Aggressive Non-melanoma Skin Cancers Research Articles

Basosquamous Carcinoma: Comprehensive Clinical and Histopathological Aspects, Novel Imaging Tools, and Therapeutic Approaches.

Basosquamous carcinoma (BSC), an uncommon and aggressive nonmelanoma skin cancer exhibiting characteristics ranging from basal cell carcinoma (BCC) to squamous cell carcinoma (SCC), is a subject of controversy in terms of its classification, pathogenesis, histologic morphology, biologic behavior, prognosis, and management. This narrative review is based on an electronic search of English-language articles in PubMed that included the terms "basosquamous carcinoma" and/or "metatypical carcinoma of the skin" in their titles. The review aims to succinctly present and assess current data on the epidemiology, clinical presentation, dermoscopic, LC-OCT, and histopathologic characteristics, as well as the genetics and management of BSC, providing insight into this intriguing entity. As a conclusion, dermoscopy, deep incisional biopsies, and immunohistologic techniques should be applied in clinically suspicious lesions to achieve an early diagnosis and better prognosis of this tumor. Surgical treatments, including wide excision and Mohs' micrographic surgery, remain the treatment of choice. Finally, Hedgehog pathway inhibitors and checkpoint inhibitors, must be thoroughly investigated with large controlled trials, since they may offer an alternative solution to irresectable or difficult-to-treat locally advanced cases of basosquamous carcinoma.

DERMOSCOPY OF BASOSQUAMOUS CARCINOMA IN SITU

Basosquamous carcinoma (BSC) is a rare, aggressive non-melanoma skin cancer with features that lie between those of basal cell carcinoma (BSC) and squamous cell carcinoma (SCC). BSC incidence is less than 2% of all non-melanoma skin cancers. A lot of controversies have been raised around the classification, pathogenesis, histologic morphology, biologic behavior, prognosis, and management of this tumor. Clinical differentiation from other BCC subtypes is difficult, although dermoscopic evaluation may provide some important clues. The dermoscopic pattern of BSC combines characteristics of both BCC and SCC including unfocused arborizing vessels, white structureless areas, keratin masses, ulceration or blood crusts, white structures, blue-gray blotches, and blood spots on keratin masses.
 Biopsy and histologic examination remain the gold standard diagnostic method for BSC. The main published literature describes the presence of both BCC and SCC histologic characteristics with a transition zone between them. However, there is a certain controversy regarding how these features are arranged within the lesions. The correct histologic diagnosis of a BSC can be jeopardized when the biopsy is superficial and not incisional. In this scenario, the lack of deep areas of the lesion in the sample may result in the incorrect interpretation of the tumor as a classic BCC.
 Intraepidermal carcinoma (IEC) has long been considered a precancerous disease due to the fact that dysplastic and atypical cells are concentrated in the epidermis. They lack the fact of penetration through the basement membrane in order to become SCC. Modern practice refers to IEC as an SCC in situ localized extragenital.
 We present a case of 63 years old patient. Erythematous macula with desquamation up to 1.3 cm in diameter, located on the chest, was revealed during the survey. At a non-polarised dermoscopy with fluid immersion there was a "gelatinous stroma" through which the dense network of multiple branched vessels is clearly visible, this is typical for BCC. But unfocused arborizing vessels were visible in some sectors, white structureless areas, keratin masses, blue-gray blotches, and blood spots on keratin masses that allow us to suspect a focal transformation in BSC. In the center, there were everal sectors filled with glomerular vessels, which is typical for IEC. The results of clinical and laboratory tests were within normal ranges. The dermoscopic picture combines changes that may point out BSC in the periphery and IEC in the central part of the formation. The fact of BSC worsens the patient's prognosis. BSC is characterized by an aggressive subclinical spread with higher rates of recurrence: 12–51%. We decided that immediate removal should be preferred. Taking into account the patient's age and accompanying pathology, a radical treatment method of removal by cryodestruction was chosen. During follow-up examinations, a normotrophic scar with a characteristic vascular pattern was formed on the patient's skin at the site of tumor removal. 
 Conclusions. In our opinion, such a vascular pattern in the center of the lesion can testify to the picture of the transformation of BCC to BSC. At this stage, BSC, in some parts of the formation, is within the epidermis, and can probably be considered BSC in situ, which could be usefully explored in further research.

Mammalian target of rapamycin inhibitors for prolonged secondary prevention of nonmelanoma skin cancer in solid organ transplant recipients

Immunosuppressive agents are essential for graft survival in solid-organ transplant recipients (SOTRs), but they have substantial durable side effects, including a higher incidence of aggressive nonmelanoma skin cancers (NMSCs). Hitherto, only one class of immunosuppressants, mammalian target of rapamycin inhibitors (mTORi), may inhibit skin tumor formation, however their durable effectiveness is controversial. To evaluate the sustained effectiveness of mTORi in reducing NMSCs' incidence in SOTRs, a retrospective study was conducted in a specialized dermatology clinic for SOTRs of a tertiary university-affiliated medical center. SOTRs with a history of at least one histologically proven NMSC were followed for 6 years: 3 years after transplantation, before initiation of mTORi, and 3 years under mTORi treatment. The cohort consisted of 44 SOTRs. Treatment with mTORi was initiated on average 6.27 (3.34-6.34) years following transplantation. In the 3 years before mTORi treatment initiation, the mean number of new NMSCs per patient was 2.11 (1-14). This value decreased to 1.2 (0-19) in the 3 years under mTORi treatment (p= 0.0007). Analysis by NMSC type yielded a significant decrease in both SCCs and BCCs. This study found that mTORi are effective for prolonged secondary prevention of NMSCs in SOTRs.

Management of Patients With Aggressive Nonmelanoma Skin Cancers

Nonmelanoma skin cancers (NMSCs), which encompass a variety of cutaneous malignancies, are frequently managed with surgery, radiation therapy, cytotoxic chemotherapy, systemic immunotherapy, and active surveillance. In this tumor board–style forum, a panel of experts used several case studies as a basis to review these approaches and to describe existing clinical challenges. The current NCCN Guidelines for NMSC, which reflect the most up-to-date, evidence-based data relating to the evaluation and management of NMSCs, also provide key considerations and recommendations for the treatment of this patient population.

Basosquamous Carcinoma: A Commentary.

Simple SummaryBasosquamous carcinoma is a rare, aggressive non-melanoma skin cancer with features that lie between those of basal cell carcinoma and squamous cell carcinoma. A lot of controversy has been raised around the classification, pathogenesis, histologic morphology, biologic behavior, prognosis and management of this tumor. This is a narrative review based on articles published on PubMed in English language which had in their title the terms “basosquamous carcinoma” and/or “metatypical carcinoma of the skin”. The aim of this review was to summarize and evaluate the latest data of the English literature regarding epidemiology, clinical presentation, dermoscopic and histopathologic characteristics, as well as the genetics and management of BSC to better characterize basosquamous skin lesions.Basosquamous carcinoma is a rare, aggressive non-melanoma skin cancer with features that lie between those of basal cell carcinoma and squamous cell carcinoma. A lot of controversy has been raised around the classification, pathogenesis, histologic morphology, biologic behavior, prognosis and management of this tumor. This is a narrative review based on an electronic search of articles published in PubMed in English language which had in their title the terms “basosquamous carcinoma” and/or “metatypical carcinoma of the skin”. The aim of this review was to summarize and evaluate current data regarding epidemiology, clinical presentation, dermoscopic and histopathologic characteristics, as well as the genetics and management of BSC, in order to shed some more light onto this intriguing entity. As a conclusion, dermoscopy, deep incisional biopsies and immunohistologic techniques (Ber-EP4) should be applied in clinically suspicious lesions in order to achieve an early diagnosis and better prognosis of this tumor. Surgical treatments, including wide excision and Mohs’ micrographic surgery, remain the treatment of choice. Finally, vismodegib, a Hedgehog pathway inhibitor, must be thoroughly investigated, with large controlled trials, since it may offer an alternative solution to irresectable or difficult-to-treat, locally advanced cases of basosquamous carcinoma.

Merkel Cell Carcinoma of the Head and Neck.

Merkel cell carcinoma (MCC) of the head and neck is a rare and aggressive non-melanoma skin cancer. The objective of this study was to assess the oncological outcome of MCC by retrospective review of electronic and paper records of a population-based cohort of 17 consecutive cases of the head and neck MCC without distant metastasis, diagnosed in Manitoba between 2004 and 2016. The average age of the patients at initial presentation was 74.1 ± 14.4 years with 6 patients presenting with stage I, 4 with stage II, and 7 with stage III disease. Both surgery or radiotherapy alone were the primary treatment modalities in 4 patients each and the remaining 9 patients had a combination of surgery with adjuvant radiotherapy. During the median follow-up of 52 months, 8 patients had recurrent/residual disease and 7 eventually died of it (P = .001). Metastatic spread of disease to the regional lymph nodes was observed in 11 patients either at presentation or during the follow-up and to the distant sites in 3 patients. At the time of the last contact on November 30, 2020, 4 patients were alive and disease-free, 7 had died of disease, and 6 had died of other causes. The case fatality rate was 41.2%. Five-year disease-free and disease-specific survivals were 51.8% and 59.7%, respectively. The 5-year disease-specific survival was 75% for early stage MCC (stage I and II) and 35.7% for stage III MCC. Early diagnosis and intervention are crucial for disease control and improving survival.

Cost Analysis Comparison of Mohs Micrographic Surgery in the United States of America and United Kingdom

Introduction: Mohs Micrographic Surgery (MMS) is globally acknowledged as the gold standard for treatment of recurrent, infiltrative and aggressive non-melanoma skin cancers (NMSC). It achieves maximal tissue preservation, less scarring and deformity. USA is one of the advanced countries where it is widely used and has been found to be cost effective. This paper aims to review the differences in policy and cost analysis in both regions.

Advanced Merkel cell carcinoma-A focus on medical drug therapy.

Merkel cell carcinoma (MCC) is a rare but aggressive non-melanoma skin cancer with significant morbidity and mortality. Treatment of choice for primary and locoregional MCC is complete surgical removal with sentinel lymphonodectomy and postsurgical radiotherapy of tumor basin and locoregional lymph nodes. In nonresectable and advanced tumors, drug therapy is indicated. While cytotoxic chemotherapy has resulted in higher response rates, overall survival remained nearly unaffected. With a better insight into tumor development and biology, new treatment s became available. Immune checkpoint inhibitors result in durable responses with a better safety profile that classical combined chemotherapy. Combinations of immune checkpoint inhibitors with and without radiotherapy help to overcome acquired drug-resistance. New compounds for vaccination and oral use are on the horizon. Despite all progress, treatment of MCC remains a challenge that needs close interdisciplinary teamwork.

632 UVB induced EMT-like phenotype in keratinocytes is mediated by TLR3 activation

Risk factors for non-melanoma skin cancer (NMSC) include UVB exposure, genetic mutations, immunosuppression, and chronic inflammation. Activation of Toll-Like-Receptor 3 (TLR3), which recognizes dsRNA, leads to downstream activation of NF-κB and an upregulation of inflammatory cytokines. TLR3 protein expression is higher in moderately differentiated squamous cell carcinomas (SCCs) and infiltrative basal cell carcinomas (BCCs) compared to well-differentiated SCCs by immunohistochemistry (n > 6) suggesting TLR3 expression correlates with more aggressive NMSCs.

Itch and pain intensity in skin cancer: Why should dermatologic surgeons assess it?

Nonmelanoma skin cancer is the most common type of cancer in the United States. Due to its rising incidence, better screening modalities assessing patient symptomatology are imperative. We reviewed the literature regarding pain and pruritus as presenting clinical manifestations of cutaneous malignancies and elucidate the clinical presentations among skin cancer subtypes. Multiple studies have indicated a higher prevalence of reported pain for squamous cell carcinoma than basal cell carcinoma, but no statistically significant difference was found between these subtypes for itch. Transplant patients, a subset of patients commonly affected with aggressive nonmelanoma skin cancers, ranked the severity of their pain higher in comparison to nontransplant patients. The following cutaneous tumors: keratoacanthomas, infiltration sclerosing BCCs, morpheaform BCCs types and those with perineural invasion, were reported as eliciting the most pain. With the increasing incidence of skin cancer, it is important to recognize the associated presenting clinical manifestations of pruritus and pain, which are shown to be useful in the identification of undiagnosed cutaneous malignancies. Implementation of a numerical rating scale should be considered when evaluating patients with a history of skin cancer or those at high risk, such as transplant recipients.

Current Research in Melanoma and Aggressive Nonmelanoma Skin Cancer.

There have been several significant advances in cancer treatment in the last decade that are applicable to the treatment of melanoma and advanced nonmelanoma skin cancers. Among these are the development of immune checkpoint inhibitors targeting the programmed death protein-1 (PD-1)/programmed death legand-1 (PDL-1) axis, as well as targeted inhibitors of the BRAF/MEK signaling cascade in melanoma, and the hedgehog signaling pathway in basal cell carcinoma (BCC). These immune-based and targeted therapies have dramatically changed the treatment options for locally advanced and metastatic melanoma, Merkel's cell carcinoma, cutaneous squamous cell carcinoma (cSCC), and BCC. In this article, we will briefly review the currently approved targeted and immunotherapy-based treatments for locally advanced and metastatic melanoma, Merkel's cell carcinoma, and cSCC and discuss various combinations of approved therapies, as well as emerging therapeutic candidates that are currently in clinical trials, including novel checkpoint inhibitors in development, intratumoral oncolytic agents (viral and nonviral), and various immune-based therapies such as toll-like receptor (TLR) agonists, adoptive T-cell therapy, T-cell costimulation, and innate immune cell therapy. For advanced BCC, we will discuss trials investigating the currently approved smoothened (SMO) inhibitors for neoadjuvant use, emerging SMO inhibitors in development, topical SMO inhibitors, alternative targets in the hedgehog signaling pathway, and the use of anti-PD-1 agents for advanced BCC both alone and in combination with SMO inhibitors.

Field Therapy in Solid Organ Transplant Recipients: Are We Initiating Early Enough?

Organ transplant recipients (OTRs) are at increased risk for more aggressive non-melanoma skin cancer (NMSC). Recent emphasis on field therapy has complimented the canonical surgical treatment paradigm. This retrospective analysis of survey responses by patients seen at Oregon Health and Science University from 2013-2018 offers insights into patient trends and practice gaps in caring for OTRs. All patients completed a 57-point questionnaire at their first clinic visit, which included questions regarding demographics, transplant history, dermatologic history, and use of field therapy. Of the 295 patients (mean age, 56 years; M/F: 193/102) who completed the questionnaire, field therapy was reported by 31 (11%) patients. Field therapy patients noted an overall higher AK and SCC burden, with a greater proportion of patients reporting >20 AKs and >10 SCCs. Field therapy use was sparse in the low AK/low SCC group (n=25) when compared to those reporting high AK/high SCC (n=11) burden (n=4 (16%) vs n=8 (73%), P<0.01). This data suggests that OTRs with several clinically evident AKs and/or a low number of SCCs are less likely to have been treated with field therapy modalities compared to OTRs who have developed >10 AKs or ≥6 SCCs. A delay in initiation of preventative measures or field therapy in this population, however, may be a missed opportunity for intervention. Early intervention with field therapy in particularly high-risk OTRs with a low skin cancer burden may mitigate future skin cancer development.J Drugs Dermatol. 2020;19(3): doi:10.36849/JDD.2020.4759.

Neuroendocrine Key Regulator Gene Expression in Merkel Cell Carcinoma

Merkel cell carcinoma (MCC) is a highly aggressive non-melanoma skin cancer of the elderly which is associated with the Merkel cell polyomavirus (MCPyV). MCC reveals a trilinear differentiation characterized by neuroendocrine, epithelial and pre/pro B-cell lymphocytic gene expression disguising the cellular origin of MCC. Here we investigated the expression of the neuroendocrine key regulators RE1 silencing transcription factor (REST), neurogenic differentiation 1 (NeuroD1) and the Achaete-scute homolog 1 (ASCL1) in MCC. All MCCs were devoid of REST and were positive for NeuroD1 expression. Only one MCC tissue revealed focal ASCL1 expression. This was confirmed in MCPyV-positive MCC cell lines. Of interest, MCPyV-negative cell lines did express REST. The introduction of REST expression in REST-negative, MCPyV-positive MCC cells downregulated the neuroendocrine gene expression. The lack of the neuroendocrine master regulator ASCL1 in almost all tested MCCs points to an important role of the absence of the negative regulator REST towards the MCC neuroendocrine phenotype. This is underlined by the expression of the REST-regulated microRNAs miR-9/9* in REST-negative MCC cell lines. These data might provide the basis for the understanding of neuroendocrine gene expression profile which is expected to help to elucidate the cellular origin of MCC.

Merkel Cell Polyomavirus Small T Antigen Targets the NEMO Adaptor Protein To Disrupt Inflammatory Signaling

Merkel cell carcinoma (MCC) is a highly aggressive nonmelanoma skin cancer arising from epidermal mechanoreceptor Merkel cells. In 2008, a novel human polyomavirus, Merkel cell polyomavirus (MCPyV), was identified and is strongly implicated in MCC pathogenesis. Currently, little is known regarding the virus-host cell interactions which support virus replication and virus-induced mechanisms in cellular transformation and metastasis. Here we identify a new function of MCPyV small T antigen (ST) as an inhibitor of NF-κB-mediated transcription. This effect is due to an interaction between MCPyV ST and the NF-κB essential modulator (NEMO) adaptor protein. MCPyV ST expression inhibits IκB kinase α (IKKα)/IKKβ-mediated IκB phosphorylation, which limits translocation of the NF-κB heterodimer to the nucleus. Regulation of this process involves a previously undescribed interaction between MCPyV ST and the cellular phosphatase subunits, protein phosphatase 4C (PP4C) and/or protein phosphatase 2A (PP2A) Aβ, but not PP2A Aα. Together, these results highlight a novel function of MCPyV ST to subvert the innate immune response, allowing establishment of early or persistent infection within the host cell.

Cyclical thrombocytosis, acquired von Willebrand syndrome and aggressive non-melanoma skin cancers are common in patients with Philadelphia-negative myeloproliferative neoplasms treated with hydroxyurea

Cyclical thrombocytosis, acquired von Willebrand syndrome, aggressive non-melanoma skin cancers and other hydroxyurea complications have been reported in Philadelphia-negative myeloproliferative neoplasms (MPNs), but their incidence and clinical consequences have not been defined in a large cohort of patients. We conducted a retrospective analysis of 188 consecutive patients with MPNs specifically addressing the incidence of these complications. Cyclical thrombocytosis was documented in 29 patients (15%), the majority of whom were receiving hydroxyurea. Acquired von Willebrand syndrome was identified in 17 of the 84 screened patients (20%), but was not associated with any major bleeding complications. Non-melanoma skin cancers were reported in 51 patients (27%). Hydroxyurea-related fever occurred in nine of 149 patients (6%) who received hydroxyurea. Seventy-three patients (39%) experienced a total of 98 major thrombotic events, with the majority of these occurring prior to or within 3 months of the diagnosis. Cyclical thrombocytosis, acquired von Willebrand syndrome, aggressive non-melanoma skin cancers and other hydroxyurea-related complications are not infrequent in MPNs and have important clinical consequences for management.

The mTOR inhibitor rapamycin opposes carcinogenic changes to epidermal Akt1/PKBα isoform signaling

Epidermal squamous cell carcinoma (SCC) is the most aggressive non-melanoma skin cancer and is dramatically increased in patients undergoing immunosuppression following solid organ transplantation, contributing substantially to morbidity and mortality. Recent clinical studies show that use of the mammalian target of rapamycin (mTOR) inhibitor rapamycin as a post-transplantation immunosuppressive significantly reduces SCC occurrence compared with other immunosuppressives, though the mechanism is not fully understood. We show that rapamycin selectively upregulates epidermal Akt1, while failing to upregulate epidermal Akt2. Rapamycin increases epidermal Akt1 phosphorylation via inhibition of the mTOR complex 1-dependent regulation of insulin receptor substrate-1. Epidermal Akt1 is commonly downregulated in SCC while Akt2 is upregulated. We now demonstrate similar Akt1 downregulation and Akt2 upregulation by ultraviolet (UV) radiation, the most important skin carcinogen. Hence, rapamycin's upregulation of Akt1 signaling could potentially oppose the effects of UV radiation and/or tumor-associated changes on Akt1 signaling. We show in skin culture that rapamycin does enhance restoration of Akt1 phosphorylation in skin recovering from UV radiation, suggesting a mechanism for rapamycin's antitumor activity in epidermis in spite of its efficient immunosuppressive properties.

Procarcinogenic effects of cyclosporine A are mediated through the activation of TAK1/TAB1 signaling pathway

Cyclosporine A (CsA) is an immunosuppressive drug commonly used for maintaining chronic immune suppression in organ transplant recipients. It is known that patients receiving CsA manifest increased growth of aggressive non-melanoma skin cancers. However, the underlying mechanism by which CsA augments tumor growth is not fully understood. Here, we show that CsA augments the growth of A431 epidermoid carcinoma xenograft tumors by activating tumor growth factor β-activated kinase1 (TAK1). The activation of TAK1 by CsA occurs at multiple levels by kinases ZMP, AMPK and IRAK. TAK1 forms heterodimeric complexes with TAK binding protein 1 and 2 (TAB1/TAB2) which in term activate nuclear factor κB (NFκB) and p38 MAP kinase. Transcriptional activation of NFκB is evidenced by IKKβ-mediated phosphorylation-dependent degradation of IκB and consequent nuclear translocation of p65. This also leads to enhancement in the expression of its transcriptional target genes cyclin D1, Bcl2 and COX-2. Similarly, activation of p38 leads to enhanced inflammation-related signaling shown by increased phosphorylation of MAPKAPK2 and which in turn phosphorylates its substrate HSP27. Activation of both NFκB and p38 MAP kinase provide mitogenic stimuli to augment the growth of SCCs.

Prevalence of Underdiagnosed Aggressive Non-Melanoma Skin Cancers Treated with Mohs Micrographic Surgery

Prevalence of Underdiagnosed Aggressive Non-Melanoma Skin Cancers Treated with Mohs Micrographic Surgery

Multiple aggressive squamous skin cancers in association with nonbullous congenital ichthyosiform erythroderma

Nonbullous congenital ichthyosiform erythroderma (NBCIE) is one of the autosomal recessive inherited non-syndromic ichthyoses and is currently diagnosed on clinical grounds alone. Skin cancer is not a recognized complication of NBCIE. We report here two NBCIE patients who have developed multiple aggressive nonmelanoma skin cancers, predominantly cutaneous squamous cell carcinoma. NBCIE may be a risk factor for skin cancer development.

Parotidectomy in the treatment of aggressive cutaneous malignancies.

Aggressive nonmelanoma skin cancer (ANMSC) of the head and neck may require parotidectomy because of neurotropic spread, direct invasion of the parotid gland, or parotid metastasis. To review our experience with parotidectomy in the treatment of these tumors to examine the indications for this procedure and to analyze treatment outcomes. We emphasize the importance of early identification of an ANMSC and a systematic approach to treatment. Review of 23 patients with an ANMSC who required parotidectomy with or without facial (VII) nerve sacrifice between January 5, 1996, and December 27, 1999. Median follow-up for all patients was 24 months. Academic tertiary care referral center. This study focused on 23 (median age, 71 years) of 54 patients treated for an ANMSC. Most tumors were in the periauricular (n = 9) and the frontozygomatic (n = 6) areas. Seven patients presented with facial weakness or paralysis. Three patients had clinically evident parotid metastasis, while 14 patients had tumors directly invading the parotid gland. Eighteen patients had recurrent disease that had been treated previously with Mohs micrographic surgery. Following wide local excision of the ANMSC, 12 patients had resection of the lateral parotid lobe with preservation of the nerve, while 11 required radical parotidectomy with sacrifice of 1 or more branches. Nineteen patients received cervical lymphadenectomy. Postoperative radiotherapy was administered in 19 patients. Tumor pathologic findings (specifically, perineural invasion of the facial nerve), locoregional control or recurrence, disease-free survival, disease-specific survival, and overall survival. Neurotropic spread to the facial nerve was present in 6 patients and was more likely to occur in younger patients (51 vs 75 years, P =.006). Locoregional failures occurred in 9 patients following treatment. Patients who required parotidectomy in their surgical treatment for an ANMSC were more likely to have recurrent disease (P =.0002). Disease-specific and overall survival was 79% and 69%, respectively, at 42 months. Patients with ANMSC may require parotidectomy in the context of neurotropic spread, regional metastasis, or direct invasion into the parotid gland. Surgery combined with postoperative radiotherapy is necessary in most patients because of adverse clinical and pathologic findings. A systematic approach to the management of the parotid and facial nerve in the presence of these aggressive tumors is required. Despite comprehensive treatment, local recurrence of ANMSC and mortality remain high.