Jwu Jin Khong

Complications of mitomycin C therapy in 100 eyes with ocular surface neoplasia

Aim: To determine the complications associated with mitomycin C (MMC) in the treatment of ocular surface neoplasia. Methods: A retrospective and consecutive study of 100 eyes in 91 patients with ocular surface neoplasia treated with MMC in a single centre between November 1998 and January 2005. Outcome measures included complications of MMC and the treatment required for these complications. Results: One to three 7 day cycles of topical MMC 0.04% four times a day were given to 59 eyes with localised corneal-conjunctival intraepithelial neoplasia (CIN), 19 eyes with diffuse CIN, six eyes with recurrent CIN, one eye with ocular surface squamous cell carcinoma, three eyes with primary acquired melanosis (PAM) with atypia, nine eyes with conjunctival malignant melanoma (MM), two eyes with sebaceous carcinoma with pagetoid spread, and one eye with recurrent atypical fibroxanthoma. Nine patients had bilateral CIN. 31 (34%) cases developed an allergic reaction to MMC and 14 (14%) eyes had epiphora secondary to punctal stenosis at a mean follow up period of 26.5 months. Conclusion: In the largest study looking at complications of topical MMC in the treatment of ocular surface neoplasia, allergic reaction and punctal stenosis are relatively common. Serious complications were not observed suggesting the safe use of MMC in mid-term follow up.

Ocular Adnexal Diffuse Large B-cell Lymphoma: A Multicenter International Study

IMPORTANCE The clinical features of diffuse large B-cell lymphoma (DLBCL) subtype of ocular adnexal lymphoma have not previously been evaluated in a large cohort to our knowledge. OBJECTIVE To investigate the clinical features of ocular adnexal DLBCL (OA-DLBCL). DESIGN, SETTING, AND PARTICIPANTS This retrospective international cooperative study involved 6 eye cancer centers. During 30 years, 106 patients with OA-DLBCL were identified, and 6 were excluded from the study. The median follow-up period was 52 months. MAIN OUTCOMES AND MEASURES Overall survival, disease-specific survival (DSS), and progression-free survival were the primary end points. RESULTS One hundred patients with OA-DLBCL were included in the study (median age, 70 years), of whom 54 (54.0%) were female. The following 3 groups of patients with lymphoma could be identified: primary OA-DLBCL (57.0%), OA-DLBCL and concurrent systemic lymphoma (29.0%), and ocular adnexal lymphoma relapse of previous systemic lymphoma (14.0%). Of 57 patients with primary OA-DLBCL, 53 (93.0%) had Ann Arbor stage IE disease, and 4 (7.0%) had Ann Arbor stage IIE disease. According to the TNM staging system, 43 of 57 (75.4%) had T2 tumors. Among all patients, the most frequent treatments were external beam radiation therapy with or without surgery (31.0%) and rituximab-cyclophosphamide, hydroxydaunorubicin, vincristine sulfate, prednisone (CHOP) or rituximab-CHOP-like chemotherapy with or without external beam radiation therapy (21.0%). The 5-year overall survival among the entire cohort was 36.0% (median, 3.5 years; 95% CI, 2.5-4.5 years). Relapse occurred in 43.9% (25 of 57) of patients with primary OA-DLBCL. Increasing T category of the TNM staging system was predictive of DSS (P = .04) in primary OA-DLBCL, whereas the Ann Arbor staging system was not. However, when taking all 100 patients into account, Ann Arbor stage was able to predict DSS (P = .01). Women had a longer median DSS than men (9.8 years; 95% CI, 1.9-17.7 years vs 3.3 years; 95% CI, 1.6-5.0; P = .03). CONCLUSIONS AND RELEVANCE Most patients with primary OA-DLBCL were seen with Ann Arbor stage IE and TNM T2 disease. The 5-year overall survival was between 2.5 and 4.5 years, which is the 95% CI around the median of 3.5 years in this cohort. Increasing T category appears to be associated with decreased DSS among patients with primary OA-DLBCL. When taking all patients into account, sex and Ann Arbor stage also seem to be DSS predictors.

Pathogenesis of thyroid eye disease: review and update on molecular mechanisms

Orbital changes in thyroid orbitopathy (TO) result from de novo adipogenesis, hyaluronan synthesis, interstitial oedema and enlargement of extraocular muscles. Cellular immunity, with predominantly CD4+ T cells expressing Th1 cytokines, and overexpression of macrophage-derived cytokines, perpetuate orbital inflammation. Orbital fibroblasts appear to be the major effector cells. Orbital fibroblasts express both thyrotropin receptor (TSHR) and insulin-like growth factor-1 receptor (IGF-1R) at higher levels than normal fibroblasts. TSHR expression increases in adipogenesis; TSHR agonism enhances hyaluronan production. IGF-1R stimulation leads to adipogenesis, hyaluronan synthesis and production of the chemokines, interleukin (IL)-16 and Regulated on Activation, Normal T Cell Expression and Secreted, which facilitate lymphocyte trafficking into the orbit. Immune activation uses a specific CD40:CD154 molecular bridge to activate orbital fibroblasts, which secrete pro-inflammatory cytokines including IL-1β, IL-1α, IL-6, IL-8, macrophage chemoattractant protein-1 and transforming growth factor-β, to perpetuate orbital inflammation. Molecular pathways including adenylyl cyclase/cyclic adenosine monophosphate, phophoinositide 3 kinase/AKT/mammalian target of rapamycin, mitogen-activated protein kinase are involved in TO. The emergence of a TO animal model and a new generation of TSHR antibody assays increasingly point towards TSHR as the primary autoantigen for extrathyroidal orbital involvement. Oxidative stress in TO resulting from imbalances of the oxidation-reduction state provides a framework of understanding for smoking prevention, achieving euthyroidism and the use of antioxidants such as selenium. Progress has been made in the understanding of the pathogenesis of TO, which should advance development of novel therapies targeting cellular immunity, specifically the CD40:CD40 ligand interaction, antibody-producing B cells, cytokines, TSHR and IGF-1R and its signalling pathways. Further studies in signalling networks and molecular triggers leading to burnout of TO will further our understanding of TO.

Serum selenium status in Graves’ disease with and without orbitopathy: a case–control study

Selenium is effective in improving quality of life and reducing the progression of active Graves’ orbitopathy. The effect of correcting relative selenium deficiency on improving Graves’ orbitopathy is unknown, as baseline selenium levels have not previously been measured. The study aims to determine whether serum selenium levels are reduced in patients with Graves’ disease with orbitopathy (GO) compared with without orbitopathy (GD).

Malignant fibrous histiocytoma of the eyelid: differential diagnosis and management.

Purpose: Malignant fibrous histiocytoma (MFH) is a pleomorphic soft tissue sarcoma that occurs rarely in the periocular region. The purpose of this study was to present a case series of periocular MFH and to discuss the differential diagnosis and management. Methods: This is a retrospective case review of patients diagnosed with periocular MFH from tertiary hospitals and private practices. Results: Four patients, two women and two men with periocular MFH, had a mean age of 81 years (range, 72 to 85 years). All tumors were <5 cm in diameter and of storiform pleomorphic histologic subtype. One was located deep and 3 presented superficially. The initial diagnoses were sarcomatoid carcinoma, atypical fibroxanthoma, and leiomyosarcoma that were subsequently reclassified as MFH. One patient had a frozen section, 1 had fast track paraffin section margin control, and 2 had no frozen section margins at the initial excisions. Histology showed 2 negative margins, 1 close margin, and 1 positive margin that were cleared with wide local excision. Local recurrence occurred in 3 cases, and of these, 1 required orbital exenteration. Adjuvant radiotherapy was given to 3 patients. One had regional node metastases. There were no distant metastases or tumor-related deaths. Mean follow-up period was 36 ± 35 months (median, 30; range, 1 to 84 months). Conclusions: This study highlights the difficulties in the clinicopathologic diagnosis of periocular MFH and in particular the distinction of more superficial tumors from atypical fibroxanthoma. The mainstay of treatment is complete surgical excision with wide margins, and consideration should be given to histologic margin control in addition to adjuvant radiotherapy.

Differential Effects of FGFR2 Mutation in Ophthalmic Findings in Apert Syndrome

Apert syndrome is mostly caused by one of the two specific point mutations in the fibroblast growth factor receptor 2 (FGFR2). The objective of this study was to determine whether there were any differences in the prevalence of ophthalmic features in Apert syndrome when comparing the Ser252Trp and Pro253Arg mutations in FGFR2. This was a retrospective study of patients with Apert syndrome with genotype analysis. The prevalence of five ophthalmic features, visual impairment, amblyopia, strabismus, corneal abnormality, and pale optic discs, were compared between the two FGFR2 genotypes. There were 25 (74%) cases with Ser252Trp mutation, and 9 (26%) cases with the Pro253Arg mutation in FGFR2. Ophthalmic findings in 20 cases of FGFR2 Ser252Trp and 9 cases of Pro253Arg mutation were compared. Visual acuity worse than 6/12 in at least one eye was present in 60% patients with FGFR2 Ser252Trp mutation compared with 12.5% patients with Pro253Arg mutation (P < 0.05). Forty percent of eyes with FGFR2 Ser252Trp mutation compared with 12.5% eyes with Pro253Arg mutation were worse than 6/12. There was a trend of more frequent amblyopia and strabismus in FGFR2 Ser252Trp mutation and more frequent optic disc pallor in the FGFR2 Pro253Arg mutation. There was a differential effect of FGFR2 mutations in ophthalmic findings in patients with Apert syndrome, with significantly greater prevalence of visual impairment in the Ser252Trp mutation compared with the Pro253Arg mutation. Further study would elucidate whether the trends in differential effects between the two mutations in amblyopia, strabismus, and optic disc pallor represent real differences.

Differential Gene Expression Profiling of Orbital Adipose Tissue in Thyroid Orbitopathy

PURPOSE We aimed to determine differentially expressed genes relevant to orbital inflammation and orbital fat expansion in thyroid orbitopathy (TO) using microarray gene profiling in a case-control study. METHODS Human orbital adipose samples were obtained from individuals with active TO (n = 12), inactive TO (n = 21), and normal controls (n = 21). Gene expression profiles were examined using microarray analysis and were compared between active and inactive TO, and between active TO and normal controls. Top ranked differentially expressed genes were validated by real-time RT-PCR in an additional eight active TO, 13 inactive TO, and 11 normal controls and correlated with gene set enrichment analysis (GSEA) and molecular pathways analysis. RESULTS Seven hundred twenty-one probes (683 genes) and 806 probes (735 genes) were significantly differentially expressed in comparing active to inactive TO and in comparing active TO to healthy controls, respectively. All selected genes were confirmed to be differentially expressed by real-time RT-PCR. Multiple top ranked genes in active versus inactive TO comparison are overrepresented by immune and inflammatory response genes. They include defensins (DEFA1, DEFA1B, DEFA3), which were overexpressed by 3.05- to 4.14-fold and TIMD4 by 4.20-fold. Markers for adipogenesis were overexpressed including SCD, FADS1, and SCDP1. Gene set enrichment analysis revealed dysregulation of epigenetic signatures, T-cell activation, Th1 differentiation, defensin pathway, cell adhesion, cytoskeleton organization, apoptosis, cell cycling, and lipid metabolism in active TO. CONCLUSIONS Active TO is characterized by upregulation of genes involved in cell-mediated immune, innate immune, and inflammatory response and enhanced orbital adipogenesis. TIMD4, DEFA1, DEFA1B, and DEFA3 genes may be involved in the innate immune-mediated orbital inflammation in TO. Epigenetic mechanisms may play a role in the pathogenesis of TO.

Apocrine adenocarcinoma of the eyelid: case series and review.

Purpose: To report 2 patients with apocrine adenocarcinoma of the eyelid and review the literature. Design: Noncomparative, retrospective case series and review. Participants: Clinical data of 2 patients with histopathologic diagnoses of apocrine adenocarcinoma of the eyelid were obtained from medical records. The histopathology and immunohistochemistry data for the 2 cases were studied. A retrospective review was performed on all reported cases of eyelid apocrine carcinoma. Main Outcome Measures: Clinical features, histopathology, immunohistochemistry, and clinical course following treatment are reported. The results of a retrospective review of clinical presentations, local and systemic spread, treatment method, and prognosis from published case reports on eyelid apocrine adenocarcinoma are discussed. Results: One patient had orbital invasion at presentation. This patient had radiotherapy alone and had no systemic or local recurrence at 2 years. One patient underwent a 4-mm margin wide surgical excision. This patient had no local or systemic recurrences at 1 year. A review of the literature suggests that the prognosis of adnexal apocrine tumors is indeterminate and variable. Most patients have successful outcomes following local surgical excision. Radiotherapy has been used as an adjunctive treatment for local metastatic disease. Conclusions: Apocrine adenocarcinoma is a rare adnexal tumor of the eyelid, which may present with orbital invasion.

Medial Transconjunctival Intrinsic Optic Nerve Biopsy: Surgical Technique and Indications

Aim: To describe a method of intrinsic optic nerve biopsy and its indications. Methods: Retrospective case series. Results: We report four cases that required intrinsic optic nerve biopsy for progressive optic neuropathy with uncertain diagnosis after negative systemic investigations. In all cases, a medial transconjunctival approach was used. There were no complications noted with this technique in the series, specifically there was no reported deterioration in vision. One case of neurosarcoidosis was confirmed. In the other three cases, the pathology results were non-diagnostic but ruled out serious causes such as central nervous system leukaemia relapse. Conclusion: Medial transconjunctival intrinsic optic nerve biopsy is a minimally invasive and safe technique. The technique is suitable for sampling pathology in the distal portion of the optic nerve. Optic nerve biopsy is indicated when there is significant loss of vision from an isolated optic nerve disease and all systemic investigations have failed to identify the cause, or where the clinical course of a presumed diagnosis is atypical.

Clinicopathological Features of Ocular Adnexal Mantle-Cell Lymphoma in an International Multicenter Cohort

Importance To our knowledge, the clinical features of ocular adnexal mantle-cell lymphoma (OA-MCL) have not previously been evaluated in a large multicenter cohort. Objective To characterize the clinical features of OA-MCL. Design, Setting, and Participants This retrospective multicenter study included patient data collected from January 1, 1980, through December 31, 2015, at 6 eye cancer centers in 4 countries. Medical records of 55 patients with OA-MCL were reviewed; the median length of follow-up was 33 months. Main Outcomes and Measures Overall survival, disease-specific survival, and progression-free survival were the primary end points. Results Fifty-five patients were included; ocular adnexal MCL was found to be most common in older individuals (mean age, 70 years) and men (n = 42 of 55; 76%). Patients with OA-MCL frequently presented with disseminated lymphoma (n = 34 of 55; 62%), and were likely to experience stage IVE disease (n = 35 of 55; 64%), with bilateral involvement (n = 27 of 55; 47%), tumor masses (n = 27 of 36; 75%), and involvement of the orbit (n = 32 of 55; 58%). Chemotherapy with or without external beam radiation therapy was the most frequently used treatment. Overall survival rates for the entire cohort were 65% at 3 years (95% CI, 52%-78%) and 34% at 5 years (95% CI, 21%-47%). Disease-specific survival after 5 years was 38% for the entire cohort (95% CI, 25%-51%); the disease-specific survival adjusted by eye cancer center was better in patients who had received rituximab in addition to the chemotherapy regimen (hazard ratio, 3.3; 95% CI, 1.0-14.7; P = .06). The median progression-free survival was 2.3 years (95% CI, 1.8-2.7 years) in patients who experienced recurrence after primary treatment, and 4.1 years (95% CI, 3.9-4.3 years) in patients who presented with a relapse of systemic lymphoma in the ocular adnexal region. Conclusions and Relevance These results suggest that the distinctive features of OA-MCL are its appearance in older male individuals, advanced stage and bilateral manifestation at the time of diagnosis, and aggressive course. The prognosis of patients with OA-MCL might be improved by addition of rituximab to chemotherapy treatment.