Squamous cell carcinoma (SCC) of the skin is a common cutaneous malignant tumor, with progressively increasing incidence and rising cost of management. Although most of these tumors can be effectively treated by surgical resection alone, a small fraction of patients can develop metastases and die, since there are very few effective therapeutic options for the management of metastatic SCC. Certain clinical and histopathologic parameters have been shown to correlate to some extent with aggressive behavior of SCC. However, identification of driver mutations that can be effectively targeted for therapeutic benefit has been problematic, since several studies focusing on gene expression, cytogenetic abnormalities, genomic alterations and epigenetic changes have demonstrated high mutational burden in cutaneous SCC due to chronic ultraviolet light exposure. Therefore, there is an ever-increasing need for identification of specific genetic and epigenetic markers that predict aggressive behavior and/or are targetable in cutaneous SCC. The objective of this review is to summarize the clinical and histopathologic characteristics of aggressive SCC as well as molecular events (genetic and epigenetic changes) that might contribute to squamous carcinogenesis and/or promote aggressive behavior in cutaneous SCC.
skin, squamous cell carcinoma, genes, mutations, amplifications
Cutaneous squamous cell carcinoma (cSCC) is the 2nd most common cutaneous malignant tumor, primarily affecting the Caucasian population worldwide . cSCC account for about 0.7 to 1 million cases annually in the US [2,3], of which 0.2 to 0.4 million cases are invasive, and the incidence continues to rise . Recent reports show that, cSCC is the most common form of cancer among chronically immunosuppressed patients . In particular, solid organ transplant recipients are at 65 to 250-fold risk of developing cSCC and their tumors tend to be more numerous, larger and exhibit greater aggressiveness compared to those in the general population [6,7]. Along with increased incidence of cSCC , the cost of management of these patients is also escalating rapidly [3,9].
Although cSCC constitute only 20% of all non-melanoma skin cancers or keratinocyte carcinomas, approximately 3-7% do metastasize and over 70% of patients that developed nodal metastasis died due to the disease (~2% of patients with cSCC) [4,10,11]. Prospective identification of such aggressive tumors may aid in identifying patients at high-risk for developing metastasis. Some histopathologic and clinical characteristics of the primary tumor correlate with aggressive behavior [12,13]. Identification of molecular events associated with high-risk behavior is pivotal to determining the risk of cSCC recurrence and metastasis and to determine which of these alterations could be targeted in a meaningful way. However, this process is hampered due to the presence of high background mutational burden in cSCC. We review the key clinical and histopathologic features that are typically associated with high-risk cutaneous squamous cell carcinomas (HR-cSCC) and summarize the most common and relevant molecular changes that accompany such a behavior.
Etiopathogenesis of cutaneous squamous cell carcinoma
Cutaneous SCC is a multifactorial disease, with fairly well established etiologic factors
(summarized in Table 1) that frequently play synergistic roles. Chronic exposure to the sunlight, in particular to ultraviolet-B radiation (UVR) plays a seminal role in squamous carcinogenesis [14-16]. Sun exposure has increased substantially in the past few years due to a multitude of causes including aging, recreational activities, tanning and occupational exposure . There is a dose-dependent risk for developing cSCC with cumulative exposure to UVR [18,19], since UVR-induced C→T transitions and CC→TT mutations lead to generation of genotoxic bipyrimidine photoadducts . In addition to direct DNA damage, UVR-induced immunomodulation is also contributory to squamous carcinogenesis . Patients with Fitzpatrick types I and II skin as well as those with defective DNA repair processes are at increased risk for developing UVR-induced malignancies .
Table 1. Etiologic factors of cutaneous squamous cell carcinomas.
Human Papilloma Viruses- types β and γ
Human Immunodeficiency Virus
Severe combined immunodeficiency
Chronic lymphocytic leukemia
Iatrogenic: Immunosuppressive therapy for
Transplant: solid organ, stem cell
Defective DNA repair mechanism:
Rothmund Thomson syndrome
Recessive dystrophic epidermolysis bullosa
Ferguson Smith syndrome
Discoid lupus erythematosus
Exposure to medications such as cytotoxic or chemotherapeutic agents including azathioprine, cyclosporine and voriconazole is associated with increased risk for cSCC development [23-27], especially in chronically sun-exposed/damaged (CSD) skin. Squamous carcinogenesis has also been associated with chronic exposure to arsenic  and wood tar derivatives such as creosote . Though a direct causative role for tobacco smoking has not been established in cSCCs, its inhibitory effect on wound healing may indirectly attribute to chronic inflammation  and thus, increase the risk of developing cSCC . Unmitigated chronic inflammation is also an established cause of cSCC and is commonly seen in the setting of non-healing wounds secondary to burns, hidradenitis suppurativa, chronic osteomyelitis, discoid lupus erythematosus, etc. [32,33]
Primary and acquired immunodeficiency and the resulting impairment of tumor surveillance mechanisms is a major risk factor for development of cSCC [34,35]. This association is a growing concern in view of increasing number of organ transplant recipients and patients that require immunosuppressive therapy for management of inflammatory disorders such as rheumatoid arthritis [6,7]. cSCC are major health hazards in patients with hematologic malignancies such as chronic lymphocytic leukemia (CLL) and Hodgkin lymphoma [36-38]. The higher prevalence of beta and gamma type-human papilloma viral (HPV) infection in immunocompromised patients is a major predisposing factor for SCC development [39-41].
In addition, genetic predisposition for developing a range of cutaneous tumors including cSCC is well established in patients with defective DNA repair . Mutations in genes encoding for structural proteins (COL7A1)  and transmembrane channels (EVER/TMC) [43,44] also render patients susceptible to development of intractable cSCC.
High-risk cutaneous squamous cell carcinomas
Though most tumors are amenable to cure by surgical resection, a small fraction (5-10%) of cSCCs may be difficult to excise with clear margins. They may recur locally and/or metastasize to regional lymph nodes and rarely to distant organs. Metastases are most commonly encountered within the first two years after the initial diagnosis [11,38]. Prospective identification of patients at risk for developing such high-risk cSCC could facilitate early deployment of preventive measures . Several clinical and histologic features have been associated with aggressive behavior in cSCC (Table 2) and some of these have been included in the 7th edition American Joint Committee on Cancer (AJCC) staging system .
Table 2. Characteristics of high-risk cutaneous squamous cell carcinomas.
Age at diagnosis > 70 years
Solid organ transplant
Chronic lymphocytic leukemia
Preauricular area / cheek
Dorsum of hands
Non-healing wound / sites of chronic inflammation
Tumor diameter / size > 20.0 mm
Tumor depth > 2.0 mm
Invasion beyond subcutaneous tissue
Tumor cell type / growth pattern
Poor differentiated / grade 3
Local recurrence after surgical resection
cSCC located in certain anatomic sites such as external ear, cheek, cutaneous lip, temple, nose, dorsum of hands and anogenital area tend to behave in an aggressive fashion [11,46,47]. Tumors of ear, cutaneous lip and temple are associated with increased risk for recurrence and disease-specific death; while those from ear, lip, temple and cheek tend to have a higher rate of metastasis . In general, cSCC of the head and neck region have higher rates of metastasis and decreased overall and disease-specific survival . One study reported that cSCC of lower extremities may require multiple resections to achieve clear margins ; however, high incidence of aggressive behavior have not been documented in cSCC arising at this site.
Systemic immunosuppression is associated with enhanced aggressiveness in cSCC . In particular, solid organ transplant recipients are at 65 to 250-fold risk for developing greater numbers of cSCC and these tumors tend to be highly aggressive, sometimes with intractable clinical course [6,7]. Patients with CLL are at 7-17 fold increased risk for developing HR-SCC [52,53]. Local immune-deregulation in the form of persistent chronic inflammation is a major causative factor in the development of cSCC [32,33,54]. Inflammatory mediators, in particular MIF is reported to be upregulated in UVR-damaged skin as well as cSCC and inhibition of this pro-inflammatory cytokine has been reported to be beneficial at several stages of UVR-mediated squamous carcinogenesis .
Older age at diagnosis (over 70 years) is in general a risk-factor for having an aggressive cSCC . This could be due to life-long exposure to sunlight leading to higher cumulative dose of UVR; age-associated, UVR-induced and sometimes iatrogenic reduction in immunity as well as inadequate access to or under-utilized health care. cSCC are more common in men compared to women; occupational exposure to sunlight and inherent differences in DNA damage, inflammation and repair mechanisms between male and female skin could be attributed to this dissimilarity . However, it is unclear how these differences contribute to aggressive biologic behavior in males .
The size and thickness of the primary cSCC have been established to be important risk factors for recurrence and metastasis and have been included in the recent AJCC staging system (Figure 1) . Though not always predictive, the maximum tumor diameter or size more than 20.0 mm has been associated with almost 3-fold increased risk for metastasis and 2 times propensity for local recurrence, metastasis and disease-specific survival (DSS) [48,56-58]. Also, tumors ≥ 40.0 mm were associated with increased risk for mortality .
While it is conceivable that greater tumor thickness might be correlated with high-risk features, multiple cut-off values have been reported in the literature to predict aggressive behavior [49,56]; for instance, >6.0 mm is correlated with increased local recurrence and shorter metastasis- free survival . Recent studies have demonstrated that any tumor with depth more than 2.0 mm has increased risk for local recurrence and metastasis [48,57]. cSCC of identical tumor thickness located in different sites of the body might behave differently, depending on the thickness of reticular dermis and subcutaneous fibroadipose tissue. Therefore, invasion into reticular dermis and subcutaneous fibroadipose tissue could be potentially associated with aggressive behavior . Invasion beyond subcutaneous tissue, particularly into underlying muscle or bone is associated with higher risk for metastasis [10,11,48,60].
Poor differentiation of the tumor cells is associated with 2-fold increased risk of local recurrence and 3 times risk for metastasis , as well as increased disease-specific mortality . Predominance of acantholysis, spindled morphology and/or desmoplastic growth pattern has been shown to be more frequently associated with local recurrence and metastasis in some studies [60-63].
Perineural invasion is identified in up to 14% of all cSCC, and is particularly common and associated with worse prognosis in head and neck cSCC . Perineural invasion is associated in increased risk for local recurrence (up to 47%), nodal metastasis (~35%), distant metastasis (almost 5-fold) and disease-specific death [48,64].
Local recurrence after surgical resection is frequent in cSCC in men and is often associated with the presence of perineural invasion, large dimensions and deep invasion . This may necessitate several surgical resections for complete clearance with satisfactory margins. Local recurrence of cSCC is associated with increased rates of metastasis as well [56,65].
Molecular alterations in cutaneous squamous cell carcinomas
Surgical resection with clear margins is the standard of care for most cSCC cases; however, many HR-cSCC are typically not amenable surgical cure. Therefore, identification of specific molecular changes that are potentially targetable is of paramount importance for control of disease in patients with aggressive cSCC. Currently available advanced molecular screening assays have contributed to amassing inventories of molecular alterations in various neoplasms, including cSCC. However, identification of specific targetable genes, gene products and/or signaling pathways has been challenging in cSCC, due to the high mutational burden seen in these tumors secondary to chronic UVR exposure [66-70]. Therefore, differentiating oncogenic driver mutations from passenger mutations is challenging and the most frequent molecular events are reviewed below (Figure 2).
Figure 1. Histologic features of high-risk cutaneous squamous cell carcinoma. (A) Deeply invasive cSCC extending to the dermal subcutaneous interface with tumor depth of 53.0 mm. (B) Perineural and intraneural invasion (arrow heads mark tumor cells). (C) Poorly differentiated cSCC (grade 3). (D) cSCC with acantholysis.
Figure 2. Schematic representing progressive acquisition of genetic and epigenetic alterations (listed below) during the development of cutaneous squamous cell carcinoma.
Frequently identified mutations in cSCC
Gene expression analyses using microarrays have revealed that several potentially oncogenic genomic alterations may exist in histologically normal CSD skin . Gene expression profiles were similar between actinic keratoses (AK) and cSCC, but were found to be distinct from that of CSD and sun-shielded skin . MMP1, a matrix metalloprotease, keratinocyte activation markers such as Keratin6a, transcription factors including STAT1, and the Wnt signaling cascade protein WNT5A were among genes that were upregulated in cSCC compared to normal skin. In contrast, IGFL1, markers of differentiating spinous keratinocytes such as SPRR1A, SPRR1B and involucrin were differentially expressed in AKs when compared to CSD skin and cSCC . Bioinformatics analyses highlight several signaling pathways operative in SCC and enrichment of adhesion proteins such as integrins α2 and α6, MMP1, inflammatory mediators such as IL8, and HIF1 to be upregulated in SCC .
Next generation sequencing (NGS) analyses have revealed that though cSCC are predominantly driven by UVR exposure, they share similar molecular alterations with SCC arising in other parts of the body , compared to other non-squamous cell carcinomas. The most frequently mutated genes included PIK3CA, CCND1, CDKN2A, SOX2, NOTCH1, and FBXW7, while KRAS mutations were conspicuously absent in SCCs, suggesting that this gene alteration profile imparted ‘squamousness’ to these tumors. The authors also identified 2 molecularly divergent groups of SCCs containing either p53 and cyclin pathway alterations or PIK3CA mutations.
Whole exome sequencing (WES) on fresh-frozen tumor tissue from aggressive cSCC arising from head and neck skin (metastatic and/or displaying high-risk features) revealed mutations involving 23 genes including TP53, CDKN2A, NOTCH1, NOTCH2, AJUBA, HRAS, CASP8, FAT1, KMT2C, PARD3, RASA1 and RIPK4 . Of these KMT2C mutations were associated with increased risk for bone invasion and hence, a worse prognosis. Sequencing of advanced cSCC (77 primary and 45 metastatic tumors) identified TP53, CDKN2A, NOTCH1, KMT2D, LRPIB, and TERT to be commonly mutated (in approximately 20% of the tumors tested) . Other clinically relevant mutations were identified involving PTCH1, BRCA2, HRAS, ATM, ERBB4, NF1, PIK3CA, CCND1, EGFR and FBXW7 genes. Sequencing of 29 metastatic cSCC also confirmed the presence of commonly identified mutations involving TP53, CDKN2A, NOTCH1 and NOTCH2 . Functional mutations of BRAF, KRAS, FGFR3, KIT, HRAS, EGFR, ERBB4, EZH2, MTOR, PIK3CA, HGF, and CARD11 were also detected in some cases and several of these are actionable.
Commonly mutated genes in cutaneous squamous cell carcinomas
Data from the genomic analyses mentioned above have identified some genes to be frequently mutated in cSCC. For instance, more than 90% of cSCCs and their precursors including most AKs harbor UVR induced TP53 mutations [75-77], which are easily detectable by immunostains, even in histologically unremarkable CSD skin . Loss-of-function mutation involving both p53 alleles is a critical molecular event that triggers transformation of AK into cSCC . The level of p53 protein expression in SCCs have also been correlated to the histologic grade, high-risk features, and therefore, to the stage and prognosis .
NOTCH is a direct target of p53 contributing to differentiation of epidermal keratinocytes; while NOTCH1 is expressed throughout the epidermis, NOTCH2 is localized principally to the basal layer [81-83]. Inactivation of NOTCH1 or NOTCH2 through point mutations in functional domains as well as truncation mutations is a common event in cSCC and has been identified in more than 75% of these tumors . NOTCH1 mutation is an early event in squamous carcinogenesis of the skin and has been identified as patchy loss of expression in histologically normal epidermis , and can be induced by exposure to UVR . Inhibition of NOTCH by HPV-derived proteins also contributes to oncogenic transformation of keratinocytes .
CDKN2A encodes for p16INK4a and p14ARF, of which inactivation of p16INK4a (also referred to as p16) by loss of heterozygosity (LOH), mutations and homozygous deletions has been associated with progression of cSCC from AK and increased expression of p16 has been reported in up to 50% of all cSCC [87-89]. Gain-of-function mutations of HRAS have been identified in up to 20% of cSCC [66,68,79]. However, the incidence of HRAS mutations is more prevalent in squamous lesions developing in patients receiving BRAF inhibitor therapy (~40%) . EGFR overexpression is a common feature of SCC and EGFR activation appears to be an early event in squamous carcinogenesis, more than 50% of AKs and ~70% of cSCC exhibit several EGFR signals, while EGFR amplification was identified 12% of AK . EGFR inhibitor therapy has shown promise in treatment of aggressive cSCC in the neoadjuvant setting .
Increased expression of the transcriptional coactivator p300 is common in aggressive cSCC and has been associated with shorter recurrence-free-survival and overall survival in these patients . UVR-induced mutations are common in cSCC compared to SCC of other organs and are identified in 50-70% of cSCC cases [94,95]. UVR-signature mutations in KNSTRN, a kinetochore protein have also been detected in up to 19% of cSCC . Point mutations of KNSTRN affect chromatid adhesion, leading to aneuploidy in keratinocytes, a feature associated with high-risk cSCC . These mutations can be identified in histologically normal epidermis, AK and cSCC. CARD11 is a scaffold protein that regulates NFkB signaling cascade; point mutations of CARD11 can lead to constitutive activation of the NFkB pathway, which in turn contributes to transformation of keratinocytes . CARD11 mutations are identified in the surrounding histologically normal epidermis, suggesting that these are also early events in squamous carcinogenesis.
MAPK and PI3K/AKT pathways are mostly commonly altered in cSCC. Altered expression of TP63, NOTCH-1,2,4 RIPK4, CARD11, in conjunction with CREBBP and p300 enhance proliferation while blocking terminal differentiation of keratinocytes, leading to malignant transformation. Inactivating mutations of p53 and rarely Rb as well as activating mutations of cyclinD1 provide survival advantage and resistance to apoptosis to the transformed keratinocytes .
Chromosomal alterations in cSCC
Single nucleotide polymorphism (SNP) assays reveal fewer genomic alterations in well-differentiated SCC compared to moderately and poorly differentiated tumors ; allelic imbalances were identified in a median of 5 and 9 chromosomes in well-differentiated and moderately or poorly differentiated tumors, respectively. Copy number gains were identified on chromosomes 3q, 5q, 7, 8q, 9q, 11q (CCND1), 14, and 20, while loss of 3p, 4, 5q, 8p, 9p, 11, 17p, 18, 19, and 21 were frequent . Genome-wide association study of primary cSCC identified SNPs in 10 common loci, 6 of which contained genes controlling pigmentation such as SLC45A2, IRF4, TYR, HERC2/OCA2, DEF8 and RALY . FOXP1, TP63, HLA-DQA1 and BNC2 were located at regions of other SNPs.
Epigenetic changes in cSCC
Loss-of-heterozygosity (LOH) at 9p was the most frequent epigenetic event identified in approximately 75% of cSCCs, while the 2nd most common event was LOH at 3p was found in 65% of the cases . Homozygous microdeletions at 9p23, corresponding to PTPRD locus was identified in 15% of the examined cSCC and most of these tumors were poorly differentiated, while only a few of those had given rise to metastasis. In addition, homozygous microdeletions at 9p21.2 or 9p21.3 were also identified, corresponding to the CDKN2A locus. Microdeletions at 3p14.2, were also detected in some cSCCs in conjunction with LOH of the other allele and this was the location of FHIT gene. Other frequent loci of LOH included 13q, 8p and 9q. Analysis of methylation status of specific genes revealed that methylation of DAPK1 promoter was identified in the tumor as well as the surrounding tissues, suggesting that this was an early event in squamous carcinogenesis . On the other hand, methylation of CDKN2A and CDH13 gene promoters were detected most frequently in the tumor tissue. Analysis of epigenetic profiles of metastatic cSCC identified methylation at FRZB, a member of the Wnt signaling pathway to be the most common event , in addition to transcription factors TFAP2C and ASCL2, while ACTG2 was hypomethylated.
MicroRNAs in cSCC
MicroRNAs are non-coding RNAs that regulate post-transcriptional gene expression and miRNA profiling studies have revealed altered expression of miRNAs in cSCC. For instance, Let-7a targeting caspase3 is upregulated in SCC, while miR-9 is over-expressed in SCC and metastases and is associated with loss of expression of α-catenin . miR-21 is also upregulated in cSCC and psoriasis, resulting in decreased expression of MSH2, DND1, GRHL3 and PTEN, leading to aggressive behavior . miR-365 is another microRNA that is upregulated in SCC and other carcinomas that functions by mediating the downregulation of nuclear factor, NF-I/B . miRNAs that are specifically over-expressed in cSCC include miR-135b, miR-424 and miR-766 , miR-31 and miR-223 . MicroRNAs that are specifically downregulated in cSCC include miR-125b, miR-34a, miR-124, miR-483-3p, and miR-193b/365a targeting MMP13, SIRT6, ERK1/2, CDC25A and KRAS, respectively . miR-30a*, miR-378, miR-145, miR-140-3p, miR-30a, miR-26a, miR-375, miRNA-125a, let-7b, let-7c, let-7d, let-7f, let-7g, miR-99a, miR-99b, miR-100, miR-101 and miR-143 levels are significantly reduced in cSCC compared to histologically normal tissue [104,105]. Comparison of primary and metastatic cSCC revealed that miR-4286, miR-200a-3p, miR-148a-3p were upregulated while, miR-1915-3p, miR-205-5p, miR-4516 and miR-150-5p were down-regulated specifically in the metastatic tumors .
Carcinogenic transformation of epidermal keratinocytes into cutaneous squamous cell carcinoma is a complex process involving the interaction of numerous gene products converging in signaling cascades that regulate several biologic processes. Deregulation of several checkpoints is necessary for carcinogenic transformation. Ultraviolet radiation, particularly its B-fraction functions as complete carcinogen by promoting DNA-damage, sustaining such altered cells, promoting their proliferation while preventing apoptosis, lowering immune response and thus, promoting carcinogenic transformation. Altered expression and function of several other proteins is critical before the actual tumorigenesis begins. While our understanding of this complex interplay has increased by leaps and bounds in the past few decades, identification of clinically relevant and targetable genetic alterations has not been very successful so far, but is essential for optimal treatment of these patients.
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