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.

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.

Consensus-Based Recommendations on the Prevention of Squamous Cell Carcinoma in Solid Organ Transplant Recipients: A Delphi Consensus Statement.

IMPORTANCE: There is a paucity of evidence to guide physicians regarding prevention strategies for cutaneous squamous cell carcinoma (CSCC) in solid organ transplant recipients (SOTRs). OBJECTIVE: To examine the development and results of a Delphi process initiated to identify consensus-based medical management recommendations for prevention of CSCC in SOTRs. EVIDENCE REVIEW: Dermatologists with more than 5 years' experience treating SOTRs were invited to participate. A novel actinic damage and skin cancer index (AD-SCI), consisting of 6 ordinal stages corresponding to an increasing burden of actinic damage and CSCC, was used to guide survey design. Three sequential web-based surveys were administered from January 1, 2019, to December 31, 2020. Pursuant to Delphi principles, respondents thoroughly reviewed all peer responses between rounds. Supplemental questions were also asked to better understand panelists' rationale for their responses. FINDINGS: The Delphi panel comprised 48 dermatologists. Respondents represented 13 countries, with 27 (56%) from the US. Twenty-nine respondents (60%) were Mohs surgeons. Consensus was reached with 80% or higher concordance among respondents when presented with a statement, question, or management strategy pertaining to prevention of CSCC in SOTRs. A near-consensus category of 70% to less than 80% concordance was also defined. The AD-SCI stage-based recommendations were established if consensus or near-consensus was achieved. The panel was able to make recommendations for 5 of 6 AD-SCI stages. Key recommendations include the following: cryotherapy for scattered actinic keratosis (AK); field therapy for AK when grouped in 1 anatomical area, unless AKs are thick in which case field therapy and cryotherapy were recommended; combination lesion directed and field therapy with fluorouracil for field cancerized skin; and initiation of acitretin therapy and discussion of immunosuppression reduction or modification for patients who develop multiple skin cancers at a high rate (10 CSCCs per year) or develop high-risk CSCC (defined by a tumor with approximately ≥20% risk of nodal metastasis). No consensus recommendation was achieved for SOTRs with a first low risk CSCC. CONCLUSIONS AND RELEVANCE: Physicians may consider implementation of panel recommendations for prevention of CSCC in SOTRs while awaiting high-level-of-evidence data. Additional clinical trials are needed in areas where consensus was not reached.

Teledermatology in Norway using a mobile phone app.

Rashes, ulcers and skin lesions are well suited for telemedicine. We have developed a smartphone app, the first of its kind in Norway, where a referring physician can write a short medical history and take clinical and dermatoscopic photographs with a smartphone, which is then sent to and evaluated by a dermatologist. In the period from June 1st, 2017, to September 1st, 2019, clinical information and photographs of rash and skin lesions from 171 patients were sent by 40 primary care and nursing home physicians via the smartphone app to four dermatologists for diagnosis and therapeutic advice. A wide range of dermatological conditions were diagnosed, most commonly chronic ulcers (17%), eczema (15%) and pigmented lesions (13%). Assessed later by a dermatologist, referral for regular consultations with a specialist was avoided in 119 patients (70%). Sixteen patients (9%) were recommended a regular consultation with a dermatologist; information for prioritization in the specialist healthcare service was then provided. In 36 patients (21%), further measures by the referring physician were recommended. Our experience indicates that many ordinary consultations on rash, ulcers and skin lesions in the specialist healthcare services can be avoided when using the smartphone app.

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.

Long-term Change in the Risk of Skin Cancer After Organ Transplantation: A Population-Based Nationwide Cohort Study.

Importance: The high risk of skin cancer after organ transplantation is a major clinical challenge and well documented, but reports on temporal trends in the risk of posttransplant cutaneous squamous cell carcinoma (SCC) are few and appear contradictory. Objective: To study temporal trends for the risk of skin cancer, particularly SCC, after organ transplantation. Design, Setting, and Participants: Population-based, nationwide, prospective cohort study of 8026 patients receiving a kidney, heart, lung, or liver transplant in Norway from 1968 through 2012 using patient data linked to a national cancer registry. The study was conducted in a large organ transplantation center that serves the entire Norwegian population of approximately 5.2 million. Exposures: Receiving a solid organ transplant owing to late-stage organ failure, followed by long-term immunosuppressive treatment according to graft-specific treatment protocols. Main Outcomes and Measures: Occurrence of first posttransplant SCC, melanoma, or Kaposi sarcoma of the skin. Risk of skin cancer was analyzed using standardized incidence ratios (SIRs) and, for SCC, multivariable Poisson regression analysis of SIR ratios, adjusting for 5-year time period of transplantation, different follow-up time, age, sex, and type of organ. Results: The study cohort included 8026 organ transplant recipients, 5224 men (65.1%), with a mean age at transplantation of 48.5 years. Median follow-up time was 6.7 years per recipient; total follow-up time, 69 590 person-years. The overall SIRs for SCC, melanoma, and Kaposi sarcoma were 51.9 (95% CI, 48.4-55.5), 2.4 (95% CI, 1.9-3.0), and 54.9 (95% CI, 27.4-98.2), respectively. In those who underwent transplantation in the 1983-1987 period, the unadjusted SIR for SCC was 102.7 (95%, 85.8-122.1), declining to 21.6 (95% CI, 16.8-27.0) in those who underwent transplantation in the 2003-2007 period. Adjusting for different follow-up times and background population risks, as well as age, graft organ, and sex, a decline in the SIR for SCC was found, with SIR peaking in patients who underwent transplantation in the 1983-1987 period and later declining to less than half in patients who underwent transplantation in the 1998-2002, 2003-2007, and 2008-2012 periods, with the relative SIRs being 0.42 (95% CI, 0.32-0.55), 0.31 (95% CI, 0.22-0.42), and 0.44 (95% CI, 0.30-0.66), respectively. Conclusions and Relevance: The risk of SCC after organ transplantation has declined significantly since the mid-1980s in Norway. Less aggressive and more individualized immunosuppressive treatment and close clinical follow-up may explain the decline. Still, the risk of SCC in organ transplant recipients remains much higher than in the general population and should be of continuous concern for dermatologists, transplant physicians, and patients.

Folliculotropic Mycosis Fungoides with Skewed T-cell Receptor CDR3 Motif: Suggestive of Lipid-antigen Selection?

Folliculotropic mycosis fungoides (FMF), a variant of mycosis fungoides (MF) with distinct clinical features, is characterized by infiltration of malignant T cells in hair follicles. This raises the hypothesis that antigens in the hair follicle may contribute to the pathogenesis of FMF. T-cell receptor ß gene (TRB) sequences as well as dendritic cell subsets in patients with FMF (n = 21) and control patients with MF (n = 20) were studied to explore this hypothesis. A recurrent usage of the TRB junctional genes TRBJ2-1 and TRBJ2-7 was found in patients with FMF compared with those with MF. These genes contribute to an amino acid motif in the complementarity-determining region 3 (CDR3) of the T-cell receptor. This motif was previously found in T cells stimulated by lipids bound to CD1 on antigen-presenting cells. Additional immunohistochemical analysis revealed abundant CD1c- and CD1a- expressing dendritic cells in FMF. The combined findings support a role for lipid-antigen stimulation in FMF.

Treatment of basal cell carcinoma in Scandinavia: evidence or eminence based?

BACKGROUND: Basal cell carcinoma (BCC) is a locally destructive form of skin cancer, mainly affecting Caucasians. There are multiple treatment options for BCC, with excisional surgery being most widely used. Choice of treatment may be dependent on clinical guidelines, local therapeutic traditions, and/or personal experience. Sweden is the only Scandinavian country with treatment guidelines for BCC. METHODS: Eighty-six dermatologists from Sweden, Denmark, and Norway that were attending a meeting on photodynamic therapy were presented case history and clinical photographs of nine different BCCs and asked to select their treatment of choice among multiple options by the use of an electronic audience response system. RESULTS: Treatment of choice differed substantially between dermatologists from the three countries. Swedish dermatologists more often chose excisional surgery (median 50%, range 0-90%) than their Danish (median 19%, range 0-44%) and Norwegian (median 35%, range 0-65%) colleagues. Very few Swedish dermatologists chose radiation therapy in the four cases where this was an option. Photodynamic therapy was more often selected by Norwegian dermatologists compared to Swedish and Danish dermatologists. CONCLUSIONS: The treatment choices of Swedish dermatologists in cases of BCC are generally in line with Swedish treatment guidelines. National treatment guidelines for BCC should be established in all countries, including Denmark and Norway.