Histopathologic reassessment of melanoma and other melanocytic skin lesions excised in 2009 and 2018-2019. / Histopatologisk revurdering av melanom og andre melanocytære hudlesjoner eksidert i 2009 og 2018­19.

BACKGROUND: Histopathological assessment of melanoma and other melanocytic skin lesions can be difficult and can vary between pathologists. MATERIAL AND METHOD: Histopathological slides of 196 melanocytic skin lesions from 2009 and 2018-2019 were obtained from the archive of the Department of Pathology at Oslo University Hospital and classified into six diagnostic categories: 1) benign nevus, 2) irregular/dysplastic nevus, i.e. dysplastic nevus with moderate atypia, 3) nevus with severe atypia, i.e. dysplastic nevus with severe atypia, 4) melanoma in situ, 5) superficial spreading or lentiginous melanoma and 6) nodular melanoma. The slides were then examined independently and blindly by three experienced pathologists and categorised in the same way. Interobserver agreement was assessed with Cohen's kappa, and agreement with the original diagnosis was assessed by the proportion of assessments in the same diagnostic category. RESULTS: The kappa values for the assessments from the three pathologists ranged from 0.45 to 0.50. The proportion of reassessments in agreement with the original diagnostic category was 85.7 % (95 % CI 75.7 to 92.1), 29.2 % (19.9 to 40.5), 27.8 % (20.9 to 36.0), 78.3 % (70.4 to 84.5), 81.2 % (73.7 to 86.9) and 93.3 % (82.1 to 97.7), respectively, i.e. highest for nodular melanoma. The proportion of reassessments in which the diagnosis was more serious or less serious than the original diagnosis was higher and lower, respectively, for slides from 2009 than for slides from 2018-2019. INTERPRETATION: The differences between the pathologists' assessments and deviations from the original diagnoses can be explained by poorly reproducible diagnostic criteria, diagnostic entities with overlapping morphology and increasing awareness of early signs of malignancy. Some evolution in diagnostic practice cannot be ruled out.

Man with macrocephaly, learning disability and multiple basal cell carcinomas.

Gorlin syndrome is a rare genetic condition in which patients may develop medulloblastomas, jaw cysts and basal cell carcinomas and show congenital skeletal malformations. If left undiagnosed, Gorlin syndrome can have a number of negative consequences. Early diagnosis and good follow-up is important for all patients with rare disorders. We wish to make doctors and dentists aware of Gorlin syndrome so that, whenever the syndrome is suspected or a patient has been diagnosed, the patient is referred for assessment, treatment and follow-up by specialists who know the disorder well. Dermatology departments at university hospitals and departments of medical genetics have a key role to play in assessment and follow-up. A national support group for Gorlin syndrome has been established, consisting of a dermatologist, oncologist, geneticist, paediatrician, specialist dentist, ophthalmologist, orthopaedic surgeon, plastic surgeon, oral and maxillofacial surgeon and counsellors. Patients, relatives and health professionals can contact the Centre for Rare Disorders directly for information about Gorlin syndrome, or to be put in touch with members of the group.

Sensitization to skin-associated microorganisms in adult patients with atopic dermatitis is of importance for disease severity.

Atopic dermatitis (AD) is a chronic inflammatory skin disease. Environmental and genetic factors, as well as microbial products from yeasts and bacteria, play a role in triggering the disease. A cohort of 619 adult patients with AD was screened for severity of AD, sensitization to Malassezia sympodialis, Candida albicans, Staphylococcus aureus enterotoxins and Dermatophagoides pteronyssinus. Serum levels of interleukin (IL)-18 were measured. Immunoglobulin E (IgE) sensitization to the combination of both yeast and mite antigens was found to be associated with more severe disease and higher levels of total IgE. AD patients with IgE sensitization to several microbial antigens had more severe disease than those with no IgE sensitization to microbial antigens. Sera from patients with IgE-associated AD showed higher levels of IL-18. Skin-associated microorganisms are exogenous factors triggering IgE-response and severity of AD. These findings are clinically important, and sensitization to these organisms should be assessed and considered in treatment strategies.

Rates of Second Tumor, Metastasis, and Death From Cutaneous Squamous Cell Carcinoma in Patients With and Without Transplant-Associated Immunosuppression.

Importance: Cutaneous squamous cell carcinoma (cSCC) may occur with multiple primary tumors, metastasize, and cause death both in immunocompetent and immunosuppressed patients. Objective: To study the rates of second cSCC, metastasis, and death from cSCC in patients with and without organ transplant-associated immunosuppressive treatment. Design, Setting, and Participants: This population-based, nationwide cohort study used Cancer Registry of Norway data from 47 992 individuals diagnosed with cSCC at 18 years or older between January 1, 1968, and December 31, 2020. Data were analyzed between November 24, 2021, and November 15, 2022. Exposures: Receipt of a solid organ transplant at Oslo University Hospital between 1968 and 2012 followed by long-term immunosuppressive treatment. Main Outcomes and Measures: Absolute rates of second cSCC, metastasis, and death from cSCC were calculated per 1000 person-years with 95% CIs. Hazard ratios (HRs) estimated using Cox proportional hazard regression were adjusted for age, sex, and year of first cSCC diagnosis. Results: The study cohort comprised 1208 organ transplant recipients (OTRs) (median age, 66 years [range, 27-89 years]; 882 men [73.0%] and 326 women [27.0%]) and 46 784 non-OTRs (median age, 79 years [range, 18-106 years]; 25 406 men [54.3%] and 21 378 women [45.7%]). The rate of a second cSCC per 1000 person-years was 30.9 (95% CI, 30.2-31.6) in non-OTRs and 250.6 (95% CI, 232.2-270.1) in OTRs, with OTRs having a 4.3-fold increased rate in the adjusted analysis. The metastasis rate per 1000 person-years was 2.8 (95% CI, 2.6-3.0) in non-OTRs and 4.8 (95% CI, 3.4-6.7) in OTRs, with OTRs having a 1.5-fold increased rate in the adjusted analysis. A total of 30 451 deaths were observed, of which 29 895 (98.2%) were from causes other than cSCC. Death from cSCC was observed in 516 non-OTRs (1.1%) and 40 OTRs (3.3%). The rate of death from cSCC per 1000 person-years was 1.7 (95% CI, 1.5-1.8) in non-OTRs and 5.4 (95% CI, 3.9-7.4) in OTRs, with OTRs having a 5.5-fold increased rate in the adjusted analysis. Conclusions and Relevance: In this cohort study, OTRs with cSCC had significantly higher rates of second cSCC, metastasis, and death from cSCC than non-OTRs with cSCC, although most patients with cSCC in both groups died from causes other than cSCC. These findings are relevant for the planning of follow-up of patients with cSCC and for skin cancer services.

[Mohs surgery in basal cell carcinoma on the face]. / Mohs' kirurgi ved basalcellekarsinom i ansiktet.

BACKGROUND: Basal cell carcinoma may have a locally aggressive growth pattern. This type of cancer is often located on the face and is difficult to limit clinically. Normal excision and tumour destructive treatment often lead to recurrence of the tumour. Mohs surgery is a radical technique for removing this type of lesion. MATERIAL AND METHOD: This review article is based on articles identified by searching in PubMed with the search words "Mohs surgery" and "basal cell carcinoma", as well as personal experience. RESULTS: 10-15 % of all basal cell carcinomas have an aggressive growth pattern with sub clinical ramifications. Mohs surgery involves use of peroperative histological assessment of horizontal frozen sections, meaning that 100 % of the resection surface can be assessed. The objective is to reduce the risk of recurrence. Since the method saves tissue, simpler reconstruction can often be chosen. Mohs surgery is resource-demanding, but with the lower risk of recurrence, the method can be cost-effective when used for the correct indications. INTERPRETATION: Mohs surgery should be considered in basal cell carcinoma with an aggressive growth pattern on the face.

Use of Antidepressants and Risk of Cutaneous Melanoma: A Prospective Registry-Based Case-Control Study.

PURPOSE: Melanoma is the cancer with the most rapidly rising incidence rate in Norway. Although exposure to ultraviolet radiation (UVR) is the major environmental risk factor, other factors may also contribute. Antidepressants have cancer inhibiting and promoting side effects, and their prescription rates have increased in parallel with melanoma incidence. Thus, we aimed to prospectively examine the association between use of antidepressants and melanoma by using nation-wide data from the Cancer Registry of Norway, the National Registry, the Norwegian Prescription Database and the Medical Birth Registry of Norway. PATIENT AND METHODS: All cases aged 18-85 with a primary cutaneous invasive melanoma diagnosed during 2007-2015 (n=12,099) were matched to population controls 1:10 (n=118,467) by sex and year of birth using risk-set sampling. We obtained information on prescribed antidepressants and other potentially confounding drug use (2004-2015). Conditional logistic regression was used to estimate adjusted rate ratios (RRs) and 95% confidence intervals (CIs) for the association between overall and class-specific use of antidepressants and incident melanoma. RESULTS: Compared with ≤1 prescription, ≥8 prescriptions of antidepressants overall were negatively associated with melanoma (RR 0.81 CI 0.75-0.87). Class-specific analyses showed decreased RRs for selective serotonin reuptake inhibitors (RR 0.82 CI 0.73-0.93) and mixed antidepressants (RR 0.77 CI 0.69-0.86). The negative association was found for both sexes, age ≥50 years, residential regions with medium and highest ambient UVR exposure, all histological subtypes, trunk, upper and lower limb sites and local disease. CONCLUSION: Use of antidepressants was associated with decreased risk of melanoma. There are at least two possible explanations for our results; cancer-inhibiting actions induced by the drug and less UVR exposure among the most frequent users of antidepressants.

Cardiovascular, antidepressant and immunosuppressive drug use in relation to risk of cutaneous melanoma: a protocol for a prospective case-control study.

INTRODUCTION: The incidence of cutaneous melanoma (hereafter melanoma) has increased dramatically among fair-skinned populations worldwide. In Norway, melanoma is the most rapidly growing type of cancer, with a 47% increase among women and 57% among men in 2000-2016. Intermittent ultraviolet exposure early in life and phenotypic characteristics like a fair complexion, freckles and nevi are established risk factors, yet the aetiology of melanoma is multifactorial. Certain prescription drugs may have carcinogenic side effects on the risk of melanoma. Some cardiovascular, antidepressant and immunosuppressive drugs can influence certain biological processes that modulate photosensitivity and immunoregulation. We aim to study whether these drugs are related to melanoma risk. METHODS AND ANALYSIS: A population-based matched case-control study will be conducted using nation-wide registry data. Cases will consist of all first primary, histologically verified melanoma cases diagnosed between 2007 and 2015 identified in the Cancer Registry of Norway (14 000 cases). Ten melanoma-free controls per case (on date of case melanoma diagnosis) will be matched based on sex and year of birth from the National Registry of Norway. For the period 2004-2015, and by using the unique personal identification numbers assigned to all Norwegian citizens, the case-control data set will be linked to the Norwegian Prescription Database for information on drugs dispensed prior to the melanoma diagnosis, and to the Medical Birth Registry of Norway for data regarding the number of child births. Conditional logistic regression will be used to estimate associations between drug use and melanoma risk, taking potential confounding factors into account. ETHICS AND DISSEMINATION: The project is approved by the Regional Committee for Medical Research Ethics in Norway and by the Norwegian Data Protection Authority. The study is funded by the Southeastern Norway Regional Health Authority. Results will be published in peer-reviewed journals and disseminated further through scientific conferences, news media and relevant patient interest groups.

Validating 4 Staging Systems for Cutaneous Squamous Cell Carcinoma Using Population-Based Data: A Nested Case-Control Study.

Importance: Cutaneous squamous cell carcinoma (cSCC) has metastatic potential, but the prognostic value of current staging systems in nonselected patients is uncertain. Objective: To assess the effect of risk factors for metastasis and to evaluate validity and usefulness of 4 staging systems for cSCC using population-based data. Design, Setting, and Participants: This was a nationwide, population-based, nested case-control study. The Cancer Registry of Norway, which receives compulsory data on all cancers in the Norwegian population of approximately 5.2 million inhabitants. All patients diagnosed as having a primary invasive cSCC in the period 2000 to 2004 (n = 6721) were identified. Of these, 112 patients were diagnosed with metastasis within 5 years. As control patients, 112 patients with cSCC without metastases, matched for sex and age at diagnosis, were identified by random. Clinical data and biopsy specimens of primary cSCC were collected for all 224 patients. The biopsies were reexamined histologically by an experienced pathologist using well-established criteria for cSCC, yielding 103 patients with metastasis (cases) and 81 cSCC without metastasis (controls). Main Outcomes and Measures: The ability of 4 cSCC staging systems (ie, the American Joint Committee on Cancer, 7th edition [AJCC 7] staging system, the staging system used by Breuninger et al, the Brigham and Women's Hospital [BWH] staging system, and the AJCC, 8th edition [AJCC 8] staging systems) to identify patients who developed metastasis with 5 years of follow-up. External validation was performed by logistic regression, discrimination (sensitivity, specificity, proportion correctly classified, concordance index), and calibration (R2, Hosmer-Lemeshow test, plots) statistics. Results: Of 6721 patients; 3674 (54.7%) were men and 3047 (45.3%) were women, with a mean age at diagnosis of 78 years. Of the 103 patients with cSCC diagnosed with metastasis within 5 years, 60 [58.3%] were men, and mean [SD] age 72.7 [13.5] years. Of the 81 patients with cSCC without metastasis, 51 [63.0%] were men, and mean [SD] age 74.6 [11.7] 15 years. The staging systems distinguished poorly to moderately between patients who developed metastasis and those who did not. The ability to cluster patients with similar outcomes within the same staging category was low, particularly when using the AJCC 7 system. Using the AJCC 7 system, the risk of metastasis for T2 patients was 3-fold, compared with T1 patients (OR, 2.96; 95% CI, 1.43-6.15). In the system used by Breuninger et al, high-risk categories for diameter and tumor thickness and the BWH system's T2b category collected relatively homogeneous groups. In the systems used by Breuninger et al and Brigham-Women's Hospital, risk of metastasis was significantly elevated with increasing stage or risk category. Using the system by Breuninger et al, the risk of metastasis was less than 3-fold for tumors in the high-risk category of the combined variable (OR, 2.72; 95% CI, 1.29-5.74). The BWH system gave ORs for metastasis at 4.6 (95% CI, 2.23-9.49) and 21.31 (95% CI, 6.07-74.88) for the T2a and T2b categories, respectively. Conclusions and Relevance: Using population-based data, 4 current staging systems for cSCC were unsatisfactory in identifying nonselected cSCC patients at high risk for metastasis. The system used by Breuninger gave the best results.

Decreased frequency of intracellular IFN-gamma producing T cells in whole blood preparations from patients with atopic dermatitis.

There have been contradictory reports on the shift in the T-cell cytokine expression pattern of peripheral blood mononuclear cells from patients with atopic dermatitis (AD); more specifically the interleukin (IL)-4 and interferon (IFN)-gamma profiles. The aim of this study was to shed further light on this contradiction by measuring the intracellular cytokines IL-4 and IFN-gamma by flow cytometry on unseparated whole blood to obtain results that, as accurately as possible, reflect the situation in circulating cells in vivo. The patient group including 64 patients with AD was compared with 18 nonatopic healthy adults. The results showed that the percentage of CD4+ T cells expressing IFN-gamma was significantly decreased (P < or = 0.001), as well as the percentage expressing IL-4 (P < 0.05) in AD patients compared with healthy controls. Furthermore, in supernatants from whole blood samples stimulated with phorbol 12-myristate 13-acetate and ionomycin, production of IFN-gamma was significantly decreased, while IL-4 production remained unchanged in AD patients compared with healthy controls. We also investigated if there was a relationship between serum IgE level and Phadiatop, a screening test for atopy, vs. the levels of IL-4 and IFN-gamma, but found no correlation with either. However, there was a significant correlation between disease severity and the level of total IgE (r = 0.67, P < 0.05). In conclusion, our results support the evidence for a decreased ability of peripheral CD4+ T cells to produce IFN-gamma among AD patients.