Gynecologic Cancers

Epidemiology

Cancer of the uterine cervix is the third most common gynecologic cancer in the United States. A more than 80% decrease in the incidence of cervical cancer since the 1950s is related to screening, initially for abnormal cervical cytology with the Papanicolaou (Pap) test and now for high-risk human papillomavirus (HPV) infection. These demographic trends are seen throughout the developed world, yet cervical cancer remains a major cause of cancer-related deaths in women worldwide, particularly in Central and South America and in Africa, owing to lack of access to screening and treatment. In the United States, over 14,000 new cases of cervical cancer and over 4000 cancer-related deaths occur annually.

HPV infection is central to the development of preinvasive and invasive disease and is detected in more than 99% of cervical cancers. Risk factors for cervical cancer ( Table 184-1 ) are mostly related to increased risk of acquiring HPV or increased virulence of HPV infection.

Of the more than 200 strains of HPV ( Chapter 344 ), about 40 infect the genital tract. Low-risk HPV causes genital warts, whereas high-risk HPV causes cancers of the anogenital tract, including cervical, vaginal, vulvar, anal, and penile cancers, as well as oral and throat cancers. Among the approximately one dozen high-risk HPVs, two types, HPV 16 and HPV 18, cause 70% of cervical cancers, and HPV types 31, 33, 45, 52, and 58 cause an additional 20% of cases. HPV is transmitted sexually through genital-genital or genital-oral contact, and the majority of sexually active individuals will be infected with HPV at some time, usually near the beginning of sexual activity, even though its transmission is significantly diminished with the use of condoms.

Pathobiology

HPVs are small, nonenveloped, double-stranded DNA viruses protected by a capsid formed by late proteins, L1 and L2 ( Chapter 344 ). The regulation of viral gene expression is complex and controlled by host cellular and viral transcription factors. HPV infection occurs at the basal cell layer of stratified squamous epithelial cells, thereby resulting in cellular proliferation, with pathologic findings from benign hyperplasia to dysplasia to invasive carcinoma. The E6 and E7 proteins of the high-risk HPV types act as viral oncoproteins that suppress normal, negative growth regulation. E6 binds to and degrades the tumor suppressor protein p53, thereby inhibiting normal apoptotic cell death, contributing to immortalization of HPV-infected cells. Similarly, E7 binds to and degrades the pRB tumor suppressor protein and targets cellular cyclins and cyclin-dependent kinases that are critical for cell cycle regulation. Both E6 and E7 have immunosuppressive effects that contribute to immune evasion and induction of peripheral tolerance in cytotoxic T lymphocytes.

HPV infects cutaneous and mucosal epithelial tissues with tropism for the anogenital tract. Most HPV infections are transient, asymptomatic, and without clinical consequences. They clear within 1 to 2 years. In about 10% of infected women, HPV DNA will continue to produce viral proteins, thereby resulting in persistent infection. In some cases, the HPV DNA is silenced, thereby resulting in latency of variable duration, but can be reactivated later. The persistence of HPV in a latent state requires maintenance of the viral genome in the infected cell, either as an episome or integrated into the host cell DNA. Persistent HPV infection is necessary for the development of precancerous cervical changes and, subsequently, cervical cancer.

The cervical cells targeted by HPV are in the squamocolumnar junction, where the squamous cells of the ectocervix meet the columnar cells of the endocervix. The position of the squamocolumnar junction migrates with age and is altered by hormonal and reproductive factors. The susceptibility of the squamocolumnar junction to the carcinogenic effects of HPV is higher in adolescents and younger women and declines with hormonal maturation of the cervix. The carcinogenic effects of HPV take approximately a decade to develop into malignancy. Cervical cancer presents at a median age of 48 years.

Clinical Manifestations and Diagnosis

Early-stage cervical cancer is largely asymptomatic, and detection is generally made by colposcopy and biopsy for abnormalities that are detected by screening. Cervical cancer frequently spreads by local extension to the uterine corpus, vagina, bladder, and parametria. In advanced stages, patients may present with pain with intercourse, vaginal discharge or bleeding, pelvic pain, or abnormalities of bowel, bladder, or sexual function.

In advanced cases, direct visualization of the cervix may reveal an obvious lesion for biopsy. In these cases, Pap smear is not adequate for diagnostic purposes, and the patient should be referred for biopsy.

Careful and thorough clinical evaluation by a gynecologic oncologist is required. In addition to pelvic and rectovaginal examination, staging may include examination under anesthesia, cystoscopy, proctoscopy, and imaging such as magnetic resonance imaging (MRI), computed tomography (CT), or positron emission tomography (PET).

Treatment and Prognosis

The treatment of cervical cancer is guided predominantly by the stage of the disease ( Table 184-2 ). Survival from cervical cancer is higher when women are managed by a gynecologic oncologist, and prompt referral is important. In addition to clinical stage, treatment decisions must consider the patient’s age, desire for fertility, and comorbid conditions, as well as the size of the tumor.

In some cases, a cervical cone biopsy (excision of a cone-shaped circumferential wedge from the cervix, the transformation zone, and at least a portion of the endocervical canal, called conization) or loop electrosurgical excision procedure (LEEP) may be sufficient for women with microscopic disease.

However, treatment of low-volume disease limited to the cervix is generally radical hysterectomy, although simple hysterectomy is an alternative in very-low-risk disease. In women undergoing radical hysterectomy, open surgery is indicated because it provides better disease-free survival compared with minimally invasive approaches (e.g., laparoscopic or robot-assisted laparoscopic). In limited situations in which the preservation of fertility is desired, a radical trachelectomy (removal of the cervix only) can be performed.

When hysterectomy reveals invasion of the lymphovascular space, deep cervical stromal involvement, larger-than-expected tumor size, positive surgical margins, parametrial involvement, or nodal involvement, adjuvant postoperative radiation therapy is typically recommended under expert supervision (see Table 184-2 ). Patients with stages IIB to IVA cancers should be treated with definitive chemoradiation therapy using radiation-sensitizing weekly cisplatin in combination with radiation therapy. Patients with persistent recurrent or metastatic cervical cancer are generally treated with systemic therapy containing a platinum taxane doublet. Bevacizumab, which is an antibody to vascular endothelial growth factor (VEGF), provides an incremental survival benefit when combined with initial chemotherapy for advanced cervical cancer. The immune checkpoint inhibitor pembrolizumab can be combined with chemotherapy, with or without bevacizumab, for patients whose tumors express PD-L1.

Highly selected patients with a central recurrence of cervical cancer may be candidates for pelvic exenteration, which is a very morbid procedure that cures 25 to 50% of patients. Otherwise, recurrent cervical cancer, though treatable, is usually not curable. Systemic chemotherapy under expert supervision is the usual approach. Palliative localized radiation may be used to manage symptoms.

Prevention

Interpretation of Screening Tests

Pap smear results are typically reported as normal, atypical squamous cells of undetermined significance (ASC-US), low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), or atypical glandular cells. These cytologic findings generally correlate with subsequent histologic findings of varying degrees of dysplasia, cervical intraepithelial neoplasia (CIN), and carcinoma in situ or invasive carcinoma ( Table 184-3 ). However, cytologic results may be associated with a subsequent histologic finding that is either more or less severe, so the results of cervical cytology are generally not used alone to make a definitive diagnosis or initiate treatment.

TABLE 184-3

CERVICAL CYTOLOGY AND HISTOPATHOLOGY

CIN = cervical intraepithelial neoplasia; HSIL = high-grade squamous intraepithelial lesion; LSIL = low-grade squamous intraepithelial lesion.

The recommended follow-up of an abnormal screening test follows an algorithm that incorporates current and prior test results, screening history, and age to estimate the risk of precancer. The finding of atypical squamous cells of undetermined significance conveys a low risk for progression to carcinoma. A low-grade squamous intraepithelial lesion, particularly in young women, is generally caused by a transient HPV infection. A high-grade squamous intraepithelial lesion is more likely to be associated with persistent HPV infection and a higher rate of progression to invasive cervical cancer. Colposcopy is recommended for most patients with positive HPV tests and abnormal Pap tests. The presence of atypical glandular cells on cervical cytology is a significant marker for premalignant disease of the cervix or endometrium, and evaluation should include testing of both these sites.

The colposcope is a lighted binocular microscope that magnifies the tissue of interest. Cervical colposcopy is used to examine the entire surface of the cervix, with emphasis on the squamocolumnar junction and transformation zones. Abnormal colposcopic findings are used to choose the sites to biopsy. In addition to cervical biopsy, repeat cervical cytology (with HPV testing, if indicated) and endocervical curettage may be obtained. The pathologic findings will guide follow-up and therapy, if necessary. Women with high-risk cytologic findings during pregnancy can still undergo colposcopy, although the endocervical curettage is omitted.

Prognosis

Five-year survival rates are 92% for localized disease, about 60% for disease that has spread regionally, and about 20% for disease with distant spread. Cervical cancer survivors are also at risk for HPV-associated oropharyngeal ( Chapter 176 ) and anal ( Chapter 131 ) cancer.

The predominant site of recurrence for cervical cancer is locoregional at the vaginal apex or pelvic sidewall. Distant metastatic spread to lymph nodes, peritoneum, liver, lung, or bone can also be seen.

Median overall survival for individuals with advanced disease is less than 18 months. Death is usually associated with local recurrence and may also be associated with organ dysfunction such as hydronephrosis, bowel obstruction, and the formation of fistulas.

Epidemiology

Endometrial cancer rates are rising in parallel with increasing obesity rates, with an estimated 67,000 new cases of endometrial cancer and 13,000 cancer-related deaths in the United States annually. Endometrial cancer is the fourth most common cancer in women after breast, lung, and colorectal cancers. Nearly 3% of women in the United States are expected to develop the disease. The average age of endometrial cancer diagnosis is 60 years, and it is rare in women before age 45 years. Endometrial cancer is more common in White women but has a higher mortality rate in Black women. A major factor for the development of endometrial cancer is estrogen exposure. Trends in the incidence of endometrial cancer may be largely explained by trends in exposure to endogenous estrogens and the use of exogenous estrogen in perimenopausal and postmenopausal women. Obesity is related to increased circulating estrogens due to increased aromatase activity in adipose tissue, thereby contributing to the conversion of adrenal androgens to estrogen ( Table 184-4 ).

Women with a history of complex atypical hyperplasia have a nearly 30-fold risk for subsequently developing endometrial cancer. As the population ages, the incidence of endometrial cancer increases. The combination of improved life expectancy, decreasing parity, and rising rates of diabetes and obesity make endometrial cancer an increasing challenge in many developing and middle-income countries.

Most endometrial cancers are sporadic, but a small percentage (3 to 5%) of endometrial cancers are attributed to a genetic predisposition. Women with a family history of endometrial cancer are at a 1.5- to 2-fold increased risk for the disease. Lynch syndrome (also called hereditary nonpolyposis colorectal cancer [HNPCC; Chapter 179 ]) is the most common genetic syndrome associated with endometrial cancer and is caused by germline mutations in one of the DNA mismatch repair genes, MLH1, MSH2, MSH6, PMS2 , or EPCAM ( Chapter 166 ). Women with Lynch syndrome have up to a 80% lifetime risk for colorectal cancer and up to a 60% risk for developing endometrial cancer.

Cowden syndrome is a rare condition resulting from a mutation in the PTEN tumor suppressor gene. The lifetime risk for endometrial cancer is 13 to 20% in women with Cowden syndrome, a five-fold elevation compared with the general population.