Table of Contents
- Definition and Epidemiology of Squamous Cell Carcinoma
- Classification of Squamous Cell Carcinoma
- Etiology and Pathogenesis of Squamous Cell Carcinoma
- Clinical Manifestations of Squamous Cell Carcinoma
- Investigations for Squamous Cell Carcinoma
- Management of Squamous Cell Carcinoma
- Prevention of Squamous Cell Carcinoma
Definition and Epidemiology of Squamous Cell Carcinoma
Cutaneous squamous cell carcinoma is a non-melanoma skin cancer arising from the suprabasal epidermal keratinocytes that invades the dermis as well.
Non-melanoma skin cancers are the most common type of skin cancers affecting humans. SCC is the second most common non-melanoma skin cancer followed by basal cell carcinoma, affecting tropical population the most. It is seen most frequently in sun exposed areas in people aged more than 40 years. White males are more likely to be affected by this cancer, however, quite notably, SCC is the most common skin cancer in patients with darker skin types.
Classification of Squamous Cell Carcinoma
- Actinic keratosis (AK)
- SCC in situ (Bowen’s disease)
Direct exposure to the sun
- SCCI (invasive SCC)
- Clear cell SCC
- Spindle cell SCC
- SCC with single cell infiltrates
Unrelated to sun exposure
- De novo SCC
- Verrucous carcinoma
- LELCS (lymphoepithelioma-like carcinoma of skin)
Etiology and Pathogenesis of Squamous Cell Carcinoma
Most patients harbour a multitude of factors, both acquired and genetic, that are sufficient to induce the malignant growth in the skin.
Most SCC develop from precursor lesions of AK or Bowen’s disease.
- Predominant risk factor
- Linear relationship between UV exposure and SCC incidence
- Incidence of SCC doubles with every 8-10 degree decline in latitude
- Highest incidence at equator
- Relates more to development of SCC than BCC
Patients whose skin is likely to have sunburns exhibit strong association between ionising radiation and SCC development.
- Strong correlation between exposure to chemical agents and SCC
- Except anthramine and 3-methylcholanthrene, chemical carcinogens generally produce more SCC than BCC
- Strong association between alcohol and smoking and SCC of oral cavity
- Patients on long term corticosteroid, azothioprine or cyclosporine therapy found to be susceptible to SCC
- 18-fold rise in patients with renal transplant
- More aggressive behaviour in patients with HIV, leukaemia, lymphoma
Human papilloma virus
- Verruca pus carcinoma is associated with many variants of HPV
- SCC of head, neck and periungual region are associated with HPV
Chronic heat exposure is a predisposing factor.
Scars and underlying diseases
- SCC found to be associated with burns scars and chronic infection
- Exception is vaccination scars found to be associated more with BCC than SCC
- Variety of heritable diseases predispose to SCC
- Xeroderma pigmentosum, dystrophic form of epidermolysis bullosum, epidermodysplastic verruciferous, oculocutaneous albinism etc.
- Chromosomal deletions in chromosomes 3,7,9,11
- Involvement of p53 tumour suppression genes
Involvement of p53 genes
- Apoptosis of keratinocytes with sustained UV damage are called sunburn cells.
- They require p53 tumour suppressors that are defence mechanisms against malignant transformation.
- UV exposure up-regulates p53 expression that delays cell cycle progression (till DNA is repaired) or mediates apoptosis of damaged cells.
- Loss of function of p53 leads to increased resistance of UV damaged cells to apoptosis; they proliferate and survive better – ultimately lead to SCC.
Other apoptotic regulators
Apart from p53, other regulators are:
- Bcl-2 inhibition in vulvar SCC
- Bcl-XL in tumour invasion and metastasis
- Bax in SCC tongue
Clinical Manifestations of Squamous Cell Carcinoma
Development from precursor lesions
- Multiple lesions
- Pin point to over 2cm in size
- Ill defined borders
- Rough gritty texture
- Isolated lesions
- Variable size
- Sharply demarcated lesions
- Scaling papules or plaques that are non-pruritic
The development of tenderness, induration, erosion, increased scaling or enlarging diameter indicate evolution into SCC.
Morphologies of SCC
The clinical picture of SCC is variable with a wide range of different morphologies presenting in the skin clinic. The most common presentation is that of a firm, erythematous, keratotic plaque or papule, however, ulcers, thick cutaneous horns or modules are not uncommon.
In periungual location, the abscess or verrucous form of SCC are more commonly seen. As the tumour progressively invades, it loses the free character and fixes to the underlying tissue. In the head and neck region, enlarged lymph nodes are indicative of tumour metastasis.
Usual sites of presentation include oral cavity (involving palate and tongue), and more commonly, lower lip and genital region (most common site being anterior labia majora of vulva).
Keratocanthoma is viewed as a clinical subtype of SCC despite its tendency towards spontaneous resolution as it can be locally aggressive and destructive. The hallmark feature of this otherwise benign neoplasm is its rapid growth, over several centimetres in a matter of weeks followed by spontaneous resolution over a period of months. An elderly patient presenting with a large, smooth, dome shaped verrucous lesion with a central keratotic crater on the extremities arises strong suspicion of this tumor.
Investigations for Squamous Cell Carcinoma
The diagnosis of SCC is always made on biopsy. In elevated lesions, punch biopsy is performed while in flat lesions or lesions with minimal elevation (less than 1mm), superficial shave technique is not only adequate but also minimises wound size and scarring.
Of note is the depth of the biopsy which should be sufficient to distinguish between in situ carcinoma and invasive SCC.
What to expect in the histopathological report?
- The hallmark of SCC is extension of atypical keratinocytes beyond the basement membrane and into the dermis.
- Absence of connection between epidermis and tumour cells indicates metastatic SCC.
- Clues to underlying etiology, for example, presence of scar tissue indicates recurrent SCC, while solar elastosis and keratinocyte atypia indicates actinically derived SCC. These clues hold important implications for treatment and prognosis.
- Bowen’s disease may have an eczematous appearance and at first sight may be taken for eczema, psoriasis or lichen simplex. These lesions are however pruritic, a finding characteristically absent in Bowen’s disease.
- For verrucous lesions – warts, seborrhoeic keratosis, AK, chromomycosis, metastatic SCC, Merkel cell carcinoma
- For ulcerative lesions – trauma, BCC, herpes virus infection
- For pigmented lesions – melanoma
Management of Squamous Cell Carcinoma
Selection of the best modality of treatment for SCC is based on an assessment of risk factors for recurrence and metastasis.
Non-excisional ablative techniques
- These include:
- Electrodesiccation and curettage
- Liquid nitrogen cryotherapy
- Carbon dioxide laser
- Intralesional chemotherapy
- Photodynamic therapy
- Superficial technique
- Do not allow histology cal margin control
- Status: to be used in in situ disease only, in special circumstances. Inappropriate for invasive SCC.
- These include:
- Conventional surgical excision
- Treatment of choice for primary SCC
- Recommended margins – 4mm for low risk lesions with depth less than 2mm
- Mohs microscopically controlled surgery (MMCS)
- Recommended in specific cases where highest cure rate and minimal tissue destruction is desired
- Indications of MMCS
- History of radiation at site
- Involvement of nerve, muscle, or bone
- Recurrent tumour
- Infiltrative SCC
- Important tissue preservation sites (lip, eyelid, nasal tip, ear, genitilia)
- Verrucous carcinoma
- Conventional surgical excision
- Used for superficially invasive to moderate risk lesions, particularly in lesions of external auditory canal
- As adjuvant therapy:
- To excisional surgery in residual microscopic disease
- Perineural SCC
- As prophylaxis against metastatic disease
Prevention of Squamous Cell Carcinoma
Patients with a prior history of non-melanoma skin cancer or with any of the predisposing factors as mentioned above must receive regular complete skin examinations.
It is the most effective method of prevention if taken care of since childhood. This requires behavioural changes and includes regular application of sunscreen, proper clothing, wearing sunglasses and avoiding exposure to sun during peak hours.
Treatment of precursor lesions
A variety of treatment options are available for management of AK. While isolated lesions can be treated with liquid nitrogen cryotherapy, multiple lesions are treated with a course of 5-fluorouracil.
Other preventive measures
- Use of condoms to prevent the transmission of HPV
- Decrease alcohol consumption
- Smoking cessation
- Use of low dose retinoids and interferons as systemic chemopreventive agents, for example Accutane
- Topical application of DNA repair enzymes in liposomes
- Topical immune modifiers that stimulate cutaneous immunity to kill malignant cells