Monday, June 3, 2019

Genetics of Skin Cancer (PDQ®) 1/4 —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. 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 OMIM 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 familialcomponents, 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 largely acellular matrix.[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] PTCH2displays 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 BAP1pathogenic 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 haploinsufficiencyof 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] congenitalpulmonary 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 pathogenic variants 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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