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Cervical Cancer & Pap Smears

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Epidemiology

• 16,000 cases / year

• Incidence but mortality from cervical cancer over the past 50 years

• Cervical CA is still the 7th most common cancer in females and the 8th most common cause of death

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Etiology

• Human Papiloma Virus (HPV) + an unidentified co-carcinogen

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Risk Factors

• Multiple sexual partners (> 1)• Promiscuous partner• Age of first intercourse experience• Early childbearing• Prior STDs (HSV II, genital warts, vaginal infections)• Cigarette Smoking• Oral Contraceptive usage• Intrauterine exposure to DES• Immunodeficiency

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Age of Onset

• Carcinoma In-Stiu (CIS) 30 years

• Cervical Intraepithelial Neoplasia (CIN) 35 years

• Invasive Cervical Cancer 45 years

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Histological Types

• Squamous Cell Carcinoma 80-95%

• Adenocarcinoma 5-20%

• Other: Clear cell, sarcomas

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Symptoms

• CIN: Asymptomatic

• Invasive Cancer– No classic presentation–May present with abnormal vaginal bleeding–May present with postcoital bleeding

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Physical Exam

• CIN– Cervix appears normal to general inspection

• Invasive Cancer– Exophytic growth seen on cervix

– Growth: Cauliflower-like, friable, deeply ulcerated

• Advanced Cancer– Pelvic Masses Palpable

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Metastasis

• Morbidity and Mortality associated with regional spread of the cancer

• Spreads to pelvic nodes, ureters, bladder, rectum.

• Dangerous when cancer blocks ureters resulting in uremia --> death

• Hematogenous spread- uncommon

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Pathogenesis

• Site where squamous epithelium of vagina meets columnar epithelium of endocervix known as squamocolumnar junction (SCJ)

• Before puberty: SCJ located just inside the cervical os

• At puberty, increasing levels of estrogen lead to squamous metaplasia of columnar epithelium to squamous epithelium

• Results in repositioning of the SCJ further towards the uterus

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Pathogenesis (2)• Region between the old and new SCJs known as the

transformation zone• Transformation zone is the site of 95% of the cervical

cancer development• Since zone is located within the cervical os, unable to be

viewed during routine pelvic exam• Exposure of transformation zone to carcinogens begins

process of intraepithelial neoplasia• While exact role of carcinogens in this process remains

poorly understood, it is clear that HPV and cigarette smoking can cause dysplasia at the transformation zone

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Human Papiloma Virus (HPV)

• Certain types of HPV are responsible for genital warts, others for dysplasia/cancer

• HPV Types 6 & 11– associated with development of genital warts

• Types 16,18,31,33,35,39,45,51,52,56,58– associated with development of dysplasia/cancer

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Pap Smears

• Strong sensitivity and specificity

• Accuracy of Smear Requires– adequate sample

– presence of enough inflamation and dysplasia

– quick fixation of specimen to glass slide

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When to Get Pap Smears

• ACOG Recommendations– 1st Pap Smear at age when patient becomes

sexually active (or by age 18)– Yearly pap smears thereafter

• Others contend that monogamous women with no history of abnormal pap smears can have them done every 3 years

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Performing Pap Smear• Patient asked to lie on her back at edge of exam table

with feet in stirrups

• Metal or plastic speculum is inserted into vagina to expand the wall of vagina to enable access to cervix

• Cells are collected using cotton swab, wooden spatula, or cervical brush and smeared onto glass slide

• Preservative sprayed to prevent cells from drying and artifacts from forming

• Slide evaluated by lab technician who looks for abnormalities in the 50,000 to 300,000 cells on slide

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Pap Smear Classification Systems

• The Class System (I to V)

• The CIN System (CIN I to III)– characterizes the degree of cellular abnormalities

• The SIL System (Bethesda System)– Lesions characterized as LGSIL or HGSIL

– Presence of HPV noted

– This scheme is most widely used system these days

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Evaluating the Pap Smear

• First, the smear is evaluated for adequacy of sample

• Secondly the sample is categorized as “normal” or “other”

• Lastly, all sample categorized as “other” are further specified as infection, inflammation, or various stages of cancer

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What to Inform Patients Prior to Obtaining Pap Smear

• No douching or usage of vaginal medications, lubricants, or spermicides within 2-3 days of exam (these products may hide abnormal cells)

• Schedule Pap Smear between days 12-16 of menstrual cycle, if possible

• Abstain from intercourse 1-2 days prior to smear

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Pitfalls of Diagnosing Cervical Cancer

• 30% of cases of cervical cancer are missed due to errors interpreting results of pap smears

• Ways of Improving Pap Smears– rescreen portions of slide deemed negative to

reduce false-negatives

– new liquid smears may be have higher sensitivty and specificity

– usage of computerized devices to analyze smear (PAPNET, VIRAPAP)

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Improving Access to Pap Smears

• 50% of patients who die of cervical cancer have never had a Pap Smear

• Uninsured, minorities, older patients and those who live in rural areas have limited access to Pap Smears

• These groups must be targeted to further reduce rates of cervical cancer in the US

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Precursor Lesions• Reason for thorough classification schemes for

intraepithelial lesions is to determine the likelihood of such lesions progressing to overt cancer

• Usual progression from mild dysplasia to overt cancer takes 7-8 years

• Precursor lesions characterized as mild dysplasia have 65% chance of spontaneously regressing, 20% chance of remaining the same, 15% chance of worsening

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Precursor Lesions (2)• Unfortunately, we are unable to predict with

much accuracy, which lesions will regress and which will worsen over time

• For this reason, ACOG recommends any patient with a mildly abnormal smear undergo further evaluation with culposcopy and/or biopsy

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Culposcopy

• Culposcope: A stereomicroscope that enables investigators to examine areas of dysplasia and select best sites to biopsy

• device has green filter that helps identify presence of blood vessels (an ominous sign)

• Before culposcopy, cervix coated with acetic acid which enhances presence of dysplasia

• Key to culposcopy is complete visualization of transformation zone

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Cone Biopsy

• Reasons for Performing Cone Biopsy– Investigator is unable to visualize the entire

transformation zone– Endocervical curretage shows dysplastic changes– Results of Pap Smear are remarkably different than

results from culposcopy

• Cone biopsy is a minor surgical procedure to further investigate the transformation zone

• Performed using a scalpel or laser

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Treatment of CIN

• Most effective treatment is excision of precursor lesions

• Ways to Remove Lesions– Cryocautery- freezing, thawing, & refreezing lesion– Culposcopic Laser Therapy- more accurate, capable

of removing low and high grade lesions– Excisional Biopsy- performed on low grade lesion

• Always schedule follow-up Pap Smears to assure lesions have not returned

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Managing Cervical Cancer• All visible lesions should be biopsied

• Lesions must be properly staged to determine whether cancer has spread and help determine therapeutic approach

• Cervical Cancer spreads by lymphatics or direct invasion

• Lymphatic Spread:– Cervical/paracervical nodes regional nodes deep

pelvic nodes

– Direct spread: To bladder, vagina, parametria, rectum

– CT Scan helpful in assessing cancer that has spread

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Treatment of Invasive Cervical Cancer

• Option 1: Surgery– Useful in patients with Stage I and II cancer

– Radical hysterectomy is procedure of choice for overt cancer

– When performing surgery, spare ovaries so they can continue to manufacture estrogen

– Potential pitfalls of surgery: hemorrhage, damage to nerves supplying bladder, formation of fistula

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Treatment of Cervical Cancer

• Option 2: Radiation– Reserved for poor surgical candidates or

patients with advanced disease

– Problems with radiation- infertility, radiation cystitis, fibrosis

– Usually ineffective in patients with recurrent cervical cancer

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Prognosis

• Patients with CIS and cancer limited to cervix- cure rate 90-100%

• Patients with advanced cervical cancer- cure rate is 25-50%

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Reasons for Such Good Prognosis for Cervical Cancer

• Presence of an easily identifiable precursor lesion

• Slow progression of cancer

• Access to cheap non-invasive diagnostic tools (Pap Smears and Culposcopy)

• Simple and effective treatments