Basal Cell Carcinoma

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.

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.

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. The deoxyribonucleic acid (DNA) of certain genes is often damaged in patients with BCC; therefore, inheritance may be a factor. Most DNA alterations result from damage caused by exposure to sunlight. (See Pathophysiology.)

Body distribution of BCCs is as follows:

• Head and neck (most frequently on the face ^[9] ; most common location is the nose, specifically the nasal tip and alae) - 85%
• Trunk and extremities ^[3] -15%
• Penis, ^[10] vulva, ^{[11, 12]} or perianal skin - Infrequent

The anatomic distribution of BCCs correlates with embryonic fusion planes. After adjusting for surface area, BCC occurrence is greater than 4 times more likely on embryonic fusion planes than on other regions of the midface, a finding that supports the possibility of an embryologic role for BCC pathogenesis.[13]

BCC can develop on unexposed areas. In some patients, contributing factors are exposure to or contact with arsenic,[14] tar, coal, paraffin,[15] certain types of industrial oil, and radiation. BCC can also be associated with scars (eg, burn complications),[16] xeroderma pigmentosum,[17] , previous trauma.[18] 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,[19, 20, 21, 22, 23, 24] and topical 5-fluorouracil 5% cream may be used to treat small, superficial BCCs.[25] 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.)

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 3 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.[26, 27]

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. Mutations in the PTCH gene prevent it from binding 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 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.[28]

UV-induced mutations in the TP53 tumor suppressor gene, which resides on band 17p13.1, have been found in some cases of BCC.[29]  A germline single-nucleotide polymorphism (SNP) in the TP53 gene, rs78378222, has also been associated with susceptibility to BCC.[29] 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], interleukin 10 [IL-10]) are believed to be pathogenic to 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.[30]

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.[31]

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.[32]

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.[33]

In a 2012 systematic review and meta-analysis of 12 studies with 9328 cases of non-melanoma 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 basal cell carcinoma, corresponding to more than 170,000 cases of non-melanoma skin cancer annually caused by indoor tanning.[34] In another 2012 study of 376 patients with basal cell carcinoma and 390 control patients with minor benign skin conditions, indoor tanning was strongly associated with early-onset basal cell carcinoma, particularly in women.[35]

X-ray and Grenz-ray exposure are also associated with basal cell carcinoma 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 exposure through ingestion

Arsenic has been used as a medicinal agent, predominantly the Fowler solution of potassium arsenite, which was used to treat many disorders, including asthma and psoriasis. Historically, a contaminated water source has been the most common source of arsenic ingestion.[14]

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 patients with AIDS.

Organ transplant patients must be instructed to limit sun exposure and 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 patients than in the general population; up to 65-75% of patients with long-term immunosuppression develop skin cancer. Skin cancers can significantly alter and reduce the transplant recipients’ quality of life; some patients may develop more than 100 skin cancers per year.

Xeroderma pigmentosum

This autosomal recessive disease results in the inability to repair ultraviolet-induced DNA damage. Pigmentary changes are seen early in life, followed by the development of basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. Other features include corneal opacities, eventual blindness, and neurological deficits.

Nevoid basal cell carcinoma syndrome

In addition to basal cell carcinoma, this autosomal dominant disorder can result in the early formation of multiple odontogenic keratocysts, palmoplantar pitting, intracranial calcification, and rib anomalies. Various tumors such as medulloblastomas, meningioma, fetal rhabdomyoma, and ameloblastoma also can occur.[36]

Odontogenic keratocysts, palmoplantar pitting, intracranial calcification, and rib anomalies may be seen. Mutations in the hedgehog signaling pathway, particularly the patched gene, are causative.[37]

Go to Nevoid Basal Cell Carcinoma Syndrome to see more complete information on this topic.

Bazex syndrome

Features of Bazex syndrome include follicular atrophoderma (so-called ice pick marks, especially on dorsal hands), multiple basal cell carcinomas, and local anhidrosis (decreased or absent sweating).[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.[38]

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.

Rombo syndrome

Rombo syndrome is an autosomal dominant condition distinguished by basal cell carcinoma and atrophoderma vermiculatum, trichoepitheliomas, hypotrichosis milia, and peripheral vasodilation with cyanosis.[39]

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.[40]

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.[41]

The study results supported a dose-response relationship between HCTZ use and BCC, as follows[41] :

• High cumulative use of HCTZ (≥50,000 mg) increased the odds ratios (ORs) of BCC by 1.29.
• Patients with the highest HCTZ exposure (>200,000 mg) had an OR of 1.54 for BCC.

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).[41]

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 deaths annually, and that number has been decreasing in recent years.[42]

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 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.[43] 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, and it 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.[44]

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.[45] 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 now 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.[46]

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,[47] and bones.[48]

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.[49]

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.[50]

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

• Surgical excision - 10.1%
• Radiation therapy - 8.7%
• Curettage and electrodesiccation - 7.7%
• Cryotherapy - 7.5%
• All non-Mohs modalities - 8.7%
• Mohs micrographic surgery - 1%

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 the rate reached 50% after the third and fourth operations.[51] 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.[52, 53] 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:

• Nonhealing ulceration
• Tissue destruction
• Scar that becomes red, scaled, or crusted or enlarges with large adjacent telangiectasia
• Scar that slowly enlarges over time (months)
• Development of papule/nodule within a scar

Histologic types of BCC at higher risk for recurrence include morpheaform (sclerotic), micronodular, infiltrative, and superficial (multicentric). Other conditions that contribute to a higher recurrence rate include recurrent tumors that have been treated previously, large tumors (>2 cm), and deeply infiltrating tumors.

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.[54]

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,[55] while the American Academy of Dermatology (AAD) advises use of a sunscreen with an SPF rating of at least 30.[56] Both organization recommend use of a broad spectrum sunscreen, which will also provide protection against UVA 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 recommends a dermatologic examination every 3 years for people aged 20-40 years and every year for people older than 40 years.

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

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 non-melanoma 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.

Characteristic features of BCC tumors include the following:

• Waxy papules with central depression
• Pearly appearance
• Erosion or ulceration, often central
• Bleeding, especially when traumatized
• Crusting
• Rolled (raised) border
• Translucency
• Telangiectases over the surface
• Slow growing (0.5 cm in 1-2 y)

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.

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.

Though a literature review showed all authors agreed that periocular BCC most commonly occurs in the lower eyelid, the remaining anatomical 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.[57] Childhood BCC is exceedingly rare in the absence of other underlying conditions. Only 107 cases of de novo childhood BCC have 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.[58]

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 - Cystic, pigmented, keratotic
• Infiltrative
• Micronodular
• Morpheaform
• Superficial

Nodular basal cell carcinoma

Nodular basal cell carcinoma is the most common type of basal cell carcinoma and usually presents as a round, pearly, flesh-colored papule with telangiectases. More than 60% of BCCs belong to this subtype. 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 basal cell carcinoma, 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, one can see the typical features of a nodular basal cell carcinoma 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.

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 (see the images below) is an uncommon variant of nodular basal cell carcinoma 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.

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.

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

Infiltrative basal cell carcinoma

With this variant of BCC, tumor infiltrates the dermis in thin strands between collagen fibers, making tumor margins less clinically apparent. Mohs micrographic surgery is the treatment of choice for infiltrative basal cell carcinoma. Because of its growth pattern, electrodesiccation and curettage has a significantly higher recurrence rate when used to treat infiltrative BCC compared to the treatment of nodular BCC; other treatment methods should be sought.

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 basal cell carcinoma 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 basal cell carcinoma 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).

Large, scarlike morpheaform basal cell cancer.

Superficial basal cell carcinoma

Superficial basal cell carcinomas are seen 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.

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

Large, superficial basal cell carcinoma.

Gorlin syndrome or basal cell nevus syndrome

Basal cell carcinoma (BCC) is also a feature of basal cell nevus syndrome (ie, Gorlin syndrome),[59] an autosomal dominant inherited condition. The lesions in these patients cannot be distinguished histologically 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.[60]

Other features associated with Gorlin syndrome (fortunately, uncommon) include the following[61] :

• Mental retardation
• Congenital agenesis of the corpus callosum and medulloblastoma
• Odontogenic jaw cysts
• Bifid ribs and pectus excavatum
• Absent or undescended testes
• Mesenteric lymphatic cysts
• Palmar and plantar pits
• Ectopic calcification (particularly of the falx cerebri)
• Ocular and skeletal abnormalities (eg, hypertelorism, shortening of the fourth and fifth metacarpals)

Other basal cell carcinomas

Other types of basal cell carcinoma include the following:

• Metatypical
• Infundibulocystic
• Follicular
• Pleomorphic

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, such as bone, is clinically suspected. In such cases, CT scans or radiography can be used.

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.

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 histological 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%.[62] These values were compared to a second group of patients who had incisional biopsy and histological examination followed by excision with histological confirmation. The second group showed a sensitivity of 100% in diagnosing BCC with a predictive accuracy of 96%.

Several histologic types of BCC exist. Distinctions are important because clinical detection of tumor margins is more difficult with certain histologic types.[63] 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).

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.

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 2 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.

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

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.[64]

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.

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.

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 basal cell carcinoma (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).

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.

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 basal cell carcinoma 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.

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

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.

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 basal cell carcinoma (BCC) with differentiation towards 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 when one evaluates 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).

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 basal cell carcinoma.[65, 66, 67]

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.[68]

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:

• Stage 0: Cancer involves only the epidermis and has not spread to the dermis

• Stage I: Cancer is not large (ie, < 2 cm) and has not spread to the lymph nodes or other organs

• Stage II: Cancer is large (ie, >2 cm) but has not spread to lymph nodes or other organs

• Stage III: Cancer has spread to tissues beneath the skin (eg, muscle, bone, cartilage), and/or to regional lymph nodes but not to other organs.

• Stage IV: Cancer can be any size and has spread to other organs

High-risk tumors

High-risk BCCs include the following:

• Recurrent or incompletely excised BCC

• Primary BCC with clinically indistinct borders

• Lesions in high-risk (the H, or mask) areas, mainly the embryonic fusion planes (eg, eyelids, nose, ear, nasolabial folds, upper lip, vermillion border, columella, periorbital region, temples, preauricular and postauricular areas, and scalp)

• Lesions that develop in cosmetically and functionally important areas (eg, face, genitals, anal and perianal regions, hands and feet, and the nail unit areas)

• Tumors with aggressive clinical behavior (ie, growing rapidly or >2 cm)

• Tumors with aggressive histologic subtype, including sclerosing (morpheaform), basosquamous (metatypical or keratinizing), perineural, periappendageal, or perivascular invasion, infiltrating, adenoidal, or multicentric

• Tumors that develop in sites with previous radiation therapy

• Tumors that develop in immunosuppressed patients

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 patient's particular risk factors and preferences.[7]

In nearly all cases of BCC, the recommended treatment modality is surgery.[69, 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).[70, 71, 72]

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 is approved by the FDA for the treatment of superficial BCC, administered twice daily for 3-6 weeks.[73] 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, likely by treating 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.[74]

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

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.[75, 76, 77, 78]

National Comprehensive Cancer Network (NCCN) guidelines recommend that low-risk BCC in non–hair-bearing areas be treated 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.[79]

Some studies suggest that dermato-oncological surgery is associated with a high risk of infection.[40] 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.

Several topical creams are used in the management of BCC that is nonrecurring and superficial. NCCN guidelines state that low-risk patients with superficial BCC 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[25] may be used to treat small, superficial BCCs in low-risk areas. 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.[80]

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.

Interferon

Interferon alfa-2b is a protein product manufactured using recombinant DNA technology. It has shown some success in treating small (< 1 cm), nodular, and superficial BCCs. In appropriate BCC tumors, cures rates of up to 80% have been obtained.

Several early studies have shown variable responses of BCC to intralesional interferon alfa. In a small study by Greenway et al, 1.5 million IU interferon alfa-2b injected intralesionally 3 times per week for 3 weeks resulted in the clearing of 3 cases of primary nonrecurrent BCC and 5 cases of primary superficial BCC.[81]

Because larger studies are needed, most practitioners consider this an experimental therapeutic modality. Further data are needed before this treatment modality is recommended for routine ophthalmic practice.

Interferon has not become a mainstay in BCC treatment because of its cost, the inconvenience of multiple visits, the discomfort of administration, and its adverse effects, which include flulike symptoms. Acetaminophen may alleviate the flulike symptoms associated with this therapy.

Imiquimod

Imiquimod 5% cream (Aldara) is approved by the US Food and Drug Administration for the treatment of nonfacial superficial BCC.[82, 83] 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. Studies for other histologic types of BCC are under way.[19, 20, 23, 22, 21, 24]

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.[84, 85] 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.[75]

In a study of 601 patients with histologically proven superficial basal-cell carcinoma, 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.[86]

Tazarotene

The receptor-selective acetylenic retinoid tazarotene (Tazorac) 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.[87]

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/irritating skin that is relieved after discontinuation of tazarotene.

Basal cell carcinomas (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,[88] or facial tumors). In a retrospective analysis of 1715 histologically confirmed primary cutaneous carcinomas (712 BCCs, 994 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. Recurrence rates for SCC at 2 and 5 years were 1.8% and 5.8%, respectively.[89] 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 basal cell carcinomas may result in complete remission in approximately 70% of patients.[90]

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, and 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 radiated 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 (PDT) for basal cell carcinomas (BCCs) has been used for more than 20 years.[91, 92] PDT 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. 5-Aminolevulinic acid (ALA-PDT) is the only US Food and Drug Administration approved photoreactive molecule for PDT in the United States, and it is only approved for actinic keratoses. It is photoactivated with blue light for 1000 seconds after 1 hour of incubation.

PDT is administered orally or parenterally, as well as applied topically, and localizes into tumor cells before activation by exposure to light (eg, laser). The efficacy 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.[93] At present, PDT has no distinct advantage over other well-established therapies for BCC of the eyelid. In a study by Puccioni et al, PDT using methyl aminolevulinate showed notable success and appears to be a viable option in the treatment of BCC of the eyelid in selected patients.[94]

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

• Tumor recurrence with tissue atrophy and scar formation
• Elderly patients or patients with medical conditions preventing extensive oculoplastic reconstructive surgery
• Tumor with poorly defined borders based on clinical examination
• Tumor requiring difficult or extensive oculoplastic surgery

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.[95]

The strongest support for PDT as a modality for BCCs comes with data on thin lesions treated with methylaminolevulinate (used outside the United States), but at least one long-term follow-up trial has also shown surgical excision to be superior.[96]

Christensen et al reported a 10-year lesion complete response rate of 87% with two sessions of dimetylsulfoxide-supported topical 5-aminolaevulinic acid-PDT and curettage for primary, small BCC. Favourable cosmetic outcomes also were reported for nearly all cases.[97]

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.

Also see the British Association of Dermatologists Therapy Guidelines and Audit Subcommittee’s clinical guidelines summary, Guidelines for topical photodynamic therapy: update.[92]

Although several clinical trials have shown some efficacy for available systemic retinoids in chemotherapy and chemoprevention, the long-term toxicity of these agents generally excludes them as treatment choices for most patients.[98] Studies are exploring their value as cancer preventive agents in patients at high risk for developing multiple tumors.

Vismodegib

Vismodegib (Erivedge) is the first FDA-approved drug for advanced forms of basal cell carcinoma (BCC). It selectively inhibits Smoothened (SMO), a key transmembrane protein involved in Hedgehog signal transduction of cancerous epithelial cells.[99] FDA approval was based on a single, international, open-label trial (n=104). 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.[100]

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 basal cell carcinoma. Patients were randomized in a 1:2 ratio to receive 200 mg or 800 mg oral sonidegib daily, stratified by disease, histological subtype, and geographical region. For the 66 patients in the 200 mg group, the overall response rate was 58%; 3 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.[101]

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 II, nonrandomized, open-label trial, Study 1620. Patients (n=112) with locally advanced or metastatic BCC (mBCC) 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.[102]

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

• Surgical excision - 10.1%
• Radiation therapy - 8.7%
• Curettage and electrodesiccation - 7.7%
• Cryotherapy - 7.5%
• All non-Mohs modalities - 8.7%
• Mohs micrographic surgery - 1.0%

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

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.

Researchers are investigating chemoprevention with systemic administration of retinoids as cancer preventive agents in patients at high risk for developing basal cell carcinoma; the efficacy of these agents will take several years to evaluate, however.

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.[103]

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

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

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.[49] 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.[49, 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 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 2012, the U.S. Preventive Services Task Force (USPSTF) recommended counseling children, adolescents, and young adults aged 10 to 24 years who have fair skin about minimizing their exposure to ultraviolet radiation (UVR) to reduce risk for skin cancer.[104]

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[105] :

• Health-supervision practices should include advice about UVR exposure, such as avoiding sunburn and suntan, wearing clothing and hats with brims, using sunglasses, and applying sunscreen; if possible, outdoor activities should be scheduled to limit exposure to peak-intensity midday sun (10 am to 4 pm).
• When a child or adolescent might sunburn, he or she should use sunscreen to reduce the known risks for sun exposure and sunburn, including the increased risk for skin cancer. Sunscreen with a sun-protection factor (SPF) of at least 15 should be applied every 2 hours and after swimming, sweating, or drying off with a towel. People may prefer to avoid sunscreens containing oxybenzone, as these may have weak estrogenic effects when absorbed through the skin.
• Although all children need counseling about UVR exposure, this is particularly true for children at high risk for the development of skin cancer, including those with light skin, nevi, and/or freckling; and/or a family history of melanoma.
• Skin cancer prevention is a lifelong effort, and beginning in infancy, at least one health maintenance visit per year should include advice about UVR exposure. All children are at risk for adverse effects of UVR exposure on the eyes and immune system, although not all children sunburn. Especially appropriate times for counseling about UVR exposure include during the spring and summer in northern states, before anticipated sunny vacations, and during visits for sunburns.
• Because outdoor physical activity should be strongly encouraged, this should be promoted in a sun-safe manner.
• Sun-protection practices tend to wane in early childhood. Beginning at age 9 or 10 years, it may be helpful for pediatricians to discuss sun protection with children, together with parents, to encourage joint responsibility for the child's sun protection.
• Infants younger than 6 months should be kept out of direct sunlight and covered with protective clothing and hats. When sun avoidance is impossible, parents may apply sunscreen only on exposed areas. Absorption of sunscreen ingredients may be higher in preterm infants.
• Pediatricians should become familiar with chemical photosensitizing agents. People using these oral or topical agents should limit sun exposure and avoid all ultraviolet A (UVA) light from artificial sources. When sun exposure is inevitable, they should wear fully protective clothing and high-SPF sunscreen that also blocks UVA wavelengths.
• Breast-fed and formula-fed infants and other children should receive vitamin D supplementation in accordance with guidelines, for a total intake of at least 400 IU of vitamin D daily. Children at risk for hypovitaminosis D may need laboratory testing of 25-hydroxyvitamin D concentration.
• Deliberate UVR exposure to artificial sources and overexposure to sun with the goal of increasing vitamin D concentrations or for other reasons should be avoided.
• Pediatricians should advocate for adoption of sun-protective policies (eg, shaded playgrounds, outdoor time before 10 am, and allowing hats at schools and child care facilities).
• Pediatricians should support and advocate for legislation banning use of tanning parlors by children younger than 18 years.

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.[106]  For all individuals, regardless of age, the ACS recommends the following:

• Wearing protective clothing when out in the sun
• Wearing a hat that shades your face, neck, and ears
• Wearing a sunscreen with an SPF of 15 or higher
• Planning outdoor activities to avoid the midday sun
• Wearing sunglasses to protect eyes and the tender skin around them from harmful UV rays
• Avoiding tanning booths

Skin Cancer Screening

In 2016, the U.S. Preventive Services Task Force (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 adult general population.[103]

The USPSTF did note the following clinical considerations:

• Skin cancer of any type occurs more commonly in men than in women and among persons with a fair complexion, persons who use indoor tanning beds, and persons with a history of sunburns or previous skin cancer. 
• Specific risk factors for melanoma include having an atypical mole, multiple (ie, ≥100) moles, and having a family history of melanoma.
• The risk of melanoma increases with age; the median age at diagnosis is 63 years, and the median age at death is 69 years.
• Clinical visual skin examination should assess skin lesions for asymmetry, border irregularity, color variability, diameter greater than 6 mm or evolution over time (ABCDE criteria)

The American Cancer Society recommends a cancer-related checkup by a physician, including a skin examination, during a periodic health examination for people age 20 years or older and monthly skin self-examination by all individuals.[107]  The Skin Cancer Foundation also recommends monthly skin self-examinations and 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.

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

• National Comprehensive Cancer Network (NCCN) ^[7]
• American Academy of Dermatology (AAD) ^[110]
• European Dermatology Forum(EDF) ^[6]
• German Cancer Society and the German Society of Dermatology ^[111]

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

• Complete skin exam to identify other pre-cancer or cancer lesions, usually located at other sun-exposed skin sites
• Biopsy of any suspicious lesion, including the deep reticular dermis
• Imaging studies for extensive disease with involvement of bone, perineural disease, or deep soft tissue
• MRI is preferred over CT scan if perineural disease is suspected, because of its higher sensitivity

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

• Punch biopsy
• Shave biopsy
• Excisional biopsy

AAD recommendations regarding biopsy are as follows:

• The biopsy technique chosen will depend on the characteristics of the suspected malignancy (eg, morphology, location) and the judgment of the physician.
• The biopsy specimen size and depth should be adequate to provide the recommended clinical information and pathology report elements to permit accurate diagnosis and guide therapy.
• Repeat biopsy may be considered if initial biopsy specimen is inadequate for accurate diagnosis.

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

• Patient age and sex
• Anatomic location of the specimen
• Whether the lesion is recurrent

   Providing the following information is recommended:

• Size of lesion
• Immunosuppression
• History (especially radiation burn, organ transplant)

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

• Histologic subtype
• Invasion beyond reticular dermis
• Perineural involvement

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] :

• In a patient with multiple BCCs occurring before the age of 20 years, a diagnostic workup should be performed to rule out a genetic syndrome (eg, Gorlin‐Goltz syndrome, basal cell nevus syndrome, Bazex‐Dupré‐Christol syndrome, Rombo syndrome).
• Examination of the patient without additional tools is suitable for making a suspected clinical diagnosis.
• Following the diagnosis of BCC, a total-body skin examination should be performed or recommended.
• Dermoscopy may contribute to improving the reliability of the clinical diagnosis of BCC.
• Confocal laser microscopy may be useful in the diagnosis of BCC.
• Optical coherence tomography may be useful in the diagnosis of BCC.
• Confocal laser microscopy and optical coherence tomography may be useful in assessing the effect of topical therapies for BCC.
• If there is clinical suspicion of osseous infiltration, CT and/or contrast‐enhanced magnetic resonance imaging (MRI) should be performed to assess the extent of intraosseous tumor spread.
• If orbital invasion is clinically suspected, CT of the orbit should be performed to assess bone destruction, and contrast‐enhanced MRI of the orbit performed to assess intraorbital tumor spread.
• If metastasis is clinically suspected, cross‐sectional imaging studies should be performed, and the primary histology should be reevaluated.
• If basal cell carcinoma syndrome is suspected, imaging studies to rule out additional malignancies and to detect associated abnormalities should be done, using MRI in order to prevent radiation‐induced neoplasms.
• The diagnosis of BCC should be confirmed by histological examination of the excised specimen following a biopsy and/or therapeutic excision, depending on the size of the tumor and the therapeutic approach. Exceptions may be made for multiple superficial tumors or in the case of basal cell carcinoma syndrome.
• Subclinical spread can be assessed with sufficient certainty only histologically; this applies to the sclerosing subtype in particular, which is histologically characterized by fibrosis. The highest accuracy for histological detection of subclinical spread is achieved by microscopically controlled surgery.
• During tissue processing, the potential inhomogeneity of tumors should be taken into account. If necessary, serial sections should be examined.
• The histopathological diagnosis is performed on routine hematoxylin and eosin (H&E)–stained sections; only in rare, specific situations are special stains or immunohistology useful.
• In addition to the diagnosis, the dermatopathology report should include information on the vertical tumor diameter (tumor thickness) and the excision margins. Moreover, the report should contain—if applicable—information about the histological subtype, in particular if there is evidence of infiltrative growth (narrow strands) and/or fibrosing/sclerosing or perineural growth.

Risk Stratification

Basal cell carcinoma rarely metastasizes and is usually not staged. The NCCN and EDF 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:

• Location
• Size
• Borders/clinical margins
• Histological subtype
• Features of aggression
• Failure of previous treatment
• Immunosuppression

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

• 2 cm or more in diameter in low-risk locations (L-area): the trunk and extremities, but not including the pretibia, hands, feet, ankles, and nail units

• 1 cm or more in diameter in moderate-risk locations (M-area): cheeks, forehead, scalp, neck, and pretibia

• 6 mm or more in diameter in high-risk locations (H-area): “mask area” of face (central face, eyelids, eyebrows, periorbital, nose, lips [cutaneous and vermilion], chin, mandible, preauricular and postauricular skin/sulci, temple, ear), genitalia, hands, and feet

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] :

• Basosquamous (metatypical)
• Micronodular
• Infiltrative
• Sclerosing
• Morpheaform (desmoplastic)

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

• Keratotic variant
• Infundibulocystic variant
• Fibroepithelioma of Pinkus

According to the National Comprehensive Cancer Network (NCCN) guidelines, the goal of treatment of basal cell carcinomas (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] :

• The treatment plan should consider recurrence rate, preservation of function, patient expectations, and potential adverse effects.
• Curettage and electrodessication (C&E) may be considered for low-risk tumors in non–terminal hair–bearing locations.
• For low-risk primary BCC, surgical excision with 4-mm clinical margins and histologic margin assessment is recommended.
• Standard excision may be considered for select high-risk tumors. However, strong caution is advised when selecting a treatment modality without complete margin assessment for high-risk tumors.
• MMS is recommended for high-risk BCC.

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

• Cryosurgery may be considered for low-risk BCC when more effective therapies are contraindicated or impractical.
• If surgical therapy is not feasible or preferred, topical therapy (eg, imiquimod or 5-fluorouracil), photodynamic therapy with aminolevulinic acid (ALA) or methyl aminolevulinate (MAL), and radiation therapy (eg, superficial radiation therapy, brachytherapy, external electron beam, and other traditional radiotherapy forms for BCC) can be considered when tumors are low risk, with the understanding that the cure rate may be lower.
• Adjustment of topical therapy dosing regimen on the basis of side effect tolerance is recommended.
• There is insufficient evidence to recommend the routine use of laser or electronic surface brachytherapy in the treatment of BCC.

In 2015, the American Society for Dermatologic Surgery (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.[112]

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[113] :

• Offer standard surgical excision as a first-line treatment to adults with low-risk BCC.
• Offer standard surgical excision with immediate reconstruction as a first-line treatment option to adults with primary BCC with a high-risk factor, if the BCC has well-defined clinical margins under bright lighting and magnification or dermoscopy.
• Offer standard surgical excision with delayed definitive reconstruction, or Mohs micrographic surgery, as the first-line treatment option to adults with high-risk BCC in a high-risk anatomical site if the BCC has poorly defined clinical margins under bright lighting and magnification or dermoscopy.
• For excision, recommended peripheral clinical surgical margins are 4 mm for low-risk BCC and at least 5 mm for primary BCC with a high-risk factor.
• Ensure adequate excision at the deep margin to a clear plane, including a fat layer where present, and other deeper structures if needed.
• Consider Mohs micrographic surgery in adults with primary BCC with at least one high-risk factor, or with advanced BCC. Offer it as a first-line treatment to adults with recurrent BCC with at least one other high-risk factor, especially if the tumor is at a high-risk site.
• In adults with recurrent BCC with at least one other high-risk factor, consider standard surgical excision with at least a 5 mm margin and delayed definitive reconstruction.

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.[113]

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.[113]

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

• Topical imiquimod
• Topical 5-fluorouracil
• Cryosurgery
• Topical photodynamic therapy

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.[113]

BAD recommendations for follow-up include the following:

• Do not routinely offer follow-up to patients with adequately treated isolated BCC, unless for a postoperative review.
• Offer, if possible, at least yearly follow-up to adults with a history of multiple BCCs who are likely to develop further tumors or recurrence within 12 months.

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, and the American Society for Mohs Surgery published appropriate use criteria (AUC) for Mohs micrographic surgery (MMS). The recommendations were based on the expert opinion and consensus of a rating panel of 17 Mohs surgeons and non-Mohs dermatologists.[79]

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

• Previously irradiated skin
• Traumatic scars
• Areas of osteomyelitis
• Areas of chronic inflammation or ulceration
• Patients with genetic conditions such as xeroderma pigmentosum, basal cell nevus syndrome, or other syndromes that increase risk for skin cancer

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):

• All recurrent basal cell tumors
• Primary histologically aggressive and nodular tumors
• Primary superficial tumors in non-immunocompromised individuals with lesions ≥0.6 cm in diameter

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

• Recurrent histologically aggressive and nodular basal cell cancers
• Primary, histologically aggressive tumors ≥0.6 cm
• Primary nodular tumors >2 cm
• Prmary nodular tumors ≥1.1 cm in immunocompromised patients

Use of MMS was considered inappropriate solely in Area L for the following[79] :

• Recurrent superficial BCCs
• Primary nodular tumors ≤1 cm
• Primary nodular tumors ≤0.5 cm in immunocompromised patients
• Superficial BCCs in healthy individuals
• Superficial tumors ≤1 cm in immunocompromised patients

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:

• Hedgehog (Hh) pathway inhibitor treatment with vismodegib; a second Hh inhibitor, sonidegib, was approved by the FDA in 2015, but not for metastatic disease, so the NCCN rates it as category 2B
• Surgery
• Radiation therapy
• Clinical trial enrollment

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

• Multidisciplinary consultation and smoothened inhibitors (eg, vismodegib) are recommended for patients with metastatic BCC.
• If treatment of metastatic BCC with smoothened inhibitors is not feasible, platinum-based chemotherapy or best supportive care is recommended.
• If surgery and radiation therapy are contraindicated or inappropriate for the treatment of locally advanced BCC, or if residual tumor persists following surgery and/or radiation therapy and further surgery and radiation therapy are contraindicated or inappropriate, systemic therapy with a smoothened inhibitor should be considered.
• Patients with advanced disease should be provided with or referred for best supportive and palliative care, to optimize symptom management and maximize quality of life.

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:

• RT is recommended as curative treatment in patients with BCC who cannot undergo or who decline surgical resection.
• RT is conditionally recommended as curative treatment in patients with BCC in anatomic locations where surgery can endanger function or cosmesis.
• RT is conditionally not recommended for patients with BCC who have genetic diseases that predispose to increased radiosensitivity.

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:

• BCC with narrow or positive margins that is refractory to further surgical correction owing to morbidity or adverse cosmetic outcome
• BCC associated with recurrence after a previous margin-negative resection
• BCC associated with locally advanced or neglected tumors that involve bone or those infiltrating muscle

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

• Therapeutic lymphadenectomy followed by adjuvant RT (Exception: Patients with a single, small (< 3 cm) cancerous cervical lymph node, without extracapsular extension)
• Definitive RT only recommended if patient is medically inoperable or surgically unresectable

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

• Imaging and sentinel lymph node biopsy, in order to guide the need for and target of lymph node basin RT
• If tumor thickness is greater than 6 mm, elective lymph node basin RT only in patients undergoing RT on the primary site, with overlap of the adjacent nodal basin

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:

• Conventional (180-200 cGy/fx): BED10 (biologically effective dose assuming an α/β = 10) 70-93.5 (delivered 5 days/wk)
• Hypofractionation (210-500 cGy/fx): BED10 56-88 (delivered daily or 2-4 times/wk)

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

• Conventional (180-200 cGy/fx): BED10 59.5-79.2 (delivered 5 days/wk)
• Hypofractionation (210-500 cGy/fx): BED10 56-70.2 (delivered daily or 2-4 times/wk)

Follow-up and surveillance

The NCCN recommends the following measures[7] :

• Complete skin examination every 6-12 months for life
• Sun protection
• Self-examination

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

• After diagnosis of a first BCC, skin cancer screening for new keratinocyte cancers (BCC or cutaneous squamous cell carcinoma) and for melanoma should be performed on at least an annual basis.
• Patients with a history of BCC should be counseled on skin self-examination and sun protection.
• The use of topical and oral retinoids (eg, tretinoin, retinol, acitretin, isotretinoin) is not recommended to reduce the incidence of future keratinocyte cancers in those with a history of BCC.
• Dietary supplementation of selenium and β-carotene is not recommended to reduce the incidence of future keratinocyte cancers in those with a history of BCC.
• There is insufficient evidence to make a recommendation on the use of oral nicotinamide, α-difluoromethylornithine (DFMO), or celecoxib in the chemoprevention of BCC.

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

• Topical antineoplastic agents (eg, 5-fluorouracil, imiquimod)
• The photosensitizing agent methyl aminolevulinate cream
• The acetylenic retinoid tazarotene
• Hedgehog pathway inhibitors (HHIs)
• A programmed death–1 (PD-1) inhibitor

Class Summary

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

Fluorouracil topical (Efudex)

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)

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 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.

Vismodegib (Erivedge)

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)

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.

Cemiplimab (Cemiplimab-rwlc, Libtayo)

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 metastatic BCC previously treated with a HHI or for whom a HHI is not appropriate.

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.

Methyl aminolevulinate (Metvixia)

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

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

Tazarotene (Avage, Fabior, Tazorac)

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

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

Imiquimod (Aldara)

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.