Cervical cancer screening has become one of the cornerstones for preventative screening in the gynecological world. George Papanicolaou invented this screening event, hence the name Pap smear, and first used in 1943. The test collects cervical cells near the cervical transitional (transformation) zone and determines if any of them have precancerous changes. Since 1943, few classification systems have been put in place to detail the different types of cells that are collected. While the current system followed in the United States is the 2014 Bethesda System for Reporting Cervical Cytology.
Guidelines for Pap smear testing frequency vary between United States Preventative Service Task Force (USPSTF) and American College of Obstetricians and Gynecologists (ACOG) but is recommended for women between the ages of 21 and 65. Screening is not a recommendation under the age of 21. The prevalence of abnormal pap smears is around 3.8%. At least 50 million pap smears are performed yearly. In 2019, there were an estimated 13,000 females diagnosed with cervical cancer and 4,000 females who died from cervical cancer.
Pap smears are the screening tool to assess cellular changes within the cervix. Documentation exists for are varying levels of sensitivity and specificity for the test. Because the test is not 100% sensitive, it is important to conduct pap smears routinely.
From a societal lens, there are racial disparities with the timeliness of cervical cancer diagnosis. The localized diagnosis of cervical cancer is 47% in whites and 36% in blacks. The regionalized diagnosis of cervical cancer is 35% in whites and 41% in blacks. There is a decrease in the early detection of cervical cancer in black females, which results in detection when the disease has further progressed.
The primary cause of abnormal pap smears is associated with infection by human papillomavirus (HPV). HPV serotypes 16/18 are the most common strains that cause cervical cancer. Both of these serotypes appear in 70% of cervical cancer cases. Lower-risk HPV serotypes include serotypes 6 and 11. Smoking has also shown to increase the risk of cervical cancer.
The carcinogens in the smoke disseminate throughout the body and are identifiable in cervical mucus. These carcinogens can alter the oncogene balance within these cells results in cancerous growth. Research also shows that women who have a high number of full-term pregnancies are at an increased risk of developing cervical cancer. Women who take oral contraception for prolonged periods have a temporary increase in the risk of acquiring cervical cancer.
Additionally, patients who have HIV or are immunocompromised have an increased risk of acquiring HPV, which can lead to cervical cancer. Both of these reduce the ability of the immune system to clear the virus.
From a more historical reference, children who had their mother take diethylstilbestrol (DES) during the pregnancy are at elevated risk of clear cell adenocarcinoma of the vagina and cervix. DES has prescribed pregnant mothers between 1938 and 1974 to help reduce the risks of premature labor. It is no longer prescribed.
Cervical cancer screening requires acquiring cervical cells in the transitional zone in the cervix. The transitional zone is also called the squamocolumnar junction because it is the joining process of the ectocervix and the endocervix. The ectocervix is comprised of non-keratinized stratified squamous epithelium, while the endocervix is simple columnar epithelium. The simple columnar cells also have glandular cells that secrete mucus.
The anatomic pathology for cervical cytology mainly arises from the two cell types found in the transitional zone: epithelial and glandular. Epithelial cell pathology is graded in an ascending fashion:
If the pathologist can determine that there is a morphological change within the cells, the following is the nomenclature used:
In addition to the epithelial cells, the pathologist can identify abnormal glandular cells and are graded in an ascending fashion:
Less commonly, abnormal pap smears can arise from other histological subtypes. Cervical cancer can arise by a neuroendocrine origin, with the two main subtypes being large cell and small cell. Other types of tumors that can cause cervical cancer include sarcoma, lymphoma, and melanoma.
Abnormal pap smears can present without any symptoms; it is important to ask about bleeding between periods, changes in the menstrual cycle, abnormal vaginal discharge, dyspareunia. An increase in either unexplained bleeding or menstrual bleeding should raise concerns to evaluate the possibility of cervical cancer. Bleeding in postmenopausal women is especially concerning for neoplasms. If the patient has a more advanced case of cervical cancer, she can experience pelvic pain and dysuria.
The most common etiology of abnormal pap smears is due to HPV infections. HPV is an enveloped, circular, double-stranded DNA virus. The High-Risk HPV (HR-HPV) serotypes are 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68 because they make the oncoproteins, E6, and E7. Both of these oncoproteins result in the immortalization of the infected cervical cells. E6 binds to intracellular p53 causing it to degrade. p53 is primarily utilized in the apoptotic pathway to upregulate the transcription of PUMA and NOXA, leading to cell death. E7 focuses on activating the cell cycle, allowing for replication.
In non-infected cells, one of the ways the cell cycle becomes arrested in G1 is with the binding of Rb to E2F. E2F is a transcriptional activator that needed to progress the cell into the S phase but is unable to when bound to Rb. In the high-risk strains of HPV, E7 binds to Rb, causing E2F to be released. With E2F unbound from Rb, the infected cells are signaled to begin the S phase.
Genetically, BRCA mutations play a role in the susceptibility of developing cervical cancer. BRCA stands for the breast cancer gene, and its translational product is a tumor suppressor protein. BRCA1/2 are integral in many pathways but are especially important for DNA repair. When there are double-stranded DNA breaks, these proteins help with homologous recombination repair. Without these proteins, there is genomic instability that can lead to neoplastic changes.
The morphological changes recognized in abnormal pap smears include multinucleation, hyperchromasia, and perinuclear cytoplasmic vacuolization. The nuclei of the cells can also become enlarged around three times greater than the normal cell nucleus. Other nucleic features include higher levels of keratinization but an absence of nucleoli. These changes that squamous cells undergo are categorized a koilocytosis.
A pap smear is collected with a brush inserted into the cervical os. It is important to have the brush extend beyond the visualized portion to increase the chance of successfully collecting cells from the transition zone. A similar tool to the brush is a spatula or broom.
The two mechanisms for analyzing the collects cells are liquid-based cytology(Thin prep, sure path) and conventional cytology. There are two subtypes of this cytology. One allows for the collection device to be broken off and kept with the sample that is to be analyzed. Another requires the aggravation of the collection tool since the tool does not go with the sample to be analyzed.
Liquid-based cytology preserves the cells in a buffered alcoholic solution. It has been suggested that liquid-based can better identify glandular pathology. The conventional cytology method directly transfers the cells collected from the brush onto a slide. This transfer is why this technique is called a pap smear. When transferring the specimen onto the slide, it is important to minimize drying artifact due to prolonged contact with the air. According to the American College of Obstetricians and Gynecologists (ACOG), both the liquid-based and conventional techniques are equally effective at screening for cervical cancer.
Abnormal pap smear findings for ACG in the setting of patients with HPV serotype 16/18 are at increased risk for AIS and should have more careful screening. When there is AIS with concomitant LSIL, the physician should progress the workup as if it is an AIS diagnosis.
The Papanicolaou smear is an effective screening test that detects cervical cancer as well as cellular changes that have the potential to develop into cervical cancer. Any diagnosis of an atypical pap smear results in more frequent and/or further testing. Below are the current recommendations from ACOG for each abnormal result.
Guidelines for recommendations can vary when looking at different societies and groups.
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