Cervical cancer usually presents in several premalignant stages ranging from mild dysplasia (cervical intraepithelial neoplasia grade 1 [CIN1]) to more severe degrees of neoplasia and microinvasive lesions (CIN2 or CIN3), to invasive cancer (1). Classification of the disease according to this CIN System forms the basis of diagnosis and treatment approaches including therapeutic options and secondary preventive measures (Table 1). Importantly, CIN1 lesions can regress spontaneously with the risk of progression to severe dysplasia being 1% per year (1). Risk of progression of moderate dysplastic lesions is 16% within 2 years and 25% within 5 years. The etiologic course of such HPV-associated cancers has been suggested to involve infection by HPV, persistence of the infection, progression to an immediate precursor of cancer, and finally invasion. Successful screening programs based on the appearance of abnormal cells in cytology specimens (Pap tests, reported according to the Bethesda classification system â€“ Table 1), and more recently HPV-type have been implemented for cervical cancer.
According to the NCCN Clinical Practice Guidelines in Oncology for Cervical Cancer Screening, women over 21 with ASC-US are variously recommended to undergo HPV testing, or repeat cervical cytology, or coloposcopy. In the two former cases, a patient with a positive finding is recommended for colposcopy. Those with ASC-H, LSIL, or HSIL are currently recommended to undergo colposcopic examination. At this stage of patient management, the success of screening heavily depends on the accuracy of the colposcopically-directed biopsies of the approximately 2,000,000 women each year in the US who undergo colposcopy. Patients with normal or CIN1 results may be followed with repeat cervical cytology or HPV DNA testing, and those with CIN2/3, further treatment is indicated such as loop electrosurgical excision procedure (LEEP), cryotherapy, cold-knife conization (CKC), or laser ablation (1). Total hysterectomy may be considered for women with CIN3. Diagnosis with invasive carcinoma requires total hysterectomy or external beam high-energy radiotherapy and implants with 192Ir, depending on the stage. Selected patients also benefit from chemotherapy.
Table 1. Bethesda Classification System for Cervical Squamous Cell Dysplasia
|Bethesda System||CIN System||Interpretation|
|NIL: Negative for intraepithelial lesions or malignancy||Normal||No abnormal cells|
|ASC-US: Atypical squamous cells of undetermined significance|
ASC-H: Atypical squamous cells, cannot exclude HSIL
|Squamous cells with abnormalities greater than those attributed to reactive changes but do not meet the criteria for a squamous intraepithelial lesion|
|LSIL: Low-grade squamous intraepithelial lesions||CIN 1||Mildly abnormal squamous cells|
|HSIL: High grade intraepithelial lesions with features suspicious for invasion if suspected||CIN 2/3||Moderately or severely abnormal squamous cells|
|Carcinoma||Invasive squamous cell carcinoma, invasive glandular cell adenocarcinoma||The possibility of cancer is high enough to warrant immediate evaluation but does not mean that the patient has cancer.|
Thus, there is a great need to identify additional biomarkers to increase the sensitivity with which precancer and cancer are detected in cytology specimens.Â CGI has designed and developed the FISH-based HPV-Associated Cancer Test (FHACTÂ®) that assesses biomarkers commonly detected in HPV-associated cancers and that are observed with higher frequencies in cervical lesions with increasing cytologic severity.
1. Burd EM. Human papillomavirus and cervical cancer. Clin Microbiol Rev 2003;16(1):1-17.