• Nathan Riley, MD

Obgyno Wino Podcast Episode 93 - Cervical Cancer Screening and Prevention

“All photographs are memento mori. To take a photograph is to participate in another person’s (or thing’s) mortality, vulnerability, mutability. Precisely by slicing out this moment and freezing it, all photographs testify to time’s relentless melt." - Susan Sontag

2017 Malbec from BenMarco

PB #168, Published October 2016 (Reaffirmed 2018)

Five Pearls

1. Regular screening through cytology and/or HPV detection can prevent cervical cancer, which takes years on years to develop.

2. Most HPV infections or even early dysplasia are cleared by immune system spontaneously.

3. Screening can be discontinued at age 65 for healthy women who have been consistent with screening and who have no history of high-grade dysplasia or carcinoma

4. If your patient has had CIN 2, CIN 3, HSIL, or carcinoma at any point in 20 years prior to total hysterectomy, routine screening should be continued (cytology alone q3 years is reasonable).

5. HIV complicates HPV/cervical dysplasia management significantly.

Western medicine's best guess as to how this happens

- human papilloma virus (HPV) enters the epithelial cells of the cervix and forces them to begin misbehaving, eventually lead to neoplasia (cancer)

- some types of HPV are oncogenic (cancer-causing) while others are not

- HPV-16 and HPV-18 are most commonly cited oncogenic strains

- HPV-16 accounts for 55-60% of infections; HPV-18 an additional 10-15% (an additional 12 strains comprise the remainder)

- HPV is passed through sexual activity/exchange of bodily fluids

Cervical cancer doesn't happen overnight

- regular screening is worth your time

- 50% of women diagnosed with cervical cancer never had a single cytology screening (ie PAP screen)

- 10% hadn't been screened within 5 years prior to diagnosis

- HPV infection (and associated neoplasia) is cleared by most people in 1-2 years, though less likely if strains 16 or 18, smoking history, HIV, and in patients >30 years old

- persistent infection beyond 1-2 years indicates higher likelihood of progression to cancer

- it takes decades to develop cervical cancer

Note: for this practice bulletin, all "HIV" recommendations should be applied to non-HIV immunocompromised patients (not a ton of data, but it'll have to do for now)

Before we continue...a lesson on cervices

- the vagina and cervix are lined with squamous epithelial cells

- the endocervical canal is lined with columnar cells

- the line demarcating where the squamous cells meet the columnar cells is called squamocolumnar junction or SCJ

- when a woman reaches puberty, the SCJ will be visible on speculum exam

- as she gets older, the columnar cells gradually convert squamous epithelial cells, a process known as squamous metaplasia

- with time, the location of the SCJ crawls its way from the outside of the cervix (ectocervix) into the endocervical canal out of sight from speculum exam

- the region between the original location of the SCJ and the present SCJ location is known as the transformation zone

SCJ barely visible at the external os

- any clusters of columnar cells that haven't fully converted to squamous cells will appear as little pockets on ultrasound (nabothian cysts)

- squamous epithelial cells produce glycogen in response to estrogen

- glycogen stains brown with application of iodine (Lugol's solution)

- with age, glycogen production decreases du to drop in estrogen

- acetic acid will also be taken up into the cytoplasm of epithelial cells

- with age, these cells have increasing nuclear-cytoplasmic ratio (N/C ratio) and therefore less staining (interestingly, atypical cells also have an increased N/C ratio...keep this in mind)

Classification of cervical intraepithelial neoplasia (CIN)

- will be reported on tissue biopsy

- CIN 1: reflect acute HPV infection

- CIN 2: wide inter-observer variability, so optimal management is controversial

- CIN 3: 30% will progress to cancer within 30 years if left untreated (this is why surveillance is never more frequent than 12 months)

- new classification system being used by ASCCP has just two categories: high-grade squamous intraepithelial lesion or low-grade (HSIL and LSIL, respectively)

Note: cytology (e.g. from PAP smear) will be described as high grade or low grade if abnormal. The CIN system is used for describing histologically what a tissue biopsy looks like under a microscope. Cytology versus histology.

Dysplasia screening

- PAP: liquid or conventional ("smear") methods are available

- lubes, discharge, or blood can interfere with interpretation if using the liquid technique

- liquid technique has several advantages: single swab can be used for cytology, HPV testing, and chlamydial/gonorrheal infection evaluation

- also is easier to interpret than the conventional method

- despite the advantages, studies haven't found an improvement in detection rate of CIN through liquid-based screen

- the way that the results are reported is incorrigibly complicated...see box 1

- 1st key component: the collection is not satisfactory if it doesn't include transformation zone, aka the squamocolumnar junction, aka where squamous epithelial cells meet columnar epithelial cells); this metaplastic region is a likely location for dysplasia to arise so watch out!

- 2nd key component: if negative for intraepithelial neoplasia or malignancy, don't sweat it; if cells look abnormal, they may be described as merely atypical or as being reflective of high- or low-grade intraepithelial neoplasia

- 3rd key component: any other findings may be clarified, such as the presence of endometrial cells on PAP in a peri- or postmenopausal woman

What's the role of HPV testing?

- for detection of top 13-14 oncogenic HPV strains (no use is looking for the non-oncogenic strains)

- can be useful in determining the need for colposcopy in the case of abnormal cells of unknown significant (ASC-US) on cytology ("reflex testing"

- can also be used as an adjunct screen with PAP ("cotesting") in women 30-65 years of age

- there is also a specific HPV test that was approved in 2014 by the FDA as a primary means of screening for cervical cancer in women 25+

Note: If HPV testing alone is utilized as a primary screen, repeat q3 years is adequate for negative results. If positive, genotyping for HPV 16 or 18 should be conducted. If genotyping is negative, then cytology should be performed. If this is negative, then repeat HPV testing should be performed 1 year later.

When is HPV genotyping useful?

- can check specifically for HPV 16 and/or 18

- useful for women who undergo cotesting and are reported to have negative PAP but positive high-risk HPV test

HPV vaccine for prevention of cervical cancer

- three vaccine options in the U.S.

- bivalent: covers 16 and 18 (+cross-coverage for up to 30% of other oncogenic strains)

- quadrivalent: 16, 18, 6, and 11 (+cross-coverage for up to 30% of other oncogenic strains)

- bivalent and quadrivalent vaccines are comprised of three doses

- 9-valent: 16, 18, 6, 11, and five others (getting this one as an addition to a full course of the bivalent or quadrivalent options is not recommended)

- series can begin as early at age 9, and it's recommended that the course be completed by age 26

- in some countries with adherence to universal cervical cancer vaccination (e.g. Australia), cervical cancer rates have dropped

At what age should screening begin?

- age 21 (earlier can be considered if patient has HIV or is otherwise immunocompromised)

- risk of cervical cancer at younger ages is so darn low (and likelihood of clearing dysplasia and HPV infection so high) that screening in young girls isn't cost effective

- besides, screening is invasive and uncomfortable and abnormal results carry significant stigma

- if a young woman has HIV, then screening should begin within the first year of sexual activity or within 1 year of HIV diagnosis (whichever comes sooner), but no later than age 21

Note: even though we aren't screening young girls, this doesn't mean that creating a safe space for safe sex education isn't appropriate for young girls...

How often should we be screening?

- dependent on age and prior results

- as long as results are a-ok:

- 21-29 years: cytology alone q3 years; cotesting not recommended (risk of HPV is super high along with their likelihood of clearing infection)

- 30-65 years: costesting q5 years is preferred (extremely low risk of developing CIN 2 or 3 in the 5 years following negative cotesting); cytology alone q3 years is acceptable

- more frequent screening may be recommended in HIV or if history of high-grade dysplasia

- in the case of HIV, cytology alone is recommended at <30 years, and it should be done annually; after 3 negative PAPs, you can transition to q3 years for life

- for HIV patients >30 years, cytology or cotesting are both reasonable; again, after 3 negative annual PAPs, you can transition to q3yr screening; after 1 negativ cotest, you can transition to q3yr cotesting

When is it reasonable to discontinue screening?

- again...depends on history, but age 65 is a good time to stop OR if they undergo total hysterectomy

- age 65 IF (a) screening has been consistent and adequate in the years leading up to age 65 and (b) no history of CIN 2 or higher

- if your patient is undergoing total hysterectomy (i.e. removal of the cervix), then screening can stop after the surgery IF they have no history of CIN 2 or higher

- in the event that your patient undergoes hyst but does have a history of high-grade dysplasia (CIN2, CIN3, or HSIL on any screening/biopsy/excision), CIN or carcinoma can reappear at the vaginal cuff

- if your patient has had CIN 2, CIN 3, HSIL, or carcinoma at any point in 20 years prior to her hyst, routine screening should be continued (cytology alone q3 years is reasonable)

- patients with HIV should continue to be screened for life

- HPV testing alone is not recommended for women without a cervix

How is ASC-US managed?

- not really a diagnosis but rather a reflection of diagnostic uncertainty (likely that there are patches of normal epithelium, low grade epithelium, and potentially high grade epithelium all in the same sample!)

- if HPV wasn't checked, test for that

- if that's negative, then cotesting is repeated in 3 years (if negative again, can return to regular progamming)

- super low risk of CIN 3 in setting of negative HPV, but slightly higher than truly "negative" cytology result

- if your patient has HIV w/ ASCUS on cytology, management depends on age:

>21 years: check HPV. If negative, return to regular screening. If positive, refer for colpo. If HPV testing not available, repeat cytology in 6-12 months

<21 years: repeat cytology in 6-12 mos (if you accidentally collected an HPV test that resulted as negative, they can return to regular screening)

What if on cotest HPV is positive, cytology negative?

- first you curse at the sky

- then you relax because significant pathology is small in this cohort

- over 5 years, CIN3 risk is 5%, cancer risk is 0.3%

- remember that most HPV infections will clear within 6-12 months

- if HPV 16 or 18 is present, 10% chance of developing CIN 3 in a matter of a few years (shit's nasty ya'll...)

- see table 2 for management (no exception for HIV)

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