Phosphorylation of pRb: mechanism for RB pathway inactivation in MYCN-amplified retinoblastoma.

A small, but unique subgroup of retinoblastoma has been identified with no detectable mutation in the retinoblastoma gene (RB1) and with high levels of MYCN gene amplification. This manuscript investigated alternate pathways of inactivating pRb, the encoded protein in these tumors. We analyzed the mutation status of the RB1 gene and MYCN copy number in a series of 245 unilateral retinoblastomas, and the phosphorylation status of pRb in a subset of five tumors using immunohistochemistry. There were 203 tumors with two mutations in RB1 (RB1(-/-) , 83%), 29 with one (RB1(+/-) , 12%) and 13 with no detectable mutations (RB1(+/+) , 5%). Eighteen tumors carried MYCN amplification between 29 and 110 copies: 12 had two (RB1(-/-) ) or one RB1 (RB1(+/-) ) mutations, while six had no mutations (RB1(+/+) ). Immunohistochemical staining of tumor sections with antibodies against pRb and phosphorylated Rb (ppRb) displayed high levels of pRb and ppRb in both RB1(+/+) and RB1(+/-) tumors with MYCN amplification compared to no expression of these proteins in a classic RB1(-/-) , MYCN-low tumor. These results establish that high MYCN amplification can be present in retinoblastoma with or without coding sequence mutations in the RB1 gene. The functional state of pRb is inferred to be inactive due to phosphorylation of pRb in the MYCN-amplified retinoblastoma without coding sequence mutations. This makes inactivation of RB1 by gene mutation or its protein product, pRb, by protein phosphorylation, a necessary condition for initiating retinoblastoma tumorigenesis, independent of MYCN amplification

Corneal Edema Associated With Degenerating Soemmering Ring Cataract: Clinical-Pathologic Correlation

Purpose: To report three patients with an uncommon delayed complication of cataract extraction: corneal edema following dispersion of calcific lens particles from a degenerating Soemmering ring cataract. Observations: We report three patients, 75-92 years old, presenting with corneal edema and dispersed, degenerated calcific lens material in the anterior chamber and vitreous 20-30 years after cataract surgery. In all patients, calcific particles studded the posterior surface of the cornea in a gravity-dependent distribution without apparent inflammation and were associated with localized corneal edema. In one patient, calcific particles were also associated with secondary open angle glaucoma. Deposits originated from the calcified Soemmering ring cataract. Histopathological examination demonstrated extracellular calcific deposits compatible with cataractous lens material on the posterior surface of stripped Descemet membrane of two patients. The deposits were associated with prominent localized loss of corneal endothelium and were not associated with inflammation. Morphologically similar acellular material was identified in the biopsied aqueous and vitreous fluid of one patient. Management included endothelial keratoplasty, anterior chamber lavage, pars plana vitrectomy, aspiration/removal of a portion of Soemmering ring cataract without intraocular lens implant explantation, and the removal of the entire capsular bag/implant complex. Cornea cleared and visual acuity improved in both patients who underwent endothelial keratoplasty. Persistent elevated intraocular pressure led to visual deterioration in one patient with secondary glaucoma. Conclusions and importance: Dispersion of calcific Soemmering ring cataract can occur decades following cataract surgery leading to corneal edema, secondary glaucoma, and vitreous opacities. Timely recognition of this phenomenon may prevent ocular morbidity, including corneal edema and glaucoma

Intratumoral Bacteria in Uveal Melanoma: A Case Report

Purpose Intratumoral bacteria and their potential application to cancer immunotherapy have been a topic of interest in recent studies. To our knowledge, bacteria in uveal melanoma have not been previously reported. Observations We describe a patient with a large choroidal melanoma, measuring 18 × 16 mm in basal dimension and 15 mm in ultrasonographic thickness, managed by plaque brachytherapy. At the time of plaque removal, a prophylactic scleral patch graft was placed to protect from anticipated scleral necrosis. Progressive ocular ischemia led to a blind and painful eye. The enucleated eye demonstrated an extensively necrotic and heavily pigmented mushroom-shaped regressed cilichoroidal mass deep to the scleral patch graft. Numerous Gram-positive cocci were noted within the regressed uveal melanoma and the adjacent sclera. Conclusions and Importance This case highlights the fact that regressed uveal melanomas can contain intra-tumoral bacteria

Unilateral Acute Iris Transillumination Syndrome With Glaucoma and Iris Pigment Epithelium Dispersion Simulating Iris Melanoma

Purpose To report a patient with a unilateral presentation of glaucoma, pain, and acute iris transillumination syndrome simulating iris melanoma. Observations A 53-year-old male presented with blurred vision and pain in his right eye several weeks following a respiratory sinus infection managed by oral azithromycin. Examination of the right eye was notable for elevated intraocular pressure of 46 mm Hg, an irregular mid-dilated pupil, and diffuse iris transillumination with pigmentary seeding on the iris surface, in the anterior chamber angle, and on the sclera, suspicious for diffuse iris melanoma with glaucoma and extrascleral extension. Ultrasound biomicroscopy (UBM) of the right eye revealed circumferential anterior chamber angle and trabecular meshwork involvement by an infiltrative process corresponding to the pigmented cells noted clinically, while the ciliary body was unremarkable. Following enucleation, histopathology showed extensive necrosis of the iris pigment epithelium, sphincter, and dilator muscles with melanophagic infiltration in the anterior chamber angle and episclera, mild chronic non-granulomatous iridocyclitis, and no evidence of a melanocytic neoplasm. Although immunohistochemical studies for herpes simplex virus (HSV) types 1 and 2, varicella-zoster virus, and cytomegalovirus were negative, qualitative real-time polymerase chain reaction on paraffin-embedded tissue detected HSV-1 DNA. The combined clinical, pathologic, and molecular findings were compatible with unilateral acute iris transillumination syndrome, likely HSV-1 associated. Conclusion and Importance Unilateral acute iris transillumination syndrome with diffuse iris pigment epithelial loss can simulate iris melanoma. Prompt herpes viral studies may be informative

Ocular Manifestations of Rosai-Dorfman Disease

History of Rosai-Dorfman Disease In 1969, Dr. Juan Rosai and Dr. Ronald F. Dorfman reported four cases of an entity that previously had puzzled pathologists and clinicians. The four cases had failed to fit under any diagnosis, but shared a few common characteristics. Each patient presented with painless, massive lymphadenopathy, most commonly of the cervical lymph nodes1. Other locations included the inguinal, intra-parotid, and axillary lymph nodes. The patients all presented with fever and leukocytosis1. The differential diagnosis included malignant lymphoma, malignant histiocytosis, reticuloendotheliosis, and chronic inflammation. However, the histopathological characteristics of the cases did not fit the classical characteristics of these diagnoses. Based on the pathologic findings, Dr. Rosai and Dr. Dorfman created a new entity, which they called “sinus histiocytosis with massive lymphadenopathy (SHML).”

Melanocytoma of the optic disk: A review.

Melanocytoma is a deeply pigmented variant of melanocytic nevus that classically occurs in the optic disk, sometimes with contiguous involvement of the adjacent retina or choroid. Historically, this tumor was often confused with malignant melanoma both clinically and histopathologically. Today, however, it is generally recognized by its typical clinical features that differ from most melanomas and erroneous enucleation is rarely done. Histopathologically, melanocytoma is composed of intensely pigmented round to oval nevus cells with benign features. Although traditionally believed to be a relatively stationary lesion, it is now known to exhibit minor enlargement in 10--15% of cases and can cause minor visual loss by a variety of mechanisms. In rare instance, it can induce severe visual loss due to spontaneous necrosis of the lesion or compressive optic neuropathy. More importantly, it can exhibit malignant transformation into melanoma in 1--2% of cases. Ophthalmologists should be familiar with melanocytoma of the optic disk and affected patients should be followed periodically

Corneal edema associated with degenerating Soemmering ring cataract: Clinical-pathologic correlation

Purpose: To report three patients with an uncommon delayed complication of cataract extraction: corneal edema following dispersion of calcific lens particles from a degenerating Soemmering ring cataract. Observations: We report three patients, 75–92 years old, presenting with corneal edema and dispersed, degenerated calcific lens material in the anterior chamber and vitreous 20–30 years after cataract surgery. In all patients, calcific particles studded the posterior surface of the cornea in a gravity-dependent distribution without apparent inflammation and were associated with localized corneal edema. In one patient, calcific particles were also associated with secondary open angle glaucoma. Deposits originated from the calcified Soemmering ring cataract. Histopathological examination demonstrated extracellular calcific deposits compatible with cataractous lens material on the posterior surface of stripped Descemet membrane of two patients. The deposits were associated with prominent localized loss of corneal endothelium and were not associated with inflammation. Morphologically similar acellular material was identified in the biopsied aqueous and vitreous fluid of one patient. Management included endothelial keratoplasty, anterior chamber lavage, pars plana vitrectomy, aspiration/removal of a portion of Soemmering ring cataract without intraocular lens implant explantation, and the removal of the entire capsular bag/implant complex. Cornea cleared and visual acuity improved in both patients who underwent endothelial keratoplasty. Persistent elevated intraocular pressure led to visual deterioration in one patient with secondary glaucoma. Conclusions and Importance: Dispersion of calcific Soemmering ring cataract can occur decades following cataract surgery leading to corneal edema, secondary glaucoma, and vitreous opacities. Timely recognition of this phenomenon may prevent ocular morbidity, including corneal edema and glaucoma

Ocular pneumoplethysmography can help in the diagnosis of giant-cell arteritis.

We compared the results of ocular pneumoplethysmography in nine patients who had a temporal artery biopsy (TAB) diagnostic of giant-cell arteritis with results of ocular pneumoplethysmography in nine patients with normal TAB results and 112 patients with anterior ischemic optic neuropathy or central retinal artery occlusion assumed to be nonarteritic. The mean +/- SD ocular pulse amplitude with ocular pneumoplethysmography was 3.9 +/- 1.8 mm in the group with abnormal TAB results and 10.6 +/- 4.0 mm in the group with normal TAB results. Every patient with abnormal TAB results had an average calculated ocular blood flow less than 0.60 mL/min, while only one patient with normal TAB results fell in this range. The average calculated ocular blood flow had a sensitivity of 100% and a specificity of 93.4% in the diagnosis of giant-cell arteritis, with a diagnostic accuracy of 93.9%. These results rival the diagnostic accuracy of the erythrocyte sedimentation rate and TAB results

Necrotic Orbital Melanoma Arising de Novo.

A 76-year-old man with compressive optic neuropathy secondary to a retrobulbar mass was managed by orbitotomy and removal of the mass. The lesion proved histopathologically to be an unusual orbital melanoma with massive central necrosis. There was no histopathological evidence of congenital melanocytosis. Dermatological and systemic evaluation before and after orbital surgery revealed no evidence of primary melanoma elsewhere. The patient developed hepatic metastasis 2 years after excision of the orbital tumour. It appears that the melanoma was a primary orbital tumour and not a metastatic melanoma from an occult primary lesion