Cervical Cancer

Carcinoma of the cervix was once the most common cause of cancer in women.

Epidemiology

Prevalence – estimated 12,200 new cases in the U.S. in 2010
- Third most common cancer in women worldwide
Age – median is 48 years; infection with oncogenic strain of human papillomavirus (HPV) associated with earlier age of onset
- High-grade dysplasia in 30s
- Invasive carcinoma in 40s

Risk Factors

Sexual activity
- Infection with oncogenic (high-risk) types of HPV
  - 15% of U.S. women 14-59 years test positive for a high-risk strain of HPV
- History of early sexual activity, especially with multiple sex partners
- Sexual partner who began sexual activity at an early age and/or who had many previous sexual partners
- History of sexually transmitted infections (STIs)
Family history of cervical cancer
Previous diagnosis of dysplasia on a Pap test or prior gynecological malignancy
Tobacco use
Exposure to diethylstilbestrol (DES) before birth
HIV infection
Weakened immune system (eg, organ transplant, chemotherapy, chronic corticosteroid use)

Pathophysiology

Etiology – HPV, particularly the oncogenic types
- HPV 16 and 18 are responsible for >70% of invasive cervical cancers
Tumor types – 80% are squamous cell carcinoma, 20% are adenocarcinomas
- Increased incidence of adenocarcinomas over last 30 years
  - Cytologic screening methods are less effective for adenocarcinomas, but HPV testing may improve detection rates
Usually evolves from cervical dysplasia
- 30-35% of high-grade dysplasias progress to invasive carcinoma

Clinical Presentation

Earliest stage may be asymptomatic or have a watery vaginal discharge
Abnormal vaginal bleeding or a significant unexplained change in menstrual cycle
A friable cervix that bleeds easily following intercourse or contact (eg, insertion of a diaphragm, collection of a Pap smear)
Pain during sexual intercourse
Abnormal vaginal discharge containing blood-tinged mucous

Treatment

Disease management guidelines available from the American Society for Colposcopy and Cervical Pathology (ASCCP)

Prevention

FDA-approved recombinant vaccine (Gardasil^®) is effective against HPV types 6, 11, 16 and 18 and is approved for use in males and females 9-26 years

Indications for Testing

Abnormal Pap smear; abnormal vaginal bleeding or discharge

Histology

Colposcopy and/or cervical biopsy necessary for a definitive diagnosis
- Should be considered for all grades of dysplasia on Pap smear
- Refer to ASCCP algorithms on suggested management of atypical squamous cells of undetermined significance (ASC-US), low-grade squamous intraepithelial lesion (LSIL), atypical squamous cells: cannot exclude high grade lesion (ASC-H), high-grade squamous intraepithelial lesion (HSIL) and atypical glandular cells (AGC)

Differential Diagnosis

Sexually transmitted diseases
Other gynecologic cancer – endometrial, vaginal

Screening guidelines for cervical cancer

Screening Guidelines for Cervical Cancer
Guideline source:	American Cancer Society (Oct 2010)	American College of Obstetricians and Gynecologists (Aug 2003)	U.S. Preventive Services Task Force (May 2011)	National Comprehensive Cancer Network (Dec 2010)
When to initiate screening	Approximately 3 years after onset of vaginal intercourse or age 21, whichever comes first		Screening at 21 years	Screening at 21 years; counseling and testing for sexually transmitted infections for patients <21 years
Recommended screening intervals	Conventional Pap
	Annually; every 2-3 years for women ≥30 with 3 negative cytology tests	Annually; every 2-3 years for women ≥30 with 3 negative cytology tests	At least every 3 years	Every 2 years for women 21-29 years; every 3 years for women ≥30 years with negative cytology and HPV testing
	Liquid-based cytology
	Every 2 years; every 2-3 years for women ≥30 with 3 negative cytology tests	Annually; every 2-3 years for women ≥30 with 3 negative cytology tests		Same as conventional Pap
	If HPV testing used
	Every 3 years if HPV negative, cytology negative	Every 3 years if HPV negative, cytology negative		Same as conventional Pap, including women previously immunized against HPV-16 and HPV-18
When to discontinue screening	Women ≥70 years of age with ≥3 recent, consecutive negative cytology tests, and no abnormal tests in the past 10 years		Women ≥65 years of age with negative cytology tests, who are not in a high-risk category for cervical cancer	Women ≥65 years of age with ≥3 consecutive negative cytology tests and no abnormal test within the past 10 years
Women who are status post total hysterectomy	May discontinue testing if hysterectomy was for benign reasons and there is no history of high-grade dysplasia (CIN)	May discontinue testing if hysterectomy was for benign reasons and there is no history of high-grade dysplasia (CIN)	May discontinue if hysterectomy was performed for benign indications	Discontinue testing if hysterectomy was for benign reasons and no prior history of high-grade dysplasia (CIN)

Cervicovaginal cytology (Pap test) is used for screening, particularly for detecting early pre-cancerous lesions
HPV genotyping recommended for women >30 years with negative cytology and positive HPV test

Biomarker – SCCA (squamous cell carcinoma antigen)
- Potentially useful marker of recurrence
Pap smear – not sensitive enough for monitoring

Tests generally appear in the order most useful for common clinical situations

Test name: Cytology, SurePath™ Liquid-Based Pap Test (AutoCyte PREP™ System)

ARUP #: 8100400

Methodology: PrepStain™ Slide Processor/Routine Cytopathologic Evaluation

Use:

Replacement for conventional gynecologic Pap smears for use in the screening and detection of cervical cancer, precancerous lesions, atypical cells and all other cytologic categories as defined by the Bethesda System for Reporting Cervical/Vaginal Cytologic Diagnoses

Limitations:

Although this screening test has a low probability of error, patient should be reminded to consult physician immediately if she experiences any suspicious signs or symptoms, regardless of her Pap test result

Test name: Cytology, SurePath™ Liquid-Based Pap Test (AutoCyte PREP™ System) with Reflex to Human Papillomavirus (HPV) DNA Probe, High Risk

ARUP #: 8100214

Methodology: PrepStain™ Slide Processor/Routine Cytopathologic Evaluation/Nucleic Acid Probe

Use:

Triage ASC-US cervical cytology

Follow up treated/untreated histologic CIN1

Follow up LSIL in adolescent females

When results are negative, no testing is recommended for 3 years because the negative predictive value of this test is very high

Limitations:

Results should be correlated with cytologic and histologic findings

False-negatives due to inadequate cellularity can occur

Cross-reactions with other genotypes (eg, low-risk) may occur

Follow-up:

See 2006 Consensus Guidelines for the Management of Women with Cervical Cytologic Abnormalities in Guidelines section of topic

Test name: Cytology, ThinPrep® Pap Test™

ARUP #: 8100211

Methodology: ThinPrep® 2000 System

Use:

Replacement for conventional gynecologic Pap smears for use in the screening and detection of cervical cancer, precancerous lesions, atypical cells and all other cytologic categories as defined by the Bethesda System for Reporting Cervical/Vaginal Cytologic Diagnoses

Limitations:

Although this screening test has a low probability of error, patient should be reminded to consult physician immediately if she experiences any suspicious signs or symptoms, regardless of her Pap test result

Test name: Cytology, ThinPrep® Pap with Reflex to Human Papillomavirus (HPV) DNA Probe, High Risk

ARUP #: 8100212

Methodology: ThinPrep® 2000 System/Routine Cytopathologic Evaluation/Nucleic Acid Probe

Use:

Initial screening for cervical pathology

When results are negative, no testing is recommended for 3 years because the negative predictive value of this test is very high

Limitations:

Results should be correlated with cytologic and histologic findings

False-negatives due to inadequate cellularity can occur

Cross-reactions with other genotypes (eg, low-risk) may occur

Follow-up:

See 2006 Consensus Guidelines for the Management of Women with Cervical Cytologic Abnormalities in Guidelines section of topic

Test name: Human Papillomavirus (HPV) DNA Probe, High Risk, Cervical Brush (Digene)

ARUP #: 0065999

Methodology: Qualitative Nucleic Acid Probe

Use:

Triage ASC-US cervical cytology in women greater than or equal to 21 years

Primary screening in conjunction with cervical pap test in women greater than or equal to 30 years

Follow up treated/untreated histologic CIN1

Follow up LSIL in adolescent females

Determine “test of cure” following treatment (LEEP, Cone) for histologic-proven cervical abnormalities (CIN2,3/Ca)

Detects high-risk genotypes 16, 18; 31, 33, 35, 39, 45, 51, 56, 58, 59, 68 (associated with cervical cancer and precursor lesions)

Limitations:

Results should be correlated with cytologic and histologic findings

Cross-reactions with other genotypes (eg, low-risk) may occur

False-negative results due to inadequate cellularity can occur

Test name: Human Papillomavirus (HPV) DNA Probe, High Risk Surepath® (AutoCyte)

ARUP #: 0060744

Methodology: Qualitative Nucleic Acid Probe

Use:

Triage ASC-US cervical cytology in women greater than or equal to 21 years

Primary screening in conjunction with cervical pap test in women greater than or equal to 30 years

Follow up treated/untreated histologic CIN1

Follow up LSIL in adolescent females

Determine “test of cure” following treatment (LEEP, Cone) for histologic-proven cervical abnormalities (CIN2,3/Ca)

Detects high-risk genotypes 16, 18; 31, 33, 35, 39, 45, 51, 56, 58, 59, 68 (associated with cervical cancer and precursor lesions)

Limitations:

Results should be correlated with cytologic and histologic findings

Cross-reactions with other genotypes (eg, low-risk) may occur

False-negative results due to inadequate cellularity can occur

Test name: Human Papillomavirus (HPV) DNA Probe, High Risk (ThinPrep®)

ARUP #: 0060750

Methodology: Qualitative Nucleic Acid Probe

Use:

Triage ASC-US cervical cytology in women greater than or equal to 21 years

Primary screening in conjunction with cervical pap test in women greater than or equal to 30 years

Follow up treated/untreated histologic CIN1

Follow up LSIL in adolescent females

Determine “test of cure” following treatment (LEEP, Cone) for histologic-proven cervical abnormalities (CIN2,3/Ca)

Detects high-risk genotypes 16, 18; 31, 33, 35, 39, 45, 51, 56, 58, 59, 68 (associated with cervical cancer and precursor lesions)

Limitations:

Results should be correlated with cytologic and histologic findings

Cross-reactions with other genotypes (eg, low-risk) may occur

False-negative results due to inadequate cellularity can occur

Test name: Squamous Cell Carcinoma Antigen, Serum

ARUP #: 0081054

Methodology: Quantitative Enzyme-Linked Immunosorbent Assay

Use:

May be helpful in monitoring for recurrent disease

Limitations:

Results obtained with different assay methods or kits cannot be used interchangeably

Follow-up:

SCC antigen levels alone should not be interpreted as evidence of the presence or absence of malignant disease

In patients with known or expected cancer, other tests and procedures must be considered for diagnosis and patient management

Additional Tests Available

Test name: Human Papillomavirus (HPV) High Risk in situ Hybridization, Paraffin

ARUP #: 2002899

Methodology: In situ Hybridization

Comments:

Detects high-risk genotypes16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 66 (associated with cervical cancer and precursor lesions)

Used to test FFPE tissue biopsy samples

Guidelines

General

ARUP Institute for Clinical and Experimental Pathology®

Comprehensive Review: January 2011
Last Update: May 2011

Human Immunodeficiency Virus

Human Papillomavirus

Sexually Transmitted Infections

Tumor Markers