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To investigate correlations between clinical and histopathologic characteristics of idiopathic epiretinal membrane (ERM).Retrospective interventional case series.In total, 87 eyes from 87 patients with idiopathic ERM who underwent pars plana vitrectomy with peeling of the ERM from 2019 to 2020 were included.The outcomes of clinical ophthalmic examination, including measurement of best-corrected visual acuity (BCVA) and spectral-domain OCT (SD-OCT), before and after surgery were reviewed. Surgical specimens were fixed in formalin and embedded in paraffin for histologic and immunohistochemical analysis.The association between morphological characteristics revealed on SD-OCT images and the cellular composition of the surgically excised ERM demonstrated with immunohistochemical staining were the main outcome measures. Changes in the BCVA and central macular thickness (CMT) were assessed through a comparison of preoperative and postoperative measurements.Based on SD-OCT morphological characteristics in the foveal area, 15 cases were classified into group 1A (mainly outer retinal thickening), 39 into group 1B (more tenting of the outer retina and distorted inner retina), and 33 into group 1C (prominent inner retina thickening). Overall, postoperative final BCVA and CMT at 1 year improved in all groups. Patients who presented with a better initial BCVA exhibited a more favorable final BCVA. Epiretinal membranes in group 1C demonstrated the greatest decrease in CMT compared with those in groups 1B and 1A, but the final CMT did not differ among the groups. A negative correlation between the density of hyalocytes (P = 0.003) and myofibroblasts (P = 0.047) was noted between the 3 groups. Total cell density and glial cell density of the ERMs were strongly associated with poor final BCVA and BCVA improvement.The present study provides new histopathologic information regarding the formation and progression of idiopathic ERM. Glial cell proliferation plays a predominant role in these processes. Epiretinal membranes with high cellularity and glial cell density may cause damage to the retina structure, resulting in poor postoperative visual outcomes. These findings provide additional evidence supporting early surgical intervention in patients with idiopathic ERM reported with visual disturbance.

Microsporidial stromal keratitis is an increasingly well-known vision-threatening disease. A large proportion of cases are initially misdiagnosed as herpes simplex keratitis and treated with topical steroids. In most of such cases, medical treatment failed, and corneal transplantation was required. This study reported the results of 0.02% topical chlorhexidine used to treat three cases of microsporidial stromal keratitis and reviewed the literature on the outcomes of microsporidial stromal keratitis treatment. In the first case, histopathology of a specimen from penetrating keratoplasty (PK) revealed severe chronic inflammation involving the entire stromal layer but no microorganism activity after the application of topical chlorhexidine for 10 months. The second case exhibited complete resolution of keratitis after topical chlorhexidine. The patient in the third case did not respond to medical treatment, and therapeutic PK was performed. Histopathological examination revealed numerous microsporidial spores that had colonized in the mid and deep stroma, where few inflammatory cells were observed. These findings explain the variable microsporidial susceptibility to chlorhexidine, suggesting the crucial role of host immunity. In cases of host immunity, topical chlorhexidine may represent a promising option for the treatment of microsporidial stromal keratitis.

Background Intraocular osseous metaplasia is a rare histological finding associated with benign cellular transformation. Its development requires inflammatory cytokines and the process takes many years. Previous case reports of intraocular ossification manifested as linear calcification or white plaques. In contrast, our case presented with a tumor-like solid mass, in which a long-standing chronic inflammatory stimulation may contribute to the stunning appearance. Case presentation This is a 48-year-old woman with past history of advanced Coat’s-like retinopathy and chronic retinal detachment in the left eye for 12 years. She underwent vitreoretinal surgery to prevent phthisis bulbi. During the operation, a 9 mm solid mass was found embedded within the proliferative tissue above the retina and was removed. Pathological findings revealed bone formation in the center of the mass surrounded by fibrous metaplasia and focal gliotic changes. Layers of cohesive cells were found lining on the external side of the mass, and further immuno-histochemical study suggested them retinal pigment epithelial cells. Postoperatively, the retina was attached with stable visual acuity and normal intraocular pressure. Conclusion To our knowledge, the appearance of a tumor-like mass representing intraocular osseous metaplasia in eyes with chronic inflammation or retinal detachment has not been reported in previous case reports. This case emphasizes the importance of considering osseous metaplasia as one of the differential diagnoses of an unknown intraocular mass, especially in eyes with great severity of chronic inflammation. Also, our immuno-histochemical study provided more evidence on the pathological role of retinal pigment epithelial cells in developing ossification.

Primary signet ring cell/histiocytoid carcinoma of the eyelid is a rare ocular malignancy and its diagnosis is often delayed. This neoplasm presents as an insidious, diffusely infiltrative mass in the periocular area that later infiltrates the orbit. An exenteration is usually indicated; however, nearly one-third of patients develop local recurrence or metastasis. Morphologically, it resembles signet ring cell carcinoma of the stomach and breast, raising the possibility of mutations in CDH1, the gene encoding E-cadherin. To determine whether primary signet ring cell/histiocytoid carcinoma harbors the CDH1 mutation or other actionable mutations, we analyzed the tumor tissue via next-generation sequencing. We identified only one case of primary signet ring cell carcinoma of the eyelid with adequate DNA quality for sequencing from the pathological archive during the period 2000 to 2020. A comprehensive evaluation including histopathology, immunohistochemistry, and next-generation sequencing assay was performed on tumor tissue. Immunohistochemically, the tumor exhibited E-cadherin membranous staining with the aberrant cytoplasmic staining of β-catenin. Using next-generation sequencing, we demonstrated the mutation in the CDH1 gene. In addition, other clinically actionable mutations including ERBB2 and PIK3CA were also detected. The alterations in other actionable genes indicate a need for larger studies to evaluate the pathogenesis and potential therapies for primary signet ring cell/histiocytoid carcinoma of the eyelid.

Immune checkpoint blockade therapy has revolutionized non-small cell lung cancer treatment. However, not all patients respond to this therapy. Assessing the tumor expression of immune checkpoint molecules, including programmed death-ligand 1 (PD-L1), is the current standard in predicting treatment response. However, the correlation between PD-L1 expression and anti-PD-1/PD-L1 treatment response is not perfect. This is partly caused by tumor heterogeneity and the common practice of assessing PD-L1 expression based on limited biopsy material. To overcome this problem, we developed a novel method that can make formalin-fixed, paraffin-embedded tissue translucent, allowing three-dimensional (3D) imaging. Our protocol can process tissues up to 150 μm in thickness, allowing anti-PD-L1 staining of the entire tissue and producing high resolution 3D images. Compared to a traditional 4 μm section, our 3D image provides 30 times more coverage of the specimen, assessing PD-L1 expression of approximately 10 times more cells. We further developed a computer-assisted PD-L1 quantitation method to analyze these images, and we found marked variation of PD-L1 expression in 3D. In 5 of 33 needle-biopsy-sized specimens (15.2%), the PD-L1 tumor proportion score (TPS) varied by greater than 10% at different depth levels. In 14 cases (42.4%), the TPS at different depth levels fell into different categories (

Hepatitis C virus (HCV) infection is the major etiology for cirrhosis and hepatocellular carcinoma (HCC). The severity of liver fibrosis is a crucial factor in prognostic prediction. We aimed to evaluate the prognostic role of Metavir fibrosis stage in HCV-related HCC and its association with noninvasive liver reserve models. Between 2004 and 2016, 172 patients with HCV-related HCC undergoing surgical resection were enrolled. Multivariate Cox proportional hazards model was used to identify prognostic predictors. The area under receiver operating curve (AUROC) was used for comparison in predicting cirrhosis among different noninvasive liver reserve models. In the multivariate Cox analysis, AST > 45 IU/mL, multiple tumors, tumor size greater than 3 cm, and serum AFP > 20 ng/mL were independent risk factors linked with tumor recurrence. There was no significant association between Metavir fibrosis stage/ inflammatory activity and tumor recurrence. In the Cox model, Child-Turcotte-Pugh class B, tumor size greater than 3 cm, and Metavir fibrosis stage F3-F4 were independent predictors associated with decreased survival (all p 3 cm) HCC group. Among the noninvasive models, FIB-4 had the highest predictive accuracy (AUROC = 0.768, p

Hepatitis C virus (HCV) infection is the major etiology for cirrhosis and hepatocellular carcinoma (HCC). The severity of liver fibrosis is a crucial factor in prognostic prediction. We aimed to evaluate the prognostic role of Metavir fibrosis stage in HCV-related HCC and its association with noninvasive liver reserve models.Between 2004 and 2016, 172 patients with HCV-related HCC undergoing surgical resection were enrolled. Multivariate Cox proportional hazards model was used to identify prognostic predictors. The area under receiver operating curve (AUROC) was used for comparison in predicting cirrhosis among different noninvasive liver reserve models.In the multivariate Cox analysis, AST 45 IU/mL, multiple tumors, tumor size greater than 3 cm, and serum AFP 20 ng/mL were independent risk factors linked with tumor recurrence. There was no significant association between Metavir fibrosis stage/ inflammatory activity and tumor recurrence. In the Cox model, Child-Turcotte-Pugh class B, tumor size greater than 3 cm, and Metavir fibrosis stage F3-F4 were independent predictors associated with decreased survival (all p 0.001). In subgroup analysis, survival differences were consistently observed between patients with fibrosis stage F0-F2 and F3-F4 (p 0.05) in either small (≤ 3 cm) or large ( 3 cm) HCC group. Among the noninvasive models, FIB-4 had the highest predictive accuracy (AUROC = 0.768, p 0.001) to indicate cirrhosis compared to other models.Metavir fibrosis stage can predict survival in HCV-related HCC patients independent of tumor size. FIB-4 is the best noninvasive model to predict cirrhosis in these patients.

Angiomatoid fibrous histiocytoma is a peculiar borderline neoplasm with indolent behavior, predominantly arising in the superficial area of extremities. We encountered a unique case of asymptomatic angiomatoid fibrous histiocytoma presenting on the chest wall and being adjacent to the parietal pleura, expanding the spectrum of anatomic sites in which angiomatoid fibrous histiocytoma would occur.

Immune checkpoint blockade therapy has revolutionized cancer treatment, achieving sustained remission even in a proportion of patients with metastatic disease. However, not all patients respond to these therapies. Currently, histological detection of PD-L1 expression in tumor specimens is the standard method for guiding checkpoint blockade therapies involving anti-PD-1/PD-L1 antibodies. Nevertheless, accumulating evidence from clinical studies indicates that the pathological assessment of PD-L1 expression is neither a consistent nor a reliable predictor of anti-PD-1/PD-L1 treatment outcome. This inconsistency can be partly attributed to tumor heterogeneity in PD-L1 expression, as well as the common practice of assessing PD-L1 expression based on a single tissue section made from limited tumor biopsy specimen. In order to overcome this obstacle, we developed a novel method that can make formalin-fixed, paraffin-embedded (FFPE) tissue translucent to light, allowing three-dimensional imaging of the specimen. Our specialized protocol can process non-small cell lung cancer tissue up to 150 micrometer in thickness, allowing fluorescence-labeled anti-PD-L1 antibody staining throughout the entire tissue, and produce high-resolution 3D images. Compared to a traditional single 4-micrometer section of the same specimen, our 3D image provides 30 times more coverage of the specimen, assessing PD-L1 expression of approximately 15 times more cells. We also developed a computer-assisted PD-L1 signal quantitation algorithm, integrating artificial intelligence (AI) models of tumor region segmentation and PD-L1 positive cell classifier to generate PD-L1 tumor proportion score (TPS) along the specimen depth. Both AI models have greater than 90% accuracy compared to pathologist's assessment. Analysis of 3D images from seven lung adenocarcinoma specimens showed that TPS variation may reach up to 23.76% at different tissue depth levels. One of the seven cases has TPS below 1% at certain depth level but above 1% at other levels, a difference that can potentially influence clinical decision making. Importantly, our technology permits recovery of the processed tissue for subsequent analysis, including traditional histology examination, immunohistochemistry, and DNA analysis, such as EGFR mutation test. In conclusion, our novel method has the potential to increase the accuracy of tumor PD-L1 expression assessment and enable precision deployment of cancer immunotherapy. Citation Format: Yen-Yu Lin, Lei-Chi Wang, Yu-Han Hsieh, Sih-Kai Chuang, Yung-An Chen, Yu-Chieh Lin, Yen-Yin Lin, Teh-Ying Chou. Computer-assisted three-dimensional quantitation of programmed death-ligand 1 expression in non-small cell lung cancer using tissue clearing technology on formalin-fixed, paraffin-embedded specimen [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 488.

The goal of this project was to demonstrate the feasibility of coupling the indirect ophthalmoscope laser delivery system with the 690 nm wavelength diode laser used to perform photodynamic therapy (PDT) in the treatment of retinoblastoma. For phase 1, a total of six pigmented rabbits were treated with the indirect laser delivery system. The laser source was provided by the Lumenis Opal 690 nm laser unit, delivered through a 810 nm Indirect ophthalmoscope headpiece and a hand-held 28-diopter indirect lens (1.0 mm spot size). Four rabbits received intravenous verteporfin at doses of 0.43 or 0.86 mg/kg, and two rabbits did not receive verteporfin (controls). A second phase of the study involved eight rabbits using a retinoblastoma xenograft to determine the effect of indirect PDT on subretinal tumors. For phase 1, a total of 20 laser treatments were performed in the right eyes of six rabbits. Laser power levels ranged between 40 and 150 mW/cm2 and treatment duration ranged between 1 and 3 min. In the four rabbits that received verteporfin, focal retinal scars were noted at 40 mW/cm2 and higher power levels. In the two control rabbits that did not receive verteporfin, thermal burns were confirmed at 75 mW/cm2 and higher power levels. Histopathology showed focal retino-choroidal scars at the site of PDT treatment, without evidence of generalized ocular damage. Using the retinoblastoma xenograft, the indirect PDT system was shown to cause areas of tumor necrosis on histopathology. The results of this pre-clinical study suggest verteporfin may be activated in the rabbit retina with the indirect delivery system and the 690 nm laser unit (i.e., Indirect PDT). Using verteporfin, treatment effects were observed at 40–50 mW/cm2 in the rabbit retina, while photocoagulation was achieved at 75 mW/cm2 and higher power levels. Fundoscopic and histopathologic examination of treated areas showed circumscribed areas of retinal damage and a lack of generalized ocular toxicity, suggesting that this modality may represent a safe and localized method for treating intraocular retinoblastoma.

OBJECTIVES Patients with oesophageal squamous cell carcinoma have a high risk of disease recurrence even after trimodality treatments, which include preoperative chemoradiotherapy and oesophagectomy. We aimed to identify the histological factors that are associated with loco-regional and distant recurrence. METHODS A retrospective review of a prospectively established database identified patients who received preoperative chemoradiotherapy and oesophagectomy for squamous cell carcinoma. The impact of histological factors, including surgical resection margins, lymphovascular invasion (LVI), perineural invasion (PNI), extracapsular invasion (ECI) and tumour regression grade (TRG), on disease recurrence was analysed. RESULTS A total of 116 patients treated between 2009 and 2015 were included. Sixty-one patients developed disease recurrence, including 25 loco-regional and 49 distant recurrences, with a median disease-free interval of 6 months. Positive histological surgical resection margins were significantly associated with loco-regional recurrence, whereas pre-treatment N stage, ypT stage, ypN stage, positive surgical resection margins, TRG, LVI, PNI, ECI and TRG were significant prognostic factors for distant recurrence. Upon multivariate analysis, cN stage [hazard ratio (HR): 4.049; 95% confidence interval (CI): 1.242-13.200, P = 0.020], LVI (HR: 3.658; 95% CI: 1.891-7.078, P

Purpose To characterize histologic changes in the optic nerve and the retina of an end-stage retinitis pigmentosa (RP) patient after long-term implantation with the Argus II retinal prosthesis system. Methods Serial cross sections from the patient's both eyes were collected postmortem 6 years after implantation. Optic nerve from both eyes were morphometrically analyzed and compared. Retina underneath and outside the array was analyzed and compared with corresponding regions in the fellow eye. Results Although the optic nerve of the implant eye demonstrated significantly more overall atrophy than the fellow eye (P < 0.01), the temporal quadrant that retinotopically corresponded to the location of the array did not show additional damage. The total neuron count of the macular area was not significantly different between the two eyes, but the tack locations and their adjacent areas showed significantly fewer neurons than other perimacular areas. There was an increased expression of glial fibrillary acidic protein (GFAP) throughout the retina in the implant eye versus the fellow eye, but there was no significant difference in the cellular retinaldehyde-binding protein (CRALBP) expression. Except for the revision tack site, no significant increase of inflammatory reaction was detected in the implant eye. Conclusion Long-term implantation and electrical stimulation with an Argus II retinal prosthesis system did not result in significant tissue damage that could be detected by a morphometric analysis. Translational Relevance This study supports the long-term safety of the Argus II device and encourages further development of bioelectronics devices at the retina-machine interface.

Here, we present the first cytological report of a primary splenic inflammatory pseudotumor-like follicular dendritic cell sarcoma. The 57 year-old male was incidentally found with a 2.2 cm well-demarcated splenic nodule. A sonography guided fine needle aspiration of the lesion was performed. The cytologic smears revealed loosely cohesive fragments of oval to spindle cells in a background of prominent lymphoplasmacytic infiltration. The cells showed sparse chromatin, distinct nucleoli, syncytial cell borders, and occasional cytoplasmic processes. On the liquid-based preparation, several histiocyte-like cells with emperipolesis phenomenon were noted. Scant large atypical cells with prominent, cherry-red nucleoli were found on the cell block sections. The initial cytologic interpretation was "atypical cells cannot exclude classical Hodgkin lymphoma." The subsequent partial splenectomy showed an inflammatory pseudotumor-like follicular dendritic cell sarcoma. The tumor cells were positive for CD21, CD35, smooth muscle actin, and EBER in situ hybridization. The cytologic differential diagnoses are briefly discussed. The knowledge of this rare entity, awareness of its cytomorphology, and proper ancillary tests would be helpful for correct cytologic diagnosis. Diagn. Cytopathol. 2017;45:230-234. © 2016 Wiley Periodicals, Inc.

To describe an unusual case of panuveitis in coexisting choroidal melanoma and phacoanaphylaxis.Clinical records of the patient with intraocular melanoma and pathologic findings of the affected eye were reviewed. Composition of inflammatory infiltrates involving the tumor and lens was evaluated immunohistochemically.Histologically, tumor showed a choroidal mixed cell type malignant melanoma with infiltration of inflammatory cells. The globe also showed typical features of phacoanaphylaxis, characterized by disruptions of the lens capsule with zonal granulomatous inflammation. The inflammatory infiltration revealed the predominant presence of both cytotoxic T cells and histiocytes in phacoanaphylaxis and intra-tumoral inflammation.The current clinico-pathologic case report suggests that a long standing intraocular melanoma can present with phacoanaphylaxis. The immunophenotype of the inflammatory infiltrates at both sites, lens and the tumor, is similar, cytotoxic T cells and histiocytes, favoring a common immune inflammatory process directed at the tumor and the lens.

To investigate the change of serum IgG4 concentrations correlated with clinical evolution in patients with ocular adnexal marginal zone B cell lymphoma associated with IgG4-related ophthalmic disease (IgG4-ROD).Three consecutive patients with histopathologically confirmed ocular adnexal marginal zone B cell lymphoma associated with IgG4-ROD were evaluated. Two patients received radiotherapy and 1 patient received steroid therapy. Treatment outcome was evaluated by clinical symptoms, radiologic examination, and change of serum IgG4 level in these patients.All patients had elevated serum IgG4 before treatment (462, 338, and 780 mg/dL respectively.) The 2 patients who received radiotherapy achieved complete remission and the serum IgG4 decreased to 345 and 92 mg/dL, respectively. The patient who underwent systemic steroid achieved partial remission and the serum IgG4 decrease to 161 mg/dL.Our study showed elevated serum IgG4 in all patients with ocular adnexal marginal zone B cell lymphoma associated with IgG4-ROD. In addition, the elevated serum IgG4 may decrease or keep stable after treatment, accompanied by improvement in clinical symptoms and reduction of lesions.

Intraocular involvement of T-cell lymphoma is rare. We report a case presented with inflammatory glaucoma, neurotrophic keratopathy, and choroidal detachment. An 81-year-old man presented with unilateral high intraocular pressure and keratic precipitates. Polymerase chain reaction of the aqueous humor was negative for herpes simplex virus type 1 and 2, varicella zoster virus, and cytomegalovirus. Progressive pupil dilatation, cornea anesthesia with large epithelial defect, and choroidal detachment were noted in the following month. Diagnostic vitrectomy was then performed, and cytology of the vitreous suggested malignant lymphoma. Further systemic workup revealed ulcerative lesions in the stomach, and biopsy with special stains led to the diagnosis of peripheral T-cell lymphoma of the stomach with ocular involvement. Intraocular involvement of T-cell lymphoma is very rare. Most typically, the skin, followed by the central nervous system, has the most frequently occurring concurrent systemic involvement. In fact, stomach involvement has not been reported. Most cases of intraocular lymphomas presented with vitritis and anterior uveitis, and elevated intraocular pressure was not commonly observed. A review of the literature indicates that a large corneal epithelium defect has been described only in a case of peripheral T-cell lymphoma with the involvement of sclera and oropharynx. Although very rare, inflammatory glaucoma, neurotrophic keratopathy, and choroidal detachment can be the initial presentation of intraocular involvement of T-cell lymphoma.

Here, we present the first cytological report of a primary splenic inflammatory pseudotumor-like follicular dendritic cell sarcoma. The 57 year-old male was incidentally found with a 2.2 cm well-demarcated splenic nodule. A sonography guided fine needle aspiration of the lesion was performed. The cytologic smears revealed loosely cohesive fragments of oval to spindle cells in a background of prominent lymphoplasmacytic infiltration. The cells showed sparse chromatin, distinct nucleoli, syncytial cell borders, and occasional cytoplasmic processes. On the liquid-based preparation, several histiocyte-like cells with emperipolesis phenomenon were noted. Scant large atypical cells with prominent, cherry-red nucleoli were found on the cell block sections. The initial cytologic interpretation was "atypical cells cannot exclude classical Hodgkin lymphoma." The subsequent partial splenectomy showed an inflammatory pseudotumor-like follicular dendritic cell sarcoma. The tumor cells were positive for CD21, CD35, smooth muscle actin, and EBER in situ hybridization. The cytologic differential diagnoses are briefly discussed. The knowledge of this rare entity, awareness of its cytomorphology, and proper ancillary tests would be helpful for correct cytologic diagnosis. Diagn. Cytopathol. 2017;45:230-234. © 2016 Wiley Periodicals, Inc.

Background The definite etiology of epiretinal membrane (ERM) is unknown. Clinically, ERM may cause metamorphopsia and decreased vision during the disease exacerbation. Several theories of pathogenesis emphasize a glial tissue origin. However, in some studies, surgically removed ERM specimens were found to contain retinal pigment epithelial (RPE) cells. The actual mechanism by which RPE cells gain access into the inner retina and what roles they play in the formation of ERM remain controversial. The purpose of this study was to evaluate the incidence of RPE cells in ERM and discuss the possible mechanisms. Methods A retrospective review of the histological findings in 23 surgically removed specimens of ERM was done. The samples were studied using light microscopy and immunohistochemistry. Results Glial cells were the main components in all 23 cases, and RPE cells were found in five of the specimens. Two of these five cases were clinically diagnosed as idiopathic macular pucker, whereas the other three cases were identified as macular pucker associated with previous retinal detachment. A much higher density of myofibroblasts was noted in these five specimens than in the other 18 cases. Conclusion The incidence of RPE cells found in ERM is 21.7% (5 out of 23 specimens). A strong association between RPE cells and myofibroblasts in cases of ERM with or without retinal detachment indicates that RPE cells may contribute to the formation of ERM via a wound healing process.