Cutaneous squamous cell carcinoma of the eyelid in northern latitudes, a 25-year experience in Finland.

PURPOSE: To evaluate the incidence, clinical features, diagnostic challenges, management and prognosis of cutaneous squamous cell carcinoma of the eyelid (ecSCC) in southern Finland, northern Europe, latitude 62° N. METHODS: Patients were identified from the Finnish Cancer Registry and the Helsinki University Hospital databases during a 25-year period (1998-2022). Age, sex, location, clinical and histopathological diagnosis, treatment and outcome were retrieved. RESULTS: Cutaneous squamous cell carcinoma of the eyelid (ecSCC) was diagnosed in 58 patients. The mean age-standardized incidence was 1.03 per 100 000. Median age at the time of histopathological diagnosis was 79 (range 55-93) years; sex ratio was 0.52. Clinical diagnosis in the referral was ecSCC in only three patients. The most frequent misdiagnosis (38%) was basal cell carcinoma (BCC). One or more of the known risk factors (smoking, history of extensive sun exposure, systemic immunosuppression and previous in situ cSCC/cSCC) were documented in 71% of the patients. More than one third (38%) of the patients developed in situ SCC elsewhere on the skin; one third (31%) of the patients had invasive cSCC elsewhere. During the median follow-up time of 24 months, three patients experienced local recurrence, four patients developed metastatic disease (median 19 months) and two patients died of metastatic ecSCC. CONCLUSION: The estimated incidence of ecSCC in Finland (predominantly white Caucasian) was higher than in a previous study from Europe. Clinical diagnosis of ecSCC is difficult and often misdiagnosed as BCC. Immunosuppression as a risk factor should noticed. Recurrences of ecSCC, which may be lethal, were infrequent.

Sebaceous carcinoma of the eyelid: 21-year experience in a Nordic country.

PURPOSE: To evaluate the clinical features, diagnostic challenges, management, and prognosis of sebaceous carcinoma (SC) of the eyelids and periocular region in a Nordic country. METHODS: Patients were identified from the Finnish Cancer Registry and the Helsinki University Hospital databases during the 21-year period 1998-2018. Age, sex, location, clinical and histopathologic diagnosis, treatment and outcome were registered. RESULTS: Sebaceous carcinoma (SC) was diagnosed in 32 patients. The incidence was 0.6 per million. Median age at the time of histopathologic diagnosis was 74 years, and 72% of patients were women. Diagnostic delay was often long, median 12 months. The most common cause for delay was misdiagnosis (72%): a chalazion in 34% and a benign tumour in 22%. The most common location was the upper eyelid (53%) and tumour type a solitary nodule (94%). The SC was not correctly diagnosed in 12 (40%) of 30 preoperative biopsies. The treatment for 31 (97%) patients was complete surgical removal with reconstruction. Conjunctival intraepithelial growth was found in 50%. The leading postoperative problem was ocular irritation (30%). During a median follow-up of 58 months, two patients (6%) experienced a local recurrence and one patient died from metastatic SC. CONCLUSIONS: The estimated incidence of SC in Finland was somewhat higher than in other Western countries. The diagnosis was often markedly delayed. Especially differentiation from chalazion continues to be essential. To improve outcomes, it is essential to inform the pathologist about the possibility of SC in eyelid biopsies and specimens and ideally submit them to an ophthalmic pathology service.

Identification of two highly antigenic epitope markers predicting multiple sclerosis in optic neuritis patients.

BACKGROUND: Optic neuritis (ON) can occur as an isolated episode or will develop to multiple sclerosis (MS) a chronic autoimmune disease. What predicts ON progression to MS remains poorly understood. METHODS: We characterised the antibody epitope repertoire in three independent clinical cohorts (discovery (n = 62), validation (n = 20) and external cohort (n = 421)) using mimotope variation analysis (MVA), a next generation phage display technology to identify epitopes that associate with prognosis of ON. FINDINGS: We observed distinct epitope profiles for ON, MS and the controls, whereas epitope repertoires of sera and CSF were highly similar. Two unique and highly immunogenic epitopes A and B were detected in subjects with ON progressing to MS. These epitopes A and B were strongly associated with herpesviral antigens (VCA p18 of  Epstein-Barr virus (EBV); gB of Cytomegalovirus (CMV)). ROC addressed 75% of MS subjects with ON onset correctly (at 75% sensitivity and 74.22% specificity) based on the two-epitope biomarker analysis. INTERPRETATION: This is the first report on epitope diagnostics for MS employing the unbiased strategy of MVA for identification of novel immunological features of disease. FUNDING: The Estonian Ministry of Education, The Estonian Research Council (PRG573, PRG805 and PSG691), H2020-MSCA-RISE-2016 (SZTEST), H2020-NMBP-2017 (PANBIORA), Helsinki University Hospital, Mary and Georg C. Ehrnrooth, Finnish Eye, Sigrid Jusélius and Magnus Ehrnrooth Foundations.

The clinical spectrum and prognosis of idiopathic acute optic neuritis: A longitudinal study in Southern Finland.

BACKGROUND: To analyse in a population-based setting the clinical features, prognostic factors, and seasonality of patients diagnosed with acute idiopathic optic neuritis (ON). METHODS: Retrospective analysis of ophthalmological records, laboratory parameters, and magnetic resonance imaging (MRI) of patients with symptoms suggestive of ON referred to the Helsinki University Hospital (serving a population of 1.53 million in Southern Finland) were analysed between May 1, 2008 and April 14, 2012. RESULTS: Of the 291 patients with suspected ON, 184 (63%) were diagnosed with ON (mean age 34 years, 76% females). Intravenous methylprednisolone treatment was administered in 131 (71%) patients. First ON was diagnosed in 123 patients (67%), 55 (30%) had a previous diagnosis of multiple sclerosis (MS) and two patients with their first ON were diagnosed with neuromyelitis optica. Evolution of best corrected visual acuity (BCVA) was analysed in 132 (72%) patients, who were reviewed median of 38 days after onset. Median and mean BCVAs in these reviewed patients were 0.4 and 0.2 at the time of diagnosis and 1.0 and 0.5 at the time of the review. Recovery was relatively good in the majority of patients; 82% (n = 108) had reached BCVA of ≥0.5 and 70% (n = 92) and BCVA of ≥0.8 at the time of the review, while thirteen (10%) had poor prognosis, BCVA ≤0.1 at review. Accessory clinical features included optic disc swelling (21%), colour vision impairment (75%), and pain with eye movements (65%). Relative afferent pupillary defect was abnormal in 76% of the patients with their first ON. Baseline visual acuity was most strongly associated with visual outcome at review (P < 0.001, linear regression). Optic disc swelling and the presence of lesions in the optic nerve on MRI had a more modest association with poorer recovery (P = 0.033 and P = 0.049, respectively), while age, sex, previous history of ON, and previous diagnosis of multiple sclerosis were not associated with outcome at review. Incidence of ON showed a clear seasonal pattern; there were two times more cases in April to June versus October to December (P = 0.03), confirming previous results from Sweden. CONCLUSIONS: Our data suggest that besides baseline visual acuity, optic disc swelling and lesions in the optic nerve on MRI are associated with poorer prognosis. As in previous studies, we observed that diagnostics of ON is difficult, accessory clinical findings such as pain and RAPD are not always present. Although the diagnosis of ON is clinical, the role of MRI should be considered in differential diagnostics and in defining potential prognostic markers.

Incidence and Mimickers of Acute Idiopathic Optic Neuritis: Analysis of 291 Consecutive Patients from Southern Finland.

PURPOSE: To estimate the population-based incidence of acute idiopathic optic neuritis (ON) and analyse its differential diagnosis in patients referred with symptoms suggestive of ON. METHODS: Patients with suspected ON referred to the Helsinki University Hospital, serving a population of 1.5 million in Southern Finland, were reviewed between 1st May 2008 and 14th April 2012. Brain and optic nerve magnetic resonance imaging (MRI) was performed within 24 hours in 83% of patients. RESULTS: Of 291 referred patients, 184 (63%; 95% confidence interval [CI], 57-69%) were diagnosed with ON whereas 107 (37%) had another condition. The estimated crude incidence of ON in Southern Finland was 3.0 (95% CI 2.8-3.3) per 100,000 (females, 4.6 and males, 1.4). Mean age was 34 years (range 15-61), 76% were female. Two (1%) were diagnosed with neuromyelitis optica. ON as the first demyelinative episode was diagnosed in 108 (59%) patients, and MRI showed demyelinating lesions (MRI+) in 82% (95% CI, 75-89) of them. MRI+ predicted the development of multiple sclerosis (MS): 54% of MRI+ vs. 5% MRI- patients were diagnosed as MS during a mean follow-up of 7.7 years. The most common differential diagnosis was non-arteritic anterior ischemic optic neuropathy (12%). Six (2%) intracranial compressive lesions were found upon MRI scan. CONCLUSIONS: More than a third of patients with symptoms suggestive of ON had another condition. Demyelinative lesions on MRI indicated higher risk of developing MS. We recommend the use of MRI to improve the differential diagnostic accuracy of ON and to identify patients with high risk of MS.

Exome and regulatory element sequencing of neuromyelitis optica patients.

Neuromyelitis optica (NMO) is rare in Finland. To identify rare genetic variants contributing to NMO risk we performed whole exome, HLA and regulatory region sequencing in all ascertained cases during 2005-2013 (n=5) in a Southern Finnish population of 1.6 million. There were no rare variant shared by all patients. Four missense variants were shared by two patients in C3ORF20, PDZD2, C5ORF47 and ZNF606. Another PDZD2 variant was found in a third patient. In the non-coding sequence two predictably functional rare variants were shared by two patients. Our results do not support a homogeneous genetic etiology of NMO in Finland.

Neuromyelitis optica and aquaporin-4 (AQP4) autoantibodies in consecutive optic neuritis patients in Southern Finland.

PURPOSE: To analyse the frequency of neuromyelitis optica (NMO) among consecutive optic neuritis (ON) patients in Southern Finland and the feasibility of Aquaporin-4 (AQP4) autoantibody assay in the diagnosis of NMO. METHODS: Consecutive patients with symptoms suggestive of acute ON and managed in the Helsinki University Central Hospital were evaluated critically screened for AQP4 autoantibody during a 47.5-month period. The antibodies were determined using radioimmunoprecipitation method. AQP4 index >15 was considered positive, 10-15 borderline and <10 normal. Brain magnetic resonance imaging (MRI) was performed for all patients. RESULTS: Of the 300 patients with suspected ON, 191 were eventually diagnosed as ON, and 66 (35%) of them had a previous diagnosis or were diagnosed with multiple sclerosis (MS). Of the 125 patients without MS diagnosis, 62 (50%) had demyelinative lesions in MRI, which is a risk factor for developing MS. Two patients (1.1%; 95% CI 0.3-4.5) fulfilled the criteria of NMO. Positive AQP4 antibodies were found in three patients (1.6% 95% CI 0.3-4.5), one of them had NMO, one had MS and one became diagnosed with MS a month later. Borderline autoantibody levels were found in 10 patients, 7 of whom had MS. CONCLUSIONS: NMO is rare among ON patients in the population of Southern Finland. In this small cohort, the sensitivity and positive predictive values of the AQP4 autoantibody index for NMO were low, 1/2 and 1/3 respectively, and do not support initiating routine screening.