Squamous cell carcinoma (SCC) is a cutaneous skin cancer arising from malignant proliferation of epidermal keratinocytes. Squamous cell carcinoma is the second most common skin cancer after basal cell carcinoma (BCC). Incidence of SCC have increased over the past 20 years probably due to high levels of sun exposure, tanning bed use, aging and early detection.
Etiology and Risk factors
Like Basal cell carcinoma (BCC), both environmental and genetic factors contribute to the development of cutaneous SCC. Other established risk factors include chronic arsenic exposure, iatrogenic radiation therapy, long-term immune suppression, genetic mutations and the basal cell nevus syndrome from genetic predisposition and other risk factors that increase UV damage events.
- Sunlight UV exposure is the most important environmental cause of SCC just like BCC. Exposure to ultraviolet (UV) radiation (UVB is most important although UVA also plays a significant role). The type of UV that plays a role in BCC is unclear but it is the intermittent intense exposure that is most important factor for BCC and Melanoma, whereas UVB is more important for cutaneous SCC. The p53 tumor suppressor gene in particular is highly associated with damage caused by UVB radiation hence up to 45-60% of SCC cases have p53 mutation.
- Individuals with genetic mutations abnormalities such as Albinism, xeroderma pigmentosum (seen in NER – nucleotide Excision Repair mutation) have higher chances of getting skin cancer in general. Other phenotypic difference that increase susceptibility to UV damage include those having fair skin (Caucasians), light-colored eyes, red hair, older age, childhood freckling.
Tanning beds (UVA radiation mainly)
- The use of tanning beds may increase the risk for early development of SCC and BCC.
- Population-based case-control studies have shown that tanning increase the by up to 60% for SCC and BCC.
Therapeutic exposure (UVA)
- Therapeutic exposure to psoralen plus ultraviolet A light (PUVA) for cutaneous disorders such as psoriasis increases the risk of non-melanoma skin cancer, particularly SCC. Studies have shown that PUVA treated patients have up to 35 times higher risk for getting SCC.
- The fact that UVA plays a role (but not as much as UVB) in the development of SCC is also demonstrated in individual who frequent tanning beds.
- Due to the association of squamous cell carcinoma (SCC) and BCC with UV light exposure, there are questions as to whether the use of photosensitizing medication can increase risk of development of SCC.
- An association between prior use of photosensitizing drugs such as tetracycline and increased risk for SCC and BCC has been documented in several observational studies. However, additional studies are necessary to clarify the relationship.
- Smoking increases the risk of squamous cell carcinoma (SCC) but there has been conflicting results to demonstrate the increase risk of BCC in smokers.
Chronic Arsenic Exposure
- Consumption of arsenic in chronic setting has been associated with BCC and SCC.
- These exposure usually requires about 30 to 40 years duration typically via ingestion of contaminated medication, water and seafood etc.
- Chronic superficial ionizing radiation exposure has been associated with increased risk of developing non-melanoma skin cancer, especially basal cell carcinoma. This is because the ionizing radiation tend to reach the basal layer more than the superficial layer, however, the risk of SCC is still significant higher in patients exposed to ionizing radiation. The pathogenesis, like BCC has to do with damage to the DNA structures which ultimately lead to carcinogenesis.
- Immune suppression following HIV or medication induced after solid organ transplant have been associated with increased risk for basal cell carcinoma. While the extend of increase is more prominently for squamous cell carcinoma (SCC) skin cancer, immune suppression is a recognized risk factor for basal cell carcinoma.
- Patients whose immune system are chronically suppressed (such as HIV and solid organ transplant recipient) are therefore at increased risk for the development of basal cell carcinoma, although the increase in risk is less than that observed for SCC.
- As mentioned, the increased risk for SCC skin cancer is more significant than BCC. The risk for BCC after solid organ transplantation tend to increase linearly whereas for SCC, the risk increases exponentially.
- Although the increased risk for BCC in immune suppressed individuals are clearly elucidated, the association between use of systemic corticosteroid and BCC has not been clearly demonstrated, but the increased risk for SCC has been demonstrated with corticosteroids. Studies in the Netherlands and Norway have shown that the rate of SCC were 65 to 250 times more often in solid organ transplant patients like (renal and heart transplant).
- The DNA damage from UV radiation may have enhanced by both direct immune suppressive effect and decrease immune surveillance resulting in decreased ability to destroy precancerous cells in skin. Cutaneous SCCs are more aggressive in patients who are transplant recipients as evidenced by their increase rate of metastasis and local recurrence.
- Chronic inflammation, as seen in some lesions like burns, ulcers, sinus tracts or inflammatory skin conditions like lichen sclerosus et atrophicus have been associated with increased risk for SCC development. The word, Marjolin’s ulcer is used to describe a wound where SCC develops. However, SCC arising from chronic inflammation is very rare at a rate of about 1 %.
Several inherited disorders have been shown to predispose individuals to basal cell carcinoma.
- Oculocutaneous albinism consists of at least 10 different inherited skin diseases characterized by a generalized decrease of pigmentation in the skin, eyes, and hair due to abnormal melanocyte function. Individuals with albinism must protect themselves from sunlight, or they risk the early development of both cutaneous SCC and BCC
- Xeroderma pigmentosum (XP) is a rare genetic disorder due to multigenic, multiallelic autosomal recessive disease mutations that affect the DNA repair system (Nucleotide excision repair), resulting in an impaired ability to repair UV-induced DNA damage. Individuals with XP have an increased risk of skin cancer up to 2000 times than patient without.
- The epidermolysis bullosa (EB) syndromes are a group of mechanobullous skin diseases that share a common feature of blister formation occurring with little or no trauma. It is associated with increased risk of developing BCC and SCC.
- Human papillomavirus (HPV) infection can cause Squamous Cell Carcinoma in individuals who have genetic predisposition such as individuals with epidermodysplasia verruciformis and verrucous carcinoma (penis).
- Studies have shown significant association between HPV types 5, 8, 15, 17, 20, 24, 36, and 38 and the risk of SCC.
- Drugs such as Oral contraceptives, antifungal Voriconazole, Photosensitivity drug (tetracycline) have been associated with SCC.
- BRAF inhibitorssuch as vemurafenib and dabrafenib, develop squamous cell carcinoma or keratoacanthomas. Lesions typically appear within weeks of the start of treatment with these medication. The mechanism might be due to paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in cells with preexisting RAS or receptor tyrosine kinase mutations which contribute to rapid proliferation of SCC.
Symptoms and Clinical Presentations
Most of the SCC are thought to arise from solar keratosis also known as Actinic keratosis but can also develop from chronic ulcer (marjolin ulcers) and HPV infection. SCC presents in locations like BCC. The most commonly involved area include the head and neck (55%) and extremities (upper extremities 18% and lower extremities 13%). However, the trunk involvement are not as common as extremities like the case in BCC.
Genital and periungual squamous cell carcinoma are usually rare and mostly associated with high risk HPV or treatment with psoralen plus ultraviolet A (PUVA) phototherapy without genital shields.
The appearance of SCC depends on the type and site of involvement:
- SCC in situ (Bowen’s disease)— Cutaneous SCC in situ typically presents as a well-demarcated, scaly patch or plaque. Lesions are often erythematous but can also be skin colored or pigmented. It can be confused with inflammatory reaction based on appearance, but unlike inflammatory reaction, SCC are usually asymptomatic.
- Erythroplasia of Queyrat: Erythroplasia of Queyrat is a term used to describe SCC in situ of the penis. The lesion is usually well demarcated with velvety, red plaque. Other associated symptoms include pruritus, pain and occasionally bleeding.
- Squamous cell carcinoma of the lip— SCC of the lip usually involves the lower lip and the lesion appear as ulcers, nodules with white plaques.
- Invasive SCC:The appearance of invasive SCC often varies with the extend of differentiation. Well-differentiated SCC typically appear firm, indurated with, hyperkeratotic papules, plaques, or nodules. Lesions are usually 5 to 15 mm in diameter with or without ulceration. Lesions of invasive SCC often have no symptomatic but may present with painful or pruritic lesion. If there is invasion of nerves, local neurologic symptoms may present as numbness, burning sting or paresthesia. If severe, paralysis can occur. Invasion of neural structures are usually poor prognostic factor.
- Keratoacanthoma— Keratoacanthomas is considered a variant of SCC that compose of keratocytic epithelial tumors that clinically and histologically resemble SCC. There is controversy as to whether keratoacanthomas represent a subtype of well-differentiated SCC or a separate entity. The lesion is usually found on damaged skin with AK. Lesion usually exhibit rapid initial growth with dome-shaped/crateriform nodules with a keratotic core in the center within weeks.
- Verrucous carcinoma (VC): This is also a subtype or variant of SCC that have well defined exophytic, cauliflower-like growths similar to a large wart. They can be subclassified according to site:
- Oral florid papillomatosis: present with verrucous carcinoma (VC) on the oral mucosa
- Epithelioma cuniculatum: present with verrucous carcinoma on the plantar foot
- Anogenital(sometimes called giant condyloma acuminatum of Buschke Loewenstein) present with Verrucous carcinoma involving the perianal region, including the penis, scrotum)
Diagnosis is usually based on clinical suspicion based on risk factors and confirmed with histopathological examination. Biopsy can be shave, punch or excisional.
- SCC in situ— SCC in situ also known as Bowen’s disease is diagnosed when biopsy reveals keratinocytic dysplasia that involve the entire full thickness of the epidermis without dermis infiltration of atypical cells. The keratinocytes are pleomorphic cells with hyperchromatic nuclei, and numerous mitoses are present. Actinic keratosis (AK) on the other hand, represent partial-thickness epidermal dysplasia.
- Invasive SCC— Invasive SCC have dysplastic keratinocytes that involve the entire full-thickness of the epidermis with invasion of the epidermal basement membrane into the dermis or beyond.
Treatment and Management
The treatment approach for cutaneous squamous cell carcinoma (SCC) is largely depend on the risk of local, regional or distant metastasis. Characteristic features that determine the risk for recurrence and spread depends on the location, size, histological features and any comorbidities that the patient may have.
LOW RISK LESIONS:
Common treatment options for low risk SCC include the following:
- Surgical Excision
- Surgical excision of the lesion has been shown to be effective in both low risk and high risk SCC obtaining low recurrence less than 10%. In addition, histological margin can be assessed
- Cryotherapy using liquid nitrogen to freeze and thaw the SCC cells. This procedures are typically done by doctors who are trained in skin cancer because this does not permit histologic confirmation of the adequacy of treatment margins. Contraindication to cryotherapy include patients with high risk SCC, critical areas such as (nose, ears, periocular, periauricular and genitals), lower legs, scalps, tumors overlying nerves, deep invasive SCC and tumors in dark pigmented patients, patient with cold intolerance such as cryoglobulinemia, raynaud’s disease, cold urticarial.
- Electrosurgery (electrodesiccation and curettage)
- Electrodesiccation and curettage (ED&C) are typically used for well-defined superficial SCC. In addition, this is a quick well tolerated procedures. However, the disadvantage is the lack of histologic confirmation of tumor margins. ED&C is contraindicated for recurrent, large, poorly-defined high risk tumors.
- Topical treatment (5-fluorouracilor imiquimod)
- Topical 5-FU: 5-FU has been approved for treatment of actinic keratosis which are precursor lesions of SCC. It is commonly used for patients who refuse surgical procedures. It is very commonly used in situation where postoperative healing is suboptimal such as in patient with peripheral venous stasis. 5-FU is usually not recommend for bowen’s disease.
- Topical Imiquimod: Imiquimodis a topical immune response modifier approved by the FDA for the treatment of anogenital warts, actinic keratosis (AK), and superficial basal cell carcinomas (BCC). The anti-tumor mechanism is via stimulation of local cytokine production, cell-mediated immunity, and promotion of apoptosis.
- Imiquimod has been used to treat Bowen’s disease but the efficacy is typically more superior if used together with 5-FU and require long course of treatment.
- Radiation therapy
- Radiation therapy is an option for the initial management of primary SCC that are small with well-defined appearance. However, due to the potential long-term adverse effects of radiation treatment, this modality is primarily reserved for older patients and patients who are not surgical candidates.
- Photodynamic therapy
- Photodynamic therapy can be used for the treatment of Bowen’s disease (cutaneous SCC in situ) but not recommended for invasive SCC due to high risk of recurrence.
- PDT treatment is based upon the ability of porphyrins to cause cytotoxicity after stimulation by ligh in the presence of oxygen. Topical application of aminolevulinic acid (ALA) or methyl aminolevulinate (MAL) are utilized as a photosensitizer.
High risk features include the following:
- Location/size (Size ≥ 2 cm on trunk or extremities (excluding hands, feet, pretibia, nail units, and ankles); size ≥ 1 cm on forehead, pretibial, scalp, cheeks; size ≥ 0.6 cm on so called “mask areas” of the face which include the (periorbital nose, central face, eyelids, eyebrows) and other areas including chin, mandible, preauricular and postauricular skin/sulci, temple, ear, hands, feet and genitalia)
- Site that has been previously treated with radiation or presence of chronic inflammation
- Tumors that are rapidly growing
- Neurological presentations or Perineural or vascular involvement
- Tumors that are poor to moderately differentiated
- Tumors with poorly-defined borders
- Patient with a history of current tumor recurrence
- Patient who are immunosuppressed and therefore with increased risk for skin cancer
- Adenoid (acantholytic), adenosquamous, or desmoplastic subtypes
- Depth ≥ 0.2 cm or Clark level IV or V
Common treatment options for High risk SCC include the following:
- High risk lesions often require aggressive treatment attempting to obtain a cure with initial treatment. Surgery is often the initial treatment option with either Mohs surgery or conventional surgical resection.
- For locoregional disease involving the lymph nodes, surgery plus adjuvant radiation therapy is often used for the management of nodal disease.
- Systemic chemotherapy is an option for patients with local advanced or distant metastases that cannot be managed with conventional surgery or radiation.