Preinvasive Disease and Cervical Carcinoma

Case: You are a Family Physician, who has known Janice since she was 13 years old; she is now 26 years old and has come to you wondering when she should have her first PAP?

Objectives

Session Level Objectives (SLO) 22:

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• Discuss an approach to screening for HPV infection, cervical dysplasia and neoplasia.
• Discuss investigation and management of cervical dysplasia including the role of colposcopy.

Background

Classification of Preinvasive Cervical Disease

• “Carcinoma in situ” (CIN I, II, III) → replaced with high grade and low grade classification (LSIL, and HSIL)
• This lowers the intraobserver differences, and CIN II and CIN III are really representing the same thing

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Clerk tip: what is a layperson way of saying the lesion “will regress”?

Background

• Non-enveloped ds DNA virus
• Infect mucous and cutaneous membranes of the male and female anogenital tract
• Encodes 6 early proteins (E1, D2, E4, E5, E6, E7), and 2 late proteins (L1, L2)
• Replicates through E6 and E7 proteins
• E6: binds to p53 and degrades it, so it removes the cell cycle restriction checkpoint
• E7: extends cell life and increases HPV infected cell number through many different pathways
• Overall- they cause host cell genome instability and makes this more susceptible to oncogenesis
• Over 100 types of HPV but ~40 infect the genital tract
• HR HPV subtypes: HPV 16, 18, 45, 31, 33, 35, 52, 58
• LR HPV subtypes: HPV 6, 11

Human Papillomavirus (HPV)

Background

Human Papillomavirus (HPV)

• HPV is the most common STI
• Considered ubiquitous
• Over 80% of men & women will be infected at some point in their life
• Skin and mucosal surfaces: Condoms help but are not 100% at protecting [“boxer short area”]
• Infects at sites of epithelial microtrauma
• Increase in prevalence after onset of sexual activity
• HPV exposure → Most clear within 2 years
• Median time from HPV HR exposure to HSIL: Within 5 years
• If not treated, then ~30% by 30 years will progress to invasive cancer
• Clearance is complex
• Negative HPV testing does NOT mean negative HPV, but could be subclinical, or latent
• Younger women and low risk HPV clear quicker
• HPV subtype is the strongest predictor of viral persistence (ie HR HPV subtype)

Background

Human Papillomavirus (HPV) Risk Factors for Persistence and Recurrence

• Early age of first sexual encounter
• Multiple sexual partners
• Multiparity
• Long-term oral contraceptive use
• Immunocompromised
• Steroids
• Smoking
• Renal failure
• Diabetes
• HIV

Background

HPV Infection

• HPV infection of the transformation zone with an oncogenic HPV strain

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Persistent Infection

• Persistence of the HPV infection → Atypical Squamous Cells of Undetermined Significance (ASC-US) → Low-grade Squamous Intraepithelial Lesion (LSIL)

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Pre Cancer

• Progression to High Grade Squamous Intraepithelial Lesion (HSIL)

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Cancer

• Progression to invasive carcinoma

How does HPV lead to Cervical Cancer?

QUIZ TIME!

TRUE OR FALSE:

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Most people who become infected with HPV are infected for life.

QUIZ TIME!

TRUE OR FALSE:

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Once a patient has been infected with HPV, they are protected from re-infection with that HPV strain

Transformation Zone

• Transformation zone is the area around the opening of the cervix where the endocervix (inner part) and ectocervix (outer part) come together
• This area contains both glandular cells from the endocervix and squamous cells from the ectocervix
• Most abnormal cell changes and most cervical cancers begin in this squamocolumnar junction, or what we sometimes call the transformation zone

Background

Cervical Cancer Screening

• Cervical cancer screening programs are really designed at a population level to detect the preinvasive disease that represent the majority (ie HPV related, following the typical natural history)
• Primary Prevention
• HPV Vaccination
• Secondary Prevention
• HPV Vaccination (can still prevent another strain/re-infection)
• Pap Smears: Sampling of the Transformation Zone, HPV testing
• Treating precancerous lesions
• Treatment of Cervical Cancer
• Surgery
• Radiotherapy
• Systemic treatments

Background

Primary Prevention: HPV Vaccination

HPV Vaccine Efficacy

Background

HPV Vaccination: Dosing Schedule

A lot of work to do…

QUIZ TIME!

TRUE OR FALSE:

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Men and women can develop HPV related cancer or warts around the anus without ever having had anal intercourse.

QUIZ TIME!

TRUE OR FALSE:

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HPV can be passed on by deep kissing.

Background: Secondary Screening

(PAP TEST)

• Alberta Cervical Cancer Screening Guidelines: https://www.albertadoctors.org/media/w3vpspf2/cervical-cancer-screening-cpg.pdf

Background: Secondary Screening

Background: Secondary Screening

Background: Secondary Screening

Background: Secondary Screening

Background: Transition to HPV Primary Screening

What is Cervix Self-Screening?

• Uses a small, Q-tip like swab to collect a sample from your vagina
• You don’t need to see a healthcare provider; you can do it yourself in the privacy of your home
• Your sample is mailed to the lab using the pre-paid envelope included with the Cervix Self-Screening Test Kit.

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What is Cervix Self-Screening Pilot Projects?

• Led by Alberta Cervical Cancer Screening Program in Alberta Health Services
• The purpose of the project is to increase cervical cancer screening access & participation in 3 under-screened populations in Alberta:
• 1) Indigenous
• 2) Newcomer
• 3) Rural/Remote

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Background: Transition to HPV Primary Screening

Who is eligible?

• May be eligible to self-screen as part of the pilot project if identify as:
• 1) Indigenous
• 2) Newcomer (someone who has lived in Canada less than 10 years)
• 3) Live in a rural or remote part of Alberta (Lives outside of the following communities: Fort McMurray, Grande Prairie, Edmonton, Red Deer, Calgary, Lethbridge, Medicine Hat)
• Must also be:
• 1) 25-69yo
• 2) Have a cervix
• 3) Have had sexual contact with another person of any gender
• 4) Have a valid Alberta Health Care number

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Do not complete cervix self-screening if:

• 1) Have had a PAP test in last 3 years Or completed cervix self-screening in last 11 months
• 2) Currently pregnant
• 3) Had invasive cervical cancer
• 4) Last PAP test abnormal
• 5) Currently in colposcopy care or have been discharged in last 11 months
• 6) Have bleeding after sex, between periods or after menopause

Background: Transition to HPV Primary Screening

Background: Resources

Additional Resources (If Interested):

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https://screeningforlife.ca/wp-content/uploads/Cervix-Self-Screening-Instructions.pdf

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https://ubccpd.ca/sites/default/files/documents/June%205%20Webinar%20Slides_0.pdf

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https://screeningforlife.ca/cervical/get-screened/cervix-self-screening-pilot-project/

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https://screeningforlife.ca/wp-content/uploads/Cervix-Self-Screening-Instructions.pdf

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https://screeningforlife.ca/wp-content/uploads/Cervix-Self-Screening-Results.pdf

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Gynecological History

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• History of Presenting Illness
• OPQRST/SOCRATES
• Review of Systems:
• Genitourinary: Pelvic pain, uterine/prolapse, vaginal dryness, discharge, vulvar pruritus, bleeding
• Urinary: Frequency, urgency, hematuria, dysuria, incontinence, retention, pain
• Gastrointestinal: Nausea/vomiting, bowel movements, hematuria, melena stools, incontinence
• Gynecological History
• Menses: Age of menarche, LMP, cycle length, regular flow, pain, intermenstrual bleeding, abnormal bleeding, fatigue
• Contraception: Current method, satisfaction, past methods, complications, why discontinued
• Last PAP, history of abnormal paps (if so, diagnosis, treatment and follow-up)
• Persistent varginal discharge, irritations, known cervical lesions?
• Sexual History: Age at first sexual encounter, number of lifetime sexual partners, postcoital bleeding, dyspareunia/pain during intercourse, history of STIs/PID
• Prior vaccination against HPV
• History of procedures to uterus/cervix
• Obstetrical History
• GTPAL
• Year, GA, type of delivery, complications, fetal weight, current health
• Past Medical History
• Past Surgical History
• Family History: Breast, ovarian, colon cancer
• Medications
• Allergies
• Social History
• Occupation
• Smoking
• ETOH
• Substance Use

Physical

Exam

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What should you look for on exam?

• Soft/rigid, distention, tenderness, uterus midline/firm, palpable masses, bowel sounds, peritonitic

Abdominal Exam

• Erythema? Dermatoses?

External Vulvar Exam

• Location of cervix
• Fixed adnexae? Masses? Tenderness?

Bimanual Exam

• Visualize cervix & examine if friable, visible cervical lesions, erosions, masses, bleeding with exam?
• Complete PAP
• Swabs for Bacterial Vaginosis, Yeast, Trichomonas, Gonorrhea/Chlamydia if indicated

Speculum Exam

• Vitals
• Well or unwell?
• Informed consent
• Patient positioning

General

Case: You are a Family Physician, who met Janice when she was 13 years old, she is now 26 years old and has come to you wondering when she should have her first PAP?

Janice: All my friends have had their PAPs recently? When am I due for mine Doctor?

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You (The Family Doctor): Janice! So nice to see you again! Asymptomatic average risk women who are or have ever been sexually active, will start after 3 years from onset of sexual activity or age 25yo, whichever is LATER. It's been a while since I've seen you, would it be okay if I asked you some questions & we plan to complete your PAP today?

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Janice: Yes, let's do it!

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Case 1: Janice 26yo nulliparous woman presents for routine PAP screening

Gynecological History

• Janice notes following pertinent history:
• Regular menses, LMP August 3rd, 28 day cycles, no history of intermenstrual bleeding
• First age of sexual encounter 20yo, history of two sexual partners, currently in monogamous relationship, IUD in situ, satisfied with contraceptive method, nil postcoital bleeding, nil history of STIs/PID
• Nil history of PAPs
• Has received Gardasil 9 Vaccines x 2 doses in school system
• 3 year pack history
• Nil family history of cancer

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Physical Exam

• VS: BP 118/77, HR 72, RR 16, Temp 36.8C, O2 sat 100% RA
• You review the steps to PAP test with Janice & obtain informed consent. You gather your instruments/materials: Gloves, speculum, light, lubricant, PAP smear
• Your nursing colleague is present in the room as a chaperone
• Patient positioned in Lithotomy
• Abdominal exam otherwise unremarkable, external genitalia & bimanual exam otherwise unremarkable
• Speculum exam with cervix visualized & not friable, nil lesions/erosions/bleeding. PAP smear completed.

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Counselling

• You discuss smoking cessation with Janice, reviewing association with HPV infection
• You inform her that you will follow-up with her on her PAP test results

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Case 1: Janice 26yo nulliparous woman presents for routine PAP screening

• Janice is asked to return to the office to review Pap Smear Results
• Pathology report notes Atypical Squamous Cells of Undetermined Significance (ASC-US)
• What does this mean?

Case 1: ASC-US

Atypical Squamous Cells of Undetermined Significance (ASC-US)

• Given Janice is 26 years old, we will plan to repeat her PAP test every 6 months for one year

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Case 2: Janice returns in 6 months for repeat PAP Test

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Gynecological History

• Follow aforementioned template
• Janice’s history is primarily unchanged from previous, though she notes that she has now stopped smoking

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Physical Exam

• VS: BP 120/60, HR 69, RR 16, Temp 36.2C, O2 sat 100% RA
• You review the steps to PAP test with Janice & obtain informed consent. You gather your instruments/materials: Gloves, speculum, light, lubricant, PAP smear
• Your nursing colleague is present in the room as a chaperone
• Patient positioned in Lithotomy
• Abdominal exam otherwise unremarkable, external genitalia & bimanual exam otherwise unremarkable
• Speculum exam with cervix visualized & not friable, nil lesions/erosions/bleeding. PAP smear completed.

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Pathology Results from PAP test return as:

• Low Grade Squamous Intraepithelial Lesion (LSIL)
• What does this mean?

Case 2: LSIL

Low-Grade Squamous Intraepithelial Lesion (LSIL)

• Given Janice is 26 years old, her first PAP test was ASC-US & now her repeat PAP test 6 months from previous is LSIL, she will be referred to Colposcopy

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Case 3: You haven’t seen Janice for a few years now, & she returns to your office at 29yo

Janice: Hi Doc! Things have been so busy for me these last few years. I haven’t been able to go to Colposcopy. Do you have their number?

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You (The Family Doctor): Janice! So nice to see you again! Given that it has now been greater than 3 years after your last Pap test, we will need to repeat it today if that’s okay with you? I’d like to ask you some questions first.

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Janice: That sounds great!

Case 3: 29yo nulliparous woman, history of ASC-US & LSIL, lost to follow-up

Gynecological History

• Follow aforementioned template
• Janice notes following pertinent history:
• Regular menses, LMP November 4th, 28 day cycles, no history of intermenstrual bleeding
• First age of sexual encounter 23yo, history of five sexual partners, currently in polyamorous relationship, IUD previously removed due to pain as per patient, now on birth control pill, denies postcoital bleeding, nil history of STIs/PID
• Has received Gardasil 9 Vaccines x 2 doses in school system, did get another dose last year
• Previous smoker, though nil x4 years now
• Nil family history of cancer

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Physical Exam

• VS: BP 114/68, HR 70, RR 16, Temp 36C, O2 sat 100% RA
• You review the steps to PAP test with Janice & obtain informed consent. You gather your instruments/materials: Gloves, speculum, light, lubricant, swabs for BV/yeast/trichomonas and Gonorrhea/Chlamydia, PAP smear
• Your nursing colleague is present in the room as a chaperone
• Patient positioned in Lithotomy
• Abdominal exam otherwise unremarkable, external genitalia & bimanual exam otherwise unremarkable
• Speculum exam with cervix visualized. Cervix appears friable & query erosion. Nil lesions noted. Aforementioned swabs & PAP smear completed.

Case 3: 29yo nulliparous woman, history of ASC-US & LSIL, lost to follow-up

You (The Family Doctor): Hi Janice, your PAP test results have returned as High Grade Squamous Intraepithelial Lesion (HSIL), HPV positive. We’ll have to refer you to Colposcopy.

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Janice: What do they do at Colposcopy?

Case 3: HSIL

High-Grade Squamous Intraepithelial Lesion (HSIL)

• 30% will turn into cancer in 30 years (with an average of 10-12 years)
• Referred to Colposcopy: See, rule out cancer, complete biopsies, treat HSIL lesions
• 1. Characterize the transformation zone

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• 2. Topical Agents to identify cancer cells
• Acetic Acid - 3% Acetic Acid placed onto the cervix (temporarily denatures proteins & and dysplastic cells have more protein in them so they become more opaque)
• Lugol's Iodine - Schiller's Iodine test; Glycophilic (Stains glycogen containing tissue), therefore mature squamous epithelium stains brown while immature/columnar epithelium/CIN/invasive cancer do NOT
• 3. Cervical Biopsy (if indicated)
• Biopsy at acetic white changes
• 4. Endocervical Curettings & Endometrial biopsy (if indicated)
• If it appears that going into endocervical canal, can complete endocervical curettings

Case 3: HSIL

High-Grade Squamous Intraepithelial Lesion (HSIL)

• Often progresses to invasive disease, so needs biopsy of focal suspicious lesions & treatment
• Treatment:

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• Follow-Up after Treatment: Should have follow-up Colposcopy with HPV test of cure in 6 months
• If negative → Yearly PAP thereafter
• If positive → Follow-up Colposcopy every 6 months

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Case 4: Mary (Janice’s friend) has heard about Janice’s gynecological history, and now presents to you at 34yo with history of new post-coital bleeding & is due for a PAP

Gynecological History

• Follow aforementioned template
• Mary notes following pertinent history:
• G2 P1 (Uncomplicated spontaneous vaginal delivery in 2020)
• Regular menses, LMP August 7th, 28 day cycles, history of intermenstrual bleeding & new post-coital bleeding
• First age of sexual encounter 15yo, history of 7 sexual partners, currently in monogamous relationship, using withdrawal method for contraception, history of Gonorrhea & PID when she was 16yo
• Last PAP 6 years ago and was Negative for Intraepithelial Lesion (NIL)
• Has received Gardasil 9 Vaccines x 2 doses in school system
• Nil family history of cancer

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Physical Exam

• VS: BP 120/77, HR 72, RR 16, Temp 36C, O2 sat 100% RA
• You review the steps to PAP test with Janice & obtain informed consent. You gather your instruments/materials: Gloves, speculum, light, lubricant, PAP smear, endometrial biopsy (given history of abnormal uterine bleeding as well)
• Your nursing colleague is present in the room as a chaperone
• Patient positioned in Lithotomy
• Abdominal exam otherwise unremarkable. External genitalia appeared otherwise unremarkable. On bimanual exam, cervix posterior, cervical motion tenderness noted, query palpable mass at level of cervix/near to lower uterine segment, uterus otherwise anteverted/midline/firm, small amount of blood noted on glove after exam
• Speculum exam with cervix visualized. Cervix appears friable with visible erosion. Nil lesion or mass of external cervix itself noted. PAP smear completed. Swabs collected for BV/yeast/trichomonas and Gonorrhea/Chlamydia. Endometrial biopsy completed. Some difficulty with completing endometrial biopsy, resistance felt near the internal cervical os, query mass palpated.

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Case 4: Mary (Janice’s friend) has heard about Janice’s gynecological history, and now presents to you at 34yo with history of new post-coital bleeding & is due for a PAP

Mary’s PAP results come back as HSIL, HPV positive. She is seen in Colposcopy and unfortunately results return for squamous cell carcinoma.

Case 4: Invasive Cervical Carcinoma

Invasive Cervical Carcinoma

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• Epidemiology
• 90% are in low/middle income countries
• 40% are in those who have not had screening
• 10% in those who had had no screening in preceding 5 years
• Risk Factors
• Lower SEs
• LMIC
• Reproductive factors: Early coitarche, multiple partners, Hx of STIs, ?OCP use
• Immunosuppression
• HPV infection
• Smoking
• Diagnosis
• Microscopic tumors (ie you cannot tell)
• Colposcopy: Most consistent sign is atypical vessels
• LEEP, biopsy
• Macroscopic tumors
• Examine
• Biopsy
• Imaging
• Pattern of Spread
• Direct invasion
• Lymphatic: Usually sequential (very uncommon for there to be positive nodes higher up with negative pelvic nodes!)
• Hematogenous

Case 4: Invasive Cervical Carcinoma

Invasive Cervical Carcinoma

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Diagnosis & Staging

• Colposcopy and biopsy, endocervical curettage, conization
• CBC, lytes, liver function, hCG
• CXR (or CT chest)
• MR Pelvis (protocolized specifically for cervix cancer at the Cross Cancer Institute), determines tumor size, parametrial involvement, vaginal extension, nodes (not as good as CT), depth of invasion
• CT Abdo/Pelvis - Evaluates lymph nodes, liver, urinary tract, bony structures, not as good at depth of invasion as MR
• CT PET - FDG (labelled glucose), size needs to be >1cm to be accurate, inflammation can be overcalled, helpful for lymph nodes affected but not enlarged

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Histological Types

1. Squamous Cell - 69% cervical cancer
• Precursor = HSIL
• 99% HPV-related - Subtypes 16, 18, 58, 35, 45
• Decreasing (Due to screening)
• Pathology: Endophytic/ulcerative
2. Adenocarcinoma - 25% cervical cancer
• Precursor = AIS ("skip lesions")
• HPV Subtypes 16, 18 45, 31, 33
• Pathology: Exophytic, "barrel shape"
3. Adenosquamous
4. Mucinous - Rare
5. Small and Large Cell Neuroendocrine - Aggressive

Case 4: Invasive Cervical Carcinoma

Invasive Cervical Carcinoma: Staging

2018 FIGO Staging

https://pubs.rsna.org/doi/abs/10.1148/radiol.2019190088?journalCode=radiology

Case 4: Invasive Cervical Carcinoma

Invasive Cervical Carcinoma: Treatment

Based on specific staging, will vary between:

1. Surgery
1. Radical Trachelectomy (For those who are Stage IA1 with Lymphovascular Space Invasion or Stage IA2 who want to preserve fertility)
2. Radical Hysterectomy (Removal of uterus, cervix, parametria)

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1. Curative Intent Chemotherapy/Radiotherapy
1. Curative Intent
2. Adjuvant Therapy
3. Palliative

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1. Systemic Therapy (For Stage IVB)
1. (1) Chemotherapy (Carboplatin & Placlitaxel)
2. (2) Bevacizumab
3. (3) Pembrolizumab or Immunotherapy

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A word on counselling

Every appointment is an opportunity to inquire about vaccination status

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Affects both men (oropharyngeal, penile, anal) and women (cervical, vaginal, vulvar, oropharyngeal, anal), and the rates of oropharyngeal cancers are on the rise

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Also take this moment to reflect on YOUR OWN vaccination and screening status

Authors

Case author, Dr Preety Najar

Thank you to Dr Ameeta Singh, Infectious Disease Specialist, for contributing slides

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References

Alberta Health Services. (n.d.). Cervical cancer screening. Alberta Health Services.

https://www.albertahealthservices.ca/findhealth/service.aspx?Id=1016155

Aubrey, C. (2022). Preinvasive disease and cervical carcinoma. [PowerPoint slides].

Berek, J. S., & Hacker, N. F. (2020). Berek & Hacker’s gynecologic oncology (6th ed.).

Lippincott Williams & Wilkins.

Canadian Partnership Against Cancer. (2022). HPV vaccine access in Canada: 2022

report. Canadian Partnership Against Cancer.

https://www.partnershipagainstcancer.ca/topics/hpv-vaccine-access-2022/

Cohen, P. A., Jhingran, A., Oaknin, A., & Denny, L. (2017). Cervical cancer. In Cancer: Disease control

priorities, third edition (volume 3): Cancer (3rd ed.). The International Bank for Reconstruction and Development / The World Bank. https://www.ncbi.nlm.nih.gov/books/NBK431093/

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Keener, A. B., Rodrigues, L., & Zhang, J. (2023). Innovations in cancer therapy: A review of recent

developments. Current Oncology, 30(6), 431. https://doi.org/10.3390/curroncol30060431

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Lakhman, Y., Park, K. J., Akin, O., Sohn, M. J., Zheng, J., Goldman, D. A., & Soslow, R. A. (2019).

Differentiation of low-grade from high-grade endometrial stromal sarcoma: Diagnostic accuracy of MRI. Radiology, 293(2), 540-550. https://doi.org/10.1148/radiol.2019190088