Basal Cell Carcinoma

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Practice Essentials

Basal cell carcinoma (BCC) is a nonmelanocytic skin cancer (ie, an epithelial tumor) that arises from basal cells (ie, small, round cells found in the lower layer of the epidermis).[1, 2] The prognosis for patients with BCC is excellent, but if the disease is allowed to progress, it can cause significant morbidity.[3]

The image below depicts BCC of the right lower lid.



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Basal cell carcinoma of the right lower lid.

Signs and symptoms

Approximately 85% of BCCs occur on the face, head (scalp included), and neck; others appear on the trunk or extremities; rarely, they may occur on the hands.[3, 4] Other characteristic features of BCC tumors include the following:

Periocular tumors most commonly involve the following:

Clinicopathologic types of BCC, each of which has a distinct biologic behavior, include the following:

See Presentation for more detail.

Diagnosis

Given that BCC rarely metastasizes, laboratory and imaging studies are not commonly clinically indicated in patients presenting with localized lesions. Imaging studies may be necessary when involvement of deeper structures is clinically suspected (eg, CT for suspected bone involvement, MRI for soft-tissue or perineural ay be used for assessment of .

Biopsy

Types of skin biopsy that may be used to confirm the diagnosis and determine the histologic subtype of BCC include the following:

Histology

Histologically, BCC is divided into the following 2 categories:

See Workup for more detail.

Management

Surgery

In nearly all cases of BCC, surgery is the recommended treatment modality.[5, 6] Techniques used include the following[7] :

Radiation therapy

BCCs are usually radiosensitive; radiation therapy (RT) can be used in patients with advanced and extended lesions, as well as in those for whom surgery is not suitable. Postoperative radiation can also be a useful adjunct when patients have aggressive tumors that were treated surgically or when surgery has failed to clear the margins of the tumor.[8]

Photodynamic therapy

Photodynamic therapy (PDT) as an adjunct is a reasonable choice in the following cases:

Pharmacologic therapy

Topical agents used in the treatment of superficial BCC include the following[7] :

Oral agents approved by the US Food and Drug Administration (FDA) for advanced forms of BCC include the following hedgehog pathway inhibitors (HHIs):

The checkpoint inhibitor cemiplimab (Libtayo) is approved for patients with locally advanced BCC and has been granted accelerated approval for use in patients with metastatic BCC previously treated with an HHI or for whom an HHI is not appropriate.

See Treatment and Medication for more detail.

Background

Basal cell carcinoma (BCC) is the most common skin cancer in humans, yet it accounts for less than 0.1% of patient deaths from cancer. Basal cell skin cancer tumors typically appear on sun-exposed skin, are slow growing, and rarely metastasize (0.028-0.55%). BCC usually appears as a flat, firm, pale area that is small, raised, pink or red, translucent, shiny, and waxy, and the area may bleed following minor injury. Tumor size can vary from a few millimeters to several centimeters in diameter. (See Presentation.)

See the clinical images below of basal cell carcinoma.



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Basal cell carcinoma.



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A 68-year-old patient presenting with an advanced basal cell carcinoma (BCC) of the right periorbital region, frontal view. Courtesy of M Abraham Kuri....

BCC is a nonmelanocytic skin cancer (ie, an epithelial tumor) that arises from basal cells, which are small round cells found in the lower layer of the epidermis. Basal cells invade the dermis but seldom invade other parts of the body. Most of the DNA alterations involved in BCC result from damage caused by exposure to sunlight, but inheritance may be a factor in some cases. (See Pathophysiology.)

Body distribution of BCCs is as follows:

The anatomic distribution of BCCs correlates with embryonic fusion planes. After adjusting for surface area, BCC occurrence is more than 4 times more likely to develop on embryonic fusion planes than on other regions of the midface, a finding that supports the possibility of an embryologic role for BCC pathogenesis.[12]

BCC can develop on unexposed areas. In some patients, contributing factors are exposure to or contact with arsenic,[13] tar, coal, paraffin,[14] certain types of industrial oil, and radiation. BCC can also be associated with scars (eg, burn complications),[15] xeroderma pigmentosum,[16] , previous trauma.[17] vaccinations, or even tattoos. (See Etiology.)

A skin biopsy (most often a shave biopsy is sufficient) may be necessary to confirm the diagnosis and is often required to determine the histologic subtype of BCC. A punch biopsy may be used to obtain a thick specimen, especially when the clinical suspicion of a BCC is still present after shave biopsy results are negative. (See Workup.)

Neglected tumors can continue to grow and lead to significant local destruction and even disfigurement. Surgery, in almost all cases, is the recommended treatment,[5, 7] with treatments varying on the basis of cancer size, depth, and location. (See Treatment.)

Superficial BCCS have been successfully treated with imiquimod 5% cream,[18, 19] and topical 5-fluorouracil 5% cream may be used to treat small, superficial BCCs.[20] Several studies have shown success in treating small nodular BCCs with imiquimod 5% cream, although this is an off-label indication and patients should be informed of this fact. (See Medication.)

Pathophysiology

Although the exact etiology of BCC is unknown, a well-established relationship exists between BCC and the pilosebaceous unit, as tumors are most often discovered on hair-bearing areas.

Many believe that BCCs arise from pluripotential cells in the basal layer of the epidermis or follicular structures. These cells form continuously during life and can form hair, sebaceous glands, and apocrine glands. Tumors usually arise from the epidermis and occasionally arise from the outer root sheath of a hair follicle, specifically from hair follicle stem cells residing just below the sebaceous gland duct in an area called the bulge.

Signaling pathways

The patched/hedgehog intracellular signaling pathway plays a role in both sporadic BCCs and nevoid BCC syndrome (Gorlin syndrome). This pathway influences differentiation of various tissues during fetal development. After embryogenesis, it continues to function in regulation of cell growth and differentiation. Loss of inhibition of this pathway is associated with human malignancy, including BCC.

The hedgehog gene encodes an extracellular protein that binds to a cell membrane receptor complex to start a cascade of cellular events leading to cell proliferation. Of the three known human homologues, sonic hedgehog (SHH) protein is the most relevant to BCC. Patched (PTCH) is a protein that is the ligand-binding component of the hedgehog receptor complex in the cell membrane. The other protein member of the receptor complex, smoothened (SMO), is responsible for transducing hedgehog signaling to downstream genes.[21, 22]

When SHH is present, it binds to PTCH, which then releases and activates SMO. SMO signaling is transduced to the nucleus via Gli. When SHH is absent, PTCH binds to and inhibits SMO. Mutated forms of PTCH are unable to bind to SMO, simulating the presence of SHH. The unbound SMO and downstream Gli are constitutively activated, thereby allowing hedgehog signaling to proceed unimpeded. The same pathway may also be activated via mutations in the SMO gene, which also allows unregulated signaling of tumor growth.

How these defects cause tumorigenesis is not fully understood, but most BCCs have abnormalities in either PTCH or SMO genes. Some authors even consider defects in the hedgehog pathway to be requirements for BCC development.

BCC most commonly develops on sun-exposed areas. Zhang et al reported that ultraviolet (UV)-specific nucleotide changes in PTCH, as well as the tumor suppressor gene TP53, are implicated in the development of early-onset BCC.[23]

UV-induced mutations in the TP53 tumor suppressor gene, which resides on band 17p13.1, have been found in some cases of BCC.[24]  A germline single-nucleotide polymorphism (SNP) in the TP53 gene, rs78378222, has also been associated with susceptibility to BCC.[24] In addition, frameshift mutations of the BAX gene (BCL2-associated X protein) have been found in sporadic cases of BCC. A reduction of bcl-2 proteins is observed in the aggressive, infiltrative type of BCC.

Radiation and immunologic origins

Radiation has proven to be tumorigenic by two mechanisms. The first entails the initiations of prolonged cellular proliferation, thereby increasing the likelihood of transcription errors that can lead to cellular transformation. The second mechanism is direct damage of DNA replication, leading to cellular mutation that may activate proto-oncogenes or deactivate tumor suppressor genes.

Immunologically, the mechanism by which prolonged ultraviolet radiation exposure leads to the development of BCC includes suppression of the cutaneous immune system and immunologic unresponsiveness to cutaneous tumors. This local effect includes a decrease in Langerhans cells, dendritic epidermal T cells, and Thy1+ cells. Furthermore, systemic proliferation of suppressor T cells and the release of immunosuppressive factors (eg, tumor necrosis factor–alpha [TNF-alpha], interleukin-1 [IL-1], prostaglandin [PG], IL-10) are believed to be involved in the development of BCC.

DNA mismatch repair proteins

DNA mismatch repair (MMR) proteins are a group of proteins that physiologically stimulate G2 cell cycle checkpoint arrest and apoptosis. Failure of MMR proteins to detect induced DNA damage results in the survival of mutating cells. MMR protein levels have been found to be higher in nonmelanoma skin cancers than in normal skin, and there is also some evidence of MMR dysregulation.[25]

Etiology

The exact cause of BCC is unknown, but environmental and genetic factors are believed to predispose patients to BCC.

Radiation exposure

Sunlight, particularly long-term exposure, is the most frequent association with development of BCC; risk correlates with the amount and nature of accumulated exposure, especially during childhood. Patient geographic location affects the risk of developing skin cancer. A latency period of 20-50 years is typical between the time of ultraviolet (UV) damage and BCC clinical onset.

The prevalence of BCC increases in areas of higher altitude and in areas of lower latitude. The incidence of BCC is rising, potentially because of atmospheric changes and the increased popularity of sunbathing.

Radiation exposure that contributes to BCC development may also include tanning booths and UV light therapy. Both short-wavelength UVB radiation (290-320 nm, sunburn rays) and longer wavelength UVA radiation (320-400 nm, tanning rays) contribute to the formation of BCC. UVB is believed to play a greater role in the development of BCC than UVA, however, and is the primary agent responsible for most skin cancer.[26]

UVB and UVC can modify unsaturated chemical bonds of nucleic acids, which may lead to mutations. UVC does not penetrate the atmospheric ozone layer. The UVA spectrum is absorbed by melanin and, through free-radical transfer, affects cellular deoxyribonucleic acid (DNA). Mutations caused by UV radiation typically include cytosine (C) to thymine (T), or CC to TT, translocation. This process can cause activation of oncogenes or inactivation of tumor suppressor genes, leading to tumor initiation and progression.[27]

The skin can repair superficial damage, but the underlying cumulative damage remains, including DNA damage. The damage worsens with each successive sun exposure, causing a lifetime progression.[28]

In a 2012 systematic review and meta-analysis of 12 studies with 9328 cases of nonmelanoma skin cancer, Wehner et al found that indoor tanning was associated with a significantly increased risk of both basal and squamous cell skin cancer. The risk was highest among users of indoor tanning before age 25. The authors estimate that the population-attributable risk fraction in the United States is 8.2% for squamous cell carcinoma and 3.7% for BCC, corresponding to more than 170,000 cases of nonmelanoma skin cancer annually caused by indoor tanning.[29] In another 2012 study of 376 patients with BCC and 390 control patients with minor benign skin conditions, indoor tanning was strongly associated with early-onset BCC, particularly in women.[30]

X-ray and Grenz-ray exposure are also associated with BCC formation.

Gene mutations

Studies have demonstrated a high incidence of TP53 gene mutations in BCC. Researchers speculate that ultraviolet sunlight may play an important role in the genesis of this mutation; yet, genetic involvement has been demonstrated on chromosome 9 only in patients with familial basal cell nevus syndrome (Gorlin syndrome). Such mutation involves the patched (PTCH) gene, a tumor suppressor gene.

Inappropriate activation of the hedgehog signaling pathway is found in both sporadic and familial cases of BCC. This results in loss-of-function mutations in tumor-suppressor protein patched homologue 1 (PTCH1) and gain-of-function mutations in sonic hedgehog (SHH), smoothened (SMO), and Gli.

Arsenic ingestion

Arsenic — particularly in the form of inorganic arsenic compounds — has been identified as carcinogenic in humans. High levels of arsenic occur naturally in drinking water in various parts of the world, including the western United States.[31] Arsenical skin lesions, which are the hallmark of chronic arsenic poisoning, are considered an indication of elevated skin cancer risk.[13]

Immunosuppression

A modest increase in the lifetime risk of BCC has been noted in chronically immunosuppressed patients, such as recipients of organ or stem cell transplants and people with AIDS.[32]

Organ transplant patients must be instructed to limit sun exposure and be alerted that skin cancer is a serious problem for them. In fact, immunosuppression and sun damage may cooperate to cause skin cancer. The skin cancer incidence is 10-fold higher in transplant recipients than in the general population; up to 65-75% of patients with long-term immunosuppression develop skin cancer. Transplant recipients who have who developed a posttransplant skin cancer are at elevated risk of developing a subsequent skin cancer within 2 years, with approximately 1 in 20 developing 10 or more skin cancers.[33]  

Previous nonmelanoma skin cancer

Persons who have been diagnosed with one nonmelanoma skin cancer are at increased risk of developing tumors in the future. The risk of developing new nonmelanoma skin cancers is reported to be 35% at 3 years and 50% at 5 years after an initial skin cancer diagnosis.[34]

Skin type

Albinism has been implicated in BCC. The Fitzpatrick skin-type scale, which ranges from very fair (skin type I) to very dark (skin type VI), categorizes cutaneous sensitivity to ultraviolet radiation. It is based on the individual's tendency to burn and tan and is a good predictor of relative risk among Whites.

Alcohol consumption

A study among adults in the United States reports a strong association between excessive alcohol drinking and higher incidence of sunburn, suggesting a linkage between alcohol consumption and skin cancer.[35]

Hydrochlorothiazide use

The widely used diuretic hydrochlorothiazide (HCTZ) is a potent photosensitizer. Slightly increased risk for BCC (and dramatically increased risk for cutaneous squamous cell carcinoma [SCC]) was documented in a case-control study that cross-referenced 71,533 cases of BCC and 8629 cases of SCC from the Danish Cancer Registry with data on cumulative HCTZ exposure in these cases with that country’s National Prescription Registry. No association was found between nonmelanoma skin cancer and other antihypertensive drugs.[36]

The study results supported a dose-response relationship between HCTZ use and BCC, as follows[36] :

The association of BCC with HCTZ use was strongest in younger individuals (age 50 years and younger). In these patients, the OR was 1.91. Overall, the proportion of BCCs attributable to HCTZ use was 0.6%. HCTZ showed the strongest association with skin cancers on heavily sun-exposed sites such as the lower limbs (versus the trunk).[36]

Hereditary disorders

The following inherited conditions are associated with increased risk of BCC:

Epidemiology

The American Cancer Society (ACS) reports skin cancer as being the most common cancer in the United States, with basal cell carcinoma (BCC) constituting the majority of cases. The ACS cites an estimate that about 5.4 million basal and squamous cell skin cancers are diagnosed each year in about 3.3 million persons in the US, with about 80% of those being BCCs. Although the number of these skin cancers has been increasing for years, death from them remains uncommon: non-melanoma skin cancers are estimated to cause about 2000-8000 deaths annually (mostly from squamous cell skin cancers), and that number has been decreasing in recent years.[39]

The estimated lifetime risk for BCC in the White population is 33-39% for men and 23-28% for women. BCC incidence doubles every 25 years.

In the US states near the equator, such as Hawaii, BCC incidence is approaching three-fold that of states in the Midwest, such as Minnesota. BCC incidence also varies globally. The highest rates of skin cancer occur in South Africa and Australia, areas that receive high amounts of UV radiation.[40] Australia has a trend toward increasing BCC incidence, while Finland has a low reported incidence that is approximately one quarter that in Minnesota; BCC incidence in Finland also appears to be increasing, however, especially among young women.

BCC is the least likely cancer to metastasize. BCC differs from squamous cell carcinoma, which accounts for 16% of skin cancers and is more life-threatening.

Race

Although BCC is observed in people of all races and skin types, dark-skinned individuals are rarely affected; BCC is most often found in light-skinned individuals (type 1 or type 2 skin). Those with type 1 skin are very fair and have red or blond hair and freckles; these individuals always burn and never tan. Those with type 2 skin are fair and burn easily while tanning minimally. Whites of Celtic ancestry have the highest risk for BCC. Incidence is low in persons with type 5 and 6 skin.[41]

Sex

Historically, men are affected twice as often as women. The higher incidence in men is probably due to increased recreational and occupational exposure to the sun, although these differences are becoming less significant with changes in lifestyle. The current male-to-female ratio is approximately 2.1:1.

For tumors involving the periocular skin, Cook et al reported the incidence of BCC to be equal in men and women.[42] In addition, this investigative team found that the age-adjusted incidence rates for all malignant tumors of the eyelid in men and women, respectively, were 19.6 cases and 13.3 cases per 100,000 population per year. The age-adjusted incidence rates for BCC of the eyelid for men and women, respectively, were 16.9 and 12.4 cases per 100,000 population per year.

Age

The likelihood of developing BCC increases with age. Data indicate that BCC incidence is far higher (more than 100-fold) in persons aged 55-70 years than in those aged 20 years and younger. Patients 50-80 years of age are affected most often. The median age at diagnosis is 67 years and the mean age is 64 years.

Nevertheless, BCC can develop in teenagers and appears frequently in fair-skinned patients aged 30-50 years. Approximately  5% to 15% of cases of BCC occur in patients aged 20-40 years. Aggressive-growth types of BCC are more frequently noted in patients younger than 35 years than in older individuals.

Zhang et al reported an inverse association between body mass index (BMI) and onset of BCC before age 40 years. The multivariate odds ratio for early-onset BCC in obese versus normal individuals was 0.43 for adult BMI and 0.54 for BMI at age 18.[43]

Prognosis

The prognosis for patients with BCC is excellent, with a 100% survival rate for cases that have not spread to other sites. Nevertheless, if BCC is allowed to progress, it can result in significant morbidity, and cosmetic disfigurement is not uncommon.

Typically, basal cell tumors enlarge slowly, relentlessly and tend to be locally destructive. Periorbital tumors can invade the orbit, leading to blindness, if diagnosis and treatment are delayed. BCC arising in the medial canthus tends to be deep and invasive and more difficult to manage; this type of BCC can result in perineural extension and loss of nerve function.

Although BCC is a malignant neoplasm, it rarely metastasizes. The incidence of metastatic BCC is estimated to be less than 0.1%. The most common sites of metastasis are the lymph nodes, lungs,[44] and bones.[45]

Although treatment is curative in more than 95% of cases, BCC may recur, especially in the first year, or develop in new sites. Therefore, regular skin screenings are recommended.[46]

Recurrence

The 5-year recurrence rate is about 5%, but it depends on the histologic subtype and type of treatment; the recurrence rate is less than 1% for primary (previously untreated) BCCs treated with Mohs micrographic surgery. Most reports show that the distance to the closest resection margin is an important predictor of recurrence.[47]

The following is a list of treatments and their 5-year recurrence rates for primary (previously untreated) BCCs:

These rates are probably affected by the fact that clinicians use cryotherapy, curettage, and desiccation mostly on smaller and better-demarcated lesions.

Pieh et al reported a recurrence rate of 5.36% after the first excision of the tumor; the rate increased to 14.7% after the second operation and reached 50% after the third and fourth operations.[48] The highest recurrence, approximately 60%, was seen with lesions arising from the medial canthus.

Recurrences usually occur 4-12 months after initial treatment. One meta-analysis found that the 3-year cumulative risk of devloping a second BCC after an index BCC is about 44%, which is a 10-fold increase over that of the general population.[49, 50] Tumors on the nose or T-zone of the face have a higher incidence of recurrence. Recurrence is most common on the nose and nasolabial fold, but this observation may be secondary to lack of adequate margins obtained in these areas. Infiltrative, micronodular, and multifocal types are more likely than nodular types to recur.

A recurrence of BCC should be suspected when one of the following conditions occurs:

Histologic types of BCC at higher risk for recurrence include morpheaform (sclerotic), micronodular, infiltrative, and superficial (multicentric). Higher recurrence rates are also seen with the following:

Patient Education

Adequate patient education is essential in the prevention of recurrence and spread of basal cell carcinoma. Patients should avoid possible potentiating factors (eg, sun exposure, ionizing radiation, arsenic ingestion, tanning beds). The regular use of sun-protecting clothing (eg, wide-brimmed hat, long-sleeved shirts, sunglasses with ultraviolet [UV] protection) is recommended when outdoors.

Instruct patients to avoid sun exposure particularly during the middle of the day (ie, 11 am to 3 pm), which is the most dangerous time. Also, the sun's rays are especially intense in sunny climates and at high altitudes, and UV radiation can also pass through clouds and water. Patients should be instructed to be careful on the beach and in the snow because sand, water, and snow reflect sunlight and increase the amount of received UV radiation.[51]

During the initial consultation, the patient should be counseled regarding the extent of resection, type of reconstructive procedure, and attendant morbidity. High importance should be attached to adequately preparing the patient regarding the cosmetic and functional result of treatment. During posttreatment follow-up, the patient should be counseled regarding sunlight exposure and the risk of developing additional primary skin tumors.

Sunscreen

Regular application and reapplication of sunscreen is recommended prior to sun exposure. People who use sunscreens have a 40% reduction in skin cancer incidence versus nonusers.

Note that the sun protection factor (SPF) ratings of sunscreens correspond to their ability to protect the skin from harmful UVB rays. The Centers for Disease Control and Prevention (CDC) recommends use of a sunscreen with an SPF rating of at least 15,[52] while the American Academy of Dermatology (AAD) advises use of a sunscreen with an SPF rating of at least 30.[53] Both organizations recommend use of a broad spectrum sunscreen, which provides protection against both UVA and UVB radiation.

Emphasize also that sunscreens must be applied generously, 20-30 minutes before going outside, and reapplied about every 2 hours, more often if swimming or sweating; the AAD recommends use of water-resistant sunscreen, which maintains its SPF for 40 minutes of immersion (or, in the case of "very water resistant" products, for 80 minutes). For lip protection, a lip balm with an SPF of 15 or higher should be applied.

Instruct parents to protect their children's skin with sunscreen or protective clothing to reduce the risk of BCC later in life. It has been estimated that intensive sun protection before age 18 years can reduce nonmelanoma skin cancer by 78%.

Advise parents not to expose children younger than 12 months to direct sunlight and to cover up children aged 12-24 months with a hat, shirt, and a small amount of sunscreen on the remaining exposed areas. Similarly, for children older than 2 years, instruct parents to consider using sunscreens, covering the child's skin with clothing, and, when possible, restricting the child to shaded areas.

Self-examination for skin changes

Educate patients on how to recognize any unexplained changes in their skin, especially changes that last for more than 3-4 weeks. Also, educate patients on how to examine their own and their partner's skin. The knowledge of mole distribution on the skin is helpful.

Tell the patient to first look at the front and back of his or her body in a full-length mirror, using a hand mirror. The patient also should use the hand mirror to look at the back of the neck and scalp, the back, and the breeches. The patient then should turn and look at each side of the body with the arms raised. Next, the patient should bend the elbows and look carefully at the forearms, the back of the upper arms, and the palms. Instruct the patient to sit down and check the backs of the legs and feet, including the spaces between the toes and bottoms of the feet.

The American Cancer Society also offers instructions on how to conduct a skin self-exam.

For additional patient education information, see Skin Cancer and Basal Cell Carcinoma.

History

Patients presenting with basal cell carcinoma (BCC) often report a slowly enlarging lesion that does not heal and that bleeds when traumatized. As tumors most commonly occur on the face, patients often give a history of an acne bump that occasionally bleeds.

People who sunburn are more likely to develop skin cancer than those who do not; however, sunlight damages the skin with or without sunburn. Consider BCC in any patient with a history of a sore or skin anomaly that does not heal within 3-4 weeks and occurs on sun-exposed skin, especially if it is dimpled in the middle. These tumors may take many months or years to reach even 1 cm in diameter.

Patients often have a history of chronic sun exposure, including recreational sun exposure (eg, sunbathing, outdoor sports, fishing, boating) and occupational sun exposure (eg, farming, construction).

History of any prior treatment to the index tumor should be elicited, as well as history of any prior nonmelanoma skin cancer. In patients with recurrent tumors, deeper invasion should be expected. Recurrence following radiation therapy is often biologically more aggressive.

Occasionally, patients have a history of exposure to ionizing radiation. X-ray therapy for acne was commonly used until 1950. Though not common, patients may have a history of arsenic intake; arsenic is found in well water in some parts of the United States.

Physical Examination

Characteristic features of BCC tumors include the following:

Basal cell carcinoma occurs mostly on the face, head (scalp included), neck, and hands.[4] It rarely develops on the palms and soles. BCC usually appears as a flat, firm, pale area that is small, raised, pink or red, translucent, shiny, and waxy, and the area may bleed following minor injury. BCCs may have one or more visible and irregular blood vessels, an ulcerative area in the center that often is pigmented, and black-blue or brown areas. Large BCCs may have oozing or crusted areas. The lesion grows slowly, is not painful, and does not itch.

Periocular tumors most commonly involve the lower eyelid (48.9-72.1%), followed by the medial canthus (25-30%), the upper eyelid (15%), and the lateral canthus (5%). Examples are shown in the images below.



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Basal cell carcinoma of the right lower lid.



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Biopsy-proven basal cell carcinoma of the upper lid margin. Note the loss of cilia (madarosis) in the area of the tumor.



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Medial canthal/lower lid basal cell. Note the pearly nodular surface with characteristic telangiectatic vessels. Proximity to the lacrimal system will....

Though a literature review showed all authors agreed that periocular BCC most commonly occurs in the lower eyelid, the remaining anatomic locations and the incidence of occurrence differ among the studies.

Younger patients (< 40 y) may have a lower prevalence of BCC on the head and neck and a higher prevalence on the trunk, with greater tendency to superficial BCC, than in older patients.[54] Childhood BCC is exceedingly rare in the absence of other underlying conditions. As of 2007, only 107 cases of de novo childhood BCC had been reported in the literature, but the majority (90%) occurred on the head and neck, and aggressive subtypes were observed in 20% of the total cases.[55]

Clinical presentation of BCC varies by type. Physical examination of the skin aids in determination of tumor extent, subtype, and involvement of important cosmetic and functional structures. Matted BCCs may indicate deeper tumor invasion and involvement of deeper underlying structures.

In patients with recurrent or deeply infiltrative tumors, involvement of the facial nerve or branches of the trigeminal nerve should be investigated. Facial nerve function can be monitored by comparing facial symmetry during voluntary facial movements with that at rest. Sensory nerve function can be tested and compared to the nonaffected side by means of light touch and pinprick. Orbital invasion can cause diplopia, proptosis, and ophthalmoplegia. Any limitation in ocular movements and/or diplopia should be tested.

BCC seldom causes regional or distant metastasis, with the exception of the metatypical basosquamous type. To evaluate for lymph node metastasis, particular attention should be taken to examine the parotid posterior auricular, suboccipital, and upper cervical groups of lymph nodes.

Several different clinicopathologic types of BCC exist, each with distinct biologic behavior:

Nodular basal cell carcinoma

Nodular basal cell carcinoma is the most common type of BCC; more than 60% of BCCs belong to this subtype. It usually presents as a round, pearly, flesh-colored papule with telangiectases. As it enlarges, it frequently ulcerates centrally, leaving a raised, pearly border with telangiectases, which aids in making the diagnosis. Fine vessels may bleed, resulting in hemosiderin deposition.

The tumor may present as a cyst, which can be mistaken for inclusion cysts of the eyelid. Cystic BCC is an uncommon variant of nodular BCC and is often clinically indistinguishable from nodular BCC, although it might have a polypoid, cystic appearance. Typically, a bluish-gray cystlike lesion is observed. The cystic center of the tumor is filled with clear mucin that has a gelatinlike consistency. Often, the lesion has the typical features of a nodular BCC in addition to the cystic features.

Most tumors are observed on the face, although the trunk and extremities also are affected. See the images below.



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Nodular basal cell carcinoma.



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Nodular basal cell carcinoma appearing as a waxy, translucent papule with central depression and a few small erosions.

Pigmented basal cell carcinoma (see the images below) is an uncommon variant of nodular BCC that usually has brown-black macules in some areas or affecting nearly the entire tumor, occasionally making it difficult to differentiate from melanoma.

Typically, some areas of these tumors do not retain pigment, and pearly, raised borders with telangiectases that are typical of a nodular basal cell carcinoma can be observed. This aids clinically in differentiating this tumor from a malignant melanoma. See the images below.



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Pigmented basal cell carcinoma.



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Pigmented basal cell carcinoma.



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Pigmented basal cell carcinoma has features of nodular basal cell carcinoma with the addition of dark pigmentation from melanin deposition. The pigmen....

Keratotic BCC is a variant of nodular BCC and is usually clinically indistinguishable from nodular BCC histologically.

Infiltrative basal cell carcinoma

In this variant of BCC, tumor infiltrates the dermis in thin strands between collagen fibers, making tumor margins less clinically apparent. Because of its growth pattern, infiltrative BCC is significantly more likely than nodular BCC to recur after electrodesiccation and curettage, so other treatment methods should be sought. Mohs micrographic surgery is the treatment of choice for infiltrative BCC.

Micronodular basal cell carcinoma

This aggressive BCC subtype has the typical BCC distribution. It is not prone to ulceration, it may appear yellow-white when stretched, and it is firm to the touch. It may have a seemingly well-defined border.

Morpheaform (sclerosing) basal cell carcinoma

Morpheaform BCC is an uncommon variant in which tumor cells induce a proliferation of fibroblasts within the dermis and an increased collagen deposition (sclerosis) that clinically resembles a scar. This form accounts for 10% of lesions.

Such lesions appear as flat or slightly depressed, fibrotic, and firm. The tumor appears as a white or yellow, waxy, sclerotic plaque that rarely ulcerates. The morpheaform (sclerosing) type of basal cell carcinoma is often the most difficult type to diagnose, as it bears little resemblance to the typical nodular BCC.

Because the tumor infiltrates in thin strands between collagen fibers, treatment is difficult because the clinical margins are difficult to distinguish from normal, uninvolved skin. Mohs micrographic surgery is the treatment of choice for morpheaform BCC because recurrence is more likely with other treatment modalities.

Ulceration, bleeding, and crusting are uncommon and these tumors are commonly mistaken for scar tissue (see the image below).



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Large, scarlike morpheaform basal cell cancer.

Superficial basal cell carcinoma

Superficial BCCs occur mostly on the upper trunk or shoulders. This type of BCC grows slowly, has minimal tendency to be invasive, and appears clinically as an erythematous, well-circumscribed patch or plaque, often with a whitish scale. Occasionally, minute eschars may appear within the patch or plaque. The tumor often appears multicentric, with areas of clinically normal skin intervening among clinically involved areas.

A threadlike border is common but not always present. Erosion is less common in superficial BCC than in nodular BCC, although pinpoint areas of hemorrhage or eschar may be present. The papules may mimic psoriasis or eczema, but they are slowly progressive and are not prone to fluctuate in appearance. Numerous superficial BCCs may indicate arsenic exposure. See the images below.



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Scale, erythema, and a threadlike raised border are present in this superficial basal cell carcinoma on the trunk.



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Large, superficial basal cell carcinoma.

Gorlin syndrome or basal cell nevus syndrome

BCC is also a feature of basal cell nevus syndrome (ie, Gorlin syndrome),[56] an autosomal dominant inherited condition. The lesions in these patients are histologically indistinguishable from ordinary BCCs. The gene responsible for this syndrome is located on arm 9q, and chromosome abnormalities develop in some patients. The number of BCCs in patients with this syndrome may number from one to hundreds. Multiple BCCs begin to appear after puberty on the face, trunk, and extremities. In many cases, the tumors are highly invasive and may involve areas around the eyes and nose.[57]

Other features associated with Gorlin syndrome (fortunately, uncommon) include the following[58] :

Other basal cell carcinomas

Other types of basal cell carcinoma include the following:

Approach Considerations

Given that basal cell carcinoma rarely metastasizes, laboratory and imaging studies are not commonly clinically indicated in patients presenting with localized lesions. Imaging studies may be necessary when involvement of deeper structures is clinically suspected. In such cases, CT scans can be used for assessment of bone, and MRI for suspected soft-tissue or perineural involvement.[6]

Skin Biopsy

A skin biopsy is often required to confirm the diagnosis and determine the histologic subtype of basal cell carcinoma (BCC). Most often, a shave biopsy is all that is required. Nevertheless, in the case of a pigmented lesion where there may be difficulty distinguishing between pigmented BCC and melanoma, an excisional or punch biopsy may be indicated; this is to ensure that the depth of the lesion can be determined if it proves to be a malignant melanoma.

In most cases, a superficial biopsy specimen that contains dermis is all that is required to confirm the diagnosis of BCC, although it is possible to miss the tumor. For example, an ulcerated BCC may reepithelialize with normal epidermis while tumor is still present at a deeper level. Part or all of the BCC may be sampled, but avoid going beyond the clinical margins if the biopsy is only for diagnostic purposes.

Punch biopsy is an easy method to obtain a thick specimen, but is rarely required. The most suspicious area of a lesion may be sampled, or multiple biopsy samples may be taken if the tumor is large or has a varied appearance in different areas. Avoid punch biopsy if curettage is planned for final treatment.

Occasionally, suspected tumors may require more than a single biopsy to make the diagnosis; therefore, with a high clinical index of suspicion, a second biopsy may be needed to obtain a pathological diagnosis of BCC.

Cytology

To accurately and definitively diagnose BCC of the eyelid, histological confirmation is required and is most commonly obtained through excisional (shave or punch) biopsy, which provides more information regarding the histologic subtype of BCC. Cytology does provide a rapid alternative that may yield and even help confirm a diagnosis during the initial visit, however.

The accuracy of this technique has been reported to be good, but its sensitivity in diagnosing BCC of the eyelid is unknown. It is not considered to be sufficiently sensitive in planning surgical management.

A study by Barton et al showed that for patients who underwent cytology followed by excisional biopsy, cytology had a sensitivity of 92% in diagnosing BCC with a predictive accuracy of 75%.[59] These values were compared with those in a second group of patients who had incisional biopsy and histologic examination followed by excision with histologic confirmation, which showed a sensitivity of 100% in diagnosing BCC with a predictive accuracy of 96%.

Histologic Findings

Several histologic types of BCC exist. Distinctions are important because clinical detection of tumor margins is more difficult with certain histologic types.[60] Usually, BCCs are well differentiated and cells appear histologically similar to basal cells of the epidermis.

Tumor cells of nodular BCC, sometimes called basalioma cells, typically have large, hyperchromatic, oval nuclei and little cytoplasm. Cells appear uniform, and if present, mitotic figures are usually few. The nuclei resemble that of the basal cells of the epidermis, although they have a larger nuclear-to-cytoplasmic ratio and lack intercellular bridges. A mitotic figure is very rarely observed. Nodular tumor aggregates may be of varying sizes, but tumor cells tend to align more densely in a palisade pattern at the periphery of these nests (see the image below).



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Nodular basal cell carcinoma. Nodular aggregates of basalioma cells are present in the dermis and exhibit peripheral palisading and retraction artifac....

Cleft formation, known as retraction artifact, commonly occurs between BCC nests and stroma because of shrinkage of mucin during tissue fixation and staining. Some lobules may have areas of pseudoglandular change, and this is the predominant change in adenoid BCC. In other instances, large tumor lobules may degenerate centrally, forming pseudocystic spaces filled with mucinous debris. These changes are seen in the nodulocystic variant of BCC.

Early lesions usually have some connection to the overlying epidermis, but such contiguity may be difficult to appreciate in more advanced lesions. Increased mucin is often present in the surrounding dermal stroma.

A histopathologic examination of paraffin-embedded sections of BCC usually reveals solid cellular strands, collections of cells with dark-staining nuclei and scant cytoplasm.

The peripheral cell mass is in a palisade arrangement that resembles the basal layer of the epidermis, sometimes with pseudocystic aspects, and with a variable number of mitoses.

The connective tissue stroma surrounding the tumor islands is arranged in parallel bundles and often shows young fibroblasts immediately adjacent to the tumor. The specific histologic pattern of each type of BCC varies in terms of desmoplastic reaction of the morpheaform type and in the stromal islands separated by basal cells strands of the fibroepithelial type. Artificial retraction of the stroma from the tumor islands is frequently observed histologically. Additionally, the stroma is often mucinous. Cells from recurrent BCC often show squamous aspects.

Histologically, BCC is divided into two categories: undifferentiated and differentiated. When there is little or no differentiation, it is referred to as solid BCC and includes pigmented BCC, superficial BCC, sclerosing BCC, and infiltrative BCC (a histologic subtype).

Differentiated BCC often has slight differentiation toward cutaneous appendages, including hair (keratotic BCC), sebaceous glands (BCC with sebaceous differentiation), or tubular glands (adenoid BCC). Noduloulcerative (nodular) BCC is usually differentiated. See the images below.



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Histologic pattern of a well-differentiated basal cell carcinoma (original magnification X140). Courtesy of Prof Pantaleo Bufo, University of Foggia, ....

When the presence of a dense inflammatory infiltrate obscures the histologic margins of BCC, immunohistochemical stains for cytokeratins can help to identify tumor cells. These stains can be used with fixed or frozen tissue. Such staining with frozen tissue can take as little as 19 minutes, making it practical for use with Mohs micrographic surgery or with standard excision with frozen section margin control.[61]

Nodular basal cell carcinoma

Nodular or noduloulcerative basal cell carcinoma, the most common type, generally consists of large, round or oval tumor islands within the dermis, often with an epidermal attachment. The solid (nodular) type accounts for approximately 70% of all cases. Artificial retraction of the tumor islands from the surrounding stroma is commonly seen. Ulcerations may be seen in large tumors.

Micronodular basal cell carcinoma

Another aggressive variant, micronodular BCC, appears as small, nodular aggregates of basaloid cells. See the image below.



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Micronodular basal cell carcinoma often has an absence of retraction artifact. The characteristic histology is small size and uniformity of the tumor ....

Retraction artifact tends to be less pronounced than in the nodular form of BCC, and subclinical involvement is often significant. Micronodular basal cell carcinoma is similar to the noduloulcerative type, although the tumor islands are small (often < 15 cells in diameter).

Pigmented basal cell carcinoma

In pigmented BCC, benign melanocytes in and around the tumor produce large amounts of melanin. These melanocytes contain many melanin granules in their cytoplasm and dendrites.

Adenoid basal cell carcinoma

The adenoid type consists of strands of basaloid cells in a reticulate pattern, frequently with prominent stromal mucin. It may occur with the solid type.

Morpheaform (sclerosing) basal cell carcinoma

The more aggressive morpheaform BCCs have growth patterns resulting in strands of cells rather than round nests, within a fibrous stroma. They constitute approximately 5% of BCCs. Morpheaform BCC arises as thin strands of tumor cells (often only 1 cell in thickness) that are embedded in a dense fibrous stroma. The morpheaform basal cell carcinomas exhibit islands of tumor extending into the tissue and may exhibit perineural invasion in 3% of patients. This finding helps classify these 2 histotypes as the most aggressive, with the highest rates of recurrence and positive margins after excision.

Infiltrative basal cell carcinoma

This type of BCC accounts for 10% of BCCs. Tumor cells have growth patterns resulting in strands of cells infiltrating between collagen bundles rather than round nests.

The strands of infiltrating BCC tend to be somewhat thicker than those seen in morpheaform BCC, and they have a spiky, irregular appearance (see the image below).



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Infiltrative basal cell carcinoma. Tumor cells are arranged in narrow strands, and mucin-rich stroma is often present. Courtesy of Shang I Brian Jiang....

Infiltrating BCC usually does not exhibit the scarlike stroma seen in morpheaform BCC. Peripheral palisading and retraction are less pronounced in morpheaform and infiltrating BCC than in less aggressive forms of the tumor, and subclinical involvement is often extensive.

Cystic basal cell carcinoma

Cystic BCC consists of large, round or oval tumor islands within the dermis with mucin present in the center of the island. This space is caused by central tumor cell degeneration.

Superficial basal cell carcinoma

Superficial BCC appears as buds of basaloid cells attached to the undersurface of the epidermis. Nests of various sizes are often seen in the upper dermis. The tumor cell aggregates typically show peripheral palisading.

The (multifocal) superficial type (see the image below) is characterized by numerous small nests of tumor cells usually attached to the undersurface of the epidermis by a broad base. Approximately 10-15% of all BCCs are of this type. This is the most common pattern seen in BCCs of the shoulder.



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Histology of superficial basal cell carcinoma. Nests of basaloid cells are seen budding from the undersurface of the epidermis. Courtesy of Michael L ....

Keratotic basal cell carcinoma

The keratotic type resembles the solid type and its nests of basaloid cells with peripheral palisading. The island centers display keratinization and squamous differentiation. See the image below.



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Keratotic basal cell carcinoma. Rare type characterized by keratocysts. Courtesy of Shang I Brian Jiang, MD.

Infundibulocystic basal cell carcinoma

The infundibulocystic type is rare and is usually found on the face. It resembles the keratotic type. Nests are arranged in an anastomosing pattern and lack stroma. Many small, infundibular cyst-like structures with keratinous material are present. Melanin is sometimes present.

Metatypical basal cell carcinoma

Metatypical BCC is rare. In this type, nests and strands of cells mature into larger and paler cells, and peripheral palisading, if any, is less developed than in other types. Prominent stroma, prominent mitotic activity, and many apoptotic cells may be present. This form may be best diagnosed when one evaluates a BCC with features between those of a nodular BCC and squamous cell carcinoma. These tumors are often aggressive, with an increased tendency for lymphatic and perineural spread.

Basosquamous carcinoma

The basosquamous type is controversial. It has been defined as a BCC with differentiation toward squamous cell carcinoma (SCC). It is made up of basaloid cells that are a larger, paler, and rounder than those of a solid BCC. It also consists of squamoid cells and intermediate cells. Some consider the diagnosis of this type most appropriate for a tumor with contiguous areas of BCC and SCC. This type is considered to have metastatic potential and is considered an aggressive skin cancer (see the image below).



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Basosquamous basal cell carcinoma. Foci of neoplastic cells with squamous differentiation are present. Courtesy of Shang I Brian Jiang, MD.

Fibroepithelioma of Pinkus

The fibroepithelioma type consists of thin, anastomosing strands of basaloid cells in a prominent stroma.

According to some studies, the so-called fibroepithelioma of Pinkus, considered to be a premalignant skin condition, must be considered as a fenestrated variant of BCC.[62, 63, 64]

Ultrasonography

The use of ultrasonography is controversial. High-frequency (20 MHz) and ultra-high-frequency (40-100 MHz) ultrasound systems have been used; their accuracy in delineating malignant lesions from benign lesions remains inadequate, however, with a success rate of approximately 20%. Furthermore, the claims of reliable tumor sizing and depth of invasion are promising but still passionately debated.

Laser Doppler

As an adjunct tool, laser Doppler may assist ophthalmologists in distinguishing between benign and malignant adnexal skin lesions and in establishing the tumor margin.

It is reported that cutaneous perfusion to the eyelids is statistically significantly higher than other regions of the body (eg, forearm). Furthermore, the mean perfusion in pretarsal skin has been shown to be 50% greater than that in preseptal skin. In histologically documented basal cell carcinoma of the eyelid, cutaneous perfusion was significantly greater.[65]

Staging

Basal cell carcinoma rarely metastasizes and is usually not staged, unless the cancer is very large and is suspected of spreading to other parts of the body. BCC staging may be similar to the staging of squamous cell carcinoma, which is according to the following scheme:

High-risk tumors

High-risk BCCs include the following:

Approach Considerations

According to the National Comprehensive Cancer Network (NCCN), the goal of treatment for basal cell carcinoma (BCC) is elimination of the tumor with maximal preservation of function and physical appearance. As such, treatment decisions should be individualized according to the tumor characteristics and the patient's particular risk factors and preferences.[7]

In nearly all cases of BCC, the recommended treatment modality is surgery.[66, 7, 6] The surgical approach varies according to tumor size, depth, and location. Dermatologists may perform nearly all of the therapeutic options in an outpatient setting. Most therapies are well established and widely applied; in addition, some other options are available (eg, photodynamic therapy with photosensitizers).[67, 68, 69]

Local therapy with chemotherapeutic and immune-modulating agents is useful in some cases of BCC. In particular, small and superficial BCCs may respond to these compounds.

Topical 5% imiquimod is approved by the US Food and Drug Administration (FDA) for the treatment of nonfacial superficial BCCs that are less than 2 cm in diameter. Lesions are generally treated once daily, 5 days per week, for a duration of 6-12 weeks.

Likewise, topical fluorouracil 5% is approved by the FDA for the treatment of superficial BCC, administered twice daily for 3-6 weeks.[70] Although no formal restrictions on fluorouracil have been determined based on lesion size or location, it is most commonly used on smaller superficial BCCs on the trunk and extremities. Both imiquimod and fluorouracil may be used topically for prophylaxis or maintenance in patients who are prone to having many BCCs; efficacy in this setting likely involves regression of subclinical tumors.

For tumors that are more difficult to treat (ie, infiltrative BCC, morpheaform [sclerosing] BCC, micronodular BCC, and recurrent BCC) or those in which sparing normal (noncancerous) tissue is paramount, Mohs micrographic surgery should be considered and discussed with the patient.

Radiation therapy is a primary treatment option in patients who are not surgical candidates. It may also be used as adjuvant therapy in cases with positive surgical margins. However, radiation therapy is contraindicated in patients with genetic conditions that predispose to skin cancer.[7]

A Hedgehog pathway inhibitor (HHI) can be used to treat patients with locally advanced BCC who are not candidates for surgery or radiation therapy, or whose disease has recurred after surgery or radiation therapy, and those with metastatic BCC.[7] The FDA approved the first HHI pathway inhibitor, vismodegib (Erivedge), in 2012 and the second, sonidegib (Odomzo), in 2015. Those agents inhibit Smoothened (SMO), a transmembrane protein involved in hedgehog pathway signal transduction.

In patients with metastatic BCC resistant to HHIs, treatment with arsenic trioxide and itraconazole may offer some benefit. Ally and colleagues reported that three of five men with resistant metastatic BC responded to a regimen of intravenous arsenic trioxide, 5 days every 28 days, and oral itraconazole on days 6 to 28. Although some patients experienced stable disease for 3 months, none had tumor shrinkage; the authors suggest that continuous dosing may be required to fully inhibit the hedgehog pathway and achieve clinical response in such cases.[71]

In 2021, the first immunotherapy, cemiplimab (Libtayo), was fully approved for locally advanced BCC and granted accelerated approval for patients with metastatic BCC previously treated with an HHI or for whom an HHI is not appropriate.

Surgical Modalities and Guidelines

The goal of therapy for patients with BCC is removal of the tumor with the best possible cosmetic result. By far, surgical modalities are the most studied, most effective, and most used BCC treatments. The effectiveness of surgical modalities depends heavily on the surgeon's skills; considerable differences in cure rates have been observed among surgeons. Modalities used include electrodesiccation and curettage, excisional surgery, Mohs micrographically controlled surgery, and cryosurgery.[72, 73, 74, 75]

National Comprehensive Cancer Network (NCCN) guidelines recommend treating low-risk BCC in non–hair-bearing areas with curettage and electrodessication. If fat is reached, surgical excision should generally be performed. Standard excision is an alternative, if the lesion can be excised with 4-mm clinical margins and second-intention healing, linear repair, or skin graft. Margins should be assessed postoperatively. High-risk patients should undergo excision with postoperative margin assessment or a Mohs resection.[7]

The American Academy of Dermatology, in collaboration with the American College of Mohs Surgery, the American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery, has developed appropriate use criteria for Mohs micrographic surgery. These include criteria for rating the appropriateness of Mohs micrographic surgery in 69 basal cell carcinoma scenarios.[76]

Line-field confocal optical coherence tomography (LC-OCT) is a recently developed technique that allows noninvasive high-resolution (1–2 μm) skin imaging. It can be used for presurgical imaging and margin mapping, with the goal of facilitating complete and accurate excision of BCC with narrow margins.

Some studies suggest that dermato-oncologic surgery is associated with a high risk of infection.[35] This risk is greater in patients with diabetes and in those having such surgery in the thigh or lower leg and foot.

See Surgical Treatment of Basal Cell Carcinoma for more complete information on this topic.

Topical Treatments

Several topical creams are used in the management of BCC that is nonrecurring and superficial. NCCN guidelines state that low-risk patients with superficial BCCs who cannot undergo surgery or radiation can be treated with topical therapies, although the cure rate may not be as high. Such treatments may also be used in patients with a high risk of multiple primary tumors.[7]

Topical 5-fluorouracil 5%

Topical 5-fluorouracil 5% cream may be used to treat small, superficial BCCs in low-risk areas.[20] It interferes with DNA synthesis by blocking methylation of deoxyuridylic acid and inhibiting thymidylate synthetase and, subsequently, cell proliferation.

In properly selected (eg, thin) tumors, cure rates of approximately 80% have been obtained. The cream is generally applied twice daily and must be used for at least 6 weeks for the treatment of superficial BCC.[77]

Given that 5-fluorouracil can act on BCCs that are too small to be seen with the unaided eye, it may be used in patients with basal cell nevus syndrome or to preemptively treat subclinical tumors. Nevertheless, because not all tumors respond completely, careful patient monitoring is essential.

The use of 5-fluorouracil for other types of BCC is generally not recommended because it may not penetrate deeply enough into the dermis to eradicate all tumor cells. Irritation and crusting are common and expected; significant irritation and discomfort are not uncommon, but scars are unusual. The recurrence rate is very high.

Imiquimod

Imiquimod 5% cream (Aldara) is approved by the US Food and Drug Administration for the treatment of nonfacial superficial BCC.[78, 79] Several studies have shown imiquimod to be curative in all patients with superficial BCC if used twice daily and in 73-82% of patients when used once a day for 6-12 weeks. Smaller studies have shown similar responses for nodular BCC.[18]

Treatment is often initiated at 3-7 times per week and the dosage is increased as tolerated to once or twice daily, to maintain mild-to-moderate skin irritation.[80, 81] Patients can titrate the frequency of application to maintain low-to-moderate skin irritation. A 12-week course of treatment is often used, which does not need be contiguous.[72]

In a study of 601 patients with histologically proven superficial BCC, topical imiquimod cream (once daily, 5 times a week, for 6 weeks) was superior, and topical fluorouracil (twice daily for 4 weeks) was noninferior, to methylaminolevulinate photodynamic therapy (2 sessions with an interval of 1 week). At both 3- and 12-month follow-up, the proportion of patients who were tumor-free was 72.8% for methylaminolevulinate photodynamic therapy, 83.4% for imiquimod cream, and 80.1% for fluorouracil cream.[82]

Tazarotene

The receptor-selective acetylenic retinoid tazarotene, which is approved for treatment of acne, psoriasis, and wrinkles, can also be used to treat small low-risk BCCs. Tazarotene is thought to cause BCC regression by increasing apoptosis and by decreasing cell proliferation in the skin cancer cells. In one case series, about 70.8% of the BCCs had clinical and dermoscopic regression of more than 50%, and 30.5% healed without recurrence after 3 years; most unresponsive tumors showed keratotic differentiation. The study involved the application of tazarotene 0.1% gel for 24 weeks in 154 small, superficial, and nodular BCCs (109 patients). Changes were followed up by dermoscopy and histologic examination.[83]

In addition to being an off-label indication, another drawback to topical tazarotene for the treatment of BCC is that it requires long-term therapy, for 5-8 months. The only reported adverse effect is dry/irritated skin, which resolves after discontinuation of tazarotene.

Radiation Therapy

BCCs are usually radiosensitive, and radiation therapy (RT) can be used for advanced and extended lesions and in those patients for whom surgery is not suitable (eg, because of allergy to anesthetics, current anticoagulant therapy, a tendency to form keloids,[84] or facial tumors). In a retrospective analysis of 1715 histologically confirmed primary cutaneous carcinomas (712 BCCs, 994 squamous cell carcinomas [SCCs], nine tumors with distinct BCC and SCC characteristics) treated with superficial radiation therapy, recurrence rates for BCC at 2 and 5 years were 2% and 4.2%, respectively.[85]

Postoperative radiation can also be a useful adjunct when patients have aggressive tumors that were treated surgically or when surgery has failed to clear the margins of the tumor.[8]  The treatment of locally advanced BCCs may result in complete remission in approximately 70% of patients.[86]

In the past, RT was a common treatment modality because of its high cure rate (97% for primary tumors). It is now used sparingly, because it is time consuming and extremely expensive. With the advancement in surgical techniques and other treatment modalities, RT is a reasonable treatment choice for recurrent tumors. It may be reserved for primary lesions requiring difficult or extensive oculoplastic surgery. It also eliminates the need for skin grafting when surgery would result in an extensive defect.

RT is contraindicated in young patients because of the high risk of radiodermatitis and scars; in lesions on the trunk and extremities; and in delayed cancer recurrence (eg, especially in patients previously treated with radiation). RT requires multiple visits. Treatment results in radiation damage and, therefore, should be reserved for older patients. RT is less effective for nonfacial tumors.

RT also is contraindicated in patients with connective tissue diseases or genetic conditions predisposing to skin cancer (eg, xeroderma pigmentosum, epidermodysplasia verruciformis, basal cell nevus syndrome). This histologic type in conjunction with RT may induce more tumors in the treated area. Radiation adverse effects include dermatitis, keratinization of the conjunctiva, and chronic keratitis.

Cosmetic results are generally good to excellent, with a small amount of hypopigmentation or telangiectasia in the treatment port. This therapy can be less disfiguring than surgical excision. Nevertheless, long-term results after several years can be deforming. Another disadvantage of this technique is that surgical margins cannot be examined. Tumors recurring in previously irradiated sites tend to be aggressive and difficult to treat and reconstruct. RT remains an important, feasible option in selected patients with BCC.

The NCCN guideline supports RT for patients whose condition is appropriate, with the reservation that in order to achieve its benefits (high cure rates and good comesis), it must be administered carefully and with attention to algorithm details by well-trained specialists. Training and proper support are particularly essential to the use of intensity-modulated RT as primary treatment. Medical physicists must provide the necessary support and training in this new technology.[7]

Photodynamic Therapy

Photodynamic therapy (PDT)  has been approved in over 18 countries worldwide for use in at least one nonmelanoma skin cancer,   including BCCs.[87, 88] PDT uses specific wavelengths of light to photoexcite porphyrins that have been applied to neoplastic and preneoplastic cells. This increased energy is rapidly absorbed by adjacent tissue oxygen, causing the formation of singlet oxygen radicals. These radicals rapidly react with adjacent tissue and destroy it.

Photoreactive molecules for ADT include the following[88] :

ALA is the only US Food and Drug Administration approved photoreactive molecule for PDT in the United States. It is photoactivated with blue light for 1000 seconds after 1 hour of incubation.

Photoreactive molecules for PDT are administered orally or parenterally, as well as applied topically, and localizes into tumor cells before activation by exposure to light (eg, laser). The efficacy of PDT is low, and this treatment is frequently palliative. PDT may cause local edema, erythema, blistering, and ulceration, but the final cosmetic effect is good.

PDT yielded only a 50% cure rate for superficial BCC, versus an 83% cure rate for nodular BCC, in a study by Calzavara-Pinton et al.[89] For BCC of the eyelid, PDT has no distinct advantage over other well-established therapies, althoug in a study by Puccioni et al, MAL-PDT showed notable success and appears to be a viable option in the treatment of BCC of the eyelid in selected patients.[90]

British guidelines include the following recommendations for use of PDT[88] :

PDT as an adjunct is a reasonable choice in the following cases:

Although its use is off label, PDT has been used for treatment and prevention of BCCs, including those patients with immunosuppression and nevoid BCC syndrome. Shallow tumors, such as superficial BCCs, respond most consistently. Surgical excision has been shown to be significantly more effective than ALA-PDT in the treatment of nodular BCC.[91]

The strongest support for PDT as a modality for BCCs comes with data on thin lesions treated with MAL-PDT (used outside the United States), but at least one long-term follow-up trial has also shown surgical excision to be superior.[92]

Christensen et al reported a 10-year lesion complete response rate of 87% with two sessions of dimethylsulphoxide (DMSO)-supported ALA-PDT and curettage for primary, small BCC. Favorable cosmetic outcomes also were reported for nearly all cases.[93]

Various protocols have been followed to achieve varying levels of success: increasing incubation time, increasing occlusion time, and using longer and/or deeper-penetrating wavelengths of light (eg, red light or pulse-dye laser). Many patients continue to prefer PDT because of its short healing time, excellent cosmesis, and relative affordability.

Hedgehog Pathway Inhibitors

Vismodegib

Vismodegib (Erivedge) is the first FDA-approved drug for advanced forms of BCC. It selectively inhibits Smoothened (SMO), a key transmembrane protein involved in hedgehog signal transduction of cancerous epithelial cells.[94] FDA approval was based on a single, international, open-label trial. Of the 104 participants, 96 were evaluable. Of those with metastatic BCC (n=33), 30.3% had partial response, but none had complete response. With locally advanced BCC (n=63), 22% showed a partial response and 20% showed complete response.[95]

Sonidegib

A second hedgehog pathway inhibitor (HHI), sonidegib (Odomzo), was approved by the FDA in 2015. Approval was based on the BOLT trial in patients had locally advanced BCC not amenable to curative surgery or radiation, or metastatic BCC. Patients were randomized in a 1:2 ratio to receive 200 mg or 800 mg oral sonidegib daily, stratified by disease, histologic subtype, and geographic region. For the 66 patients in the 200 mg group, the overall response rate was 58%; three patients (5%) achieved a complete response and 35 (53%) achieved a partial response. The duration of response ranged from 1.9 to 18.6 months, and in approximately half of the responding patients, the tumor shrinkage lasted at least 6 months.[96]

Checkpoint Inhibitor

Cemiplimab, a programmed death 1 (PD-1) inhibitor,  was the first immunotherapy approved by the FDA for advanced BCC after hedgehog pathway inhibition. In 2021, it was fully approved for patients with locally advanced BCC and granted accelerated approval for patients with metastatic BCC (mBCC).

Approval for locally advanced BCC was based on a phase 3, nonrandomized, open-label trial, Study 1620. Patients (n=138) with locally advanced or metastatic BCC whose BCC had progressed on HHI or who were not candidates for HHI therapy received cemiplimab until disease progression, unacceptable toxicity, or completion of planned treatment. The confirmed objective response rate was 29% (95% CI: 19%-40%) for patients with locally advanced BCC and 21% (95% CI: 8%-41%) for those with mBCC. Observed duration of response (DOR) for at least 6 months was reported in 79% of locally advanced BCC responders and all mBCC responders. For both treatment groups, median DOR was not reached.[97]

Extended analysis of results in the study patients with locally advanced BCC (n=84) showed that on median follow-up of 15.9 months, the objective response rate was 38.1% in patients who were intolerant of HHIs and 30.2% in those with disease resistant to HHIs. In responders, 83.8% had ongoing response at 12 months. The most common treatment-emergent adverse event leading to treatment discontinuation was colitis.[98]

Final analysis of results in the study patients with mBCC (n=54) showed that on median follow-up of 8 months, median progression-free survival was 10 months, median overall survival was 50 months, and median DOR was still not reached. The most common treatment-emergent adverse events were fatigue, in 43% of patients, and diarrhea, in 37%.[99]

Recurrence

The following is a list of treatments and their 5-year recurrence rates for primary BCCs:

These rates are probably affected by the fact that most clinicians use cryotherapy, curettage, and desiccation mostly on smaller and better-demarcated lesions.

Prevention

Avoid possible potentiating factors (eg, sun exposure, ionizing radiation, arsenic ingestion, tanning beds). The regular use of sun-protecting clothing (eg, wide-brimmed hat, long-sleeved shirts, sunglasses with ultraviolet [UV] protection) is recommended when outdoors. Instruct patients to avoid sun exposure particularly during the middle of the day (ie, 11 am to 3 pm), which is the most dangerous time. Also, the sun's rays are especially intense in sunny climates and at high altitudes, and UV radiation can also pass through clouds and water. Patients should be instructed to be careful on the beach and in the snow because sand, water, and snow reflect sunlight and increase the amount of received UV radiation.

The American Cancer Society recommends a dermatologic examination every 3 years for people aged 20-40 years and every year for people older than 40 years. The US Preventive Services Task Force determined that insufficient evidence exists to make a recommendation on asymptomatic adults receiving skin cancer screenings from a clinician.[100]

Nicotinamide (vitamin B3) has been shown to protect against damage caused by UV radiation and to reduce the rate of new actinic keratoses. A phase 3 trial, in 386 participants who had had at least two nonmelanoma skin cancers in the previous 5 years, found that after 12 months the rate of new nonmelanoma skin cancers was lower by 23% in participants taking 500 mg of nicotinamide twice daily, compared with those taking a placebo (P = 0.02).[101]  However, a similar phase 3 trial in immunosuppressed solid-organ transplant recipients reported no significant difference in the number of new keratinocyte cancers with nicotinamide versus placebo.[102]

Nonablative fractional lasers (NAFL) have FDA approval for the treatment of actinic damage. In a study by Benson et al that included 43 patients with a history of facial keratinocyte carcinomas (ie, basal or squamous cell skin cancers) and 52 matched control subjects, new facial keratinocyte carcinomas developed in 20.9% of patients treated with NAFL, compared with 40.4% of control subjects (relative risk 0.52, P = 0.049). New keratinocyte carcinomas also developed significantly more slowly in the treatment versus the control arm.

Consultations

Ideally, treatment options for the patient with BCC should be evaluated jointly by a surgeon, dermatologist, and radiotherapist and based on histologic diagnosis.

Although early BCC can be treated adequately by means of local excision, advanced and recurrent tumors are best managed by a multidisciplinary team involving head and neck surgical oncologists, Mohs micrographic surgeons, reconstructive plastic surgeons, pathologists, prosthetists, and radiation oncologists.

Long-Term Monitoring

Mc Loone et al found that patients who are diagnosed with BCC have a 35% chance of developing another tumor within 3 years and a 50% chance of developing another (not recurrent) BCC within 5 years.[46] The NCCN guidelines state that 30-50% of patients will develop another nonmelanoma skin cancer within 5 years. These patients are also at an increased risk of developing cutaneous melanoma.[7] Therefore, regular skin screenings are recommended.[46, 7]

Fewer than 1% of BCCs spread to another site in the body; nevertheless, after treatment, which is curative in more than 95% of cases, BCC may develop in new sites. Recommend appropriate prolonged or lifelong follow-up care.

Tumors occurring after radiotherapy tend to be more aggressive and infiltrative than other tumors. Metastasis is rare but has been reported with rates of 0.01-0.1%. Metastases most often originate from large, ulcerated tumors. Metastases usually occur in regional lymph nodes. Follow-up visits are scheduled 3 months after therapy and every 6 months to 1 year thereafter for the life of the patient.

Guidelines Summary

Guidelines Contributors: Wesley Wu, MD Resident Physician, Department of Dermatology, Baylor College of Medicine and Mohsin R Mir, MD Director, High Risk Skin Cancer Clinic, Assistant Professor, Mohs Surgery, Laser and Cosmetic Surgery, Department of Dermatology, Baylor College of Medicine

Skin Cancer Counseling and Prevention

In 2018, the U.S. Preventive Services Task Force (USPSTF) updated its guidelines on behavioral counseling on skin cancer prevention.[103]  Recommendations were as follows:

In a 2011 policy statement, the American Academy of Pediatrics issued guidelines on limiting sun exposure in children. Specific recommendations for pediatricians include the following[104] :

The American Cancer Society (ACS) advises the importance of protecting children from the sun because of the increased risk for cancer resulting from severe sunburns in childhood.[105]  For all individuals, regardless of age, the ACS recommends the following[106] :

Skin Cancer Screening

In 2023, the USPSTF renewed its conclusion that there is not enough evidence to recommend for or against routine screening (total body examination by a primary care doctor or patient self-examination) for early detection of skin cancers in the adolescent and adult general population.[100]

The USPSTF did note the following clinical considerations:

The American Cancer Society does not have guidelines for the early detection of skin cancer but notes that many physicians recommend regular self skin examinations, typically once a month and with the help of a partner for areas that are hard to see, along with prompt evaluation by a clinician of any lesions that are new or demonstrate a progressive change in appearance.[107] The Skin Cancer Foundation also recommends skin self-examinations and, for people with a history of basal cell carcinoma, yearly professional skin exams.[108]

Moreover, the American Academy of Dermatology (AAD) promotes free skin examinations by volunteer dermatologists for the general population through the Academy's SPOTme™ Screening Program.[109] The AAD also encourages regular self-examination by individuals, such as on one’s birthday.

Diagnosis

Guidelines covering the diagnosis of basal cell skin cancer have been issued by the following organizations:

The NCCN guidelines recommend the following workup for diagnosis of basal cell skin cancer[7] :

The AAD guidelines recommend the following biopsy techniques for basal cell carcinoma (BCC)[110] :

AAD recommendations regarding biopsy are as follows:

In cases of suspected BCC, the AAD guidelines strongly recommend providing the following clinical information when sending a biopsy specimen to the pathologist:

   Providing the following information is recommended:

   On the final pathology report (on excision specimens), inclusion of the following information is recommended:

The European multidisciplinary guidelines contain the following recommendations on the diagnosis of BCC[6] :

For the staging workup, the European multidisciplinary guidelines recommend collecting a detailed medical history and performing a physical examination, with an emphasis on a complete skin examination. Recommendations on imaging studies for staging of BCC are as follows[6] :

The German Cancer Society and the German Society of Dermatology guidelines contain the following recommendations, based on strong consensus, on the diagnosis of BCCs[111] :

Risk Stratification

Basal cell carcinoma rarely metastasizes and is usually not staged. The NCCN and European multidisciplinary guidelines classify tumors as low or high risk, on the basis of risk factors associated with recurrence and metastasis.[7, 6]

The risk factors evaluated include the following:

The NCCN guidelines classify high-risk lesions by size and location, as follows[7] :

Immunosuppression such as from antirejection therapy in organ transplant recipients and long-term use of psoralen and ultraviolet A light (PUVA) confers a higher risk of basal cell carcinoma recurrence and metastasis. Perineural involvement and previous radiotherapy are also associated with higher risk.[7]

In addition, histologically aggressive subtypes in any portion of the tumor are more likely to recur than nodular and superficial basal cell carcinomas. Histologically aggressive subtypes include the following patterns[7] :

Low-risk, non-aggressive subtypes include the following[7] :

Treatment

According to the National Comprehensive Cancer Network (NCCN) guidelines, the goal of treatment of BCCs is elimination of the tumor with maximal preservation of function and physical appearance. As such, treatment decisions should be individualized according to the patient's particular risk factors and preferences. In nearly all cases, the recommended treatment modality is surgery, but patient preference may lead to choosing radiation therapy in order to achieve optimal results.[7]

Treatments vary according to cancer size, depth, and location. In select patients at high risk for multiple primary tumors, increased surveillance and prophylactic measures may be appropriate.[7]

In low-risk lesions, several options are recommended by the NCCN. Curettage and electrodessication in non–hair-bearing areas is appropriate. If lesions extend to adipose tissue, surgical excision is necessary.

A standard excision with 4 mm margins with postoperative margin assessment is also appropriate, reportedly with a higher 5-year cure rate. Tissue rearrangement (eg, flap reconstruction, extensive undermining) should not be undertaken until clear margins are identified. Second-intention healing, linear repair, or skin graft are acceptable modalities.

Radiotherapy is another potential treatment, especially for nonsurgical candidates over 60 years of age. In superficial cancers, topical therapies such as 5-fluorouracil, imiquimod, photodynamic therapy (eg, aminolevulinicacid [ALA], porfimer sodium), or cryotherapy may be considered, even though the cure rate may be lower. If margins are positive, treatment options include Mohs micrographic surgery (MMS); other forms of peripheral and deep en face margin assessment (PDEMA); or re-excision, if clinically feasible.[7]

More aggressive treatments should be pursued for basal cell skin cancer with any high-risk feature. Comprehensive intraoperative margin control is the NCCN’s preferred treatment modality; if standard excision with postoperative margin assessment is chosen, wider surgical margins and increased recurrence rates should be expected. Radiotherapy may also be used in high-risk tumors in non-surgical candidates, but may also be used if residual disease, extensive perineural involvement, or large-nerve involvement is present.[7]

In complicated lesions where radiation and surgery have been exhausted or are impractical, the NCCN guidelines recommend multidisciplinary tumor board consultation with consideration of vismodegib or clinical trial enrollment.[7]    

The American Academy of Dermatology (AAD) guidelines include the following recommendations for surgical treatment[110] :

AAD recommendations for non-surgical treatment are as follows[110] :

The European consensus-based interdisciplinary guideline contains the following recommendations for treatment of BCC[6] :

The European guidelines include the following recommendations on nonsurgical treatment[6] :

Updated guidelines on the management of BCC in adults, published by the British Association of Dermatologists (BAD) in 2021, include the following recommendations for surgical treatment[112] :

For systemic therapy, the BAD guidelines recommend offering vismodegib, if available, to adults with advanced BCC who are unsuitable for Mohs micrographic surgery, standard surgical excision, or radiotherapy, including patients with Gorlin syndrome, following multidisciplinary team discussion.

The BAD guidelines recommend offering radiotherapy as an option to adults (suggested age ≥ 60 years) with low-risk or high-risk BCC who are iunsuitable for or decline Mohs micrographic surgery or standard surgical excision and who express a preference for radiotherapy, and in whom the lesion is a nodular BCC; an infiltrative subtype of BCC, provided a sufficient planning margin is used; or an excised BCC with involved margins.[112]

The BAD guidelines recommend against offering radiotherapy for recurrent BCC following previous radiotherapy, or for lesions associated with certain genetic syndromes predisposing to skin cancers, for example Gorlin syndrome or xeroderma pigmentosum. Treatment alternatives should be discussed in a multidisciplinary team meeting. The BAD guidelines recommend against routinely offering radiotherapy for a BCC that is on an area of poor blood supply (eg, the lower limbs); in a younger patient (suggested age < 60 years), in whom the late effects of radiotherapy could be an issue; or invading bone or cartilage.[112]

In adult patients with low-risk BCC who are unsuitable for or decline standard surgical excision, BAD guidelines recommend offering the following as options:

In adults with excised high-risk BCC with an involved histological margin, BAD guidelines recommend offering further standard surgical re-excision, if not contraindicated, after multidisciplinary team discussion. The BAD guidelines recommend referring all adults with excised high-risk BCC with a close histological margin (< 1 mm) for multidisciplinary team discussion of management options, which may include surgical re-excision, Mohs micrographic surgery, radiotherapy, or monitoring.[112]

BAD recommendations for follow-up include the following:

Mohs micrographic surgery

In 2012, the American Academy of Dermatology in collaboration with the American College of Mohs Surgery, the American Society for Dermatologic Surgery (ASDS), and the American Society for Mohs Surgery published appropriate use criteria for MMS. The recommendations were based on the expert opinion and consensus of a rating panel of 17 Mohs surgeons and non-Mohs dermatologists.[76]

The report deemed MMS appropriate for all BCCs — regardless of location, size, and histologic subtype — in the following:

MMS was also considered appropriate for all primary and recurrent BCCs in Area H (central face, eyelids [including inner/outer canthi], eyebrows, nose, lips [cutaneous/mucosal/vermilion], chin, ear and periauricular skin /sulci, temple, genitalia [including perineal and perianal], hands, feet, nail units, ankles, and nipples/areola).

MMS was endorsed for the following BCCs in Area M (cheeks, forehead, scalp, neck, jawline, pretibial surface):

MMS was also deemed appropriate for the following BCCs in Area L (trunk and extremities, excluding pretibial surface, hands, feet, nail units and ankles):

Use of MMS was considered inappropriate solely in Area L for the following[76] :

In 2015, the ASDS released consensus guidelines for the treatment of BCCs that recommended MMS as the treatment of choice for high-risk BCCs and for those in cosmetically sensitive locations. The guidelines also noted that MMS offers complete tumor margin analysis while other surgical options do not.[113] The NCCN prefers MMS for high-risk tumors and as adjuvant therapy if margins are positive after excision.[7]

Recurrence and metastatic disease

For recurrent or advanced disease that is local, the NCCN guidelines recommend following primary treatment pathways. For nodal or distant metastases, the NCCN recommends multidisciplinary consultation to consider one or more of the following options:

AAD guidelines include the following recommendations for managing locally advanced or metastatic BCC[110] :

Radiation therapy

In 2020, the American Society for Radiation Oncology published clinical practice guidelines on definitive and postoperative radiation therapy (RT) for basal and squamous cell cancers of the skin.[114] Recommendations regarding definitive radiation therapy for BCC are as follows:

Postoperative RT is recommended in cases of gross perineural spread that is apparent clinically or radiologically. Postoperative RT is conditionally recommended in the following clinical scenarios:

Recommendations for cutaneous BCC that has metastasized to clinically apparent regional lymph nodes are as follows:

Conditional recommendations for cutaneous BCC in patients who are at high risk of regional nodal metastasis are as follows:

The recommended radiation dose for patients with cutaneous BCC who are undergoing adjuvant RT after therapeutic lymphadenectomy is 6000-6600 cGy (conventional fractionation [180-200 cGy/fx]).

Recommended radiation techniques/dose-fractionation schedules for patients with BCC who are receiving RT in a definitive setting are as follows:

Recommended dose-fractionation schedules for patients with BCC who are receiving RT in a postoperative setting are as follows:

Follow-up and surveillance

The NCCN recommends the following measures[7] :

AAD recommendations for the follow-up of BCC and reduction of risk for future skin cancer are as follows[110] :

Medication Summary

Medications used for the treatment of basal cell carcinoma (BCC) include the following:

Fluorouracil topical (Efudex)

Clinical Context:  5-Fluorouracil topical 5% cream or solution is used topically for the management of superficial BCC. It interferes with DNA synthesis by blocking methylation of deoxyuridylic acid and inhibiting thymidylate synthetase and, subsequently, cell proliferation.

Interferon alfa-2b (Intron-A)

Clinical Context:  Interferon alfa-2b is a protein product manufactured with recombinant DNA technology. The mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may be important.

As an investigational drug for nodular BCC, interferon alfa-2b was used in a randomized, placebo-controlled multicenter study with 172 patients. Intralesional injections of 1.5 million U administered 3 times/wk for 3 wk yielded an 86% complete-response rate, compared with 29% for placebo. A similar study did not show efficacy for morpheaform or aggressive BCCs.

Class Summary

The most common chemotherapeutic agent used in superficial basal cell carcinoma is topical 5-fluorouracil.

Vismodegib (Erivedge)

Clinical Context:  Vismodegib is a Hedgehog (Hh) pathway inhibitor. Vismodegib binds to and inhibits SMO, a transmembrane protein involved in Hedgehog signal transduction. This agent is indicated for treatment of adults with metastatic basal cell carcinoma or with locally advanced basal cell carcinoma that has recurred following surgery, or those who are not candidates for surgery or radiation.

Sonidegib (Odomzo)

Clinical Context:  Sonidegib binds to and inhibits SMO, a transmembrane protein involved in Hedgehog signal transduction. Indicated for adults with locally advanced basal cell carcinoma that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy.

Class Summary

The Hedgehog signaling pathway is important in embryogenesis, but in adults, it is mostly inactive. Signaling is relayed by key proteins including Smoothened homologue (SMO). Hedgehog ligand-expressing cancerous epithelial cells that are activated by the hedgehog signaling pathway may cause growth-promotion.

Cemiplimab (Cemiplimab-rwlc, Libtayo)

Clinical Context:  Recombinant human immunoglobulin G4 monoclonal antibody binds to PD-1 and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. It is indicated for locally advanced BCC and granted accelerated approval for patients with metastatic BCC previously treated with a HHI or for whom a HHI is not appropriate.

Methyl aminolevulinate (Metvixia)

Clinical Context:  Methyl aminolevulinate cream is a porphyrin precursor used in combination with narrow-band, red-light illumination for nonhyperkeratotic, nonpigmented actinic keratoses. When used with photodynamic therapy, the accumulation of photoactive porphyrins produces a photodynamic reaction that results in a cytotoxic process dependent upon the simultaneous presence of oxygen.

Class Summary

Photodynamic therapy (PDT) for basal cell carcinomas is the process of using specific wavelengths of light to photoexcite porphyrins that have been applied to neoplastic and preneoplastic cells. This increased energy is rapidly absorbed by adjacent tissue oxygen, causing the formation of singlet oxygen radicals. These radicals rapidly react with adjacent tissue and destroy it.

Tazarotene (Avage, Fabior, Tazorac)

Clinical Context:  Tazarotene is a retinoid prodrug with an active metabolite that modulates differentiation and proliferation of epithelial tissue; it also may have anti-inflammatory and immunomodulatory properties. It is not approved by the US Food and Drug Administration for treating basal cell carcinoma.

Class Summary

These agents decrease cohesiveness of abnormal hyperproliferative keratinocytes and may reduce potential for malignant degeneration. It modulates keratinocyte differentiation.

Imiquimod (Aldara)

Clinical Context:  The precise mechanism of imiquimod for superficial BCC is unknown. It may increase tumor infiltration by lymphocytes, dendritic cells, and macrophages. It is indicated for biopsy-confirmed primary nonfacial superficial BCC in adults with normal immune systems. Additionally, tumors must not exceed 2 cm in diameter on certain areas of the body. Imiquimod is indicated only when surgical methods are not appropriate.

Class Summary

Products that induce cytokines, including interferon alpha, have been shown to be effective.

What is basal cell carcinoma (BCC)?What are the signs and symptoms of basal cell carcinoma (BCC)?Where is basal cell carcinoma (BCC) most commonly located?What are the clinicopathologic types of basal cell carcinoma (BCC)?What is the role of imaging studies in the diagnosis of basal cell carcinoma (BCC)?How is a diagnosis of basal cell carcinoma (BCC) confirmed?Which histology findings are characteristic of basal cell carcinoma (BCC)?Which surgery techniques are performed in the treatment of basal cell carcinoma (BCC)?What is the role of radiation therapy in the treatment of basal cell carcinoma (BCC)?What is the role of photodynamic therapy in the treatment of basal cell carcinoma (BCC)?What is the role of topical agents in the treatment of basal cell carcinoma (BCC)?Which medications are FDA approved for the treatment of basal cell carcinoma (BCC)?What is basal cell carcinoma (BCC)?What are the most common sites for basal cell carcinoma (BCC) lesions?How is the diagnosis of basal cell carcinoma (BCC) confirmed?What is the recommended treatment for basal cell carcinoma (BCC)?What are the treatment options for superficial basal cell carcinoma (BCC)?What is the pathophysiology of basal cell carcinoma?What is the role of the patched/hedgehog signaling pathways in the pathogenesis of basal cell carcinoma (BCC)?What is the role of radiation in the pathogenesis of basal cell carcinoma (BCC)?What is the role of DNA mismatch repair (MMR) proteins in the pathogenesis of basal cell carcinoma (BCC)?What causes of basal cell carcinoma (BCC)?What is the role of radiation exposure in the etiology of basal cell carcinoma (BCC)?What is the role of genetics in the etiology of basal cell carcinoma (BCC)?What is the role of arsenic ingestion to the etiology of basal cell carcinoma (BCC)?How much does immunosuppression increase the risk for basal cell carcinoma (BCC)?What is the role of xeroderma pigmentosum in the etiology of basal cell carcinoma (BCC)?What is nevoid basal cell carcinoma syndrome?What are the features of Bazex syndrome?What is the risk for development of basal cell carcinoma (BCC) in patients with a history of nonmelanoma skin cancer?Which skin types are at higher risk for basal cell carcinoma (BCC)?What is Rombo syndrome?What is the link between alcohol consumption and the development of basal cell carcinoma (BCC)?What is the role of hydrochlorothiazide (HCTZ) in the etiology of basal cell carcinoma (BCC)?What is the prevalence of basal cell carcinoma (BCC) in the US?What is the racial predilection of basal cell carcinoma (BCC)?How does the incidence of basal cell carcinoma (BCC) vary by sex?How does the incidence of basal cell carcinoma (BCC) vary by age?What is the prognosis of basal cell carcinoma (BCC)?What is the rate of recurrence for basal cell carcinoma (BCC)?What are signs of recurrence of basal cell carcinoma (BCC)?What is included in patient education about basal cell carcinoma (BCC)?What is the role of sunscreen in the prevention of basal cell carcinoma (BCC)?How should patients with basal cell carcinoma (BCC) be taught to perform self-exam for skin changes?What is the clinical history characteristic of basal cell carcinoma (BCC)?How are nodular basal cell carcinoma characterized?How is superficial basal cell carcinoma characterized?How are basal cell carcinoma tumors characterized?What are the most common sites for basal cell carcinoma?Which physical findings are characteristic of basal cell carcinoma?What are the clinicopathologic types of basal cell carcinoma (BCC)?How are pigmented basal cell carcinoma characterized?How is infiltrative basal cell carcinoma characterized?How is micronodular basal cell carcinoma characterized?How is morpheaform (sclerosing) basal cell carcinoma characterized?Which physical findings are characteristic of basal cell nevus syndrome (Gorlin syndrome)?What are the types of basal cell carcinoma (BCC)?What are diagnostic considerations in basal cell carcinoma?Which conditions should be included in the differential diagnoses of basal cell carcinoma (BCC)?What are the differential diagnoses for Basal Cell Carcinoma?What studies are included in the workup of basal cell carcinoma (BCC)?What is the role of skin biopsy in the workup of basal cell carcinoma?What is the role of cytology in the workup of basal cell carcinoma?Which histologic findings are characteristic of basal cell carcinoma (BCC)?Which histologic findings are characteristic of nodular basal cell carcinoma?Which histologic findings are characteristic of micronodular basal cell carcinoma?Which histologic findings are characteristic of pigmented basal cell carcinoma?Which histologic findings are characteristic of adenoid basal cell carcinoma?Which histologic findings are characteristic of morpheaform (sclerosing) basal cell carcinoma?Which histologic findings are characteristic of infiltrative basal cell carcinoma?Which histologic findings are characteristic of cystic basal cell carcinoma?Which histologic 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radiation therapy indicated in the treatment of basal cell carcinoma (BCC)?What is the role of Hedgehog (Hh) pathway inhibitors in the treatment of basal cell carcinoma (BCC)?What are the surgical options for the treatment of basal cell carcinoma (BCC)?What is the role of topical creams in the treatment of basal cell carcinoma (BCC)?What is the role of topical 5-fluorouracil 5% cream in the management of basal cell carcinoma (BCC)?What is the role of interferon in the management of basal cell carcinoma (BCC)?What is the role of imiquimod in the management of basal cell carcinoma (BCC)?What is the role of tazarotene in the management of basal cell carcinoma (BCC)?What is the role of radiation therapy for the management of basal cell carcinoma?What are the contraindications for radiation therapy to treat basal cell carcinoma (BCC)?What is the role of photodynamic therapy (PDT) in the management of basal cell carcinoma (BCC)?When is photodynamic therapy (PDT) indicated in the treatment of basal cell carcinoma (BCC)?What is the efficacy of photodynamic therapy (PDT) for the treatment for basal cell carcinoma (BCC)?What is the role of vismodegib in the management of basal cell carcinoma (BCC)?What is the role of sonidegib in the management of basal cell carcinoma (BCC)?What is the role of cemiplimab in the treatment of basal cell carcinoma?What are the 5-year recurrence rates following treatment for basal cell carcinoma (BCC)?How is basal cell carcinoma (BCC) prevented?Which medical personnel provide consultation to patients with basal cell carcinoma (BCC)?What is included in the long-term monitoring of basal cell carcinoma (BCC)?What is the role of retinoids in the management of basal cell carcinoma (BCC)?What are the USPSTF guidelines for skin cancer counseling and prevention of basal cell carcinoma (BCC)?What the American Academy of Pediatrics (AAP) guidelines for prevention of basal cell carcinoma (BCC) in children and adolescents?What are the American Cancer Society (ACS) recommendations or prevention of severe sunburns and basal cell carcinoma (BCC)?What are the USPSTF guidelines for screening and early detection of basal cell carcinoma (BCC)?What are the American Cancer Society and the American Academy of Dermatology (AAD) guidelines for screening and early detection of basal cell carcinoma (BCC)?Which organizations have issued treatment guidelines for basal cell carcinoma?What are the National Comprehensive Cancer Network (NCCN) guidelines for the workup of basal cell carcinoma (BCC)?What are the AAD biopsy diagnostic guidelines for basal cell carcinoma (BCC)?What are the German Cancer Society and the German Society of Dermatology guidelines for the workup of basal cell carcinoma (BCC)?How are basal cell carcinoma classified in the NCCN and EDF guidelines?What are histologically aggressive subtypes of basal cell carcinoma?What are low-risk, non-aggressive subtypes of basal cell carcinoma?What are the National Comprehensive Cancer Network (NCCN) treatment guidelines for basal cell carcinoma (BCC)?What are the American Society for Dermatologic Surgery (ASDS) treatment guidelines for basal cell carcinoma (BCC)?What are the AAD treatment guidelines for basal cell carcinoma (BCC)?What are the appropriate use criteria for Mohs micrographic surgery (MMS) in the treatment of basal cell carcinoma (BCC)?What are the guidelines on the treatment of recurrent and metastatic basal cell carcinoma (BCC)?What are the guidelines on the follow-up and surveillance of patients with basal cell carcinoma (BCC)?What are the American Society for Radiation Oncology guidelines on radiation therapy for basal cell carcinoma (BCC)?Which medications are used for the treatment of basal cell carcinoma (BCC)?Which medications in the drug class Keratolytic Agents are used in the treatment of Basal Cell Carcinoma?Which medications in the drug class Photosensitizing Agent, Topical are used in the treatment of Basal Cell Carcinoma?Which medications in the drug class PD-1/PD-L1 Inhibitors are used in the treatment of Basal Cell Carcinoma?Which medications in the drug class Antineoplastics, Hedgehog Pathway Inhibitor are used in the treatment of Basal Cell Carcinoma?Which medications in the drug class Antineoplastic Agents are used in the treatment of Basal Cell Carcinoma?Which medications in the drug class Topical Skin Products are used in the treatment of Basal Cell Carcinoma?

Author

Robert S Bader, MD, Dermatologist, Section of Dermatology, Department of Medicine, Broward Health - North

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

William D James, MD, Emeritus Professor, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier<br/>Served as a speaker for various universities, dermatology societies, and dermatology departments.

Chief Editor

Mark S Granick, MD, FACS, Professor of Surgery, Division of Plastic Surgery, Rutgers New Jersey Medical School; Professor of Surgery, Rutgers Robert Wood Johnson Medical School; Medical Director, University Hospital Wound Care Center

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: PolarityTE; Misonix<br/>Serve(d) as a speaker or a member of a speakers bureau for: Misonix, PolarityTE<br/>Received income in an amount equal to or greater than $250 from: Misonix, PolarityTE.

Additional Contributors

Andrew S Kennedy, MD, FACRO, Physician-in-Chief, Radiation Oncology, Sarah Cannon; Director, Radiation Oncology Research, Sarah Cannon Research Institute

Disclosure: Nothing to disclose.

Laura Diomede, University of Bari School of Medicine, Italy

Disclosure: Nothing to disclose.

Luigi Santacroce, MD, Assistant Professor, Medical School, State University at Bari, Italy

Disclosure: Nothing to disclose.

Acknowledgements

Sanjiv S Agarwala, MD Chief of Oncology and Hematology, St Luke's Cancer Center, St Luke's Hospital and Health Network; Professor, Temple University School of Medicine

Sanjiv S Agarwala, MD is a member of the following medical societies: American Association for Cancer Research, American Society for Head and Neck Surgery, American Society of Clinical Oncology, Eastern Cooperative Oncology Group, and European Society for Medical Oncology

Disclosure: BMS Honoraria Speaking and teaching; Novartis Consulting fee Consulting; Merck Consulting fee Consulting

Michael G Barkett, MD, MS Cardiovascular Diseases, Department of Medicine, Advocate Aurora Health

Disclosure: Nothing to disclose.

Daniel Berg, MD, FRCP(C) Professor of Dermatology, Director of Dermatologic Surgery, University of Washington School of Medicine

Daniel Berg, MD, FRCP(C) is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Mohs Micrographic Surgery and Cutaneous Oncology, and American Society for Dermatologic Surgery

Disclosure: Genentech Honoraria Review panel membership

Gregory Caputy, MD, PhD, FICS Chief Surgeon, Aesthetica Plastic and Laser Surgery Center, Inc

Gregory Caputy, MD, PhD, FICS is a member of the following medical societies: American Society for Laser Medicine and Surgery, International College of Surgeons, International College of Surgeons US Section, Pan-Pacific Surgical Association, and Wound Healing Society

Disclosure: Syneron Corporation Salary Speaking and teaching

Edward F Chan, MD Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania School of Medicine

Edward F Chan, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Robert A Copeland Jr, MD Chair, Professor, Department of Ophthalmology, Howard University College of Medicine

Robert A Copeland Jr, MD is a member of the following medical societies: American Academy of Ophthalmology

Disclosure: Nothing to disclose.

Mark T Duffy, MD, PhD Consulting Staff, Division of Oculoplastic, Orbito-facial, Lacrimal and Reconstructive Surgery, Green Bay Eye Clinic, BayCare Clinic; Medical Director, Advanced Cosmetic Solutions, A BayCare Clinic

Mark T Duffy, MD, PhD is a member of the following medical societies: American Academy of Ophthalmology, American Medical Association, American Society of Ophthalmic Plastic and Reconstructive Surgery, Sigma Xi, and Society for Neuroscience

Disclosure: Allergan - Botox Cosmetic Honoraria Speaking and teaching

Hon-Vu Q Duong, MD Clinical Instructor of Ophthalmology and Ophthalmic Pathology, Westfield-Nevada Eye and Ear; Senior Lecturer of Neurosciences:Anatomy and Physiology, Nevada State College

Hon-Vu Q Duong, MD is a member of the following medical societies: American Academy of Ophthalmology

Disclosure: Nothing to disclose.

Dirk M Elston, MD Director, Ackerman Academy of Dermatopathology, New York

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Jaime R Garza, MD, DDS, FACS Consulting Staff, Private Practice

Jaime R Garza, MD, DDS, FACS is a member of the following medical societies: Alpha Omega Alpha, American Academy of Otolaryngology-Head and Neck Surgery, American College of Surgeons, American Society for Aesthetic Plastic Surgery, American Society of Maxillofacial Surgeons, Texas Medical Association, and Texas Society of Plastic Surgeons

Disclosure: Allergan None Speaking and teaching; LifeCell None Consulting; GID, Inc. Grant/research funds Other

Shahin Javaheri, MD Chief, Department of Plastic Surgery, Martinez Veterans Affairs Outpatient Clinic; Consulting Staff, Advanced Aesthetic Plastic & Reconstructive Surgery

Shahin Javaheri, MD is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery and American Society of Plastic Surgeons

Disclosure: Nothing to disclose.

Shang I Brian Jiang, MD Associate Clinical Professor of Medicine and Dermatology, Director, Dermatologic and Mohs Micrographic Surgery, Program Director, UCSD Dermatologic and Mohs Surgery Fellowship, University of California School of Medicine, San Diego

Shang I Brian Jiang, MD, is a member of the following medical societies: American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery, and Association of Professors of Dermatology

Disclosure: DUSA Corporation Grant/research funds PI for Industry Sponsored Clincal Trial

Klaus-Dieter Lessnau, MD, FCCP Clinical Associate Professor of Medicine, New York University School of Medicine; Medical Director, Pulmonary Physiology Laboratory; Director of Research in Pulmonary Medicine, Department of Medicine, Section of Pulmonary Medicine, Lenox Hill Hospital

Klaus-Dieter Lessnau, MD, FCCP is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Medical Association, American Thoracic Society, and Society of Critical Care Medicine

Disclosure: Nothing to disclose.

Arlen D Meyers, MD, MBA Professor of Otolaryngology, Dentistry, and Engineering, University of Colorado School of Medicine

Arlen D Meyers, MD, MBA is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, and American Head and Neck Society

Disclosure: Covidien Corp Consulting fee Consulting; US Tobacco Corporation Unrestricted gift Unknown; Axis Three Corporation Ownership interest Consulting; Omni Biosciences Ownership interest Consulting; Sentegra Ownership interest Board membership; Medvoy Ownership interest Management position; Cerescan Imaging Consulting; Headwatersmb Consulting fee Consulting; Venturequest Royalty Consulting

Maurice Y Nahabedian, MD, FACS Associate Professor, Department of Plastic Surgery, Georgetown University Hospital

Maurice Y Nahabedian, MD, FACS is a member of the following medical societies: American Association of Plastic Surgeons, American College of Surgeons, American Society for Reconstructive Microsurgery, American Society of Plastic Surgeons, Johns Hopkins Medical and Surgical Association, and Northeastern Society of Plastic Surgeons

Disclosure: Lifecell corp Honoraria Speaking and teaching

Samia Nawaz, MBBS, MD Associate Professor, Department of Pathology, University of Colorado Health Science Center

Samia Nawaz, MBBS, MD is a member of the following medical societies: American Society for Clinical Pathology, American Society of Cytopathology, and International Academy of Pathology

Disclosure: Nothing to disclose.

Ron W Pelton, MD, PhD Private Practice, Colorado Springs, Colorado

Ron W Pelton, MD, PhD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, American Society of Ophthalmic Plastic and Reconstructive Surgery, AO Foundation, and Colorado Medical Society

Disclosure: Nothing to disclose.

Michael L Ramsey, MD Director, Mohs Surgery Fellowship, Co-Director, Procedural Dermatology Fellowship, Department of Dermatology, Geisinger Medical Center

Michael L Ramsey, MD is a member of the following medical societies: American Academy of Dermatology, American College of Mohs Micrographic Surgery and Cutaneous Oncology, and Pennsylvania Academy of Dermatology

Disclosure: Nothing to disclose.

Rana Rofagha Sajjadian, MD Clinical Instructor, Department of Dermatology, University of Irvine, California; Division of Mohs Surgery, Department of Dermatology, Southern California Permanente Medical Group

Rana Rofagha Sajjadian, MD is a member of the following medical societies: American Academy of Dermatology, American Society for Dermatologic Surgery, and American Society for MOHS Surgery

Disclosure: Nothing to disclose.

Thomas M Roy, MD Chief, Division of Pulmonary Diseases and Critical Care Medicine, Quillen Mountain Home Veterans Affairs Medical Center; Professor, Department of Internal Medicine, Division of Pulmonary Medicine, Fellowship Program Director, East Tennessee State University, James H Quillen College of Medicine

Thomas M Roy, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Medical Association, American Thoracic Society, Southern Medical Association, and Wilderness Medical Society

Disclosure: Nothing to disclose.

M Sherif Said, MD, PhD Associate Professor of Pathology, Director of Head and Neck Pathology, Department of Pathology, University of Colorado School of Medicine

M Sherif Said, MD, PhD is a member of the following medical societies: American Society for Clinical Pathology and College of American Pathologists

Disclosure: Nothing to disclose.

Ali Sajjadian, MD, FACS Private Practice, Newport Beach, California; Former Assistant Professor of Plastic Surgery, Former Director of Aesthetic Plastic Surgery Satellite Centers, University of Pittsburgh Medical Center

Ali Sajjadian, MD, FACS is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, American College of Surgeons, American Medical Association, American Society of Plastic Surgeons, American Society of Plastic Surgeons, American Society of Plastic Surgeons, California Medical Association, Northeastern Society of Plastic Surgeons, and PennsylvaniaMedical Society

Disclosure: Nothing to disclose.

Negar Sajjadian, MD Assistant Professor of Pediatrics, Tehran University of Medical Sciences, Shariati Hospital

Disclosure: Nothing to disclose.

Wayne Karl Stadelmann, MD Stadelmann Plastic Surgery, PC

Wayne Karl Stadelmann, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Surgeons, American Society of Plastic Surgeons, New Hampshire Medical Society, Northeastern Society of Plastic Surgeons, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Katherine Szyfelbein, MD Staff Physician, Department of Dermatology, Boston University, Boston Medical Center

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

R Stan Taylor, MD The JB Howell Professor in Melanoma Education and Detection, Departments of Dermatology and Plastic Surgery, Director, Skin Surgery and Oncology Clinic, University of Texas Southwestern Medical Center

R Stan Taylor, MD is a member of the following medical societies: American Academy of Dermatology, American College of Mohs Surgery, American Dermatological Association, American Medical Association, American Society for Dermatologic Surgery, Christian Medical & Dental Society, and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

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Basal cell carcinoma of the right lower lid.

Basal cell carcinoma.

A 68-year-old patient presenting with an advanced basal cell carcinoma (BCC) of the right periorbital region, frontal view. Courtesy of M Abraham Kuriakose, DDS, MD.

Basal cell carcinoma of the right lower lid.

Biopsy-proven basal cell carcinoma of the upper lid margin. Note the loss of cilia (madarosis) in the area of the tumor.

Medial canthal/lower lid basal cell. Note the pearly nodular surface with characteristic telangiectatic vessels. Proximity to the lacrimal system will impact its treatment and reconstruction.

Nodular basal cell carcinoma.

Nodular basal cell carcinoma appearing as a waxy, translucent papule with central depression and a few small erosions.

Pigmented basal cell carcinoma.

Pigmented basal cell carcinoma.

Pigmented basal cell carcinoma has features of nodular basal cell carcinoma with the addition of dark pigmentation from melanin deposition. The pigmentation often has the appearance of dark droplets in the lesion, as shown here.

Large, scarlike morpheaform basal cell cancer.

Scale, erythema, and a threadlike raised border are present in this superficial basal cell carcinoma on the trunk.

Large, superficial basal cell carcinoma.

Nodular basal cell carcinoma. Nodular aggregates of basalioma cells are present in the dermis and exhibit peripheral palisading and retraction artifact. Melanin is also present within the tumor and in the surrounding stroma, as seen in pigmented basal cell carcinoma.

Histologic pattern of a well-differentiated basal cell carcinoma (original magnification X140). Courtesy of Prof Pantaleo Bufo, University of Foggia, Italy.

Micronodular basal cell carcinoma often has an absence of retraction artifact. The characteristic histology is small size and uniformity of the tumor nodules. Courtesy of Shang I Brian Jiang, MD.

Infiltrative basal cell carcinoma. Tumor cells are arranged in narrow strands, and mucin-rich stroma is often present. Courtesy of Shang I Brian Jiang, MD.

Histology of superficial basal cell carcinoma. Nests of basaloid cells are seen budding from the undersurface of the epidermis. Courtesy of Michael L Ramsey, MD.

Keratotic basal cell carcinoma. Rare type characterized by keratocysts. Courtesy of Shang I Brian Jiang, MD.

Basosquamous basal cell carcinoma. Foci of neoplastic cells with squamous differentiation are present. Courtesy of Shang I Brian Jiang, MD.

A pink, scaly lesion on the skin. Superficial basal cell carcinoma (BCC) is often misdiagnosed as eczematous dermatitis or guttate psoriasis and is often difficult to distinguish clinically from Bowen disease (squamous cell carcinoma in situ). Features that suggest the diagnosis of superficial BCC are the absence of significant white, adherent scale and a history of the lesion remaining unchanged for several months or years. Treatment options for this tumor include electrodesiccation and curettage, surgical excision, cryosurgery, 5-fluorouracil, 5% imiquimod cream, and superficial radiotherapy. Electrodesiccation and curettage is the modality most commonly used, with a cure rate of approximately 95%.

Basal cell carcinoma.

A 68-year-old patient presenting with an advanced basal cell carcinoma (BCC) of the right periorbital region, frontal view. Courtesy of M Abraham Kuriakose, DDS, MD.

Lateral view of face showing extent of tumor. Courtesy of M Abraham Kuriakose, DDS, MD.

Basal cell carcinoma of the right lower lid.

Biopsy-proven basal cell carcinoma of the upper lid margin. Note the loss of cilia (madarosis) in the area of the tumor.

Medial canthal/lower lid basal cell. Note the pearly nodular surface with characteristic telangiectatic vessels. Proximity to the lacrimal system will impact its treatment and reconstruction.

Nodular basal cell carcinoma.

Nodular basal cell carcinoma appearing as a waxy, translucent papule with central depression and a few small erosions.

Scale, erythema, and a threadlike raised border are present in this superficial basal cell carcinoma on the trunk.

Large, superficial basal cell carcinoma.

Basal cell carcinoma. Courtesy of Hon Pak, MD.

Pigmented basal cell carcinoma.

Pigmented basal cell carcinoma.

Pigmented basal cell carcinoma has features of nodular basal cell carcinoma with the addition of dark pigmentation from melanin deposition. The pigmentation often has the appearance of dark droplets in the lesion, as shown here.

This infiltrating basal cell cancer has ill-defined borders and telangiectases.

This translucent pink papule has telangiectases and a crusted erosion, characteristic of nodular basal cell carcinoma.

Large, scarlike morpheaform basal cell cancer.

Nodular basal cell carcinoma. Nodular aggregates of basalioma cells are present in the dermis and exhibit peripheral palisading and retraction artifact. Melanin is also present within the tumor and in the surrounding stroma, as seen in pigmented basal cell carcinoma.

Histologic pattern of a well-differentiated basal cell carcinoma (original magnification X140). Courtesy of Prof Pantaleo Bufo, University of Foggia, Italy.

Histologic pattern of a well-differentiated basal cell carcinoma (original magnification X250). Courtesy of Prof Pantaleo Bufo, University of Foggia, Italy.

Micronodular basal cell carcinoma often has an absence of retraction artifact. The characteristic histology is small size and uniformity of the tumor nodules. Courtesy of Shang I Brian Jiang, MD.

Infiltrative basal cell carcinoma. Tumor cells are arranged in narrow strands, and mucin-rich stroma is often present. Courtesy of Shang I Brian Jiang, MD.

Keratotic basal cell carcinoma. Rare type characterized by keratocysts. Courtesy of Shang I Brian Jiang, MD.

Basosquamous basal cell carcinoma. Foci of neoplastic cells with squamous differentiation are present. Courtesy of Shang I Brian Jiang, MD.

Histology of superficial basal cell carcinoma. Nests of basaloid cells are seen budding from the undersurface of the epidermis. Courtesy of Michael L Ramsey, MD.