Epidemiology of Gynecologic Cancers, Clinical Trials, and Statistical Considerations

Wendy R. Brewster and Krishnansu S. Tewari

EPIDEMIOLOGY OF GYNECOLOGIC CANCERS

The burden of cancer on our population is expected to rise sharply over the next 20 years. This is the result of the aging and growth of the world’s population, alongside an increasing adoption of cancer-causing behaviors, particularly smoking and increasing obesity. Overall, cancer incidence is expected to increase by 45% between 2010 and 2030, with the greatest increase borne by older adults and minorities. By 2030, approximately 70% of all cancers will be diagnosed in older adults, and 28% of all cancers will be diagnosed in minorities.¹ Resources will be required to effect and optimize cancer prevention, screening, and early detection. Meaningful improvements in cancer therapy and/or prevention strategies will be required to prevent a dramatic increase in the number of cancer deaths over the next 20 years.

Uterine Corpus Cancer

Endometrial cancer is the most common gynecologic cancer and the fourth most common cancer of women in the United States; 43,470 new cases diagnosed are predicted for 2010, with 7950 deaths.² A 50-year old woman in the United States has a 1.3% probability of being diagnosed with endometrial cancer before age 70 years.

Eighty-seven percent of all endometrial cancers are of endometrioid histology. The most common nonendometrioid histology is papillary serous (10%), followed by clear cell (2%-4%), mucinous (0.6%-5%), and squamous cell (0.1%-0.5%). Some nonendometrioid endometrial carcinomas behave more aggressively than the endometrioid cancers such that even women with clinical stage I disease often have extrauterine metastasis at the time of surgical evaluation.³ Features of type 1 (endometrioid) carcinoma include increased exposure to estrogen (nulliparity, early menarche, chronic anovulation, and unopposed exogenous estrogen), obesity, and responsiveness to progesterone therapy. Patients more often are white, younger in age, present with a low-grade cancer, and have a better prognosis. The precursor to this malignancy is endometrial hyperplasia. Type 1 endome-trial cancers often have a phosphatase and tensin homolog (PTEN) mutation and a higher incidence of microsatellite instability. In contrast, type 2 endometrial cancers are unrelated to estrogen exposure and occur in older, thinner women. The most common forms of type 2 endometrial cancer include uterine papillary serous carcinoma and clear cell carcinoma. Uterine papillary serous cancers are aggressive, with an increased incidence of p53 and HER-2/neu overexpression.

Risk factors for endometrial cancer include diabetes, obesity, hypertension, nulliparity, polycystic ovarian syndrome, unopposed estrogen therapy, tamoxifen usage, infertility or failure to ovulate, and late meno-pause.⁴ A number of studies have reported a positive association between diabetes and incidence of mortality from endometrial cancer.⁵ Diabetes mellitus (both types 1 and 2) has been associated with up to a 2-fold increased risk of endometrial cancer.

Adult overweight/obesity is one of the strongest risk factors for endometrial cancer. In affluent societies, adult obesity accounts for approximately 40% of the endometrial cancer incidence.⁶ In postmenopausal women, adiposity is thought to enhance endometrial cancer risk through the mitogenic effects of excess endogenous estrogens that are produced in the adipose tissue through aromatization of androgens. In addition, obesity is accompanied by increased bioavailable estrogen as a result of decreased sex hormone–binding globulin concentration.⁶ Although obesity increases endometrial cancer risk independent of other factors, it is not associated with stage or grade of disease.⁷

Tamoxifen citrate is an antiestrogen agent that binds to estrogen receptors but acts as a weak estrogen agonist in postmenopausal endometrial tissue. A spectrum of endometrial abnormalities is associated with its use (including polyps and hyperplasia). Endometrial carcinoma is also associated with long-term tamoxifen treatment.⁸

Endometrial Hyperplasia

In a nested case-control retrospective review of predominantly white participants from Kaiser Permanente Northwest, in the northwest of the United States, the average age at the time of diagnosis of endometrial hyperplasia was 52 years. The endometrial carcinoma risk among women with non-atypical endometrial hyperplasia—who represent the majority of all endometrial hyperplasia diagnoses—is 3 times higher than that of the average population. The risk of endometrial cancer among women with atypical hyperplasia (27.5%) is 21 times higher than the average population risk. The absolute and cumulative risk of progression are represented in Figures 1-1 and 1-2. Cumulative 20-year progression risk among women who remain at risk for at least 1 year is less than 5% for non-atypical endometrial hyperplasia but is 28% for atypical hyperplasia.⁹ A Gynecologic Oncology Group (GOG) prospective cohort study designed to estimate the prevalence of concurrent carcinoma in patients who have a biopsy diagnosis of atypical endometrial hyperplasia found that the prevalence of carcinoma in hysterectomy specimens was 42.6%.¹⁰

FIGURE 1-1. Absolute risk of subsequent endometrial carcinoma by endometrial hyperplasia (EH) type at index biopsy over intervals of 1 to 4, 5 to 9, and 10 to 19 years. Vertical bars indicate 95% CIs. Data points are plotted at the mean time to diagnosis within each time interval. Size of data points is proportional to the number of case patients diagnosed with endometrial carcinoma during that time interval. AH, atypical hyperplasia; DPEM, disordered proliferative. (Reproduced, with permission, from Lacey JV Jr, Sherman ME, Rush BB, et al. Absolute risk of endometrial carcinoma during 20-year follow-up among women with endometrial hyperplasia. J Clin Oncol. 2010;28(5):788-792.)

FIGURE 1-2. Cumulative risk of subsequent endometrial carcinoma by endometrial hyperplasia (EH) type at index biopsy. Vertical bars indicate 95% CIs. Data points are plotted at the mean time to diagnosis within each time interval. Size of data points is proportional to the number of case patients diagnosed with endometrial carcinoma during that time interval. AH, atypical hyperplasia; DPEM, disordered proliferative endometrium. (Reproduced, with permission, from Lacey JV Jr, Sherman ME, Rush BB, et al. Absolute risk of endometrial carcinoma during 20-year follow-up among women with endometrial hyperplasia. J Clin Oncol. 2010;28(5):788-792.)

Hormonal Therapy

Menopausal estrogen therapy (ET) increases the risk of endometrial cancer in postmenopausal women; however, the risk of endometrial cancer varies with the duration, dose, and type of estrogen used. It is generally believed that daily use of low-dose progestin opposes the effect of exogenous and endogenous estrogen on the endometrium, resulting in a lower risk of endometrial cancer. The California Teachers Study cohort analyzed the association between long-term hormonal therapy use and endometrial cancer risk and the modifying effect of body mass index (BMI) in a case-control study. Long-term (≥10 years) use of ET, sequential estrogen–progesterone therapy (with < 10 days per month of progestin), and continuous combined estrogen and progesterone therapy (≥25 days/month of progestin) were all associated with an elevated risk of endometrial cancer (odds ratio [OR], 4.5; 95% confidence interval [CI], 2.5-8.1; OR, 4.4; 95% CI, 1.7-11.2; and OR, 2.1; 95% CI, 1.3-3.3, respectively). The risk associated with short-term use was elevated only for ET preparations. The association for continuous combined estrogen–progesterone therapy was confined to thinner women . Among heavier women , use of continuous combined estrogen–progesterone therapy was associated with a nonsignificant reduction in risk. These findings confirm that long-term use of ET, sequential estrogen–progesterone therapy, or continuous combined estrogen–progesterone therapy among normal-weight women is associated with increased risk of endometrial cancer.¹¹

Genetics of Endometrial Cancer

A somatic mutation or deletion of the PTEN tumor suppressor gene has been reported in approximately 40% and 40% to 76%, respectively, of endometrial adenocarcinomas.¹² It is well established that estrogen increases endometrial cancer risk, whereas progesterone opposes the estrogen effects. PTEN regulates proliferation, growth, and apoptosis in a phosphatidylinositol-3-OH kinase (PI3K)–dependent pathway. Genetic variation in the progesterone receptor gene region is associated with endometrial cancer risk.¹³

Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer)

Individuals with Lynch syndrome, also called hereditary nonpolyposis colorectal cancer (HNPCC), are at an increased risk for colorectal cancer, endometrial cancer, and other associated cancers such as gastric cancer, ovarian cancer, urothelial cancer, hepatobiliary tract cancer, brain cancer, cancer of the small intestine, pancreatic cancer, and particular skin cancers. HNPCC-associated cancers are caused by defects in DNA mismatch repair genes. Lynch syndrome is primarily due to germline mutations in one of the DNA mismatch repair genes, mainly hMLH1 or hMSH2 and less frequently hMSH6 and rarely hPMS2.¹⁴ These genetic defects in the DNA mismatch repair system result in microsatellite instability and the absence of protein expression in the tumor. Currently, the diagnosis of Lynch syndrome is based on either clinical (revised Amsterdam criteria) or molecular criteria. The Bethesda Guidelines were revised in 2004 to include extra-colonic tumors to improve the sensitivity of detecting families with Lynch syndrome and to determine which individuals should have microsatellite instability or immunohistochemical testing of their tumors (Table 1-1). Low BMI, age less than 50 years, and positive family history have all been identified as risk factors in endometrial cancer patients who might benefit from HNPCC screening.¹⁵

Table 1-1 Amsterdam Criteria II and Revised Bethesda Guidelines

FAP, familial adenomatous polyposis; MSI-H, high probability of microsatellite instability.

^aLynch syndrome–related tumors include colorectal, endometrial, stomach, ovarian, pancreas, ureter, renal pelvis, biliary tract and brain tumors, sebaceous gland adenomas and keratoacanthomas, and carcinoma of the small bowel.

Reproduced, with permission, from Vasen HF, Möslein G, Alonso A, et al. Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet. 2007;44(6):353-362.

Uterine Sarcomas

Uterine sarcomas are rare tumors of the uterus that comprise 4% to 9% of all invasive uterine cancers and 1% of female genital tract malignancies.¹⁶ Carcinosarcoma, previously referred to as malignant mixed mullerian tumor, is a biphasic neoplasm composed of distinctive and separate, but admixed, malignant-appearing epithelial and mesenchymal elements. The sarcomatous components are heterogeneous, and almost all are high grade. The homologous components of carcinosarcoma are usually spindle cell sarcoma without obvious differentiation; many resemble fibrosarcomas or pleomorphic sarcomas. The most common heterologous elements are malignant skeletal muscle or cartilage resembling either pleomorphic rhabdomyosarcoma or embryonal rhabdomyosarcoma. Carcinosarcomas comprise almost half of all uterine sarcomas. One-third of all cases are diagnosed at an advanced stage. Up to 37% of patients with carcinosarcomas have a history of pelvic irradiation. These tumors tend to occur in younger women, often contain heterologous elements, and are found at advanced stage. Carcinosarcomas are highly aggressive tumors and are fatal in the vast majority of cases.

After excluding carcinosarcoma, leiomyosarcoma is the second most common subtype of uterine sarcoma; however, it accounts for only 1% to 2% of uterine malignancies. Most occur in women over 40 years of age who usually present with abnormal vaginal bleeding (56%), palpable pelvic mass (54%), and pelvic pain (22%).¹⁶ The vast majority of uterine leiomyosarcomas are sporadic. These are very aggressive tumors, even when diagnosed at an early stage. Patients with germline mutations in fumarate hydratase are believed to be at increased risk for developing uterine leiomyosarcomas as well as uterine leiomyomas.¹⁷

The next common subset of uterine sarcomas, termed endometrial stromal tumors, are divided into 3 groups: endometrial stromal nodule, low-grade endometrial stromal sarcoma, and undifferentiated endometrial sarcomas. Endometrial stromal nodules can occur in women at any age. Patients with endometrial stromal nodules have an excellent prognosis and can be cured by hysterectomy.¹⁶ Endometrial stromal sarcomas are indolent tumors with a favorable prognosis. They occur in women between 40 and 55 years of age. Some cases have been reported in patients with ovarian polycystic disease, after estrogen use, or tamoxifen therapy. In contrast, undifferentiated endometrial sarcomas have very poor prognosis. Endometrial stromal tumors often contain estrogen and progesterone receptors. However, the prognostic implication of these findings is uncertain.¹⁸

Cervical Cancer

Cervical cancer is the second most frequent cancer in women worldwide and the principal cancer in most developing countries, where 80% of the cases occur.¹⁹ During the years 1973 and 1997, cervical cancer rates decreased in most parts of the world. Incidence rates are almost 2-fold higher in less-developed compared with more-developed countries (19.1 and 10.3 per 100,000 person-years, respectively). The incidence is highest in Africa and Central/South America (approximately 29 per 100,000 person-years) and lowest in Oceania and North America (approximately 7.5 per 100,000 person-years).¹⁹ India, the second most populous country in the world, accounts for 27% (77,100) of the total cervical cancer deaths¹ (Figure 1-3). In the United States, cervical cancer is the third most common gynecologic cancer of women. For 2010, 12,200 new cases and 4210 deaths were predicted.²

FIGURE 1-3. Age-standardized cervical cancer incidence and mortality rates by world area. (Reproduced, with permission, from Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69-90.)

The search for an infectious etiology of cervical cancer dates back to observations made centuries ago, when the Greeks and Romans observed that genital warts were associated with sexual promiscuity and regarded them as infectious. In 1842, Rigoni-Stern, an Italian physician in Verona, observed the higher frequency of cervical cancer among married women, prostitutes, and widows than among virgins or nuns. Subsequently, the medical literature displayed reports of rare malignant conversion of condylomata acuminate into squamous cell carcinoma. In 1976, 2 morphologically distinct human papilloma virus (HPV) lesions were described in the uterine cervix, known currently as a flat and an inverted condyloma. Koilocytes were identified. These new HPV lesions were shown to be frequently associated with concomitant cervical intraepithelial neoplasia (CIN) and carcinoma in situ (CIS) lesions and occasionally with invasive cervical carcinomas as well. Harald zur Hausen identified HPV16 DNA in cervical cancers in 1983 and then identified HPV18 in 1984 by Southern blot hybridization. He was awarded the Nobel Prize in Medicine in 2008 for his research on the role of the papilloma virus in cervical cancer. Cervix cancer is the result of the progression of a clone of persistently infected cells from intraepithelial neoplasia to invasive disease.

More than 200 genotypes of HPV have been identified, and approximately 30 types of HPV specifically cause anogenital infections.²⁰ HPV is classified into high-risk and low-risk virus types, depending on its ability to cause malignancy in the infected epithelium. The high-risk types (16, 18, 31, 33, 45, 51, 52, 58) are associated with more than 90% of cervical cancers. HPV16 accounts for approximately half of all cervical cancers, whereas HPV18 is involved in another 10% to 20%.

Age-specific HPV prevalence in women over the age of 30 years generally declines from a peak at younger ages; however, the prevalence remains consistently above 20% in many low-resource regions. In middle-aged women (age 35-50 years), maximum HPV prevalence differs across geographical regions: Africa (approximately 20%), Asia/Australia (approximately 15%), Central and South America (approximately 20%), North America (approximately 20%), Southern Europe/Middle East (approximately 15%), and Northern Europe (approximately 15%). Women aged 30 years and older who test negative for carcinogenic HPV with cytologically normal Pap tests are at an extremely low risk for incipient precancer of the cervix over the next 10 years.²¹

In the United States, the prevalence of HPV in women 14 to 59 years is estimated to be 27%, with the highest prevalence (44.8%) among women aged 20 to 24 years. The overall prevalence of HPV among females aged 14 to 24 years is 33.8%. This prevalence corresponds to 7.5 million females with HPV infection²² (Figure 1-4). The acquisition of HPV occurs soon after sexual initiation and typically resolves very quickly. HPV acquisition is associated with nonpenetrative sexual activity, but much less frequently than with sexual intercourse. Risk factors for HPV infection are primarily related to sexual behavior, including the number of sex partners, introduction of new partners, lifetime history of sex partners, and partner’s sexual history²³ (Figure 1-5).

FIGURE 1-4. Prevalence of human papilloma virus (HPV) types among females aged 14 to 59 years. (Reproduced, with permission, from Dunne EF, Unger ER, Sternberg M, et al. Prevalence of HPV infection among females in the United States. JAMA. 2007;297(8):813-819.)

FIGURE 1-5. Cumulative incidence of human papilloma virus from time of first sexual intercourse. (Reproduced, with permission, from Winer RL, Lee SK, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students. Am J Epidemiol. 2003;157(3):218-226.)

The risk factors for cervical neoplasia and HPV infection are very similar. The risk factors are a high number of lifetime sexual partners, young age at first sexual activity, sexual contact with high-risk individuals, and early age at first pregnancy. However, the lifetime number of sexual partners is the major determinant of acquisition of oncogenic HPV.²⁴ HPV types 16, 18, and 33 seropositivity is strongly correlated with the lifetime number of sexual partners but reaches a plateau at 6 to 10 lifetime partners, with an overall seroprevalence for HPV types 16, 18, and 33 of 53%. The probability of infection per any sexual act and the difference in infection per HPV type are unknown.

Studies on the association between the age at sexual debut on HPV positivity are few. However, there is a weak, nonsignificant excess of HPV positivity in women who started having intercourse before age 15 after adjustment for the number of sexual partners.²⁴ Interpretation of the effect of lifetime number of sexual partners and age at first intercourse on cervical cancer risk is made difficult by the fact that these variables do not fully describe a woman’s risk profile for HPV infection. In many of the study populations reviewed, most women reported only 1 sexual partner. For these women, the risk of exposure to HPV—and consequently of developing cervical cancer—chiefly depends on the lifetime number of sexual partners of their husband/partner.²⁵

HPV infection is most prevalent in young women and adolescents, and the lower prevalence of HPV infection in older women as compared with younger women has been found to be independent of sexual behavior. Infection with high-risk HPV is more common than with low-risk types. It is possible that infections acquired at later ages have a greater potential for progression in women who have accumulated more years of exposure to known progression cofactors. It is also possible that, biologically, adolescent young women may be more susceptible to infection. The prevalence of HPV infection ranges from 28% to 36% in women younger than 25 years and 2% to 4% in women older than 45 years.²⁶

Genital HPV is primarily associated with sexual intercourse; however, nonpenetrative sexual contact, such as genital–genital contact, can also result in HPV transmission.²⁶ HPV can be cleared even after 1 to 3 years of persistence, and the risk of developing cancer and its precursor, CIN 3, requires at least several years of viral persistence.²⁷ Screening programs to identify CIN have significantly reduced the morbidity and mortality of this disease (Figure 1-6).

FIGURE 1-6. Penetrance to age 70 years of breast cancer (BC) and ovarian cancer (OC) by numbers of affected relatives. (Reproduced, with permission, from Metcalfe K, Lubinski J, Lynch HT, et al. Hereditary Breast Cancer Clinical Study Group. Family history of cancer and cancer risks in women with BRCA1 or BRCA2 mutations. J Natl Cancer Inst. 2010;102(24):1874-1878.)

Oral Contraceptives

HPV16 infection alone is probably insufficient to cause cervical cancer, and several possible cofactors have been identified, including the steroid hormones. Steroid hormones are proposed to act with human papillomaviruses as cofactors in the etiology of cervical cancer. A few mechanisms have been proposed whereby use of hormonal contraceptives might affect the development of HPV infection and risk of cervical neoplasia. Steroid hormone–activated nuclear receptors (NRs) are thought to bind to specific DNA sequences within transcriptional regulatory regions on the HPV DNA to either increase or suppress transcription of dependent genes.²⁸ Hormones may inhibit the immune response to HPV infection. Hormone-related mechanisms may influence the progression from premalignant to malignant cervical lesions by promoting integration of HPV DNA into the host genome, which results in deregulation of E6 and E7 expression. Hormones influence cervical epithelial differentiation and maturation. HPV gene expression and cellular proliferation is increased by estrogen and progestin in vitro.

Several but not all epidemiologic studies have identified oral contraceptive (OC) use as a cofactor in cervical carcinogenesis among HPV high-risk type DNA-positive women.²⁹ In the studies that demonstrate an association between women with oncogenic HPV and hormonal contraceptive use, there was no increase in the risk of cervical neoplasia for the duration of OC use for up to 4 years. However, use of OCs for longer than 5 years was significantly associated with cervical neoplasia (OR, 3.4; 95% CI, 2.1-5.5). OC use for longer than 5 years increased risk for invasive cervical cancer 4-fold (OR, 4.0; 95% CI, 2.0-8.0) and risk for carcinoma in situ 3-fold (OR, 3.4; 95% CI, 2.1-5.5).²⁹

Cervical Cancer and Parity

Parity has been consistently associated with cervical carcinogenesis. Traumatic, nutritional, and immunologic mechanisms for this association have been postulated. High parity maintains the transformation zone on the ectocervix for many years, and hormonal changes induced by pregnancy may also affect the immune response to HPV and influence risk of persistence or progression.²⁹

Cervical Adenocarcinoma

Most cancers of the uterine cervix are of squamous cell histology. Although the incidence of squamous cell carcinomas of the cervix is in decline, cervical adenocarcinoma has risen in recent years.³⁰ Whereas smoking and high parity have been associated with increased risk of squamous cell carcinoma, there is none or an inverse association with adenocarcinoma. More than 3 lifetime sexual partners is a risk factor for adenocarcinoma (OR, 2.1; 95% CI, 1.1-4.0), and obesity seems to be a risk factor for adenocarcinoma, but not for squamous cell carcinoma.³¹ Hormonal factors, both endogenous (ie, parity) and exogenous (ie, use of hormonal contraceptives), are cofactors in the pathogenesis of cervical adenocarcinoma.

Although HPV16 remains the most common viral type in both histologic types, a greater percentage of glandular malignancies contain HPV18 DNA as the sole infective agent. An analysis of 8 case-control studies of cervical cancer conducted in 8 countries with a range in the incidence of cervical cancer showed that the prevalence of HPV18 in adenocarcinomas (39%) is statistically significantly greater than that in squamous cell carcinoma (18%).³⁰

Ovarian Cancer

Germ Cell Tumors

Teratomas are neoplasms containing tissue from all 3 germ cell layers. Mature cystic teratomas, commonly called dermoid cysts, are the most common benign germ cell tumors of the ovary in women of reproductive age. They arise from primordial germ cells and comprise dysgerminomatous and nondysgerminomatous tumors, including yolk sac tumors (endodermal sinus tumors), immature teratomas, mixed germ cell tumors, pure embryonal carcinomas, and nongestational choriocarcinomas.³² In 85% of women the presenting signs and symptoms include abdominal pain and a palpable pelvic-abdominal mass. Approximately 10% of patients present with acute abdominal pain mimicking appendicitis, usually caused by rupture, hemorrhage, or torsion of the ovarian tumor. Less common signs and symptoms include abdominal distension (35%), fever (10%), and vaginal bleeding (10%). A small proportion of patients exhibit isosexual precocity related to human chorionic gonadotropin (hCG) production by the tumor.³³ Dysgerminoma is one of the most common ovarian neoplasms noted in pregnancy. In patients examined because of primary amenorrhea, it is not infrequently associated with gonadal dysgenesis and a gonadoblastoma (Table 1-2).

Table 1-2 Classification of Germ Cell Cancers

Modified from the World Health Organization histologic classification of tumors of the ovary. (Tavassoli FA, Deville P. Pathology and Genetics of Tumours of the Breast and Female Genital Organs. Lyon, France: International Agency for Research on Cancer; 2003.)

Malignant ovarian germ cell tumors have specific tumor markers that can aid in diagnosis and management and are very chemosensitive. Yolk sac tumor and choriocarcinoma are the prototypes of α- fetoprotein (AFP) and hCG production, respectively. Both embryonal carcinoma and polyembryoma may produce hCG and AFP, the former more commonly. A small percentage of dysgerminomas produce low levels of hCG related to the presence of multinucleated syncytiotrophoblastic giant cells, and approximately one-third of immature teratomas produce AFP. Mixed germ cell tumors may produce either, both, or none, depending on the type and quantity of elements present. Occasionally, other serum tumor markers, such as lactic dehydrogenase, may be elevated in patients with malignant ovarian germ cell tumors, particularly dysgerminoma.³³

Approximately 60% to 70% of cases are International Federation of Gynecologic Oncology (FIGO) stage I or II, 20% to 30% are stage III, and stage IV is relatively uncommon. Bilateral ovarian involvement is uncommon, even when metastatic disease is present. Bilateral involvement occurs in approximately 10% to 15% of dysgerminoma patients.³³ With optimal therapy, the prognosis is excellent, and most patients may retain reproductive function. For those with early-stage disease, cure rates approach 100%, and for those with advanced-stage disease, cure rates are reportedly at least 75%.

Ovarian Stromal Tumors

Sex cord–stromal tumors account for approximately 7% of all malignant ovarian neoplasms, and their extreme rarity represents a limitation in our understanding of their natural history, management, and prognosis.³³ The incidence in developed countries varies from 0.4 to 1.7 patient cases per 100,000 women. Most of these occur in perimenopausal women, but they may occur at any age. The juvenile granulosa cell tumors represent approximately 5% of granulosa cell neoplasms. The reported 5-year survival rate for patients with stage I granulosa cell tumors ranges from 75% to 95%, with the majority of studies demonstrating a greater than 90% survival rate.³⁴

One hypothesis for the development of granulosa cell tumors is that the degeneration of follicular granulosa cells after oocyte loss and the consequent compensatory rise in pituitary gonadotrophins may induce irregular proliferation and eventually granulosa cell neoplasia. This hypothesis is consistent with the observation that most granulosa cell tumors occur soon after menopause, when a similar situation of oocyte depletion and high levels of gonadotrophins are observed. However, this explanation cannot be applied to those tumors developing during the reproductive years or even before menarche³⁴ (Table 1-3).

Table 1-3 Classification of Sex Cord–Stromal Ovarian Tumors

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