Version May 2024
INTRODUCTION — Cutaneous squamous cell carcinoma (cSCC) is among the most common of human cancers, with an estimated 1,000,000 new cases annually in the United States alone. Cutaneous ultraviolet (UV) radiation exposure is among the environmental exposures most closely linked to cSCC. It is estimated that some 5 percent of primary cSCCs become locally advanced or metastatic, most often to lymph nodes. Despite being the second most common skin cancer (after basal cell carcinoma), the exact incidence of cSCC is unknown. cSCCs as well as basal cell carcinomas are not typically reported to cancer registries, making it difficult to assess the global public health burden and social costs associated with these cancers [1].
This topic will discuss the molecular pathogenesis of cSCC. The epidemiology, clinical presentation, diagnosis, staging, and management of cSCC are discussed separately.
●(See "Cutaneous squamous cell carcinoma: Epidemiology and risk factors".)
●(See "Cutaneous squamous cell carcinoma: Primary and secondary prevention".)
●(See "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis".)
●(See "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma (cSCC)".)
●(See "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma".)
MOLECULAR PATHOGENESIS — Skin carcinogenesis is a multistep process of progressive and accumulating genetic and epigenetic alterations in key signaling pathways that regulate cell survival, cell cycle, and genome maintenance. Although the precise sequence of events leading to the development of invasive cSCC has not been defined, an increasing number of genetic alterations have been identified in cSCC and precursor lesions [2,3].
Cell of origin — The keratinocyte is the cell of origin of cSCC. Histologically, typical cSCC manifests as a malignant, keratinizing, squamous proliferation, emanating from the epidermis. As such, these cells are highly susceptible to ultraviolet (UV) radiation-mediated deoxyribonucleic acid (DNA) damage, which is manifest in the typical site distribution for cSCC and frequent findings of concomitant dermatoheliosis and solar elastosis. Although the risk of cSCC can be linked to many exposures, including UV radiation, ionizing radiation, human papillomaviruses (HPVs), and chemicals (arsenic), it is not known whether the development of cSCC results from distinct sets of genes or pathways being affected. The primary limitation is that cSCC has not been profiled as extensively, and data on subtypes linked to specific exposures are extremely limited and often difficult to compare [4-6].
The mutational landscape and impact of ultraviolet radiation exposure — The mutational landscape of cSCC is dominated by a large number of mutations, overwhelmingly represented by cytidine-to-thymidine transitions associated with repair of ultraviolet B (UVB) radiation-mediated DNA damage [7-14]. The majority of these mutations represent inactivation or alteration of function of tumor suppressor genes in the absence of widely prevalent, dominant, oncogenic drivers, in contrast to the genetic landscape of melanoma (table 1) [15]. Tumor mutational burdens of >45 mutations per megabase have been estimated, on par with those previously described for cutaneous melanoma [15] and basal cell carcinoma [16-18].
A UV-induced cSCC model in hairless mice replicated the spectrum of mutations and putative driver genes observed in human cSCC very closely, thus providing a preclinical model for prevention and treatment of cSCC [19].
The role of ionizing radiation in modifying the risk of cSCC is less relevant than for basal cell carcinoma, and molecularly distinct causes or signatures of cSCC attributed to ionizing versus UV radiation have not been identified [20,21].
Key genes and pathways — Multiple genomic studies have contributed to the delineation of the mutational landscape of cSCC [7-13]. The key genes and pathways involved in the cSCC carcinogenesis are summarized in the table (table 1). NOTCH and TP53 pathways are prominently affected, broadly abrogating normal squamous differentiation and classical tumor suppression pathways [22-27].
TP53 mutations were among the first to be identified in human cSCC [28]. So-called "p53-mutant clones" were also described in normal-appearing, sun-damaged skin [29]. Because mutation of TP53 often leads to stabilization of the protein, these clones are assumed to represent cells expressing mutated TP53. As a prototypical tumor suppressor gene altered in some 50 percent of all human cancers, these findings were among the first to link TP53 mutation to human cancer and to specify a role for UV-induced mutagenesis in this process [28,30-32].
In experimental systems, the disruption of NOTCH signaling is well established to result in the establishment of tumors in skin. Even removal of NOTCH signaling in the dermis alone can cause multifocal cSCC in mice [33]. Taken across published exome and targeted sequencing studies, the other most frequently mutated tumor suppressor genes (other than TP53 and NOTCH family members) are CDKN2A, atypical cadherin FAT family members, and the histone methyltransferases KMT2C and KMT2D [7-10,12,34]. Other potential tumor suppressors include CASP8, CREBBP, and CARD11 [35]. Mutant HRAS was present in 20 percent of cSCCs in at least one series [9]. Amplifications in c-MYC, CCND1, and EGFR, as well as loss of CKS1B and INPP5A, have been reported in cSCC [13,36-39].
A 2021 meta-analysis of whole-exome or whole-genome sequencing studies was performed to nominate a set of mutations likely to drive the formation of cSCC [13]. Using a relatively small set of publicly available data, a group of likely "driver" mutations was codified, identifying those most likely to directly contribute to pathogenesis and the tumor phenotype (figure 1) [13]. The results reiterated the key important drivers, such as inactivation of TP53, NOTCH1, NOTCH2, and CDKN2A, and also importantly highlighted potentially targetable mutations in HRAS and PIK3CA, suggesting potential avenues of future targeted therapies.
Some of these candidate drivers are corroborated by forward genetic mouse models based upon transposon mutagenesis across the entire genome, which can be studied in the context of specific tumor development (including cSCC) to identify novel drivers [40]. This type of cross-species analysis has the potential to quickly identify key drivers of biologic import.
One such example is IKK-alpha (CHUK), an upstream regulator of nuclear factor kappa B (NF-kB) signaling identified in both the human meta-analysis [13] and in the transposon mutagenesis model [40]. Removal of CHUK function in the skin of mice results in profound differentiation defects and formation of cSCC [41,42] and likely reflects a part of the spectrum of known roles of the NF-kB pathway in ectodermal dysplasias such as incontinentia pigmenti [43].
Additional key pathways — Proteomic interrogation of key cancer pathways shows upregulation of extracellular signal-regulated kinase (ERK) and mammalian (mechanistic) target of rapamycin (mTOR) signaling across the progression sequence of cSCC development [44,45]. Transcriptional profiling implicates transcription factors, such as E2F and ETS2, as well as WNT, beta-catenin, and ERK signaling [12].
ERK signaling is a canonical cell signaling pathway. In normal cells, this pathway is required for linking growth factor signaling to cell proliferation. It is frequently co-opted and hyperactivated in cancer.
The importance of the ERK pathway signaling is additionally manifest in two scenarios of drug-induced cSCC:
●cSCC/keratoacanthoma-like lesions were described in the initial clinical trials of the B-Raf proto-oncogene (BRAF) inhibitor vemurafenib, in which approximately 22 percent of treated patients with melanoma developed cSCC/keratoacanthoma-like lesions [46-48] (see "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy", section on 'BRAF inhibitors'). Mechanistically, the development of cSCC/keratoacanthoma-like lesions has been attributed to both paradoxical ERK signaling in BRAF wild-type cells [49,50], occurring most often in the context of oncogenic mutant HRAS [51], and to the suppression of apoptosis, which occurs as a result of off-target suppression of c-Jun N-terminal kinase (JNK) signaling [52]. Accordingly, the concomitant use of mitogen-activated protein kinase kinase (MEK) with BRAF inhibitors, which is now standard of care, suppresses the emergence of these lesions [53].
●Long-term therapy of basal cell carcinoma with the Smoothened (SMO) inhibitor vismodegib has been associated with the evolution of treated tumors to a cSCC-like morphology that is associated with drug resistance and activation of ERK signaling [54,55]. (See "Systemic treatment of advanced basal cell and cutaneous squamous cell carcinomas not amenable to local therapies", section on 'Basal cell carcinoma'.)
Collectively, these data strongly implicate ERK signaling as an important pathway in the pathogenesis of cSCC. This has also been validated in a UV radiation-driven preclinical model in which MEK inhibition had potent therapeutic and chemopreventive effects [56].
Chemical carcinogenesis — Chemical carcinogenesis of cSCC has been studied with the classical two-stage chemical carcinogenesis model in mice, in which a mutagen (eg, DMBA) is combined with a promoter (eg, a phorbol ester or UV radiation) to drive cancer formation [57]. The main advantage of this model is the ability to precisely temporally and molecularly dissect tumor initiation, progression, and metastasis. The molecular genetic analysis of tumor development in this model identified HrasQ61R as the primary oncogenic driver of tumors [58] one year following the cloning of HRAS as the first human proto-oncogene [59]. Tumors in this model also show Trp53 mutations at high frequency [60]. However, in model systems, choice of mutagen matters greatly.
The roles of human papillomavirus — The relationship between human papillomavirus (HPV) and cSCC has long been an area of intense interest. High-risk alpha-papillomaviruses are well-established, obligate drivers of most cervical squamous cell carcinomas (SCCs) and a minority of head and neck SCCs.
The predominant HPVs found in skin are beta-HPV species, which share the same viral oncoprotein activities as alpha-HPV. However, TP53 is commonly mutated, raising the question of whether viral oncogenic activities commonly ascribed to inactivation of p53 and pRB family members are necessary in this context. Ribonucleic acid (RNA) sequencing data fail to reveal HPV transcripts in cSCC, suggesting that HPV is not required for tumor maintenance [12,61]. There is evidence to suggest that beta-HPV may contribute to tumorigenesis by being critically important at early stages of tumor development but dispensable in later ones [62,63].
A study using a mouse model of murine papillomavirus skin infection suggested that, as a commensal, beta-HPV in human skin may contribute to inciting a CD8+ T cell-dependent immunity that protects against SCC development driven by chemical carcinogen or UV exposure [64]. However, how this finding can be reconciled with data suggesting a role of beta-HPV in promoting tumorigenesis through a "hit and run" mechanism, whereby beta-HPV plays an early cocarcinogenic role (eg, by suppressing cell death responses to UV radiation), remains to be defined. The "hit and run" mechanism implies the sustained maintenance of malignancy after the loss of viral "presence" in cancer cells [65]. This is mechanistically distinct from how alpha-HPV species cause anogenital and cervical SCC, in which viral genome integration and elaboration of viral oncoproteins is required for both tumor initiation and maintenance.
The genomic relationship between cSCC and SCC at other sites — The genomic data assembled for cutaneous squamous cell carcinoma (cSCC) show important similarities between cSCC and squamous cell carcinoma (SCC) arising in other anatomic sites. Stratified squamous epithelia are exposed to a multitude of environmental insults, including carcinogens such as alcohol and tobacco, and genomic data likely reflect common molecular consequences to diverse exposures.
For example, TP53 mutations occur at over 70 percent frequency across all extensively profiled SCCs, such as head and neck, lung, and esophageal SCC. NOTCH family genes are mutated in over 70 percent of cSCCs [7,8,10], 20 percent of oral (mucosal) head and neck SCCs [66-68], 13 percent of lung SCCs [69], and 10 percent of esophageal SCCs [70]. SOX2 amplification is a common lineage-specific driver of SCC [71].
These findings show that SCCs from diverse sites share pathway alterations, reflected in global gene expression and in TP53, TP63, NOTCH family, and SOX2 signaling (in particular delta-Np63 activation) [72]. There are less published transcriptomic and proteomic data, although the correspondence across nonviral SCCs is quite high [12].
DRUGS AND INTERACTIONS WITH ULTRAVIOLET RADIATION — Azathioprine, an immunosuppressant occasionally used for inflammatory dermatoses, gives rise to a novel mutational signature, which likely results from a unique interaction with ultraviolet A (UVA) radiation [73]. This signature has been shown to reduce the overall contribution of the classic ultraviolet (UV) signature in exome data from cSCC arising in patients exposed to long-term azathioprine therapy [74]. It is unclear how much this modifies risk of cSCC development or disease progression. (See "Epidemiology and risk factors for skin cancer in solid organ transplant recipients", section on 'Role of specific immunosuppressants'.)
SPECIAL SUBSETS OF CUTANEOUS SQUAMOUS CELL CARCINOMA — Two circumstances where cSCC has a distinctly different clinical behavior is in immunosuppressed patients and in genodermatoses that predispose to cSCC.
Immunosuppressed patients — As has been well established in clinical experience with solid organ transplant recipients, the risk of developing cSCC in the context of pharmacologic immunosuppression to maintain graft integrity is at least 100-fold higher than in the general population [75]. In this population, cSCCs are also known to be more aggressive, recur more frequently, and are potentially fatal [76-78].
In solid organ transplant recipients, immune surveillance is globally suppressed by drug therapy directed at T cells to prevent rejection. Moreover, immunosuppressive drugs given to solid organ transplant recipients may also contribute to specific mutations leading to oncogenesis. A gene mutation signature seen in cSCC arising in patients on azathioprine has also been demonstrated [74]. (See "Epidemiology and risk factors for skin cancer in solid organ transplant recipients" and "Prevention and management of skin cancer in solid organ transplant recipients".)
Recessive dystrophic epidermolysis bullosa — Recessive dystrophic epidermolysis bullosa (RDEB) is a devastating genodermatosis caused by loss of function of collagen VII, resulting in subepidermal blisters; chronic wounds; and aggressive, lethal cSCCs. (See "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features", section on 'Dystrophic epidermolysis bullosa'.)
Mutational profiling of these tumors implicates different drivers of mutations. First, it appears that the ultraviolet (UV) signature is significantly less dominant. Instead, these tumors have a high apolipoprotein B messenger RNA (mRNA) editing enzyme, catalytic polypeptide-like (APOBEC) signature as well as decreased APOBEC3A/B expression, with approximately two-thirds of the mutations being attributed to this mutation driver [79]. The APOBEC enzymes are cytidine deaminases, which can drive endogenous mutational processes independently from external, UV radiation-mediated mutagenesis. The accelerated pace of the APOBEC-driven mutational process in the context of the chronic inflammation of chronic wounds in patients with RDEB may explain the early onset of cSCC in these patients.
Xeroderma pigmentosum — Xeroderma pigmentosum (XP) is a rare genodermatosis caused by mutations in any of eight genes involved in the recognition and repair of UV radiation-induced DNA damage in a pathway called nucleotide excision repair [80]. This crucial mechanism of DNA repair is required for removal of mutagenic ultraviolet B (UVB) induced DNA photoproducts. Thus, affected individuals who have inherited these disease-associated alleles in autosomal recessive fashion are exquisitely photosensitive and at >10,000-fold higher risk of developing skin cancers, including keratinocytic carcinomas and melanoma, compared with nonaffected individuals. (See "Xeroderma pigmentosum".)
The mutational spectrum does not appear to be drastically different from that of sporadic, UV radiation-driven cSCC. However, the mutational burden in transcribed areas of the genomes is fivefold higher in cSCC in patients with XP as compared with cSCC not associated with XP and likely represents the mechanistic basis for the vastly increased susceptibility to skin cancer in childhood among these patients [81].
CHRONICALLY ULTRAVIOLET-DAMAGED SKIN AND PRENEOPLASTIC INTERMEDIATES
●Chronically ultraviolet-damaged skin – Through whole-exome sequencing [12] and targeted sequencing [82], it has been shown that chronically ultraviolet (UV) exposed skin has a mutational burden comparable with that of many human cancers [83]. Nonlesional, UV-damaged skin contains clones of keratinocytes, potentially up to several mm2 in size, bearing mutations known to be relevant in cSCC. In genomic terms, these areas are considered preneoplastic. At a very basic level, these observations suggest that a large mutation burden alone is insufficient to drive tumor formation and that additional constraints, perhaps structural and immunologic, play key roles in suppressing tumor formation.
●Actinic keratosis – The rate of progression of preneoplastic actinic keratoses (AKs) to cSCC is thought to be as high as 2.6 percent in four years [84], though data regarding the natural history of AKs are likely imprecise. At the genomic level, many of the key mutated genes observed in cSCC and irradiated skin are also found in AK [12,85], with no consistently identified transcriptional differences. Instead, the molecular profiles of most AKs are largely indistinguishable from those of well-differentiated invasive cSCC, suggesting that chemoprevention directed against mutagenized, sun-exposed skin may be effective in halting the development of cancer [12]. (See "Actinic keratosis: Epidemiology, clinical features, and diagnosis", section on 'Progression to skin cancer' and "Actinic keratosis: Epidemiology, clinical features, and diagnosis", section on 'Risk for skin cancer in other sites'.)
IMPLICATIONS FOR THERAPY AND PREVENTION
Therapy for advanced disease — One of the best established, though not universal, determinants of immunotherapy response is tumor mutation burden (TMB). This is expected to correlate positively with neoantigen load (NAL). Neoantigens are peptides produced by tumor tissue bearing mutations bound to major histocompatibility complex (MHC) class I molecules [86]. For many cutaneous malignancies, the response to immunotherapy is likely related to the high TMB related to ultraviolet (UV) radiation-mediated mutagenesis [87]. An exception is virally driven Merkel cell carcinoma, in which it is likely that very high-quality viral oncoprotein antigens drive responses to immunotherapy. (See "Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma".)
Systemic therapies for cSCC are dominated by the inhibition of the immune checkpoints cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). Only anti-PD-1 therapy is approved by the US Food and Drug Administration for advanced and metastatic disease, with very promising trial results in the neoadjuvant setting for cemiplimab [88]. (See "Systemic treatment of advanced basal cell and cutaneous squamous cell carcinomas not amenable to local therapies", section on 'Cutaneous squamous cell carcinoma'.)
Although not approved for the therapy of cSCC, epidermal growth factor receptor (EGFR) inhibition has long been employed to treat cSCC, based upon limited trial evidence. Two phase 2 trials demonstrated benefit of using cetuximab first line in unresectable squamous cell carcinoma (SCC) [89] and gefitinib in the neoadjuvant setting, some in combination with surgery [90]. However, this success with gefitinib was not replicated in incurable, recurrent, or metastatic cSCC [91]. This experience highlights a lack of understanding of mechanism and biomarkers of response. Oncogenic EGFR mutations found in lung cancer are not frequently observed in cSCC, and responses to EGFR inhibitors are not linked to EGFR expression level, amplification, or activation [89-92]. Clear relationships to the function of other members of the ErbB family have not been clearly established, indicating that there are still multiple opportunities to address important, unmet needs in cSCC.
Chemoprevention — While there has been tremendous progress in the development of novel approaches to skin cancer treatment, the management of field cancerization, especially in consideration of the high mutation burden of sun-exposed skin, remains largely uninformed by genomics data. While mitogen-activated protein kinase kinase (MEK) inhibition may be such a targeted approach, other targetable pathways, such as WNT, beta-catenin, and E2F/cell cycle pathways, may potentially be leveraged as well for prevention.
Data suggest that epigenetic modulation through histone deacetylase (HDAC) inhibition may be useful as well [93-95]. HDAC1 and HDAC2 are required for maintenance of proliferative capacity of basal keratinocytes; removal of their enzymatic activity promotes aberrant differentiation and apoptosis. In preclinical studies, chemical inhibition of HDAC activity exhibits antitumor activity and induces differentiation, suggesting that these approaches may be useful therapeutically [96].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cutaneous squamous cell carcinoma".)
SUMMARY
●Cell of origin and mutational landscape of cutaneous squamous cell carcinoma – The keratinocyte is the cell of origin of cutaneous squamous cell carcinoma (cSCC). These cells are highly susceptible to ultraviolet (UV) radiation-mediated DNA damage and also to other exposures, including ionizing radiation, human papillomaviruses (HPVs), and chemicals. The mutational landscape of cSCC is dominated by a large number of mutations, overwhelmingly represented by cytidine-to-thymidine transitions associated with repair of ultraviolet B (UVB) radiation-mediated DNA damage. Key genes and pathways involved in cSCC carcinogenesis include TP53, NOTCH, FAT1, and CDKN2A (table 1). The extracellular signal-regulated kinase (ERK) signaling appears to be an additional important pathway in the pathogenesis of cSCC. (See 'Cell of origin' above and 'The mutational landscape and impact of ultraviolet radiation exposure' above and 'Key genes and pathways' above.)
●Role of human papillomavirus – The predominant human papillomaviruses (HPVs) found in skin are beta-HPV species, which share the same viral oncoprotein activities as alpha-HPV involved in the oncogenesis of most cervical cancers. HPV may promote tumorigenesis through a "hit and run" mechanism, whereby the virus plays an early cocarcinogenic role without viral genome integration in the tumor cell. (See 'The roles of human papillomavirus' above.)
●Implications for therapy and prevention – The therapeutic implications of the molecular pathogenic mechanisms can lead to targeted approaches based on potential mutational, epigenetic, and transcriptional drivers. (See 'Implications for therapy and prevention' above and "Systemic treatment of advanced basal cell and cutaneous squamous cell carcinomas not amenable to local therapies", section on 'Eligible for immunotherapy'.)
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