Pathogenesis of basal cell carcinoma

Pathogenesis of basal cell carcinoma DEFAULT

Molecular Pathogenesis of Basal Cell Carcinoma

Skin Cancer after Organ Transplantation pp 193-204 | Cite as

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Part of the Cancer Treatment and Research book series (CTAR, volume 146)

Basal cell carcinoma (BCC) is the most frequent cancer among the white population, representing 75% of all skin cancers [1]. The incidence of BCC cases is increasing, probably because of changes of leisure activities and migration to regions with higher solar radiation. BCCs rarely metastasize (<0.1%), and mortality rates are low; however, some tumors grow aggressively and may cause extensive tissue damage. Aggressive growth of BCC correlates with histological subtypes. Nodular and superficial BCC, representing 60% and 25% of all BCC, respectively, are usually considered less aggressive than morpheaform, infiltrative, micronodular, and metatypic BCC, which are associated with a higher rate of local recurrences [2, 3]. Several risk factors for the development of BCC have been described, which include physical characteristics, exposures to environmental carcinogens, immunosuppression, and genetic predisposition. Other genetic changes, acquired subsequently and affecting cell proliferation and apoptosis, may also be involved in tumorigenesis. In the following sections, some recently identified molecular mechanisms are described that are involved in BCC development and which potentially represent targets of new pharmacologic treatment modalities.

Keywords

Hair Follicle Basal Cell Carcinoma Sonic Hedgehog Hedgehog Signalling Xeroderma Pigmentosum 

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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Institute of Medical Microbiology Virology and HygieneUniversity Hospital Hamburg-Eppendorf, University of HamburgHamburgGermany
Sours: https://link.springer.com/chapter/10.1007/978-0-387-78574-5_17

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) 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 (which is sometimes referred to as cutaneous melanoma) is a less common type of skin cancer, but 5% to 10% of all melanomas arise in multiple-case families and may be inherited in an autosomal dominant fashion. It is the most lethal of the common skin cancers.

  • 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. Syndromes such as oculocutaneous albinism, epidermolysis bullosa, and Fanconi anemia are associated with an increased risk of SCC. The autosomal recessive disease xeroderma pigmentosum (XP) is associated with an increased risk of BCC, SCC, and melanoma. The major germline 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. Germline pathogenic variants in several other genes, including CDK4, MITF, and BAP1 have also been found to be associated with melanoma.

    Genome-wide association studies show 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 fluorouracil (5-FU) 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 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 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.

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, along with interspersed melanocytes. 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, lose their nuclei and form the spinous cell layer; the granular cell layer; and the keratinized outer layer, or stratum corneum, which serves as a protective covering of the body.

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.[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) sun-exposed 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. Melanocytes contain melanin, which is packaged into melanosomes and transported to nearby keratinocytes to induce pigmentation of the skin. Melanin provides a barrier for the nuclei of keratinocytes against ultraviolet radiation and also plays a role in the immune system.[5]

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.[6]

The dermis is largely composed of an extracellular matrix. Prominent cell types and organelles in this compartment are fibroblasts, endothelial cells, smooth muscle cells, transient immune system cells, blood vessels, and nerves. When malignant transformation occurs, fibroblasts form fibrosarcomas and endothelial cells form angiosarcomas, Kaposi sarcoma, or 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.[7]

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.[8]

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.[9]

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 (extensive reddening of the skin) associated with severe sunburn, 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 helper T cells (TH)1, TH2, or TH17.[10] In innate immunity, the immune system produces numerous peptides with antibacterial and antifungal capacity. Even small breaks in the skin can potentially lead to infection. The skin-associated lymphoid tissue is one of the largest arms of the immune system and has a role in the prevention of infection. It may also be important in immune surveillance against cancer. Immunosuppression, such as when it is induced intentionally after solid-organ transplantation to reduce the risk of transplanted organ rejection, 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 dark pigment with 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).
EnlargePhotographs showing a pink, scaly lesion on the skin (left panel) and flesh-colored nodules on the skin (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).

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).
References
  1. Vandergriff TW, Bergstresser PR: Anatomy and physiology. In: Bolognia JL, Jorizzo JL, Schaffer JV: Dermatology. 3rd ed. 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. 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. Lin JY, Fisher DE: Melanocyte biology and skin pigmentation. Nature 445 (7130): 843-50, 2007. [PUBMED Abstract]
  6. Koster MI, Loomis CA, Koss TK, et al.: Skin development and maintenance. In: Bolognia JL, Jorizzo JL, Schaffer JV: Dermatology. 3rd ed. Elsevier Saunders, 2012, pp 55-64.
  7. 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. Elsevier Saunders, 2012, pp 1961-77.
  8. McCalmont TH: Adnexal neoplasms. In: Bolognia JL, Jorizzo JL, Schaffer JV: Dermatology. 3rd ed. Elsevier Saunders, 2012, pp 1829-50.
  9. Kaddu S, Kohler S: Muscle, adipose and cartilage neoplasms. In: Bolognia JL, Jorizzo JL, Schaffer JV: Dermatology. 3rd ed. Elsevier Saunders, 2012, pp 1979-92.
  10. 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. 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 (lighter 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 not as large (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 family history of melanoma in the same cohorts, plus the Nurses’ Health Study 2, showed a similar increased risk (hazard ratio [HR], 1.27; 95% CI, 1.12–1.44).[4] 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).[5]

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.[6] Additionally, the cumulative risk of NMSC was 1.9-fold higher for monozygotic than for dizygotic twins (95% CI, 1.8–2.0).[6]

Previous personal history of BCC or SCC

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 cancers is the mid-60s.[7-12] In addition, several studies have found that individuals with a history of BCC or SCC have an increased risk (range, 9%–61%) of a subsequent diagnosis of a noncutaneous cancer;[13-18] however, other studies have contradicted this finding.[19-22] 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

Inherited pathogenic variants in the gene coding for the transmembrane receptor protein PTCH1, or PTCH, are associated with basal cell nevus syndrome (BCNS), and somatic mutations are associated with 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.[23] 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.[24,25] 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.[26,27] Further investigation identified a pathogenic variant in PTCH1 that localized to the area of allelic loss.[28] Up to 30% of sporadic BCCs demonstrate PTCH1 pathogenic variants.[29] 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 germlinePTCH1 pathogenic variants, predominantly truncation in type.[30]

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.[31,32] PTCH2 displays 57% homology to PTCH1.[33] While the exact role of PTCH2 remains unclear, there is evidence to support its involvement in the hedgehog signaling pathway.[31,34]

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 not known, there are several BAP1 families that report diagnoses of BCC.[35,36] 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.[35] A second report noted that four individuals from families with BAP1 germline pathogenic variants 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.[37] 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.[38]

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.[39] 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.[30,40] The clinical features of BCNS differ more among families than within families.[41] 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.[42-44]

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.[39] The resulting haploinsufficiency of PTCH1 in BCNS has been associated with structural anomalies such as odontogenic keratocysts, with evaluation of the cyst lining revealing loss of heterozygosity for PTCH1.[45] 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.[46-50] However, haploinsufficiency or dominant negative isoforms have also been implicated for the inactivation of PTCH1.[51]

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).[52-55] 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.[55] PTCH1 pathogenic variants are found in 60% to 85% of patients who meet clinical criteria.[56,57] 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.[49,53,58] BCNS-associated ovarian fibromas are more likely to be bilateral and calcified than sporadic ovarian fibromas.[59] Ameloblastomas, aggressive tumors of the odontogenic epithelium in the jaw, have also been proposed as a diagnostic criterion for BCNS, but most groups do not include it at this time.[60]

Other associated benign neoplasms include gastric hamartomatous polyps,[61] congenital pulmonary cysts,[62] cardiac fibromas,[63] meningiomas,[64-66] craniopharyngiomas,[67] fetal rhabdomyomas,[68] leiomyomas,[69] mesenchymomas,[70] basaloid follicular hamartomas,[71] 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.[72-74] 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.[48,49,69]

The diagnostic criteria for BCNS are described in Table 1 below.

Evans et al. 1993 [52]Kimonis et al. 1997 [53]Veenstra-Knol et al. 2005 [54]BCNS Colloquium Group 2011b [55]
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 of jaw or polyostotic bone cystHistologically proven odontogenic keratocyst of jaw Histologically proven odontogenic keratocyst of jaw Odontogenic 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) falx calcifications in brainBilamellar calcification of falx cerebri in brainEctopic calcification (lamellar or early falx cerebri) in brainLamellar calcification of falx cerebri in brain
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 feet on x-rayBridging of sella turcica, vertebral abnormalities (hemivertebrae, fusion or elongation of vertebral bodies), modeling defects of the hands and feet Skeletal 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 cysts  Lymphomesenteric 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.[75] Nonpigmented BCCs are more common than pigmented lesions.[76] 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.[53,58] 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.[76] Case series have suggested that up to 1 in 200 individuals with BCC demonstrate findings supportive of a diagnosis of BCNS.[39] BCNS has rarely been reported in individuals with darker skin pigmentation; however, significantly fewer BCCs are found in individuals of African or Mediterranean ancestry.[53,77,78] Despite the rarity of BCC in this population, reported cases document full expression of the noncutaneous manifestations of BCNS.[78] However, in individuals of African ancestry who have received radiation therapy, significant basal cell tumor burden has been reported within the radiation port distribution.[53,69] Thus, cutaneous pigmentation may protect against the mutagenic effects of UV but not against ionizing radiation.

Variants in other genes 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) (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).[79]

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.[49,53,58,80] A desmoplastic phenotype occurring around age 2 years is very strongly associated with BCNS and carries a more favorable prognosis than sporadic classic medulloblastoma.[81,82] Up to three times more males than females with BCNS are diagnosed with medulloblastoma.[83] As with other malignancies, treatment of medulloblastoma with ionizing radiation has resulted in numerous BCCs within the radiation field.[49,64] Other reported malignancies include ovarian carcinoma,[84] ovarian fibrosarcoma,[85,86] astrocytoma,[87] melanoma,[88] Hodgkin disease,[89,90] rhabdomyosarcoma,[91] and undifferentiated sinonasal carcinoma.[92]

Odontogenic keratocysts–or keratocystic odontogenic tumors (KCOTs), as renamed by the World Health Organization working group–are one of the major features of BCNS.[93] Demonstration of clonal loss of heterozygosity (LOH) of common tumor suppressor genes, including PTCH1, supports the transition of terminology to reflect a neoplastic process.[45] Less than one-half of KCOTs from individuals with BCNS show LOH of PTCH1.[51,94] 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.[93,95] In a recent case series of 183 consecutively excised KCOTs, 6% of individuals demonstrated an association with BCNS.[93] 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.[96] Individuals with germline PTCH1 pathogenic variants had an early age of KCOT presentation. KCOTs occur in 65% to 100% of individuals with BCNS,[53,97] with higher rates of occurrence in young females.[98]

Palmoplantar pits are another major finding in BCC and occur in 70% to 80% of individuals with BCNS.[58] When these pits occur together with early-onset BCC and/or KCOTs, they are considered diagnostic for BCNS.[99]

Several characteristic radiologic findings have been associated with BCNS, including lamellar calcification of falx cerebri in the brain;[100,101] fused, splayed or bifid ribs;[102] and flame-shaped lucencies or pseudocystic bone lesions of the phalanges, carpal, tarsal, long bones, pelvis, and calvaria by diagnostic x-ray imaging.[57] 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.

FindingFrequency (%)Median Age of Onset
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.[103]

A 9p22.3 microdeletion syndrome that includes the PTCH1locus has been described in ten children.[104] 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.[43,44,105] These pathogenic variants were first identified in individuals with childhood medulloblastoma,[106] 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.[43] SUFU pathogenic variants may also be associated with an increased predisposition to meningioma.[66,105,107] 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.

DNA repair genes

In addition to pathogenic variants in genes primarily associated with BCC, other cancer-associated genes may confer an increased risk for BCC. A study of 61 individuals with a high number of BCCs (mean, 11 BCCs; range, 6–65) underwent genetic testing for 29 high-penetrance cancer susceptibility genes. Thirteen pathogenic variants were found in 12 of 61 individuals (19.7%). This was higher than expected compared with individuals in the Exome Aggregation Consortium (ExAC) database (3%). All of the genes with pathogenic variants were involved in DNA repair, suggesting that defects in DNA repair pathways may increase the risk of BCC. Of these 61 individuals, 21 (34.4%) had a previous diagnosis of another cancer including melanoma, breast, colon, and prostate cancers.

Rare syndromes

Rombo syndrome

Rombo syndrome is a very rare genodermatosis or genetic disorder associated with BCC. It is thought to have an autosomal dominant inheritance pattern, and it has been outlined in three case series in the literature.[108-110] The cutaneous examination is within normal limits until age 7 to 10 years, with the development of distinctive cyanoticerythema of the lips, hands, and feet and early atrophoderma vermiculatum of the cheeks, with variable involvement of the elbows and dorsal hands and feet.[108] Development of BCC occurs in the fourth decade.[108] A distinctive grainy texture to the skin, secondary to interspersed small, yellowish, follicular-based papules and follicular atrophy, has been described.[108,110] Missing, irregularly distributed, and/or misdirected eyelashes and eyebrows are another associated finding.[108,109] 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.[111-113] 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.[114] Further work has narrowed the potential location to an 11.4-Mb interval on chromosome Xq25-27; however, the causative gene remains unknown.[115]

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.[111] Documented hair changes with Bazex-Dupré-Christol syndrome include reduced density of scalp and body hair, decreased melanization,[116] a twisted/flattened appearance of the hair shaft on electron microscopy,[117] and increased hair shaft diameter on polarizing light microscopy.[113] The milia, which may be quite distinctive in childhood, have been reported to regress or diminish substantially at puberty.[113] 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.[118,119]

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).[120] EBS-DM is one of the most severe types of EBS and occasionally results in mortality in early childhood.[121] 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.[122] One report cites an incidence of BCC of 44% by age 55 years in this population.[123] Individuals who inherit two EBS pathogenic variants may present with a more severe phenotype.[124] Other less phenotypically severe subtypes of EBS can also be caused by pathogenic variants in either KRT5 or KRT14.[120] Approximately 75% of individuals with a clinical diagnosis of EBS (regardless of subtype) have KRT5 or KRT14 pathogenic variants.[125]

Characteristics of hereditary syndromes associated with a predisposition to BCC are described in Table 3 below.

SyndromeInheritanceGene or Chromosomal LociClinical Findings
Basal cell nevus syndrome, Gorlin syndrome ADPTCH1,[126,127] PTCH2,[42] SUFU [66]BCC (before age 20 y)
Rombo syndrome ADUnknownMilia, atrophoderma vermiculatum, acrocyanosis, trichoepitheliomas, and BCC (age 30–40 y)
Bazex-Dupré-Christol syndrome XD > ADXq24-27 [114]Hypotrichosis (variable),[111] hypohidrosis, milia, follicular atrophoderma (dorsal hands), and multiple BCCs (aged teens to early 20s) [111]
Brooke-Spiegler syndromeADCYLD [128,129] Cylindroma (forehead, scalp, trunk, and pubic area),[130,131] trichoepithelioma (around nose), spiradenoma, and BCC
Multiple hereditary infundibulocystic BCCAD [132] UnknownMultiple BCC (infundibulocystic type)
Schopf-Schultz-Passarge syndromeAR > ADUnknownEctodermal dysplasia (hypotrichosis, hypodontia, and nail dystrophy [anonychia and trachyonychia]), hidrocystomas of eyelids, palmoplantar keratosis and hyperhidrosis, and BCC [133]
Xeroderma pigmentosumARXPA, XPB/ERCC3, XPC, XPD/ERCC2, XPE/DDB2, XPF/ERCC4, XPG/ERCC5SCC, BCC, melanoma, severe sun sensitivity, ophthalmologic and neurologic abnormalities
Xeroderma pigmentosum variantARPOLH/XPVSCC, BCC, melanoma, severe sun sensitivity, ophthalmologic abnormalities

(Refer to the Brooke-Spiegler Syndrome, Multiple Familial Trichoepithelioma, and Familial Cylindromatosis section in the Syndromes Associated With Rare Types of Skin Cancer 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.[134]

Table 4 summarizes available clinical practice guidelines for the surveillance of individuals with BCNS.

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) [55]
 • Low risk (PTCH1): No radiographic screening unless concerning neurological exam, head circumference change, or other unusual signs/symptoms [135]
 • High risk (SUFU): Brain MRI every 4 months through age 3 years, then every 6 months until age 5 years [135]
• Cardiac ultrasound (baseline)
• Dermatologic examination (baseline)
 • Annual by age 10 years, increased frequency after first basal cell carcinoma is diagnosed [135]
• 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)
 • Beginning at age 8 years, then every 12–18 months [135]
 • Some dermatologists recommend waiting until symptomatic to begin Panorex in order to limit radiation exposure [135]
• 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.[136] 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.[137] 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.[137] 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.[137-139] 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.[140] 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.[141] 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.[142] 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 keratinocyte carcinomas (BCC or SCC) within 5 years before study enrollment.[143] 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 keratinocyte carcinomas 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.[144,145] However, given the radiosensitivity of patients with BCNS, radiation as a therapeutic option for large tumors should be avoided.[53] 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.[144,145]

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.[146] 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;[147] 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.[148] Another small study found that four of six patients who took 150 mg of vismodegib daily had a reduction in the size of KCOTs.[149] 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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  74. Moss SD, Rockswold GL, Chou SN, et al.: Radiation-induced meningiomas in pediatric patients. Neurosurgery 22 (4): 758-61, 1988. [PUBMED Abstract]
  75. Chiritescu E, Maloney ME: Acrochordons as a presenting sign of nevoid basal cell carcinoma syndrome. J Am Acad Dermatol 44 (5): 789-94, 2001. [PUBMED Abstract]
  76. Tom WL, Hurley MY, Oliver DS, et al.: Features of basal cell carcinomas in basal cell nevus syndrome. Am J Med Genet A 155A (9): 2098-104, 2011. [PUBMED Abstract]
  77. Lo Muzio L, Nocini PF, Savoia A, et al.: Nevoid basal cell carcinoma syndrome. Clinical findings in 37 Italian affected individuals. Clin Genet 55 (1): 34-40, 1999. [PUBMED Abstract]
  78. Goldstein AM, Pastakia B, DiGiovanna JJ, et al.: Clinical findings in two African-American families with the nevoid basal cell carcinoma syndrome (NBCC). Am J Med Genet 50 (3): 272-81, 1994. [PUBMED Abstract]
  79. Yasar B, Byers HJ, Smith MJ, et al.: Common variants modify the age of onset for basal cell carcinomas in Gorlin syndrome. Eur J Hum Genet 23 (5): 708-10, 2015. [PUBMED Abstract]
  80. Mazzola CA, Pollack IF: Medulloblastoma. Curr Treat Options Neurol 5 (3): 189-198, 2003. [PUBMED Abstract]
  81. Amlashi SF, Riffaud L, Brassier G, et al.: Nevoid basal cell carcinoma syndrome: relation with desmoplastic medulloblastoma in infancy. A population-based study and review of the literature. Cancer 98 (3): 618-24, 2003. [PUBMED Abstract]
  82. Cowan R, Hoban P, Kelsey A, et al.: The gene for the naevoid basal cell carcinoma syndrome acts as a tumour-suppressor gene in medulloblastoma. Br J Cancer 76 (2): 141-5, 1997. [PUBMED Abstract]
  83. Evans DG, Farndon PA, Burnell LD, et al.: The incidence of Gorlin syndrome in 173 consecutive cases of medulloblastoma. Br J Cancer 64 (5): 959-61, 1991. [PUBMED Abstract]
  84. Berlin NI, Van Scott EJ, Clendenning WE, et al.: Basal cell nevus syndrome. Combined clinical staff conference at the National Institutes of Health. Ann Intern Med 64 (2): 403-21, 1966. [PUBMED Abstract]
  85. Jackson R, Gardere S: Nevoid basal cell carcinoma syndrome. Can Med Assoc J 105 (8): 850 passim, 1971. [PUBMED Abstract]
  86. Lindeberg H, Halaburt H, Larsen PO: The naevoid basal cell carcinoma syndrome. Clinical, biochemical and radiological aspects. J Maxillofac Surg 10 (4): 246-9, 1982. [PUBMED Abstract]
  87. CAWSON RA, KERR GA: THE SYNDROME OF JAW CYSTS, BASAL CELL TUMOURS AND SKELETAL ABNORMALITIES. Proc R Soc Med 57: 799-801, 1964. [PUBMED Abstract]
  88. Kedem A, Even-Paz Z, Freund M: Basal cell nevus syndrome associated with malignant melanoma of the iris. Dermatologica 140 (2): 99-106, 1970. [PUBMED Abstract]
  89. Zvulunov A, Strother D, Zirbel G, et al.: Nevoid basal cell carcinoma syndrome. Report of a case with associated Hodgkin's disease. J Pediatr Hematol Oncol 17 (1): 66-70, 1995. [PUBMED Abstract]
Sours: https://www.cancer.gov/types/skin/hp/skin-genetics-pdq
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Nonmelanoma Skin Cancer

Introduction

Nonmelanoma skin cancer (NMSC), is the most common malignancy in humans. The incidence of NMSC is not consistently reported to cancer registries; however, an estimated 5.4 million cases of NMSC were diagnosed in the United States in 2012.1,2 The average treatment cost of NMSC in the United States from 2007 to 2011 was estimated to be $4.8 billion annually.3

Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the 2 most common subtypes of NMSC and are sometimes referred to as keratinocyte carcinoma (KC). While BCC has traditionally thought to be approximately 4 times more common than SCC, recent evidence suggests that BCC and SCC may have similar incidences, a trend that may be related to an aging population, in which SCC is more common.2

The etiology of NMSC is strongly tied to ultraviolet (UV) radiation.4,6 Given the overwhelming incidence and cost of NMSC each year, prevention has become a public health priority. The American Academy of Dermatology recommends use of broad spectrum (long wave UV [UVA], 315-400 nm and short wave UV [UVB], 280-315 nm) sunscreen with a sun protection factor (SPF) of 30 or greater, abstinence from indoor tanning, and covering exposed skin from harmful sunlight whenever possible.7

Although the number of NMSC is staggering, both BCC and SCC have a better than 95% cure rate if detected and treated early.

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Basal Cell Carcinoma

Definition

BCC is the single most common cutaneous malignancy in humans. Although BCCs grow slowly and rarely metastasize, they can cause extensive tissue destruction through direct extension, leading to significant patient morbidity if untreated.

Epidemiology and Risk Factors

Over 1 million BCCs were diagnosed in the United States Medicare population alone in 2012.2 Although the incidence of BCC increases with age, it is becoming more common in younger adults, especially women.9 Factors such as excessive, chronic sun exposure, indoor tanning, fair complexion, prior exposure to ionizing radiation, exposure to chemical carcinogens such as arsenic, and genetic determinants are significant risks factors. Because of the increasing incidence in younger populations, health campaigns aimed at education and sun avoidance have been initiated with promising results.10

Pathophysiology and Natural History

The pathophysiology of BCC is not completely understood. Recent investigations suggest that BCC may arise from the stem cells of the hair follicle bulge or interfollicular epidermis rather than basal keratinocytes.8

The most common causative factor of BCC is UV radiation. UVB radiation has been shown to induce characteristic DNA mutations in keratinocytes called dipyrimidine dimers and manifest as signature mutations in tumor protein 53 (TP53), an important tumor suppressor gene.11TP53 is responsible for arresting the cell cycle so that induced mutations can be repaired. Mutated TP53 is nonfunctional and leads to dysregulation of the cell cycle, with resultant unlimited cell proliferation. Inactivation of TP53 is the second most frequently encountered mutation in BCC pathogenesis.12

Although the exact mechanism of BCC propagation remains unclear, it is believed to arise when mutations that control cell growth activate pluripotential stem cells in the epidermis. Patched 1 (PTCH1), a tumor suppressor gene that negatively regulates the hedgehog signaling pathway, is the most common mutation identified in BCC. Through a series of complex interactions, the hedgehog signaling cascade has a central role in activation and repression of an important transcription factor, glioma-associated oncogene. Dysregulation of this pathway results in the development and progression of numerous malignancies, including BCC.13 Other mutations less frequently associated with BCC involve ras oncogenes and smoothened (SMO).14

The natural progression of untreated BCC is persistent, slow growth with invasion and destruction of adjacent tissues. Metastasis is very rare in BCC, with an estimated incidence of 0.0028% to 0.55%.15 Risk factors for metastasis include increased size (3cm diameter is associated with 2% risk of metastasis),16 location on the face, longer duration, aggressive features on histology, perineural/perivascular involvement and recurrent tumors.17

When metastasis occurs, the face is most often the site of the primary lesion and regional lymph nodes are most often the site of tumor spread, followed by lung, bone, and skin. The average interval from the first signs of BCC to metastasis is approximately 9 years.15 Metastatic BCC traditionally has a poor prognosis, with a median survival of approximately 8 months to 3.6 years.15,18-19

Signs and Symptoms

BCCs primarily occur on the head and neck with the nose being the most common site. The typical lesion is a small, pearly (waxy) nodule with a central depression and rolled border containing dilated blood vessels. A history of ulceration, crusting, or bleeding is common. Over 20 different clinicopathologic subtypes of BCC have been reported though most major dermatology texts detail 4 or 5 major subtypes.20-21 Five clinicopathologic subtypes are described in this review: nodular-ulcerative, superficial, pigmented, diffuse (infiltrating, morpheaform and sclerosing) and fibroepithelial (also referred to as fibroepithelioma of Pinkus).

Nodular-Ulcerative

The nodular-ulcerative variant (Figure 1) is the most common type of BCC. It manifests as a small, pearly dome-shaped papule with surface telangiectasias and a typical rolled border. Over time, central ulceration with bleeding or crusting is often seen. Differential diagnosis of this lesion includes sebaceous hyperplasia, SCC, verruca vulgaris (wart), molluscum contagiosum, intradermal nevus, appendageal tumors (tumors of the hair follicle and sweat ducts), amelanotic melanoma, and stasis ulcers (when located on the shins).

Superficial

Superficial BCC (Figure 2) is the least aggressive subtype of BCC. They often manifest as several scaly, dry, round-to-oval erythematous plaques with a threadlike raised border on the trunk and extremities. If untreated, superficial BCCs can enlarge to 10 to 15 cm in diameter without ulceration. Differential diagnosis of superficial BCC includes eczema, psoriasis, seborrheic keratosis, and Bowen's disease (ie, SCC in situ).

Pigmented

Pigmented BCC (Figure 3) is seen more often in darker-skinned persons such as Latin Americans and Asians. This subtype has all the characteristics of the nodular-ulcerative variety plus brown or black pigmentation from melanin. A history of arsenic ingestion has been noted with pigmented and superficial BCCs.

Diffuse (Morpheaform, Sclerosing, Infiltrative)

An indurated yellow to white plaque with an indistinct border and an atrophic surface characterizes morpheaform or sclerosing BCC (Figure 4). Ulceration and crusting are usually absent. This variety has an aggressive growth pattern, and invasion of muscle, nerve, and bone may occur. Morpheaform BCC is particularly insidious because of its benign scar-like appearance. Differential diagnosis of morpheaform BCC includes scar, localized superficial scleroderma (morphea), sebaceous hyperplasia, dermatofibrosarcoma protuberans, and microcystic adnexal carcinoma.

Fibroepithelial (fibroepithelioma of Pinkus)

Fibroepithelial BCC is a rare and unusual variant of BCC. Clinically, they appear as skin colored to pink, smooth, pedunculated papules or nodules (Figure 5). The most common location is the trunk, especially the lower back and thigh. This entity often mimics various benign skin tumors and the differential diagnosis includes intradermal nevus, fibroepithelial polyp, acrochordon, and seborrheic keratosis.22 Some consider the fibroepithelial BCC to be a form of trichoblastoma.23

Related Syndromes

Multiple BCCs are features of several syndromes such as nevoid basal cell carcinoma syndrome (as called Gorlin-Goltz syndrome or Gorlin syndrome), Bazex–Dupré–Christol syndrome, and Rombo syndrome.

Gorlin syndrome is characterized by BCCs; odontogenic jaw cysts; pitted depression of the hands and feet; osseous anomalies of the ribs, spine, and skull; and characteristic facies (frontal bossing, hypoplastic maxilla, a broad nasal root, and true ocular hypertelorism).24 This genetic disorder occurs in an autosomal dominant pattern. There is a mutation of the PTCH1 tumor suppressor gene located on chromosome 9.25

Bazex–Dupré–Christol syndrome is a rare familial syndrome associated with the development of BCCs early in life. It is characterized by a triad of multiple BCCs, follicular atrophoderma of the extremities, and hypotrichosis.26 Other less common findings include milia, ichthyosis, hypohidrosis, and visceral malignancies. The inheritance pattern is X-linked dominant in most cases.

Rombo syndrome has similar features to Bazex–Dupré–Christol syndrome, but is inherited in an autosomal dominant pattern. Clinical characteristics include early onset BCCs, atrophoderma vermiculatum-like appearance on the cheeks, milia, hypotrichosis, trichoepitheliomas, telangiectases, and acral erythema.27

Diagnosis

Clinical diagnosis of BCC is confirmed by biopsy of the suspected lesion for histopathologic interpretation. Biopsy techniques include shave biopsy, punch biopsy, and excisional biopsy. The goal of the biopsy is to provide adequate tissue for accurate diagnosis. For the majority of BCC subtypes, a shave biopsy suffices. However, when the lesion is believed to be a morpheaform or infiltrative BCC, a deep shave, punch biopsy, or excisional biopsy is recommended to obtain a sufficient tissue sample for correct interpretation.28

Treatment

BCC can be effectively treated by a variety of therapeutic modalities. Among the clinical subtypes of BCC, superficial BCCs respond to most treatment options; large nodular, ulcerative or morpheaform lesions can require more aggressive therapy. No single treatment method is ideal or appropriate for all tumors. The treating physician should carefully evaluate each BCC on an individual basis and choose the modality that is most appropriate for the lesion's size, site, and histologic type, as well as the patient's age, functional status, and post-procedural expectations.28

Electrodesiccation and Curettage

Electrodesiccation and curettage (ED&C) is a commonly employed, relatively simple and cost effective method for treatment of BCC. A significant disadvantage of the ED&C is the lack of histological margin assessment. Current guidelines recommend ED&C as an appropriate treatment for primary, well defined lesions, measuring 1 to 2 cm on the trunk and extremities of relatively healthy, immunocompetent patients. Superficial and thin nodular BCCs are best treated by ED&C. ED&C is less effective in the cure of recurrent lesions, morpheaform or infiltrative type BCCs, and tumors of terminal hair bearing skin (due to the risk of follicular extension of malignant cells).28-29 Select low-risk lesions (ie, small, well defined primary lesions with nonaggressive histology not involving skin of the central face, ears, genitals, hands, and feet) can achieve 5-year cure rates of up to 97% when treated with ED&C.30

Primary nondiffuse type basal cell carcinomas are more friable than surrounding normal skin and are initially debulked with a curette. The stroma and surrounding dermis are then electrodesiccated. This process is usually repeated 2 additional times. The resulting wound heals with a hypopigmented scar over 2 to 6 weeks. The main disadvantage of this treatment is the absence of histologic margin control. Treatment of facial lesions with this modality is generally not advocated because of the risk of deep invasion in embryonal fusion planes, the difficulty of adequate curettage in the sebaceous skin of the nose, and poor cosmetic appearance.

Cryosurgery

Cryosurgery (also referred to as cryotherapy) may be considered in the treatment of low-risk BCC when other therapies are impractical or contraindicated.28 Like, ED&C, cryosurgery of BCC lacks histological margin assessment. Randomized trials comparing cryosurgery to alternative therapies for BCC have reported recurrence rates ranging as high as 15% to 39% within 5 years.31-33 Liquid nitrogen (temperature −196°C) produces tissue destruction by reducing the temperature of the skin cancer to tumoricidal levels. It is not indicated for tumors deeper than 3 mm or those with indistinct margins. The main disadvantages include a hypopigmented scar, prolonged healing, pain during the procedure, and risk of recurrence. Cosmetic results of excision are favored over cryosurgery.34

Surgical Excision

Recent guidelines recommend standard excision with a 4 mm peripheral margin to a depth of mid-subcutaneous adipose tissue for primary, low-risk BCC.28 This margin accounts for the characteristic subclinical extension of BCC and yields a clearance rate of 95% for BCC with a diameter of 2 cm or less.35 There is insufficient data to recommend standard excision margins for high-risk BCC. However if standard excision is chosen for the treatment of high-risk BCC, margins greater than 4 mm should be employed and higher recurrence rates should be expected.36 Following the procedure, surgical margins of the specimen are examined histologically for assessment of adequate tumor removal. The wound defect can be closed primarily with side-to-side (primary) closures, flaps, grafts, or it may be allowed to heal by secondary intention. A disadvantage of surgical excision is incomplete margin control. Because the routine vertical sectioning technique (“bread loafing and quartering” methods of margin assessment) only assess approximately 1% of the margin.37-38

Mohs Micrographic Surgery

Mohs micrographic surgery (MMS) is a surgical technique utilized for the removal and complete margin assessment of skin cancer. MMS is the treatment of choice for high-risk BCC according to the American Academy of Dermatology (AAD) and National Comprehensive Cancer Network (NCCN).28,36 Given the incidence of NMSC and the cost of MMS, 4 major dermatological societies jointly proposed appropriate use criteria for MMS in 2012. The criteria is based on evidence-based medicine, clinical experience, and expert opinion, and outlines a rating system for the appropriate use of MMS based on tumor characteristics (type, location, size, aggressiveness) and patient characteristics (immunosuppression or genetic predisposition for skin cancer).39

MMS consists of the removal of the tumor by scalpel in sequential horizontal layers. Each tissue specimen is mapped, frozen, stained, and microscopically examined. This procedure is especially suited for tumors in high-risk anatomical locations; recurrent, large or aggressive tumors; and in patients with risk for aggressive and recurrent tumors (Table 1).39

Table 1: Tumor Features Suited for Mohs Micrographic Surgery39
Location
  • Area H: “Mask areas” of face (central face, eyelids [including inner/outer canthi], eyebrows, nose, lips [cutaneous/mucosal/vermillion], chin, ear and periauricular skin/sulci, temple), genitalia (including perineal and perianal), hands, feet, nail units, ankles, and nipples/areola.
  • Area M: Cheeks, forehead, scalp, neck, jawline, pretibial surface.
  • Area L: Trunk and extremities (excluding pretibial surface, hands, feet, nail units, and ankles).
Patient characteristics
  • Immunocompromised: patient with HIV, organ transplant, hematologic malignancy, or pharmacologic immunosuppression.
  • Genetic syndromes: basal cell nevus syndrome, xeroderma pigmentosum, or other syndromes at high risk for skin cancer.
  • Healthy: no immunosuppression, prior radiation therapy, chronic infections, or genetic syndromes.
  • Prior radiated skin: patient has previously received therapeutic radiation in this area of the body.
  • Patient known to have high-risk tumors: patient without other known health risk factors but with a history of unexpectedly more aggressive tumors than suggested by clinical appearance.
Tumor characteristics
  • Positive margin on recent excision
  • Unexpected tumor involvement at lateral and/or deep edges after prior excision presumed to have been definitive.
  • Basal cell aggressive features
    1. Morpheaform/fibrosing/sclerosing
    2. Infiltrating
    3. Perineural
    4. Metatypical/keratotic
    5. Micronodular
    6. Squamous cell aggressive features
    7. Sclerosing
    8. Basosquamous (excluding keratotic basal cell carcinoma)
    9. Small cell
    10. Poorly differentiated or undifferentiated (characterized by a high degree of nuclear polymorphism, high mitotic rate, or low degree of keratinization)
    11. Perineural/perivascular
    12. Spindle cell
    13. Pagetoid
    14. Infiltrating
    15. Keratoacanthoma type: central facial
    16. Single cell
    17. Clear cell
    18. Lymphoepithelial
    19. Sarcomatoid
    20. Breslow depth 2 mm or greater
    21. Clark level IV or greater
Reprinted from the Journal of the American Academy of Dermatology, J Am Acad Dermatol, Vol 67/4), Connolly SM, Baker DR, Coldiron BM, Fazio MJ, et al, AAD/ACMS/ASDSA/ASMS 2012 appropriate use criteria for Mohs micrographic surgery: a report of the American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery, 536, 2012, with permission from the American Academy of Dermatology, Inc. and the American Society for Dermatologic Surgery, Inc.

The MMS procedure is predicated on histologically inspecting the entire perimeter and undersurface of the excised specimen to ensure a tumor-free margin. MMS has an extremely high cure rate. A randomized controlled trial in the Netherlands analyzed recurrence rates between MMS and standard excision in treatment of high-risk BCC of the face. A 10-year recurrence rate for primary facial BCC was 12.2% for standard excision and 4.4% for MMS. The 10-year recurrence rate for recurrent facial BCC was 13.5% for standard excision and 3.9% for MMS.40-41

Defects after MMS can be closed immediately or a delayed repair may be performed in select cases. Repair can be achieved with primary linear closure, adjacent tissue transfer (flap), skin grafting, or healing by second intention.

Radiation

Radiation may be considered for the treatment of BCC when surgical intervention is impractical, contraindicated, or if the patient prefers radiation therapy. Superficial high-dose x-rays are administered in multiple, divided doses over several weeks. Brachytherapy and electronic brachytherapy are newer techniques used to radiate the skin in treatment of BCC.28 Five-year recurrence rates for radiation therapy of BCC range from 4% to 16%.36 Radiation therapy is contraindicated in patients genetically predisposed to develop BCC (ie, basal cell nevus syndrome) and those with connective tissue disease.42 Adverse effects include radiation-related toxicity, alopecia, and increased risk for secondary malignancy.

Vismodegib and Sonidegib

Vismodegib and sonidegib are oral medications that inhibit the protein smoothened in the hedgehog signaling pathway, and function as novel therapy for the down-regulation of BCC tumorigenesis. Sonic hedgehog inhibitors (SHHi) are used in the treatment of locally advanced and metastatic BCC. Early studies show promising results in this previously difficult to treat population, with a recent meta-analysis suggesting that most patients receiving SHHi experience at least a partial response and nearly 95% have at least stable disease.43 Side effects can be severe and include muscle spasms, dysgeusia, alopecia, myalgia, nausea, and vomiting. A recent study identified a mechanism by which some BCC tumor cells are able to evade SHHi via transcriptional alterations that change cell identity.44 This mechanism may explain why some BCCs are not effectively treated with SHHi or rebound once treatment is discontinued.

Topical Therapy and Photodynamic Therapy

Topical imiquimod is an immunomodulating medication approved by the U.S. Food & Drug Administration for treatment of superficial BCC of the extremities, trunk, and neck. Treatment is once daily to several times weekly (the latter is preferred) for up to 16 weeks with clearance rates ranging from 60% to 80%.28 Side effects include local irritation and rare reports of systemic flu-like symptoms when used over larger surfaces. Topical 5-fluorouracil (5-FU) is an antimetabolite with less evidence for use in treatment of BCC. For low-risk tumors, twice-daily application for up to 6 weeks results in clearance of 50% to-90%.28 Side effects are similar to imiquimod.

Photodynamic therapy (PDT) involves application of a photosensitizing medication (5-aminolevulinic acid or methylaminolevulinate) followed by incubation with a light source leading to formation of reactive oxygen species and cytotoxic effects.45 In a study examining PDT treatment for nodular BCC, aggressive, repeated PDT treatments, after debulking with curettage, resulted in histological clearance rates of greater than 70% (nearly 90% clearance for tumors of the face) with good cosmetic results.46

Outcomes

Five-year recurrence rates after treatment of primary BCC are 1% for MMS, 7.5% for cryotherapy, 7.7% for ED&C, 8.7% for radiation therapy, and 10.1% for surgical excision.47 It is important to note that recurrence of primary BCC may occur greater than 5 years after treatment, highlighting the importance of long term follow-up.41 The primary goal in the treatment of BCC is using the most appropriate therapy for complete removal of the malignancy with the highest cure rate and least cosmetic disfigurement or functional impairment.

Prevention and Screening

Patients with a history of BCC have a higher propensity to develop new cutaneous malignancies, including melanoma.48-49 Long term follow-up and self- or family-examination in patients who have had a BCC are important methods for monitoring for recurrence and detecting new skin cancers. Sun protective behaviors include sun avoidance, wearing sun protective clothing, repeated sunscreen application, and avoiding tanning beds.28 Evidence from a recent randomized, controlled trial reported a 23% reduction in the rate of new NMSC in a high-risk population with use of oral nicotinamide 500 mg twice daily.50 Prevention, screening, and education are integral parts of the total care of a patient with BCC.

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Squamous Cell Carcinoma

Definition and Cause

Squamous cell carcinoma (SCC) is a malignant tumor arising from the keratinocytes of the epidermis or dermal appendages. SCC is the second most common cutaneous malignancy after basal cell carcinoma (BCC). Unlike BCC, cutaneous SCC is associated with a greater risk of metastasis.51 Like BCC, exposure to UV radiation is the most common cause of SCC in fair-skinned populations and immunosuppression is increasingly recognized as a risk factor.52

Prevalence and Risk Factors

An estimated 200,000 to 400,000 new cases of invasive cutaneous SCC occur in the United States annually.51 In 2012, as many as 12,000 nodal metastases and 8,500 deaths were associated with invasive cutaneous SCC.53 Compared with BCC, the incidence of SCC seems to be increasing more rapidly, with an estimated lifetime risk of 9% to 14% among men and 4% to 9% among women.51 The most significant risk factors for the development of SCC include sun exposure, fair skin, age, and immunosuppression.53-54

Pathophysiology and Natural History

Cumulative UV exposure is the primary etiological factor for SCC in fair-skinned individuals.55 Although UVB is mainly responsible, UVA also plays a role. As in the pathogenesis of BCC, UV radiation leads to the formation of dipyrimidine dimers and mutagenesis of the p53 tumor-suppressor gene. A nonfunctional p53 protein leads to dysregulation of the cell cycle, uncontrolled growth and proliferation of aberrant keratinocytes.11 Many other factors associated with the pathogenesis of SCC are detailed in Table 2.

Table 2: Risk Factors for Squamous Cell Carcinoma
UV exposure from sunlight
Other UV exposures
  • Photochemotherapy [eg, psoralen (methoxsalen) plus ultraviolet light of A wavelength (treatment)] for skin disorders such as psoriasis
  • Indoor tanning
  • Occupational exposures (ie, laboratory transilluminators, UV germicidal lamps)
Ionizing radiation (ie, X-rays, nuclear radiation, soil, cosmic sources at high altitudes [ie, airline pilots])
Thermal injury to the skin
Exposure to chemical carcinogens
Arsenic
Chromates
Mineral oil
Polycyclic aromatic hydrocarbons
Mechlorethamine (nitrogen mustard)
Tars
Tobacco smoke
Others
Human papillomavirus (HPV) infections, especially from HPV types 16, 18, 30, and 33
Previously injured or chronically diseased skin
Burn sites
Chronic ulcers
Chronic radiation dermatitis
Scars of various causes
  • Chronic inflammatory diseases of the skin (ie, discoid lupus, lichen planus, lichen sclerosis)
Fair skin – easily burns, never tans, freckling, red hair
Genetic determinants
  • Xeroderma pigmentosum
  • Oculocutaneous albinism
  • Dystrophic epidermolysis bullosa
  • Epidermodysplasia verruciformis
Immunosuppression
  • Organ transplantation
    Acquired immune deficiency syndrome (HIV/AIDS)
  • Chronic lymphocytic leukemia (CLL)
  • Iatrogenic immunosuppression (ie, chronic glucocorticoid or thiopurine use)

Signs and Symptoms

SCC can arise in any cutaneous epithelial site though sun exposed skin of the head and neck, dorsal hands, and dorsal forearms are the most common sites. Rates of metastatic SCC range from 4% to 16%, with tumor thickness (greater than 2 mm), localization to the ear and immunosuppression being key risk factors for metastasis.56 Tumors of the vermilion lip have a fivefold risk of nodal metastasis compared with tumors of the cutaneous lip. Tumors of the external ear are reported to have up to 10.5% occurrence of regional nodal metastasis.57-58

Actinic Keratosis

Actinic keratosis (AK) is a premalignant macule or papule, found on chronically sun exposed skin, chiefly the face, ears, dorsal hands, and forearms. AK growths vary in morphological appearance: they can be multiple, discrete, flat or raised, verrucous, keratotic, pigmented, erythematous or skin-colored. The surface is usually scaly (Figure 6).

AK is considered a precursor to SCC. The transformation rate to SCC is estimated to range from 0.25% to 20% a year for each AK.59-60 The transformation may be heralded by the development of erosion, induration, inflammation, tenderness or enlargement.

Clinically, and even histologically, it is difficult to differentiate low- and high-risk AK and treatment is recommended for any AK macule or papule.61 Options for treatment include cryosurgery, ED&C, topical 5-FU, photodynamic therapy, dermabrasion, chemical peel, and laser resurfacing. It has been estimated that there is a 10.2% chance of at least 1 AK on a given patient transforming into an SCC within 10 years.20 However, this rate might actually be much higher, especially in immunocompromised patients such as organ transplant recipients.

Bowen's Disease

Bowen’s disease, or SCC in situ, is characterized by well demarcated, erythematous, scaly, slowly enlarging plaques that can occur on any part of the body (Figure 7). It may initially be confused with psoriasis, nummular dermatitis, or tinea and treated unsuccessfully with topical corticosteroids or antifungals prior to diagnosis. When it occurs on the glans penis, it is referred to as erythroplasia of Queyrat. The development of ulceration or induration can portend transformation to invasive SCC, which occurs in at least 5% of cases.62 Bowen's disease affects mostly older white men. Chronic sun damage and arsenic exposure have been implicated in Bowen's disease. Treatment options include excision, ED&C, photodynamic therapy, cryosurgery, topical 5-FU (off-label), topical imiquimod (off-label), and MMS.

Keratoacanthoma

A rapidly growing tumor, the pathogenesis and natural history of keratoacanthoma (KA) this is poorly understood and presents both diagnostic and therapeutic challenges. KA is generally believed to be a low-grade SCC. It usually starts as a 1-mm flesh-colored macule or papule and grows to a 1 to 2 cm nodule with a keratin-filled crater within several weeks to several months (Figure 8). “Giant” KAs have been reported as large as 20 cm. In most cases, solitary keratoacanthomas involute over 2 to 6 months, often healing with scarring. Multiple KAs can arise sporadically or in genetically predisposed individuals (rare familial cases and those with genetic predispositions to carcinogenesis, ie, xeroderma pigmentosa).63 Keratoacanthomas are generally found on sun-exposed skin, although they can occur anywhere on the body including the mucosa. Although keratoacanthomas may ultimately involute, the duration of regression is unpredictable.

KAs may mimic invasive SCC with regard to rapid growth pattern and clinical characteristics. Histological diagnosis is highly dependent on the clinician’s biopsy technique. A method of removal that ensures adequate depth for histopathologic review is important. Management of KAs remains controversial. Options for therapy include observation (generally not recommended), surgical excision (preferred treatment), ED&C, cryosurgery, MMS, radiotherapy, photodynamic therapy, topical 5-FU, topical Imiquimod and intralesional, and injections of 5-FU, bleomycin, methotrexate, or interferon.63

Squamous Cell Carcinoma

SCC can arise on any skin surface including the mucous membranes. It most often occurs in fair-skinned, middle-aged to older adult males. The most common sites affected are the scalp, dorsal hands, ears, lower lip, neck, forearms, and legs. Clinically, SCC presents as an enlarging, indurated, erythematous papule, nodule, or plaque with overlying scale (Figure 9). Ulceration and crusting occur later, followed by possible invasion of underlying structures and development of regional lymphadenopathy. On the lower lip, SCC arises on the chronically sun-damaged skin of the vermilion border. Patients usually note the presence of a firm nodule growing either inward or outward with ulceration. Squamous cell carcinomas of the vermillion lip are important to recognize as they carry a fivefold increased risk of metastasis compared with SCC of the cutaneous lip.57

Verrucous Carcinoma

Verrucous carcinoma (VC) is considered a low-grade variant of well differentiated SCC. VC typically presents as an indolent, exophytic papule, nodule, or plaque that resembles a wart (Figure 10). The oral cavity, genital area, and plantar foot are most commonly involved.64 VC can be locally aggressive but rarely metastasizes. The most effective treatment is excision with MMS required in some cases.

Diagnosis

As with BCC, a total body skin examination is the only screening test available for cutaneous SCC. Findings associated with high-risk SCC include

  1. any lesion involving central face, eyelids, eyebrows, periorbital skin, nose, lips, chin, mandible, pre- and postauricular skin/sulci, temple, ear, genitals, hands, and feet
  2. lesions greater than 1 cm involving the cheeks, forehead, scalp, neck and pretibia; or lesions greater than 2 cm elsewhere on the trunk and extremities
  3. SCC in immunosuppressed patients or in areas of prior radiation or chronic inflammation
  4. any lesion that is clinically poorly defined, recurrent, rapidly growing or histologically poorly differentiated, has a histological depth of 2 mm or greater, or with any perineural, lymphatic, or vascular involvement.

A physical examination of patient with high-risk SCC should include thorough examination of the areas of lymphatic drainage. The clinical presence of lymphadenopathy necessitates exclusion of metastatic disease. Cutaneous lesions suspicious for SCC should be promptly biopsised. Biopsy methods include shave, punch and excisional biopsy. The goal of any biopsy is to provide adequate tissue for an accurate diagnosis. No single biopsy technique for SCC is recommended above another in the literature.51

Treatment

An exhaustive review of all treatment modalities for SCC is beyond the scope of this publication. However, the reader should know that many treatment modalities are available for SCCs and no single technique suites every tumor. Treatment can be customized depending on the characteristics of the SCC, patient characteristics/preferences, and the experience of the physician. Treatment techniques for SCC include: ED&C, excision, MMS, cryosurgery, photodynamic therapy, topical 5-FU, topical Imiquimod, carbon dioxide laser, and radiotherapy.65

Bowen’s Disease (Squamous Cell Carcinoma in situ)

Evidence based treatment recommendations for SCC are excluded from the 2018 AAD guidelines on SCC treatment. However, in the AAD 2006 guidelines for management of Bowen’s disease, the British Association of Dermatologists (BAD) identified ED&C, phototherapy, and excision as having an overall strength of recommendation “A-rating” for the treatment of SCCs.66 It should be noted that MMS has an important role in treatment of SCCs in high-risk locations but is not necessary or cost effective in all situations.

Invasive Squamous Cell Carcinoma

Electrodessication and Curettage (ED&C)

ED&C is a relatively simple and expeditious treatment of SCC that is regularly used by dermatologists in practice. According to current AAD guidelines, ED&C may be suitable for the treatment of small, low-risk, primary invasive SCC on sun-exposed skin.28 ED&C is discouraged for treatment of recurrent lesions that have associated scar tissue or tumors of terminal hair-bearing skin due to potential involvement of follicular keratinocytes.

This technique sequentially scrapes the tumor cells from the epidermis and dermis, followed by destruction of a margin of normal skin by electrodessication. While curettage is performed the physician is able to differentiate soft, friable tumor cells from firm, normal dermis. Curettage followed by electrodessication is generally performed in 3 cycles to maximize the possibility of complete removal. Recurrence of SCC following ED&C has been reported to be 1.7% in small, low-risk tumors.67

Limitations of ED&C include the lack of tissue available for histologic evaluation and possibly poor cosmetic outcomes. Because of this and potential for follicular extension, ED&C is not recommended for treating tumors of the face.

Cryosurgery

Cryosurgery, also called cryotherapy, utilizes the extremely cold (-196°Celsius) tumoricidal activity of liquid nitrogen to destroy a volume of tissue containing a cutaneous malignancy. A 3 mm to 4 mm margin of normal tissue should be included. Although the cost of cryosurgery is low and it is relatively simple to perform, limited data are available on the use of cryosurgery in the treatment of cutaneous SCC.

A meta-analysis of 8 studies identified an overall pooled average recurrence rate of 0.8% in 273 patients with SCC.67 These tumors were primarily small and low risk. Cosmetic outcomes were not included. A randomized controlled trial comparing treatment of SCC with either PDT, topical 5-FU, or cryosurgery, demonstrated inferior complete response rates at 12 months postintervention for lesions treated with cryosurgery compared with other modalities. Cosmetic outcomes were also inferior in patients treated with cryosurgery.68 Given the lack of margin analysis and notorious risk of subclinical extension of SCC, current AAD guidelines recommend use of cryosurgery for only low-risk SCC.51

Excision

As with BCC, surgical excision is a common and effective method to treat SCC. Excision involves making an elliptical incision around the SCC with a margin of 4 mm to 6 mm of normal appearing skin.69 The incision is taken down to mid-subcutaneous adipose tissue and removed at that plane. Histological margin assessment occurs following tissue fixation. A 2013 systematic review based on pooled analysis of 1,144 patients in 12 observational studies reported a local recurrence rate of 5.4% following excision of SCC with 2mm to 10 mm margins.67

According to recent AAD guidelines, low risk SCC may be treated by standard excision with a 4 mm to 6 mm margin of normal skin.51 Standard excision may be considered in high-risk tumors, however complete margin assessment is preferred due to the characteristic subclinical extension in these tumors.70 Overall, standard excision is a commonly utilized and effective treatment modality for SCC.

Mohs Micrographic Surgery

Dr. Frederic Mohs designed the “chemosurgery” procedure (ie, Mohs micrographic surgery) to account for subclinical extension of various cutaneous malignancies. The procedure initially involved in vivo fixation of tissue with zinc chloride followed by excision with conservative margins, then immediate and complete histological margin assessment.71 MMS is ideal for the complete removal of cutaneous malignancies while preserving as much normal surrounding tissue as possible.

A retrospective cohort study from the Netherlands compared the use of MMS with excision in the treatment of 579 patients with 672 SCCs (380 by MMS, 292 by excision). Risk of recurrence was 3% following MMS (median follow-up 4 to 9 years) compared with 8% following excision (median follow-up 5 to 7 years).72 In a meta-analysis by Lansbury, a five-year cure rate of 97.4% was reported after pooled analysis of 16 studies with 2,133 SCCs at all sites.67 A meta-analysis by Rowe of treatment for recurrent SCC reported a 5-year recurrence rate of 10% for MMS and 23.3% for excision.73

According to current AAD guidelines, MMS is recommended for the treatment of high risk SCC. Established criteria for appropriate use of MMS guide practitioners in clinical practice (Table 1).

Laser Surgery

Current AAD guidelines do not include the use of laser modalities for the treatment of SCC due to lack of evidence in the literature.51 Though evidence is limited, in practice ablative lasers may be considered for excision or destruction of SCC with excellent hemostasis. A recent, small prospective study examined the treatment of SCC in situ with a single pass of fractional CO2 laser treatment followed by application of 5-FU under occlusion. At 9 months post treatment, 92% of patients remained clear of tumor.74 While laser assisted delivery of topical chemotherapeutics may have a role in treatment of small, low-risk tumors in the future, use of ablative lasers alone for treatment of SCC in situ have not demonstrated promising results.75

Ionizing Radiation

Radiation therapy utilizes highly energized atomic and subatomic particles to kill cancer cells. Modalities used in treating cutaneous SCC include external radiotherapy and brachytherapy. These methods minimize the exposure of surrounding normal skin to ionizing radiation. Existing data on the use of radiation in the treatment of SCC is limited; however, it may be suitable for the primary treatment of SCC in situations where surgery is not possible or contraindicated. In a large study, recurrence rates of 6.4% and 5.2% were reported following external radiation and brachytherapy, respectively.67 Adjunctive radiotherapy may be used in high-risk SCC, perineural invasion, involvement of underlying muscle or bone, and nodal involvement.51,76 The most common adverse events include local erythema, desquamation, and alopecia.

Photodynamic Therapy

Photodynamic therapy (PDT) involves application of a photosensitizing topical medication (often 5-aminolevulinic acid) followed by irradiation of the area under a light source. This results in the production of reactive oxygen species within tumor cells. Evidence for the use of photodynamic therapy in treating SCC is limited. Like ED&C, cryotherapy, and radiation therapy, PDT does not allow for the histological confirmation of tumor clearance. Penetration of photosensitizing agents to adequate depths for complete tumor lysis appears to be a limiting factor.77 Pooled recurrence data from 8 studies with a total of 119 SCCs yielded a 26.4% odds of recurrence following PDT. Despite this, PDT may have an important future role in treatment of superficial SCC in patients unable to undergo surgery and research is ongoing. Current AAD guidelines do not advocate the use of PDT as a primary treatment for SCC.51

Evolving Treatments

Evolving therapies for treatment of SCC include continued investigation aimed at improving the efficacy of the treatments already discussed above, namely photodynamic therapy. Human papillomavirus (HPV) is known to have a role in SCC. HPV vaccination may have a role in prevention of SCC in certain patient populations.78 Treatment of metastatic SCC with epidermal growth factor receptor inhibitors (cetuximab, panitumumab) and immune check-point inhibitors (pembrolizumab) are currently being explored with promising results.51

Outcomes

Most patients with primary cutaneous SCC have a very good prognosis. However, patients with more advanced disease may have poor outcomes. Population-based SCC outcomes data is lacking in the United States; however, an estimated 3,932 to 8,791 Americans died from cutaneous SCC in 2012.79 Several large European population based studies indicate relative 5-year survival of 93.6% in Germany and 75% to 98% in Norway with 5-year survival for advanced SCC being as low as 51%.80-81

Prevention and Screening

With the increased incidence, associated morbidity, and cost of treating SCC in the United States, there has been increased interest in prevention and screening. The AAD recommends at least annual screening of patients diagnosed with SCC or BCC.51 This recommendation is based on studies that have identified an increased risk of additional NMSC as well as melanoma in individuals that have had at least 1 NMSCs.48-49 In fact, according to Wehner et al, patients with a history of 2 or more NMSC have an 82.0% risk of an additional NMSC at 5 years and a 91.2% risk of an additional NMSC at 10 years48

Screening consists of a full body skin exam as well as a lymph node exam in high-risk patients. Patients should be counseled on sun protection and self-examination (Table 3). More aggressive screening should be considered in patients with genetic predisposition to developing SCC and immunosuppressed populations (eg, organ transplant patients).

The AAD currently does not recommend routine use of topical or oral retinoids for the chemoprevention of SCC, with the exception of acitretin in solid organ transplant patients.51 Due to limited evidence, the AAD does not recommend use of oral nicotinamide, difluoromethylornithine, celecoxib, selenium or beta-carotene for the chemoprevention of SCC. Although not currently recommended, oral nicotinamide may be a safe an effective method for reducing risk of subsequent NMSC in certain populations.50 Additional randomized controlled trials investigating strategies for the prevention of NMSC are needed.

Table 3: Sun Protection and Skin Cancer Prevention Recommendations
Perform skin self-exams.
Notify your dermatologist of any growing, bleeding, or in any way changing findings on your skin.
Protect your skin from the sun.
Avoid tanning and never use a tanning bed or sun lamp
Wear sunscreen and lip balm daily, even in the winter, that provide:
  1. SPF 30 or higher
  2. Broad-spectrum (UVA/UVB) protection
  3. Water resistance
Apply sunscreen and lip balm to dry skin 15 minutes before going outdoors to every part of your body that will not be covered by clothing
Reapply sunscreen every 2 hours, especially after swimming or heavy perspiration
Whenever possible wear a wide-brimmed hat, long sleeves, and pants
Wear sunglasses to protect the skin around your eyes
Avoid outdoor activities when the sun is strongest between 10 am and 2 pm
Use condoms to prevent an HPV infection, which reduces the risk of squamous cell carcinoma of the genitals
Limit of alcohol consumption and do not smoke.
Drinking alcohol and smoking can increase the risk of squamous cell carcinoma in the mouth.
HPV = human papilloma virus; SPF = sun protection factor; UVA = ultraviolet A; UVB = ultraviolet B.; Adapted from AAD website.7

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Summary

  • Basal and squamous cell carcinomas are the most common cancer in humans.
  • Sun exposure is the primary etiological factor driving the development of nonmelanoma skin cancer.
  • Most nonmelanoma skin cancers have a high cure rate with early diagnosis and appropriate treatment.
  • Patients with a history of skin cancer should have a full skin examination on a regular basis, coupled with education about ultraviolet sun exposure and the regular use of sunscreen.
  • Immunosuppressed patients have a higher incidence of skin cancer, especially squamous cell carcinoma, which can be more aggressive with appreciable morbidity and mortality.

Acknowledgments

The authors wish to acknowledge the contributions of Rebecca Tung, MD, to a previous version of this chapter.

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Basal Cell Carcinoma - For Medical Students

What is Nevoid Basal Cell Carcinoma Syndrome?

Nevoid Basal Cell Carcinoma Syndrome (NBCCS) is also known as Gorlin syndrome. NBCCS is a hereditary condition characterized by multiple basal cell skin cancers. Other common signs include jaw cysts, pits on the palms of the hands or soles of the feet, calcium deposits in the brain, developmental disability, and skeletal (bone) changes. The appearance of a person with NBCCS may include a larger head size, a prominent forehead, broad bridge of the nose, widely spaced eyes, skin cysts, and small skin bumps called milia.

The jaw cysts and basal cell skin cancers may develop in the first 10 years of a person’s life, but they may not appear until the teenage years or any time during adulthood. Children with NBCCS may have the appearance features described above, including pits on their hands and feet. There is a small (5%) chance for children with NBCCS to develop a type of brain cancer called medulloblastoma. Rarely, benign (not cancerous) growths in the ovaries and heart may also be found.

Multiple basal cell skin cancers and jaw cysts are the most common features of NBCCS and are present in about 90% of people who have the condition. There are several other features that have been associated with NBCCS. The number of features present and the severity of symptoms can vary among people with NBCCS, even within the same family. People with darker skin with NBCCS may have jaw cysts as the primary feature of the disease and may develop far fewer sun-related basal cell skin cancers than people with lighter skin with NBCCS. Jaw cysts may cause symptoms such as bone deformity, infections and pain, or they may be seen through an x-ray.

What causes NBCCS?

NBCCS is a genetic condition. This means that the cancer risk and other features of NBCCS can be passed from generation to generation in a family. The major gene associated with NBCCS is called PTCH. A mutation (alteration) in the PTCH gene gives a person an increased risk of basal cell skin cancer and other symptoms of NBCCS. Research is ongoing to learn more about NBCCS and to identify other genes involved, such as SUFU.

Sun exposure and radiation therapy increase the number of basal cell skin cancers that a person with NBCCS develops. Some individuals may have thousands of basal cell cancers in areas of skin that are exposed to the sun or radiation therapy.

How is NBCCS inherited?

Normally, every cell has 2 copies of each gene: one inherited form the mother and one inherited from the father. NBCCS follows an autosomal dominant inheritance pattern, in which a mutation needs to happen in only 1 copy of the gene for a person to have the increased risk. This means that a parent with a gene mutation may pass along a copy of the normal gene or a copy of the gene with the mutation. Therefore, a child who has a parent with a mutation has a 50% chance of inheriting that mutation. A brother, sister, or parent of a person who has a mutation also has up to a 50% chance of having the same mutation. However, if the parents test negative for the mutation (meaning each person's test results found no mutation), the risk to the siblings significantly decreases but their risk may still be higher than an average risk. It is also possible that the NBCCS in an individual was caused not by an inherited mutation but, rather, by a spontaneous gene mutation (see below).

Options exist for people interested in having a child when a prospective parent carries a gene mutation that increases the risk for this hereditary cancer syndrome. Preimplantation genetic diagnosis (PGD) is a medical procedure done in conjunction with in-vitro fertilization (IVF). It allows people who carry a specific known genetic mutation to reduce the likelihood that their children will inherit the condition. A woman’s eggs are removed and fertilized in a laboratory. When the embryos reach a certain size, 1 cell is removed and is tested for the hereditary condition in question. The parents can then choose to transfer embryos which do not have the mutation. PGD has been in use for over 2 decades, and has been used for several hereditary cancer predisposition syndromes. However, this is a complex procedure with financial, physical, and emotional factors to consider before starting. For more information, talk with an assisted reproduction specialist at a fertility clinic.

How common is NBCCS?

It is estimated that about 1 in 40,000 people have NBCCS. As many as 30% of people with NBCCS do not have any family history of the condition. They have a de novo (new) mutation in the PTCH gene.

How is NBCCS diagnosed?

NBCCS is diagnosed when a person has at least 2 major features of NBCCS and 1 minor feature, or 1 major feature and at least 3 minor features.

Major Features:

  • Multiple (more than 2) basal cell skin cancers that appear earlier in life than is usual

  • Increased calcium deposits in the head that can be seen on an x-ray

  • Jaw or bone cyst(s)

  • 3 or more pits on the palms of the hands or soles of the feet

  • A parent, sibling, or child with NBCCS

Minor Features:

  • Medulloblastoma

  • Increased head size and large forehead

  • Cleft lip or palate, extra fingers or toes

  • Abnormal shape of the ribs or spinal bones

  • Eye problems such as cataracts, small eyes, or tumors in the iris

  • Fibromas, meaning benign fibrous tumors, of the ovaries or heart

  • Abdominal cysts

If a person has a family history of NBCCS, that person is also suspected of having NBCCS if they have jaw cysts, multiple basal cell skin cancers, pits on the palms of the hands or soles of the feet, or calcium deposits in the head. Genetic testing for mutations in the PTCH gene is available for people suspected to have NBCCS. A mutation in the PTCH gene is found in up to 85% of people diagnosed with NBCCS.

What are the estimated cancer risks associated with NBCCS?

People with NBCCS have a 90% risk of developing multiple basal cell skin cancers. About 5% of children with NBCCS will develop medulloblastoma, a type of brain stem tumor.

Researchers have studied the use of medications that target the so-called “hedgehog pathway”, which is affected by the PTCH mutation in people with NBCCS.There are 2 medications called vismodegib (Erivedge) and sonidegib (Odomzo) that have been approved by the U.S. Food and Drug Administration to treat people with basal cell cancers that have spread in the body or that cannot be treated with surgery or radiation. This treatment is a pill which blocks the activated pathway that results in basal cell cancers. Talk with your doctor for more information about treatment options.

What are the screening options for NBCCS?

Current screening recommendations for people who are known or suspected to have NBCCS include:

  • Neurologic evaluation every 6 months from birth to age 3, then every year to age 7 to look for signs of medulloblastoma or developmental disability

  • Measurement of head size regularly throughout childhood

  • Yearly dental x-rays, beginning at age 8, to look for jaw cysts

  • At least yearly skin exams to watch for basal cell skin cancer. The frequency of exams will vary based on how many basal cell cancers or other skin problems a person has experienced. Early treatment of basal cell skin cancer reduces the amount of surgery and scarring. Regular exams should begin by the teenage years.

Due to the high risk for multiple skin cancers, people with NBCCS should avoid sun exposure and protect their skin when outside. People with NBCCS should not receive radiation therapy, as this will increase the risk of basal cell skin cancers.

Screening recommendations may change over time as new technologies are developed and more is learned about NBCCS. It is important to talk to your health care team about appropriate screening tests. In general, if there is a good screening option that doesn’t use radiation, that screening option should be used to avoid skin damage and basal cell cancers.

Learn more about what to expect when having common tests, procedures, and scans.

Questions to ask the health care team

If you are concerned about your risk of skin cancer, talk to your health care team. It can be helpful to bring someone along to your appointments to take notes. Consider asking your health care team the following questions:

  • What is my risk of skin cancer?

  • What can I do to reduce my risk of skin cancer?

  • What are my options for cancer screening?

If you are concerned about your family history and think you or other family members may have NBCCS, consider asking the following questions:

  • Does my family history increase my risk of skin cancer?

  • Does it suggest the need for a cancer risk assessment?

  • Will you refer me to a genetic counselor or other genetics specialist?

  • Should I consider genetic testing?

  • What preventive measures would you recommend?

Related Resources

The Genetics of Cancer

Genetic Testing

What to Expect When You Meet With a Genetic Counselor

Collecting Your Family Cancer History

Sharing Genetic Test Results with Your Family

Family Genetic Testing Q&A

More Information

National Cancer Institute

National Organization for Rare Disorders

To find a genetic counselor in your area, ask your health care team or visit this website:

National Society of Genetic Counselors

Sours: https://www.cancer.net/cancer-types/nevoid-basal-cell-carcinoma-syndrome

Of carcinoma cell pathogenesis basal

Basal cell carcinoma: pathophysiology

Basal cell carcinoma (BCC) is the most common skin cancer in humans, which typically appears over the sun-exposed skin as a slow-growing, locally invasive lesion that rarely metastasizes. Although the exact etiology of BCC is unknown, there exists a well-established relationship between BCC and the pilo-sebaceous unit, and it is currently thought to originate from pluri-potential cells in the basal layer of the epidermis or the follicle. The patched/hedgehog intracellular signaling pathway plays a central role in both sporadic BCCs and nevoid BCC syndrome (Gorlin syndrome). This pathway is vital for the regulation of cell growth, and differentiation and loss of inhibition of this pathway is associated with development of BCC. The sonic hedgehog protein is the most relevant to BCC; nevertheless, the Patched (PTCH) protein is the ligand-binding component of the hedgehog receptor complex in the cell membrane. The other protein member of the receptor complex, smoothened (SMO), is responsible for transducing hedgehog signaling to downstream genes, leading to abnormal cell proliferation. The importance of this pathway is highlighted by the successful use in advanced forms of BCC of vismodegib, a Food and Drug Administration-approved drug, that selectively inhibits SMO. The UV-specific nucleotide changes in the tumor suppressor genes, TP53 and PTCH, have also been implicated in the development of BCC.

Sours: https://pubmed.ncbi.nlm.nih.gov/25134314/
Basal Cell Carcinoma (BCC) 101 - Dermpath Basics Explained by a Dermatopathologist

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