Overview

Cervical cancer

• Cancer of the uterine cervix
• Major histologic types:
  • Squamous cell carcinoma Squamous cell carcinoma Cutaneous squamous cell carcinoma (cSCC) is caused by malignant proliferation of atypical keratinocytes. This condition is the 2nd most common skin malignancy and usually affects sun-exposed areas of fair-skinned patients. The cancer presents as a firm, erythematous, keratotic plaque or papule. Squamous Cell Carcinoma: approximately 80% of cervical cancers
  • Adenocarcinoma: 15%
  • Adenosquamous carcinoma: 3%–5%
• Associated with human papillomavirus Human papillomavirus Human papillomavirus (HPV) is a nonenveloped, circular, double-stranded DNA virus belonging to the Papillomaviridae family. Humans are the only reservoir, and transmission occurs through close skin-to-skin or sexual contact. Human papillomaviruses infect basal epithelial cells and can affect cell-regulatory proteins to result in cell proliferation. Papillomaviridae: HPV ( HPV HPV Human papillomavirus (HPV) is a nonenveloped, circular, double-stranded DNA virus belonging to the Papillomaviridae family. Humans are the only reservoir, and transmission occurs through close skin-to-skin or sexual contact. Human papillomaviruses infect basal epithelial cells and can affect cell-regulatory proteins to result in cell proliferation. Papillomaviridae: HPV): 
  • Detected in 99.7% of cervical cancers
  • Subtypes HPV HPV Human papillomavirus (HPV) is a nonenveloped, circular, double-stranded DNA virus belonging to the Papillomaviridae family. Humans are the only reservoir, and transmission occurs through close skin-to-skin or sexual contact. Human papillomaviruses infect basal epithelial cells and can affect cell-regulatory proteins to result in cell proliferation. Papillomaviridae: HPV 16 and 18 found in > 70% of cervical cancers

Epidemiology

• Among gynecologic cancers, cervical cancer is:
  • The 3rd most common cancer diagnosis
  • The 3rd most common cause of death 
• More than 80% of new cases worldwide are from less developed countries.
• In the United States: 
  • 14,000 new cases of invasive cervical cancer are diagnosed annually.
  • Mean age at diagnosis: 50 years

Risk factors

• HPV HPV Human papillomavirus (HPV) is a nonenveloped, circular, double-stranded DNA virus belonging to the Papillomaviridae family. Humans are the only reservoir, and transmission occurs through close skin-to-skin or sexual contact. Human papillomaviruses infect basal epithelial cells and can affect cell-regulatory proteins to result in cell proliferation. Papillomaviridae: HPV-related:
  • Early onset of sexual activity
  • Multiple sexual partners
  • Multiparity and early age at 1st birth
  • History of vulvar or vaginal squamous intraepithelial neoplasia or cancer
  • Immunosuppression
  • Human immunodeficiency virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview (HIV) infection
  • Co-infection with Chlamydia Chlamydia Chlamydiae are obligate intracellular gram-negative bacteria. They lack a peptidoglycan layer and are best visualized using Giemsa stain. The family of Chlamydiaceae comprises 3 pathogens that can infect humans: Chlamydia trachomatis, Chlamydia psittaci, and Chlamydia pneumoniae. Chlamydia trachomatis or herpes simplex virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview
• Non- HPV HPV Human papillomavirus (HPV) is a nonenveloped, circular, double-stranded DNA virus belonging to the Papillomaviridae family. Humans are the only reservoir, and transmission occurs through close skin-to-skin or sexual contact. Human papillomaviruses infect basal epithelial cells and can affect cell-regulatory proteins to result in cell proliferation. Papillomaviridae: HPV related:
  • Low socioeconomic status
  • African American race
  • Use of oral contraceptives
  • Cigarette smoking (associated with squamous cell carcinoma)
  • Family history
  • Negative risk factor: circumcised male partners

Screening Rationale

• Screening is recommended because:
  • Women 21‒65 years of age are at risk for cervical cancer due to potential exposure to high-risk human papillomavirus Human papillomavirus Human papillomavirus (HPV) is a nonenveloped, circular, double-stranded DNA virus belonging to the Papillomaviridae family. Humans are the only reservoir, and transmission occurs through close skin-to-skin or sexual contact. Human papillomaviruses infect basal epithelial cells and can affect cell-regulatory proteins to result in cell proliferation. Papillomaviridae: HPV (hrHPV) through sexual intercourse.
  • A 75% decline in the incidence and mortality of cervical cancer occurred in the past 50 years due to screening.
  • Most cases of cervical cancer are found in women who have not been adequately screened.
  • Cervical cancer usually does not cause symptoms.
• Screening is not recommended earlier than age 21 because:
  • Cancerous and precancerous lesions are rare before the age of 21.
  • Prolonged progression from hrHPV infection, development of precancerous lesions, to cervical cancer
  • Many precancerous lesions and HPV HPV Human papillomavirus (HPV) is a nonenveloped, circular, double-stranded DNA virus belonging to the Papillomaviridae family. Humans are the only reservoir, and transmission occurs through close skin-to-skin or sexual contact. Human papillomaviruses infect basal epithelial cells and can affect cell-regulatory proteins to result in cell proliferation. Papillomaviridae: HPV infections will regress.
  • May lead to more harm from psychological distress and unnecessary procedures

Strategies for Screening

Screening strategies can be done independently or concurrently (co-testing).

• Cervical cytology:
  • Ectocervical and endocervical cells are collected to evaluate the transformation zone (area at risk for cervical cancer).
  • The procedure is performed with an endocervical brush and ectocervical spatula.
  • Preparation methods:
    • Conventional Papanicolaou (Pap) smear: Ectocervical spatula is smeared and the brush rolled onto a slide, with fixative applied immediately
    • Liquid-based thin layer cytology: Collection device is placed and swirled in the liquid fixative solution, which is then processed by the laboratory.
• HPV HPV Human papillomavirus (HPV) is a nonenveloped, circular, double-stranded DNA virus belonging to the Papillomaviridae family. Humans are the only reservoir, and transmission occurs through close skin-to-skin or sexual contact. Human papillomaviruses infect basal epithelial cells and can affect cell-regulatory proteins to result in cell proliferation. Papillomaviridae: HPV testing:
  • Identifies hrHPV subtypes
  • Samples are collected from the endocervix.
  • If liquid-based cytology is performed, the same cytology specimen can be used.

Cervical Cancer Screening for Average-Risk Individuals

The following recommendations are for average-risk individuals.

• United States Preventive Services Task Force (USPSTF) recommendations:
  • Routine cytology screening every 3 years starting at the age of 21, regardless of sexual history 
  • For ages 21‒29: cytology alone every 3 years
  • For ages 30‒65, options are:
    • Cervical cytology alone every 3 years
    • hrHPV every 5 years
    • Cytology with hrHPV co-testing every 5 years 
  • Screening ends at the age of 65 if the patient has adequate negative screening.
• Updated American Cancer Society recommendations (2020):
  • Initiate screening at the age of 25, regardless of sexual history, with primary HPV HPV Human papillomavirus (HPV) is a nonenveloped, circular, double-stranded DNA virus belonging to the Papillomaviridae family. Humans are the only reservoir, and transmission occurs through close skin-to-skin or sexual contact. Human papillomaviruses infect basal epithelial cells and can affect cell-regulatory proteins to result in cell proliferation. Papillomaviridae: HPV testing (approved testing that is adequate for screening by itself) every 5 years
  • If primary HPV HPV Human papillomavirus (HPV) is a nonenveloped, circular, double-stranded DNA virus belonging to the Papillomaviridae family. Humans are the only reservoir, and transmission occurs through close skin-to-skin or sexual contact. Human papillomaviruses infect basal epithelial cells and can affect cell-regulatory proteins to result in cell proliferation. Papillomaviridae: HPV testing cannot be done: 
    • Co-testing with HPV HPV Human papillomavirus (HPV) is a nonenveloped, circular, double-stranded DNA virus belonging to the Papillomaviridae family. Humans are the only reservoir, and transmission occurs through close skin-to-skin or sexual contact. Human papillomaviruses infect basal epithelial cells and can affect cell-regulatory proteins to result in cell proliferation. Papillomaviridae: HPV and Pap smear every 5 years
    • Pap smear alone every 3 years 
  • Screening ends at age 65 with adequate negative screening.
  • Rationale for the above:
    • Low incidence of cervical cancer in those < 24 years of age
    • HPV HPV Human papillomavirus (HPV) is a nonenveloped, circular, double-stranded DNA virus belonging to the Papillomaviridae family. Humans are the only reservoir, and transmission occurs through close skin-to-skin or sexual contact. Human papillomaviruses infect basal epithelial cells and can affect cell-regulatory proteins to result in cell proliferation. Papillomaviridae: HPV testing is more specific.
    • About 70% of adolescents have received at least 1 dose of the HPV HPV Human papillomavirus (HPV) is a nonenveloped, circular, double-stranded DNA virus belonging to the Papillomaviridae family. Humans are the only reservoir, and transmission occurs through close skin-to-skin or sexual contact. Human papillomaviruses infect basal epithelial cells and can affect cell-regulatory proteins to result in cell proliferation. Papillomaviridae: HPV vaccine Vaccine A vaccine is usually an antigenic, non-virulent form of a normally virulent microorganism. Vaccinations are a form of primary prevention and are the most effective form due to their safety, efficacy, low cost, and easy access. Vaccination.
• Adequate negative prior screening is defined as 1 of the following:
  • 3 consecutive negative cytology results, with the last result within the past 3 years
  • 2 consecutive negative co-test results within the past 10 years, with the most recent test within the past 5 years
  • 2 consecutive negative primary HPV HPV Human papillomavirus (HPV) is a nonenveloped, circular, double-stranded DNA virus belonging to the Papillomaviridae family. Humans are the only reservoir, and transmission occurs through close skin-to-skin or sexual contact. Human papillomaviruses infect basal epithelial cells and can affect cell-regulatory proteins to result in cell proliferation. Papillomaviridae: HPV test results within the past 10 years, with the most recent test within the past 5 years

Cervical Cancer Screening for Special Populations

High-risk individuals

Certain conditions have a high risk for cervical cancer, so screening must be individualized and more frequent:

• HIV infection HIV infection Human immunodeficiency virus (HIV), a single-stranded RNA virus belonging to the Retroviridae family, is the etiologic agent of acquired immunodeficiency syndrome (AIDS). The human immunodeficiency virus is a sexually transmitted or blood-borne infection that attacks CD4+ T lymphocyte cells, macrophages, and dendritic cells, leading to eventual immunodeficiency. HIV Infection and AIDS: Screening may start < 21 years of age, regardless of sexual history.
• Immunocompromised: Screening may start < 21 years of age, regardless of sexual history.
• In utero exposure to diethylstilbestrol (last used in the 1970s, so most relevant in women born after 1980)
• Previous treatment of a high-grade precancerous lesion or cervical cancer

Prior hysterectomy

• Screening is still recommended in women:
  • With history of subtotal hysterectomy (cervix intact)
  • With history of cervical intraepithelial neoplasia (CIN), even after hysterectomy
• No screening is recommended in women:
  • With history of hysterectomy with removal of the cervix for a benign disease
  • Without history of a high-grade precancerous lesion (CIN grade 2 or 3) or cervical cancer

Individuals > 65 years of age

• Screening may be indicated in older women with inadequate screening. 
  • Those at risk for inadequate screening:
    • Patients with limited access to care
    • Women from racial or ethnic minority groups
    • Immigrant women from countries where screening is not available 
  • Duration of screening is based on: 
    • A life expectancy of ≥ 10 years
    • An informed decision-making discussion with the patient
• Continued screening is recommended for at least 20 years after a precancerous lesion regresses or is treated, even if screening goes past the age of 65.