Version July 2025
INTRODUCTION —
Basal cell carcinoma (BCC) is a very common skin cancer arising from the basal layer of the epidermis and its appendages. BCC and cutaneous squamous cell carcinomas (cSCC) are also collectively called "nonmelanoma skin cancer" or "keratinocytic carcinomas" [1].
The epidemiology, pathogenesis, clinical presentation, and differential diagnosis of BCC will be reviewed here. The treatment and prognosis of BCC and nevoid basal cell carcinoma syndrome are discussed separately. cSCC is also discussed separately.
●(See "Treatment and prognosis of basal cell carcinoma at low risk of recurrence".)
●(See "Treatment of basal cell carcinomas at high risk for recurrence".)
●(See "Nevoid basal cell carcinoma syndrome (Gorlin syndrome)".)
●(See "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis".)
●(See "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma (cSCC)".)
●(See "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma".)
EPIDEMIOLOGY
Incidence and prevalence — BCC is the most common human malignancy. It is particularly common in White populations but very uncommon in people with darkly pigmented skin.
Estimates of the incidence of BCC are imprecise since most countries do not have a cancer registry that collects data on BCC [2]. In 2012, the American Cancer Society estimated that 5.4 million cases of nonmelanoma skin cancers (NMSC) were diagnosed in 3.3 million people, of which approximately 8 in 10 cases would have been BCC [3].
●One study using data from a commercially insured population in the United States estimated an age-adjusted incidence and prevalence of BCC of 226 and 343 per 100,000 persons per year, respectively [4].
●Similar rates were reported in a population-based study in Olmsted County, Minnesota [5], whereas higher rates were estimated in the Nurses' Health Study (1986 to 2006) and Health Professionals Follow-up Study, where the age-adjusted BCC incidence rates were 519 cases per 100,000 person-years in females and 606 cases per 100,000 person-years in males [6].
An increasing incidence of BCC over time has been noted in the United States and other countries, including Canada, Finland, France, Iceland, and Australia [6-11]. In the United States from 1986 to 2006, the incidence of BCC increased to 1019 cases per 100,000 person-years and 1488 cases per 100,000 person-years in female and male patients, respectively [6].
The incidence of BCC increases with age; persons aged 55 to 75 have approximately a 100-fold higher incidence of BCC than those younger than 20 [12]. Although increasing longevity may underlie some of the increasing incidence of BCC, the incidence of BCC among Americans younger than 40 also appears to be increasing, particularly among females [13].
Geographic variation — There are prominent global variations in BCC incidence.
●Within the United States, there is striking geographic variation in incidence. States closer to the equator, such as Hawaii and California, have an incidence of BCC at least twice that of the midwestern United States [14,15].
●In northern European countries, such as Finland, the incidence of BCC is one-fourth of that of the midwestern United States. In contrast, the incidence rate in Australia is 40 times that of Finland [7,8,16].
RISK FACTORS —
Phenotypic traits, exposure to ultraviolet (UV) radiation from sunlight, and genetic predisposition are the primary risk factors for BCC. Other established risk factors include older age, childhood freckling, increased number of past sunburns, chronic arsenic exposure, radiation therapy, long-term immunosuppressive therapy, and nevoid basal cell carcinoma syndrome. (See "Nevoid basal cell carcinoma syndrome (Gorlin syndrome)".)
Phenotypic traits — Light skin pigmentation, light hair and eye color, and poor tanning ability, which reflect the skin sensitivity to sunlight, are well-known risk factors for BCC [17-19]. A meta-analysis of 29 observational studies found that red hair, lightly pigmented skin, and skin that burns but never tans were associated with a twofold risk of developing a BCC [20].
Ultraviolet radiation
Sun exposure — Exposure to UV radiation from sunlight is the most important environmental cause of BCC. The type, quantity, and timing of sun exposure associated with an increased risk of BCC are not clearly defined.
●Timing – Childhood sun exposure appears to be more important than exposure during adult life [17,21]. Evidence supporting this hypothesis comes from case-control studies and clinical trials [18,19,21,22].
In a Canadian case-control study that included 226 males with BCC and 406 age-matched controls, the development of BCC was strongly correlated with childhood and adolescent sun exposure but not cumulative or recent sun exposure [21]. In other studies, however, adult sun exposure was a risk factor for BCC [18].
●Frequency and amount – The frequency and amount of sun exposure may also be important. Solar exposure in intermittent, intense increments increases the risk of BCC more than a similar dose delivered more continuously over the same period of time [23].
A French case-control study that included more than 1000 females with BCC and more than 3600 controls found that a history of severe sunburn before the age of 25 and after the age of 25 were both independently associated with a twofold increased risk of BCC after adjusting for skin sensitivity to sunlight and hair, eye, and skin color [24].
The role of chronic occupational sun exposure remains uncertain [25].
Tanning beds — The use of tanning beds may increase the risk for early development of BCC [26-28].
●A cohort study of approximately 73,000 female nurses found that females who used tanning beds more than six times per year during high school or college were more likely to develop BCC than those who did not use tanning booths during these time periods (adjusted hazard ratio [HR] 1.73, 95% CI 1.52-1.98) [29].
●A 2012 meta-analysis of 12 observational studies (9328 nonmelanoma skin cancer [NMSC] cases) found that individuals with a history of any tanning bed use were more likely to develop BCC than those who had never used tanning beds (relative risk [RR] 1.29, 95% CI 1.08-1.53) [30]. The risk was slightly higher for those reporting their first use of tanning devices before the age of 25 (RR 1.40, 95% CI 1.29-1.52).
●A population-based case-control study that included approximately 650 patients with BCC and 450 controls found that tanning bed users had a 60 percent increased risk of developing a BCC at or before the age of 50 years (odds ratio [OR] 1.6, 95% CI 1.3-2.1) [27]. In this study, the risk of BCC was doubled for those reporting their first use of tanning devices before the age of 20.
●A Canadian study found that the RR of BCC associated with ever using tanning beds was 1.39 (95% CI 1.10-1.76) and estimated that 5 percent of BCC were attributable to ever use of indoor tanning devices [31].
Tanning bed use may also be a marker of populations more exposed to the sun. Studies have shown that tanning bed users are more likely to be regular sunbathers and to have poorer sun-protection behavior than nonusers [32,33].
Phototherapy
●PUVA – Therapeutic exposure to psoralen plus ultraviolet A (PUVA) light for cutaneous disorders such as psoriasis increases the risk of NMSC, mostly cutaneous squamous cell carcinoma (cSCC) [34]. In a 30-year cohort study of patients receiving PUVA for psoriasis, the BCC and cSCC incidence rates were approximately 5- and 30-fold higher than that expected in the general population, respectively [35]. (See "Psoralen plus ultraviolet A (PUVA) photochemotherapy", section on 'Skin cancer'.)
●UVB phototherapy – Broadband ultraviolet B (UVB; 280 to 320 nm) and narrowband ultraviolet B (NBUVB; 311 to 313 nm) phototherapy appear to be less likely to promote the development of NMSC compared with PUVA [36]. However, evidence from observational studies is conflicting. (See "UVB phototherapy (broadband and narrowband)".)
Some observational studies have reported a modest increased risk for BCC after UVB therapy [37,38]. In a cohort of 4815 patients receiving NBUVB phototherapy in Finland followed for a mean of 8.4 years, the standardized incidence ratio of BCC was 2.5 (95% CI 1.8-3.5) [39].
In contrast, other studies have reported no increased risk [40-44]. As an example, in a retrospective study of 3867 phototherapy patients (of whom 352 received ≥100 NBUVB treatments), NBUVB was not associated with an increased risk of BCC except in cases where patients were treated with both NBUVB and PUVA [40]. In another retrospective cohort study of 3505 patients treated with broadband UVB, NBUVB, and/or combined ultraviolet A (UVA)/UVB followed up for a mean of 7.3 years, there was no difference in the age-standardized incidence rates of BCC compared with the general population [44].
Less is known about whether UV exposure or phototherapy is associated with increased risk of BCC in skin of color. A systematic review examining the association between UV exposure and NMSC among individuals with skin of color found no association between exposure to UVB phototherapy and BCC or cSCC among East Asian populations [45].
Photosensitizing agents — The association of BCC with UV light exposure has led to questions about the impact of photosensitizing drugs on the development of BCC. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Photosensitivity due to exogenous agents'.)
An association between prior use of photosensitizing tetracyclines, calcium channel blockers, beta blockers, or thiazide diuretics and a modest increase in risk for BCC has been reported in observational and case-control studies [46-51].
●A meta-analysis of eight observational studies with nearly 400,000 participants found a weak association between the use of thiazide diuretics and the risk of BCC (OR 1.19, 95% CI 1.02-1.38) [52].
●Another meta-analysis of 42 studies with nearly 17 million participants found that exposure to diuretics was associated with an increased risk for NMSC (OR 1.27, 95% CI 1.09-1.47) [53]. However, no increased risk was found when the analysis was restricted to studies adjusting for potential confounders such as sun exposure and skin phototype (OR 1.08, 95% CI 0.98-1.19).
Beyond drugs, dietary consumption of photosensitizing agents (eg, furocoumarins in citrus fruit) may contribute to the risk of developing BCC. An analysis of data from the Health Professionals Follow-up Study and the Nurses' Health Study found that higher intake of total furocoumarins was associated with a small increased risk of BCC (HR 1.16, 95% CI 1.11-1.21) after adjusting for known risk factors for BCC [54].
Other environmental risk factors
Chronic arsenic exposure — Superficial multicentric BCC may occur due to chronic exposure to arsenic from ingestion of contaminated drinking water, seafood, or medications [55-59]. (See "Arsenic exposure and chronic poisoning", section on 'Cancer'.)
In a nationwide population-based study using registry data from the National Taiwan Cancer Registry Center between 1979 and 2007, the risk of BCC was three- to fourfold higher in the blackfoot disease (a form of peripheral vascular disease associated with arsenic exposure) endemic areas compared with other areas of Taiwan [58].
The risk of BCC associated with arsenic exposure may be influenced by genetic factors, such as variants of the AS3MT gene (encoding the arsenite methyltransferase enzyme) and telomer length [59,60]. In a study including 528 arsenic-exposed cases with BCC and 533 healthy controls, within each tertile of arsenic exposure, individuals with shorter telomeres were at increased risk of BCC, with the highest risk in the highest exposure group [60].
Ionizing radiation — Superficial therapeutic ionizing radiation increases the risk of NMSC, including BCC [61-63]. The latency period for development of BCC is approximately 20 years, and lesions are limited to sites within the radiation field.
The treatment of noncutaneous disorders with radiation therapy (eg, thymic enlargement in infancy and ankylosing spondylitis) as well as the use of radiation therapy for conditioning prior to hematopoietic stem cell transplantation have also been associated with the appearance of BCC, particularly with exposure at a younger age [62,64,65].
Ionizing radiation used to treat childhood cancers also increases the risk for the subsequent development of BCC. This was illustrated in a study of 776 subjects, 5 of whom developed BCC (approximately 10-fold more than was expected in this population) [66]. All of the BCC were located within the radiation field. In addition, a case-control study of 199 patients with a history of both childhood cancer and BCC and 597 controls with a history of childhood cancer without BCC found a linear dose-response relationship between the radiation dose and risk for BCC [67]. An increase in risk was detected among patients who received at least 1 Gy of radiation to the skin, and patients who received 35 Gy or more were 40 times more likely to develop BCC than those who were not treated with radiation (OR 39.8, 95% CI 8.6-185). Occupational exposure to ionizing radiation (ie, as a radiation technologist) may also increase the risk of BCC development [68].
BCC development is strikingly absent in Black survivors of irradiated childhood cancer [69] and substantially lower in Black versus White patients who received radiation for tinea capitis [70] for reasons that are not understood or completely explained by darker skin pigmentation alone [69].
Studies of survivors of the atomic bomb explosions in Japan support the role of exposure to ionizing radiation in the development of BCC in the nonmedical setting [71-74].
Predisposing genetic variants — In addition to specific mutational drivers of BCC (see 'Pathogenesis' below), germline polymorphisms in genes that determine pigmentary traits, such as melanocortin 1 receptor (MC1R), human homolog of agouti signaling protein (ASIP), and tyrosinase (TYR), are associated with increased risk of BCC [75-77]. However, independent of MCR1 phenotype, a family history of skin cancer is associated with increased risk of BCC under age 40 (OR 2.49, 95% CI 1.80-3.45) [78].
Specific gene polymorphisms have been associated with the truncal phenotype and clustering of BCC. Patients are often younger, male, and have more clusters of BCC compared with those with BCC arising in sun-exposed sites. The associated genes include those encoding the detoxifying enzyme genes cytochrome P450 CYP2D6 and glutathione S-transferase, the vitamin D receptor, and tumor necrosis factor [79-83]. The links among these genetic polymorphisms, tumorigenesis, and the clinical phenotype are not clear.
Genome-wide association studies have identified genetic variants that may influence BCC risk through other pathways, such as an effect on the growth or differentiation of the basal layers of the epidermis or an effect on the TP53 tumor suppressor gene [84-87]. A genome-wide association meta-analysis found that single nucleotide polymorphisms in genes involved in deoxyribonucleic acid (DNA) excision repair may be involved in the pathogenesis of BCC [88].
Genes that affect the immune response may also impact susceptibility to BCC. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is expressed on regulatory T cells and is involved in UV-induced immune tolerance. In a case-control study, genetic variation at the CTLA-4 locus influenced the risk of BCC, particularly among patients with a higher number of severe sunburns [89].
Personal history of basal cell carcinoma — Individuals with a history of BCC are at increased risk for subsequent lesions. Approximately 40 to 50 percent of patients who have had one BCC will develop another lesion within five years [90,91]. However, the probability of developing a subsequent BCC is significantly less after a first BCC than after a nonfirst BCC (13 versus 34 percent at one year, 20 versus 52 percent at two years, and 35 versus 75 percent at five years) [92]. (See "Treatment of basal cell carcinomas at high risk for recurrence", section on 'Prognosis and follow-up'.)
Inherited disorders — Inherited disorders that are associated with a greatly increased risk of developing BCC at an early age and with increased morbidity include:
●Nevoid basal cell carcinoma syndrome – Nevoid basal cell carcinoma syndrome, also known as basal cell nevus syndrome or Gorlin syndrome, is a rare multisystem disorder of autosomal dominant inheritance in most cases caused by germline mutations of the human patched gene (PTCH1) [93]. Affected patients have both developmental anomalies and postnatal tumors, including multiple BCC, at an average age of 20 to 21 years; odontogenic keratocysts; and medulloblastoma [94]. (See "Nevoid basal cell carcinoma syndrome (Gorlin syndrome)" and 'PTCH1 gene' below.)
●Rombo syndrome – Rombo syndrome was first described in a family with vermiculate atrophoderma and peripheral vasodilation with cyanosis in childhood, milia, trichoepitheliomas, hypotrichosis in adulthood, and BCC developing in the third and fourth decade [95]. Rombo syndrome appears to be transmitted in a dominant pattern; however, a causative mutation has not been identified.
●Bazex-Dupré-Christol syndrome – Bazex-Dupré-Christol syndrome (also called Bazex syndrome or follicular atrophoderma and basal cell carcinomas) is an X-linked dominant disorder characterized by congenital hypotrichosis, follicular atrophoderma, milia, and multiple BCC [96].
●Xeroderma pigmentosum – Xeroderma pigmentosum is a rare autosomal recessive disorder due to mutations in any of eight genes involved in repair of UV-induced DNA damage [97]. Clinical findings include early-onset pigmentary skin changes and early development of skin cancers. Squamous cell carcinoma (SCC) and BCC develop at an average age of nine years. (See "Xeroderma pigmentosum".)
●Muir-Torre syndrome – Muir-Torre syndrome is a rare autosomal dominant condition caused by mutations in DNA mismatch repair genes MLH1, MSH2, and MSH6. Patients present with sebaceous neoplasms, including sebaceous adenomas and carcinomas, keratoacanthomas, BCC, and malignancies of the colon and genitourinary tract [95]. (See "Muir-Torre syndrome".)
●Oculocutaneous albinism – Oculocutaneous albinism (OCA) is a group of autosomal recessive disorders of melanin biosynthesis presenting with a spectrum of visual disturbances and hypopigmentation of the skin and hair. Individuals with OCA have an increased risk of early-onset skin cancer, possibly by their teenage years. SCC is the most common type of cancer occurring in patients with OCA, but BCC and melanoma also occur [98]. (See "Oculocutaneous albinism".)
Immunosuppression — Chronic immunosuppression may increase the risk of developing a BCC, although the increase in risk is less than that observed for SCC [99,100].
●Solid organ transplant recipients – The degree and duration of immunosuppression influence the risk for BCC after solid organ transplantation [99]. The specific impact of specific immunosuppressive agents on BCC risk is unclear. Studies performed in patients without a history of organ transplantation conflict on whether systemic glucocorticoid therapy significantly increases risk for BCC [101-106]. As in other populations, sun exposure, phenotype, and other factors influence the likelihood that an organ transplant recipient will develop a BCC [107]. (See "Epidemiology and risk factors for skin cancer in solid organ transplant recipients", section on 'Cutaneous squamous cell carcinoma and basal cell carcinoma'.)
●Allogeneic stem cell transplant recipients – There is an increased risk of skin cancer in the allogeneic stem cell transplant population as well. A Danish study of 1007 patients who received allogeneic stem cell transplants found an HR for BCC of 3.1 (95% CI 1.9-5.2) compared with the background population [108]. This rate was on par with the renal transplant recipients. Another study of adult allogeneic stem cell transplant recipients reported an incidence rate ratio of 2.5 for BCC development (95% CI 1.9-3.2) [109]. The reasons for the increase are not clear and have been attributed, in part, to the conditioning regimen (including total body irradiation), disease prior to transplant (ie, chronic lymphocytic leukemia), and the presence of graft-versus-host disease [108-110].
●Nontransplant patients – Less is known about the risk for skin cancer in nontransplant patients treated with immunosuppressants. In a retrospective cohort study of 405 patients with rheumatoid arthritis or psoriatic arthritis, the use of methotrexate and methotrexate with cyclosporine A or D-penicillamine was associated with an increased risk of NMSC [111]. Among patients treated with methotrexate, a dose-response relationship was noted only for BCC, with a standardized incidence ratio of 5.77 (95% CI 4.19-7.74) for those treated with a cumulative dose greater than 8 g versus 2.21 (95% CI 1.35-3.41) for those treated with a cumulative dose less than 5 g.
However, these results should be interpreted with caution, as the possibility of ascertainment bias due to increased medical surveillance for patients with rheumatoid arthritis or psoriatic arthritis cannot be excluded. In a nationwide Danish case-control study, a cumulative methotrexate dose greater than or equal to 2.5 g was associated with a modest increase in the risk of BCC after adjusting for age, sex, use of photosensitizing drugs, exposure to PUVA therapy, or other immunosuppressants or biologics (OR 1.29, 95% CI 1.20-1.38) [112].
●HIV infection – Support for an increased risk for BCC among individuals with human immunodeficiency virus (HIV) was demonstrated in a retrospective cohort study of non-Hispanic White patients with HIV (n = 6560) and without HIV (n = 36,821) from a northern California health care system [100]. The study found that patients with HIV infection were approximately twice as likely to develop BCC as patients without HIV infection (adjusted rate ratio 2.1, 95% CI 1.8-2.3). Similar results were obtained in a Danish nationwide population-based cohort study that included 4280 patients with HIV; compared with age- and sex-matched individuals, the incidence rate ratio for BCC was 1.79 (95% CI 1.44-2.22) [113].
Other factors — Other factors that have been associated with an increased risk of BCC include:
●Nevus sebaceous – Nevus sebaceous is an uncommon congenital hamartoma of the skin composed of epidermal, follicular, sebaceous, and apocrine elements. BCC may develop within a nevus sebaceous, though this occurrence is rare. In a retrospective study of 596 nevus sebaceous excisions from adults and children, BCC was detected in specimens from five adults (0.8 percent) [114]. A separate review of 631 children with 651 lesions of nevus sebaceous found that BCC may also develop within nevus sebaceous in children [115]. BCC was found in excisional specimens from five patients (0.8 percent). (See "Nevus sebaceus and nevus sebaceus syndromes".)
●Lifestyle factors – Smoking increases the risk of SCC [91] and has been evaluated for an association with BCC [22,116]. Although a case-control study performed in 333 disease-discordant twin pairs found an increased risk of BCC in smokers and in females compared with males [116], a subsequent meta-analysis failed to find a significant association between BCC and smoking [117]. A small, dose-dependent increase in BCC risk of 1.07 (95% CI 1.04-1.09) has been shown with every 10 g/day increase in ethanol consumption [118]. Other lifestyle factors possibly affecting the risk for BCC include higher education and coffee consumption [116,119,120]. Additional studies are needed to confirm these findings before firm conclusions can be drawn.
●Human papillomavirus – Although an epidemiologic and biologic relationship between human papillomavirus (HPV) and BCC has not been established, some studies in organ transplant patients and psoriasis patient populations have noted an increased number of NMSC, including BCC, associated with evidence of HPV in the skin [121,122].
PATHOGENESIS
Molecular pathogenesis — Our understanding of the pathogenesis of BCC was greatly enhanced with the discovery of germline loss-of-function variants in the PTCH1 gene on chromosome 9q22.3 in patients with inherited nevoid basal cell carcinoma syndrome [123] (see "Nevoid basal cell carcinoma syndrome (Gorlin syndrome)"). Subsequently, somatic mutations of PTCH1 were identified in over 70 percent of sporadic BCC and BCC associated with xeroderma pigmentosum [124-130]. In a manner similar to the retinoblastoma gene, two somatic "hits" in the same cell are required for sporadic cases, while one somatic "hit" plus the inheritance of one defective allele are responsible for BCC associated with inherited disorders.
PTCH1 gene — PTCH1 encodes a protein acting as a transmembrane receptor for the hedgehog (HH) protein family, an important component of the highly conserved HH signaling pathway, which directs embryonic development of a variety of organs in vertebrates (figure 1) [131]. Three HH ligands are present in mammals: sonic hedgehog (SHH), Indian hedgehog (IHH), and desert hedgehog (DHH). SHH is the most studied HH ligand. It binds a cell membrane receptor complex that is formed by PTCH and a second protein, smoothened (SMO), relieving the inhibition of the pathway induced by unbound PTC1 and thus activating the HH pathway [124,132].
However, the mechanism by which HH signal overexpression leads to tumorigenesis is unclear. It may involve the activation of the transcription factors Gli (glioma-associated oncogene homolog) 1 and/or 2.
TP53 gene — The second most important gene in BCC carcinogenesis is TP53, encoding the P53 protein involved in maintaining genomic stability by regulating the cell cycle, inducing apoptosis, and activating DNA repair. TP53 mutations have been detected in 20 to over 60 percent of sporadic BCC [130].
Other genes — In addition to PTCH1 and TP53, other tumor-related genes have been implicated in BCC pathogenesis [128,130,133,134]. However, the relevance of these mutations in BCC pathogenesis is unclear.
●In a series of 293 BCC, 85 percent harbored variants in genes involved in the HH pathway (PTCH1, SMO, and SUFU), and 61 percent harbored variants in TP53 [128]. However, 85 percent of BCC also harbored variants in multiple other cancer-related genes (eg, MYCN, PPP6C, PTPN14, STK19, LATS1).
●In a series of 57 BCC, somatic variants were found in PTCH1, CSMD1, TP53, NOTCH1, TERT promoter, DPH3 promoter, and DPP10 [135].
●In a whole-exome sequencing study of 12 sporadic BCC and normal skin, mutations were found in a number of known or putative cancer genes, including CSMD1, DPP10, NOTCH1, and PREX2 [134]. Mutational hotspots were detected in STAT5B, CRNKL1, and NEBL.
Ultraviolet radiation — Ultraviolet (UV) radiation is the most important driver of the high mutational burden in BCC [130,134,136]. An analysis of the mutational profiles of 13 cancer genes in 57 BCC detected somatic variants in seven genes (PTCH1, CSMD1, TP53, NOTCH1, TERT promoter, DPH3 promoter, and DPP10) in 56 of 57 BCC (98 percent) [135]. Overall, 81 percent of single nucleotide variants were UV signature variants (C>T changes and CC>TT tandem variants), consistent with UV-induced mutagenesis.
PATHOLOGY —
On histopathologic examination, common findings of BCC are nodules and/or strands of atypical basaloid cells that show nuclear palisading, cellular apoptosis, and scattered mitotic activity in the dermis (picture 1A-B). Artifactual cleft formation may be seen between the tumor lobules and the surrounding stroma, which may be mucinous. Solar elastosis is usually present in the dermis. The histologic patterns of BCC (nodular, superficial, morpheaform/infiltrative, basosquamous, micronodular, and pigmented) on hematoxylin and eosin (H&E) staining are often reflected in the clinical appearance.
●Nodular BCC, the most common subtype, reveals discrete nests of basaloid cells in the dermis. There is peripheral palisading of the malignant keratinocytes and a mucinous-surrounding tumor stroma. Between the tumor and the dermis, a separation (or "cleft") is often apparent due to retraction artifact in tissue processing (picture 2).
●Superficial BCC is characterized histologically by foci of malignant basaloid palisading tumors "budding" off the epidermis.
●In morpheaform/infiltrative BCC, there are thin cords of basaloid tumor cells penetrating the surrounding collagen, which may appear sclerotic.
●Micronodular BCC appear as numerous small collections of malignant basaloid cells within the dermis and exhibit more subtle findings of peripheral palisading and retraction compared with nodular BCC.
●Pigmented BCC represent approximately 6 percent of BCC and are so named due to melanin and melanophages found within the tumor nodules.
●Basosquamous BCC have a component of nodular or superficial BCC overlying an invasive portion that has features of BCC and squamous cell carcinoma (SCC) [137,138].
●Fibroepithelial BCC (fibroepitheliomas of Pinkus), a less common and indolent subtype, exhibit thin strands of basaloid keratinocytes in a reticular pattern and a spindle cell stroma.
Morpheaform/infiltrative, micronodular, and basosquamous are considered more "aggressive growth" subtypes of BCC [139]. Some lesions have a mixed histology, and up to 40 percent have features of more than one histologic subtype [138,140].
CLINICAL PRESENTATION —
Approximately 70 percent of BCC occur on the face, consistent with the etiologic role of solar radiation, and 15 percent present on the trunk. Only rarely is BCC diagnosed on areas like the penis, vulva, or perianal skin [141]. The clinical presentation of BCC can be divided into three groups based upon lesion histopathology: nodular, superficial, and morpheaform.
Nodular — Nodular BCC, which represent approximately 80 percent of cases, typically present on the face as a pink or flesh-colored papule (picture 5D) [142]. The lesion usually has a pearly or translucent quality, and a telangiectatic vessel is frequently seen within the papule. The papule may often be described as having a "rolled" border, where the periphery is more raised than the middle. Ulceration is frequent (picture 5G and picture 3), and the term "rodent ulcer" refers to these ulcerated nodular BCC (picture 4A and picture 4B).
Superficial — Approximately 15 percent of BCC are superficial BCC [142]. For unclear reasons, males have a higher incidence of superficial BCC than females.
Superficial BCC most commonly occur on the trunk and typically present as slightly scaly, nonfirm macules; patches; or thin plaques light red to pink in color (picture 5C and picture 5A and picture 5H and picture 5B and picture 5I and picture 5J). The center of the lesion sometimes exhibits an atrophic appearance, and the periphery may be rimmed with fine, translucent papules. A shiny quality may be evident when a superficial BCC is illuminated. Occasionally, spotty brown or black pigment is present, which may contribute to confusion with melanoma (picture 5B).
Superficial BCC tend to grow slowly and can vary in size from macules measuring just a few millimeters in diameter to lesions several centimeters in diameter or more if left untreated. Superficial BCC are usually asymptomatic.
Morpheaform/infiltrative — Morpheaform or sclerosing BCC constitute 5 to 10 percent of BCC. These lesions are typically smooth, flesh-colored or very light pink papules or plaques that are frequently atrophic. They usually have a firm or indurated quality with ill-defined borders (picture 6 and picture 7). Infiltrative and micronodular subtypes are less common than the morpheaform BCC.
Other subtypes — Several other BCC subtypes have been described.
●Basosquamous cell carcinoma is a rare tumor that behaves aggressively.
●Both nodular and superficial BCC can produce pigment. These lesions are referred to as pigmented BCC (picture 5E).
Multiple basal cell carcinoma syndromes — Several rare syndromes have been described that present with multiple BCC. The most common is nevoid basal cell carcinoma syndrome. (See "Nevoid basal cell carcinoma syndrome (Gorlin syndrome)".)
Patients with xeroderma pigmentosum and Muir-Torre syndrome are at increased risk for BCC as well as other skin cancers. The incidence of BCC, squamous cell carcinomas (SCC), and melanomas for individuals with xeroderma pigmentosum under the age of 20 is approximately 2000 times greater that seen in the general population. (See "Xeroderma pigmentosum" and "Muir-Torre syndrome".)
NATURAL HISTORY —
Most BCC remain localized, and the growth rate is variable. However, a few become locally aggressive or, rarely, metastatic. The acquisition of cytogenetic aberrations may be associated with aggressive biologic behavior. In one series, for example, trisomy 6 was identified in none of 22 nonaggressive BCC, two of four locally aggressive BCC, and all four metastatic BCC [143].
DIAGNOSIS
Clinical and dermoscopic examination — Clinicians who are familiar with the clinical presentation of BCC are often able to make the diagnosis based on clinical examination (picture 5A-G). Examination of the lesion with a dermatoscope may assist in the clinical diagnosis of BCC [144-146]. (See "Dermoscopic evaluation of skin lesions", section on 'Criteria for basal cell carcinoma'.)
Dermoscopic features of BCC include (figure 2 and picture 8):
●Lack of a pigmented network (which is typically associated with melanocytic lesions)
●Arborizing vessels
●Blue-gray ovoid nests
●Ulceration
A meta-analysis of 13 studies found that the pooled sensitivity and specificity of dermoscopy for the diagnosis of BCC were 91 and 95 percent, respectively [147]. In a subgroup of five studies comparing the accuracy of naked eye examination followed by dermoscopy with naked eye examination alone, the sensitivity and specificity were 85 and 98 percent, respectively.
However, a skin biopsy is usually performed to confirm the diagnosis and to determine the histologic subtype.
Biopsy — We suggest performing a biopsy prior to definitive treatment in the following situations (see "Treatment of basal cell carcinomas at high risk for recurrence", section on 'Features associated with high risk for recurrence'):
●The lesion exhibits features atypical for BCC.
●The patient lacks a prior history of BCC.
●The lesion exhibits clinical features suggestive of a BCC with a high risk for recurrence.
●The lesion is pigmented and is suspicious for melanoma.
Obtaining a histopathologic diagnosis prior to definitive treatment provides more accurate information on the risk for tumor recurrence and guidance to the appropriate treatment approach, thus reducing the risk of mismanagement.
Shave biopsies, punch biopsies, and excisional biopsies can be used for the diagnosis of BCC. Although shave and punch biopsies are frequently performed for diagnosis due to the simplicity of these procedures, clinicians should be aware that biopsies that remove only a portion of the lesion do not always provide an accurate assessment of the histologic subtype of a tumor [148-152].
With punch biopsies, an aggressive histologic subtype may be missed in up to 20 percent of cases [148-150]. A retrospective study in which the majority of biopsy procedures were shave biopsies (230 shave biopsies and 27 punch biopsies) found that an aggressive histologic subtype was missed in 7 percent of cases [151]. (See "Skin biopsy techniques", section on 'Biopsy techniques'.)
Imaging — In rare cases where patients may present with suspicion for extensive regional disease or metastases, imaging could be performed to assess the extent of deep soft tissue involvement, perineural invasion, or bone involvement. In the setting of suspected perineural invasion, magnetic resonance imaging (MRI) with or without contrast could be used; computed tomography (CT) with contrast could be used to assess for bone disease [153]. Given the lack of high-quality data in this exceptional scenario, imaging modality and extent should be done at the discretion of the treatment team.
DIFFERENTIAL DIAGNOSIS —
The differential diagnosis varies with the subtype of BCC (ie, nodular, superficial, morpheaform, or pigmented).
●Nodular BCC
•Early nodular variants with little ulceration clinically may be identical to benign growths such as dermal nevi (picture 9), small epidermal inclusion cysts, or even sebaceous hyperplasia (picture 10). A single lesion of molluscum contagiosum has a similar appearance, as does amelanotic melanoma.
•Larger lesions with central ulceration can appear cup shaped. These can resemble squamous cell carcinoma (SCC), keratoacanthomas, or dermal metastases from internal organs, such as the colon [154]. (See "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis" and "Keratoacanthoma: Epidemiology, risk factors, and diagnosis".)
●Superficial BCC
•Superficial BCC may be confused with inflammatory disorders of the skin such as nummular eczema (also known as nummular dermatitis (picture 11)) or psoriasis (picture 12), especially when a peripheral rim of small, pearly papules is absent. In particular, the possibility of superficial BCC should be considered when a lesion presumed to be inflammatory fails to respond to topical corticosteroids. (See "Nummular eczema" and "Psoriasis: Epidemiology, clinical manifestations, and diagnosis".)
•Benign lichenoid keratoses (picture 13), actinic keratoses (picture 14), and rarely amelanotic melanoma (picture 15A-B) presenting as scaly, erythematous macules may also be mistaken for superficial BCC. (See "Actinic keratosis: Epidemiology, clinical features, and diagnosis" and "Melanoma: Clinical features and diagnosis".)
●Morpheaform BCC – Morpheaform BCC frequently appear similar to a scar or other site of trauma. The induration of the lesion simulates localized scleroderma. (See "Morphea (localized scleroderma) in adults: Pathogenesis, clinical manifestations, and diagnosis".)
●Pigmented BCC – Pigmented nodular or superficial BCC may resemble melanoma (picture 15A-B) or, less likely, a benign nevus. (See "Melanoma: Clinical features and diagnosis".)
PREVENTION
Sun protection — The primary approach to the prevention of BCC is protection from sun exposure. The various techniques to minimize solar exposure are discussed elsewhere. (See "Selection of sunscreen and sun-protective measures".)
While several studies demonstrated that regular daily use of sunscreen reduces the risk of developing actinic keratoses and cutaneous squamous cell carcinoma (cSCC), the role of sunscreen in the prevention of BCC remains unclear [155-157]. A randomized trial evaluating the effects of sunscreen and the antioxidant beta-carotene over a four-year period in 1621 residents of Nambour, Queensland, found that participants using topical sunscreen had a 40 percent reduction in squamous cell carcinoma (SCC) but no decrease in BCC [155]. Similarly, no reduction in the incidence rate of BCC was observed among the participants of the Nambour trial after an overall follow-up period of eight years [156].
Chemoprevention — The role of chemoprevention as a secondary prevention strategy for individuals at high risk of developing BCC is uncertain.
Nonsteroidal anti-inflammatory drugs — Data conflict on the impact of nonsteroidal anti-inflammatory drugs (NSAIDs) on the risk for BCC [158-161]:
●The results of an 11-month randomized trial suggested that celecoxib (a cyclooxygenase-2 inhibitor) may be beneficial for chemoprevention of BCC [162]. In this trial of 240 patients with actinically damaged skin, patients treated with celecoxib (200 mg twice daily for nine months) developed fewer BCC than patients who were given placebo (adjusted rate ratio 0.4, 95% CI 0.18-0.93).
●In contrast, a Danish population-based case-control study failed to find an association between the use of celecoxib or other prescription NSAIDs and overall risk for BCC [163].
●Another population-based case-control study including over 65,000 cases with incident first-time diagnosis of BCC and the same number of matched controls selected from the United Kingdom Clinical Practice Research Datalink did not find an association between the use of any NSAIDs and the overall risk of BCC [164]. Subgroup analyses showed a reduced BCC risk among regular users of aspirin and ibuprofen (odds ratio [OR] 0.92, 95% CI 0.85-0.99, and OR 0.61, 95% CI 0.48-0.78, respectively). However, these results must be interpreted with caution because of the lack of information on potential confounders or effect-modifying factors such as sun exposure and skin phototype.
Although not explicitly mentioned in those studies, adverse effects of NSAID therapy on multiple organ systems (eg, cardiovascular, gastrointestinal, renal) warrant additional consideration when recommending long-term use as chemoprevention. (See "Nonselective NSAIDs: Overview of adverse effects".)
Oral nicotinamide — The efficacy of oral nicotinamide (vitamin B3), a dietary supplement available over the counter, for the prevention of BCC remains unclear.
●In a phase 3 trial that included 386 immunocompetent participants with ≥2 histologically confirmed nonmelanoma skin cancers (NMSC) in the past five years, participants were randomized to receive 500 mg of nicotinamide twice daily or placebo for 12 months [165]. At 12 months, patients in the nicotinamide group had a lower number of NMSC compared with patients in the placebo group (1.8 versus 2.4), corresponding to an overall rate reduction of 23 percent (95% CI 4-38 percent). The rate reduction for BCC was 20 percent (95% CI -6 to 0.39). There was no significant difference in adverse events between the placebo and nicotinamide groups.
●In a randomized trial, 158 solid organ transplant recipients were assigned to oral nicotinamide 500 mg or placebo twice daily for 12 months [166]. During the intervention period, the mean number of BCC per participant was 0.9 in the nicotinamide group and 0.8 in the placebo group.
Topical fluorouracil — A single course of topical fluorouracil has been shown to reduce the development of new actinic keratoses, a marker for increased risk of keratinocyte cancers (ie, BCC and SCC) in older male patients with multiple previous keratinocyte cancers [167,168]. However, topical fluorouracil does not seem to be effective in preventing the development of BCC in high-risk patients.
In a randomized trial, 932 participants with a history of at least two keratinocyte cancers in the previous five years were instructed to apply topical fluorouracil 5% cream or vehicle cream twice daily to the face and ears for four weeks (a total of 56 doses) [169]. During a median follow-up time of 2.8 years, the proportion of patients who developed a BCC was similar in the topical fluorouracil and vehicle groups (10 versus 11 percent, risk ratio 0.89, 95% CI 0.61-1.31).
Other agents
●Oral capecitabine – Oral capecitabine has been examined for the treatment and prevention of precancerous and cancerous skin lesions, particularly cSCC. A systematic review of studies documented the reduction of BCC in one small case series [170]. However, adverse effects were common, including fatigue (39 percent), diarrhea (26 percent), hand-foot syndrome (26 percent), nausea/vomiting (22 percent), anemia (13 percent), mucositis (13 percent), and warranted discontinuation in 43 percent of cases.
●Oral acitretin – In a randomized trial, 70 nontransplant patients at high risk of developing BCC were treated with oral acitretin 25 mg per day for five days per week or placebo for two years [171]. During the trial period, fewer patients developed a BCC in the acitretin group compared with patients in the placebo group (19 [54 percent] versus 26 [74 percent], respectively). However, the difference was not statistically significant (OR 0.41, 95% CI 0.15-1.13).
INFORMATION FOR PATIENTS —
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Non-melanoma skin cancer (The Basics)" and "Patient education: Sunburn (The Basics)")
●Beyond the Basics topics (see "Patient education: Sunburn (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Definition and epidemiology – Basal cell carcinoma (BCC) is a common skin cancer arising from the basal layer of the epidermis and its appendages. BCC is the most common malignancy in White populations, and its incidence is increasing worldwide. BCC has been linked to exposure to ultraviolet (UV) light, especially during childhood. Most other risk factors act through an interaction with UV exposure. (See 'Epidemiology' above and 'Risk factors' above.)
●Clinical presentation – Approximately 80 percent of BCC present on the face and head. The most common presentations for BCC are the nodular (picture 5D) and superficial forms (picture 5A-C, 5H-J), which together account for over 90 percent of cases. Although these tumors have a low metastatic potential, they are locally invasive and can be destructive of skin and the surrounding structures (picture 4A-B). (See 'Clinical presentation' above.)
●Diagnosis – Clinicians who are familiar with the clinical manifestations of BCC are often able to make the diagnosis based on clinical examination and dermoscopic features. However, a skin biopsy is usually performed to provide pathologic confirmation of the diagnosis and determine the histologic subtype and the risk of recurrence. A biopsy is particularly indicated in cases in which the diagnosis is uncertain, the patient lacks a history of BCC, the lesion exhibits features suggestive of an increased risk for tumor recurrence after treatment, or when the tumor exhibits atypical clinical features. (See 'Diagnosis' above.)
●Prevention – Protection from sun exposure is the most important measure to prevent the development of BCC (see "Selection of sunscreen and sun-protective measures"). The role of chemoprevention for BCC remains uncertain. (See 'Chemoprevention' above.)
