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Molecular Markers in Cutaneous Squamous Cell Carcinoma

Molecular Markers in Cutaneous Squamous Cell Carcinoma Hindawi Publishing Corporation International Journal of Surgical Oncology Volume 2011, Article ID 231475, 5 pages doi:10.1155/2011/231475 Review Article 1, 2 2 3 4 Anthony P. Tufaro, Jim C.-M. Chuang, Nijaguna Prasad, Alice Chuang, 5 6 Tony C. Chuang, and Anne C. Fischer Department of Plastic & Reconstructive Surgery, Johns Hopkins Medical Institutions, Baltimore, MD, USA Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, USA Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, MD, USA Division of Gastroenterology, Department of Medicine, University of Chicago, Chicago, IL, USA Division of Otolaryngology, Head and Neck Surgery, Department of Surgery, Samaritan Medical Center, Watertown, NY, USA Department of Surgery and Cancer Immunobiology Center, UT Southwestern Medical, Dallas, TX, USA Correspondence should be addressed to Anthony P. Tufaro, aptufaro@jhmi.edu Received 16 March 2011; Accepted 4 June 2011 Academic Editor: Richard Martin Copyright © 2011 Anthony P. Tufaro et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Nonmelanoma skin carcinoma (NMSC) is the most frequent cancer in the USA with over 1.3 million new diagnoses a year; however due to an underappreciation of its associated mortality and growing incidence and its ability to be highly aggressive, the molecular mechanism is not well delineated. Whereas the molecular profiles of melanoma have been well characterized, those for cutaneous squamous cell carcinoma (cSCC) have trailed behind. This importance of the new staging paradigm is linked to the ability currently to better clinically cluster similar biologic behavior in order to risk-stratify lesions and patients. In this paper we discuss the trends in NMSC and the etiologies for the subset of NMSC with the most mortality, cutaneous SCC, as well as where the field stands in the discovery of a molecular profile. The molecular markers are highlighted to demonstrate the recent advances in cSCC. 1. Introduction the mutagenic effects of ultraviolet (UV) light which is inten- sified by geographic latitude [1, 7]. cSCC and BCC are more Nonmelanoma skin carcinoma (NMSC) is the most frequent common in fair skinned and anatomic sites exposed to the cancer in the USA and worldwide [1]; it has been increasing sun, such as head, neck, and extremities: head and neck is the in overall incidence since the 1960’s at a rate of 3–8% per year most common site. Other known risk factors are male sex, [2]. With over 1.3 million new diagnoses of NMSC a year in advanced age, immunosuppression (induced or acquired), the United States [3], it is both the diversity of types, of which human papilloma viruses (HPV), chronic inflammation, and there are 82, and biologic variability in phenotype that make genetic diseases manifested in the skin [7–9]. Immunocom- the analysis of NMSC even more challenging. Although the promised states are associated with a marked escalation of incidence of basal cell carcinoma (BCC) exceeds cSCC by a cSCC of up to 64–250 times greater than that in the general 5 : 1 ratio, cSCC is associated with the burden of mortality population compared to the 10-fold increased risk in BCC, with a disease-specific yearly mortality rate of 1% per year causing a reversal of the typical ratio in immunocompetent as reported in the early 1990’s [4]. Despite the fact that individuals from 5 : 1 to a range between 1 : 1.8 and 1 : 15 [10, the majority of these tumors present at early stages, cSCC 11]. Immunosuppression significantly impacts the biology accounts for the majority of NMSC deaths [5] and 20% of all of cSCC. In solid organ transplant patients, cSCC tumors skin-cancer-related deaths [6]. tend to be numerous, exhibit a strong propensity to recur, Multiple etiologies exist for cSCC, including environ- and metastasize at a high rate regardless of lesional size [12]. mental, genetic, viral and altered host immunity and virally Malignant lesions develop within 10 years after organ trans- mediated. The high incidence of cSCC and BCC is caused by plantation and up to 80% of these lesions contain HPV DNA 2 International Journal of Surgical Oncology [13]. HPV has also been associated with cSCC with evidence Table 1: High risk factors for NMSC tumor characteristics . of a higher viral load of HPV DNA in immunosuppressed Histologic differentiation patients [13, 14]. Likewise cSCC that arises in sites of chronic Poor differentiation inflammation, such as scars, sinus tracts, and burns, can also Spindle cell characteristics demonstrate more aggressive clinical behavior and a greater Necrosis propensity to metastasize with an overall metastatic rate of High mitotic activity 40% [6, 15]. Cutaneous genetically inherited skin conditions that have a known propensity of risk for developing cSCC are Deep invasion albinism, xeroderma pigmentosum, and epidermodysplasia Depth of invasion verruciformis [5, 16, 17]. >2mm Clark level IV 2. Staging Perineural invasion High risk anatomic sites With a cure rate of greater than 90% for the routine lesion, Nonglabrous Lip and the large number of low risk lesions, the significance Ear of the diverse spectrum and numerous subtypes of cSCC Advanced T stage (T3 and T4) has been underappreciated given the often quoted 5-year Bony extension or involvement recurrence and metastatic rates of 8% and 5%, respectively [6, 18, 19]. However recent changes to the American Joint Maxilla, mandible, orbit, temporal bone Committee on Cancer Staging (AJCC) presented in the 7th Perineural invasion Edition focus on identifying clinical parameters that portend Invasion of skull base a worse prognosis to identify and stage appropriately that Invasion of axial or appendicular skeleton subset of cSCC that progresses to metastatic disease [9]. The ∗ 7th Edition of American Joint Commission on Cancer Staging Manual high risk characteristics determined by the 7th Edition AJCC [18]. Staging Manual include lesional size (>2 cm), and high risk features such as a depth of invasion (>2 mm, ≥Clark level outcome of metastatic cSCC is not universally recognized as IV), perineural invasion, tumor grade (poorly differentiated dismal at a-5 year survival of less than 35% [6]. or undifferentiated), as well as high-risk anatomic sites (see Prognostic features have not been universally accepted in Table 1). The paradigm shift in the 7th Edition recognizes cSCC and the histologic features delineated above are advised that the classification of lesions with similar histopathologic for uniformity in standardizing clinical staging guidelines. features is more likely to have similar aggressive behavior and Since cSCC is typically deemed to have a good prognosis, the features chosen were based on that behavior. For instance, the variants with the worst biology, by not being grouped tumor grade alone is significantly associated with mortality together, are underpowered numerically in an outcome given a 5-year cure after therapy of 61.5% for poorly differen- analysis.Thusthe varietyofsubtypesofcSCCcertainly tiated cSCC compared to 94.6% for well differentiated cSCC necessitates a comprehensive clinicopathologic classification [6]. High risk histologic features were defined as showing system to group variants of SCC based on their biologic poor differentiation, spindle cell characteristics, necrosis, aggressiveness or indolence. The 7th Edition introduces the high mitotic activity, and deep invasion [9]. Both the depth histologic features that need to be tracked and classified; of invasion and presence of perineural invasion significantly yet a clinicopathologic classification system would allow correlate with prognosis: it clearly has been shown that lesions to be stratified based on biologic behavior and thus thicker lesions have a higher rate of nodal metastases and patients accordingly to optimize therapy. Clinicopathologic recurrence. In fact a depth of >4 mm thickness or ≥Clark classification of cSCC has been characterized by Cassarino Level IV is associated with a twofold increased rate of et al. [24] to stratify lesions based on their malignant poten- recurrence or 5-fold increase metastatic rate [6]. Similarly, tial (Table 2). In the era of personalized medicine, molec- perineural invasion is associated with a 5-fold increase in ular markers have been used in many tumors to prog- both the recurrence rate and metastatic rate [20]. Although nosticate and risk-stratify patients. Given the relative lack not identified in the 7th Edition, other histologic features of recognition of the growing incidence of cSCC and the that are important in prognosis include lymphovascular inability to track the worst subset of cSCC given the abun- invasion and the presence of inflammatory features such as dance of low risk lesions and the practice of not banking or the presence of eosinophils and plasma cells [21]. cSCC in staging lesions, these molecular studies have been relatively immunocompromised patients or those that arise in scars, limited compared to the field of melanoma. A summary of sinus tracts, or burns all demonstrate a more aggressive bio- the current literature on the molecular markers in cSCC logic phenotype with a greater metastatic rate of up to 40% highlights some promising areas of research. [6, 15, 22]. So subsetswithaworseprognosis arecriticalto correctly stage and classify together in order to appropriately reveal a previously unrecognized metastatic potential. Like- 3. Pathogenesis wise recurrent or persistent disease portends a worse survival of 78% 5-year survival compared to 97% for a primary lesion 3.1. Viral Pathogenesis. The increased incidence of cSCC in [20, 23]. Since the incidence of metastatic cSCC is low, the immunocompromised patients compared to BCC suggests a International Journal of Surgical Oncology 3 Table 2: Clinicopathologic classification for cSCC . also be found in a minority of these cancers, implying that these low-risk HPV types are not entirely benign in HNSCC. High risk behavior cSCC HPV DNA is closely associated with poorly differentiated Bowen’s disease with invasion cancers, positive lymph nodes, and late-stage disease, which Adenosquamous carcinoma portend a worse diagnosis. HPV status is also associated with cSCC in proliferating pilar tumor/cysts p16 expression and HPV+ tumours are less likely to harbour Tricholemmal cysts p53 mutations [28]. AsubsetofHNSCC patients whohad Epidermoid cysts HPV 16 infection confers a better prognosis. On the other hand, β papillomaviruses (β-HPVs) also play a role in the Desmoplastic cSCC tumorigenesis of cSCC as shown by both European and US De novo cSCC studies [29]. However, no high-risk types have been identi- cSCC in chronic conditions fied although there is an association of β species 1 in SCC. Ulcers, sinus tracts, burns Other viruses, such as polyomavirus (MCPyV) have been Osteomyelitis shown to be causative agent in Merkel cell carcinoma [30]. Chronic inflammatory disorders Radiation-induced cSCC 3.2. Allelic Imbalance and Loss of Heterozygosity. The genetic progression model for head and neck squamous cell car- Indeterminate risk cSCC cinoma (HNSCC) demonstrates that loss of heterozygosity Clear cell SCC (LOH) is common during the progression from premalig- Signet ring cell nant lesion to malignant tumors [31]. Tumor suppressor Papillary cSCC genes (TSGs) are usually found in the area of loss rendering Pigmented cSCC the cells more susceptible to tumorigenesis [32]. Follicular cSCC Several regions of chromosomal loss are identified in cSCC from benign adnexal cyst HNSCC. One of the most common regions, 9p21, has been reported in both HNSCC [33] and cSCC [34]. This region Putative cSCC versus low grade cSCC contains several TSGs, including p16INK4A (CDKN2A), Keratoacanthoma (KA) p15INK4B, and MTAP. Allelic imbalances are also found in Not a bona fide cSCC other regions of cSCC, including LOH on 3p, 2q, 8p, and Low grade behavior 13 and allelic gain on 3q and 8q [35]. Such studies indicate Giant KA, that allelic imbalance and LOH are recognized and relevant Subungual KA events in cSCC and can be used for early diagnosis and tumor KA with Immunosuppression surveillance. Modified Classification system from Cassarino et al. [24]. 3.3. Epigenetics. Epigenetics refers to the molecular mech- anisms that regulate gene expression without changes in mechanism of viral pathogenesis. HPV is important in im- the DNA sequence. Epigenetic alterations include DNA munosuppressed patients, which are known to have higher methylation and histone modifications, which consist of levels of HPV DNA in cSCC lesions. Evidence of a higher methylation, acetylation, phosphorylation, ubiquitination, viral load has been reported in cSCC in organ transplant and sumoylation, chromatin remodeling and microRNAs patients with up to 80% of lesions containing HPV DNA [36–38]. Changes in genomic DNA methylation associated [14]. However the variable quantity of HPV in immunocom- with cancer include global DNA hypomethylation and gene- petent individuals can range between 27–70% depending specific hyper- or hypomethylation. Tumor progression on detection techniques [13, 17]. Thus the type of HPV, involved chromatin-mediated changes such as DNA methy- β-papillomavirus species 2, is more often associated with lation yet the role of histone variants in tumorogenesis is cSCC as opposed to the total amount of HPV DNA present unclear. All of these modifications of gene expression have [17]. Three theories have been suggested for the mechanism been associated with the development of various tumor of HPV carcinogenesis: (1) UV radiation-induced immuno- types, including HNSCC and cSCC [39, 40]. A higher suppression to explain enhanced interaction between HPV frequency of FOXE1 promoter hypermethylation was found and UV radiation [25, 26], (2) E6/E7 oncoprotein-related in cSCC compared to normal skin, indicating that FOXE1 changes in p53 and Rb tumor suppressor gene, and (3) may be a target for aberrant methylation in cSCC [39]. integration of HPV DNA disrupting genomic stability Epigenetic dysregulation is thought to be involved in [17, 25]. Viral expression of E6 and E7 oncoproteins can tumor biology and progression and thus may be relevant inactivate p53 and Rb tumor suppressor genes, leading to an biomarkers for clinical prognosis [39]. Promoter DNA uncontrolled system of cell proliferation and apoptosis [27]. methylation gene panels have been described for screening of Association of viral pathogens such as human papillo- primary HNSCC [41, 42], for determination of tumor recur- mavirus (HPV) with head and neck squamous cell cancer rence and assessment of margin status during surgery. Recent (HNSCC), especially oropharyngeal cancer has been recog- evidence does show that the loss of histone variants, such as nized over the past two decades. HPV16 is the most common macro-H2A, positively correlates with an increasing malig- genotype in these tumours, whereas HPV6 and HPV11 can nant phenotype of melanoma cells and that macro-H2A is 4 International Journal of Surgical Oncology a critical component of chromatin that suppresses malignant [5] M. Alam and D. Ratner, “Cutaneous squamous cell carci- noma,” New England Journal of Medicine, vol. 344, no. 13, pp. progression of melanoma [43]. 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Abstract

Hindawi Publishing Corporation International Journal of Surgical Oncology Volume 2011, Article ID 231475, 5 pages doi:10.1155/2011/231475 Review Article 1, 2 2 3 4 Anthony P. Tufaro, Jim C.-M. Chuang, Nijaguna Prasad, Alice Chuang, 5 6 Tony C. Chuang, and Anne C. Fischer Department of Plastic & Reconstructive Surgery, Johns Hopkins Medical Institutions, Baltimore, MD, USA Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, USA Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, MD, USA Division of Gastroenterology, Department of Medicine, University of Chicago, Chicago, IL, USA Division of Otolaryngology, Head and Neck Surgery, Department of Surgery, Samaritan Medical Center, Watertown, NY, USA Department of Surgery and Cancer Immunobiology Center, UT Southwestern Medical, Dallas, TX, USA Correspondence should be addressed to Anthony P. Tufaro, aptufaro@jhmi.edu Received 16 March 2011; Accepted 4 June 2011 Academic Editor: Richard Martin Copyright © 2011 Anthony P. Tufaro et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Nonmelanoma skin carcinoma (NMSC) is the most frequent cancer in the USA with over 1.3 million new diagnoses a year; however due to an underappreciation of its associated mortality and growing incidence and its ability to be highly aggressive, the molecular mechanism is not well delineated. Whereas the molecular profiles of melanoma have been well characterized, those for cutaneous squamous cell carcinoma (cSCC) have trailed behind. This importance of the new staging paradigm is linked to the ability currently to better clinically cluster similar biologic behavior in order to risk-stratify lesions and patients. In this paper we discuss the trends in NMSC and the etiologies for the subset of NMSC with the most mortality, cutaneous SCC, as well as where the field stands in the discovery of a molecular profile. The molecular markers are highlighted to demonstrate the recent advances in cSCC. 1. Introduction the mutagenic effects of ultraviolet (UV) light which is inten- sified by geographic latitude [1, 7]. cSCC and BCC are more Nonmelanoma skin carcinoma (NMSC) is the most frequent common in fair skinned and anatomic sites exposed to the cancer in the USA and worldwide [1]; it has been increasing sun, such as head, neck, and extremities: head and neck is the in overall incidence since the 1960’s at a rate of 3–8% per year most common site. Other known risk factors are male sex, [2]. With over 1.3 million new diagnoses of NMSC a year in advanced age, immunosuppression (induced or acquired), the United States [3], it is both the diversity of types, of which human papilloma viruses (HPV), chronic inflammation, and there are 82, and biologic variability in phenotype that make genetic diseases manifested in the skin [7–9]. Immunocom- the analysis of NMSC even more challenging. Although the promised states are associated with a marked escalation of incidence of basal cell carcinoma (BCC) exceeds cSCC by a cSCC of up to 64–250 times greater than that in the general 5 : 1 ratio, cSCC is associated with the burden of mortality population compared to the 10-fold increased risk in BCC, with a disease-specific yearly mortality rate of 1% per year causing a reversal of the typical ratio in immunocompetent as reported in the early 1990’s [4]. Despite the fact that individuals from 5 : 1 to a range between 1 : 1.8 and 1 : 15 [10, the majority of these tumors present at early stages, cSCC 11]. Immunosuppression significantly impacts the biology accounts for the majority of NMSC deaths [5] and 20% of all of cSCC. In solid organ transplant patients, cSCC tumors skin-cancer-related deaths [6]. tend to be numerous, exhibit a strong propensity to recur, Multiple etiologies exist for cSCC, including environ- and metastasize at a high rate regardless of lesional size [12]. mental, genetic, viral and altered host immunity and virally Malignant lesions develop within 10 years after organ trans- mediated. The high incidence of cSCC and BCC is caused by plantation and up to 80% of these lesions contain HPV DNA 2 International Journal of Surgical Oncology [13]. HPV has also been associated with cSCC with evidence Table 1: High risk factors for NMSC tumor characteristics . of a higher viral load of HPV DNA in immunosuppressed Histologic differentiation patients [13, 14]. Likewise cSCC that arises in sites of chronic Poor differentiation inflammation, such as scars, sinus tracts, and burns, can also Spindle cell characteristics demonstrate more aggressive clinical behavior and a greater Necrosis propensity to metastasize with an overall metastatic rate of High mitotic activity 40% [6, 15]. Cutaneous genetically inherited skin conditions that have a known propensity of risk for developing cSCC are Deep invasion albinism, xeroderma pigmentosum, and epidermodysplasia Depth of invasion verruciformis [5, 16, 17]. >2mm Clark level IV 2. Staging Perineural invasion High risk anatomic sites With a cure rate of greater than 90% for the routine lesion, Nonglabrous Lip and the large number of low risk lesions, the significance Ear of the diverse spectrum and numerous subtypes of cSCC Advanced T stage (T3 and T4) has been underappreciated given the often quoted 5-year Bony extension or involvement recurrence and metastatic rates of 8% and 5%, respectively [6, 18, 19]. However recent changes to the American Joint Maxilla, mandible, orbit, temporal bone Committee on Cancer Staging (AJCC) presented in the 7th Perineural invasion Edition focus on identifying clinical parameters that portend Invasion of skull base a worse prognosis to identify and stage appropriately that Invasion of axial or appendicular skeleton subset of cSCC that progresses to metastatic disease [9]. The ∗ 7th Edition of American Joint Commission on Cancer Staging Manual high risk characteristics determined by the 7th Edition AJCC [18]. Staging Manual include lesional size (>2 cm), and high risk features such as a depth of invasion (>2 mm, ≥Clark level outcome of metastatic cSCC is not universally recognized as IV), perineural invasion, tumor grade (poorly differentiated dismal at a-5 year survival of less than 35% [6]. or undifferentiated), as well as high-risk anatomic sites (see Prognostic features have not been universally accepted in Table 1). The paradigm shift in the 7th Edition recognizes cSCC and the histologic features delineated above are advised that the classification of lesions with similar histopathologic for uniformity in standardizing clinical staging guidelines. features is more likely to have similar aggressive behavior and Since cSCC is typically deemed to have a good prognosis, the features chosen were based on that behavior. For instance, the variants with the worst biology, by not being grouped tumor grade alone is significantly associated with mortality together, are underpowered numerically in an outcome given a 5-year cure after therapy of 61.5% for poorly differen- analysis.Thusthe varietyofsubtypesofcSCCcertainly tiated cSCC compared to 94.6% for well differentiated cSCC necessitates a comprehensive clinicopathologic classification [6]. High risk histologic features were defined as showing system to group variants of SCC based on their biologic poor differentiation, spindle cell characteristics, necrosis, aggressiveness or indolence. The 7th Edition introduces the high mitotic activity, and deep invasion [9]. Both the depth histologic features that need to be tracked and classified; of invasion and presence of perineural invasion significantly yet a clinicopathologic classification system would allow correlate with prognosis: it clearly has been shown that lesions to be stratified based on biologic behavior and thus thicker lesions have a higher rate of nodal metastases and patients accordingly to optimize therapy. Clinicopathologic recurrence. In fact a depth of >4 mm thickness or ≥Clark classification of cSCC has been characterized by Cassarino Level IV is associated with a twofold increased rate of et al. [24] to stratify lesions based on their malignant poten- recurrence or 5-fold increase metastatic rate [6]. Similarly, tial (Table 2). In the era of personalized medicine, molec- perineural invasion is associated with a 5-fold increase in ular markers have been used in many tumors to prog- both the recurrence rate and metastatic rate [20]. Although nosticate and risk-stratify patients. Given the relative lack not identified in the 7th Edition, other histologic features of recognition of the growing incidence of cSCC and the that are important in prognosis include lymphovascular inability to track the worst subset of cSCC given the abun- invasion and the presence of inflammatory features such as dance of low risk lesions and the practice of not banking or the presence of eosinophils and plasma cells [21]. cSCC in staging lesions, these molecular studies have been relatively immunocompromised patients or those that arise in scars, limited compared to the field of melanoma. A summary of sinus tracts, or burns all demonstrate a more aggressive bio- the current literature on the molecular markers in cSCC logic phenotype with a greater metastatic rate of up to 40% highlights some promising areas of research. [6, 15, 22]. So subsetswithaworseprognosis arecriticalto correctly stage and classify together in order to appropriately reveal a previously unrecognized metastatic potential. Like- 3. Pathogenesis wise recurrent or persistent disease portends a worse survival of 78% 5-year survival compared to 97% for a primary lesion 3.1. Viral Pathogenesis. The increased incidence of cSCC in [20, 23]. Since the incidence of metastatic cSCC is low, the immunocompromised patients compared to BCC suggests a International Journal of Surgical Oncology 3 Table 2: Clinicopathologic classification for cSCC . also be found in a minority of these cancers, implying that these low-risk HPV types are not entirely benign in HNSCC. High risk behavior cSCC HPV DNA is closely associated with poorly differentiated Bowen’s disease with invasion cancers, positive lymph nodes, and late-stage disease, which Adenosquamous carcinoma portend a worse diagnosis. HPV status is also associated with cSCC in proliferating pilar tumor/cysts p16 expression and HPV+ tumours are less likely to harbour Tricholemmal cysts p53 mutations [28]. AsubsetofHNSCC patients whohad Epidermoid cysts HPV 16 infection confers a better prognosis. On the other hand, β papillomaviruses (β-HPVs) also play a role in the Desmoplastic cSCC tumorigenesis of cSCC as shown by both European and US De novo cSCC studies [29]. However, no high-risk types have been identi- cSCC in chronic conditions fied although there is an association of β species 1 in SCC. Ulcers, sinus tracts, burns Other viruses, such as polyomavirus (MCPyV) have been Osteomyelitis shown to be causative agent in Merkel cell carcinoma [30]. Chronic inflammatory disorders Radiation-induced cSCC 3.2. Allelic Imbalance and Loss of Heterozygosity. The genetic progression model for head and neck squamous cell car- Indeterminate risk cSCC cinoma (HNSCC) demonstrates that loss of heterozygosity Clear cell SCC (LOH) is common during the progression from premalig- Signet ring cell nant lesion to malignant tumors [31]. Tumor suppressor Papillary cSCC genes (TSGs) are usually found in the area of loss rendering Pigmented cSCC the cells more susceptible to tumorigenesis [32]. Follicular cSCC Several regions of chromosomal loss are identified in cSCC from benign adnexal cyst HNSCC. One of the most common regions, 9p21, has been reported in both HNSCC [33] and cSCC [34]. This region Putative cSCC versus low grade cSCC contains several TSGs, including p16INK4A (CDKN2A), Keratoacanthoma (KA) p15INK4B, and MTAP. Allelic imbalances are also found in Not a bona fide cSCC other regions of cSCC, including LOH on 3p, 2q, 8p, and Low grade behavior 13 and allelic gain on 3q and 8q [35]. Such studies indicate Giant KA, that allelic imbalance and LOH are recognized and relevant Subungual KA events in cSCC and can be used for early diagnosis and tumor KA with Immunosuppression surveillance. Modified Classification system from Cassarino et al. [24]. 3.3. Epigenetics. Epigenetics refers to the molecular mech- anisms that regulate gene expression without changes in mechanism of viral pathogenesis. HPV is important in im- the DNA sequence. Epigenetic alterations include DNA munosuppressed patients, which are known to have higher methylation and histone modifications, which consist of levels of HPV DNA in cSCC lesions. Evidence of a higher methylation, acetylation, phosphorylation, ubiquitination, viral load has been reported in cSCC in organ transplant and sumoylation, chromatin remodeling and microRNAs patients with up to 80% of lesions containing HPV DNA [36–38]. Changes in genomic DNA methylation associated [14]. However the variable quantity of HPV in immunocom- with cancer include global DNA hypomethylation and gene- petent individuals can range between 27–70% depending specific hyper- or hypomethylation. Tumor progression on detection techniques [13, 17]. Thus the type of HPV, involved chromatin-mediated changes such as DNA methy- β-papillomavirus species 2, is more often associated with lation yet the role of histone variants in tumorogenesis is cSCC as opposed to the total amount of HPV DNA present unclear. All of these modifications of gene expression have [17]. Three theories have been suggested for the mechanism been associated with the development of various tumor of HPV carcinogenesis: (1) UV radiation-induced immuno- types, including HNSCC and cSCC [39, 40]. A higher suppression to explain enhanced interaction between HPV frequency of FOXE1 promoter hypermethylation was found and UV radiation [25, 26], (2) E6/E7 oncoprotein-related in cSCC compared to normal skin, indicating that FOXE1 changes in p53 and Rb tumor suppressor gene, and (3) may be a target for aberrant methylation in cSCC [39]. integration of HPV DNA disrupting genomic stability Epigenetic dysregulation is thought to be involved in [17, 25]. Viral expression of E6 and E7 oncoproteins can tumor biology and progression and thus may be relevant inactivate p53 and Rb tumor suppressor genes, leading to an biomarkers for clinical prognosis [39]. Promoter DNA uncontrolled system of cell proliferation and apoptosis [27]. methylation gene panels have been described for screening of Association of viral pathogens such as human papillo- primary HNSCC [41, 42], for determination of tumor recur- mavirus (HPV) with head and neck squamous cell cancer rence and assessment of margin status during surgery. Recent (HNSCC), especially oropharyngeal cancer has been recog- evidence does show that the loss of histone variants, such as nized over the past two decades. HPV16 is the most common macro-H2A, positively correlates with an increasing malig- genotype in these tumours, whereas HPV6 and HPV11 can nant phenotype of melanoma cells and that macro-H2A is 4 International Journal of Surgical Oncology a critical component of chromatin that suppresses malignant [5] M. Alam and D. Ratner, “Cutaneous squamous cell carci- noma,” New England Journal of Medicine, vol. 344, no. 13, pp. progression of melanoma [43]. 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