Skin Cancer Pathobiology at a Glance: A Focus on Imaging Techniques and Their Potential for Improved Diagnosis and Surveillance in Clinical Cohorts.

Early diagnosis is essential for completely eradicating skin cancer and maximizing patients' clinical benefits. Emerging optical imaging modalities such as reflectance confocal microscopy (RCM), optical coherence tomography (OCT), magnetic resonance imaging (MRI), near-infrared (NIR) bioimaging, positron emission tomography (PET), and their combinations provide non-invasive imaging data that may help in the early detection of cutaneous tumors and surgical planning. Hence, they seem appropriate for observing dynamic processes such as blood flow, immune cell activation, and tumor energy metabolism, which may be relevant for disease evolution. This review discusses the latest technological and methodological advances in imaging techniques that may be applied for skin cancer detection and monitoring. In the first instance, we will describe the principle and prospective clinical applications of the most commonly used imaging techniques, highlighting the challenges and opportunities of their implementation in the clinical setting. We will also highlight how imaging techniques may complement the molecular and histological approaches in sharpening the non-invasive skin characterization, laying the ground for more personalized approaches in skin cancer patients.

Neuroendocrine Factors in Melanoma Pathogenesis.

Melanoma is one of the most aggressive skin cancers with a sharp rise in incidence in the last decades, especially in young people. Recognized as a significant public health issue, melanoma is studied with increasing interest as new discoveries in molecular signaling and receptor modulation unlock innovative treatment options. Stress exposure is recognized as an important component in the immune-inflammatory interplay that can alter the progression of melanoma by regulating the release of neuroendocrine factors. Various neurotransmitters, such as catecholamines, glutamate, serotonin, or cannabinoids have also been assessed in experimental studies for their involvement in the biology of melanoma. Alpha-MSH and other neurohormones, as well as neuropeptides including substance P, CGRP, enkephalin, beta-endorphin, and even cellular and molecular agents (mast cells and nitric oxide, respectively), have all been implicated as potential factors in the development, growth, invasion, and dissemination of melanoma in a variety of in vitro and in vivo studies. In this review, we provide an overview of current evidence regarding the intricate effects of neuroendocrine factors in melanoma, including data reported in recent clinical trials, exploring the mechanisms involved, signaling pathways, and the recorded range of effects.

Skin endometriosis: A case report and review of the literature.

Skin endometriosis is a rare disease with variable clinical and histopathological characteristics that depend on hormonal stimuli. The skin is not a common location, as most cases of endometriosis involve pelvic sites, such as the ovaries, peritoneum and bowel. However, the most common extrapelvic site affected is the abdominal wall and this location of the disease is frequently associated with obstetric and gynecologic surgery. Here we report a case of skin endometriosis emerged as a painful subcutaneous nodule located near to the left side of an obstetrical surgery procedure scar. The patient affected was a woman in her reproductive age, with a history of right ovary endometriotic cyst laparoscopically removed and histologically confirmed as a primary endometriosis. Dermatologists should be aware of this condition in any woman with a painful lump located in the proximity of a pelvic surgery-induced scar. Its non-specific clinical appearance may confuse the clinician and may delay the diagnosis and management.

In vivo Diagnosis of Primary Cutaneous Amyloidosis -the Role of Reflectance Confocal Microscopy.

Primary cutaneous amyloidosis (PCA) is a form of localized amyloidosis. It is characterized by the deposition of a fibrillar material in the superficial dermis, without affecting other systems or organs. The diagnosis can be made clinically, but usually a skin biopsy is performed in order to exclude other skin diseases with similar appearance. Reflectance confocal microscopy (RCM) is a novel imaging tool that enables in vivo characterization of various skin changes with a high, quasi-microscopic resolution. This technique might have an important role in the differential diagnosis of cutaneous amyloidosis, by the in vivo assessment of epidermal changes and dermal amyloid deposition. Moreover, it is completely non-invasive and can be safely repeated on the same skin area. However, to date, there is only one published paper presenting the confocal features of primary cutaneous amyloidosis. Hereby, we describe the in vivo RCM features of PCA lesions from a patient with diabetes and correlate them with histologic findings. This strengthens the clinical usefulness of in vivo RCM examination for the non-invasive diagnosis of cutaneous amyloidosis, especially in patients that might associate diseases with impaired wound healing.

Non-invasive imaging techniques for the in vivo diagnosis of Bowen's disease: Three case reports.

Bowen's disease (BD) is a relatively frequent non-melanoma skin cancer occurring mostly in elderly people. Until now, the usual way to establish the diagnosis is histopathological examination of a skin biopsy. Dermoscopy and reflectance confocal microscopy (RCM) are modern alternative methods that can be used as quick and non-invasive diagnostic techniques and as follow-up instruments in cases in which a conservative treatment is chosen for the management of BD. There are no very specific dermoscopic criteria for the diagnosis of this disease, but some dermoscopic features (scaly surface, vascular structures and pigmentation) can be found more frequent and can be helpful for the diagnosis. RCM of BD shows an acanthotic epidermis with two types of targetoid cells: the first, a large cell with bright center and dark peripheral halo, the second, a cell with dark center and a bright rim surrounded by a dark hallo, related with dyskeratotic cells on histological examination. BD management could be improved by using non-invasive, in vivo imaging techniques that allow a fast and easy diagnosis and can be used as follow-up tools. However, larger studies are necessary for the validation of our observations.

Current and future applications of confocal laser scanning microscopy imaging in skin oncology.

Confocal laser scanning microscopy (CLSM) is a modern imaging technique that enables the in vivo or ex vivo characterization of skin lesions located in the epidermis and superficial dermis with a high quasi-microscopic resolution. Currently, it is considered to be the most promising imaging tool for the evaluation of superficial skin tumors. The in vivo mode adds the advantage of noninvasive, dynamic, in real-time assessment of the tumor associated vasculature and inflammation. It offers the possibility to repeatedly examine the same skin area without causing any damage and to monitor disease progression and treatment outcome. Furthermore, this novel technology allows the evaluation of the entire lesion and can be used to guide biopsies and to define tumor margins before surgical excision or other invasive therapies. CLSM diagnostic features may differentiate between the various histologic subtypes of skin tumors and therefore helps in choosing the best therapeutic approach. In this study, we present the CLSM characteristic features of the most common melanocytic and non-melanocytic skin tumors, as well as future possible CLSM applications in the study of experimental skin tumorigenesis on animal models.

Role of modern imaging techniques for the in vivo diagnosis of lichen planus.

Lichen planus (LP) is a chronic inflammatory skin disease that can sometimes affect mucosal surfaces, with unknown pathogenesis, even though it appears to be an autoimmune disease. The diagnosis of lichen planus is usually based on histopathological examination of the lesions. Nowadays, the classical invasive diagnostic methods are replaced by modern non-invasive techniques. In this review, we present the main non-invasive imaging methods (dermoscopy, reflectance confocal microscopy, optical coherence tomography, ultrasound and diffuse reflection spectrophotometry) used in the diagnosis and therapeutic monitoring of lichen planus. Dermoscopy is a non-invasive method initially used for diagnosis of pigmented tumors but now is used also for inflammatory and infectious skin diseases. In lichen planus, the dermoscopy increases the accuracy of diagnosis, avoids skin biopsies commonly used and can be useful in the therapeutic monitoring by repeated investigation at different stages of treatment. Reflectance confocal microscopy (RCM) is a novel non-invasive imaging technique that is prevalently used for the diagnosis of skin tumors and inflammatory skin diseases. This technology has been mostly employed for bedside, real-time microscopic evaluation of psoriasis, lichen planus, contact dermatitis, revealing specific confocal features to support clinical diagnosis and assist with patient management. Optical coherence tomography (OCT) is an emergent imaging technique, developed over the last decade, based on the interaction of the infrared radiation (900-1,500 nm) and the living tissues. A limited information exists on the benefits of OCT technology for the in vivo diagnosis of LP but could be a useful auxiliary tool in the in vivo differential diagnosis, especially in clinical equivocal settings like mucosal lesions, and in monitoring the response to treatment. Our review shows the possibility of using modern imaging techniques for the in vivo diagnosis and also for evaluation of the treatment response.

Neuroendocrine Factors and Head and Neck Squamous Cell Carcinoma: An Affair to Remember.

Head and neck squamous cell carcinoma (HNSCC) is one of the most aggressive malignancies. Therefore, the major goal of cancer treatment is inhibition of tumor cell growth and of metastasis development. In order to choose the best management option for HNSCC patients, we need to identify reliable prognostic factors and to develop new molecular techniques in order to obtain a better understanding of therapy resistance. By acting as neurohormones, neurotransmitters, or neuromodulators, the neuroendocrine factors are able to signal the maintenance of physiological homeostasis or progression to malignant disease. Certain neuropeptides possess strong antitumor properties acting as tumor suppressors and immunomodulators, providing additional benefits for future potential therapeutic strategies. In light of the current understanding, cancer starts as a localized disease that can be effectively treated if discovered on proper time. Unfortunately, more than often cancer cells migrate to the surrounding tissues generating distant metastases, thus making the prognosis and survival in this stage much worse. As cellular migration is mandatory for tumor invasion and metastasis development, searching for alternate controllers of these processes, such as the neuroendocrine factors, it is an active tremendous task.

Human papilloma virus: Apprehending the link with carcinogenesis and unveiling new research avenues (Review).

Human papilloma viruses (HPV) are a small group of non­enveloped viruses belonging to the Papillomaviridae family with strong similarities to polyoma viruses. The viral particles consist of a genome in the form of a circular double­stranded DNA, encompassing eight open reading frames, as well as a non­enveloped icosahedral capsid. HPV infection is considered the most common sexually transmitted disease in both sexes and is strongly implicated in the pathogenesis of different types of cancer. 'High­risk' mucosal HPV types, predominantly types 16, 18, 31, 33 and 35, are associated with most cervical, penile, vulvar, vaginal, anal, oropharyngeal cancers and pre­cancers. Screening for HPV is necessary for the prognosis and for determining treatment strategies for cancer. Novel HPV markers, including proteomic and genomic markers, as well as anti­papillomavirus vaccines are currently available. The aim of this comprehensive review was to thoroughly present the updated information on virus development, cancer occurrence, treatment and prevention strategies, in an attempt to shed further light into the field, including novel research avenues.

Capsaicin: Friend or Foe in Skin Cancer and Other Related Malignancies?

Capsaicin is the main pungent in chili peppers, one of the most commonly used spices in the world; its analgesic and anti-inflammatory properties have been proven in various cultures for centuries. It is a lipophilic substance belonging to the class of vanilloids and an agonist of the transient receptor potential vanilloid 1 receptor. Taking into consideration the complex neuro-immune impact of capsaicin and the potential link between inflammation and carcinogenesis, the effect of capsaicin on muco-cutaneous cancer has aroused a growing interest. The aim of this review is to look over the most recent data regarding the connection between capsaicin and muco-cutaneous cancers, with emphasis on melanoma and muco-cutaneous squamous cell carcinoma.

Neuroendocrine factors: The missing link in non­melanoma skin cancer (Review).

Non­melanoma skin cancer (NMSC) is the most common form of cancer worldwide, comprising 95% of all cutaneous malignancies and approximately 40% of all cancers. In spite of intensive efforts aimed towards awareness campaigns and sun­protective measures, epidemiological data indicate an increase in the incidence of NMSC. This category of skin cancers has many common environmental triggers. Arising primarily on sun­exposed skin, it has been shown that ultraviolet radiation is, in the majority of cases, the main trigger involved in the pathogenesis of NMSC. Aside from the well­known etiopathogenic factors, studies have indicated that several neuroactive factors are involved in the carcinogenesis of two of the most common types of NMSC, namely basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), with the exception of penile SCC, for which a paucity of specific data on their pathogenic role exists. The complex interaction between the peripheral nervous system and target cells in the skin appears to be mediated by locally released neuroendocrine factors, such as catecholamines, substance P, calcitonin gene­related peptide and somatostatin, as well as neurohormones, such as proopiomelanocortin and its derived peptides, α­melanocyte­stimulating hormone and adrenocorticotropin. All these factors have been, at least at some point, a subject of debate regarding their precise role in the pathogenesis of NMSC. There is also a significant body of evidence indicating that psychological stress is a crucial impact factor influencing the course of skin cancers, including SCC and BCC. Numerous studies have suggested that neuroendocrine factor dysregulation, as observed in stress reactions, may be involved in tumorigenesis, accelerating the development and progression, and suppressing the regression of NMSC. Further studies are required in order to elucidate the exact mechanisms through which neuroactive molecules promote or inhibit cutaneous carcinogenesis, as this could lead to the development of more sophisticated and tailored treatment protocols, as well as open new perspectives in skin cancer research.