staining was largely localized in corneal epithelium (preterm and neonatal), limbal epithelium, mast cells, and matrix surrounding limbal vessels (preterm, neonatal, child, and adult). CONCLUSIONS: TN-C may play a role in corneal development and in growth and differentiation of stem cells because it is widely expressed in the preterm cornea, less so in the neonate, and is restricted to the limbus in the child and adult. The differential patterns of expression of TN-C variants in normal corneas (preterm and neonatal), and in the limbus (preterm, neonatal, child, and adult), suggest specific roles played by each variant, and cell type-specific expression of the different variants.