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.

Acute versus late endoscopic dacryocystorhinostomy in treatment of acute dacryocystitis: A prospective randomised trial with an 18-month follow-up.

PURPOSE: To compare the long-term symptom resolution and use of resources of performing endoscopic dacryocystorhinostomy (enDCR) in acute or delayed phase in patients with acute dacryocystitis (AD). METHODS: This prospective, randomised controlled trial was conducted in Helsinki University tertiary Eye and Ear, Nose and Throat (ENT) Hospitals between September 2013 and January 2019. Fifty patients aged 18 and above presenting with AD in the emergency care were randomised into acute and delayed enDCR surgery groups, performed in 1 week or 4 months from the diagnosis of AD. The follow-up time was 18 months. Outcome measures were subjective epiphora, lacrimal symptoms and visual analogue scale (VAS) pain scores, the number of hospitalised and unhealthy days, use of medication and openness in lacrimal syringing and dye test. RESULTS: EnDCR was performed on 24 patients in the acute and 19 in the delayed group. There were no significant differences between the groups in follow-up lacrimal symptoms, syringing test, dye test or use of resources. At the 18 months' follow-up, 21/23 (91.3%) in the acute group and 12/13 (92.3%) in the delayed group had no disturbing lacrimal symptoms. When reoperations and dropouts are considered, beneficial outcome was 22/24 (91.7%) in the acute and 12/16 (75%) (p = 0.195) in the delayed group. The acute group had significantly fewer pain medication days than the delayed group, 3 versus 10.5 (p = 0.03). CONCLUSION: Acute enDCR is associated with fewer pain medication days and equal resolution of lacrimal symptoms and use of resources.

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.

Nordic treatment practices survey and consensus for treatment of eyelid sebaceous carcinoma.

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.

IgG4-related disease mimicking chalazion in the upper eyelid with skin manifestations on the trunk.

IgG4-related disease is a recently defined inflammatory process characterized by IgG4-bearing plasma cells in the involved tissues. The most common sites of involvement are the pancreas, hepatobiliary tract, salivary glands, lymph nodes, retroperitoneum and orbit, especially the lacrimal glands. Other ocular or ocular adnexal sites are rare. To our knowledge, there is one reported case of a conjunctival involvement. We describe a patient, who had an IgG4-RD mimicking chalazion in the upper eyelid, confined to the tarsus, with multiple skin lesions on the trunk. This is a case report of a 55-year-old female. A 55-year-old female presented with an upper eyelid lesion, which was clinically diagnosed as chalazion and drained three times. Histopathological diagnoses were chalazion and inflammation with mixed cells, respectively. Additionally, the patient had had skin nodules on the trunk for several years. Finally, after a third recurrence, the tarsal eyelid lesion was completely excised. The tarsal pathology specimen showed 85 IgG4 positive plasma cells per HPF and the IgG4/IgG ratio was 0.64, suggesting a probable IgG4-related disease. The re-examined skin lesions resembled histologically the eyelid lesion. It is essential to be aware of IgG4-related disease, including in recurrent chalazia.

Collagen XVIII/endostatin shows a ubiquitous distribution in human ocular tissues and endostatin-containing fragments accumulate in ocular fluid samples.

BACKGROUND: The endostatin domain of type XVIII collagen (ColXVIII) inhibits neovascularization and regulates cell migration and matrix turnover. This study was designed to demonstrate the protein and gene expression patterns of ColXVIII/endostatin in the human eye and to ascertain whether endostatin is detectable in ocular fluid samples. METHODS: Twenty human eyes enucleated on account of choroidal melanoma were used for immunohistochemical stainings with antibodies against ColXVIII and endostatin. In situ hybridization was used to localize cells responsible for the production of mRNA for ColXVIII. Tear fluid, aqueous humor, and vitreous gel samples were used for Western immunoblotting to detect endostatin fragments in these samples. RESULTS: ColXVIII was immunolocalized to almost all ocular structures, namely the basement membranes (BMs) of the corneal and conjunctival epithelia, Descement's membrane, the anterior border layer and posterior pigmented epithelium of the iris, the BMs of the pigmented and non-pigmented ciliary epithelia, the internal wall of Schlemm's canal and trabeculae, the ciliary and iris muscle cells, the BMs of the pigment epithelium of the retina, and the internal limiting membrane. Universal expression was seen in the BMs of vascular endothelial cells, and in fibroblasts located in the conjunctiva, the iris, and the ciliary body. Endostatin showed a corresponding pattern, but additional immunostaining was present in the corneal and conjunctival epithelial cells. Most epithelial and mesenchymal cells expressed the mRNA for ColXVIII. Endostatin-containing fragments varying in size were detected in tear fluid, aqueous humor and vitreous gel samples. CONCLUSIONS: Practically all structures of the human eye contain ColXVIII/endostatin, emphasizing its possible important structural and functional role in the human eye. Furthermore, ocular fluid samples contain endostatin fragments, which may contribute to the antiangiogenic properties of the eye.

Cyclosporin a inhibits calcineurin/nuclear factor of activated T-cells signaling and induces apoptosis in retinoblastoma cells.

PURPOSE: Although the clinical efficacy of cyclosporin A (CSA) in retinoblastoma (RB) has been attributed to multidrug resistance reversal activity, the authors hypothesized that CSA is also directly toxic to RB cells through inhibition of calcineurin (CN)/nuclear factor of activated T-cells (NFAT) signaling. METHODS: Antiproliferative effects of CSA, PSC-833 (a CSA analogue that does not inhibit CN), and FK506 (a CN inhibitor structurally unrelated to CSA) were evaluated in Y79 and Weri-RB1 cells by WST-1 assay. Apoptosis induction by CSA and PSC-833 was measured by detection of caspase 3/7 activity and by flow cytometry, using annexin-V and 7-AAD stains. Expression of CN was assayed in RB cells by immunocytochemistry. Expression of NFAT, a CN-dependent transcription factor family, and FK506 binding protein 12/12.6 (FKBP12/12.6), effectors of CN inhibition by FK506, was assayed in RB cells by Western blot analysis. NFAT activity was assayed in CSA-treated and -untreated Y79 cells transfected with an NFAT-sensitive reporter gene. RESULTS: CSA induced dose-dependent antiproliferative and proapoptotic effects at clinically achievable levels in Y79 and Weri-RB1 cells. PSC-833 induced antiproliferative effects only at nonphysiologic concentrations with minimal associated apoptosis. FK506 induced minimal antiproliferative effects in RB cell lines, probably due to trace or absent FKBP12/12.6 expression. RB cell lines expressed CN-alpha, CN-beta, NFATc1, and NFATc3. CSA treatment also potently inhibited NFAT-mediated reporter gene transcription. CONCLUSIONS: These results demonstrate functional integrity of the CN/NFAT signaling cascade in RB cells and suggest that CSA is cytotoxic to RB cells through inhibition of this pathway and consequent apoptosis induction.

Geographic disparities in diagnostic screening for metastatic uveal melanoma.

PURPOSE: To evaluate current practice patterns in diagnostic screening for asymptomatic metastatic uveal melanoma. DESIGN: Survey. PARTICIPANTS: Ocular oncologists practicing in North America (United States, Canada) and Europe. METHODS: Questionnaire sent to specialists participating in the Collaborative Ocular Melanoma Study (COMS) or listed in the Ophthalmic Oncology Task Force of the European Organization for Research and Treatment of Cancer. MAIN OUTCOME MEASURES: Methods used to screen patients with uveal melanoma for asymptomatic metastasis at initial presentation and follow-up. RESULTS: Thirty-six of 43 (84%) North American (COMS) specialists and 57 of 103 (55%) European specialists responded to the survey. At presentation, 6 of 36 (17%) North American specialists, versus 54 of 57 (95%) European specialists, performed at least one type of liver imaging study (computed tomography, magnetic resonance imaging, ultrasonography, or nuclear medicine) (P<0.0001). On follow-up, only 1 of 36 (3%) North American specialists, versus 45 of 57 (79%) European specialists, obtained a liver imaging study (P<0.0001). Thirty-six of 36 (100%) North American specialists, versus 49 of 57 (86%) European specialists, ordered chest x-rays at presentation (P<0.02). This disparity was greater at the time of follow-up, when 28 of 36 (78%) North American specialists, versus 28 of 57 (49%) European specialists, ordered chest x-rays (P<0.01). Similar proportions of specialists in North America and Europe obtained a physical examination and liver function tests at the time of presentation and on subsequent follow-up examination. CONCLUSIONS: Significant differences exist between ocular oncologists in North America and Europe in the use of techniques to screen for metastatic uveal melanoma. North American COMS centers rely primarily upon liver function tests and chest x-rays. The majority of European centers use liver ultrasonography at initial diagnosis and continue to do so every 6 months. Cost-effective screening protocols for patients with uveal melanoma should be designed and implemented uniformly among ocular oncologists.

Rapid identification of germline mutations in retinoblastoma by protein truncation testing.

OBJECTIVE: To demonstrate the utility of protein truncation testing (PTT) for rapid detection and sequencing of germline mutations in the retinoblastoma tumor suppressor gene (RB1). METHODS: We performed PTT, a technique based on the in vitro synthesis of protein from amplified RNA, on 27 probands from 27 kindreds with hereditary retinoblastoma. In 4 kindreds, PTT was also performed on 1 additional affected relative. Ten unrelated patients without retinoblastoma were included as negative control subjects. All PTT-detected mutations were further analyzed by focused sequencing of genomic DNA. When no mutation was detected by PTT, we performed exon-by-exon sequencing, as well as cytogenetic analysis by Giemsa-trypsin-Giemsa banding and by fluorescent in situ hybridization for RB1. The results of proband testing were used for direct genetic testing by polymerase chain reaction and sequencing in 11 relatives from 7 of the 27 kindreds. RESULTS: Of the probands tested, 19 (70%) of 27 tested positive for germline mutations by PTT. In 1 kindred, the proband had negative PTT results but an additional affected relative had positive PTT results. Focused DNA sequencing of 1 patient with positive PTT results from each of the 20 kindreds with positive PTT results revealed truncating mutations in 19 kindreds. Four demonstrated frameshift deletions, 6 had splice site mutations, and 9 showed nonsense mutations. Further analysis by genomic exon-by-exon sequencing and karyotype analysis of the 8 probands who tested negative for germline mutations by PTT revealed 1 splice site mutation, 2 missense mutations, and 1 chromosomal deletion. Focused sequencing based on positive PTT results was successfully used to confirm shared truncating mutations in additional affected family members in 2 kindreds. Using a multitiered approach to genetic testing, 23 (85%) of 27 kindreds had mutations identified and those detected by PTT received a positive result in as few as 7 days. In control subjects, PTT produced no false-positive results. CONCLUSIONS: Protein truncation testing is an effective, rapid single-modality screen for germline mutations in patients with retinoblastoma. When used as an initial screen, PTT can increase the yield of additional testing modalities, such as sequencing and chromosomal analysis, providing a timely and cost-effective approach for the diagnosis of heritable germline mutations in patients with retinoblastoma.Clinical Relevance The clinical application of PTT in retinoblastoma will improve detection of germline retinoblastoma mutations, which will supply critical information for prognosis, treatment planning, follow-up care, and genetic counseling.

Ultrastructural localization of the HNK-1 carbohydrate epitope to glial and neuronal cells of the human retina.

PURPOSE: To localize the cell adhesion-related HNK-1 carbohydrate epitope in the human retina at cellular and subcellular levels. METHODS: Retinas were obtained from seven normal human eyes at autopsy (age, 43-78 years). The specimens were embedded in medium-grade resin and studied by postembedding immunoelectron microscopy using the primary mouse mAb HNK-1 (Leu 7) to the HNK-1 epitope and secondary antibodies conjugated to 10-nm colloidal gold particles. RESULTS: Prominent immunolabeling with mAb HNK-1 was observed on the outer surface of the entire plasma membrane of Müller radial glial cells, including their microvilli between the inner segments of rods and cones, on the plasma membranes of astrocytes in the ganglion cell layer, in bipolar cells in the inner nuclear layer, and in photoreceptor cells in the outer nuclear layer. Fewer gold particles were present on plasma membranes of other main types of retinal neurons, including ganglion cells. Only the outer segments of rods and cones and the endothelial cells of retinal capillaries were never labeled. In the ciliary epithelium, gold particles localized to the basement membrane of the nonpigmented and pigmented layers and to the cytoplasm of the pigmented epithelium. CONCLUSIONS: Unlike in many other species, the HNK-1 epitope in the human retina is found on both glial and neuronal cells, including photoreceptors. This epitope potentially contributes to neuron-to-neuron and glia-to-neuron adhesion of human retinal cells.

The HNK-1 Carbohydrate Epitope and the Human Eye in Health and Disease.

The HNK-1 carbohydrate epitope is part of many cell membrane and extracellular matrix molecules, several of which have been implicated in cell adhesion. It is a versatile tool in eye research. In the human eye this epitope is present in the retina, the optic and ciliary nerves, the ciliary and iris epithelia, the zonular lamella, and the sclera. It is phylogenetically conserved, but the positive cell types vary from species to species. In addition to revealing interspecies differences in the vertebrate retina, the HNK-1 epitope has been used to identify a novel cell type in the eye: the subepithelial matrix cells that reside in the inner connective tissue layer (ICTL) of the ciliary body. Although these cells resemble fibroblasts in ultrastructure, they form a distinct cell population that differs in antigenic profile from fibroblasts in other tissues. The HNK-1 epitope is also associated with the elastic fiber system of the ICTL, which may be produced by the subepithelial matrix cells. It may help to structurally stabilize the ciliary body and the retina. The HNK-1 epitope is also involved in many important eye diseases. The subepithelial matrix cells seem to be susceptible to irrreversible atrophy as a result of glaucoma, thermal injury, and tissue compression. On the other hand, the HNK-1 epitope is found in the extracellular matrix of secondary cataracts and may contribute to its pathogenesis. Finally, this epitope has proved to be useful in identifying deposits of exfoliation material, and in tracing neuroepithelial derivatives in developmental anomalies and tumors of the eye.