Cervical Cancer

By: Learning in 10

Today, we will be discussing cervical cancer. Learning objectives for today. At the end of this talk, the student will be able to understand common presentations of cervical cancer; describe the importance of HPV and cervical cancer; describe basic screening for cervical cancer; understand the basis of cervical cancer staging; describe the basic treatment strategies; and discuss prognosis and post treatment issues. An outline for today's talk. We'll begin with a patient vignette. Our patient is a 36-year-old gravida 4, para 3 013 who presents to clinic with vaginal bleeding. Upon further questioning, she reveals that her bleeding is worse after having sex.

She uses condoms intermittently, and her last exam was six years ago at the birth of her last child. The clinical presentation of cervical cancer can be quite heterogeneous. Most cervical cancer in the US is asymptomatic at diagnosis and is found on routine pap screening.

However, some details are useful to remember, and they are highlighted in the above vignette. First, the fact that she does not have regular care is emphasized by her last exam being six years ago. She also has post-coital bleeding, which is a buzzword for cervical disease.

Finally, she only intermittently uses barrier contraception, which increases her exposure to HPV. The rate of cervical cancer is much higher in developing nations as opposed to developed nations. This is attributed to lack of screening programs, which in the US typically diagnose and treat dysplastic changes of the cervix before they develop into a neoplastic process.

Cervical Cancer

As we know, cervical cancer is driven by HPV. Therefore, risk factors are all related to this. Early onset of sexual activity, multiple sexual partners, and high-risk sexual activity all lead to increased exposure to HPV. Immunosuppression can also take many forms. Rheumatic diseases, which require chronic steroid use, can suppress the immune system, allowing HPV to take hold. Additionally, transplant patients are at higher risk of developing cervical cancer because of their immunosuppression. Finally, HIV patients are at a dramatically increased risk. Specifically, patients with low CD4 counts and high viral loads are not able to clear the HPV virus and are more likely to undergo malignant transformation.

If HAART is unable to decrease viral load and improve CD4 counts, then the risk of cervical cancer decreases. HIV patients also have much higher risks of treatment failure and recurrence. They may be worthy of increased screening. Low socioeconomic status is linked with lack of screening and treatment of dysplasia, which can lead to development of invasive disease. Finally, tobacco use increases the risk of cervical cancer in a yet to be elucidated way. Most likely, this leads to suppression of the immune response against HPV-infected cells. As mentioned before, the presentation of cervical cancer can be quite variable. Pre-invasive or minimally invasive disease is generally asymptomatic and detected with screening pap smear.

More advanced disease can present as post-coital bleeding. This occurs because trauma during intercourse to the friable cervical cancer causes bleeding. Rarely, cervical cancer can present as a sudden, massive, life-threatening bleed which requires emergent treatment. Finally, a large cervical mass can become necrotic and present with profuse, malodorous vaginal discharge. The development of cervical cancer is driven by the human papillomavirus. HPV is very common and can be seen in a large portion of sexually active adults. HPV is seen in greater than 99% of cervical cancer specimens.

It is prevalent in both squamous cell carcinoma of the cervix as well as adenocarcinoma. There are over 100 subtypes of HPV, but subtypes 16 and 18 are what drive cervical cancer in the US. Oncogenic transformation generally occurs in the transformation zone. This area is the border between the endo- and ectocervix, where the epithelium transitions from squamous to columnar. The location of the transformation zone is dependent on the hormonal milieu and changes over the course of a woman's life. Persistent HPV infection in this area causes insertion of the E6 and E7 oncogenes into the epithelium over an extended time. The E6 oncogene inactivates p53, and E7 inactivates pRb, both of which are tumor suppressor genes.

The latency period for this process is extended, and it generally takes 15 years from first sexual contact until development of cervical cancer. As you may have gathered, the true key to cervical cancer is prevention. Cervical cancer screening consists of regular pap smears. Different professional societies have different recommendations, but ACOG recommends beginning annual pap smears at age 21. At age 30, in a low-risk patient with three consecutively normal pap smears, screening can be spaced to every two to three years. Pap smears are analyzed using cytology. Cytology is graded based on either squamous or glandular abnormalities, based on the Bethesda criteria.

Early changes can just be followed with repeat pap smear at an appropriate interval, whereas moderate or severe changes are followed with colposcopy and directed cervical biopsies. Colposcopy consists of examining the cervix using a microscope and using-- with acetic acid stains. Abnormal areas will appear as leukoplakia, acetowhite changes, or abnormal vascular patterns such as punctaicism or mosaicism. These areas are suspicious for cervical dysplasia and should be biopsied if the entire transformation zone is visualized and the colposcopy is considered adequate. If colposcopy is inadequate, an endocervical curettage can be performed to evaluate the endocervix. Once cervical cancer has been diagnosed, generally with histology from a cervical biopsy, it must be staged. Cervical cancer is unique to gynecologic cancers in that it is staged clinically.

This is driven by the fact that cervical cancer is seen at increased frequency in low-resource settings and staging should take this into account. Therefore, a detailed pelvic examination is performed to assess the cervix, parametria, rectum, and lymph nodes. Often, this exam is performed under anesthesia to allow the practitioner to perform the exam with a fully relaxed patient. Endoscopy consists of cystoscopy and proctoscopy and are allowed for use in staging to determine if the tumor has invaded into the bladder or rectum. Finally, simple imaging, including chest X-ray and intravenous pyelogram are used to assess for a lung metastasis or ureteral obstruction. Many high-resource settings will supplement or replace these tests with computed tomography, with or without positron emission tomography. This allows for further assessment of lymph node status and tumor invasion, which would change treatment and prognosis but not staging.

Early stage disease is disease that is limited to the cervix and is less than four centimeters in size. If disease is pre-invasive, then a simple hysterectomy can be performed. Disease limited to the cervix and less than four centimeters in size can be treated using radical hysterectomy with lymphadenectomy. This consists of end-block resection of the cervix, uterus, parametria, tubes, and upper one-third of the vagina. The pelvic and periaortic lymph nodes are also excised to further define the extent of disease. If the patient is young and future fertility is desired, radical trachelectomy can be considered, which consists of end-block resection of the cervix, parametria, tubes, and upper one-third of the vagina. In this case, the corpus of the uterus and the tubes are left in place. Finally, a patient may decline surgery and instead undergo definitive chemoradiation, which consists of daily pelvic radiation with weekly cisplatin for a total of usually five weeks.

Advanced stage disease is disease that has extended past the cervix or greater than four centimeters in size. It can invade the lymph nodes, bladder, rectum, or extend beyond the pelvis. Advanced stage disease is treated with definitive chemoradiation, as it is beyond the stages of surgical resection. Additionally, advanced stage disease may require placement of percutaneous nephrostomy tubes, if the ureters are obstructed, or colostomy, if the rectum is obstructed. Prognosis is generally dependent on spread.

Early stage disease that is fully resected leads to excellent prognosis. For example, carcinoma in situ, treated with simple hysterectomy, leads to survival rates approaching 100%. Stage 1B disease, the largest disease amenable to surgical resection, is associated with an 85% survival rate. As stage increases, survival drops precipitously. More subtle prognostic factors include nodal status, with positive status portending worsening survival; lymphovascular space invasion, which also decreases survival by increasing metastasis risk; and persistent HPV 18 at the surgical margins, which leads to increased recurrence risk. In advanced cases, death usually occurs from uremia, infection, or hemorrhage. Even though treatment of early stage cervical cancer can be quite successful, close follow-up is required to evaluate for disease recurrence. Recurrence, if it occurs, is most likely to recur at the surgical margins-- in this case, the vaginal cuff.

Therefore, a full physical exam, with speculum and bimanual exam to assess for recurrence, should occur every three months for the first two years, and then every six months until the patient is five years away from treatment. She should receive pap smears of the vaginal cuff at least yearly, with some providers performing them more often. There is no set imaging guidelines, but imaging should occur if there is any suspicion of disease recurrence. Finally, as patients survive this disease, post-treatment quality of life is an issue. Ovarian failure is a common occurrence after chemoradiation. This early menopause can cause distressing effects, including vasomotor symptoms, vaginal dryness, and irritation, as well as increased cardiovascular risk and decreased bone mineral density.

These symptoms should be treated in order to maximize the patient's quality of life. With surgical management, the ovaries are left in situ, but there are still psychosocial factors which can decrease the quality of patients' life. Psychosocial factors relating to having cancer of the female organs can cause sexual dysfunction, which is exacerbated by physical factors related to radiation or surgical changes. In summary, cervical cancer is decreasing in incidence secondary to screening efforts. HPV infection is key to the development of cervical cancer. Staging is based primarily on physical exam.

Treatment includes surgical management for early stage disease and chemoradiation for high stage disease. And there are significant post-treatment quality of life issues. Here are key references for further reading.

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