Squamous Cell Carcinoma: Causes, Symptoms, and Top Treatment Options — Overview, Diagnosis & Treatment Options | MyMedicPlus

Squamous cell carcinoma (SCC) is a malignant tumour arising from squamous (flat, scale-like) epithelial cells and can develop at multiple anatomical sites including the skin, head and neck (oropharynx, oral cavity, larynx, hypopharynx), lung, oesophagus, cervix, vagina, vulva, anus, and penis. As a group, SCC represents the second most common skin cancer (after basal cell carcinoma), with over one million new cutaneous SCC diagnoses per year in the United States alone. Head and neck SCC collectively represents approximately 4% of all malignancies in the US. Lung SCC constitutes approximately 25-30% of all non-small cell lung cancers, and cervical SCC is among the most common gynaecological malignancies worldwide. The molecular biology, natural history, treatment, and prognosis of SCC vary significantly by anatomical site of origin, HPV status, immune status of the host, and disease stage. The advent of checkpoint immunotherapy — particularly anti-PD-1 agents cemiplimab and pembrolizumab — has substantially changed the therapeutic landscape for advanced SCC across multiple primary sites.

Risk factors for SCC vary by anatomical site but share common themes of carcinogen exposure, viral oncogenesis, and immune dysregulation. Ultraviolet (UV) radiation — from sunlight and tanning beds — is the primary driver of cutaneous SCC, causing CDKN2A, NOTCH, and TP53 mutations and accounting for the dose-dependent and cumulative nature of skin cancer risk with age. Tobacco smoking is the dominant risk factor for SCC of the lung, larynx, pharynx, oral cavity, and oesophagus; alcohol acts synergistically with tobacco for upper aerodigestive tract SCC. Human papillomavirus infection — particularly HPV-16 and HPV-18 — is causally implicated in oropharyngeal SCC (approximately 70% of US cases), cervical SCC (virtually 100%), vulvar SCC (approximately 40-50%), vaginal SCC (60-70%), anal SCC (approximately 90%), and penile SCC (approximately 50%). Immunosuppression dramatically amplifies cutaneous SCC risk: solid organ transplant recipients have a 65-100-fold increased risk attributable to impaired immune surveillance of HPV-infected and UV-damaged keratinocytes. Chronic inflammatory and precancerous conditions — actinic keratosis (cutaneous SCC precursor), oral leukoplakia and erythroplakia, lichen sclerosus (vulvar SCC), Barrett's oesophagus — serve as local carcinogenic environments promoting malignant transformation.

Clinical presentation of SCC varies substantially by primary site. Cutaneous SCC presents as a firm, hyperkeratotic, scaly nodule or plaque — often with central ulceration, crusting, or raised rolled edges — arising on sun-exposed skin of the face, scalp, ears, dorsal hands, and lower lips. It may arise within a pre-existing actinic keratosis. Tenderness, rapid growth, and fixation to underlying tissue indicate locally aggressive behaviour. Head and neck SCC presents according to subsites: oropharyngeal SCC with sore throat, dysphagia, and painless neck mass (frequently the first sign of HPV-positive disease); laryngeal SCC with persistent hoarseness and later stridor or haemoptysis; oral cavity SCC with non-healing ulcer or red or white mucosal patch. Cervical SCC classically causes irregular postcoital or intermenstrual vaginal bleeding, blood-tinged or foul-smelling vaginal discharge, and pelvic pain. Lung SCC presents centrally with productive cough, haemoptysis, obstructive pneumonia, and chest pain. Oesophageal SCC causes progressive dysphagia from solids to liquids, odynophagia, and weight loss. Perineural invasion may produce neurological symptoms including pain, numbness, and progressive motor deficit along affected nerve distributions.

Tissue biopsy with histopathological confirmation is essential for the diagnosis of all SCC subtypes. For cutaneous SCC, punch, shave, or excisional biopsy guided by dermoscopy provides tissue for pathology including assessment of differentiation grade, perineural invasion, lymphovascular invasion, and invasion depth. CT, MRI, and PET/CT provide staging of locoregional and distant disease across all anatomical sites; MRI provides superior assessment of perineural spread along named nerves in head and neck SCC. HPV testing (p16 IHC as a surrogate marker or direct HPV genotyping) is mandatory for all oropharyngeal SCC, as HPV-positive disease is staged by the AJCC 8th Edition p16-positive staging system with markedly different stage groupings reflecting its better prognosis. For lung SCC, PD-L1 expression (TPS score by 22C3 assay) and TMB guide immunotherapy selection; EGFR, ALK, and ROS1 testing is less relevant given low driver mutation frequency in squamous histology. Sentinel lymph node biopsy is recommended for high-risk cutaneous SCC with perineural invasion, poor differentiation, or tumour diameter greater than 2 cm. MSI/dMMR and TMB testing guide immunotherapy use in advanced cervical SCC and other sites.

Treatment of SCC is site-specific and stage-adapted. Cutaneous SCC: excision with clinically guided margins or Mohs micrographic surgery (for high-risk locations — face, ears, scalp, digits — and recurrent tumours) is the gold standard for localised disease. Cemiplimab or pembrolizumab are the preferred systemic treatments for locally advanced or metastatic cutaneous SCC not amenable to surgery or radiation, achieving objective response rates of 45-50%. Head and neck SCC: localised disease is managed with surgery and/or definitive radiotherapy for early stages; locally advanced disease requires concurrent cisplatin-based chemoradiation (100 mg/m² every 3 weeks or weekly 40 mg/m²) plus cetuximab for cisplatin-ineligible patients. Advanced/metastatic HNSCC: pembrolizumab monotherapy for PD-L1 CPS ≥1 or pembrolizumab plus platinum-5FU as first-line standard (KEYNOTE-048). Lung SCC with high PD-L1 (TPS ≥50%): pembrolizumab monotherapy first-line; combined platinum doublet plus anti-PD-1 for all comers. Cervical SCC: concurrent cisplatin chemoradiation for locally advanced disease; immunotherapy-based regimens for recurrent/metastatic disease. Oesophageal SCC: perioperative chemotherapy (FLOT or CROSS protocol: carboplatin-paclitaxel-RT), neoadjuvant chemoradiation plus surgery, plus nivolumab adjuvant (CheckMate 577).

Prevention strategies for SCC are highly effective and focus on avoiding established risk factors and cancer vaccination. For cutaneous SCC, regular use of broad-spectrum (UVA + UVB) sunscreen with SPF 30 or above, protective clothing, wide-brimmed hats, and avoidance of peak-UV sunlight hours (10am-4pm) substantially reduces cumulative UV exposure. Tanning bed use should be prohibited, particularly in those under 35 years of age. Immunosuppressed transplant recipients should undergo annual dermatological surveillance and are candidates for actinic keratosis field treatment with fluorouracil cream or photodynamic therapy to prevent malignant transformation. HPV vaccination (Gardasil 9) targeting HPV 16/18/31/33/45/52/58 strains should be offered to all individuals aged 9-26 years; vaccination of adults up to age 45 is recommended by ACIP on a shared decision-making basis. Vaccination prevents the substantial majority of HPV-related SCCs of the cervix, oropharynx, anus, vulva, and vagina. Smoking cessation reduces SCC risk of the lung, larynx, pharynx, and oesophagus. Alcohol moderation additively reduces upper aerodigestive tract SCC risk in smokers. Regular cervical cancer screening (Pap smear and HPV co-testing) detects CIN before progression to invasive cervical SCC.

Seek prompt medical evaluation for any new or changing skin lesion, particularly on sun-exposed areas, that meets the following criteria: a non-healing sore or ulcer lasting more than 4 weeks; a rapidly growing, crusted, or bleeding nodule; a raised, rough, or scaly plaque that does not resolve; or any lesion in a previously irradiated or scarred area. Immunosuppressed patients including transplant recipients should report any new or changing skin lesion without delay and attend at least annual skin checks with a dermatologist. Persistent sore throat, hoarseness, or swallowing difficulty lasting more than 3 weeks — especially in a smoker or person with significant alcohol use — warrants urgent ENT evaluation. A painless neck lump in an adult requires investigation to exclude HPV-positive oropharyngeal SCC, particularly in non-smokers in the 40-60 age group. Any postcoital vaginal bleeding or abnormal cervical appearance on speculum examination requires colposcopy. Haemoptysis, regardless of volume, in a smoker demands urgent chest imaging. An anal or perianal ulcer or mass in any individual should be biopsied if not healing within 4-6 weeks, particularly in HIV-positive individuals or men who have sex with men.

Cutaneous SCC: over 95% 5-year survival for localised disease; approximately 25-50% with nodal involvement. Head and neck SCC: stage-dependent; HPV-positive oropharyngeal SCC has approximately 80% 5-year survival. Lung SCC: 5-year OS approximately 15-20% overall. Cervical SCC: localised approximately 85%, metastatic approximately 20%. Prognosis varies significantly by primary site, HPV status, immune status, and stage at diagnosis. Immunotherapy has substantially improved outcomes for advanced disease across all SCC primary sites. The prognosis for Squamous Cell Carcinoma: Causes, Symptoms, and Top Treatment Options varies depending on severity at diagnosis, the patient's overall health, and how promptly treatment is initiated. With early diagnosis and appropriate management, many patients achieve good outcomes and maintain quality of life. Regular follow-up with healthcare providers is essential to monitor progress, adjust treatment as needed, and detect any complications early. Adherence to prescribed treatments and lifestyle modifications significantly improves long-term prognosis.