Gynecologic Malignancies in Older Women

Introduction

The 20th century has witnessed the aging of a significant portion of the population, with major changes in the social structure, particularly in developed countries. The world’s elderly population is growing at a rate of 2.4% per year.[1] Sweden has the highest proportion of elderly, with 17.5% of its population aged 65 years and older in 1997. This age shift is the result of reduced birth rates, improvements in health and nutrition, and increased longevity.

The aging population has a direct effect on health-care delivery because it is associated with new disease patterns as well as transitions in economic, social, and even ethical issues. Medical policy makers are calling for health promotion and disease prevention initiatives aimed at the population older than 50 years.[2]

Diseases of Older Women

The concept of "elderly" seems to be an inadequate generalization that covers a wide range of years as well as a diverse population from the personal and social points of view. Age definitions are relevant in gynecologic oncology because ovarian, endometrial, and vulvar cancers tend to be diseases of "older" women in their postmenopausal years. Elderly women are usually defined as being more than 70 to 75 years of age in the few studies that address this particular issue. Women older than age 80 to 85 years are considered the "old-old" or "very old." This group comprises 22% of the overall elderly population in developed countries.

As baby boomers born between 1945 and 1964 enter menopause, they will have a direct effect on clinical practice. By the year 2010, the number of postmenopausal women will exceed the number of women of reproductive age for the first time in the history of the United States.[3] On average, in developed countries, women outlive men by 5 to 7 years. According to the United States Bureau of the Census in 1997, the life expectancy of a female at birth was 79.5 years vs 72.8 years for a male. Women account for about two-thirds of the population aged 75 years and older, and the number of women aged 85 or older is expected to double between 2030 and 2050.[4]

The risk of developing a gynecologic tumor is highest in elderly women. When compared with women aged 40 to 65 years, those over age 65 have a higher risk of developing cancer of the uterus (twofold), ovaries (threefold), and cervix (10% increased risk).[5] There is also an increased risk of cancer-related death in elderly women that seems to be independent of the increased incidence. One possible explanation is related to stage of disease. Ovarian, endometrial, and cervical cancers tend to be diagnosed at a more advanced stage in elderly women.[6,7] Biological differences are possible, but other factors, including decreased screening, have been reported.[8-10]

Screening for Gynecologic Malignancies

Elderly women fail to undergo routine gynecologic examinations and screening procedures.[8,9,11] Even in the presence of symptoms, Kennedy and colleagues found the diagnosis of cancer delayed by 8.3 months and no previous pelvic examination performed for an average of 4.5 years.[11] Although women’s awareness of health problems appears to be increasing, preventive screening rates do not seem to be changing accordingly. A recent survey found that 66% of all respondents said they had undergone a clinical breast examination and Papanicolaou (Pap) smear within the previous year.[12]

Many barriers to compliance with cancer screening procedures exist, including socioeconomic, cultural, and educational factors as well as physician attitudes.[13] After age 65 years, the number of medical office visits decreases by about half when compared to women aged 45 to 64 years (7.3% vs 13.6%).[14] Thus, any physician visit should be taken as a major opportunity to educate patients and offer screening services. Physician recommendation is a major predictor of compliance with screening tests.[15]

CERVICAL CANCER

The Pap Test: The Pap test continues to be the gold standard screening test for cervical carcinoma. Implementation of Pap testing is considered to be the main reason for the decrease in the incidence and mortality of cervical carcinoma in women in the United States, with two exceptions: older women and black women. Women over age 65 years have the highest percentage of late-stage cervical cancer at diagnosis regardless of race or ethnic background.[16,17] Most patients diagnosed with invasive cervical carcinoma have not had a recent Pap test,[18] even at early stages of the disease.[19]

The false-negative rate of Pap smears is about 20%. Sampling errors contribute greatly to the incidence of false-negative tests. Recession of the squamocolumnar junction in postmenopausal patients results in limited sampling of cells. Cervical stenosis resulting from atrophy also limits sampling of the transformation zone.[20]

HPV Testing: Human papillomavirus (HPV) testing with the Hybrid Capture II has proven to be a sensitive marker for detecting dysplasia in the presence of a minimally abnormal Pap test result.[21] Persistent HPV infection has been associated with a higher risk of cervical carcinoma.[22] The rate of HPV positivity and distribution of HPV types has been found to be similar between tumors developing in younger and older patients.[23]

In a population-based study, the prevalence of high-grade squamous intraepithelial lesions was found to have a bimodal distribution with peaks at age 30 and 65 years and older. Human papillomavirus was found in 89% of high-grade squamous intraepithelial lesions and 88% of cancers.[24] One of the likely general screening applications for HPV DNA testing would be the evaluation of mildly abnormal Pap tests with atypical squamous cells of undetermined significance (ASCUS). This application would also be valid for older women.[25]

OVARIAN CANCER

Screening methods for ovarian cancer continue to be investigated. Early diagnosis is difficult because of lack of symptoms and the difficulty of detecting small adnexal masses on pelvic examination. Three-quarters of patients have stage III and IV disease at the time of initial diagnosis. Symptoms in the months preceding diagnosis are nonspecific and include bloating, abdominal pain, frequent indigestion, a feeling of fullness, and fatigue.

CA-125 Screening: CA-125 is the most extensively studied antigen associated with ovarian cancer. A normal value is generally considered to be 35 U/mL or less. CA-125 is elevated in 90% of women with stage III and IV ovarian cancer, but in only 50% of women with stage I disease. The test has a low specificity because the level of the antigen may be elevated in other pelvic and gastrointestinal malignancies as well as in benign conditions, including endometriosis, pelvic inflammatory disease, pregnancy, and leiomyomas.[26] Therefore, CA-125 has no application for screening of the general population.

The role of CA-125 as a screening tool in postmenopausal women was evaluated in a study conducted at the Royal London Hospital. This prospective study of 22,000 postmenopausal women used serum CA-125 measurements as a primary screening method for ovarian cancer.[27] Although the test was associated with high specificity (98%), for each case of ovarian cancer diagnosed, 50 false-positives occurred. Further analysis of the data demonstrated that elevation of CA-125 over 100 U/mL significantly increases the relative risk of developing an index cancer.[28]

Transvaginal Ultrasonography: Much effort has been dedicated to the evaluation of transvaginal ultrasonography as a screening tool for ovarian cancer. The potential success of sonography is based on its ability to detect early morphologic changes that cannot be detected by examination. Because stage I disease has an excellent 5-year survival (approximately 90%), requires less radical surgery, and often does not require adjuvant chemotherapy, any intervention that can accurately detect early-stage disease would have the greatest effect on outcomes.

Morphologic scoring systems have been developed to increase the specificity of transvaginal ultrasound. The most reliable criteria are ovarian size or volume, presence of papillary projections, and cyst complexity. Papillary projections correlate highly with malignancy.[29] A recent report from a large study defined the utility of ultrasound in detecting ovarian cancer in asymptomatic women.[30] Annual transvaginal ultrasound was performed in 14,469 asymptomatic women aged 50 years and over and in women with a family history of ovarian cancer aged 25 and older. As expected, a large number of ultrasounds (57,214) had to be performed in order to detect a few ovarian cancers.[11] The sensitivity of the screening was 81% and the specificity was 98.9%.

On the other hand, it was possible to detect early-stage disease in 72% of the cancers identified. A survival advantage was also demonstrated. In screened patients, the 5-year survival for epithelial cancer was 86.6% vs 50% in unscreened patients. Although color Doppler imaging may reduce the false-positive rate in ovarian cancer detection, its utility as a primary screening tool is limited, and the expenses are significant.