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Squamous Cell Carcinoma (SCC)

Cutaneous squamous cell carcinoma (cSCC) is caused by malignant proliferation of atypical keratinocytes Keratinocytes Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. Skin: Structure and Functions. 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. Skin: Structure and Functions malignancy Malignancy Hemothorax and usually affects sun-exposed areas of fair-skinned patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship. The cancer presents as a firm, erythematous, keratotic plaque Plaque Primary Skin Lesions or papule Papule Elevated lesion < 1 cm in diameter Generalized and Localized Rashes. 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, mimic the appearance of SCC. Surgical excision is the mainstay of treatment. Overall prognosis Prognosis A prediction of the probable outcome of a disease based on a individual's condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas is excellent for completely excised lesions, but certain high-risk features may predispose to metastatic disease and poor outcomes.

Last updated: Sep 22, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Defintion

Cutaneous squamous cell carcinoma (cSCC) is a malignant tumor Tumor Inflammation 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. Skin: Structure and Functions arising from epidermal keratinocytes Keratinocytes Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. Skin: Structure and Functions.

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. Skin: Structure and Functions 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 (BCC)
  • 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. Skin: Structure and Functions cancers
  • Men > women
  • Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency increases with age.
  • Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency 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. Skin: Structure and Functions

Risk factors

  • Exposure to ultraviolet (UV) radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma:
    • UVB: primary factor
    • UVA exposure, from tanning beds and phototherapy Phototherapy Treatment of disease by exposure to light, especially by variously concentrated light rays or specific wavelengths. Hyperbilirubinemia of the Newborn, also increases risk.
  • Exposure to ionizing radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma
  • Carcinogens Carcinogens Substances that increase the risk of neoplasms in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included. Carcinogenesis:
    • Arsenic Arsenic A shiny gray element with atomic symbol as, atomic number 33, and atomic weight 75. It occurs throughout the universe, mostly in the form of metallic arsenides. Most forms are toxic. According to the fourth annual report on carcinogens, arsenic and certain arsenic compounds have been listed as known carcinogens. Metal Poisoning (Lead, Arsenic, Iron)
    • Radon
  • Immunosuppression:
  • Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics:
    • Family history Family History Adult Health Maintenance increases risk.
    • Genetic syndromes with increased risk of cSCC:
      • Xeroderma pigmentosum Xeroderma pigmentosum A rare, pigmentary, and atrophic autosomal recessive disease. It is manifested as an extreme photosensitivity to ultraviolet rays as the result of a deficiency in the enzyme that permits excisional repair of ultraviolet-damaged DNA. Lentigo Maligna ( 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 damage DNA Damage Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a mutation or a block of DNA replication. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (pyrimidine dimers) or interstrand crosslinking. Damage can often be repaired (DNA repair). If the damage is extensive, it can induce apoptosis. DNA Repair Mechanisms)
      • 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. Skin: Structure and Functions disease with no trauma)
      • Oculocutaneous albinism Oculocutaneous albinism Heterogeneous group of autosomal recessive disorders comprising at least four recognized types, all having in common varying degrees of hypopigmentation of the skin, hair, and eyes. The two most common are the tyrosinase-positive and tyrosinase-negative types. Albinism (disorder of melanin Melanin Insoluble polymers of tyrosine derivatives found in and causing darkness in skin (skin pigmentation), hair, and feathers providing protection against sunburn induced by sunlight. Carotenes contribute yellow and red coloration. Seborrheic Keratosis synthesis Synthesis Polymerase Chain Reaction (PCR))
      • 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. Papillomavirus (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. Papillomavirus (HPV) infection
  • Less well-defined risk factors:
    • Smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases
    • Drugs ( voriconazole Voriconazole A triazole antifungal agent that specifically inhibits sterol 14-alpha-demethylase and cytochrome p-450 cyp3a. Azoles, azathioprine Azathioprine An immunosuppressive agent used in combination with cyclophosphamide and hydroxychloroquine in the treatment of rheumatoid arthritis. According to the fourth annual report on carcinogens, this substance has been listed as a known carcinogen. Immunosuppressants, thiazide Thiazide Heterocyclic compounds with sulfur and nitrogen in the ring. This term commonly refers to the benzothiadiazines that inhibit sodium-potassium-chloride symporters and are used as diuretics. Hyponatremia diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication)
    • Dietary supplements (e.g., selenium Selenium An element with the atomic symbol se, atomic number 34, and atomic weight 78. 97. It is an essential micronutrient for mammals and other animals but is toxic in large amounts. Selenium protects intracellular structures against oxidative damage. It is an essential component of glutathione peroxidase. Trace Elements)

Pathophysiology

Molecular pathogenesis

  • Multistep process involving accumulation of genetic and epigenetic alterations
  • Multiple genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure and pathways involved:
    • TP53 ( tumor Tumor Inflammation suppressor gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics) mutations:
      • Common early event in carcinogenesis Carcinogenesis The origin, production or development of cancer through genotypic and phenotypic changes which upset the normal balance between cell proliferation and cell death. Carcinogenesis generally requires a constellation of steps, which may occur quickly or over a period of many years. 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
    • Other mutations involve NOTCH, HRAS, and CDKN2A 
  • Multiple germline single nucleotide polymorphisms also influence cancer initiation and involve loci associated with:
    • 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. Skin: Structure and Functions pigmentation
    • Cell-mediated immunity
    • Anti-apoptotic pathways and cellular proliferation

Cutaneous squamous cell carcinoma precursor lesions

  • 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:
    • Proliferation of atypical epidermal keratinocytes Keratinocytes Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. Skin: Structure and Functions
    • 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
  • Bowen’s disease:
    • cSCC in situ
    • Grows slowly and enlarges over many years
    • Present as erythematous or skin-colored, well-demarcated scaly patches Patches Vitiligo 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: Anatomy 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 on the scalp of a 55-year-old man

Image: “ 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 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 Scarring Inflammation lesions.

Morphology:

Color: varies from flesh-colored to erythematous

Symptoms:

  • Commonly asymptomatic, but may present with pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways and pruritus Pruritus An intense itching sensation that produces the urge to rub or scratch the skin to obtain relief. Atopic Dermatitis (Eczema)
  • Paresthesias Paresthesias Subjective cutaneous sensations (e.g., cold, warmth, tingling, pressure, etc.) that are experienced spontaneously in the absence of stimulation. Posterior Cord Syndrome 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: Histology:
    • 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 Warts Benign epidermal proliferations or tumors; some are viral in origin. Female Genitourinary Examination
  • Sites of lesions: oral, anogenital, or plantar lesions

SCC of the lip: nodule Nodule Chalazion or plaque Plaque Primary Skin Lesions usually on the lower lip

Oral SCC: ulcer, nodule Nodule Chalazion or plaque Plaque Primary Skin Lesions in the oral cavity

Diagnosis and Staging

Diagnostic approach

History:

  • Excessive sun exposure (occupational or recreational)
  • Radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma exposure
  • Family history Family History Adult Health Maintenance, genetic disorders
  • HIV HIV Anti-HIV Drugs, 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. Skin: Structure and Functions 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. Skin: Structure and Functions 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 Dermoscopy A noninvasive technique that enables direct microscopic examination of the surface and architecture of the skin. Seborrheic Keratosis: 

  • Bowen’s disease (cSCC in situ): surface scales Scales Dry or greasy masses of keratin that represent thickened stratum corneum. Secondary Skin Lesions with red-yellowish background
  • Invasive SCC:
    • White and structureless areas
    • Hairpin and linear-irregular vessels

Biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma:

  • Must be performed for definitive diagnosis
  • Techniques: shave, punch, or excisional
  • If invasive SCC is suspected, biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma should go down to the level of the midreticular dermis Dermis A layer of vascularized connective tissue underneath the epidermis. The surface of the dermis contains innervated papillae. Embedded in or beneath the dermis are sweat glands; hair follicles; and sebaceous glands. Skin: Structure and Functions, regardless of technique.
  • SCC in situ histopathology:
    • Atypical keratinocytes Keratinocytes Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. Skin: Structure and Functions with no infiltration of the dermis Dermis A layer of vascularized connective tissue underneath the epidermis. The surface of the dermis contains innervated papillae. Embedded in or beneath the dermis are sweat glands; hair follicles; and sebaceous glands. Skin: Structure and Functions
    • Usually with thickened epidermis Epidermis The external, nonvascular layer of the skin. It is made up, from within outward, of five layers of epithelium: (1) basal layer (stratum basale epidermidis); (2) spinous layer (stratum spinosum epidermidis); (3) granular layer (stratum granulosum epidermidis); (4) clear layer (stratum lucidum epidermidis); and (5) horny layer (stratum corneum epidermidis). Skin: Structure and Functions and hyperkeratosis Hyperkeratosis Ichthyosis Vulgaris of the stratum corneum Stratum corneum Skin: Structure and Functions
  • Invasive SCC histopathology: 
    • Atypical keratinocytes Keratinocytes Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. Skin: Structure and Functions with basement membrane Basement membrane A darkly stained mat-like extracellular matrix (ecm) that separates cell layers, such as epithelium from endothelium or a layer of connective tissue. The ecm layer that supports an overlying epithelium or endothelium is called basal lamina. Basement membrane (bm) can be formed by the fusion of either two adjacent basal laminae or a basal lamina with an adjacent reticular lamina of connective tissue. Bm, composed mainly of type IV collagen; glycoprotein laminin; and proteoglycan, provides barriers as well as channels between interacting cell layers. Thin Basement Membrane Nephropathy (TBMN) and dermis Dermis A layer of vascularized connective tissue underneath the epidermis. The surface of the dermis contains innervated papillae. Embedded in or beneath the dermis are sweat glands; hair follicles; and sebaceous glands. Skin: Structure and Functions infiltration
      • Well differentiated: keratinocytes Keratinocytes Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. Skin: Structure and Functions appear with close-to-normal nuclei and abundant cytoplasm
      • Poorly differentiated: anaplastic keratinocytes Keratinocytes Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. Skin: Structure and Functions, noted to have more nuclear atypia Atypia Fibrocystic Change 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 Keratin A class of fibrous proteins or scleroproteins that represents the principal constituent of epidermis; hair; nails; horny tissues, and the organic matrix of tooth enamel. Two major conformational groups have been characterized, alpha-keratin, whose peptide backbone forms a coiled-coil alpha helical structure consisting of type I keratin and a type II keratin, and beta-keratin, whose backbone forms a zigzag or pleated sheet structure. Alpha-keratins have been classified into at least 20 subtypes. In addition multiple isoforms of subtypes have been found which may be due to gene duplication. Seborrheic Keratosis 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 Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis

  • Rate of metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis: 2%–5%
  • Lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node evaluation:
    • Lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs nodes are the most common metastatic site:
      • Lip and anterior mouth: submental lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs nodes
      • Nose Nose The nose is the human body’s primary organ of smell and functions as part of the upper respiratory system. The nose may be best known for inhaling oxygen and exhaling carbon dioxide, but it also contributes to other important functions, such as tasting. The anatomy of the nose can be divided into the external nose and the nasal cavity. Nose and Nasal Cavity: Anatomy and cheek: submandibular lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs nodes
      • External ear: posterior auricular lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs nodes
      • Anterior scalp, forehead Forehead The part of the face above the eyes. Melasma, temple: parotid lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs nodes
      • Posterior scalp: occipital Occipital Part of the back and base of the cranium that encloses the foramen magnum. Skull: Anatomy lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs nodes
    • Palpable lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs nodes evaluated via the following options:
      • Fine-needle aspiration
      • Surgical removal and pathologic examination
    • Imaging options (done if with lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs nodes positive):
      • CT 
      • MRI
  • If there are no palpable lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs nodes, consider imaging if the following high-risk features are present
    • Tumor Tumor Inflammation diameter:
      • ≥ 6 mm MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma: central face (mask area), ears, hands, feet
      • ≥ 10 mm MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma: other face areas, pretibia
      • ≥ 20 mm MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma: rest of trunk and extremities
    • Poorly differentiated histology
    • Perineural and/or deep invasion
    • Immunosuppressed patient
    • Site of previous radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma, chronic wounds/scars
    • Recurrent tumors
  • Other sites of metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and 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: Anatomy
    • 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: Anatomy
    • Brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification
    • Bones

Staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. Grading, Staging, and Metastasis

American Joint Commission on Cancer 2018 TNM system TNM system Grading, Staging, and Metastasis:

Only applicable to SCC of the head and neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess area (lip, ear, face, scalp, and neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess).

  • Stage 0: cancer involves only the epidermis Epidermis The external, nonvascular layer of the skin. It is made up, from within outward, of five layers of epithelium: (1) basal layer (stratum basale epidermidis); (2) spinous layer (stratum spinosum epidermidis); (3) granular layer (stratum granulosum epidermidis); (4) clear layer (stratum lucidum epidermidis); and (5) horny layer (stratum corneum epidermidis). Skin: Structure and Functions (in situ)
  • Stage I: 
    • Cancer is not large (≤ 2 cm)
    • No spread to the lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs nodes or other organs
  • Stage II: 
    • Cancer is large (>2 cm but ≤ 4 cm). 
    • No spread to lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs 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. Bones: Structure and Types invasion and/or to 1 ipsilateral lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node (no extranodal extension Extension Examination of the Upper Limbs)
    • No spread to other organs
  • Stage IV: lesion of any size and has spread to other organs (distant metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis)

Brigham and Women’s Hospital (BWH) staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. Grading, Staging, and Metastasis:

Management

Treatment approach

Standard surgical excision:

  • 1st-line treatment
  • Negative margins need to be achieved.
  • Generally with margins of 4–6 mm MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma (low-risk lesions) or > 6 mm MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma (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 Electrodesiccation Seborrheic Keratosis and curettage Curettage A scraping, usually of the interior of a cavity or tract, for removal of new growth or other abnormal tissue, or to obtain material for tissue diagnosis. It is performed with a curet (curette), a spoon-shaped instrument designed for that purpose. Benign Bone Tumors
  • Cryotherapy Cryotherapy A form of therapy consisting in the local or general use of cold. The selective destruction of tissue by extreme cold or freezing is cryosurgery. Chondrosarcoma
  • Topical fluorouracil Fluorouracil A pyrimidine analog that is an antineoplastic antimetabolite. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. Bowen Disease and Erythroplasia of Queyrat and photodynamic therapy Photodynamic Therapy Actinic Keratosis are additional options for Bowen’s disease.

Radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma:

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

Systemic treatment:

  • Immunotherapy: 
    • For metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and 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 Chemotherapy Osteosarcoma and/or epidermal growth factor receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors (EGFR) inhibitor ( cetuximab Cetuximab A chimeric monoclonal antibody that functions as an antineoplastic agent through its binding to the epidermal growth factor receptor, where it prevents the binding and signaling action of cell growth and survival factors. Targeted and Other Nontraditional Antineoplastic Therapy): 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 Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas

  • 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 Benign Fibroadenoma neoplasm consisting of immature keratinocytes Keratinocytes Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. Skin: Structure and Functions 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 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: precancerous Precancerous Pathological conditions that tend eventually to become malignant. Barrett’s Esophagus lesion affecting sun-exposed areas (e.g., scalp and hands) in elderly people. 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 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. Skin: Structure and Functions 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 Pyoderma gangrenosum An idiopathic, rapidly evolving, and severely debilitating disease occurring most commonly in association with chronic ulcerative colitis. It is characterized by the presence of boggy, purplish ulcers with undermined borders, appearing mostly on the legs. The majority of cases are in people between 40 and 60 years old. Its etiology is unknown. Crohn’s Disease, venous stasis ulcers. All of these disorders can present with scaly pink or flesh-colored plaques, patches Patches Vitiligo, 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. Skin: Structure and Functions malignancies: 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 (BCC) is the most important differential diagnosis. 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 (BCC) 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. Skin: Structure and Functions cancer arising from the basal cell Basal Cell Erythema Multiforme layer of the epidermis Epidermis The external, nonvascular layer of the skin. It is made up, from within outward, of five layers of epithelium: (1) basal layer (stratum basale epidermidis); (2) spinous layer (stratum spinosum epidermidis); (3) granular layer (stratum granulosum epidermidis); (4) clear layer (stratum lucidum epidermidis); and (5) horny layer (stratum corneum epidermidis). Skin: Structure and Functions. Most patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship 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. Skin: Structure and Functions lesion with telangiectasia Telangiectasia Permanent dilation of preexisting blood vessels creating small focal red lesions, most commonly in the skin or mucous membranes. It is characterized by the prominence of skin blood vessels, such as vascular spiders. Chronic Venous Insufficiency 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. Skin: Structure and Functions 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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