Squamous Cell Carcinoma Antigen

Squamous cell carcinoma antigen (SCC-Ag, SERPINB3 and SERPINB4) is a serine protease inhibitor of the ovalbumin family, produced by normal squamous epithelium of the skin, cervix, oesophagus and respiratory tract and overexpressed by squamous cell carcinomas. It is measured in serum by immunoassay, in microg/L (ng/mL). Saliva, sweat and skin contamination cause falsely high values.

The test is used mainly as a tumour marker for squamous cell carcinoma of the cervix, head and neck, lung and oesophagus. It supports prognosis and monitoring of treatment, and detection of recurrence. It is not a screening or diagnostic test.

Cervical cancer is the fourth commonest cancer in women worldwide, with over 600 000 new cases and 340 000 deaths a year, and about 85% of deaths occur in low income and middle income countries. Squamous histology accounts for about 70 to 80% of cervical cancers. Squamous cell carcinoma makes up 25 to 30% of lung cancers and most head and neck and oesophageal cancers in smokers and drinkers.

Indications. Pre-treatment staging and prognosis in cervical squamous carcinoma, monitoring after chemoradiation or surgery, detection of recurrence in cervix, head and neck, lung, oesophageal and anal squamous cancers, and distinction of squamous from adenocarcinoma histology in lung cancer when tissue is limited.

Specimen. Serum. The sample is taken without contamination from saliva, sweat or skin flakes, and the collector avoids talking or coughing over the tube. No fasting is needed. Stable for days at 2 to 8 °C.

Reference range. Under 1.5 to 2.0 microg/L in most assays (healthy adults, with 95% under 1.5 microg/L). Values vary with assay.

Cervical squamous carcinoma.

• Sensitivity is 30 to 50% in early stage disease (stage IB) and 60 to 90% in advanced disease (stage III and IV), with specificity of about 90%.
• A pre-treatment value over 2 microg/L (and especially over 10 microg/L) is associated with lymph node involvement, larger tumour, deep stromal invasion, and poorer survival.
• After treatment, SCC-Ag normalises in 1 to 2 weeks if disease is controlled. A failure to fall, or a rise, suggests residual disease or recurrence, often with a lead time of 3 to 6 months before clinical signs.
• A rise over 2.5 microg/L after treatment has a positive predictive value of 80 to 95% for recurrence.

Head and neck cancer. Raised in 30 to 50% of squamous cancers, with values correlating with stage and used for monitoring after treatment, as an adjunct to examination and imaging.

Lung cancer. Raised in 30 to 70% of squamous cell lung cancers, and used with CYFRA 21-1 (cytokeratin fragment) to support squamous histology and to follow treatment.

Oesophageal and anal squamous cancers. Raised in 30 to 50%, with the level related to tumour burden.

Benign causes of raised SCC-Ag.

• Skin disease: psoriasis, eczema, pemphigus, erythroderma, and other dermatoses (can reach 5 to 20 microg/L).
• Respiratory: tuberculosis, bronchitis, sarcoidosis and asthma.
• Kidney failure (reduced clearance), and liver disease including cirrhosis.
• Benign gynaecological conditions, and ulcerative and burn skin injury.
• Contamination by saliva or sweat.

Critical values and findings needing immediate action.

• A raised or rising SCC-Ag after cervical cancer treatment with pelvic pain, vaginal bleeding, leg swelling, or flank pain from hydronephrosis.
• A pre-treatment value over 10 microg/L in cervical cancer, which indicates probable lymph node involvement and need for imaging and referral.
• Stridor, dysphagia or haemoptysis with a raised value in a smoker.

Interferences and pitfalls.

• It is not a screening test for cervical or other cancers, and the cervical screening programme uses cytology and HPV testing.
• A normal value does not exclude squamous cancer.
• Skin disease, kidney failure and contamination give false positives, and an unexplained mild rise is repeated with a clean sample.
• Different assays give different values, and serial testing uses the same method.
• Biotin and heterophile antibodies can interfere.
• Early disease and well differentiated tumours give low values.
• Adenocarcinoma of the cervix has low sensitivity, and CEA and CA 125 are more useful.

Special groups.

• Women with HIV infection: higher risk and more aggressive cervical cancer, and SCC-Ag is useful in follow up.
• Pregnancy: no major change.
• Older adults with kidney failure: baseline is raised.
• Patients with skin disease: interpret with caution.
• Regions: in settings with limited imaging and late presentation, SCC-Ag may support follow up after chemoradiation.

Follow up tests. Pelvic examination under anaesthesia, MRI of pelvis, PET-CT, chest imaging, cystoscopy and proctoscopy as indicated, HPV testing, CYFRA 21-1, CEA, CA 125, creatinine and urinary tract imaging for hydronephrosis, and biopsy with histology and immunohistochemistry (p16).