Genetics of Skin Cancer (PDQ®): Genetics - Health Professional Information [NCI]

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Genetics of Skin Cancer

Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of skin cancer. This summary is reviewed regularly and updated as necessary by the Cancer Genetics Editorial Board.

The following information is included in this summary:

  • Risk factors for skin cancer, including family history.
  • Major genes associated with skin cancer risk.
  • Screening and risk modification for skin cancer.
  • Genetic testing for hereditary skin cancer.

The summary also contains level-of-evidence designations. These designations are intended to help readers assess the strength of the evidence in relation to specific studies or strategies. A description of how level-of-evidence designations are made is described in detail in the PDQ summary Cancer Genetics Overview.

This summary is intended to provide clinicians a framework (1) for discussing genetic testing, screening, and risk modification options with individuals at risk for hereditary skin cancer and (2) for making referrals to cancer risk counseling services. It does not provide formal guidelines or recommendations for making health care decisions. Information in this summary should not be used as a basis for reimbursement determinations.

Introduction

Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.

Many of the genes described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.

Structure of the Skin

The genetics of skin cancer is an extremely broad topic. There are more than 100 types of tumors that are clinically apparent on the skin; many of these are known to have familial components, either in isolation or as part of a syndrome with other features. This is, in part, because the skin itself is a complex organ made up of multiple cell types. Furthermore, many of these cell types can undergo malignant transformation at various points in their differentiation, leading to tumors with distinct histology and dramatically different biological behaviors, such as squamous cell cancer (SCC) and basal cell cancers (BCC). In addition to malignant tumors, there are also many types of benign tumors.

Figure 1 is a simple diagram of normal skin structure. It also indicates the major cell types that are normally found in each compartment. Broadly speaking, there are two large compartments—the avascular cellular epidermis and the vascular dermis—with many cell types distributed in a largely acellular matrix.

Schematic representation of normal skin; drawing shows normal skin anatomy, including the epidermis, dermis, hair follicles, sweat glands, hair shafts, veins, arteries, fatty tissue, nerves, lymph vessels, oil glands, and subcutaneous tissue. The pullout shows a close-up of the squamous cell and basal cell layers of the epidermis, the basement membrane in between the epidermis and dermis, and the dermis with blood vessels. Melanin is shown in the cells. A melanocyte is shown in the layer of basal cells at the deepest part of the epidermis.
Schematic representation of normal skin. The relatively avascular epidermis houses both basal cell keratinocytes and squamous epithelial keratinocytes, the source cells for BCC and SCC, respectively. Melanocytes are also present in normal skin, and serve as the source cell for melanoma. The separation between epidermis and dermis occurs at the basement membrane zone, located just inferior to the basal cell keratinocytes.

The outer layer or epidermis is made primarily of keratinocytes but has several other minor cell populations. The bottom layer is formed of basal keratinocytes abutting the basement membrane. BCC histologically resembles these cells, which gives the cancer its name. The basement membrane is formed from products of keratinocytes and dermal fibroblasts, such as collagen and laminin, and is an important anatomical and functional structure. As the basal keratinocytes divide and differentiate, they lose contact with the basement membrane and form the spinous cell layer, the granular cell layer, and the keratinized outer layer or stratum corneum.

The true origin of BCC remains in question. While the histologic similarities between basal cell keratinocytes and BCC suggests a common histogenic pathway, the histologic and immunologic similarities between the outer root sheath cells of the hair follicle provide an alternative etiologic association.[1]

SCC is derived from a more differentiated keratinocyte. A variety of tissues, such as lung and uterine cervix, can give rise to SCC, and this cancer has somewhat differing behavior depending on its source. Even in cancer derived from the skin, SCC from different anatomic locations can have moderately differing aggressiveness; for example SCC from glabrous skin has a lower metastatic rate than SCC arising from the vermillion border of the lip or from scars.

Additionally, in the epidermal compartment, melanocytes distribute singly along the basement membrane and can transform into melanoma. Melanocytes are derived from neural crest cells and migrate to the epidermal compartment near the eighth week of gestational age. Langerhans cells are a third cell type in the epidermis and have a primary function of antigen presentation. These cells reside in the skin for an extended time and respond to different stimuli, such as ultraviolet light or topical steroids, that cause them to migrate out of the skin.

The dermis is largely composed of an extracellular matrix. Prominent cell types in this compartment are fibroblasts, endothelial cells, and transient immune system cells. When transformed, fibroblasts form fibrosarcomas and endothelial cells form angiosarcomas, Kaposi sarcoma and other vascular tumors. There are a number of immune cell types that move in and out of the skin to blood vessels and lymphatics; these include mast cells, lymphocytes, mononuclear cells, histiocytes, and granulocytes. These cells can increase in number in inflammatory diseases and can form tumors within the skin. For example, urticaria pigmentosa is a condition that arises from mast cells and is occasionally associated with mast cell leukemia; cutaneous T-cell lymphoma is often confined to the skin throughout its course. Overall, 10% of leukemias and lymphomas have prominent expression in the skin.

Epidermal appendages are also found in the dermal compartment. These are derivatives of the epidermal keratinocytes, such as hair follicles, sweat glands, and the sebaceous glands associated with the hair follicles. These structures are generally formed in the first and second trimesters of fetal development. These can form a large variety of benign or malignant tumors with diverse biological behaviors. A surprising number of these tumors are associated with familial syndromes. Overall, there are dozens of different histological subtypes of these tumors associated with individual components of the adnexal structures.

Finally, the subcutis is a layer that extends below the dermis with varying depth, depending on the anatomic location. The subcutis extends to the layer under the skin, which varies according to anatomic location. This deeper boundary can include muscle, fascia, bone, or cartilage. The subcutis can be affected by inflammatory conditions such as panniculitis and malignancies such as liposarcoma.

These compartments give rise to their own malignancies but are also the region of immediate adjacent spread of localized skin cancers from other compartments. For example, an in situ melanoma or SCC is defined as one that it is confined to the epidermis. Especially in the case of melanoma, these boundaries define a staging system. Noncutaneous malignancies also commonly metastasize to the skin. The dermis and subcutis are the most common locations, but the epidermis can also be involved in conditions such as Pagetoid breast cancer.

Function of the Skin

The skin has a wide variety of functions, including biologic, social, cosmetic, communicative, and sensory, among others. First, the skin is an important barrier preventing extensive water and temperature loss and providing protection against minor abrasions. These functions can be aberrantly regulated in cancer. For example, in the erythroderma associated with advanced cutaneous T-cell lymphoma, alterations in the regulations of body temperature can result in profound heat loss. Second, the skin has important adaptive and innate immunity functions. In adaptive immunity, antigen-presenting cells engender a TH1, TH2, and TH17 response.[2] In innate immunity, the immune system produces numerous peptides with antibacterial and antifungal capacity. Consequently, even small breaks in the skin can lead to infection. The skin-associated lymphoid tissue is one of the largest arms of the immune system. It may also be important in immune surveillance against cancer. Immunosuppression, which occurs during organ transplant, is a significant risk factor for skin cancer. The skin is cosmetically significant through facial expression and hand movements. Unfortunately, areas of specialized function, such as the area around the eyes and ears, are common places for cancer to occur. Even small cancers in these areas can lead to reconstructive challenges.

References:

1. Schirren CG, Rütten A, Kaudewitz P, et al.: Trichoblastoma and basal cell carcinoma are neoplasms with follicular differentiation sharing the same profile of cytokeratin intermediate filaments. Am J Dermatopathol 19 (4): 341-50, 1997.
2. Harrington LE, Mangan PR, Weaver CT: Expanding the effector CD4 T-cell repertoire: the Th17 lineage. Curr Opin Immunol 18 (3): 349-56, 2006.

Basal Cell Carcinoma

Introduction

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 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. 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, or chronic sun exposure, or both.

Different patterns of sun exposure appear to lead to different types of skin cancer among susceptible individuals. Intermittent sun exposure seems to be the most important risk factor for melanoma. BCC appears to share some risk factors with melanoma.[2,3] Some BCC may be caused by chronic sun exposure, but a large portion (one-third or more) is apparently caused by intermittent sun exposure, similar to that implicated in melanoma. Occupational exposures are associated with SCC risk and recreational exposures with BCC risk. This exposure-response pattern is consistent with the results from a randomized trial of sunscreen efficacy that found statistically significant protection for the development of squamous cell carcinoma but no evidence at all for protection from the development of BCC.[4] It is unlikely that such a trial could be carried out for melanoma because of a lack of statistical power. Therefore, the similarities between BCC and melanoma are all the more critical to understand.

Other environmental factors

An important exposure that is consistently associated with nonmelanoma skin cancer is exposure to arsenic in drinking water and combustion.[5,6]

Environmental factors other than sun exposure, may also contribute to the formation of BCC and SCC. Petroleum byproducts (asphalt, tar, soot, paraffin, pitch), organophosphate compounds, and arsenic are all occupational exposures associated with cutaneous non-melanoma cancers.[7,8,9]

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. Medicinal arsenical solutions (Fowler's solution, 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.[10,11] 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.[12,13]

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 (CCA)–treated wood produce airborne arsenical particles when burned.[14,15,16] Burning of these products in enclosed unventilated settings (such as for heat generation) is particularly hazardous.[17]

Pigmentary characteristics

The high-risk phenotype is fairly conserved across skin cancer types:

  • Fair skin.
  • Lightly pigmented irides (blue, green).
  • Presence of freckles.
  • Poor ability to tan.

Specifically, people with more highly pigmented skin demonstrate lower incidence of BCC than do people with lighter pigmented skin. (Refer to the Pigmentary characteristics section in the Melanoma section of this summary for a more detailed discussion of skin phenotypes based upon pigmentation.)

Immunosuppression

Immunosuppression also contributes to the formation of nonmelanoma 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.[18,19,20] Nonmelanoma skin cancers in high-risk patients (recipients of solid organ transplants and patients with chronic lymphocytic leukemia) occur at a younger age and are more common, more aggressive, and at a higher risk of recurrence and metastatic spread than nonmelanoma skin cancers the general population.[21,22] Among patients with an unmodified immune system, BCCs outnumber SCCs by a 4:1 ratio; in transplant patients, SCCs outnumber BCC by a 2:1 ratio.

This increased risk has been linked to the level of immunosuppression and ultraviolet radiation (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 which much lower levels of immunosuppression are needed to avoid rejection.[18,23] 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.[24] This speaks to the importance of rigorous sun avoidance, particularly 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 basal cell carcinoma, a positive family history of any skin cancer is a strong predictor of the development of BCC. Even after adjustment for age, gender and pigmentary traits, one Mediterranean population demonstrated a significant predilection for development of basal cell carcinoma among those with a family history of skin cancer (odds ratio = 17.8).[25]

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 for 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 middle of the sixth decade of life.[26,27,28,29,30,31]

Major Genes for Basal Cell Carcinoma

PTCH1

Mutations in the gene coding for the transmembrane receptor protein PTCH, or PTCH1, are associated with basal cell nevus syndrome (BCNS) and sporadic cutaneous BCCs. PTCH, 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 PTCH acts catalytically to suppress the seven-transmembrane protein Smoothened (Smo), preventing further downstream signal transduction.[32] Stoichiometric binding of the hedgehog ligand to PTCH releases inhibition of Smo, with resultant activation of transcription factors (GLI1, GLI2), cell proliferation genes (cyclin D, cyclin E, myc), and regulators of angiogenesis.[33,34] Thus, the balance of PTCH (inhibition) and Smo (activation) manages the essential regulatory downstream hedgehog signal transduction pathway. Loss-of-function mutations of PTCH 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 basal cell carcinomas suggested the potential presence of an associated tumor suppressor gene.[35,36] Further investigation identified a mutation in PTCH that localized to the area of allelic loss.[37] Up to 30% of sporadic BCC demonstrate PTCH mutations.[38] In addition to BCC, medulloblastoma and rhabdomyosarcoma, along with other human tumors, have been associated with PTCH mutations. All three malignancies are associated with BCNS, and most people with clinical features of BCNS demonstrate PTCH mutations, predominantly truncation in type.[39]

PTCH2

Truncating mutations in PTCH 2, a homolog of PTCH1 mapping to chromosome 1p32.1-32.3, has been demonstrated in both BCC and medulloblastoma.[40,41]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.[42] While the exact role of PTCH2 remains unclear, there is evidence to support its involvement in the hedgehog signaling pathway.[40,43] Recently, a BCNS kindred of Chinese ethnicity was identified with an associated novel PTCH 2 mutation.[44]

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.[45] The syndrome is notable for complete penetrance and extremely variable expressivity, as evidenced by evaluation of individuals with identical genotypes, but widely varying genotypes.[39,46] The clinical features of BCNS differ more among families than within families.[47]

As detailed above, PTCH provides both developmental and regulatory guidance; spontaneous or inherited germline mutations of PTCH 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.[45] The resulting haploinsufficiency of PTCH in BCNS has been associated with structural anomalies such as odontogenic keratocysts, with evaluation of the cyst lining revealing heterozygosity for PTCH.[48] 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 PTCH mutation as the first hit, with the second hit due to mutagen exposure such as ultraviolet radiation or ionizing radiation.[49,50,51,52,53]

The diagnosis of BCNS is typically based upon characteristic clinical and radiologic examination findings. Genetic testing demonstrates PTCH mutations in approximately 60% of individuals with clinical manifestations supporting a diagnosis of BCNS; prenatal testing is available.[54,55] While the diagnostic criteria are outlined in Table 1, several clinical features warrant further discussion. 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.[52,56,57] BCNS-associated ovarian fibromas are more likely to be bilateral and calcified than sporadic ovarian fibromas.[58]

Other associated benign neoplasms include gastric hamartomatous polyps,[59]congenital pulmonary cysts,[60] cardiac fibromas,[61] meningiomas,[62,63] craniopharyngiomas,[64] fetal rhabdomyomas,[65] leiomyomas,[66] mesenchymomas,[67] and nasal dermoid tumors. Development of meningiomas and ependymomas occurring post–radiation 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.[68,69,70]

Table 1. Diagnostic Criteria for Basal Cell Nevus Syndrome (BCNS)

BCC = basal cell carcinoma.
Diagnosis of BCNS supported by the presence of two major or one major and two minor criteria:
 
MAJOR CRITERIA
1. BCC: More than 2 BCCs or 1 BCC diagnosed in persons younger than 20 years.
2. Odontogenic keratocysts of the jaw (histologically proven).
3. Palmar or plantar pits (3 or more).
4. Bilamellar calcification of the falx cerebri.
5. Bifid, fused, or markedly splayed ribs.
6. First-degree relative with BCNS.
 
MINOR CRITERIA
1. Macrocephaly determined after adjustment for height.
2. Congenital malformations.
  Cleft lip or palate.
  Frontal bossing.
  Coarse facies.
  Moderate/severe hypertelorism.
3. Other skeletal abnormalities.
  Sprengel deformity.
  Marked pectus deformity.
  Marked syndactyly of the digits.
4. Radiological abnormalities.
  Bridging of the sella turcica.
  Vertebral anomalies (hemivertebrae, fusion or elongation of vertebral bodies, modeling defects of the hands and feet, or flame-shaped lucencies of the hands or feet).
5. Ovarian fibromas.
6. Medulloblastoma.

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.[71] 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 the age of 20 years.[56,57] Case series have suggested that up to 1 in 200 individuals with BCC demonstrates findings supportive of a diagnosis of BCNS.[45] BCNS has rarely been reported in individuals with darker skin pigmentation; however, significantly fewer BCCs are found in individuals of African or Mediterranean ancestry.[57,72,73] Despite the rarity of BCC in this population, reported cases document full expression of the non-cutaneous manifestations of BCNS.[73] However, in individuals of African ancestry who have received radiation therapy, significant basal cell tumor burden has been reported within the radiation port distribution.[57,66] Thus, cutaneous pigmentation may protect against the mutagenic effects of ultraviolet 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 the ages of 2 and 3 years, sporadic medulloblastoma is usually diagnosed later in childhood, between 6 and 10 years.[52,56,57,74] A desmoplastic phenotype occurring around age 2 years is very strongly associated with BCNS and carries a more favorable prognosis than sporadic classic medulloblastoma.[75,76] Up to three times more males than females with BCNS are diagnosed with medulloblastoma.[77] As with other malignancies, treatment of medulloblastoma with ionizing radiation has resulted in numerous BCCs within the radiation field.[52,62] Other reported malignancies include ovarian carcinoma,[78] ovarian fibrosarcoma,[79,80] astrocytoma,[81] melanoma,[82] Hodgkin disease,[83,84] rhabdomyosarcoma,[85] and undifferentiated sinonasal carcinoma.[86]

Odontogenic keratocysts–or keratocystic odontogenic tumors (KCOTs) as renamed by the World Health Organization working group–are one of the major features of basal cell nevus syndrome.[87] Demonstration of clonal loss of heterozygosity of common tumor suppressor genes, including PTCH, supports the transition of terminology to reflect a neoplastic process.[48] 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.[87,88] In a recent case series of 183 consecutively excised KCOTs, 6% of individuals demonstrated an association with BCNS.[87] KCOTs occur in 65% to 100% of individuals with BCNS,[57,89], with higher rates of occurrence in young females.[90]

Several characteristic radiologic findings have been associated with BCNS, including lamellar calcification of falx cerebri;[91,92] fused, splayed or bifid ribs;[93] and flame-shaped lucencies or pseudocystic bone lesions of the phalanges, carpal, tarsal, long bones, pelvis, and calvaria.[94] 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.

Rare syndromes

Rombo syndrome

Rombo syndrome, a rare genetic disorder associated with BCC, has been outlined in two case series in the literature.[95,96] 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.[95] Development of BCC occurs in the fourth decade.[95] A distinctive grainy texture to the skin, secondary to interspersed small, yellowish, follicular-based papules and follicular atrophy, has been described.[95,97] Missing, irregularly distributed and/or maldirected eyelashes and eyebrows are another associated finding.[95,96]

Bazex-Dupré-Christol syndrome

Bazex-Dupré-Christol syndrome, another 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.[98,99,100] 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.[101]

Characteristic physical findings include hypotrichosis, hypohidrosis, milia, follicular atrophoderma of the cheeks, and multiple basal cell carcinomas, which manifest in the late second decade to early third decade.[98] Documented hair changes with Bazex-Dupré-Christol syndrome include reduced density of scalp and body hair, decreased melanization,[102] a twisted/flattened appearance of the hair shaft on electron microscopy,[103] and increased hair shaft diameter on polarizing light microscopy.[100] The milia, which may be quite distinctive in childhood, have been reported to regress or diminish substantially at puberty.[100] Other reported findings in association with this syndrome include trichoepitheliomas, hidradenitis suppurativa, hypoplastic alae, and a prominent columella.[104,105]

Table 2. Basal Cell Carcinoma (BCC) Syndromes

AD = autosomal dominant; AR = autosomal recessive; OMIM = Online Mendelian Inheritance in Man; XD = x-linked dominant
Syndrome (OMIM link) Inheritance Chromosome Gene Clinical Findings
Basal cell nevus syndrome, Gorlin syndrome AD 9q22.3-q31[45] PTCH1[106,107] BCC (before age 20 years)
3.597 to 6.457[45] PTCH2[44]
Rombo syndrome AD     Milia, atrophoderma vermiculatum, acrocyanosis, trichoepitheliomas, and BCC (aged 30s to 40s)
Bazex-Dupré-Christol syndrome XD > AD Xq24-27[101] Unknown Hypotrichosis (variable),[98] hypohidrosis, milia, follicular atrophoderma (dorsal hands), and multiple BCCs (aged teens to early 20s)[98]
Brooke-Spiegler syndrome AD 16q12-q13[108,109] CYLD[110,111] Cylindroma (forehead, scalp),[112] trichoepithelioma (around nose), spiradenoma, and BCC
Multiple hereditary infundibulocystic BCC AD[113] Unknown Unknown Multiple BCC (infundibulocystic type)
Schopf-Schultz-Passarge syndrome AR > AD Unknown Unknown Ectodermal dysplasia (hypotrichosis, hypodontia, and nail dystrophy [anonychia and trachyonychia]), hidrocystomas of eyelids, palmo-plantar keratosis and hyperhidrosis, and BCC[114]

Interventions

Screening

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 (NCCN) guidelines of care for nonmelanoma skin cancers recommends complete skin examinations every 6 to 12 months for life.[115]

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 ultraviolet 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.

Chemoprevention

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.[116] 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.[116] 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.[116,117,118] In summary, the use of systemic retinoids for chemoprevention of BCC is reasonable in high-risk patients.

Level of evidence: 3aii

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.

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2. Zanetti R, Rosso S, Martinez C, et al.: Comparison of risk patterns in carcinoma and melanoma of the skin in men: a multi-centre case-case-control study. Br J Cancer 94 (5): 743-51, 2006.
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4. Green A, Whiteman D, Frost C, et al.: Sun exposure, skin cancers and related skin conditions. J Epidemiol 9 (6 Suppl): S7-13, 1999.
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9. Letzel S, Drexler H: Occupationally related tumors in tar refinery workers. J Am Acad Dermatol 39 (5 Pt 1): 712-20, 1998.
10. Farber EM: History of the treatment of psoriasis. J Am Acad Dermatol 27 (4): 640-5, 1992.
11. Boonchai W, Green A, Ng J, et al.: Basal cell carcinoma in chronic arsenicism occurring in Queensland, Australia, after ingestion of an asthma medication. J Am Acad Dermatol 43 (4): 664-9, 2000.
12. Garvey GJ, Hahn G, Lee RV, et al.: Heavy metal hazards of Asian traditional remedies. Int J Environ Health Res 11 (1): 63-71, 2001.
13. Soignet SL, Maslak P, Wang ZG, et al.: Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med 339 (19): 1341-8, 1998.
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92. Ratcliffe JF, Shanley S, Ferguson J, et al.: The diagnostic implication of falcine calcification on plain skull radiographs of patients with basal cell naevus syndrome and the incidence of falcine calcification in their relatives and two control groups. Br J Radiol 68 (808): 361-8, 1995.
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Squamous Cell Carcinoma

Introduction

Squamous cell carcinoma (SCC) is the second most common type of skin cancer and accounts for approximately 20% of cutaneous malignancies. Although most cancer registries do not include information on the incidence of nonmelanoma skin cancer, the American Cancer Society estimates that more than a million cases of basal cell carcinoma (BCC) and SCC of the skin will be diagnosed in the United States in 2009.[1]

Mortality is rare from this cancer; however, the morbidity and costs associated with its treatment are considerable.

Risk Factors for Squamous Cell Carcinoma

Sun exposure

Sun exposure is the major known environmental factor associated with the development of skin cancer of all types; however, different patterns of sun exposure are associated with each major type of skin cancer. (Refer to the Sun exposure section in the Basal Cell Carcinoma section of this summary for more information.) This section focuses on sun exposure and increased risk of cutaneous squamous cell carcinoma.

Unlike BCC, SCC is associated with chronic rather than intermittent intense exposure to ultraviolet radiation (UV). The characteristic pattern of sun exposure linked with SCC is occupational exposure.[2] A case-control study in southern Europe showed increased risk of SCC when lifetime sun exposure exceeded 70,000 hours. People whose lifetime sun exposure equaled or exceeded 200,000 hours had an odds ratio 8 to 9 times that of the reference group.[3] A Canadian case-control study did not find an association between cumulative lifetime sun exposure and SCC; however, sun exposure within ten years and occupational exposure were found to be risk factors.[4]

Other radiation exposure

In addition to environmental radiation, exposure to therapeutic radiation is another risk factor for squamous cell carcinoma. Individuals with skin disorders treated with psoralen and ultraviolet-A radiation (PUVA) had a threefold to sixfold increase in SCC.[5] This effect appears to be dose-dependent, as only 7% of individuals who underwent fewer than 200 treatments had SCC, compared to more than 50% of those who underwent more than 400 treatments.[6] Therapeutic use of ultraviolet-B (UVB) radiation has also been shown to cause a mild increase in SCC (adjusted incidence rate ratio, 1.37).[7] Devices such as tanning beds also emit UV radiation and have been associated with increased SCC risk, with a reported odds ratio (OR) of 2.5 (95% confidence interval [CI], 1.7–3.8).[8]

Investigation into the effect of ionizing radiation on SCC carcinogenesis has yielded conflicting results. One population-based case-control study found a relative risk of 2.94 for SCC at the site of previous radiation, as compared with individuals who had not undergone radiation treatments.[9] Cohort studies of radiology technicians, atomic-bomb survivors, and survivors of childhood cancers have not shown an increased risk of SCC, although the incidence of BCC was increased in all of these populations.[10,11,12] For those who do develop SCC at previously radiated sites that are not sun-exposed, the latent period appears to be quite long; these cancers may be diagnosed years or even decades after the radiation exposure.[13]

The effect of other types of radiation, such as cosmic radiation, is also controversial. Pilots and flight attendants have a reported incidence of SCC that ranges between 2.1 and 9.9 times what would be expected; however, the overall cancer incidence is not consistently elevated. Some attribute the high rate of nonmelanoma skin cancers in airline flight personnel to cosmic radiation, while others suspect lifestyle factors.[14,15,16,17,18,19]

Other environmental factors

The influence of arsenic on risk of nonmelanoma skin cancer is discussed in detail above. Like BCCs, SCCs appear to be associated with exposure to arsenic in drinking water and combustion products.[20,21] However, this association may hold true only for the highest levels of arsenic exposure. Individuals who had toenail concentrations of arsenic above the 97th percentile were found to have an approximately twofold increase in SCC risk.[22]

Current or previous cigarette smoking has been associated with a 1.5-fold to 2-fold increase in SCC risk,[23,24,25] although one large study showed no change in risk.[26] Available evidence suggests that the effect of smoking on cancer risk seems to be greater for SCC than for BCC.

Additional reports have suggested weak associations between SCC and exposure to insecticides, herbicides, or fungicides.[27]

Characteristics of the skin

Like melanoma and basal cell carcinoma, squamous cell carcinoma occurs more frequently in individuals with lighter skin than in those with darker skin.[2,28] However, SCC can also occur in individuals with darker skin. An Asian registry based in Singapore reported an increase in skin cancer in that area, with an incidence rate of 8.9 per 100,000 person-years. Incidence of squamous cell carcinoma, however, was shown to be on the decline.[28] Squamous cell carcinoma is the most common form of skin cancer in black individuals in the United States, and the mortality rate for this disease is relatively high in this population.[29] Epidemiologic characteristics of, and prevention strategies for, squamous cell carcinoma in those with darker skin remain areas of investigation.

Freckling of the skin and reaction of the skin to sun exposure have been identified as other risk factors for SCC.[30] Individuals with heavy freckling on the forearm were found to have a 14-fold increase in SCC risk if freckling was present in adulthood and an almost 3-fold risk if freckling was present in childhood.[30,31] The degree of SCC risk corresponded to the amount of freckling. The inability of the skin to tan and propensity to burn were also significantly associated with risk of SCC in this study (OR of 2.9 for severe burn and 3.5 for no tan).

The presence of scars on the skin can also increase the risk of SCC as well, although the process of carcinogenesis in this setting may take years or even decades. Squamous cell carcinomas arising in chronic wounds are referred to as Marjolin's ulcers. The mean time for development of carcinoma in these wounds is estimated at 26 years.[32] One case report documents the occurrence of cancer in a wound that was incurred 59 years earlier.[33]

Immunosuppression

Immunosuppression also contributes to the formation of nonmelanoma 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 that observed in the general population.[34,35,36] Nonmelanoma skin cancers in high-risk patients (recipients of solid organ transplants and patients with chronic lymphocytic leukemia) occur at a younger age, are more common and more aggressive, and have a higher risk of recurrence and metastatic spread when compared to these cancers in the general population.[37,38] 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 an interaction between the level of immunosuppression and UV radiation exposure. As the duration and dosage of immunosuppressive agents increase, 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.[34,39] The risk appears to be highest in geographic areas with high UV 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.[40] This finding underlines the importance of rigorous sun avoidance, particularly among high-risk immunosuppressed individuals.

Certain immunosuppressive agents have been associated with increased risk for SCC. Kidney transplant patients who received cyclosporine in addition to azathioprine and prednisolone had a 2.8-fold increase in risk of SCC over those on azathioprine and prednisolone alone.[34] In cardiac transplant patients, increased incidence of SCC was seen in individuals who had received OKT3 (muromonab-CD3), a murine monoclonal antibody against the CD3 receptor.[41]

Personal history of nonmelanoma skin cancer

A personal history of BCC or SCC is strongly associated with subsequent SCC. A study from Ireland showed that individuals with a history of BCC had a 14% higher incidence of subsequent SCC; for men with a history of BCC, the subsequent SCC risk was 27% higher.[42] In the same report, individuals with melanoma were also 2.5 times more likely to report a subsequent SCC. There is an approximate 20% increased risk for 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 middle of the sixth decade of life.[24,43,44,45,46,47]

Major Genes and Syndromes Associated with a Predisposition for Squamous Cell Carcinoma

Major genes have been defined elsewhere in this summary as genes that are necessary and sufficient for disease, with important mutations of the gene as causal. The disorders resulting from single-gene mutations within families lead to a very high risk of disease and are relatively rare. The influence of the environment on the development of disease in individuals with these single-gene disorders is often very difficult to determine owing to the rarity of the genetic mutation.

Identification of a strong environmental risk factor—chronic exposure to UV radiation—makes it difficult to apply genetic causation for SCC of the skin. Although the risk of ultraviolet radiation exposure is well known, quantifying its attributable risk to cancer development has proven challenging. In addition, ascertainment of squamous cell skin cancer cases is not always straightforward. Many registries and other epidemiologic studies do not fully assess the incidence of squamous cell skin cancers owing to (1) the common practice of treating lesions suspicious for SCC without a diagnostic biopsy and (2) the relatively low potential for metastasis. Moreover, nonmelanoma skin cancer is routinely excluded from the major cancer registries such as the Surveillance, Epidemiology, and End Results registry.

With these considerations in mind, the discussion below will address genes associated with disorders that have an increased incidence of skin cancer.

Xeroderma pigmentosum

Xeroderma pigmentosum (XP) is a hereditary disorder of nucleotide excision repair that results in cutaneous malignancies in the first decade of life. Affected individuals have an increased sensitivity to sunlight, resulting in a markedly increased risk of SCCs, BCCs, and melanomas. One report found that nonmelanoma skin cancer was increased 150-fold in individuals with XP; for those younger than 20 years, the prevalence was almost 5,000 times what would be expected in the general population.[48]

The natural history of this disease begins in the first year of life, when sun sensitivity becomes apparent, and xerosis and pigmentary changes may occur in the skin. These manifestations progress to skin atrophy and formation of telangiectasias. Approximately one-half of people with this disorder will develop nonmelanoma skin cancers, and approximately one-quarter of the individuals these will develop melanoma.[48] The median age of diagnosis for any skin cancer is 8 years.[48]

Noncutaneous manifestations of XP include ophthalmologic and neurologic abnormalities. Disorders of the cornea and eyelids associated with this disorder are also linked to exposure to UV light and include keratitis, corneal opacification, ectropion or entropion, hyperpigmentation of the eyelids, and loss of eyelashes. Microcephaly, sensorineural hearing loss, diminished deep tendon reflexes, seizures, and cognitive impairment are also found in some affected individuals. DeSanctis-Cacchione syndrome is found in a subgroup of these patients, who exhibit severe neurologic manifestations, dwarfism, and delayed sexual development. A variety of noncutaneous neoplasms, most notably SCC of the tip of the tongue, have been reported in people who have XP.[48,49] The relative risk for these cancers is estimated to be at least fivefold higher than in the general population.

The inheritance for XP is autosomal recessive. Seven complementation groups have been associated with this disorder. Of these, complementation group A, due to mutation in XPA, is the most severe and accounts for approximately 25% of cases. Another 25% of cases are caused by mutations in XPC.[50] Other mutated genes in this disorder include ERCC3 (XPB), ERCC2 (XPD), DDB2 (XPE), ERCC4 (XPF), and ERCC5 (XPG). An XPH group had been described but is now considered to be a subgroup of the XPD group.[51] Heterozygotes for mutations in XP genes are asymptomatic.

The function of the XP genes is to recognize and repair photoproducts from UV radiation. The product of XPC is involved in the initial identification of DNA damage; it binds to the lesion to act as a marker for further repair. The DDB2 (XPE) protein is also part of this process and may work with XPC. The XPA gene product maintains single-strand regions during repair and works with the TFIIH transcription factor complex. The TFIIH complex includes the gene products of both ERCC3 (XPB) and ERCC2 (XPD), which function as DNA helicases in the unwinding of the DNA. The ERCC4 (XPF) and ERCC5 (XPG) proteins act as DNA endonucleases to create single-strand nicks in the 5' and 3' sides of the damaged DNA. DNA polymerases replace the lesion with the correct sequence, and a DNA ligase completes the repair.[52,53]

Work on genotype-phenotype correlations among the XP complementation groups continues. The main distinguishing features appear to be the presence or absence of skin cancer and neurologic abnormalities. Most complementation groups are characterized by the presence of cutaneous neoplasia and the absence of neurologic symptoms. However, multiple exceptions to this rule have been described. Mild to severe neurologic impairment has been described in individuals with XPA mutations. A very small number of people in the XPB, XPD, and XPG complementation groups has been identified as having xeroderma pigmentosum-Cockayne syndrome complex. These individuals have characteristics of both disorders, including an increased predisposition to cutaneous neoplasms and developmental delay, visual and hearing impairment, and central and peripheral nervous system dysfunction. It should be noted that people with Cockayne syndrome without XP do not appear to have an increased cancer risk.[54] Similarly, trichothiodystrophy (TTD) is another genetic disorder that can occur in combination with XP. Individuals affected solely with TTD do not appear to have an increased cancer incidence, but some affected with XP/TTD have an increased risk of cutaneous neoplasia. The complementation groups associated with XP/TTD are XPB and XPD. In addition, individuals in the XPD and XPG groups may exhibit severe neurologic abnormalities without symptoms of Cockayne syndrome or TTD. Cerebro-oculo-facio-skeletal syndrome, which has been described with some ERCC2 (XPD) mutations, does not appear to confer an increased risk of skin cancer.[55,56,57,58]

An XP variant that is associated with mutations in POLH (XP-V) is responsible for approximately one-fifth of reported cases.[50] This gene encodes for the error-prone polymerase POL-ETA and, unlike other genes associated with XP, is not involved in nucleotide excision repair. People with this variant have the cutaneous and ocular findings consistent with XP, but the neurologic findings are generally not present.

The diagnosis of XP is made on the basis of clinical findings and family history. Functional assays for DNA repair capabilities after exposure to UV radiation have been developed, but these tests are not clinically available. Sequence analysis testing may be done to confirm mutations in XPA and XPC previously identified in an affected family; however, molecular testing for mutations associated with other complementation groups is currently done only in research laboratories.

Multiple self-healing squamous epitheliomata (Ferguson-Smith syndrome)

Ferguson-Smith syndrome, first described in 1934, is characterized by invasive skin tumors that are histologically identical to sporadic cutaneous SCC, but they resolve spontaneously without intervention. The causative gene, previously known as ESS1 and now designated MSSE, has proven elusive. Linkage analysis of affected families has shown loss of the long arm of chromosome 9, and haplotype analysis has localized this gene to 9q22.3 between D9S197 and D9S1809.[59]PTCH (mutated in nevoid basal cell carcinoma syndrome) and XPA (one of the genes associated with xeroderma pigmentosum) are among the candidate genes in this area; however, neither of these genes was found to be mutated in the families affected with multiple self-healing squamous epitheliomata.[60] Two fructose bisphosphatase genes (FBP1 and FBP2), a possible membrane alanine aminopeptidase (C9orf3), and three other genes of unknown function (AL133071, FLJ14753, and CDC14B) are additional candidates.[61]

Somatic loss of heterozygosity in Ferguson-Smith-related SCC has been demonstrated at this genomic location, suggesting that this gene is likely a tumor suppressor gene.[61] The long arm of chromosome 9 has also been a site of interest in sporadic SCC. Up to 65% of sporadic SCCs have been found to have loss of heterozygosity at 9q22.3 between D9S162 and D9S165.[61]

Oculocutaneous albinism

Two types of oculocutaneous albinism are known to be associated with increased risk of SCC of the skin. Oculocutaneous albinism type 1, or tyrosinase-related albinism, is caused by mutations in the tyrosinase gene, TYR, located on the long arm of chromosome 11. The OCA2 gene, also known as the P gene, is mutated in oculocutaneous albinism type 2, or tyrosinase-positive albinism. Both disorders are autosomal recessive, with frequent compound heterozygosity.

Tyrosinase acts as the critical enzyme in the synthesis of melanin in melanocytes. Mutation in this gene in oculocutaneous albinism type 1 produces proteins with minimal to no activity, corresponding to the OCA1B and OCA1A phenotypes, respectively. Individuals with OCA1B have light skin, hair, and eye coloring at birth but develop some pigment during their lifetimes, while the coloring of those with OCA1A does not darken with age.

The gene product of OCA2 is a protein found in the membrane of melanosomes. Its function is unknown, but it may play a role in maintaining the structure or pH of this environment.[62] Murine models with mutations in this gene had significantly decreased melanin production compared with normal controls.[63]

Mutations in the genes MATP (OCA4) and TYRP1 (tyrosinase-related protein) are associated with less common types of oculocutaneous albinism. The increased risk of SCC of the skin in people with these mutations has not been quantified. It is generally assumed to be similar to other types of albinism.

A subgroup of oculocutaneous albinism type 2 includes people who exhibit a triad of albinism, prolonged bleeding time, and deposition of a ceroid substance in organs such as the lungs and gastrointestinal tract. This syndrome, known as Hermansky-Pudlak syndrome, is inherited in an autosomal recessive manner but may have a pseudodominant inheritance in Puerto Rican families, owing to the high prevalence in this population.[64] The underlying cause is believed to be a defect in melanosome and lysosome transport. A number of mutations at disparate loci have been associated with this syndrome, including HPS1, HPS3, HPS4, HPS5, HPS6, HPS7 (DTNBP1), and HPS8 (BLOC1S3).[65,66,67,68,69,70,71] Hermansky-Pudlak syndrome type 2, which includes increased susceptibility to infection due to congenital neutropenia, has been attributed to defects in AP3B1.[72]

Two additional syndromes are associated with decreased pigmentation of the skin and eyes. The autosomal recessive Chediak-Higashi syndrome is characterized by eosinophilic, peroxidase-positive inclusion bodies in early leukocyte precursors, hemophagocytosis, increased susceptibility to infection, and increased incidence of an accelerated phase lymphohistiocytosis. Mutations in the LYST gene underlie this syndrome, which is often fatal in the first decade of life.[73,74,75]

Griscelli syndrome, also inherited in an autosomal recessive manner, was originally described as decreased cutaneous pigmentation with hypomelanosis and neurologic deficits, but its clinical presentation is quite variable. This combination of symptoms is now designated Griscelli syndrome type 1 or Elejalde disease. It has been attributed to mutations in the MYO5A gene, which affects melanosome transport.[76] Individuals with Griscelli syndrome type 2 have decreased cutaneous pigmentation and immunodeficiency but lack neurological deficits. They also may have hemophagocytosis or lymphohistiocytosis that is often fatal, like that seen in Chediak-Higashi syndrome. Griscelli syndrome type 2 is caused by mutations in RAB27A, which is part of the same melanosome transport pathway as MYO5A.[77] Griscelli syndrome type 3 presents with hypomelanosis and does not include neurologic or immunologic disorders. Mutations in the melanophilin (MLPH) gene and MYO5A have been associated with this variant.[78]

Dystrophic epidermolysis bullosa

Approximately 95% of individuals with the heritable disorder dystrophic epidermolysis bullosa have a detectable germline mutation in the gene COL7A1. This gene, which is located at 3p21.3, is expressed in the basal keratinocytes of the epidermis and encodes for type VII collagen. This collagen forms a part of the fibrils that anchor the basement membrane to the dermis, thereby providing structural stability and resistance to mild skin trauma.[79]

There are two recessively-inherited subtypes of dystrophic epidermolysis bullosa: Hallopeau-Siemens type (RDEB-HS) and non–Hallopeau-Siemens type (non-HS RDEB); and a dominantly inherited form, dominant dystrophic epidermolysis bullosa (DDEB). RDEB-HS is the most severe form, with a lifetime SCC risk of more than 75%.[80] The rate of de novo mutation for DDEB is approximately 30%; maternal germline mosaicism has been reported.[81,82]

Glycine substitutions in exons 73 to 75 are the most common mutations in DDEB. G2034R and G2043R account for half of these mutations. Less frequently, splice junction mutations and substitutions of glycine and other amino acids may cause the dominant form of dystrophic epidermolysis bullosa. In contrast, more than 400 mutations have been described for the 2 types of recessive epidermolysis bullosa. The recessive form of the disease is caused primarily by null mutations, although amino acid substitutions, splice junction mutations, and missense mutations have also been reported. In-frame exon skipping may generate a partially functional protein in recessive disease. Genotype-phenotype correlations suggest an inverse correlation between the amount of functional protein and severity.

Mutations in COL7A1 result in abnormal triple helical coiling and decreased function, which causes increased skin fragility and blistering. In studies of Ras-driven carcinogenesis in RDEB-HS keratinocytes, retention of the amino-terminal NC1, the first noncollagenous fragment of type VII collagen, is tumorigenic in mice.[83] This retained sequence may mediate tumor-stroma interactions that promote carcinogenesis.

Epidermodysplasia verruciformis

Mutations in either of two adjacent genes on chromosome 17q25 can cause epidermodysplasia verruciformis, a rare heritable disorder associated with increased susceptibility to human papillomavirus (HPV). Infection with certain HPV subtypes can lead to development of generalized nonresolving verrucous lesions, which have the potential to develop into in situ and invasive SCCs. Malignant transformation is thought to occur in about half of these lesions. Approximately 90% of these lesions are attributed to HPV types 5 and 8,[84] although types 14, 17, 20, and 47 have occasionally been implicated. The association between HPV infection and increased risk of SCC has also been demonstrated in people without epidermodysplasia verruciformis; one case-control study found that HPV antibodies were found more frequently in the plasma of individuals with SCC (OR = 1.6; 95% CI, 1.2–2.3) than in plasma from cancer-free individuals.[85]

The genes associated with this disorder, EVER1 and EVER2, were identified in 2002.[86] The inheritance pattern of these genes appears to be autosomal recessive; however, autosomal dominant inheritance has also been reported.[87,88] Both of these gene products are transmembrane proteins localized to the endoplasmic reticulum, and they likely function in signal transduction. This effect may be through regulation of zinc balance; it has been shown that these proteins complex with the zinc transporter 1 (ZnT-1), which is, in turn, blocked by certain HPV proteins.[89]

A recent case-control study examined the effect of a specific EVER2 polymorphism (rs7208422) on the risk of cutaneous SCC in 239 individuals with prior SCC and 432 controls. This polymorphism is a (A > T) coding single nucleotide polymorphism in exon 8, codon 306 of the EVER2 gene. The frequency of the T allele among controls was 0.45. Homozygosity for the polymorphism caused a modest increase in SCC risk, with an adjusted OR of 1.7 (95% CI, 1.1–2.7) relative to wild-type homozygotes. In this study, those with one or more of the T alleles were also found to have increased seropositivity for any HPV and for HPV types 5 and 8, as compared with the wild-type.[90]

Some evidence suggests a nonallelic heterogeneity in epidermodysplasia verruciformis. Another susceptibility locus associated with this disorder has been identified at chromosome regions 2p21-p24 through linkage analysis of an affected consanguineous family. Unlike those with mutations in the EVER1 and EVER2 genes, affected individuals linked to this genomic region were infected with HPV 20 rather than the usual HPV subtypes associated with this disorder, and this family did not have a history of cutaneous SCC.[91]

Fanconi anemia

Fanconi anemia is a complex disorder that is characterized by increased incidence of hematologic and solid tumors, including SCC of the skin. Leukemia is the most commonly reported cancer in this population, but increased rates of gastrointestinal, head and neck, and gynecologic cancers have also been seen.[92] By age 40 years, individuals affected with Fanconi anemia have an 8% risk per year of developing a solid tumor;[92] the median age of diagnosis for solid tumors is 26 years.[93] Multiple cases of cancers of the brain, breast, lung, and kidney (Wilms tumor) have been reported in this population.[93] Data on the incidence of nonmelanoma skin cancers in this population are sparse; however, review of the literature suggests that the age of diagnosis is between the mid-20s and early 30s and that women seem to be affected more often than men.[93,94,95,96,97]

Individuals with this disease have increased susceptibility to DNA cross-linking agents (e.g., mitomycin-C or diepoxybutane) as well as ionizing and ultraviolet radiation. Cells from individuals with Fanconi anemia have shown decreased ability to excise pyrimidine dimers.[98] The diagnosis of this disease is made by observing increased chromosomal breakage, rearrangements, or exchanges in cells after exposure to carcinogens such as diepoxybutane.

Thirteen complementation groups have been identified for Fanconi anemia; details regarding the genes associated with these groups are listed in Table 3 below.[99]

Table 3. Genes Associated with Fanconi Anemia

AR = autosomal recessive; XLR = X-linked recessive
Gene Locus Approximate Incidence Among FA Patients (%) Pattern of Disease Transmission
FANCA (OMIM) 16q24.3 ~70 AR
FANCB (OMIM) Xp22.31 Rare XLR
FANCC (OMIM) 9q22.3 ~10 AR
FANCD1 (BRCA2) (OMIM) 13q12.3 Rare AR
FANCD2 (OMIM) 3p25.3 Rare AR
FANCE (OMIM) 6p21.3 ~10 AR
FANCF (OMIM) 11p15 Rare AR
FANCG (XRCC9) (OMIM) 9p13 ~10 AR
FANCI (KIAA1794) (OMIM) 15q25-26 Rare AR
FANCJ (BACH1/BRIP1) (OMIM) 17q22.3 Rare AR
FANCL (PHF9/POG) (OMIM) 2p16.1 Rare AR
FANCM (Hef) (OMIM) 14q21.3 Rare AR
FANCN (PALB2) (OMIM) 16p12.1 Rare AR

Further investigation has revealed that FANCD1 is the same gene as BRCA2, a gene that causes predisposition to breast and ovarian cancer.[100] Other Fanconi anemia genes, FANCJ (BRIP1) and FANCN (PALB2), have also been identified as rare breast cancer susceptibility genes.[101] (Refer to the PDQ summary on Genetics of Breast and Ovarian Cancer for more information on BRCA2, BRIP1, and PALB2.) Individuals who are heterozygous carriers of other Fanconi anemia-associated mutations do not appear to have an increased risk of cancer, with the possible exception of a twofold increase in breast cancer incidence in FANCC mutation carriers.[102]

Rothmund-Thomson syndrome

Rothmund-Thomson syndrome, also known as poikiloderma congenitale, is a heritable disorder characterized by chromosomal instability. The cutaneous presentation of this condition is an erythematous, blistering rash appearing on the face, buttocks, and extremities in early infancy. Other characteristics of this syndrome include telangiectasias, skeletal abnormalities, short stature, cataracts, and increased risk of osteosarcoma. Areas of hyperpigmentation and hypopigmentation of the skin develop later in life, and nonmelanoma skin cancers can develop at an early age.[103] Reports of multiple SCCs in situ have been reported in individuals as young as 16 years.[104] The precise increased risk of skin cancer is not well characterized, but the point prevalence of nonmelanoma skin cancer, including both BCC and SCC, is 2% to 5% in young individuals affected by this syndrome.[105] This prevalence is clearly greater than that found in individuals in the same age group in the general population. Although increased ultraviolet sensitivity has been described, SCCs are also found in areas of the skin that are not exposed to the sun.[106]

A detectable mutation in the gene RECQL4 is present in 66% of clinically affected individuals. This gene is located at 8q24.3, and inheritance is believed to be autosomal recessive. RECQL4 encodes the ATP-dependent DNA helicase Q4, which promotes DNA unwinding to allow for cellular processes such as replication, transcription, and repair. A role for this protein in repair of DNA double-strand breaks has also been suggested.[107] Mutations in similar DNA helicases lead to the inherited disorders Bloom syndrome and Werner syndrome.

At least 19 different truncating mutations in this gene have been identified as deleterious.[108] These mutations cause severe down-regulation of RECQL4 transcripts in this subset of individuals with Rothmund-Thomson syndrome.[109] Cells deficient in RECQL4 have been found to be hypersensitive to oxidative stress, resulting in decreased DNA synthesis.[110] Deficiencies in the RecQ helicases permit hyperrecombination, thereby leading to loss of heterozygosity. Loss of heterozygosity associated with deficiencies of this protein suggests that the helicases are caretaker-type tumor suppressor proteins.[111]

Bloom syndrome

Loss of genomic stability is also the major cause of Bloom syndrome. This disorder shows increased chromosomal breakage and is diagnosed by increased sister chromatid exchanges on chromosomal analysis. Clinical manifestations of Bloom syndrome include severe growth retardation, recurrent infections, diabetes, chronic pulmonary disease, and an increased susceptibility to cancers of many types. The typical skin lesion seen in this disorder is a photosensitive erythematous telangiectatic rash that occurs in the first or second year of life. Although it is most commonly found on the face, it can also be present on the dorsa of hands or forearms. SCC of the skin is the third most common malignancy associated with this disorder. Skin cancer accounts for approximately 14% of tumors in the Bloom Syndrome Registry.[112] Skin cancers occur at an earlier age in this population, with a mean age of 31.8 years at the time of diagnosis.

The BLM gene, located on the short arm of chromosome 15, is the only gene known to be mutated in Bloom syndrome. This gene encodes a 1,417-amino acid protein that is regulated by the cell cycle and demonstrates DNA-dependent ATPase and DNA duplex-unwinding activities. Its helicase domain shows considerable similarity to the RecQ subfamily of DNA helicases. Absence of this gene product is thought to destabilize other enzymes that participate in DNA replication and repair.[113]

This rare chromosomal breakage syndrome is inherited in an autosomal recessive manner and is characterized by loss of genomic stability. Sixty-four deleterious mutations described in the BLM gene include nucleotide insertions and deletions (41%), nonsense mutations (30%), mutations resulting in mis-splicing (14%), and missense mutations (16%).[114,115] A specific mutation identified in the Ashkenazi Jewish population is a 6-bp deletion/7-bp insertion at nucleotide 2,281, designated as BLMASH.[116] Many of these mutations result in truncation of the C-terminus, which prevents normal localization of this protein to the nucleus. Absence of functional BLM protein can cause increased rates of mutation and recombination. This somatic hypermutability can thereby lead to an increased risk of cancer at an early age in virtually every organ, including the skin.

Cells from people with Bloom syndrome have been found to have abnormal responses to UV radiation. Normal nuclear accumulation of TP53 after UV radiation was absent in 2 of 11 primary cultures from individuals with Bloom syndrome; in contrast, responses in cultures from people who have XP and ataxia-telangiectasia were normal.[117] The gene product of the BLM gene has also been found to complex with Fanconi proteins, raising the possibility of connections between the BLM and Fanconi anemia pathways for DNA stability.[118]

Werner syndrome

Like Bloom syndrome, Werner syndrome is characterized by spontaneous chromosomal instability, resulting in increased susceptibility to cancer and premature aging. Diagnostic criteria, often in the setting of consanguinity, include cataracts, short stature, premature graying or thinning of hair, and a positive 24-hour urinary hyaluronic acid test. Cardinal cutaneous manifestations of this disorder consist of sclerodermatous skin changes, ulcerations, atrophy, and pigmentation changes. Individuals with this syndrome have an early onset of cancer and an average life expectancy of fewer than 50 years.[119] The spectrum of cancers associated with this disorder has primarily been described in the Japanese population and includes an increased incidence of sarcoma, thyroid cancers and skin cancers.[120] Approximately 20% of the cancers reported in this syndrome are cutaneous, with melanoma and SCC of the skin accounting for 14% and 5%, respectively.[121] Acral lentiginous melanomas are overrepresented, and SCCs may exhibit more aggressive behavior, with metastasis to lymph nodes and internal organs.[120,122]

Mutations in the WRN gene on chromosome 8p12-p11.2 have been identified in approximately 90% of individuals with this syndrome; no other genes are known to be associated with Werner syndrome. Inheritance of this gene is believed to be autosomal recessive. The product of the WRN gene is a multifunctional protein including a DNA exonuclease and an ATP-dependent DNA helicase belonging to the RecQ subfamily. This protein may play a role in processes such as DNA repair, recombination, replication, transcription, and combined DNA functions.[123,124,125,126,127,128,129,130] Other helicases with similar function are altered in other chromosomal instability syndromes, such as BLM in Bloom syndrome and RecQL4 in Rothmund-Thomson syndrome.

Deleterious mutations described in the WRN gene include stop codons, insertions or deletions, or splicing site mutations causing a frameshift. Of the approximately 35 mutations identified, the most common is 1336C?T, which is found in 20% to 25% of the Japanese and Caucasian populations.[131] In the Japanese population, a founder mutation (IVS 25-1G?C) is present in 60% of affected individuals.[132]

Mutation in the WRN gene causes loss of nuclear localization of the gene product. Intracellular levels of the mRNA and protein associated with the mutated gene are also markedly decreased, compared with those of the wild-type. Half-lives of the mRNA and protein associated with the mutated gene are also shorter than those associated with the wild-type mRNA and protein.[131,133]

Table 4. Hereditary Syndromes Associated with Squamous Cell Carcinoma of the Skin

a For more up-to-date information on genetic testing laboratories, see GeneTests: Laboratory Directory.
Condition Gene Clinical Testing Availabilitya Pathway
Xeroderma pigmentosum (complementation group A, group B, group C, group D, group E, group F, and group G) XPA, XPB/ERCC3, XPC, XPD/ERCC2, XPE/DDB2 , XPF/ERCC4, and XPG/ERCC5 XPA, XPC Nucleotide excision repair
Xeroderma pigmentosum variant POLH (XP-V) No Error-prone polymerase
Multiple self-healing squamous epithelioma (Ferguson-Smith syndrome) MSSE No Unknown
Oculocutaneous albinism (type IA, type IB, type II, type III, and type IV) TYR, OCA2, MATP/OCA4, and TYRP1 TYR, OCA2, TYRP1 Melanin synthesis
Hermansky-Pudlak syndrome HPS1, HPS3, HPS4, HPS5, HPS6, HPS7/DTNBP1, and HPS8/BLOC1S3 HPS1, HPS3, HPS4, HPS7 Melanosomal and lysosomal storage
Hermansky-Pudlak syndrome, Type 2 AP3B1 No Melanosomal and lysosomal storage
Chediak-Higashi syndrome LYST LYST Lysosomal transport regulation
Griscelli syndrome (Type 1, Type 2, and Type 3) MYO5A, RAB27A, and MLPH RAB27A Pigment granule transport
Elejalde Disease MYO5A No Pigment granule transport
Dystrophic epidermolysis bullosa (dominant and autosomal recessive subtypes) COL7A1 COL7A1 Collagen anchor of basement membrane to dermis
Epidermodysplasia verruciformis EVER1 and EVER2 No Signal transduction in endoplasmic reticulum
Fanconi anemia FANCA, FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG/XRCC9, FANCI, FANCJ/BRIP1, FANCL, FANCM, and FANCN/PALB2 Chromosomal breakage testing; BRIP1, FANCA, FANCC, FANCE, FANCF, FANCG, PALB2 DNA repair
Rothmund-Thomson syndrome RECQL4 RECQL4 Chromosomal stability
Bloom syndrome BLM/RECQL3 Sister chromatid exchange, BLM Chromosomal stability
Werner syndrome WRN/RECQL2 No Chromosomal stability

Interventions

Prevention and treatment

Because many of the syndromes described above are rare, few clinical trials have been conducted in these specific populations. However, valuable information has been developed from the clinical management experience related to skin cancer risk and treatment in the XP population. Strict sun avoidance beginning in infancy, use of protective clothing, and close clinical monitoring of the skin are key components to management of XP. Full-body photography of the skin, conjunctivae, and eyelids is recommended to aid in follow-up. Although few studies on treatment of SCC in the XP population have been done, in most cases treatment is similar to what would be recommended for the general population. Actinic keratoses are treated with topical therapies such as 5-fluorouracil (5-FU), cryotherapy with liquid nitrogen, or dermabrasion, whereas cutaneous cancers are generally managed surgically.

Level of evidence: 5

Oral isotretinoin has been used as chemoprevention in XP patients with promising results. A small study of daily use of isotretinoin (13-cis retinoic acid; given as 2 mg/kg/day) reduced nonmelanoma skin cancer incidence by 63% in a small number of people with XP. Toxicities associated with this treatment included mucocutaneous symptoms, abnormalities in liver function tests and triglyceride levels, and musculoskeletal symptoms such as arthralgias, calcifications of tendons and ligaments, and osteoporosis.[134,135] Dose reduction to 0.5 mg/kg/day reduced toxicity and decreased skin cancer frequency in three of seven subjects (43%); increasing the dose to 1 mg/kg/day resulted in decreased skin cancer frequency in three of the four subjects who did not respond at the lower dose.[136]

Level of evidence: 3aii

Topical T4N5 liposome lotion, containing the bacterial enzyme T4 endonuclease V, was also investigated as a chemopreventive agent in a randomized, placebo-controlled trial of 30 XP patients.[137] Although no effect was seen on incidence of SCC, 17.7 fewer actinic keratoses per year were seen in the treatment group. Additionally, 1.6 fewer BCCs per year were observed in patients being treated with this therapy. Both of these results were statistically significant. The risk of BCC was reduced by 47%, which was of borderline statistical significance. No significant adverse effects of this agent were reported.

Level of evidence 1aii

For patients with XP and unresectable SCC, therapy with 5-FU has been investigated. Several treatment methods were used in this prospective study, including topical therapy to the lesions, short systemic infusion with folic acid, and continuous systemic infusion in combination with cisplatin. Topical 5-FU demonstrated some efficacy, but in some cases viable tumor remained in the deeper dermis. The systemic chemotherapy resulted in one complete response and three partial responses in a total of five patients, suggesting that this therapy may be an option for treatment of extensive lesions.[138]

Level of evidence:3diii

For people who have genetic disorders other than XP, data are lacking, but general sun safety measures remain important. Careful protection of the skin and eyes is the mainstay of prevention in all patients with increased susceptibility to skin cancer. Key points include avoidance of sun exposure at peak hours, protective clothing and lenses, and vigilant use of sunscreen. Some experts recommend dermatologic evaluation every 6 months and ophthalmologic evaluation at least annually in these high-risk populations.

Level of evidence: 5

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Melanoma

Introduction

Both rare, high-penetrance and common, low-penetrance genetic factors for melanoma have been identified, and approximately 5% to 10% of all melanomas arise in multiple-case families. However, a significant fraction of these families do not have detectable mutations in specific susceptibility genes. The frequency with which multiple-case families are ascertained and specific genetic mutations are identified varies significantly between populations and geographic regions. A major population-based study has concluded that high-penetrance susceptibility genes do not make a significant contribution to the incidence of melanoma in the Icelandic population, an observation which must be interpreted in the context of the relatively low levels of sunlight exposure in this region.[1]

Risk Factors for Melanoma

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: basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma.

While there is no standard measure, sun exposure has generally been classified as intermittent or chronic, and its effects may be considered short-term or cumulative. Intermittent sun exposure is, by definition, sporadic, and is commonly associated with recreational activities, particularly among indoor workers who use weekend or vacation time to be outdoors and whose skin has not adapted to the sun. Chronic sun exposure is incurred by consistent, repetitive sun exposure, usually during outdoor work or more extensive recreational activities. Acute sun exposure is obtained over a short time on skin that has not adapted to the sun. Depending on the time of day and the skin type of the individual, acute sun exposure may result in sunburn. In epidemiology studies, sunburn is usually defined an injury associated 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. The impact of cumulative sun exposure likely reflects the additive effects of intermittent sun exposure or chronic sun exposure, or both.

Different patterns of sun exposure appear to lead to different types of skin cancer among susceptible individuals. Intermittent sun exposure seems to be the most important risk factor for melanoma.[2,3] Analytic epidemiologic studies have shown only modest risks related to sun exposure in melanoma development; three systematic reviews have demonstrated similar estimates for the role of intermittent sun exposure, i.e., odds ratios (ORs) of 1.6 to 1.7.[4,5,6] Chronic sun exposure, as observed in those occupationally exposed to sunlight, is either protective or without increased risk for the development of melanoma, with an OR of 0.7; or shows no increased risk (see Table 5). The biological mechanisms underlying these differences in melanoma risk by sun exposure type have not been fully elucidated.

Table 5. Meta-Analysis Results: Intermittent and Chronic Sun Exposure and Melanoma Risk

CI = confidence interval; OR = odds ratio.
Intermittent Sun Exposure (OR, 95% CI) Chronic Sun Exposure (OR, 95% CI) Comments
1.6 (1.3–1.9) [4] 0.7 (0.6–0.9) Lack of standardized measures an issue.
1.7 (1.5–1.9) [5] 0.9 (0.8–0.9) Mechanisms for the differences in types of sun exposure not understood.
1.6 (1.3–1.9) [6] 0.9 (0.7–1.0) None.

Although these meta-analyses have yielded very similar risk estimates, the measurement of sun exposure is complex; new studies using comparable protocols in different populations with varying levels of sun exposure are needed.

One explanation offered for the rise in melanoma incidence relates to the differential effects of chronic and intermittent sun exposure; as people have replaced outdoor occupations with indoor occupations, they have engaged in more intermittent sun exposure.[7] Data from very different settings seems to suggest that intermittent sun exposure is critical to the risk for developing melanoma.

The evidence relating lifetime cumulative exposure to melanoma risk comes from two sources: migrant studies and studies of lifetime exposure, controlling for intermittent and occupational exposure. Data from Australia and Italy show that individuals who migrate from areas of low exposure to ultraviolet (UV) radiation, such as the United Kingdom, to areas of high exposure, such as Australia or Israel, before they reach age 10 years have a lifetime risk of developing melanoma that is similar to that of people in the new country.[8,9,10] Alternatively, adolescents or older individuals who migrate from areas of low solar exposure to areas of high solar exposure have a risk that is more similar to that of people from their area of origin than to that of people in the new area. These data have often been cited as indicating that childhood sun exposure is more important than adult sun exposure in melanoma development. However, the data could also be interpreted as suggesting that the length of high-level exposure is more critical than the age at exposure. Thus, people who migrate early in life to a high-insolation region have a longer potential period for intense exposure compared than do those who migrate later in life.

Data from Connecticut have shown that cumulative lifetime exposure to ultraviolet-B (UVB) radiation does not differ between melanoma cases and controls; rather, intermittent sun exposure is the more important risk factor.[11] The risks related to intermittent sun exposure are even greater if this pattern is experienced both early in life and later in life. These data can also be interpreted as suggesting that sun exposure patterns are rather consistent and stable throughout one's lifetime, i.e., that individuals who receive a great deal of intermittent sun exposure during early life are also likely to receive a great deal of intermittent sun exposure during later life. Nonetheless, an intermittent pattern of sun exposure over many years appears to significantly increase melanoma risk.

The relationship between sun exposure, sunscreen use, and the development of skin cancer is also complex. It is complicated by "negative confounding," i.e., subjects who are extremely sun sensitive deliberately engage in fewer activities in direct sunlight, and they are more likely to wear sunscreen when they do. These subjects are genetically susceptible to the development of skin cancer by virtue of their cutaneous phenotype and thus may develop skin cancer regardless of the amount of sunlight exposure or the sun protection factor of the sunscreen.[12,13]

Other environmental factors

There are a number of additional environmental factors that are important to melanoma development (Table 6).

Table 6. Environmental Exposures Other Than Sunlight Associated with Melanomaa

Cl = confidence interval; OR = odds ratio; PCB = polychlorinated biphenyls; PVC = polyvinyl chloride; RR = relative risk; SIR = standardized incidence ratio; SMR = standard mortality rate.
a Adapted from Gruber et al.[14]
Study Citation Subjects Time and Place Point Estimate
SOLVENTS
[15] Cohort (N = 23,718) 1970–1994; Sweden RR = 2.7 (95% CI, 1.1–5.6)
IONIZING RADIATION
[16] Various cohorts (N = 80,000) Hiroshima, Japan Excess RR per Sievert = 2.1 (95% CI, <0.01–12)
[17] U.S. Radiologic Technologists Cohort (N = 90,305) United States SIR = 1.59 (95% CI, 1.38–1.80)
[18] French Atomic Energy Commission workers (N = 58,320) France SMR = 1.50 (90% CI, 1.04–2.11) among males
[19] (N = 3,737) Canada SIR = 1.16 (90% CI, 1.04–1.30)
AIRLINE FLIGHT CREWS
[20] Male pilots (N = 10,032) Scandinavia SIR = 2.3 (95% CI, 1.7–3.0)
ELECTROMAGNETIC FIELDS
[21] (N = 807 cases, 1,614 controls) 1980–1996; Norway OR = 1.87 (95% CI, 1.23–2.83)
VINYL CHLORIDE
[22] Men in PVC processing plants (N = 717) Sweden SMR = 3.4 (95% CI, 1.1–7.9)
[23] Workers exposed to PVC (N = 428) Norway SIR = 2.06, (95% CI, 1.36–6.96)
PCBS
[24] Occupational cohort of men exposed to PCBs (N = 138,905) United States RR = 1.29 (95% CI, 0.96–1.82), 5% increase per 2,000 h of exposure

Occupational exposure for airline flight personnel, particularly pilots and flight attendants, appears to be particularly significant.[20,25,26,27,28,29,30,31,32] Since the risk of internal cancers is not consistently elevated in these very large cohort studies, most investigators think that the excess melanoma cancers observed are caused by lifestyle factors such as excessive intermittent sun exposure (i.e., UV radiation that does not penetrate beyond the surface of the skin) rather than cosmic (i.e., ionizing) radiation, which would be expected to increase the risk of radiation-related solid tumors.

Other occupational exposures have been variously and inconsistently associated with melanoma risk. If these reports are genuine, these exposures are likely to account for only a small fraction of cases.[33,34,35]

Arsenic exposure (both from drinking water and from exposure to combustion products) has been consistently associated with nonmelanoma skin cancer and has more recently has been linked to melanoma.[34,36,37,38] Heavy metals bind to melanin,[39] and occupational studies show that printers and lithographers have increased melanoma risk.[34,40,41,42,43] Further clarification of the occupational exposures associated with the development of melanoma in people employed in the printing/lithography trade has been difficult owing to the small numbers of workers; the exposure of workers to numerous chemicals, solvents, pigments, and dyes; the extended latency of disease presentation, and changing work practices and environments over the past 50 years.[41] Five studies have shown increased risk of melanoma among electronics workers.[24,43,44,45,46] However, more persuasive evidence of metal-related melanoma risk has been documented in the long-term follow-up of individuals with metal-on-metal hip replacements.[47,48,49]

Pigmentary characteristics

Pigmentary characteristics are important determinants of melanoma susceptibility. There is an inverse correlation between melanoma risk and skin color that goes from lightest skin to darkest skin. Darker-skinned ethnic groups (blacks, darker Hispanics, Asians) have a very low risk of melanoma; however, individuals in these groups develop melanoma on less pigmented acral surfaces (palms, soles, nailbeds). Among relatively light-skinned individuals, skin color is modified by genetics and behavior. MC1R is one of the major genes controlling pigmentation (see below); other pigmentation genes are under investigation.

Clinically, several pigmentary characteristics are evaluated to assess risk of melanoma and other types of skin cancer. These include the following:

  • Fitzpatrick skin type. The following six skin phenotypes were defined on the basis of response to sun exposure at the beginning of summer.[50]
    1.Type I: Extremely fair skin, always burns, never tans.
    2.Type II: Fair skin, always burns, sometimes tans.
    3.Type III: Medium skin, sometimes burns, always tans.
    4.Type IV: Olive skin, rarely burns, always tans.
    5.Type V: Moderately pigmented brown skin, never burns, always tans.
    6.Type VI: Markedly pigmented black skin, never burns, always tans.
  • Number of nevi or nevus density.
  • Abnormal or atypical nevi.
  • Freckling.

Nevi

Patients with multiple nevi demonstrate increased risk of melanoma. While there is evidence that both the presence of multiple nevi and the presence of multiple clinically atypical nevi are associated with an increased risk of melanoma, most studies demonstrate a stronger risk of melanoma with the presence of atypical nevi.[51,52,53,54] In addition, patients with multiple atypical nevi, regardless of personal and/or family history of melanoma, are at significantly increased risk of developing melanoma compared with patients without atypical nevi.[55]

Immunosuppression

Melanoma is 1.6 to 2.5 times more common among recipients of organ transplants than in the general population,[56] an excess that has generally been attributed to the effects of immunosuppressive therapy administered to avoid allograft rejection.

Family history

Generally, a family history of melanoma appears to increase risk of melanoma by about twofold. Rarely, however, in some families many generations and multiple individuals develop melanoma, and have much higher risk. The major hereditary melanoma susceptibility gene, CDKN2A, is not responsible for all familial melanoma; it is found to be mutated in approximately 20% to 40% of melanomas in individuals with a family history of melanoma. The definition of a "familial" cluster of melanoma varies by geographical region, worldwide, owing to the role played by UV radiation in melanoma pathogenesis. In heavily insolated regions (regions with high ambient sun exposure), three or more affected family members is required; in regions with lower levels of ambient sunlight, two or more affected family members is considered sufficient to define a familial cluster.

Personal history of melanoma

A previous melanoma places one at high risk of developing additional primary melanomas, particularly for people with the most common risk factors for melanoma, such as cutaneous phenotype, family history, a mutation in CDKN2A, a great deal of early-life sun exposure, and numerous or atypical nevi. In the sporadic setting, approximately 5% of melanoma patients develop more than one primary cancer, while in the familial setting, the corresponding estimate is 30%. This greater-than-expected rate of multiple primary cancers of the same organ is a common feature of hereditary cancer susceptibility syndromes; it represents a clinical finding that should raise the level of suspicion that a given patient's melanoma may be related to an underlying genetic predisposition. Risk of a second primary melanoma following diagnosis of a first primary melanoma is approximately 5% and is greater for males and older patients.[57,58,59,60]

Personal history of nonmelanoma skin cancer

Having a personal history of BCC or SCC is also associated with an increase in risk of a subsequent melanoma.[61,62,63] Depending on the study, this risk ranges from a non-significant increase for melanoma with a previous SCC of 1.04 (95% confidence interval [CI], 0.13–8.18) to a highly significant risk of 7.94 (95% CI, 4.11–15.35).[64,65] It is likely that this relationship is due to shared risk factors (of which sun exposure is presumably one) rather than a specific genetic factor that increases risk for both. Pigmentary characteristics are critically important for the development of melanoma, and cutaneous phenotype (described above), in combination with excessive sun exposure, is associated with an increased risk of all three types of skin cancers.

Major Genes for Melanoma

CDKN2A/p16, CDKN2B/p15

The major familial gene associated with melanoma is CDKN2A/p16, cyclin-dependent kinase inhibitor 2A, which is located on chromosome 9p21. This gene has multiple names (MTS1, INK4, MLM) and is commonly called by the name of its protein, p16. It is an upstream regulator of the retinoblastoma gene pathway, acting through the cyclin D1/cyclin-dependent kinase 4 complex. This tumor suppressor gene has been intensively studied in multiple-case families and in population-based series of melanoma cases. CDKN2A controls the passage of cells through the cell cycle and provides a mechanism for holding damaged cells at the G1/S checkpoint, to permit repair of DNA damage prior to cellular replication. Loss of function of tumor suppressor genes—a good example of which is CDKN2A—is a critical step in carcinogenesis for many tumor systems.

CDKN2A encodes two proteins, p16INK4a and p14ARF, both inhibitors of cellular senescence. The protein produced when the alternate reading frame (ARF) for exon 1 is transcribed instead of the standard reading frame exerts its biological effects through the p53 pathway. It mediates cell cycle arrest at the G1 and G2/M checkpoints, complementing p16's block of G1/S progression—thereby facilitating cellular repair of DNA damage.

Mutations in CDKN2A probably account for 18% or less of familial melanomas.[66] Many mutations reported among families consist of founder mutations, which are unique to specific populations and the geographic areas from which they originate.[67,68,69,70,71,72]

Depending on the study design and target population, melanoma penetrance related to deleterious CDKN2A mutations differ widely. One study of 80 multiple-case families demonstrated that the penetrance varied by country, an observation that was attributed to major differences in sun exposure.[66] For example, in Australia, the penetrance was 30% by the age of 50 years and 91% by age 80 years; in the United States, the penetrance was 50% by age 50 years and 76% by age 80 years; in Europe, the penetrance was 13% by age 50 years and 58% by the age 80 years. Another study of individuals with melanoma identified in eight population-based cancer registries and one hospital-based sample obtained a self-reported family history and sequenced CDKN2A in all individuals. The penetrance was estimated as 14% by age 50 years and 28% by age 80 years.[60] The explanation for these differences lies in the method of identifying the individuals tested with penetrance estimates increasing with the number of affected family members. The method of family ascertainment in the latter study made it much less likely that "heavily loaded" melanoma families would be identified.

The CDKN2A homolog, CDKN2B, is located in close physical proximity to CDKN2A on 9p21 and likely serves to regulate tumor growth and mediate senescence.[73] Despite the physical proximity and structural similarity to CDKN2A, evaluation of multiple familial melanoma kindreds lacking CDKN2A mutations has failed to reveal germlineCDKN2B mutations.[74,75,76,77]

Melanoma and pancreatic cancer

A subset of CDKN2A mutation carrier families also displays an increased risk of pancreatic cancer.[78,79] The overall lifetime risk of pancreatic cancer in these families ranges from 11% to 17%.[80] The relative risk has been reported as high as 47.8.[81] Although at least 18 different mutations in p16 have been identified in such families, specific mutations appear to have a particularly elevated risk of pancreatic cancer.[82] Mutations affecting splice sites or Ankyrin repeats were found more commonly in families with both pancreatic cancer and melanoma than in those with melanoma alone. The p16 Leiden mutation is a 19-basepair deletion in CDKN2A exon 2 and is a founder mutation originating in the Netherlands. In one major Dutch study, 19 families with 86 members who had melanoma also had 19 members with pancreatic cancer in their families, a cumulative risk of 17% by age 75 years. In this study, the median age of pancreatic cancer onset was 58 years, similar to the median age at onset for sporadic pancreatic cancer.[83] However, other reports indicate that the average age at diagnosis is 5.8 years earlier for these mutation carriers than for those with sporadic pancreatic cancer.[84] Geographic variation may play a role in determining pancreatic risk in these mutation carrier families. In a multicontinent study of the features of germline CDKN2A mutations, Australian families carrying these mutations did not have an increased risk of pancreatic cancer.[85] It was also reported that similar CDKN2A mutations were involved in families with and without pancreatic cancer;[86] therefore, there must be additional factors involved in the development of melanoma and pancreatic cancer. Families with CDKN2A mutations do not appear to have a pattern of site-specific pancreatic cancer only; all of the families identified to date also have some evidence of increased melanoma incidence.[87] Conversely, melanoma-prone families that do not have a CDKN2A mutation have not been shown to have an increased risk of pancreatic cancer.[83]

Melanoma-astrocytoma syndrome

The Melanoma-Astrocytoma Syndrome is another phenotype caused by mutations in CDKN2A. The possible existence of this disorder was first described in 1993.[88] A study of 904 individuals with melanoma and their families found 15 families with 17 members who had both melanoma and multiple types of tumors of the nervous system.[89] Another study found a family with multiple melanoma and neural cell tumors that appeared to be caused by loss of p14ARF function or to disruption of expression of p16.[90]

CDK4 and CDK6

Cyclin-dependent kinases have important roles in progression of cells from G1 to S phase. CDK4 and CDK6 partner with the cyclin–D associated kinases to accelerate the function of the cell cycle. Phosphorylation of the retinoblastoma (Rb) protein in G1 by cyclin-dependent kinases releases transcription factors, inducing gene expression and metabolic changes that precede DNA replication, thus allowing the cell to progress through the cell cycle. These genes are of conceptual significance because they are in the same signaling pathway as CDKN2A.

Germline CDK4 mutations are very rare, being found in only a handful of familial melanoma kindreds.[91,92,93] All described families demonstrated a substitution of amino acid 24, suggesting this position as a mutation hotspot within the CDK4 gene. Mutation of CDK4 affects binding of p16 with its subsequent inhibition of CDK4 functionality. With constitutive activation of germline CDK4, CDK4 acts as a dominant oncogene.

Despite its functional similarity to CDK4, germline mutations in CDK6 have not been identified in any melanoma kindreds.[94]

Possible new susceptibility locus at 1p22

A new melanoma susceptibility locus has been identified through a linkage analysis of 49 Australian families containing at least 3 melanoma cases, in which CDKN2A and CDK4 mutations had been excluded.[1] However, the specific gene responsible for this statistical association has not yet been identified.

Additional evidence for 9p21 loci

When the first data linking CDKN2A mutations to melanoma risk became available, it was clear that these mutations did not account for all the melanoma tumors in which 9p21 loss of heterozygosity could be demonstrated. In fact, 51% of informative cases had deletions that did not involve somatic mutations in CDKN2A.[95] The specific genes involved have remained elusive but are still under intense investigation.

Minor genes (genetic modifiers) for melanoma

MC1R

The melanocortin 1 receptor (MC1R) gene, otherwise known as the alpha melanocyte-stimulating hormone receptor, is located on chromosome 8. Partial loss-of-function mutations are associated with fair skin, poor tanning, and increased skin cancer risk. Three common alleles (Arg151Cys, Arg 160 Trp and Asp294His) seem to have the greatest impact on melanoma risk.[96] Unfortunately, although variants in this gene are associated with increased risk for all three types of skin cancer, adding MC1R information to predictions based on age, sex, and cutaneous melanin density offers only a small improvement to risk prediction.[97]

Melanoma Risk Assessment

Patients with a personal history of melanoma or dysplastic nevi should be asked to provide information regarding a family history of melanoma and other cancers in order to detect the presence of familial melanoma. Age at diagnosis in family members and pathologic confirmation, if available, should also be sought. The presence of multiple primary melanomas in the same individual may also provide a clue to an underlying genetic susceptibility. Approximately 30% of affected individuals in hereditary melanoma kindreds have more than one primary melanoma, versus 4% of sporadic melanoma patients.[98] Family histories should be updated regularly; an annual review is often recommended.

For individuals without a personal history of melanoma, several models have been suggested for prediction of melanoma risk. Data from the Nurses' Health Study were used to create a model that included gender, age, family history of melanoma, number of severe sunburns, number of moles larger than 3 mm on the limbs, and hair color.[99] The concordance statistic for this model was 0.62 (95% CI, 0.58–0.65). Another measure of baseline melanoma risk was derived from a case-control study of individuals with and without melanoma in the Philadelphia and San Francisco areas.[100] This model focused on gender, history of blistering sunburn, color of the complexion, number and size of moles, presence of freckling, presence of solar damage to the skin, absence of a tan, age, and geographic area of the United States. Attributable risk with this model was 86% for men and 89% for women. This predictive tool, the Melanoma Risk Assessment Tool, is available online. However, this tool was developed using a cohort of primarily white individuals without a personal or family history of melanoma or non-melanoma skin cancer. It is designed for use by health professionals, and patients are encouraged to discuss results with their physicians. Additional external validation is appropriate before this tool can be adopted for widespread clinical use.

Genetic testing

Clinical testing is available to identify germline mutations in CDKN2A. Multiple centers in the United States and overseas offer sequence analysis of the entire coding region, and a number of centers perform deletion and duplication analysis. For information on genetic testing laboratories, see GeneTests: Laboratory Directory.

Expert opinion regarding testing for germline mutations of CDKN2A in familial melanoma follows two divergent schools of thought. Arguments for genetic testing include the value of identifying a cause of disease for the individual tested, the possibility of improved compliance with prevention protocols in individuals with an identified mutation, and the reassurance of a negative testing result in individuals in a mutation-carrying family. However, a negative test result in a family that does not have a known mutation is uninformative; the genetic cause of disease in these patients must still be identified. It should also be noted that members of CDKN2A mutation–carrying families who do not carry the mutation themselves remain at increased risk of melanoma. At this time, identification of a CDKN2A mutation does not affect the clinical management of the affected patient or family members. Close dermatologic follow-up of these people is indicated, regardless of genetic testing result, and pancreatic cancer screening has unclear utility, as discussed below.[101]

If genetic testing is undertaken in this population, experts suggest that it be performed after complete genetic counseling by a qualified genetics professional who is knowledgeable about the condition.

Interventions

High-risk population

Management of familial melanoma family members

High-risk individuals, including first-degree family members in melanoma-prone families should be educated about sun safety and warning signs of melanoma. Regular examination of the skin by a health care provider experienced in the evaluation of pigmented lesions is also recommended. One guideline suggests initiation of examination at age 10 years and conducting exams on a semi-annual basis until nevi are considered stable, followed by annual examinations.[102] These individuals should also be taught skin self-examination techniques, to be performed on a monthly basis. Observation of lesions may be aided by techniques such as full-body photography and dermoscopy.

Biopsies of skin lesions in the high-risk population should be performed using the same criteria as those used for lesions in the general population. Prophylactic removal of nevi without clinically worrisome characteristics is not recommended. The reasons for this are practical: many individuals in these families have a large number of nevi, and complete removal of them all is not feasible, particularly new atypical nevi continue to develop. In addition, individuals with increased susceptibility to melanoma may have cancer arise de novo, without a precursor lesion such as a nevus.[103]

At present, chemoprevention of melanoma in high-risk individuals remains an area of active investigation; however, no medications are recommended for melanoma risk reduction at this time.

Level of evidence: 5

Pancreatic cancer screening in CDKN2A mutation carriers

Screening for pancreatic cancer remains an area of investigation and controversy for carriers of CDKN2A mutations. At present, no effective means of pancreatic cancer screening is available for the general population; however, serum and radiographic screening measures are under study in high-risk populations. One proposed protocol [104] suggested starting pancreatic screening in high-risk families at age 50 years or 10 years before the youngest age at diagnosis of pancreatic cancer in the family, whichever came first. In this algorithm, asymptomatic patients would be screened annually with serum CA 19-9 and endoscopic ultrasound, whereas symptomatic patients or those with abnormal test results would undergo endoscopic retrograde cholangiopancreatography (ERCP) and/or spiral computed tomography (CT) scanning. A study evaluating use of endoscopic ultrasound and ERCP in high-risk families concluded that these procedures were cost-effective in this setting.[105]

The disadvantages of screening include the limitations of available noninvasive testing methods and the risks associated with invasive screening procedures. ERCP is the gold standard for identifying early cancers and precancerous lesions in the pancreas. However, serious complications such as bleeding, pancreatitis, and intestinal perforation can occur with this procedure. Implementation of pancreatic screening in the CDKN2A mutation carrier population is further complicated by the apparent lack of increased incidence of pancreatic cancer in many of these families.

Most experts suggest that pancreatic cancer screening should be considered for CDKN2A mutations carriers only if there is a family history of pancreatic cancer and, even then, only in the context of a clinical trial.

Level of evidence: 5

General population

Screening

Screening for melanoma is not recommended by the U.S. Preventive Services Task Force (USPSTF), although the American Cancer Society, the Skin Cancer Foundation, and the American Academy of Dermatology recommend monthly skin self-examination as well as regular examination by a physician for people older than 50 years or those with multiple melanomas or dysplastic nevus syndrome. USPSTF does not recommend screening because they judge that the evidence for efficacy is not strong. On the other hand, the groups who recommend screening base their support on the logic that screening will find melanomas early in their development and that those melanomas will not progress further. This position is supported by the unusually detailed prognostic information that can be obtained through histopathology examination of primary melanoma tumors, in which a variety of features (lack of invasion through the basement membrane, "thin" cancers (= 0.76 mm), absence of vertical growth phase disease, ulceration, and histologic regression) have been solidly linked to favorable prognosis.[106]

The question of whether the lesions found through screening are "programmed" to progress or whether they will grow very slowly and never progress to metastatic disease has not been answered.[107] One study showed that skin self-examination might prevent the formation of melanomas and that skin self-examination was associated with reduced 5-year mortality. The primary preventive effect could be biased by the fact that healthy individuals who participate in studies are somewhat more likely to participate in screening activities.[108] The 63% reduction in mortality observed in that study was not statistically significant. Therefore, until a randomized trial of screening and mortality is undertaken, the utility of general population screening remains uncertain.

Nonetheless, it is well documented that, when a patient is under the care of a dermatologist, his or her second melanoma is diagnosed at a thinner Breslow depth than the index melanoma.[109,110] As survival is inversely correlated with Breslow depth for melanoma, early diagnosis leads to better prognosis.

Level of evidence: 5

Primary prevention

Primary prevention for melanoma consists of avoiding intense intermittent exposure to UV radiation, both solar and nonsolar. It should be stressed that the dose-response levels for such exposure are not defined, but that large, sporadic doses of UV radiation on skin are those epidemiologically most associated with later development of melanoma. Sunburn is a marker of that exposure, so that the amount of time spent in the sun should be calculated to avoid sunburn if at all possible.[111]

Primary prevention should stress the need for caution in the sun and protection in the form of clothing, shade and sunscreens when long periods of time are spent outdoors or at times of day when sunburn is likely. High-risk patients should understand that the application of sunscreens should not be used to prolong the time they spend in the sun because UV radiation makes its way through the block over time.[112,113]

Level of evidence: 3aii

Treatment

As described in the PDQ summary on Melanoma Treatment therapeutic options range widely from local excision in early melanoma to chemotherapy, radiation, and aggressive management in metastatic melanoma. Our best defense against melanoma as a whole is to encourage sun-protective behaviors, regular skin examinations, and patient skin self-awareness in an effort to decrease high-risk behaviors and optimize early detection of potentially malignant lesions.

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