Cancer arising in or near the ovary is actually a collection of diverse malignancies. This collection of malignancies, often referred to as “ovary cancer,” is the most lethal gynecologic malignancy in the United States and other countries that routinely screen women for cervical neoplasia. In 2014, it was estimated that there were 21,980 cases of ovarian cancer with 14,270 deaths in the United States. The ovary is a complex and dynamic organ and, between the ages of approximately 11 and 50 years, is responsible for follicle maturation associated with egg maturation, ovulation, and cyclical sex steroid hormone production. These complex and linked biologic functions are coordinated through a variety of cells within the ovary, each of which possesses neoplastic potential. By far the most common and most lethal of the ovarian neoplasms arise from the ovarian epithelium or, alternatively, the neighboring specialized epithelium of the fallopian tube, uterine corpus, or cervix. Epithelial tumors may be benign (50%), malignant (33%), or of borderline malignancy (16%). Age influences risk of malignancy; tumors in younger women are more likely benign. The most common of the ovarian epithelial malignancies are serous tumors (50%); tumors of mucinous (25%), endometrioid (15%), clear cell (5%), and transitional cell histology or Brenner tumor (1%) represent smaller proportions of epithelial ovarian tumors. In contrast, stromal tumors arise from the steroid hormone–producing cells and likewise have different phenotypes and clinical presentations largely dependent on the type and quantity of hormone production. Tumors arising in the germ cell are most similar in biology and behavior to testicular tumors in males (Chap. 45).
Tumors may also metastasize to the ovary from breast, colon, appendiceal, gastric, and pancreatic primaries. Bilateral ovarian masses from metastatic mucin-secreting gastrointestinal cancers are termed Krukenberg tumors.
OVARIAN CANCER OF EPITHELIAL ORIGIN
Epidemiology and pathogenesis
A female has approximately a 1 in 72 lifetime risk (1.6%) of developing ovarian cancer, with the majority of affected women developing epithelial tumors. Each of the histologic variants of epithelial tumors is distinct with unique molecular features. As a group of malignancies, epithelial tumors of the ovary have a peak incidence in women in their sixties, although age at presentation can range across the extremes of adult life, with cases being reported in women in their twenties to nineties. Each histologic subtype of ovarian cancer likely has its own associated risk factors. Serous cancer, the most common type of epithelial ovarian cancer, is seen with increased frequency in women who are nulliparous or have a history of use of talc agents applied to the perineum; other risk factors include obesity and probably hormone replacement therapy. Protective factors include the use of oral contraceptives, multiparity, and breast-feeding. These protective factors are thought to work through suppression of ovulation and perhaps the associated reduction of ovulation associated inflammation of the ovarian epithelium or, alternatively, the serous epithelium located within the fimbriae of the fallopian tube. Other protective factors, such as fallopian tube ligation, are thought to protect the ovarian epithelium (or perhaps the distal fallopian tube fimbriae) from carcinogens that migrate from the vagina to the tubes and ovarian surface epithelium. Mucinous tumors are more frequent in women with a history of cigarette smoking, whereas endometrioid and clear cell tumors are more frequent in women with a history of endometriosis.
Considerable evidence now suggests that the precursor cell to serous carcinoma of the ovary might actually arise in the fimbria of the fallopian tube with extension or metastasis to the ovarian surface or capture of preneoplastic or neoplastic exfoliating tubal cells into an involuting ovarian follicle around the time of ovulation. Careful histologic and molecular analysis of tubal epithelium demonstrates molecular and histologic abnormalities, termed serous tubular intraepithelial carcinoma (STIC) lesions, in a high proportion of women undergoing risk-reducing salpingo-oophorectomies in the context of high-risk germline mutations in BRCA1 and BRCA2, as well as a modest proportion of women with ovarian cancer in the absence of such mutations.
A variety of genetic syndromes substantially increase a woman’s risk of developing ovarian cancer. Approximately 10% of women with ovarian cancer have a germline mutation in one of two DNA repair genes: BRCA1 (chromosome 17q12-21) or BRCA2 (chromosome 13q12-13). Individuals inheriting a single copy of a mutant allele have a very high incidence of breast and ovarian cancer. Most of these women have a family history that is notable for multiple cases of breast and/or ovarian cancer, although inheritance through male members of the family can camouflage this genotype through several generations. The most common malignancy in these women is breast carcinoma, although women harboring germline BRCA1 mutations have a marked increased risk of developing ovarian malignancies in their forties and fifties with a 30–50% lifetime risk of developing ovarian cancer. Women harboring a mutation in BRCA2 have a lower penetrance of ovarian cancer with perhaps a 20–40% chance of developing this malignancy, with onset typically in their fifties or sixties. Women with a BRCA2 mutation also are at slightly increased risk of pancreatic cancer. Likewise women with mutations in the DNA mismatch repair genes associated with Lynch syndrome, type 2 (MSH2, MLH1, MLH6, PMS1, PMS2) may have a risk of ovarian cancer as high as 1% per year in their forties and fifties. Finally, a small group of women with familial ovarian cancer may have mutations in other BRCA-associated genes such as RAD51, CHK2, and others. Screening studies in this select population suggest that current screening techniques, including serial evaluation of the CA-125 tumor marker and ultrasound, are insufficient at detecting early-stage and curable disease, so women with these germline mutations are advised to undergo prophylactic removal of ovaries and fallopian tubes typically after completing childbearing and ideally before age 35–40 years. Early prophylactic oophorectomy also protects these women from subsequent breast cancer with a reduction of breast cancer risk of approximately 50%.
Neoplasms of the ovary tend to be painless unless they undergo torsion. Symptoms are therefore typically related to compression of local organs or due to symptoms from metastatic disease. Women with tumors localized to the ovary do have an increased incidence of symptoms including pelvic discomfort, bloating, and perhaps changes in a woman’s typical urinary or bowel pattern. Unfortunately, these symptoms are frequently dismissed by either the woman or her health care team. It is believed that high-grade tumors metastasize early in the neoplastic process. Unlike other epithelial malignancies, these tumors tend to exfoliate throughout the peritoneal cavity and thus present with symptoms associated with disseminated intraperitoneal tumors. The most common symptoms at presentation include a multimonth period of progressive complaints that typically include some combination of heartburn, nausea, early satiety, indigestion, constipation, and abdominal pain. Signs include the rapid increase in abdominal girth due to the accumulation of ascites that typically alerts the patient and her physician that the concurrent gastrointestinal symptoms are likely associated with serious pathology. Radiologic evaluation typically demonstrates a complex adnexal mass and ascites. Laboratory evaluation usually demonstrates a markedly elevated CA-125, a shed mucin (Muc 16) associated with, but not specific for, ovarian cancer. Hematogenous and lymphatic spread are seen but are not the typical presentation. Ovarian cancers are divided into four stages, with stage I tumors confined to the ovary, stage II malignancies confined to the pelvis, and stage III tumors confined to the peritoneal cavity (Table 46-1). These three stages are subdivided, with the most common presentation, stage IIIC, defined as tumors with bulky intraperitoneal disease. About 60% of women present with stage IIIC disease. Stage IV disease includes women with parenchymal metastases (liver, lung, spleen) or, alternatively, abdominal wall or pleural disease. The 40% not presenting with stage IIIC disease are roughly evenly distributed among the other stages, although mucinous and clear cell tumors are overrepresented in stage I tumors.
TABLE 46-1Staging and Survival in Gynecologic Malignancies ||Download (.pdf) TABLE 46-1 Staging and Survival in Gynecologic Malignancies
|Stage ||Ovarian ||5-Year Survival, % ||Endometrial ||5-Year Survival, % ||Cervix ||5-Year Survival, % |
|0 ||— || ||— || ||Carcinoma in situ ||100 |
|I ||Confined to ovary ||90–95 ||Confined to corpus ||89 ||Confined to uterus ||85 |
|II ||Confined to pelvis ||70–80 ||Involves corpus and cervix ||73 ||Invades beyond uterus but not to pelvic wall ||65 |
|III ||Intraabdominal spread ||20–50 ||Extends outside the uterus but not outside the true pelvis or to lymph nodes ||52 ||Extends to pelvic wall and/or lower third of vagina, or hydronephrosis ||35 |
|IV ||Spread outside abdomen ||1–5 ||Extends outside the true pelvis or involves the bladder or rectum ||17 ||Invades mucosa of bladder or rectum or extends beyond the true pelvis ||7 |
Ovarian cancer is the fifth most lethal malignancy in women in the United States. It is curable in early stages, but seldom curable in advanced stages; hence, the development of effective screening strategies is of considerable interest. Furthermore, the ovary is well visualized with a variety of imaging techniques, most notably transvaginal ultrasound. Early-stage tumors often produce proteins that can be measured in the blood such as CA-125 and HE-4. Nevertheless, the incidence of ovarian cancer in the middle-aged female population is low, with only approximately 1 in 2000 women between the ages of 50 and 60 carrying an asymptomatic and undetected tumor. Thus effective screening techniques must be sensitive but, more importantly, highly specific to minimize the number of false-positive results. Even a screening test with 98% specificity and 50% sensitivity would have a positive predictive value of only about 1%. A large randomized study of active screening versus usual standard care demonstrated that a screening program consisting of six annual CA-125 measurements and four annual transvaginal ultrasounds in a population of women age 55–74 was not effective at reducing death from ovarian cancer and was associated with significant morbidity in the screened arm due to complications associated with diagnostic testing in the screened group. Although ongoing studies are evaluating the utility of alternative screening strategies, currently screening of normal-risk women is not recommended outside of a clinical trial.
TREATMENT Ovarian Cancer
In women presenting with a localized ovarian mass, the principal diagnostic and therapeutic maneuver is to determine if the tumor is benign or malignant and, in the event that the tumor is malignant, whether the tumor arises in the ovary or is a site of metastatic disease. Metastatic disease to the ovary can be seen from primary tumors of the colon, appendix, stomach (Krukenberg tumors), and breast. Typically women undergo a unilateral salpingo-oophorectomy, and if pathology reveals a primary ovarian malignancy, then the procedure is followed by a hysterectomy, removal of the remaining tube and ovary, omentectomy, and pelvic node sampling along with some random biopsies of the peritoneal cavity. This extensive surgical procedure is performed because approximately 30% of tumors that by visual inspection appear to be confined to the ovary have already disseminated to the peritoneal cavity and/or surrounding lymph nodes.
If there is evidence of bulky intraabdominal disease, a comprehensive attempt at maximal tumor cytoreduction is attempted even if it involves partial bowel resection, splenectomy, and in certain cases more extensive upper abdominal surgery. The ability to debulk metastatic ovarian cancer to minimal visible disease is associated with an improved prognosis compared with women left with visible disease. Patients without gross residual disease after resection have a median survival of 39 months, compared with 17 months for those left with macroscopic tumor. Once tumors have been surgically debulked, women receive therapy with a platinum agent, typically a taxane. Debate continues as to whether this therapy should be delivered intravenously or, alternatively, whether some of the therapy should be delivered directly into the peritoneal cavity via a catheter. Three randomized studies have demonstrated improved survival with intraperitoneal therapy, but this approach is still not widely accepted due to technical challenges associated with this delivery route and increased toxicity. In women who present with bulky intraabdominal disease, an alternative approach is to treat with platinum plus a taxane for several cycles before attempting a surgical debulking procedure (neoadjuvant therapy). Subsequent surgical procedures are more effective at leaving the patient without gross residual tumor and appear to be less morbid. Two studies have demonstrated that the neoadjuvant approach is associated with an overall survival that is comparable to the traditional approach of primary surgery followed by chemotherapy.
With optimal debulking surgery and platinum-based chemotherapy (usually carboplatin dosed to an area under the curve [AUC] of 6 plus paclitaxel 175 mg/m2 by 3-h infusion in 21-day cycles), 70% of women who present with advanced-stage tumors respond, and 40–50% experience a complete remission with normalization of their CA-125, computed tomography (CT) scans, and physical examination. Unfortunately, a small proportion of women who obtain a complete response to therapy will remain in remission. Disease recurs within 1–4 years from the completion of their primary therapy in 75% of the complete responders. CA-125 levels often increase as a first sign of relapse; however, data are not clear that early intervention in relapsing patients influences survival. Recurrent disease is effectively managed, but not cured, with a variety of chemotherapeutic agents. Eventually all women with recurrent disease develop chemotherapy-refractory disease at which point refractory ascites, poor bowel motility, and obstruction or pseudoobstruction due to a tumor-infiltrated aperistaltic bowel are common. Limited surgery to relieve intestinal obstruction, localized radiation therapy to relieve pressure or pain from masses, or palliative chemotherapy may be helpful. Agents with >15% response rates include gemcitabine, topotecan, liposomal doxorubicin, pemetrexed, and bevacizumab. Approximately 10% of ovarian cancers are HER2/neu positive, and trastuzumab may induce responses in this subset.
Five-year survival correlates with the stage of disease: stage I, 85–90%; stage II, 70–80%; stage III, 20–50%; and stage IV, 1–5% (Table 46-1). Low-grade serous tumors are molecularly distinct from high-grade serous tumors and are, in general, poorly responsive to chemotherapy. Targeted therapies focused on inhibiting kinases downstream of RAS and BRAF are being tested. Patients with tumors of low malignant potential are managed by surgery; chemotherapy and radiation therapy do not improve survival.
OVARIAN SEX CORD AND STROMAL TUMORS
Epidemiology, presentation, and predisposing syndromes
Approximately 7% of ovarian neoplasms are stromal or sex cord tumors, with approximately 1800 cases expected each year in the United States. Ovarian stromal tumors or sex cord tumors are most common in women in their fifties or sixties, but tumors can present in the extremes of age, including the pediatric population. These tumors arise from the mesenchymal components of the ovary, including steroid-producing cells as well as fibroblasts. Essentially all of these tumors are of low malignant potential and present as unilateral solid masses. Three clinical presentations are common: the detection of an abdominal mass; abdominal pain due to ovarian torsion, intratumoral hemorrhage, or rupture; or signs and symptoms due to hormonal production by these tumors.
The most common hormone-producing tumors include thecomas, granulosa cell tumor, or juvenile granulosa tumors in children. These estrogen-producing tumors often present with breast tenderness as well as isosexual precocious pseudopuberty in children, menometrorrhagia, oligomenorrhea, or amenorrhea in premenopausal women, or alternatively as postmenopausal bleeding in older women. In some women, estrogen-associated secondary malignancies, such as endometrial or breast cancer, may present as synchronous malignancies. Alternatively, endometrial cancer may serve as the presenting malignancy with evaluation subsequently identifying a unilateral solid ovarian neoplasm that proves to be an occult granulosa cell tumor. Sertoli-Leydig tumors often present with hirsutism, virilization, and occasionally Cushing’s syndrome due to increased production of testosterone, androstenedione, or other 17-ketosteroids. Hormonally inert tumors include fibroma that presents as a solitary mass often in association with ascites and occasionally hydrothorax also known as Meigs’ syndrome. A subset of these tumors present in individuals with a variety of inherited disorders that predispose them to mesenchymal neoplasia. Associations include juvenile granulosa cell tumors and perhaps Sertoli-Leydig tumors with Ollier’s disease (multiple enchondromatosis) or Maffucci’s syndrome, ovarian sex cord tumors with annular tubules with Peutz-Jeghers syndrome, and fibromas with Gorlin’s disease. Essentially all granulosa tumors and a minority of juvenile granulosa cell tumors and thecomas have a defined somatic point mutation in the FOXL2 gene at C134W generated by replacement of cysteine with a guanine at position 402. About 30% of Sertoli-Leydig tumors harbor a mutation in the RNA-processing gene DICER in the RNAIIIb domain.
TREATMENT Sex Cord Tumors
The mainstay of treatment for sex cord tumors is surgical resection. Most women present with tumors confined to the ovary. For the small subset of women who present with metastatic disease or develop evidence of tumor recurrence after primary resection, survival is still typically long, often in excess of a decade. Because these tumors are slow growing and relatively refractory to chemotherapy, women with metastatic disease are often debulked because disease is usually peritoneal-based (as with epithelial ovarian cancer). Definitive data that surgical debulking of metastatic or recurrent disease prolongs survival are lacking, but ample data document women who have survived years or, in some cases, decades after resection of recurrent disease. In addition, large peritoneal-based metastases also have a proclivity for hemorrhage, sometimes with catastrophic complications. Chemotherapy is occasionally effective, and women tend to receive regimens designed to treat epithelial or germ cell tumors. Bevacizumab has some activity in clinical trials but is not approved for this specific indication. These tumors often produce high levels of müllerian inhibiting substance (MIS), inhibin, and, in the case of Sertoli-Leydig tumors, α fetoprotein (AFP). These proteins are detectable in serum and can be used as tumor markers to monitor women for recurrent disease because the increase or decrease of these proteins in the serum tends to reflect the changing bulk of systemic tumor.
GERM CELL TUMORS OF THE OVARY
Germ cell tumors, like their counterparts in the testis, are cancers of germ cells. These totipotent cells contain the programming for differentiation to essentially all tissue types, and hence the germ cell tumors include a histologic menagerie of bizarre tumors, including benign teratomas and a variety of malignant tumors, such as immature teratomas, dysgerminomas, yolk sac malignancies, and choriocarcinomas. Benign teratoma (or dermoid cyst) is the most common germ cell neoplasm of the ovary and often presents in young woman. These tumors include a complex mixture of differentiated tissue including tissues from all three germ layers. In older women, these differentiated tumors can develop malignant transformation, most commonly squamous cell carcinomas. Malignant germ cell tumors include dysgerminomas, yolk sac tumors, immature teratomas, and embryonal carcinoma and choriocarcinomas. There are no known genetic abnormalities that unify these tumors. A subset of dysgerminomas harbor mutations in c-kit oncogenes (as seen in gastrointestinal stromal tumors [GIST]), whereas a subset of germ cell tumors have isochromosome 12 abnormalities, as seen in testicular malignancies. In addition, a subset of dysgerminomas is associated with dysgenetic ovaries. Identification of a dysgerminoma arising in genotypic XY gonads is important in that it highlights the need to identify and remove the contralateral gonad due to risk of gonadoblastoma.
Germ cell tumors can present at all ages, but the peak age of presentation tends to be in females in their late teens or early twenties. Typically these tumors will become large ovarian masses, which eventually present as palpable low abdominal or pelvic masses. Like sex cord tumors, torsion or hemorrhage may present urgently or emergently as acute abdominal pain. Some of these tumors produce elevated levels of human chorionic gonadotropin (hCG), which can lead to isosexual precocious puberty when tumors present in younger girls. Unlike epithelial ovarian cancer, these tumors have a higher proclivity for nodal or hematogenous metastases. As with testicular tumors, some of these tumors tend to produce AFP (yolk sac tumors) or hCG (embryonal carcinoma, choriocarcinomas, and some dysgerminomas) that are reliable tumor markers.
TREATMENT Germ Cell Tumors
Germ cell tumors typically present in women who are still of childbearing age, and because bilateral tumors are uncommon (except in dysgerminoma, 10–15%), the typical treatment is unilateral oophorectomy or salpingo-oophorectomy. Because nodal metastases to pelvic and para-aortic nodes are common and may affect treatment choices, these nodes should be carefully inspected and, if enlarged, should be resected if possible. Women with malignant germ cell tumors typically receive bleomycin, etoposide, and cisplatin (BEP) chemotherapy. In the majority of women, even those with advanced-stage disease, cure is expected. Close follow-up without adjuvant therapy of women with stage I tumors is reasonable if there is high confidence that the patient and health care team are committed to compulsive and careful follow-up, as chemotherapy at the time of tumor recurrence is likely to be curative.
Dysgerminoma is the ovarian counterpart of testicular seminoma. The 5-year disease-free survival is 100% in early-stage patients and 61% in stage III disease. Although the tumor is highly radiation-sensitive, radiation produces infertility in many patients. BEP chemotherapy is as effective or more so without causing infertility. The use of BEP following incomplete resection is associated with a 2-year disease-free survival rate of 95%. This chemotherapy is now the treatment of choice for dysgerminoma.