The overwhelming majority of ovarian masses are benign and the lifetime risk of developing ovarian cancer is about 2%. Age is the most important factor in determining risk of malignancy. Adnexal masses are common during the reproductive years. During this stage of life, such masses are usually caused by functional ovarian cysts, benign neoplasms of the ovary or by postinfectious changes in the fallopian tubes. In girls under 20 and in women over 50, about 10% of all palpable ovarian masses are malignant. Between 85 and 90% of ovarian cancer occurs in postmenopausal women.
Benign Neoplasms Of The Ovary
Benign and malignant neoplasms can develop from any cell type found in the ovary. Simple cysts can be functional and form at the site of ovulation or during the development of the corpus luteum. These are very common and distinguishable from true neoplasms by their transitory nature. They typically disappear within 6 weeks of discovery. Complex or solid masses and those that are persistent are more likely to be truly neoplastic and require histologic diagnosis.
Dermoids are a unique type of benign ovarian tumor that arises from more mature germ cells than the other germ-cell tumors (GCTs) found in women (Table 42.1). On gross examination, dermoids may contain hair, bone, cartilage and large amounts of greasy fluid that rapidly becomes sebaceous at room temperature. On histologic examination, the tumors contain disarrayed clusters of many of the cell types normally seen in fetuses. Like other GCTs, the molecular event(s) that lead to activation of the germ cells in dermoids can occur in utero and benign ovarian teratomas have been detected in the fetus and newborn infant. Ovarian dermoid tumors display abnormalities in imprinting and are discussed in more detail in Chapter 45.
Ovarian cancer is the most lethal gynecologic malignancy. While over 90% of testicular malignancies are GCTs, 65–70% of ovarian malignancies are epithelial cell cancers. GCTs of the testis have good early detection and high cure rates (Chapter 40). Ovarian epithelial cell cancers are usually detected after widespread intraperitoneal dissemination. At this point, cure is almost impossible.
There are five distinct histologic types of epithelial ovarian tumors: serous, mucinous, endometrioid, clear cell and Brenner. Of the five, serous neoplasms account for almost half of all tumors. Mucinous tumors comprise about 25%, endometrioid tumors about 5%, clear cell cancers under 5% and Brenner cell tumors 2–3% of the total. The remainder of ovarian cancers are too poorly differentiated at diagnosis to be classified.
Epithelial ovarian cancer typically spreads both locally and by intraperitoneal dissemination. Contiguous spread is to the fallopian tube and uterus. Dissemination occurs to the contralateral ovary and peritoneum. Implants of epithelial ovarian cancer may be found on the cul-de-sac, bowel, mesentery, omentum and diaphragm. Malignant ascites forms when diaphragmatic metastases block the lymphatic drainage of the peritoneal cavity. Patients with these cancers may not develop symptoms until the tumor mass compresses other intraperitoneal organs or the associated ascites causes abdominal bloating, dyspepsia or urinary frequency. This relative lack of early symptoms leads to late diagnosis and poor prognosis. Treatment for epithelial ovarian cancer involves cytoreductive surgery and aggressive chemotherapy, and only 15% of patients with advanced disease will survive. These tumors often develop resistance to chemotherapy. When disease is confined to the ovary, survival dramatically improves to 50–90%. Unfortunately, ovarian epithelial tumors are seldom diagnosed at this early stage.
About 15% of all epithelial ovarian cancers have histologic and biologic behaviors that are neither clearly benign nor frankly malignant. These “borderline” ovarian carcinomas share a common genetic lineage with their corresponding benign cystic neoplasms. Borderline tumors have a 95% 10-year survival rate but can recur as many as 20 years after excision. Late recurrences are often identical to the primary tumor, but malignant transformation to high-grade epithelial ovarian cancer can occur in a minority of cases.
Epidemiology of epithelial ovarian cancer Family history is the most important risk factor, followed by age. The mean age of disease onset is 59 years. Other risk factors are early menarche, late menopause, regular and uninterrupted menstrual cycles, short menstrual cycle length, low parity and a history of infertility. High parity and use of oral contraceptives reduce the risk of ovarian cancer. Both also decrease the number of lifetime ovulation events. These epidemiologic data suggest that the number of ovulations over a lifetime is significant in the pathogenesis of the disease.
As with other prevalent epithelial cancers, environmental factors influence the development of ovarian cancers, with the highest rates being found in highly industrialized countries. Japan is the single notable exception, with rates of malignant neoplasms of the ovary that are among the lowest in the world. However, the rates in Japanese immigrants in the USA approach those of Caucasian natives within two to three generations, suggesting that carcinogens in the immediate environment are responsible. Chemical carcinogens from the outside world can reach the pelvic peritoneum of women through the vagina and upper reproductive tract. In fact, investigators have shown that more women with ovarian cancer use talc as a dusting powder on their perineum or sanitary napkins than matched controls. The association between talc and ovarian cancer is also biologically plausible. Talc is chemically related to asbestos and ovarian cancer is similar to the mesotheliomas that can develop after pulmonary exposure to asbestos.
Familial Ovarian Cancer
Various syndromes have been have been associated with increased risk for the development of cancers. Three include a predisposition to ovarian cancer: familial ovarian cancer syndrome, hereditary breast/ ovarian cancer syndrome and Lynch cancer family syndrome II (hereditary nonpolyposis colorectal cancer syndrome, HNPCC). These syndromes account for less than 10% of ovarian cancer diagnoses. Virtually all the hereditary breast/ovarian cancers and site-specific ovarian cancer syndromes are caused by mutations in the tumor suppressor genes BRCA1 or BRCA2. Individuals with BRCA1 mutations have a 20-fold increase in their risk for developing both breast and ovarian cancers, and those with BRCA2 mutations a 5–10-fold increase in their risk for developing ovarian cancer. The estimated frequency of BRCA1 mutations in the general population is 1 in 800, but is greater than 1 in 100 among Ashkenazi Jewish women. BRCA2 mutations have a very similar carrier frequency among the Ashkenazi and a frequency of 1 in 250 among Icelanders.
HNPCC is caused by mutations in any one of several genes important in DNA mismatch repair. The most common extracolonic malignancy in women with HNPCC is endometrial cancer, followed by ovarian cancer.
Pathogenesis Of Nonfamilial Epithelial Ovarian Cancer
The typical advanced stage of epithelial ovarian cancers at clinical presentation, combined with the lack of identifiable precursor lesions for the more common serous and mucinous adenocarcinomas, have made biologic study of their development difficult. Originally, some investigators proposed that epithelial ovarian cancers arise in small inclusion cysts that develop when surface epithelial cells become entrapped in the physical defects left in the ovarian surface after ovulation while others hypothesized that the ovarian epithelium is a coelomic mesothelium that is more prone to metaplasia than other epithelia. More recent studies suggest that many ovarian tumors may actually originate in other pelvic organs and involve the ovary second- arily. Serous tumors may arise from fallopian tube epithelium that either implants or is trapped in the ovary at the time of ovulatory capsule disruption. Endometrioid and clear cell tumors, both of which are associated with the clinical condition of endometriosis (Chapter 34), may arise when endometrium menstruates retrograde onto the ovary although coelomic metaplasia may also be involved. Metaplasia of tissue at the tubal mesothelial junction may give rise to mucinous and Brenner tumors. It has been argued by some that ovarian malignancies are more appropriately classified into two groups of tumors based both on morphology and molecular genetic features. When this is done, the members of one group each share lineage with a paired benign neoplasm and behave rather indolently while the other group frequently displays tumor suppressor abnormalities that involve p53, the product of a tumor suppressing cell checkpoint gene located on chromosome 17p, and progress rapidly. The first group is comprised low-grade serous, low-grade endometrioid, clear cell, mucinous and transitional (Brenner) tumors. Each histologic group exhibits a distinctive molecular genetic profile and all lack p53 mutations. The second group includes high-grade serous carcinoma, undifferentiated carcinomas and mixed mesodermal tumors (carcinosarcoma).
As with other malignancies, ovarian cancer probably develops after multiple genetic “hits” cause a cell to display invasive, neoplastic behavior. One “hit” typically involves activation of an oncogene and the second “hit” involves the loss of one or more genes with tumor suppressor activity. BRCA1 and BRCA2 are tumor suppressor genes and inheritance of one abnormal allele makes “second hits” a high statistical probability.
Other Ovarian Malignancies
Only 10% of ovarian cancers are GCTs. These occur largely in girls and young women. Like GCTs in men, GCTs in women arise from immature germ cells and include five distinct histologic types: dysgerminomas, choriocarcinomas, endodermal sinus tumors (yolk sac carcinomas), embryonal carcinomas and teratomas. The dysger- minoma is the female equivalent of the seminoma. GCTs of the testes are typically detected early in their development; GCTs of the ovary are not. For this reason, far less is known about GCT tumorigenesis in the female than in the male (Chapter 40).
Stromal cell tumors are the rarest ovarian malignancies, accounting for 5% of the total. They may contain granulosa, theca, Leydig or Sertoli cells, and usually make large amounts of steroid hormones: granulosa or theca cell tumors make estrogens and Leydig or Sertoli cell tumors make androgens. The occurrence of stromal cell tumors is not age dependent. Those secreting androgens can cause virilization while those secreting estrogens can cause endometrial hyperplasia and irregular vaginal bleeding.