Cervical cancer: Can it be prevented?

Table 1 Risk factors for cervical cancer

Causal agent	Relative risk
Low socio-economic class	1.5
Low educational level	2-3
Early age at first coitus	2-4
Multiple sexual partners	2-5
Early age at first pregnancy	2-4
Multiparity	2-4
Long term use of oral contraceptives	1.5-2
History of sexually transmitted infections	4-10
History of genital warts	18
Cigarette smoking	2-4
Diet low in folates, carotene and vitamin C	2-3
Lack of routine cytological screening or prior abnormal smears	2-6
HIV	2.5
Immunosuppression	5.7

HIV: Human immunodeficiency virus.

Table 2 American College of Obstetricians and Gynecologists guidelines for cervical cancer screening

Commence	Frequency of smears (Pap or LBC) and HPV testing	Discontinue	HPV DNA
21 yr	1 3 yearly smears for < 30 yr 2 3 yearly smears or 5 yearly co-testing for> 30 yr (if previous smears normal) 3 3 yearly smears or 5 yearly co-testing for those previously treated for CIN2/3 or cancer (up to 20 yr)	1 > 65 yr 2 After hysterectomy for benign disease with no history of CIN	For women > 30 yr, two options to manage Positive test: Repeat co-testing at 12 mo; Test for HPV 16/18 and colposcopy if positive

HPV vaccination does not change these guidelines. HPV: Human papilloma virus; LBC: Liquid based cytology.

Table 3 Biomarkers in cervical dysplasia

Biomarker	Significance
L1 capsid protein	Represents approximately 90% of the total protein on the virus surface and is generally detectable during the reproductive phase of HPV infection. The L1 protein is abundant in productive infections (CIN 1), found only in rare cases of CIN2/3, and not produced in carcinomas
p16INK4a (CINtecTM)	Surrogate marker of HPV E7-mediated pRb catabolism, providing evidence of transformation of the cervical mucosa. On immunohistochemistry, diffuse staining for p16INK4a is present in almost all cases of CIN2, CIN3, squamous cell carcinoma and endocervical glandular neoplasia; however, it is rarely detected in benign squamous mucosa or CIN 1 lesions caused by low risk HPV types
Ki-67	Proliferation marker confined to the parabasal cell layer of normal stratified squamous mucosa but shows expression in the stratified squamous epithelium in CIN lesions in correlation with the extent of disordered maturation, but cannot discriminate HPV-mediated dysplasia from proliferating cells in benign reactive processes
DNA Aneuploidy	HPV infection leads to DNA hypermethylation, disruption of the normal cell cycle, and chromosomal aberrations, all of which may lead to changes in DNA content. Aneuploidy increases progressively from CIN1 to CIN3
MCMs (ProExC testTM)	MCMs are required for the origination of DNA replication and are overexpressed in cervical high-grade dysplasia and carcinoma, but can also be seen in some benign cycling squamous and glandular cells
FISH technology	One of the most consistent chromosomal abnormalities in cervical carcinoma is gain of chromosome arm 3q (in about 70%), which can be detected by FISH. TERC gene in this region is amplified in progression to CIN3

FISH: Fluorescent in situ hybridization; MCAs: Minichromosome maintenance proteins; TERC: Telomerase RNA component.

Table 4 Management of preinvasive cancer (American Society for Colposcopy and Cervical Pathology 2012 guidelines)

Lesion on biopsy	Other features	Management
CIN 1	Preceding cytology of ASC-US, ASC-H, LSIL	Follow up with cytology (6, 12 mo) and HPV testing (12 mo)
CIN 1	Preceding cytology of HSIL, AGC-NOS	Either of these: Diagnostic excisional procedure or review of findings or observation with HPV and cytology (12 and 24 mo) (only if colposcopy satisfactory and ECC negative)
CIN 1	Adolescent (< 20 yr)	Follow up with cytology (12 mo)
CIN 1	21-24 yr	Follow up with cytology and colposcopy (6 monthly, up to 2 yr)
CIN 2/3	Satisfactory colposcopy	Either excision or ablation of transformation zone
CIN 2/3	Unsatisfactory colposcopy or recurrence or endocervical disease	Diagnostic excisional procedure
CIN 2/3	Adolescent (< 20 yr) and young women (21-24 yr)	Observation with cytology and colposcopy (only if colposcopy satisfactory) or treatment using excision or ablation of transformation zone
Adenocarcinoma in situ	Specimen from diagnostic excisional procedure	Hysterectomy preferred (rarely conservative management if margins negative and future fertility desired)

HPV: Human papilloma virus. CIN: Cervical intraepithelial neoplasia, ASC-US: Atypical squamous cells - undetermined significance; ASC-H: Atypical squamous cells - cannot exclude; LSIL: Low-grade squamous intraepithelial lesion HSIL: High-grade squamous intraepithelial lesion; ECC: Endocervical curettage.