Basal and Squamous Cell Carcinoma:
Cause, Mechanism, and Cure
Todd Alderman
Vertebrate Physiology
April 12, 2005
To be sure that everything is held together in one glob the body needs skin. Being the largest organ in the body, it packages everything in and keeps some things out. The main purpose of skin deals with homeostasis. Contributions to this can be seen in thermoregulation, disease prevention, fluid loss, and even metabolism (through the production of Vitamin D). In order to interact with the surrounding environment the skin also has receptors to monitor outside the body for things such as temperature, movement, pressure, and sunlight exposure. Sunlight is a little different in that we don’t usually respond to it consciously unless the eyes are exposed or the skin is warmed by it. Our skin however naturally responds to sunlight. Different mechanisms are triggered, in particular, by ultraviolet light which causes deviation from normal skin. Although the body usually prevents these changes naturally, if we abuse the system, UV light will have its way with us. In light of this phenomenon our skin develops cancer. The following will be a discussion on how Basal cell and Squamous cell carcinoma is initiated, the cells involved in the course of the disease, and what can now be done to cure it.
The epidermis, the top layer of skin is where we will begin. It consists mainly of four types of cells (8). Melanocytes are the major contributors of pigment in skin. These form a facing at the base of the epidermis that distinguishes it from the underlying dermis. Melanocytes produce melanin (pigment). It is then passed on to the keratinocytes which are what is seen on the surface. Melanin is particularly present in the extremities and the nipples presenting a darkened area from the rest of the body. In addition the melanin, keratinocytes contain keratin (pigment) which also contributes to the yellow-orange complexion of the skin. Examples of this are more pronounced in people of Asian origin. Keratinocytes fill in the majority of the epidermis and are constantly pushed outward and sloughed off the surface. Merkel cells are randomly interspersed throughout the melanocyte layer for communication. At each merkel cell is a neuron in the dermis that receives information to pass into the body for processing. Much of our topic will deal with the Langerhans cells. Located sparingly, compared to the others, throughout the epidermis, Langerhans cells deal with the affects of ultraviolet light in the skin. As if in retaliation, these become the target of UV light because, “-UV inhibits their antigen-presenting activity and their capacity to stimulate—T cells,” therefore hindering the restoration process (1).
Our sun produces a full spectrum of light from visible to the deadly radiations unseen by the naked eye. In dealing with skin cancer, ultraviolet A, B, and C radiation are of main concern. UVC is the most dangerous of the three. With its high energy and short wavelengths (100-290 nm), the potential for carcinogenesis becomes substantially elevated (10,12). Fortunately, for now, our ozone fully blocks these death rays. UVA, while having the longest wavelengths (315-400 nm) and the lowest energy are the deepest penetrating (10,12). These generally do not cause skin cancer. However sunlight contains twenty times more UVA than UVB. UVA does not penetrate DNA well and therefore can not directly cause carcinogenic mutations. What it can do is penetrate other molecules causing radicals, like oxygen, that will damage DNA and membranes. Connective tissue is also damaged promoting early aging affects such as dark spots and leathery texture. UVA is the radiation preferred by the best tanning bulbs! At last we come to UVB radiation…the major contributor to carcinogenesis. At wavelengths of 280-315 nm, it comes equipped with the high energy attributes of the UVC complemented by some penetrating effects from the UVA (10,12). The UVB only contacts the top layers of the epidermis and what it contacts is affected greatly because of the high energy that it packs. This light is the cause of skin cancer.
Our process begins when UV light contacts our skin. The radiation penetrates into DNA and alters the proteins. More specifically, it tends to target the sequence of two thymines and join them generating a thymine dimer (11). These dimers produce several mutations in DNA sequences that ultimately distort cellular composition. One particular change is in the gene that encodes for tumor suppression (p16). This gene is what controls cell growth rate and multiplication. “--Overerexpression of oncogenes and other genes related to enhanced growth—and tissue invasion” occurs (2). When these become damaged or altered the cells are allowed to grow without restriction. Unregulated growth gives rise to a tumor. This is the definition of cancer.
Another possible pathway, more common through exposure to UVA light, is the creation of free radicals in oxygen. These highly reactive scavenging oxygens will sometimes react directly with DNA to interfere with protein synthesis. More commonly the radicals interacted with xanthone analogues that cleave “—specifically at 5’-G of the GG sequence—,” in DNA, thus mutating cellular functions (3).
The very second that UV radiation hits the keratinocytes of the top layers of skin, the immune system will respond. Some studies have shown that hair follicles are “—specialised UV receptor[s] in the skin responding to nuances of photic input” (4). This is because the follicle consists of melanocytes and keratinocytes that are arranged similarly to that of industrial fiber optic cable. This allows a concentrated signal to be received in order to trigger expeditious immune responses. The receptors are activated to begin the immune system’s correctional steps. DNA will then elevate the production of the p53 gene. The wild type of p53, in particular, is the cause of the corrections, thus it has to be mutated by the radiation in order to begin restoration. In a case study done in 1998 two processes were discovered to be possible based on the amount of radiation exposure which directly determines the amount of p53 produced (5).
Under low-dose radiation, p53 (wild type) is found to promote nucleotide excision repair. This is done by taking out the thymine dimers from the sequence that are corrupting production. Langerhans cells now step in using specialized receptor and detect the compromised DNA sequences. These Langerhans cells phagocytize the dimers and migrate to the lymph nodes. Here the dimers are released to be discarded and the Langerhans cell returns to the epidermis. Over time this process will return the cells to their original make-up and the immune system is victorious. All “—UV radiation is known to result in epidermal thickening and increase the number of cell layers—” but returns to normal after a few days (9).After a full day in the sun one can notice that the skin seems more taut due to the increased activity in the epidermis. The increase in the number of cells allows the response to become more effective and the return to normal more rapid.
In the case of high-dose radiation, the p53 (still wild type) takes on a different strategy. Discovering the overwhelming DNA corruption due to high dosage, p53 instigates apoptosis. It utilizes this action to prevent this cell from replicating and creating more problems. It is easier to destroy the leader before he has any followers. The interesting point is that the corrupted leader kills itself for the sake of the organism. Keratinocytes naturally migrate up towards the surface through slow cell death in order to create a smooth flattened layer on the outside. This process takes several weeks. In the case of apoptosis, these cells are raised to the surface in 48-72 hours so as to export these mutants from the body. If it has not become apparent yet, this is called peeling. Again the body triumphs over solar insults. In the cases of repairs or apoptosis, once the epidermis is returned to normal p53 production is decreased to normal levels.
As humans are naturally prone to do, we tend to push our system to the limits. The body can only take so much exposure to the sun before the system looses repair efficiency. In this event the ultraviolet radiation inactivates the p16 tumor-suppressor gene. The cell no longer has a pathway to apoptosis thus p53 cannot successfully achieve its goal and a tumor is born. Langerhans cells still have some success in seeking these small tumors out and consuming them. If Langerhans cells become overwhelmed they shut down. This causes a snowball effect for the rest of the understaffed Langerhans cell. Now the tumor has grown beyond any regulation by the body and outer visibility is possible.
These tumors have an overabundance of Hedgehog proteins. Without getting into a soap opera of genes, let me explain what these accomplish. During embryological development Hedgehog proteins decide how an organism is going to grow. Specifics such as anterior/posterior orientation and limb-buds are decisions controlled by the signaling molecules of the Sonic Hedgehog Signaling Pathway (2). In the case of basal cell carcinoma, this pathway has become irreversibly activated allowing growth to become erratic.
Skin cancer boasted one million cases for 2002 in the United States alone (2). In Australia cases were increased by 51% from 1985-1990. The United Kingdom experienced a 66% increase from 1988-1998 (2). There are three major forms of skin cancer that can be described. Melanoma is one of the worst types. Fortunately it only constitutes 4% of all cases reported. This one acts differently from the second two which are discussed in this paper. Basal cell carcinoma is responsible for 80% of all skin cancer patients. Although this is a high number, basal cell has the best cure rate. Most cases are found on the head and neck. Here a spot of raised flesh or a pinkish nodule is seen with a pearly, translucent rim. The process of forming this nodule may take many months or years for one to reach a diameter of one half inch. This cancer is more common to ages of 40+. Basal cell carcinoma is rarely metastasized making it less threatening to the entire body. Squamous cell carcinoma, on the other hand, is a little more prone to metastasize into cells in different areas of the body. Because of this they can be seen on parts of the body not exposed to UV. Their origins are on the face and ears. These form just above the basal layer of the skin and boast 16% of all skin cancer cases. Cases are most common from ages 55+. Records show approximately 2,000 deaths per year are due to basal cell contributions. In comparing the last two carcinomas, the basal cell comes out ahead with a 5:1 ratio from squamous cell. Both are manufactured by UV radiation in the same way but react in different areas of the epidermis. Men are twice as likely to develop squamous as women.
Once the patient is diagnosed with basal or squamous cell carcinoma the options for curing it usually consist of removal in some form (6). Cryotherapy is used to freeze the lesion with liquid nitrogen. Once the dead cells blister and crust off, a scar will always remain. This however is not used for recurrent carcinoma. Curretage/electrodessication involves two or three sessions of scraping the cancer cells off and using an electric needle to destroy the remaining cancer. This will also leave a scar after treatment. It is still not recommended for recurrent carcinomas. Moh’s micrograph surgery has the best cure rate for difficult treat carcinomas. It is the treatment of choice for patients with recurrent skin cancer. This is a painstaking process, is very time consuming and is only performed by specialists (meaning more expensive also). It involves taking off a thin layer if skin and immediately looking at it under the microscope to check for cancer cells. If present, then the doctor will continue with another layer until the cells are absent. By doing this the scar is reduced too because of the careful attention spent on salvaging the normal skin cells. Radiation and chemotherapy are also options. These are used more in the case of squamous cells that have metastasized and are not accessible from the surface. In some cases even lymph node surgery may be required. All treatments have basically equal success rates depending on the area being treated although the scar that is left behind gives scientists reason to search for better treatments that allow the patient to return to their original appearance without draining the nest egg.
In analyzing different treatment options doctors discover new details into the mechanisms by which the body’s immune system defends against tumorigenesis. An Australian study stated that patients on immunosuppressive drugs are at much higher risk of developing skin cancer. “ -–the cumulative incidence of developing skin cancer in renal transplant patients increased progressively from 7% after one year of immunosuppression to 45% after eleven years and to as high as 70% after twenty years of immunosuppression” (2). This emphasizes the contribution of our immune system against skin cancer. In looking at the Langerhans cells again scientists have discovered that T helper cells directly assist them in removal of the damaged cells after a tumor has become present. These can be broken down into interferon-γ and interleukins. Recognized as secreting cytokines, these cells are the main defense once a tumor has begun. They have even been known to cause spontaneous regression of skin cancer without outside influence. They directly “interfere” with cell replication and, through the immune system, are somehow directed at tumor cells. Keratinocytes also release small amounts of cytokines that assisted with regression. By applying this knowledge to breakthroughs in modern medicine, scientists have been able to synthetically reproduce these cytokines in attempts to cure skin cancer.
At the University of Maryland School of Medicine, a study was conducted in 2003 using two strategies to instigate regression of tumors in basal cell carcinoma. Intralesional injections of synthetically produced interferon was one method studied, and was first attempted with success in 1986 by Dr. Greenway (2). Since that time many cases have also had success. There are many disadvantages to this treatment. “Side affects include local pain, swelling, erythema, and flu-like symptoms-.” Treatments are long and must be administered five times per week making it costly in time and money. Outcomes from this treatment still have not reached the success rate of current options without some surgical procedure. Also “-there has been no definitive large-scale studies that have determined the initial and long-term efficacy of this treatment-.”
Five percent Imiquimod was the other treatment that was tested for regression of tumors. This is applied topically in the form of a cream that gives the overall immune system a boost. It induces the synthesis of interferon from the Langerhan’s cells and tumor necrosis factor from the keratinocytes. “Imiquimod enhances the migration of Langerhan’s cells to the regional lymph node, potentially enhancing the antigen presentation to the T cells. The mechanism of the Imiquimod causes tumor regression secondarily. As seen in the diagram below, Imiquimod matures the Langerhan’s cells so they can activate T cells which will secrete the interferon-γ and interleukins to destroy the tumor (2).
By applying different doses the outcomes were varied. Groups were also treated in different time spans. Outcomes base on Table 1 describe the highest frequency of applications as the most successful. Skin reactions, however, were also experienced when applied twice a day. The best results without complications proved to be application once a day for up to twelve weeks depending on severity. The results also displayed a higher success rate if the cream was applied under the occlusion but was even more sensitive to high frequency applications (2).
Even though Imiquimod still has a lower tumor regression rate than current conventional methods, it still had much success in the market today. It is used as an assistant to the surgical procedures to present a better aesthetic result. Studies show that by using Imiquimod before surgery will reduce the size of the tumor. This will allow doctors to lessen their incision and minimize the size and severity of scar tissue. Small steps in the search for a cure will prove, over time, to present significant results.
To recognize the potential harm from basal or squamous cell carcinomas can help in taking the correct precautionary measure to stop the cycle before it begins. Certain people have genetic dispositions which make them more prone to develop these cancers. Type I skin is described as always burned and never capable of holding a tan. Also people with red/blond hair or blue/green eyes have been reported as more likely to develop skin cancer (2). Previous patients of skin cancer have a high risk of recurrent development. “It has been proposed that the risk of developing BCC is associated with severe sunburn in childhood and that there is a higher risk for those with increased recreational sunlight exposure in childhood and adolescence.” Where a person lives will also determine the amount of UV light absorbed on a daily basis. Sunscreen…wear it!! All these factors, when considered for a healthy lifestyle can contribute to a longer, more enjoyable life.
A professor once told me that basal or squamous cell carcinoma is described as, “the best of the worst.” Many cases are diagnosed every day and every day most of these are removed with complete success. Improvements are constantly made in treatment of these and other cancers. Pathways and mechanisms for cancer are still so vast that scientists are overwhelmed with the information and have difficulty collating it to produce a feasible solution. Until that day prevention is still the most effective cure.
Our skin has astonishing adaptive qualities. It can recognize changes in the environment and accommodate the interior to better efficiency. Even when overrun by UV radiation, the skin fights back to maintain control over the detriments of mutation. Its very function is to protect the body and sustain homeostasis. By moderation of exposure to ultraviolet light, we can provide our skin the opportunity to maximize its ability without compromising our immune system.