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One hundred well-documented cases of uveal melanoma accessioned at the Armed Forces Institute of Pathology before 1970 were reviewed and reclassified to identify changes made in the Callender classification. We compared the new classification with the original classification to determine the effect of the changes on the prediction of outcome for the patient after enucleation. Staff pathologists had originally classified 52 of the 100 cases as spindle-cell type melanoma. Only 31 of the 100 cases were reclassified as spindle-cell types (two spindle-cell nevi and 29 spindle-cell melanomas). Tumors classified as mixed-cell type were further subdivided into groups based on the percentage and size of the epithelioid cells. Tumors formerly classified as spindle-cell type that contained small or rare epithelioid cells were reclassified as mixed-cell type. This improved the prediction of outcome for the patient. We found that nucleolar size and pleomorphism are important variables that should be considered in the classification of uveal melanomas., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To describe the clinical and histopathologic finding of very limited ophthalmic Wegener granulomatosis (WG)., Methods: Thirteen patients with scleritis, orbitopathy, episcleritis, and panuveitis were studied. They presented without evidence of lung or kidney disease, though eight had sinus involvement. We reviewed the biopsies for histopathologic findings consistent with WG, and tested for antineutrophil cytoplasmic antibodies antineutrophil cytoplasmic antibody (ANCA)., Results: WG was suggested by granulomatous foci, collagen necrosis, neutrophils/nuclear dust, plasma cells and infiltrating eosinophils. Granular degeneration of the interstitial collagen; mummification of the collagen with disappearance of fibroblastic nuclei; and a polymorphous infiltrate exhibiting plasma cells, lymphocytes, neutrophils, and eosinophils within the epithelioid granulomas should suggest the diagnosis. ANCA test results supported the diagnosis of WG in all cases., Conclusion: The described histologic characteristics are highly suggestive of WG. These findings along with clinical or laboratory findings, allow the diagnosis of very limited ophthalmic WG in the absence of systemic involvement.

Purpose: To report a case of metastatic malignant amelanotic melanoma to the skin from a patient diagnosed with bilateral diffuse uveal melanocytic proliferation (BDUMP). This dermatological finding is a unique phenomenon associated with BDUMP., Design: Retrospective case report., Methods: We studied the case of a 66-year-old Caucasian woman with gradual onset of blurred vision in her right eye followed by her left eye. She had previously been diagnosed with ovarian carcinoma, and findings of funduscopic examinations were consistent with BDUMP. Metastatic examination revealed no evidence of liver involvement. Clinical and histopathological examinations of both enucleated eyes were consistent with BDUMP., Results: The hematoxylin and eosin, S-100, and HMB-45 stains were consistent with metastatic malignant amelanotic melanoma to the skin., Conclusions: Although believed to have a low potential for metastasis, patients should be monitored and evaluated regularly to detect any new lesions not associated with their primary inciting carcinoma.

Comparative genomic hybridization (CGH) was used to elucidate DNA sequence copy number imbalances in 100 archival formalin-fixed, paraffin-embedded (FFPE) uveal melanoma cases. Of these 100 cases, 51 were from patients who survived >or=9 years post diagnosis without evidence of metastasis; the remaining 49 patients died from metastatic disease. Viable probe was generated from 82 of the 100 cases, allowing correlation of CGH findings with survival for all but 18 cases. Copy number imbalances revealed by CGH were tested for univariate prognostic significance. The most powerful predictor of a poor prognosis was gain of 18q11.2, which was subsequently compared with other significant chromosomal regions, as well as histologic and clinical factors, in a multivariate analysis. There was also evidence of differential X chromosome involvement in the survival correlations between male and female cases, which may be of significance to prognosis. This large-scale CGH analysis of archival material is intended to direct further gene-specific study of malignancy in uveal melanoma.

Uveal melanoma is the most common intraocular tumor in adults and often results in unilateral blindness and/or death. Previous cytogenetic characterizations of this tumor consistently revealed chromosomal abnormalities involving chromosomes 3, 6, and 8; reports of other abnormalities vary in frequency. We defined cytogenetic abnormalities of this tumor using complementary in situ hybridization techniques on 10 uveal melanoma cell lines. Synthesis of comparative genomic hybridization (CGH) and spectral karyotyping (SKY) results revealed that chromosomal rearrangement is involved in DNA sequence copy number abnormalities throughout the genome, but monosomy 3 was not found. Monosomy 3 is thought to be a significant prognostic indicator, so its absence was investigated further. Fluorescence in situ hybridization (FISH) for chromosome 3 revealed approximately 1 centromere signal per cell, but probes for 3p and 3q revealed multiple telomere signals per cell, suggesting chromosomal rearrangement without whole-chromosome loss. Based on combined CGH, SKY, and FISH data, we propose that chromosome 3 is more frequently involved in chromosomal rearrangements than whole-chromosome loss in uveal melanoma. Future approaches should be designed to confirm and enhance the resolution of regions of imbalance in primary tumors. Once identified, conserved chromosomal alterations that contribute to uveal melanoma may reveal the underlying aspects of uveal melanoma onset, metastasis and resistance to current treatment modalities.

Uveal melanomas may arise in the iris, ciliary body or choroid. Choroidal melanomas are the most common and usually display a discoid, collar-button or mushroom-shaped growth pattern. Uveal melanomas are composed of spindle and epithelioid cells and are classified histopathologically as either spindle-cell-type or mixed-cell-type tumours. The most important factors predicting clinical behaviour and underlying biology are cell type, cytomorphometric features, largest tumour dimension, scleral invasion and mitotic figures. Other valuable prognostic factors are tumour-infiltrating lymphocytes and macrophages, and the presence of vascular loops.

Background: The expression of cyclooxygenase-2 (COX-2), an inducible prostaglandin (PG) synthase, has been investigated in various human malignant diseases, such as cutaneous melanoma. We investigated the expression of COX-2 in uveal melanoma and related the findings to prognostic factors., Methods: In 40 cases of uveal melanoma, immunostaining for COX-2 was done. COX-2 expression was related to histopathological prognostic markers, such as cell type, the presence of lymphocytic infiltration and vascular closed loops in the tumour, and cytomorphometry results., Results: COX-2 expression was found in 58% of the cases, and it correlated with markers of poor prognosis, such as epithelioid cell type and the presence of lymphocytic infiltration and vascular closed loops. The uveal melanomas expressing COX-2 had larger nuclei, as determined by cytomorphometry., Interpretation: Whereas epithelioid tumours carry a worse prognosis than spindle cell tumours, until now it has not been possible to give a strong indication of prognosis in mixed-cell tumours. This study showed that mixed-cell tumours, representing the majority of uveal melanomas, may be further subclassified according to COX-2 expression, which serves as a marker of poor prognosis. The role of COX-2 in uveal melanoma should be further elucidated, and the use of COX-2 inhibitors warrants investigation as adjuvant treatment for this life-threatening malignant disease.

Objective: To study the clinicopathologic features of the histiocytoid variant of adenocarcinoma of the eccrine sweat gland of the eye and orbit., Design: Retrospective case series., Participants: Five patients undergoing orbital and eyelid biopsy as a diagnostic procedure., Methods: The authors examined the clinical histories and pathologic findings of five patients with eccrine adenocarcinoma of the eyelid with orbital invasion., Main Outcome Measures: Clinical and histopathologic examinations, including routine histopathology, immunohistochemistry, and electron microscopy studies., Results: The tumors presented as insidious, diffusely infiltrative, firm cutaneous masses in the periocular area that later infiltrated the orbit. Histopathologic examination revealed that the tumors infiltrated the dermis and were composed of cells with a histiocytic to signet ring appearance. Tumor cells exhibited intracellular mucin production. Immunohistochemical stains were positive in tumor cells for low and high molecular weight cytokeratins, carcinoembryonic antigen, and epithelial membrane antigen. Electron microscopic examination showed lumen formation and intracytoplasmic mucin in tumor cells., Conclusions: The histiocytoid variant of adenocarcinoma of the eccrine sweat gland of the eyelid may present as an insidious tumor and diffusely invade the orbit. These cases may be confused with metastatic adenocarcinoma.

Objective: A clinicopathologic study to evaluate the histopathologic features associated with Acanthamoeba keratitis and chorioretinitis., Design: Retrospective observational case report., Methods: On the basis of the clinical history and histologic appearance, the enucleated eye and native corneal button were examined using hematoxylin-eosin stains and special periodic acid-Schiff and Gomori methenamine silver stains., Results: Results of histologic examination of the cornea and retina showed numerous Acanthamoeba cysts in the cornea stromal layers, the necrotic retina, and preretinal and subretinal spaces., Conclusions: To the authors' knowledge, this is the first proven histologic case of ipsilateral chorioretinitis secondary to primary chronic keratitis caused by Acanthamoeba. The patient had a 30-month history of recurrent keratitis requiring four penetrating keratoplasties. We believe the chorioretinitis resulted from direct spread of the corneal amebic infection. The spread of the Acanthamoeba may have been facilitated by a combined keratoplasty, extracapsular cataract extraction, and intraocular lens insertion. In both specimens, the native corneal button and the enucleated eye with a corneal transplant, the general pathologists overlooked the presence of Acanthamoeba.

Purpose: To report the histopathologic and immunohistochemical findings from the iridectomy specimen of a patient with acquired unilateral iris heterochromia due to latanoprost., Patient and Methods: A 45-year-old woman with open-angle glaucoma and unilateral iris heterochromia was evaluated for uncontrolled intraocular pressure increase. Subsequently, the patient underwent trabeculectomy with mitomycin C and an iridectomy specimen was obtained for analysis., Results: The histopathologic analysis of the iridectomy specimen did not reveal any nuclear atypia, nuclear crowding, or mitotic figures. Immunohistochemical studies showed that the iris melanocytes were negative for HMB45 and S-100, and weakly positive for Melan A., Conclusion: Latanoprost-associated iris color change may exhibit a diffuse, uniform, dark velvet-brown appearance, thereby simulating diffuse iris melanoma. Histopathologic and immunohistochemical analysis confirmed the benign characteristics of the affected iris melanocytes.

Purpose: To evaluate whether ocular changes indicating an increased exposure to UV irradiation are associated with the development of age-related macular degeneration (ARMD)., Methods: Using histology, we have investigated a possible association of ocular changes that might be attributed to actinic damage, namely pinguecula and scleral plaque, with findings of both atrophic and disciform ARMD. A total of 74 eyes, could be used for evaluation., Results: Features of ARMD were present in 36 eyes (11 with disciform degeneration and 25 with an atrophic form). A pinguecula was identified in 36 eyes (small in 22 eyes, large in 14 eyes), and a scleral plaque was seen in 5 eyes. While scleral plaque showed an association with ARMD, there was no significant association between pinguecula and ARMD., Conclusions: Our results support the concept of solar radiation having an effect on the development of ARMD but also indicate that it is a multifactorial disease.

Purpose: To summarize and compare the various histologic methodologies for using nucleoli to assess the malignant potential of uveal melanoma., Methods: This was an observational series of 100 samples of uveal melanoma in which histologic sections were studied. The cases were selected so that approximately half (n = 49) of the tumors were from patients who had died of metastatic malignant melanoma. The 51 remaining tumors were from patients who had survived at least 9 years without development of metastasis. Central sections from the uveal melanomas were stained using the colloidal silver nitrate stain for nucleolar organizing regions (AgNOR). These were compared with an adjacent hematoxylin and eosin (H&E)-stained section. A light microscope with a micrometer inset into the eyepiece (x10) was used at a final magnification of x1000 under oil immersion to measure the length of the nucleolus along the longest axis and the width perpendicular to that axis. From at least twenty cells selected from random fields throughout the tumor, the mean of the 10 longest and widest nucleoli (MLN) was calculated. Seven samples had to be discarded because the nucleoli were unmeasurable., Results: T-tests and Cox proportional hazard regression analysis indicated that the MLN of nucleolar length as measured on AgNOR-stained slides was as significant as cell type but was more significant than other histopathologic prognosticating variables measured and evaluated in this study. These prognosticators included tumor size, calculated as the largest tumor dimension; MLN width; and MLN length, as measured on H&E-stained sections., Conclusions: It has previously been demonstrated that AgNOR-stained nucleoli, unlike H&E-stained nucleoli, can be captured and measured by an automated image analyzer with prognostically significant results. This new method of simple oil-immersion measurements of the longest AgNOR-stained nucleoli length in microscopic sections of uveal melanoma provides an inexpensive and highly significant method for predicting outcome in patients with uveal melanoma. Because of the high contrast with the background, the silver-stained nucleoli clearly define the nucleolar boundaries, rendering them readily discernible and allowing greater ease and speed of measurement when compared with H&E-stained nucleoli. The method of random sampling that was used was comparable with linear sampling in predicting outcome. Highly necrotic tumors, however, had to be excluded from the study because of loss of nucleolar morphology.

Purpose: To determine if moderate numbers of low fluence, 193-nm excimer laser pulses modify or damage the corneal stroma., Methods: The corneal epithelium of fresh bovine eyes was scraped off and the exposed stroma was irradiated with 200 low fluence laser pulses from an argon fluoride excimer laser. This process was performed on five eyes each at two laser fluences, 10 mJ/cm2 and 30 mJ/cm2. The ten irradiated and three control (unirradiated) corneas were sectioned and studied by electron microscopy. The maximum and minimum thickness of the anterior layer of randomly oriented collagen fibers was measured using electron microscopy., Results: The mean maximum thickness of the anterior randomly oriented layer of collagen was 1.23 +/- 0.45 microm in the control corneas, 0.67 +/- 0.32 microm in the corneas irradiated at 10 mJ/cm2, and 0.10 +/- 0.12 microm in the corneas irradiated at 30 mJ/cm2. The mean thickness of corneal stroma removed was 0.7 microm at a fluence of 10 mJ/cm2 and 1.1 microm at a fluence of 30 mJ/cm2. A thin, electron-dense pseudomembrane was present at both fluences., Conclusion: We report removal of bovine corneal stroma at 10 mJ/cm2--below the previously reported ablation threshold of 20 mJ/cm2.

Purpose: To report a rare ectopic chordoma within the orbital wall., Methods: Case report., Results: A 63-year-old woman developed swelling of the eyelid, tearing, blurred vision, and progressive proptosis RE of 1 month's duration. Neuroimaging studies revealed an osteolytic mass with epicenter at the sphenozygomatic suture that eroded intracranially, invaded into the orbit, and compressed orbital soft tissues. Surgical debulking was done followed by radiation treatment. The pathologic findings of physaliphorous epithelial cells with multiple vacuoles containing mucin, prominent nuclei, and positive immunohistochemical staining for S-100, Vimentin, epithelial membrane antigen, and pancytokeratin were diagnostic for chordoma., Conclusion: Orbital wall ectopic localization of a chordoma distant from the clivus is a rare occurrence.

Purpose: To report associations between prognosis, total tumor necrosis, scleritis, and episcleritis in choroidal and ciliary body melanomas., Methods: In this retrospective observational histopathologic study, 157 totally necrotic melanomas and 177 melanomas that were not totally necrotic of choroidal and ciliary body were retrieved from the Registry of Ophthalmic Pathology. The eyes were examined for the histologic evidence of inflammatory cells within the sclera and episcleral tissues. Contingency table, Kaplan-Meier, and Cox proportional hazard regression analyses were performed. In the survival analyses, only deaths with metastatic melanoma were considered as events in the statistical analysis., Results: Among the totally necrotic melanomas, 118 of 157 (75.1%) had both episcleritis and scleritis; two of 157 (1.3%) had scleritis only; 29 of 157 (18.5%) had episcleritis only; and eight of 157 (5.1%) had neither episcleritis nor scleritis. Among the non-necrotic melanomas, 23 of 177 (12.9%) had both episcleritis and scleritis; eight of 177 (4.5%) had scleritis only; 71 of 177 (40.1%) had episcleritis only; and 75 of 177 (42.3%) had neither episcleritis nor scleritis. Cox regression indicated that total necrosis and scleritis were prognostically significant (P <.05) when analyzed univariately but not significant when analyzed multivariately with tumor size., Conclusions: Scleritis and episcleritis were statistically significantly associated with total tumor necrosis. There was a higher incidence of episcleritis than scleritis in both the necrotic and non-necrotic tumor types. Associations with patient outcome were identified for necrosis and scleritis. However, these associations were statistically insignificant when the prognostic effect of tumor size was also considered in a multivariate model.

Objective: Primary graft failure (PGF) corneal tissues were analyzed for herpes simplex virus (HSV) and varicella-zoster virus (VZV)., Design: Retrospective, noncomparative case series., Materials: Formalin-fixed, paraffin-embedded tissue of 21 donor corneas and 14 recipient corneas of PGF cases, as well as 10 control corneas., Methods: Clinical, histologic, immunohistochemical, polymerase chain reaction (PCR), and, in selected cases, transmission electron microscopic characteristics were studied., Main Outcome Measures: Evidence of HSV or VZV in donor tissues., Results: Median patient age was 65 years, and median donor age was 48 years. Donor cornea parameters, including endothelial cell counts, death-to-preservation time, and time in storage, were generally within accepted standards. Stromal edema was found in all 21 donor corneas with PGF. Eighteen donor corneas demonstrated severely reduced or absent endothelium and mild to moderate lymphocytic infiltration without necrosis. Three donor corneas (14%) had necrotizing stromal keratitis (NSK) with keratic precipitates. Positive immunohistochemical staining of keratocytes for HSV was present in two of two donor corneas with NSK and was negative in 18 other donor corneas. Polymerase chain reaction analysis revealed the DNA of HSV type 1 (HSV1) in all donor corneas with NSK and in four donor corneas without NSK (33%). Recipient corneal tissue was negative for HSV1 DNA in three patients with NSK and positive in two of the four other PCR-positive patients. Transmission electron microscopy analysis showed viral particles in two donor corneas with NSK. Polymerase chain reaction analysis revealed no evidence of HSV type 2 or VZV in any cornea. All control corneas were negative for viral DNA. Sixteen corneas remained clear and two had failed after regraft for PGF, with a median follow-up of 3.6 years., Conclusions: Herpes simplex virus type 1 DNA was present in 33% of patients of PGF. Herpetic stromal keratitis was found in some failed corneas; the lack of HSV in the paired recipient suggests importation within the donor cornea. The overall prognosis for regrafting after PGF is good.

Purpose: The purpose of this study was to report a case of bilateral blindness, bilateral necrotizing scleritis, and bilateral deafness in a patient with myelodysplastic syndrome (MDS). In such a patient, the possibility of relapsing polychondritis (RPC) associated with MDS must be considered., Case Report/methods: A 66-year-old patient suffered from myelodysplastic syndrome (MDS). Shortly before his death, he became bilaterally blind and deaf. A biopsy was taken from the conjunctiva and the bone marrow, and both eyes were obtained after death for further investigation. Findings of the clinical and laboratory work-up for the patient's hematologic disorder as well as an examination of the eyes by light microscopy and immunohistochemistry are presented., Results: Ocular sections showed a diffuse necrotizing scleritis with moderate uveitis and no identifiable infectious agent. Neither was there any evidence of a leukemic infiltration. The deafness had been due to inner ear failure, and the patient died of a cardiac failure., Conclusions: Non-infectious scleritis associated with inner ear deafness is a strong indication of relapsing polychondritis (RPC). Furthermore, RPC can be associated with MDS. Thus, in addition to leukemic infiltration and infection involving ocular structures, ophthalmologists and otolargyngologists should be aware of the association between MDS and RPC and the potential complications.

Purpose: Maroteaux-Lamy syndrome is one of the mucopolysaccharidoses (MPSs) that is caused by the incomplete degradation and storage of dermatan sulfate., Methods: We describe a 49-year-old female patient with the mild form of the disease (MPS VI-B) who developed bilateral increasing corneal opacification and increased intraocular pressure after cervical-fusion surgery. After treatment of the increased intraocular pressure, she underwent a penetrating keratoplasty of her right eye., Results: The histopathologic and ultrastructural features of the corneal button were the accumulation of membrane-bound vacuoles containing fibrillogranular and lamellated material in keratocytes and endothelial cells and thinning of Descemet's membrane with excrescences., Conclusion: Our review of the literature reveals only two prior histologic studies of corneas affected by MPS VI B.

The conjunctival melanoses are a group of diseases that share the common clinical findings of flat granular melanin-pigmentation of the conjunctival epithelium. Because differential diagnosis of these lesions is difficult, there is much confusion in the literature regarding taxonomy of these lesions. A histopathologic classification of benign melanosis; primary acquired melanosis with atypia, and primary acquired melanosis with melanoma is proposed. Benign melanosis should be divided based on clinical findings into complexion-associated melanosis, secondary melanosis, ephelis, and primary acquired melanosis without atypia.

A retrospective histopathologic review of 97 patients with basal cell carcinoma of the eyelid was performed to determine the prevalence and behavior of tumors with a mixed pattern of growth. A mixed type basal cell carcinoma was defined as a tumor having a significant nodular or ulcerative component combined with an infiltrative component. Histologic classification of the 97 tumors yielded four (4.1%) that were multicentric, 67 (69.1%) that were nodular, one (1%) that was ulcerative, 13 (13.4%) that were infiltrative, and 12 (12.4%) that were the mixed variant. Follow-up was obtained on 8 of the 12 patients with mixed basal cell carcinoma. Three tumors recurred, but there were no tumor-related deaths. One of these patients underwent numerous eyelid resections over a 2-year period and then underwent an orbital exenteration. The authors conclude that mixed type basal cell carcinomas are not infrequent and behave as aggressively as basal cell carcinomas of the morphea type. A greater awareness and recognition of mixed type basal cell carcinomas by ophthalmologists and pathologists should result in fewer recurrences and better patient management.

Aims: In order to determine the clinicopathological features and optimum management of a series of patients with adenoid squamous cell carcinoma of the conjunctiva, all cases of squamous cell carcinoma (SCC) of the conjunctiva and cornea on file in the registry of the ophthalmic pathology at the Armed Forces Institute of Pathology were reviewed., Methods: On histopathological examination, a predominant adenoid or pseudoglandular pattern due to islands of neoplastic squamous or epidermoid cells surrounded by acantholytic cells was necessary for inclusion in the study. Histochemical and transmission electron microscopic studies (TEM) were performed. Clinical features of all the patients were extracted from the charts., Results: The anatomical location of the 14 tumours was corneoscleral limbus (seven patients) and bulbar conjunctiva (seven patients). Eight patients presented with inflammatory signs and irritation (red eye, tearing, foreign body sensation), while six patients developed a slowly growing, painless mass. Histochemical and TEM studies showed extracellular hyaluronic acid and no intracellular mucin. Of the two patients initially treated by enucleation, one was free of disease after 2 years while the second patient had recurrence in the socket and died of brain metastases despite wide orbital excision and radiotherapy. All five patients with recurrent tumours initially had irritated red eyes and two required enucleation. One such patient, after orbital exenteration and radiotherapy, died of unrelated disease., Conclusion: The study demonstrates that adenoid SCC of the conjunctiva often presents with inflammatory signs. The tumour is locally aggressive and may metastasize and should, therefore, be histopathologically differentiated from the less aggressive conventional squamous cell carcinoma. Optimum treatment includes wide excision with documented histological clear margins of resection on permanent sections and frequent follow up.

Objective: To see if there is a correlation between histologic features of these tumors and final outcome., Design: A small series of cases of adenoid cystic carcinomas of the lacrimal gland in patients 18 years of age or younger were evaluated., Participants: A total of 11 cases of adenoid cystic carcinoma of the lacrimal gland in patients 18 years of age or younger found in the registry of Ophthalmic Pathology at the Armed Forces Institute of Pathology were studied., Intervention: Histologic material obtained by excision of lacrimal gland tumors was evaluated for different morphologic parameters. Clinical follow-up information was reviewed., Main Outcome Measures: All cases were evaluated for proportion of a basaloid histologic pattern: necrosis, hemorrhage, mitotic count, and perineural, vascular, intraosseous, leptomeningeal, and optic nerve invasion. These parameters were examined for an association with the clinical follow-up that was obtained for eight of the patients (mean follow-up, 10 years; range, 2-14 years)., Results: Most of the patients were female (M:F = 2:9). Mean age was 14 years (range, 6.5-18 years). Of the patients with follow-up, 5 (62.5%) of 8 survived. Estimated survival rate at 15 years was 58% (Kaplan-Meier analysis). Survivors had 25% or less basaloid histology. Necrosis, hemorrhage, perineural invasion, and mitotic count were less prominent in survivors than in those who died of disease. Vascular invasion was seen only in fatal cases., Conclusions: Young patients with adenoid cystic carcinomas have a better prognosis than do adult patients, which may be due to their tumors having less aggressive histologic features.

Purpose: This study was performed to determine the prognostic significance of the presence of loops defined as periodic acid-Schiff-positive fibrovascular septa that completely surround lobules of tumor cells in cases of uveal melanoma., Methods: The presence of loops was evaluated using an ordinary light microscope and routinely stained periodic acid-Schiff and hematoxylin sections from 496 posterior uveal melanomas without knowledge of the follow-up data on the patient., Results: At 15 years, survival decreased from 67.5% to 33.8% when complete loops were present. Univariate Cox regression analysis indicated that the presence of loops was an indicator of poor outcome, and was better than age but not as good as the mean diameter of the largest nucleoli, cell type, or tumor size., Conclusions: The presence of loops, as evaluated in this study, was not as strong an indicator of poor outcome as were loops assessed in a previous study of 234 cases from another laboratory. The authors suspect this difference may be due to their only using routinely stained sections without a green filter, as was used in previously reported studies. The authors description of loops does not require any special equipment and gives sufficiently useful results to justify its inclusion by the pathologist in reports of such specimens. A description of vascular loops should be added to the use of the modified Callender cell type, tumor dimensions, mitotic count, extraocular extension, and lymphocytic infiltration in the final pathologic report.

Objective: To determine the frequency of herpes simplex virus type 1 (HSV-1) in primary corneal graft failures., Methods: The clinical data submitted about all cases of corneal graft failure on file at the Armed Forces Institute of Pathology, Washington, DC, from the last 25 years (1970-1995) were evaluated. Cases that met the definition of primary graft failure were examined microscopically and analyzed using polymerase chain reaction (PCR) for the DNA of HSV-1., Results: Three (2.8%) of the 106 cases of graft failure were primary graft failures. The DNA from 2 of the 3 corneal buttons was amplifiable by PCR analysis and results of the PCR analysis and Southern blotting were positive for HSV-1. None of the results of the PCR analysis and Southern blotting of the corneal buttons from the 3 graft failures occurring later than 30 days were positive for HSV-1. Results of the PCR analysis and Southern blotting indicated that 2 of 3 corneal buttons in the control group of clinically suspected herpetic keratitis were positive for HSV-1. The cornea from the first case of primary graft failure showed acute inflammation with stromal necrosis. The cornea in the second case had loss of endothelium without inflammation., Conclusions: The finding of DNA from HSV-1 in corneal buttons from 2 cases of primary graft failure supports similar observations by Cleator et al and suggests that HSV-1 may be pathogenic in some cases of primary graft failure. A larger study is needed to determine if HSV-1 is a causative factor in primary graft failure.

Background: Automated image capture and analysis (AICA) has not previously been used to measure the size of nucleoli in uveal melanoma. In this study, the measurements were tested for a possible association with patient outcome., Methods: Sections from 63 uveal melanomas were stained using the silver stain for nucleolar organizing regions (AgNOR). AICA was used to measure the following five nucleolar features in ten microscopic fields of the tumor: area, circularity, maximum diameter, width, and length of the perimeter. For each tumor, the mean and standard deviation of each of the features were calculated based on all the nucleoli and on subsets of nucleoli with larger areas. For the five nucleolar features the mean of the largest value (MLV) in each of the ten fields was calculated. For comparison, a related visually measured nucleolar feature (MLN) was obtained from hematoxylin and eosin stained sections using a filar micrometer., Results: Thirty-four patients died with metastatic disease and 29 patients survived at least 5 years without metastasis. A greater proportion of nucleoli larger than 3 mm2 in greatest dimension were from patients who died of their disease. The means of the nucleolar features were less significant outcome discriminators than the standard deviations. Means and standard deviations based on subgroups of nucleoli larger than 3 or 3.5 mm2 in greatest dimension were better discriminators. The MLVs were as effective discriminators as the corresponding standard deviations of the larger nucleoli and were better discriminators than MLN., Conclusions: AICA of AgNOR stained sections of uveal melanoma provides an excellent method for predicting the outcome of patients with uveal melanoma.

Purpose: Primary orbital melanomas are rare tumors with a poorly defined biologic course. Most recorded experiences concern single case reports. The authors evaluated the applicability of several of the histopathologic prognostic indicators used for uveal melanomas to a series of primary orbital melanomas with known clinical follow-up., Methods: Twenty-one primary orbital melanomas, each with at least a 1-year follow-up after diagnosis, were evaluated for (1) modified Callender cell type, (2) mitotic count per 40 high-power fields, (3) lymphocyte count (less than versus greater than 100/20 high-power fields), (4) blue nevus component, and (5) largest tumor diameter., Results: All patients for whom race was recorded were white. The mean age at diagnosis was 42 years (range, 15-84 years). There was an associated blue nevus in 19 patients (90 percent), and in 10 patients (47.5 percent) there was some form of congenital melanosis. With a mean follow-up period of 4.5 years (range, 1-13 years), mortality from metastatic tumor occurred in 8 (38 percent) of 21 patients. Of these eight patients, there were liver metastases in seven (88 percent) and brain metastases in one (12 percent). Indicators of poor prognosis were tumors of mixed cell type with high mitotic count and greater patient age with underlying congenital melanosis., Conclusion: Most primary orbital melanomas occur in white patients and are associated with blue nevi. These tumors are similar to uveal melanomas with respect to prognostic indicators and pattern of metastasis.

The case of a patient with a lacrimal fossa mass that was believed to be a primary lacrimal gland tumor is reported. However, at lateral orbitotomy the tumor was found within the lacrimal fossa, but distinct from the lacrimal gland. Histopathology revealed a benign fibrous histiocytoma. The tumor was totally excised, has not recurred over a 3-year follow-up period. This mesenchymal tumor should be included in the differential diagnosis of lacrimal fossa mass in adults.

Background: Posterior uveal melanomas with ciliary body involvement have greater mortality when compared with choroidal melanomas. This study was conducted to determine if this association is due to an independent effect or to correlations with other parameters., Methods: From the 4335 cases of uveal melanoma with follow-up data in the Registry of Ophthalmic Pathology, 664 were selected; therefore, approximately two thirds of the patients died of metastatic melanoma. Ciliary body involvement was determined by the location of the anterior tumor margin. Kaplan-Meier survival, Cox regression, and Gamel-Boag log-normal regression analyses were performed. Covariables included ciliary body involvement, largest tumor dimension, mean diameter of the largest ten nucleoli, and modified Callender classification., Results: Kaplan-Meier and univariate Cox analyses indicated a significant association between ciliary body involvement and tumor-related death but when included in a multivariate Cox model, ciliary body involvement was not statistically significant. Similarly, when ciliary body involvement was included in a multivariate Gamel-Boag model, ciliary body involvement was not statistically significant. Melanomas that involve the ciliary body were more likely to be larger (Student's t = 10.5; P = 10(-6)), contain larger nucleoli (Student's t = 2.43; P = 0.015), and be of mixed cell type (chi-square = 17.2; P = 3 x 10(-5))., Conclusions: Ciliary body involvement is associated with tumor-related mortality but this association is primarily due to ciliary body tumors being larger with more malignant cytology.

A 92-year-old man has had multiple recurrent oncocytic tumors involving the right paranasal sinuses and orbit. A benign oncocytoma that arose from the right lacrimal sac was initially diagnosed at age 80 years. The tumor recurred at 3 and 7 years after initial resection. There was greater histologic atypia in the first recurrent tumor, which extended into the right paranasal sinuses. The second recurrence had zones on oncocytic adenocarcinoma exhibiting prominent nuclear atypia and mitotic activity; this tumor massively invaded the right paranasal sinuses and orbit. We describe the clinical and pathologic features of this rare case.

Objective: To characterize granulomatous reactions around Bowman's layer., Design: Case series., Setting: Registry of Ophthalmic Pathology, Armed Forces Institute of Pathology, Washington., Patients: All patients with a code for granulomatous reactions to Bowman's (membrane) layer or Descemet's membrane. In addition, all corneas identified as having elastotic or calcific degeneration of Bowman's layer were reexamined to identify a possible granulomatous reaction to Bowman's layer., Results: Review of 210 corneal buttons and enucleated eyes yielded eight cases in which evidence of a granulomatous reaction to Bowman's layer was present: five patients with chronic keratitis, including three with herpetic keratitis (disciform in two and ulcerative in one), and three patients whose corneas had old degenerative pannus with calcification of Bowman's layer. In the patients with chronic keratitis the reaction tended to be focal and accompanied by inflammation; in those with degenerative pannus the reaction was diffuse and accompanied by minimal inflammation., Conclusions: Granulomatous reactions to Bowman's layer are observed much less frequently than granulomatous reactions to Descemet's membrane. Although the pathogenesis of granulomatous reaction to Bowman's layer is unclear, a change in the antigenic properties of Bowman's layer may be implicated.

We report the clinical and scanning electron microscopic findings in an older adult patient with unilateral posterior keratoconus. Clinically, the cornea showed typical posterior concavity with focal underlying anterior ectasia and an epithelial iron ring. Scanning electron microscopy of the cornea removed at penetrating keratoplasty revealed a pericentral posterior concavity. The endothelial layer was intact, with moderate endothelial cell pleomorphism. There were no excrescences of Descemet's membrane or endothelial tags. The lack of discrete irregularities on the posterior corneal surface in this case is different from previous descriptions of the pathological appearance of posterior keratoconus, which have been used to support a relationship of this condition to central corneal mesenchymal dysgenesis. This is the first report of scanning electron microscopic findings in posterior keratoconus.

Purpose: To characterize intraocular tumors that arise by in situ transformation in the choroid-retinal pigment epithelium (RPE) in transgenic mice bearing the SV40 oncogene under the control of the mouse tyrosinase promoter., Methods: Tumors from TySV40 transgenic mice were characterized in vivo and in vitro by immunohistology, compound microscopy, and electron microscopy. Tumor cell lines were established and characterized for growth and metastatic potential in the eyes of nude mice., Results: On light microscopy, ocular tumors were predominantly epithelioid, although occasional clusters of spindle cells were also present. Transmission electron microscopy revealed the presence of numerous basal infoldings and abundant multilaminated basement membranes on the ocular tumors. Tumors stained with antibodies to melanoma-associated antigens, gangliosides GD2 and GD3, and the SV40 T antigen. Radiolabeled transgenic tumor cells preferentially localized in the liver after intravenous injection in normal mice. Intracamerally transplanted transgenic tumors metastasized from the eyes to the livers of nude mice., Conclusions: In TySV40 transgenic mice, intraocular tumors develop that arise at the choroid-RPE interface, and they display morphologic and ultrastructural features consistent with RPE carcinomas. However, the transgenic tumors express melanoma-associated antigens and a propensity to metastasize to the liver, two features characteristic of uveal melanomas. The TySV40 transgenic murine tumors represent potentially useful tools for investigations into the biology and metastasis of intraocular neoplasms.

Juvenile xanthogranuloma is a benign cutaneous disorder which occasionally involves the eye, orbit, and ocular adnexa in children. Iris and ciliary body manifestations are commonly seen, but retinal and choroidal lesions are exceedingly rare. We report a unique case of retinal, choroidal, iris, and ciliary body infiltration in a 12-year-old patient diagnosed by excisional biopsy of the iris. The diagnosis was confirmed by routine histology and oil-red-o staining. Immunohistochemistry revealed predominantly macrophages, monocytes, and T-helper lymphocytes. Unusual features of this case include the late age at diagnosis, posterior pole involvement, and lack of cutaneous lesions. The presence of cellular adhesion molecules and T lymphocytes implicate a lymphocyte-driven inflammatory process. Apolipoprotein A was the predominant apolipoprotein present within the foamy histiocytes. We also present a critical review of the literature.

When applied to survival data from a population of cancer patients, the log-normal model provides estimates of three important parameters: cured fraction, mean log survival time, and standard deviation log survival time. In the original model, however, these parameters are unrelated to prognostic covariates. Furthermore, the original algorithm is computationally unstable and highly dependent on initial parameter estimates. We have developed an extension of the log-normal model that stabilizes computation and expresses survival parameters as functions of prognostic covariates. We have also developed an ancillary algorithm that provides reliable initial estimates.

Purpose: To investigate using immunohistochemistry the unusual finding that tumor infiltrating lymphocytes (TIL) in uveal melanomas are associated with a higher mortality rate., Methods: We performed immunohistochemistry for B and T lymphocytes on 80 uveal malignant melanomas, which previously had been reported to contain more than 100 TIL per 20 high-powered fields. In a second study of 90 patients, we counted the number of immunohistochemically stained T lymphocytes per 20 high-powered fields in uveal melanomas from 30 patients who survived at least 15 years after enucleation, from 30 patients who died with metastasis within 2 years, and from 30 patients who died with metastasis more than 10 years after enucleation., Results: T cells predominated in 73.8% of the 80 patients, and B cells were more prevalent in 13.8%. T cells were usually scattered, and B cells were usually in clumps. Post-enucleation 18-yr mortality from metastasis was 73% for patients with either T- or B-cell predominance of their TIL. The mortality rate was 32% for patients with few TIL. The patients who survived at least 15 yrs after enucleation had fewer T lymphocytes infiltrating their uveal melanomas than the two groups of patients who died with metastasis., Conclusions: The pattern of the TIL was different for T and B cells in uveal melanomas. T-lymphocytic infiltration is associated with death due to metastasis.

Background: For certain types of cancer, resection alone rarely achieves a cure, but patients nevertheless tend to have a prolonged survival before they die of the tumor. For other types of cancer, the opposite scenario prevails, suggesting that those biologic mechanisms that allow a curative resection are not identical to those that determine survival time among uncured patients., Methods: The multivariate log-normal model can be used to detect the association of cured fraction and median survival time of patients with specific prognostic covariates. This model was applied to survival data from 2892 patients with intraocular melanoma who were treated by enucleation., Results: This analysis showed that large tumor size and pleomorphic nucleoli within the tumor were associated independently with a low probability of cure and short median survival time. Advanced patient age and mixed cell type, however, were highly associated with only a short median survival time., Conclusions: For patients with intraocular melanoma treated only by enucleation, the median survival time is not modulated by the same biologic factors that determine the likelihood of a curative resection.

An immunohistochemical study was conducted on 29 cases of sympathetic ophthalmia (SO). Monoclonal antibodies against T, B, NK cells, macrophages, and MHC class II antigen (HLA-DR) were used. The choroidal infiltrate in 20 eyes was predominantly T cell while B cell predominated in four cases. All eyes with a B cell predominance came from males. A predominance of B cells was correlated to a longer duration of the disease (> 9 months) and in eyes showing phthisical changes. There was no correlation between a predominance of B cells with age, race, corticosteroid treatment or histological type (typical or atypical). These findings suggest that, although SO is a T cell mediated disease, the predominance of B cells in some cases may represent the end stage of the disease process, or seems a secondary pathological process. The kinetic change in cell populations during the disease may have therapeutic implication.

Using data on 4726 cases of uveal melanoma collected by the Registry, of Ophthalmic Pathology at the Armed Forces Institute of Pathology, my co-workers and I have been studying the biology of haematogenous metastasis. We have developed methods for evaluating separately the relationships between prognostic factors and cure-rate and median survival time for uncured patients. We have discovered that size of the tumour and size of the largest nucleoli in the cells of the uveal melanomas related equally to cure-rate and median survival time. The presence of Callender's epitheloid-type cells in the tumour and increased patient age had little effect on cure-rate but dramatically reduced the median survival time.

For 740 selected cases of uveal melanoma from the Armed Forces Institute of Pathology, the following features were determined: the age and sex of the patient, Callender cell type (CT), and largest tumor dimension (LTD). In addition, special morphometric devices were used to measure the standard deviation of nucleolar area (SDNA) and the mean of the largest nucleoli (MLN) from a single routine hematoxylin and eosin-stained section of each tumor. Univariate analysis using the Cox proportional-hazards model revealed that LTD, CT, SDNA, and MLN correlated equally with death from metastatic melanoma (P greater than 10(-6). Age correlated less highly (P less than 0.002), and sex had no relationship to mortality. Multivariate analysis revealed that adding LTD as a prognostic covariate to either CT, SDNA, or MLN yielded a substantial increase in prognostic value. Because MLN can be measured more easily than SDNA and is more reproducible than CT, it can be a useful cytologic index of the malignant potential of uveal melanomas.