Screening for Cervical Cancer y de Seno

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Screening for cervical cancer

INTRODUCTION — The Papanicolaou (Pap) smear screening test for cervical cancer was introduced in

the United States in 1941, and led to the first systematic effort to detect early cancer. It soon gained

widespread acceptance, and has been associated with a sustained reduction in cervical cancer incidence

and mortality.

The Pap smear has become a model for cancer screening against which other such tests are measured.

However, the effectiveness of Pap smear screening for cervical cancer has never been demonstrated in a

randomized trial. Cervical cancer screening remains an evolving field with ongoing reevaluation of well-

established Pap smear screening practices and development of new screening technologies.

The conventional Pap smear consists of cells, sampled from the cervix and vagina using a brush or

spatula, that are placed directly on a slide and fixed with a chemical fixative in the office or clinic. Newer

technology (liquid-based cytology) consists of cells that are sampled similarly, but then suspended in a

liquid transport medium in the office or clinic; subsequently, the cells are spun or filtered in the laboratory

and plated as thin layers on slides. Cytologists review the slides for both techniques. Both the

conventional Pap smear and liquid-based cytology are in current practice. Collectively, these tests are

referred to as Pap tests or cervical cytology.

This discussion will focus on the effectiveness of screening tests for detecting cervical abnormalities and

specific recommendations for screening. Management of cytologic abnormalities is discussed separately

(see "Cervical cytology: Evaluation of atypical and malignant glandular cells" and see "Cervical cytology:

Evaluation of atypical squamous cells (ASC-US and ASC-H)" and see "Cervical cytology: Evaluation of

low grade squamous intraepithelial lesions") and techniques for performing and reporting cervical cancer

screening are discussed separately. (See "Cervical cancer screening tests: Techniques for cervical

cytology and human papillomavirus testing" and see "Cervical cytology: Interpretation of results").

Screening in HIV positive women, in whom the natural history of preclinical disease may be different, isdiscussed separately. (See "Screening for cervical cancer in HIV infected women").

EPIDEMIOLOGY AND RISK FACTORS — There are two main types of cervical cancer: squamous cell

carcinoma and adenoocarcinoma. Squamous cell carcinoma of the cervix is more prevalent than

adenocarcinoma. Both types are found in sexually active women. Infection with specific high risk strains

of human papillomavirus (HPV) is central to the pathogenesis of cervical cancer [1-4] . (See "Virology of

human papillomavirus infections and the link to cancer" and see "Cervical intraepithelial neoplasia:

Definition, incidence, and pathogenesis").

Risk factors which predispose to infection with HPV include early onset of intercourse, multiple sexual

partners over time, and having sexual partners who themselves have had multiple sexual partners.

Cigarette smoking increases the risk of cervical cancer up to 4-fold [5] . Immunosuppression also

significantly increases the risk of developing cervical cancer.

In the United States (US) in 2008, there were estimated to be 11,070 new cases of invasive cervical

cancer, and 3870 cancer-related deaths are expected; this represents approximately 1 percent of cancer

deaths in women [6] . Cervical cancer is the second most common cancer among women worldwide, with



83 percent of cases occurring in developing countries [7] . (See "Invasive cervical cancer: Epidemiology,

clinical features, and diagnosis").

The burden of cervical cancer extends beyond the impact of the disease itself, to the resources devoted to

cervical cancer screening. Between 50 and 60 million Pap tests are performed in the US each year.

Approximately 3.5 million of these are read as abnormal, and an estimated 2.5 million women undergo

diagnostic colposcopy as a result [8,9] .

PATHOGENESIS AND NATURAL HISTORY — The spectrum of HPV- related genital disease ranges

from external genital warts or condyloma acuminata (which develop in only 1 percent of infected women)

to cytologic abnormalities that represent active replication and associated cellular changes, to cervical

dysplasia and malignancy. (See "Cervical intraepithelial neoplasia: Definition, incidence, and

pathogenesis").

Cervical intraepithelial neoplasia (CIN) refers to pre-invasive dysplasia of cervical epithelial cells, the

precursor of malignant disease. CIN is categorized according to the depth and atypicality of cells within

the cervical epithelium and ranges from CIN I (the most mild) to CIN III (formerly termed carcinoma in

situ). The slow malignant transformation of these precursor lesions leads to a long latency period for

cervical carcinoma. Cervical lesions, particularly CIN I and CIN II, may regress to normal; rates of

regression for low grade lesions are as high as 75 percent at five years for adults [10-12] and up to 91

percent at three years in adolescents [13] . (See "Cervical intraepithelial neoplasia: Definition, incidence,

and pathogenesis").

THE PAPANICOLAOU SMEAR — George N. Papanicolaou, a zoologist by training, developed a

microscopic technique that involved examination of vaginal debris to study the estrous cycle of guinea

pigs. In 1941, he reported that the technique, which he had extended to human volunteers, had led to a

chance discovery of malignant cells, and therefore might be applied to detect cervical cancer in humans

through examination of cervical scrapings [14-16] .

Test description — The Pap test aims to identify abnormal cells sampled from the transformation zone,

the junction of the ecto- and endocervix, where cervical dysplasia and cancers arise. Examples of normal

and abnormal Pap smears are shown (show figure 1 and show figure 2). For conventional Pap smears,

cervical samples obtained by brush and spatula are plated on a microscope slide and preserved with

fixative. (See "Cervical cancer screening tests: Techniques for cervical cytology and human

papillomavirus testing").

Thin layer (or liquid-based) cytology is an alternative to conventional cytologic sampling and has been

widely implemented in the US. At least three commercially available tests have been approved: ThinPrep

(1996), SurePath (2000), and MonoPrep (2006). Testing involves transferring samples from the brush and

spatula into a liquid fixative solution; the cytology lab subsequently traps the loose cells onto a filter from

which they are plated in a monolayer onto a glass slide. The collected specimen can also be used for other

diagnostic assessments (ie, testing for gonorrhea, chlamydia, and HPV), although only Thin Prep is FDA

approved for that purpose. (See "Cervical cancer screening tests: Techniques for cervical cytology and

human papillomavirus testing").



Cytology report — Components of a cytology report include the following: A description of specimen

type — conventional Pap smear, liquid based cytology, or other A description of specimen adequacy A

general categorization (optional) — negative, epithelial cell abnormality, or other An interpretation/result

— either the specimen is negative for intraepithelial lesions and malignancy (although organisms or

reactive changes may be present) or there is an epithelial cell abnormality as defined by the Bethesda

2001 classification or there is another finding. This latter category may indicate some increased risk, as anexample: endometrial cells in a woman over 40 years of age [4] . A description of any ancillary testing or

automated review that was performed (eg, HPV, AutoPap) Educational notes and suggestions by the

pathologist (optional)

Details of this report are discussed separately. (See "Cervical cytology: Interpretation of results").

Bethesda classification system — The Papanicolaou test yields cytologic results, permitting examination

of cells but not tissue structure. The diagnosis of cervical intraepithelial neoplasia or cervical carcinoma

requires a tissue sample, obtained by biopsy of suspicious lesions, to make a histologic diagnosis.

Pap smear results are now widely classified according to the Bethesda system, first introduced in 1988,

and revised in 2001, to standardize and improve the clinical usefulness of Pap smear reports [17] (show

table 1). The intent of the Bethesda system is to distinguish between abnormalities which are unlikely to

progress to cancer and those which are more likely to indicate a precancerous or cancerous lesion. The

Bethesda system also includes guidelines for determination of specimen accuracy. Cellular atypia is

categorized in the Bethesda system as low grade squamous intraepithelial lesion (LSIL) or high grade

squamous intraepithelial lesion (HSIL).

The original Bethesda system specified a classification for cellular abnormalities that do not fulfill criteria

for dysplasia, using the categories 'atypical squamous cells of undetermined significance' (ASCUS), and

the less common 'atypical glandular cells of undetermined significance' (AGUS).

The 2001 revision of the Bethesda system provides subcategories for atypical squamous cells (ASC)

indicating the level of suspicion of underlying neoplasia: 'atypical squamous cells – cannot exclude high-

grade SIL' (ASC-H); and 'atypical squamous cells of undetermined significance' (ASC-US) (show table

1). The ASC-H designation, believed to represent 5 to 10 percent of ASC cases overall, is intended to aid

in the more rapid evaluation of potential CIN II or III, although reproducibility of the classification

among pathologists is not high [17] .

There is clearly some correlation between abnormal cytologic results (eg, LSIL) and the histology

subsequently demonstrated by biopsy (eg, CIN I), but direct correspondence occurs only in about half of

patients. In one trial, 45 percent of patients with LSIL had CIN I by biopsy, one-third had no identifiable

pathology, and 16 percent were diagnosed with CIN II or CIN III [18] . Particularly among young

women, LSIL often regresses, and represents a self-limited infection with HPV. (See "Cervical

intraepithelial neoplasia: Definition, incidence, and pathogenesis").

The most common cervical cytologic abnormality is atypical squamous cells (both ASC-US and ASC-H),

assigned to an average 3 to 4 percent of smears. In some laboratories, rates for atypical smears may

exceed 9 percent. LSIL and HSIL comprise approximately 2 percent and 0.5 to 1 percent of cervical

cytology readings, respectively [19,20] .



It is important to distinguish the atypical glandular cell (AGC) category from the more common atypical

squamous cells (ASC). The presence of AGC or AIS (adenocarcinoma in situ) on cervical cytology is a

significant marker for neoplasia of the endometrium, as well as of the cervix. A smear with AGC is

associated with a premalignant or malignant lesion of the endocervix or endometrium in 10 to 40 percent

of cases [17,21-24] . All women (including adolescents) with atypical glandular cells or AIS should be

referred for colposcopy with directed cervical biopsies and sampling of the endocervical canal; womenover age 35 should also have an endometrial biopsy [25,26] .

Test characteristics — The Papanicolaou smear is designed as a screening test (to be administered to large

numbers of asymptomatic patients), rather than a diagnostic test (to confirm or refute the suspicion of

disease). Reports of test sensitivity and specificity vary significantly, and the screening test is far from

perfectly accurate [27] . Considerable interobserver variability in smear interpretation is seen, although

variability decreases for smears with more severe abnormalities [28] .

Sources of potential error in sampling and evaluating the Pap smear include: The clinician may not

sample the area of cervical abnormality. The abnormal cells may not be plated on the slide or transferred

to the liquid medium. The cells may not be adequately preserved with fixative. The cytopathologist maynot identify the abnormal cells. The cytologist may inaccurately report the findings.

Determination of the true characteristics for a screening test depends on the availability of a gold standard

for a truly random sample of tests. The gold standard for abnormal cervical cytology is a colposcopic

biopsy. A 2000 systematic review of the sensitivity and specificity of conventional cervical cytology

found bias in many studies, and wide variation in estimates of sensitivity and specificity [27] . Limiting

the systematic analysis to 12 studies with the best methodology and valid controls, the sensitivity of a

conventional Pap smear for the diagnosis of LSIL for CIN I (or worse) ranged from 30 to 87 percent, with

specificity 86 to 100 percent [27] .

Liquid-based cytology has several theoretical advantages over conventional cytology: lower incidence of inappropriate fixation and drying artifact, and less cellular obscuration on the slide resulting in fewer

unsatisfactory tests than conventional smears [29] . Systematic reviews of studies comparing conventional

and liquid-based cytology, however, have not consistently shown that liquid-based cytology detects

significant cancer precursors more effectively than conventional cytology [20,30-36] . The opportunity to

re-test the liquid preparation at a later date for HPV (ie, as a reflex test for women whose cytology results

show equivocal or low-grade abnormalities) may prove advantageous in certain circumstances. (See

"Cervical cancer screening tests: Techniques for cervical cytology and human papillomavirus testing").

Effectiveness — In the US, cases of invasive cervical cancer are more likely to represent failure to

perform appropriate screening than inaccuracies of screening when performed. More than half of women

who develop cervical cancer either have never had cervical cytology, have been screened sporadically, orhave not been screened within the previous five years [37-40] .

Among women with invasive cancer who did receive prior screening, one study noted a failure of original

cervical cytology interpretations to detect dysplastic cells that could be identified retrospectively in up to

two-thirds of cases [39] . This study, however, contained no control group.



Cytologic screening for cervical cancer has never been evaluated in a randomized controlled trial.

Evidence of its effectiveness in reducing the incidence of and mortality from cervical cancer comes

exclusively from observational studies. Such studies provide consistent and compelling evidence that has

led to the adoption of cervical cytology screening in all developed and many developing nations

worldwide.

Evidence of conventional cervical cytology (Pap smear) effectiveness includes the following: Pap smear

screening was introduced sequentially over time into five Canadian provinces. Analysis of mortality data

from carcinoma of the uterus (including carcinoma of the cervix) found a strong inverse correlation across

the provinces between intensity of cervical screening and change in mortality [41] . For screening rates

below 2.5 percent, mortality from uterine and cervical cancer increased by 27.5 per 100,000 women; for

screening rates above 25 percent, mortality decreased by 28.7 per 100,000 women. In an early study, 212

cases of invasive cervical cancer were compared with 1,060 age-matched neighborhood controls. Absence

of a cervical smear over the five years prior to the cancer diagnosis or study enrollment almost tripled the

risk for invasive cervical cancer (odds ratio 2.7); this effect persisted in analyses stratified by age,

smoking, income, education, and access to care [42] . The International Agency for Research on Cancer

(IARC) combined data from national programs in eight countries and projected a 90 percent reduction incervical cancer incidence for periodic screening of the entire (non-elderly) adult female population [43] .

Programs for population screening were implemented in Finland, Sweden and Iceland in the 1960s, but

not in neighboring (and demographically similar) Norway. Incidence rates for cervical cancer in the four

countries were comparable before screening but fell by 50 percent within 20 years in the countries that

implemented screening while Norway saw no such decrease [44-47] . Reductions in cervical cancer

incidence and mortality have been observed as screening is implemented in other countries, including

Australia, Norway, and Japan [48-51] .

It should be noted that cervical cytological screening for adenocarcinoma is much less effective than for

the more common squamous cell carcinoma. Adenocarcinoma involves the glandular tissue of the internal

cervical canal, in contrast to squamous lesions which are more likely to be visually apparent.

Adenocarcinomas may occur at several sites within the canal ("skip lesions") and can be more difficult to

detect by routine Pap screening. In a case control study, the rate of cervical screening in the 10 years prior

to the diagnosis of adenocarcinoma (82 percent) was similar to the screening rate in control patients

without cancer, and significantly higher than in women with squamous cell carcinoma (57 percent) [52] .

FOLLOW-UP OF ABNORMAL CYTOLOGY — Patients who have abnormal screening tests should

have indicated follow-up, based on findings of the screening test. Strategies for appropriate follow-up are

discussed in separate topics (see "Cervical cytology: Evaluation of atypical and malignant glandular cells"

and see "Cervical cytology: Evaluation of atypical squamous cells (ASC-US and ASC-H)" and see

"Cervical cytology: Evaluation of low grade squamous intraepithelial lesions" and see "Cervical cytology:

Evaluation of high grade squamous intraepithelial lesions" and see "Cervical intraepithelial neoplasia:

Management").

HPV TESTING — Testing for high-risk HPV types has been proposed both as a primary screening

modality (in concert with, or instead of, cervical smear testing) and as a method to triage Pap smear

results that are equivocal or show low-grade abnormalities.



In the United States, two types of HPV tests are available [53] . The Hybrid Capture 2 (the first test to

receive FDA approval, in 2003) and the Cervista HPV HR test (approved in 2009) are designed to

identify the presence of any of the 13 or 14 high risk HPV types. These tests will be referred to as "HPV

testing." A second type of HPV test, marketed in 2009 as Cervista HPV 16/18, is designed to detect the

presence of HPV types 16 and 18. These two HPV types are responsible for 70 percent of cervical cancer

in the United States, and have been shown to confer much higher rates of development of HSIL than otherhigh risk HPV types. The HPV 16/18 test (hereafter referred to as "HPV genotyping") is intended to be

used as follow-up to a less specific HPV test, adjunctively with cytology. (See "Cervical cancer screening

tests: Techniques for cervical cytology and human papillomavirus testing").

Primary HPV screening — HPV testing, either alone or in combination with cervical cytology, has been

shown in multiple studies to be more sensitive than cervical cytology alone in detecting high or low grade

cervical histopathology [18,54-58] . However, poor specificity and correspondingly poor positive

predictive value may limit the use of HPV testing as a primary screening modality [59] .

The prevalence of high-risk HPV at the time of cervical cancer screening among a geographically diverse

group of 9657 US women aged 14 to 65 was measured by Hybrid Capture 2 testing [60] . The proportionof women testing positive for high risk HPV ranged from 35 percent for women aged 14 to 19 years, to 6

percent among women aged 50 to 65. If colposcopy were performed for HPV tests indicating high-risk

HPV, the majority of colposcopies would be performed in young women with transient HPV infections.

HPV testing has better specificity in women over age 30 than in younger women. The sensitivity and

specificity in such women was evaluated in a community setting in the Canadian Cervical Cancer

Screening Trial (CCCaST), comparing HPV testing with conventional Pap smears in 10,154 women aged

30 to 69 years who underwent both tests [58] . Women with an abnormal Pap smear (ASCUS, AGC, or

worse) or a positive HPV test were advised colposcopy. A random sample of 15 percent of women whose

screening test results were normal were also invited for colposcopy, to overcome verification bias that

results when only positive screening tests are evaluated with a "gold standard" procedure.

Sensitivity (corrected for verification bias) for the detection of confirmed CIN Grade 1B or worse was

significantly higher with HPV testing (94.6 versus 55.4 percent with conventional Pap smears).

Specificity was significantly lower with HPV testing (94.1 versus 96.8 percent). Sensitivity and

specificity of different test combinations was estimated (show table 2); no testing strategy proved

dominant (ie both superior specificity and sensitivity). Because all women in this study underwent

intervention based on the results of both tests, outcomes of different screening strategies cannot be

determined.

Another trial of screening with HPV testing and conventional Pap smear, the Population Based Screening

Study Amsterdam (POBASCAM) trial, analyzed data on 17,000 women aged 30 to 59 randomly assignedto initial screening with conventional Pap plus HPV (intervention group), or Pap alone (control group)

[61] . At five years (the routine screening interval in the Netherlands), all women underwent both Pap and

HPV testing. CIN3 or worse was detected in 70 percent more women in the intervention than control

group at the initial screen; at five year follow-up, women in the intervention group had 55 percent fewer

CIN3 lesions than controls. The number of CIN3 lesions did not differ between the two groups over the

two testing rounds. Thus, HPV testing led to earlier detection of lesions. These data suggest that most of

the lesions detected in the baseline round would have persisted.



The improved sensitivity of HPV alone, or in combination, must be weighed against its lower specificity.

A screening strategy for women age 30 and older that includes HPV testing with a lengthened screening

interval could balance improved sensitivity with an acceptable rate of false positive results over time.

Further study will be needed to develop appropriate screening strategies, intervals, and follow up

algorithms.

Use in areas with limited resources — A randomized trial in 131,746 women aged 30 to 59 years in rural

India compared one-time screening by one of three screening modalities (HPV testing, cytology, or visual

inspection of the cervix with acetic acid (VIA)) with standard care [62] . Rates of a positive screening test

across the 3 screened groups were 10.3 percent (HPV testing), 7.0 percent (cytology showing ASCUS or

worse), and 13.9 percent (VIA); over 88 percent of those with positive tests underwent colposcopy. Rates

of advanced cervical cancer and cancer-related death within eight years of screening were halved in the

group that underwent HPV testing (HR 0.47, 95% CI 0.32-0.69 and HR 0.52, 0.33-0.83, respectively),

compared to the control group; there were no significant differences for the groups screened by cytology

or VIA compared to control.

Costs of follow-up testing and treatment may limit the feasibility of screening with HPV testing in otherlimited-resource settings if the baseline HPV prevalence is significantly higher than 10.3 percent observed

in this population.

Follow-up of HPV testing — Women 30 years and older who have been screened with an HPV test alone

should have a Pap smear performed if the HPV test is positive; further evaluation should be based on the

combined results of the HPV test and Pap smear. Women under age 30 are not recommended to undergo

primary HPV testing.

For women 30 years and older screened with a combination of Pap smear and HPV testing, a positive or

negative HPV test can help inform the management of an abnormal Pap smear. A negative HPV test, in

combination with a normal Pap smear, confers an extremely low risk of developing CIN3 or greaterwithin the next ten years. Studies in Denmark and in the US have found this risk to be less than 2 percent

[63-65] .

Over 50 percent of women aged 30 and older in some studies will have a positive HPV test in

combination with a normal Pap smear [66] . Only a fraction of these women have undetected CIN2 or

greater at the time of screening, and most will clear their high risk HPV [67,68] . However, among those

who do not become negative for high risk HPV, over 10 percent will develop CIN3 within one year [69] .

Consensus guidelines — Consensus recommendations were developed by the Cytopathology Education

and Technology Consortium [70] , based upon guidelines from the American Cancer Society [63,71] andthe American Society for Colposcopy and Cervical Pathology [72] . These consensus guidelines

recommend the following [70] : Women with negative HPV testing and negative cytology should not be

rescreened for at least three years. Women with a positive HPV test and negative cytology should have

both tests repeated in 12 months. If both tests at 12 months are negative, they can proceed to routine

screening every three years. If the HPV test is persistently positive, they should undergo colposcopy. If



the cytology is positive, they should have appropriate evaluation, regardless of HPV results (see "Follow-

up of abnormal cytology" above).

An alternative to this algorithm is based upon the differential risk conferred by HPV 16/18, compared

with other high risk HPV types. Because women who are positive for HPV 16/18 with a normal Pap

smear have an 18 to 21 percent ten year risk of developing CIN3 (compared with a risk as low as 1.5

percent among those with non-16/18 high risk types) [65,73] , the new HPV genotyping test may prove

useful. It has been suggested that women with a negative Pap smear and positive HPV test could undergo

HPV genotyping. Women who are HPV 16/18 positive should be referred directly for colposcopy. Those

with a negative HPV 16/18 would return in 12 months for a Pap smear and HPV test. However, this

strategy has not been evaluated.

HPV testing as triage — Reflex HPV testing for equivocal cytology test results (ASC-US) or those with

low-grade abnormalities (LSIL) has been evaluated as an alternative to conventional follow-up

(immediate colposcopy or repeat cytology every 6 months) in a large randomized trial [18,74] .

Immediate colposcopy was found to be the preferred strategy for LSIL [18] ; for ASC-US, however, HPV

triage was a promising strategy [74] . Reflex HPV testing in adolescents may be of little use as a means of triage, since as many as 80 percent may test positive for HPV [75] . (See "Cervical cytology: Evaluation

of atypical squamous cells (ASC-US and ASC-H)").

One modeling study, designed to characterize the tradeoff between risks and benefits of various screening

strategies, predicted that screening women with both cytology and HPV would result in nearly three times

as many colposcopies as any other strategy, but results in a modestly lower lifetime risk of cervical cancer

[76] . In this model, HPV testing followed by reflex cytology resulted in the fewest colposcopies and

second highest efficacy among the four strategies evaluated.

OTHER SCREENING MODALITIES

Visual inspection — Lesions identified by visual inspection warrant biopsy even in the presence of a

normal cervical smear.

Visual inspection with acetic acid (VIA) or Lugol's iodine is used for cervical cancer screening in some

developing countries with inadequate resources for population-based cytologic screening [77] . A

randomized study in India of clusters of women aged 30 to 59 years assigned to screening with acetic acid

by trained nurses, followed by colposcopy and biopsy as needed, compared to usual care (no screening),

found that visual inspection decreased both incidence of and mortality from cervical cancer (HR 0.75,

95% CI 0.55-0.95 and HR 0.65, 0.47-0.89, respectively) [78] . In another randomized trial in India,

however, the number of advanced cervical cancers or deaths among patients who received screening withVIA did not differ from the control group [62] . This trial found that HPV screening was the most

effective screening modality in a resource-poor area. (See "HPV testing" above and see "Cervical cancer

screening tests: Techniques for cervical cytology and human papillomavirus testing").

Computerized screening or rescreening — Computerized automated screening of Pap slides has been

developed, but the role for this technology has not been definitively determined. Available technologies

include Autopap, PapNet, and ThinPrep. Proposals for use include initial screening to identify slides for





incidence of CIN and carcinoma in situ peaks in the mid-reproductive years and begins to decline in the

fourth decade of life [59] . Cervical cancer is no more aggressive in older women than in younger, and

high grade lesions are rare among older women who have been previously screened. A Swedish

prospective observational study involving 660,000 women, however, found that the risk of developing

cervical cancer following three negative cervical smears was the same for women aged 45 to 54 as for

women age 30 to 44 (HR 0.85; 95% CI 0.59-1.21) [96] .

Several studies illustrate the low yield and poor positive predictive value of screening among previously

screened older women: Among 312,000 participants in the National Breast and Cervical Cancer Early

Detection Program (NBCCEDP), a federally funded program for low-income and uninsured women [97] ,

those aged 65 and older had the lowest risk of an abnormal Pap smear (2.8 percent ASCUS; 1.0 percent a

more severe abnormality) and the lowest risk of serious pathology (0.2 percent had CIN II or worse

confirmed at biopsy) [98] . The risk of an abnormality on a subsequent smear was even lower for the

130,000 women from the same program who had a normal Pap smear result at program entry and at least

one additional smear [99] . Women aged 65 and older again had the lowest risk of any abnormality (2.2

percent ASCUS, 0.4 percent a more severe abnormality). Pap smear abnormalities among previously

screened older women have poor positive predictive value for significant pathology. The incidence of new cytologic abnormalities within 2 years of a normal Pap smear was 2.3 percent per year among 2,561

post-menopausal women (median age 67 years) participating in the Heart and Estrogen/progestin

Replacement Study (HERS) [100] . Only one of the 110 abnormal Pap smears proved to have high-grade

cervical histology (positive predictive value 0.9 percent). One additional woman had high grade vaginal

intraepithelial neoplasia. Cytology results were evaluated for 17,000 women aged 50 to 79 participating in

the Women's Health Initiative who underwent Pap smear screening at baseline, 3 years, and 6 years (and

more frequently if indicated) [101] . The risk of high grade cytological abnormalities (HSIL or cancer) for

women with a normal smear at baseline was low (7.1 per 10,000 person-years). Colposcopic data were

not available for this study. The prevalence of ASC-H was compared for pre- and postmenopausal women

[102] . High grade histology was found in 6 percent of postmenopausal women, compared with 22

percent of pre-menopausal women.

No published studies directly evaluate the effectiveness of screening for older women [103] . Although

cervical cancer mortality increases after age 65, the benefit of screening declines with age, due to

competing causes of death and lag time in the realization of screening benefits.

Potential screening benefits need to be balanced against the potential harms of cervical cancer screening

in elderly women. (See "Risks of screening" below). Follow-up procedures are common among older

women; among women over age 65 insured by Medicare in the US, 39 in 1000 require follow-up, with 9

patients requiring colposcopy or more invasive procedures [104] . Pitfalls of screening in this population

include patient refusal or failure to follow-up, false positive tests leading to unnecessary procedures

including hysterectomy, and mortality due to unrelated causes while undergoing evaluation [105-107] .

There are currently no data to guide screening guidelines in women over age 65. In time, it may be found

best to individualize cervical cancer screening recommendations, incorporating age as one component but

also possibly including life expectancy, results of prior screening, HPV status, and current sexual activity.



Given existing information, it is generally agreed that older women who have not been adequately

screened should have Pap tests annually until they have had three negative tests. It may also be reasonable

to screen women over age 65 who have favorable life expectancies and known risks for cervical disease

(eg, sexually active with a new male partner). We suggest that other women aged 65 and older who have

tested negative (at least three times) throughout the past 10 years not undergo screening for cervical

cancer.

Outside the realm of screening, older women who have signs or symptoms of cervical disease (eg,

abnormality on visualization or palpation of the cervix, postmenopausal bleeding, abnormal discharge,

pelvic pain, or change in bowel or bladder function) should undergo appropriate diagnostic evaluation.

Screening frequency — The primary determinants of screening frequency should be the duration of the

preclinical treatable phase of the disease (up to 10 to 20 years for cervical cancer), and the sensitivity of

the screening test (modest for cervical cytology) [108] . Pap smear screening in the United States was

initially implemented as an annual test, with subsequent reconsideration of optimal screening frequency.

Determining the relative effectiveness of different cervical smear screening intervals in reducing the

incidence and mortality of cervical cancer is limited by the need to rely on observational data, in the

absence of randomized trials. The International Agency for Research on Cancer (IARC) modeled the

effectiveness of different screening intervals, using data from large screening programs in eight countries

[43] . Protection from cervical cancer remained high for at least three years after the last negative cervical

cytology screen, and was substantial up to ten years. The estimated reduction in cumulative incidence of

invasive cervical cancer among women aged 35 to 64 fell minimally when the screening interval was

increased from one year (93.5 percent reduction) to two years (92.5 percent) to three years (90.8 percent).

Additional studies have also addressed the relative benefits of different cervical smear screening intervals.

Note that these studies evaluated conventional, rather than liquid based, cervical cytology smears, and

none included HPV testing. Representative findings include: Rates of high grade cytologic abnormalities(HSIL or worse) in the observational NBCCEDP study were similar, regardless of whether women had

their next cervical smear one, two, or three years after their three consecutive normal cervical cytology

tests (incidence 25, 29, and 33 per 10,000, respectively) [99] . The risk of serious cervical histology (CIN

II or worse) within 2 years of a normal smear was negligible in the HERS study (1 case per 4,895 person-

years of follow-up) [100] . As noted above, 231 additional interventions in 110 women were necessary to

detect the single case. (See "Discontinuing screening" above). A matched case-control study of invasive

squamous cell cervical cancer found that, compared with a one-year screening interval, the odds of

cervical cancer increased for two-year (OR 1.72) and three-year (OR 2.06) screening intervals [109] . The

authors cautioned that these results should be interpreted in the context of the low absolute risk of

developing cervical cancer. In a nested case-control study, the duration of protection conferred by a

negative cervical cytology result was greater at older ages. Among women aged 55 to 69, screening every5 years was strongly protective (estimated 83 percent risk reduction) and annual screening conferred little

advantage (87 percent) [110] . Among women aged 20 to 39 years, relative risk reduction for annual

screening was lower (76 percent) and declined steeply with increasing interval (61 percent for 3 years);

intermediate risk reductions were found for women aged 40 to 54. Using a Markov model, based on data

from 31,000 women, it was predicted that after three or more negative cervical smears, annual compared

to triennial Pap smear would detect 3 more cases of cervical cancer among 100,000 women aged 30 to 44



years; 1 more case among 100,000 women aged 45 to 59 years, and no excess cases in women 60 to 64

years [111] . Women under age 30 showed the greatest benefit of annual screening (5 fewer cases per

100,000).

Annual screening has been shown to triple the number of downstream interventions, including

colposcopies, compared with triennial screening [111] .

HPV vaccine — Introduction of the HPV vaccine for female adolescents is anticipated to have a

significant impact on their risk for cervical abnormalities [112] . (See "Recommendations for the use of

human papillomavirus vaccines"). A cost-effectiveness model based on assumptions of vaccine

effectiveness suggests that screening could be initiated later and performed less frequently in women who

were vaccinated as preadolescents [113] . However, the optimal approach to cervical cancer screening in

women who have received an HPV vaccine remains uncertain and, until data from clinical trials are

available, standard screening recommendations should be observed [114,115] .

Prior hysterectomy — Women who have undergone a hysterectomy in which the cervix was removed(representing over 95 percent of hysterectomies currently performed in the United States [116] ) are at a

vanishingly small risk of cervical cancer. Although it was once believed that women without a uterus

were at increased risk for vaginal cancer [117-121] , studies show no association between total

hysterectomy for benign disease and subsequent vaginal carcinoma [121-126] . In one study of over

10,000 vaginal cuff smears obtained from 6,265 women, 1 percent of cervical cytology smears were

abnormal, and the positive predictive value of the smear for predicting vaginal cancer was 0 percent [123]

. There has never been a randomized controlled trial of screening in women with hysterectomy.

Certain groups of women may warrant continued screening after hysterectomy, although there are limited

studies of cervical cytology screening in these groups (see "Cervical intraepithelial neoplasia:

Management", section on Post-hysterectomy). Women who have undergone subtotal hysterectomy,

leaving the cervix intact, likely share the same risk of cervical cancer as women with an intact uterus and

cervix. Such women represent a small minority of women who have undergone hysterectomy. For women

who are uncertain if their cervix was removed at the time of hysterectomy, a pelvic exam is essential to

determine the ongoing need for cervical cancer screening. Women who have undergone hysterectomy

because of uterine or cervical cancer typically undergo cervical cytology tests for surveillance for local

recurrence at the anastomotic site. Prospective studies of this practice are unavailable and retrospective

studies, which all lack control groups, show variable yields on cytology [127-130] . (See "Invasive

cervical cancer: Management of stages IB2, bulky IIA, and locally advanced disease", section on

Posttreatment follow-up). The risk of vaginal cancer subsequent to hysterectomy for CIN is low, with one

case reported among 5037 women who underwent hysterectomy for CIN 3 [131] . Therefore, it isreasonable (and recommended by several professional organizations [71,132] ) that women who have a

history of CIN 2 or 3 and subsequently undergo a hysterectomy may safely discontinue Pap smear

screening after three consecutive negative screening tests (either the three most recent Pap smears prior to

the hysterectomy or three consecutive screening examinations subsequent to the hysterectomy). Women

exposed in utero to diethylstilbestrol (DES), who are at elevated (although low) risk of gynecologic

malignancies, particularly clear cell adenocarcinoma of the vagina, may warrant continued screening

[133] . The American Cancer Society recommends ongoing screening for these women [71] .



However, it should be noted that the average age of vaginal cancer in DES exposed women is 19, and

there are virtually no reported cases over age 35. The association between DES exposure and vaginal

cancer was reported in 1971, and the youngest women (in the United States) are likely to be over 35 years

of age. Since DES was first synthesized in 1938, the oldest exposed women are younger than age 70.

Evidence is not available regarding the need for ongoing Pap surveillance in older DES-exposed women.

The role of screening in women with HIV infection who have had a hysterectomy is discussed separately.(See "Screening for cervical cancer in HIV infected women").

RISKS OF SCREENING — Abnormal cervical cytology results are relatively common. It is estimated

that between 50 and 60 million cervical cytology tests (Pap tests) are performed each year in the US.

Approximately 3.5 million of these are read as abnormal, and an estimated 2.5 million women undergo

diagnostic colposcopy as a result [8,9] . A population-based study in Australia estimated that a 15-year-

old woman faces a 77 percent lifetime risk of undergoing at least one colposcopy [134] .

Adverse effects of screening fall into four categories: discomfort and inconvenience, psychosocial

consequences, adverse health outcomes, and costs.

Discomfort and inconvenience — The discomfort and inconvenience of Pap smear screening are

apparent, although not easily measurable; both increase with the frequency and duration of screening, and

may be particularly relevant for adolescents and the elderly.

Psychosocial consequences — A number of studies have examined the psychosocial consequences of

screening. High levels of anxiety are associated with colposcopy referral for women with both high grade

[135] and low grade [136] abnormalities, and with surveillance for mild smear abnormalities [137] .

Anxiety is heightened in women with a positive HPV test [138] and in younger women [136,138] .

Adverse health effects — Adverse health outcomes related to cervical cancer screening arise from the

downstream consequences of diagnosing and treating abnormalities. Large scale studies on the long-term

effects of loop electrosurgical excisional procedure (LEEP), laser ablation and conization on fertility and

pregnancy are not available [139] ; a 2006 meta-analysis of smaller studies found an association between

cold knife conization and preterm delivery (RR 2.59, 95% CI 1.80-3.72) and low birthweight (RR 2.53,

1.19-5.46) [140] . Findings were similar for LEEP and showed a similar but nonsignificant trend for laser

conization. (See "Cervical intraepithelial neoplasia: Management", section on Long-term complications of

treatment).

Costs — The costs of cervical cancer screening include both monetary and opportunity costs. Annual

spending on cervical cancer screening is estimated to exceed $7.5 billion. Opportunity costs relate to

overlooking potentially more important health care issues during medical visits in which Pap smear

screening is discussed and performed.

RECOMMENDATIONS OF US PROFESSIONAL ORGANIZATIONS — Cervical cancer screening

guidelines in the US are issued by three major organizations: the US Preventive Services Task Force

(USPSTF), the American Cancer Society (ACS), and the American College of Obstetrics and Gynecology

(ACOG). Guidelines issued by these groups since 2002 are specific with respect to starting age, stopping

age, screening frequency, and groups for whom the standard recommendations do not apply. The three

sets of recommendations have much in common (show table 3) [71,132,141] .



Starting age — All three organizations strongly recommend screening for cervical cancer in women who

have been sexually active and have a cervix. Each recommends initiating screening at age 21 or 3 years

after the onset of sexual activity, whichever comes first.

Stopping age — The USPSTF recommends stopping screening at age 65, and the ACS suggests stopping

at age 70 for women who have had adequate recent screening with normal Pap smears and are not

otherwise at high risk; ACOG advises that the determination of when an older woman may stop screening

should be made on an individual basis.

Frequency — The USPSTF recommends screening at least every three years; ACS and ACOG advocate

annual screening for women under age 30 (ACS specifies biennial if using liquid-based testing), and

reducing the frequency to every two to three years for women aged 30 and older who have had three

consecutive normal Pap tests, or every three years if they also are tested for HPV DNA.

ACS specifies certain risk groups that may require more frequent screening: HIV infection,

immunosuppression, or in utero DES exposure. ACOG recommends annual screening for women whohave been treated in the past for CIN2, CIN3, or cervical cancer.

Women who have undergone hysterectomy — All three organizations concur that women who have

undergone total hysterectomy for benign disease may (or should, in the case of USPSTF) discontinue

screening for cervical cancer. Both the ACS and ACOG recommend screening until three annual tests are

negative for women who have had CIN 2 or 3, unless three negative tests were documented prior to their

hysterectomy. ACS recommends ongoing screening for DES-exposed women.

Screening modality — Both ACS and ACOG allow for screening using liquid based cytology and/or

routine HPV testing (the latter for women 30 and older), provided suitable adjustments to the screening

interval are made (see above). The USPSTF makes no recommendation for or against liquid-basedtechnology, computerized rescreening, or HPV testing as a primary screening modality, due to

insufficient evidence.

INTERNATIONAL PERSPECTIVE — In most industrialized Western nations, Pap smear tests are

performed as part of large scale national or provincial centrally organized programs. Most countries have

designated national screening policies with marked variation between countries.

table 4 summarizes the national screening policies of over a dozen industrialized nations (show table 4).

Starting age for Pap smears ranges from age 18 (in Australia and Canada) to 30 (in the Netherlands and

Finland). Stopping age ranges from 58 (in Sweden) to 70 (in Australia and Canada), or indefinite (in

Germany). Screening frequency ranges from annual (Germany) to every 5 years (the Netherlands,Finland, and the United Kingdom). These policies result in a recommended (minimum) number of

lifetime smears between 7 and 50 or more.

ADEQUACY OF SCREENING AND FOLLOW-UP — The two most hotly debated aspects of cervical

cancer screening - frequency and age - have less impact on overall screening effectiveness than whether

women receive any screening, or have appropriate follow-up for abnormal tests. Half of women with



newly diagnosed invasive cervical carcinoma have never had a Pap smear; another 10 percent have not

had a smear in the past five years [114] .

Actively inviting women to schedule an appointment for cervical cancer screening appears to be the most

effective way to obtain participation in a screening program [142] , though even active solicitation

resulted in less than a 20 percent increase in screening in one systematic review [143] . The most effective

single intervention used a dedicated nurse practitioner, and offered same-day screening (33 percent

increase in screening).

In a 2006 survey in the United States, 84 percent of women aged 18 years and older had had a Pap test

within the preceding three years [144] . Never screened and under-screened women tend to be those with

no usual source of health care, the uninsured, and women who immigrated to the US within the past ten

years [145] . Urgent care clinic visits can be used as an opportunity to obtain a cervical cytology test in

women who are unlikely to otherwise comply with cervical cancer screening recommendations; such an

approach dramatically increases the number of women screened [146] . However, patient follow-up in

this setting can be more difficult than in the longitudinal care setting.

The effectiveness of Pap test screening hinges on adequate follow-up and treatment for abnormal

cytologic results. Patients with abnormal cervical cytology require further evaluation, which may include

HPV testing, colposcopy, cervical biopsy, endometrial sampling, or a diagnostic excisional procedure,

depending upon the severity and nature of the cytologic results. (See "Cervical cytology: Interpretation of

results").

Inadequate follow-up of abnormal Pap smears performed months or years prior to the diagnosis of cancer

was found in up to 13 percent of women with invasive cervical cancer [39,147-149] . The median time

from the date of the "failed" abnormal Pap smear to the cancer diagnosis was 22 months in one study;

older age and poverty were associated with greater likelihood of a failed follow-up process [150] .

Initiating a reminder system is helpful for ensuring compliance with follow-up [151,152] .

Despite demonstrated health benefits from Pap testing, some women remain unwilling to undergo

screening, and furthermore may be reluctant to pursue other health care because of their concerns

regarding the pelvic exam. Women who decline Pap smear screening after having been informed in a

clear and culturally sensitive manner of the expected benefits (and risks) of such screening, should be

made to feel welcome to receive ongoing health care without risk of blame or discrimination as a result of

their decision.

Screening for breast cancer

INTRODUCTION — There is more scientific evidence supporting screening for breast cancer, the most

common non-skin cancer and second deadliest cancer in women, than for any other cancer. The relevantissues include determining who should be screened (risk stratification, age to begin screening, age to stop)

and what method should be used for screening.

There is a strong consensus that routine screening mammography, with or without clinical breast

examination, should be offered to women ages 50 to 69. Consensus is not as strong for routine screening

among women ages 40 to 49 or women over age 70, for screening with breast self-examination, or for

how frequently to screen.



Discoveries of genetic mutations that increase the risk of breast cancer and the development of breast

cancer risk prediction models have stimulated efforts to develop screening strategies stratified according

to risk level. In tandem with mammography, breast magnetic resonance imaging (MRI) has been studied

as a screening method for high-risk women.

The evidence for screening for breast cancer in women and recommendations for breast cancer screening

are discussed here. Performance characteristics of mammography, patient risk stratification, management

options for women with a genetic predisposition to breast cancer, and surveillance in women with a

personal history of breast cancer are discussed in detail separately. (See "Breast imaging: Mammography

and ultrasonography" and see "Risk prediction for breast cancer screening" and see "Options for women

with a genetic predisposition to breast and ovarian cancer" and see "Follow-up for breast cancer

survivors: Recommendations for surveillance after therapy").

EPIDEMIOLOGY — Breast cancer incidence in the United States (US) doubled over the last 60 years of

the 20th century, from about 55 per 100,000 in 1940 to 118 per 100,000 in 1998 [1] . Annually,

approximately 182,460 American women are diagnosed with breast cancer, and 40,480 women die from

the disease [2] . The majority of breast cancers in the US are diagnosed as a result of an abnormalscreening study, although a significant number are also first brought to attention by a patient or clinician

breast examination. US breast cancer incidence peaked in 1998 and decreased 3.5 percent per year from

2001 to 2004 [3] . There has been an even greater decline among women aged 50 to 69 years. (See

"Epidemiology and risk factors for breast cancer").

The increase in breast cancer incidence through the 1990's was seen mostly in early stage and in situ

cancers, and was attributed to increased detection of early stage disease because of screening. However,

environmental factors such as improved nutrition, and increased lifetime estrogen exposure, likely also

contributed to the higher incidence. (see "Risk factors" below)

A sharp decline in breast cancer incidence starting in 2003 may relate, in part, to reduction inpostmenopausal hormone therapy since publication of the Women's Health Initiative report in 2002 [4-6] .

Findings that the decline leveled off somewhat in 2004, and that it was primarily in estrogen receptor

positive tumors in women over age 50, support a role for decreased use of hormone therapy in the

declining incidence of breast cancer [7,8] . The decline may also reflect lower detection rates due to some

reduction in mammogram screening rates [8] . Mammogram screening rates for US women aged 40 years

and older fell from 70 percent in 2000 to 66 percent in 2005 [9] .

Breast cancer mortality rates were remarkably stable during the latter half of the 20th century, at about 30

to 32 per 100,000, making breast cancer second only to lung cancer in cancer mortality among women [2]

. However, in 1990, the mortality rate began declining an average of 2.1 percent annually; the 2003 age-

adjusted mortality rate was 25.2 per 100,000, the lowest level since 1969 when national statistics began[10] . Most of this decline was in white women.

It is likely that at least some of the decline in mortality is due to screening, although adjuvant therapy also

may contribute and likely accounts for the approximately 20 percent mortality decline among white

women in their 30s [11] . Using seven different statistical models, estimates of the proportion of total

reduction in overall US breast cancer mortality attributable to mammogram screening ranged from 28 to

65 percent (median 46 percent), with adjuvant treatment accounting for the rest [12] . These results



suggest that breast cancer mortality in the US has dropped about ten percent because of screening. The

decline in rates of mammogram screening raises some concern about future trends in breast cancer

mortality [9] .

Breast cancer mortality rates in black women in the US declined somewhat less, from 38.0 to 34.5 per

100,000 from 1990 to 2001 [2,10] . Black women may have their breast cancer diagnosed at a later stage

due to lower use of mammography. A study of over one million women who had at least one

mammogram between 1996 and 2002 found that African American women were more likely to have

inadequate mammographic screening than white women (RR 1.2, 95% CI 1.2-1.2) [12] . This discrepancy

was even more striking among women diagnosed with breast cancer (RR 1.6, 1.5-1.8). African American

women were more likely to have large, advanced-stage, high-grade, and lymph node positive breast

tumors. Differences in size, stage, and lymph-node positivity (though not grade) were no longer

significant when African-American and white women with the same screening history were compared.

Differences in the incidence of breast cancer, available medical resources, and health priorities in

different populations and geographic areas may influence policies regarding population screening [13-16]

.

RISK FACTORS — The major risk and protective factors for the development of breast cancer are listed

in the table (show table 1).

Major risk factors for breast cancer in women are age, genetic predisposition and estrogen exposure. A

detailed discussion of the risk factors for breast cancer is presented elsewhere. (See "Epidemiology and

risk factors for breast cancer"). Combined effects of several different risk factors can be calculated (See

"Risk prediction for breast cancer screening").

Age/Gender — Age and gender are among the strongest risk factors for breast cancer. Breast cancer

occurs 100 times more frequently in women than in men. In the US, there are an estimated 182,460

invasive breast cancers diagnosed annually among women versus 1900 in men [2] . (See "Male breast

cancer").

Increasing age is the primary risk factor for breast cancer in most women (show table 2). Approximately

85 percent of breast cancers occur after women reach 50 years of age. Even in older age groups, many

women must be screened in order to identify a single cancer (show table 3).

Genetic predisposition — On average, a positive family history of breast cancer confers a modest

increased risk (RR 2.6). However, multiple first-degree relatives with premenopausal breast cancer

confers a lifetime risk of breast cancer as high as 50 percent. Much of this risk is associated with a genetic

defect in BRCA1 or BRCA2 [17,18] . (See "Genetic testing for breast and ovarian cancer").

Estrogen exposure — Aside from age and genetics, most other risk factors for breast cancer are likely

related to increased exposure to estrogen (show table 1) [19] . Risk factors include a breast biopsy

showing atypical hyperplasia (RR 3.7), increased breast density (RR 1.8 to 6.0), and increased bone

density (RR 2.7 to 3.5) [20] . (See "Postmenopausal hormone therapy and the risk of breast cancer").



Hormone therapy with estrogen plus progestin, as studied in the Women's Health Initiative (WHI) over a

5.2 year period, was associated with increased breast cancer, compared to placebo (HR 1.24, 95% CI

1.02-1.50) [21] . The increased risk for breast cancer continued for at least three years after the trial [22] .

On the other hand, the Women's Health Initiative Estrogen-Alone trial demonstrated that unopposed

conjugated estrogen in women with prior hysterectomy, compared to placebo, did not increase the

incidence of breast cancer (HR 0.80, 0.62-1.04) [23] . However, the use of estrogen alone did increase thefrequency of abnormal mammograms requiring short-term follow-up (9.2 percent compared to 5.5 percent

for the placebo group).

Breast cancer risk prediction tools — Several breast cancer risk prediction tools have been developed that

combine major risk factors. The purpose of the models is to stratify women into risk categories that can

be used to determine optimal screening strategies and indications for possible prophylactic therapies. (see

"Risk prediction for breast cancer screening")

The most widely used tool to calculate breast cancer risk is the Breast Cancer Risk Assessment Tool

(BCRAT), sometimes called the Gail Model after Dr. Mitchell Gail, its developer at the National Cancer

Institute [24,25] . The Gail Model tool, applicable to all women, taking into account race and ethnicity, isavailable online at www.cancer.gov/bcrisktool/.

Cancer risk assessment tools can be helpful in clarifying the risk group a patient is in. However, their

accuracy for predicting whether an individual woman will develop cancer is modest, partly because not

all important risks have been identified and partly because accurate stratification requires strong risk

factors and most risk factors for breast cancer are relatively small.

Genetic profiling — The future potential exists to use genetic profiling to stratify women for breast cancer

screening programs according to genetic risk [26] . Several breast cancer susceptibility loci have been

found. Although in isolation they confer far lower risk than BRCA mutations, in combination they could

identify subgroups of women at moderate to high risk. As more such alleles are identified, the precisionof risk estimates will improve. The strategy to implement genetic risk assessment to determine age to

initiate screening, screening frequency, and type of screening remains theoretical at this time.

IMAGING STUDIES — A variety of imaging modalities have been developed for identifying lesions

that are suspicious for breast cancer. Mammography remains the mainstay of screening for breast cancer.

UItrasonography is commonly used for diagnostic follow-up of an abnormality seen on screening

mammography, to clarify features of a potential lesion. The role of magnetic resonance imaging (MRI)

for breast cancer screening is emerging; currently MRI screening is targeted to high risk patients. Newer

tests, such as tomography, are under evaluation [27] .

Imaging studies cannot establish a diagnosis of cancer. Rather, they identify patients with abnormal

findings who must then be further evaluated, either with follow-up imaging or biopsy. The diagnosis of

cancer is dependent on obtaining a tissue sample.

Mammography — Features of mammography, including test performance characteristics, and

interpretation of mammogram reports, are discussed in greater detail separately (see "Breast imaging:

Mammography and ultrasonography").



Film mammography — Film mammography can clearly detect asymptomatic early stage breast cancer.

US surveillance data from 1996 to 2001 (n = 1,664,032) found that breast biopsy was performed within

one year of screening mammography in 1.6 percent of women [28] . Overall, breast cancer was diagnosed

within one year of screening in 8815 women (0.53 percent); 78 percent of the invasive breast cancers

were lymph node negative.

The clinically important question, however, is whether screening with mammography decreases breast

cancer mortality. Nine randomized controlled trials, including more than 650,000 women, have been

conducted and reported mortality data. All used mammography with or without clinical breast

examination [29] . Results of all trials showed a protective effect occurring relatively quickly among

women ages 50 and older. A meta-analysis found a significant 34 percent reduction in breast cancer

mortality by seven years of follow-up [30] . As more time passed, studies found decreased mortality in

women screened in their 40s. A systematic review of screening mammography including studies of fair

quality or better concluded that, after 14 years of follow-up, the summary relative risk for breast cancer

mortality was 0.78 (95% CI 0.70-0.87) for women 50 years of age and older, and 0.85 (0.73-0.99) for

women 40 to 49 years of age [31] . Other analyses have also concluded that screening with

mammography decreases breast cancer mortality in women ages 40 to 69 [32-37] .

Strong evidence for an effective screening test is demonstrated by randomized trials of a decrease in all-

cause, as well as disease-specific, mortality. All-cause mortality is rarely documented because the

required sample size for such a study is so large. Breast cancer screening was associated with reduced all-

cause mortality in an analysis of four randomized studies in Sweden. The four trials followed 247,010

women for a median of 15.8 years; age-adjusted relative risk for total mortality was 0.98 (95% CI 0.96-

1.00) [32] .

It is unclear whether the results of careful randomized controlled trials are replicated in the community

setting. One case-control study of women in six community health plans did not show a statistical

difference in screening rates (clinical breast exam and mammography) for women who died of breastcancer compared with control patients matched for age and breast cancer risk, although there was a trend

towards screening benefit among higher risk women [38] . However, the authors pointed out that study

limitations make it difficult to draw firm conclusions from this report. Another study using statistical

modeling suggested that the decrease in breast cancer mortality due to screening is more modest than that

found in the trials [11] .

Full-field digital mammography — Full-field digital mammography is similar to traditional film-screen

mammography except that the image is captured by an electronic detector and stored on computer [39] .

Several studies have found little difference in cancer detection rates between digital and film

mammography [40-44] . The largest study, DMIST, found that while the overall diagnostic accuracy of

film and digital mammography was similar, digital mammography was more accurate for premenopausaland perimenopausal women, and for women with dense breasts [45] . (See "Breast imaging:

Mammography and ultrasonography").

In general, film mammography remains an acceptable screening modality for all women. Digital

mammography, when available, may offer a small screening advantage in women younger than 50 years

old.



Computer-aided detection — Computer-aided detection (CAD) refers to computer-based technology

designed to recognize mammographic patterns and help radiologists identify suspicious areas. CAD

reading of digitalized mammograms places marks in areas of concern, often calcifications, for special

attention in review by the radiologist; on average, four marks are placed per mammogram.

CAD slightly increases sensitivity for breast cancer but also increases recall rate. This is discussed in

more detail separately. (see "Breast imaging: Mammography and ultrasonography").

Frequency of mammography — Data are limited on the optimal frequency for performing mammography.

Randomized trials evaluating the effectiveness of mammogram screening have used varying time

intervals, without apparent effect on study results. An observational study comparing mammogram

screening annually or every two years for predominantly Caucasian women aged 50 to 69 years in

Vermont, US (annual) and Norway (biennial) found no significant difference in breast cancer detection

rate or prognostic stage [46] .

Breast cancers on average grow more slowly in older women than younger women. Longer intervals

between screening may be reasonable for women over 50, with annual to biannual screening in younger

women when screening women in this age group (see "Frequency" below).

Magnetic resonance imaging — Magnetic resonance imaging (MRI) requires injection of intravenous

contrast material and costs more than mammography in the US (2006 US Medicare fee reimbursement is

$965.57 for bilateral MRI versus $49.76 for bilateral mammography [47] ). No studies of the effect of

screening breast MRI on breast cancer mortality have been published.

A systematic review of 11 studies comparing test performance of screening MRI to mammography in

high-risk women found the following [48] : The mean or median age of women in the studies ranged from

40 to 47 years. The women were at very high risk of breast cancer, with a prevalence of disease of 2

percent (about 13 times the overall prevalence of approximately 0.15 percent in women of similar age).

Sensitivity of MRI was significantly better than that of mammography (0.77, 95% CI 0.70-0.84 versus

0.39, 0.37-0.41). Specificity of MRI was worse than that of mammography (0.86, 95% CI 0.81-0.92

versus 0.95, 0.93-0.97). Sensitivity of MRI and mammography together was 0.94 (95% CI 0.90-0.97) and

specificity was 0.77 (0.75-0.80).

The combination of MRI and mammography is recommended by the American Cancer Society in women

at very high risk of breast cancer (≥ 20 to 25 percent lifetime risk), as defined by risk prediction models

based primarily on family history [49] . The cancer mortality risk in this population is assumed to be high

enough to justify the increased cost and numbers of follow-up procedures that would be generated

because of low specificity (see "Germline predisposition (BRCA1 or BRCA2)" below).

The lack of evidence of mortality benefit, relatively low specificity and the high cost of MRI becomemore worrisome when there is a lower risk of breast cancer, because fewer women will benefit and more

women will experience adverse effects. The 2007 guidelines from the American Cancer Society explicitly

recommend against MRI screening in women with less than a 15 percent lifetime risk [49] . For women

with lifetime risks of breast cancer greater than 15 percent but less than those at very high risk,

recommendations for screening breast MRI are less clear.



The use of MRI for evaluating known breast masses or abnormalities detected on mammography is

discussed separately. (See "Diagnostic evaluation of women with suspected breast cancer", section on

Breast MRI).

BREAST PALPATION

Clinical breast examination — Because several randomized trials included both mammography and

clinical examination, the extent of independent contribution of these methods is not clear. In these studies,

mammography detected approximately 90 percent of screen-detected cancers and clinical breast

examination approximately 50 percent. There is some but not total overlap.

Only one study compared the effects of careful clinical breast examination (CBE) alone with CBE plus

mammography on subsequent breast cancer mortality in women in their 50s [50,51] . After 13 years of

follow-up, breast cancer mortality was the same in both groups [51] . The CBE used was standardized and

took an average of 10 minutes, far different than typical clinical practice. A review of controlled trials and

case-control studies in which CBE was at least part of the screening modality estimated CBE sensitivity

to be 54 percent and specificity 94 percent [52] . It was concluded that the available indirect evidence

supports the effectiveness of CBE for breast cancer screening. A subsequent study found that CBE plus

mammography (with CBE performed by trained nurses) had greater sensitivity than mammography alone,

but a higher false positive rate (12.5 versus 7.4 percent) [53] . Among 10,000 women screened with CBE

and mammography, for each additional cancer detected by CBE there were 55 additional false positive

screens.

A key factor is the quality of each examination: mammography is better standardized than CBE. The

preferred technique for CBE includes: proper patient positioning (to flatten the breast tissue against the

chest); examining in vertical strips beginning in the axilla and extending in a straight line down the

midaxillary line to the bra line, with the fingers then moving medially and continuing up and down

between the clavicle and the bra line; making circular motions with the pads of the middle three fingersand examining each breast area with three different pressures; examining each breast for at least three

minutes [52] .

CBE sensitivity in community practice appears to be substantially lower than that reported in randomized

trials. The National Breast and Cervical Cancer Early Detection Program, which studied the value of CBE

in the community setting where procedural guidelines for performing the examination were not dictated,

found that CBE still detected about 5 percent of cancers that were not visible on mammography [54] .

Despite good specificity in women without symptoms (96.2 percent), the sensitivity was low (36.1

percent). In another community-based study, the specificity of screening CBE in average risk women was

even higher (99.4 percent), suggesting a lower sensitivity; specificity was slightly lower in women at

increased risk (97.1 percent) and for diagnostic, rather than screening, examinations [55] .

These studies suggest that CBE may modestly improve early detection of breast cancer, but at potential

significant expense when performed as an adjunct to mammography. CBE alone may be a reasonably cost

effective screening strategy, however, in developing countries where the relative cost of mammography is

prohibitive for population screening [56] .



Breast self-examination — There are few randomized trials of breast-self examination [57] . One study

performed in China randomly assigned 266,064 women to a breast self-examination instruction group or a

control group [58] . The instruction group received initial instruction in breast self-examination,

reinforcement sessions one and three years later, supervised self-examination every six months for five

years, and ongoing reminders. Over ten years, there was no difference between the two groups in breast

cancer deaths. More benign breast lesions were diagnosed in the self-examination group.

A review of eight other studies also failed to show a benefit of regular breast self-examination in rates of

breast cancer diagnosis, breast cancer death, or tumor stage or size [59] . In addition, several studies

found the rate of breast biopsy for benign disease was significantly higher among women taught breast

self-examination [60] .

The results of two case-control studies suggest that technique is important in breast self-examination: A

nested case-control study comparing Canadian women who died of breast cancer or had metastatic

disease with control women found increased risk for death or metastatic disease (OR 2.20, 95% CI 1.30-

3.71) in women who did not perform technically correct breast self-examination [61] . A case-control

study showed no overall effect of breast self-examination on detecting breast cancer at an earlier stage[62] . The small number of women, however, reporting more thorough examinations had about a 35

percent decrease in advanced-stage breast cancer compared with women not performing breast self-

examination.

PATIENT AGE — Randomized trials have shown that the sensitivity of mammography and clinical

breast examination is higher in older, compared to younger, women [29] . It has been estimated that

mammography detects about 75 percent of breast cancers in women in their 40s and 90 percent of breast

cancers in women in their 50s and 60s [63] . A large prospective cohort study of 329,495 women

confirmed that while controlling for breast density and postmenopausal hormone therapy use (HT),

sensitivity and specificity of mammography were higher in women aged 80 to 89 years (83.3 and 94.4

percent, respectively) than in women aged 40 to 44 years (68.6 and 91.4 percent) [64] .

Women in their 40s — The benefits of screening are lower for women in their 40s because of both

decreased incidence of breast cancer and sensitivity of mammography in younger women [65] .

Additionally, compared to older women, younger women have faster growing cancers for which

mammographic screening would not be as beneficial [66] . A rapidly growing tumor may be too small to

detect at one screening, but already progressed to advanced stage by the subsequent screening. In one

study, interval cancers, compared to cancers detected by routine screening mammogram, were more likely

to have greater than 20 percent proliferating cells (OR 4.09) [67] . In addition, the odds ratio for

mammographic failure was 2.96 among cancers that expressed p53 (a marker of more aggressive biology)

compared with cancers that did not. Younger women had a higher proportion of rapidly growing, more

aggressive cancers.

Nonetheless, as the period of follow-up has lengthened, meta-analyses have demonstrated significant

protection in women who began screening in their 40s [32] . The review conducted by the USPSTF found

a 15 percent decrease in breast cancer mortality (RR 0.85, 95% CI 0.73-0.99) after 14 years of

observation among women younger than 50 [31] . Benefits must be weighed against the risks of

screening, including significant false positive rates and potential overdiagnosis for women found to have

DCIS (see "Overdiagnosis" below and see "Ductal carcinoma in situ" below).



The Age trial in the United Kingdom evaluated the effect on mortality of a screening intervention in

which randomly assigned women at age 40 (n = 161,000) were invited for breast cancer screening (a two-

view initial mammogram and annual single-view follow-up), compared with a control group that received

usual care [68] . Breast cancer mortality in the intervention group was decreased, though not significantly

(RR 0.83, 95% CI 0.66-1.04) at a mean follow-up of 10.7 years. Risk reduction for breast cancer

mortality was greater, though still not statistically significant, when only those women who actuallyattended the first screening were compared to the control group (RR 0.76, 95% CI 0.51-1.01). Previous

trials of screening women in their 40s for breast cancer had included women who were up to age 49 years

at the time of trial entry, and therefore in their 50s during the screening intervention; the Age trial was the

first study to assess the effectiveness of screening restricted to women who had not yet passed age 50

years. A meta-analysis combining the Age trial data with other randomized trials of mammogram

screening in women under age 50 years suggests that screening starting at age 40 could reduce breast

cancer mortality by 16 percent (RR 0.84, 95% CI 0.69-1.01).

Another useful way to interpret the available data on screening mammography in younger women is to

look at the numbers needed to screen (NNS) to prevent one woman from dying of breast cancer.

Published estimates vary somewhat according to the calculated relative risk, the baseline risk in thecontrol group, and the length of follow-up. The US Preventive Services Task Force (USPSTF) estimated

that 1792 women ages 40 to 50 (credible interval 764 to 10,540 women) would need to be screened to

prevent one death from breast cancer after 14 years of observation [31] . Another estimate, based on the

results from eight available randomized trials, is that 1500 to 2500 women in their 40s would need to be

screened regularly for a minimum of 10 years to prevent one breast cancer death [66] . In a hypothetical

cohort of 10,000 40-year-old women, 160 would develop breast cancer over 10 years and about 30 would

die from the disease over 15 years. Based upon the NNS cited above, annual screening for 10 years would

prevent four to six deaths from breast cancer in this cohort [66] . However, over one-half of the cohort

would have at least one abnormal mammogram and need further investigation during the screening

period.

The cost-effectiveness of screening mammography for women in their 40s has added to the controversy

and difficulty of determining guidelines for this age group. One study, as an example, used a Markov

model to compare the life expectancy of women undergoing different breast cancer screening strategies

[69] . The cost-effectiveness ratios were $21,400 per year of life saved for women 50 to 69 years of age

and $105,000 for women in their 40s. Thus, the cost of screening mammography in women in their 40s

was almost five times that of older women, although both are within a generally accepted range for cost-

effectiveness.

Older women — Screening mammography may be less beneficial in women aged 70 and older. A shorterlife expectancy decreases the potential for screening to prolong life. Screening mammography in older

women may result in lower stage cancer at diagnosis, but the effect on mortality is unclear [70-72] . In

addition, the incidence of ductal carcinoma in situ (DCIS) increases with age and it is not clear that

treatment of DCIS affects mortality (see "Ductal carcinoma in situ" below).

Data from randomized controlled trials in women older than 70 years are limited. Two case-control

studies of the same population in Holland, but done slightly differently, found that screening women aged



65 to 74 decreased breast cancer mortality 55 percent (RR 0.45, 95% CI 0.20-1.02) or 66 percent (RR

0.34, 0.12-1.41); there was no protective effect beyond age 75 [73,74] . A cohort study of 2,011 women

80 years and older found no difference in breast cancer rate, stage, or death comparing women who did

and did not undergo mammography after age 80; 11 percent of the 1,034 older women who underwent

mammography screening had a false positive result [75] .

A decision and cost-effectiveness analysis modeled three strategies in women over the age of 65: biennial

mammography to 69 years; biennial mammography to 79 years; and determination of distal radial bone

mineral density (BMD) at the age of 65 to decide need for ongoing screening after age 69 [76] . The

inclusion of BMD data was based upon the increased risk of breast cancer among women with high BMD

(see "Risk factors" above). To prevent one death, the analysis found that 1064 women with high BMD

would need to be screened routinely from age 69 to 79 years, compared with 7143 women with low

BMD. Screening was cost-effective only in women with higher BMD. These results do not suggest that

all women should have BMD screening at age 65; this decision should be based upon a number of factors.

However, in older women who have had BMD measured for other purposes, it is reasonable to use this

information to assist in the decision to undergo screening. (See "Screening for osteoporosis")

A systematic review of cost-effectiveness analyses for the USPSTF concluded that extending biennial

mammography screening to age 75 or 80 was estimated to cost $34,000 to $88,000 per life-year gained

compared with stopping screening at age 65, and it was particularly likely to be cost-effective in women

who were healthy [77] .

One group presented a framework for guiding decision making in screening elderly women for various

cancers that included life expectancy, risk of dying of cancer, and the number needed to screen over the

remaining lifetime to prevent cancer death (show table 4) [78] . As an example, 240 healthy 80-year-old

women would need to have regular mammography screening to prevent one breast cancer-related death,compared with 642 70-year-old women with multiple medical problems and a life expectancy that is

below the norm for that age group. Thus, age should not be the sole determining factor in determining

indications for screening. Ideally, such decision-making should incorporate individual estimates of risk

and benefit, and take into account patient preferences; decision aids are being investigated that may

provide support for informed decision-making regarding screening mammography [79] .

We suggest that breast cancer screening with mammography be continued as long as a woman has a life

expectancy of at least 10 years. In addition, the breast becomes easier to examine as a woman ages, with

replacement of glandular tissue by fat. It is therefore likely that careful clinical breast examinations would

be particularly useful in older women, although a study to confirm this hypothesis has not yet been

conducted.

FAMILY HISTORY OF BREAST CANCER — Women with a known genetic predisposition to breast

cancer (ie, BRCA-1 or BRCA-2) should receive counseling for several preventive options, as well as

more intensive screening for breast cancer. (See "Germline predisposition (BRCA1 or BRCA2)" below

and see "Options for women with a genetic predisposition to breast and ovarian cancer").



For women without a known genetic syndrome, but who have a history of breast cancer in a first-degree

relative, it has been suggested that screening mammography be initiated at an earlier age, particularly if

the family member had premenopausal breast cancer. One study compared the performance of

mammography in almost 390,000 women ages 30 to 69 years with and without a family history of breast

cancer [80] . More cancers were detected in women with a family history of breast cancer than in those

without (RR 3.2 versus 1.6 for ages 30 to 39 years, 4.7 versus 2.7 for ages 40 to 49, 6.6 versus 4.6 forages 50 to 59, and 9.3 versus 6.9 for ages 60 to 69 years).

There are no data from randomized controlled trials on the efficacy of mammography in reducing

mortality in younger women with a family history of breast cancer; a case control study showed a non-

statistical trend towards greater protection among women in their 40s at increased risk, but no trend

among older women [38] .

Alternative or adjunctive screening modalities for younger women at increased risk for breast cancer,

including magnetic resonance imaging and ultrasound, may improve screening sensitivity [49,81-83] (See

"Germline predisposition (BRCA1 or BRCA2)" below and see "Options for women with a genetic

predisposition to breast and ovarian cancer").

GERMLINE PREDISPOSITION (BRCA1 OR BRCA2) — Although a family history of breast cancer is

common in women who develop breast cancer, only 5 to 6 percent of all breast cancers are associated

with germline (inherited) genetic mutations. The majority of these involve two genes, BRCA1 and

BRCA2, and testing for mutations in these genes is commercially available. (See "Genetic testing for

breast and ovarian cancer").

Women who test positive for BRCA1 or BRCA2 mutations are at increased risk of both breast and

ovarian cancer. Such women should be referred for appropriate counseling, to consider options for

reducing risk and intensified surveillance. (See "Options for women with a genetic predisposition to

breast and ovarian cancer")

For women with an inherited predisposition, guidelines from major groups (including the National

Comprehensive Cancer Network (NCCN) [84] and the American Cancer Society [49] ) recommend a

combination of annual mammography and breast MRI for breast cancer surveillance in women who are

BRCA mutation carriers.

There is no clear evidence regarding the optimal frequency of breast imaging screening for asymptomatic

BRCA carriers. The following screening strategy has been recommended by expert groups for women

with BRCA1 or BRCA2 mutations who have not undergone risk-reducing surgery [84] : Monthly breast

self-examination (BSE) beginning at age 18 Clinical breast examination two to four times annually

beginning at age 25 Annual mammography and breast MRI screening beginning at age 25 or

individualized based on the earliest age of onset in the family.

The efficacy of early and increased surveillance (mammography, breast MRI, clinical breast examination,

and breast self-examination screening for breast cancer) in these women in terms of mortality reduction is

not known. The rationale for recommending unproven increased surveillance is the high risk of

developing breast cancer.



Screening with mammography — The sensitivity of mammography for detecting breast cancer in

mutation carriers appears to be lower than in other high-risk women [85-88] . The low sensitivity of

mammography in women with BRCA mutations may be due to higher breast density [88] or differences

in morphologic features (eg, less spiculation due to lack of tumor-surrounding fibrosis) [87] .

As many as 57 percent of women undergoing prophylactic mastectomy because of a strong family history

of breast cancer have high-risk histopathology in their mastectomy specimens, many of which (eg,

atypical lobular or ductal hyperplasia, lobular carcinoma in situ) are not detectable mammographically

[89,90] .

One analysis of women with deleterious BRCA mutations found that among 165 women with breast

tissue who opted for breast cancer screening, 12 were diagnosed with breast cancer over a two-year

period [85] . One-half of these were interval cancers not detected by annual mammography; most were

detected by BSE.

Because of the frequent development of interval malignancies, more frequent mammography (eg, every

six months) is sometimes considered [85,91,92] . However, there are no known studies that compare

semi-annual versus annual screening and thus no data to develop evidence-based recommendations [59] .

Screening with MRI — Screening with MRI may be particularly useful for young women (particularly

those with dense breasts) with an inherited risk of breast cancer, in whom mammographic sensitivity is

limited. MRI has been found to be more sensitive but less specific than mammography for the detection

of invasive cancers in high-risk women in both retrospective [87,93-95] and prospective [82,96-99]

studies and in a systematic review [48] .

The following illustrates the range of findings: In the largest prospective study, 1909 Dutch women with

an estimated breast cancer risk of >15 percent (358 proven BRCA mutation carriers) underwent CBEevery six months and yearly mammography and MRI [96] . Breast cancers developed in 51 women; one

tumor was found only on clinical exam, and four were interval cancers. MRI had higher sensitivity than

mammography for all cancers (71.1 versus 40.0 percent) and for invasive cancers (79.5 versus 33.3

percent), but lower specificity (89.8 versus 95.0 percent). MRI was less sensitive than mammography for

detecting ductal carcinoma in situ (17 versus 83 percent). In a study of 236 Canadian women with

BRCA1 or BRCA2 mutations who underwent twice yearly clinical breast examination (CBE) and yearly

screening with mammography, MRI, and ultrasound, the sensitivity of MRI was higher than

mammography and ultrasound (77 versus 36 and 33 percent) [94] . Sensitivity of combined

mammography and MRI was 86 percent. The benefits of screening with a combination of MRI and

mammography was shown in a United Kingdom study of 639 women (ages 35 to 49) with a strong family

history of breast cancer or a high likelihood of BRCA1, BRCA2, or p53 mutation [98] . MRI was more

sensitive than mammography (77 versus 40 percent) but less specific (81 versus 93 percent). The

combination of MRI and mammography had a sensitivity of 94 percent and specificity of 77 percent.

The lower specificity of MRI is a concern, since this could lead to increased numbers of follow-up

procedures: In the Dutch study, MRI led to more additional examinations than mammography (420 versus

207) and more unneeded biopsies (24 versus 7) [96] . In the UK study, MRI led to more women



undergoing additional assessments than mammography (10.7 versus 3.9 percent per year) [100] .

However, in the Canadian study, biopsy rates were only slightly lower for MRI than mammography (95.4

versus 99.8 percent) [94] . Furthermore, while 24 percent of patients underwent further testing after a

false-positive first MRI screen; this dropped to 10 percent after the third screen. The corresponding

numbers for mammography were 0.4 and 0.0 percent, respectively.

In addition to the need for additional examinations and biopsies to evaluate false-positive findings,

additional negative features of breast MRI are its cost and the unknown influence that the enhanced

detection rates from breast MRI will have on survival in populations of high-risk women. Randomized

trials are needed to assess whether screening high-risk women with MRI improves survival rates.

Age to initiate screening — The age at which mammographic screening should commence in high-risk

populations is unclear.

While the risk of radiation-associated breast cancer from breast imaging for average risk women is

thought to be small to nonexistent [101] , women at high genetic risk may be more susceptible to

radiation-induced carcinogenesis because of the role of BRCA proteins in DNA repair. (See "Genetic

testing for breast and ovarian cancer", section on Normal function of BRCA genes).

However, the available data are conflicting regarding the impact of x-ray exposure on the incidence of

breast cancer [102-105] . It has also been projected that radiation harms associated with annual

mammography started at age 25 for average risk women may exceed benefits, although this model did not

address relative harms and benefits in higher risk individuals [106] . Despite uncertainty, the risks of

radiation exposure should be considered when counseling young BRCA mutation carriers about the

appropriate age at which to begin screening. (See "Radiation" below).

We advise that mutation carriers begin annual mammography, as well as MRI in alternate 6 months, at

age 25, as in the NCCN guidelines [84] . This recommendation may be modified based upon individual

factors (eg, breast density). It remains unclear whether the age at initiation of screening should be altered

based on a pattern of late-onset cancers within the family, or patient concerns about the risks associated

with radiation exposure.

OTHER VARIABLES AFFECTING SCREENING ACCURACY — A number of factors, in addition to

age and genetic or family risk, influence screening test performance characteristics:

Radiologist — The ability to accurately interpret mammograms differs among individual radiologists.

Studies conflict on whether accuracy is greater for radiologists who interpret a high volume of

mammograms [107-110] .

Radiologist experience does appear to be associated with interpretation of mammography. A study of theactual performance of 124 radiologists in interpreting 469,512 screening mammograms found that less

experienced radiologists had higher sensitivity for breast cancer but also higher recall rates and lower

specificity [110] . The effect of experience in this study was to shift the threshold for calling a

mammogram positive rather than on the actual ability to detect cancer.



Availability of prior studies — Comparing a mammogram to one taken previously, especially one taken a

year previously, improves specificity [111] .

Body habitus — Mammography may have lower sensitivity in thin women. In a multivariate analysis

from a 12-month prospective study of 122,355 women ages 50 to 64, mammography had a lower

sensitivity in women with a body mass index below 25 (86 versus 91 percent) [112] .

Ethnicity — Ethnicity does not appear to affect the accuracy of mammography. The sensitivity of

mammography was the same comparing cancer detection rates within a year of screening mammograms

performed in white, Chinese, and Filipino women (81.6 to 84.3 percent) [113] . Similarly, mammography

accuracy was equivalent in white and black women undergoing screening [114] .

Breast density — Reduced sensitivity of mammography in younger women is in part related to increased

mammographic density, determined by a higher proportion of breast epithelial and stromal elements in

younger breasts [115,116] . The impact of breast density on mammogram interpretation is discussed in

more detail separately (see "Breast imaging: Mammography and ultrasonography").

Digital mammography is more sensitive than film mammography for dense breasts [43] and may bepreferred, when available, for women with increased breast density. The role of ultrasound or MRI

screening, as an adjunct to mammography, is uncertain, as there have been no randomized controlled

trials evaluating the impact of these modalities on mortality or stage of diagnosed breast cancer in women

with dense breasts [117] .

Menstruating women have variable breast density during different phases of the menstrual cycle

[118,119] . Breast density is increased in the luteal compared with follicular phase, suggesting that

mammographic sensitivity can be improved by obtaining mammograms during the first and second week

after menstruation begins, particularly for women who have used oral contraceptives at some time

[118,119] .

The BI-RADS guidelines for mammogram interpretation recommend that breast density be reported in a

sentence in every mammogram report [120] . The inter-observer reproducibility of BI-RADS breast

density reports is only moderate, however [121] . (See "Breast imaging: Mammography and

ultrasonography").

Postmenopausal hormone therapy — The normal involution of breast tissue with age appears to be

inhibited by postmenopausal hormone therapy (HT), which increases breast density and may decrease the

sensitivity of mammography [122,123] . (See "Postmenopausal hormone therapy and the risk of breast

cancer", section on Mammographic density).

A large prospective cohort study of 329,495 women found that HT prevented the usual improvement inmammographic accuracy with increasing age, and that this effect was mediated through increases in

breast density [64] . Data from a subset of the Women's Health Initiative (WHI) trial show that among

413 postmenopausal women who were randomly assigned to combination estrogen/progesterone therapy

or placebo, mammogram density increased 6 percent at year one in the treatment group, compared to a

0.91 percent decrease in the placebo group [124] . Although breast density may not similarly increase

with estrogen therapy alone [123] , a reduction in mammographic sensitivity and a slight reduction in



specificity has been seen in women taking preparations of either combination estrogen/progesterone or

estrogen alone [112] .

In the WHI trial, in addition to a higher rate of breast cancer, women on combination postmenopausal

hormone therapy (HT) had a significantly higher rate of at least one abnormal mammogram (31.5 versus

21.2 percent on placebo) [21] . The risk of having an abnormal mammogram at year one was four times

greater in the HT group compared to the control group [124] . (See "Postmenopausal hormone therapy

and the risk of breast cancer", section on Women's Health Initiative).

In another large cohort study, both combination HT and estrogen therapy alone increased the risk of recall

after mammography in women who subsequently were found not to have breast cancer (false-positive

recall) [125] .

Breast surgery — Breast augmentation surgery may reduce the sensitivity of screening mammography. A

prospective cohort study found that mammogram sensitivity was lower in asymptomatic women with

breast implants than in women without implants (45 versus 67 percent); specificity was slightly higher inwomen with implants [126] .

Other breast surgery may also affect the sensitivity and specificity of mammography. In a study that did

not distinguish between removal of benign breast lumps and other benign breast surgery, mammography

in women with a history of such surgery had lower sensitivity and slightly lower specificity [112] .

HARMS FROM SCREENING — Apart from any risks of the screening procedure itself, screening for

breast cancer can cause harm when false-positive results occur.

Additionally, women may suffer harm if breast cancer is overdiagnosed. Overdiagnosis refers to the

diagnosis of conditions that would not have become clinically significant, if not detected by screening.Overdiagnosis leads to unnecessary testing and treatment, and psychological and other consequences of

being diagnosed with and treated for cancer.

Women should understand the possibility of both benefits and harms from screening, as summarized in

figures (show figure 1A-1B).

False-positive tests — Although both sensitivity and specificity of the tests are important, patients and

clinicians are often most concerned by false-positive readings. The clinical consequence of this error is

recommendation for additional tests and procedures in a woman who does not have cancer. In the United

States, for example, 11 percent of mammograms require additional evaluation; the lesion turns out to be

benign in more than 90 percent of cases [127] .

False-positive readings are more common in younger women, both because the tests are less specific and

because breast cancer is less common [128,129] . As a result, more follow-up procedures, including

invasive procedures such as biopsies, will be done in younger women even though fewer cancers will be

found. Furthermore, because breast cancer screening occurs repeatedly, the risk of a false-positive study

is likely to rise with repeated screening [130] .



These points were illustrated in a 10-year retrospective cohort study of 2400 women who were 40 to 69

years of age at study entry [131] . A median of four mammograms and five clinical breast examinations

were performed per woman over the course of the study; 23.8 percent had at least one false-positive

mammogram, 13.4 percent had at least one false-positive breast examination, and 31.7 percent had at

least one false-positive result for either test. The estimated cumulative risk of a false-positive result was

49.1 percent after 10 mammograms and 22.3 percent after 10 clinical breast examinations. In anotherstudy, 10-year estimates of the percentage of women who would experience a false-positive mammogram

reading ranged from 41 to 45 percent for women in their 50s and from 31 to 36 percent for women in

their 60s [132] .

The cumulative risk of a false-positive mammogram varied substantially according to both patient and

radiology-related factors [133] . The risk of a false-positive study at the first, and by the ninth screening

mammogram, was 98 and 100 percent in those women with the highest risk variables (young age, prior

breast biopsies, a family history of breast cancer, current estrogen use, three years between screenings, no

comparison to prior mammograms, and the tendency of the radiologist to call mammograms abnormal

[radiologist's random effect]). In contrast, those with the lowest risk variables had estimated risks of 0.7

and 4.6 percent for the first and ninth mammogram, respectively. The authors postulated that if womenunderstood their relative risk of a false-positive study based on these factors, their anxiety might be less

when an abnormal mammogram was reported.

Similar concerns apply to elderly women and possibly women taking estrogen therapy: In a study of

23,000 women over the age of 65 undergoing one time screening mammography, 8 percent had an

abnormal result that required additional evaluation [134] . However, even in this group of women who

were at high risk for breast cancer because of age, the majority with abnormal results (92 percent of those

ages 65 to 69 and 86 percent age 70 or older) did not have cancer. Hormone therapy increases the density

of breast tissue, limiting the diagnostic utility of mammography [122] . In one report, stopping estrogen

for 10 to 30 days resulted in resolution of mammographic abnormalities in 35 of 47 women (74 percent)

[135] .

Practice variation may contribute to the rate of false-positive mammograms [136] . As an example, a

study that compared results from large screening programs in the United States and the United Kingdom

found that the rate of recommendations for further evaluation after a mammogram was twice as high in

the United States as in the United Kingdom, but cancer detection rates were similar [132] . These data

suggest that it may be possible to reduce the rate of false-positive mammography results in the United

States without significantly increasing the rate of false-negative results.

Women have heightened anxiety about breast cancer and mammography for several months after a false-

positive reading [137,138] . One study evaluated 68 women with high-suspicion abnormal mammograms

but negative subsequent work-ups: 47 percent reported substantial mammography-related anxiety and 41percent worried about breast cancer three months later [139] . A meta-analysis found that anxiety,

following a false-positive mammogram, was specific to breast cancer and mammography, and did not

lead to a generalized anxiety disorder [138] . Anxiety associated with false-positive readings can be

decreased by the immediate reading of screening mammograms, which allows for additional

mammographic views or ultrasound to be performed during the same appointment [140] .



The impact of a false positive mammogram on future screening behavior has been reported as variable. In

a meta-analysis, women in the US were more likely to have routine screening following a false positive

screen, while there was no effect on European women and Canadian women were less likely to return for

routine screening [138] . Having a false-positive mammogram result may to lead to increased utilization

of health care services [141] , though further studies regarding the effects on trust and utilization are

indicated [138] .

Overdiagnosis — Some cancers are slow-growing, and some even regress. Overdiagnosis refers to

disease that is detected by screening that would not have caused morbidity or mortality if it had not been

found. (See "Evidence-based approach to prevention").

Ductal carcinoma in situ — As breast cancer screening has increased, the detection of ductal carcinoma in

situ (DCIS) has risen dramatically, more than threefold in the 10-year period of 1983 to 1992 [142] .

DCIS now accounts for approximately 21 percent of all new breast cancers diagnosed in the US, over 90

percent of which are detected only on imaging studies (most commonly by the presence of

microcalcifications) [143] .

Concerns have been raised that detection of DCIS by mammography may lead to overdiagnosis of breast

cancer, especially because it appears difficult to diagnose DCIS pathologically. In one report, six

experienced pathologists were asked to interpret 24 slides; among the 10 slides in which at least one

pathologist diagnosed DCIS, there was complete agreement among the six pathologists in only two cases

[144] . The natural history of DCIS is not clear, and many cases may not proceed to invasive cancer [145]

. (See "Breast ductal carcinoma in situ and microinvasive carcinoma").

Invasive cancer — A population-based cohort study found that as a result of screening, the recorded

incidence of invasive breast cancer (not including ductal carcinoma in situ) in women ages 50 to 69

increased by 54 percent in Norway and 45 percent in Sweden without any corresponding decline in

incidence after the age of 69 (when screening stopped) [146] . The study concluded that one-third of allinvasive breast cancers in women ages 50 to 69 would not have been detected in the patients' lifetime,

raising the possibility that mammographic screening leads to high rates of overdiagnosis of breast cancer.

In another study in Norway, biennial screening mammography for women was introduced in 1996 for

women aged 50 to 64 years [147] . The incidence of invasive breast cancer from 1992 to 1997 among

109,784 women (unscreened group) was compared with the incidence from 1996 to 2001 for a second

group of 119,472 women who were offered regular mammograms (regularly screened group). The

unscreened group were offered one time mammogram screening at the end of the observation period,

which established their prevalence of breast cancer. Over the six year period, the incidence of breast

cancer was 22 percent higher in the group who underwent regular screening (1909 versus 1564 per

100,000 population, RR 1.22, 95% CI 1.16-1.30). Assuming no other factors would account for a higherincidence of breast cancer during the later time period, this implies that some of the cancers identified by

regular mammography screening would have resolved over the six years if not treated.

The estimated rate of overdiagnosis due to mammogram screening has been variably calculated as one in

three to one in six breast cancers detected by screening [148,149] .

Radiation



Ionizing radiation increases the risk for breast cancer, but most cohort studies of the phenomenon have

included women exposed to much larger radiation doses than the mean glandular dose for a two-view per

breast film mammogram at American College of Radiology accredited facilities [150,151] . Excess risk of

breast cancer, after a 10 year latent period, appears to be linearly dependent on [150] Radiation dose

(higher doses increase risk) Age at onset of screening (younger age at exposure increases risk) Attained

age or number of years since exposure (risk increases with increased time since exposure).

(See "Epidemiology and risk factors for breast cancer", section on Exposure to ionizing radiation)

A model compared the risk of increased breast cancer mortality from mammography radiation to the

mortality benefit from mammogram screening, using data from studies of women with comparable

radiation exposure and estimates extrapolated from a risk model [152] . Screening was associated with a

net positive benefit when the following assumptions were modeled: screening effectiveness at least 10

percent and onset of screening at age 40 or later; the positive effect increased for women who begin

screening at an older age, and for women with a family history of breast cancer. Screening was associated

with a net negative effect for average-risk women younger than age 40, both because younger women are

more sensitive to radiation and have a lower incidence of breast cancer. The assumptions used in thismodel may not be applicable to women with BRCA1 or BRCA2 mutations.

In sum, although no direct prospective studies on mammography are available, radiation risk from

mammography is low enough that a screening mammogram program for average risk women over age 40

saves lives.

While the risk of radiation-associated breast cancer from breast imaging for average risk women is felt to

be small or nonexistent, women at high genetic risk may be more susceptible to radiation-induced

carcinogenesis because of the role of BRCA proteins in DNA repair. (See "Genetic testing for breast and

ovarian cancer", section on Normal function of BRCA genes).

Studies differ on the effect of radiation in this group of women. In a report that was based upon a

questionnaire sent to known BRCA mutation carriers, exposure to mammographic screening (mean age at

first screening mammogram 35 years of age) was not associated with an increased risk of breast cancer

when adjusted for parity, oral contraceptive use, family history, and ethnicity [102] . On the other hand,

two studies evaluating the effect of chest x-rays on BRCA mutation carriers found a significantly elevated

risk of breast cancer [103,104] . In one study, individuals who reported any exposure were 54 percent

more likely to develop breast cancer compared to individuals without any exposure (HR 1.54) [103] . The

risk was highest for women who reported having more than five chest x-rays (HR 2.69) and for those who

were exposed before the age of 20 (HR 5.21).

Discomfort — Mammographic screening can be uncomfortable or painful, as the breast needs to be

compressed to achieve adequate images. There are few high quality studies examining methods to reduce

discomfort [153] . One well-designed study found that patient-controlled breast compression reduced

patient discomfort while achieving good image quality [154] . Another randomized trial in women with

high expectation of pain from the procedure found that topical application of 4 percent lidocaine gel to the

breast and chest wall reduced discomfort but premedication with acetaminophen or ibuprofen did not

[155] . Reduced discomfort correlated with increased intent to return for another screening examination.



RECOMMENDATIONS FOR SCREENING BY EXPERT GROUPS

Screening with mammography

Age to initiate — All major North American groups making recommendations about breast cancer

screening recommend routine screening with mammography with or without clinical breast examination

for women aged 50 and older. There is controversy, however, about routine screening for women in their

40s, with some groups recommending shared decision making because of trade-offs of benefits and

harms: The American Cancer Society [156] , American College of Radiology [157] , American Medical

Association [158] , the National Cancer Institute [159] , and American College of Obstetrics and

Gynecology [160] all recommend starting routine screening at age 40. The United States Preventive

Services Task Force (USPSTF) and the 2002 statement by the American Academy of Family Physicians

recommend screening mammography every one to two years for women ages 40 and older [161,162] .

The American College of Physicians and the Canadian Task Force on the Periodic Health Examination

recommend beginning routine screening at age 50 [163,164] . The American College of Physicians (ACP)

advises individual risk assessment and shared decision-making with patients regarding mammogram

screening for women 40 to 49 years of age [163] . For women who do not wish to participate in shareddecision-making, the ACP suggests mammograms every 1 to 2 years for women age 40 to 49 years. In

2000, the Advisory Committee on Cancer Prevention in the European Union recommended women

between the ages of 50 and 69 be offered mammogram screening in the context of an organized screening

program with quality assurance [165] . Women aged 40 to 49 should be advised of potential harms of

screening, and if mammograms are offered to these women, they should be performed with strict quality

standards and double reading.

Frequency — Most North American expert groups recommending breast cancer screening suggest a

frequency of every year for women over age 50 and every one to two years for women aged 40 to 49.

Groups recommending screening for women in their 40s have tended to shift towards annual

examinations because of the evidence of more rapid tumor growth in younger women [166] .

There has been a tendency for recommendations to extend the interval to two years for older women. The

Advisory Committee on cancer screening in the European Union has recommended mammograms be

performed at intervals of two to three years for women 50 to 69, and if performed for women 40 to 49,

they should be done at intervals of 12 to 18 months [165] .

Screening with clinical breast examination — The American Cancer Society recommends clinical breast

examination every three years from age 20 to 39, and annually thereafter [156] . The US Preventive

Services Task Force recommends mammography with or without clinical breast examination every 1 to 2

years, and the Canadian Task Force on Preventive Health Care recommends clinical breast examination

with mammography every 1 to 2 years beginning at age 40 and 50, respectively(www.ctfphc.org/Full_Text/Ch65full.htm) [156] . Neither recommends clinical breast examination alone.

Screening with breast self-examination — There is less consensus among expert groups about teaching

and promoting breast self-examination (BSE). The Canadian Task Force on Preventive Health Care

concluded that "there is fair evidence to recommend that routine teaching of BSE be excluded from the

periodic health examination of women aged 40 to 49 (grade D recommendation)" because of excessive

work-ups for false-positive examinations and lack of firm evidence for decreasing breast cancer mortality



[59] . The third US Preventive Services Task Force found insufficient evidence to recommend for or

against the procedure [161] . In 2003, the American Cancer Society changed its previous recommendation

in favor of monthly BSE to a recommendation that women be educated about the benefits and limitations

of BSE [167] . The American College of Obstetricians and Gynecologists recommends routine teaching

of BSE [160] . The Advisory Committee on Cancer Prevention in the European Union states that there is

"no convincing evidence for the effect of screening based on breast self-examination or clinical breastexamination" [165] .

Screening with breast MRI — Most groups issuing guidelines about breast cancer screening have not

commented on breast MRI.

The 2007 American Cancer Society (ACS) recommends offering annual MRI, in addition to

mammography, to women within certain high-risk groups including [168] : Known BRCA mutation

carriers First degree relatives of known BRCA mutation carriers Women with an approximate lifetime

risk of breast cancer from 20 to over 25 percent, according to risk prediction models primarily using

family history (show table 5).

The ACS recommends against MRI screening for women with less than a 15 percent lifetime risk and

states that evidence is insufficient to support recommendations for women with risks between 15 and 20

percent.

Guidelines from the National Comprehensive Cancer Network (NCCN) recommend annual breast MRI in

addition to mammography for women with a strong family history or genetic predisposition [169] .

The National Institute for Health and Clinical Excellence (NICE) guidelines recommends offering annual

MRI in addition to mammography to the following high risk groups [170] : BRCA1 and BRCA2

mutations carriers, starting at age 30 TP53 mutation carriers, starting at 20 Women in their 30s with a 10-

year risk >= 8 percent Women in their 40s with a 10-year risk >= 20 percent Women in their 40s with

dense breasts and a 10-year risk >= 12 percent

The recommendations of other groups vary, but many predate the publication of several key studies on

the utility of breast MRI in high-risk women.

FOLLOW-UP OF DETECTED ABNORMALITIES — The evaluation of abnormalities detected by

screening mammography, clinical breast examination, or breast self-examination is discussed separately.

(See "Primary care evaluation of breast lumps").

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See

"Patient information: Breast cancer screening"). We encourage you to print or e-mail this topic review, or

to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.

SUMMARY AND RECOMMENDATIONS An approach to breast cancer screening should incorporate

an individual's level of breast cancer risk, established by history and by use of a risk prediction model.

The model most commonly used is the Breast Cancer Risk Assessment Tool (Gail model) (See "Risk

prediction for breast cancer screening" and see "Breast cancer risk prediction tools" above).



Lifetime breast cancer risk below 15 percent — A reasonable approach to breast cancer screening in

average risk women is summarized below (show table 6): We recommend that women between the ages

of 50 and 70 be screened with mammography (Grade 1A). Information about the risk of breast cancer and

the benefits and harms of screening should be reivewed (show figure 1A-1B). (See "Mammography"

above). We suggest discussion of the risks and benefits of mammography between women aged 40 to 50

and their clinician; the decision to perform mammography should be determined by individual patientvalues (Grade 2B). The clinician can help women with this decision by reviewing information about their

risk of breast cancer and about false-positive mammography results and overdiagnosis (show figure 1A-

1B) (see "Women in their 40s" above). We suggest that women over the age of 70 be screened with

mammography if their life expectancy is at least 10 years (Grade 2B). Frameworks have been developed

that may assist with decision making in older women (show table 4) (see "Older women" above). The

ideal interval for screening mammography is not known, but we suggest screening every one to two years

(Grade 2C). We recommend that women being screened for breast cancer also undergo clinical breast

examination (Grade 1B). Clinical breast examination may be particularly useful in older women (see

"Clinical breast examination" above). The efficacy of breast self-examination (BSE) is unproven. We

suggest that BSE not be performed except by women who express a desire to do so and who have

received careful instruction to differentiate normal tissue from suspicious lumps (Grade 2B). BSE should

only be performed as an adjunct to mammography and clinical breast examination, not as a substitute for

these screening methods (see "Breast self-examination" above).

Lifetime breast cancer risk 20-25 percent or higher Women at high risk for breast cancer (lifetime risk ≥

20 to 25 percent) should be referred for genetic counseling, to determine the likelihood of a BRCA

mutation and to decide on management options (See "Risk assessment and clinical characteristics of

women with a family history of breast and/or ovarian cancer" and see "Options for women with a genetic

predisposition to breast and ovarian cancer"). For women with a lifetime risk of breast cancer ≥ 20 to 25

percent (mutation carriers and others) who choose intensified surveillance for breast cancer, we suggest

annual mammography and MRI, as well as clinical breast examinations every three to six months, and

monthly breast self examinations (Grade 2C). The appropriate age to begin annual screening is not

established. Until further data is available, we suggest that screening be initiated at age 25 for these

women (Grade 2C). (See "Germline predisposition (BRCA1 or BRCA2)" above).

Mild to moderately increased lifetime breast cancer risk It is not known whether increased screening,

either by beginning at an earlier age or by adding breast MRI, would result in greater benefits than harms

for women with mild to moderately elevated lifetime breast cancer risks (15 percent or greater and less

than 20 to 25 percent). We suggest that women with mild to moderately increased breast cancer risk

follow the recommendations for women at average risk (Grade 2C). (See "Family history of reast cancer"

above and see "Magnetic resonance imaging" above).

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