Increasing melanoma incidence and survival trend shifts with improved melanoma-specific survival between 1990 and 2020 in Sweden.

BACKGROUND: Melanoma-specific survival (MSS) is heterogenous between stages and is highly dependent on the T stage for primary localized disease. New systemic therapies for metastatic cutaneous melanoma (CM) have been introduced since 2012 in Sweden. OBJECTIVES: To analyse the incidence and MSS time trends between 1990 and 2020 in Sweden. METHODS: Nationwide, population-based and prospectively collected clinico-pathological data on invasive CM from the Swedish Melanoma Registry (SweMR) were analysed for survival trends between 1990 and 2020 using Kaplan-Meier curves and Cox proportional hazard ratios (HRs). RESULTS: In total, 77 036 primary invasive CMs were diagnosed in 70 511 patients in Sweden between 1990 and 2020. The 5-year MSS [95% confidence interval (CI)] was 88.9% (88.3-89.4) for 1990-2000, 89.2% (88.7-89.6) for 2001-2010 and 93.0% (92.7-93.9) for 2011-2020. The odds ratios for being diagnosed with nodular melanoma (vs. superficial spreading melanoma) was significantly reduced by 20% (2001-2010) and by 46% (2011-2020) vs. the reference period 1990-2000. Overall, the MSS improved over both diagnostic periods (2001-2010 and 2011-2020) vs. the reference period 1990-2000 among men and women, respectively [HRmen: 2001-2010: 0.89 (95% CI 0.82-0.96) and 2011-2020: 0.62 (95% CI 0.56-0.67); HRwomen: 2001-2010: 0.82 (95% CI 0.74-0.91) and 2011-2020: 0.62 (95% CI 0.56-0.70)]. The risk of death from CM was significantly lower in all age groups for both men and women in the most recent diagnostic period (2011-2020 vs.1990-2000). CONCLUSIONS: The results emphasize the improved MSS among men and women in Sweden. The MSS improvements, specifically for the period 2011-2020, may be correlated to the introduction of new systemic therapies and are here shown for the first time in detail for Sweden.

The spectrum of genital human papillomavirus infection among men attending a Swedish sexually-transmitted infections clinic: human papillomavirus typing and clinical presentation of histopathologically benign lesions.

There have been a number of Swedish studies on human papillomavirus (HPV) typing in men, most of which have used less sensitive HPV-typing techniques. The present study included male patients with genital HPV-induced lesions planned for surgery. Samples were prepared for histopathology and PCR. HPV was detected in 233/253 (92%) and HPV 6 or 11 in 89% of the HPV-positive lesions. There were statistically significant differences regarding morphology (p=0.002), location (p=0.000001) and colour (p=0.005) of the lesions for low- vs. mixed or high-risk HPV types. For example, acuminate lesions were mostly found among men with low-risk HPV types, whereas macular lesions were over-represented among them with mixed or high-risk types. The HPV type distribution is similar to that in earlier studies, but we also found correlations with some clinical parameters.

Simultaneous visualization of Propionibacterium acnes and Propionibacterium granulosum with immunofluorescence and fluorescence in situ hybridization.

Propionibacterium acnes (P. acnes) and Propionibacterium granulosum (P. granulosum) are common skin colonizers that are implicated as possible contributing factors in acne vulgaris development. We have established direct visualization tools for the simultaneous detection of these closely related species with immunofluorescence assay and fluorescence in situ hybridization (FISH). As proof of principle, we were able to distinguish P. acnes and P. granulosum bacteria in multi-species populations in vitro as well as in a mock skin infection model upon labelling with 16S rRNA probes in combinatorial FISH as well as with antibodies. Furthermore, we report the co-localization of P. acnes and P. granulosum in the stratum corneum and hair follicles from patients with acne vulgaris as well as in healthy individuals. Further studies on the spatial distribution of these bacteria in skin structures in various skin disorders are needed.

Mohs micrographic surgery revisited: A multidisciplinary, collaborative approach for the treatment of aggressive and recurrent basal cell carcinoma on the head and neck.

Mohs micrographic surgery is the preferred surgical option for high-risk basal cell carcinomas. In our institution, the method is exclusively used for the treatment of aggressive and recurrent facial tumours selected via multidisciplinary team meetings and consistently managed using a multidisciplinary approach. The aim of this retrospective patient-record study was to examine the outcomes for basal cell carcinomas managed with Mohs micrographic surgery and to present our experience from multidisciplinary team meetings and interdisciplinary collaborations. All patients treated between September 2009 and March 2019 at Karolinska University hospital were included. In a total of 143 facial basal cell carcinomas in 138 patients, 86 primary and 57 recurrent, the recurrence rate was 4.9% after a median follow-up of 24 months. In regions, where highly specialised Mohs surgeons performing all the steps of the procedure are limited, interdisciplinary collaboration can be an effective strategy for appropriate patient selection and for performing all steps of Mohs surgery with dermatosurgeons eradicating the tumour, pathologists evaluating the histopathology, followed by reconstructive surgery by plastic surgeons. The approach we present here provides a robust and functioning Mohs surgical service during the build-up of the organisation, while providing the opportunity to train new surgeons. Once the clinic has been set up, the multidisciplinary approach should always be considered and applied when dealing with complex cases.

Trend Shifts in Age-Specific Incidence for In Situ and Invasive Cutaneous Melanoma in Sweden.

BACKGROUND: The incidence of invasive cutaneous melanoma (CM) is increasing in Sweden. The aim was to present age- and sex-specific trends of the age-standardised incidence and the average annual percentage change (AAPC) for in situ and invasive CM. METHODS: Joinpoint regression models were used to analyse data from the Swedish Cancer Register and the Swedish Melanoma Registry 1997-2018 (N = 35,350 in situ CM; 59,932 CM). RESULTS: The AAPC of CM for women was 4.5 (4.1-5.0; p < 0.001) for the period 1997-2018. For men, the APCC was 4.2 (3.0-5.4; p < 0.001), with a significantly higher annual percentage change (APC) for the period 2000-2018 (5.0; 4.6-5.4; p < 0.001) compared to 1997-1999. An increasing annual incidence of CM ≤ 0.6 mm and 0.7 mm Breslow tumour thickness was found for men with a significant incidence shift for the period 2006-2015, respectively. Similarly for women, with a significantly higher APC for CM ≤ 0.6 mm from 2005. The incidence of intermediate thick CM (2.1-4.0 mm) has not increased since 2011. The incidence of CM > 4.0 mm has been increasing among both sexes, with a significantly lower APC among women from 2005. CONCLUSIONS: The incidence of in situ and low-risk CM ≤ 1.0 mm in tumour thickness has been rising among both sexes since the 2000s.

The impact of standardized care pathway on reporting time for invasive melanoma - results from one pathology department in Sweden.

Background: Standardized care pathway (SCP) was introduced by the Swedish health authorities to eliminate unwanted delay in the diagnostics of cancer patients; for melanoma, SCP started in 2016. The aim of this study was to investigate the impact of SCP on reporting time for invasive melanomas.Materials and methods: Information on reporting time was collected on all samples handled according to the SCP and on all invasive melanomas diagnosed in 2016-2018 at the Department of Clinical Pathology, Akademiska University Hospital, Uppsala, Sweden.Results: During the study period, 205 samples were handled according to the SCP, resulting in 53 cases (26%) diagnosed with invasive melanomas. A total of 301 invasive melanomas from 286 patients were diagnosed during the study period; 67 (22%) were submitted as SCP, 36 (12%) as a general priority case, and 198 (66%) as non-priority. The reporting time for the SCP cases was 8 days, for general priority cases 6 days, and for non-priority cases it was 24 days. The reporting time increased from 18 to 31 days for the non-priority cases and from 15 to 25 days for all cases with invasive melanomas during the study period.Conclusion: This study demonstrates prolonged reporting times for invasive melanomas since the implementation of SCP. This is probably caused by the crowd-out effect of the SCP samples, limited personnel resources, and inaccuracy of the clinical diagnosis. SCP might therefore be a suboptimal method to shorten reporting times for invasive melanomas.

Feasibility and diagnostic agreement in teledermatopathology using a virtual slide system.

We investigated the feasibility and diagnostic agreement of a virtual slide system (VSS) in teledermatopathology. Forty-six biopsy specimens from inflammatory skin diseases were selected and scanned with a VSS at the Research Unit of Teledermatology, Medical University of Graz, Graz, Austria. Images were stored on a virtual slide server on which a specific Web application suited for telepathology (http://telederm.org/research/dermatopath/) runs. Twelve teleconsultants from 6 different countries reviewed the 46 cases, working directly on the Web application. Telediagnoses agreed with gold standard and conventional diagnosis with an average of 73% and 74%, respectively. Complete concordance among all teleconsultants with gold standard and conventional diagnosis was found in 20% of the cases. In 10 cases in which complete clinical data were missing, the average agreement of telediagnosis with gold standard diagnosis and conventional diagnosis decreased to 65% and 66%, respectively. Only 3 of 4 cases of inflammatory skin diseases were correctly diagnosed remotely with VSS. The system that we have used, despite its usability, is not completely feasible for teledermatopathology of inflammatory skin disease. Moreover, the performance seems to have been influenced by the availability of complete clinical data and by the intrinsic difficulty of the pathology of inflammatory skin diseases.

BRAFV600E protein expression in primary cutaneous malignant melanomas and paired metastases.

IMPORTANCE: BRAFV600E mutations are present in approximately 50% of cutaneous malignant melanomas (CMMs). The use of BRAFV600E mutation-specific monoclonal antibody VE1 immunohistochemical analysis may facilitate rapid detection of BRAFV600E mutations in CMMs and demonstrate heterogeneity among tumors. OBJECTIVES: To characterize the pattern of BRAFV600E protein expression in primary CMMs with matched metastases and to analyze the use of VE1 immunohistochemical analysis in clinical practice using formalin-fixed, paraffin-embedded tumor tissue. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cohort study performed at Karolinska University Hospital from September 2012 to September 2013, we examined CMMs (124 primary tumors and 76 metastases) with VE1 immunohistochemical analysis, and results were compared with DNA mutation analyses. MAIN OUTCOMES AND MEASURES: Determination of intratumoral and intertumoral heterogeneity as well as the sensitivity and specificity of VE1 immunohistochemical analysis. RESULTS: Positive staining results with the VE1 antibody were detected in 94 of 200 tumors (47.0%). In general, VE1 staining was homogeneous. However, VE1 staining intensity varied among the primary tumors and corresponding metastases in 63 of 135 tumors (46.7%), but a change of mutational status based on DNA analysis was found in only 4 matched tumors (3.0%). Discordant findings between DNA mutation analysis and immunohistochemical analysis were observed in 12 tumors. The overall sensitivity and specificity of VE1 immunohistochemical analysis were 96.7% and 94.5%, respectively. A comparable sensitivity was obtained for primary and metastatic CMMs. The specificity was lower among primary CMMs (92.4%) compared with metastases (98.0%). CONCLUSIONS AND RELEVANCE: We found VE1 immunohistochemical analysis to be a useful and rapid assay for BRAFV600E mutations that may contribute to the detection of intratumoral and intertumoral heterogenetic subclones. Tumors with positive results, including strong staining, should be expedited for confirmatory BRAF mutation testing. If this test result is negative, a false-negative result of the mutation analysis should be considered. Validation of VE1 immunohistochemical analysis in clinical practice is needed.

KIT, NRAS, BRAF and PTEN mutations in a sample of Swedish patients with acral lentiginous melanoma.

BACKGROUND: Acral lentiginous melanoma (ALM) accounts for <10% of all melanomas in Caucasians. Although the involvement of KIT, NRAS and BRAF mutations is well known in ALM, the impact of these mutations on clinicopathological features has not been established. OBJECTIVE: To define the KIT, NRAS, BRAF and PTEN mutation frequencies in Swedish patients with ALM and to evaluate the impact of mutation status on patient and tumor characteristics. METHODS: Tumor cells were microdissected from 88 primary ALMs and 16 paired metastases and analyzed for KIT, NRAS and BRAF mutations. A subset of 25 ALMs was also evaluated for PTEN mutations. RESULTS: BRAF mutations were identified in 17% of the primary ALMs. Both NRAS and KIT mutations were found at a similar frequency of 15%. Only one of the ALMs that were screened for PTEN harbored a mutation (4%). The KIT, NRAS and BRAF mutation status in paired primary and metastatic ALMs was identical. Patients with BRAF mutated tumors were significantly younger (57 years) than those with BRAF wild-type tumors (73 years, p=0.028). BRAF mutations were significantly more common in females (p=0.011) and more often found in tumors located on the feet (p=0.039). Anatomical site was an independent prognostic factor for overall survival; patients with ALMs on the hands or under fingernails had a better prognosis than those with tumors on the feet or under toenails (p=0.025). CONCLUSION: Our results confirm the presence of KIT, NRAS and BRAF mutations in ALM and provide evidence that mutations in these genes occur at similar frequencies. Our results also show that PTEN is mutated in a small subset of ALM tumors.

High Ro52 expression in spontaneous and UV-induced cutaneous inflammation.

Ro52 is an E3 ubiquitin ligase with a recently identified regulatory role in inflammation. The protein is targeted by autoantibodies in rheumatic diseases, and Ro52 autoantibodies are specifically associated with cutaneous lupus erythematosus (CLE) and photosensitivity. The aim of this study was to investigate cutaneous Ro52 expression in CLE patients and to examine whether UVR might modulate Ro52. Ro52 expression was assessed by immunohistochemistry in biopsies derived from CLE lesions (n=25), nonlesional (n=7), and healthy control skin using four anti-Ro52 mAbs generated by us. Ro52 expression was also analyzed in psoriatic, lichenoid, and eczematous lesions. It was increased in the epidermis of spontaneous CLE lesions as compared with unaffected skin of patients and healthy controls. High epidermal Ro52 expression was also observed in other inflammatory dermatoses investigated. Ro52 was upregulated in experimentally photoprovoked CLE lesions as observed by immunohistochemistry in sequential biopsies, which was confirmed in vitro both at the mRNA and protein levels by exposing cultured patient-derived primary keratinocytes to UVR. In conclusion, Ro52 expression is upregulated in keratinocytes in inflammatory skin conditions and in response to UVR. High Ro52 expression might lead to the breaking of tolerance and the generation of Ro52 autoantibodies in genetically susceptible subjects. Further, the upregulation of Ro52 in keratinocytes after sun exposure might also be a triggering factor for skin lesions in patients with Ro52 antibodies.