Abnormal Pap Smear

Basics

Description

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 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

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 18
- Responsible 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 smear
- Annual pelvic exams should be performed regardless of frequency of Pap smears
American College of Obstetricians and Gynecologists (ACOG) recommendations:
- Begin screening at age 21
- For women <30 years, screen every 2 years
- For 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 OR
  - Screen q3 years with Pap smear and HPV testing if initial Pap smear and HPV both are negative
- 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
American Cancer Society (ACS) recommendations:
- Begin screening 3 years after the onset of sexual activity or age 21 years, whichever is earlier
- For women <30 years, screen annually with conventional Pap smear or q2 years with liquid-based Pap smear
- For women >30 years, screen q2-3 years after 3 consecutive (-) Pap smears and no increased risk
- Discontinue 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 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

Physical Exam

Cervical exam can be grossly normal
- Superficial ulceration
- Exophytic tumor
- Endophytic 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 smear
- Liquid-based system is slightly more sensitive than traditional slide system
- Liquid-based cytology performed more frequently than q3 years may not be cost effective
Biopsy
- Colposcopy with directed biopsy if abnormal cervical cytology without visible lesion
- Cone biopsy is necessary for the diagnosis of microinvasive disease
- Punch biopsy and endocervical curettage for an unusually firm or expanded cervix

Pathological Findings
According to Revised 2001 Bethesda System:

Unsatisfactory specimen:
- Repeat Pap smear
Negative for intraepithelial lesion or malignancy:
- Rescreen in 1-2 years if age <30 years
- Rescreen 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 OR
- Rescreen q6 months — 2. If (-) — 2, then return to q year screening OR
- Perform HPV testing (only available with liquid-based cytology):
  - If (+) for high-risk strains, perform colposcopy
  - If (-) for high-risk strains, rescreen in 1 year
  - "Reflex"ť testing available such that automatically sent for HPV testing if ASCUS
- For 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 <age 21 years, rescreen in 1 year
  - For postmenopausal women, follow ASCUS algorithm
- High-grade squamous intraepithelial lesion (HGSIL), which has 2 categories:
  - Moderate dysplasia (CIN II)
  - Severe dysplasia (CIN III, carcinoma in situ)
- Atypical glandular cells of unknown significance (AGUS):
  - May also need endometrial biopsy

No endocervical cells, excessive blood, inflammation, reactive changes:
- Repeat in 6 months if
  - History of abnormal Pap smears, HPV infection, immunosuppression, HIV
- Rescreen in 1 year if no high-risk factors
HIV (+) women
- Repeat Pap smear q6 months until (-) — 2, then screen q year
Postmenopausal women:
- No endocervical cells: Rescreen in 1 year
- ASCUS: Estrogen cream — 7 days, then repeat Pap smear
- AGUS: Colposcopy and endometrial biopsy

Differential Diagnosis

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

Treatment

Medication

Chemotherapy: Cisplatin as adjuvant therapy
- For bulky and higher stage tumors
- Postoperatively 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 organs
- Radiation therapy with chemotherapy
Stage IVb: Distant metastases
- Chemotherapy 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 surgery
- In stage I disease, can delay therapy until fetal survival is assured
- In more advanced disease, delay of therapy is not recommended
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

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 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

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.

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