Cervical Neoplasia and Cancer

• Prior to the 20th century, cervical cancer was the most common cancer in women and the most common cause of cancer death in women in the United States
• Since the advent of the Papanicolaou (Pap) smear, which gained widespread acceptance in the 1950s and 1960s, it has been easier to detect and treat premalignant changes before they develop into cancer
• As a result of public health initiatives involving population-based screening, detection, and treatment, cervical cancer has dropped to the 11th leading cause of death from cancer in women in the United States, accounting for about 4,000 deaths per year
• Further advances in detection and screening have resulted from identification of the human papillomavirus (HPV) as the causal agent in the vast majority of cervical intraepithelial neoplasias (CIN) and cervical cancers
• The combination of Pap smear screening and HPV testing reduces a woman's risk of dying of cervical cancer by 90%
• Vaccines have been developed that protect against HPV infection and reduce the risk of cervical cancer by 70%
• Because developing countries often lack available screening, vaccination, and treatment modalities, cervical cancer continues to be the second most common cancer in women worldwide and is the number one cancer killer of women in the developing world
• Cervical intraepithelial neoplasia (CIN)


  Premalignant changes in the cervical epithelium that have the potential to progress to cervical cancer
• Histologic features of cervical dysplasia

  • Cellular immaturity
  • Cellular disorganization
  • Nuclear abnormalities
  • Increased mitotic activity
• Degrees of CIN


  • CIN I (formerly mild dysplasia): Changes restricted to lower one-third of epithelium
  • CIN II (formerly moderate dysplasia): Two-thirds of epithelium involved
  • CIN III (formerly severe dysplasia): More than two-thirds of epithelium shows abnormal changes
• The atypical cells in CIN III can expand the full thickness of the epithelium (formally CIS or carcinoma in situ)
• During menarche


  Estrogen stimulates metaplasia in the transformation zone (TZ) of the cervix
• CIN most commonly occurs during menarche and after pregnancy when metaplasia is most active
• CIN is thought to begin as a single focus in the TZ but can develop into a multifocal lesion
• HPV is now accepted as the primary causative agent in CIN and cervical cancer
• HPV serotypes


  • Serotypes 6 and 11: Lowest oncogenic potential, responsible for 90% of condylomas
  • Serotypes 16 and 18, 31 and 41: Higher oncogenic potential, responsible for about 70% and 5-10% of cervical cancers respectively
• HPV testing allows providers to more accurately predict which precancerous lesions have the potential to progress to cancer if left untreated and which will most likely spontaneously regress
• HPV vaccines (Gardasil and Cervarix) prevent HPV infections and reduce the risk of cervical cancer by 70%
• HPV vaccines


  • Gardasil: Immunizes against types 6, 11, 16, and 18
  • Cervarix: Immunizes against types 16, 18, 31, and 45
• CIN is most commonly diagnosed in women in their 20s; CIS is diagnosed most commonly in women of 25 to 35 years age; and invasive cancer is typically diagnosed after the age of 40
• Risk factors for cervical dysplasia

  • Early intercourse
  • Multiple sexual partners
  • Early childbearing
  • "High-risk" partners
  • Low socioeconomic status
  • Sexually transmitted infections
• At least 80% of sexually active individuals will have acquired a genital HPV infection by age 50
• Other factors that influence CIN

  • Cigarette smoking
  • Immunodeficiency (HIV infection)
  • Immunosuppression (systemic lupus erythematosus, transplant recipients, chemotherapy, chronic steroid use)
• Approximately 10% of women with CIN have concomitant vulvar (VIN), vaginal (VAIN), or perianal (PAIN) intraepithelial lesions
• Pap smear


  Samples endocervical and ectocervical cells from the external os of the cervix to identify premalignant changes before cancer arises
• Liquid-based Pap tests (ThinPrep and SurePath) are more sensitive than conventional glass slide Pap smears
• Cervical cancer screening guidelines

  • Women aged 21-29 should have Pap testing every 3 years
  • Women aged 30 and above should have co-testing with Pap and HPV test every 5 years if both are negative
  • If HPV testing is unavailable, screening with Pap smear alone every 3 years is acceptable for women 30 and over
• Women over age 65 to 70 can stop cervical cancer screening if they have had three or more normal Pap tests in a row and have not had CIN 2/3 or higher in the past 20 years, or if they have had a total hysterectomy for benign indications and do not have a history of CIN 2/3 or higher
• Women with a history of CIN II or III who undergo hysterectomy may safely discontinue Pap smear screening after three consecutive negative screening tests
• Women who have undergone a supracervical hysterectomy and have an intact cervix still need to continue routine Pap smear screening appropriate for their age
• Women who should continue annual vaginal screening

  • Women with history of invasive cervical cancer and other GYN malignancies
  • Women with risk factors such as in utero diethylstilbestrol (DES) exposure, HIV infection, or immunosuppression
• Atypical squamous cells (ASC)


  May represent benign inflammatory response or herald a preinvasive neoplastic lesion
• Categories of atypical squamous cells


  • ASC-US (atypical squamous cells of unknown significance)
  • ASC-H (atypical squamous cells cannot rule out high-grade lesion)
• Patients in the ASC-H category should be evaluated with colposcopy. Patients with ASC-US should undergo HPV testing to determine whether colposcopy is indicated or not
• Pap smear results that require direct referral to colposcopy


  • ASC-H
  • LSIL (low-grade squamous intraepithelial lesion)
  • HSIL (high-grade squamous intraepithelial lesion)
• Major Classes of Epithelial Cell Abnormalities Found on Pap Smears

  • ASC-US: Atypical squamous cells of undetermined significance
  • ASC-H: Atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion
  • LSIL: Low-grade squamous intraepithelial lesion
  • HSIL: High-grade squamous intraepithelial lesion
  • SCC: Squamous cell carcinoma
  • AGC: Atypical glandular cells
• ASC-H


  Atypical squamous cells cannot rule out high-grade lesion
• Management of ASC-H, LSIL, or HSIL Pap smear result

  Proceed directly to colposcopy
• AGC


  Atypical glandular cells
• Management of AGC Pap smear result

  1. Undergo colposcopy, high-risk HPV testing, and endocervical sampling

  2. Endometrial biopsy for women aged 35 and older and those younger than 35 with risk factors for endometrial hyperplasia or endometrial cancer