Patricia Polgar-Bailey
Genital Tract Cancers
Gynecologic malignant neoplasms are cancers of the female genital tract; they include cancers of the endometrium, ovary, fallopian tube, vulva, vagina, and cervix. In the United States, endometrial cancer is the most commonly diagnosed gynecologic malignant neoplasm, and ovarian cancer accounts for the most deaths annually.1 Although endometrial cancer is more common than ovarian cancer, it is easier to cure with surgery alone. Ovarian cancer is usually diagnosed at a later stage and therefore is difficult to cure. Fallopian tube cancers are rare and are managed like ovarian cancers.
Vulvar and vaginal cancers are rare and are less familiar to patients. Few women are aware that a cancer of the vulva or vagina can develop and therefore do not seek health care at the onset of symptoms, usually burning or itching. Most vulvar or vaginal cancers are detected during a careful gynecologic examination. Of the gynecologic cancers, cervical cancer is the only one with a standardized screening tool—the Papanicolaou (Pap) test.
As a primary care provider, it is important to have a clear understanding of these six types of gynecologic cancers.
Endometrial Cancer
Definition and Epidemiology
The endometrium is the inner glandular lining of the myometrium (muscle) of the uterus. This layer proliferates to prepare for implantation of a fertilized egg and sloughs on a regular cycle during the reproductive years. Once a woman reaches menopause, the endometrium remains thin because estrogen is no longer secreted from the ovaries. The proliferative characteristic of this lining is what can lead to neoplasia.
Endometrial cancer is the most common female genital tract cancer, but it is rare in women younger than 45. Three out of four cases are found in women ages 55 and older. Only 20% to 25% of endometrial cancers are diagnosed before menopause.2 In 2015, approximately 55,000 new cases of uterine cancer were projected to be diagnosed in the the United States, and approximately 10,000 of these women will die of the disease.1 Up to 8% of uterine body cancers are sarcomas, so the actual number of endometrial cancers is actually slightly lower.1 The 5-year relative survival rate is approximately 84%.3 Whereas more white women are diagnosed with endometrial cancer, more African American women die of the disease; this occurs because of a variety of socioeconomic issues related to access to care and education.4
Pathophysiology
Endometrial cancers are divided into two types, type I and type II. Type I is associated with excess estrogen that is unopposed by progesterone. It typically occurs in women who are overweight and have the following characteristics: hyperlipidemia, hyperestrogenism, anovulatory bleeding, infertility, low parity, and late menopause.5 Type I is associated with a favorable prognosis and usually is at an early stage on presentation. The excess androgen in the obese patient is converted to estrogen. Type II is not associated with these risk factors; it is most often seen in normal-weight women and has a poor prognosis.6
Type I endometrial cancer is associated with exposure to abnormal estrogen levels. Estrogen that is not opposed by progesterone causes the endometrium to become thicker and hypervascular (hyperplasia). Without progesterone, the structural support needed to sustain vascularity of the thickened endometrium is not present, and spontaneous superficial random hemorrhages occur.7
This hyperplastic appearance is classified by pathologists into two categories: benign endometrial hyperplasia and endometrial intraepithelial neoplasia (EIN). This is a recent change in the classification system intended to stratify the patient’s risk for development of malignant endometrial cells. Benign endometrial hyperplasia shows cysts, remodeled glands, vascular thrombi, and stromal microinfarcts; these are changes resulting from the duration and combination of hormonal exposures. In contrast, EIN is the premalignant state that is demonstrated microscopically as cells with altered cytologic features and crowded architecture. Patients with EIN have a 45-fold greater risk for development of an endometrial cancer, and hysterectomy is recommended.8 According to a recently published paper by the Collaborative Group on Epidemiological Studies on Endometrial Cancer, medium- to long-term use of oral contraceptives (i.e., for 5 years or longer) results in substantially reduced risk of endometrial cancer.9 The reduction in risk associated with ever having used oral contraceptives differed depending on the type of tumor, with the risk reduction being stronger for carcinomas than sarcomas. In high-income countries, use of oral contraceptives for 10 years was estimated to reduce the absolute risk of endometrial cancer arising before age 75 years from 2.3 to 1.3 per 100 women.9
Factors that influence the risk of endometrial cancer include things that affect hormone levels (e.g., estrogen after menopause, birth control pills, tamoxifen), the number of menstrual cycles (over a lifetime), pregnancy, obesity, certain ovarian tumors, polycystic ovarian syndrome, use of an intrauterine device, age, diet and exercise, diabetes, a history of breast or ovarian cancer, history of endometrial hyperplasia, and a history of radiation therapy to the pelvis to treat another type of cancer.10
The risk of endometrial cancer is increased among first-degree relatives of patients with endometrial cancer and those with a personal history of colon and breast cancers. Patients with Lynch II syndrome, or hereditary nonpolyposis colorectal cancer (HNPCC), have a 40% to 60% lifetime risk for development of endometrial cancer.10,11 HNPCC is an autosomal dominant inherited cancer that is caused by a germline mutation in a DNA mismatch repair gene. These patients should be referred to an oncologist to ensure careful and frequent screening.
Clinical Presentation and Physical Examination
The most important sign or symptom of endometrial cancer in the postmenopausal patient is bleeding. Patients often have complaints of a single episode of postmenopausal bleeding or a fullness or pressure in the pelvis. For some women who may not bleed because of cervical stenosis, a transvaginal ultrasound examination is a helpful tool. In a postmenopausal woman, endometrial thickness (also called endometrial stripe) on transvaginal ultrasonography should not be more than 5 mm. An endometrial thickness of more than 5 mm should be assessed with either biopsy in the office or dilation and curettage in the operating room. These procedures are usually performed by gynecologists.12
The perimenopausal presentation is more challenging. These patients often have irregular menses that are heavier and more frequent than their cycle previously. This is an important sign because bleeding should become lighter and less frequent during perimenopause, not heavier and more frequent. Providers must be careful not to assume that changes in menses are related to the onset of menopause.6
A detailed history of menstruation, dyspareunia, pelvic pain, fever, trauma, and intrauterine contraceptive device use should be elicited, and risk factors for endometrial cancer reviewed.
Other complaints that either premenopausal or postmenopausal women might express to the primary care provider are painful urination, dyspareunia, pelvic pain, cramping, pelvic discomfort, and postcoital bleeding. These symptoms warrant further evaluation, and transvaginal ultrasound examination is a good place to start.
In addition to a thorough general physical examination, the patient should undergo bimanual pelvic examination (including rectovaginal examination) and transvaginal ultrasound examination. If endometrial cancer is considered as a differential diagnosis, the patient requires endometrial sampling, either in the office with a Pipelle (a small suction catheter that is passed into the uterus in the office) or in the operating room with dilation and curettage. Endometrial biopsy is accurate 90% of the time; if there is high suspicion for cancer and the biopsy finding is normal, dilation and curettage should also be performed. If abnormalities are palpated on general or pelvic examination, a computed tomography (CT) scan with contrast enhancement of the abdomen and pelvis should be obtained to assess for spread of disease to adjacent organs or lymph nodes. Most common spread of disease is to the pelvic and para-aortic lymph nodes.
Workup for endometrial cancer is most often performed by the gynecologist. On occasion, if the sampling is difficult or there is high suspicion for cancer, these patients should be referred directly to a gynecologic oncologist.
Diagnostics and Differential Diagnosis
There are multiple benign causes of dysfunctional uterine bleeding; however, bleeding in the postmenopausal woman should be assumed to be cancer until proven otherwise. If a postmenopausal patient has vaginal bleeding, the priority should be tissue sampling; 20% of these patients will have a malignant neoplasm on biopsy.6 If a perimenopausal patient has worsening vaginal bleeding, tissue sampling should be obtained to rule out malignant disease.
Once a malignant neoplasm has been ruled out, the provider can sift through the myriad benign causes to determine the correct one. Atrophic vaginitis is a common cause of postmenopausal bleeding.
Management and Indications for Referral or Hospitalization
Surgery is the treatment of choice for endometrial cancer. In early-stage disease, surgery can be curative; approximately 75% of patients with endometrial cancer have stage I disease (confined to the uterus) on presentation for evaluation.6 Ideally, even patients with disease that has spread outside the uterus will undergo hysterectomy to remove the bulk of the disease and the source of bleeding.
Endometrial cancer surgery includes removal of the uterus, fallopian tubes, ovaries, and lymph nodes. Recently, there is a trend toward minimally invasive staging surgeries that use laparoscopy or robotically assisted vaginal hysterectomy with lymph node sampling. The surgery should be performed in collaboration with a gynecologic oncologist who is trained to perform lymphadenectomy and lymph node sampling. Adjuvant treatment (in addition to surgery) includes radiation therapy, hormonal therapy, and chemotherapy. Treatment decisions are made after surgery is complete and the stage (where it is located) and grade (type and morphologic features) of the disease have been assigned.
Life Span Considerations
The average age at diagnosis of endometrial cancer is 60 years, and the incidence increases with advancing age. When endometrial cancer occurs before the age of 40 years, it is usually associated with chronic obesity or anovulation.13
Patient and Family Education
Patients should understand that the use of estrogen plus progesterone for postmenopausal hormone replacement therapy does not increase the risk of endometrial cancer. It is also necessary that women understand the importance of evaluation for any postmenopausal bleeding even if it occurs only once or is a small amount.
Ovarian Cancer
Definition and Epidemiology
Among women, ovarian cancer represents the fifth leading cause of death from cancer.1 In 2015, the American Cancer Society estimated that there were approximately 21,290 new cases diagnosed and 14,180 deaths from ovarian cancer. A woman’s lifetime risk of getting ovarian cancer is about 1 in 75, and the lifetime chance of dying from ovarian cancer is about 1 in 100. This cancer develops mainly in older women, and approximately half of the women who are diagnosed with ovarian cancer are 63 years or older. It is more common in white women than African-American women.1 The rate at which women are diagnosed with ovarian cancer has gradually decreased over the past 20 years.
Because of socioeconomic factors, there is a big difference in survival of white women versus black women. The 5-year relative survival is 45.4% for white women and 36.8% for black women.14
During the last decade, advances have been made in the treatment of ovarian cancer; however, little advance has been made in the development of tools for early diagnosis of ovarian cancer. This disease often progresses to advanced stages with only subtle signs and symptoms. It is important that the primary care provider be tuned in to the possible signs of early disease.
Pathophysiology
Ovarian cancer develops in the ovary. Typically, it occurs in women 65 years and older. There are numerous histologic types of ovarian cancer: epithelial, germ cell, and mesenchymal (stromal and sex cord). The epithelial ovarian cancers are further subdivided: serous, mucinous, endometrioid, clear cell, transitional cell tumors (Brenner tumors), carcinosarcoma, mixed epithelial tumor, and undifferentiated carcinoma. Clear cell and endometrioid ovarian carcinomas are often associated with endometriosis. Serous carcinomas are often discovered at more advanced stages (III and IV); clear cell and endometrioid carcinomas are more often confined to the ovary and therefore are at an earlier stage at diagnosis. Although all of these types are labeled ovarian cancers, it is important for the provider to understand that each histologic type is slightly different from its counterparts, and therefore the oncologist might manage the disease for each type slightly differently.15 Although the management of each type of ovarian cancer might differ, what does not differ is the need for all patients with suspected ovarian cancer or pelvic mass to undergo surgery.
The risk for development of ovarian cancer is influenced by genetic, hormonal, and environmental factors. Approximately 5% to 10% of women have a genetically acquired risk of ovarian cancer because of inherited mutations in the BRCA1 and BRCA2 tumor suppressor genes. The overall risk for development of ovarian cancer is 20% to 60% for those with BRCA1 mutations and 10% to 35% for those with BRCA2 mutations. Some data suggest that women with BRCA mutation–mediated ovarian cancer may have survival rates better than those of woman with sporadic ovarian cases. This may be a result of improved tumor response to platinum-based chemotherapy in those with BRCA-related cancer.16
Increased age and family history are risk factors; family history is the best predictor of risk. One second-degree relative with ovarian cancer increases the lifetime risk to 2.9%; one first-degree relative with ovarian cancer increases the lifetime risk to 4% to 5%; and two or more affected first-degree relatives increases the risk to 30% to 50%.7 Whereas these hereditary syndromes are rare, if a patient with a family history of ovarian cancer reports pelvic pain, fullness, early satiety, or urinary frequency, the provider must carefully evaluate the patient and rule out malignant disease.
Other risk factors include late menopause, nulliparity, and early menarche. There is debate as to whether or not infertility drugs increase the risk for ovarian cancer; at this time, the data do not fully support either argument. In general, these theories are based on a theory of ovulation without stopping, in which the ovary itself is somehow disrupted and is sensitive to events of ovulation. Therefore, methods to suppress ovulation, such as oral contraceptive use, multiparity, late menarche, and early menopause, would potentially decrease a patient’s risk. The use of oral contraceptives confers protection for up to 10 years after they are discontinued.7
Clinical Presentation and Physical Examination
In 2007, Goff and colleagues17 developed a symptom index to improve early detection of ovarian cancer. These specific symptoms, if persistent, should be considered red flags for the provider: pelvic pain, abdominal pain, urinary urgency, urinary frequency, increased abdominal size, abdominal bloating, difficulty eating, and early satiety. The provider must consider all differential diagnoses for these symptoms and should not presume that they are related to menopause or stress. Ovarian cancer must be considered as a differential diagnosis in these cases. Goff’s research was groundbreaking in that it brought new public attention to common symptoms that warrant suspicion of ovarian cancer.
A pelvic examination that includes a rectovaginal examination should be done but is not sensitive for detection of ovarian cancer. This examination should be done routinely on all women to adequately assess the entire pelvis for mass, fullness, or tenderness. Despite a careful examination, it is rare that an ovarian cancer is detected. DiSaia and Creasman6 stated that it takes 10,000 routine pelvic examinations to detect one ovarian cancer.
Diagnostics and Differential Diagnosis
Other conditions can manifest as a pelvic mass. These include sigmoid diverticulitis; pregnancy; a distended bladder; a low-lying distended cecum; stool in the sigmoid colon; a pelvic kidney; and a fallopian tube, uterine, or gastrointestinal tumor. Included in the differential diagnosis are fallopian tube carcinomas, which are rare and are managed and treated like ovarian cancers.
The differential diagnoses can be sorted out through the use of radiographic imaging. Transvaginal ultrasonography is the gold standard assessment of the pelvis. If the ultrasound study is inconclusive, pelvic CT scan and pelvic magnetic resonance imaging (MRI) are both useful. However, if a primary care provider suspects a pelvic mass or diagnoses a mass on ultrasound examination, the patient should be referred to a gynecologist for further workup.
If the provider suspects a pelvic mass, the first diagnostic test that should be ordered is a transvaginal pelvic ultrasound study. Once the diagnosis of a pelvic mass is established, a serum cancer antigen 125 (CA-125) test should be ordered. CA-125 is a serum protein that is produced by ovarian cancer cells. It is elevated in most epithelial ovarian cancers. CA-125 can be elevated in myriad conditions including many nonmalignant conditions (Box 163-1). Because it is also elevated in nonmalignant conditions, it is not an adequate screening tool. When the CA-125 test and transvaginal ultrasound examination are used in the general population, they are found to be inadequate screening tools, with false-positive rates that are greater than 75%. As a result, women undergo unnecessary surgery. However, if the patient has a pelvic mass and plans to undergo surgery, a CA-125 value that is above the laboratory’s designated normal value (usually 35 U/mL) may guide the surgeon to plan a cancer staging operation rather than a simple removal of the mass.
