Basal Cell Carcinoma

Abstract

Globally, Basal cell carcinoma is the most prevalent form of skin cancer, which originates from basal cells of the epidermis. Sun-exposed parts of the body (head, face, and neck) are mostly affected by BCC. Characteristics of BCC include local invasiveness, low potential of metastasis, and slow growth. Despite its relatively low rate of mortality, it presents a significant public health concern, as its incidence rate is continuously rising. Different factors like aging population, sun-exposure, and behavior changes in lifestyle plays an important role in increasing BCC incident rate. UV exposure remains the dominant factor, immunosuppression, environmental influences, and genetic susceptibility also play important roles in amplifying the impact of UV on the skin. Different signaling pathways are involved in BCC pathogenesis which leads to tumor formation and cell proliferation. Targeting these pathways could lead to new diagnostic tools and treatment therapies. Clinically, there are different subtypes of BCC with unique features, morphologies, and characteristics. After early detection through visual inspection, Dermascopy, biopsy, and confocal microscopy techniques are used to diagnose BCC. Available treatment options include surgical excision. Cryosurgery, Mohs micrographic surgery, photodynamic therapy (PDT), radiotherapy, curettage and electrodessication therapy, and targeted molecular therapies.

1. Introduction

Basal cell carcinoma (previously called basal cell epithelioma), is regarded as the most common and frequently occurring type of skin cancer worldwide, comprising about 80% of all cases of skin cancer. This specific type of cancer arises in the basal cells of the skin, which are the deepest layer of the cells in the epidermis [1]. The clinical presentation can be highly variable, from isolated erythematous/pigmented patch to papule, nodule, or ulcer of red-colored spots on different areas of the skin, including the scalp, face, and sometimes extremities. Although the rate at which it spreads is lower than the two other types, it can very rarely metastasize to other organs. Most of the time, it is associated with damage to DNA caused by ultraviolet radiation from the sun, and without any proper care, it can metastasize to other organs (in some of rare cases), but if left untreated it can cause serious implications [2].

According to reported literature, there are almost 26 different subtypes of skin cancer, from which the most reoccurring are micronodular, superficial, nodular, infiltrative, morpheaform, and fibroepithelioma of Pinkus (fibroepithelial skin cancer). Sometimes these subtypes can appear in a groups of 2–3 [3]. Clinical examination of BCC shows pink-colored cells with telangiectatic vessels (malformation of blood vessels). Treatment strategy for BCC includes surgical excision, Cryosurgery, Electrodesiccation, and Mohs surgery, and these treatments are good for localized BCC (shows more than 95% cure rate).

Exposure to Ultra-Violet (UV) rays is by far the most reported factor throughout the literature. Mostly UV-B radiations are associated with the development of BCC, but UV-A can also cause the predisposition to mutations in normal basal cells. The rate of incidence is typically higher in males than females due to more sun-exposure, but with the passage of time, this gender-related difference is becoming less significant as lifestyles of females changed considerably (use of tanning bed or smoking) [4]. Workers are at greater risk of BCC due to frequent accumulation of UV-rays, and the Fritzpatrick scale is quite often used for the prediction of skin cancer, usually white individuals are at a greater risk [5]. Types of skin and the exposure to ultraviolet rays are not the only predictors; the intensity of rays combined with the duration of exposure (mainly in childhood) plays a crucial role in the development of BCC (Figure 1).

Figure 1.

Generalized overview of the formation and progression of BCC in the basal cells of the skin. The formation of these sorts of tumors is promoted by exposure to UV radiation, the most common etiological factor in the development of BCC, ultimately leading toward the uncontrolled growth of the cells [6].

2. Epidemiology

The incidence rate of BCC is rising at an alarming rate worldwide, and males are mostly affected by this type of cancer than females. The rate of incidence is also based on geographical regions and those regions which have lower or higher attitudes. A previous history of BCC is one of the best predictors of the development of this skin cancer, and according to recently published data, people with previous exposure to this disease are at a greater risk of developing BCC again compared to those patients who do not have such history [7]. According to data published over the last 25 years, the rate of incidence has increased to approximately 45%, and it is intricately linked with age (age more than 50 years). The mortality rate is preferably lower than the other two main types of skin tumors, and mostly patients with a weakened immune system are at risk. Tumors that show aggressive patterns in histopathological analysis are the common cause of metastasis, and if a tumor does metastasize, it usually invades lymph nodes, lungs, bones along with the skin [7].

The rate of incidence of Basal cell carcinoma in different races is given below, and most of the people affected by this cancer are Hispanics, Caucasians, Japanese and Chinese Asians [8, 9, 10]. Among different ethnicities, the incidence rate in Blacks is comparatively lower than the other (1–2 per million), and Africans residents have the lowest rate (0.065 per million). On the contrary, Chinese men and women are at a greater risk of developing this cancer, with 6.4 and 5.8 cases per million in men and women respectively. Furthermore, the prevalence of BCC is much higher in residents of Okinawa and Kawaii, with the rate of incidence reaching almost 30% [11]. Contrary to this, it is highly prevalent in Asian Indians and Blacks, and there are rare chances of this type to occur in Blacks, while most of the time, Whites are more affected [12]. According to data collected from different medical centers, the prevalence of Basal cell carcinoma accounts for 2–3% of the total annual cases [8]. The Figure 2 shows cancer on different skin types [14]. The incidence of this cancer is highly dependent on the age factor and advances with the increase in age and approximately 40% of the patients that are diagnosed with this disease develop more lesions within the next 4–6 years [2, 15].

Figure 2.

Generalized overview of the Hedgehog pathway in the activation of transcription factors. In the absence of the ligand (Hh), Smo is inhibited by the PTCH1 and Gli 3 is degraded by the proteasome system and targeted genes were not activated (Left). However, in the presence of the ligand, Smo is activated and PKA does not phosphorylate the Gli 2, which then translocates into the nucleus and causes the activation of transcription factors (Right) [13].

3. Etiology

Several factors (Genetic, Environmental) participate in the progression and development of BCC and all of those are summarized below:

3.1 Environmental factors

Environmental factors are among the fundamental and mostly analyzed risk factors in the study of basal cell carcinoma. Among these, exposure to UV light is the leading cause of the development of this disease (both UV-A and UV-B radiations are responsible). Too much exposure to these radiations causes the disruptions in the Deoxyribonucleic acid (DNA) that lead to mutations in the pro-oncogenes (that are close to developing cancer) and tumor suppressor genes (that controls the rate of mutations and protects the genome), and this in turn leads to the development of Basal cell carcinoma [7]. Other dominant factors are ionizing rays, includes gamma and X-rays, and exposure to arsenic further increases the risk of this disease.

3.2 Genetic factors

Genetic factors also play a key role in basal cell carcinoma progression and invasion. Mostly, mutations are seen in the sonic hedgehog pathway (SHH). This pathway performs a crucial role in developmental biology, responsible for cells differentiation in complex multicellular organisms (the pathway itself contains a series of complex interconnected molecules). The main proteins involved in this pathway are the transmembrane protein known as patched (Ptch) and another protein called smoothened (Smo). Smoothened is restricted by the patched protein, and the degradation of Ptch lead to the activation of Smo, which in turns favors the activation of Gli (Glioma associated oncogene transcription factor) that are involved in the activation of genes that controls cell growth and development [16].

Other dominant mutation is seen in Gorlin’s syndrome (another name used for basal cell nevus syndrome [BCNS]), caused by mutations in the PTCH1 gene. This syndrome is closely linked with the progression and development of a lot of BCCs at early age, and the key characteristic abnormalities of this syndrome are ectopic calcifications, jaw cysts, and plantar. The PTCH1 gene participates in the suppression of tumors in the genome, and a loss of function is associated with the progression of Gorlin’s syndrome [17].

3.3 Individual susceptibility factors

Several individuals also contributes toward the pathogenesis of basal cell carcinoma, including immunosuppression (those people who have weak immune system or those with disease like AIDS (acquired immune deficiency syndrome) are at a greater risk of developing BCC), type of skin (dark colored individuals are protected from BCC than light colored and fair colored skin due to large concentrations of melanin produced by the melanocytes), age (people with increasing age, greater than 50 years, are at a risk of developing bcc).

4. Pathophysiology of BCC

Excessive sunlight exposure appears as the primary risk factor contributing to BCC. Direct DNA damage is responsible for the development of basal cell carcinoma, accompanied by indirect damage to the DNA through the suppression of the immune system and ROS [4, 18]. Melanin also plays a role in indirect damage by absorbing UV-A radiation, and causes damage to DNA, while UV-B is responsible for direct damage to RNA (ribonucleic acid) and DNA with a transition of the CC/TT [4]. Exposure to ultraviolet radiation also causes immune suppression of cutaneous cells, leading to the dysregulation of the immune system. According to studies published in the near past, BCC arises in those cells that are immature or are transiting from the immature to mature stage, cells related to hair follicles. One of the key genes dysregulated in BCC is PTCH1, and mutation in this gene is associated with 70% of the cases of BCC, while 20% of the patients of this type depicts the mutation the SMO gene. The inactivation of the PTCH1 or the high expressions of the Gli, by the trans activation of the smoothened is good enough to drive the progression of basal cell carcinoma. Second most vital dysregulation in basal cell carcinoma is the mutation in the gatekeeper gene P53 [19, 20].

4.1 Canonical hedgehog pathway

The HH pathways participate in mitogenesis and division of cells, and this pathway is activated when hedgehog protein binds to its receptors, and activates interlinked pathways. Vertebrates consists of three main kinds of Hh proteins: Desert hedgehog (DHH), Sonic hedgehog (SHH), and Indian hedgehog (IHH), and all these three are involved in the activation of the same pathway but do so by activating several different genes [4]. The receptor for Shh is Ptch (a transmembrane protein), and after binding of Shh, the receptor is degraded by the proteosome system inside the cell. This degradation leads to the migration of Smo into membrane, and Gli family of proteins are activated, that translocates from the cell into the nucleus and there acts a transcription factor by modulating several key genes that are engaged in control of cell development. If the pathways are not functional, Gli proteins are phosphorylated (a phosphate group is added), and they become repressor Gli proteins. This Gli-R also translocates to nucleus but here causes the suppression of all those genes that takes part in the HH pathway and hence the amount of Gli to Gli-R inside the cell plays the most crucial role in governing that which genes are to be expressed and which are to be repressed [21].

Hyper-activation of the Hedgehog (HH) signaling pathway, corresponding to the canonical hedgehog, is the most common hallmark in studying the progression of basal cell carcinoma, as reported by various studies conducted in the past [22]. This pathway plays a vital role in cell differentiation, proliferation, and embryogenesis in the preliminary stages of cell development, this facilitates the development of epidermis by the crosstalk between dermal cells of the skin and those cells that are of epithelial origin. Canonical activation of the pathway is driven by ligands names as sonic hedgehog (SHH), Indian Hedgehog (IHH), and sometimes by Desert Hedgehog (DHH) in response of the PTCH1 receptor [23]. Activation of this pathway do facilitate the activation of this gene and this Smo migrates to one of the highly specialized primary cilia and as a result, SMO drives the hyper-activation of the Gli transcription factors followed by the suppression of the fused (SUFU- suppressor of fused homolog). However, if HH does not attach to PTCH1, the Gli family of transcription factors are in their inactive form as Smo does not translocate to the primary cilia and the Gli proteins are ubiquitinated [24, 25]. The eventual results from the activation of this signaling cascade is dependent on differentiation and proliferation, self-renewal, cell survival (by the activation of the BCL-2 (B-cell lymphoma −2) protein family), transition from epithelium to mesenchymal cells, angiogenesis, and invasiveness of BCC.

4.2 Non-canonical hedgehog

However, in the case of non-canonical signaling, HH interacts with a lot of other signaling networks that are oncogenic in nature, such as IGF, TGFβ, aPKC, NF-kB, and epidermal growth factor receptor (EGFR). These pathways synergistically contribute to the progression of basal cell carcinoma. It means that, the activation of the Gli family of receptors may be done by many alternative pathways that are non-canonical, but all this happens in the absence of bypassing Smo [26, 27]. The activity of Gli is positively influenced by the RAS, PI3K, and AKT, while it is negatively regulated by the P53 family of proteins and significantly the expression of the RAS/RAF cascade, which further hyper-activates the JUN complex, causing the progression of developmental processes. TGF-beta signaling do activates the upregulation of GLI2 transcription, while GLI1 is activated by the complex protein, aPKC [28]. Furthermore, IGF-1 causes the induction of the nuclear localization of GLI1 and 2, and it has also been observed that the activation of PI3K and AKT regulates epithelial-mesenchymal transformation and the secretion of matrix metalloproteinases (MMP’s) [29]. The Figure 3 shows the dysregulation in the non-canonical pathway.

Figure 3.

Non-canonical Hedgehog pathway mediated by the phosphorylation of AKT, TSC22, and S6K1 instead of the attachement of Hh ligand. The phosphorylation of AKT by PI3K mediates the activation of the Gli family of transcription factors. Phosphorylation of S6k1 enzyme is facilitated by the inhibition of mTOR which then activates the Gli family of protein in by the help of SuFu gene. Phosphorylation of this Gli allows it to translocates from cytoplasm to the nucleus and causes the activation of potential genes [30].

4.3 Other genetic alterations

Apart from alterations in hedgehog pathway, several other genetic changes have also been reported in the literature that contribute toward the pathogenesis of basal cell carcinoma, and these alterations do not depend on the activation of the HH pathway. These includes dysregulation in the Hippo-Yap and WNT signaling (Hippo pathway is associated with the controlled growth of organs and WNT signaling pathway is associated with development of embryo) pathways. The main effector protein that is altered is the Yes-associated protein (YAP), which participates in maintaining progenitors and proliferation of the skin and upon its phosphorylation it translocates in cytoplasm, thus being unable to transcribe the associated genes [31]. While in case of WNT signaling, several changes have been observed in the activation of downstream effectors as well as the destruction of β-catenin (after the phosphorylation of disheveled and inhibition of GSK-3β). Dysregulation in this pathway is typically due to the activation of WNT by the Gli proteins, which lead to the upregulation of several stem cells markers [32].

Missense mutation in the N-Myc gene also contributes to the basal cell carcinoma progression (Myc transcription factors are responsible for cell growth, proliferation, and development of embryo) because it is one of the downstream effectors of HH signaling. Most of the time alteration arises when this gene interacts with the tumor suppressor FBXW7 that is involved in the degradation of Myc (proteosome dependent destruction of MYC) [33, 34]. Mutations in NOTCH signaling have also been reported to play a part in the progression of BCC. It is one of the targets of the guardian gene, p53, and is responsible for epidermal differentiation. Although mutation in this gene is not regarded as the driver mutations but still these are the most common mutations in BCC [35].

5. Histopathology and subtyping

The clusters of basaloid cells form the islands which exhibit the distinct appearance characteristic of BCCs. In BCCs formation, irregular arrangement of basaloid cells can be seen in the center with a palisade arrangement at periphery. Each basaloid cell contains staining nucleus that lacks a visible nucleolus and contains marginal or limited cytoplasm. Upon examining the paraffin-embedded sections between the tumor and its stromal neighbors, a retraction artifact also known as clefting.

When examined on paraffin-embedded sections, a retraction artifact, identified as clefting. Additionally, mucin deposition is also present within the tumor and its neighboring tissue. The aggressive form of disease can be indicated by the existence of perineural growth [7, 36].

Trichoblastoma and trichoepithelioma are the conditions involved in the histological differential diagnosis. Many different structural subtypes have been identified i.e., superficial, infiltrating, nodular, micronodular, pigmented, sclerosing, fibroepitheliomatous etc. In mixed patterns, combinations of above listed types were observed.

• Superficial subtypes comprise of multiple basaloid cells which are small, that extend from epidermis but do not penetrate in the dermis.

• Most cases are associated with modular type. Nodular basal cell carcinomas consist of clusters of cells which display outer lining and irregular arrangement in their central region. Ulceration can be seen in larger lesions.

• The micronodular subtype’s histological characteristics resemble nodular subtypes characteristics. Micronodular subtypes contain many nodular, which make it different from nodular subtype. For local recurrence, micronodular subtype has greater risk than solid type.

• Sclerosing subtype morphology contains thin strands of basaloid and spiky cells which are surrounded by thick fibrous stroma that invade the dermis. It is challenging to histological differentiate this from conditions like, metastatic cancer, microcystic adnexal carcinoma, or desmoplastic trichoepithelioma. The term infiltrative BCCs is used when tumor nests have spiky projections which invade deeply [37].

• Combination of melanocytes and melanin results in the pigmented BCCs. This phenomenon is mostly seen in variations of micronodular, superficial, and follicular.

• Infundibulocystic variation forms compact, and well-defined tumor consists of clusters of cells with interconnecting pattern arrangement with minimal stroma. This variation is not common and mostly found on the face. Melanin and keratinous matter are present in structure of many small infundibular cysts.

• Soft, nodular lesions are present fibroepithelioma of Pinkus, which resembles papilloma and fibroma. This subtype is often found on the lower back. Structurally it is composed of a grouping of basaloid cells and interconnected strands which are surrounded by fibrous stroma [36, 37].

6. Diagnosis

The diverse pathological presentation of basal cell carcinoma consists of many subtypes, such as nodular, fibroepithelial, superficial, and infiltrative BCC, each exhibiting distinct clinicopathological characteristics. Additionally, micronodular subtypes hold significant histopathological relevance with the basosquamous subtype which impacts both prognosis of patient and approaches of treatment. Furthermore, multiple tumor subtypes display histopathological of features within the same lesion. Dermascopy is most useful in the diagnosis of basal cell carcinoma and differentiation of non-pigmented BCC from pigmented ones. This is characterized by the development of arborizing vessels and globules of blue-gray colors with a leaf like structure. The differential diagnosis is sometimes confused with the diffusion of trichoepithelioma, while superficial basal cell carcinoma could mimic some inflammatory conditions like eczema and psoriasis [38].

Apart from dermascopy, some novel diagnostic approaches are also practiced worldwide, and these techniques provide a clearer picture about the diagnosis of BCC based on its different subtypes. These techniques include optical coherence tomography (OCT), Raman spectroscopy (RS), multiphoton tomography (MPS), and confocal laser scanning microscopy (CLSM).

6.1 Optical coherence tomography

it is a noninvasive imaging technique that provides the cross-sectional interpretation of tissues that helps in visualizing the structure of epidermis and papillary dermis up to depth of approximately 2 mm. It uses low length of coherence light as a source to visualize the skin structures properties. OCT also provides the visual characteristics of superficial and dermal tumor nests. Therefore, it is also used in differentiation of different subtypes of BCC.

6.2 Raman spectroscopy

Raman spectroscopy imaging provides quantitative view of structure. Light of infrared wavelength is used to differentiate different cutaneous structures. Different energy vibrations are generated by each structure when light is scattered on them. These vibrations of energy resemble their spectral peak, which is detected by meter, providing a quantitative view. Raman spectroscopy can be used to detect cellular alteration caused due to cancerous tumors. Generally, Raman spectroscopy is time consuming technique, therefore, to overcome this issue other modalities have been used by researchers.

6.3 Multiphoton spectroscopy

Multiphoton spectroscopy is used in vivo for dermatologic purposes. In this technique, fluorescence is excited from the target through simulating the two or more infrared light photons absorption. Then raster-scanning is used to generate the images. MPS has a spatial lateral resolution of 1 mm and a spatial axial resolution of 2 mm. Fluorescence lifetime imaging microscopy (FLIM) is used to differentiate between the corresponding tissue and fluorescence. It measures the decaying rate of the fluorescence signal and short excited pulse follows. For detection of BCC from normal skin cells multispectral FLIM multiphoton tomography is used [39].

6.4 Confocal laser scanning microscopy

Confocal laser scanning uses fluorescence or reflectance modes. Reflectance confocal microscopy (RCM) is used in vivo to produce real-time 2D horizontal image. Cellular resolution from the epidermis to papillary dermal layers can be produced from it. CLSM has a lateral resolution of 250 nm and a depth of 1 μm. The CLSM mechanism involves the laser source with a specific wavelength. This light visualizes the tissue within the skin after its transmission. After transmission, the light is reflected and passes through the pinhole in the optical conjugate plane. In the detector, a 2D image is formed. On the other hand, RCM images depend on reflectivity differences within normal and cancer tissues. High refractive index structures appear bright in images [40].

7. Treatment

As there is not much risk of metastasis in BCC, treatment for primary lesions is easy and that is why chances of fighting against it are very high. Although there are many established and well-designed therapies against it, the health of patients is the primary concern before choosing an appropriate method (condition of patient as well as recurrence of disease should be kept in mind) [34, 41]. Certain etiological factors associated with it are prior exposure to radiotherapy, poor border clarity, weakened immune system, and a recurrent tumor. Before choosing an appropriate method of treatment, a biopsy should be done to gain information about the prevalent subtype of BCC, and the following things are kept in mind while treating this condition [42].

• Complete removal of lesions to prevent the reappearance.

• Correction of any impairment that results from the lesions.

• Providing patients with the best cosmetics because most of the time BCC is diagnosed on the face.

BCC is mostly treated by surgical excision, but in some cases, it can be treated with chemotherapy as well as radiotherapy. Some of the most common treatment options are described below:

7.1 Surgical excision

Surgical excision is regarded as the standard treatment for BCC as it is highly effective and can remove all the lesions (having cure rate of more than 96%). In this technique, clinicians remove the lesions with a sharp object (some healthy cells are also removed that are near the cancerous lesions). After that, margins are analyzed with the help of microscope to confirm that there are no other cancerous cells remaining. Although considered the most effective and easiest way mode of treatment, the results of this treatment are scars that are white in color.

7.2 Mohs micrographic surgery

This technique is regarded as the gold standard for the treatment of high-risk basal cell carcinoma and is the only current option that provides a long-term cure with the potential advantage of tissue sparing. This treatment option allows accurate evaluation of the margins of the lesions, the lesions (tumors) are cut out layer by layer and microscopic evaluation of each layer is done on the spot. High rate of cure is associated with 100% accurate examination as compared to other techniques that only examine less than 1% of margins. This helps in only taking those areas where there is positive tumor by minimizing the size of wound [43].

7.3 Radiotherapy

Radiotherapy is another considerable option for the treatment of BCC if surgery is not recommended. This technique is also applicable for the treatment of cancerous lesions when further surgical excision could result in the loss of major nerves or crucial structures. The cure rate of radiotherapy is almost 93%, but the appearance of BCC after this treatment can be aggressive than the previous one and this technique also has some side effects that appear after sometimes, including fibrosis of dermal tissues, alopecia, inflammation of the skin, and necrosis. Based on these outcomes, radiotherapy is generally used for those patients only who are not ready for surgical treatment (that have lesions in those areas associated with high-risk) [44].

7.4 Photodynamic therapy

Another treatment option is photodynamic therapy (PDT), which uses a focused beam of light on the lesions for many hours after treating the skin with photosensitizing porphyrins like methyl aminolevulinate (MAL). Tumors are destroyed when reactive oxygen species, induced when photosensitizer absorbs light, cause cytotoxicity that helps in producing a local inflammatory response that aids in the destruction. Although the technique is less invasive, but still the cure rates vary (almost 87%) depending on the absorption capacity of the photosensitizer. BCC that are superficial in nature are more effectively treated among all the subtypes and is under practice in most of the European countries for effectively treating superficial BCC [45].

7.5 Imiquimod therapy

The drug imiquimod is an immune system modulator that is currently administered as a topical treatment in the US and Europe. It is used for the treatment of basal cell carcinoma in such patients that are immunocompetent. Its mechanism includes the production of proinflammatory cytokines after its binding to the specific toll-like receptors present on the cells, allowing it to induce cytotoxic T-cell mediated death of the cancerous cells [46]. The duration of this treatment is approximately 6 weeks, and the rate of cure is comparatively greater (83.4%) than that of photodynamic therapy (72.8%) and 5-flourouracil (80.1%). Furthermore, the probability of tumor free survival after a duration of 5 years was 80.5%, greater than the PDT and 5-flourouracil. Apart from its high cure rate, the main disadvantage of this medication is the inability to penetrate deeply in the skin (does not have any therapeutic effects on nodular tumors). This therapy is not recommended for such diseases that have the chances to re-appear, but is only suitable for such patients that prefer non-surgical mode of treatment [47].

7.6 Targeted therapy

Smo inhibitors are regarded as the prime method of treatment for metastatic and advanced BCC and these inhibitors include sonidegib and vismodegib (are orally administered and currently approved by the US Food and Drug administration (FDA) and European Medicines Agency (EMA)). Although they are good for controlling metastatic BCC, but these also have some side effects as loss of taste, hair loss, weight loss, and diarrhea [36].

7.7 Cryosurgery

It is considered as an effective technique for basal cell carcinoma treatment due to its cost benefit ratio and ease of use. In this procedure, lesions of BCC are destroyed by freeze-thaw cycles and the cure rate of this technique is approximately 96%. This technique has some drawbacks as it cannot do fine assessment of tumor margins and is only limited to those BCC that are superficial in origin (low-risk of metastasis) [4].

7.8 Electrodessication and curettage

This mode of treatment is primarily done for the management of low-risk BCC’s and is also a cost- effective technique recommended by the National Comprehensive Cancer Network (NCCN). The procedure applied for the treatment is cutting off lesions with the help of curette and then burning those cancerous cells with an electric needle. The main consideration when using this is to avoid such areas that have hair growth on terminals, as there is a high chance of extension of tumors in those areas (pubis, scalp, and chin). Inadequate assessment of tumor margins is the main drawback of this technique [4].

8. Discussions

Emerging trends in the incidence of basal cell carcinoma (BCC) have been reported by recent epidemiological research. These patterns indicate a changing demographic landscape, with a growing frequency among younger individuals. This demographic shift highlights the need for increased awareness and focused preventative measures to combat the growing burden of BCC.

Understanding of the etiological elements, responsible for BCC development has improved because of advances in genetic and molecular studies. Mutations in hedgehog signaling pathway genes, such as SMO and PTCH1, have been found to be important cancer drivers. BCC pathogenesis is also influenced by interactions between genetic predisposition and environmental exposures, including UV radiation and immunological dysregulation. Targeted treatment strategies are made possible by the complex interactions among immune responses, tumor microenvironment, and genetic abnormalities in the pathophysiology of BCC. In advanced or metastatic BCC, new immunotherapeutic strategies, such as immune checkpoint inhibitors and targeted biologic agents, show promise for enhancing treatment results and lowering disease recurrence.

Technological developments in diagnostic modalities including a molecular profiling, reflectance confocal microscopy, and dermascopy have improved our ability to identify and categorize BCC subtypes. By making early detection, accurate tumor margin delineation, and knowledgeable treatment decision, these techniques improve outcomes and patient care. Regarding therapy, current clinical studies have investigated cutting-edge therapeutic approaches meant to get beyond resistance mechanisms and boost response rates in BCC cases that are refractory. For individuals with few therapeutic choices, targeted treatments such as hedgehog pathway inhibitors (like vismodegib and sonidegib) have shown a hope in treating advanced or metastatic BCC.

Additionally, attempts to maximize surgical methods, such as minimally invasive treatments and Mohs micrographic surgery, try to accomplish total tumor removal while maintaining esthetic results and reducing functional impact. In high-risk or recurring BCC instances, adjuvant treatments such photodynamic therapy and radiation are helpful supplements to surgery. To sum up, the discussion about basal cell carcinoma highlights how complex the illness is, covering a wide range of topics including pathophysiology, diagnostics, etiology, epidemiology, and therapies. Continual research projects and teamwork are crucial to expanding our knowledge of BCC and converting scientific findings into novel treatments that enhance patient outcomes and quality of life.

9. Conclusions

Regarded as the most prevalent type of skin cancer, mutations and alterations have been studied extensively. Although many genetic alterations are associated with the progression of this type of skin cancer, the main one is the dysregulation in the Hedgehog signaling pathway that enables it to originate in the basal cells of the skin, but rarely metastasize. Early diagnosis leads to controlled treatment options that are favorable for the patients as well as the health practitioners, and it also enables for the better clinical presentation of different subtypes of basal cell carcinoma based on their morphology and characteristics. Although available treatment options enable the clinicians to effectively neutralize it from the skin, but still, it can reoccur and most of the time, Moh’s micrographic surgery and simple surgical excision provides the best cure rate. But recent advancements have enabled the researchers to identify potential molecules that drives BCC and based on these molecules a new approach has been in practice for the treatment of BCC; targeted therapy, that has increased the percentage of cure rate of the disease.

Acknowledgments

I would like to thank my co-author, Muhammad Ammad Jamil, and supervisor, Dr. Adeeb Shehzad, from National University of Sciences and Technology (NUST), Islamabad for their assistance and help in writing this chapter.

Conflicts of interest

The authors declare no conflict of interests in relation to this chapter.

Appendices and nomenclature

BCC	basal cell carcinoma
UV-rays	ultra-violet rays
DNA	deoxyribonucleic acid
Smo	smoothened
SHH	sonic hedgehog
Ptch	patched
BCNS	basal cell nevus syndrome
Gli	glioma associated oncogene transcription factor
AIDS	acquired immune deficiency syndrome
RNA	ribonucleic acid
DHH	desert hedgehog
IHH	Indian hedgehog
SUFU	suppressor of fused homolog
BCL-2	B-cell lymphoma-2
EGFR	epidermal growth factor receptor
MMP’s	matrix metalloproteinases
YAP	yes-associated proteins
OCT	optical coherence tomography
RS	Raman spectroscopy
CLSM	confocal laser scanning microscopy
MPS	multiphoton spectroscopy
PDT	photodynamic therapy
FLIM	fluorescence lifetime imaging microscopy
RCM	reflectance confocal microscopy
MAL	methyl aminolevulinate
FDA	food and drug administration
EMA	European medicine agency
NCCN	national comprehensive cancer network