Overview

Definition

Ovarian cancer is a malignant tumor arising from the ovarian tissues.

Epidemiology

• Incidence:
  • 11.4 per 100,000 women annually
  • The lifetime risk of ovarian cancer among women in the US is approximately 1.3%.
  • 3rd-most common gynecologic cancer (after cervical and uterine)
• Mortality impact:
  • Leading cause of gynecologic cancer death in women
  • 5th-most common cause of cancer-related deaths in women

Risk factors

• Postmenopausal women
• Family history of breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer and/or ovarian cancer
• Increasing age
• Smoking
• Early menarche and/or late menopause Menopause Menopause is a physiologic process in women characterized by the permanent cessation of menstruation that occurs after the loss of ovarian activity. Menopause can only be diagnosed retrospectively, after 12 months without menstrual bleeding. Menopause (↑ number of menstrual cycles)
• Nulliparity
• Endometriosis Endometriosis Endometriosis is a common disease in which patients have endometrial tissue implanted outside of the uterus. Endometrial implants can occur anywhere in the pelvis, including the ovaries, the broad and uterosacral ligaments, the pelvic peritoneum, and the urinary and gastrointestinal tracts. Endometriosis

Protective factors

Several common factors significantly reduce the risk of ovarian cancer, including:

• Prolonged use of oral contraceptives
• Tubal ligation
• Hysterectomy
• Breastfeeding Breastfeeding Breastfeeding is often the primary source of nutrition for the newborn. During pregnancy, hormonal stimulation causes the number and size of mammary glands in the breast to significantly increase. After delivery, prolactin stimulates milk production, while oxytocin stimulates milk expulsion through the lactiferous ducts, where it is sucked out through the nipple by the infant. Breastfeeding
• Parity
• Bilateral salpingo-oophorectomy (BSO) is the removal of fallopian tubes Fallopian tubes The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The fallopian tubes receive an ovum after ovulation and help move it and/or a fertilized embryo toward the uterus via ciliated cells lining the tubes and peristaltic movements of its smooth muscle. Posterior Abdominal Wall and ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries:
  • Performed prophylactically in women with known mutations, such as BRCA mutations, which put them at high risk for ovarian cancer
  • Cancer risk is not entirely eliminated despite surgical excision.

Pathophysiology

Pathogenesis

• Ovarian cancer develops as a result of cellular mutations → leads to dysregulated cellular growth → ↑ proliferation → tumor
• Mutations may:
  • Arise de novo (a majority of mutations)
  • Be genetically inherited
• Some tumors undergo progression from benign cysts → borderline/LMP tumors → invasive carcinoma
• Many EOCs are actually believed to originate from the epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium of adjacent fallopian tube Fallopian Tube A pair of highly specialized canals extending from the uterus to its corresponding ovary. They provide the means for ovum transport from the ovaries and they are the site of the ovum's final maturation and fertilization. The fallopian tube consists of an interstitium, an isthmus, an ampulla, an infundibulum, and fimbriae. Its wall consists of three layers: serous, muscular, and an internal mucosal layer lined with both ciliated and secretory cells. Uterus, Cervix, and Fallopian Tubes fimbriae (thus, tubal ligation and salpingectomies ↓ risk of EOC).
• Theory: regular ovulation over a prolonged period leads to an increased need to repair the surface of the ovary → constant repair, inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation, and proliferation can lead to the accumulation of genetic mutations responsible for cancer development

Associated genetic mutations

Some mutations are commonly associated with ovarian cancers, including:

• BRCA1 and 2:
  • Tumor-suppressor genes involved in DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure repair
  • Most commonly inherited mutations associated with ovarian cancer
  • Inherited in an autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance pattern
  • BRCA1: approximately 40% lifetime risk of ovarian cancer
  • BRCA2: approximately 20% lifetime risk of ovarian cancer
• P53 (de novo or as part of Li-Fraumeni syndrome)
• Some of the mismatch repair genes that cause Lynch syndrome Lynch syndrome Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC), is the most common inherited colon cancer syndrome, and carries a significantly increased risk for endometrial cancer and other malignancies. Lynch syndrome has an autosomal dominant inheritance pattern involving pathogenic variants in one of the mismatch repair (MMR) genes or epithelial cell adhesion molecule (EpCAM). Lynch syndrome:
  • MLH1
  • MSH2
  • MSH6
• Other genes involved in the double-strand break repair system:
  • CHEK2
  • RAD61
  • BRIP1
• KRAS mutations are common in mucinous carcinomas.

Mechanisms of spread

Ovarian cancers spread via:

• Direct local extension
• Metastasis within the peritoneal cavity:
  • Omentum
  • On the mesentery and serosa of the bowel
  • Undersurface of the diaphragm Diaphragm The diaphragm is a large, dome-shaped muscle that separates the thoracic cavity from the abdominal cavity. The diaphragm consists of muscle fibers and a large central tendon, which is divided into right and left parts. As the primary muscle of inspiration, the diaphragm contributes 75% of the total inspiratory muscle force. Diaphragm or surface of the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver
• Lymphatic invasion:
  • Para-aortic lymph nodes (Recall: Primary blood supply to the ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries is via the ovarian arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries, directly off the aorta.)
  • Pelvic lymph nodes
• Hematogenous dissemination to distant sites (most commonly the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs)

Clinical Presentation

Women with early disease (especially EOCs) tend to be asymptomatic or present with vague, nonspecific complaints. Most women with EOCs especially tend to present later with signs/symptoms associated with metastasis.

• Systemic signs of disease:
  • Loss of appetite
  • Unexpected weight loss
  • Fatigue
• Gynecologic symptoms:
  • Pelvic pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • Irregular uterine bleeding (with hormone-secreting SCSTs)
  • Dyspareunia ( pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain with intercourse)
  • Palpable mass on pelvic exam
• GI/abdominal:
  • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • Bloating/abdominal distension
  • Nausea/vomiting
  • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea or constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
  • Large palpable mass on abdominal exam (especially with mucinous and clear cell EOCs)
  • Ascites Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection). Ascites
  • Bowel obstruction
• Genitourinary:
  • Increased urinary frequency
  • Urinary urgency
• Musculoskeletal:
  • Back pain Back pain Back pain is a common complaint among the general population and is mostly self-limiting. Back pain can be classified as acute, subacute, or chronic depending on the duration of symptoms. The wide variety of potential etiologies include degenerative, mechanical, malignant, infectious, rheumatologic, and extraspinal causes. Back Pain
  • Weakness
• Endocrine (common with hormone-secreting SCSTs):
  • Breast development in young girls/breast growth in adults
  • Abnormal uterine bleeding Abnormal Uterine Bleeding Abnormal uterine bleeding is the medical term for abnormalities in the frequency, volume, duration, and regularity of the menstrual cycle. Abnormal uterine bleeding is classified using the acronym PALM-COEIN, with PALM representing the structural causes and COEIN indicating the non-structural causes. Abnormal Uterine Bleeding
  • Infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility due to anovulation, as estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries and testosterone suppress ovulation
  • Androgenic symptoms:
    • Acne
    • Hirsutism
    • Virilization in young girls
• Other signs of advanced disease:
  • Pleural effusion Pleural Effusion Pleural effusion refers to the accumulation of fluid between the layers of the parietal and visceral pleura. Common causes of this condition include infection, malignancy, autoimmune disorders, or volume overload. Clinical manifestations include chest pain, cough, and dyspnea. Pleural Effusion
  • Palpable lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy in the groin
  • Sister Mary Joseph nodule (metastasis to the umbilicus)

Management

The primary treatment for ovarian cancer is surgery; however, specific treatment depends upon the stage of cancer. Other treatment modalities include chemotherapy and immunotherapy.

Surgical management

• Surgical excision is typically the treatment of choice.
• Procedures may be conducted to remove:
  • 1 or both ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries
  • Ipsilateral or bilateral fallopian tubes Fallopian tubes The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The fallopian tubes receive an ovum after ovulation and help move it and/or a fertilized embryo toward the uterus via ciliated cells lining the tubes and peristaltic movements of its smooth muscle. Posterior Abdominal Wall
  • Uterus
  • Para-aortic and pelvic lymph nodes
  • Appendix (for mucinous tumors)
  • Cytoreductive (i.e., “debulking” procedures):
    • Removal of other tissues (e.g., bowel, bladder, liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver, spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen, omentum) affected by the tumor
    • The goal is to reduce the tumor burden when complete excision is not possible.
• Pelvic washings are usually obtained 1st to help with staging.
• Procedures typical for malignant tumors:
  • Standard procedure is total hysterectomy with BSO and lymphadenectomy.
  • Fertility-sparing procedures may be considered in young individuals depending on the situation.
• Issues for young women:
  • BSO → surgically-induced menopause Menopause Menopause is a physiologic process in women characterized by the permanent cessation of menstruation that occurs after the loss of ovarian activity. Menopause can only be diagnosed retrospectively, after 12 months without menstrual bleeding. Menopause → ↑ risk for early osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis
  • Fertility: Egg retrieval can be considered prior to BSO.

Chemotherapy

• Indicated in almost all women except in those with early stage-I disease
• Typical regimen:
  • For EOCs: Taxane-platinum combination
    • Taxanes: paclitaxel (preferred) or docetaxel
    • Platinums: carboplatin (preferred) or cisplatin
  • For OGCTs and SCSTs: platinum-based therapy, usually bleomycin + cisplatin + etoposide
• Timing of administration:
  • May be given after surgery (termed adjuvant therapy)
  • May be given before surgery to reduce the size of a tumor (termed neoadjuvant therapy)
  • May be used as primary treatment in individuals who are poor surgical candidates
• The exact number and timing of cycles are individualized.

Additional treatments

• Immunotherapy with monoclonal antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins:
  • Often used in combination with chemotherapy for advanced disease
  • Example: bevacizumab (Avastin), which binds to and inhibits vascular endothelial growth factor (VEGF)
• Radiation therapy may be considered but is rarely used in ovarian cancer.
• Psychosocial support is an important aspect of treatment. Affected individuals should be offered services to improve their quality of life via counseling and social support.

Surveillance

• Regular pelvic exams
• Monitor relevant tumor markers (e.g., CA-125 for EOC).
• Obtain imaging for any concerns about recurrence (e.g., symptoms, ↑ tumor markers, exam findings).
• Recurrent disease is often managed with a repeat surgical procedure and chemotherapy.

Prognosis

The prognosis depends primarily on the stage at diagnosis and the specific histology. General 5-year survival rates are noted in the table.

Differential Diagnosis

The differential diagnosis of a pelvic mass includes:

• Follicular cysts (physiologic cysts): As an oocyte develops in the 1st half of the menstrual cycle Menstrual cycle The menstrual cycle is the cyclic pattern of hormonal and tissular activity that prepares a suitable uterine environment for the fertilization and implantation of an ovum. The menstrual cycle involves both an endometrial and ovarian cycle that are dependent on one another for proper functioning. There are 2 phases of the ovarian cycle and 3 phases of the endometrial cycle. Menstrual Cycle, the follicle grows into a small cyst, approximately 2‒3 cm in size, prior to ovulation. Occasionally, an oocyte may not ovulate and the follicle can enlarge (typically < 10 cm) and persist. On ultrasound, these follicles appear as simple cysts with smooth walls. The cysts typically resolve spontaneously, although large, persistent cysts may be treated surgically.
• Corpus luteal cysts: After ovulation, the follicles transform into corpus luteal cysts, secreting both estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries and progesterone. On ultrasound, corpus luteal cysts may show slightly thicker walls and contain some internal debris. The cysts may also enlarge (< 10 cm) but still usually resolve spontaneously. A corpus luteum is critical to sustaining an early pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care and should not be confused with an ectopic pregnancy Ectopic pregnancy Ectopic pregnancy refers to the implantation of a fertilized egg (embryo) outside the uterine cavity. The main cause is disruption of the normal anatomy of the fallopian tube. Ectopic Pregnancy.
• Hemorrhagic cysts: Follicular or corpus luteal cysts bleed occasionally and are known as hemorrhagic cysts. These cysts typically present with sudden-onset pelvic pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain in ovulating women. On ultrasound, they appear as simple cysts with internal echoes (representing blood and clot). Hemorrhagic cysts resolve spontaneously over 1‒2 menstrual cycles. Emergency surgery may be warranted to stop the bleeding if it is significant at presentation.
• Endometriosis Endometriosis Endometriosis is a common disease in which patients have endometrial tissue implanted outside of the uterus. Endometrial implants can occur anywhere in the pelvis, including the ovaries, the broad and uterosacral ligaments, the pelvic peritoneum, and the urinary and gastrointestinal tracts. Endometriosis: a condition in which endometrial cells implant outside the uterine cavity. Implants on the ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries can grow into endometriomas or chocolate cysts, which are cysts filled with endometrial fluid. Endometriomas and chocolate cysts appear almost identical to hemorrhagic cysts on ultrasound, but will not resolve spontaneously and must be surgically excised. Affected individuals typically present with dysmenorrhea, dyspareunia, and/or infertility.
• Leiomyomas (uterine fibroids): common benign tumors arising from smooth muscle cells in the uterine myometrium. Leiomyomas typically present with abnormal bleeding, pelvic pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, and/or bulk symptoms. Fibroids are identified as hypoechoic, well-circumscribed, round masses on pelvic ultrasound and may be confused with solid adnexal masses if they are pedunculated. Management is surgical if the affected individuals are symptomatic.
• Ectopic pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care: implantation Implantation Endometrial implantation of embryo, mammalian at the blastocyst stage. Fertilization and First Week of the fertilized egg ( embryo Embryo The entity of a developing mammal, generally from the cleavage of a zygote to the end of embryonic differentiation of basic structures. For the human embryo, this represents the first two months of intrauterine development preceding the stages of the fetus. Fertilization and First Week) outside the uterine cavity. Affected individuals may present with abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain and/or bleeding as the developing embryo Embryo The entity of a developing mammal, generally from the cleavage of a zygote to the end of embryonic differentiation of basic structures. For the human embryo, this represents the first two months of intrauterine development preceding the stages of the fetus. Fertilization and First Week increases in size. An ectopic pregnancy Ectopic pregnancy Ectopic pregnancy refers to the implantation of a fertilized egg (embryo) outside the uterine cavity. The main cause is disruption of the normal anatomy of the fallopian tube. Ectopic Pregnancy is diagnosed by pelvic ultrasound and by monitoring β-hCG levels. Ectopic pregnancies are dangerous because a life-threatening hemorrhage may result if the fallopian tube Fallopian Tube A pair of highly specialized canals extending from the uterus to its corresponding ovary. They provide the means for ovum transport from the ovaries and they are the site of the ovum's final maturation and fertilization. The fallopian tube consists of an interstitium, an isthmus, an ampulla, an infundibulum, and fimbriae. Its wall consists of three layers: serous, muscular, and an internal mucosal layer lined with both ciliated and secretory cells. Uterus, Cervix, and Fallopian Tubes ruptures with the expanding pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care.