sábado, 26 de octubre de 2019

Genetics of Skin Cancer (PDQ®) 1/3 –Health Professional Version - National Cancer Institute

Genetics of Skin Cancer (PDQ®)–Health Professional Version - National Cancer Institute

National Cancer Institute

Genetics of Skin Cancer (PDQ®)–Health Professional Version




Executive Summary

This executive summary reviews the topics covered in this PDQ summary on the genetics of skin cancer, with hyperlinks to detailed sections below that describe the evidence on each topic.
  • Inheritance and Risk
    More than 100 types of tumors are clinically apparent on the skin; many are known to have familial and/or inherited components, either in isolation or as part of a syndrome with other features. Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), which are known collectively as nonmelanoma skin cancer, are two of the most common malignancies in the United States and are often caused by sun exposure, although several hereditary syndromes and genes are also associated with an increased risk of developing these cancers. Melanoma is less common than nonmelanoma skin cancer, but 5% to 10% of all melanomas arise in multiple-case families and may be inherited in an autosomal dominant fashion.
  • Associated Genes and Syndromes
    Several genes and hereditary syndromes are associated with the development of skin cancer. Basal cell nevus syndrome (BCNS, caused by pathogenic variants in PTCH1 and PTCH2) is associated with an increased risk of BCC, while syndromes such as xeroderma pigmentosum (XP), oculocutaneous albinism, epidermolysis bullosa, and Fanconi anemia are associated with an increased risk of SCC. The major tumor suppressor gene associated with melanoma is CDKN2A; pathogenic variants in CDKN2A have been estimated to account for 35% to 40% of all familial melanomas. Pathogenic variants in many other genes, including CDK4, CDK6, BAP1, and BRCA2, have also been found to be associated with melanoma.
    Genome-wide searches are showing promise in identifying common, low-penetrance susceptibility alleles for many complex diseases, including melanoma, but the clinical utility of these findings remains uncertain.
  • Clinical Management
    Risk-reducing strategies for individuals with an increased hereditary predisposition to skin cancer are similar to recommendations for the general population, and include sun avoidance, use of sunscreen, use of sun-protective clothing, and avoidance of tanning beds. Chemopreventive agents such as isotretinoin and acitretin have been studied for the treatment of BCCs in patients with BCNS and XP and are associated with a significant decrease in the number of tumors per year. Vismodegib has also shown promise in reducing the per-patient annual rate of new BCCs requiring surgery among patients with BCNS. Isotretinoin has also been shown to reduce SCC incidence among patients with XP.
    Treatment of hereditary skin cancers is similar to the treatment of sporadic skin cancers. One study in an XP population found therapeutic use of 5-fluorouracil to be efficacious, particularly in the treatment of extensive lesions. In addition to its role as a therapeutic and potential chemopreventive agent, vismodegib is also being studied for potential palliative effects for keratocystic odontogenic tumors in patients with BCNS.
  • Psychosocial and Behavioral Issues
    Most of the psychosocial literature about hereditary skin cancers has focused on patients with familial melanoma. In individuals at risk of familial melanoma, psychosocial factors influence decisions about genetic testing for inherited cancer risk and risk-management strategies. Interest in genetic testing for pathogenic variants in CDKN2A is generally high. Perceived benefits among individuals with a strong family history of melanoma include information about the risk of melanoma for themselves and their children and increased motivation for sun-protective behavior. A number of studies have examined risk-reducing and early-detection behaviors in individuals with a family history of melanoma. Overall, these studies indicate inconsistent adoption and maintenance of these behaviors. Intervention studies have targeted knowledge about melanoma, sun protection, and screening behaviors in family members of melanoma patients, with mixed results. Research is ongoing to better understand and address psychosocial and behavioral issues in high-risk families.

Introduction



[Note: 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.]
[Note: A concerted effort is being made within the genetics community to shift terminology used to describe genetic variation. The shift is to use the term “variant” rather than the term “mutation” to describe a difference that exists between the person or group being studied and the reference sequence, particularly for differences that exist in the germline. Variants can then be further classified as benign (harmless), likely benign, of uncertain significance, likely pathogenic, or pathogenic (disease causing). Throughout this summary, we will use the term pathogenic variant to describe a disease-causing mutation. Refer to the Cancer Genetics Overview summary for more information about variant classification.]
[Note: Many of the genes and conditions described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) catalog. Refer to OMIMExit Disclaimer for 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 carcinoma (SCC) and basal cell cancer (BCC). These have been called nonmelanoma skin cancers or keratinocyte cancers.
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 epidermis and the vascular dermis—with many cell types distributed in a connective tissue matrix, largely created by fibroblasts.[1]
ENLARGESchematic 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.
Figure 1. Schematic representation of normal skin. The relatively avascular epidermis houses 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. 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. Basal keratinocytes lose contact with the basement membrane as they divide. As basal keratinocytes migrate toward the skin surface, they progressively differentiate to form the spinous cell layer; the granular cell layer; and the keratinized outer layer, or stratum corneum.
The true cytologic origin of BCC remains in question. BCC and basal cell keratinocytes share many histologic similarities, as is reflected in the name. Alternatively, the outer root sheath cells of the hair follicle have also been proposed as the cell of origin for BCC.[2] This is suggested by the fact that BCCs occur predominantly on hair-bearing skin. BCCs rarely metastasize but can invade tissue locally or regionally, sometimes following along nerves. A tendency for superficial necrosis has resulted in the name rodent ulcer.[3]
Some debate remains about the origin of SCC; however, these cancers are likely derived from epidermal stem cells associated with the hair follicle.[4] 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 (smooth, hairless) skin has a lower metastatic rate than SCC arising from the vermillion border of the lip or from scars.[3]
Additionally, in the epidermal compartment, melanocytes distribute singly along the basement membrane and can undergo malignant transformation into melanoma. Melanocytes are derived from neural crest cells and migrate to the epidermal compartment near the eighth week of gestational age. Langerhans cells, or dendritic cells, are another 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 radiation or topical steroids, which cause them to migrate out of the skin.[5]
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.[6]
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. Several 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.[7]
Finally, the subcutis is a layer that extends below the dermis with varying depth, depending on the 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.[8]
These compartments give rise to their own malignancies but are also the region of immediate adjacent spread of localized skin cancers from other compartments. The boundaries of each skin compartment are used to define the staging of skin cancers. For example, an in situ melanoma is confined to the epidermis. Once the cancer crosses the basement membrane into the dermis, it is invasive. Internal 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. 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 (reddening of the skin) 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 T-cell responses consisting of increased levels of TH1, TH2, or TH17 cells.[9] 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 significant for communication 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 and have significant cosmetic and social ramifications.[1]

Clinical Presentation of Skin Cancers

While the appearance of any one skin cancer can vary, there are general physical presentations that can be used in screening. BCCs most commonly have a pearly rim or can appear somewhat eczematous (refer to Figure 2 and Figure 3). They often ulcerate (refer to Figure 2). SCCs frequently have a thick keratin top layer (refer to Figure 4). Both BCCs and SCCs are associated with a history of sun-damaged skin. Melanomas are characterized by asymmetry, border irregularity, color variation, a diameter of more than 6 mm, and evolution (ABCDE criteria). (Refer to What Does Melanoma Look Like? on NCI's website for more information about the ABCDE criteria.) Photographs representing typical clinical presentations of these cancers are shown below.

Basal cell carcinomas

ENLARGEPhotographs showing a red, ulcerated lesion on the skin of the face (left panel) and a red, ulcerated lesion surrounded by a white border on the skin of the back of the right ear (right panel).
Figure 2. Ulcerated basal cell carcinoma (left panel) and ulcerated basal cell carcinoma with characteristic pearly rim (right panel).
ENLARGEPhotographs showing a pink, scaly lesion on the skin (left panel) and flesh-colored nodules on the skin (right panel).
Figure 3. Superficial basal cell carcinoma (left panel) and nodular basal cell carcinoma (right panel).

Squamous cell carcinomas

ENLARGEPhotographs showing a pink, raised lesion on the skin of the face (left panel) and on the skin of the leg (right panel).
Figure 4. Squamous cell carcinoma on the face with thick keratin top layer (left panel) and squamous cell carcinoma on the leg (right panel).

Melanomas

ENLARGEPhotographs showing a brown lesion with a large and irregular border on the skin (panel 1); large, asymmetrical, red and brown lesions on the skin (panels 2 and 3); and an asymmetrical, brown lesion on the skin on the bottom of the foot (panel 4).
Figure 5. Melanomas with characteristic asymmetry, border irregularity, color variation, and large diameter.

References
  1. Vandergriff TW, Bergstresser PR: Anatomy and physiology. In: Bolognia JL, Jorizzo JL, Schaffer JV: Dermatology. 3rd ed. [Philadelphia, Pa]: Elsevier Saunders, 2012, pp 43-54.
  2. 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. [PUBMED Abstract]
  3. Soyer HP, Rigel DS, Wurm EM: Actinic keratosis, basal cell carcinoma and squamous cell carcinoma. In: Bolognia JL, Jorizzo JL, Schaffer JV: Dermatology. 3rd ed. [Philadelphia, Pa]: Elsevier Saunders, 2012, pp 1773-93.
  4. Lapouge G, Youssef KK, Vokaer B, et al.: Identifying the cellular origin of squamous skin tumors. Proc Natl Acad Sci U S A 108 (18): 7431-6, 2011. [PUBMED Abstract]
  5. Koster MI, Loomis CA, Koss TK, et al.: Skin development and maintenance. In: Bolognia JL, Jorizzo JL, Schaffer JV: Dermatology. 3rd ed. [Philadelphia, Pa]: Elsevier Saunders, 2012, pp 55-64.
  6. Kamino H, Reddy VB, Pui J: Fibrous and fibrohistiocytic proliferations of the skin and tendons. In: Bolognia JL, Jorizzo JL, Schaffer JV: Dermatology. 3rd ed. [Philadelphia, Pa]: Elsevier Saunders, 2012, pp 1961-77.
  7. McCalmont TH: Adnexal neoplasms. In: Bolognia JL, Jorizzo JL, Schaffer JV: Dermatology. 3rd ed. [Philadelphia, Pa]: Elsevier Saunders, 2012, pp 1829-50.
  8. Kaddu S, Kohler S: Muscle, adipose and cartilage neoplasms. In: Bolognia JL, Jorizzo JL, Schaffer JV: Dermatology. 3rd ed. [Philadelphia, Pa]: Elsevier Saunders, 2012, pp 1979-92.
  9. Harrington LE, Mangan PR, Weaver CT: Expanding the effector CD4 T-cell repertoire: the Th17 lineage. Curr Opin Immunol 18 (3): 349-56, 2006. [PUBMED Abstract]

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

Risk Factors for Basal Cell Carcinoma

This section focuses on risk factors in individuals at increased hereditary risk of developing BCC. (Refer to the PDQ summary on Skin Cancer Prevention for information about risk factors for BCC in the general population.)

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). (Refer to the PDQ summary on Skin Cancer Prevention for more information about sun exposure as a risk factor for skin cancer in the general population.)

Pigmentary characteristics

The high-risk phenotype consists of individuals with the following physical characteristics:
  • Fair skin that sunburns easily.
  • Lightly pigmented irides (blue and green eye color).
  • Presence of freckles in sun-exposed skin.
  • Poor ability to tan.
  • Blond or red hair color.
Specifically, people with more highly pigmented skin demonstrate lower incidence of BCC than do people with lighter pigmented skin. Individuals with Fitzpatrick type I or II skin were shown to have a twofold increased risk of BCC in a small case-control study.[2] (Refer to the Pigmentary characteristics section in the Melanoma section of this summary for a more detailed discussion of skin phenotypes based upon pigmentation.) Blond or red hair color was associated with increased risk of BCC in two large cohorts: the Nurses’ Health Study and the Health Professionals’ Follow-Up Study.[3] In women from the Nurses’ Health Study, there was an increased risk of BCC in women with red hair relative to those with light brown hair (adjusted relative risk [RR], 1.30; 95% confidence interval [CI], 1.20–1.40). In men from the Health Professionals Follow-Up Study, the risk of BCC associated with red hair was lower (RR, 1.17; 95% CI, 1.02–1.34) and was not significant after adjustment for melanoma family history and sunburn history.[3] Risk associated with blond hair was also increased for both men and women (RR, pooled analysis, 1.09; 95% CI, 1.02–1.18), and dark brown hair was protective against BCC (RR, pooled analysis, 0.89; 95% CI, 0.87–0.92).

Family history

Individuals with BCCs and/or SCCs report a higher frequency of these cancers in their family members than do controls. The importance of this finding is unclear. Apart from defined genetic disorders with an increased risk of BCC, a positive family history of any skin cancer is a strong predictor of the development of BCC. Data from the Nurses’ Health Study and the Health Professionals Follow-Up Study indicate that the family history of melanoma in a first-degree relative (FDR) is associated with an increased risk of BCC in both men and women (RR, 1.31; 95% CI, 1.25–1.37; P < .0001).[3] A study of 376 early-onset BCC cases and 383 controls found that a family history of any type of skin cancer increased the risk of early-onset BCC (odds ratio [OR], 2.49; 95% CI, 1.80–3.45). This risk increased when an FDR was diagnosed with skin cancer before age 50 years (OR, 4.79; 95% CI, 2.90–7.90). Individuals who had a family history of both melanoma and nonmelanoma skin cancer (NMSC) had the highest risk (OR, 3.65; 95% CI, 1.79–7.47).[4]
A study on the heritability of cancer among 80,309 monozygotic and 123,382 dizygotic twins showed that NMSCs have a heritability of 43% (95% CI, 26%–59%), suggesting that almost half of the risk of NMSC is caused by inherited factors.[5] Additionally, the cumulative risk of NMSC was 1.9-fold higher for monozygotic than for dizygotic twins (95% CI, 1.8–2.0).[5]

Previous personal history of nonmelanoma skin cancer

A personal history of BCC or SCC is strongly associated with subsequent BCC or SCC. There is an approximate 20% increased risk of a subsequent lesion within the first year after a skin cancer has been diagnosed. The mean age of occurrence for these NMSCs is the mid-60s.[6-11] In addition, several studies have found that individuals with a history of skin cancer have an increased risk of a subsequent diagnosis of a noncutaneous cancer;[12-15] however, other studies have contradicted this finding.[16-19] In the absence of other risk factors or evidence of a defined cancer susceptibility syndrome, as discussed below, skin cancer patients are encouraged to follow screening recommendations for the general population for sites other than the skin.

Major Genes for Basal Cell Carcinoma

PTCH1

Pathogenic variants in the gene coding for the transmembrane receptor protein PTCH1, or PTCH, are associated with basal cell nevus syndrome (BCNS) and sporadic cutaneous BCCs. (Refer to the BCNS section of this summary for more information.) PTCH1, the human homolog of the Drosophila segment polarity gene patched (ptc), is an integral component of the hedgehog signaling pathway, which serves many developmental (appendage development, embryonic segmentation, neural tube differentiation) and regulatory (maintenance of stem cells) roles.
In the resting state, the transmembrane receptor protein PTCH1 acts catalytically to suppress the seven-transmembrane protein Smoothened (Smo), preventing further downstream signal transduction.[20] Binding of the hedgehog ligand to PTCH1 releases inhibition of Smo, with resultant activation of transcription factors (GLI1, GLI2), cell proliferation genes (cyclin D, cyclin E, myc), and regulators of angiogenesis.[21,22] Thus, the balance of PTCH1 (inhibition) and Smo (activation) manages the essential regulatory downstream hedgehog signal transduction pathway. Loss-of-function pathogenic variants of PTCH1 or gain-of-function variants of Smo tip this balance toward activation, a key event in potential neoplastic transformation.
Demonstration of allelic loss on chromosome 9q22 in both sporadic and familial BCCs suggested the potential presence of an associated tumor suppressor gene.[23,24] Further investigation identified a pathogenic variant in PTCH1 that localized to the area of allelic loss.[25] Up to 30% of sporadic BCCs demonstrate PTCH1 pathogenic variants.[26] In addition to BCC, medulloblastoma and rhabdomyosarcoma, along with other tumors, have been associated with PTCH1 pathogenic variants. All three malignancies are associated with BCNS, and most people with clinical features of BCNS demonstrate PTCH1 pathogenic variants, predominantly truncation in type.[27]

PTCH2

Truncating pathogenic variants in PTCH2, a homolog of PTCH1 mapping to chromosome 1p32.1-32.3, have been demonstrated in both BCC and medulloblastoma.[28,29] PTCH2 displays 57% homology to PTCH1.[30] While the exact role of PTCH2 remains unclear, there is evidence to support its involvement in the hedgehog signaling pathway.[28,31]

Putative Genes for Basal Cell Carcinoma

BRCA1-associated protein 1 (BAP1)

Pathogenic variants in the BAP1 gene are associated with an increased risk of a variety of cancers, including cutaneous melanoma and uveal melanoma. (Refer to the BAP1 section in the Melanoma section of this summary for more information.) Although the BCC penetrance in individuals with pathogenic variants in BAP1 is yet undescribed, there are several BAP1 families that report diagnoses of BCC.[32,33] In one study, pathogenic variant carriers from four families reported diagnoses of BCC. Tumor evaluation of BAP1 showed loss of BAP1 protein expression by immunohistochemistry in BCCs of two germline BAP1 pathogenic variant carriers but not in 53 sporadic BCCs.[32] A second report noted that four individuals from BAP1 families were diagnosed with a total of 19 BCCs. Complete loss of BAP1 nuclear expression was observed in 17 of 19 BCCs from these individuals but none of 22 control BCC specimens.[34] Loss of BAP1 nuclear expression was also reported in a series of 7 BCCs from individuals with loss of function BAP1 variants, but only in 1 of 31 sporadic BCCs.[35]

Syndromes Associated With a Predisposition to Basal Cell Carcinoma

Basal cell nevus syndrome

BCNS, also known as Gorlin Syndrome, Gorlin-Goltz syndrome, and nevoid BCC syndrome, is an autosomal dominant disorder with an estimated prevalence of 1 in 57,000 individuals.[36] The syndrome is notable for complete penetrance and high levels of variable expressivity, as evidenced by evaluation of individuals with identical genotypes but widely varying phenotypes.[27,37] The clinical features of BCNS differ more among families than within families.[38] BCNS is primarily associated with germline pathogenic variants in PTCH1, but families with this phenotype have also been associated with alterations in PTCH2 and SUFU.[39-41]
As detailed above, PTCH1 provides both developmental and regulatory guidance; spontaneous or inherited germline pathogenic variants of PTCH1 in BCNS may result in a wide spectrum of potentially diagnostic physical findings. The BCNS pathogenic variant 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.[36] The resulting haploinsufficiency of PTCH1 in BCNS has been associated with structural anomalies such as odontogenic keratocysts, with evaluation of the cyst lining revealing heterozygosity for PTCH1.[42] The development of BCC and other BCNS-associated malignancies is thought to arise from the classic two-hit suppressor gene model: baseline heterozygosity secondary to germline PTCH1 pathogenic variant as the first hit, with the second hit due to mutagen exposure such as UV or ionizing radiation.[43-47] However, haploinsufficiency or dominant negative isoforms have also been implicated for the inactivation of PTCH1.[48]
The diagnosis of BCNS is typically based upon characteristic clinical and radiologic examination findings. Several sets of clinical diagnostic criteria for BCNS are in use (refer to Table 1 for a comparison of these criteria).[49-52] Although each set of criteria has advantages and disadvantages, none of the sets have a clearly superior balance of sensitivity and specificity for identifying carriers of pathogenic variants. The BCNS Colloquium Group proposed criteria in 2011 that required 1 major criterion with molecular diagnosis, two major criteria without molecular diagnosis, or one major and two minor criteria without molecular diagnosis.[52] PTCH1 pathogenic variants are found in 60% to 85% of patients who meet clinical criteria.[53,54] 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.[46,50,55] BCNS-associated ovarian fibromas are more likely to be bilateral and calcified than sporadic ovarian fibromas.[56] Ameloblastomas, aggressive tumors of the odontogenic epithelium, have also been proposed as a diagnostic criterion for BCNS, but most groups do not include it at this time.[57]
Other associated benign neoplasms include gastric hamartomatous polyps,[58] congenital pulmonary cysts,[59] cardiac fibromas,[60] meningiomas,[61-63] craniopharyngiomas,[64] fetal rhabdomyomas,[65] leiomyomas,[66] mesenchymomas,[67] basaloid follicular hamartomas,[68] and nasal dermoid tumors. Development of meningiomas and ependymomas occurring postradiation therapy has been documented in the general pediatric population; radiation therapy for syndrome-associated intracranial processes may be partially responsible for a subset of these benign tumors in individuals with BCNS.[69-71] In addition, radiation therapy of malignant medulloblastomas in the BCNS population may result in many cutaneous BCCs in the radiation ports. Similarly, treatment of BCC of the skin with radiation therapy may result in induction of large numbers of additional BCCs.[45,46,66]
The diagnostic criteria for BCNS are described in Table 1 below.
Table 1. Comparison of Diagnostic Criteria for Basal Cell Nevus Syndrome (BCNS)
Evans et al. 1993 [49]Kimonis et al. 1997 [50]Veenstra-Knol et al. 2005 [51]BCNS Colloquium Group 2011b [52]
BCC = basal cell carcinoma.
aTwo major criteria or one major and two minor criteria needed to meet the requirements for a BCNS diagnosis.[49-51]
bDiagnosis is based on one major criterion with molecular diagnosis, two major criteria without molecular diagnosis, or one major and two minor criteria without molecular diagnosis.[52]
Major Criteriaa
>2 BCCs or 1 BCC diagnosed before age 30 y or >10 basal cell nevi>2 BCCs or 1 BCC diagnosed before age 20 y>2 BCCs or 1 BCC diagnosed before age 20 yBCC before age 20 y or excessive number of BCCs out of proportion with previous skin exposure and skin type
Histologically proven odontogenic keratocyst or polyostotic bone cystHistologically proven odontogenic keratocystHistologically proven odontogenic keratocystOdontogenic keratocyst of jaw before age 20 y
≥3 palmar or plantar pits≥3 palmar or plantar pits≥3 palmar or plantar pitsPalmar or plantar pitting
Ectopic calcifications, lamellar or early (diagnosed before age 20 y) faux calcificationsBilamellar calcification of faux cerebriEctopic calcification (lamellar or early faux cerebri)Lamellar calcification of falx cerebri
Family history of BCNSFirst-degree relative with BCNSFamily history of BCNSFirst-degree relative with BCNS
(Rib abnormalities listed as minor criterion; see below.)Bifid, fused, or splayed ribsBifid, fused, or splayed ribs(Rib abnormalities listed as minor criterion; see below.)
(Medulloblastoma listed as minor criterion; see below.)(Medulloblastoma listed as minor criterion; see below.)(Medulloblastoma listed as minor criterion; see below.)Medulloblastoma (usually desmoplastic)
Minor Criteria
Occipital-frontal circumference >97th percentile and frontal bossingMacrocephaly (adjusted for height)Macrocephaly (>97th percentile)Macrocephaly
Congenital skeletal abnormalities: bifid, fused, splayed, or missing rib or bifid, wedged, or fused vertebraeBridging of sella turcica, vertebral abnormalities (hemivertebrae, fusion or elongation of vertebral bodies), modeling defects of the hands and feet, or flame-shaped lucencies of hands and feetBridging of sella turcica, vertebral abnormalities (hemivertebrae, fusion or elongation of vertebral bodies), modeling defects of the hands and feetSkeletal malformations (vertebral, short 4th metacarpals, postaxial polydactyly)
(Rib abnormalities listed as major criterion; see above.)(Rib abnormalities listed as major criterion; see above.)Rib abnormalities
Cardiac or ovarian fibromaOvarian fibromaCardiac or ovarian fibromaCardiac or ovarian fibroma
MedulloblastomaMedulloblastomaMedulloblastoma(Medulloblastoma listed as major criterion; see above.)
Congenital malformation: cleft lip and/or palate, polydactyly, cataract, coloboma, microphthalmiaCleft lip or palate, frontal bossing, moderate or severe hypotelorismCleft lip and/or palate, polydactylyCleft lip or palate
Sprengel deformity, marked pectus deformity, marked syndactylySprengel deformity, marked pectus deformity, marked syndactyly
Lymphomesenteric cystsLymphomesenteric cysts
Eye anomaly: cataract, coloboma, microphthalmiaOcular abnormalities (strabismus, hypertelorism, Congenital cataracts, coloboma)
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.[72] Nonpigmented BCCs are more common than pigmented lesions.[73] The age at first BCC diagnosis associated with BCNS ranges from 3 to 53 years, with a mean age of 21.4 years; the vast majority of individuals are diagnosed with their first BCC before age 20 years.[50,55] Most BCCs are located on sun-exposed sites, but individuals with greater than 100 BCCs have a more uniform distribution of BCCs over the body.[73] Case series have suggested that up to 1 in 200 individuals with BCC demonstrate findings supportive of a diagnosis of BCNS.[36] BCNS has rarely been reported in individuals with darker skin pigmentation; however, significantly fewer BCCs are found in individuals of African or Mediterranean ancestry.[50,74,75] Despite the rarity of BCC in this population, reported cases document full expression of the noncutaneous manifestations of BCNS.[75] However, in individuals of African ancestry who have received radiation therapy, significant basal cell tumor burden has been reported within the radiation port distribution.[50,66] Thus, cutaneous pigmentation may protect against the mutagenic effects of UV but not against ionizing radiation.
Variants associated with an increased risk of BCC in the general population appear to modify the age of BCC onset in individuals with BCNS. A study of 125 individuals with BCNS found that a variant in MC1R (Arg151Cys) was associated with an early median age of onset of 27 years (95% CI, 20–34), compared with individuals who did not carry the risk allele and had a median age of BCC of 34 years (95% CI, 30–40) (hazard ratio [HR], 1.64; 95% CI, 1.04–2.58, P = .034). A variant in the TERT-CLPTM1L gene showed a similar effect, with individuals with the risk allele having a median age of BCC of 31 years (95% CI, 28–37) relative to a median onset of 41 years (95% CI, 32–48) in individuals who did not carry a risk allele (HR, 1.44; 95% CI, 1.08–1.93, P = .014).[76]
Many other malignancies have been associated with BCNS. Medulloblastoma carries the strongest association with BCNS and is diagnosed in 1% to 5% of BCNS cases. While BCNS-associated medulloblastoma is typically diagnosed between ages 2 and 3 years, sporadic medulloblastoma is usually diagnosed later in childhood, between the ages of 6 and 10 years.[46,50,55,77] A desmoplastic phenotype occurring around age 2 years is very strongly associated with BCNS and carries a more favorable prognosis than sporadic classic medulloblastoma.[78,79] Up to three times more males than females with BCNS are diagnosed with medulloblastoma.[80] As with other malignancies, treatment of medulloblastoma with ionizing radiation has resulted in numerous BCCs within the radiation field.[46,61] Other reported malignancies include ovarian carcinoma,[81] ovarian fibrosarcoma,[82,83] astrocytoma,[84] melanoma,[85] Hodgkin disease,[86,87] rhabdomyosarcoma,[88] and undifferentiated sinonasal carcinoma.[89]
Odontogenic keratocysts–or keratocystic odontogenic tumors (KCOTs), as renamed by the World Health Organization working group–are one of the major features of BCNS.[90] Demonstration of clonal loss of heterozygosity (LOH) of common tumor suppressor genes, including PTCH1, supports the transition of terminology to reflect a neoplastic process.[42] Less than one-half of KCOTs from individuals with BCNS show LOH of PTCH1.[48,91] 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.[90,92] In a recent case series of 183 consecutively excised KCOTs, 6% of individuals demonstrated an association with BCNS.[90] A study that analyzed the rate of PTCH1 pathogenic variants in BCNS-associated KCOTs found that 11 of 17 individuals carried a germline PTCH1 pathogenic variant and an additional 3 individuals had somatic mutations in this gene.[93] Individuals with germline PTCH1 pathogenic variants had an early age of KCOT presentation. KCOTs occur in 65% to 100% of individuals with BCNS,[50,94] with higher rates of occurrence in young females.[95]
Palmoplantar pits are another major finding in BCC and occur in 70% to 80% of individuals with BCNS.[55] When these pits occur together with early-onset BCC and/or KCOTs, they are considered diagnostic for BCNS.[96]
Several characteristic radiologic findings have been associated with BCNS, including lamellar calcification of falx cerebri;[97,98] fused, splayed or bifid ribs;[99] and flame-shaped lucencies or pseudocystic bone lesions of the phalanges, carpal, tarsal, long bones, pelvis, and calvaria.[54] 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.
Table 2 summarizes the frequency and median age of onset of nonmalignant findings associated with BCNS.
Table 2. Frequency of Nonmalignant Findings in Basal Cell Nevus Syndrome (BCNS)
FindingFrequency (%)Median Age of Onset
Adapted from a report by Kimonis et al. [50] about 105 individuals with BCNS seen at the National Institutes of Health between 1985 and 1997.
Palmar/plantar pits87Usually by age 10 y
Keratogenic jaw cysts74Usually by age 20 y
Bridged sella68Congenital
Calcification of falx cerebri65Usually by age 40 y
Macrocephaly50Congenital
Hypertelorism42Congenital
Osseous lucencies in the hands30Congenital
Frontal bossing27Congenital
Bifid ribs26Congenital
Calcification of tentorium cerebelli20Not reported
Ovarian fibromas1730 y
Hemivertebra15Congenital
Pectus deformity11Congenital
Fusion of vertebral bodies10Congenital
Cleft lip/palate3Congenital
Individuals with PTCH2 pathogenic variants may have a milder phenotype of BCNS than those with PTCH1 variants. Characteristic features such as palmar/plantar pits, macrocephaly, falx calcification, hypertelorism, and coarse face may be absent in these individuals.[100]
A 9p22.3 microdeletion syndrome that includes the PTCH1 locus has been described in ten children.[101] All patients had facial features typical of BCNS, including a broad forehead, but they had other features variably including craniosynostosis, hydrocephalus, macrosomia, and developmental delay. At the time of the report, none had basal cell skin cancer. On the basis of their hemizygosity of the PTCH1 gene, these patients are presumably at an increased risk of basal cell skin cancer.
Germline pathogenic variants in SUFU, a major negative regulator of the hedgehog pathway, have been identified in a small number of individuals with a clinical phenotype resembling that of BCNS.[40,41,102] These pathogenic variants were first identified in individuals with childhood medulloblastoma,[103] and the incidence of medulloblastoma appears to be much higher in individuals with BCNS associated with SUFU pathogenic variants than in those with PTCH1 variants.[40] SUFU pathogenic variants may also be associated with an increased predisposition to meningioma.[63,102,104] Conversely, odontogenic jaw keratocysts appear less frequently in this population. Some clinical laboratories offer genetic testing for SUFU pathogenic variants for individuals with BCNS who do not have an identifiable PTCH1 variant.

Rare syndromes

Rombo syndrome
Rombo syndrome, a very rare probably autosomal dominant genetic disorder associated with BCC, has been outlined in three case series in the literature.[105-107] 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.[105] Development of BCC occurs in the fourth decade.[105] A distinctive grainy texture to the skin, secondary to interspersed small, yellowish, follicular-based papules and follicular atrophy, has been described.[105,107] Missing, irregularly distributed, and/or misdirected eyelashes and eyebrows are another associated finding.[105,106] The genetic basis of Rombo syndrome is not known.
Bazex-Dupré-Christol syndrome
Bazex-Dupré-Christol syndrome, another rare genodermatosis associated with development of BCC, has more thorough documentation in the literature than Rombo syndrome. Inheritance is accomplished in an X-linked dominant fashion, with no reported male-to-male transmission.[108-110] 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.[111] Further work has narrowed the potential location to an 11.4-Mb interval on chromosome Xq25-27; however, the causative gene remains unknown.[112]
Characteristic physical findings include hypotrichosis, hypohidrosis, milia, follicular atrophoderma of the cheeks, and multiple BCC, which manifest in the late second decade to early third decade.[108] Documented hair changes with Bazex-Dupré-Christol syndrome include reduced density of scalp and body hair, decreased melanization,[113] a twisted/flattened appearance of the hair shaft on electron microscopy,[114] and increased hair shaft diameter on polarizing light microscopy.[110] The milia, which may be quite distinctive in childhood, have been reported to regress or diminish substantially at puberty.[110] Other reported findings in association with this syndrome include trichoepitheliomas; hidradenitis suppurativa; hypoplastic alae; and a prominent columella, the fleshy terminal portion of the nasal septum.[115,116]
Epidermolysis bullosa simplex, Dowling-Meara
A rare subtype of epidermolysis bullosa simplex (EBS), Dowling-Meara (EBS-DM), is primarily inherited in an autosomal dominant fashion and is associated with pathogenic variants in either keratin-5 (KRT5) or keratin-14 (KRT14).[117] EBS-DM is one of the most severe types of EBS and occasionally results in mortality in early childhood.[118] It has an estimated prevalence of 0.02 per million individuals in the United States and an incidence of 1.16 per million live births.[119] One report cites an incidence of BCC of 44% by age 55 years in this population.[120] Individuals who inherit two EBS pathogenic variants may present with a more severe phenotype.[121] Other less phenotypically severe subtypes of EBS can also be caused by pathogenic variants in either KRT5 or KRT14.[117] Approximately 75% of individuals with a clinical diagnosis of EBS (regardless of subtype) have KRT5 or KRT14 pathogenic variants.[122]
Characteristics of hereditary syndromes associated with a predisposition to BCC are described in Table 3 below.
Table 3. Basal Cell Carcinoma (BCC) Syndromes
SyndromeInheritanceChromosomeGeneClinical Findings
AD = autosomal dominant; AR = autosomal recessive; XD = X-linked dominant.
Basal cell nevus syndrome, Gorlin syndromeAD9q22.3-q31 [36]PTCH1 [123,124]BCC (before age 20 y)
3.597–6.457 [36]PTCH2 [39]
10q24.32SUFU [63]
Rombo syndromeADMilia, atrophoderma vermiculatum, acrocyanosis, trichoepitheliomas, and BCC (age 30–40 y)
Bazex-Dupré-Christol syndromeXD > ADXq24-27 [111]UnknownHypotrichosis (variable),[108] hypohidrosis, milia, follicular atrophoderma (dorsal hands), and multiple BCCs (aged teens to early 20s) [108]
Brooke-Spiegler syndromeAD16q12-q13 [125,126]CYLD [127,128]Cylindroma (forehead, scalp, trunk, and pubic area),[129,130] trichoepithelioma (around nose), spiradenoma, and BCC
Multiple hereditary infundibulocystic BCCAD [131]UnknownUnknownMultiple BCC (infundibulocystic type)
Schopf-Schultz-Passarge syndromeAR > ADUnknownUnknownEctodermal dysplasia (hypotrichosis, hypodontia, and nail dystrophy [anonychia and trachyonychia]), hidrocystomas of eyelids, palmo-plantar keratosis and hyperhidrosis, and BCC [132]
(Refer to the Brooke-Spiegler Syndrome, Multiple Familial Trichoepithelioma, and Familial Cylindromatosis section in the Rare Skin Cancer Syndromes section of this summary for more information about Brooke-Spiegler syndrome.)

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 recommends complete skin examinations every 6 to 12 months for the first 5 years, and then at least annually for life.[133]
The BCNS Colloquium Group has proposed guidelines for the surveillance of individuals with BCNS (refer to Table 4).
Table 4. Basal Cell Nevus Syndrome (BCNS) Colloquium Group Recommendations for Surveillance in BCNS
Adapted from Bree et al.[52]
For Adults:
• MRI of brain (baseline)
• Skin examination every 4 months
• Panorex of jaw every year
• Neurological evaluation (if previous medulloblastoma)
• Pelvic ultrasound (baseline)
• Gynecologic examination every year
• Nutritional assessment
• Fetal assessment for hydrocephalus, macrocephaly, and cardiac fibromas in pregnancy
• Minimization of diagnostic radiation exposure when feasible
For Children:
• MRI of brain (annually until age 8 years)
• Cardiac ultrasound (baseline)
• Dermatologic examination (baseline)
• Panorex of jaw (baseline, then annually if no cysts apparent; after the first cyst is diagnosed, every 6 months until age 21 years or until no cysts are noted for two years)
• Spine film at age 1 year or time of diagnosis (if abnormal, follow scoliosis protocol)
• Pelvic ultrasound at menarche or age 18 years
• Hearing, speech, and ophthalmologic evaluation
• Minimization of diagnostic radiation exposure when feasible
Level of evidence: 5

Primary prevention

Avoidance of excessive cumulative and sporadic sun exposure is important in reducing the risk of BCC, along with other cutaneous malignancies. Scheduling activities outside of the peak hours of UV radiation, utilizing sun-protective clothing and hats, using sunscreen liberally, and strictly avoiding tanning beds are all reasonable steps towards minimizing future risk of skin cancer.[134] For patients with particular genetic susceptibility (such as BCNS), avoidance or minimization of ionizing radiation is essential to reducing future tumor burden.
Level of evidence: 2aii

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.[135] 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.[135] 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.[135-137] In summary, the use of systemic retinoids for chemoprevention of BCC is reasonable in high-risk patients, including patients with xeroderma pigmentosum, as discussed in the Squamous Cell Carcinoma section of this summary.
A patient’s cumulative and evolving tumor load should be evaluated carefully in light of the potential long-term use of a medication class with cumulative and idiosyncratic side effects. Given the possible side-effect profile, systemic retinoid use is best managed by a practitioner with particular expertise and comfort with the medication class. However, for all potentially childbearing women, strict avoidance of pregnancy during the systemic retinoid course—and for 1 month after completion of isotretinoin and 3 years after completion of acitretin—is essential to avoid potentially fatal and devastating fetal malformations.
Level of evidence (retinoids): 2aii
In a phase II study of 41 patients with BCNS, vismodegib (an inhibitor of the hedgehog pathway) has been shown to reduce the per-patient annual rate of new BCCs requiring surgery.[138] Existing BCCs also regressed for these patients during daily treatment with 150 mg of oral vismodegib. While patients treated had visible regression of their tumors, biopsy demonstrated residual microscopic malignancies at the site, and tumors progressed after the discontinuation of the therapy. Adverse effects included taste disturbance, muscle cramps, hair loss, and weight loss and led to discontinuation of the medication in 54% of subjects. A subsequent, open-label, phase II study included 37 patients from the same cohort who continued vismodegib for up to a total of 36 months.[139] Patients treated with vismodegib had a lower mean incidence of new, surgically eligible BCCs than did placebo-treated patients (P < .0001). However, only 17% of patients tolerated continuous vismodegib for the full 36 months. Tumors reappeared after treatment was stopped, but patients who resumed treatment again experienced tumor response. The duration of benefit after stopping vismodegib appeared to be proportional to the duration and compliance of taking the drug during treatment. Intermittent dosing schedules of vismodegib (8 weeks on/8 weeks off after an initial schedule of daily dosing for 24 weeks or 12 weeks on/8 weeks off) have also been shown to be effective in the reduction of BCCs in the BCNS population, although there has been no direct comparison between continuous dosing and intermittent dosing schedules.[140] On the basis of the side-effect profile and rate of disease recurrence after discontinuation of the medication, additional study regarding optimal dosing of vismodegib is ongoing.
Level of evidence (vismodegib): 1aii
A phase III, double-blind, placebo-controlled clinical trial evaluated the effects of oral nicotinamide (vitamin B3) in 386 individuals with a history of at least two NMSCs within 5 years before study enrollment.[141] After 12 months of treatment, those taking nicotinamide 500 mg twice daily had a 20% reduction in the incidence of new BCCs (95% CI, 6%–39%; P = .12). The rate of new NMSCs was 23% lower in the nicotinamide group (95% CI, 4%–38%; P = .02) than in the placebo group. No clinically significant differences in adverse events were observed between the two groups, and there was no evidence of benefit after discontinuation of nicotinamide. Of note, this study was not conducted in a population with an identified genetic predisposition to BCC.
Level of evidence (nicotinamide): 1aii

Treatment

Treatment of individual BCCs in BCNS is generally the same as for sporadic basal cell cancers. Due to the large number of lesions on some patients, this can present a surgical challenge. Field therapy with imiquimod or photodynamic therapy are attractive options, as they can treat multiple tumors simultaneously.[142,143] However, given the radiosensitivity of patients with BCNS, radiation as a therapeutic option for large tumors should be avoided.[50] There are no randomized trials, but the isolated case reports suggest that field therapy has similar results as in sporadic basal cell cancer, with higher success rates for superficial cancers than for nodular cancers.[142,143]
Consensus guidelines for the use of methylaminolevulinate photodynamic therapy in BCNS recommend that this modality may best be used for superficial BCC of all sizes and for nodular BCC less than 2 mm thick.[144] Monthly therapy with photodynamic therapy may be considered for these patients as clinically indicated.
Level of evidence (imiquimod and photodynamic therapy): 4
Topical treatment with LDE225, a Smoothened agonist, has also been investigated for the treatment of BCC in a small number of patients with BCNS with promising results;[145] however, this medication is not approved in this formulation by the U.S. Food and Drug Administration.
Level of evidence (LDE225): 1
In addition to its effects on the prevention of BCCs in patients with BCNS, vismodegib may also have a palliative effect on KCOTs found in this population. An initial report indicated that the use of GDC-0449, the hedgehog pathway inhibitor now known as vismodegib, resulted in resolution of KCOTs in one patient with BCNS.[146] Another small study found that four of six patients who took 150 mg of vismodegib daily had a reduction in the size of KCOTs.[147] None of the six patients in this study had new KCOTs or an increase in the size of existing KCOTs while being treated, and one patient had a sustained response that lasted 9 months after treatment was discontinued.
Level of evidence (vismodegib): 3diii

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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 (NMSC), annual incidence estimates range from 1 million to 5.4 million cases in the United States.[1-3] Multiple studies indicate an increased risk of SCC after a first NMSC; a meta-analysis and review of 45 studies estimated that after a primary SCC diagnosis, 13.3% of individuals would develop a second SCC (95% confidence interval [CI], 7.4%–22.8%).[4]
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 and other risk factors

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.[5-7] 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.[5] (Refer to the PDQ summary on Skin Cancer Prevention for more information about sun and other environmental and therapeutic exposures as risk factors for skin cancer in the general population.) Other environmental agents associated with SCC risk include tanning beds, arsenic, therapeutic radiation (such as psoralen and ultraviolet A therapy for psoriasis), and immunosuppression.[8-14]

Characteristics of the skin

Like melanoma and BCC, SCC occurs more frequently in individuals with lighter skin than in those with darker skin.[5,15] A case-control study of 415 cases and 415 controls showed similar findings; relative to Fitzpatrick type I skin, individuals with increasingly darker skin had decreased risks of skin cancer (odds ratios [ORs], 0.6, 0.3, and 0.1, for Fitzpatrick types II, III, and IV, respectively).[16] (Refer to the Pigmentary characteristics section in the Melanoma section of this summary for a more detailed discussion of skin phenotypes based upon pigmentation.) The same study found that blue eyes and blond/red hair were also associated with increased risks of SCC, with crude ORs of 1.7 (95% CI, 1.2–2.3) for blue eyes, 1.5 (95% CI, 1.1–2.1) for blond hair, and 2.2 (95% CI, 1.5–3.3) for red hair.
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.[15] 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.[17,18] 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.[19] 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.[19,20] 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.[21] One case report documents the occurrence of cancer in a wound that was incurred 59 years earlier.[22]

Immunosuppression

Immunosuppression also contributes to the formation of NMSCs. 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 and with the immunosuppressive agent used.[23-26] NMSCs 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 than these cancers do in the general population.[27,28] Additionally, there is a high risk of second SCCs.[29,30] In one study, more than 65% of kidney transplant recipients developed subsequent SCCs after their first diagnosis.[29] Among Medicare patients with an intact immune system, BCCs occur as frequently as SCCs;[3] in transplant patients, SCCs outnumber BCCs by a 2:1 ratio.

Personal history of nonmelanoma and melanoma 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.[31] 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 NMSCs is the middle of the sixth decade of life.[32-37]
A Swedish study of 224 melanoma index cases and 944 of their first-degree relatives (FDRs) from 154 CDKN2A wild-type families and 11,680 matched controls showed that personal and family histories of melanoma increased the risk of SCC, with relative risks (RRs) of 9.1 (95% CI, 6.0–13.7) for personal history and 3.4 (95% CI, 2.2–5.2) for family history.[38]

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 FDRs. In an independent survey-based study of 415 SCC cases and 415 controls, SCC risk was increased in individuals with a family history of SCC (adjusted OR, 3.4; 95% CI, 1.0–11.6), even after adjustment for skin type, hair color, and eye color.[16] This risk was elevated to an OR of 5.6 in those with a family history of melanoma (95% CI, 1.6–19.7), 9.8 in those with a family history of BCC (95% CI, 2.6–36.8), and 10.5 in those with a family history of multiple types of skin cancer (95% CI, 2.7–29.6). 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.[39,40] 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 pathogenic variants. Further analysis of the Swedish population-based data estimates genetic risk effects of 8% and familial shared-environmental effects of 18%.[41] Thus, shared environmental and behavioral factors likely account for some of the observed familial clustering of SCC.
A study on the heritability of cancer among 80,309 monozygotic and 123,382 dizygotic twins showed that NMSCs have a heritability of 43% (95% CI, 26%–59%), suggesting that almost half of the risk of NMSC is caused by inherited factors.[42] Additionally, the cumulative risk of NMSC was 1.9-fold higher for monozygotic than for dizygotic twins (95% CI, 1.8–2.0).[42]

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 pathogenic variants of the gene as causal. The disorders resulting from single-gene pathogenic variants 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 variant.
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 cases of SCC of the skin 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, NMSC 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 5 below.
Table 5. Hereditary Syndromes Associated with Squamous Cell Carcinoma of the Skin
ConditionGene(s)Clinical Testing AvailabilityaPathway
aFor more information on genetic testing laboratories, refer to the NIH Genetic Testing Registry.
Bloom syndromeBLM/RECQL3Sister chromatid exchange, BLMChromosomal stability
Chediak-Higashi syndromeLYSTLYSTLysosomal transport regulation
Dyskeratosis congenitaDKC1, TERC, TINF2, NHP2/NOLA2, NOP10/NOLA3, TERT, WRAP53, C16orf57, RTEL1DKC1, TERC, TINF2, NHP2, NOP10, TERTTelomere maintenance and trafficking
Dystrophic epidermolysis bullosa (autosomal dominant and autosomal recessive subtypes)COL7A1COL7A1Collagen anchor of basement membrane to dermis
Elejalde diseaseMYO5ANoPigment granule transport
Epidermodysplasia verruciformisEVER1/TMC6, EVER2/TMC8NoSignal transduction in endoplasmic reticulum
Fanconi anemiaFANCA, FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG/XRCC9, FANCI, FANCJ/BRIP1/BACH1, FANCL, FANCM, FANCN/PALB2, FANCO/RAD51C, FANCP/SLX4/BTBD12, FANCQ/ERCC4/XPF, FANCS/BRCA1Chromosomal breakage testing; BRIP1, FANCA, FANCC, FANCE, FANCF, FANCG, PALB2, BRCA1, BRCA2, ERCC4, RAD51C, SLX4DNA repair
Griscelli syndrome (type 1, type 2, and type 3)MYO5A, RAB27A, MLPHRAB27APigment granule transport
Hermansky-Pudlak syndromeHPS1, HPS3, HPS4, HPS5, HPS6, HPS7/DTNBP1, HPS8/BLOC1S3HPS1, HPS3, HPS4, HPS7Melanosomal and lysosomal storage
Hermansky-Pudlak syndrome, type 2AP3B1NoMelanosomal and lysosomal storage
Huriez syndromeUnknown; Locus 4q23NoUnknown
Junctional epidermolysis bullosaLAMA3, LAMB3, LAMC2, COL17A1LAMA3, LAMB3, LAMC2, COL17A1Connective tissue
Multiple self-healing squamous epithelioma (Ferguson-Smith syndrome)TGFBR1NoGrowth factor signaling
Oculocutaneous albinism (type IA, type IB, type II, type III, type IV, type V, type VI, and type VII)TYR, OCA2, TYRP1, SLC45A2/MATP/OCA4, Locus 4q24, SLC24A5, C10Orf11TYR, OCA2, TYRP1Melanin synthesis
Rothmund-Thomson syndromeRECQL4, C16orf57RECQL4Chromosomal stability
Werner syndromeWRN/RECQL2NoChromosomal stability
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, XPG/ERCC5XPA, XPCNucleotide excision repair
Xeroderma pigmentosum variantPOLH/XPVNoError-prone polymerase

Xeroderma pigmentosum

Xeroderma pigmentosum (XP) is a hereditary disorder of nucleotide excision repair that results in cutaneous malignancies in the first decade of life.[43] Affected individuals have an increased sensitivity to sunlight, resulting in a markedly increased risk of SCCs, BCCs, and melanomas. One report found that NMSC was increased 150-fold in individuals with XP; for those younger than 20 years, the prevalence has been estimated to be 5,000 to 10,000 times what would be expected in the general population.[44,45]
The natural history of this disease begins in the first year of life, when sun sensitivity becomes apparent, and xerosis (dry skin) and pigmentary changes may occur in the sun-exposed skin. About one-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 NMSCs, and approximately one-quarter of these individuals will develop melanoma.[44] In the absence of sun avoidance, the median age of diagnosis for any skin cancer is 8 to 9 years.[44-46] On average, NMSC occurs at a younger age than melanoma in the XP population.[45]
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, loss of eyelashes, and cancer, including conjunctival and corneal cancers.[47] About 25% of the XP patients examined at the National Institutes of Health (NIH) between 1971 and 2009 had progressive neurological degeneration.[45] 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 XPD, 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).[45] 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.[44,48] The RR for these cancers is estimated to be about 50-fold higher than in the general population.[44]
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) pathogenic variants were present in about 20%. Complementation group A, due to a pathogenic variant in XPA, accounts for approximately 10% of cases.[45] Other variant genes in this disorder include ERCC3 (XPB), 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.[49] Heterozygotes for pathogenic variants in XP genes are generally asymptomatic.[50] However, one study reported a threefold increase in BCC in Japanese individuals who were heterozygous for XPA pathogenic variants.[51] Founder pathogenic variants in XPA (R228A) and XPC (V548A fs X572) have been identified in North African populations, and a founder pathogenic variant 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 pathogenic variants would be appropriate in these populations.[52-55] A founder pathogenic variant at the 3’ splice acceptor site of intron 3 in the XPA gene is present in approximately 1% of the population in Japan representing nearly 1 million people.[56]
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.[43,57]
An XP variant that is associated with pathogenic variants in POLH (XPV) is responsible for approximately 10% of reported cases.[58] 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 pathogenic variants have the same cutaneous and ocular findings as other XP patients but do not have progressive neurologic degeneration.[59] A founder pathogenic variant resulting in a deletion of exon 10 was seen in 16 of 16 individuals from ten Tunisian consanguineous families.[60]
Work on genotype-phenotype correlations among the XP complementation groups continues; however, evidence suggests that the specific pathogenic variant may have more influence on the phenotype than the complementation group.[43,61] 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 neoplasias, but skin cancers may be more common in XPC, XPE, and XPV groups.[61]. There is additional clinical variation within each complementation group. Mild to severe neurologic impairment has been described in individuals with XPA pathogenic variants. Individuals with XPA pathogenic variants in the DNA binding region (amino acids 98–219) may have a more severe presentation that includes neurological findings.[62] Individuals within the XPC complementation group have higher incidences of ocular damage.[61] 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.[63] 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.[43,64] 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 XP-CS pathogenic variants, does not appear to confer an increased risk of skin cancer.[65-68]
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. Clinical genetic testing using sequence analysis to identify pathogenic variants is available for multiple XP-associated genes; the list can be found at the NIH Genetic Testing Registry.

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.[69] Transforming growth factor beta-receptor 1 (TGFBR1) was identified through next-generation sequencing as the gene responsible for MSSE. Loss-of-function pathogenic variants in TGFBR1 have been identified in 18 of 22 affected families.[70] Gain-of-function variants 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.[71] 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.[71]

Oculocutaneous albinism

Albinism is a major risk factor for skin cancer in individuals of African ancestry.[18,72] 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.[73] 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 melanoma, and 8% as BCC.[18] Of note, some melanomas found in individuals with albinism do contain melanin.[74]
SCC occurring at extremely early ages is a hallmark of oculocutaneous albinism. In a cohort of nearly 1,000 Nigerian patients with albinism, all had malignant or premalignant cutaneous lesions by age 20 years.[75]
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 pathogenic variants in the tyrosinase gene, TYR, located on the long arm of chromosome 11. This type of albinism accounts for about one-half of cases in individuals of Caucasian ancestry.[76] The OCA2 gene, also known as the P gene, is altered 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. A variant 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.[77] Murine models with variants in this gene had significantly decreased melanin production compared with normal controls.[78] In one international study of individuals with albinism, biallelic variants in OCA2 were found in 17% of participants.[79]
Genetic variants in SLC45A2 (MATP associated with OCA4), SLC24A5 (associated with OCA6), and TYRP1 (tyrosinase-related protein 1 associated with OCA3) are associated with less common types of oculocutaneous albinism. Reported incidences for these genes in an international population of patients with albinism are 7% for SLC45A2, 1% for TYRP1, and less than 0.5% for SLC24A5.[79] SLC45A2 is found in 24% of oculocutaneous albinism cases in Japan, making it the most common type of albinism among Japanese individuals with identifiable variants.[80] A study of 22 individuals of Italian ancestry without pathogenic variants in TYR, OCA2, or TYRP1 found 5 individuals with biallelic variants in SLC45A2, 4 of whom met clinical criteria for a diagnosis of oculocutaneous albinism.[81] Collectively, more than 600 unique ocular albinism–related genetic variants have been identified.[82] The increased risk of SCC of the skin in people with these variants has not been quantified. It is generally assumed to be similar to other types of albinism. Of note, a meta-analysis demonstrated that the SLC45A2 p.Phe374Leu variant was protective for melanoma, with an OR of 0.41 (95% CI, 0.33–0.50; P = 3.50 x 10-17).[83] However, at this time, it should be noted that clinical testing is not routinely performed for protective variants.
Additional genes associated with oculocutaneous albinism have been found in small numbers of patients. OCA5, located on chromosome 4q24, has been identified in a Pakistani family, whereas OCA6 appears to be caused by pathogenic variants in SLC24A5 on chromosome 15q21.[84-86] Pathogenic variants in C10orf11 (LRMDA) cause OCA7, which has been found in patients from the Faroe Islands and Denmark.[87] Small numbers of pathogenic variant carriers have been reported to date. One woman with OCA6 had actinic keratosis, but the incidence of skin cancers in these populations is unknown.
Table 6. Types of Oculocutaneous Albinism (OCA)
TypeSubtypeGeneReporting PopulationAvailability of Clinical Test
OCA Type 11ATYRJapanese,[88] Chinese,[89] White [90-94]Yes
1BTYR
OCA Type 2OCA2 (P gene)African,[95,96] African American,[97] Native American [98]Yes
OCA Type 3TYRP1African [99]Yes
OCA Type 4SLC45A2 (MATP)Japanese,[80] Italian,[81] German [100]Yes
OCA Type 5OCA5Pakistani [84]Not in the United States
OCA Type 6SLC24A5Chinese,[85] African,[101] European,[86] Indian [102]Yes
OCA Type 7C10orf11 (LRMDA)Faroe Islands,[87] Denmark [87]Yes

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.[103] The underlying cause is believed to be a defect in melanosome and lysosome transport. A number of pathogenic variants at disparate loci have been associated with this syndrome, including HPS1, HPS3, HPS4, HPS5, HPS6, HPS7 (DTNBP1), HPS8 (BLOC1S3), and HPS9 (PLDN).[104-111] Pigmentation characteristics can vary significantly in this disorder, particularly among those with HPS1 pathogenic variants, and patients report darkening of the skin and hair as they age. In a small cohort of individuals with HPS1 variants, 3 out of 40 developed cutaneous SCCs, and an additional 3 had BCCs.[112] Hermansky-Pudlak syndrome type 2, which includes increased susceptibility to infection resulting from congenital neutropenia, has been attributed to defects in AP3B1.[113]
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. Pathogenic variants in the LYST gene underlie this syndrome, which is often fatal in the first decade of life.[114-116]
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 pathogenic variants in the MYO5A gene, which affects melanosome transport.[117] 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 pathogenic variants in RAB27A, which is part of the same melanosome transport pathway as MYO5A.[118] Griscelli syndrome type 3 presents with hypomelanosis and does not include neurologic or immunologic disorders. Pathogenic variants in the melanophilin (MLPH) gene and MYO5A have been associated with this variant of Griscelli syndrome.[119]

Epidermolysis bullosa

There are numerous forms of epidermolysis bullosa (EB), which is characterized by cleavage and blistering of the skin. Dystrophic EB and junctional EB are associated with an increased risk of skin cancer, particularly SCC.[120] The type of EB can be difficult to determine clinically, although genetic testing may aid in the classification. In one study of 91 probands with features of EB, a next-generation sequencing panel of 21 genes associated with different forms of EB or skin fragility syndromes was able to predict the subtype in 76 of 87 probands of undetermined subtype (83.5%).[121] Similar multigene panels are clinically available for EB. The types, pathogenic variants involved, and phenotypic characteristics are detailed in the following review.[122]
Dystrophic epidermolysis bullosa
Approximately 95% of individuals with the heritable disorder dystrophic epidermolysis bullosa (DEB) have a detectable germline pathogenic variant 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.[123] The lack of type VII collagen results in generalized blistering, often starting from birth, and is associated with skin atrophy and scarring.[123] A registry of DEB pathogenic variants, The International DEB Patient RegistryExit Disclaimer, is accessible on the Internet.[124]
There are two recessively inherited subtypes of DEB: severe-generalized (RDEB-sev gen; previously named Hallopeau-Siemens type) and generalized-other or generalized-intermediate (RDEB-O; previously named non–Hallopeau-Siemens type); and a dominantly inherited form, dominant dystrophic epidermolysis bullosa (DDEB).[122] These syndromes are rare. The prevalence per million individuals in the United States and incidence per million live births are 0.36 and 0.57 for RDEB-sev gen, 0.14 and 0.30 for RDEB-O, and 1.49 and 2.12 for DDEB, respectively.[125] 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 an SCC risk of up to 85% by age 45 years.[126,127] These cancers arise in nonhealing wounds and usually metastasize to cause death within 5 years of the diagnosis of SCC.[128] In one case series, SCC was the leading cause of death for the 15 patients with the severe generalized subtype.[129] The incidence of SCC appears to be highest in the RDEB subtype. In a review of 69 articles that included all types of EB, 117 individuals with SCC were identified; 81 of these cases (69.2%) were in individuals with RDEB.[120] In this group, the median age of diagnosis was 36 years (range, 6–71 y). Early mortality also has been observed in this disorder, with a mortality rate of up to 40% by age 30 years.[130] Extracutaneous manifestations of RDEB-sev gen include short stature, anemia, strictures of the gastrointestinal and genitourinary tracts, and corneal scarring that may result in blindness.
Diagnosis of EB may be accomplished by immunofluorescence or electron microscopy. A list of recommended diagnostic antibodies and their suppliers is available on the Dystrophic EB Research AssociationExit Disclaimer website. Pathogenic variant testing is generally used for prenatal diagnosis rather than for the primary diagnosis of EB.[131,132]
The rate of de novo pathogenic variants for DDEB is approximately 30%; maternal germline mosaicism has also been reported.[133,134] Glycine substitutions in exons 73 to 75 are the most common pathogenic variants in DDEB. G2034R and G2043R account for half of these variants. Less frequently, splice junction pathogenic variants and substitutions of glycine and other amino acids may cause the dominant form of DEB. In contrast, more than 400 pathogenic variants have been described for the two types of recessive EB. The recessive form of the disease is caused primarily by null variants, although amino acid substitutions, splice junction variants, and missense variants have also been reported. In-frame exon skipping may generate a partially functional protein in recessive disease. A founder pathogenic variant, c.6527insC (p.R525X), has been observed in 27 of 49 Spanish individuals with recessive DEB.[135] A founder pathogenic variant in COL7A1, pVal769LeuFsXI, was identified in 11 of 15 families in Sfax, Southern Tunisia.[136] Three of 12 individuals carrying at least one copy of this variant developed SCC, including two young-onset cases at ages 16 and 29 years. Genotype-phenotype correlations suggest an inverse correlation between the amount of functional protein and severity.
Pathogenic variants 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-severe generalized keratinocytes, retention of the amino-terminal NC1, the first noncollagenous fragment of type VII collagen, is tumorigenic in mice.[137] This retained sequence may mediate tumor-stroma interactions that promote carcinogenesis.
Junctional epidermolysis bullosa
Junctional epidermolysis bullosa (JEB) is an autosomal recessive type of EB with an estimated prevalence of 0.49 per million individuals in the United States and an estimated incidence of 2.68 per million live births.[125] JEB results in considerable mortality, with approximately 50% of cases dying within the first year of life.[138] Pathogenic variants in any of the genes encoding the three basic subunits of laminin 332, previously known as laminin 5 (LAMA3, LAMB3, LAMC2), or variants in COL17A1 can result in this syndrome.[139-141] Individuals with the Herlitz type (a severe clinical form) of JEB are at increased risk of SCC, with a cumulative risk of 18% by age 25 years.[142] A study of COL17A1 in individuals with a milder subtype of JEB, called JEB-other, identified pathogenic variants in 85 of 86 alleles from 43 individuals.[143] Total loss of COL17A1 protein staining correlated with a more severe phenotype.

Epidermodysplasia verruciformis

Pathogenic variants 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.[144] 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,[145] 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.[146]
The genes associated with this disorder, EVER1 and EVER2, were identified in 2002.[147] The inheritance pattern of these genes appears to be autosomal recessive; however, autosomal dominant inheritance has also been reported.[148-150] 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.[151]
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.[152]
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 pathogenic variants in the MST1 gene.[153] 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 pathogenic variants 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.[154]

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 1 in 100 individuals of Ashkenazi Jewish ancestry.[155] 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.[156] By age 40 years, individuals affected with Fanconi anemia have an 8% risk per year of developing a solid tumor;[156] the median age of diagnosis for solid tumors is 26 years.[157] Multiple cases of cancers of the brain, breast, lung, and kidney (Wilms tumor) have been reported in this population.[157] Data on the incidence of NMSCs 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.[157-161]
Individuals with this disease have increased susceptibility to DNA cross-linking agents (e.g., mitomycin-C or diepoxybutane) and ionizing and UV radiation. The diagnosis of this disease is made by observing increased chromosomal breakage, rearrangements, or exchanges in cells after exposure to carcinogens such as diepoxybutane.
Seventeen complementation groups have been identified for Fanconi anemia; details regarding the genes associated with these groups are listed in Table 7 below.[162] Exome sequencing has revealed that a subset of individuals can carry multiple heterozygous pathogenic variants in Fanconi anemia genes,[163] which may impact phenotypic presentation.
Table 7. Genes Associated with Fanconi Anemia (FA)
GeneLocusApproximate Incidence Among FA Patients (%)Pattern of Disease Transmission
AR = autosomal recessive; XLR = X-linked recessive.
FANCA16q24.370AR
FANCBXp22.31RareXLR
FANCC9q22.310AR
FANCD1 (BRCA2)13q12.3RareAR
FANCD23p25.3RareAR
FANCE6p21.310AR
FANCF11p15RareAR
FANCG (XRCC9)9p1310AR
FANCI (KIAA1794)15q25-26RareAR
FANCJ (BACH1/BRIP1)17q22.3RareAR
FANCL (PHF9/POG)2p16.1RareAR
FANCM (Hef)14q21.3RareAR
FANCN (PALB2)16p12.1RareAR
FANCO (RAD51C)17q22RareAR
FANCP (SLX4/BTBD12)16p13.3RareAR
FANCQ (ERCC4/XPF)16p13.12RareAR
FANCS (BRCA1)17q21.31RareAR
The proteins involved with DNA crosslink repairs have been termed the FANC pathway because of their involvement with Fanconi anemia.[164] 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.[165] Other Fanconi anemia genes, FANCJ (BRIP1) and FANCN (PALB2), have also been identified as rare breast cancer susceptibility genes.[166] (Refer to the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information about BRCA2, BRIP1, PALB2, and RAD51.) Individuals who are heterozygous carriers of other Fanconi anemia–associated variants do not appear to have an increased risk of cancer, with the possible exception of a twofold increase in breast cancer incidence in carriers of FANCC pathogenic variants.[167]
In 2018, a group reported a significant increase in SCC cases (OR, 1.69; 95% CI, 1.26–2.26) associated with a specific BRCA2 allele, which is relatively prevalent in the Icelandic population (K3326X; allele frequency, 1.1%).[168] This allele results in normal production of an altered protein, and the authors hypothesized carriers have an increased sensitivity to environmental factors, which require DNA repair. This variant was also associated with an increased risk of small cell lung cancer, breast cancer, and ovarian cancer (but lower than the risk associated with the BRCA pathogenic variants that decrease protein levels).

Dyskeratosis congenita (Zinsser-Cole-Engman syndrome)

Dyskeratosis congenita, like Werner syndrome, results in premature aging and is thus 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.[169] Developmental delay may also be present in variants of dyskeratosis congenita, such as Hoyeraal-Hreidarsson syndrome (HHS) and Revesz syndrome.
Approximately 10% of individuals with dyskeratosis congenita will develop nonhematologic tumors, often before the third decade of life.[170,171] 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, RTEL1 and TERT) have been implicated in dyskeratosis congenita; approximately one-half of the individuals with a clinical diagnosis of this disease have an identified pathogenic variant in one of these seven genes.[172-179] TERC and TINF2 are inherited in an autosomal dominant manner, whereas NHP2 (NOLA2) and NOP10 (NOLA3) show autosomal recessive inheritance, and RTEL1 and TERT can be either autosomal dominant or autosomal recessive. Recessive pathogenic variants in RTEL1 can also be associated with HHS.[180] A study of more than 1,000 individuals of Ashkenazi Jewish ancestry identified a founder RTEL1 splice-site pathogenic variant, c.3791G>A (p.R1264H), that had a carrier frequency of 1% in Orthodox Ashkenazi Jewish individuals and 0.45% in the general Ashkenazi Jewish population.[181] 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.[182] Levels of TERC, the RNA component of the telomerase complex, are reduced in all dyskeratosis congenita patients.[183] Missense pathogenic variants 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.[184] Pathogenic variants in C16orf57 were identified in 6 of 132 families who did not have a variant detected in other known genes.[185] C16orf57 pathogenic variants are also associated with poikiloderma with neutropenia.[186] (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.[187] Testing of DKC1 may be performed first in male probands, as pathogenic variants in this gene account for up to 36% of those identified in dyskeratosis congenita to date. Pathogenic variants in TINF2 and TERT are responsible for 11% to 24% and 6% to 10% of cases, respectively.[169,176,177,188,189]

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 NMSCs can develop at an early age.[190] Reports of multiple SCCs in situ have been reported in individuals as young as 16 years.[191] The precise increased risk of skin cancer is not well characterized, but the point prevalence of NMSC, including both BCC and SCC, is 2% to 5% in young individuals affected by this syndrome.[192] 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.[193]
A pathogenic variant 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.[194] Pathogenic variants in similar DNA helicases lead to the inherited disorders of Bloom syndrome and Werner syndrome.
At least 19 different truncating pathogenic variants in this gene have been identified as deleterious.[195] These pathogenic variants cause severe down-regulation of RECQL4 transcripts in this subset of individuals with Rothmund-Thomson syndrome.[196] Cells deficient in RECQL4 have been found to be hypersensitive to oxidative stress, resulting in decreased DNA synthesis.[197] 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.[198]
Three of six families with Rothmund-Thomson syndrome were found to have homozygous pathogenic variants in the C16orf57 gene. Pathogenic variants in this gene have also been identified in individuals with dyskeratosis congenita and poikiloderma with neutropenia, suggesting that these syndromes are related;[185,186] 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 9% of tumors in the Bloom Syndrome Registry.[199] Skin cancers occur at an early age in this population, with a mean age of 31 years at the time of diagnosis.
The BLM gene, located on the short arm of chromosome 15, is the only gene known to be associated with 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.[200,201]
This rare chromosomal breakage syndrome is inherited in an autosomal recessive manner and is characterized by loss of genomic stability. Sixty-four pathogenic variants described in the BLM gene include nucleotide insertions and deletions (41%), nonsense variants (30%), variants resulting in mis-splicing (14%), and missense variants (16%).[202,203] A specific pathogenic variant identified in the Ashkenazi Jewish population is a 6-bp deletion/7-bp insertion at nucleotide 2,281, designated as BLMASH.[204] Many of these variants 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 pathogenic variants and recombination. This somatic hypermutability leads 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.[205] 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.[206]

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.[207] Cancers have an early onset and occur in up to 43% of these patients.[208] 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.[209] Approximately 20% of the cancers reported in this syndrome are cutaneous, with melanoma and SCC of the skin accounting for 14% and 5%, respectively.[210] A study of 189 individuals with Werner syndrome estimated melanoma risk to be elevated 53-fold in these individuals.[211] 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.[209,212]
Pathogenic variants 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.[208,213-216] 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.[217-225] Telomere dysfunction has been associated with premature aging and cancer susceptibility.[226] Other helicases with similar function are altered in other chromosomal instability syndromes, such as BLM in Bloom syndrome and RecQL4 in Rothmund-Thomson syndrome.
Pathogenic variants described in the WRN gene include all types of variants; however, the 1136C→T variant is the most common and is found in 20% to 25% of the Japanese and white populations.[227,228] In the Japanese population, a founder pathogenic variant (IVS 25-1G→C) is present in 60% of affected individuals.[229]
Pathogenic variants in the WRN gene causes loss of nuclear localization of the gene product. Intracellular levels of the mRNA and protein associated with the variant are also markedly decreased, compared with those of the wild type. Half-lives of the mRNA and protein associated with the variant are also shorter than those associated with the wild-type mRNA and protein.[228,230]


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