- Screening, is defined by the Commission on Chronic Illness, as ‘‘the presumptive identification of unrecognized disease or defect by the application of tests, examinations or other procedures that can be applied rapidly’’
- Synonymous with secondary prevention, in which earlier therapeutic intervention is possible by screening an asymptomatic population which will identify cancer at an earlier stage. The expectation is that early diagnosis and treatment lead to a reduction in mortality from the disease and/or a reduction in the severity of the disease.
- Not a diagnostic. It is application of a test to an asymptomatic population to determine who is likely to have the disease and who is not likely to have the disease.
Validity of a Screening Test
- The accuracy or validity of a screening test is measured by sensitivity and specificity .
- Sensitivity refers to the ability of the screening test to correctly identify people with the disease among the screened population and is defined as the number of people with a positive test screening test divided by those who actually have the disease.
- Specificity refers to the ability of the test to correctly identify people without the disease among the screened population and is defined as the number of people with a negative test divided by the number of people who do not have the disease. Ideally, sensitivity and specificity would be 100% accurate, but unfortunately there is no cancer screening test that performs this well.
- False positive- screening test is positive but no disease following the diagnostic work-up.
- False negative- negative screening test but disease following the diagnostic work-up.
- Positive predictive value (PPV), which is the proportion of individuals with a positive screening test who actually have the disease. The PPV can only be computed after the diagnostic examinations of those who test positive had been completed. A PPV of 10% means that only one in ten of the test positives truly had the disease. The other nine unnecessarily received the diagnostic examination and incurred unnecessary cost and risks.
Breast Cancer Screening
- Breast ca screening started in 1960s when mammography became available. Studies found decreased mortality in women screened in their 40s.
- A systematic review of screening MMR including 8 studies concluded that, with at least 11 years of follow-up, pooled relative risk for breast cancer mortality was
- 0.85 (95% CI 0.75-0.96) for women 39 to 49 yrs of age
- 0.86 (0.75-0.99) for women 50 to 59 years of age
- 0.68 (0.54-0.87) for women 60 to 69 years of age
- Women age 40 and older should have a mammogram every year
- Women in their 20s and 30s should have a clinical breast exam (CBE) preferably every 3 years. Starting at age 40, women should have a CBE every year.
- Breast self-exam (BSE) is an option for women starting in their 20s.
- Women who are at high risk for breast cancer should get an MRI and a mammogram every year.
Breast Cancer Screening Methods
- Sensitivity of mammography ranges from 53% to 92% in western countries, being low in pre-menopausal women (from 44% to 76 % in women <50*).
- Specificity ranges from 82% to 98% in western countries.
- It has two views, Craniocaudal (CC) and Mediolateral Oblique (MLO) to characterize the type and location of breast lump. Breast compression is done between the plates which increases image contrast, decreases radiation dose, reduces motion, and minimizes superimposition of tissues. Pain and discomfort may be addressed by soft radiolucent breast cushion, premedication with oral analgesics and topical lignocaine.
- It can detect cancer 1.5-4.0 years before it is clinically evident. Mean glandular dose is 0.1-0.2 rads (1-2 mGy) per exposure, and effective rose received is around the same as that from normal background radiation for 3 months.
BIRADS Scoring on Mammography
Category 0: Additional imaging evaluation and/or comparison to prior mammograms is needed.
Category 1: Negative
Category 2: Benign (non-cancerous) finding
Category 3: Probably benign finding – Follow-up in a short time frame is suggested
Category 4: Suspicious abnormality – Biopsy should be considered
Category 5: Highly suggestive of malignancy – Appropriate action should be taken
Category 6: Known biopsy-proven malignancy – Appropriate action should be taken
Film screen Vs. Digital Mammography
- According to Digital Mammographic Imaging Screening Trial (DMIST) and Oslo II study, overall diagnostic accuracy was similar but digital was more accurate for premenopausal, perimenopausal and women with dense breasts.
- Digital mammography, when available, may offer a small screening advantage in women younger than 50 years old.
Abnormalities on mammography
- The most specific mammographic feature of malignancy is a spiculated focal mass. Positive Predictive Value of mass with a spiculated margin is 81% and with irregular shape is 73%.
- The density of a non-calcified mass. 70% of masses with high density were malignant, and 22% with low density were malignant.
- Clustered microcalcifications are seen in approximately 60% of cancers detected mammographically.
- Linear branching microcalcifications have a higher predictive value for malignancy than do granular microcalcifications, especially for high grade DCIS.
- However, breast cancers, including DCIS, more often present with the granular type of calcifications.
All reports have a statement regarding the breast density. Most radiologists use the four categories described in the BI-RADS atlas, based on the proportion of glandular (radiodense) tissue with respect to fatty (radiolucent) tissue. The four main categories are:
- Predominantly fatty (0 to 25 percent dense)
- Scattered fibroglandular densities (25 to 50 percent dense)
- Heterogeneously dense (51 to 75 percent dense), and
- Dense (greater than 75 percent)
Clinical Breast Examination (CBE)
- The American Cancer Society states that its continuing recommendation to perform CBE is based on lack of conclusive evidence against it and the opportunity to use the examination as a time to discuss early breast cancer detection and other breast cancer issues.
- Sensitivity ranges from 40% to 70% in western countries and specificity ranges from 85% to 95%. Advantage of CBE over other techniques are it’s low cost and performable by non medical staff.
- Sensitivity: 40% to 70% in western countries
- Specificity: 85% to 95% in western countries
Recommendations for CBE
- The American Cancer Society recommends clinical breast examination every three years from age 20 to 39, and annually thereafter
- The American College of Obstetricians and Gynecologists recommends clinical breast examination every one to three years from age 20 to 39, and annually thereafter
- The US Preventive Services Task Force concludes that evidence is insufficient to assess additional benefits of clinical breast examination beyond mammography
- The World Health Organization does not recommend clinical breast examination
American Cancer Society indications for breast MRI-
- 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
- Had radiation therapy to the chest when they were between the ages of 10 and 30 years
- Have Li-Fraumeni syndrome, Cowden syndrome, or Bannayan-Riley-Ruvalcaba syndrome, or have first-degree relatives with one of these syndromes.
Annual MRI recommended based on evidence-
- With BRCA mutated women
- First degree relatives of BRCA mutated women
- Whole life risk of breast cancer about 20-25%
Annual MRI based on expert opinion-
- Women who received radiation to chest at the ages of 10-30
- Li-Fraumeni syndrome patients and their first degree relatives
Insufficient evidence to recommend MRI
- Lifetime breast cancer risk 15%to 20%
- Lobular carcinoma in situ
- Atypical hyperplasia(lobular or ductal)
- Extremely or heterogeneously dense breasts on mammogram
- Personal history of breast cancer, including ductal carcinoma in situ
New Methods for Breast Cancer Screening
Positron Emission Mammography (PEM)
- It has a sensitivity 86 to 91% and specificity 91 to 93%.
- PEM does not reliably detect low grade malignancies
Breast Specific Gamma Imaging (BSGI)
- It uses gamma cameras with 2 to 3 mm in-plane resolution in a mammographic configuration to provide images of the breast.
- It is based on the observation that breast cancers accumulate technetium-99m sestamibi in intracellular mitochondria.
- BSGI demonstrated equal sensitivity and greater specificity than MRI for the detection of breast cancer
- Breast tomosynthesis (“3-D mammography”) has been approved by the US Food and Drug Administration for routine clinical use.
- It is a modification of digital mammography and uses a moving X-ray source and digital detector. A three dimensional volume of data is acquired and reconstructed using computer algorithms to generate thin sections of images.
- In the screening setting, this helps to decrease recall rates by delineating true lesions from spurious lesions caused by overlapping structures seen on routine mammography.
- In the diagnostic setting, tomosynthesis improves lesion characterization, thereby decreasing the need for biopsy, leading to fewer false positive biopsies and higher rates of cancer detection.
Cervical Cancer Screening
Is Cervical Cancer Screening Justified?
- Cervical cancer is an important public health problem in many resource-poor settings.
- The natural history of the disease is adequately understood – Levels of intervention are known.
- The time between the progression of asymptomatic precancerous lesions and the occurrence of disease (cancer) is long, leaving ample time for detection and treatment
- Treatment of early lesions is inexpensive compared to the management of invasive cancer.
Screening Methods for Cervical Cancer
- George Papanicolaou in 1920 discovered that tumor cells could be found in vaginal fluid of women with cervical cancer.
- 75% reduction in the incidence of, and a 70% reduction in the mortality from invasive cancer due to the Pap test.
- IARC data suggests that even screening women just once in their lives, at age 35 could reduce cervical cancer incidence by 40% and mortality by 26%.
- The patient should not be actively menstruating. (8-12th day )
- It is preferable that the patients refrain from sexual activity or use of vaginal medications or spermicides for the 48 hours prior to the test.
- Appropriately sized bivalve speculum should be used. Instead of lubricant jelly, water should be used for easier passage of speculum.
- If mucus or small amounts of blood are on the cervix, gently removed with a large cotton swab (to avoid removing cells from the transformation zone).
- Scrape cervix with the Ayre’s spatula by inserting the larger irregularly shaped side of the spatula into the endocervix and turning 360 degrees, making sure to cover the entire transformation zone. [Endocervical brush and broom smears are optional].
- Spread the cells from the spatula onto a numbered slide, evenly, avoiding clumping. Immediately fix the smear in a coplin jar containing 95% alcohol.
Liquid Based Cytology
- It is a technique which provides a uniform thin layer of cells for examination in smear without any debris / cell contamination
- The cervex brush is used to collect the sample. Rotated 5-9times
- Central bristles inserted into cervical canal and lateral bristles fully bend against Ectocervix
- No smear needs to be prepared and the entire sample collected by the brush is transported to the laboratory in the fixative vial after proper labeling.
Visual Inspection Methods
- Simple, safe & well accepted
- Requires very low infrastructure
- Can be performed by a wide range of personnel with a short training (1-3 weeks)
- Immediate results
- >50yrs – SCJ recedes towards the endocervix. Lesions are not readily visible.
- Underlying STD increases inflammation and renders inspection difficult.
- Relatively low specificity
Visual inspection using acetic acid (VIA)
- Clinical inspection of cervix using only a speculum and light source.
- Very low sensitivity- 30-50%.
- Examination of cervix one minute after the application of 3-5% acetic aid.
- ‘Acetowhitening’ – Acetic acid causes reversible coagulation of intracellular proteins
- Decrease in the reddish hue of the cervix imparted by the subepithelial vasculature.
- The degree of opacity corresponds to the thickness of neoplastic change.
- Patient positioned in a modified lithotomy position on a couch
- Gently introduce a sterile vaginal speculum
- adequate light in the vagina and on the cervix
- apply 5% acetic acid using a cotton swab soaked in acetic acid
- carefully look at the cervix to see whether any white lesions appear, particularly in the transformation zone close to the squamocolumnar junction, or
- dense, non-removable acetowhite areas in the columnar epithelium.
- The results one minute after application of acetic acid should be reported
Reporting of VIA
|Normal||No white lesion|
|Indeterminate||Severe inflammation or cervicitis|
|Ill definite lesion||Pale white lesion / focal punctated areas of acetowhitening|
|Definite lesion||Dense white lesion with sharp border|
|Suspicious cancer||Cervical ulcer / fungating mass|
Visual inspection using Lugol’s Iodine (VILI)
- LI stains glycogen stored in the cervical epithelial cells.
|Black / Dark brown|
|Immature metaplastic epithelium||Brownish|
|Columnar epithelium||Do not stain|
|Neoplastic epithelium||Saffron yellow|
|leukoplakia||Do not stain|
HPV DNA Testing
- Persistent infection with an oncogenic type of HPV is the necessary cause of developing cervical carcinoma.
- HPV DNA is found in 99.8% of all cervical cancer cases.
- The strong NPV might suggest that it might replace co-testing, but
- Specificity is lower than conventional pap
- Follow up to HPV testing remains unclear
- Knowing HPV status biases cytology report
- No prospective trials support the use of HPV as primary screening test.
PAP vs HPV DNA Testing
- The sensitivity of both tests used together was 100%, and the specificity was 92.5%
- The risk of CIN 3 or cancer is approximately 1% among women with a negative test for HPV
|Pap||55.4 %||96.8 %|
|HPV DNA testing||94.6 %||94.1 %|
American Cancer Society (ACS), American Society for Colposcopy and Cervical Pathology (ASCCP), and American Society for Clinical Pathology (ASCP) 2012 Guidelines for Screening
Age to Begin Screening
- Begin at age 21 years.
- Women aged younger than 21 years should not be screened regardless of the age of sexual initiation or other risk factors.
Women aged 21 to 29 years
- Screening with cytology alone every 3 years.
- HPV testing should not be used to screen women in this age group, either as a stand-alone test or as a cotest with cytology.
Women aged 30 to 64 years
- Cytology with HPV co-testing every 5 yrs is preferred.
- Cytology alone every 3 years is accepted.
When to Stop Screening?
- Stop at age 65 for women with prior ‘adequate negative screening’, no CIN+ in the past 20 yrs.
- Adequate negative screening:
- 3 consecutively negative Pap tests, or
- 2 consecutively negative HPV co-tests within 10 years before the cessation of screening, the most recent performed within 5 yrs.
Women Aged Older Than 65 Years With a History of CIN2, CIN3, or adenocarcinoma In Situ
- Following spontaneous regression or appropriate management of CIN2, CIN3, or adenocarcinoma in situ, routine screening should continue for at least 20 years (even if this extends screening past age 65 years).
- Women who have been treated for CIN2+ in the past 20 years (or had it resolve spontaneously) remain at approximately a 5- to 10-fold higher risk for cervical cancer than the general population.
Screening in Developed Countries
- Despite the fact that >80% of the cervical cancer cases occur in developing countries, only 5% of women have ever been screened. (WHO 2006).
- Disadvantages of using cytology for screening
- Requires excessive resources:- lab equipments, training of personnel, transport of specimen, etc.
- Requires adequate training of cytopathologists and lab personnel for atleast 6 months
- Visual inspection based screening tests are recommended in the developing countries because:
- Less expensive than cytology
- Easy to administer & train appropriate health care workers
- Provide real time results
- Reduced no. of repeat visits
- Option of “see and treat” becomes feasible
- Similar sensitivity as cytological methods.
- The biggest gain in reducing cervical cancer incidence and mortality is by increasing screening rates among women rarely or never screened.
- Cytological methods are the standard in developing countries
- VIA is becoming the standard in developing countries.
- The screening programmes implemented must be organized streamlined till the grassroots level to enable that all women are adequately screened.
- Intensive information, education and communication (IEC) activities are required to sensitize the community for better participation.
Colorectal Cancer Screening
- CRC is infrequent before age 40; the incidence rises progressively thereafter to 3.7/1000 per year by age 80
- 90% occur after the age of 50 yrs
- Most colorectal cancers (CRCs) arise from adenomas, many of which are polyps that progress from small to large (>1 cm) polyps, and then to dysplasia and cancer.
- The progression from adenoma to carcinoma, when it occurs, apparently takes at least 10 years on average
- The risk of CRC increases with adenoma size, number, and histology
- The finding of one adenomatous polyp suggests a propensity to form polyps, and patient should be evaluated for other lesions in the colon and rectum.
- The number and types of lesions found will determine the appropriate interval for subsequent surveillance colonoscopy.
Methods of Screening
Fecal Occult Blood Testing
- Also called Stool Guaiac test
- Avoid red meat, iron supplements, certain vegetables (false Positive) and Vitamin C/ citrus fruits (false negative) 3 days before test
- Feces applied to paper with thin film of guaiac
- 1-2 drops of Hydrogen Peroxide dripped on other side of paper
- Quick, intense blue colour change is positive
Fecal Immunochemical Test
- American College of Gastroenterology recommends abandoning guaiac tests for Fecal Immunochemical Test (FIT) as CRC screening tool
- Specific for Human blood
- Superior performance and better adherence to screening
- Immudia-Hem, InSure, Hemoccult SENSA, FlexSure OBT
Fecal DNA Testing
- Version 1.0 tested for point mutations in k-ras, APC, P53, mutations in the BAT26 microsatellite instability marker, and the DNA integrity assay
- Absolute sensitivity of only 52%, Later versions show better sensitivity
- Much more expensive, lack of data
- FIT recommended over DNA testing as screening too
- Screening method of choice
- High sensitivity and specificity
- Lesions can be removed in the same procedure
- In general, colonoscopy is recommended every 10 years in those with average risk
- It is generally believed that the average time from development of a polyp to development of invasive malignancy is at least 10 years
CT Colonography (Virtual Colonoscopy)
- Sensitivity higher for larger polyps (Comparable to Optical for polyps >= 10mm [88-90%])
- More expensive and overall less effective than optical colonoscopy
- MRI colonography offers sensitivity and specificity were 65% and 67% for polyps greater than 6 mm,, and for polyps greater than 10 mm, sensitivity and specificity were 75% and 93%, respectively.
- Most current guidelines take into account only personal and family history of polyps and cancer when recommending a screening program
- Increased Risk: “Yes” to any of the following:
- Have you ever had colorectal cancer or an adenomatous polyp?
- Have you had inflammatory bowel disease (ulcerative colitis or Crohn’s disease)? Have you received abdominal radiation in for childhood cancer?
- Have any family members had colorectal cancer or an adenomatous polyp?
- If so, how many, were they first-degree relatives (parent, sibling, or child), and at what age was the cancer or polyp first diagnosed?
Prostate Cancer Screening
- In US lifetime risk of developing prostate cancer is 16 %.
- 5-year relative survival in locoregional spread is 100 % and 31.9 % in pts with distant metastases.
- Thus, a screening program that could identify asymptomatic men with aggressive localized tumors might be expected to substantially reduce prostate ca morbidity, including urinary obstruction and painful metastases, and mortality
- PSA, widely adopted for cancer screening by early 1990s
- As a result, incidence of prostate ca, peak seen in 1992 in US.
- Men whose initial PSA level is ≥2.5 ng/mL should undergo annual testing. Men with a lower initial level can be tested every 2 yrs.
- Biopsy referral threshold at 4.0 ng/mL. PSA levels from 2.5 to 4.0 ng/mL, guideline encourages individualized decision making and assessment.
American Cancer Society
- PSA test and DRE should be offered annually, beginning at age 50, to men who have a life expectancy of at least 10 years.
- Men at high risk should begin testing at age 45. Starting at age 40 can be considered.
- Initial cancer screening at 40 yrs with PSA & DRE in high risk people like African Americans, F/H/Prostate cancer, Otherwise at 50 yrs,
- If PSA<2.5ng/ml or PSAV <0.35ng/ml/yr – Annual follow up.
- If PSA 2.6-4.0ng/ml or PSAV >0.35ng/ml/yr – Bx if high risk features or annual screening.
- If PSA > 4-10 ng/ml, biopsy is preferred, if fPSA is >10%, follow may be done,
- If biopsy is negative, continue annual screening.
- Abnormality on DRE any time is an indication for biopsy.
- If PSA>10ng/ml, 67% of patients will have cancer.
- Recommends 12 core biopsies.
- USPSTF -There is insufficient evidence to assess balance of benefits and harms of prostate ca screening in younger than age 75 .
- USPSTF recommends against screening for prostate ca in ages 75 or older because harms of screening outweigh benefits.
- Canadian Task Force on Preventive Health Care recommends against screening for prostate cancer with PSA or TRUS.
- The UK National Screening Committee does not recommend screening.
- The Australian Cancer Council states that evidence does not support population-based screening and recommends a patient-centered approach that individualizes the decision.
Lung Cancer Screening
- Lung cancer remains leading cause of ca-related death among men and women in world
- 5-year survival rate of 10-15% has been roughly unchanged for past 2 decades despite treatment advances
- At diagnosis, most lung ca are already at advanced stage
- Early stage lung ca patients have a much higher 5-year survival rate (between 60 and 80%)
- Changing smoking habits could reduce lung ca incidence and deaths
- Risk for lung ca does not decrease for many years after smoking cessation
- Many characteristics of lung cancer suggest that screening would be effective:
- high morbidity and mortality;
- significant prevalence (0.5 to 2.2%),
- identified risk factors allowing targeted screening for high risk,
- a lengthy preclinical phase, and
- evidence that therapy is more effective in early stage disease.
- CXR and CT screening frequently detect early stage asymptomatic lung ca in screened individuals.
- CT screening is significantly more sensitive than CXR for identifying small, asymptomatic lung ca.
- CXR and CT screening have high rates of “false positive” (non-cancer) findings leading to additional testing which usually includes serial imaging, but may include invasive procedures.
- 1 large randomized trial of screening CT in high risk individuals has demonstrated a lung cancer mortality benefit of 20%, with all cause mortality reduced by 6.7%.
- IHC or molecular analysis of sputum for tumor markers. As examples, p16 ink4a promoter hypermethylation and p53 mutations have been shown to occur in chronic smokers before there is clinical evidence of neoplasia.
- Automated image cytometry of sputum.
- Fluorescence bronchoscopy,
- Exhaled breath analysis of volatile organic compounds, which appear to be more common in patients with lung cancer.
- Genomic and proteomic analysis of bronchoscopic samples.
- Serum protein microarrays for detecting molecular markers.
- 2010 ACS guidelines for early detection of cancer states: “At present neither ACS nor any other medical/scientific organization, recommends testing for early lung ca detection in asymptomatic individuals.
- 3 randomized trials screening for lung ca involving Johns Hopkins, Memorial Sloan-Kettering, and Mayo Clinic(CXR, sputum cytology).
- 5-year survival in these 2 studies was nearly 35%.
- Screening for lung cancer with LDCT may increase the rate of lung cancer diagnosis and treatment, but may not meaningfully reduce the risk of advanced lung cancer or death from lung cancer.
- Until more conclusive data are available, asymptomatic individuals should not be screened outside of clinical research studies.
Ovary Cancer Screening
- Ovarian ca is leading cause of death from gynecologic malignancy in US.
- Worldwide is the 7th leading cause of ca death in women.
- Survival is much improved for earlier stage disease.
- CA 125 most widely studied tumor marker for ovarian ca screening, is elevated in 50 to 90% of women with early ovarian cancer.
- TVUS as a sole screening intervention for higher risk women, is not effective in early stage cancer.
- TVUS may be more effective when used as part of multimodal screening.
- No North American expert groups recommend routine screening for ovarian ca.
- ACOG, Society of Gynecologic Oncologists (SGO) and Canadian Task Force on the Periodic Health Examination , all of whom recommend against routine screening for ovarian ca in asymptomatic women.
- For women with identified hereditary ovarian ca syndromes, ACOG, SGO and NCCN recommend screening with CA 125 and TVUS beginning between ages of 30 and 35 years or 5 to 10 years earlier than the earliest age of first diagnosis of ovarian ca in the family .
- ACOG states this screening should occur periodically, while NCCN and SGO recommend 6 month intervals.
- NCI finds there is not sufficient evidence to support screening for ovarian cancer in any population, including women at increased risk.