Squamous cell carcinoma of the skin

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aditya Govindavarjhulla, M.B.B.S. [2], Raviteja Guddeti, M.B.B.S. [3], Faizan Sheraz, M.D. [4]

Squamous cell carcinoma is a malignant tumor of epithelium that shows squamous cell differentiation. This type of cancer can be visualized if it is on the skin, lips, inside the mouth, throat or esophagus. It is characterized by red, scaly skin that turns into an open sore.Reports of non-melanoma cancer date back to biblical times. Percival Pott was the first person to report the malignant nature of squamous cell carcinoma in adolescent British chimney sweeps. This was the first described occupational and exposure-related risk factor for squamous cell carcinoma. Later, other occupational and exposure associations were reported when there were reported incidences of squamous cell carcinoma in mule spinners, and it was therefore called mule spinner’s disease. French surgeon Jean-Nicholas Marjolin, in 1828, first described this carcinoma arising in traumatic scars, and subsequently any squamous cell carcinoma associated with burns was termed Marjolin’s ulcer. Squamous cell carcinoma of the skin is a slow growing invasive non-melanoma skin tumour, which is caused mainly by prolonged exposure to sunlight and other forms of UV radiation. Patients undergo staging as a routine part of their diagnosis and treatment. Staging of the lesion assists the physician to choose which form of treatment strategy suits the patient. Squamous cell carcinoma (SCC) is type of non-melanoma skin cancer. The cancer arises as a result of uncontrolled growth of the squamous cells in the epidermis of the skin. Squamous cell carcinoma is most commonly caused by long term exposure to sunlight and other forms of UV radiation. Male sex, fair skinned people, smokers, the elderly, and people who have previous history of a skin cancer are particularly prone to the development of this non-melanomatous skin cancer. It accounts for 20% of all non-melanomatous tumors, and is fairly invasive contrary to its counterpart, basal cell carcinoma. Squamous cell carcinoma typically presents as a non-healing ulcer or growth on a sun exposed area of the skin. Squamous cell carcinoma (SCC) is one of the most common subtypes of skin cancer. Its main risk factors include prolonged exposure to sunlight and/or UV radiation. Most of the affected individuals are elderly. The risk factors for the Squamous cell carcinoma (SCC) include prolonged sunlight exposure, UV radiation, smoking, drugs etc. Once Squamous cell carcinoma (SCC) develops on the skin it grows slowly. If neglected and once it reaches the size of 2 cm and more it is three times more likely to spread to other areas than the smaller lesions. Usual size ranges from 1 cm to 5 cm. It is the mechanical interference of this fungiform exophytic lesion that brings it to the notice of the patient or the clinician. When treated early squamous cell carcinoma is completely curable by 95% – 98%. This lesion has a cure rate of 95% – 98%. But once the lesion spreads to other regions beyond skin, like lymph nodes and internal organs less than half of the patients live five years. A sub set of SCC carries the risk of local recurrence, nodal or distant metastasis (usually to the lungs) and eventually death. A biopsy is the gold standard test for the diagnosis of squamous cell carcinoma of the skin. Diagnosis is established by biopsy and histopathological confirmation. Complete excision is curative in the vast majority of cases. Occasionally squamous cell carcinoma will invade along the perineural layer of peripheral nerves and will extend well beyond the clinically apparent mass. Local recurrence is more common in these instances and when present on the head, direct intracranial extension may occur. Metastases to draining lymph nodes occurs in a minority of cases and disseminated disease is the cause of most squamous cell carcinoma-related deaths. Higher rates of metastasis (~15%) are observed with primary lesions of the lips or ears (Rowe et al., 1992). Radiation therapy is helpful in some cases of locally recurrent disease in which complete resection is difficult to achieve and in cases of limited metastatic disease. There are no CT scan findings associated with squamous cell carcinoma of the skin. However, a CT scan may be helpful in the detection of disease extent, assessment of metastasis, and perineural invasion of the tumor. Magnetic Resonance Imaging (MRI) has implications similar to that of a CT scan. It has many advantages compared to a CT scan including increased sensitive than a CT scan in identifying the extent of a lesion and its use in the evaluation of a tumor for its invasion of perineural tissue. Medical therapy for squamous cell carcinoma includes chemotherapy with cisplatin, topical fluorouracil, capecitabine, methotrexate, cetuximab, bleomycin and doxorubicin. Other treatment modalities include cryotherapy, radiation therapy and photodynamic therapy. Surgery is the mainstay of therapy for squamous cell carcinoma of the skin. Most cases of squamous cell carcinoma are the result of exposure to sunlight and other forms of ultraviolet radiation. Primary prevention focuses primarily on protecting our self from these forms of radiation. Secondary prevention aims at taking care of early symptoms and preclude the development of possible irreparable disease conditions.

Reports of non-melanoma cancer date back to biblical times. Percival Pott was the first person to report the malignant nature of squamous cell carcinoma in adolescent British chimney sweeps. This was the first described occupational and exposure-related risk factor for squamous cell carcinoma. Later, other occupational and exposure associations were reported when there were reported incidences of squamous cell carcinoma in mule spinners, and it was therefore called mule spinner’s disease. French surgeon Jean-Nicholas Marjolin, in 1828, first described this carcinoma arising in traumatic scars, and subsequently any squamous cell carcinoma associated with burns was termed Marjolin’s ulcer.

Squamous cell carcinoma of the skin is a slow growing invasive non-melanoma skin tumour, which is caused mainly by prolonged exposure to sunlight and other forms of UV radiation. Patients undergo staging as a routine part of their diagnosis and treatment. Staging of the lesion assists the physician to choose which form of treatment strategy suits the patient.

Squamous cell carcinoma (SCC) is type of non-melanoma skin cancer. The cancer arises as a result of uncontrolled growth of the squamous cells in the epidermis of the skin. Unlike it’s counter part, the basal cell carcinoma which also belongs to the group of non-melanoma cancer, squamous cell carcinoma is rapid growing and invasive. SCCs may occur on all areas of the body including the mucous membranes and genitals, but are most common in areas frequently exposed to the sun, such as the rim of the ear, lower lip, face, bald scalp, neck, hands, arms and legs. Wrinkling, changes in pigmentation, and loss of elasticity of the skin are often the telltale signs of sun damage

Squamous cell carcinoma is most commonly caused by long term exposure to sunlight and other forms of UV radiation. Male sex, fair skinned people, smokers, the elderly, and people who have previous history of a skin cancer are particularly prone to the development of this non-melanomatous skin cancer.

Squamous cell carcinoma should be differentiated from melanoma and basal cell carcinoma. It accounts for 20% of all non-melanomatous tumors, and is fairly invasive contrary to its counterpart, basal cell carcinoma. Squamous cell carcinoma typically presents as a non-healing ulcer or growth on a sun exposed area of the skin.

Squamous cell carcinoma (SCC) is one of the most common subtypes of skin cancer. Its main risk factors include prolonged exposure to sunlight and/or UV radiation. Most of the affected individuals are elderly.

The risk factors for the Squamous cell carcinoma (SCC) include prolonged sunlight exposure, UV radiation, smoking, drugs etc.

Since Squamous cell carcinoma is almost always cured without specified screening no studies have shown that such screening will improve the already high cure rates for this type of skin carcinoma.

Once Squamous cell carcinoma (SCC) develops on the skin it grows slowly. If neglected and once it reaches the size of 2 cm and more it is three times more likely to spread to other areas than the smaller lesions. Usual size ranges from 1 cm to 5 cm. It is the mechanical interference of this fungiform exophytic lesion that brings it to the notice of the patient or the clinician. When treated early squamous cell carcinoma is completely curable by 95% – 98%. This lesion has a cure rate of 95% – 98%. But once the lesion spreads to other regions beyond skin, like lymph nodes and internal organs less than half of the patients live five years. A sub set of SCC carries the risk of local recurrence, nodal or distant metastasis (usually to the lungs) and eventually death.

A biopsy is the gold standard test for the diagnosis of squamous cell carcinoma of the skin.

Most Squamous cell carcinomas (SCC) arise on the sun-exposed skin of the head and neck, with fewer lesions arising on the extremities and occasional tumors occurring on the trunk. Early lesions frequently present as a red, scaly spots. Later lesions may form nodules or firm plaques, either of which can ulcerate ( http://tray.dermatology.uiowa.edu). Diagnosis is established by biopsy and histopathological confirmation. Complete excision is curative in the vast majority of cases. Occasionally squamous cell carcinoma will invade along the perineural layer of peripheral nerves and will extend well beyond the clinically apparent mass. Local recurrence is more common in these instances and when present on the head, direct intracranial extension may occur. Metastases to draining lymph nodes occurs in a minority of cases and disseminated disease is the cause of most squamous cell carcinoma-related deaths. Higher rates of metastasis (~15%) are observed with primary lesions of the lips or ears (Rowe et al., 1992). Radiation therapy is helpful in some cases of locally recurrent disease in which complete resection is difficult to achieve and in cases of limited metastatic disease

The findings of physical exam helps us in diagnosis and provides information about the prognosis of the disease. Many times physical exam done for some other reason may give us a hint for this.

Squamous cell carcinoma of the skin is most often caused by long term exposure to the sun, and other certain risk factors. No specific laboratory tests are indicated for the diagnosis, as physical exam and biopsy are the primary means of diagnosis. Histopathological evaluation of the biopsy specimen stands out to be the most important diagnostic test.

There are no ECG findings associated with squamous cell carcinoma of the skin.

There are no x-ray findings associated with squamous cell carcinoma of the skin. However, a chest x-ray may be helpful in the diagnosis of lung metastases.

Ultrasonography is not the routine test performed for the diagnosis of SCC. It is useful in certain cases when it is difficult to delineate the border of the lesion. It can be used in addition to a physical exam for better overview of the lesion

There are no CT scan findings associated with squamous cell carcinoma of the skin. However, a CT scan may be helpful in the detection of disease extent, assessment of metastasis, and perineural invasion of the tumor.

Magnetic Resonance Imaging (MRI) has implications similar to that of a CT scan. It has many advantages compared to a CT scan including increased sensitive than a CT scan in identifying the extent of a lesion and its use in the evaluation of a tumor for its invasion of perineural tissue.

There are few modalities used for diagnosis and follow up.

• Fourier Transform Infrared Imaging (FTIR)

• Immunohistochemistry

The management of cutaneous squamous-cell carcinoma is determined by risk stratification (Low, High, or Very High risk) based on tumor size, location, and histological features.

1. Low-Risk Lesions

Definition: Typically small lesions (<2 cm) on the trunk or extremities.

First Preferred Treatment: * Curettage and Electrodessication: High cure rate (up to 95%) for small, low-risk lesions in non-hair-bearing areas.

Standard Wide Local Excision: Surgical margins of 4 to 6 mm provide cure rates between 90% and 98%.

Alternative: Radiation therapy may be considered for patients who are not surgical candidates.

2. High-Risk and Very-High-Risk Lesions

Definition: Lesions >2 cm, located on the head/neck (lips/ears), or showing perineural invasion. Very high-risk includes tumors >4 cm or deep invasion.

First Preferred Treatment: * Mohs Micrographic Surgery: The gold standard for high-risk cases, offering the lowest recurrence rates (1.2% to 4.1%).

Peripheral and Deep Exhaustive Margin Assessment (PDEMA): Recommended when Mohs is not available to ensure complete local control.

Surgical Margins: If standard excision is used instead of Mohs, wider margins of 6 to 10 mm are required.

Adjuvant Therapy: Radiation therapy is recommended for cases with positive margins, extensive perineural involvement, or involvement of large nerves (≥0.1 mm).

3. Advanced and Metastatic Disease

Nodal Involvement: * Solitary node (≤3 cm): Surgical resection alone.

Multiple/Large nodes (>3 cm): Surgery followed by adjuvant radiation therapy.

Systemic Therapy (First-Line):

Immune Checkpoint Inhibitors (PD-1 Inhibitors): Cemiplimab or Pembrolizumab are now the preferred first-line treatments for locally advanced or metastatic cSCC where surgery or radiation is not feasible. This is the major change in our most updated systemic therapy approach, which takes place of conventional chemotherapy.

Response Rates: Targeted PD-1 inhibition shows overall response rates of 34% to 52%.

Second-Line/Other: Conventional chemotherapy (cisplatin/carboplatin) or EGFR inhibitors (cetuximab) may be used, though responses are often shorter-lived compared to immunotherapy.

Surgery is the mainstay of therapy for squamous cell carcinoma of the skin. Mohs micrographic surgery has been shown to be highly effective for control of primary cutaneous squamous-cell carcinoma, with very low rates of local recurrence (1.2 to 4.1%), nodal metastasis, and disease-specific death.

Most cases of squamous cell carcinoma are the result of exposure to sunlight and other forms of ultraviolet radiation. Primary prevention focuses primarily on protecting our self from these forms of radiation.

Secondary prevention aims at taking care of early symptoms and preclude the development of possible irreparable disease conditions.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aditya Govindavarjhulla, M.B.B.S. [2], Raviteja Guddeti, M.B.B.S. [3]

Reports of non-melanoma cancer date back to biblical times. Percival Pott was the first person to report the malignant nature of squamous cell carcinoma in adolescent British chimney sweeps. This was the first described occupational and exposure-related risk factor for squamous cell carcinoma. Later, other occupational and exposure associations were reported when there were reported incidences of squamous cell carcinoma in mule spinners, and it was therefore called mule spinner’s disease. French surgeon Jean-Nicholas Marjolin, in 1828, first described this carcinoma arising in traumatic scars, and subsequently any squamous cell carcinoma associated with burns was termed ”Marjolin’s ulcer”.

Reports of non-melanoma cancer date back to biblical times. Percival Pott was the first person to report the malignant nature of squamous cell carcinoma in adolescent British chimney sweeps. This was the first described occupational and exposure-related risk factor for squamous cell carcinoma. Later, other occupational and exposure associations were reported when there were reported incidences of squamous cell carcinoma in mule spinners, and it was therefore called mule spinner’s disease.^[1] French surgeon Jean-Nicholas Marjolin, in 1828, first described this carcinoma arising in traumatic scars, and subsequently any squamous cell carcinoma associated with burns was termed ”Marjolin’s ulcer”.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Roukoz A. Karam, M.D.[2]

Category	Criteria
T – Primary tumor
TX	Primary tumor cannot be assessed
Tis	Carcinoma in situ
T1	Tumor ≤ to 2 cm
T2	Tumor > 2 cm, and ≤ to 4 cm
T3	Tumor > 4 cm or minor bone erosion or perineural invasion or deep invasion
T4	Tumor with gross cortical bone/marrow, skull base invasion and/or skull base foramen invasion
T4a	Tumor with gross cortical bone/marrow invasion
T4b	Tumor with skull base invasion and/or skull base foramen involvement
N – Regional lymph nodes
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Metastasis in a single ipsilateral lymph node, tumor size ≤ 3 cm, and no extranodal extension
N2	Metastasis in a single ipsilateral lymph node, tumor size ≤ 3 cm, and presence of extranodal extension; or Tumor size > 3 cm but ≤ 6 cm without extranodal extension; or Metastasis in a single ipsilateral lymph node, tumor size ≤ 3 cm, and presence of extranodal extension; or Metastases in multiple ipsilateral lymph nodes, tumor size ≤ 6 cm without extranodal extension; or In bilateral or contralateral lymph node(s), tumor size ≤ 6 cm without extranodal extension
N2a	Metastasis in a single ipsilateral lymph node, tumor size ≤ 3 cm, and presence of extranodal involvement; or Single ipsilateral node larger, tumor size > 3 cm and ≤ 6 cm, without extranodal extension
N2b	Metastases in multiple ipsilateral nodes, tumor size ≤ 6 cm, and without extranodal extension
N2c	Metastases in bilateral or contralateral lymph node(s), tumor size ≤ 6 cm, and without extranodal extension
N3	Metastasis in a lymph node, tumor size > 6 cm, and without extranodal extension; or In a single ipsilateral node, tumor size > 3 cm, and presence of extranodal extension; or Multiple ipsilateral, contralateral, or bilateral nodes with any extranodal exension; or Single contralateral node of any size with any extranodal extension
N3a	Metastasis in a lymph node, tumor size > 6 cm, and absence of extranodal extension
N3b	Metastasis in a single ipsilateral node, tumor size > 3 cm, and in presence of extranodal extension; or Multiple ipsilateral, contralateral, or bilateral nodes, with any extranodal extension; or Single contralateral node of any size and with any extranodal extension
M – Distant metastasis
M0	No distant metastasis
M1	Distant metastasis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aditya Govindavarjhulla, M.B.B.S. [2], Raviteja Guddeti, M.B.B.S. [3]

Squamous cell carcinoma (SCC) is type of non-melanoma skin cancer. The cancer arises as a result of uncontrolled growth of the squamous cells in the epidermis of the skin. Unlike it’s counter part, the basal cell carcinoma which also belongs to the group of non-melanoma cancer, squamous cell carcinoma is rapid growing and invasive. SCCs may occur on all areas of the body including the mucous membranes and genitals, but are most common in areas frequently exposed to the sun, such as the rim of the ear, lower lip, face, bald scalp, neck, hands, arms and legs. Wrinkling, changes in pigmentation, and loss of elasticity of the skin are often the telltale signs of sun damage.

• Malignant transformation of normal epidermal keratinocytes is the hallmark of squamous cell carcinoma of the skin.
• One critical pathogenic event is the development of apoptotic resistance through functional loss of TP53, a well-studied tumor suppressor gene.
  • TP53 mutations are seen in over 90% of skin cancers diagnosed in the United States, as well as in most precursor skin lesions, suggesting that loss of TP53 is an early event in the development of cSCC.^[1]
• UVR causes deoxyribonucleic acid (DNA) damage through the creation of pyrimidine dimers, a process known to result in the genetic mutation of TP53.
• Upon subsequent UVR exposure, keratinocytes undergo clonal expansion, acquiring further genetic defects, ultimately leading to invasive cutaneous squamous cell carcinoma.
• Many other genetic abnormalities are believed to contribute to the pathogenesis of squamous cell carcinoma of the skin, including mutations of BCL2 and RAS.
• Likewise, alterations in intracellular signal transduction pathways, including the epidermal growth factor receptor (EGFR) and cyclooxygenase (COX), have been shown to play a role in the development of squamous cell carcinoma of the skin.
• Squamous cell carcinoma in situ (CIS), sometimes referred to as Bowen disease, is a precursor to invasive cSCC. Characteristics of this lesion include nuclear atypia, frequent mitoses, cellular pleomorphism, and dyskeratosis, parakeratosis, and hyperkeratosis.
• p53 is mutated commonly in Actinic keratosis, demonstrating that dysplastic lesions have acquired the initial genetic mutations prior to becoming cutaneous squamous cell carcinoma.^[2][3][4]
• The mechanism leading to genomic instability in keratinocytes likely results from UVB-induced inactivation of p53, since approximately 58% of cutaneous squamous cell carcinoma harbor UVB signature mutations such as CC→TT and C→T transitions.^[5]
• Aberrant activation of EGFR and Fyn, a Src-family tyrosine kinase (SFK), are seen in human cutaneous squamous cell carcinoma.
• Kinases downregulate p53 mRNA and protein levels through a c-Jun–dependent mechanism revealing another mechanism for controlling p53 function^[6]
• Amplification and activating mutations of the Ras oncogene have been found in squamous cell carcinoma and actnic keratosis
• Ras is an upstream activator of the Raf/Mek/Erk1/Erk2 kinase pathway, and activating mutations in Ras can promote cutaneous squamous cell carcinoma.^[7]
• Expression of β1-integrins and their ligands correlates with tumor progression in human skin.
• Ras family members of proto-oncogenes transduce cellular growth and proliferation signals downstream of cell membrane–bound receptor tyrosine kinases (RTKs). Ras can be activated by gene amplification, activating mutations, or overexpression of upstream RTKs. Aberrant Ras activation promotes several key tumorigenic phenotypes including mitogenesis, resistance to apoptosis, drug resistance.^[8]

Squamous cell carcinoma is a potentially invasive cancer that arises from the surface epithelium.The development of squamous cell carcinoma is frequently a multistep process. Early lesions tend to be either actinic keratoses, with atypia of the basal keratinocytic layer of the epidermis or squamous cell carcinoma in situ, in which keratinocytic atypia spans the full thickness epidermis.

These precursors are frequently present adjacent to invasive squamous cell carcinomas which invade the dermis as nests, islands, or cords squamous cells with or occasionally as individual cells. Several grading schemes have been developed for squamous cell carcinoma and incorporate the extent of keratinization (a form of differentiation) and nuclear atypia. A widely used scheme divides tumors into well, moderately, or poorly differentiated.

Although poorly differentiated tumors tend to behave more aggressively, well-differentiated tumors can also give rise to metastasis and result in death. Several histological variants of squamous cell carcinoma have been documented, including verrucous, spindle cell and pseudovascular.

• Large lesions require a thorough sample that will adequately assess the entirety of the lesion.
• Findings Histopathological evaluation is important in determining the next step in the grade and treatment of the cancer. The neoplastic cells may demonstrate varying degrees of squamous differentiation and atypia uncder the microscope.

• The most conspicuous finding under a microscope are keratin pearls(well formed desmosome attachments and intracytoplasmic bundles of keratin tonofilaments).
• SCC can be graded up to grade 3.
  • Well differentiated: nuclei which are more normal, abundant cytoplasm & extracellular keratin pearls
  • Poorly differentiated: High degree of nuclear atypia, greater nuclear:cytoplasmic ratio and less keratinization. Due to poor differentiation it may mimic mesenchymal tumors. Poorly differentiated carcinoma has a higher rate of metastasis and high rates of invasion into surrounding tissues.
  • Moderately differentiated: Has an appearance that is midway between poorly differentiated and well differentiated.
  • Squamous cell carcinoma in situ – has full thick atypia of squamous cells (including surfaces) without invasion through the basement membrane.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aditya Govindavarjhulla, M.B.B.S. [2], Raviteja Guddeti, M.B.B.S. [3]

Squamous cell carcinoma is most commonly caused by long term exposure to sunlight and other forms of UV radiation. Male sex, fair skinned people, smokers, the elderly, and people who have previous history of a skin cancer are particularly prone to the development of this non-melanomatous skin cancer.

Squamous cell carcinoma (SCC) may occur in normal skin or in already damaged skin (injured or inflamed). Most skin cancers occur on skin that is repeatedly exposed to sunlight or another form of ultraviolet radiation. The effect is cumulative, with the amount of damage done to the skin building up over time. Although sun exposure is the major causative factor for most cases of squamous cell carcinoma there are some other causes for the development of this invasive form of skin cancer.

• Therapeutic radiation : Psoralen plus ultraviolet A (PUVA) used in the treatment of psoriasis, and x-rays of head and neck increase the risk of squamous cell carcinoma. The likelihood that therapeutic radiation can lead to skin cancer also depends on other factors such as pigmentation of the skin and the total cumulative dose of radiation received. PUVA is particularly phototoxic and mutations in both TP53 tumor suppressor gene and the Ras oncogee are found in PUVA associated squamous cell carcinoma.In addition to being mutagenic, UVA in association with UVB is a potent suppressor of the cutaneous immune system.

• People with a fair complexion, albinism, blue or gray eyes, and those with light colored hair are particularly prone to develop skin cancers as they lack the photo-protective melanin pigment.

• Patients with the genetic disease called Xeroderma Pigmentosa have a deficiency of an enzyme that is essential for DNA repair. Inability to repair DNA that has been damaged by the sun leaves these patients prone to innumerable squamous cell carcinomas. There is also an increased risk of oral cancers in people with polydysplastic epidermolysis bullosa and Bloom syndrome.

• Drugs like Ruxolitinib sirolimus , Trametinib

• Arsenic, a harmful toxin, is a well known cause of squamous cell carcinoma.

• The use of immunosuppressive drugs to prevent graft rejection in organ transplant recipients is associated with a 65 to 250 fold increased risk of developing SCC compared to the general population. Pretransplantation end-organ disease may also impact the development of post-transplantation SCC. For example among renal transplant patients the highest incidence of skin cancer is found in those with poly cystic kidney disease while the lowest incidence is observed in diabetic nephropathy.Cholestatic liver disease is found to have a higher association with skin cancers than other causes of liver failure post-transplantation.

• 15% of patients with SCC have a viral etiology for the cause of their cancer. Human Papilloma Virus (HPV) is a well known potential cause of squamous cell carcinoma. This sexually transmitted virus has more than 100 strains reported so far. Some strains cause genital warts and whereas others are known to cause cancer of the vagina, cervix and penis.

• Tobacco use is associated with the development of sqaumous cell carcinoma. Both smoked and smokeless forms of tobacco contain carcinogens called mutagens.

• SCC of the head and neck is commonly associated with alcohol use. The use of alcohol is associated with a 40 fold increase in the risk of developing SCC of the head and neck. The use of tobacco and alcohol together increases the risk even further, up to 100 fold. Mutations in TP53 tumor suppressor gene has a positive correlation with the use of tobacco and alcohol. ^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Roukoz A. Karam, M.D.[2] Homa Najafi, M.D.[3]

Squamous cell carcinoma should be differentiated from melanoma and basal cell carcinoma. It accounts for 20% of all non-melanomatous tumors and is fairly invasive contrary to its counterpart, basal cell carcinoma. Squamous cell carcinoma typically presents as a non-healing ulcer or growth on a sun-exposed area of the skin.

A few conditions that mimic Squamous cell carcinoma of the skin include the following:

Diseases		Skin examination					Diagnosis		Additional findings
		Type	Color	Texture	Size	Distribution	Dermoscopic Findings	Histopathology
Cutaneous squamous cell carcinoma[1]	SCC in situ (Bowen’s disease)	Patch Plaque	Erythematous Skin colored	Scaly	Variable	Fair-skinned individuals: sun-exposed areas In black individuals: legs, anus, and areas of chronic inflammation	Presence of dotted and/or glomerular vessels White to yellowish surface scales Red-yellowish background	Keratinocytic dysplasia of the epidermis No infiltration into dermis Pleomorphic keratinocytes Hyperchromatic nuclei	Slow growth over the years
	Invasive squamous cell carcinoma	Papule Plaque Nodule	Skin colored	Indurated + hyperkeratotic (well differentiated) Soft + ulceration (poorly differentiated)	0.5 to 1.5 cm	Fair-skinned individuals: sun-exposed areas In black individuals: legs, anus, and areas of chronic inflammation	White circles White structureless areas Masses of keratin Hairpin and linear-irregular vessels	Keratinocytic dysplasia of the epidermis No infiltration into dermis Pleomorphic keratinocytes Hyperchromatic nuclei	May be painful or pruritic
Keratoacanthoma[2]		Macule Papule May have telangiectasias	Skin-colored Mildly erythematous	Prominent keratinous core in the center of the nodule	1 to 2.5 cm	Sun-exposed areas Face, neck, hands, and arms	White circles Keratin Blood spots White structureless zones	Well-differentiated squamous epithelium Central keratin core Epidermal hyperplasia + large eosinophilic keratinocytes Dermal inflammatory infiltrate	Rapid growth (within weeks)
Dermatofibroma[3][4]		Nodule	Hyperpigmented	Firm	0.3- 1 cm	Mostly seen in extremities		Localized nodular proliferation of spindle-shaped fibrous cells in a mixture of histocytoid cells inside the dermis Spiculated margin of cells “Storiform” pattern Collagen bundles “Grenz zone” Epidermal hyperplasia	Slow growth over the years
dermatofibrosarcoma protuberans[5][6]		Patch Plaque	Skin–colored, violet or reddish–brown	Firm	1-5 cm	Mostly seen in trunk	Presence of vessels pigmented network pinkish background	Highly cellular with cells having following characteristics: Monomorphic Thin Spindly Scant eosinophilic cytoplasm Hyperchromatic nuclei (resembling neurofibroma)
Kaposi sarcoma[7][8]		Macule Patch	Red/violaceous	Smooth	Variable	Mucus membrane	Rainbow pattern scaly surface Small brown globules	Spindle cells with minimal nuclear atypia Excessive vascular proliferation Abundant red blood cells RBC and hemosiderin extravasation Abundant lymphocytes and monocytes Premonitory sign Intracytoplasmic PAS +ve hyaline globules	Kaposi’s sarcoma is commonly associated with acquired immune deficiency syndrome (AIDS)
Merkel cell carcinoma[9]		Intracutaneous nodule	Shiny Flesh-colored or bluish-red	Firm	< 1 cm	Sun-exposed areas Head and neck Upper limbs and shoulder Lower limbs and hip Trunk	Milky red areas Linear Irregular vessels Polymorphous vessels	Uniform cells with large basophilic nuclei Single-cell necrosis Frequent mitoses Lymphovascular invasion Perineural invasion Epidermal involvement via pagetoid spread	Older individuals with light skin tones Rapidly growing
Basal cell carcinoma[10]	Nodular basal cell carcinoma	Papule	Flesh-colored	Small bump	Variable	Face	Focused, bright red, and branching arborizing vessels Loosely arranged blue-gray dots	Nest-like infiltration with basaloid cells	May have a “rolled” border
	Superficial basal cell carcinoma	Patch	Erythematous	Scaly	1 to > 10 cm	Sun-exposed areas Head (cheek and nose) Trunk	Superficial fine telangiectasia Shiny white to red, translucent or opaque structureless areas Multiple small erosions	Large, hyperchromatic, oval nuclei Minimal cytoplasm Small basaloid nodules	Higher incidence in men
	Sclerosing basal cell carcinoma (morpheaform)[11]	Papule Plaque	Flesh-colored Slightly erythematous	Firm Indurated Indistinct borders	Variable	Sun-exposed areas	Whitish background Few fine arborizing vessels Multiple brown dots Ulceration	Thin columns + small nodules Highly collagenized stroma	Expression of smooth muscle protein alpha-actin in tumor stroma
Prurigo nodules[12][13]		Dome-shaped nodule	Flesh-colored Erythematous Brown/black	Firm	Variable	Extensor surfaces of the arms and legs and on the trunk Upper back, abdomen, and sacrum	White “starburst pattern” surrounding red/brown/yellow crusts Erosions Hyperkeratosis	Thick and compact orthohyperkeratosis Irregular epidermal hyperplasia Focal parakeratosis with irregular acanthosis Nonspecific dermal infiltrate containing WBCs	Nodules range in number from few to hundreds Worsened by heat, sweating, or irritation from clothing
Melanoma[14]	Melanoma in situ (Lentigo Maligna)[15]	Macule	Variable (from light to dark brown, black, pink, red, or white)	Smooth	Around 1 cm	Sun-damaged skin of the head or neck	Asymmetric, pigmented follicular openings Gray angulated lines Gray areas, dots, and globules Circle within a circle	↑ atypical spindle shaped melanocytes Arranged in single cells or in small nests along the dermal-epidermal junction	Darkening of pigmentation, sharpening of borders, or emergence of nodular areas are signs of progression to lentigo maligna melanoma
	Lentigo maligna melanoma[16]	Macule	Brown/tan	Freckle-like	Variable	Chronically sun-damaged areas	Asymmetric, pigmented follicular openings Gray angulated lines Gray areas, dots, and globules Circle within a circle	“Star-burst giant cells” in epidermis “Swallow’s nest” sign along the dermal-epidermal junction Minimal cytoplasm Pale nucleus with small nucleoli	Usually in older individuals
	Superficial spreading melanoma[17]	Macule Plaque with irregular borders	Variably pigmented (red, blue, black, gray, and white)	Thin	1 mm to > 1 cm	Anywhere but usually: Back (men and women) Lower extremities (women)	Asymmetry of shape > 2 colors Asymmetry of structures	Asymmetric Poorly circumscribed Lack cellular maturation	Lateral (radial) growth before vertical (invasive) growth
	Nodular melanoma[18][19]	Polypoid nodule	Dark color	Lump	6mm to > 1 cm	Trunk Head Neck	Pigment network or pseudonetwork Aggregated brown or black globules Blue pigmentation within lesion Small dotted or comma vessels	Cells proliferate downwards through the skin Dermal growth in isolation or in association with an epidermal component	Two-thirds arise in normal skin, the rest in existing moles Rapidly enlarging
	Acral lentiginous melanoma[20]	Macule Patch	Dark brown to black	Raised areas Ulceration Bleeding	Variable	Palmar Plantar Subungual Mucosal surfaces	Parallel-ridge pattern Irregular diffuse pigmentation	Asymmetric proliferation of single melanocytes at dermoepidermal junction	Most common among dark skinned individuals
	Amelanotic melanoma[21]	Patch	Skin color	Slightly elevated borders	Around 6 mm	Sun-exposed areas	No melanin pigmentation Dotted vessels Linear irregular vessels		Lesions not pigmented since they don’t produce melanin
Common nevus[22][23]		Dome-shaped nodules	Hypopigmented	Smooth surface Terminal hairs often present	1 cm to > 20 cm	Sun-exposed areas above the waist	Comma-shaped or curved vessels Structureless light brown background Residual brown thick circles around the hair follicles	Multinucleated melanocytes Melanocytes diffusely infiltrate dermis	Also called Miescher nevus
Blue nevus[24]		Macule Papule	Blue	Smooth	Variable	Head and neck, Dorsal aspect of the distal extremities Sacral area	Structureless blue pigmentation Structureless blue and white or blue and brown on some occasions	Proliferation of dendritic, dermal, melanin-producing melanocytes	Also called Mongolian spots
Spitz nevus[25][26]	Nonpigmented Spitz nevus	Nodule	Pink	Smooth	< 1 cm	Cheek	Coiled vessels White network over a pink to reddish background		In children and adolescents
	Reed-like Spitz[27]	Papule	Heavily pigmented	Smooth	< 1 cm	Head and neck Upper and lower extremities	Structureless black to gray center Hypopigmented follicular openings Peripheral streaks Pseudopods Globules	Enlarged spindle melanocytes with polyangular form “Ground glass” cytoplasm	Most commonly develops in children, adolescents, and young adults.
Solar lentigo[28]		Multiple spots	Brown	Smooth	Around 5mm	Sun-exposed areas	Faint pigmented fingerprint structures Structureless pattern Light brown pseudonetwork with well-defined borders and a “moth-eaten” edge	↑ melanin deposition in keratinocytes ↑ linear arrangement of melanocytes at the dermal-epidermal junction	Associated with UV exposure and skin aging
Sebaceous hyperplasia[29]		Papule	Skin-colored to brownish	Umbilicated	2 – 6 mm	Forehead Nose Cheeks	Structureless yellow to whitish center surrounded by short linear “crown vessels“		Usually in middle-aged or older patients
Lichen planus-like keratosis[30]		Papule Plaque	Gray to brown	Prominent	Variable	Upper trunk	Shows a coarse or fine, gray to blue, granular pigmentation Diffuse brownish gray granules	Hypergranulosis Epidermal hyperplasia Superficial bandlike infiltrate Melanophages	Appearance depends on stage of evolution

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Roukoz A. Karam, M.D.[2]

Cutaneous squamous cell carcinoma is the 2nd most common type of skin cancer in the United States. The incidence of squamous cell carcinoma of the skin increases dramatically with age. Cutaneous squamous cell carcinoma is a common disease that tends to affect people living closer to the equator.

• The exact incidence of squamous cell carcinoma of the skin is unknown since it is not included in the US national tumor registries.
• The incidence of squamous cell carcinoma of the skin was estimated to be 9 to 96 cases per 100,000 male and 5 to 68 per 100,000 female individuals in Europe.^[1]
• Cutaneous squamous cell carcinoma is the 2nd most common type of skin cancer in the United States, behind basal cell carcinoma (BCC).^[2]

• In the United States, the mortality rate of cutaneous squamous cell carcinoma is approximately 3932 to 8791.^[3]

• The incidence of squamous cell carcinoma of the skin increases with age.
• Cutaneous squamous cell carcinoma infrequently affects people under the age of 45; however, the incidence in increasing in younger individuals.^[4]

• For those over 75, the incidence is approximately 5 to 10 times higher than the incidence in younger age groups and 50 to 300 times higher than for those under 45.^[5]

• Cutaneous squamous cell carcinoma is a common disease that tends to affect people living closer to the equator.
  • In Australia, for example, there are approximately 1035 and 472 cases per 100,000 for men and women, respectively.^[6]
  • In contrast, the age-adjusted incidences for men and women in Finland are only about 6 and 4 per 100,000.^[7]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aditya Govindavarjhulla, M.B.B.S. [2], Raviteja Guddeti, M.B.B.S. [3]

The risk factors for the Squamous cell carcinoma (SCC) include prolonged sunlight exposure, UV radiation, smoking, drugs etc.

Common risk factors inlcude:^[1]

• UV light exposure^[2]
  • UV light damages DNA, initiating a series of changes can result in malignant transformation
• Having skin that burns easily and does not tan or tans poorly
• Light-colored hair
• Older age
• Smoking

• Northern European ancestry
• Exposure to PUVA phototherapy
• Immunosuppressive treatment^[3]
• Exposure to ionizing radiation and other industrial carcinogens^[4]
• Chronic inflammation^[5]
• Rare inherited disorders
  • Xeroderma pigmentosum^[6]
  • Epidermolysis bullosa^[7]
  • Albinism^[8]
  • Epidermodysplasia verruciformis
  • Fanconi’s anemia
• Arsenic exposure
• Genetic alterations^[9]
• Family history^[10]
• Drugs
  • BRAF inhibitors
  • Voriconazole^[11]
  • Other photosensitizing drugs like ibuprofen and isotretinoin^[12]

Skin

• Significant sun exposure
• Benign lesions like Chalazion
• Chronic ulcers.

Tongue and Esophagus

• Tobacco chewing/smoking
• Alcohol Abuse
• Poor dental hygiene

Nasopharynx

Persons who have SCC of this region seldom have any risk factors. It most of the times caused by EBV infection.

Lungs

• Therapeutic radiation (PUVA for psoriasis)
• Tobacco smoking

Penis

• Pre-malignant lesions (Bowen’s disease, Condyloma , Warts)
• Smoking and tobacco chewing

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aditya Govindavarjhulla, M.B.B.S. [2], Raviteja Guddeti, M.B.B.S. [3], Faizan Sheraz, M.D. [4]

Since Squamous cell carcinoma is almost always cured without specified screening no studies have shown that such screening will improve the already high cure rates for this type of skin carcinoma.

Since Squamous cell carcinoma is almost always cured without specified screening no studies have shown that such screening will improve the already high cure rates for this type of skin carcinoma.For carcinoma of prostate, prostate specific antigen (PSA) is often used for diagnosis. Squamous cell carcinoma of prostrate is very aggressive in nature. It is difficult to detect as there is no increase in prostate specific antigen levels seen; meaning that the cancer is often diagnosed at an advanced stage.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aditya Govindavarjhulla, M.B.B.S. [2], Raviteja Guddeti, M.B.B.S. [3]

Squamous cell carcinoma of the skin can develop on any cutaneous surface; however, it is most common in sites frequently exposed to the sun including: head and neck, dorsum of the hands and forearms, upper and lower limbs, back, and chest. It is not very common for cutaneous squamous cell carcinoma to arise in non-sun-exposed skin; however, in dark-skinned individuals the symptoms of squamous cell carcinoma of the skin typically develop in non-sun-exposed skin.

• Squamous cell carcinoma of the skin can develop on any cutaneous surface.
• In fair-skinned individuals the symptoms of squamous cell carcinoma of the skin typically develop in sites frequently exposed to the sun.^[1]
  • Head and neck – 55 %
  • Dorsum of the hands and forearms – 18 %
  • Legs – 13 %
  • Arms – 3 %
  • Shoulder or back – 4 %
  • Chest or abdomen – 4 %
• It is not very common for cutaneous squamous cell carcinoma to arise in non-sun-exposed skin; however, in dark-skinned individuals the symptoms of squamous cell carcinoma of the skin typically develop in non-sun-exposed skin.^[2]
  • Sites usually affected in dark-skinned individuals include the legs, anus, and sites of chronic inflammation.

• Common complications of squamous cell carcinoma of the skin include:
  • Spread to lymph nodes
  • Metastases into other tissues and organs especially the lungs and bones
  • Death

This lesion has a cure rate of 95% – 98%. But once the lesion spreads to other regions beyond skin, like lymph nodes and internal organs less than half of the patients live five years. A sub set of SCC carries the risk of local recurrence, nodal or distant metastasis (usually to the lungs) and eventually death. Tumors in this sub set are termed high risk SCC. Tumor related factors in high risk SCC are

• Tumor size greater than 2 cm (1.5 cm for lesions on ear or lip) – Lesions less than 2 cm have a metastatic potential of 9.1% whereas in those of size more than 2 cm the rates spike up to 30.3%.
• Invasion to subcutaneous fat : less than 2 mm – 95% survival rate, from 2-9 mm – 80% survival rate, more than 9 mm – 65% survival rate.
• Poorly differentiated cells
• Recurrent tumor
• Perineural involvement – the metastatic rate in such involvement can reach 45%. The degree of nerve involvement likely has a major impact on the prognosis. ^[3]

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