Keywords

Introduction

Skin cancer is an unregulated and unorderly growth of skin cells resulting from mutations in the DNA of these cells. Mutations can occur as a result of a variety of factors, the most prominent of which is exposure to ultraviolet (UV) radiations (Narayanan et al. 2010). Therefore, primarily skin cancer develops on sun-exposed areas like the face, neck, arms, feet, scalp, etc. Skin cancers usually begin in the epidermis, but have the potential to invade other parts of the body and become metastatic (Godic et al. 2014). Skin cancer can be classified on the basis of two criteria: the cell from which the cancer originates and its clinical behavior. Broadly the skin cancer is classified as non-melanoma skin cancer and melanoma skin cancer (McDaniel et al. 2018). The skin cancer particularly originates in the epidermis layer, which contains different types of cells like melanocytes, keratinocytes, Langerhans cells, and Merkel cells (Becker and Zur Hausen 2014). Non-melanoma skin cancer includes Basal cell carcinoma (BCC), and squamous cell carcinoma (SCC), which involves keratinocytes. Some rare types include Kaposi’s sarcoma, Merkel cell carcinoma (MCC), T cell lymphoma of the skin, and sebaceous gland cancer. The melanomas are the cancer of melanocytes, which account for a smaller percentage of the dermatologic cancers but have a high fatality rate. The various types of skin cancer are discussed below:

Non-Melanoma Skin Cancers (NMSC)

  1. (a)

    Basal Cell Carcinoma (BCC): This is the most common type of skin cancer, covering 75% of the cases (Crowson 2006). It develops in the deepest layer of the epidermis and is usually aggressive in nature. These rarely metastasize and cause death, but they can be quite destructive, and cause disfiguring lesions if left unattended for a long time. BCC has a pearly, translucent appearance and can appear on any sun-exposed area of the body. Based on their growth and progression, BCCs can be classified as having aggressive growth or indolent growth (Crowson 2006). The indolent growth BCC contains nodular and superficial type of BCC. While the morphea form BCC, infiltrative growth BCC and metatypical BCC fall in the category of aggressive growth BCC (Rippey 1998).

  2. (b)

    Squamous Cell Carcinoma (SCC): It is the second most common form of skin cancer and has a substantially increased metastasizing rate as compared to BCC. It represents 20–50% of skin cancer cases (Marks 1996). SCC develops from actinic keratosis (AK), which typically occurs in fair-skinned individuals in sun-exposed areas (Callen et al. 1997). AK is histologically described as a dysplasia of keratinocytes, which bear enlarged and hyperchromatic nuclei. These cells grow abnormally, resulting in a thick and scaly stratum corneum (Ratushny et al. 2012). The journey of AK to SCC is a multistep process involving mutations in different tumor suppressor and proto-oncogenes.

Rare Types of Non-Melanoma Skin Cancers

  1. (a)

    Merkel Cell Carcinoma (MCC): It is a very rare, rapidly growing neuro-endocrine cancer in the skin whose origin is debated and believed to be epidermal or dermal stem cells rather than a differentiated mature Merkel cell. It can be present as a subcutaneous nodule without any significant change in the epidermis, thus making it asymptomatic. MCC usually shows co-occurrence with BCC and SCC (Brady and Spiker 2018).

  2. (b)

    Kaposi Sarcoma: In this type, tumors with thin blood vessels grow underlying the skin and they can occur anywhere in the body, including the muco-cutaneous surfaces of major organs like the lungs, stomach, liver, and even lymph nodes. Kaposi sarcomas on the skin are particularly uncommon and occur as flat, red, blue, or brownish-colored non-itching spots. These are common in immunocompromised patients and have been widely reported in HIV-infected patients (Bishop and Lynch 2021).

  3. (c)

    Cutaneous Lymphoma: It is a diverse group of lymphocytic tumors that primarily affect the skin and do not involve the viscera, lymph nodes, or bone marrow. These can originate from any lymphocyte, but T-cell lymphomas are the most common, followed by B-cell and natural killer cell neoplasms (Sokołowska-Wojdyło et al. 2015).

  4. (d)

    Sebaceous Carcinoma: It is a very rare form of cancer that involves a tumor in the sebaceous gland of the skin. Sebaceous carcinomas are common in the periocular regions, like the eyelids, and have a tendency to metastasize from the periocular regions, making it dangerous. Other than this, sebaceous gland hyperplasia can be found on the scalp and eyebrows (Wali and Al-Mujaini 2010).

Melanomas

Melanoma is the most aggressive and deadly form of skin cancer. These tumors are typically produced from malignant melanocytes, which originate from neural crest stem cells. Melanomas typically occur on the skin, but they can also arise in the organs like brain where neural crest cells migrate (Ott 2019). They are uncommon skin cancers that account for less than 1% of all cases. These occur as asymmetric, reddish-brownish elevations with irregular borders (Duarte et al. 2021). Based on their growth, melanomas can be further divided into four types, i.e., superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, and acral lentiginous melanoma (Barnhill and Mihm 1993). In certain cases, the melanoma does not produce pigment and appears colorless with pinkish-red or brownish borders; this is referred to as amelanotic melanoma (Gong et al. 2019) (Fig. 1).

Fig. 1
figure 1

Diagrammatic representation of the major types of skin cancer, i.e., SCC, BCC, and Melanoma. These cancers originate in the epidermis and can spread to various parts of the body by metastasizing through blood and lymph. The image was created using Biorender (https://biorender.com)

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Epidemiology of Skin Cancer

The NMSCs like BCC and SCC along with cutaneous malignant melanoma (CMM) comprise 98% of the total skin cancer cases (Holterhues et al. 2010). They are more often diagnosed in elderly population undergoing multiple drug treatments as many drugs lead to increased cutaneous photosensitivity, which is linked to induction of DNA damage making them prone to developing skin cancers (Cowen et al. 2010).

The BCC and SCC make more than two third of the skin cancer cases but don’t add to mortality rate as they are treatable and can be removed surgically however, these groups of skin cancer account for high morbidity due to their highly recurring behavior, which adds burden to the health care service providers (de Vries et al. 2012). Due to their commonly occurring, frequently recurring, and treatable nature they are often excluded from the cancer statistics. According to the global cancer statistics 2020, Australia shows the highest incidence rate for NMSC followed by America and Western Europe (Sung et al. 2021). As per the trend males aged 40 years or more are the most affected group for this cancer type (Sung et al. 2021). CMM accounts for a small fraction of the total skin cancer cases but has the highest mortality rate (75%) due its aggressive metastasizing nature (de Vries et al. 2012). Melanoma is seen to occur 1.5 times more frequently in males than females (Apalla et al. 2017). The age-period cohort models used by Whiteman et al. showed that melanoma rates rose by more than 3% annually in the USA, UK, Sweden, and Norway. Because of the rising longevity and the high age-specific rate of melanoma in the elderly age group, it is predicted that the number of new melanoma cases will increase (Whiteman et al. 2016).

Looking at the skin cancer demographics for India, we can observe NMSC occupy a small percentage of skin cancer in clinical setting probably because of the protective effects of eumelanin present in the skin of Indians. On comparing the rate of incidence of BCC and SCC it was found that SCC is predominant in Indian population, which is very unlike the global trend (Panda 2010). The study performed by Shishak et al. shows that men are more affected with malignant melanoma than females accounting for up to 61% of the total reported cases. Most of the patients as close as 89% show metastases and have anorectal (24%) as the most common primary site for this cancer followed by acral and ocular region (Shishak et al. 2021).

Factors Involved in the Development of Skin Cancer

Many intrinsic, as well as extrinsic factors are involved in the development of skin cancer. Melanoma formation is due to intricate relations between phenotypic and environmental factors. The interaction between these two not only results in melanoma formation but also influences the incidence and clinical characteristics of melanoma development (Nikolaou and Stratigos 2014). NMSC arises primarily due to UV radiations. UVA and UVB cause DNA damage and immunosuppression, leading to the development of NMSC (Chen et al. 2013).

Environmental Factors

  • Exposure to Natural Ultraviolet Radiations: Long-term exposure to UV radiations is the leading and well-established cause of skin cancer development. UV radiations causes skin damage through both direct and indirect mechanisms, including damage to DNA through the formation of cyclobutane pyrimidine dimers, oxidative stress, and immunosuppression (Meeran et al. 2008). Melanin directly protects skin from harmful UV rays, as evidenced by higher melanin content in populations that have spent more time in the sun. NMSCs are typically located in sun-exposed places, and multiple studies indicate that populations moving from lower to higher ambient UVR regions have significant occurrences of melanoma development (Diepgen and Mahler 2002).

  • Exposure to Indirect or Artificial Ultraviolet Radiations: The increasing trend of artificial or indoor UV tanning in recent times among a larger section of the white population is enhancing the chances of skin carcinogenesis. Indoor tanning beds or sunbeds mostly emit harmful UVA and about 5% UVB (Ting et al. 2007). Melanoma formation has been linked to dose-dependent indoor UV radiations exposure, duration or length of exposure, and the number of treatment sessions (Veierød et al. 2010). NMSCs other than melanoma have also been reported to be associated with artificial UV radiations with two- to threefold increased risk in people using sun beds (Karagas et al. 2002).

Phenotypic Factors

The phenotypic factors comprising of phototype, freckles, multiple and dysplastic naevi, poor tanning ability, eye and hair color contribute as risk factors for melanoma development. Gandini et al. showed direct proportionality between the relative risk of melanoma development and the number of dysplastic naevi. According to Olsen et al. the density of naevi has also been linked to the location of melanoma development. Aside from naevi, skin phototypes I and II, light eye colors such as hazel, blue, and green eye color; light hair colors such as blond, red, and light brown color; and the presence of freckles are all high-risk factors for the development of melanoma (Olsen et al. 2010).

Genetic Factors

Various studies have associated variations in genes involved in pigmentation like melanocortin 1 receptor (MC1R), tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1) agouti signaling protein (ASIP) with non-melanoma and melanoma skin cancer (Liboutet et al. 2006). Other than pigmentation, genes regulating cell cycle, namely, cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase inhibitor 2A (CDKN2A) are also associated with skin cancer. Association between MC1R variants and skin carcinogenesis is the most studied one (Scherer et al. 2009). Variations in the TYR have been linked with the development of CMM, SCC, and BCC (Gudbjartsson et al. 2008). Significant association between the TYRP1 variant and the risk of melanoma development has also been reported (Duffy et al. 2010).

Molecular Basis of Skin Cancers Development

UV radiations acts as both an initiator and a carcinogen, capable of inducing mutagenesis in one or more proto-oncogenes, tumor suppressor genes, DNA repair genes, or cell-cycle pathway genes. In both non-melanoma and melanoma skin cancer development, UV radiations has been shown to be a significant factor.

Non-Melanoma Skin Cancer Development

The duration and wavelength of UV radiations that induces NMSCs, BCC, and SCC, vary depending on the type of NMSC. Therefore, the molecular pathways involved in the development of both of these NMSCs also differ (Hodges and Smoller 2002). In SCC, the initial point of carcinoma development involves the inactivation of the tumor suppressor gene p53, particularly by C → T and CC → TT transitions after exposure to UV radiations. These alterations lead to the uncontrollable expansion of cells with genomic instability as the p53 gene is normally involved in DNA repair and pro-apoptotic pathways (Bolshakov et al. 2003).

Overexpression of ras proto-oncogenes is also associated with the development of SCC. Normally, ras genes encode small proteins involved in signaling pathways activated in response to growth-factor receptors. In NMSC, phosphorylation of these growth-factor receptors occurs above the basal levels. Ras genes are also activated due to aberrant repair of UV-induced pyrimidine dimers, usually at codon 12 of the K-ras and codons 12, 13, 61 of H-ras gene (Spencer et al. 1995). Unusual activation of growth-factor receptors and ras proto-oncogene results in dysregulated cell growth of cells.

Glutathione peroxidase (GPX) is an enzyme that protects cells from oxidative damage under normal conditions. In SCC, the activity of this enzyme is somehow disturbed, which elevates the levels of peroxide and thus cell damage. GPX is reported to be an initial indicator of SCC development. A decreased GPX activity and raised peroxide levels has been reported in two of the three AK, and four of five SCCs (Walshe et al. 2007). In the development of SCC, the higher expression of anti-apoptotic genes of the Bcl-2 family has also been observed, indicating their possible role in the development of skin carcinoma (Berhane et al. 2002). Because of the increased expression of the bcl-2 protein, the mutated cells survive for a longer period of time, allowing carcinogenic mutations to accumulate over time (Bronner et al. 1995). A gradual increase in the expression of bcl-2 has also been reported in the transition of actinic keratosis to SCC and in situ to invasive SCCs.

BCC originates from deeper layers of the skin, unlike SCC, and is characterized by no precancerous lesions. The exact origin of BCC still remains unclear, as different subtypes of BCC have different points of origin in cells like hair follicles, sebaceous glands, and interfollicular basal cells. The genome-wide association studies have further linked certain loci associated only with BCC (RHOU, PADI6, TERT/CLPTM1L, KLF14, and KRT5) with pigmentation genes (TYR, SLC45A2, ASIP, MC1R), suggesting pigmentation-dependent as well as pigmentation-independent pathways in the development of BCC (Zebracka et al. 2015). The other major alteration associated with development of BCC is enhanced expression of hedgehog signaling pathway. The sonic hedgehog (Shh) protein normally binds to receptor PATCHED (PTCH), which is encoded by the downstream tumor suppressor gene, PTCH. In the absence of Shh protein, receptor PTCH negatively regulates Shh pathway, it suppresses the activation of a seven transmembrane domain protein smoothened (Smo), thereafter inhibiting the expression of downstream target genes, like, PTCH, glioma-associated oncogene homolog (Gli), and members of transforming growth factor-β (TGF-β) (Kalderon 2005). In BCC, the overexpression of hedgehog signaling could result in loss of heterozygosity of PTCH protein or gene function mutation in Smo, ultimately resulting in an increased expression of downstream genes like Gli and leading to the development of BCC (Athar et al. 2006).

Melanoma Skin Cancer Development

Melanoma development is closely linked with the skin microenvironment, where the surrounding cells, i.e., fibroblasts, keratinocytes, immune system cells, and endothelial cells, initially suppress melanoma formation but later aid in the expansion of the tumor by forming suitable conditions for melanoma development (Olbryt 2013). In melanoma, mature melanocytes lose their contact with surrounding keratinocytes because of a reduction in the expression of E-cadherin (cell adhesion protein), in response to UV radiations, which in turn activates the ET-1/ET(B) pathway. In addition to independence from keratinocytes, activation of the ET-1/ET(B) pathway increases melanocyte proliferation, invasive proteins on their surface, and apoptosis sensitivity (Olbryt 2013). In response to UV radiations, fibroblasts secrete another protein called fibroblast activation protein (FAP). In melanoma, this protein enhances the invasiveness of melanoma cells and, therefore, promotes metastasis (Wäster et al. 2011). Like SCC, bcl-2 family anti-apoptotic proteins are overexpressed in melanoma too, and avoid apoptosis (Nys and Agostinis 2012) (Fig. 2).

Fig. 2
figure 2

Molecular events in different types of skin cancers. The SCC mainly originates from the mutation in p53, which leads to uncontrolled proliferation. Other factors associated with proliferation of this cancer are increased levels of reactive oxygen species (ROS), decreased glutathione levels, and activation of ras oncogenes. BCC shows increased expression of sonic hedgehog pathway genes and suppression of apoptosis. The hyperactive ET1/ET(B) pathway in melanoma results in decreased E-cadherin expression and accelerated proliferation. This image was created using Biorender (https://biorender.com)

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Screening and Diagnosis

Screening for people with atypical mole syndrome or for people at high risk with a history of skin cancer is highly recommended. With proper screening, early detection of skin cancer is possible, and treatment can generate better outcomes. The screening process typically entails a whole-body visual examination of skin damage using the “ABCDE rule” (asymmetry, border, color, diameter, and evolving) (Friedman et al. 1985). The positive screening results are then confirmed with a skin biopsy and histopathological examination.

The survival of the patient is correlated with the thickness of the tumor, and early detection substantially improves the prognosis (Trakatelli et al. 2007). With technological advances and the need to fight against skin cancer, new detection methods have evolved that are superior to naked-eye examinations such as dermoscopy. It is an inexpensive and handheld tool that uses polarized light to magnify and visualize the morphology of the disease (Ruocco et al. 2004). The diagnosis of possible oncogenesis is done by visualizing certain characteristics of lesions, for example, globules and nests, and the presence of different blood vessel configurations (Argenziano et al. 2003). Another diagnostic modality commonly employed for the detection of skin cancer is reflectance confocal microscopy. This technique uses a laser at a near-infrared wavelength, which image the different sections of the skin at high resolution and contrast. Invasive biopsies from patients are not required in this technique (Nori et al. 2004). Optical coherence tomography is another imaging technique that also generates cross-section images of the microstructures of tissues (Pierce et al. 2004). This technique is sensitive to obstructions in the imaging process and hence detects the presence of any malignancy.

Treatment and Prevention

The necessity for new treatments for skin malignancies is rising with the growing incidence of cutaneous malignancies. The method of treatment depends upon the progression degree, dimensions, margins, and location of the tumor (Martinez and Otley 2001). Treatment therapies basically focus on three major goals: preserving the normal functioning of cells, complete eradication of the tumor, and cosmesis.

Surgical Removal

Microscopically controlled surgery is the key treatment for excision of non-melanoma skin cancers as the reoccurrence rate is low and delivers prominent cure rates (Telfer et al. 2008). With the use of this therapy excision margins are carefully marked and tumor extension to the borders is precisely identified; therefore, only affected area is excised and normal skin is spared.

Topical Treatments

A variety of topical agents is available for skin cancer treatment. 5-Fluorouracil is the most common topical agent approved by FDA for the treatment of superficial BCC (Gross et al. 2007). It is a pyrimidine analogue that binds to thymidylate synthase through the 5,10-methylene tetrahydrofolate co-factor (Thomas and Zalcberg 1998), ultimately resulting in inhibition of thymidine synthesis, flaws in DNA replication, and induction of apoptosis. Imiquimod is an FDA-approved immunomodulator, which initiate both innate and adaptive immune responses via activation of toll-like receptor (TLR) 7 and 8 (Dubas and Ingraffea 2013). This leads to the activation of NF-κB and various cytokines like tumor necrosis factor-α, interleukin 12, and interferon-α, which trigger an inflammatory cascade and induces apoptosis in malignant cells (Tyring and Rosen 2009).

Photodynamic Therapy

This therapy demands interaction among three factors: a photosensitizing agent, light at a particular wavelength successfully absorbed by the aforementioned compound, and the presence of oxygen (Henderson and Dougherty 1992). Upon activation of the photosensitizer by light, a photochemical reaction is triggered that leads to the production of singlet oxygen (O2) and other ROS that subsequently cause damage to cell membranes and ultimately result in the cell death of cancer cells (Cohen and Lee 2016).

Radiotherapy

Due to the significant risk of relapse, inadequate excision, lymph node involvement, and inoperable lesions, radiotherapy is being used. It comprises helical tomotherapy, a type of radiation therapy with intensity control that is guided by a CT scan. It employs spiral or helical imaging of cancer from a variety of angles to provide a three-dimensional image of the tumor, assisting in choosing the precise radiation dose for the tumor while reducing exposure to the nearby healthy or benign tissue (Kramkimel et al. 2014).

Prevention

Preventing carcinogenic development exposures can limit the chances of the development of skin cancer. The UV radiations from indoor tanning beds and sunbeds are classified in the same category as asbestos and tobacco, i.e., group I carcinogens. Substantial research has already shown that the trend of indoor tanning has increased the incidence of skin cancer. Despite large and extensive efforts focusing on limiting the use of tanning beds for skin cancer prevention, there has been no improvement in skin cancer incidences as their use remains widespread (Wehner et al. 2014). Sun exposure during the peak UVB period, i.e., from 10 a.m. to 4 p.m., should be minimized or avoided. Sunscreen with a solar protection factor of at least 15 should be applied thoroughly. Protective clothing, sunglasses, and wide-brimmed hats should be worn in addition to sunscreen.

The demographic data of skin cancer indicates that it has become highly dynamic and a serious concern; therefore, it generates a prima facie demand of advanced diagnostic and treatment tools and equally focus on prevention efforts.