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Abnormal Pap Smear

Basics

Description

- Safe sex practices to prevent HPV transmission - Avoidance of tobacco use - HPV vaccine - Bivalent vaccine against types 16 and 18 and quadrivalent vaccine against types 6, 11, 16, and 18 are commercially available - HPV 6, 11 responsible for 90% genital warts

- Series of 3 vaccines at 0, 1, 6 months - Effective in reducing cervical infection and associated cytological abnormalities (1)[B] - Center for Disease Control Advisory Committee on Immunization Practices (ACIP) Recommendations (2)[A]: - Offer routinely to females at 11-12 years - Can be offered to patients as young as 9 years - Catch-up vaccination for 13-26 years - For maximum benefit, HPV vaccine given before onset of sexual activity, but can still vaccinate sexually active patients

- Discontinue screening in: - Women with hysterectomy for benign reasons and no history of abnormal or cancerous cell growth - Women with hysterectomy for benign reasons and a history of CIN II or CIN III after 3 consecutive negative smears - Women aged 65-70 years if 3 consecutive (-) Pap smears and no abnormal results in last 10 years

- United States Preventative Services Task Force (USPSTF) recommendations: - Begin screening 3 years after the onset of sexual activity or age 21 years, whichever is earlier - Screen q3 years with Pap smear only - Insufficient evidence to recommend HPV test - Discontinue after hysterectomy for benign reasons and at age 65 years if not at high risk

- Cervical cancer asymptomatic in early stages - In more advanced stages, symptoms include: - Intermenstrual spotting - Postcoital bleeding - Postmenopausal bleeding - Vaginal discharge: Can be watery, mucoid, bloody, or purulent and malodorous - Severe back or pelvic pain - Alteration of bowel and bladder function - Enlarged lymph nodes - Obstructive uremia

- Cervical exam can be grossly normal - Superficial ulceration - Exophytic tumor - Endophytic tumor: Enlarged, indurated cervix with smooth surface

- Cervical cancer - Cervicitis/vaginitis - Uterine cancer - Nabothian cysts - Endometriosis

- Delivery should be performed as soon as fetal lungs are mature - Route of delivery is controversial - Cesarean delivery advocated by most experts - Vaginal delivery - Recurrence at site of episiotomy possible - Increased risk of hemorrhage, obstructed labor, infection with advanced disease

- Metastatic disease - Direct extension to uterus, vagina, parametria, peritoneal cavity, bladder, and/or rectum - Lymphatic dissemination: External iliac, common iliac, para-aortic, and/or parametrial - Hematogenous dissemination

  • Cervical cancer was the leading cause of cancer deaths in American women until widespread screening with the Pap smear began in 1941.
  • The Pap smear, which is a sampling of cervical cells, is an ideal screening test because:Cervical cancer has a premalignant phase of many years.Screening on a regular basis is likely to identify disease in its premalignant phase.It is inexpensive and can be performed on outpatients.
  • Human papillomavirus (HPV) is a sexually transmitted infection (STI) strongly associated with the development of cervical intraepithelial neoplasia (CIN) and cancer.
  • Cervical cancer cell types:Squamous cell cancer: 80%Adenocarcinoma: 15%Adenosquamous carcinoma: 5%

Epidemiology

Incidence

  • In the USA, 8 per 100,000 women.
  • Estimated 12,200 new cases per year.50% of cases among women who have never been screened.10% of cases among women who have not been screened in preceding 5 years.
  • Approximately 4,200 deaths per year.
  • In the USA, peak incidence occurs in age range 45-49 years.Only 10% of cases occur in women >75 years.

Prevalence

  • In developed countries, cervical cancer is uncommon secondary to Pap smear screening.In the USA, 3rd most common gynecologic malignancy but has low mortality rate.Over past 50 years, 75% decrease in incidence and mortality in developed countries.
  • Worldwide, cervical cancer is the most common cause of mortality from gynecologic malignancy.2nd most common cause of cancer among women.3rd most common cause of cancer death.

Risk Factors

  • HPV infection: Unprotected intercourse, early onset of sexual activity, multiple sexual partners
  • Tobacco use
  • Immunocompromise
  • Low socioeconomic status
  • African American and Hispanic ethnicity
  • History of STIs
  • History of vulvar/vaginal squamous dysplasia
  • Lack of Pap smear screening in last 5 years
  • Diethylstilbestrol exposure
  • HIV or immunosuppression

General Prevention

  • Safe sex practices to prevent HPV transmission
  • Avoidance of tobacco use
  • HPV vaccineBivalent vaccine against types 16 and 18 and quadrivalent vaccine against types 6, 11, 16, and 18 are commercially availableHPV 6, 11 responsible for 90% genital wartsSeries of 3 vaccines at 0, 1, 6 monthsEffective in reducing cervical infection and associated cytological abnormalities (1)[B]Center for Disease Control Advisory Committee on Immunization Practices (ACIP) Recommendations (2)[A]:Offer routinely to females at 11-12 yearsCan be offered to patients as young as 9 yearsCatch-up vaccination for 13-26 yearsFor maximum benefit, HPV vaccine given before onset of sexual activity, but can still vaccinate sexually active patients

Pathophysiology

  • Sexual transmission of HPV leads to malignant transformation of vaginal/cervical epithelium.
  • HPV DNA can be identified in at least 95% of dysplastic and malignant cervical lesions.
  • HPV alone is not sufficient to cause cervical neoplasia.Most HPV infections are transient.Up to 50% of sexually active women exposed to HPV, but only a small number develops high-grade CIN or invasive cervical cancer.70% of CIN I, 50% of CIN II, and 30% of CIN III infections clear spontaneously.Not all HPV types are oncogenic.
  • Because Pap smear is effective screening tool and most HPV infections are transient, some controversy exists regarding the use of HPV vaccine in countries with well-implemented Pap smear screening.

Etiology

  • HPV subtypes 16 and 18Responsible for up to 70% of cervical cancers
  • Additional high-risk subtypes include 31, 33, 35, 39, 45, 51, 52, 56, 59, and 68

Associated Conditions

Sexually transmitted infections

Diagnosis

  • Regular screening with Pap smearAnnual pelvic exams should be performed regardless of frequency of Pap smears
  • American College of Obstetricians and Gynecologists (ACOG) recommendations:Begin screening at age 21For women <30 years, screen every 2 yearsFor women >30 years without history of CIN II or III or at increased risk (HIV, DES exposure),Screen q3 years if 3 consecutive negative (-) Pap smear ORScreen q3 years with Pap smear and HPV testing if initial Pap smear and HPV both are negativeDiscontinue screening in:Women with hysterectomy for benign reasons and no history of abnormal or cancerous cell growthWomen with hysterectomy for benign reasons and a history of CIN II or CIN III after 3 consecutive negative smearsWomen aged 65-70 years if 3 consecutive (-) Pap smears and no abnormal results in last 10 years
  • United States Preventative Services Task Force (USPSTF) recommendations:Begin screening 3 years after the onset of sexual activity or age 21 years, whichever is earlierScreen q3 years with Pap smear onlyInsufficient evidence to recommend HPV testDiscontinue after hysterectomy for benign reasons and at age 65 years if not at high risk
  • American Cancer Society (ACS) recommendations:Begin screening 3 years after the onset of sexual activity or age 21 years, whichever is earlierFor women <30 years, screen annually with conventional Pap smear or q2 years with liquid-based Pap smearFor women >30 years, screen q2-3 years after 3 consecutive (-) Pap smears and no increased riskDiscontinue after hysterectomy for benign reasons and at age 70 years if 3 consecutive (-) Pap smear and no abnormal results in last 10 years

History

  • Cervical cancer asymptomatic in early stages
  • In more advanced stages, symptoms include:Intermenstrual spottingPostcoital bleedingPostmenopausal bleedingVaginal discharge: Can be watery, mucoid, bloody, or purulent and malodorousSevere back or pelvic painAlteration of bowel and bladder functionEnlarged lymph nodesObstructive uremia

Physical Exam

  • Cervical exam can be grossly normalSuperficial ulcerationExophytic tumorEndophytic tumor: Enlarged, indurated cervix with smooth surface
  • Costovertebral angle tenderness if hydronephrosis is present
  • Inguinal lymphadenopathy

Tests

Lab

Consider screening for STIs: Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, syphilis, hepatitis B and C, HIV

Imaging

CT or MRI of abdomen/pelvis for work-up of metastatic disease when indicated

Surgery

  • Pap smearLiquid-based system is slightly more sensitive than traditional slide systemLiquid-based cytology performed more frequently than q3 years may not be cost effective
  • BiopsyColposcopy with directed biopsy if abnormal cervical cytology without visible lesionCone biopsy is necessary for the diagnosis of microinvasive diseasePunch biopsy and endocervical curettage for an unusually firm or expanded cervix

Pathological Findings

According to Revised 2001 Bethesda System:

  • Unsatisfactory specimen:
  • Negative for intraepithelial lesion or malignancy:Rescreen in 1-2 years if age <30 yearsRescreen in 3 years if age >30 years and history of 3 consecutive negative smears or if HPV (-)HPV (+): Rescreen with Pap smear + HPV in 1 year
  • Atypical squamous cells of unknown significance (ASCUS):Refer to colposcopy ORRescreen q6 months — 2. If (-) — 2, then return to q year screening ORPerform HPV testing (only available with liquid-based cytology):If (+) for high-risk strains, perform colposcopyIf (-) for high-risk strains, rescreen in 1 year"Reflex"ť testing available such that automatically sent for HPV testing if ASCUSFor patients < age 21 years, rescreen in 1 year
  • Refer to colposcopy for:Atypical cells of unknown significance; cannot rule out high-grade lesion (ASC-H):Low-grade squamous intraepithelial lesion (LGSIL):Consistent with mild dysplasia (CIN I)For patients
  • No endocervical cells, excessive blood, inflammation, reactive changes:Repeat in 6 months ifHistory of abnormal Pap smears, HPV infection, immunosuppression, HIVRescreen in 1 year if no high-risk factors
  • HIV (+) womenRepeat Pap smear q6 months until (-) — 2, then screen q year
  • Postmenopausal women:No endocervical cells: Rescreen in 1 yearASCUS: Estrogen cream — 7 days, then repeat Pap smearAGUS: Colposcopy and endometrial biopsy

Differential Diagnosis

  • Cervical cancerCervicitis/vaginitisUterine cancerNabothian cystsEndometriosis

Treatment

Medication

  • Chemotherapy: Cisplatin as adjuvant therapyFor bulky and higher stage tumorsPostoperatively in patients considered to be at high risk for recurrent disease

Additional Treatment

General Measures

  • Cervical cancer is staged from 0 to IVb
  • Surgery for lower stage tumors
  • Radiation for higher stage tumors
  • Chemotherapy often used as adjuvant therapy

Issues for Referral

  • Refer to gynecology for colposcopy
  • Refer to gynecology/oncology for lesions consistent with cancer

Additional Therapies

Radiotherapy

Mainstay of treatment for higher stage tumors

  • Large, bulky tumors at stage Ib or greater:Radiation therapy with chemotherapy +/- surgery
  • Stage IIb, III, and IVa tumors: Extension to local organsRadiation therapy with chemotherapy
  • Stage IVb: Distant metastasesChemotherapy with or without radiation
  • Pregnancy does not increase the risk or change the course of cervical cancer
  • Diagnosis (with biopsy via colposcopy and confirmatory cone biopsy) carries increased risk of hemorrhage and poor perinatal outcome
  • <20 weeks of gestation: Radical hysterectomy can be performed with fetus in situ
  • >20 weeks gestation: Evacuation of fetus recommended before surgeryIn stage I disease, can delay therapy until fetal survival is assuredIn more advanced disease, delay of therapy is not recommended
  • Delivery should be performed as soon as fetal lungs are mature
  • Route of delivery is controversialCesarean delivery advocated by most expertsVaginal deliveryRecurrence at site of episiotomy possibleIncreased risk of hemorrhage, obstructed labor, infection with advanced disease

Ongoing Care

Follow-Up Recommendations

Patient Monitoring

For cervical cancer, Pap smear every 3-4 months recommended for 2 years after treatment, then every 6 months

Prognosis

5-year survival rate of cervical cancer

  • Stage Ia: >95%
  • Stage IIa/Ib: 80-90%
  • Stage IIb, III, and IVa tumors: 20-65%
  • Stage IVb: 25%

Complications

  • Metastatic diseaseDirect extension to uterus, vagina, parametria, peritoneal cavity, bladder, and/or rectumLymphatic dissemination: External iliac, common iliac, para-aortic, and/or parametrialHematogenous dissemination

References

1Kahn JA HPV vaccination for the prevention of cervical intraepithelial neoplasia. N Eng J Med 2009;361(3):271. [View Abstract]2 Recommended adult immunization schedule: United States, 2010. Ann Intern Med. 2010;152(1):36. [View Abstract]

Additional Reading

1 ACOG Practice Bulletin no. 109: Cervical cytology screening. Obstet Gynecol. 2009;114(6):1409-1420. [View Abstract]2 http://www.cancer.org3Jemal A, Siegel R, Xu J. Cancer statistics, 2010. CA Cancer J Clin. 2010;60(5):277. [View Abstract]4Shivnani AT, Rimel BJ, Schink J. Cancer of the cervix: current management and new approaches. Oncology. 2006;20(12):1553-1560. [View Abstract]5 The guide to clinical preventative services 2010-2011. 2010;AHRQ Publication no. 10-05145.6Wright TCJr, Massad LS, Dunton CJ. 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol. 2007;197(4):346-355. [View Abstract]

Codes

ICD9

  • 622.1 Dysplasia of cervix (CIN I, II, LGSIL, HGSIL)
  • 795.00 Nonspecific abnormal Pap smear of cervix, unspecified (abnormal glandular cells)
  • 795.09 Other nonspecific abnormal Pap (unsatisfactory smear, benign cellular changes)
  • 233.1 Carcinoma in situ of cervix (CIN III)
  • V76.2 Routine cervical Pap smear
  • V72.32 Pap smear to confirm findings of recent normal smear following initial abnormal smear

ICD10

  • R87.619 Unsp abnormal cytolog findings in specmn from cervix uteri
  • R87.629 Unsp abnormal cytological findings in specimens from vagina
  • R87.69 Abn cytolog find in specmn from oth female genital organs
  • N87.0 Mild cervical dysplasia
  • N87.1 Moderate cervical dysplasia
  • Z12.4 Encounter for screening for malignant neoplasm of cervix
  • Z01.42 Encntr for cerv smear to cnfrm norm smr fol init abn smear

SNOMED

  • 439888000 abnormal cervical Papanicolaou smear (finding)
  • 73391008 dysplasia of cervix (disorder)
  • 285836003 cervical intraepithelial neoplasia grade 1 (disorder)
  • 285838002 cervical intraepithelial neoplasia grade 2 (disorder)
  • 171149006 screening for malignant neoplasm of cervix (procedure)

Clinical Pearls

  • The Pap smear is an ideal screening test for cervical cancer because it can identify the disease in its premalignant phase.
  • HPV infection is strongly associated with cervical neoplasia.Spontaneous clearance of HPV can occur.Providers should encourage safe sex practices.HPV vaccine is recommended by the CDC.
  • Cervical cancer is more likely in women who have not received screening within last 5 years.