Continuing Education Activity

The Pap smear is responsible for decreasing the incidence of and mortality rates from cervical cancer. The Papanicolaou (Pap) smear is a collection of cells from the squamocolumnar junction of the cervix where the columnar epithelium is juxtaposed to the smooth squamous epithelium. In this area, squamous metaplasia is causing squamous cells to replace columnar cells. This cell growth and change can allow the entrance of human papillomavirus (HPV), the cause of more than 90% of cervical cancer. The Pap smear is a sample of cells from this area to screen a patient for abnormalities such as cervical dysplasia. This activity reviews the etiology, presentation, evaluation, and management of cervical dysplasia and reviews the role of the interprofessional team in evaluating, diagnosing, and managing the condition.

Objectives:

• Review the pathophysiology of cervical dysplasia, starting with its precursors and progressing through to its most serious sequelae.
• Describe the history, examination, and evaluation procedures for patients with suspected cervical dysplasia.
• Summarize the appropriate treatment approach to cervical dysplasia based on degree.
• Outline interprofessional team strategies for improving care coordination and communication to improve outcomes with cervical dysplasia.

Introduction

The pap smear is responsible for decreasing the incidence of and mortality rates from cervical cancer. The Papanicolaou (Pap) smear is a collection of cells from the squamocolumnar junction of the cervix where the columnar epithelium is juxtaposed to the smooth squamous epithelium. In this area, squamous metaplasia is causing squamous cells to replace columnar cells. This cell growth and change can allow the entrance of human papillomavirus (HPV), the cause of more than 90% of cervical cancer. The Pap smear is a sample of cells from this area to screen a patient for abnormalities such as cervical dysplasia. [1][2][3][4]

Etiology

Cervical dysplasia is the precursor to cervical cancer. It is caused by the persistent infection of the human papillomavirus (HPV) into the cervical tissue. The most common type is HPV 16, responsible for 50% of cervical cancer. HPV 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68 are the other HPV oncogenic types. HPV is a common, sexually transmitted infection that usually clears within eight to 24 months of exposure. Persistent infection leads to dysplasia, which, if untreated, can lead to cervical cancer. The process is usually slow and occurs over several years. Because of the slow progression of this identifiable and treatable infection, it is amenable to routine screening with a Pap smear and/or HPV testing depending on the patient's age and history. [5][6][7]

Epidemiology

The HPV virus is transmitted through skin to skin contact, most commonly through sexual contact. Nonsexual transfer can occur with fomites, but the transmission typically is seen with genital contact and sexual activity. Multiple sexual partners or a partner who has multiple sexual partners significantly increases the risk of exposure. Exposure at a young age also increases the risk of persistent HPV. This is based on the observation that HPV infection is most common in young women 18-30 years old, with prevalence sharply declining after age 30. The greatest metaplastic activity of the cervix is during puberty and the first pregnancy; HPV needs to infect these areas to have the DNA incorporated into the cell. The median age of HPV-associated cervical cancer diagnosis is 49. This implies an earlier age of exposure because it has a slow growing dysplastic process, which leads to cancer in approximately 10-30 years.

Pathophysiology

HPV infects the basal cells of the squamous epithelium of the cervix. Once inside the host cell, the HPV DNA replicates as the basal cells differentiate and progress to the surface of the epithelium. The HPV gene expression becomes unlinked to the state of cellular differentiation of infected epithelial cells, and deregulation expression of the early region of the viral genome results in a dramatic increase in the expression of the two HPV oncoproteins (E6 and E7). This results in the loss of the normal cell cycle control of the epithelium, and cells will develop morphologic features with immature "basaloid- type" squamous cells and mitotic figures in the upper half of the cervical epithelium. These features can be seen on colposcopy when acetic acid is applied to the cervix. A biopsy of this area is performed and sent to the pathologist to evaluate the degree of dysplasia present.

History and Physical

The link of papillomaviruses to squamous cancers was first discovered in the 1930s by the research of Dr. Richard Shope. By the 1950s and 1960s, a potential link between viral infections and cervical cancer was noted. In 1984, Harald zur Hausen discovered, cloned, and attributed cervical cancer to HPV 16 and 18; he would later win a Nobel Prize for his work. Over the next 15 years, scientists worked to link cervical cancer and HPV, showing that HPV is the trigger for cervical cancer.

Evaluation

The most common way to identify cervical dysplasia starts with a Pap smear. Most Pap smears are now liquid-based cytology that will identify normal and abnormal cellularity. Molecular testing for the high-risk HPV subtypes types can be performed from the liquid samples if indicated. The Pap smear is a screening test, and based on the abnormality of the screening test, the next step in evaluation may be colposcopy. During this procedure, the cervix is examined with a microscope, and 5% acetic acid is applied to the cervix to identify abnormal areas. The dysplastic areas will turn an aceto-white color. Sometimes Lugol solution may be utilized if one is unable to see abnormalities with acetic acid; this will result in a non-staining area. A biopsy of any abnormal areas is sent to the pathologist who identifies any evidence of cervical dysplasia.[8][9][10][11]

Treatment / Management

There are different degrees of dysplasia. Based on the  Lower Anogenital Squamous Terminology (LAST) project, pathologists should call the specimen low-grade squamous intraepithelial lesion (LSIL) or high-grade squamous intraepithelial lesion (HSIL). LSIL, classically referred to as CIN1 or mild dysplasia, does not require treatment and should be followed conservatively. Patients with LSIL should return in one year for co-testing. This involves a repeat Pap smear with HPV molecular testing as the majority of the lesions will regress on their own. HSIL, classically referred to as CIN2/3 or CIS, usually requires an excisional procedure for treatment. Ablative procedures can be offered, but the majority of clinicians perform excisional procedures to give the pathologist a better specimen to evaluate. Excisional procedures provide assurance that an underlying cancer is identified, and adequate treatment for the lesion is provided. A  loop electrosurgical excision procedure (LEEP) to remove the abnormal tissue with a thin electrified wire that cuts the specimen from the cervix can be performed in the office. A cold knife cone (CKC) typically is performed in the operating room, using a knife to resect a cone-shaped portion of cervical tissue. The advantage of a CKC is that the pathologist can identify the margins more clearly and because they are not obscured by the burn artifact created with the electrified wire. Following a complete excision and negative margins, patients require yearly follow-up with a pap smear.  If underlying cancer is discovered, treatment plans are expanded, and an oncologist is consulted. If an excisional procedure provides results in positive LEEP margin findings, the decision to re-excise or follow conservatively is based on the patient’s age and fertility status.  [12][13][14]

Differential Diagnosis

• Cervicitis

• Endometrial carcinoma

• Pelvic inflammatory disease

• Vaginitis

Pearls and Other Issues

A hysterectomy is not the standard of care to treat cervical dysplasia. However, the finding of recurrent cervical dysplasia may be treated with hysterectomy. Post hysterectomy patients will not develop cervical cancer as the cervix has been removed, but must still receive Pap smears of the remaining vaginal cuff for 20 years due to the risk of vaginal dysplasia and subsequent cancer. Vaginal cancer is extremely rare, with fewer than 5,000 cases a year, but individuals with a history of severe cervical dysplasia are at the greatest risk for this disease. Patients undergoing a hysterectomy for benign indications without a history significant for a high-grade cervical dysplasia no longer need cytological screening or HPV screening as her risk of vaginal cancer is very low. The three vaccines developed to prevent HPV infection are one which provides protection from HPV 16 and 18, another which covers 6, 11, 16 and 18, and most recently released, a 9-valent vaccine which protects from HPV 6, 11, 16, 18, 31, 33, 45, 52 and 58. Even though 6 and 11 are not oncogenic subtypes of HPV, they are responsible for genital warts, which are problematic to the patient and can be passed along to an infant during pregnancy. Genital warts are a significant source of medical spending in the US. Once the Gardasil 4 vaccines are depleted, the only vaccine to be manufactured in the United States will be Gardasil 9. This vaccine is indicated in girls and boys ages nine to 26, preferably before any sexual contact or exposure, to prevent cervical, vaginal, and vulvar cancers as well as penile, anal, and certain types of head and neck cancers. This is a virus-like particle vaccine which cannot reproduce in the human body and is considered safe by the Food and Drug Administration (FDA) and  Centers for Disease Control and Prevention (CDC).

Enhancing Healthcare Team Outcomes

The screening and management of cervical HPV infection are best managed by an interprofessional team that includes the nurse practitioner, primary care provider, pathologist, and gynecologist. There are different degrees of dysplasia. Based on the  Lower Anogenital Squamous Terminology (LAST) project, pathologists should call the specimen low-grade squamous intraepithelial lesion (LSIL) or high-grade squamous intraepithelial lesion (HSIL). LSIL, classically referred to as CIN1 or mild dysplasia, does not require treatment and should be followed conservatively. Patients with LSIL should return in one year for co-testing. This involves a repeat Pap smear with HPV molecular testing as the majority of the lesions will regress on their own. HSIL, classically referred to as CIN2/3 or CIS, usually requires an excisional procedure for treatment. Ablative procedures can be offered, but the majority of clinicians perform excisional procedures to give the pathologist a better specimen to evaluate. Excisional procedures provide assurance that an underlying cancer is identified, and adequate treatment for the lesion is provided. The key is for the healthcare provider to recommend positive lifestyle changes and get vaccinated against HPV.  Pharmacists often administer the vaccine and counsel patients as to the risks and benefits. Ambulatory care and pediatric nurses also administer vaccines and make sure patients follow up. [12][13][14]