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Squamous Cell Carcinoma - Skin Cancer

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Non Melanoma Skin Cancer
Skin Cancer
Prevention of Skin Cancer

Information Patients and the Public (9 links)

Information for Health Professionals / Researchers (5 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Bashline B
Skin Cancer: Squamous and Basal Cell Carcinomas.
FP Essent. 2019; 481:17-22 [PubMed] Related Publications
Approximately 1 in 5 Americans will develop skin cancer during their lifetime; 97% of these cancers will be nonmelanoma skin cancers (NMSCs). Basal cell carcinoma (BCC) comprises approximately 80% of NMSCs and most of the remainder are cutaneous squamous cell carcinomas (SCCs). The predominant risk factor for NMSC is exposure to solar UV radiation. Skin type also plays a role, with a higher incidence of NMSCs among fairer-skinned individuals. Immunocompromise can increase the risk. Biopsy of suspicious lesions should be obtained to determine histologic subtype and guide treatment. Surgical techniques include excision, curettage and electrodessication, and Mohs micrographic surgery. Nonsurgical therapies such as topical therapy or photodynamic therapy may be used for BCC lesions if surgical techniques are not appropriate. Staging and sentinel lymph node biopsy are reserved for patients with large infiltrative lesions. The prognosis for patients with NMSC is extremely favorable. Because of the low risk of metastasis, significant morbidity or mortality is rare. The American Academy of Dermatology recommends skin examinations for all patients with NMSC at least annually. Primary interventions for prevention include counseling on reducing sun exposure, use of UV-protective clothing and sunscreen, and discouragement of tanning bed use.

Hu M, Tang Y, Long G, et al.
Primary Extracranial Meningioma of Mastoid in a Patient With History of Skin Squamous Cell Carcinoma, Lung Adenocarcinoma and Prostatic Carcinoma.
Anticancer Res. 2019; 39(6):3197-3201 [PubMed] Related Publications
BACKGROUND: Meningiomas are the most common benign intracranial tumors and frequently develop in the parasagittal region, but can also present extracranially. Rarely, meningiomas may involve the middle ear and mastoid, resulting from contiguous spread of adjacent intracranial tumor, or extremely rarely, as an isolated primary tumor, which is frequently misdiagnosed and unrecognized, resulting in inappropriate clinical management.
CASE REPORT: Herein we report such a case of an 80-year-old man with history of multiple cancer who presented with ear pain, vertigo and hearing loss. Audiometry demonstrated bilateral sensorineural hearing loss. Contrast-enhanced temporal bone computed tomography revealed a soft-tissue mass in the right epitympanum without bone erosion or any intracranial involvement. Radiological and operative findings were suspicious for cholesteatoma. Histological examination showed an epithelial neoplasm arranged in nests and whorls with intranuclear inclusions. No psammoma bodies, mitotic figures, or tumor necrosis were identified. The tumor cells were positive for epithelial membrane antigen, vimentin, progesterone receptor and CD56; and negative for synaptophysin, chromogranin, pancytokeratin (AE1/AE3), cytokeratin 7, prostate-specific antigen, inhibin, S100, P63, and P40. Ki67 highlighted about 2% of the tumor cells. Based on the morphological features and immunohistochemical profile, the tumor was diagnosed as primary extracranial meningioma of the mastoid, meningothelial subtype, World Health Organization grade 1.
CONCLUSION: To the best of our knowledge, primary mastoid meningioma clinically mimicking a cholesteatoma presenting in a patient with a history of multiple primary carcinomas has not been previously reported. The pathogenesis, diagnosis and treatment of this entity are discussed.

Lin RL, Wu EM, Hale EK
Use of a Buried Intradermal (Subcutaneous) Running Suture for Superficial Repair to Optimize Cosmetic Outcome
J Drugs Dermatol. 2019; 18(5):481-482 [PubMed] Related Publications
Superficial repair after excisions helps to optimize cosmetic outcomes. Possibly due to how wound closures are traditionally taught in dermatology, simple interrupted or continuous sutures are overwhelmingly favored by dermatologic surgeons in superficial repair, especially on cosmetically sensitive areas such as face and ears. However, this repair method risks wound overgrowth around the points where the suture traverses through the epidermis, and long-term postsurgical healing frequently leaves behind scars with ‘railroad track’ suture marks rather than a fine line. Here, we present buried intradermal running suture technique as an alternative superficial repair method compared to the simple interrupted or running suture techniques. We demonstrate the superior cosmetic outcome offered by buried intradermal suture with 2 patient cases, who had defects on the temple and shin. While dermatologists can now offer energy-based devices and neuromodulators to improve cosmesis, our approach helps optimize scar appearance so that patients can have the best possible surgical outcome without necessitating further interventions. J Drugs Dermatol. 2019;18(5):481-482.

Verhave B, Goldberg M, Hashim P, Levitt J
Treatment of Arsenic-Induced Bowen’s Disease With Topical 5-Fluorouracil
J Drugs Dermatol. 2019; 18(5):477-479 [PubMed] Related Publications
Here, we present a case of arsenic-induced Bowen’s disease treated with a regimen consisting of topical 5-fluouracil and oral nicotinamide. The use of this therapy modality resulted in near complete resolution of all of the patient’s lesions except for those on her palms, soles, and scalp. Excellent wound care and treatment adherence were major factors contributing to the success of this treatment option. Our results ultimately provide an alternative approach to treating multiple arsenical keratoses in patients who are limited to a drug plan involving 5-FU and oral nicotinamide and who are able to be rigorously compliant with application of medication and wound care. J Drugs Dermatol. 2019;18(5):477-479.

Cavalieri S, Perrone F, Milione M, et al.
PD-L1 Expression in Unresectable Locally Advanced or Metastatic Skin Squamous Cell Carcinoma Treated with Anti-Epidermal Growth Factor Receptor Agents.
Oncology. 2019; 97(2):112-118 [PubMed] Related Publications
BACKGROUND: Recurrent or metastatic (R/M) skin squamous cell carcinoma (sSCC) not amenable of surgery or irradiation may benefit from systemic therapies. Epidermal growth factor receptor (EGFR) inhibitors and, more recently, immune checkpoint blockers (ICBs) showed activity in R/M sSCC. In this study, we aimed at exploring the possible role of PD-L1 expression in predicting response to anti-EGFR agents.
METHODS: Patients affected by R/M sSCC, treated with pan-HER inhibitor dacomitinib or with platinum-based chemotherapy with cetuximab (CT-cet) from 2010 to 2016, were considered. PD-L1 expression was assessed with immunohistochemistry on tumor cells (TCs) and on microenvironment (TC and tumor-infiltrating lymphocyte [IC] scores, respectively). Prognostic role of PD-L1 and the correlation with response to EGFR inhibitors and survival were analyzed.
RESULTS: Twenty-eight R/M sSCCs were analyzed (19 treated with dacomitinib, 9 with CT-cet). TC and IC were negative in 82 and 45% of cases, respectively; 15% sSCCs were both TC and IC positive. Progression-free survival (PFS) was longer in IC-positive cases (median 7.5 months vs. 2.1 in IC0, p = 0.02). No statistically significant differences were observed between PD-L1 expression and both overall survival and response rates.
CONCLUSION: PD-L1 expression in microenvironment predicted better PFS. The combination of EGFR inhibitors and ICB could help deepening the knowledge about the interrelations between the EGFR and PD-1/PD-L1 pathways.

Miolo N, Rodrigues RF, Silva ERD, et al.
Skin cancer incidence in rural workers at a reference hospital in western Paraná.
An Bras Dermatol. 2019 Mar-Apr; 94(2):157-163 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Skin cancer is common in Brazil and is related to sun exposure, among other risk factors. There are no data on the incidence of malignant skin neoplasm in rural workers in western Paraná.
OBJECTIVE: To analyze the incidence and profile of rural workers who were diagnosed with skin cancer at a reference service in Cascavel, western Paraná, in the last five years (2011-2016).
METHODS: This retrospective cross-sectional study was carried out through a review of the anatomopathological reports of rural workers diagnosed with skin cancer at Cascavel Oncology Center (CEONC), in Cascavel. The following variables were collected: year of diagnosis, age, gender, injury location and histological subtype.
RESULTS: A total of 681 cases of malignant epithelial neoplasia were identified, with a higher frequency in the 61-70 age group. Data analysis showed an increase of about 210% in the occurrence of skin cancers in the last 5 years. The cephalic region was the most affected, and the most common histological subtype was nodular basal cell carcinoma. There was no association between gender and location.
STUDY LIMITATIONS: This is a retrospective study and analysis of a secondary data bank.
CONCLUSION: This study is a regional estimation of the incidence of cutaneous neoplasms and provides evidence of a considerable increase in the number of diagnoses in rural workers from western Paraná, Brazil. Moreover, it is possible to conclude that the sample group studied is at risk of developing skin cancer.

Mikami E, Kudo M, Ohashi R, et al.
Toll‑like receptor 4 plays a tumor‑suppressive role in cutaneous squamous cell carcinoma.
Int J Oncol. 2019; 54(6):2179-2188 [PubMed] Related Publications
Toll‑like receptor 4 (TLR4), a key regulator of the innate immune system, is expressed not only in immune cells, but also in a number of cancer cells. A biological role for TLR4 in cutaneous squamous cell carcinoma (SCC), however, is unclear. In this study, we first examined TLR4 expression and localization in cases of SCC, actinic keratosis (AK) and Bowen's disease (BD) by immunohistochemistry. TLR4 expression was significantly higher in the SCC than in the AK or BD tissues. We then determined the TLR4 expression level in vivo, in 3 histological subtypes of SCC. TLR4 expression in poorly differentiated SCC was significantly lower compared with that of the moderately and well‑differentiated type. In addition, the CD44 immunoreactivity tended to be high in the cell membrane of poorly differentiated SCC. Of note, poorly differentiated SCC is a risk factor of unfavorable outcomes in affected patients. We then assessed the biological role of TLR4 in HSC‑1 and HSC‑5 SCC cells and HaCaT human keratinocytes. TLR4 knockdown by transfection with siRNA accelerated HSC‑1 and HaCaT cell migration and invasion compared to the control siRNA‑transfected cells. TLR4 knockdown resulted in an increased CD44 expression and in an enhanced filopodia protrusion formation, particularly in HSC‑1. On the whole, these results suggest that a reduced TLR4 expression enhances the malignant features in SCC cases and cultured SCC cell lines. TLR4 may thus play an anti‑tumor role in cutaneous SCC.

Tampucci S, Carpi S, Digiacomo M, et al.
Diclofenac-Derived Hybrids for Treatment of Actinic Keratosis and Squamous Cell Carcinoma.
Molecules. 2019; 24(9) [PubMed] Free Access to Full Article Related Publications
In this work, hybrid compounds

Goldie SJ, Chincarini G, Darido C
Targeted Therapy Against the Cell of Origin in Cutaneous Squamous Cell Carcinoma.
Int J Mol Sci. 2019; 20(9) [PubMed] Free Access to Full Article Related Publications
Squamous cell carcinomas (SCC), including cutaneous SCCs, are by far the most frequent cancers in humans, accounting for 80% of all newly diagnosed malignancies worldwide. The old dogma that SCC develops exclusively from stem cells (SC) has now changed to include progenitors, transit-amplifying and differentiated short-lived cells. Accumulation of specific oncogenic mutations is required to induce SCC from each cell population. Whilst as fewer as one genetic hit is sufficient to induce SCC from a SC, multiple events are additionally required in more differentiated cells. Interestingly, the level of differentiation correlates with the number of transforming events required to induce a stem-like phenotype, a long-lived potential and a tumourigenic capacity in a progenitor, a transient amplifying or even in a terminally differentiated cell. Furthermore, it is well described that SCCs originating from different cells of origin differ not only in their squamous differentiation status but also in their malignant characteristics. This review summarises recent findings in cutaneous SCC and highlights transforming oncogenic events in specific cell populations. It underlines oncogenes that are restricted either to stem or differentiated cells, which could provide therapeutic target selectivity against heterogeneous SCC. This strategy may be applicable to SCC from different body locations, such as head and neck SCCs, which are currently still associated with poor survival outcomes.

García-Sancha N, Corchado-Cobos R, Pérez-Losada J, Cañueto J
MicroRNA Dysregulation in Cutaneous Squamous Cell Carcinoma.
Int J Mol Sci. 2019; 20(9) [PubMed] Free Access to Full Article Related Publications
Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans and it can be locally invasive and metastatic to distant sites. MicroRNAs (miRNAs or miRs) are endogenous, small, non-coding RNAs of 19-25 nucleotides in length, that are involved in regulating gene expression at a post-transcriptional level. MicroRNAs have been implicated in diverse biological functions and diseases. In cancer, miRNAs can proceed either as oncogenic miRNAs (onco-miRs) or as tumor suppressor miRNAs (oncosuppressor-miRs), depending on the pathway in which they are involved. Dysregulation of miRNA expression has been shown in most of the tumors evaluated. MiRNA dysregulation is known to be involved in the development of cutaneous squamous cell carcinoma (CSCC). In this review, we focus on the recent evidence about the role of miRNAs in the development of CSCC and in the prognosis of this form of skin cancer.

Bottomley MJ, Thomson J, Harwood C, Leigh I
The Role of the Immune System in Cutaneous Squamous Cell Carcinoma.
Int J Mol Sci. 2019; 20(8) [PubMed] Free Access to Full Article Related Publications
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer. In immunosuppressed populations it is a source of considerable morbidity and mortality due to its enhanced recurrence and metastatic potential. In common with many malignancies, leucocyte populations are both protective against cancer development and also play a role in 'sculpting' the nascent tumor, leading to loss of immunogenicity and tumor progression. UV radiation and chronic viral carriage may represent unique risk factors for cSCC development, and the immune system plays a key role in modulating the response to both. In this review, we discuss the lessons learned from animal and ex vivo human studies of the role of individual leucocyte subpopulations in the development of cutaneous SCC. We then discuss the insights into cSCC immunity gleaned from studies in humans, particularly in populations receiving pharmacological immunosuppression such as transplant recipients. Similar insights in other malignancies have led to exciting and novel immune therapies, which are beginning to emerge into the cSCC clinical arena.

Amiraraghi N, Scott RA, Balaji N, Yaneza MMC
Human papillomavirus 16 and p16 positive nasal cutaneous squamous cell carcinoma in immunocompetent men in their twenties.
J Laryngol Otol. 2019; 133(4):348-352 [PubMed] Related Publications
BACKGROUND: Cutaneous squamous cell carcinoma is usually associated with long-term ultraviolet light exposure. Human papillomavirus 16 is a high-risk mucosal human papillomavirus type, usually associated with anogenital and oropharyngeal cancer. This paper describes the first two cases of human papillomavirus 16 and p16 related nasal cutaneous squamous cell carcinoma.
METHOD: Prospective case series from December 2015.
RESULTS: Two young, male, fair-skinned patients had large (greater than 20 mm), rapidly growing, ulcerated lesions of the nasal tip. The tumours were excised, with at least a 6 mm margin, and the patients' noses were subsequently reconstructed. Neither patient had cervical lymphadenopathy or underwent adjuvant radiotherapy. Both patients were registered at the same general practice. The tumours were human papillomavirus 16 and p16 positive; the latter indicated that the virus was driving the disease process. Except for superficial burns, neither patient had other risk factors.
CONCLUSION: Changes in sexual practices have led to an increase in human papillomavirus positive oropharyngeal carcinoma and there may be an associated increase in human papillomavirus type 16 positive nasal cutaneous squamous cell carcinoma.

Zhao G, Bae JY, Zheng Z, et al.
Overexpression and Implications of Melanoma-associated Antigen A12 in Pathogenesis of Human Cutaneous Squamous Cell Carcinoma.
Anticancer Res. 2019; 39(4):1849-1857 [PubMed] Related Publications
BACKGROUND/AIM: Melanoma-associated antigen A12 (MAGEA12) has recently been reported as a repressor of tumor-suppressor genes. This study aimed to investigate the implications of MAGEA12 expression in the pathogenesis of cutaneous squamous cell carcinoma (cSCC).
MATERIALS AND METHODS: MAGEA12 and p21 expression were investigated in 15 samples of normal skin and 111 of cSCC tissues by immunohistochemistry. The biological functions of MAGEA12 in cSCC were also investigated both in vitro and in vivo.
RESULTS: Expression of both MAGEA12 and p21 was significantly increased in cSCC. MAGEA12 expression showed a positive correlation, while p21 expression showed negative correlation with the recurrence-free survival of patients with cSCC. In addition, MAGEA12 knockdown significantly attenuated proliferative, migratory, invasive, and tumorigenic activities of cSCC cells and was negatively correlated with p21 expression both in vitro and in vivo.
CONCLUSION: MAGEA12-mediated down-regulation of p21 may be involved in cSCC pathogenesis and MAGEA12 may serve as a molecular biomarker in cSCC.

Hu SC, Su YS, Lai YC, et al.
Liposomal Avicequinone-B formulations: Aqueous solubility, physicochemical properties and apoptotic effects on cutaneous squamous cell carcinoma cells.
Phytomedicine. 2019; 58:152870 [PubMed] Related Publications
BACKGROUND: Avicequinone-B (Naphtho[2,3-b]furan-4,9-dione) is a furanonaphthoquinone derivative. It is a hydrophobic compound with poor aqueous solubility, which may restrict its potential pharmaceutical and biomedical applications.
PURPOSE: We synthesized different liposomal formulations of Avicequinone-B, and measured their particle size, aqueous solubility, and physicochemical properties. In addition, we investigated the anticancer activity of liposomal Avicequinone-B in human cutaneous squamous cell carcinoma (SCC) cells.
METHODS: Liposomal Avicequinone-B formulations were synthesized using the thin-film hydration method. Drug yield, encapsulation efficiency and aqueous solubility were determined by high performance liquid chromatography. Particle size and polydispersity index were measured by submicron particle size analyzer, and ultrastructural morphology was visualized by transmission electron microscopy. Thermal transitions were determined by differential scanning calorimetry. Anti-skin cancer activity was determined in HSC-1 cells (human cutaneous SCC cell line) using the MTS cytotoxicity assay, apoptosis was assessed by caspase-3/7 activity assay, mitochondrial membrane potential was determined by JC-10 assay, and signal transduction pathways were evaluated by Western blot analysis.
RESULTS: Liposomal Avicequinone-B formulations showed adequate yield and high encapsulation efficiency. These liposomal formulations produced small, uniformly sized nanoparticles, and greatly increased the aqueous solubility of Avicequinone-B. Differential scanning calorimetry showed loss of thermal phase transitions. In addition, liposomal Avicequinone-B showed significant cytotoxic effect on HSC-1 cells, through reduction of mitochondrial membrane potential, increased cytosolic cytochrome-c level, increased cleaved caspase 8 level, and induction of apoptosis. This was mediated through activation of ERK, p38 and JNK signaling pathways.
CONCLUSION: Liposomal Avicequinone-B demonstrated improved aqueous solubility and physicochemical characteristics, and induced apoptosis in cutaneous SCC cells. Therefore, liposomal Avicequinone-B may have potential uses as a topical anti-skin cancer drug formulation in the future.

Thompson JD, Avey GD, Wieland AM, et al.
Auriculotemporal Nerve Involvement in Parotid Bed Malignancy.
Ann Otol Rhinol Laryngol. 2019; 128(7):647-653 [PubMed] Related Publications
OBJECTIVE: To identify and evaluate patients with parotid bed malignancy demonstrating radiographic findings of auriculotemporal (AT) nerve involvement.
METHODS: A retrospective review of patients with parotid bed malignancy was performed to identify patients with imaging findings of AT nerve involvement and record associated clinical findings, symptoms, and pathology information. Independent, blinded review of radiographic images by a senior neuroradiologist was performed to identify imaging characteristics and categorize patients into highly likely or possible involvement groups.
RESULTS: Of 547 patients identified with parotid bed malignancy, 23 patients exhibited radiographic findings suggestive of AT nerve involvement. Thirteen patients met criteria for highly likely involvement, and 10 patients met criteria for possible involvement. Cutaneous malignancy with metastasis to the parotid bed accounted for 11 of 23 patients, and the most common histology was squamous cell carcinoma (9 patients). Primary parotid malignancy accounted for 12 of 23 patients, and the most common histology was salivary ductal carcinoma (3 patients). All 13 highly likely patients reported periauricular pain, and 11 of 13 demonstrated facial weakness. Features suggesting advanced disease included radiographic findings of intracranial involvement (10/23 patients), nonsurgical primary treatment (13/23 patients), and positive margins on pathology report (7/10 patients).
CONCLUSION: AT nerve involvement is an uncommon but important phenomenon that often occurs in the setting of advanced disease and is commonly associated with periauricular pain and coexisting facial weakness. Awareness of the associated clinical features and imaging patterns can allow for appropriate identification of this pattern of spread and help to optimize treatment planning.

Gong ZH, Zhou F, Shi C, et al.
miRNA-221 promotes cutaneous squamous cell carcinoma progression by targeting PTEN.
Cell Mol Biol Lett. 2019; 24:9 [PubMed] Free Access to Full Article Related Publications
Background: Cutaneous squamous cell carcinoma (CSCC) is a common type of skin malignancy. MicroRNA-221 (miRNA-221) is a critical non-coding RNA in tumor initiation and progression. However, the molecular mechanisms of miRNA-221 in the development of CSCC remain unknown. This study investigated the expression of miRNA-221 in CSCC and its potential tumor biological functions.
Methods: MTT assay, colony assay, PCR, and Western blot were adopted.
Results: In this study, miRNA-221 expression was significantly higher in CSCC tissues and cell lines than in normal tissues and cells (
Conclusions: Taken together, the obtained results indicated that miR-221 plays an oncogenic function in CSCC by targeting PTEN and further suggest that miR-221 may be a potential target for CSCC diagnosis and treatment.

Ventura A, Pellegrini C, Cardelli L, et al.
Telomeres and Telomerase in Cutaneous Squamous Cell Carcinoma.
Int J Mol Sci. 2019; 20(6) [PubMed] Free Access to Full Article Related Publications
The role of telomere biology and telomerase activation in skin cancers has been investigated in melanoma and basal cell carcinoma but limited evidence is available for cutaneous squamous cell carcinoma (cSCC). We will review the current knowledge on the role of telomere and telomerase pathway in cSCC pathogenesis. At the somatic level, both long and short telomere lengths have been described in cSCC. This telomere dichotomy is probably related to two different mechanisms of tumour initiation which determines two tumour subtypes. Telomere shortening is observed during the invasive progression from in situ forms of cSCC, such as Bowen's disease (BD) and actinic keratosis (AK), to invasive cSCC. At the germline level, controversial results have been reported on the association between constitutive telomere length and risk of cSCC. Approximately 75⁻85% of cSCC tumours are characterized by a high level of telomerase activity. Telomerase activation has been also reported in AKs and BD and in sun-damaged skin, thus supporting the hypothesis that UV modulates telomerase activity in the skin. Activating

Pandey A, Liaukovich M, Joshi K, et al.
Uncommon Presentation of Metastatic Squamous Cell Carcinoma of the Skin and Treatment Challenges.
Am J Case Rep. 2019; 20:294-299 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Squamous cell carcinoma is one of the most common keratinocytic skin cancers, the other being basal cell carcinoma. It is the second most common skin cancer after melanoma. Cutaneous squamous cell carcinoma is mostly a localized disease. The metastatic presentation is rare even in the presence of invasive disease. The metastatic potential depends on the presence of high-risk features at the time of diagnosis. Lung, liver, and bone are the frequent sites of metastasis. Local and locoregional disease undergoes excision with or without adjuvant radiation. However, we lack proper treatment paradigms for this metastatic disease. CASE REPORT We are reporting a case of an elderly female with a history of high-risk localized cutaneous squamous cell carcinoma treated with complete local excision and radiation presenting 5 years later with extensive disease to the lung and liver, abdominal nodes, and spinal fracture. The patient was not a candidate for chemotherapy due to kidney failure. On the basis of ongoing separate trials on different immunotherapies, she was started on nivolumab. CONCLUSIONS Treating metastatic cutaneous squamous cell carcinoma is a challenge considering the absence of phase III trials due to the rarity of this disease. Historically, platinum with or without 5-FU (fluorouracil), bleomycin, doxorubicin, and retinoic acid were used with variable responses. Data on epidermal growth factor receptor (EGFR) inhibitors on EGFR expressing tumors are available. However, even with the most recent reports on immunotherapy in patients with high programmed death-1 expression or high mutation burden, it is difficult to achieve good response.

Yom SS
Integrating the Management of Nodal Metastasis Into the Treatment of Nonmelanoma Skin Cancer.
Semin Radiat Oncol. 2019; 29(2):171-179 [PubMed] Related Publications
The two types of nonmelanoma skin cancer most apt to metastasize to lymph nodes are cutaneous squamous cell carcinoma and Merkel cell carcinoma. The clinical impact of nodal metastases of these cancers is substantial, resulting in intensification of treatment and morbidity and worsened cancer outcomes. Exact best practices are challenging to define as many specific clinical scenarios remain incompletely catalogued, characterized, or studied. In general, the role of radiation therapy is indisputably established as part of the treatment of both of these diseases although its success depends on the best available assessment of extent of disease and appropriate integration into the multimodality care plan.

Baltz GC, Chi PM, Wong PF, et al.
Development and validation of a 3D-printed bolus cap for total scalp irradiation.
J Appl Clin Med Phys. 2019; 20(3):89-96 [PubMed] Free Access to Full Article Related Publications
PURPOSE: The goal of total scalp irradiation (TSI) is to deliver a uniform dose to the scalp, which requires the use of a bolus cap. Most current methods for fabricating bolus caps are laborious, yet still result in nonconformity and low reproducibility, which can lead to nonuniform irradiation of the scalp. We developed and validated patient-specific bolus caps for TSI using three-dimensional (3D) printing.
METHODS AND MATERIALS: 3D-printing materials were radiologically analyzed to identify a material with properties suitable for use as a bolus cap. A Python script was developed within a commercial treatment planning system to automate the creation of a ready-to-print, patient-specific 3D bolus cap model. A bolus cap was printed for an anthropomorphic head phantom using a commercial vendor and a computed tomography simulation of the anthropomorphic head phantom and bolus cap was used to create a volumetric-modulated arc therapy TSI treatment plan. The planned treatment was delivered to the head phantom and dosimetric validation was performed using thermoluminescent dosimeters (TLD). The developed procedure was used to create a bolus cap for a clinical TSI patient, and in vivo TLD measurements were acquired for several fractions.
RESULTS: Agilus-60 was validated as a new 3D-printing material suitable for use as bolus. A 3D-printed Agilus-60 bolus cap had excellent conformality to the phantom scalp, with a maximum air gap of 4 mm. TLD measurements showed that the bolus cap generated a uniform dose to the scalp within a 2.7% standard deviation, and the delivered doses agreed with calculated doses to within 2.4% on average. The patient bolus was conformal and the average difference between TLD measured and planned doses was 5.3%.
CONCLUSIONS: We have developed a workflow to 3D-print highly conformal bolus caps for TSI and demonstrated these caps can reproducibly generate a uniform dose to the scalp.

Marka A, Carter JB, Toto E, Hassanpour S
Automated detection of nonmelanoma skin cancer using digital images: a systematic review.
BMC Med Imaging. 2019; 19(1):21 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Computer-aided diagnosis of skin lesions is a growing area of research, but its application to nonmelanoma skin cancer (NMSC) is relatively under-studied. The purpose of this review is to synthesize the research that has been conducted on automated detection of NMSC using digital images and to assess the quality of evidence for the diagnostic accuracy of these technologies.
METHODS: Eight databases (PubMed, Google Scholar, Embase, IEEE Xplore, Web of Science, SpringerLink, ScienceDirect, and the ACM Digital Library) were searched to identify diagnostic studies of NMSC using image-based machine learning models. Two reviewers independently screened eligible articles. The level of evidence of each study was evaluated using a five tier rating system, and the applicability and risk of bias of each study was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool.
RESULTS: Thirty-nine studies were reviewed. Twenty-four models were designed to detect basal cell carcinoma, two were designed to detect squamous cell carcinoma, and thirteen were designed to detect both. All studies were conducted in silico. The overall diagnostic accuracy of the classifiers, defined as concordance with histopathologic diagnosis, was high, with reported accuracies ranging from 72 to 100% and areas under the receiver operating characteristic curve ranging from 0.832 to 1. Most studies had substantial methodological limitations, but several were robustly designed and presented a high level of evidence.
CONCLUSION: Most studies of image-based NMSC classifiers report performance greater than or equal to the reported diagnostic accuracy of the average dermatologist, but relatively few studies have presented a high level of evidence. Clinical studies are needed to assess whether these technologies can feasibly be implemented as a real-time aid for clinical diagnosis of NMSC.

Chu Z, Zhang X, Li Q, et al.
CDC20 contributes to the development of human cutaneous squamous cell carcinoma through the Wnt/β‑catenin signaling pathway.
Int J Oncol. 2019; 54(5):1534-1544 [PubMed] Free Access to Full Article Related Publications
Cell division cycle 20 (CDC20) is a regulatory molecule and serves critical roles at multiple points of the cell cycle. Recent evidence indicates that CDC20 may serve an oncogenic role in a number of human cancer types. However, the role of CDC20 in primary cutaneous squamous cell carcinoma (cSCC) has not been studied, to the best of our knowledge. The aim of the present study was to investigate whether and how CDC20 is involved in the tumorigenesis of cSCC. The results revealed that CDC20 expression was significantly increased in cSCC tissues and cell lines, and its expression was associated with pathological differentiation. Downregulation of CDC20 inhibited cell proliferation, induced cell cycle arrest, promoted apoptosis and reduced migratory ability through inhibition of the Wnt/β‑catenin signaling pathway. Furthermore, all‑trans‑retinoic acid treatment significantly downregulated CDC20 expression in cSCC. The present results revealed that CDC20 may serve a crucial role in human cSCC, and suggested that CDC20 may be a novel biomarker for the prevention, diagnosis and treatment of cSCC.

Gandini S, Doré JF, Autier P, et al.
Epidemiological evidence of carcinogenicity of sunbed use and of efficacy of preventive measures.
J Eur Acad Dermatol Venereol. 2019; 33 Suppl 2:57-62 [PubMed] Related Publications
The International Agency for Research on Cancer classified, in July 2009, exposure to artificial tanning devices (sunbeds) as carcinogenic to humans. This classification was based on evidence from epidemiological and experimental animal studies. The present chapter will review these epidemiological evidences. The summary risk estimates from 27 epidemiological studies obtained through a meta-analysis showed an increased risk of melanoma: summary relative risk (SRR) = 1.20 [95% confidence interval (CI) 1.08-1.34]. The risk was higher when exposure took place at younger age (SRR = 1.59; 95% CI 1.36-1.85). The risk was independent of skin sensitivity or population and a dose response was evident. A meta-analysis of 12 studies was conducted for non-melanoma skin cancers and showed a significantly increased risk for basal cell carcinoma (SRR = 1.29; 95% CI 1.08-1.53) and for squamous cell carcinoma (SRR = 1.67; 95% CI 1.29-2.17). As for melanoma, the risk for other skin cancers increased for first exposures at young age. Epidemiological studies have gradually strengthened the evidence for a causal relationship between indoor tanning and skin cancer and they fit with prior knowledge on relationship between UV exposure and skin cancer. Additionally, several case-control studies provided consistent evidence of a positive association between use of sunbed and ocular melanoma, also with greater risk for first exposures at younger age. Preventive measures based on information on risk or by requiring parental authorization for young users proved to be inefficient in several studies. The significant impact of strong actions or total ban, such as performed in Iceland, or a total ban of sunbed use, as in Brazil or Australian states, needs to be further assessed.

Suppa M, Gandini S, Njimi H, et al.
Association of sunbed use with skin cancer risk factors in Europe: an investigation within the Euromelanoma skin cancer prevention campaign.
J Eur Acad Dermatol Venereol. 2019; 33 Suppl 2:76-88 [PubMed] Related Publications
INTRODUCTION: Sunbed use has been significantly associated with increased risk of melanoma and non-melanoma skin cancer (NMSC), but its relationship with melanoma's risk factors such as high nevus count, atypical nevi and lentigines is poorly studied. Euromelanoma is a skin cancer prevention campaign conducted all over Europe. It offers a once-a-year screening during which participants' data, including sunbed use and phenotype, are collected via questionnaires.
OBJECTIVES: To investigate the association of sunbed use with nevus count, atypical nevi, lentigines and suspicion of skin cancer.
METHODS: To ensure reliability of the data, we defined inclusion and exclusion criteria for countries' eligibility for the risk analysis. Multivariate logistic regression models (including age, gender, education, skin type, family history of melanoma, personal history of skin cancer, any sun exposure and any sunscreen use) were used to calculate summary odds ratios (SORs) of each clinical endpoint for ever sunbed use.
RESULTS: Overall, 227 888 individuals from 30 countries completed the Euromelanoma questionnaire. After the data quality check, 16 countries were eligible for the multivariate analysis, for a total of 145 980 participants (64.8% females; median age 43 years; 62.3% highly educated; 28.5% skin type I-II; 11.0% ever sunbed use). Ever sunbed use was independently associated with nevus count >50 [SOR = 1.05 (1.01-1.10)], atypical nevi [SOR = 1.04 (1.00-1.09)], lentigines [SOR = 1.16 (1.04-1.29)] and suspicion of melanoma [SOR = 1.13 (1.00-1.27)]. Conversely, no significant association was found between ever sunbed use and suspicion of NMSC [SOR = 1.00 (0.91-1.10)].
CONCLUSIONS: Indoor tanning is significantly associated with well-recognized risk factors for melanoma (including high nevus count, presence of atypical nevi and lentigines) as well as suspicion of melanoma within the Euromelanoma screenees. In order to reduce the prevalence of melanoma risk factors, avoidance/discontinuation of sunbed use should always be encouraged, especially but not exclusively for individuals with high-risk phenotypes.

Calzavara-Pinton PG, Arisi M, Wolf P
Sunbeds and carcinogenesis: the need for new regulations and restrictions in Europe from the Euromelanoma perspective.
J Eur Acad Dermatol Venereol. 2019; 33 Suppl 2:104-109 [PubMed] Related Publications
Experimental investigations have definitely assessed that ultraviolet A (UVA) as well as ultraviolet B (UVB) radiation induce mutagenic DNA photoproducts and other cell damages with a carcinogenic potential. Artificial tanning increases significantly the lifetime risk for basal cell carcinoma, squamous cell carcinoma and melanoma particularly in subjects with fair skin type, subjects with a history of skin cancer or frequent childhood sunburn or if exposures took place at an age younger than 18 years. In addition, experimental and clinical evidence indicate that UVA exposure promotes skin photoageing. Therefore we are dealing with a recreational activity (for customers) and a profitable business (for the tanning industry) with human costs, i.e. an increase in morbidity and mortality by skin cancer, and health and social costs leading to an increased expenditure by the European national health systems. In a few European countries, legislation has recently prohibited the use of sunbeds for minors, pregnant women, people with skin cancer or a history of skin cancer and individuals who do not tan or who burn easily from sun exposure. However, this legislation seems to be insufficient from a photobiological perspective, and importantly, it is largely disregarded by consumers and tanning industry. Therefore the Euromelanoma group proposes a new, more stringent regulation for the tanning industry and restrictions for customers, particularly for those individuals with constitutional and anamnestic risk factors. Finally, we ask for an enhanced commitment to increase the awareness of the general population on the risk of artificial tanning.

Kiyohara T, Shijimaya T, Miyamoto M, et al.
In-transit recurrence of Merkel cell carcinoma associated with Bowen's disease: The first reported case successfully treated by avelumab.
J Dermatol. 2019; 46(5):440-443 [PubMed] Related Publications
A 65-year-old Japanese man presented with a dome-shaped nodule, the base of which was contiguous with a dull brown plaque, on the left leg. After local excision of the cutaneous lesion and left inguinal lymph node dissection, several dermal and subcutaneous nodules developed successively on the left lower extremity. Hematoxylin-eosin staining of the primary cutaneous lesion demonstrated uniform neoplastic cells arranged in a trabecular pattern extending from the dermis to subcutis. Mitotic figures were abundant. Although the overlying epidermis was substantially intact, the Merkel cells had invaded the epidermis, resulting in Pautrier-like microabscesses. The hyperplastic epidermis adjacent to the nodule consisted of abnormally growing atypical keratinocytes. The enlarged left inguinal lymph node and successive secondary nodules contained Merkel cells similar to those in the primary nodule. Immunohistochemically, most tumor cells were positive for CAM5.2, synaptophysin, chromogranin A, CD56 and vimentin. The tumor cells in the left inguinal lymph node were positive for CAM5.2, synaptophysin and cytokeratin 20 but negative for CM2B4, and less than 1% of the cells expressed programmed cell death ligand 1. The patient was treated with avelumab, which showed significant efficacy against the in-transit recurrence. Two months later, all nodules had disappeared completely. We describe a case of in-transit recurrence of Merkel cell carcinoma that was associated histologically with Bowen's disease and was successfully treated with avelumab. Although accumulation of additional cases is needed, avelumab therapy may be a useful treatment for in-transit recurrence of Merkel cell carcinoma.

Zhu L, Cho E, Zhao G, et al.
The Pathogenic Effect of Cortactin Tyrosine Phosphorylation in Cutaneous Squamous Cell Carcinoma.
In Vivo. 2019 Mar-Apr; 33(2):393-400 [PubMed] Free Access to Full Article Related Publications
BACKGROUND/AIM: Cortactin (CTTN) has been considered a promising molecular prognostic factor in various types of cancers. In this study, we aimed to investigate the role of CTTN in the pathogenesis of cutaneous squamous cell carcinoma (CSCC).
MATERIALS AND METHODS: CTTN and phospho-CTTN (p-CTTN) expression was determined in 10 healthy controls and 38 CSCC tissue samples by immunohistochemistry. The influence of CTTN on the biological behavior of CSCC cells was also investigated.
RESULTS: p-CTTN expression was significantly increased in CSCC than control samples. In contrast, no significant difference in CTTN expression was found between control and CSCC tissues. Moreover, a significant association was found between recurrence-free survival with p-CTTN expression, but not with CTTN expression. Furthermore, the proliferative, migratory, and invasive abilities of CSCC cells were significantly decreased by CTTN-siRNA transfection.
CONCLUSION: CTTN phosphorylation is strongly associated with CSCC pathogenesis and may serve as a molecular biomarker of CSCC.

Roth WI, Shelling M, Fishman K
Superficial Radiation Therapy: A Viable Nonsurgical Option for Treating Basal and Squamous Cell Carcinoma of the Lower Extremities
J Drugs Dermatol. 2019; 18(2):130-134 [PubMed] Related Publications
Background: Superficial radiation therapy (SRT) is a nonsurgical method of treating basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) lesions on the lower extremities of older individuals that might otherwise suffer complications or prolonged healing following surgical intervention. Objective: The goal of this study was to evaluate the effectiveness of SRT for treating BCC and SCC lesions on the lower extremities of elderly patients in an outpatient clinic setting. Methods and Materials: A retrospective review was performed using data from consecutive patients with BCC and SCC on their lower extremities and were treated with SRT. Results: The review included patients with biopsy-proven BCC (n=38, 25%) and SCC (n=113, 75%). The mean patient age was 82.5 years and the follow-up period was ≥4 years (32%), 3 years (30%), 2 years (20%), and ≤2 years (17%). The overall success rate was over 97%. Four lesions (one BCC and three SCCs) recurred equally between genders (2 males and 2 females) with lesions >1.0 cm and all lesions were eventually cleared with other modalities. Conclusions: Superficial radiation therapy is an effective option for eliminating BCC and SCC on lower extremities of patients who opt for nonsurgical treatment. Using SRT for BCC and SCC in elderly patients resulted in a 97.4% cure rate. J Drugs Dermatol. 2019;18(2):130-134.

Hu SC, Lai YC, Lin CL, et al.
Inclusion complex of saikosaponin-d with hydroxypropyl-β-cyclodextrin: Improved physicochemical properties and anti-skin cancer activity.
Phytomedicine. 2019; 57:174-182 [PubMed] Related Publications
BACKGROUND: Saikosaponin-d (SSD) is a triterpene saponin isolated from Bupleurum plants. It has been shown to exhibit antioxidant, anti-inflammatory, and anticancer activities. However, its biomedical applications are limited by its poor water solubility. Cyclodextrins are highly water soluble oligosaccharide compounds which can form inclusion complexes with lipophilic drugs.
PURPOSE: We complexed SSD with hydroxypropyl-β-cyclodextrin (HPBCD) in various ratios to form SSD-HPBCD inclusion complexes. The inclusion complexes were evaluated for their solubility, physicochemical properties and cytotoxic effects in cutaneous squamous cell carcinoma cells.
METHODS: Surface morphology of pure SSD and SSD-HPBCD inclusion complexes was evaluated by scanning electron microscopy. Crystalline structure was determined by X-ray diffractometry. Intermolecular hydrogen bond formation between SSD and HPBCD was investigated by Fourier transform infrared spectroscopy. Human cutaneous squamous cell carcinoma HSC-1 cell viability was determined by the MTS assay, and cell apoptosis by the caspase 3/7 assay. Signal transduction pathways were investigated by Western blotting.
RESULTS: SSD-HPBCD inclusion complexes showed greatly increased water solubility. This was associated with an improvement in physicochemical properties, including transformation of crystalline structure to amorphous form, and formation of hydrogen bonds between SSD and HPBCD. In addition, SSD-HPBCD inclusion complexes induced apoptosis in HSC-1 cells, and this was mediated through activation of MAPK and suppression of Akt-mTOR signaling pathways.
CONCLUSION: SSD-HPBCD inclusion complex shows improvement in water solubility and physicochemical properties, and exhibits anticancer effects against cutaneous squamous cell carcinoma cells. Therefore, it may be a potential drug formulation for the treatment of skin cancer.

Yamanaka-Takaichi M, Ozawa T, Kusutani N, et al.
Relationship between dermoscopy and pathology in a case of clonal-type pigmented Bowen's disease: Observation with vertical-view dermoscopy.
J Dermatol. 2019; 46(5):436-439 [PubMed] Related Publications
Pigmented Bowen's disease (pBD) is a subtype of Bowen's disease, which presents clinically as a well-circumscribed, hyperpigmented plaque. Its clinical manifestations are not fully characterized, and differential diagnoses include various pigmented skin lesions. Dermoscopy could be useful for the diagnosis, although nothing has been reported on the dermoscopic features of clonal-type pBD. We herein report a first case of clonal-type pBD on the sole and its dermoscopic features. Dermoscopy showed brown to blue-gray dots/globules and focally anastomosing lines on the non-weight-bearing area, while the weight-bearing area had a brown to blue-gray fibrillar-like pattern. To investigate the relationship between dermoscopy and histopathology, we focused on the melanin distribution in the horny layer of the epidermis, and used vertical dermoscopy observation. We investigated the relationship between dermoscopy and pathology by melanin depth estimation using a color lightness value.

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