Basal cell carcinoma

What is basal cell carcinoma?

A type of cancer of the skin is basal cell carcinoma. In the basal cells, basal cell carcinoma starts, a type of cell inside the skin that creates new skin cells as old ones die off.

Basal cell carcinoma sometimes occurs as a bump on the skin that is slightly translucent, but it can take other forms. Basal cell carcinoma develops most commonly in sun-exposed areas of the skin, such as the head and neck.

Long-term exposure to ultraviolet (UV) radiation from sunlight is believed to be the source of most basal cell carcinomas. Protecting against basal cell carcinoma can help by avoiding the sun and using sunscreen.

It is unlikely that this cancer can spread to other parts of your body from your skin, however it can travel into the surrounding bone or other tissue under your skin. Multiple therapies will prevent this from happening and get rid of the cancer.

The tumors usually on your nose or other areas of your face, start off as tiny shiny bumps. But on every part of your body, including your trunk, legs and arms, you can get them. You are more likely to get this skin cancer if you have fair skin.

Basal cell carcinoma typically develops very slowly, and after severe or long-term sun exposure, it often does not show up for several years. When you’re exposed to a lot of sun or use tanning beds, you can get it at a younger age.

Symptoms of basal cell carcinoma

Basal cell carcinoma typically grows on parts of your body that are exposed to the sun, especially your head and neck. Basal cell carcinoma can grow less frequently on parts of your body that are normally shielded from the sun, such as the genitals.

Basal cell carcinoma, like a growth or a sore that will not heal, occurs as a shift in the skin. These skin changes (lesions) typically have one of the following features:

• A transparent pearly white, skin-colored or pink bump, meaning that you can see through the surface a little. There are also tiny blood vessels visible. The lesion can be darker but still relatively transparent for individuals with darker skin tones. This lesion also occurs on the face and ears, which is the most common form of basal cell carcinoma. It can rupture, bleed, and scab over the lesion.
• A brown, black or blue lesion — or a lesion with dark spots — with a slightly raised, translucent border.
• A flat, scaly, reddish patch with a raised edge is more common on the back or chest. Over time, these patches can grow quite large.
• A white, waxy, scar-like lesion without a clearly defined border, called morpheaform basal cell carcinoma, is the least common.

Causes of basal cell carcinoma

Basal cell carcinoma emerges when a mutation in its DNA occurs in one of the skin’s basal cells.

At the bottom of the epidermis, the outermost layer of the skin, basal cells are located. New skin cells are formed by basal cells. They drive older cells towards the skin’s surface as new skin cells are formed, where the old cells die and are sloughed off.

The process of forming new skin cells is controlled by the DNA of the basal cell. The DNA includes the directions that tell a cell what to do. The mutation tells the basal cell, when it would normally die, to multiply quickly and continue developing. The lesion that appears on the skin can gradually develop a cancerous tumor by accumulating abnormal cells.

Skin cancers, like BCC, are caused mainly by long-term exposure to sunlight or ultraviolet (UV) radiation. These cancers may also be caused by heavy, occasional exposure that also leads to sunburn.

In rarer cases, other factors can cause BCC. These include:

• exposure to radiation
• exposure to arsenic
• complications from scars, infections, vaccinations, tattoos, and burns
• chronic inflammatory skin conditions

Once diagnosed with BCC, there is a strong likelihood of recurrence.

What are the risk factors of basal cell carcinoma?

There are a variety of risk factors that can increase the possibility of BCC growth. Some of these risk considerations include:

• having a family history of BCC
• having light skin
• having skin that freckles or burns easily
• having inherited syndromes that cause skin cancer, like disorders of the skin, nervous system, or endocrine glands
• having fair skin, red or blonde hair, or light-colored eyes
• being a man

There are other, nongenetic risk factors. These include:

• age, with increased age correlating with increased risk
• chronic sun exposure
• severe sunburn, especially during childhood
• living in a higher altitude or sunny location
• exposure to radiation therapy
• exposure to arsenic
• taking immunosuppressing drugs, especially after a transplant surgery

Diagnosis of basal cell carcinoma

Skin examination

Skin biopsy

Treatment

The aim of basal cell carcinoma therapy is to fully eliminate the cancer. Depending on the form, location and size of your cancer, as well as your needs and capacity to do follow-up visits, which treatment is best for you. Selection of care may also depend on whether this is a first-time or chronic carcinoma of the basal cell.

Surgery in basal cell carcinoma

Procedures such as electrodessination and curettage, surgical excision, or Mohs surgery, with potential reconstruction of the skin and surrounding tissue, may be needed to remove basal or squamous cell skin cancers.

Squamous cell cancer may be aggressive, and we can need to extract more tissue from our surgeons. Additional therapies for advanced squamous cell cancer, such as drugs or radiation therapy, can also be recommended: energy beams that penetrate the skin, destroying cancer cells in the body.

It is less likely that basal cell cancer will become active, but our doctors may use surgery and other treatments to treat it if they do.

To extract both the cancer and some of the healthy tissue surrounding it, basal cell carcinoma is most commonly treated with surgery.

Electrodessication and Curettage

Doctors numb the skin using a local anesthetic during electrodessification and curettage, an outpatient operation, and scrape off cancer cells with a tool called a curette, a small scoop with sharp edges. Through a probe, they then apply electricity to stop any bleeding. This procedure is replicated several times. Doctors then placed a bandage on the treated area. A thin, raised, pink or white scar may be left behind by the procedure.

Tiny basal cell or squamous cell cancers that have not spread beyond the top layer of the skin and that are not close to sensitive areas, such as the eyes or lips, can be treated with this technique.

The simple and fast technique helps individuals prevent surgery, but for analysis, the destroyed tissue is not sent to a pathologist. That means you won’t know for sure whether you’ve killed all the cancer cells.

Standard Surgical Excision

A doctor removes a whole tumor with a border of healthy tissue during a typical surgical excision. He or she seals the incision with stitches and sends the tissue to a laboratory where it is examined under a microscope by a dermatopathologist to ensure that the whole tumor has been removed. Results of testing will take anything from several days to a week.

Typically, surgical excision is accomplished using a local anesthetic. On the same day of the operation, individuals who undergo this method will usually go home. For a couple of days, they might feel some discomfort. Stitches are normally removed after 7 to 14 days.

Mohs Surgery

The surgeon extracts skin cancer, along with a very thin border of healthy tissue, during the Mohs operation. Fellowship-trained doctors with particular experience in skin cancer removal and surgical reconstruction after skin cancer removal are Mohs surgeons. Membership is provided by the American College of Mohs Surgery to fellowship-trained Mohs surgeons who have met stringent training and management criteria for complex skin cancers.

For this treatment, local anesthesia is commonly used. The surgeon removes a thin layer of tissue after the region has become numb. Then to ensure there are no residual cancer cells, a nurse can bandage you and make you sit in a waiting room while your doctor examines the tumor and the surrounding border, or margin, of tissue. If any cancer cells remain in the margin, the surgeon removes and tests another thin layer of tissue to ensure that the cancer has been completely removed.

Mohs surgery is highly successful and leaves the smallest scar possible.

To remove a large or rapidly growing skin cancer or one that has returned, our doctors can use Mohs surgery. It may also be used to treat cancer that is present in scar tissue or on a body region that needs good cosmetic results, such as the ears or face.

Mohs surgery helps surgeons to minimize scarring by keeping the boundaries of healthy tissue small. The technique also enables physicians to determine 100% of the tissue margin compared to 2% to 3% in normal surgical excision.

The need for additional surgery is also minimized by Mohs Surgery. Usually, you will go home the same day the treatment is done. The whole process will take several hours due to the waiting period for pathology reports and the likelihood of more than one round of surgery.

Lymph Node Biopsy

If the cancer has spread to nearby nerves or blood vessels, your doctor may recommend that you have a dissection of the lymph node or surgical removal of one or more nodes in the area. The tissue is examined under a microscope by a pathologist to see if it contains cancer.

If a doctor feels a swollen lymph node under the skin near the cancer site, a needle biopsy may be used to obtain a sample of it. With this form of biopsy, to remove a tiny tissue sample and decide whether it contains cancer before extracting it a doctor sticks a needle into the lymph node.

Knowing whether lymph nodes are cancerous will help doctors determine what other treatment, like medicine or radiation therapy, you may need after surgery.

Reconstruction

Doctors may use stitches to close small incisions, but using reconstructive techniques, large ones may need to be fixed.

Reconstruction should be done on the same day as surgery by Mohs, as doctors can check immediately that the whole tumor has been removed. Reconstruction is postponed for regular surgical excision until pathologists can check the boundaries are cancer-free. In most cases, under local anesthesia, reconstruction is done by the Mohs surgeon.

The surgical procedure depends on the location of the tumor and how much tissue surrounding it has been removed. Doctors may use a skin graft, or a small portion of the top layer of healthy skin, for an area of skin that is not too deep. Typically, it’s taken from a part of the body where the missing skin, such as the inner thigh, is not visible.

Doctors may use a local flap, or a piece of nearby skin that may include the underlying fat and muscle, to fill in and close a larger or deeper opening of the skin. It is transferred while the new blood supply is still connected to it. During reconstruction, cartilage, the firm white tissue that helps provide structure to parts of the body such as the ears and nose, may also need to be transferred.

Skin flaps are also left in place while the surgical site recovers for many weeks. They are contoured to match the appearance of the underlying healthy skin and tissues in a second operation. With a local skin flap from the cheek and cartilage from the ear, for example, parts of the nose may be healed. To remove any excess flap tissue, doctors perform another operation and carefully rebuild the shape of the nose with minimal scarring to the face.

Sometimes, doctors can use free flaps of skin, fat, or muscle from a distant part of the body, such as the back or abdomen, to fill in places where the cancer has been removed, if a large skin cancer needs to be removed. Since they are separated from their blood supply, these tissue flaps are called free”. At the repair site, blood vessels are re-attached.

Our physicians help scars heal well after surgery. For instance, after surgery, they will carefully tape incisions and keep this tape in place for several days to avoid scarring. Doctors will inject the region with steroids if a scar becomes raised or red, which helps flatten the skin and eliminate the redness. Discoloration can also be treated by lasers.

Recovery from basal cell carcinoma surgery

Depending on the extent of the tumor, if the lymph nodes have been removed and if you are undergoing reconstruction, the recovery period from basal and squamous cell cancer surgery varies.

After surgery, our physicians closely track you to ensure that you recover well and to manage any pain, whether with medicines or with our integrative wellness therapies.

Other treatments

Often in such cases, other procedures may be prescribed, such as if you are unable to undergo surgery or if you don’t want to have surgery.

Other treatments include:

• Curettage and electrodessication (C and E) : Treatment with C and E involves scratching the skin cancer surface with a scraping tool (a curette) and then securing the cancer base with an electrical needle.

For small basal cell carcinomas that are less likely to recur, such as those that develop on the back, abdomen, hands and feet, C and E may be a choice to treat.

Freezing : This procedure includes freezing liquid nitrogen cancer cells with (cryosurgery). For the treatment of superficial skin lesions, it may be an option. Freezing may be performed to extract the surface of the skin cancer by using a scraping instrument (curet).

Where surgery is not a choice, cryosurgery could be considered for treating small and thin basal cell carcinomas.

• Topical treatments : Where surgery is not an option, prescription creams or ointments may be considered for treating small and thin basal cell carcinomas.
• Photodynamic therapy : To treat superficial skin cancers, photodynamic therapy combines photosensitizing drugs and light. A liquid drug that makes cancer cells sensitive to light is added to the skin during photodynamic therapy. Later, there is a light shining on the region that kills the skin cancer cells. Photodynamic therapy might be considered when surgery isn’t an option.

Radiation therapy in treatment of basal cell carcinoma

In order to destroy cancer cells, radiation therapy incorporates high-energy beams, such as X-rays and protons. When there is an increased chance that the cancer will return, radiation therapy is often used following surgery. When surgery is not an option, it might also be used.

Treatment for cancer that spreads

Basal cell carcinoma will only rarely spread (metastasize) to surrounding lymph nodes and other body areas. Additional options for care in this case include:

• Targeted drug therapy : Targeted drug therapies concentrate on particular weaknesses in cancer cells that are present. Targeted drug therapies can cause cancer cells to die by blocking these shortcomings.Targeted basal cell carcinoma therapy drugs block molecular signals that make it possible for cancers to continue to develop. After other therapies or when other treatments are not possible, they may be considered. 

Chemotherapy in basal cell carcinoma

• Chemotherapy : To kill cancer cells, chemotherapy uses strong drugs. When other therapies have not helped, it may be an option.

Systemic chemotherapy (chemo) uses anti-cancer medications that are injected or delivered by mouth into a vein. These medications pass to all areas of the body via the bloodstream. Systemic chemotherapy can target cancer cells which have spread to lymph nodes and other organs, unlike topical chemotherapy, which is administered to the skin.

Chemo could be a choice if squamous cell carcinoma has spread, but an immunotherapy treatment could be used first.

Drugs like cisplatin and 5-fluorouracil (5-FU) may be choices if chemo is used. These medications are administered in a vein (intravenously or intravenously), usually once every couple of weeks. Sometimes they will slow down the progression of these cancers and alleviate certain symptoms. They can shrink tumors enough in some cases so that other therapies such as surgery or radiation therapy can be used.

Basal cell carcinoma also rarely reaches an advanced stage, so the treatment of these cancers is not usually treated with systemic chemotherapy. It is more likely that advanced basal cell cancers can be treated with targeted therapy.

Possible side effects of chemotherapy

Side effects can be triggered by chemo medications. These depend on the form and dosage of medicines prescribed and how long they are used. Chemo side effects can include:

• Hair loss
• Mouth sores
• Loss of appetite
• Nausea and vomiting
• Diarrhea or constipation
• Increased risk of infection (from having too few white blood cells)
• Easy bruising or bleeding (from having too few blood platelets)
• Fatigue (from having too few red blood cells)

Typically, these side effects go away after treatment is done. Some medications may have specific effects that are not mentioned above, so be sure to speak about what you might expect with your cancer care team.

Sometimes there are ways to reduce these side effects. Drugs can help avoid or decrease nausea and vomiting, for instance. Tell the care staff of any side effects or changes you experience so that they can be treated promptly when having chemo.

Drugs approved for treatment of basal cell carcinoma

• Aldara (Imiquimod)
• Efudex (Fluorouracil–Topical)
• Erivedge (Vismodegib)
• 5-FU (Fluorouracil–Topical)
• Fluorouracil–Topical
• Imiquimod
• Odomzo (Sonidegib)
• Sonidegib
• Vismodegib

Immunotherapy in basal cell carcinoma

The latest basal cell cancer immunotherapy options are discussed in the following categories: immunomodulators, SMO inhibitors, inhibitors of phosphoinositide 3-kinase (PIK3) and other miscellaneous medicines.

Immunomodulators

Food and drug administration (FDA) approved immunomodulators

Imiquimod: A synthetic agent with immune response modifying activity [14]. As an immune response modifier (IRM), imiquimod stimulates cytokine production, especially interferon production, and exhibits antitumor activity, particularly against cutaneous cancers. Imiquimod’s proapoptotic activity appears to be related to B-cell lymphoma 2 (Bcl-2) overexpression in susceptible tumor cells.

Indications and use: Imiquimod is indicated for the topical treatment of non-hyperkeratotic, non-hypertrophic actinic keratoses (AK), Biopsy-confirmed, primary superficial basal cell carcinoma (sBCC) in immunocompetent adults, external genital and perianal warts/condyloma acuminata in patients of 12 years or older.

Pharmacodynamics/pharmacokinetics (PD/PK): The apparent half-life (t^1/2) was seen 10 times more with topical application compared to the subcutaneous route (t^1/2 -2 hours). It may be due to the long retention time during topical application. Mean peak drug concentration was found to be approximately 0.4 ng/ml.

Contraindications: It is contraindicated in patients with hypersensitivity.

 Warnings: Skin weeping and erosion, exposure to sunlight, urinary swelling, malaise, fever, nausea, myalgias and rigors. If such types of toxicities occur discontinue the treatment.

Adverse events: Most common adverse reactions (incidence >28%) are application site reactions or local skin reactions: itching, burning, erythema, flaking/scaling/dryness, scabbing/crusting, edema, induration, excoriation, erosion, ulceration.

SMO Inhibitors

FDA approved SMO inhibitors

Vismodegib: A small molecule with potential antineoplastic activity. Vismodegib targets the Hedgehog signaling pathway, blocking the activities of the Hedgehog-ligand cell surface receptors PTCH and/or SMO and suppressing Hedgehog signalling [15]. The Hedgehog signaling pathway plays an important role in tissue growth and repair; aberrant constitutive activation of Hedgehog pathway signaling and uncontrolled cellular proliferation may be associated with mutations in the Hedgehog-ligand cell surface receptors PTCH and SMO.

Indications and use: Vismodegib is indicated for the treatment of metastatic basal cell carcinoma, or locally advanced basal cell carcinoma that has recurred following surgery. It is also used in those subjects that cannot go through the procedure of surgery or radiation.

PD/PK: The absolute bioavailability of vismodegib was found to be 31.8%.  The volume of distribution of vismodegib was found to be 16.4 to 26.6 L. Its metabolism is done mainly through oxidation, glucuronidation, and pyridine ring cleavage. Its elimination half-life (t^1/2) is found to be 4 days after continuous once-daily dosing.

Contraindications: It is contraindicated in patients with hypersensitivity.

Warnings: Teratogenic effects including midline defects, missing digits, and other irreversible malformations. So pregnancy status should be verified before starting of vismodegib. It might be exposed through semen, so females should use contraceptives.

Adverse events: The most common adverse reactions are muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia.

Sonidegib: A small molecule with potential antineoplastic activity. It targets the Hedgehog signaling pathway, blocking the activities of the Hedgehog-ligand cell surface receptors PTCH and/or SMO and suppressing Hedgehog signalling [16]. Sonidegib binds to and inhibits Smoothened, a transmembrane protein involved in Hedgehog signal transduction.

Indications and use: It is indicated for the treatment of adult patients with locally advanced basal cell carcinoma (BCC) that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy.

PD/PK: The elimination half-life (t1/2) of sonidegib estimated from population pharmacokinetic (PK) modeling was approximately 28 days. Sonidegib is primarily metabolized by cytochrome P (CYP)3A. Sonidegib and its metabolites are eliminated primarily by the hepatic route.

Contraindications: It is contraindicated in patients with hypersensitivity.

Warnings: It can cause embryo-fetal death or severe birth defects when administered to a pregnant woman and is embryotoxic, fetotoxic, and teratogenic in animals. It might be exposed through semen, so females should use contraceptives.

Adverse events: The most common adverse reactions are muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting, and pruritus.

Non-FDA approved SMO inhibitors: The non-FDA approved SMO inhibitors have been mentioned in Table-1 below:

Table 1. Non-FDA Approved SMO Inhibitors [17]

Erismodegib: A small-molecule Smoothened (SMO) antagonist with potential antineoplastic activity. Erismodegib selectively binds to the Hedgehog (Hh)-ligand cell surface receptor SMO, which may result in the suppression of the Hh signaling pathway and hence, the inhibition of tumor cells in which this pathway is abnormally activated. The Hh signaling pathway plays an important role in cellular growth, differentiation and repair. Inappropriate activation of Hh pathway signaling and uncontrolled cellular proliferation, as is observed in a variety of cancers, may be associated with mutations in the Hh-ligand cell surface receptor SMO.

PIK3 Inhibitors

Non-FDA approved PIK3 inhibitors: The non-FDA approved PIK3 inhibitors have been mentioned in Table-2 below:

Table 2. Non-FDA Approved PIK3 Inhibitors[17]

Table 3. Non-FDA Approved Protein Kinase C[18].

Buparlisib: A specific oral inhibitor of the pan class I phosphatidylinositol 3-kinase (PI3K) family of lipid kinases with potential antineoplastic activity. Buparlisib specifically inhibits class I PIK3 in the PI3K/AKT kinase (or protein kinase B) signaling pathway in an Adenosine triphosphate (ATP)-competitive manner, thereby inhibiting the production of the secondary messenger phosphatidylinositol-3, 4, 5-trisphosphate and activation of the PI3K signaling pathway. This may result in inhibition of tumor cell growth and survival in susceptible tumor cell populations. Activation of the PI3K signaling pathway is frequently associated with tumorigenesis. Dysregulated PI3K signaling may contribute to tumor resistance to a variety of antineoplastic agents.

Protein kinase C (PKC)

Non-FDA approved protein kinase C (PKC): This non-FDA approved protein kinase includes:

Ingenol mebutate (PEP005):  A selective small-molecule activator of protein kinase C (PKC) isolated from the plant Euphorbia peplus with potential antineoplastic activity. Ingenol mebutate (I3A) activates various protein kinase C (PKC) isoforms, thereby inducing apoptosis in some tumor cells, including myeloid leukemia cells, melanoma cells, and basal cell carcinoma cells. The PKC family consists of signaling isoenzymes that regulate many cell processes including proliferation, differentiation, and apoptosis.

Conclusion

The non-melanoma type of skin cancer is basal cell carcinoma. It is produced in the epidermis of the lower half. BCC incidences are higher in white individuals. The geographical area where most BCC cases are diagnosed is Australia. It usually occurs after the age of 40 years in adults. In BCC incidences, men dominate over women. Immunotherapy has proved to be effective in the treatment of BCC, as has molecular targeted therapy. The only FDA-approved immunotherapy present for superficial BCC is Imiquimod, sonidegib and vismodegib. With knowledge of the role of the immune system, our success in treating BCC is growing and progressing. In the past few years, immunotherapy has shown a promising evolution. Our knowledge of the tumor microenvironment, different immunotherapy modalities or combination therapy has been improved by recent activities (like chemotherapy with immunotherapy).

In addition, the results of these modalities of combination therapy are still in the exploratory stage. The important foundations for understanding the future of immunotherapy in treating cancer patients are proper preclinical and clinical designs.