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Genetics of Skin Cancer (PDQ®)

Basal Cell Carcinoma


Basal cell carcinoma (BCC) is the most common malignancy in people of European descent, with an associated lifetime risk of 30%.[1] While exposure to ultraviolet (UV) radiation is the risk factor most closely linked to the development of BCC, other environmental factors (such as ionizing radiation, chronic arsenic ingestion, and immunosuppression) and genetic factors (such as family history, skin type, and genetic syndromes) also potentially contribute to carcinogenesis. In contrast to melanoma, metastatic spread of BCC is very rare and typically arises from large tumors that have evaded medical treatment for extended periods of time. BCCs can invade tissue locally or regionally, sometimes following along nerves. A tendency for superficial necrosis has resulted in the name "rodent ulcer." With early detection, the prognosis for BCC is excellent.

Risk Factors for Basal Cell Carcinoma

Sun exposure

Sun exposure is the major known environmental factor associated with the development of skin cancer of all types. There are different patterns of sun exposure associated with each major type of skin cancer (BCC, squamous cell carcinoma [SCC], and melanoma).

While there is no standard measure, sun exposure can be generally classified as intermittent or chronic, and the effects may be considered acute or cumulative. Intermittent sun exposure is obtained sporadically, usually during recreational activities, and particularly by indoor workers who have only weekends or vacations to be outdoors and whose skin has not adapted to the sun. Chronic sun exposure is incurred by consistent, repetitive sun exposure, during outdoor work or recreation. Acute sun exposure is obtained over a short time period on skin that has not adapted to the sun. Depending on the time of day and a person's skin type, acute sun exposure may result in sunburn. In epidemiology studies, sunburn is usually defined as burn with pain and/or blistering that lasts for 2 or more days. Cumulative sun exposure is the additive amount of sun exposure that one receives over a lifetime. Cumulative sun exposure may reflect the additive effects of intermittent sun exposure, chronic sun exposure, or both.

Specific patterns of sun exposure appear to lead to different types of skin cancer among susceptible individuals. Intense intermittent recreational sun exposure has been associated with melanoma and BCC,[2,3] while chronic occupational sun exposure has been associated with SCC. Given these data, dermatologists routinely counsel patients to protect their skin from the sun by avoiding mid-day sun exposure, seeking shade, and wearing sun-protective clothing, although evidence-based data for these practices are lacking. The data regarding skin cancer risk reduction by regular sunscreen use are variable. One randomized trial of sunscreen efficacy demonstrated statistically significant protection for the development of SCC but no protection for BCC,[4] while another randomized study demonstrated a trend for reduction in multiple occurrences of BCC among sunscreen users [5] but no significant reduction in BCC or SCC incidence.[6]

Level of evidence (sun-protective clothing, avoidance of sun exposure): 4aii

Level of evidence (sunscreen): 1aii

Tanning bed use has also been associated with an increased risk of BCC. A study of 376 individuals with BCC and 390 control subjects found a 69% increased risk of BCC in individuals who had ever used indoor tanning.[7] The risk of BCC was more pronounced in females and individuals with higher use of indoor tanning.[8]

Other environmental factors

Environmental factors other than sun exposure may also contribute to the formation of BCC and SCC. Petroleum byproducts (e.g., asphalt, tar, soot, paraffin, and pitch), organophosphate compounds, and arsenic are all occupational exposures associated with cutaneous nonmelanoma cancers.[9-11]

Arsenic exposure may occur through contact with contaminated food, water, or air. While arsenic is ubiquitous in the environment, its ambient concentration in both food and water may be increased near smelting, mining, or coal-burning establishments. Arsenic levels in the U.S. municipal water supply are tightly regulated; however, control is lacking for potable water obtained through private wells. As it percolates through rock formations with naturally occurring arsenic, well water may acquire hazardous concentrations of this material. In many parts of the world, wells providing drinking water are contaminated by high levels of arsenic in the ground water. The populations in Bangladesh, Taiwan, and many other locations have high levels of skin cancer associated with elevated levels of arsenic in the drinking water.[12-16] Medicinal arsenical solutions (e.g., Fowler’s solution and Bell’s asthma medication) were once used to treat common chronic conditions such as psoriasis, syphilis, and asthma, resulting in associated late-onset cutaneous malignancies.[17,18] Current potential iatrogenic sources of arsenic exposure include poorly regulated Chinese traditional/herbal medications and intravenous arsenic trioxide utilized to induce remission in acute promyelocytic leukemia.[19,20]

Aerosolized particulate matter produced by combustion of arsenic-containing materials is another source of environmental exposure. Arsenic-rich coal, animal dung from arsenic-rich regions, and chromated copper arsenate–treated wood produce airborne arsenical particles when burned.[21-23] Burning of these products in enclosed unventilated settings (such as for heat generation) is particularly hazardous.[24]

Clinically, arsenic-induced skin cancers are characterized by multiple recurring SCCs and BCCs occurring in areas of the skin that are usually protected from the sun. A range of cutaneous findings are associated with chronic or severe arsenic exposure, including pigmentary variation (poikiloderma of the skin) and Bowen disease (SCC in situ).[25]

Pigmentary characteristics

The high-risk phenotype consists of individuals with the following physical characteristics:

  • Fair skin that sunburns easily.
  • Lightly pigmented irides (blue and green).
  • Presence of freckles in sun-exposed sites.
  • Poor ability to tan.
  • Blond or red hair color.

Specifically, people with more highly pigmented skin demonstrate lower incidence of BCC than do people with lighter pigmented skin. Individuals with Fitzpatrick skin types I or II were shown to have a twofold increased risk of BCC in a small case-control study.[26] (Refer to the Pigmentary characteristics section in the Melanoma section of this summary for a more detailed discussion of skin phenotypes based upon pigmentation.) Blond or red hair color was associated with increased risk of BCC in two large cohorts: the Nurses’ Health Study and the Health Professionals’ Follow-Up Study.[27]


Immunosuppression also contributes to the formation of nonmelanoma (keratinocyte) skin cancers. Among solid-organ transplant recipients, the risk of SCC is 65 to 250 times higher, and the risk of BCC is 10 times higher than in the general population.[28-30] Nonmelanoma skin cancers in high-risk patients (i.e., solid-organ transplant recipients and chronic lymphocytic leukemia patients) occur at a younger age and are more common, more aggressive, and have a higher risk of recurrence and metastatic spread than nonmelanoma skin cancers in the general population.[31,32] Among patients with an intact immune system, BCCs outnumber SCCs by a 4:1 ratio; in transplant patients, SCCs outnumber BCCs by a 2:1 ratio.

This increased risk has been linked to the level of immunosuppression and UV exposure. As the duration and dosage of immunosuppressive agents increases, so does the risk of cutaneous malignancy; this effect is reversed with decreasing the dosage of, or taking a break from, immunosuppressive agents. Heart transplant recipients, requiring the highest rates of immunosuppression, are at much higher risk of cutaneous malignancy than liver transplant recipients, in whom much lower levels of immunosuppression are needed to avoid rejection.[28,33] The risk appears to be highest in geographic areas of high UV radiation exposure: when comparing Australian and Dutch organ transplant populations, the Australian patients carried a fourfold increased risk of developing SCC and a fivefold increased risk of developing BCC.[34] This speaks to the importance of rigorous sun avoidance among high-risk immunosuppressed individuals.

Family history

Individuals with BCCs and/or SCCs report a higher frequency of these cancers in their family members than do controls. The importance of this finding is unclear. Apart from defined genetic disorders with an increased risk of BCC, a positive family history of any skin cancer is a strong predictor of the development of BCC.

Previous personal history of nonmelanoma skin cancer

A personal history of BCC or SCC is strongly associated with subsequent BCC or SCC. There is an approximate 20% increased risk of a subsequent lesion within the first year after a skin cancer has been diagnosed. The mean age of occurrence for these nonmelanoma skin cancers is the mid-60s.[35-40] In addition, several studies have found that individuals with a history of skin cancer have an increased risk of a subsequent diagnosis of a noncutaneous cancer;[41-44] however, other studies have contradicted this finding.[45-48] In the absence of other risk factors or evidence of a defined cancer susceptibility syndrome, as discussed below, skin cancer patients are encouraged to follow screening recommendations for the general population for sites other than the skin.

Major Genes for Basal Cell Carcinoma


Mutations in the gene coding for the transmembrane receptor protein PTCH1, or PTCH, are associated with basal cell nevus syndrome (BCNS) and sporadic cutaneous BCCs. PTCH1, the human homolog of the Drosophila segment polarity gene patched (ptc), is an integral component of the hedgehog signaling pathway, which serves many developmental (appendage development, embryonic segmentation, neural tube differentiation) and regulatory (maintenance of stem cells) roles.

In the resting state, the transmembrane receptor protein PTCH1 acts catalytically to suppress the seven-transmembrane protein Smoothened (Smo), preventing further downstream signal transduction.[49] Stoichiometric binding of the hedgehog ligand to PTCH1 releases inhibition of Smo, with resultant activation of transcription factors (GLI1, GLI2), cell proliferation genes (cyclin D, cyclin E, myc), and regulators of angiogenesis.[50,51] Thus, the balance of PTCH1 (inhibition) and Smo (activation) manages the essential regulatory downstream hedgehog signal transduction pathway. Loss-of-function mutations of PTCH1 or gain-of-function mutations of Smo tip this balance toward constitutive activation, a key event in potential neoplastic transformation.

Demonstration of allelic loss on chromosome 9q22 in both sporadic and familial BCCs suggested the potential presence of an associated tumor suppressor gene.[52,53] Further investigation identified a mutation in PTCH1 that localized to the area of allelic loss.[54] Up to 30% of sporadic BCCs demonstrate PTCH1 mutations.[55] In addition to BCC, medulloblastoma and rhabdomyosarcoma, along with other tumors, have been associated with PTCH1 mutations. All three malignancies are associated with BCNS, and most people with clinical features of BCNS demonstrate PTCH1 mutations, predominantly truncation in type.[56]


Truncating mutations in PTCH2, a homolog of PTCH1 mapping to chromosome 1p32.1-32.3, have been demonstrated in both BCC and medulloblastoma.[57,58] PTCH2 displays 57% homology to PTCH1, differing in the conformation of the hydrophilic region between transmembrane portions 6 and 7, and the absence of C-terminal extension.[59] While the exact role of PTCH2 remains unclear, there is evidence to support its involvement in the hedgehog signaling pathway.[57,60]

Syndromes Associated with a Predisposition to Basal Cell Cancer

Basal cell nevus syndrome

BCNS, also known as Gorlin Syndrome, Gorlin-Goltz syndrome, and nevoid basal cell carcinoma syndrome, is an autosomal dominant disorder with an estimated prevalence of 1 in 57,000 individuals.[61] The syndrome is notable for complete penetrance and extremely variable expressivity, as evidenced by evaluation of individuals with identical genotypes but widely varying phenotypes.[56,62] The clinical features of BCNS differ more among families than within families.[63]

As detailed above, PTCH1 provides both developmental and regulatory guidance; spontaneous or inherited germline mutations of PTCH1 in BCNS may result in a wide spectrum of potentially diagnostic physical findings. The BCNS mutation has been localized to chromosome 9q22.3-q31, with a maximum logarithm of the odd (LOD) score of 3.597 and 6.457 at markers D9S12 and D9S53.[61] The resulting haploinsufficiency of PTCH1 in BCNS has been associated with structural anomalies such as odontogenic keratocysts, with evaluation of the cyst lining revealing heterozygosity for PTCH1.[64] The development of BCC and other BCNS-associated malignancies is thought to arise from the classic two-hit suppressor gene model: baseline heterozygosity secondary to germline PTCH1 mutation as the first hit, with the second hit due to mutagen exposure such as UV or ionizing radiation.[65-69] However, haploinsufficiency or dominant negative isoforms have also been implicated for the inactivation of PTCH1.[70]

The diagnosis of BCNS is typically based upon characteristic clinical and radiologic examination findings. Several sets of clinical diagnostic criteria for BCNS are in use (refer to Table 1 for a comparison of these criteria).[71-73] Although each set of criteria has advantages and disadvantages, none of the sets have a clearly superior balance of sensitivity and specificity for identifying mutation carriers. PTCH1 mutations are found in 60% to 85% of patients who meet clinical criteria.[74,75] Most notably, BCNS is associated with the formation of both benign and malignant neoplasms. The strongest benign neoplasm association is with ovarian fibromas, diagnosed in 14% to 24% of females affected by BCNS.[68,72,76] BCNS-associated ovarian fibromas are more likely to be bilateral and calcified than sporadic ovarian fibromas.[77]

Other associated benign neoplasms include gastric hamartomatous polyps,[78] congenital pulmonary cysts,[79] cardiac fibromas,[80] meningiomas,[81-83] craniopharyngiomas,[84] fetal rhabdomyomas,[85] leiomyomas,[86] mesenchymomas,[87] and nasal dermoid tumors. Development of meningiomas and ependymomas occurring postradiation therapy has been documented in the general pediatric population; radiation therapy for syndrome-associated intracranial processes may be partially responsible for a subset of these benign tumors in individuals with BCNS.[88-90] Radiation therapy of medulloblastomas may result in many cutaneous BCCs in the radiation ports. Similarly, treatment of BCC of the skin with radiation therapy may result in induction of large numbers of additional BCCs.[67,68,86]

The diagnostic criteria for BCNS are described in Table 1 below.

Table 1. Comparison of Diagnostic Criteria for Basal Cell Nevus Syndrome (BCNS)
Evans et al. 1993 [71]Kimonis et al. 1997 [72]Veenstra-Knol et al. 2005 [73]
aTwo major criteria or one major and two minor criteria needed to meet the requirements for a BCNS diagnosis.[71-73]
BCC = basal cell carcinoma.
Major Criteriaa
>2 BCCs or 1 BCC diagnosed before age 30 y or >10 basal cell nevi>2 BCCs or 1 BCC diagnosed before age 20 y>2 BCCs or 1 BCC diagnosed before age 20 y
Histologically proven odontogenic keratocyst or polyostotic bone cystHistologically proven odontogenic keratocystHistologically proven odontogenic keratocyst
≥3 palmar or plantar pits≥3 palmar or plantar pits≥3 palmar or plantar pits
Ectopic calcifications, lamellar or early (diagnosed before age 20 y) faux calcificationsBilamellar calcification of faux cerebriEctopic calcification (lamellar or early faux cerebri)
Family history of BCNSFirst-degree relative with BCNSFamily history of BCNS
(Rib abnormalities listed as minor criterion; see below.) Bifid, fused, or splayed ribsBifid, fused, or splayed ribs
Minor Criteria
Occipital-frontal circumference >97th percentile and frontal bossingMacrocephaly (adjusted for height)Macrocephaly (>97th percentile)
Congenital skeletal abnormalities: bifid, fused, splayed, or missing rib or bifid, wedged, or fused vertebraeBridging of sella turcica, vertebral abnormalities (hemivertebrae, fusion or elongation of vertebral bodies), modeling defects of the hands and feet, or flame-shaped lucencies of hands and feetBridging of sella turcica, vertebral abnormalities (hemivertebrae, fusion or elongation of vertebral bodies), modeling defects of the hands and feet
(Rib abnormalities listed as major criterion; see above.) (Rib abnormalities listed as major criterion; see above.)
Cardiac or ovarian fibromaOvarian fibromaCardiac or ovarian fibroma
Congenital malformation: cleft lip and/or palate, polydactyly, cataract, coloboma, microphthalmiaCleft lip or palate, frontal bossing, moderate or severe hypotelorismCleft lip and/or palate, polydactyly
 Sprengel deformity, marked pectus deformity, marked syndactylySprengel deformity, marked pectus deformity, marked syndactyly
Lymphomesenteric cysts  
  Eye anomaly: cataract, coloboma, microphthalmia

Of greatest concern with BCNS are associated malignant neoplasms, the most common of which is BCC. BCC in individuals with BCNS may appear during childhood as small acrochordon-like lesions, while larger lesions demonstrate more classic cutaneous features.[91] Nonpigmented BCCs are more common than pigmented lesions.[92] The age at first BCC diagnosis associated with BCNS ranges from 3 to 53 years, with a mean age of 21.4 years; the vast majority of individuals are diagnosed with their first BCC before age 20 years.[72,76] Most BCCs are located on sun-exposed sites, but individuals with greater than 100 BCCs have a more uniform distribution of BCCs over the body.[92] Case series have suggested that up to 1 in 200 individuals with BCC demonstrate findings supportive of a diagnosis of BCNS.[61] BCNS has rarely been reported in individuals with darker skin pigmentation; however, significantly fewer BCCs are found in individuals of African or Mediterranean ancestry.[72,93,94] Despite the rarity of BCC in this population, reported cases document full expression of the noncutaneous manifestations of BCNS.[94] However, in individuals of African ancestry who have received radiation therapy, significant basal cell tumor burden has been reported within the radiation port distribution.[72,86] Thus, cutaneous pigmentation may protect against the mutagenic effects of UV but not ionizing radiation.

Many other malignancies have been associated with BCNS. Medulloblastoma carries the strongest association with BCNS and is diagnosed in 1% to 5% of BCNS cases. While BCNS-associated medulloblastoma is typically diagnosed between ages 2 and 3 years, sporadic medulloblastoma is usually diagnosed later in childhood, between the ages of 6 and 10 years.[68,72,76,95] A desmoplastic phenotype occurring around age 2 years is very strongly associated with BCNS and carries a more favorable prognosis than sporadic classic medulloblastoma.[96,97] Up to three times more males than females with BCNS are diagnosed with medulloblastoma.[98] As with other malignancies, treatment of medulloblastoma with ionizing radiation has resulted in numerous BCCs within the radiation field.[68,81] Other reported malignancies include ovarian carcinoma,[99] ovarian fibrosarcoma,[100,101] astrocytoma,[102] melanoma,[103] Hodgkin disease,[104,105] rhabdomyosarcoma,[106] and undifferentiated sinonasal carcinoma.[107]

Odontogenic keratocysts–or keratocystic odontogenic tumors (KCOTs), as renamed by the World Health Organization working group–are one of the major features of BCNS.[108] Demonstration of clonal loss of heterozygosity (LOH) of common tumor suppressor genes, including PTCH1, supports the transition of terminology to reflect a neoplastic process.[64] Less than one-half of KCOTs from individuals with BCNS show LOH of PTCH1.[70,109] The tumors are lined with a thin squamous epithelium and a thin corrugated layer of parakeratin. Increased mitotic activity in the tumor epithelium and potential budding of the basal layer with formation of daughter cysts within the tumor wall may be responsible for the high rates of recurrence post simple enucleation.[108,110] In a recent case series of 183 consecutively excised KCOTs, 6% of individuals demonstrated an association with BCNS.[108] KCOTs occur in 65% to 100% of individuals with BCNS,[72,111] with higher rates of occurrence in young females.[112]

Palmoplantar pits are another major finding in BCC and occur in 70% to 80% of individuals with BCNS.[76] When these pits occur together with early-onset BCC and/or KCOTs, they are considered diagnostic for BCNS.[113]

Several characteristic radiologic findings have been associated with BCNS, including lamellar calcification of falx cerebri;[114,115] fused, splayed or bifid ribs;[116] and flame-shaped lucencies or pseudocystic bone lesions of the phalanges, carpal, tarsal, long bones, pelvis, and calvaria.[75] Imaging for rib abnormalities may be useful in establishing the diagnosis in younger children, who may have not yet fully manifested a diagnostic array on physical examination.

A 9p22.3 microdeletion syndrome that includes the PTCH1 locus has been described in ten children.[117] All patients had facial features typical of BCNS, including a broad forehead, but they had other features variably including craniosynostosis, hydrocephalus, macrosomia, and developmental delay. At the time of the report, none had basal cell skin cancer. On the basis of their hemizygosity of the PTCH1 gene, these patients are presumably at an increased risk of basal cell skin cancer.

Rare syndromes

Rombo syndrome

Rombo syndrome, a very rare genetic disorder associated with BCC, has been outlined in three case series in the literature.[118-120] The cutaneous examination is within normal limits until age 7 to 10 years, with the development of distinctive cyanotic erythema of the lips, hands, and feet and early atrophoderma vermiculatum of the cheeks, with variable involvement of the elbows and dorsal hands and feet.[118] Development of BCC occurs in the fourth decade.[118] A distinctive grainy texture to the skin, secondary to interspersed small, yellowish, follicular-based papules and follicular atrophy, has been described.[118,120] Missing, irregularly distributed and/or misdirected eyelashes and eyebrows are another associated finding.[118,119]

Bazex-Dupré-Christol syndrome

Bazex-Dupré-Christol syndrome, another rare genodermatosis associated with development of BCC, has more thorough documentation in the literature than Rombo syndrome. Inheritance is accomplished in an X-linked dominant fashion, with no reported male-to-male transmission.[121-123] Regional assignment of the locus of interest to chromosome Xq24-q27 is associated with a maximum LOD score of 5.26 with the DXS1192 locus.[124]

Characteristic physical findings include hypotrichosis, hypohidrosis, milia, follicular atrophoderma of the cheeks, and multiple BCC, which manifest in the late second decade to early third decade.[121] Documented hair changes with Bazex-Dupré-Christol syndrome include reduced density of scalp and body hair, decreased melanization,[125] a twisted/flattened appearance of the hair shaft on electron microscopy,[126] and increased hair shaft diameter on polarizing light microscopy.[123] The milia, which may be quite distinctive in childhood, have been reported to regress or diminish substantially at puberty.[123] Other reported findings in association with this syndrome include trichoepitheliomas; hidradenitis suppurativa; hypoplastic alae; and a prominent columella, the fleshy terminal portion of the nasal septum.[127,128]

Epidermolysis bullosa simplex, Dowling-Meara

A rare subtype of epidermolysis bullosa simplex (EBS), Dowling-Meara (EBS-DM), is primarily inherited in an autosomal dominant fashion and is associated with mutations in either keratin-5 (KRT5) or keratin-14 (KRT14).[129] EBS-DM is one of the most severe types of EBS and occasionally results in mortality in early childhood.[130] One report cites an incidence of BCC of 44% by age 55 years in this population.[131] Individuals who inherit two EBS mutations may present with a more severe phenotype.[132] Other less phenotypically severe subtypes of EBS can also be caused by mutations in either KRT5 or KRT14.[129] Approximately 75% of individuals with a clinical diagnosis of EBS (regardless of subtype) have KRT5 or KRT14 mutations.[133]

Characteristics of hereditary syndromes associated with a predisposition to BCC are described in Table 2 below.

Table 2. Basal Cell Carcinoma (BCC) Syndromes
Syndrome (OMIM link)InheritanceChromosomeGeneClinical Findings
AD = autosomal dominant; AR = autosomal recessive; OMIM = Online Mendelian Inheritance in Man; XD = X-linked dominant.
Basal cell nevus syndrome, Gorlin syndrome AD9q22.3-q31 [61]PTCH1 [134,135]BCC (before age 20 y)
3.597–6.457 [61]PTCH2 [136]
10q24.32SUFU [83]
Rombo syndrome AD  Milia, atrophoderma vermiculatum, acrocyanosis, trichoepitheliomas, and BCC (age 30–40 y)
Bazex-Dupré-Christol syndrome XD > ADXq24-27 [124]UnknownHypotrichosis (variable),[121] hypohidrosis, milia, follicular atrophoderma (dorsal hands), and multiple BCCs (aged teens to early 20s)[121]
Brooke-Spiegler syndrome AD16q12-q13 [137,138]CYLD [139,140]Cylindroma (forehead, scalp, trunk, and pubic area),[141,142] trichoepithelioma (around nose), spiradenoma, and BCC
Multiple hereditary infundibulocystic BCC AD[143]UnknownUnknownMultiple BCC (infundibulocystic type)
Schopf-Schultz-Passarge syndrome AR > ADUnknownUnknownEctodermal dysplasia (hypotrichosis, hypodontia, and nail dystrophy [anonychia and trachyonychia]), hidrocystomas of eyelids, palmo-plantar keratosis and hyperhidrosis, and BCC[144]

(Refer to the Brooke-Spiegler Syndrome, Multiple Familial Trichoepithelioma, and Familial Cylindromatosis section in the Rare Skin Cancer Syndromes section of this summary for more information about Brooke-Spiegler syndrome.)



As detailed further below, the U.S. Preventive Services Task Force does not recommend regular screening for the early detection of any cutaneous malignancies, including BCC. However, once BCC is detected, the National Comprehensive Cancer Network guidelines of care for nonmelanoma skin cancers recommends complete skin examinations every 6 to 12 months for life.[145]

Level of evidence: 5

Primary prevention

Avoidance of excessive cumulative and sporadic sun exposure is important in reducing the risk of BCC, along with other cutaneous malignancies. Scheduling activities outside of the peak hours of UV radiation, utilizing sun-protective clothing and hats, using sunscreen liberally, and strictly avoiding tanning beds are all reasonable steps towards minimizing future risk of skin cancer. For patients with particular genetic susceptibility (such as BCNS), avoidance or minimization of ionizing radiation is essential to reducing future tumor burden.

Level of evidence: 2aii


The role of various systemic retinoids, including isotretinoin and acitretin, has been explored in the chemoprevention and treatment of multiple BCCs, particularly in BCNS patients. In one study of isotretinoin use in 12 patients with multiple BCCs, including 5 patients with BCNS, tumor regression was noted, with decreasing efficacy as the tumor diameter increased.[146] However, the results were insufficient to recommend use of systemic retinoids for treatment of BCC. Three additional patients, including one with BCNS, were followed long-term for evaluation of chemoprevention with isotretinoin, demonstrating significant decrease in the number of tumors per year during treatment.[146] Although the rate of tumor development tends to increase sharply upon discontinuation of systemic retinoid therapy, in some patients the rate remains lower than their pretreatment rate, allowing better management and control of their cutaneous malignancies.[146-148] In summary, the use of systemic retinoids for chemoprevention of BCC is reasonable in high-risk patients, including patients with xeroderma pigmentosum, as discussed in the Squamous Cell Carcinoma section.

A patient’s cumulative and evolving tumor load should be evaluated carefully in light of the potential long-term use of a medication class with cumulative and idiosyncratic side effects. Given the possible side-effect profile, systemic retinoid use is best managed by a practitioner with particular expertise and comfort with the medication class. However, for all potentially childbearing women, strict avoidance of pregnancy during the systemic retinoid course—and for 1 month after completion of isotretinoin and 3 years after completion of acitretin—is essential to avoid potentially fatal and devastating fetal malformations.

Level of evidence (retinoids): 2aii

In a phase II study of 41 patients with BCNS, vismodegib (an inhibitor of the hedgehog pathway) has been shown to reduce the per-patient annual rate of new BCCs requiring surgery.[149] Existing BCCs also regressed for these patients during daily treatment with 150 mg of oral vismodegib. While patients treated had visible regression of their tumors, biopsy demonstrated residual microscopic malignancies at the site, and tumors progressed after the discontinuation of the therapy. Adverse effects included taste disturbance, muscle cramps, hair loss, and weight loss and led to discontinuation of the medication in 54% of subjects. Based on the side-effect profile and rate of disease recurrence after discontinuation of the medication, additional study regarding optimal dosing of vismodegib is ongoing.

Level of evidence (vismodegib): 1aii


Treatment of individual basal cell cancers in BCNS is generally the same as for sporadic basal cell cancers. Due to the large number of lesions on some patients, this can present a surgical challenge. Field therapy with imiquimod or photodynamic therapy are attractive options, as they can treat multiple tumors simultaneously.[150,151] However, given the radiosensitivity of patients with BCNS, radiation as a therapeutic option for large tumors should be avoided.[72] There are no randomized trials, but the isolated case reports suggest that field therapy has similar results as in sporadic basal cell cancer, with higher success rates for superficial cancers than for nodular cancers.[150,151]

Level of evidence: 4

In addition to its effects on the prevention of BCCs in patients with BCNS, vismodegib may also have a palliative effect on KCOTs found in this population. An initial report indicated that the use of GDC-0449, the hedgehog pathway inhibitor now known as vismodegib, resulted in resolution of KCOTs in one patient with BCNS.[152] Another small study found that four of six patients who took 150 mg of vismodegib daily had a reduction in the size of KCOTs.[153] None of the six patients in this study had new KCOTs or an increase in the size of existing KCOTs while being treated, and one patient had a sustained response that lasted 9 months after treatment was discontinued.

Level of evidence: 3diii


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  • Updated: December 5, 2014