Repro: Cervical, Vagina, Vulva Cytology

Front 1

Cervical Cancer Epidemiology

Back 1

2nd most common cancer for women (behind breast) and leading mortality cause

Incidence used to be higher than breast cancer until new screening.

Rise in pre-invasive lesion (in situ cervical carcinoma) with screening

Incidence in lesions has decreased but static mortality due to people not being screened or unresponsive to therapy

Front 2

Racial differences for cervical cancer

Back 2

African american women highest

Front 3

Clinical trials and pap smears

Back 3

Never subjected to a randomized controlled trial, would probably fail

Front 4

Pap smear benefit, use, how many use

Back 4

Pap screening lowers incidence of invasive cervical cancer (esp call-recall system in UK where follow up, not in US where it is an opportunistic screen)

65% decrease in incidence and mortality of cervical cancer

>60% of women with cervical cancer have never had a pap smear, or have been underscreened (not in last 5 years). BUT more recent data shows only 1% in AL have never been screened

Front 5

Screening statistics for pap smears

Back 5

5-10% are abnormal (MOST NORMAL PAP)
95% of abnormal are ASCUS (atypical squamous cells of unknown significance) and LGSIL (low grade squamous intraepithelial lesion). Carncinoma in situ is in minority and incidence highest between 20-30 years old then drops

Front 6

When to stop pap smears

Back 6

If 65 or older with normal screening recommended to stop because low chance of getting high grade SIL or carcinoma in situ aftewards

Front 7

Meaning of abnormal pap smear, Frequency

Back 7

Takes about 20 years to develop cervical cancer from a low grade or high grade squamous intreepithelial lesion

Frequency - Individual woman over life span has a 1/3 chance of having an abnormal test. Relates to lack of sensitivity and accuracy of cytology and pap smears

Front 8

Sensitivity of pap smear

Back 8

ONLY 50%, false negative rate is roughly 50%

Because of repeated normal pap smears the sensitivity increases (50% on 1, 75% on 2, 87.5% on 3)

Wouldn't pass randomized clinical trials but because of serial screening it is pretty good

Front 9

HPV structure and categories

Back 9

Nonenveloped dsDNA virus. MOST COMMON STI in both genders in world

Categories
a) Non-oncogenic - Includes types 6 and 11. Cause 90% of all genital warts/condyloma but very rarely induce cancer
b) Oncogenic - 15-20 types. Most common and virulent are 16 and 18. If have a persistent 16 or 18 infection, marked lifetime risk of developing carcinoma in situ

Front 10

HPV and cervical cancer

Back 10

HPV and cervical cancer are the MOST LINKED factors in any SOLID MALIGNANCY in world

WHO lists HPV as a true cancer causing agent along with smoking and ionizing radiation.

If can eradicate HPV, can markedly reduce rate of cervical cancer worldwide

Less than 30% vaccinated, less than 18% got full 3 shot round

Attributable portions for smoking and lung cancer is only 10-20%, but for HPV and cervical cancer it is 50-100% esp if persistent infection

Front 11

Prevalence of types of HPV, Guardacil

Back 11

70% of all cervical cancers are caused by HPV types 16,18

Guardacil has 6, 11, 16, and 18

If everyone vaccinated the rate of cervical cancer would drop 50-75%

Still recommend vaccine and smear because 30% cancers caused by others (45,31,33)

Front 12

Other malignancies related to HPV

Back 12

Female - vaginal, vulvar

Male - penile

Both - anal and orophoryngeal

Smoking and alcohol used to be main cause of oropharyngeal cancer but now HPV is number one cause. Type 16 oropharyngeal is good prognosis but Type 16 cervical is poor prognosis

Vaccine should be used for males too because of risk of anal and oropharyngeal cancer

Front 13

Global HPV stats

Back 13

MOST COMMON STI (doesn't always lead to disease)

especially likely if have areas of co-occuring endemic infections (HIV in sub saharan africa ex)

Front 14

US HPV Statistics

Back 14

Lifetime risk for sexually active men and women - AT LEAST 50%, by age 50, at least 80% women get genital HPV infection

Incidence 6.2 million/year; Prevalence 20 million

IN ages 15-24, 9.2 million infected. 74$ of new infections. Prevalence ranges from 28-46%

Front 15

Clearing HPV

Back 15

HPV is easily acquired, easily eradicated for most.

VAST MAJORITY WILL NOT DEVELOP DISEASE SEQUELAE

If have immune system problems may be unable to clear and it becomes chronic or leads to carcinoma intraepithelial neoplasia

Front 16

Mechanism of HPV transmission and acquisition

Back 16

1) Sexual intercourse (including anal) - MOST COMMON. ANY type of contact. Condoms can lower risk but unknown how much

2) Mother to newborn - vertical transmission leading to oralpharyngeal papillomatosis often

3) Fomite transmission - hypothesized but not documented. 40% have HPV in finger beds

Front 17

RF for HPV infection men vs women

Back 17

Women - young age, multiple sexual partners, early age of 1st encounter, male partner behavior (previous history penile cancer, previous marriage wife with history of cervical cancer), oral contraceptive use, uncircumcised male partner

SMOKING - cervix has highest concentration of continine next to lung

Men - young age, multiple sex partners, being uncircumcised

Circumcision may lower rates

Front 18

Natural history of HPV infections

Back 18

Normal cervix gets HPV, either clear or continue to have the virus

If don't clear then get mild cytologic abnormalities (ASCUS and LGSIL)

Between 2-5 years this can progress to precancerous lesion

Untreated over 20 years can develop into invasive carcinoma or in some cases may regress on own

Best treatment for precancerous lesion is excision though

Front 19

Classification for Cervical Cytology

Back 19

2001 Bethesda System

Two types of atypical squamous cells (ASC)
1) ASC of undetermined significance (ASCUS)
2) ASC, cannot exclude high-grade squamous intraepithelial lesions (ASC-H)

Squamous intraepithelial lesions (SIL)
1) Low grade SIL: mild dysplasia, cervical intraepithelial neoplasia 1 (CIN 1)
2) High grade SIL (HSIL): moderate and severe dysplasia, CIN 2/3, carcinoma in situ

In the 5-10% of abnormal smears, it is one of these

Front 20

Cervical intraepithelial neoplasia risk

Back 20

CIN begins when it contacts basement membrane (in situ)

Progresses from 1 to 2 to 3 as abnormal cells creeping up to edge of epithelium. Becomes cancer when breaks through basement membrane

CIN2 and above is worrisome, CIN1 is non-malignant/premalignant condition of the virologic disease including condyloma or mild dysplasia

MOST CIN 1 RESOLVES ON OWN

Front 21

Colposcopy, when to biopsy

Back 21

Magnification of cervix using microscope (2-15x)

1) Apply Acetic Acid (vinegar) - accentuate acetowhite changes on cervix
2) Apply Lugol's (high conc. iodine) - stains normal tissue deep brown, Precancerous lesions will be MUSTARD YELLOW because of low glycogen

Biopsy if mustard yellow, cobble stoning or cereberiform

If white just likely condyloma (wart)

Front 22

What is management of precancerous lesions based on

Back 22

BIOPSY or HISTOLOGY

NOT PAP SMEAR RESULT (b/c low sensitivity)

Front 23

What does Cobble stoning mean

Back 23

mosaicism/cobble stoning at margins are due to blood vessels

CIN 3 induces neovascularization so if see cobblestoning 90% of time it is CIN 3 and NEEDS BIOPSY.

Front 24

Risk Factors for HPV Persistence

Back 24

Age > 30 years - Immune system at prime before puberty, as age ability to eradicate infection decreases

Multiple HPV types - most only get 1 or 2 types

Immune suppression

Infection with High risk HPV

Front 25

HPV treatment options

Back 25

NO APPROVED antivirals

Treatment methods are observation and surgery to remove precancerous lesions

Front 26

Process of infection

Back 26

Sexual microtrauma introduces viral particles to epithelium and contact with basal layer

Infects basal layer and lies dormant. Divides a little then stops and remains Episome. As rises towards surface get perinuclear clearing (kioilocytosis) and eventually release of new viral particles as ruptures cell

At risk for CIN 2, CIN 3 or cervical cancer if breaks through BM

High risk lesions break through the BM and go down too

Front 27

Process of getting HPV infection, Testing

Back 27

Women have sex with HPV infected men, in some may get infection in weeks to months, may clear or persist. Low sensitivity detection on PAP or high sensitivity on HR-HPV test here

If persists takes months to years to get cervical lesions which over years will become cancer. Detected with moderate sensitivity on pap and high sensitivity on HR-HPV testing here

Pap cytology - low sensitivity (HIGH FALSE NEGATIVES)

HR-HPV - HIGH sensitivity but lower specificity (Higher false positives but better test because won't miss disease)

USUALLY screen with higher sensitivity test THEN higher specificity but it is opposite here (pap then HR-HPV)

Front 28

Single greatest risk factor for developing cervical cancer

Back 28

PERSISTENT HR-HPV infection

Front 29

3 Settings for HPV testing

Back 29

1) Serial - Cytology screening followed by HPV testing to triage ASC-US (Pap then colposcopy. Most widely used)

2) Parallel - Cytology and HPV co-testing. If BOTH NEGATIVE, can reduce screening to every 5 years because cancer risk is 0.1% during thatn time. IDEAL APROACH

3) Serial - use HPV testing as first test, then pap smear (being studied)

Front 30

Predictive value for negative HPV DNA test

Back 30

Valuable because if women >30 with negative test has extremely low risk of cervical cancer in next 3-5 years. NOT true for pap cytology b/c of false negative rate

Front 31

HPV DNA test benefits

Back 31

More sensitive and reproducible than a Pap test.

Dichotomous (yes or no) instead of interpreted by cytologists

Can be automated

Easier to find "lone renegade" cells

Better for women vaccinated against HPV infection

Pap smear sensitivity - 55% (45% false negative)
HPV sensitivity - 85%

HPV testing outperforms Pap cytology, no screening and visual inspection (if white with acetic acid treat) than any other in terms of outcome

Front 32

Rural screening recommendations

Back 32

Although serial cytology smears are very sensitive, in rural areas women cannot get yearly smears

IF can only be screened once (NOT IDEAL) at age 35 a HPV-DNA test (MORE SENSITIVE) should be used

In developing countries a one time screen at age 35 with HPV testing is the most efficient method with best outcome

Front 33

Is screening needed after vaccination

Back 33

YES, many types not covered by vaccine, vaccine can wear off

Front 34

Prevalence vs Positive Predictive Value

Back 34

Positive predictive value depends on prevalence

IF prevalence drops, PPV plummets because screening test loses inherent value

For HPV, as more people vaccinated, rates will drop slowly and then cytologic abnormalities will be less frequent. This leads to lower PPV of cytology. Pap smear results may not be reliably negative and normal

Because of lowering PPV (due to lowered prevalence) cytology is less valuable and HPV-DNA testing is MORE IMPORTANT

HR-HPV DNA testing is better for primary testing

Front 35

Suggested model for screening

Back 35

Start at age 25 (not 21 b/c cervical cancer extremely rare)
Repeat HPV testing is leading test, if positive perform cytology. 90-95% will never need the cytology because HPV testing likely to be normal and it is more sensitive

Front 36

US doctor education about guidelines

Back 36

75% do not test appropriately b/c US changes guidelines several times in last decade.

60% use HPV testing for HSIL and 40% use HPV testing for women <30. Both should be zero

Front 37

Conclusions

Back 37

HPV testing more efficient and robust primary screening test than cytology ESP. with increasing vaccination (lowered PPV)

HPV vaccination will have a negative impact on performance of cytology, further straining efficacy of screening in low and middle resource areas that cannot get annual screens

New paradigm of HPV test then pap cytology is best and can monitor effectiveness of HPV infection