Classification of melanocytic lesions using direct illumination multispectral imaging.

With rising melanoma incidence and mortality, early detection and surgical removal of primary lesions is essential. Multispectral imaging is a new, non-invasive technique that can facilitate skin cancer detection by measuring the reflectance spectra of biological tissues. Currently, incident illumination allows little light to be reflected from deeper skin layers due to high surface reflectance. A pilot study was conducted at the University Hospital Basel to evaluate, whether multispectral imaging with direct light coupling could extract more information from deeper skin layers for more accurate dignity classification of melanocytic lesions. 27 suspicious pigmented lesions from 23 patients were included (6 melanomas, 6 dysplastic nevi, 12 melanocytic nevi, 3 other). Lesions were imaged before excision using a prototype snapshot mosaic multispectral camera with incident and direct illumination with subsequent dignity classification by a pre-trained multispectral image analysis model. Using incident light, a sensitivity of 83.3% and a specificity of 58.8% were achieved compared to dignity as determined by histopathological examination. Direct light coupling resulted in a superior sensitivity of 100% and specificity of 82.4%. Convolutional neural network classification of corresponding red, green, and blue lesion images resulted in 16.7% lower sensitivity (83.3%, 5/6 malignant lesions detected) and 20.9% lower specificity (61.5%) compared to direct light coupling with multispectral image classification. Our results show that incorporating direct light multispectral imaging into the melanoma detection process could potentially increase the accuracy of dignity classification. This newly evaluated illumination method could improve multispectral applications in skin cancer detection. Further larger studies are needed to validate the camera prototype.

[Paraneoplastic subacute cutaneous lupus erythematosus]. / Paraneoplastischer subakut kutaner Lupus erythematodes.

The genesis of subacute cutaneous lupus erythematosus (SCLE) is multifactorial and includes idiopathic, drug-related and paraneoplastic etiologies. This article reports the case of a 70-year-old female patient with paraneoplastic SCLE in whom a lung adenocarcinoma was detected during the extended examination. A paraneoplastic SCLE should be considered when a patient with SCLE presents with lesions in regions of the skin not exposed to sunlight and beginning B symptoms.

Cutaneous leukocytoclastic vasculitis secondary to COVID-19 infection leading to extensive skin necrosis.

A wide range of extrapulmonary manifestations in patients with COVID-19 has been reported during the ongoing pandemic, thus making the clinical spectrum of this new disease very heterogeneous. While COVID-19-associated vasculitis and vasculopathy have been described, cutaneous leukocytoclastic vasculitis (cLcV) due to SARS-CoV-2 has rarely been reported, and if it has, with relatively mild courses. We present the case of a 93-year-old man who, after having survived classic COVID-19 infection, developed a fulminant cLcV leading to extensive skin necrosis and tissue damage that resulted in his death. Considering the negative workup for other triggers of vasculitis, we find that cLcV is a secondary manifestation of COVID-19, even though SARS-CoV-2 polymerase chain reaction in the skin biopsy was not present in the tissue. We hypothesize this by providing a pathophysiologic rationale (eg, SARS-CoV-2-induced endotheliitis, complement activation, and interleukin 6 dominant intra- and perivascular inflammation).

Radiotherapy as a Treatment Option for Local Disease Control in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type.

BACKGROUND: Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT) is an aggressive lymphoma variant. Anthracycline-based chemotherapy with rituximab is recommended as first-line treatment. Radiotherapy (RT) has been considered as a therapeutic option for local disease control in patients with solitary or localized lesions. METHODS: We report the results of a retrospective analysis of PCDLBC, LT patients treated either with RT alone or with physician's decision as first-line treatment, aiming to assess disease progression and/or first recurrence in these treatment groups. RESULTS: We retrospectively analyzed 20 patients treated either with RT alone (n = 8) or with investigator's choice treatment (n = 12), which included chemotherapy alone or combined with local therapy (RT and wide local excision). Complete response (CR) was achieved in 8 patients from the first group and 9 patients from the second group, with 1 treatment failure. Six patients treated with RT alone progressed with a median time to progression (TTP) of 12.5 months. In the second group, 5 patients progressed with a median TTP of 5.2 months. RT showed good local disease control in both groups without any skin relapses during the follow-up period. CONCLUSION: RT as first-line monotherapy followed by watchful waiting did not significantly improve the overall risk of disease progression but resulted in good local disease control. After progression, RT could still easily be combined with systemic treatment. The strength of this analysis needs to be evaluated in a larger patient cohort.

Standardized diagnostic algorithm for spitzoid lesions aids clinical decision-making and management: a case series from a Swiss reference center.

IMPORTANCE: Spitzoid lesions are a group of melanocytic tumors characterized by spindle-like or epithelioid cells with variable malignant potential. While some spitzoid lesions are classified as evidently benign or malignant by clinic and histology, others present with unclear clinical and histological characteristics and are categorized as lesions of intermediate biologic potential. These lesions represent a challenge for pathologists and clinicians alike. No consensus on ancillary diagnostics and clinical management exists. Prediction of their clinical course is difficult. The implementation of ancillary diagnostics is currently subject of extensive discussions. OBSERVATIONS: We report three cases of spitzoid lesions in three young female patients (3-, 15- and 17 years old) from a single reference center with different clinical and histological manifestations. In each case, uncertain clinical and histological presentation led to the stepwise application of additional diagnostics using immunohistochemistry and a custom next generation sequencing panel optimized for melanocytic lesions (MelArray). Combining ancillary diagnostics helped determine clinical management in all cases by characterizing the biology of these lesions. CONCLUSIONS AND RELEVANCE: We illustrate how clinical, histological and molecular features contribute to an optimized management plan in these critical situations and present a possible algorithm for the assessment of spitzoid neoplasms.

Novel morphological and genetic features of fumarate hydratase deficient renal cell carcinoma in HLRCC syndrome patients with a tailored therapeutic approach.

The hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC) is defined by germline mutations in the fumarate hydratase (FH) gene and associated with leiomyomas and aggressive renal cell carcinomas with FH deficiency. Here, we comprehensively characterize two new patients with HLRCC syndrome on a morphological, immunohistochemical and genetic level. The patients developed aggressive HLRCC syndrome-associated RCCs, uterine leiomyomas and dermal leiomyomas. One HLRCC syndrome-associated RCC exhibited an unusual morphology with accumulation of "colloid-like" cytoplasmic inclusions, which might serve as a novel sentinel feature to trigger further testing. This case showed partially retained FH expression, initially hampering correct diagnosis. Comprehensive next-generation sequencing analyses of HLRCC syndrome-associated RCC and leiomyomas in our patients revealed divergent genetic changes in the FH gene in different tumors from the same patient. While all leiomyomas (uterine and cutaneous) showed a FH loss of heterozygosity (LOH) as a wildtype allele inactivating event, one HLRCC-RCC showed a second, undescribed NM_000143.3; c.947C>T; p.Ala316Val FH mutation accompanying the preexisting splice site mutation c.378+2T>C. In the other HLRCC syndrome-associated RCC, the FH mutation (NM_000143.3; c.462T>G; p.Asn154Lys with a somatic LOH) represents another variant of unknown significance that we link to HLRCC - and thus classify as likely pathogenic. Due to the specific diagnosis of metastatic HLRCC syndrome-associated RCC, both cases were treated in first line with bevacizumab/erlotinib and showed remarkable and long lasting responses. These findings allow new morphological and molecular insights into the biology of the HLRCC syndrome, corroborate the "second hit" hypothesis of tumor formation in HLRCC patients and may promote a distinct therapeutic approach.

Squamous cell carcinoma of the skin induces considerable sustained cost of care in organ transplant recipients.

BACKGROUND: Squamous cell carcinoma (SCC) is the most frequent cancer in organ transplant recipients (OTR). OBJECTIVE: We retrospectively analyzed the cost of dermatologic care in our OTR specialty clinic. METHODS: We collected billing data for OTR (n = 198) seen at the Dermatology Department of Zurich University Hospital over 4 years (2004-2007). Grouping by histology yielded the groups: SCC (n = 70), with SCC occurring within the observation period; past SCC (n = 40), with SCC before the observation period; in situ SCC (n = 13), when only in situ SCC had been diagnosed; biopsy negative (n = 49) for SCC and in situ SCC; and no biopsy ever (n = 26) within the observation period. RESULTS: Median annual costs for dermatologic care were US$1398 for SCC; US$776 for past SCC; US$308 for in situ SCC; US$211 for biopsy negative; and US$156 for no biopsy ever. Median cost per case of invasive SCC (US$1830) was higher than cost per case of in situ SCC (US$603). Regression analysis showed male sex (P = .006), age at transplantation (P = .001), and time since transplantation (P < .001) as independent cost factors. LIMITATIONS: This was an open, retrospective, single-center study with limited patient numbers. CONCLUSION: Dermatologic care for OTR is costly, and the majority of the costs are associated with SCC. Once SCC occurs, costs increase in a pronounced and sustained fashion. Interventions reducing the progression from in situ SCC to SCC could lead to considerable financial savings. We advocate sun protection, early diagnosis, and intervention to minimize the costs associated with SCC.

Pronounced allelic imbalance at D9S162 in skin squamous cell carcinoma of organ transplant recipients.

OBJECTIVE: To evaluate chromosomal instability at 9p21-22 with p16 protein expression in organ transplant recipients (OTRs) compared with immunocompetent patients with squamous cell carcinoma (SCC). DESIGN: In a select population of intraepithelial and subsequent invasive SCC from the same anatomic region of the same patient at different times, we assessed loss of heterozygosity at 3 microsatellites­IFNA, D9S162, and D9S925­in the course of carcinogenesis in OTRs and immunocompetent patients. SETTING: Department of Dermatology, University Hospital Zurich. PATIENTS: Immunocompetent patients and OTRs with SCC on sun-damaged skin. MAIN OUTCOME MEASURE: Chromosomal allelic balance in SCC of OTRs and immunocompetent patients. RESULTS: Reduced allelic balance at IFNA, D9S162, and D9S925 in intraepithelial forms of SCC and similar allelic imbalance in invasive forms of SCC were found. Allelic balance at D9S162 was reduced for SCC in OTRs compared with SCC in immunocompetent patients. The study revealed broadly reduced allelic balance at 9p21-22 in all cutaneous SCCs, and OTRs presented a further reduced allelic balance for D9S162, suggesting a common trait for SCC in OTRs. Actinic keratosis and Bowen disease differed in allelic balance at D9S162, suggesting substantial differences in their carcinogenesis. CONCLUSION: Reduced allelic balance around locus D9S162 is a genomic correlate for enhanced carcinogenesis in OTRs.

IL-31 expression by inflammatory cells is preferentially elevated in atopic dermatitis.

Interleukin-31 (IL-31) is a recently discovered cytokine expressed in many human tissues, and predominantly by activated CD4(+) T cells. IL-31 signals through a heterodimeric receptor consisting of IL-31 receptor alpha (IL-31RA) and oncostatin M receptor beta (OSMR). Earlier studies have shown involvement of IL-31 and its receptor components IL-31RA and OSMR in atopic dermatitis, pruritus and Th2-weighted inflammation at the mRNA level. The aim of this study was to investigate IL-31 protein expression in skin of such conditions. Immunohistochemical staining for IL-31, IL-31RA and OSMR was performed in formalin-fixed paraffin-embedded biopsy specimens. IL-31 expression was increased in the inflammatory infiltrates from skin biopsies taken from subjects with atopic dermatitis, compared with controls (p ≤ 0.05). IL-31, IL-31RA and OSMR protein immunoreactivity was not increased in biopsies from subjects with other Th2-weighted and pruritic skin diseases. Our results confirm, at the protein level, the relationship between IL-31 expression and atopic dermatitis. Our results do not support a general relationship between expression of IL-31/IL-31R and pruritic or Th2-mediated diseases.

Cathelicidin antimicrobial peptide LL-37 in psoriasis enables keratinocyte reactivity against TLR9 ligands.

Here we show that keratinocytes in psoriatic lesional skin express increased Toll-like receptor (TLR) 9 that similarly localizes with elevated expression of the cathelicidin antimicrobial peptide LL-37. In culture, normal human keratinocytes exposed to LL-37 increased TLR9 expression. Furthermore, when keratinocytes were exposed to LL-37 and subsequently treated with TLR9 ligands, such as CpG or genomic DNA, they greatly increased production of type I IFNs. This response mimicked observations in the epidermis of psoriatic lesional skin as keratinocytes in psoriatic lesions produce greater amounts of IFN-ß than normal skin lacking LL-37. The mechanism for induction of type I IFNs in keratinocytes was dependent on TLR9 expression but not on a DNA-LL-37 complex. These findings suggest that keratinocytes recognize and respond to DNA and can actively participate in contributing to the immunological environment that characterizes psoriasis.

Immunosuppression affects CD4+ mRNA expression and induces Th2 dominance in the microenvironment of cutaneous squamous cell carcinoma in organ transplant recipients.

Squamous cell carcinoma (SCC) is the most frequent cancer in organ transplant recipients (OTRs). The immune system plays a major role in the fight against SCC, however, little is known about the local inflammatory response in SCC at all. We analyzed quantity and quality of the perineoplastic inflammatory SCC microenvironment in immunocompetent patients and immmunosuppressed OTRs. RNA expression profile of SCC patients was analyzed for 8 different sets of genes relating to Th1 versus Th2 response using Gene Set Enrichment Analysis. SCC from immunocompetent patients and OTRs were analyzed by real-time polymerase chain reactions for CD4, CD8, TBET, GATA-3, FOXP3, RORC, IFN-gamma, IL-4, TGF-beta, IL-10, and IL-17A mRNA expression. Immunohistochemistry was carried out in SCC for CD3, CD4, CD8, and FOXP3 expression. Considerable inflammation was seen in both patient groups. SCC in immunocompetent patients and OTRs was associated with a mixed Th1 and Th2 gene expression signature. CD4(+) mRNA was diminished in immunosuppression. Skin adjacent to SCC in OTRs showed Th2 expression pattern as compared with immunocompetent patients. T-BET and IFN-gamma mRNA expression were decreased in the OTR group. Although Th17-weighted inflammation was unchanged, IL-17A mRNA level was markedly decreased with immunosuppression. Regulatory T cells, characterized by FOX-P3 and TGF-beta mRNA level, were decreased in OTRs. Our findings support the hypothesis that nontumor-bearing skin adjacent to SCC in OTRs is not necessarily normal and that the local microenvironment may contribute to a field effect contributing to higher recurrence rates and more aggressive behavior observed in these patients.

Pictorial Representation of Illness and Self Measure (PRISM): A novel visual instrument to measure quality of life in dermatological inpatients.

OBJECTIVES: To validate the PRISM (Pictorial Representation of Illness and Self Measure) tool, a novel visual instrument, for the assessment of health-related quality of life in dermatological inpatients compared with the Dermatology Life Quality Index (DLQI) and the Skindex-29 questionnaires and to report qualitative information on PRISM. DESIGN: In an open longitudinal study, PRISM and Skindex-29 and DLQI questionnaires were completed and HRQOL measurements compared. SETTING: Academic dermatological inpatient ward. PARTICIPANTS: The study population comprised 227 sequential dermatological inpatients on admission. INTERVENTION: Patients completed the PRISM tool and the Skindex-29 and DLQI questionnaires at admission and discharge. MAIN OUTCOME MEASURES: PRISM Self-Illness Separation (SIS) score; Skindex-29 and DLQI scores; and qualitative PRISM information by Mayring inductive qualitative context analysis. RESULTS: The PRISM scores correlated well with those from the Skindex-29 (rho = 0.426; P < .001) and DLQI (rho = 0.304; P < .001) questionnaires. Between PRISM and Skindex-29 scores, the highest correlations were for dermatitis (rho = 0.614) and leg ulcer (rho = 0.554), and between PRISM and DLQI scores, the highest correlations were for psoriasis (rho = 0.418) and tumor (rho = 0.399). The PRISM tool showed comparable or higher sensitivity than quality of life questionnaires to assess changes in the burden of suffering during hospitalization. Inductive qualitative context analysis revealed impairment of adjustment and self-image as major aspects. Patients overall expected symptomatic and functional improvement. In patients with psoriasis and leg ulcers, many expected no treatment benefit. CONCLUSIONS: The PRISM tool proved to be convenient and reliable for health-related quality of life assessment, applicable for a wide range of skin diseases, and correlated with DLQI and Skindex-29 scores. With the PRISM tool, free-text answers allow for the assessment of individual information and potentially customized therapeutic approaches.

Progression of cutaneous squamous cell carcinoma in immunosuppressed patients is associated with reduced CD123+ and FOXP3+ cells in the perineoplastic inflammatory infiltrate.

AIMS: Squamous cell carcinoma of the skin (SCC) increases dramatically in organ transplant recipients (OTRs). The aim was to determine whether qualitative and quantitative differences in perineoplastic inflammation in OTRs contribute to the increased carcinogenesis. METHODS AND RESULTS: We studied the perineoplastic inflammatory infiltrate in SCC, assessing depth, density and phenotype (CD3, 4, 8, FOXP3, CD123 and STAT1) by immunohistochemistry in paired biopsy specimens of intraepithelial and invasive SCC in immunocompetent patients and OTRs. Considerable inflammation was observed in all intraepithelial SCC (inflammatory infiltrate depth 2.80 +/- 2.21 mm immunocompetent patients, 2.15 +/- 2.95 mm OTRs). Inflammation was more pronounced in invasive SCC of immunocompetent patients (4.60 +/- 4.67 mm) and OTRs (3.30 +/- 5.90 mm) (P < 0.005). The density of perineoplastic inflammatory infiltrates increased from intraepithelial to invasive SCC (P = 0.005). OTRs showed a lower density of perineoplastic inflammatory infiltrate (P = 0.041). OTRs also showed reduced CD3+ T-lymphocyte and CD8+ cytotoxic T-lymphocyte proportions in intraepithelial SCC (P = 0.025 and 0.027, respectively). FOXP3+ regulatory T-lymphocyte proportions in OTRs' invasive SCC were markedly diminished (P = 0.048). CD123+ plasmacytoid dendritic cells increased in the progression from intraepithelial to invasive SCC in immunocompetent patients (P = 0.040). CD123+ cells were reduced in all SCC of OTRs (P = 0.036). CONCLUSIONS: Perineoplastic inflammation in intraepithelial SCC is pronounced both in immunocompetent patients and OTRs. Inflammation increases further in invasive SCC. OTRs show reduced proportions of FOXP3+ regulatory T cells and CD123+ plasmacytoid dendritic cells. This distinct inflammatory infiltrate may result in increased cutaneous carcinogenesis and more aggressive behaviour of SCC in OTRs.

Weight of decision-making impairs clinical assessment of melanocytic lesions.

BACKGROUND AND OBJECTIVE: We studied the weight of decision-making on clinical assessment of melanocytic lesions judging benign, atypical, and malignant lesions; common mistakes; and total removal rates, comparing dermatologists with nondermatologists. METHODS: Of 11,246 histopathology specimens, 3,768 had a clinical assessment of melanocytic lesions. Histopathologic diagnosis served as the gold standard. RESULTS: Benign nevi were assessed most accurately (77%). Dermatologists assessed benign nevi better (p < .0001). The accuracy of clinical assessment in atypical nevi and melanoma was lower (23% and 42%, respectively). Seborrheic keratosis was the most common mistaken diagnosis. Complete removal of clinically benign nevi, atypical nevi, and melanoma was 84%, 90%, and 89%. Decision-making impaired clinical assessement of melanocytic lesions by 5% for dermatologists and 9% for nondermatologists. CONCLUSION: The accuracy of clinical assessment of melanocytic lesions is high for benign nevi, with dermatologists outperforming nondermatologists. Clinicians overestimated malignant potential. Complete removal was more frequent in suspicious lesions. Clinical decision-making impaired assessment by 5 to 9%.