Case 4: Arielle D - Cervical Cancer

Immunologic Memory

1. Vaccine-induced exposure to antigen

2. Primary Immune Response: B + T cell activation

3. Memory Cell Formation:

• B Cell: Specialized plasma cells arrested in differentiation 

• T Cell: Specialized T cells differentiated into…

  • Effector memory T cells

    • CD4+: Produce proinflammatory cytokines

    • CD8+: Contain preformed perforin granules

  • Central memory T cells

    • In secondary lymphoid tissue

    • Activation = Differentiate into effector memory T cells

4. Re-Exposure: Memory cell activation

• B Cells: Secrete specific antibiotics = Rapid secondary immune response

• T Cells: Release cytokines + cytotoxic perforin

Herd Immunity

Percentage of population immunized against infectious pathogens to protect unvaccinated individuals

Threshold depend on infectiousness of pathogen

• 1 - 1/R0

• Easier spread = Higher immunity levels

Cervical Cancer: Description

Invasive carcinoma in transformation zone of cervix

• Transformation Zone: Transition from squamous epithelium (ectocervix) → Columnar epithelium (endocervix)

Cervical Cancer: Classifications

Squamous cell carcinomas

Adenocarcinomas

Cervical Cancer: Squamous Cell Carcinomas

Epithelial cancer from squamous cells

Types:

• Large cell keratinizing

• Large cell nonkeratinizing

• Papillary squamous cell

Epidemiology: 80%

Cervical Cancer: Adenocarcinomas

Epithelial cancer from glandular tissue

Types:

• Mucinous

• Endometrioid

• Serous

• Clear-cell

  • Rare

  • From Diethylstilbestrol (DES) exposure

Epidemiology: 20%

Cervical Cancer: Epidemiology

Risk factors…

• STI

  • HPV

  • HIV

  • HSV

  • Chlamydia

• Smoking 

• Multiparity

• Pregnancy ≤ 19 years

• Family history

• Long-term use of hormonal contraceptives

• Multiple sex partners

• Low SES

• Systematic

  • No free screening program

  • No care coordination + follow-up

  • Medical system mistrust

  • No vaccinations

Cervical Cancer: Etiology

HPV infection

• HPV 16 + 18

Cervical Cancer: Pathophysiology

1. HPV infect basal epithelial layer cells (Transformation zone) = Infiltrate through small tears in mucosa from sexual activity

2. HPV integrate into cells = Synthesize oncogene + tumor suppressor proteins = Arrest cell cycle + increase DNA damage

3. Persistent infection = Squamous intraepithelial lesions = Cervical cell dysplasia → Invasive cancer

Cervical Cancer: Common Metastasis Sites

Lung

Liver

Bone

Cervical Cancer: Clinical Presentation

Usually asymptomatic

Early:

• Abnormal vaginal bleeding

  • Irregular

  • Heavy

  • Postcoital

• Abnormal vaginal discharge

  • Blood-stained

  • Purulent

  • Foul odour

• Dyspareunia

• Pelvic pain

Late:

• Hydronephrosis

• Lymphedema

• Fistulas

Physical Exam:

• Ulceration

• Induration (thickening)

• Exophytic tumor (growing outward)

Cervical Cancer: Investigations

hrHPV genotyping

Pap smear

HPV/Pap cotesting

Colposcopy

Punch biopsy

PET scan + CT

Cervical Cancer Investigations: hrHPV Genotyping

PCR analysis

Findings:

• Positive: Active infection + 1+ high-risk HPV genotype

• Negative: No active infection + high-risk HPV genotype

Cervical Cancer Investigations: Pap Smears

Cervical cytology

Grading:

• Bethesda System

• Cervical intraepithelial neoplasia (CIN)

Pap Smears: Besthesda System

Low-Grade Squamous Intraepithelial Lesion (LSIL): Mild epithelial dysplasia

High-Grade Squamous Intraepithelial Lesion (HSIL): Moderate to severe epithelial dysplasia

LSIL

Transient HPV infection → Regressible

Findings:

• Negative: No malignant + premalignant changes

• Atypical Squamous Cells of Undetermined Significance: Changes in squamous cells

• Cytological LSIL: Mild dysplasia (CIN1)

Management: Observation

HSIL

Persistent HPV infection → Precursor to cancer

Findings:

• Cytological HSIL: Moderate to severe dysplasia (CIN2/3)

• Atypical Squamous Cells LIkely Containing HSIL: Changes in squamous cells

• Atypical Glandular Cells: Abnormal glandular epithelium

Management: Screen + treat

Pap Smears: CIN

Epithelial dysplasia from basal layer extending outward

• CIN1: Mild dysplasia

• CIN2: Moderate dysplasia

• CIN3: Severe dysplasia

Cervical Cancer Investigations: HPV/Pap Cotesting

Cervical cytology + HPV DNA testing

Cervical Cancer Investigations: Colposcopy

Indications:

• Symptomatic

• Abnormal pelvic exam

• Abnormal pap smear + screening

Findings:

• Precancerous lesion: Acetowhitening

  • White area after acetic acid application

• Invasive cancer:

  • Exophytic or endophytic neoplasm

  • Ulceration

  • Necrosis

• Cervical leukoplakia: White membrane on cervix

  • Cannot be scraped off

• Friable tissue

• Erosion

Cervical Cancer Investigations: Punch Biopsy

Indications: 

• Abnormal colposcopy 

• Expedited treatment for high-risk asymptomatic women

• FIGO Staging

Punch Biopsy: FIGO Staging

I: Tumor confined to cervix

• IA: Invasion ≤ 5mm

• IB: Invasion > 5mm

II: Tumor invade beyond uterus

• Not in pelvic wall or lower ⅓ of vagina

• IIA: Upper ⅔ vagina

• IIB: + Parametrial invasion

III: Tumor invade pelvic wall + lower ⅓ of vagina

• IIIA: Lower ⅓ vagina

• IIIB: Pelvic wall + hydronephrosis/kidney dysfunction

• IIIC: Pelvic + paraaortic lymph nodes

IV: Tumor invade beyond pelvis + Involve vesical or rectal mucosa

• IVA: Spread to adjacent organs

• IVB: Spread to distant organs

Cervical Cancer Investigations: PET Scan + CT

Determine metastases

Cervical Cancer: Prevention

Abstinence

Physical barriers

HPV vaccine

Screening

Cervical Cancer Prevention: HPV Vaccine

MOA: Prophylactic HPV exposure = Decrease persistent infection (HSIL) = Decrease cancer development

Types:

• Gardasil: 9 variant HPV, 4 variant HPV

  • Gardasil 9: Most common

• Cervarix: 2 variant HPV

Ages:

• Primary: Female 9-14

• Secondary:

  • Female ≥ 15

  • Male

Cervical Cancer Prevention: Screening

HPV DNA testing

Ages: 25-65

Frequency: Every 4 years

Cervical Cancer: Treatment/Management

By stage

• Early/localized tumor

• Locally advanced tumor

• Distant metastasis

Cervical Cancer Treatment: Early/Localized

Surgery

Radiotherapy

Localized Cervical Cancer: Surgery

Preferred

Methods:

• Cold-knife: Scalpel

  • General/regional anesthesia

  • Loop electrosurgical excision procedure (LEEP): Think electric wire loop

    • Local anesthesia

  • Laser

Procedures:

• Conization: Cone-shaped excision from cervix

  • Preserve fertility

• Trachelectomy: Remove cervix + Form uterus/vaginal anastomosis

  • Preserve fertility

• Pelvic lymphadenectomy

• Hysterectomy

Localized Cervical Cancer: Radiotherapy

Alternative

Cervical Cancer Treatment: Locally Advanced

Surgery + Chemoradiotherapy (CCRT)

• Platinum-based agents

Cervical Cancer Treatment: Distant Metastasis

Palliative

• Chemotherapy

• Radiotherapy

• CCRT

• Immunotherapy

Cervical Cancer: Complications

Hydronephrosis

Fistulas

Metastasis

Cancer anorexia-cachexia syndrome (skeletal muscle wasting)

Cervical Cancer Complication: Hydronephrosis

Pathophysiology: Tumor infiltrate + compress ureter = Urinary obstruction = Hydronephrosis + kidney failure