Fill the details/instructions form and checkout for your essay - pro writers; top college graduates only in less than 5 mins, NO AI—Plagiarism-free!.
Posted: August 29th, 2022
Basal Cell Carcinoma
Table of Contents
Introduction
The Skin
Basal Cell Carcinoma
Aetiology
Ultra Violet Radiation
Genodermatoses
Xeroderma pigmentosum
Nevoid Basal Cell Syndrome (Gorlin syndrome)
Personal/Family History of BCC
Immune-Supressing Drugs
Exposure to Arsenic
Pathophysiology
Molecular
Hedgehog-Signalling pathway
TP53 Defects
Epidemiology
Clinical Features
Diagnostic Tests and Staging
Histological Analysis
Healthy Skin
Basal Cell Carcinoma
Stages and Grades
Stages
Grades
Treatment
Moh’s Micrographic Surgery (MMS)
Curettage and Electrocautery
Surgical Excision
Photodynamic Therapy (PDT)
Case Study
Future and Summary
Future………………………………………………………
SMO & Gli inhibitors……………………………………………
Naproxen
Training Cell-Level Classifiers……………………………………..
Summary…………………………………………………….
References
The skin is considered one of, if not, the largest organ in the human body. The skin has numerous roles to ensure our bodies run efficiently and effectively. Primarily the skin acts as a physical barrier, protecting internal organs from any external noxious substances and radiation. The skin is important in homeostatic functions, including temperature and fluid regulation. Most notably, the skin is essential in the sensation “touch” acting as first contact with the environment. The skin is also involved in some metabolic processes, such as the synthesis of vitamin D and triglyceride (Ryan, 2015; MacKie, 1981).
The skin consists of three separate layers with their own structure and function. The most superficial layer is known as the epidermis and is primarily made up of four to five layers of squamous epithelium, along with keratinocytes, melanocyte, Langerhans cells and Merkel Cells. The deepest layer of the epidermis is known as the basement membrane and resides in a palisade configuration. It is this layer of cells, which connects the epidermis to the dermis (Losquadro, 2017).
The dermis consists of two distinct layers, the superficial papillary section and the deeper reticular section. Sebaceous and sweat glands are also found within the dermis along with hair follicles, blood vessels, and nerves. Consisting of mostly collagen, elastin, and reticulin, the dermis is also home to fibroblasts, macrophages, masts cells, and lymphocytes (Losquadro, 2017).
Below the dermis lies the subcutaneous fatty tissue layer which is used as a support for the overlying skin as well as a link between the superficial layers of skin and deeper tissues, such as bone and muscle (MacKie, 1981)
Basal Cell Carcinoma (BCC) is one of the most prevalent forms of skin malignancy, especially in individuals of European ancestry (Epstein, 2008). BCC are usually found on areas of the skin over exposed to UV light. These areas include, but are not restricted to, the scalp, face, neck, and hands (Damjanov, 2005). This variation of skin cancer gets its name from the visual histological similarity to the cells found in the epidermis, running along the basal layer (Epstein, 2008). BCC is nonmelanocytic, meaning it is in fact an epithelium tumour, however some BCC’s can present with pigmentation. BCC have been known as rodent ulcers due to their rolled edges and characteristic central depression or plateau (BAD, 2015).
There are three main subtypes of basal cell carcinomas: nodular BCC that is the most commonly occurring variant, followed by superficial BCC’s, which are the second most common variant, and morpheaform BCC, which is an uncommon variant seen in around 5-10% of BCC cases (Marzuka and Book, 2015).
The skins physiology is greatly affected by UV radiation, and the damaged caused can manifest fairly quickly, as is the case in the acute inflammatory responses where UVB initiates the release of cytokines, vasoactive and neuroactive molecules, which together lead to sunburn (Slominski and Wortsman, 2000; Clydesdale et al., 2001; D’Orazio et al., 2013). Keratinocytes, after being exposed to UV radiation above their threshold, activate their apoptotic pathway and die in the process, these cells are identifiable via the pyknotic nuclei (Bayerl et al., 1995). The skin has a defence against UV radiation in the form of the melanin production pathway, and links have been made between defects in this pathway and cancer susceptibility (D’Orazio et al., 2013).
UV is also capable of causing damage in a delayed manor, with manifestations not surfacing until after years or decades of exposure. UVA damage is indirect and is mediated by the formation of free radicals and corruption of the cellular membranes, playing an important role in the carcinogenesis of stem cells within the skin (Gordon, 2013). UVB on the other hand is able to damage the DNA directly through tumorigenesis and inflammatory responses (Gordon, 2013).
UV exposure is also known to cause damage to cellular signalling pathways and has a temporary effect on mRNA. Disturbances to cellular pathways, such as the Hedgehog signalling pathway, are caused by the absorption of long wavelength UV by the linear repeats or ring structures, found within organic molecules. Such molecules can be found within DNA bases, and therefore genes are readily damaged by UV radiation (de Gruijl et al., 2001).
Mechanisms behind UV’s induced damage developing into cancer are intricate and convoluted process involving mutations to the p53 gene responsible for tumour suppression (Benjamin and Ananthaswamy, 2007). These genes are involved in apoptosis of UV damaged DNA, and mutations result in p53 gene being unable to assist in DNA repair process. Dysregulation of apoptosis caused by the mutation leads to mitosis of keratinocytes going unchecked, initiating the growth of skin cancer (Benjamin and Ananthaswamy, 2007; Brenner and Hearing, 2007).
As UV damage does not account for the cases of BCC that develop in areas not ordinarily exposed, such as in the groin or axilla (Betti et al., 1997). UV damage is not the singular cause of BCC.
Xeroderma pigmentosum is an autosomal recessive condition that causes premature aging to areas of the skin, which are exposed, to UV. This condition reduces the cells ability to repair DNA damage caused by UV radiation (Roewert-Huber et al., 2007). Affecting only 2.3 live births per million within Europe, this is not a common condition, be that as it may, individuals with this condition have an extreme sensitivity to sunlight, and therefore increases the likelihood of DNA mutations and skin cancer (Lehmann et al., 2011).
Gorlin syndrome is characterised by the development of multiple BCC lesions from a young age. In this condition the cause of the BCC lesions are not related to UV exposure, rather a defect in the Hedgehog signalling pathway, which results in constitutive pathway activity and tumour cell proliferation (Bresler et al., 2016; Yamamoto et al., 2011). It is estimated that 1 in 55,600 people in England suffer from this condition, and 2% of cases of BCC in individuals under the age of 45, are also diagnosed with Gorlin syndrome (Muzio, 2008).
Family history of a patient is attained not only to investigate any genetic susceptibility, but it can also provide information on shared lifestyle, which could point to environmental or behavioural markers.
A study by Berlin et al., (2015) found that 62.2% of individuals with a BCC had some family history of a non-melanoma skin cancer. It was also discovered that individuals with a family history of non-melanoma or melanoma skin cancer, were three times more likely to develop early on set BCC, than those with no family history. The age at which the family member developed a BCC was also found to have an impact on the likelihood of developing BCC. It was stated that if the relative was ≥50 years old then the individual would be twice as likely to develop a BCC, compared to the individuals who reported no family history. This statistic increased when the relative was ≤50 years old (Berlin et al., 2015).
Although genetics play a part in BCC susceptibility, they are not the only reason it is necessary to attain a complete family history. It is a likely assumption that family members share behavioural and environmental characteristics, which can increase their risk of developing BCC. This is especially the case when these activities or behaviours involve UV exposure. Families are known to participate in group activities together and children develop behaviours and habits from their parents. Family members are likely to participate in outdoor activities and/or vacation together, sharing similar UV-protective behaviours e.g. using sun cream, therefore it is not illogical to assume they receive similar UV radiation exposure (Berlin et al., 2015). Recent studies have hypothesised that intense, intermittent outdoor UV exposure, as experienced by endurance athletics, can increase the risk of developing early onset BCC’s (Lee et al., 2017).
In countries with a predominantly white population, non-melanoma skin cancers (NMSK) are the most common malignancy developed, after an organ transplant (Birkeland et al., 2000; Moloney et al., 2006). It has been found that individuals who are on immune-supressing drugs are more likely to develop NMSC at an earlier age, develop multiple lesions, experience local reoccurrences, and are at a higher risk of developing regional and or distant metastasis (Gutierrez-Dalmau and Campistol, 2007). There are factors effecting the risk of developing a post-transplant malignancy including the length of drug therapy, the type of immunosuppressant drug used, the number of drugs taken simultaneously, and the strength or intensity of the therapy (Gutierrez-Dalmau and Campistol, 2007). A supressed immune system results in the inability to detect and eradicate cancerous cells and viruses known to cause cancer (Epstein-Barr virus, and Hepatitis B&C amongst others). The risk of developing a NMSK post transplant was found increase sixfold compared to the general public (Krynitz et al., 2016).
After exposure, arsenic is known to build up within the ectodermal tissues. Dangerous levels of arsenic within the tissues result in BCC’s as well as other types of skin cancer. It is difficult to determine histologically the causation of a BCC, as morphologically and histologically arsenic induced BCC’s do not differ from others(Centeno et al., 2002; Sarkar et al., 2016). Arsenic exposure has been linked to changes in gene expression associated with the molecular signalling pathways involved in arsenic-induced skin carcinogenesis. These changes include, increased transcription of keratinocyte growth factors and oxidative stress(Bailey et al., 2010; Martinez et al., 2011). It is the location of a BCC that can give an insight into the causation, and diagnosis of arsenic exposure usually relies on finding the BCC on sun-protected areas along with other related symptoms of arsenic poisoning (Centeno et al., 2002; Sarkar et al., 2016).
BCC has seen many hypotheses into the pathophysiology of the condition over the past 80 years, yet it has been the genodermatoses studies, which have provided the greatest breakthrough into the molecular changes associated with BCC.
The histopathologic variability seen within BCC tumours does not correspond with being derived from a singular epithelial cell type (Bale and Yu, 2001; Sehgal et al., 2014). As a generalisation, it is thought and accepted that BCC tumours arise from pluripotential cells. As these cells are responsible for the formation of hair, sebaceous glands, and apocrine glands in the basal layer of the epidermis, this possibly explains the tumour cells capacity to differentiate into any of the structures found in the epithelium. It is this well-established relationship between BCC and pilosebaceous units, that can explain why BCC’s are often found on areas of the skin that have hair (Sehgal et al., 2014).
The hair follicles in the epidermis are the source of pluripotential and stem cells, which are usually the origin of BCC’s. These stem cells are found just below the sebaceous gland duct in the bulge of the follicle (Sehgal et al., 2014), see Figure 1. This potential origin is justified as BCC’c rarely arise from precursory lesions, rather they arise due to cellular damage from radiation or inherited mutations (Sehgal et al., 2014).
Figure 1. A diagram of a hair follicle, illustrating the location and positioning of the bulge and
associated stem cells in the epidermis. Image retrieved from (Lyubovitsky et al., 2007).
The bulge section of the hair follicle is known to be a rich source of stem cells, which rapidly proliferate to heal damaged cells as well as replace dead cells. There is further evidence that suggest that these stem cells even have the ability to migrate out of the hair follicle to regenerate the epidermis after injury (Lyubovitsky et al., 2007). This rapid proliferation of stem cells, which also aid in molecular signalling between the mesenchymal dermal papillae and the developing hair follicle, have been found to be critical in understanding the histo-genesis of BCC (Sehgal et al., 2014).
The hedgehog-signalling pathway (Hh) controls the differentiation of tissues during embryonic development. After embryonic development the Hh pathway is responsible for the regulation of proliferation and differentiation of cells(Sehgal et al., 2014). Defects within this pathway are seen within 30% of sporadic BCC, and in almost all nevoid BCC cases (Sehgal et al., 2014; Van Domarus and Stevens, 1984; Hahn et al., 1996). In a fully functioning Hh pathway a Hh receptor, PTCH, inhibits the SMO signalling, see Figure 2a 
(Yang et al., 2010).
Figure 2. Simplified Hh signalling pathway model found in mammalian cells. (a) In the absence of Hh ligands, PTCH inhibits the SMO signalling. Gli molecules are changed into repressor forms, which switch off the Hh pathway (b) when Hh proteins are present PTCH is unable to bind to SMO. The SMO will then undergo conformational changes. Gli molecules are now changed to their active forms, activating the Hh targets genes. Taken from (Yang et al., 2010)
Over the past few years it has come to attention that the Hh signalling pathway is proprietor to tumour initiation and progression(Yang et al., 2010; Teglund and Toftgard, 2010). The deregulation of the Hh pathway is due to either a disruption of the PTCH1 signalling repressor, found in a majority of cases, or in some rare cases a mutated Smoothened signalling effector (SMO)(Wong and Dlugosz, 2014).
The PTCH receptor binds to hedgehog proteins (usually Sonic hedgehog, SHH, in mammals), which shuttles the PTCH receptor out of the cilium, hindering the PTCH’s ability to bind to SMO, See Figure 2b. This changes the SMO allowing them to couple with the G proteins forming SMO-G (Ogden et al., 2008; Yang et al., 2010). This unhindered SMO activity leads to the activation of the Hh pathways and high-level expressions of the Hh target genes, which ultimately plays a vital role in tumour pathogenesis(Wong and Dlugosz, 2014). These processes start a series of cell events leading to proliferation due to increased expression of transcription factor Gil 1 (Roewert-Huber et al., 2007) (Sehgal et al., 2014)
It was discovered by Brash et al., (1996) that 50% of individuals with BCC’s also process a defect in their TP53 gene, usually responsible for the synthesis of the p53 protein, and involved in genomic stability as it activates the repair of DNA and can promote apoptosis (Jayaraman et al., 2014). The TP53 mutation allows for the proliferation of abnormal cells created by UV exposure. The defect on the TP53 gene is not specific for BCC and has been found to play a role in other types of human cancer including squamous cell carcinoma (Brash et al., 1996; Roewert-Huber et al., 2007). Mutated TP53 genes have been identified in between 30 – 70% of basal cell tumours (Lacour, 2002; Reifenberger et al., 2005; Tang, 2011)
BCC is one of the most common and easily preventable forms of skin cancer. The likelihood of a caucasian individual developing BCC in their lifetime is 30% (Glud et al., 2016). BCC’s are most commonly seen in the elderly population, yet it is possible to experience early on set BCC’s as a child or adolescent. It has been found that individuals with fair skin, red/blonde hair and light eyes are at a greater risk of developing BCC compared to individuals with dark skin, hair and eyes (Wu et al., 2013). Skin which has been subjected to severe or multiple bouts of sun damage are also at a higher risk of developing a BCC (Roewert-Huber et al., 2007).
An Australian study by (Staples et al., 1998) found that the incidences of males with BCC were double that of women. However within the <40y age group more cases of BCC are seen in women than men. This change is likely linked to the growing popularity of sun bed use over the past decade (Lim and Stern, 2005; Roewert-Huber et al., 2007; Karagas et al., 2014)
Currently in England the rate of BCC and other types of non-melanoma skin cancer is thought to be greater than reported by the government. This is due to the lack of efficient monitoring and reporting system for BCC, which is often omitted from, or represented as NMSK in the official cancer statistics, as little is known about the true scope of the condition (Levell et al., 2013). One reason for this being, many registries only include cancers confirmed by histological analysis, which does not take into consideration the cases of BCC which have been diagnosed by clinicians without histology (Reinau et al., 2014; Levell et al., 2013). English women are now overtaking men, as the incidences of NMSC, including BCC and squamous cell carcinoma, are increasing. Cancer research UK stated that during 2014 in England, there were 6490 NMSK cases in males and 6503 NMSK cases in females (Cancer Research UK, 2014).
Ethnicities which have a higher level of skin pigmentation are found to be 19 times less likely to develop a BCC compared to fairer skin caucasian (Roewert-Huber et al., 2007). This risk increases as the geographical location resided in, moves closer to the equator. Individuals most at risk of developing BCC’s are those of Caucasian origin, living close to the equator in countries with a higher UV radiance levels. (Roewert-Huber et al., 2007) stated that the Caucasian population of Australia were at the highest risk of developing BCC’s followed by the United States and Europe.
BCC are one of the most common types of skin cancer and are known for their slow growing, yet locally destructive tendencies. BCC’s tend to be an indolent form of NMSK, rarely metastasising. Despite this, untreated BCC’s have the potential to extend through the dermis and subcutaneous fatty layer to the underlying muscles, bones and cartilage. Consequences of untreated 
BCC’s can be excessive and cause debilitating damage see figure 3.
Figure 3. 76-year-old man presented with an osseous and muscular tumour spreading through both of the orbits and nasal bridge. Histology Confirmed ulcerated BCC, which had been growing for 20 years. Taken from (Maul et al., 2016).
BCC’s usually present with a set of features, similar to those observed in other forms of skin cancers and non-malignant neoplasms (Lamberg, 2002) Table 1 identifies the clinical features associated with the three main variants of BCC.
Table 1. Clinical features of the Basal cell carcinoma variants. Created using information and images from (Oakley, 2015).
After a dermatologist has visually inspected a suspicious lesion for signs of BCC, they may also choose to use a dermatoscope, which uses polarized light to examine the skin and lesions in more detail. The only way to definitively diagnose a BCC is through histological analysis of a biopsy, and no lesion suspected of being a BCC or other form of skin cancer should be treated without histological analysis. There are a few forms of biopsy, punch, shave, incisional, and excisional biopsies. The ideal biopsy method to use is the excisional biopsy of the whole lesion, as this can act as evidence for histological diagnosis and definitive therapy, however as BCC’s often occur in areas such as the face, clinicians must take into consideration the cosmetic outcome of such a procedure (Marzuka and Book, 2015).
The epidermis consists almost entirely of stratified, squamous epithelium. The four main cell types identifiable in the epidermis are described in Table 2. Alongside these; within the epidermis there are also paccinian corpuscles that are capsules of cells sensitive to pressure. The epidermis is devoid of any, and all blood vessels, and is reliant upon the dermis for all nutritional and waste disposal needs (Amirlak et al., 2015; University of Leeds, unknown).
Table 2. A description and illustration of the main four cell types found within the epidermis.
| Name of Cell | Description | Image |
Every student wants the best grades and that’s our Focus
Our team consists of outstanding writers who have specialized knowledge in specific subject areas and professionals experienced in academic research writing. They hold at least a graduate degree—230 with Masters and MSN, experts carefully selected and trained to ensure the best quality of our work. .
We are committed to hiring the most skilled writers who can deliver high-quality work at a reasonable price for college students. Thus, we offer the best value for money without sacrificing the standard of our essay writing services; the quality of the paper's content. #Remember to activate the DISCOUNT Code on the order form COUPONS' section before making payment for your essay.
The service guarantees that our final work is 100% original, rearched and human written. We are committed to delivering plagiarism-free and AI-free work to each university/college student's 'write my paper' request. To uphold this promise, we check every draft for any possible instances of duplication, wrong citation, grammar errors and artificiality before we send it to you. Thus, you can always rely on us to write genuine and high-standard content for your essay assignments.
When you decide to place an order with Homework Ace Tutors, here is what happens: