Squamous Cell Carcinoma

Cutaneous squamous cell carcinoma (cSCC) is caused by malignant proliferation of atypical keratinocytes. This condition is the 2nd most common skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin malignancy and usually affects sun-exposed areas of fair-skinned patients. The cancer presents as a firm, erythematous, keratotic plaque or papule. Histopathologic examination should be done for all suspected cases, as many lesions, such as actinic keratosis Actinic keratosis Actinic keratosis (AK) is a precancerous skin lesion that affects sun-exposed areas. The condition presents as small, non-tender macules/papules with a characteristic sandpaper-like texture that can become erythematous scaly plaques. Actinic Keratosis (AK), mimic the appearance of SCC. Surgical excision is the mainstay of treatment. Overall prognosis is excellent for completely excised lesions, but certain high-risk features may predispose to metastatic disease and poor outcomes.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Defintion

Cutaneous squamous cell carcinoma (cSCC) is a malignant tumor of the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin arising from epidermal keratinocytes.

Epidemiology

  • The 2nd most common skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin cancer after basal cell carcinoma Basal cell carcinoma Basal cell carcinoma is the most common skin malignancy. This cancer arises from the basal layer of the epidermis. The lesions most commonly appear on the face as pearly nodules, often with telangiectatic blood vessels and ulceration in elderly individuals. Basal Cell Carcinoma
  • Accounts for 20% of all nonmelanoma skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin cancers
  • Men > women
  • Incidence increases with age.
  • Incidence higher in people with fair skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin

Risk factors

  • Exposure to ultraviolet (UV) radiation:
    • UVB: primary factor
    • UVA exposure, from tanning beds and phototherapy, also increases risk.
  • Exposure to ionizing radiation
  • Carcinogens:
    • Arsenic
    • Radon
  • Immunosuppression:
    • HIV
    • Immunosuppressive medications
  • Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics:
    • Family history increases risk.
    • Genetic syndromes with increased risk of cSCC:
      • Xeroderma pigmentosum ( mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in repair of UV-induced DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure damage)
      • Epidermolysis bullosa (blistering skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin disease with no trauma)
      • Oculocutaneous albinism Oculocutaneous albinism Albinism refers to a group of inherited disorders that result in the disruption of melanin production, causing hypopigmentation and visual impairment. The condition is classified according to the clinical phenotype. Oculocutaneous albinism results in hypopigmentation of the skin, eyes, and hair. Ocular albinism affects only the eyes. Albinism (disorder of melanin synthesis)
      • Epidermodysplasia verruciformis (increased risk of HPV HPV Human papillomavirus (HPV) is a nonenveloped, circular, double-stranded DNA virus belonging to the Papillomaviridae family. Humans are the only reservoir, and transmission occurs through close skin-to-skin or sexual contact. Human papillomaviruses infect basal epithelial cells and can affect cell-regulatory proteins to result in cell proliferation. Papillomaviridae: HPV and cSCC)
  • Chronic inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation:
    • Burn scars, chronic ulcers, inflammatory dermatoses, sinus tracts
    • SCC arising in a chronic wound: Marjolin’s ulcer
  • HPV HPV Human papillomavirus (HPV) is a nonenveloped, circular, double-stranded DNA virus belonging to the Papillomaviridae family. Humans are the only reservoir, and transmission occurs through close skin-to-skin or sexual contact. Human papillomaviruses infect basal epithelial cells and can affect cell-regulatory proteins to result in cell proliferation. Papillomaviridae: HPV infection
  • Less well-defined risk factors:
    • Smoking
    • Drugs (voriconazole, azathioprine, thiazide diuretics Thiazide diuretics Thiazide and thiazide-like diuretics make up a group of highly important antihypertensive agents, with some drugs being 1st-line agents. The class includes hydrochlorothiazide, chlorothiazide, chlorthalidone, indapamide, and metolazone. Thiazide Diuretics)
    • Dietary supplements (e.g., selenium)

Pathophysiology

Molecular pathogenesis

  • Multistep process involving accumulation of genetic and epigenetic alterations
  • Multiple genes and pathways involved:
    • TP53 (tumor suppressor gene) mutations:
      • Common early event in carcinogenesis Carcinogenesis Carcinogenesis is the development of cancer by transforming healthy cells into cancer cells. This complex process occurs because of mutations in DNA that prevent the normal process of cell division. Normal cells have programmed cell death, but cancer cells proliferate without regulation. Carcinogenesis
      • Noted in 90% of cSCCs and usually UV-related
      • Also found in actinic keratosis Actinic keratosis Actinic keratosis (AK) is a precancerous skin lesion that affects sun-exposed areas. The condition presents as small, non-tender macules/papules with a characteristic sandpaper-like texture that can become erythematous scaly plaques. Actinic Keratosis (AK)
    • Other mutations involve NOTCH, HRAS, and CDKN2A 
  • Multiple germline single nucleotide polymorphisms also influence cancer initiation and involve loci associated with:
    • Skin pigmentation
    • Cell-mediated immunity
    • Anti-apoptotic pathways and cellular proliferation

Cutaneous squamous cell carcinoma precursor lesions

  • Actinic keratosis:
    • Proliferation of atypical epidermal keratinocytes
    • Risk factors similar to those cSCC
    • Rate of progression to cSCC: 0.03%–20% per year
    • May spontaneously regress or may persist as actinic keratosis Actinic keratosis Actinic keratosis (AK) is a precancerous skin lesion that affects sun-exposed areas. The condition presents as small, non-tender macules/papules with a characteristic sandpaper-like texture that can become erythematous scaly plaques. Actinic Keratosis (AK)
  • Bowen’s disease:
    • cSCC in situ
    • Grows slowly and enlarges over many years
    • Present as erythematous or skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin-colored, well-demarcated scaly patches or plaques
    • Often located in lower extremities (especially in women)
    • When penis Penis The penis is the male organ of copulation and micturition. The organ is composed of a root, body, and glans. The root is attached to the pubic bone by the crura penis. The body consists of the 2 parallel corpora cavernosa and the corpus spongiosum. The glans is ensheathed by the prepuce or foreskin. Penis involved, referred to as erythroplasia of Queyrat Erythroplasia of Queyrat Bowen disease and erythroplasia of Queyrat are 2 related entities that describe squamous cell carcinoma (SCC) in situ of the skin. Bowen disease usually presents in sun-exposed areas (e.g., face and forearms) as a red, scaly skin lesion. When the glans penis is involved, the lesion is called erythroplasia of Queyrat, with uncircumcised males being at high risk. Bowen Disease and Erythroplasia of Queyrat
Actinic keratosis of the scalp

Multiple lesions of actinic keratosis Actinic keratosis Actinic keratosis (AK) is a precancerous skin lesion that affects sun-exposed areas. The condition presents as small, non-tender macules/papules with a characteristic sandpaper-like texture that can become erythematous scaly plaques. Actinic Keratosis (AK) on the scalp of a 55-year-old man

Image: “Actinic keratosis of the scalp” by C. Morice, A. Acher, N. Soufir, M. Michel, F. Comoz, D. Leroy, and L. Verneuil. License: CC BY 4.0

Clinical Presentation

General clinical presentation

Occurence:

cSCC can occur on any cutaneous surface, including trunk, extremities, face, and oral and anogenital mucosa.

  • In fair-skinned individuals: most common in sun-exposed areas 
  • In dark-skinned individuals: 
    • Majority present in non–sun-exposed areas
    • Up to 40% arise from chronic scarring lesions.

Morphology:

  • Well differentiated: 
    • Indurated hyperkeratotic nodules, plaques, or papules
    • +/– ulceration
  • Poorly differentiated: 
    • Fleshy granulomatous papules or nodules (hyperkeratosis usually absent)
    • May have areas of ulceration, hemorrhage, and necrosis

Color: varies from flesh-colored to erythematous

Symptoms:

  • Commonly asymptomatic, but may present with pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain and pruritus
  • Paresthesias may occur with high-risk cSCCs, indicating local perineural invasion.

Clinical variants

Marjolin’s ulcer:

  • Appears as a slow-growing nonhealing lesion/ulcer 
  • SCC associated with chronic wounds are aggressive.
  • In areas of chronically irritated epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium:
    • Burn scars
    • Nonhealing ulcers (e.g., venous ulcers) 

Keratoacanthoma:

  • Well-differentiated cSCC (sometimes classified as a separate entity)
  • Dome-shaped or crateriform nodules with a central keratotic core

Verrucous carcinoma:

  • Present as large cauliflower-like warts
  • Sites of lesions: oral, anogenital, or plantar lesions

SCC of the lip: nodule or plaque usually on the lower lip

Oral SCC: ulcer, nodule or plaque in the oral cavity

Diagnosis and Staging

Diagnostic approach

History:

  • Excessive sun exposure (occupational or recreational)
  • Radiation exposure
  • Family history, genetic disorders
  • HIV, immunosuppressive medications
  • History of other skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin cancers or papillomas
  • Chronic poorly healing wounds (for Marjolin’s ulcers)

Physical exam:

  • Thorough skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin examination should be performed to evaluate for concomitant lesions.
  • Look for lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy, which may indicate advanced disease.

Dermoscopy: 

  • Bowen’s disease (cSCC in situ): surface scales with red-yellowish background
  • Invasive SCC:
    • White and structureless areas
    • Hairpin and linear-irregular vessels

Biopsy:

  • Must be performed for definitive diagnosis
  • Techniques: shave, punch, or excisional
  • If invasive SCC is suspected, biopsy should go down to the level of the midreticular dermis, regardless of technique.
  • SCC in situ histopathology:
    • Atypical keratinocytes with no infiltration of the dermis
    • Usually with thickened epidermis and hyperkeratosis of the stratum corneum
  • Invasive SCC histopathology: 
    • Atypical keratinocytes with basement membrane and dermis infiltration
      • Well differentiated: keratinocytes appear with close-to-normal nuclei and abundant cytoplasm
      • Poorly differentiated: anaplastic keratinocytes, noted to have more nuclear atypia with less cytoplasm; numerous mitoses 
    • Perineural infiltration signifies poorly differentiated SCC with metastatic potential.
    • Immunohistochemical staining for poorly differentiated (anaplastic) lesions: positive for cytokeratin
Invasive squamous cell carcinoma (scc)

Invasive SCC:
Well-differentiated lesions showing prominent keratinization structures (keratin pearls)

Image: “Micrograph of well-differentiated and invasive squamous-cell carcinoma” by Valerie R. Yanofsky, Stephen E. Mercer, and Robert G. Phelps. License: CC BY 4.0

Evaluation of metastasis

  • Rate of metastasis: 2%–5%
  • Lymph node evaluation:
    • Lymph nodes are the most common metastatic site:
      • Lip and anterior mouth: submental lymph nodes
      • Nose and cheek: submandibular lymph nodes
      • External ear: posterior auricular lymph nodes
      • Anterior scalp, forehead, temple: parotid lymph nodes
      • Posterior scalp: occipital lymph nodes
    • Palpable lymph nodes evaluated via the following options:
      • Fine-needle aspiration
      • Surgical removal and pathologic examination
    • Imaging options (done if with lymph nodes positive):
      • CT 
      • MRI
  • If there are no palpable lymph nodes, consider imaging if the following high-risk features are present
    • Tumor diameter:
      • ≥ 6 mm: central face (mask area), ears, hands, feet
      • ≥ 10 mm: other face areas, pretibia
      • ≥ 20 mm: rest of trunk and extremities
    • Poorly differentiated histology
    • Perineural and/or deep invasion
    • Immunosuppressed patient
    • Site of previous radiation, chronic wounds/scars
    • Recurrent tumors
  • Other sites of metastasis:
    • Lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs
    • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver
    • Brain
    • Bones

Staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis

American Joint Commission on Cancer 2018 TNM system:

Only applicable to SCC of the head and neck area (lip, ear, face, scalp, and neck).

  • Stage 0: cancer involves only the epidermis (in situ)
  • Stage I: 
    • Cancer is not large (≤ 2 cm)
    • No spread to the lymph nodes or other organs
  • Stage II: 
    • Cancer is large (>2 cm but ≤ 4 cm). 
    • No spread to lymph nodes or other organs
  • Stage III: 
    • Cancer > 4 cm or cancer of any size with deep, perineural, or minor bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones invasion and/or to 1 ipsilateral lymph node (no extranodal extension)
    • No spread to other organs
  • Stage IV: lesion of any size and has spread to other organs (distant metastasis

Brigham and Women’s Hospital (BWH) staging:

  • Alternative tumor staging system based on presence of high-risk factors
  • Can be applied to SCC in all body sites

Management

Treatment approach

Standard surgical excision:

  • 1st-line treatment
  • Negative margins need to be achieved.
  • Generally with margins of 4–6 mm (low-risk lesions) or > 6 mm (high-risk lesions)

Mohs micrographic surgery:

  • Used for cosmetically sensitive areas where procedure could be disfiguring
  • Can also be used for reexcision if original margins were positive

Alternatives to surgery (not for high-risk lesions):

  • Electrodesiccation and curettage
  • Cryotherapy
  • Topical fluorouracil and photodynamic therapy are additional options for Bowen’s disease.

Radiation:

  • Rarely used as primary treatment
  • Adjunctive treatment for high-risk lesions
  • Salvage therapy after excision with positive margins

Systemic treatment:

  • Immunotherapy: 
    • For metastasis, locally advanced disease not amenable to surgery or radiotherapy
    • Programmed death-ligand 1 (PD-L1) or PD-L1 inhibitor: 
      • Cemiplimab
      • Pembrolizumab 
  • Cisplatin-based chemotherapy and/or epidermal growth factor receptor (EGFR) inhibitor (cetuximab): considered for advanced SCC due to immunosuppression for organ transplantation Organ Transplantation Transplantation is a procedure that involves the removal of an organ or living tissue and placing it into a different part of the body or into a different person. Organ transplantations have become the therapeutic option of choice for many individuals with end-stage organ failure. Organ Transplantation 

Prognosis

  • Overall 5-year cure rate is 90%.
  • 95% of recurrences occur within 5 years.
  • If distant metastases are present, 5-year survival is < 10%.

Differential Diagnosis

  • Seborrheic keratosis Seborrheic keratosis Seborrheic keratosis (SK) is the most common benign epithelial cutaneous neoplasm. The condition consists of immature keratinocytes. Seborrheic keratosis is the most common benign skin tumor in middle-aged and elderly adults and presents as a sharply demarcated, exophytic, skin lesion that may be tan or black and has a "stuck-on" appearance. Seborrheic Keratosis: benign neoplasm consisting of immature keratinocytes occurring commonly in the elderly. Seborrheic keratosis Seborrheic keratosis Seborrheic keratosis (SK) is the most common benign epithelial cutaneous neoplasm. The condition consists of immature keratinocytes. Seborrheic keratosis is the most common benign skin tumor in middle-aged and elderly adults and presents as a sharply demarcated, exophytic, skin lesion that may be tan or black and has a "stuck-on" appearance. Seborrheic Keratosis is well demarcated, waxy, and has a stuck-on appearance. 
  • Actinic keratosis: precancerous lesion affecting sun-exposed areas (e.g., scalp and hands) in elderly people. Actinic keratosis appears as a scaly, slightly elevated lesion that can eventually progress to invasive SCC.
  • Inflammatory skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin disorders: psoriasis Psoriasis Psoriasis is a common T-cell-mediated inflammatory skin condition. The etiology is unknown, but is thought to be due to genetic inheritance and environmental triggers. There are 4 major subtypes, with the most common form being chronic plaque psoriasis. Psoriasis, eczema Eczema Atopic dermatitis, also known as eczema, is a chronic, relapsing, pruritic, inflammatory skin disease that occurs more frequently in children, although adults can also be affected. The condition is often associated with elevated serum levels of IgE and a personal or family history of atopy. Skin dryness, erythema, oozing, crusting, and lichenification are present. Atopic Dermatitis (Eczema), pyoderma gangrenosum, venous stasis ulcers. All of these disorders can present with scaly pink or flesh-colored plaques, patches, and nodules.
  • Other skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin malignancies: Basal cell carcinoma is the most important differential diagnosis. Basal cell carcinoma is the most common skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin cancer arising from the basal cell layer of the epidermis. Most patients present with a pearly nodular skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin lesion with telangiectasia that grows slowly. Other skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin cancers that can appear similar to SCC are amelanotic melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma, Merkel’s cell carcinoma, and atypical fibroxanthoma.

References

  1. Aasi S. Z., Hong A. M. (2020). Treatment and prognosis of low-risk cutaneous squamous cell carcinoma. UpToDate. Retrieved January 18, 2021, from https://www.uptodate.com/contents/treatment-and-prognosis-of-low-risk-cutaneous-squamous-cell-carcinoma
  2. DeSimone J. A., Karia P. S., Hong A. M., Ruiz E. S., Jambusaria-Pahlajani A. (2020). Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma.UpToDate. Retrieved January 18, 2021, from https://www.uptodate.com/contents/recognition-and-management-of-high-risk-aggressive-cutaneous-squamous-cell-carcinoma
  3. Lim J. L., Asgari M. (2020). Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis. UpToDate. Retrieved January 18, 2021, from https://www.uptodate.com/contents/cutaneous-squamous-cell-carcinoma-cscc-clinical-features-and-diagnosis
  4. Lim J. L., Asgari M. (2020). Cutaneous squamous cell carcinoma: Epidemiology, risk factors, and molecular pathogenesis. Retrieved January 18, 2021, from https://www.uptodate.com/contents/cutaneous-squamous-cell-carcinoma-epidemiology-risk-factors-and-molecular-pathogenesis
  5. Lonsdorf A. S., Hadaschik E.N. (2019). Squamous cell carcinoma and keratoacanthoma. Kang S, et al. (Ed.), Fitzpatrick’s Dermatology, 9th ed. McGraw-Hill.
  6. Martins, R. (2020). Systemic treatment of advanced cutaneous squamous and basal cell carcinomas. UpToDate. Retrieved Feb 4, 2021, from https://www.uptodate.com/contents/systemic-treatment-of-advanced-cutaneous-squamous-and-basal-cell-carcinomas
  7. Sarin, K. Y., Lin, Y., Daneshjou, R. et al. (2020). Genome-wide meta-analysis identifies eight new susceptibility loci for cutaneous squamous cell carcinoma. Nat Commun 11, 820. https://doi.org/10.1038/s41467-020-14594-5
  8. Turnbull N. (2014). Squamous cell carcinoma pathology. https://www.dermnetnz.org/topics/squamous-cell-carcinoma-pathology

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