Mohs micrographic surgery challenges and new technologies to optimize care of cutaneous malignancies of the ear.

Cutaneous malignancies affecting the ear, exacerbated by extensive ultraviolet (UV) exposure, pose intricate challenges owing to the organ's complex anatomy. This article investigates how the anatomy contributes to late-stage diagnoses and ensuing complexities in surgical interventions. Mohs Micrographic Surgery (MMS), acknowledged as the gold standard for treating most cutaneous malignancies of the ear, ensures superior margin control and cure rates. However, the ear's intricacy necessitates careful consideration of tissue availability and aesthetic outcomes. The manuscript explores new technologies like Reflectance Confocal Microscopy (RCM), Optical Coherence Tomography (OCT), High-Frequency, High-Resolution Ultrasound (HFHRUS), and Raman spectroscopy (RS). These technologies hold the promise of enhancing diagnostic accuracy and providing real-time visualization of excised tissue, thereby improving tumor margin assessments. Dermoscopy continues to be a valuable non-invasive tool for identifying malignant lesions. Staining methods in Mohs surgery are discussed, emphasizing hematoxylin and eosin (H&E) as the gold standard for evaluating tumor margins. Toluidine blue is explored for potential applications in assessing basal cell carcinomas (BCC), and immunohistochemical staining is considered for detecting proteins associated with specific malignancies. As MMS and imaging technologies advance, a thorough evaluation of their practicality, cost-effectiveness, and benefits becomes essential for enhancing surgical outcomes and patient care. The potential synergy of artificial intelligence with these innovations holds promise in revolutionizing tumor detection and improving the efficacy of cutaneous malignancy treatments.

Visualising cancer in 3D: 3-Dimensional Tissue Imaging for management of cutaneous basal cell carcinoma.

Surgical management of basal cell carcinoma (BCC) typically involves surgical excision with post-operative margin assessment using the bread-loafing technique; or gold-standard Mohs micrographic surgery (MMS), where margins are iteratively examined for residual cancer after tumour removal, with additional excisions performed upon detecting residual tumour at margins. There is limited sampling of resection margins with bread loafing, with detection of positive margins 44% of the time using 2 mm intervals. To resolve this, we have developed three-dimensional (3D) Tissue Imaging for: (1) complete examination of cancer margins and (2) detection of tumour proximity to nerves and blood vessels. 3D Tissue optical clearing with a light sheet imaging protocol was developed for margin assessment in two datasets assessed by two independent evaluators: (1) 48 samples from 29 patients with varied BCC subtypes, sizes and pigmentation levels; (2) 32 samples with matching Mohs' surgeon reading of tumour margins using two-dimensional haematoxylin & eosin-stained sections. The 3D Tissue Imaging protocol permits a complete examination of deeper and peripheral margins. Two independent evaluators achieved negative predictive values of 92.3% and 88.24% with 3D Tissue Imaging. Images obtained from 3D Tissue Imaging recapitulates histological features of BCC, such as nuclear crowding, palisading and retraction clefting and provides a 3D context for recognising normal skin adnexal structures. Concurrent immunofluorescence labelling of nerves and blood vessels allows visualisation of structures closer to tumour-positive regions, which may have a higher risk for neural and vascular infiltration. Together, this method provides more information in a 3D spatial context, enabling better cancer management by clinicians.

High-throughput lipidomic profiles sampled with electroporation-based biopsy differentiate healthy skin, cutaneous squamous cell carcinoma, and basal cell carcinoma.

BACKGROUND: The incidence rates of cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC) skin cancers are rising, while the current diagnostic process is time-consuming. We describe the development of a novel approach to high-throughput sampling of tissue lipids using electroporation-based biopsy, termed e-biopsy. We report on the ability of the e-biopsy technique to harvest large amounts of lipids from human skin samples. MATERIALS AND METHODS: Here, 168 lipids were reliably identified from 12 patients providing a total of 13 samples. The extracted lipids were profiled with ultra-performance liquid chromatography and tandem mass spectrometry (UPLC-MS-MS) providing cSCC, BCC, and healthy skin lipidomic profiles. RESULTS: Comparative analysis identified 27 differentially expressed lipids (p < 0.05). The general profile trend is low diglycerides in both cSCC and BCC, high phospholipids in BCC, and high lyso-phospholipids in cSCC compared to healthy skin tissue samples. CONCLUSION: The results contribute to the growing body of knowledge that can potentially lead to novel insights into these skin cancers and demonstrate the potential of the e-biopsy technique for the analysis of lipidomic profiles of human skin tissues.

Beyond the Label: Real-World Side Effects Experienced With FDA-Approved Drugs for Non-Melanoma Skin Cancers.

With immunotherapy historically focused on cutaneous melanoma, there has been a new wave of systemic medications available for treating non-melanoma skin cancers including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and Merkel cell carcinoma (MCC). The immune checkpoint inhibitors approved by the FDA target programmed cell death protein 1 (PD-1) and the Hedgehog (Hh) signaling pathway. These medications have expanded treatment options; however, side effects are an important consideration. We used the FDA Adverse Events Reporting System (FAERS) to characterize the most prevalent, real-world side effects experienced by patients on these agents. Muscle spasms (23.45%), alopecia (16.06%), ageusia (12.02%), taste disorder (11.91%), and fatigue (11.67%) were the five most common side effects reported with medications used for BCC treatment. Logistic regression analysis showed males on vismodegib for BCC having greater odds of experiencing muscle spasms (aOR 1.33, P<0.001) and ageusia (aOR 1.34,  P<0.001) versus females, who were more likely to exhibit alopecia (aOR 1.82, P<0.001) and nausea (aOR 1.96, P<0.001). With SCC treatment, the 5 most reported adverse events were fatigue (5.58%), rash (3.59%), asthenia (3.59%), pruritus (3.19%), and pyrexia (2.79%). Patients taking cemiplimab-rwlc for BCC compared to SCC were more likely to experience disease progression (aOR 10.98, P=0.02). With medication labels providing an excessively daunting list of side effects, we characterize practical side effects seen in patients receiving systemic treatments for non-melanoma skin cancers.  J Drugs Dermatol. 2024;23(5):301-305. doi:10.36849/JDD.7968.

A rare case of facial cutaneous Rosai-Dorfman disease clinically mimicking basal cell carcinoma followed by multiple myeloma after 2 years.

Rosai-Dorfman disease (RDD) is a rare non-Langerhans cell histiocytosis disorder characterized by the proliferation of histiocytes within the lymph nodes. Extranodal involvement can occur; however, only 10% of extranodal RDD involve the skin. We present a unique case of a 66-year-old woman with cutaneous RDD followed by the development of multiple myeloma (MM). To our knowledge, this is only the second reported case where RDD preceded a diagnosis of MM, with the first documented instance occurring in 2018. The patient presented to the dermatology clinic with a 5-year history of painless, solitary lesion over the right cheek. Local examination revealed a single 6 mm x 7 mm well-circumscribed pearly telangiectatic lesion resembling basal cell carcinoma over the right nasolabial fold and cheek. The lesion was excised with a 3 mm circumferential margin. Histopathology showed a mixed lymphohistiocytic cell infiltrate with emperipolesis and immunohistochemical staining patterns consistent with RDD. Two years later, the patient presented with hip pain and was diagnosed with MM. She was treated with lenalidomide, bortezomib, and dexamethasone, and was later maintained on lenalidomide. Our case adds to the limited evidence suggesting a potential association between RDD and MM. Further research in this field is required to promptly identify and manage patients with such a presentation in the future.

Nasal ala V-Y island flap with a superior vascular pedicle based on inferior perforators of the superior alar artery.

For small defects of the anterior nasal ala, a V-Y pedicle advancement flap within the subunit is a useful repair option. Here we propose a modification of this technique, utilising careful dissection to identify inferior perforators of the superior alar artery. Basing this flap on a visualised vascular pedicle aims to prevent common complications of internal mucosal buckling and free margin notching, by allowing more extensive dissection without compromising the vascularity of the flap.

Basal cell carcinoma in situ of the skin revisited: case reports of the superficial type and fibroepithelioma type of this in situ cutaneous neoplasm.

Cutaneous basal cell carcinoma in situ is a recently proposed subtype of this skin cancer. It is characterized by either restriction of the tumor cells within the epidermis or the presence of tumor cells contiguous with the overlying epidermis that extend into the underlying dermis, or both. Importantly, cancer invasion-demonstrated by non-contiguous aggregates of basaloid tumor cells in the dermis-is not a feature of in situ basal cell carcinoma of the skin. A 63-year-old woman with cutaneous basal cell carcinoma in situ-superficial type that presented as an erythematous scaly plaque on her abdomen and a 61-year-old man with a cutaneous basal cell carcinoma in situ-fibroepithelioma type that presented as a flesh-colored smooth exophytic nodule on his back are reported. The characteristics of in situ basal cell carcinoma of the skin in these individuals are summarized. In conclusion, similar to other cutaneous malignant neoplasms-such as squamous cell carcinoma, malignant melanoma, and Merkel cell carcinoma-basal cell carcinoma of the skin can also present as an in situ cancer.

Fast and safe clinical response to sonidegib in a 98-year old woman affected by locally advanced basal cell carcinoma.

A 98-year-old woman presented with histologically confirmed locally advanced basal cell carcinoma of the face. A multidisciplinary approach excluded surgery because of the site near sensitive organs, extension, age, and comorbidities. Patient and caregivers declined radiotherapy considering the necessity of multiple hospital appointments. The patient was then placed on therapy with sonidegib, an oral inhibitor of the Hedgehog signaling pathway. There was a very rapid clinical response after only 28 days of treatment. The basal cell carcinoma improved progressively, with no adverse events reported. This case illustrates the efficacy and safety of this treatment in an advanced age patient. This treatment had a remarkably positive impact on quality of life, including that of the caregivers.

Carcinogenic risk in patients treated with UVA-1 phototherapy: A 5-year retrospective study.

BACKGROUND: UVA-1 phototherapy was first used to treat atopic dermatitis and afterwards to several other skin diseases. The contribution of UVA-1 in human photocarcinogenesis, skin photoaging, immune suppression, and hyperpigmentation is now well established. The actual contribution of UVA-1 radiation to the development of malignant melanoma (MM) in humans cannot be excluded. PURPOSE: The aim of the study is to evaluate the risk of developing skin cancers (non-melanoma skin cancers (NMSCs) and MM) in patients treated with UVA-1 phototherapy with a 5-year dermatological follow-up. METHODS: We conducted a retrospective cohort study with 31 patients with morphea and atopic dermatitis treated with medium dose UVA-1 phototherapy (34 J/cm2). All enrolled patients underwent an oncologic prevention visit annually with a 5-year follow-up with clinical evaluation of the entire skin surface. RESULTS: During the 5-year follow-up, we recorded a case of basal cell carcinoma (BCC) in the cervical region and one case of MM on the back (pT1a). In both cases, the patients were female and affected by morphea. The Glogau 3 group is prevalent (42%), which is consistent with moderate to severe aging; the data appear to be compatible with the age. CONCLUSIONS: This study attests that medium-dose UVA-1 phototherapy does not increase the risk of developing skin tumors and that UVA-1 phototherapy is not a worsening factor of facial photoaging. The main limitation of the study is the small sample size, avoiding to obtain statistically significant values. It was not possible to analyze individually the actual daily sun exposure during the 5-year observation period and to correlate it in terms of time and tumor development. Further studies with large sample sizes will be needed to confirm our data. Our study reaffirms how the dermatological examination performed annually is essential in the follow-up of patients undergoing this type of therapy.

Ultrasound features of high-risk basal cell carcinoma: a systematic review.

Basal Cell Carcinoma (BCC) is the most prevalent skin cancer and continues to witness a surge in incidence rates. The categorization of BCC subtypes into low or high risk, guided by recurrence and invasiveness metrics, underscores the need for precise differentiation. While the punch biopsy remains the gold standard for diagnosis, its invasiveness prompts a need for non-invasive alternatives. Ultrasound (US) has emerged as a noteworthy candidate, gaining momentum in its potential to offer a less intrusive diagnostic approach. We conducted a systematic review regarding features of the high-risk subtypes of BCC on US. A thorough literature search of PubMed Medline, Embase, and CINAHL databases was conducted according to PRISMA guidelines and a total of nine studies meeting our inclusion criteria were included in this review. Evidence is still nascent but US features such as lesional shape, depth, hyperechoic spots, and color doppler may be helpful in differentiating high-risk BCC subtypes. However, further prospective studies with standardized interventions and outcome measures are required.

Causal relationship between genetically determined plasma metabolites and skin cancer: a two-sample Mendelian randomization study.

We aimed to unveil the underlying pathogenic mechanisms of skin cancer in relation to metabolic factors and pathway mechanisms. This study utilized the TwoSample Mendelian randomization (MR) method to investigate the causal relationship between 1400 plasma metabolites and skin cancer. The primary method employed was the inverse variance weighting (IVW). Through IVW analysis, we found 105 plasma metabolites associated with Basal Cell Carcinoma (BCC), with the highest association observed for Prolylglycine levels (OR [95% CI]: 1.1902 [1.0274, 1.3788]). For Malignant Melanoma of Skin (MSS), 68 plasma metabolites were linked, with the highest causal relationship seen for 3-Hydroxybutyrate levels (OR [95% CI]: 1.0030 [1.0013, 1.0048]). Regarding actinic keratosis (AK), and the highest association observed for Hexadecadienoate (16:2n6) levels (OR [95% CI]: 1.3302 [1.0333, 1.7125]). Glycerol to palmitoylcarnitine (16: n6) levels (OR [95% CI]: 1.3302 [1.0333, 1.125]) were found to be significant for BCC and AK. Palmitoylcarnitine (C16) had the most positive causal effect for BCC (OR [95% CI]: 1.1777 [1.0493, 1.3218]), while 5-hydroxy-2-methylpyridine sulfate levels had the highest effect for AK (OR [95% CI]: 1.1788 [1.0295, 1.3498]). And 4-guanidinobutanoate levels had the largest positive causal effect (OR [95% CI]: 1.0857 [1.0417, 1.1317]) for BCC, and X-11880 levels for MSS (OR [95% CI]: 1.0013 [1.0000, 1.0025]). The study revealed a positive association between hereditary Glycerol to palmitoylcarnitine (C16) and 5-hydroxy-2-methylpyridine sulfate levels with the risk of developing BCC and AK. Additionally, 4-guanidinobutanoate levels and X 11880 levels were found to be positively associated with the risk of BCC and MMS.

Clinical versus Histological Assessment of Basal Cell Carcinoma Subtype and Thickness of Tumours Selected for Photodynamic Therapy.

Photodynamic therapy is an approved treatment for primary, superficial, and small nodular basal cell carcinomas with a thickness of < 2 mm located on low-risk sites. Histologically verified basal cell carcinomas clinically assessed as suited for photodynamic therapy were included. The study aimed to investigate the agreement between clinical and histological assessments of basal cell carcinoma subtypes and thickness of tumours selected for photodynamic therapy with histopathological evaluation as a reference. A total of 343 tumours were included. The agreement between clinical and histological diagnosis of basal cell carcinoma subtype was 72% (p < 0.001). Clinical assessment of subtype had a sensitivity of 93% and specificity of 55% for superficial tumours and a sensitivity of 55% and specificity of 85% for nodular tumours. The mean ± SD thickness values by clinical and histological assessments were 0.95 ± 0.53 and 0.86 ± 0.75. The difference of 0.09 mm was statistically significant (p = 0.017), but not considered to be clinically relevant, although the differences between specific subgroups could be relevant. Among basal cell carcinomas clinically diagnosed as superficial, 91% were histologically consistent with the current photodynamic therapy criteria. The main results suggest that histopathological evaluation should precede photodynamic therapy to ensure selection of suitable basal cell carcinomas. In selected cases, the clinical diagnosis alone may be adequate before proceeding with photodynamic therapy.

Interdisciplinary management of skin cancer. / Die interdisziplinäre Behandlung von Hautkrebs.

The interdisciplinary treatment of skin cancer in the head and neck area requires close collaboration between different specialist disciplines. The most common non-melanoma skin cancer tumor entities are cutaneous squamous cell carcinoma and basal cell carcinoma as well as their precursor lesions. One of the less common tumors is Merkel cell carcinoma, which also occurs primarily in light-exposed areas and, in contrast to squamous and basal cell carcinoma, is more likely to metastasize. Due to the low tendency of basal cell carcinoma as well as cutaneous squamous cell carcinoma to metastasize, a cure can often be achieved by surgery. If the tumor growth exceeds certain levels it may require collaboration between dermatology and otorhinolaryngology. The primary goal of this interdisciplinary collaboration is to achieve a functional, cosmetically and aesthetically acceptable result in addition to adequate tumor treatment. Depending on the stage of the tumor and the clinical course, a case may be discussed in an interdisciplinary tumor board in order to determine a personalised, appropriate and adequate treatment concept for each patient, including prevention, therapy and follow-up.

An Explorative Study on Calcium Electroporation for Low-risk Basal Cell Carcinoma.

In electrochemotherapy, permeabilization of the cell membrane by electric pulses increases the anti-tumour effect of chemotherapeutics. In calcium electroporation, chemotherapy is replaced by calcium chloride with obvious benefits. This study explores the effect and underlying mechanisms of calcium electroporation on basal cell carcinomas using either high- or low-frequency electroporation. Low-risk primary basal cell carcinomas were treated in local anaesthesia with intratumoral calcium chloride followed by electroporation with high (167 kHz) or low (5 kHz) frequencies. Non-complete responders were retreated after 3 months. The primary endpoint was tumour response 3 months after last calcium electroporation. Plasma membrane calcium ATPase was examined in various cell lines as plasma membrane calcium ATPase levels have been associated with calcium electroporation efficacy. Twenty-two out of 25 included patients complete the study and 7 of these (32%) achieved complete response at 3 months with no difference in efficacy between high- and low-frequency pulses. High-frequency calcium electroporation was significantly less painful (p=0.03). Plasma membrane calcium ATPase was increased 16-32-fold in basal cell carcinoma cell lines compared with 4 other cancer cell lines. Calcium electroporation for low-risk basal cell carcinomas does not fulfil the requirements of a new dermatological basal cell carcinoma treatment but may be useful as adjuvant treatment to surgery in more advanced basal cell carcinomas. The elevated PMCA levels in basal cell carcinomas may contribute to low efficacy.

Novel insights into rosacea's role in cancer risk: A Mendelian randomization approach.

BACKGROUND: Chronic inflammation has been shown to promote cancer progression. Rosacea is indeed a long-term inflammatory skin condition and had been reported to link with increased risk for several types of malignancies, but evidence for causality is lacking. OBJECTIVES: To systematically estimate the causal relationship between rosacea and several types of cancer, including cutaneous malignant melanoma (CMM), cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC), actinic keratosis (AK), thyroid cancer, breast cancer, glioma and hepatic cancer, as well as explore the potential underlying pathogenesis. METHODS: We conducted a bidirectional two-sample Mendelian randomization study to probe the potential causal relationships between rosacea and several types of cancer. Instrumental variables were established using genome-wide significant single nucleotide polymorphisms associated with rosacea and cancers. The assessment of causality was carried out through multiple methods, and the robustness of the results was evaluated via sensitivity analyses. RESULTS: There was no significant indication of causal effects of rosacea on CMM (pivw = 0.71), cSCC (pivw = 0.45), BCC (pivw = 0.90), AK (pivw = 0.73), thyroid cancer (pivw = 0.59), glioma (pivw = 0.15), and hepatic cancer (pivw = 0.07), but the genetic risk of rosacea was associated with an increased susceptibility to human epidermal growth factor receptor (HER)-negative malignant neoplasm of breast (odds ratio [OR], 1.10; 95% confidence interval [CI], 1.02-1.18; pivw = 0.01). TANK (TRAF family member associated nuclear factor kappa B (NFKB) activator) was identified as a common protective gene for both rosacea (OR, 0.90; 95% CI, 0.82-0.99; pivw = 0.048) and HER-negative malignant neoplasm of the breast (OR, 0.86; 95% CI, 0.75-0.98; pivw = 0.032), which was primarily enriched in the negative regulation of NF-κB signal transduction and may contribute to the genetic links between rosacea and this subtype of breast cancer. CONCLUSIONS: Our findings provide suggestive evidence for causal links between rosacea and HER-negative malignant neoplasm of the breast risk.

A prospective cohort study exploring the joint influence of sunlight exposure and tanning bed use on basal cell carcinoma, squamous cell carcinoma, and melanoma risk.

Exposure to solar ultraviolet (UV) radiation and use of UV-emitting tanning devices are known risk factors for skin cancer. Few studies have explored the interaction between these risk factors, namely how the risk of skin cancer increases among those who both have been exposed to high levels of natural sunlight and regularly use tanning beds. Nurses' Health Study II followed 116,430 women, aged 25-42, from 1991 to 2011. Cumulative average UV exposure was based on participants' residences at follow-up periods. History of severe sunburn during ages 15-20 was used as a proxy for early-life sunlight exposure. Tanning bed use in early life data was collected. Participants reported melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC) diagnoses. We built multivariable Cox regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of skin cancer associated with joint effects of sunlight exposure and tanning bed use. Participants with high sunlight exposure and tanning bed use during high school/college had an increased risk of BCC (HR = 1.53, 95% CI 1.37-1.71, Pinteraction=0.01; vs. low sun exposure and no tanning bed use). Participants with a history of severe sunburns and tanning bed use during high school/college were at increased risk of BCC (HR = 1.62, 95% CI 1.47-1.79, Pinteraction=0.02; vs. no sunburns and no tanning bed use). No significant interactions were found between sunlight exposure and tanning bed use on SCC and melanoma risk. We found significant interactions between sunlight exposure and tanning bed use on the risk of BCC.