Primary/Secondary Cervical Cancer prevention

Question 1

General trend in HPV screening recommendations

Answer 1

• initial screening at progressively later ages
• introduce new technologies (test for high risk HPV types)
• progressive lengthening of recommended baseline screening intervals

Question 2

2013 ACS recommendations for cervical cancer screening

Answer 2

• Screen starting at age 21
• Cytology every 3 years between ages of 21 and 29
• Cytology with HPV co-test every 5 years between 30-65
• stop cervical cytology at 65 if adequately screened and not had CIN 2 or CIN 3 lesions for previous 20 years

Question 3

Cytology screening

Answer 3

• 2 main categories: slide-based and liquid-based

Slide-based: fix sample of cervical cells on slide and send to lab

liquid-based: immerse collection in small vial and send to lab

histology= gold standard against which cytology is measured. Sensitivity/specificity of liquid-based higher than slide-based

Question 4

Where do you collect your cervical cell sample

Answer 4

Need to include cells from both sides of squamo-columnar junction-

• premalignant squamous lesions of cervix almost always originate at this junction, so sample must include both squamous and columnar cells to be interpreted

Question 5

normal apperance of cells on pap

Answer 5

• stratified sq epithelium 8-12 cell layers thick
• Superficial squamous cells have abundant cytoplasm with dark pyknotic nucleus
• Endo-cervical– may appear in “honeycomb” array, with distinct cell membranes due to cytplasmic mucin

Question 6

HPV co-testing

Answer 6

use in women > 30 to assess for high risk HPV strains

Question 7

Main categories of cervical dysplasia

Answer 7

Patten (Histology: Mild dysplasia, moderate dysplasia, severe dysplasia, Carcinoma in situ

Richart (histology): CIN (grade I), CIN II, CIN III, CIN IV

Bethesda (cytology)

• AGUS
• ASC-US
• ASC-H
• LSIL (associated with CIN I)
• HSIL (associated with CIN II-IV)

Question 8

ASC-US

Answer 8

Atypical squamous cells of undetermined dignificance

• alterations in squamous cells to warrant close clinical attention but not abnormal enough to be LSIL or HSIL

Question 9

LSIL

Answer 9

cells with unequivocal evidence of HPV infection (perinuclear cytoplasmic clearing)–attributed to aggregation of virally derived proteins around nucleus
- may have markedly enlarged hyper-chromatic nuclei with an abnormal chromatin distribution, irregular nuclear contour, abundant cytoplasm

Question 10

HSIL

Answer 10

changes thought to represent presence of significant premalignant lesion. Higher nuclear to cytoplasmic ratio than LSIL

CINII– moderate dysplasia
CIN III- severe dysplasia and carcinoma in situ

Question 11

What is the chance of progression of SIL

Answer 11

about 25% of all grades of SIL progress to higher grade lesions; of these, about 10% progress to carcinoma in situ and 1% to invasive cancer

Question 12

Histology of cervix

Answer 12

• basal cells cuboidal and they become progressively flattened as they reach surface with small nucleus. Superficial cells are collected during Pap
• with CIN I-III, you lose that progression so that the cells look the same from bottom to top (high nuclear to cytoplasmic ratio)

Question 13

HPV association with cervical cancer

Answer 13

• considered necessary but not sufficient precursor to msot cervical dysplasia/carcinoma
• associated with most cases of invasive squamous cell carcinoma, LSIL, HSIL, endo-cervical adenocarcinoma
• most common STD in America, with lifetime risk about 80% for sexually active individuals
• about half of new infections in 15-24 year olds
• In general population, prevalence is 15%
• infection cleared most of the time in 1-3 years. Those present >1 year associated with increased risk of progression to cervical dysplasia

Question 14

HPV types

Answer 14

• lots of types but GENERALLY

Low risk: 6, 11 (31, 33, 45)- responsible for about 90T of genital warts
High risk: 16, 18–responsible for about 70% cervical cancers

• can use a HPV test screen for 13 of most common high risk types but can’t tell you specific strain
• another test only for 16/18 (Cervista assay)

Question 15

Management of abnormal screening

Answer 15

• depends on pt age, degree of abnormality on current screen, recent screening/treatemnt hx, and pregnancy status

RISK OF CIN III in next 5 yrs:
- 5%: refer for colposcopy

Question 16

Management of abnormal biopsy

Answer 16

• depends on age, current screen, recent screening/treatment hx, pregnancy status
• if therapy indicated treat entire transition zone: cryotherapy, laser ablation, excision
• success rates as high as 95%

Question 17

Gardasil

Answer 17

• HPV vaccine approved in 2006
• quadrivalent: 6, 11, 16, 18 virus-like particle (subunit)
• series of 3 doses at 0, 2, 6 months for women between 9 and 26
• efficacy of 98.8% in trails of reduction of genital warts, CIN2, CIN3 and adenocarcinoma in situ among women naiive to 4 subtypes

Question 18

Cervarix

Answer 18

• bivalent vaccine covers HPV 16/18
• approved 2009
• 3 doses (0, 2, 6 months)

Question 19

efficacy of HPV vaccine

Answer 19

• quadrivalent better for disease related to HPV 6/11 but bivalent appears more effective preventing disease attributable to viral types not covered by vaccine (i.e. HPV 31 and 45)
• goal to give all 3 doses prior to sexual activity

Question 20

Gardasil -9

Answer 20

9-valent vaccine recently approved adds protection against 31, 33, 45, 52, 48, hoping to prevent 90% of cervical cancer.

Question 21

Acceptance of vaccine

Answer 21

• relatively good receptance among physicians
• variable rates of parental acceptance; less likely in eclectic subgroups
• CDC study: about 25% didn’t intend to vaccinate daughters in next 12 months
• top 5 reasons parents wouldnt vaccinate in next 12 months– not needed, vaccine not recommended, vaccine safety concerns, lack of knowledge about vaccine/disease, daughter not sexually active
• lower rates in boys
• generally well accepted in young adults (college ages)–higher when cover HPV 6/11

Question 22

Predicted economic impact of vaccine

Answer 22

first positive peak for genital warts and second for CIN, third/final peak for cervical cancer reduction about 30 years into vaccination program

Question 23

HPV vaccine impact on men

Answer 23

• helps reduce genital warts, anal/penile/OP cancers
• about 25% squamous cell OP cancers assciated with HPV
• possible risk reduction for penile/anile cancers
• herd immunity– will decrease female disease
• immunologic responses similar to women
• CIP recommend vaccination for boys 9026 with quadrivalent vaccine

Question 24

Vaccine in developing world

Answer 24

• burden of HPV_related dz larger than in developed world
• cervical cancer single largest cause of years of life lost from cancer in developing world
• Cost! very expensive- look at ways to reduce
• hard to administer especially 3 separate times, esp with variable school attendance
• prevalence rates for various types different, so various impact
• governments likely to prioritize vaccinations for food, water, and airborne illnesses instead of cervical cancer

Question 25

HPV vaccination in HIV infected individuals

Answer 25

• benefit being researched
• potential difference in vaccination strategies with those born with HIV vs getting later in life.
• Issues: point in HIV infection when vaccinated, preexisting exposure to HPV, viral load, CD4 count, potential role of highly active antiretroviral therapy
• study in south africa showed promising results, equivalent immune responses regardless of HIV status, CD4 count viral load, and use of anti-retroviral therapy with no big impact on HIV dz measured by viral load or CD4 count