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Nonmelanoma Skin Cancers: Basal Cell and Squamous Cell Carcinomas


Summary of Key Points

  • Incidence

  • More than 5 million new cases of nonmelanoma skin cancer (NMSC) occur annually in the United States, including 80% basal cell carcinomas (BCCs), 20% squamous cell carcinomas (SCCs), and a few rarer types.

  • Annual incidence is increasing by 4% for SCC and 1% for BCC in the United States.

  • Of solid organ transplant recipients, 15% to 43% will develop NMSC within 10 years.

  • Biologic Characteristics

  • Ultraviolet radiation from sun exposure is a major risk factor, causes mutations in key genes, and explains the predilection of NMSC for sun-exposed skin.

  • Hedgehog signaling pathway mutations are involved in BCC pathogenesis.

  • p53 Mutations are involved in both SCC and BCC pathogenesis, and in the development of actinic keratoses, which are the precursors of SCCs.

  • There are several histopathologic subtypes of each NMSC.

  • The more infiltrative or poorly differentiated variants are more clinically aggressive (e.g., morpheaform BCC and spindle cell SCC).

  • Staging Evaluation

  • TNM staging classifications exist for most types of NMSC and depend on clinical characteristics, pathologic features, and radiologic evaluation of the primary tumor, adjacent structures, lymph nodes, and viscera.

  • BCCs that are large, deep, or infiltrative may be locally aggressive and recurrent, but metastasize only rarely (0.003% to 0.55%).

  • SCCs have a greater metastatic rate, especially those that are large, deep, or poorly differentiated; have perineural invasion; or are located on the lip, ear, temple, cheek, or sites of chronic infection, ulceration, or radiation.

  • Primary Therapy and Results

  • Primary treatment for both BCCs and SCCs is surgical. Mohs micrographic surgery is preferred for ill-defined or aggressive lesions because it allows microscopic control of tumor margins.

  • The 5-year local recurrence rate for primary BCC is 1% for Mohs surgery compared with 5% for other types of surgical excision.

  • The 5-year local recurrence rate for primary cutaneous SCC is 3.1% for Mohs surgery compared with 7.9% for non-Mohs modalities.

  • Alternative primary therapies include various forms of physical destruction and radiation therapy.

  • Interferons and inducers of interferons (e.g., imiquimod) are useful in selected cases. Hedgehog pathway agents, retinoids, vitamin D 3 , and inhibitors of PD-1/PD-L1 and epidermal growth factor receptor (EGFR) are other promising adjunctive and chemopreventive modalities.

  • Locally Advanced and Metastatic Disease

  • Local recurrence is a problem for large, deep, or histologically infiltrative variants. SCCs with these features may also metastasize. The 5-year survival for patients with metastatic SCC is less than 50%.

  • The rarer forms of NMSC have a significantly more aggressive clinical course as compared with BCC and SCC. These include sebaceous carcinoma, Merkel cell carcinoma, dermatofibrosarcoma protuberans (DFSP), and cutaneous angiosarcoma.

  • Combinations of surgery, radiation therapy, and chemotherapy can be used for metastatic disease.

  • Palliation

  • Palliation is directed mainly at managing complications such as local recurrence, destruction of adjacent structures, scarring, and loss of function.

Most nonmelanoma skin cancers (NMSCs) are basal cell carcinomas (BCCs) or squamous cell carcinomas (SCCs). However, several rarer forms of NMSC exist, including four malignant neoplasms discussed in this chapter: sebaceous gland carcinoma, Merkel cell carcinoma (MCC), angiosarcoma, and dermatofibrosarcoma protuberans (DFSP). Each of these neoplasms is discussed separately after a summary of genetic alterations in BCC, SCC, and selected genodermatoses. Understanding the genetic basis of skin cancer is an important step in improving prognosis among patients with these neoplasms. Analysis of germline mutations in familial cancer syndromes and somatic mutations in sporadic skin cancers is providing new information that will facilitate the diagnosis of cutaneous malignant diseases and revolutionize their management.

Best Practices for Patient Screening and Tumor Prevention

A full-body skin examination is advised as part of an annual physical examination, especially for older adults and those with a family history of skin cancer. For those with a personal history of skin cancer, examination every 4 to 6 months is advised. For NMSC, special attention is paid to sites of previous skin cancer, changing or new skin lesions, and sun-exposed areas in general. Peripheral lymph nodes are palpated if there is a history of skin cancer with above average metastatic potential, such as SCC of the lip.

Prevention of NMSC mainly involves protection from the sun. Suntans should be avoided because they are a sign of, and response to, ultraviolet (UV) damage. The skin should be protected with a combination of clothing and sunblock of at least sun protective factor (SPF) 30 that is effective against both UVA and UVB wavelengths. Hats should have a 360-degree brim to protect the neck and ears, in addition to the face. Sunglasses that block UV light should be worn to protect the eyes, eyelids, and periorbital skin. Outdoor daylight activities are best restricted to the early morning, late afternoon, and early evening. The peak sunlight hours of 10 a.m. to 3 p.m. are best avoided by planning indoor activities during this period. The UV index is a daily rating of local UV intensity on a scale of 1 through 10. Although the scale can be useful in assessment of relative sun exposure risk, the best practice is always to follow the sun protection measures just outlined. Protect children, because sun-induced genetic damage begins in childhood, and most persons receive most of their lifelong sun exposure before adulthood. Retinoids and antioxidants may be beneficial for chemoprevention of NMSC.

When and How to Perform Biopsy

Unless logistical reasons preclude it, biopsy should be performed on all lesions suspected of being NMSC in order to establish the correct diagnosis, plan definitive therapy, and obtain prognostic information. The most important subjective symptoms can be summarized under the heading “change.” The changes may be appearance of a new growth or a change in the size, shape, color, sensation (itch or pain), crusting, or bleeding of a preexisting lesion.

For most cases of NMSC, standard shave biopsy performed with a scalpel or razor blade is adequate. Well-differentiated SCC and keratoacanthoma (KA) can be difficult to diagnose unless the deepest portions are included in the biopsy specimen, because these often are the areas most likely to yield enough information for a diagnosis. Deep shave, punch, incisional, or excisional biopsy often is preferable to standard shave biopsy in these cases. For large or ill-defined tumors, it is frequently helpful to perform multiple mapping biopsies to identify the most biologically aggressive features, define margins, and plan treatment.

Genetics of Nonmelanoma Skin Cancer

Advances in molecular genetics have allowed for key advances in our understanding of NMSC, the most common cancer in the United States. Like visceral malignant neoplasms, cancer of the integument is caused by defects in the normal genetic code. These genomic defects are either germline mutations (those caused by inherited mutations) or somatic mutations (those caused by acquired mutations). Actual tumor formation, however, is a complicated process, usually requiring more than a single mutation, and sometimes a combination of germline and somatic mutations. In addition, these cancerous cells are frequently altered in ways that help them escape detection by the host's immune system.

As in other malignancies, tumor suppressor genes and proto-oncogenes are two basic classes of genes that undergo mutations leading to skin cancer. The mutations in these genes lead to pathophysiologic changes, such as sustaining proliferative signaling, evading growth suppressors, resisting cell death, displaying replicative immortality, inducing angiogenesis, and activating invasion and metastasis, described as hallmarks of cancer. Examples of tumor suppressor genes (whose loss of function contributes to tumor development) include the Patched ( PTCH1 and PTCH2 ) genes involved in development of BCC, p53 involved in development of SCC, and the xeroderma pigmentosum (XP) genes involved in development of BCC, SCC, and melanoma.

Proto-oncogenes are another class of genes whose mutations contribute to skin cancer formation. They become oncogenes after acquiring gain-of-function genetic alteration. These are generally growth-signaling molecules that once mutated can perpetually cause normal cells to become malignant cells by altering cellular growth. Some examples are the ras oncogene, implicated in the development of SCC, and Smoothened (SMO), mutated in a subset of BCC.

Fundamental Science and Clinical Relevance

Hedgehog Signaling Pathway

The role of the Hedgehog (Hh) signaling pathway has been well documented in vertebrate embryonic development, stem cell maintenance, and tumorigenesis (reviewed in Riobo and Manning and Rubin and de Sauvage ). Activation of the Hh signaling pathway is a driving force in the development of both hereditary and sporadic cases of BCC. Each of the three Hh genes—Sonic hedgehog (SHH), Desert hedgehog (DHH), and Indian hedgehog (IHH) —encodes a secreted signaling peptide that binds to a membrane-bound 12-span transmembrane receptor called Patched (PTCH1 or PTCH2). Binding of Hh ligand to the PTCH receptor on the target cell alleviates PTCH-mediated suppression of the 7-span transmembrane protein called Smoothened (SMO). SMO activation initiates an intracellular signal transduction cascade that ultimately activates the expression of Hh target genes. Transcriptional activation of Hh target genes in mammals occurs through the actions of three related proteins: GLI1, GLI2, and GLI3. GLI3 acts primarily as a transcriptional repressor, whereas GLI2 is reported to be the primary activator of Hh signaling, and GLI1 is a secondary target, downstream of GLI2, that also acts as a transcriptional activator.

Aberrant regulation of the Hh pathway contributes to the development of many human cancers. Activating mutations of SMO or suppressing mutations of PTCH has been shown to constitutively activate the Hh signaling pathway (reviewed in Wicking and colleagues ). Involvement in human BCC was found through analysis of nevoid BCC kindreds (Gorlin syndrome, basal cell nevus syndrome). Persons with this autosomal dominant disease have odontogenic cysts, skeletal defects, palmar pits, various associated visceral tumors (medulloblastoma, meningioma, fibrosarcoma, cardiac fibroma, and ovarian fibroma), and multiple BCCs by a median age of 20 years. Early analyses mapped the defect to a tumor suppressor gene, PTCH1, on chromosome 9q22-q31. It was later elucidated that patients with nevoid BCC syndrome inherit one defective chromosome 9q region with loss of heterozygosity (LOH) in the PTCH1 locus. Many BCCs from these patients show inactivation of the remaining PTCH1 gene through acquired somatic mutations, consistent with the view that the BCC phenotype develops once both alleles are nonfunctional. Thus PTCH1 acts as a classic tumor suppressor gene in the skin. Mutations in PTCH1 also are common in many sporadic BCCs, as are mutations in other Hh pathway genes, including SMO, PTCH2, and SHH (reviewed in Li and colleagues ).

In addition to genetic abnormalities that result in constitutive activation of Hh signaling pathways, other rare hereditary syndromes that predispose to early onset of BCC have been described, including X-linked dominant Bazex-Dupré-Christol syndrome and autosomal dominant Rombo syndrome.

p53 Mutations

The protein p53 is encoded by the TP53 gene on chromosome 17p and is an important regulator of the cell cycle, DNA repair, and apoptosis. Inactivation of the p53 gene plays a principal role in the development of both premalignant actinic keratosis and SCC. Mutations in p53 associated with SCC are usually UV induced, and many are pyrimidine alterations with CC to TT (cysteine to threonine) changes. Both the loss of the tumor suppressor ability of p53 and the impact of UV irradiation on p53-induced apoptosis are linked to SCC development.

Mutations of TP53 have also been implicated in development of sporadic BCC. UV-induced alterations similar to those in SCC are involved in BCC induction. Many of the mutations are CC to TT or C to T alterations, consistent with UV damage.

ras Mutations

Mutations in the family of ras proto-oncogenes have been implicated in development of sporadic BCC, premalignant actinic keratosis, and sporadic SCC. They are among the most common mutations in human malignant disease. ras Proteins are small G proteins responsible for transducing intracellular signaling. Activation of ras occurs only when guanosine triphosphate (GTP) is bound. The signal is attenuated by hydrolysis of GTP to guanosine diphosphate (GDP). Mutations in ras alter the rate of this hydrolysis, resulting in activated protein that constitutively activates tumor promoting Ras-Raf-MAP kinase and PI3-K–AKT signaling pathways.

Mutations of Other Genes Predisposing to Nonmelanoma Skin Cancers

A variety of genetic syndromes are associated with cutaneous malignant tumors. These syndromes, caused by inherited mutations, include XP, Bloom syndrome, Rothmund-Thomson syndrome, Werner syndrome, Muir-Torre syndrome (MTS), multiple self-healing squamous epithelioma (Ferguson-Smith syndrome), dystrophic epidermolysis bullosa, junctional epidermolysis bullosa, epidermodysplasia verruciformis, Fanconi anemia, dyskeratosis congenita (Zinsser-Cole-Engman syndrome), and certain albinism syndromes.

The protein products of tumor suppressor genes involved in XP, Bloom syndrome, Rothmund-Thomson syndrome, Werner syndrome, MTS, dyskeratosis congenita, and Fanconi anemia have the common feature of being involved in chromosomal stability and DNA repair.

XP is a collection of autosomal recessive disorders characterized by severe photosensitivity with the onset of cutaneous malignant lesions at a very early age. BCC, actinic keratosis, SCC, and melanoma develop during the first decade of life in persons without adequate photoprotection. Mutations in eight genes have been implicated in different XP phenotypes, which vary in severity of cutaneous neoplasia and frequency of neurologic delay. All XP-associated genes encode proteins that are part of a DNA repair process known as nucleotide excision repair, which responds to UV-induced DNA damage. These proteins recognize the damaged DNA, unwind the coiled DNA structure, and repair the damaged strand. Germline mutations in these genes result in defects in the repair process and their genomic caretaker role; however, actual tumor production is still caused by mutagenic inactivation of tumor suppressor genes such as TP53 and activation of oncogenes such as ras.

Rothmund-Thomson syndrome, Bloom syndrome, and Werner syndrome are rare autosomal recessive disorders that have known defects in helicase genes and affect nucleotide excision repair. As in XP, these defects allow development of malignant skin lesions in affected patients. Both Rothmund-Thomson and Bloom syndromes are marked by early onset of SCC; however, patients with Werner syndrome seem to only have an increased risk of melanoma. Other syndromes with helicase gene defects, such as Cockayne syndrome and photosensitive trichothiodystrophy, have no associated increase in cutaneous malignant tumors. It is becoming clear that development of cutaneous malignant tumors is a complex process in which the ability to repair DNA is but one part of an intricate pathway. It seems that other mutations in tumor suppressor genes and oncogenes, whether germline or somatic, are necessary to invoke a tumor phenotype, as seen in XP.

MTS is an autosomal dominant syndrome characterized by various sebaceous gland tumors, ranging from benign sebaceous adenoma to malignant sebaceous carcinoma, and internal malignancies, mainly colon cancer. KA is another cutaneous neoplasm reported in as many as 20% of patients with MTS. Germline mutations in the human MSH2 and MLH1 genes have been identified in patients with MTS. Human MSH2 and MLH1 encode a type of DNA-mismatch repair enzyme involved in repairing errors in DNA replication that occur naturally at a low rate. Such defects result in varying lengths of repetitive DNA sequences known as microsatellite instability, which leads to functional gene mutations observed in KA and sebaceous tumors in MTS patients.

Dyskeratosis congenita is a progeroid disease associated with abnormalities in telomere function. The mutations in TERT, TERC, DKC1, TINF2, NHP2, TCAB1, and NOP10 may lead to shortening of telomeres resulting in premature aging, chromosomal rearrangements, and altered cell proliferation (reviewed in Mason and Bessler ). These patients often develop cutaneous squamous cell carcinoma (cSCC) in their teens or 20s, about half having SCC by the age of 50 years. This syndrome has a varied pattern of inheritance depending on the gene affected: DKC1, X-linked recessive; TERC and TINF2, autosomal dominant; NHP2, TCAB1, and NOP10, autosomal recessive; and TERT, autosomal dominant or autosomal recessive.

Fanconi anemia is associated with mutations in 1 of 15 genes involved in DNA cross-link repairs. This syndrome is characterized by early onset of a variety of hematologic and solid malignancies, including SCC. These patients have increased susceptibility to ultraviolet radiation (UVR) (and other DNA cross-linking agents) because the cells have altered ability to excise pyrimidine dimers. The majority of Fanconi anemia cases are autosomal recessive. Rarely, patients bearing FANCB mutations have an X-linked recessive pattern.

SCC is also a common feature in syndromes that are caused by structural abnormalities in skin, such as dystrophic epidermolysis bullosa with mutations in the gene encoding type VII collagen (COL7A1) that normally connects the basement membrane to the dermis or junctional epidermolysis bullosa with mutations in genes encoding basic subunits of laminin 332 ( LAMA3, LAMB3, and LAMC2 ), or COL7A1.

Because melanin protects keratinocytes from UVR, the number of inherited disorders that affect melanin synthesis, melanosomal and lysosomal storage, and pigment granule transport are associated with predisposition to SCC. These syndromes are characterized by an autosomal recessive pattern of inheritance and include oculocutaneous albinism, which is usually associated with mutations in TYR, OCA2, or TYRP1 , which affect melanin synthesis ; Hermansky-Pudlak syndrome, characterized by abnormal melanosome and lysosome transport (mutations in HSP1, HSP3, HSP4, HSP5, HSP7, HSP8, and HSP9 genes) ; Chediak-Higashi syndrome, characterized by abnormal lysosome transport (mutations in LYST ); and Griscelli syndrome, characterized by abnormal pigment granule transport (mutations in MYO5A or RAB27A ).

In addition to aforementioned mutations in the ras family, alterations in other genes involved in signal transduction have been shown to play a causative role in the development of SCC. Loss-of-function mutations in transforming growth factor-β receptor 1 (TGFBR1) are associated with multiple self-healing squamous epithelioma (Ferguson-Smith syndrome), and mutations in EVER1 and EVER2 are associated with increased susceptibility to human papillomavirus (HPV) types 5 and 8 in epidermodysplasia verruciformis.

What the Future Holds

Delineation of genetic alterations in genes involved in signal transduction pathways that drive skin tumor development have already resulted in the development of targeted therapies (e.g., managing BCC by suppressing the Hh signaling pathway at the level of SMO , or at the final effector, GLI ). Whole-genome sequencing of DNA from a large number of skin tumors (made possible with next-generation sequencing) combined with functional analysis of detected mutations is bound to identify novel targets and open new avenues for the treatment of cutaneous malignancies.

Basal Cell Carcinoma

BCC is the most common malignant tumor in the United States and in other areas with predominantly white populations.

Epidemiology

BCC accounts for approximately 80% of all skin cancers. A study estimated that over 5.4 million BCCs and SCCs are diagnosed in about 3.3 million Americans each year. Surprisingly, this study also demonstrated equal incidence rates for BCC and SCC in the Medicare population. Worldwide, the incidence for NMSC varies widely across different geographic locations. For instance, the BCC incidence rates (per 100 000 person-years) for men 80 years and older ranged from 475 in Trento, Italy to 14,173 in Townsville, Australia. The corresponding SCC incidence rates ranged from 79 in New Hampshire to 12,149 in Townsville, Australia. The study, which accounted for age, sex, and ambient UVR, provided an estimated annual increase in incidence rate of 4% for SCC and 1% for BCC.

Etiology and Biologic Characteristics

In addition to mutations in the Hh signaling pathway genes and TP53, exposure to UVR is the major risk factor for the development of BCC, especially severe sunburn during childhood and adolescence. Interesting to note, the risk of BCC is significantly increased by recreational, intermittent intense exposure to the sun, whereas SCC appears to be strongly related to cumulative sun exposure. Other associated risk factors are Fitzpatrick skin types 1 and 2, red hair, freckling in childhood, family history of skin cancer, male sex, and Celtic ancestry. Immunodeficiency secondary to acquired immunodeficiency syndrome or organ transplantation also is associated with increased risk of BCC. Other uncommon risk factors include exposure to arsenic, oral methoxsalen (psoralen), UVA radiation, and ionizing radiation, especially among patients who have received radiation for acne.

Keratin pattern and immunohistochemical results suggest that the origin of BCC is the outer root sheath of the hair follicle below the isthmus. Recent work using genetic mouse models of BCC has shown that stem and progenitor cells are the most probable sources of BCC initiation. The locally invasive characteristic of BCC could be related to the presence of an abnormal hemidesmosome-anchoring fibril complex.

Prevention and Early Detection

Patients need to be educated regarding skin self-examination and protection against sun exposure. Photoprotection is essential to prevent NMSCs and should begin at a young age to reduce the cumulative damage induced by the sun. Recently, chemopreventive agents for BCC have been explored, including retinoids, nonsteroidal antiinflammatory drugs, and difluoromethylornithine. Targeted skin cancer screening of high-risk populations is effective for early detection of BCC.

Pathology and Pathways of Spread

In common nodular BCC, nodular masses of basaloid cells extend from the epidermis or outer root sheath into the dermis with surrounding connective tissue stroma ( Fig. 67.1 ). Peripheral palisading of cells and stroma retraction artifact aid in diagnosis. There are several subtypes histologically, including pigmented, superficial, nodular, micronodular, infiltrative, morpheaform, and adenocystic, etc. Morpheaform BCC is distinct in that strands of deeply infiltrating tumor cells are embedded in a dense fibrous tissue stroma. The morpheaform and infiltrative types are in general the most locally invasive variants of BCC. It is common for BCCs to show mixed histologic patterns of these various types. Even the less invasive variants may invade deeply when located in regions of embryonic fusion planes, such as around the nose and ears. BCC can be locally aggressive but metastasis is rare, with rates ranging from 0.003% to 0.55%.

Figure 67.1, Histopathologic features of basal cell carcinoma.

Clinical Manifestations, Patient Evaluation, and Staging

The most common location for BCC is the head and neck, especially the nose. BCC occurs on hair-bearing skin; mucosal surfaces are not involved. The major types of BCC include nodular, superficial, pigmented, and morpheaform. The typical nodular BCC is a dome-shaped, pearly papule with a telangiectatic surface and translucent rolled borders ( Fig. 67.2 ). The surface might become ulcerated ( Fig. 67.3 ). In darker-skinned individuals, especially African Americans, the more darkly pigmented BCCs may be misdiagnosed as seborrheic keratosis or nodular melanoma. Superficial BCC is a well-demarcated erythematous scaly plaque with elevated borders that often occurs on the trunk or extremities. It might be confused with Bowen disease or nummular eczema. The most difficult BCC to diagnose and manage is the morpheaform or sclerosing variant. This ill-defined, white, indurated plaque can be mistaken for a scar or localized patch of scleroderma and therefore is ignored by patient and physician, with resulting wide subclinical extension.

Figure 67.2, Typical presentation of basal cell carcinoma on the nose.

Figure 67.3, Ulcerated basal cell carcinoma with rolled borders on posterior ear.

Patients with lesions clinically suspected to be BCC should undergo skin biopsy for histologic evaluation. Pertinent history is taken, such as the rate of growth, prior therapy, local neurologic symptoms, and evidence of immunosuppression, and a thorough skin examination is recommended. No formal staging system has been developed specifically for BCC. The American Joint Committee on Cancer (AJCC) staging system for cSCC of the head and neck ( Table 67.1 ) applies to BCC in addition to SCC. It is important to stratify BCC into high-risk or low-risk lesions to guide treatment. Criteria for high-risk BCC include size greater than 2 cm, location in the midface (H zone) or ear, morpheaform or other aggressive histologic pattern, long duration, incomplete excision, perineural or perivascular involvement, and recurrent lesion.

Table 67.1
TNM Staging System for Cutaneous Squamous Cell Carcinoma of the Head and Neck
T: PRIMARY TUMOR
TX Primary tumor cannot be assessed
Tis Carcinoma in situ
T1 Tumor <2 cm in greatest dimension
T2 Tumor ≥2 cm, but <4 cm in greatest dimension
T3 Tumor ≥4 cm in maximum dimension or minor bone erosion or perineural invasion a
T4 Tumor with gross cortical bone/marrow, skull base invasion and/or skull base foramen invasion
T4a Tumor with gross cortical bone/marrow invasion
T4b Tumor with skull base invasion and/or skull base foramen involvement
a Deep invasion is defined as invasion beyond the subcutaneous fat or >6 mm(as measured from the granular layer of adjacent normal epidermis to the base of the tumor); perineural invasion for T3 classification is defined as tumor cells within the nerve sheath of a nerve lying deeper than the dermis or measuring ≥0.1 mm in caliper, or manifesting with clinical or radiographic involvement of named nerves without skull base invasion or transgression.
N: REGIONAL LYMPH NODES
Clinical N (cN)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE(−)
N2 Metastasis in single ipsilateral lymph node, >3 cm but not >6 cm in greatest dimension and ENE(−); or in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension; or in bilateral or contralateral lymph nodes and ENE(−), none >6 cm in greatest dimension and ENE(−)
N2a Metastasis in single ipsilateral lymph node, >3 cm but no >6 cm in greatest dimension and ENE(−)
N2b Metastasis in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension and ENE(−)
N2c Metastasis in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension and ENE(−)
N3 Metastasis in lymph node, >6 cm in greatest dimension and ENE(−); or metastasis in any node(s) and clinically overt ENE [ENE(+)]
N3a Metastasis in a lymph node >6 cm in greatest dimension and ENE(−)
N3b Metastasis in any node(s) and ENE(+)
Pathologic N (pN)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE(−)
N2 Metastasis in single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE(+), or >3 cm but not >6 cm in greatest dimension and ENE(−); or metastases in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension and ENE(−); or in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension and ENE(−)
N2a Metastasis in single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE(+), or a single ipsilateral node >3 cm but not >6 cm in greatest dimension and ENE(−)
N2b Metastasis in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension and ENE(−)
N2c Metastasis in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension and ENE(−)
N3 Metastasis in lymph node, >6 cm in greatest dimension and ENE(−); or in a single ipsilateral node >3 cm in greatest dimension and ENE(+), or multiple ipsilateral, contralateral, or bilateral nodes, any with ENE(+)
N3a Metastasis in a lymph node >6 cm in greatest dimension and ENE(−)
N3b Metastasis in a single ipsilateral node >3 cm in greatest dimension and ENE(+), or multiple ipsilateral, contralateral, or bilateral nodes, any with ENE(+)
Note : A designation of U or L may be used for any N category to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L).
Similarly, clinical and pathologic ENE should be recorded as ENE(−) or ENE(+).
M: METASTASIS
M0 No distant metastasis
M1 Present distant metastasis
STAGING FOR CUTANEOUS SQUAMOUS CELL CARCINOMA
Stage 0 Tis N0 M0
Stage I T1 N0 M0
Stage II T2 N0 M0
Stage III T3 N0 M0
Stage III T1 N1 M0
Stage III T2 N1 M0
Stage III T3 N1 M0
Stage IV T1 N2 M0
Stage IV T2 N2 M0
Stage IV T3 N2 M0
Stage IV Any T N3 M0
Stage IV T4 Any N M0
Stage IV Any T Any N M1
From American Joint Committee on Cancer Staging Manual, Eighth Edition, 2017.
ENE, Extranodal extension.

Two-thirds of BCC recurrences occur during the first 3 years after treatment. The average risk of development of another BCC is approximately 36% within 5 years. The risk of development of another NMSC is associated with the number of previous NMSCs. In an Australian study of patients with three to nine previous NMSCs, the risk of development of a new cancer was 93%. Patients treated for BCC need to be examined at least once a year for the first few years, preferably for 5 years after the last cancer was diagnosed. For patients with a history of multiple skin cancers, more frequent follow-up examinations are recommended.

Primary Therapy

BCC is rarely metastatic but can be locally invasive ( Fig. 67.4 ). Consequently, eradicating the primary tumor is the goal of therapy. Several treatment options are available, both surgical and nonsurgical. Selection depends on the tumor type, patient profile, size and location of tumor, recurrence, physician's experience, and patient preference. Nonsurgical options include radiation therapy and photodynamic therapy. Other treatment modalities, such as immunotherapy with intralesional interferon and topical 5% imiquimod (Aldara), chemotherapy with 5-fluorouracil, and retinoids, have been reported with variable success ( Fig. 67.5 ).

Figure 67.4, Basal cell carcinoma of 10 years’ duration invading the scapula.

Figure 67.5, Treatment algorithm for basal cell carcinoma. EDC, Electrodesiccation and curettage; 5-FU, 5-fluorouracil; PDT, photodynamic therapy.

A systematic review of studies in which investigators reported recurrence rates of BCC after different treatment modalities showed that the mean 5-year recurrence rates after Mohs surgery and surgical excision were approximately 1% and 5.3%, respectively. High-risk BCC with increased risk for recurrence should be completely resected, preferably with Mohs technique or excision with margin control. Mohs surgery should be used in areas where preserving maximum tissue is important, such as eyelids, nose, and lips. It is also indicated for recurrent BCC and tumors with ill-defined clinical margins. In 2012, the American Academy of Dermatology (AAD) developed its first appropriate use criteria (AUC) on Mohs micrographic surgery (MMS) in collaboration with the American College of Mohs Surgery (ACMS), American Society for Mohs Surgery (ASMS), and American Society for Dermatologic Surgery (ASDS). If simple excision is used, the margin for excision, according to the newest National Comprehensive Cancer Network (NCCN) guidelines, should be at least 4 mm for low-risk tumors, and wider for high-risk tumors. If there are contraindications to surgery, or for a low-risk tumor that is small and located on less critical sites, such as the trunk, cryotherapy or electrodesiccation and curettage (EDC) can be used with good outcome. Because of the less favorable long-term cosmetic results and the possibility of secondary radiation-induced skin cancer, radiation therapy is best avoided in the care of relatively young patients.

Treatment of Locally Advanced and Metastatic Disease

Very large or poorly controlled BCC may necessitate a coordinated approach of standard surgical excision, Mohs surgery, radiation therapy, immunotherapy, chemotherapy, or targeted therapy suppressing the Hh signaling pathway. Vismodegib and sonidegib are both synthetic oral inhibitors of SMO which have been approved by the US Food and Drug Administration (FDA) for adults with locally advanced BCC that has recurred after surgery, or who are not candidates for surgery or radiation. Vismodegib is also approved to treat patients with metastatic BCC. Side effects, costs, and tumor recurrence when the treatment is discontinued are the main drawback of targeted therapy.

Challenges and Future Possibilities

Other potential new BCC therapies include vitamin D 3 , which works through blocking Hh signaling, topical treatment with the RARB/RARG-selective retinoid tazarotene, molecules targeting epidermal growth factor receptor (EGFR) pathway, and monoclonal antibodies blocking programmed cell death receptor 1/programmed cell death ligand 1 (PD-1/PD-L1). It remains to be determined whether the strategy of inhibiting Hh signaling will truly result in the eradication of BCC and why certain tumors are refractory to such treatment.

Squamous Cell Carcinoma and Bowen Disease

SCC is a malignant tumor of keratinocytes of the skin or mucosal surfaces. SCC has greater metastatic potential than BCC and causes the majority of NMSC deaths.

Epidemiology

SCC is the second most common skin cancer in the United States, representing approximately 20% of NMSCs. Interesting to note, SCC occurs more than BCC in African Americans and Asians. It is more common in men than in women.

Etiology and Biologic Characteristics

SCC and BCC share many common risk factors, the most important being solar radiation. The incidence of SCC is increasing, especially on the head and neck area as a result of exposure to sunlight. SCC is thought to be correlated with recent (in the 10 years preceding diagnosis) chronic sunlight exposure and cumulative sun exposure. Phototherapy with PUVA (psoralen plus UVA) increases the risk of SCC. Other risk factors for SCC include fair skin, red hair, albinism, and Celtic origin. Nonsolar risk factors include exposure to chemicals (insecticides and herbicides), arsenic, organic hydrocarbons, chronic thermal injury and scars, ionizing radiation, and chronic immunosuppression. Tobacco is a risk factor for oral SCC. Viruses, especially HPV, have been linked to epithelial malignancies, including SCC. This is especially true among patients with epidermodysplasia verruciformis, who have an underlying immunodeficiency and can develop SCCs within HPV-infected warts.

Carcinogens such as UVR, certain chemicals, and viruses play a role in the pathogenesis of SCC by damaging keratinocyte DNA and other cellular contents. It is known that UVR, especially UVB, causes mutations in DNA of keratinocytes. Early repair of these mutations is important for the prevention of SCC. Patients with NMSC are thought to have decreased ability for DNA repair compared with controls, thus making them more susceptible to the effects of UVR. UVR also causes cutaneous immunosuppression, weakening the host's immune response against tumor cells and promoting tumor growth.

The development of SCC does not occur by a simple single step, but rather through a multistage process. Conversion of susceptible keratinocytes to premalignant cells and then progression to carcinoma occurs as a result of successive genetic hits. In the initiation stage of carcinogenesis, there is clonal expansion of premalignant cells. The next stage is increased proliferation of premalignant cells and subsequent chromosomal aberrations. The final stage is conversion to SCC. DNA aneuploidy with a single peak was detected with flow cytometry in lesions of Bowen disease, suggesting a monoclonal proliferation of abnormal keratinocytes and a clonal basis for skin cancer. Aberrant expression of P-cadherin, and changes in expressions of cytokeratins and transforming growth factors, all play a role in tumor progression.

Prevention and Early Detection

Prevention of SCC is similar to that of BCC, that is, an emphasis on photoprotection is essential. Interesting to note, one study showed that regular application of sunscreen has prolonged preventive effects on SCC but no statistically significant benefit in reducing BCC. Treatment of precursor actinic keratoses with field therapy such as photodynamic therapy, topical 5-fluorouracil, and imiquimod cream may reduce the number of lesions transformed into SCC. Promising chemopreventive agents for lesions in the actinic keratosis–SCC spectrum include retinoids, cyclooxygenase-2 (COX-2) inhibitors, difluoromethylornithine, and epigallocatechin gallate (EGCG), a green tea catechin. In organ transplant recipients, systemic retinoids and reduction of immunosuppression are used as preventative means in reducing the incidence of NMSCs. One study showed that high-dose topical tretinoin, however, is ineffective at reducing risk of NMSCs in high-risk patients.

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