Womens Health: Contemporary Screening and Diagnostic Strategies

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Emerging Technology and Womens Health
Contemporary Screening and Diagnostic Strategies

• Barbara Winkler, MD
• Associate Director for Gynecologic Pathology and
  Womens Health
• Quest Diagnostics, NY/NJ

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Evidence Based Screening

• Disease common
• Effects duration /or quality of life
• Acceptable effective therapy available
• Asymptomatic period
• Intervention (detection therapy) ? improved
  outcome
• Rx asymptomatic gt symptomatic Rx
• Test
• Safe, affordable
• Adequate sensitivity and specificity

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Diagnostic Strategies

• Screening Risk stratification early
  intervention
• Accurate targeting of follow-up/therapy to level
  of risk
• Minimize morbidity/toxicity
• Maximize benefit and cost efficacy
• Annual screening visit
• Monitoring
• Compliance ? EMR
  Informatics
• Counseling

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Integrated Patient Summary
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Customizable Flowsheet
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Graphic Monitoring
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ACS
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USPSTF Recommendations for Women

• Strongly recommends (A)
• Blood pressure (A) 18
• Lipid disorders (A ) 45
• Cervical cancer (A) Sexually active, have cx
• Colorectal cancer (A) 50
• Recommends (B)
• Lipid disorders 20 45 yo if other risk
• Osteoporosis 65
• 60 in high risk
• Breast cancer 40

US Preventive Services Task Force
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CARDIOVASCULAR DISEASE
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Traditional Coronary Risk Factors

• Age
• Hypertension
• Smoking
• Diabetes
• Hyperlipidemia

Framingham Study, 1957-1966
Does not incorporate modern concepts of the
pathophysiology of atherothrombosis and CAD
(hemostasis, thrombosis, inflammation,
endothelial dysfunction, plaque instability)
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Cardiovascular Disease in Women - Factoids

• Leading cause of mortality in women 38 of all
  deaths
• Women living with CVD in US 34
• 70 of CV events occur in patients defined as
  intermediate risk
• 4 out of 10 patients no prior symptoms
• 50 of all heart attack stroke patients have
  normal cholesterol (Greenland et al, JAMA.
  2003 290)
• 10 20 no major risk factors (Khot et al,
  JAMA. 2003 290)

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AHA Screening Guidelines

• Screening in general population
• Adults over age 20
• Fasting lipoprotein profile q 5 years
• Total cholesterol
• HDL cholesterol
• LDL
• Triglycerides
• LDL 130 mg/dl more frequent monitoring
• Patients on cholesterol-reducing medications
• Post 4-6 wks at 3 mos
• Then q 4 mos

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New Lipid Target Goals

• Total cholesterol - lt 200
• LDL - lt 100 (?from 130)
• HDL - gt 40 (?from 35)
• Triglycerides - lt150

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The Reynolds Risk Scorewww.reynoldsriskscore.org

• More predictive than Framingham or ATP III
  scoring
• Re-classified 40-50 of intermediate risk women
  into higher or lower categories

Ridker et al, JAMA. 2007 297
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Reynolds Risk ScoreClinical Risk Algorithms

• Clinically Simplified Model B
• Age
• HbA1c (diabetic)
• BP
• Current smoking
• hsCRP
• Parental Hx lt 60 yo
• Non-HDL-C
• HDL-C

• Best Fitting Model A
• Age
• HbA1c (diabetic)
• BP
• Current smoking
• hsCRP
• Parental Hx lt 60 yo
• ApoB100
• Apo A-1
• Lp(a) if Apo B100 gt100

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Cardio CRP(high sensitivity C-reactive Protein)

• Independent marker for CVD
• Non-specific acute-phase liver protein produced
  with tissue injury/inflammation
• lt 1 Low risk
• 1-3 mg/L Average risk
• gt 3 mg/L High risk
• gt 10 Non-CV inflammation

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Osteoporosis - Factoids

• Osteoporotic fracture
• 40-50 of women
• 700,000 vertebral fractures 300,000 hip
  fractures annually
• lt half recover fully
• In ?, lifetime risk of death following hip
  fracture risk of death from breast cancer

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Traditional Risk Factors for Fracture

• Low BMD
• Advanced age
• Hx of fracture over age 50
• Corticosteroid use
• Family hx
• Smoker
• Rheumatoid arthritis

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OsteoporosisScreening

• BMD ? DXA ( dual energy x-ray absorpitometry)
• Bone size bone volume
• Bone markers ? surrogate markers of fracture
  efficacy

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Vitamin D

• Vitamin D deficiency Epidemic in US
• 50 of women with osteoporosis are Vit D
  deficient or insufficient
• Skeletal health neuromuscular function
• Positive association between 25(OH) D Total BMD
• Direct effect on muscles (type 2 fibers) and
  proximal musculature
• Cancers, immune competence, diabetes
• Critical level 30 ng/ml (70-80 nmol/ml) or less
  ? 2o hyperparathyroidism

Holick, MF NEJM 357 266- 81, July 2007
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Vitamin D

• 25-Hydroxyvitamin D (25OHD) major circulating
  form of Vit D
• Precursor of active form (1,5-dihydroxyvitamin D)
• 2 forms of Vit D
• Vitamin D3 - Cholecalciferol
• Foods of animal origin, Conversion of
  7-dehydrocholesterol in skin (UV light)
• Vitamin D 2 Ergocalciferol
• Foods of plant origin

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Vitamin D Insufficiency/Deficiency

• Deficiency - lt 20 ng/ml (50 nmol/l)
• Insufficiency Range 21 29 ng/ml
• Critical to assess Vit D level
• Low BMD
• Osteoporosis, osteomalacia
• Subclinical myopathy - Muscle pain weakness

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Clinical Targets for Vitamin D Testing

• Vitamin D deficiency
• Elderly
• Housebound nursing home
• Asian
• Light restricting clothing
• Orthodox Jewish Muslim women
• Bariatric surgery/malabsorption
• Patients under treatment
• Suspected toxicity

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Prevention

• Sun Exposure Vit D
• Sunscreen
• SPF 8 ?Vit D 95
• 5-15 minutes sunlight 2-3 X week (arms legs)
• Rx 1000 IU

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Advanced Methodology for Vitamin D Testing

• LC/MS/MS
• Liquid chromatography, tandem mass spectrometry
• Accurate, Sensitive, Specific for Vitamin D3 D2
• Reference Range 20-100 ng/ml
• Correlate with levels of parathyroid hormone
  calcium

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Clinical Applications of Vitamin D Testing

• Identify Vitamin D deficiency
• Yearly monitoring in high risk older
• Monitor therapeutic response compliance
• Diagnose intestinal malabsorption
• Identify Vitamin D intoxication

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Cancer in Women ACS Statistics for 2007

• New Cases
• Breast
• Lung Bronchus
• Colon rectum
• Uterine corpus (Em)

• Deaths
• Lung Bronchus
• Breast
• Colon rectum
• Pancreas

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Breast CarcinomaACS - 2007

• New cases 178,480
• Deaths 40, 460

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ACS Guidelines - Breast

• 20 39 yo CBE at least q 3 yrs
• Breast self examination
• 40 - Annual CBE at minimum
• Annual Mammography
• Reduces mortality by 35 in women over 50 yo
• Reduces mortality by 25-35 in women 40-50 yo
• High risk
• Earlier initiation, screening at shorter
  intervals
• Digital mammography
• Screening MRI
• 20-25 or greater lifetime risk of breast
  cancer
• Strong family history of breast or ovarian cancer
  or Rx for Hodgkins disease

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Mammogram Prevalence (), by Educational
Attainment and Health Insurance Status, Women 40
and Older, US, 1991-2006
All women 40 and older
Women with less than a high school education
Women with no health insurance
A mammogram within the past year. Note Data
from participating states and the District of
Columbia were aggregated to represent the United
States. Source Behavior Risk Factor Surveillance
System CD-ROM (1984-1995, 1996-1997, 1998, 1999)
and Public Use Data Tape (2000, 2002, 2004,
2006), National Centers for Chronic Disease
Prevention and Health Promotion, Centers for
Disease Control and Prevention, 1997, 1999, 2000,
2000, 2001, 2003, 2005, 2007.
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Breast Cancer Risk Recognition

• Prior history of breast cancer or pre-malignant
  breast changes
• Familial clustering
• Inherited syndromes
• BRCA1, BRCA2

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Limitations of Mammography

• Sensitivity 83-97
• Most sensitive in 50-70 yo
• High false positive rate
• Expensive resource intensive
• Quality variable
• Early Detection ? Cure
• 500?detection of DCIS
• Not cost effective in women lt 50 yo

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Breast Masses Breast Cancer Diagnosis

• All breast masses should be evaluated!
• Young age
• Negative imaging
• FNA or open biopsy

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New Technologies in Breast Cancer Screening

• Digital mammography
• Computer assisted triage
• Remote consultation
• ?recall rate
• ?efficiency
• Improved retention storage
• MRI
• Expensive, low specificity
• Hi risk women women with dense breast tissue

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Colorectal CarcinomaACS - 2007

• New cases 57,050
• Deaths 26,180

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Colon Cancer

• Third leading cause of cancer death
• 30 ? Familial clustering
• 3-5 ? High risk inherited syndromes
• FAP (familial adenomatous polyposis) , HNPCC
  (hereditary nonpolyposis cancer)
• 1 ? Inflammatory bowel disease

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Colon Cancer - Risk Recognition

• Colon cancer lt 45 yo
• Adenomas gt 2 cm dx at lt 40 yo
• Multiple colonic malignancies
• Multiple primary cancers
• 10 or more adenomas with family hx
• Multiple closely related family members with
  colon carcinoma
• Colon cancer in more than one generation
• Clustering of extracolonic cancers in family (esp
  gastric, breast, thyroid and endometrium)

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ACS Guidelines - Colorectal

• 50 yo
• Options
• Flexible sigmoidoscopy q 5 yrs
• Colonoscopy q 10 yrs
• DCBE q 5 yrs
• CT colonography q 5 yrs
• Annual FIT or FOBT
• FIT gt FOBT
• Stool DNA test (interval uncertain)

Moderate or high risk - different testing
schedule
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Testing for Occult Blood

• Single digital FOBT poor performance, no longer
  recommended
• At home guaiac FOBT x3 Poor compliance, lower
  sensitivity than FIT
• FIT fecal immunochemistry test
• Detects globin protein of hemoglobin molecule
• Improved patient compliance accuracy

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Fecal Globin, Immunochemistry(Insure ) FDA
Approved

• Does not react with non-human hemoglobin or heme
  peroxidase
• Food restrictions not required
• Specific for lower GI bleeding
• Target the globin portion of hemoglobin
• Improved sensitivity and specificity
• 88.9 sensitivity for ca
• Improved patient compliance (?66)

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History of Pap Smear Screening

• 1928 First scientific paper
• 1943 Atlas
• 1945 ACS
• 1963 ? deaths from cervical cancer
• 2007 death from cervical cancer ? 80

Dr. George Papanicolaou 1883-1962
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Cervical CarcinomaACS - 2007

• New cases 11,150
• Deaths 3,670

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Prevalence of HPV Infection

• Overall prevalence 26.8 in women aged 14 59
  yrs (n1921)
• Highest prevalence 44.8 in women aged 20 24
  years
• Independent risk factors age, marital status,
  increasing numbers of lifetime and recent sex
  partners

JAMA Vol 297, Feb 2007 Dunne et al
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HPV Prevalence and Incidence of Cervical Cancer
by Age
Sources Sellors et al. CMAJ. 2000163503. Ries
et al. Surveillance, Epidemiology and End
Results (SEER) Cancer Stats NCI, 1973-1997. 2000.
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ACS Guidelines - Cervix

• 3 yrs post sexual debut or at age 21 then q 2 yrs
  with LBC
• 30
• Annual until 3 normals then q 2-3 yrs with LBC or
  q 3 yrs with HR HPV
• 70
• Consider D/C if 3 neg w/in past 10 yrs
• S/P total hyst - not necessary
• Exceptions Hx of SIL/Ca, DES, or
  immunosuppressed

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2006 ASCCP Guidelineswww.asccp.org

• Incorporate HR HPV screening in women over 30 yo
  into official guidelines
• HR HPV testing ? Standard of care

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HPV DNA Testing and Cervical Cancer Prevention

• Digene hc2
• Cocktail of the 13 most frequent HR HPV types
• Includes HR HPVs 16 18 identified in 70 of cx
  cancers
• DNAwithPap Combines Pap test HR HPV for
  screening in women 30 yo
• Sensitivity approaching 100 for HSIL CxCa
• NPV 99.2
• 4-6 of women with neg Pap are HR HPV
• Recommended by ASCCP, ACS, ACOG SGO

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Sensitivity Predictive Value Double Blinded
Controlled Studies

• HPV DNA vs Pap - Mayrand et al, NEJM, 10/2007
  (Canada)
• 10,154 women
• HPV DNA Sensitivity 94.6 (Spec 94.1)
• Pap Sensitivity 55.4 (Spec 96.8)
• HPV Pap to Screen for Cx Ca Naucler et al,
  NEJM, 10/2007 (Sweden)
• 12, 527 women followed for 4 yrs
• At enrollment detection by HPV was 51 greater
  than Pap
• Subsequent screening exams 40 reduction in
  risk for CIN 2/3
• Persistent HR HPV positivity 24 developed CIN
  2/3

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Trends in STD 2006www.CDC.gov

• Chlamydia, Gonorrhea, Syphilis
• 19 million new cases annually
• 50 in young, 15-24 yo

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CDC Trends

• CT
• Estimated 2.8 million new cases per year
• Increased 5.6 from 2005
• GC
• Increased 5.5 from 2005
• Syphilis
• Increased 13.8 from 2005, esp MSM
• Increased 11.1 in women

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CDC Screening Recommendations

• Annual CT for all sexually active women lt 26 yo
  (inc GC if prev gt 1)
• Estimate 56 reduction in PID if compliant
• Older women with new or multiple partners, hx
  unprotected sex
• High risk GC, CT, syphilis, HIV, Hep, HSV 2)
• Pregnancy (esp Syphilis)
• Diagnose and treat partner
• Test of cure 3 months following therapy
• HEDIS lt40 of eligible are screened

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NAATS

• Critical tools
• Substantially improved sensitivity
• Can substitute non-invasive testing (urine)
• Expand venues for testing
• Can detect CT GC in same specimen
• Can be performed OTV

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NAATS Platforms

• Roche Amplicor PCR
• Abbot LCx Ligase CR (LCR)
• BD ProbeTec Strand displacement amplification
• CT target Cryptic plasmid
• GC target Pillin protein homologue
• GenProbe APTIMA transcription mediated
  amplification (TMA)
• Target Ribosomal RNA

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Autoimmune Allergic Disease

• Mystery illnesses, subclinical, quality of life
• Thyroid disease
• Celiac disease (Sprue)
• Allergies
• Respiratory
• Food
• Skin (eczema urticaria)

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Epidemiology of Primary Thyroid Disease

• Incidence of Hashimotos and hypothyroidism
  increase with age
• Overt 0.6-5 of elderly, 7 over 80 yo
• Subclinical
• Age 30 3-5
• Age 50 7-8
• Age 80 14-20

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Thyroid Screening Recommendations

• ATA Women over 35 yo
• ACP Women over 50 yo, geriatric
• USPSTF Insufficient evidence

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Screening for Hypothyroidism

• High Risk
• Hx of thyroid or autoimmune disease
• Family hx of thyroid disease
• TSH
• T4
• Thyroid antibodies
• Peroxidase antibodies

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ImmunoCAPSpecific IgE Blood Test

• Simple blood test
• Objective laboratory results
• Sensitive, accurate, reproducible
• Respiratory Food Allergens
• Profiles for Adults Children
• Avoidance, immunotherapy
• Adjust medication to exposure

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ImmunoCAP Indications

• Eczema chronic urticaria
• Asthma
• Allergic asthma 60
• Recurrent ear infection
• Rhinitis
• GI distress

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Malabsorption Osteoporosis

• Celiac disease
• Osteoporotic individuals Prevalence 3.4
• Non-osteoporotic individuals Prevalence 0.2
• Infertility

Stenson et al, Increased prevalence of celiac
disease and need for routine screening among
patients with osteoporosis. Arch Int Med 2005
165.
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Summary of Discussion

• Electronics Computerization
• EMR informatics
• Mammography
• Cardiovascular Disease
• Redefining risk in women using updated markers
  Reynolds Risk Score
• Cardio CRP
• Bone Musculoskeletal Health
• Vitamin D

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Summary of Discussion

• Cancer screening
• Breast
• Digital imaging, MRI, Genetic testing
• Colon
• Epidemiology, FIT
• Cervix
• HR HPV
• STD screening
• Annual in lt 26 yo high risk, NAATS
• Autoimmune Disease Allergy
• Hypothyroidism
• ImmunoCAP

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Screening Diagnostic Testing

• Not standardized
• Define stratify risk
• Emphasize health maintenance in the context of
  evidence-based guidelines
• Keeping the annual visit annual !!!
• Coordinate with personal family history
• Behavioral, social occupational factors
• Coordinate with physical exam

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ACS
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