Afrogheh AH, Jakobiec FA, Hammon R, Grossniklaus HE, Rocco J, Lindeman NI, Sadow PM, Faquin WC.
Evaluation for High-risk HPV in Squamous Cell Carcinomas and Precursor Lesions Arising in the Conjunctiva and Lacrimal Sac. Am J Surg Pathol 2016;40(4):519-28.
AbstractHigh-risk human papilloma virus (HR-HPV) is a well-established causative agent of oropharyngeal squamous cell carcinoma (SCC). In addition, HR-HPV has occasionally been reported to be present in dysplastic and malignant lesions of the conjunctiva and lacrimal sac, although its overall incidence and etiological role in periocular SCC are controversial. Sequential surgical samples of 52 combined cases of invasive SCC (I-SCC) and SCC in situ (SCCIS) from 2 periocular sites (conjunctiva and lacrimal sac) diagnosed over a 14-year period (2000 to 2014) were selected for evaluation, and relevant patient characteristics were documented. p16 immunohistochemistry was performed as a screening test. All p16-positive cases were further evaluated for HR-HPV using DNA in situ hybridization (DNA ISH), and a subset was also analyzed by polymerase chain reaction (PCR). Of 43 ocular surface squamous neoplasias (OSSNs), 30% (n=13; 8 SCCIS and 5 I-SCC cases) were positive for HR-HPV. HPV-positive OSSNs occurred in 8 men and 5 women with a mean age of 60 years (range, 39 to 94 y). HPV type-16 was detected in all conjunctival cases evaluated by PCR. All 5 conjunctival I-SCCs were nonkeratinizing (n=4) or partially keratinizing (n=1) and managed by simple excision. In contrast, HPV-negative conjunctival I-SCCs were predominantly keratinizing (11 keratinizing and 2 nonkeratinizing). Of 9 lacrimal sac I-SCCs (LSSCCs), 66.7% (n=6) were positive for HR-HPV by p16 and DNA ISH; HPV subtypes were HPV-16 (n=5) and HPV-58 (n=1). In addition, 2 p16-positive cases with negative DNA ISH results were HR-HPV positive (HPV-16 and HPV-33) when evaluated by PCR, suggesting that the rate of HR-HPV positivity among the LSSCCs may be as high as 89% (n=8). The combined group of HR-HPV-positive LSSCCs was seen in 4 men and 4 women with a mean age of 60 years (range, 34 to 71 y). Seven of the 8 HPV-positive LSSCCs (87.5%) had a nonkeratinizing or partially keratinizing histomorphology, whereas 1 case (12.5%) was predominantly keratinizing. The presence of HR-HPV in 30% of OSSNs and at least 66.7% of LSSCCs suggests the possibility of an etiologic role for HR-HPV at these sites.
Aggarwal S, Jakobiec FA, Hamrah P.
Bilateral adult epibulbar xanthogranulomas suspicious for Erdheim-Chester disease. Cornea 2014;33(10):1113-7.
AbstractPURPOSE: The aim of this study was to report the clinical, imaging, and histopathological findings of bilateral, conjunctival adult-onset xanthogranulomas that raised the prospect of a mild form of Erdheim-Chester disease. METHODS: This is a case report. RESULTS: A 35-year-old white male complaining of ocular irritation, presented with bilateral, nasal and temporal, yellow, elevated conjunctival lumps first noticed 1.5 years back, which were not associated with other ocular findings. The lesions were firm, attached to the underlying episclera, and measured 1.1 × 0.9, 1.1 × 0.8, 1.2 × 0.5, and 0.5 × 0.5 cm in the temporal and nasal right and left eyes, respectively. Each mass was fleshy with vascularity at the peripheral margin. Histopathologic evaluation after excisional biopsy revealed lipidized xanthoma cells, multiple Touton giant cells, and lymphocytes. Immunohistochemical staining was positive for adipophilin (lipid), CD68, CD163 histiocytes, CD3 T cells (with CD8 cytotoxic T cells > CD4 T-helper cells), and virtually no CD20 B cells or IgG4 plasma cells. The patient later acquired similar xanthogranulomatous subcutaneous lesions on the extremities. Positron emission tomography scans showed sclerosis in the medullary cavities of the tibia and the radius of both legs and arms, and an absence of retroperitoneal lesions. A normal serum immunoelectrophoresis and the absence of a BRAF gene mutation were demonstrated. CONCLUSIONS: Adult-onset xanthogranuloma can present as a solitary conjunctival mass without periocular or orbital involvement. The clinical, histopathologic, and radiologic findings in this case are suggestive of Erdheim-Chester disease without displaying any life-threatening lesions to date. Histopathologic and imaging studies can help in obtaining a diagnosis. Ophthalmologists should be aware that xanthogranulomatous conditions may have potential systemic implications, and a thorough systemic evaluation is recommended for lesions that initially seemed to be isolated in nature.
Ahmed AH, Foster SC, Shields CL.
Association of Disease Location and Treatment With Survival in Diffuse Large B-Cell Lymphoma of the Eye and Ocular Adnexal Region. JAMA Ophthalmol 2017;135(10):1062-1068.
AbstractImportance: Primary diffuse large B-cell lymphoma (DLBCL) of the ocular region is rare, and the utility of surgery and radiation therapy remains unresolved. Objective: To explore the clinical characteristics and determine factors associated with overall survival in primary vitreoretinal lymphoma (PVRL) and ocular adnexal (OA)-uveal DLBCL. Design, Setting, and Participants: This retrospective analysis included 396 patients with ophthalmic DLBCL from January 1, 1973, through December 31, 2014, using the Surveillance, Epidemiology, and End Results database. The median follow-up was 39.0 months (interquartile range, 5.1-72.9 months). All patients diagnosed with primary DLBCL of the eye or retina (PVRL) or the eyelid, conjunctiva, choroid, ciliary body, lacrimal gland, or orbit (OA-uveal lymphoma) were included. Patients diagnosed at autopsy or with additional neoplastic disease were excluded. Main Outcomes and Measures: Patient demographic characteristics, disease location, treatment modalities, and overall survival. Results: Forty-seven patients with PVRL (24 women [51.1%] and 23 men [48.9%]) and 349 with OA-uveal DLBCL (192 women [55.0%] and 157 men [45.0%]) had a similar mean (SD) age at diagnosis (69.6 [12.3] vs 66.1 [17.7] years). No difference in the use of surgery or radiation therapy by location was found. For all PVRL and OA-uveal DLBCL, a Cox proportional hazards regression model affirmed that age older than 60 years was associated with increased risk for death (hazard ratio [HR], 2.7; 95% CI, 1.9-4.0; P < .001). Gross total resection was associated with a decreased risk for death (HR, 0.5; 95% CI, 0.3-0.9; P = .04), whereas radiation therapy was not. The 5-year overall survival among patients with PVRL was 41.4% (SE, 8.6%); among those with OA-uveal DLBCL, 59.1% (SE, 2.8%; Mantel-Cox test, P = .007). Median overall survival was lower in PVRL (38.0 months; 95% CI, 14.2-61.8 months) than in OA-uveal DLBCL (96.0 months; 95% CI, 67.3-124.7 months; Mantel-Cox test, P = .007). In addition, median overall survival in ophthalmic-only disease was higher (84.0 months; 95% CI, 63.2-104.8 months) than that in primary DLBCL that occurred outside the central nervous system and ophthalmic regions (46.0 months; 95% CI, 44.4-47.6 months; Mantel-Cox test, P < .001). Conclusions and Relevance: The 5-year survival in PVRL vs OA-uveal DLBCL differed by 17.7%, and overall survival was greater in ophthalmic DLBCL than in DLBCL located outside the central nervous system and ophthalmic regions. Younger age (≤60 years) and gross total resection were associated with increased survival.
Al-Moujahed A, Nicolaou F, Brodowska K, Papakostas TD, Marmalidou A, Ksander BR, Miller JW, Gragoudas E, Vavvas DG.
Uveal melanoma cell growth is inhibited by aminoimidazole carboxamide ribonucleotide (AICAR) partially through activation of AMP-dependent kinase. Invest Ophthalmol Vis Sci 2014;55(7):4175-85.
AbstractPURPOSE: To evaluate the effects and mechanism of aminoimidazole carboxamide ribonucleotide (AICAR), an AMP-dependent kinase (AMPK) activator, on the growth of uveal melanoma cell lines. METHODS: Four different cell lines were treated with AICAR (1-4 mM). Cell growth was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay. Cell cycle analysis was conducted by flow cytometry; additionally, expression of cell-cycle control proteins, cell growth transcription factors, and downstream effectors of AMPK were determined by RT-PCR and Western blot. RESULTS: Aminoimidazole carboxamide ribonucleotide inhibited cell growth, induced S-phase arrest, and led to AMPK activation. Aminoimidazole carboxamide ribonucleotide treatment was associated with inhibition of eukaryotic translation initiation factor 4E-BP1 phosphorylation, a marker of mammalian target of rapamycin (mTOR) pathway activity. Aminoimidazole carboxamide ribonucleotide treatment was also associated with downregulation of cyclins A and D, but had minimal effects on the phosphorylation of ribosomal protein S6 or levels of the macroautophagy marker LC3B. The effects of AICAR were abolished by treatment with dipyridamole, an adenosine transporter inhibitor that blocks the entry of AICAR into cells. Treatment with adenosine kinase inhibitor 5-iodotubericidin, which inhibits the conversion of AICAR to its 5'-phosphorylated ribotide 5-aminoimidazole-4-carboxamide-1-D-ribofuranosyl-5'-monophosphate (ZMP; the direct activator of AMPK), reversed most of the growth-inhibitory effects, indicating that some of AICAR's antiproliferative effects are mediated at least partially through AMPK activation. CONCLUSIONS: Aminoimidazole carboxamide ribonucleotide inhibited uveal melanoma cell proliferation partially through activation of the AMPK pathway and downregulation of cyclins A1 and D1.
Al-Moujahed A, Brodowska K, Stryjewski TP, Efstathiou NE, Vasilikos I, Cichy J, Miller JW, Gragoudas E, Vavvas DG.
Verteporfin inhibits growth of human glioma in vitro without light activation. Sci Rep 2017;7(1):7602.
AbstractVerteporfin (VP), a light-activated drug used in photodynamic therapy for the treatment of choroidal neovascular membranes, has also been shown to be an effective inhibitor of malignant cells. Recently, studies have demonstrated that, even without photo-activation, VP may still inhibit certain tumor cell lines, including ovarian cancer, hepatocarcinoma and retinoblastoma, through the inhibition of the YAP-TEAD complex. In this study, we examined the effects of VP without light activation on human glioma cell lines (LN229 and SNB19). Through western blot analysis, we identified that human glioma cells that were exposed to VP without light activation demonstrated a downregulation of YAP-TEAD-associated downstream signaling molecules, including c-myc, axl, CTGF, cyr61 and survivin and upregulation of the tumor growth inhibitor molecule p38 MAPK. In addition, we observed that expression of VEGFA and the pluripotent marker Oct-4 were also decreased. Verteporfin did not alter the Akt survival pathway or the mTor pathway but there was a modest increase in LC3-IIB, a marker of autophagosome biogenesis. This study suggests that verteporfin should be further explored as an adjuvant therapy for the treatment of glioblastoma.
Aronow ME, Wiley HE, Gaudric A, Krivosic V, Gorin MB, Shields CL, Shields JA, Jonasch EW, Singh AD, Chew EY.
VON HIPPEL-LINDAU DISEASE: Update on Pathogenesis and Systemic Aspects. Retina 2019;39(12):2243-2253.
AbstractPURPOSE: To provide an update summarizing the biologic pathways governing von Hippel-Lindau (VHL) disease pathogenesis and to provide an overview of systemic manifestations as well as screening recommendations. METHODS: A PubMed search of the English language literature was reviewed using the following search terms: von Hippel-Lindau, von Hippel-Lindau disease, and VHL. Of 6,696 publications, the most current and pertinent information related to the pathogenesis and systemic aspects of VHL disease were included in this review. RESULTS: von Hippel-Lindau disease is one of the most frequently occurring multisystem familial cancer syndromes. The disease results from germline mutation in the VHL tumor suppressor gene on the short arm of chromosome 3. Mutation in the VHL gene affects multiple cellular processes including transcriptional regulation, extracellular matrix formation, apoptosis, and, in particular, the cellular adaptive response to hypoxia. As a result, there is widespread development of vascular tumors affecting the retina, brain, and spine, as well as a spectrum of benign and malignant tumors and/or cysts in visceral organs. CONCLUSION: The ophthalmologist plays a key role in VHL disease diagnosis, as retinal hemangioblastoma is frequently the first disease manifestation. Screening guidelines for individuals with known VHL disease, and those at risk of VHL disease, help to ensure early detection of potentially vision-threatening and life-threatening disease.
Avedschmidt SE, Stagner AM, Eagle RC, Harocopos GJ, Dou Y, Rao RC.
The Targetable Epigenetic Tumor Protein EZH2 is Enriched in Intraocular Medulloepithelioma. Invest Ophthalmol Vis Sci 2016;57(14):6242-6246.
AbstractPurpose: Intraocular medulloepithelioma (IM), the second most common primary neuroepithelial tumor of the eye, can lead to blindness in the affected eye and in rare cases, is deadly. Intraocular medulloepithelioma lacks targetable biomarkers for potential pharmacologic therapy. The purpose of this study was to identify actionable, tumor-specific proteins for potential diagnostic or therapeutic strategies. We hypothesize that the tumor-specific epigenetic enzyme EZH2 is selectively expressed in IM. Methods: We conducted a retrospective case series study of five IM from five eyes of four children and one adult. Hematoxylin and eosin (H&E) stains of sections from formalin-fixed, paraffin-embedded blocks of IM tumors were used to localize IM tumor cells in each case. Using an EZH2-specific antibody for immunohistochemistry, we semiquantitatively calculated the proportion of IM tumor cells positive for EZH2, and also assayed for EZH2 staining intensity. Results: We found that EZH2 was expressed in all IM cases but this protein was absent in nontumor ciliary body or retinal tissues. However, not all IM tumor cells expressed EZH2. Similar to retinoblastoma, moderately to poorly differentiated (primitive appearing) IM tumor cells strongly expressed EZH2; expression was weaker or absent in areas of well-formed neuroepithelial units. Conclusions: To our knowledge, this is the first study to identify an actionable tumor-specific maker, EZH2, in IM. Our findings point to the possibility of exploring the potential of EZH2 inhibitors, already in clinical trials for other cancers, for IM.
