This report describes a 68-year-old woman who presented with progressive, painless protrusion of the left eye. Findings included unilateral proptosis, superonasal displacement, motility restrictions, and dilated, tortuous conjunctival vessels. MRI and CT scans revealed a well-defined 41 × 19 mm orbital tumor extending along the lateral rectus muscle. Incisional biopsy revealed a spindle cell tumor with a fascicular to storiform pattern in a myxoid to collagenous stroma, showing mild to moderate cellular atypia and skeletal muscle infiltration. Immunohistochemistry was positive for smooth muscle actin and calponin, but negative for caldesmon and desmin. Next-generation sequencing identified an HMGA2-NAV3 gene fusion and amplifications of CDK4, MDM2, and GLI1. The findings were consistent with a low-grade myofibroblastic sarcoma (LGMS). The tumor was treated with en bloc orbital resection. No recurrence was observed after 18 months. This case highlights the role of histological and immunohistochemical evaluation in diagnosing this rare cause of unilateral proptosis.

PURPOSE:The association between thyroid dysfunction and exudative age-related macular degeneration (AMD) is unknown. METHODS:In this Danish longitudinal nationwide registry-based cohort study we included all Danish residents aged 50-100 between 2008 and 2018. Using the Danish national registries, we studied the association between thyroid dysfunction and exudative AMD. Thyroid dysfunction was classified as two consecutive redeemed prescriptions of thyroid hormones (hypothyroidism) or anti-thyroid medication (hyperthyroidism). Exudative AMD was classified as an ICD diagnosis of AMD and a code for anti-VEGF treatment. All patients are treated for exudative AMD in a hospital in Denmark, and we therefore have complete registration of this patient group. RESULTS:We included 2 087 305 individuals, of which 1 072 567 (51.4%) were women; 59 318 (2.8%) had hypothyroidism, and 33 922 (1.6%) had hyperthyroidism. During a median follow-up of 11 years, 26 998 (1.3%) people developed exudative AMD. Hypothyroidism (adjusted hazard ratio [HR]: 1.17; 95% confidence interval [CI] 1.10-1.25; p < 0.001) and hyperthyroidism (HR: 1.23; 95% CI:1.13-1.34; p < 0.001) were both associated with the development of exudative AMD. The age-stratified analyses yielded similar results to the main analyses, except that the risks were exaggerated in the older part of the population. CONCLUSION:This is the first longitudinal nationwide study showing that both hypo- and hyperthyroidism are associated with an increased risk of exudative AMD. AMD is a quantitative problem in the population and our findings could have a public health impact. Further studies are needed to study the underlying mechanisms of the association.

Importance Thyroid eye disease (TED) is a serious condition that can cause proptosis and strabismus and, in rare cases, lead to blindness. Incidence data for TED and strabismus and surgical interventions after TED are sparce. Objective To investigate the nationwide incidence of TED, strabismus, and surgical interventions associated with TED. Design, Setting, and Participants A Danish nationwide registry-based cohort study between 2000, which marks the beginning of uniform coding for the decompression surgery nationwide, and 2018. The cohort consisted of a mean 4.3 million people aged 18 to 100 years with no prior TED diagnosis each year. Total observation time was 8.22 × 107 person-years (women, 4.18 × 107 person-years; men, 4.04 × 107 person-years). Main Outcome Measures The annual numeric and age-standardized incidence of hospital-treated TED and cumulative incidence of strabismus, strabismus surgery, and orbital decompression surgery in patients with TED. The incidence was stratified by sex, thyroid diagnosis, and age. Results A total of 4106 incident diagnoses of TED were identified during 19 years among 3344 women (81.4%) and 762 men (18.6%). The mean numeric annual nationwide incidence rate of TED was 5.0 per 100 000 person-years overall, 8.0 per 100 000 person-years in women, and 1.9 per 100 000 person-years in men, resulting in a 4:1 ratio of women to men with TED. The age-standardized incidence was similar. The mean (SD) age at onset was 51.3 (14.5) years. At the time of TED diagnosis, 611 patients (14.9%) were euthyroid, 477 (11.6%) were hypothyroid, and 3018 (73.5%) were hyperthyroid. In patients with TED who were euthyroid, the 4-year cumulative incidence was 41% for antithyroid medication and 13% for L-thyroxine. In patients with TED, the 4-year cumulative incidence for strabismus was 10%. The 4-year cumulative incidence of surgical interventions after TED was 8% for strabismus surgery and 5% for orbital decompression. At 4 years, strabismus surgery was more common in men (13.3%; 95% CI, 10.75-15.86) than in women (7.2%; 95% CI, 6.24-8.08), and the absolute difference was 6.1% (95% CI, 3.42-8.14; P < .001). Conclusions and Relevance This study in Denmark provides nationwide empirical incidence of TED and strabismus and surgical interventions after TED that required inpatient or outpatient hospital treatment, and might be used for patient information and health care planning.

The pathogenesis of squamous cell neoplasms arising in the lacrimal drainage system is poorly understood, and the underlying genomic drivers for disease development remain unexplored. We aimed to investigate the genomic aberrations in carcinomas arising in the LDS and correlate the findings to human papillomavirus (HPV) status. The HPV analysis was performed using HPV DNA PCR, HPV E6/E7 mRNA in-situ hybridization, and p16 immunohistochemistry. The genomic characterization was performed by targeted DNA sequencing of 523 cancer-relevant genes. Patients with LDS papilloma (n = 17) and LDS carcinoma (n = 15) were included. There was a male predominance (68%) and a median age at diagnosis of 46.0 years (range 27.5–65.5 years) in patients with papilloma and 63.8 years (range 34.0–87.2 years) in patients with carcinoma. Transcriptional activity of the HPV E6/E7 oncogenes was detected in the whole tumor thickness in 12/15 (80%) papillomas (HPV6, 11, 16) and 10/15 (67%) squamous cell carcinomas (SCC) (HPV11: 3/15 (20%) and HPV16: 7/15 (47%)). Pathogenic variants in PIK3CA, FGFR3, AKT1, and PIK3R1, wildtype TP53, p16 overexpression, and deregulated high-risk E6/E7 transcription characterized the HPV16-positive SCC. The deregulated pattern of HPV E6/E7 expression, correlating with HPV DNA presence and p16 positivity, supports a causal role of HPV in a subset of LDS papillomas and carcinomas. The viral and molecular profile of LDS SCC resembles that of other HPV-driven SCC.

To investigate the epidemiology and clinical characteristics of infants presenting with conjunctival, palpebral, or orbital congenital choristomas (dermolipomas, epidermoids, and dermoid cysts) and children undergoing surgery for congenital choristomas in the ocular adnexa. We reviewed the medical files of congenital choristomas in children seen in The Capital Region of Denmark during a 5-year period (2014–2018). Children (< 18 years) were divided into two groups: those referred < 1 year of age (Group I) and those undergoing surgery to remove the lesion (Group II). Group I was used to calculate a population-based incidence of congenital choristomas by comparing our data to birth statistics from the Danish Medical Birth Registry. A total of 97 children were included, 43 in Group I and 70 in Group II (including 16 patients from Group I). The total incidence of congenital choristomas was 1 in 2537 live born children. Most lesions were palpebral choristomas (27/43, 63%) located in the superotemporal region (17/27, 63%), followed by the superonasal region (7/27, 26%). The main reasons for surgical removal of a congenital choristoma were growth (28/70, 40%) or cosmesis (25/70, 36%). The total incidence of congenital choristomas in the ocular adnexa of infants < 1 year of age, including both conjunctival and palpebral congenital choristomas, is about 1 in 2537 live born children in The Capital Region of Denmark. Hence, congenital choristomas are common masses found in the ocular adnexa.

It has come to our attention that there has been an error in the previous work [...].

PURPOSE. The genomic alterations contributing to the pathogenesis of conjunctival squamous cell carcinomas (SCCs) and their precursor lesions are poorly understood and hamper our ability to develop molecular therapies to reduce the recurrence rates and treatment-related morbidities of this disease. We aimed to characterize the somatic DNA alterations in human papillomavirus (HPV)-positive and HPV-negative conjunctival SCC. METHODS. Patients diagnosed with conjunctival SCC in situ or SCC treated in ocular oncology referral centers in Denmark were included. HPV detection (HPV DNA PCR, p16 immunohistochemistry, and mRNA in situ hybridization) and targeted capture-based next-generation sequencing of 523 genes frequently involved in cancer were performed to describe the mutational profile based on HPV status. RESULTS. Tumor tissue was available in 33 cases (n = 8 conjunctival SCCs in situ, n = 25 conjunctival SCCs), constituting 25 male and 8 female patients. Nine cases were HPV positive. The HPV-positive SCCs in situ and SCCs were characterized by transcriptionally active high-risk HPV (types 16 and 39) within the tumor cells, frequent mutations in PIK3CA (n = 5/9), and wild-type TP53, CDKN2A, and RB1, while the HPV-negative counterparts harbored frequent mutations in TP53 (n = 21/24), CDKN2A (n = 7/24), and RB1 (n = 6/24). CONCLUSIONS. Our findings have delineated two potentially distinct distributions of somatic mutations in conjunctival SCC based on HPV status-pointing to different biological mechanisms of carcinogenesis. The present findings support a causal role of HPV in a subset of conjunctival SCC.

PURPOSE:To evaluate the tolerability and usability of topical anaesthesia in single rectus muscle recession for strabismus caused by Graves' orbitopathy (GO). To compare the perioperative pain score and surgical outcome between GO patients and non-GO patients.METHODS:A retrospective comparative study of consecutive single rectus muscle recession performed under topical anaesthesia was carried out. All patients scheduled for one-stage single rectus muscle recession under topical anaesthesia were included. Numerical visual analogue pain score scale (NVAS) points, rates of motor success (horizontal deviation < 8 prism diopters (PD) and vertical deviation ≤ 6 PD) and sensory success (no diplopia without prisms), complications and postoperative adjustment frequencies were compared between GO and non-GO patients.RESULTS:A total of 111 patients were included. The mean perioperative pain scores were 2.3 (SD ± 1.3) in GO and 1.6 (SD ± 1.1) in non-GO patients (p = 0.06 adjusted for gender). The postoperative mean alignments in GO and non-GO patients were 2 versus 3 PD horizontally and 1 versus 1 PD vertically respectively. Both motor and sensory success rates were 98% in GO patients and 94% versus 93% in non-GO patients. Adjustments as a second procedure the day after surgery was performed in 10% of the GO patients and 15% of the non-GO patients. The oculocardiac reflex was not triggered in any of the GO patients.CONCLUSION:Topical anaesthesia in single muscle recession for GO is safe, well-tolerated and gives comparable surgical outcomes to those achieved in non-GO patients.

Chondromyxoid fibroma (CMF) is a very rare entity, accounting for <1% of all bone tumours. So far, only 4 cases have been reported with the orbit as primary location. Here, we present a case of orbital CMF with periocular pain as the presenting symptom and as the only symptom when the tumour recurred after surgery. A 41-year-old man underwent a CT scan and later an MRI as part of evaluation for left periocular pain that had persisted for a year. Clinical examination was normal. CT and MRI revealed an irregular mass in the lateral part of the left orbital roof. The tumour was removed by curettage, and histopathological examination showed a CMF. The pain was absent for 3 months. A second MRI 5 months postoperatively revealed a recurrence, which was removed surgically, resulting in pain alleviation. In conclusion, CMF is a potential cause of periocular pain, and persistent periocular pain with normal clinical findings should warrant a CT or MRI scan.

Aims Human papillomavirus (HPV) is considered a causative agent for the development of a broad range of human carcinomas. The role of HPV in the development of conjunctival intraepithelial neoplasia (CIN) and carcinoma (cSCC) remains unclear. The purpose of the present study was to investigate the HPV prevalence in a nationwide cohort and to describe clinical and histopathological features in relation to HPV status. Methods All cases of CIN and cSCC in Denmark from 1980 to 2016 were included. We combined p16 immunohistochemistry (IHC), RNA in situ hybridisation (RNA ISH) and HPV DNA PCR to detect HPV. The results were correlated to clinical and histopathological parameters. Results One hundred twelve primary tumours and 33 recurrent tumours were included for HPV analysis. Twenty-four (21%) of the primary tumours were HPV positive by PCR. Eighteen of out 19 HPV-positive tumours were positive by RNA ISH. HPV16 was the most prevalent genotype (n=18, 75%). The patients with HPV-positive tumours were significantly younger (mean difference 11.5 years, 95% CI 5.2 to 17.9, p=0.0005) and had a higher recurrence compared with patients with HPV-negative tumours (HR 2.30, 95% CI 1.02 to 5.21, p=0.046). The HPV-positive tumours were associated with a positive p16 IHC and a non-keratinising morphology. Conclusion We describe distinct clinical and histopathological features associated with HPV status in cSCC. The finding of transcriptionally active HPV in this material lends support to a causal role of HPV in a subset of cSCC.

Loss of vision is a feared consequence of idiopathic intracranial hypertension (IIH). Optic nerve sheath fenestration (ONSF) may be an effective surgical approach to protect visual function in medically refractory IIH. In this study, we evaluate the impact of unilateral superomedial transconjunctival ONSF on bilateral visual outcome using a comprehensive follow-up program. A retrospective chart review of IIH patients who underwent unilateral ONSF between January 2016 and March 2021 was conducted. Patients fulfilling the revised Friedman criteria for IIH and who had exclusively received ONSF as a surgical treatment were included. Main outcomes were visual acuity (VA); perimetric mean deviation (PMD); papilledema grade; and optic nerve head elevation (maxONHE) 1 week, 2 weeks, and 1, 3, and 6 months after surgery. VA (p < 0.05), PMD (p < 0.05), papilledema grade (p < 0.01), and maxOHNE (p < 0.001) were improved after 6 months on both the operated and non-operated eye. Prolonged surgical delay impedes PMD improvement (r = −0.78, p < 0.01), and an increasing opening pressure initiates a greater ganglion cell loss (r = −0.79, p < 0.01). In this small case series, we demonstrate that unilateral superonasal transconjunctival ONSF is a safe procedure with an effect on both eyes. Optic nerve head elevation and PMD are feasible biomarkers for assessing early treatment efficacy after ONSF.

Background: Separately, cryotherapy and brachytherapy have shown promising results when adjuvating the excision of squamous cell carcinoma of the conjunctiva (SCCC). The aim of this paper is to assess the combined effect in terms of complications and recurrence rate. Summary: We describe 2 patients suffering from SCCC, and we review the current literature on adjuvant cryotherapy and brachytherapy. Both patients, one of whom suffered from recurrent SCCC, underwent surgical excision followed by combined cryotherapy and brachytherapy. Cryotherapy was performed using a retinal cryoprobe, and 2 rounds each of 5 s with N2O as a cryogen were applied. Brachytherapy was performed using a ruthenium-106 plaque, delivering a dosage of 100 Gy at 2-mm depth. Key Messages: By reviewing the current literature and describing 2 case reports, this paper illustrates the use of combined cryotherapy and brachytherapy after surgical excision of SCCC. The current literature presents promising results of each treatment, and the 2 cases showed promising results by combining the 2 adjuvant therapies showing no signs of recurrence or complications during a follow-up period of 26 and 38 months.

Purpose: To evaluate the safety and feasibility of injecting allogeneic adipose-derived mesenchymal stem cells (ASCs) into the lacrimal gland (LG) as a treatment of aqueous deficient dry eye disease (ADDE). Methods: In this open-label, 5-visit clinical trial (baseline, treatment and weeks 1, 4 and 16) seven subjects with ADDE received one transconjunctival injection of allogeneic ASCs into the LG in one eye. The ASC product contained 22 million ASCs/ml and the injected volume was maximally 50% of the LG volume as determined on magnetic resonance imaging (MRI). Treatment related adverse events (AEs) were assessed at each visit (primary endpoint). Ocular Surface Disease Index (OSDI), tear osmolarity, tear film breakup time (TBUT), corneal staining (Oxford grade) and Schirmer's I test were assessed at each timepoint. Results: No AEs related to the study treatment were observed. Mean follow-up time was 126 days after treatment. The mean OSDI score decreased from 58.9 +/- 20.6 at baseline to 34.1 +/- 21.6 (p < 0.002). In the study eye mean tear osmolarity decreased from 312.9 +/- 10.4 to 291.6 +/- 10.9 mosm/l (p < 0.002), mean TBUT increased from 3.7 +/- 1.5 to 7.1 +/- 1.9 s (p < 0.002), mean Schirmer's I test increased from 4.6 +/- 0.7 to 8.1 +/- 3.1 mm/5 min (p < 0.03), while mean Oxford grade showed a trend towards a decrease from 2.4 +/- 0.7 to 1.3 +/- 1 (p < 0.10). Conclusion: Our trial suggests that injection of allogeneic ASCs into the LG is a safe and feasible treatment of severe ADDE. A randomized placebo-controlled trial aimed at elucidating the therapeutic effect of allogeneic ASCs in a larger patient cohort from our research group is currently underway.

Background The purpose was to describe the Nordic treatment practices and to reach a Nordic consensus for the treatment of sebaceous eyelid carcinoma. Methods The treatment practices data was collected by a questionnaire with 37 questions to the Nordic oculoplastic surgeons and analyzed. A PubMed MEDLINE database search was done to gather data on the published treatment practices and recommendations. A working group that consisted of in minimum one senior consultant from each leading Nordic University Eye Hospital was assigned. A structured interactive method was used to establish the consensus. Results Twenty-four doctors responded to the questionnaire. 23/24 (96%) of the respondents took a biopsy before surgery. Regional lymph node scanning was routinely done by 14/23 (61%) and a systemic screening of a metastatic disease by 13/23 (57%). 6/22 (27%) never took conjunctival mapping biopsies and 12/23 (52%) never screened for Muir- Torre. Respondents used Mohs surgery, frozen section or multi-stage excision with delayed closure, and 5–6 mm was the mostly preferred margin. Sentinel lymph node biopsy was a possible option for 9/22 (41%) and cryotherapy and Mitomycin C for 6/22 (27%) respondents. 50% of respondents considered radiation as a treatment option. 15/16 (94%) respondents always followed-up their patients, most for 5 years. Two thirds scanned regional lymph nodes during the follow-up. Consensus was reached for 18 statements representing three domains: preoperative work-up, treatment and follow-up. Conclusion Treatment practices differ in between the five Nordic countries which have similar public health care systems. In the article the authors present a Nordic consensus for the treatment of eyelid sebaceous carcinoma.

PURPOSE:We aimed to study the prevalence of human papillomavirus (HPV) in conjunctival intraepithelial neoplasia and carcinoma. Furthermore, we aimed to explore whether geographical differences or different detection modalities are associated with the conflicting information regarding HPV and the development of the disease.METHODS:We searched the MEDLINE, EMBASE and Scopus databases for studies reporting on HPV and conjunctival intraepithelial neoplasia or carcinoma. The pooled prevalence proportions, odds ratio (OR) and corresponding 95% confidence intervals were calculated assuming a random-effects model. Subgroup analyses and meta-regression explored possible sources of heterogeneity.RESULTS:A total of 39 studies were included in the systematic review. The pooled prevalence of HPV in conjunctival intraepithelial neoplasia and carcinoma was 26%, with HPV16, 18, and 33 being the most frequently reported genotypes. Human papillomavirus (HPV) infection was associated with an increased risk of conjunctival intraepithelial neoplasia and carcinoma (OR 8.4, 95% confidence interval (CI) 3.7-19.1); lower in studies from African countries (OR 1.7, 95% CI 0.9-3.5) than other countries (OR 16.1, 95% CI 5.8-44.3), p = 0.013.CONCLUSION:Human papillomavirus infection increases the odds of conjunctival intraepithelial neoplasia and carcinoma by 8.4 compared to healthy conjunctival mucosa or other ocular surface diseases. There seem to be geographical differences regarding HPV in conjunctival intraepithelial neoplasia and carcinoma. HPV16 was the most prevalent genotype, followed by HPV18 and HPV33, meaning that most of the HPV-related conjunctival intraepithelial neoplasia and carcinoma may be prevented by the HPV vaccines that are currently available.

Herein, we wanted to explore the molecular landscape of mucosal melanoma from different sites and identify potential molecular targets for future therapy. Mucosal melanomas ( N = 40) from different sites (conjunctiva, sinonasal cavity, rectum, and vagina) were investigated. Targeted next-generation sequencing along with Nanostring gene expression profiling was performed. Genetically, conjunctival melanoma was characterized by BRAF -V600E (30%) and NF1 mutations (17%). Mucosal melanomas at nonsun-exposed sites harbored alterations in NRAS , KIT , NF1 , along with atypical BRAF mutations. When comparing the gene expression profile of conjunctival melanoma and nonsun-exposed mucosal melanoma, 41 genes were found to be significantly deregulated. Programmed death-ligand 1 (PD-L1) presented a significant sixfold upregulation in conjunctival melanoma compared to the other mucosal melanomas. While melanomas of the sinonasal cavity, vagina, and rectum are molecularly similar, conjunctival melanoma is characterized by a higher frequency of BRAF -V600E mutations and differential expression of several genes involved in the immune response.

Malignant tumors of epithelial origin are the most frequent neoplasms of the lacrimal drainage system (LDS). A total of 539 cases are reported in the literature from 1960 to 2019. LDS carcinoma is a disease of the middle-aged and elderly population, with a median age at diagnosis of 57 years. Overall, there is a slight male predominance. Reported risk factors are chronic inflammation, LDS papilloma, and infection with oncogenic viruses. Symptoms of an LDS carcinoma resemble those of benign, inflammatory diseases, with epiphora from obstruction of the LDS as the most frequently encountered symptom. The median time from symptoms to diagnosis is 12 months and even longer for patients reporting epiphora as the only initial symptom. This diagnostic delay leads to a substantial fraction of patients with locally advanced tumors and lymph node spread at the time of diagnosis. Surgery with adjuvant radiotherapy is the treatment of choice for most patients; however, the extension and aggressiveness of the disease and the patient's general health and preferences determine the definite treatment. Five-year overall survival is reported to range from 61 to 87.6%. A large tumor size and positive lymph node status correlate with a decreased overall and disease-free survival.