Squamous Cell Carcinoma
Risk Factors for Squamous Cell Carcinoma
Other radiation exposure
Other environmental factors
Characteristics of the skin
Personal history of nonmelanoma skin cancer
Family history of squamous cell carcinoma or associated premalignant lesions
Syndromes and Genes Associated with a Predisposition for Squamous Cell Carcinoma
Multiple self-healing squamous epitheliomata (Ferguson-Smith syndrome)
Other albinism syndromes
Dystrophic epidermolysis bullosa
Junctional epidermolysis bullosa
Dyskeratosis congenita (Zinsser-Cole-Engman syndrome)
Prevention and treatment of skin cancers
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, annual incidence estimates range from 1 million to 3.5 million cases in the United States.[1,2]
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 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 SCC.
Unlike basal cell carcinoma (BCC), SCC is associated with chronic exposure, rather than intermittent intense exposure to ultraviolet (UV) radiation. Occupational exposure is the characteristic pattern of sun exposure linked with SCC. 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. A Canadian case-control study did not find an association between cumulative lifetime sun exposure and SCC; however, sun exposure in the 10 years before diagnosis and occupational exposure were found to be risk factors.Other radiation exposure
In addition to environmental radiation, exposure to therapeutic radiation is another risk factor for SCC. Individuals with skin disorders treated with psoralen and ultraviolet-A radiation (PUVA) had a threefold to sixfold increase in SCC. This effect appears to be dose-dependent, as only 7% of individuals who underwent fewer than 200 treatments had SCC, compared with more than 50% of those who underwent more than 400 treatments. Therapeutic use of ultraviolet-B (UVB) radiation has also been shown to cause a mild increase in SCC (adjusted incidence rate ratio, 1.37). 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).
Investigation into the effect of ionizing radiation on SCC carcinogenesis has yielded conflicting results. One population-based case-control study found that patients who had undergone therapeutic radiation had an increased risk of SCC at the site of previous radiation (OR, 2.94) as compared with individuals who had not undergone radiation treatments. 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.[11-13] For those who 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.
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.[15-20]Other environmental factors
The influence of arsenic on the risk of nonmelanoma skin cancer is discussed in detail in the Other environmental factors section in the Basal Cell Carcinoma section of this summary. Like BCCs, SCCs appear to be associated with exposure to arsenic in drinking water and combustion products.[21,22] 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. For arsenic, the latency period can be lengthy; invasive SCC has been found to develop at an average of 20 years after exposure.
Current or previous cigarette smoking has been associated with a 1.5-fold to 2-fold increase in SCC risk,[25-27] although one large study showed no change in risk. 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.Characteristics of the skin
Like melanoma and BCC, SCC occurs more frequently in individuals with lighter skin than in those with darker skin.[3,30] However, SCC can also occur in individuals with darker skin. An Asian registry based in Singapore reported an increase in skin cancer in that geographic area, with an incidence rate of 8.9 per 100,000 person-years. Incidence of SCC, however, was shown to be on the decline. SCC is the most common form of skin cancer in black individuals in the United States and in certain parts of Africa; the mortality rate for this disease is relatively high in these populations.[31,32] Epidemiologic characteristics of, and prevention strategies for, SCC in those individuals 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. 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 threefold risk if freckling was present in childhood.[33,34] The degree of SCC risk corresponded to the amount of freckling. In this study, the inability of the skin to tan and its propensity to burn were also significantly associated with risk of SCC (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, although the process of carcinogenesis in this setting may take years or even decades. SCCs 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. One case report documents the occurrence of cancer in a wound that was incurred 59 years earlier.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, although the risks vary with transplant type.[37-40] Nonmelanoma skin cancers in high-risk patients (solid-organ transplant recipients and chronic lymphocytic leukemia patients) 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.[41,42] Additionally, there is a high risk of second SCCs.[43,44] In one study, over 65% of kidney transplant recipients developed subsequent SCCs after their first diagnosis. 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.[37,45,46] 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. This finding underlines the importance of rigorous sun avoidance, particularly among high-risk immunosuppressed individuals.
Certain immunosuppressive agents have been associated with increased risk of 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 kidney transplant patients on azathioprine and prednisolone alone. 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.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. 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 of a subsequent lesion within the first year after a skin cancer has been diagnosed. The mean age of occurrence for these nonmelanoma skin cancers is the middle of the sixth decade of life.[26,50-54]Family history of squamous cell carcinoma or associated premalignant lesions
Although the literature is scant on this subject, a family history of SCC may increase the risk of SCC in first-degree relatives (FDRs). Review of the Swedish Family Center Database showed that individuals with at least one sibling or parent affected with SCC, in situ SCC (Bowen disease), or actinic keratosis had a twofold to threefold increased risk of invasive and in situ SCC relative to the general population.[55,56] Increased number of tumors in parents was associated with increased risk to the offspring. Of note, diagnosis of the proband at an earlier age was not consistently associated with a trend of increased incidence of SCC in the FDR, as would be expected in most hereditary syndromes because of germline mutations. Further analysis of the Swedish population-based data estimates genetic risk effects of 8% and familial shared-environmental effects of 18%. Thus, shared environmental and behavioral factors likely account for some of the observed familial clustering of SCC.Syndromes and Genes 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 because of 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 UV exposure is well known, quantifying its attributable risk to cancer development has proven challenging. In addition, ascertainment of SCC of the skin cases is not always straightforward. Many registries and other epidemiologic studies do not fully assess the incidence of SCC of the skin 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.
Characteristics of the major hereditary syndromes associated with a predisposition to SCC are described in Table 3 below.Table 3. Hereditary Syndromes Associated with Squamous Cell Carcinoma of the Skin
|Condition||Gene(s)||Clinical Testing Availabilitya||Pathway|
|aFor more information on genetic testing laboratories, refer to the NIH Genetic Testing Registry.|
|Xeroderma pigmentosum (complementation group A [OMIM], group B [OMIM], group C [OMIM], group D [OMIM], group E [OMIM], group F [OMIM], and group G [OMIM])||XPA (OMIM), XPB/ERCC3 (OMIM), XPC (OMIM), XPD/ERCC2 (OMIM), XPE/DDB2 (OMIM), XPF/ERCC4 (OMIM), XPG/ERCC5 (OMIM)||XPA, XPC||Nucleotide excision repair|
|Xeroderma pigmentosum variant (OMIM)||POLH/XPV (OMIM)||No||Error-prone polymerase|
|Multiple self-healing squamous epithelioma (Ferguson-Smith syndrome) (OMIM)||TGFBR1 (OMIM)||No||Growth factor signaling|
|Oculocutaneous albinism (type IA [OMIM], type IB [OMIM],type II [OMIM], type III [OMIM], and type IV [OMIM])||TYR (OMIM), OCA2 (OMIM), MATP/OCA4 (OMIM), TYRP1 (OMIM)||TYR, OCA2, TYRP1||Melanin synthesis|
|Hermansky-Pudlak syndrome (OMIM)||HPS1 (OMIM), HPS3 (OMIM), HPS4 (OMIM), HPS5 (OMIM), HPS6 (OMIM), HPS7/DTNBP1 (OMIM), HPS8/BLOC1S3 (OMIM)||HPS1, HPS3, HPS4, HPS7||Melanosomal and lysosomal storage|
|Hermansky-Pudlak syndrome, Type 2 (OMIM)||AP3B1 (OMIM)||No||Melanosomal and lysosomal storage|
|Chediak-Higashi syndrome (OMIM)||LYST (OMIM)||LYST||Lysosomal transport regulation|
|Griscelli syndrome (type 1 [OMIM], type 2 [OMIM], and type 3 [OMIM])||MYO5A (OMIM), RAB27A (OMIM), MLPH (OMIM)||RAB27A||Pigment granule transport|
|Elejalde Disease (OMIM)||MYO5A (OMIM)||No||Pigment granule transport|
|Dystrophic epidermolysis bullosa (dominant [OMIM] and autosomal recessive [OMIM] subtypes)||COL7A1 (OMIM)||COL7A1||Collagen anchor of basement membrane to dermis|
|Junctional epidermolysis bullosa (OMIM)||LAMA3 (OMIM), LAMB3 (OMIM), LAMC2 (OMIM), COL17A1 (OMIM)||LAMA3, LAMB3, LAMC2, COL17A1||Connective tissue|
|Epidermodysplasia verruciformis (OMIM)||EVER1 (OMIM), EVER2 (OMIM)||No||Signal transduction in endoplasmic reticulum|
|Fanconi anemia (OMIM)||FANCA ( OMIM), FANCB (OMIM), FANCC (OMIM), FANCD1/BRCA2 (OMIM), FANCD2 (OMIM), FANCE (OMIM), FANCF (OMIM), FANCG/XRCC9 (OMIM), FANCI (OMIM), FANCJ/BRIP1 (OMIM), FANCL (OMIM), FANCM (OMIM), FANCN/PALB2 (OMIM)||Chromosomal breakage testing; BRIP1, FANCA, FANCC, FANCE, FANCF, FANCG, PALB2||DNA repair|
|Dyskeratosis congenita (OMIM)||DKC1 (OMIM), TERC (OMIM), TINF2 (OMIM), NHP2/NOLA2 (OMIM), NOP10/NOLA3 (OMIM), TERT (OMIM), WRAP53 (OMIM), C16orf57 (OMIM),||DKC1, TERC, TINF2, NHP2, NOP10, TERT||Telomere maintenance and trafficking|
|Rothmund-Thomson syndrome (OMIM)||RECQL4 (OMIM), C16orf57 (OMIM)||RECQL4||Chromosomal stability|
|Bloom syndrome (OMIM)||BLM/RECQL3 (OMIM)||Sister chromatid exchange, BLM||Chromosomal stability|
|Werner syndrome (OMIM)||WRN/RECQL2 (OMIM)||No||Chromosomal stability|
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.
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. About half of XP patients have a history of severe burning on minimal sun exposure. Other XP patients do not have this reaction but develop freckle-like pigmentation before age 2 years on sun-exposed sites. 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 these individuals will develop melanoma. In the absence of sun avoidance, the median age of diagnosis for any skin cancer is 8 to 9 years.[58-60] On average, nonmelanoma skin cancer occurs at a younger age than melanoma in the XP population.
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 radiation and include keratitis, corneal opacification, ectropion or entropion, hyperpigmentation of the eyelids, and loss of eyelashes. About 25% of the XP patients examined at the National Institutes of Health (NIH) between 1971 and 2009 had progressive neurological degeneration. Features included microcephaly, progressive sensorineural hearing loss, diminished deep tendon reflexes, seizures, and cognitive impairment. Neurological degeneration, which is most commonly observed in individuals with complementation groups XPA and XPC, was associated with a shorter lifespan (median age of death was 29 years in individuals with neurological degeneration and 37 years in individuals without neurological degeneration). De Sanctis-Cacchione syndrome is found in a subgroup of XP 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, central nervous system cancers, and lung cancer in smokers, have been reported in people who have XP.[58,61] The relative risk for these cancers is estimated to be about 50-fold higher than in the general population.
The inheritance for XP is autosomal recessive. Seven complementation groups have been associated with this disorder. About 40% of the XP cases seen at the NIH were XPC. ERCC2 (XPD) mutations were present in about 20%. Complementation group A, due to mutation in XPA, accounts for approximately 10% of cases. 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. Heterozygotes for mutations in XP genes are generally asymptomatic. Founder mutations in XPA (R228A) and XPC (V548A fs X572) have been identified in North African populations, and a founder mutation in XPC resulting in a splice alteration (IVS 12-1G>C) has been found in an East African (Mahori) population. It has been proposed that direct screening for these mutations would be appropriate in these populations.[64-67]
The function of the XP genes is to recognize and repair photoproducts from UV radiation. The main photoproducts are formed at adjacent pyrimidines and consist of cyclobutane dimers and pyrimidine-pyrimidone (6-4) photoproducts. 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 works 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 with resulting excision of about 28 to 30 nucleotides, including the photoproduct. DNA polymerases replace the lesion with the correct sequence, and a DNA ligase completes the repair.[68,69]
An XP variant that is associated with mutations in POLH (XPV) is responsible for approximately 10% of reported cases. This gene encodes for the error-prone bypass polymerase (polymerase eta) which, unlike other genes associated with XP, is not involved in nucleotide excision repair. People with polymerase eta mutations have the same cutaneous and ocular findings as other XP patients but do not have progressive neurologic degeneration.
Work on genotype-phenotype correlations among the XP complementation groups continues. The main distinguishing features appear to be the presence or absence of burning on minimal sun exposure, skin cancer, and progressive neurologic abnormalities. All complementation groups are characterized by the presence of cutaneous neoplasia. There is clinical variation within each complementation group. 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 have been identified as having xeroderma pigmentosum-Cockayne syndrome (XP-CS) 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. 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 connected with XP/TTD (XPD and XPB) and XP-CS (XPB, XPD, and XPG) are associated with defects in both transcription-coupled nucleotide excision repair and global genomic nucleotide excision repair. In contrast, XP complementation groups C and E have defects only in global genomic nucleotide excision repair. In addition, individuals in the XPA, 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) or CS mutations, does not appear to confer an increased risk of skin cancer.[74-77]
The diagnosis of XP is made on the basis of clinical findings and family history. Functional assays to assess DNA repair capabilities after exposure to radiation have been developed, but these tests are currently not clinically available in the United States. 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)
Multiple self-healing squamous epitheliomata (MSSE), or 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. Linkage analysis of affected families showed association with the long arm of chromosome 9, and haplotype analysis localized the gene to 9q22.3 between D9S197 and D9S1809. Transforming growth factor beta-receptor 1 (TGFBR1) was identified through next-generation sequencing as the gene responsible for MSSE. Loss-of-function mutations in TGFBR1 have been identified in 18 of 22 affected families. Gain-of-function mutations in TGFBR1 are associated with unrelated Marfan-like syndromes, such as Loeys-Dietz syndrome, which have no described increase in skin cancer risk.
Somatic loss of heterozygosity in Ferguson-Smith-related SCC has been demonstrated at this genomic location, suggesting that TGFBR1 can act as a tumor suppressor gene. 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.Oculocutaneous albinism
SCC occurring at extremely early ages is a hallmark of oculocutaneous albinism. Albinism is a major risk factor for skin cancer in individuals of African ancestry.[32,81] One report describing a cohort of 350 albinos in Tanzania found 104 cutaneous cancers; of these, 100 were SCCs, three were BCCs, and one was melanoma. The median age for this population was 10 years. Similar proportions of skin cancer diagnoses were observed in a Nigerian population, with 62% of dermatological malignancies diagnosed as SCC, 16% as malignant melanoma, and 8% as BCC.
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. Murine models with mutations in this gene had significantly decreased melanin production compared with normal controls.
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.Other albinism syndromes
A subgroup of albinism 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. 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), HPS8 (BLOC1S3), and HPS9 (PLDN).[86-93] Pigmentation characteristics can vary significantly in this disorder, particularly among those with HPS1 mutations, and patients report darkening of the skin and hair as they age. In a small cohort of individuals with HPS1 mutations, 3 out of 40 developed cutaneous SCCs, and an additional 3 had BCCs. Hermansky-Pudlak syndrome type 2, which includes increased susceptibility to infection resulting from congenital neutropenia, has been attributed to defects in AP3B1.
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.[96-98]
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. 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. 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.Dystrophic epidermolysis bullosa
Approximately 95% of individuals with the heritable disorder dystrophic epidermolysis bullosa (DEB) 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. The lack of type VII collagen results in generalized blistering, often starting from birth, and is associated with skin atrophy and scarring. A registry of DEB mutations, The International DEB Patient Registry, is accessible on the Internet.
There are two recessively inherited subtypes of DEB: severe-generalized (HDEB-sev gen; previously named Hallopeau-Siemens type) and generalized-other (HDEB-O; previously named non–Hallopeau-Siemens type); and a dominantly inherited form, dominant dystrophic epidermolysis bullosa (DDEB). The clinical manifestations demonstrate a continuum of severity that complicates definitive diagnosis, especially early in life. The severe generalized subtype, associated with formation of pseudosyndactyly (a mitten-like deformity secondary to fusion of interdigital webbing) in early childhood, carries a SCC risk of up to 85% by the age of 45 years.[104,105] These cancers arise in nonhealing wounds and usually metastasize to cause death within 5 years of the diagnosis of SCC. In one case series, SCC was the leading cause of death for the 15 patients with the severe generalized subtype. Early mortality also has been observed in this disorder, with a mortality rate of up to 40% by the age of 30 years. Extracutaneous manifestations of HDEB-severe generalized include short stature, anemia, strictures of the gastrointestinal and genitourinary tracts, and corneal scarring that may result in blindness.
Diagnosis of epidermolysis bullosa may be accomplished by immunofluorescence or electron microscopy. A list of recommended diagnostic antibodies and their suppliers is available at the Web site of the Dystrophic EB Research Association. Mutation testing is generally used for prenatal diagnosis rather than for the primary diagnosis of epidermolysis bullosa.[109,110]
The rate of de novo mutation for DDEB is approximately 30%; maternal germline mosaicism has also been reported.[111,112] 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 two 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. A founder mutation, c.6527insC (p.R525X), has been observed in 27 of 49 Spanish individuals with recessive DEB. 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 HDEB-severe generalized keratinocytes, retention of the amino-terminal NC1, the first noncollagenous fragment of type VII collagen, is tumorigenic in mice. This retained sequence may mediate tumor-stroma interactions that promote carcinogenesis.Junctional epidermolysis bullosa
Junctional epidermolysis bullosa (JEB) is an autosomal recessive type of epidermolysis bullosa. JEB results in considerable mortality with approximately 50% of cases dying within the first year of life. Mutations in any of the genes encoding the three basic subunits of laminin 332, previously known as laminin 5 (LAMA3, LAMB3, LAMC2), or mutations in COL17A1 can result in this syndrome.[116-118] Individuals with the Herlitz type (a severe clinical form) of JEB are at increased risk of SCC, with a cumulative risk of 18% by the age of 25 years. A mutational study of COL17A1 in individuals with a milder subtype of JEB, called JEB-other, identified mutations in 85 of 86 alleles from 43 individuals. Total loss of COL17A1 protein staining correlated with a more severe phenotype.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 develop into in situ and invasive SCCs in 30% to 60% of patients. 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, 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.
The genes associated with this disorder, EVER1 and EVER2, were identified in 2002. The inheritance pattern of these genes appears to be autosomal recessive; however, autosomal dominant inheritance has also been reported.[125-127] 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 form a complex with the zinc transporter 1 (ZnT-1), which is, in turn, blocked by certain HPV proteins.
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.
Some evidence suggests nonallelic heterogeneity in epidermodysplasia verruciformis. An individual born to consanguineous parents with epidermodysplasia verruciformis and additional bacterial and fungal infections was found to have homozygous R115X mutations in the MST1 gene. 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.Fanconi anemia
Fanconi anemia is a complex disorder that is characterized by increased incidence of hematologic and solid tumors, including SCC of the skin. Fanconi anemia is inherited as an autosomal recessive disease. It is a relatively rare syndrome with an estimated carrier frequency of one in 181 individuals in the United States (range: 1 in 156 to 1 in 209) and a carrier frequency of up to one in 100 individuals of Ashkenazi Jewish ancestry. 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. By age 40 years, individuals affected with Fanconi anemia have an 8% risk per year of developing a solid tumor; the median age of diagnosis for solid tumors is 26 years. Multiple cases of cancers of the brain, breast, lung, and kidney (Wilms tumor) have been reported in this population. 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.[134-138]
Individuals with this disease have increased susceptibility to DNA cross-linking agents (e.g., mitomycin-C or diepoxybutane) and ionizing and UV radiation. Cells from individuals with Fanconi anemia have shown decreased ability to excise pyrimidine dimers. 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 4 below.Table 4. Genes Associated with Fanconi Anemia (FA)
|Gene||Locus||Approximate Incidence Among FA Patients (%)||Pattern of Disease Transmission|
|AR = autosomal recessive; XLR = X-linked recessive.|
|FANCD1 (BRCA2) (OMIM)||13q12.3||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|
The proteins involved with DNA crosslink repairs have been termed the FANC pathway because of their involvement with Fanconi anemia. They interact with several other proteins associated with hereditary cancer risk, including those for Bloom syndrome and ataxia-telangiectasia. Further investigation has revealed that FANCD1 is the same gene as BRCA2, a gene that causes predisposition to breast and ovarian cancer. Other Fanconi anemia genes, FANCJ (BRIP1) and FANCN (PALB2), have also been identified as rare breast cancer susceptibility genes. (Refer to the PDQ summary on Genetics of Breast and Ovarian Cancer for more information about BRCA2, BRIP1, PALB2, and RAD51.) 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.Dyskeratosis congenita (Zinsser-Cole-Engman syndrome)
Dyskeratosis congenita, like Werner syndrome, results in premature aging and is considered a progeroid disease. The classic clinical triad for diagnosis includes dysplastic nails, reticular pigmentation of the chest and neck, and oral leukoplakia. In addition, individuals with this disorder are at markedly increased risk of myelodysplastic syndrome, acute leukemia, and bone marrow failure. Ocular, dental, neurologic, gastrointestinal, pulmonary, and skeletal abnormalities have also been described in conjunction with this disease, but clinical expressivity is variable. Developmental delay may also be present in variants of dyskeratosis congenita, such as Hoyeraal Hreidarsson syndrome and Revesz syndrome.
Approximately 10% of individuals with dyskeratosis congenita will develop nonhematologic tumors, often before the third decade of life.[146,147] Solid tumors may be the first manifestation of this disorder. Head and neck cancers were the most commonly reported, accounting for nearly half of the cancers observed. Cutaneous SCC occurred in about 1.5% of the subjects, and the median age at diagnosis was 21 years. These cancers are generally managed as any other SCC of the skin.
Several genes associated with telomere function (DKC1, TERC, TINF2, NHP2, NOP10, and TERT) have been implicated in dyskeratosis congenita; approximately half of the individuals with a clinical diagnosis of this disease have an identified mutation in one of these six genes.[148-154] TERC and TINF2 are inherited in an autosomal dominant manner, whereas NHP2 (NOLA2) and NOP10 (NOLA3) show autosomal recessive inheritance and TERT can be either autosomal dominant or autosomal recessive. DKC1 shows an X-linked recessive pattern. Alterations in these genes result in shortening of telomeres, which in turn leads to defects in proliferation and spontaneous chromosomal rearrangements. Levels of TERC, the RNA component of the telomerase complex, are reduced in all dyskeratosis congenita patients. Missense mutations in WRAP53, a gene with a protein product that facilitates trafficking of telomerase, have also been associated with an autosomal recessive form of dyskeratosis congenita. Mutations in C16orf57 were identified in 6 of 132 families who did not have a mutation detected in other known genes. C16orf57 mutations are also associated with poikiloderma with neutropenia. (Refer to the Rothmund-Thomson syndrome section of this summary for more information about poikiloderma congenitale.)
The recommended approach for diagnosis begins with a six-cell panel assay for leukocyte telomere length testing. If telomere length is in the lowest 1% for three or more cell types, molecular genetic testing is indicated. Testing of DKC1 may be performed first in male probands, as mutations in this gene account for up to 36% of those identified in dyskeratosis congenita to date. Mutations in TINF2 and TERT are responsible for 11% to 24% and 6% to 10% of cases, respectively.[145,152,153,161,162] Clinical testing is available for all six genes.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. Reports of multiple SCCs in situ have been reported in individuals as young as 16 years. 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. This prevalence is clearly greater than that found in individuals in the same age group in the general population. Although increased UV sensitivity has been described, SCCs are also found in areas of the skin that are not exposed to the sun.
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. Mutations in similar DNA helicases lead to the inherited disorders of Bloom syndrome and Werner syndrome.
At least 19 different truncating mutations in this gene have been identified as deleterious. These mutations cause severe down-regulation of RECQL4 transcripts in this subset of individuals with Rothmund-Thomson syndrome. Cells deficient in RECQL4 have been found to be hypersensitive to oxidative stress, resulting in decreased DNA synthesis. Deficiencies in the RecQ helicases permit hyper-recombination, 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.
Three of six families with Rothmund-Thomson syndrome were found to have homozygous mutations in the C16orf57 gene. Mutations in this gene have also been identified in individuals with dyskeratosis congenita and poikiloderma with neutropenia, suggesting that these syndromes are related;[158,159] however, skin cancer risk in these conditions is not well characterized. (Refer to the Dyskeratosis congenita (Zinsser-Cole-Engman syndrome) section of this summary for more information.)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. 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.[174,175]
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%).[176,177] A specific mutation identified in the Ashkenazi Jewish population is a 6-bp deletion/7-bp insertion at nucleotide 2,281, designated as BLMASH. 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. 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.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 average life expectancy of fewer than 50 years. Cancers have an early onset and occur in up to 43% of these patients. The spectrum of tumors associated with this disorder has primarily been described in the Japanese population and includes an increased incidence of sarcoma, thyroid cancers, and skin cancers. Approximately 20% of the cancers reported in this syndrome are cutaneous, with melanoma and SCC of the skin accounting for 14% and 5%, respectively. A study of 189 individuals with Werner syndrome estimated melanoma risk to be elevated 53-fold in these individuals. SCC was less frequently diagnosed. Acral lentiginous melanomas are overrepresented, and SCCs may exhibit more aggressive behavior, with metastasis to lymph nodes and internal organs.[183,186]
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.[182,187-190] 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.[191-199] Telomere dysfunction has been associated with premature aging and cancer susceptibility. 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 all types of mutations; however, the 1136C→T mutation is the most common and is found in 20% to 25% of the Japanese and white populations.[201,202] In the Japanese population, a founder mutation (IVS 25-1G→C) is present in 60% of affected individuals.
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.[202,204]Interventions
Prevention and treatment of skin cancers
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.
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.[206,207] 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.
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. 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. To date, this agent has not been approved for use by the U.S. Food and Drug Administration.
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. A dose reduction of 30% to 50% has been recommended for systemic chemotherapeutic agents in this population because of the increased sensitivity of XP cells.
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. Avoidance of x-ray therapy has also been advocated for some groups with hereditary skin cancer syndromes, such as those with epidermodysplasia verruciformis. However, XP patients with nonresectable skin cancers or internal cancers, such as spinal cord astrocytoma or glioblastomas of the brain, have been treated successfully with standard therapeutic doses of x-ray radiation. Some experts recommend dermatologic evaluation every 6 months and ophthalmologic evaluation at least annually in these high-risk populations.
For individuals with dystrophic epidermolysis bullosa, wound care is paramount. Use of silver sulfadiazine cream, medical grade honey, and soft silicone dressings can be helpful in these settings. Attention to nutritional status, which may be compromised because of esophageal strictures, iron-deficiency anemia, infection, and inflammation, is another critical consideration for wound healing for these patients. Multivitamin supplementation, often at higher doses than those routinely recommended for the general population, may be warranted. Bone marrow transplantation has been explored in patients with dystrophic epidermolysis bullosa, but there is no evidence for a reduction of skin cancer with this intervention.References
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