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Ovarian Cancer

By Pedro T. Ramirez, MD, The University of Texas MD Anderson Cancer Center ; David M. Gershenson, MD, The University of Texas MD Anderson Cancer Center ; Gloria Salvo, MD

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Ovarian cancer is often fatal because it is usually advanced when diagnosed. Symptoms are usually absent in early stages and nonspecific in advanced stages. Evaluation usually includes ultrasonography, CT or MRI, and measurement of tumor markers (eg, cancer antigen 125). Diagnosis is by histologic analysis. Staging is surgical. Treatment requires hysterectomy, bilateral salpingo-oophorectomy, excision of as much involved tissue as possible (cytoreduction), and, unless cancer is localized, chemotherapy.

In the US, ovarian cancer is the 2nd most common gynecologic cancer (affecting about 1/70 women). It is the 5th leading cause of cancer-related deaths in women and, in the US, will cause an estimated 22,440 new cases and 14,080 deaths in 2017. Incidence is higher in developed countries.

Etiology

Ovarian cancer affects mainly perimenopausal and postmenopausal women.

Risk of ovarian cancer is increased by

  • A history of ovarian cancer in a 1st-degree relative

  • Nulliparity

  • Delayed childbearing

  • Early menarche

  • Delayed menopause

  • A personal or family history of endometrial, breast, or colon cancer

Risk is decreased by

  • Oral contraceptive use

Probably 5 to 10% of ovarian cancer cases are related to mutations in the autosomal dominant BRCA gene, which is associated with a 50 to 85% lifetime risk of developing breast cancer. Women with BRCA1 mutations have a 20 to 40% lifetime risk of developing ovarian cancer; risk among women with BRCA2 mutations is increased less. Incidence of these mutations is higher in Ashkenazi Jews than in the general population. Mutations in several other genes, including TP53, PTEN, STK11/LKB1, CDH1, CHEK2, ATM, MLH1, and MSH2, have been associated with hereditary breast and/or ovarian cancer.

XY gonadal dysgenesis predisposes to ovarian germ cell cancer.

Pathology

Ovarian cancers are histologically diverse (see Table: Types of Ovarian Cancers).

At least 80% of ovarian cancers originate in the epithelium; 75% of these cancers are serous cystadenocarcinoma, and about 10% are invasive mucinous carcinoma. At presentation, nearly 27% of patients with stage I epithelial ovarian cancers have mucinous histology, but < 10% with stage III or IV do.

About 20% of ovarian cancers originate in primary ovarian germ cells or in sex cord and stromal cells or are metastases to the ovary (most commonly, from the breast or GI tract). Germ cell cancers usually occur in women < 30.

Types of Ovarian Cancers

Origin

Types

Epithelium

Brenner tumor

Clear cell carcinomas

Endometrioid carcinomas

Mucinous carcinomas

Serous cystadenocarcinomas (most common overall)

Transitional cell carcinomas

Unclassified carcinomas

Primary germ cells

Choriocarcinomas

Dysgerminomas

Embryonal carcinomas

Endodermal sinus tumors

Immature teratomas

Polyembryoma

Sex cord and stromal cells

Granulosa-theca cell tumors

Sertoli-Leydig cell tumors

Metastases

Breast cancer

Cancer of the GI tract

Ovarian cancer spreads by

  • Direct extension

  • Exfoliation of cells into the peritoneal cavity (peritoneal seeding)

  • Lymphatic dissemination to the pelvis and around the aorta

  • Less often, hematogenously to the liver or lungs

Symptoms and Signs

Early ovarian cancer is usually asymptomatic; an adnexal mass, often solid, irregular, and fixed, may be discovered incidentally. Pelvic and rectovaginal examinations typically detect diffuse nodularity. A few women present with severe abdominal pain secondary to torsion of the ovarian mass.

Most women with advanced cancer present with nonspecific symptoms (eg, dyspepsia, bloating, early satiety, gas pains, backache). Later, pelvic pain, anemia, cachexia, and abdominal swelling due to ovarian enlargement or ascites usually occur.

Germ cell or stromal tumors may have functional effects (eg, hyperthyroidism, feminization, virilization).

Diagnosis

  • Ultrasonography (for suspected early cancers) or CT or MRI (for suspected advanced cancers)

  • Tumor markers (eg, cancer antigen [CA] 125)

  • Surgical staging

Ovarian cancer is suspected in women with the following:

  • Unexplained adnexal masses

  • Unexplained abdominal bloating

  • Changes in bowel habits

  • Unintended weight loss

  • Unexplained abdominal pain

An ovarian mass is more likely to be cancer in older women. Benign functional cysts can simulate functional germ cell or stromal tumors in young women.

A pelvic mass plus ascites usually indicates ovarian cancer but sometimes indicates Meigs syndrome (a benign fibroma with ascites and right hydrothorax).

Imaging

If early cancer is suspected, ultrasonography is done first; the following findings suggest cancer:

  • A solid component

  • Surface excrescences

  • Size > 6 cm

  • Irregular shape

  • Low vascular resistance detected by transvaginal Doppler flow studies

If advanced cancer is suspected (eg, based on ascites, abdominal distention, or nodularity or fixation detected during physical examination), CT or MRI is usually done before surgery to determine extent of the cancer.

Tumor markers

Tumor markers, including the beta subunit of human chorionic gonadotropin (beta-hCG), LDH, alpha-fetoprotein, inhibin, and CA 125, are typically measured in young patients, who are at higher risk of nonepithelial tumors (eg, germ cell tumors, stromal tumors). In perimenopausal and postmenopausal patients, only CA 125 is measured because most ovarian cancers in this age group are epithelial tumors. CA 125 is elevated in 80% of advanced epithelial ovarian cancers but may be mildly elevated in endometriosis, pelvic inflammatory disease, pregnancy, fibroids, peritoneal inflammation, or nonovarian peritoneal cancer.

A mixed solid and cystic pelvic mass in postmenopausal women, especially if CA 125 is elevated, suggests ovarian cancer.

Biopsy

A biopsy is not routinely recommended unless a patient is not a surgical candidate. In those rare cases, samples are obtained by needle biopsy for masses or by needle aspiration for ascitic fluid.

For masses that appear benign on ultrasonography, histologic analysis is not required, and ultrasonography is repeated after 6 wk. Such benign-appearing masses include benign cystic teratomas (dermoid cysts), follicular cysts, and endometriomas.

Staging

Suspected or confirmed ovarian cancer is staged surgically (see Table: FIGO Surgical Staging of Ovarian, Fallopian Tube, and Peritoneal Cancer).

FIGO Surgical Staging of Ovarian, Fallopian Tube, and Peritoneal Cancer

Stage

Description

I

Tumor limited to the ovaries or fallopian tubes

IA

Tumor limited to one ovary (capsule intact) or fallopian tube; no tumor on the external surface of ovary or fallopian tube; and no malignant cells in ascitic fluid or in peritoneal washings*

IB

Tumor limited to both ovaries (capsule intact) or fallopian tubes; no tumor on the external surface of ovary or fallopian tube; and no malignant cells in ascitic fluid or in peritoneal washings*

IC

Tumor limited to one or both ovaries (stage IA or IB), plus any of the following:

IC1

  • Surgical spill

IC2

  • Capsule ruptured before surgery or tumor on the surface of the ovary or fallopian tube

IC3

  • Malignant cells in ascitic fluid or in peritoneal washings*

II

Tumor involving one or both ovaries or fallopian tubes with pelvic extension (below pelvic brim) or primary peritoneal cancer

IIA

Extension and/or implants on the uterus, fallopian tubes, and/or ovaries

IIB

Extension to other pelvic intraperitoneal tissues

III

Tumor involving one or both ovaries or fallopian tubes or primary peritoneal cancer with cytologically or histologically confirmed peritoneal metastases outside the pelvis and/or metastasis to the retroperitoneal lymph nodes

IIIA

Positive retroperitoneal lymph nodes, with or without microscopic peritoneal metastases that extend beyond the pelvis

IIIA1

Positive retroperitoneal lymph nodes only (cytologically or histologically proved)

IIIA1(I)

Metastasis ≤ 10 mm in largest dimension

IIIA1(II)

Metastasis > 10 mm in largest dimension

IIIA2

Microscopic extrapelvic (beyond the pelvic brim) peritoneal involvement, with or without positive retroperitoneal lymph nodes

IIIB

Macroscopic peritoneal metastases that extend beyond the pelvis and that are 2 cm in largest dimension, with or without positive retroperitoneal lymph nodes

IIIC

Macroscopic peritoneal metastases that extend beyond the pelvis and are > 2 cm in largest dimension, with or without metastasis to retroperitoneal lymph nodes (includes extension of tumor to the capsule of the liver and spleen without parenchymal involvement of either organ)

IV

Distant metastases, excluding peritoneal metastases

IVA

Pleural effusion with positive cytology

IVB

Parenchymal metastasis and metastases to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside the abdominal cavity)

*For stages IC, knowing whether capsule rupture was spontaneous or caused by the surgeon and whether the source of malignant cells was ascites or peritoneal washings helps determine prognosis.

Based on staging established by the International Federation of Gynecology and Obstetrics (FIGO) in Prat J, FIGO Committee on Gynecologic Oncology. Staging classification for cancer of the ovary, fallopian tube, and peritoneum. Int J Gynecol Obstet 124 (1):1-5, 2014. Copyright Elsevier (2013). (See also Prat J, FIGO Committee on Gynecologic Oncology: FIGO's staging classification for cancer of the ovary, fallopian tube, and peritoneum: Abridged republication. Journal of Gynecologic Oncology 26(2): 87–89, 2015.)

If early-stage cancer is suspected, staging may be done by laparoscopy or robotic-assisted laparoscopic surgery. Otherwise, an abdominal midline incision that allows adequate access to the upper abdomen is required. All peritoneal surfaces, hemidiaphragms, and abdominal and pelvic viscera are inspected and palpated. Washings from the pelvis, abdominal gutters, and diaphragmatic recesses are obtained, and multiple biopsies of the peritoneum in the central and lateral pelvis and in the abdomen are done. For early-stage cancer, the infracolic omentum is removed, and pelvic and para-aortic lymph nodes are sampled.

Cancers are also graded histologically from 1 (least aggressive) to 3 (most aggressive). The most recent classification distinguishes epithelial ovarian cancers as low-grade (grade 1) or high-grade (grade 2 or 3).

Screening

There is no screening test for ovarian cancer. However, women with a known hereditary risk, such as those with BRCA mutations, should be followed closely.

Although data from large trials indicate that CA 125 has a high specificity (up to 99.9% in one study), sensitivity is only moderate (71% in one study), and positive predictive value is low; thus, CA 125 is not recommended as a screening test for asymptomatic, average-risk women. Screening asymptomatic women using both ultrasonography and serum CA 125 measurements can detect some cases of ovarian cancer but has not been shown to improve outcome, even for high-risk subgroups (including women with BRCA mutations).

However, women should be screened for abnormalities in the BRCA gene if their family history includes any of the following:

  • Diagnosis of ovarian cancer in a 1st-degree relative before age 40

  • Diagnosis of breast and ovarian cancer in only one 1st-degree relative if one of the cancers was diagnosed before age 50

  • Two cases of ovarian cancer among 1st- and 2nd-degree relatives of the same lineage

  • Two cases of breast cancer and one case of ovarian cancer among 1st- or 2nd-degree relatives of the same lineage

  • One case of breast and one case of ovarian cancer among 1st- or 2nd-degree relatives of the same lineage if breast cancer was diagnosed before age 40 or if ovarian cancer was diagnosed before age 50

  • Two cases of breast cancer among 1st- or 2nd-degree relatives of the same lineage if both cases were diagnosed before age 50

  • Two cases of breast cancer among 1st- or 2nd-degree relatives of the same lineage if one was diagnosed before age 40

Also, if Ashkenazi Jewish women have one family member with breast cancer diagnosed before age 50 or with ovarian cancer, screening for abnormalities in the BRCA gene should be considered.

Prognosis

The 5-yr survival rates with treatment are

  • Stage I: 85 to 95%

  • Stage II: 70 to 78%

  • Stage III: 40 to 60%

  • Stage IV: 15 to 20%

Prognosis is worse when tumor grade is higher or when surgery cannot remove all visibly involved tissue; in such cases, prognosis is best when the involved tissue can be reduced to < 1 cm in diameter or ideally to a microscopic residual amount (cytoreductive surgery).

With stages III and IV, recurrence rate is about 70%.

Treatment

  • Usually hysterectomy and bilateral salpingo-oophorectomy

  • Cytoreductive surgery

  • Usually postoperative chemotherapy, often with carboplatin and paclitaxel

Hysterectomy and bilateral salpingo-oophorectomy are usually indicated except for stage I nonepithelial or low-grade unilateral epithelial cancers in young patients; fertility can be preserved by not removing the unaffected ovary and uterus. In patients with extensive spread, surgery is not indicated or can be deferred if they have one or more of the following:

  • Multiple liver metastases

  • Lymphadenopathy in the porta hepatis

  • Suprarenal para-aortic lymph nodes

  • Diffuse mesenteric disease

  • Evidence of pleural or parenchymal lung disease

These patients are treated with neoadjuvant chemotherapy (eg, with carboplatin plus paclitaxel). Surgery can sometimes be done after initial chemotherapy.

When hysterectomy and bilateral salpingo-oophorectomy are done, all visibly involved tissue is surgically removed if possible (cytoreduction). Cytoreduction is associated with increased survival time; the volume of residual disease remaining after cytoreduction correlates inversely with survival time. Cytoreduction may be

  • Complete: Cytoreduction to no grossly visible disease

  • Optimal: Cytoreduction with residual disease that is ≤ 1 cm in maximum tumor diameter, as defined by the Gynecologic Oncology Group

  • Suboptimal: Cytoreduction with tumor nodules > 1 cm remaining

Cytoreductive surgery usually includes

  • Supracolic omentectomy, sometimes with rectosigmoid resection (usually with primary reanastomosis)

  • Radical peritoneal stripping

  • Resection of diaphragmatic peritoneum or splenectomy

Predicting feasibility of cytoreduction

Because cytoreduction is associated with increased survival, being able to predict when cytoreduction to no gross residual disease can be done is important, but doing so is difficult; there are no uniform criteria.

Optimal cytoreduction is less likely if patients have the following:

  • Poor performance status

  • Age > 60 yr

  • American Society of Anesthesiologists physical status 3 or 4

  • Medical comorbidities

  • Poor nutritional status

  • Extra-abdominal disease

  • Large tumor bulk

  • Involvement of large bowel

  • Metastases to retroperitoneal lymph nodes above the renal vessels > 1 cm in largest dimension

  • Parenchymal liver involvement

  • A preoperative CA 125 > 500 U/mL

Algorithms based on results of preoperative imaging (eg, CT, MRI, PET/CT) to assess optimal cytoreduction have not been reliably reproducible.

Diagnostic laparoscopy before laparotomy could spare patients an unnecessary laparotomy resulting in suboptimal cytoreduction. Laparoscopy enables clinicians to do a tissue biopsy, make a definitive diagnosis, and analyze the biopsy sample. Thus, patients who are not candidates for cytoreduction can begin chemotherapy treatment earlier. Laparoscopic findings indicating that optimal cytoreduction is unlikely include

  • Omental cake

  • Extensive peritoneal or diaphragmatic carcinomatosis

  • Mesenteric retraction

  • Bowel and stomach infiltration

  • Spleen and/or liver superficial metastasis

The Fagotti score, based on 7 laparoscopic findings, can help predict the likelihood of optimal cytoreduction in patients with advanced ovarian cancer (see Table: Calculating the Fagotti Score to Predict the Likelihood of Optimal Cytoreduction). This scoring system assigns a value of 0 or 2 depending on whether disease is present in certain locations. If patients score ≥ 8, optimal cytoreduction is very unlikely. If they score < 8, they are considered candidates for cytoreductive surgery.

Calculating the Fagotti Score to Predict the Likelihood of Optimal Cytoreduction

Laparoscopic feature

Score

0

2

Peritoneal carcinomatosis

Carcinomatosis involving a limited area (along the paracolic gutter or the pelvic peritoneum) and surgically removable by peritonectomy

Unresectable massive peritoneal involvement with a miliary pattern of distribution

Diaphragmatic involvement

No infiltrating carcinomatosis and no nodules confluent with most of the diaphragmatic surface

Widespread infiltrating carcinomatosis or nodules confluent with most of the diaphragmatic surface

Mesenteric involvement

No large infiltrating nodules and no involvement of the root of the mesentery (ie, movement of intestinal segments is not limited)

Large infiltrating nodules or involvement of the root of the mesentery indicated by limited movement of intestinal segments

Omental involvement

No tumor diffusion observed along the omentum up to the greater curvature of the stomach

Tumor diffusion observed along the omentum up to the greater curvature of the stomach

Bowel infiltration

No bowel resection assumed and no miliary carcinomatosis observed on the bowel ansae

Bowel resection assumed or miliary carcinomatosis observed on the ansae

Stomach infiltration

No obvious neoplastic involvement of the gastric wall

Obvious neoplastic involvement of the gastric wall

Liver metastases

No surface lesions

Any surface lesion

Adapted from Fagotti A, Ferrandina G, Fanfani F, et al: Prospective validation of a laparoscopic predictive model for optimal cytoreduction in advanced ovarian carcinoma. Am J Obstet Gynecol 199:642, e1-642.e6, 2008. doi: 10.1016/j.ajog.2008.06.052.

Postoperative treatment

Postoperative treatment depends on the stage and grade (see Table: Postoperative Treatment of Ovarian Cancer by Stage and Type).

Postoperative Treatment of Ovarian Cancer by Stage and Type

Stage and Type

Treatment

Stage IA or B/grade 1 epithelial adenocarcinoma

No postoperative therapy

Stage IA or B/grade 2 or 3 cancers

Stage II cancers

6 courses of chemotherapy (typically, paclitaxel and carboplatin)

Stage III cancer

6 courses of chemotherapy* as for stage IA or B/grade 2 or 3

Consideration of intraperitoneal cisplatin and paclitaxel

Stage IV cancer

Infrequently, radiation therapy

Germ cell tumors

Stage II or III stromal tumors

Most often, combination chemotherapy, usually bleomycin, cisplatin, and etoposide

*Intraperitoneal chemotherapy with cisplatin plus paclitaxel results in longer survival than IV chemotherapy but may have a higher complication rate.

Even if chemotherapy results in a complete clinical response (ie, normal physical examination, normal serum CA 125, negative CT scan of the abdomen and pelvis), about 50% of patients with stage III or IV cancer have residual tumor. Of patients with persistent elevation of CA 125, 90 to 95% have residual tumor. Recurrence rate in patients with a complete clinical response after initial chemotherapy (6 courses of carboplatin and paclitaxel) is 60 to 70%.

If cancer recurs or progresses after effective chemotherapy, chemotherapy is restarted. Other useful drugs may include liposomal doxorubicin, docetaxel, paclitaxel, gemcitabine, bevacizumab, and a combination of cyclophosphamide plus bevacizumab or of gemcitabine plus cisplatin. Targeted therapy with biologic agents is under study.

Prevention

For patients with BRCA1 or BRCA2 gene mutations, risk of ovarian and, to a lesser degree, breast cancer is reduced if prophylactic bilateral salpingo-oophorectomy is done after childbearing is completed. Cancer risk appears to be lower with this approach than with surveillance. Patients with BRCA1 or BRCA2 gene mutations should be referred to a gynecologic oncologist for counseling.

Key Points

  • Ovarian cancer affects mostly postmenopausal and perimenopausal women; nulliparity, delayed childbearing, early menarche, delayed menopause, and certain genetic markers increase risk.

  • Early symptoms (eg, dyspepsia, bloating, early satiety, gas pains, backache) are nonspecific.

  • If cancer is being considered, do CT, measure tumor markers (eg, CA 125), and surgically stage tumors.

  • Screening asymptomatic women with ultrasonography and/or CA 125 is not useful unless risk of BRCA mutations is high.

  • Diagnostic laparoscopy before laparotomy could spare patients an unnecessary laparotomy that results in suboptimal cytoreduction.

  • Typically, treatment is hysterectomy, bilateral salpingo-oophorectomy, and cytoreductive surgery followed by chemotherapy (eg, carboplatin and paclitaxel).

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* This is the Professional Version. *