Ovarian Cancer

Ovarian cancer is a malignant tumor arising from the ovarian tissue and is classified according to the type of tissue from which it originates. The 3 major types of ovarian cancer are epithelial ovarian carcinomas (EOCs), ovarian germ cell tumors (OGCTs), and sex cord-stromal tumors (SCSTs). By far, EOCs are the most common, tend to present in postmenopausal women with advanced disease, and carry a poor prognosis. On the other hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand, OGCTs and SCSTs frequently affect younger women, tend to present earlier, and carry a better prognosis. Affected individuals are frequently asymptomatic, although they may present with nonspecific symptoms such as fatigue, increasing abdominal girth, GI symptoms, and 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. Moreover, if the tumor secretes hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview, abnormal bleeding may be a presenting symptom. Diagnosis is suspected based on imaging studies and confirmed with histologic examination. Treatment is primarily surgical and often with adjuvant chemotherapy.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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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.

Classification

Overview of ovarian tumor classification

  • Ovarian tumors are classified according to the type of cell from which they originate:
    • Epithelial tumors
    • Germ cell tumors
    • Sex cord-stromal tumors
    • Metastatic tumors (originating in other tissues and metastasizing to the ovary)
  • There are multiple histologic subtypes within each major tumor class.
  • Tumors may be classified as either:
    • Benign (adenomas): neoplasms exhibiting abnormal growth but not invading into the surrounding tissue
    • Borderline/low malignant potential (LMP) tumors: malignant neoplasms that are not very aggressive and have excellent prognosis
    • Malignant (carcinomas or adenocarcinomas): tumors that invade into the surrounding tissue
Image depicting the different types of ovarian cancer and their location of origin

Image depicting different types of ovarian cancer and their location of origin

Image by Lecturio.
Table: Summary of ovarian cancer classification
Proportion of primary malignant ovarian tumors Commonly affected age group Major types
Epithelial tumors 90% Postmenopausal women
  • Serous
  • Mucinous
  • Endometrioid
  • Clear cell
Germ cell tumors 5% 10‒30 years
  • Teratoma
  • Dysgerminoma
  • Yolk sac tumors
  • Choriocarcinoma
Sex cord-stroma 5% Perimenopausal women
  • Granulosa cell tumors
  • Theca cell tumors
  • Fibroma
  • Fibrosarcoma
Metastasis to 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 Variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables From:
  • Endometrium
  • Cervix
  • Breast
  • Stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach (Krukenberg tumors)
  • Colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix

Epithelial ovarian tumors

Epithelial ovarian carcinomas (EOCs) originate from surface epithelial cells and account for 90%‒95% of ovarian malignancies. Major types of EOCs include:

  • Serous adenocarcinoma:
    • Most common type accounting for 50% of malignant EOCs
    • Papillary structures within the cystic area
    • Psammoma bodies:
      • Intracellular calcium deposits
      • Key feature of serous EOCs
    • Usually high grade at diagnosis
    • Generally associated with a poor prognosis
  • Endometrioid adenocarcinoma:
    • Approximately 15%‒20% of malignant EOCs
    • Complex glandular architecture with back-to-back glandular growth
    • Better prognosis compared with serous types:
      • Typically low grade at diagnosis
      • More chemosensitive
    • Associated with:
      • Coexisting endometrial adenocarcinoma (15%‒20% of cases) 
      • 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 (40%‒50% of cases)
  • Clear cell adenocarcinoma:
    • Approximately 5%‒10% of malignant EOCs
    • Present as a large cystic mass (average size: 15 cm)
    • Sheets of cells with clear cytoplasm
    • Typically presents at an early stage
    • Poor chemosensitivity
    • Associated with endometriosis
  • Mucinous adenocarcinoma:
    • Large cystic masses that are typically 8‒20 cm, but can be much larger
    • Pseudomyxoma peritonei:
      • Clinical syndrome of abundant mucoid material in the abdominopelvic cavity
      • While possible in mucinous EOCs, pseudomyxoma peritonei is typically associated with mucinous tumors of the appendix
  • Less common types of EOC:
    • Squamous cell carcinoma Squamous cell carcinoma Cutaneous squamous cell carcinoma (cSCC) is caused by malignant proliferation of atypical keratinocytes. This condition is the 2nd most common skin malignancy and usually affects sun-exposed areas of fair-skinned patients. The cancer presents as a firm, erythematous, keratotic plaque or papule. Squamous Cell Carcinoma
    • Small cell carcinoma
    • Transitional cell tumors: Brenner tumors
    • Mixed carcinoma
    • Undifferentiated carcinoma
Psammoma bodies in an ovarian adenocarcinoma

Psammoma bodies in an ovarian adenocarcinoma

Image: “Moderately differentiated ovarian adenocarcinoma” by Pusiol T, Parolari AM, Piscioli I, Morelli L, Del Nonno F, Licci S. License: CC BY 2.0, cropped by Lecturio.

Germ cell tumors

Ovarian germ cell tumors (OGCTs) originate from primordial germ cells (i.e., primordial oocytes).

  • May be benign or malignant
  • Malignant OGCTs account for 5% of malignant ovarian cancers.
  • Typically arise in young women aged 10‒30 years
  • Excellent prognosis because:
    • Typically present at stage I
    • Excellent chemosensitivity

Histologic types of malignant OGCTs:

  • Dysgerminomas:
    • Most common malignant OGCT accounting for approximately 30% of cases
    • Less aggressive than many other ovarian cancers
    • Composed of undifferentiated germ cells
    • Associated with gonadal dysgenesis (which occurs in phenotypic females with a Y chromosome):
      • 46XY pure gonadal dysgenesis
      • 45X/46XY Turner-mosaic mixed gonadal dysgenesis
      • 46XY complete androgen insensitivity syndrome Androgen insensitivity syndrome Androgen insensitivity syndrome (AIS) is an X-linked recessive condition in which a genetic mutation affects the function of androgen receptors, resulting in complete (CAIS), partial (PAIS), or mild (MAIS) resistance to testosterone. All individuals with AIS have a 46,XY karyotype; however, phenotypes vary and include phenotypic female, virilized female, undervirilized male, and phenotypic male individuals. Androgen Insensitivity Syndrome
    • Develop from malignant transformation of gonadoblastomas (benign OGCTs)
  • Immature teratomas:
    • Approximately 20% of malignant OGCTs
    • Typically solid masses with some cystic areas
    • Contain a disordered mix of all 3 primary germ layer tissue types ( ectoderm Ectoderm The outer of the three germ layers of an embryo. Gastrulation and Neurulation, mesoderm, and endoderm Endoderm The inner of the three germ layers of an embryo. Gastrulation and Neurulation)
    • Neuroectoderm typically predominates.
    • ↑ Risk of torsion due to the “lopsided” nature of masses
    • Develop from malignant transformation of mature teratomas (benign OGCTs that are also known as dermoid cysts)
  • Yolk sac tumors:
    • Previously known as endodermal sinus tumors
    • Approximately 15% of malignant OGCTs
    • Derived from cells of the primitive yolk sac
    • Schiller-Duval bodies: glomerulus-like structure composed of central blood vessels surrounded by germ cells
    • Most dangerous OGCT
  • Choriocarcinoma:
    • Derived from germ cells, but have an appearance similar to gestational choriocarcinoma (derived from trophoblastic tissue found in pregnancies)
    • Worse prognosis compared with that of gestational choriocarcinoma
  • Other less common types:
    • Embryonal carcinoma
    • Mixed germ cell tumors
Mature cystic teratoma

Mature cystic teratoma (benign ovarian germ cell tumor (OGCT)):
Note the hair, sebaceous material, and tooth. Mature cystic teratomas are the most common type of benign OGCTs and can undergo malignant transformation into immature teratomas.

Image: “Mature Cystic Teratoma of the Ovary” by Ed Uthman. License: CC BY 2.0

Sex cord-stromal tumors (SCSTs)

Ovarian SCSTs originate from sex cord cells, stromal cells, or both.

  • May be benign or malignant
  • Malignant SCSTs account for approximately 5% of malignant ovarian cancers.
  • Most common in perimenopausal women (average age at diagnosis: 50 years)

Histologic types of SCSTs:

  • Granulosa cell tumors (often malignant):
    • 90% (most common type) of malignant SCSTs
    • Made up of granulosa cells (cells that normally line the developing follicles)
    • Usually secrete estrogens; occasionally secrete androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens → present with hormonally driven symptoms (e.g., abnormal bleeding, virilization)
    • Call-Exner bodies: small follicles with eosinophilic material
  • Theca cell tumors (usually benign):
    • Much rarer than granulosa cell tumors
    • Composed of theca cells (supportive cells that produce hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview)
    • Often secrete estrogens and/or androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens
  • Fibroma (benign):
    • Benign tumor arising from fibroblasts in connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. Connective Tissue
    • The most common SCST overall
  • Fibrosarcoma (malignant):
    • Malignant soft-tissue tumor (i.e., sarcoma) arising from fibroblasts in the connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. Connective Tissue
    • Extremely rare
  • Sertoli-Leydig cell tumors:
    • Abnormal cells that are typically only found in men (but found in women with this condition)
    • Secrete androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens → present with virilization
    • Rare

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)

Diagnosis and Staging

The diagnosis of ovarian cancer relies upon tissue biopsy. The initial detection of cancer is based on physical examination and imaging techniques, including ultrasound.

Physical exam

  • Mass characteristics that are particularly suspicious for ovarian cancer:
    • Nonmobile (i.e., “fixed”)
    • Nodular
    • Grossly enlarged
  • Exam should include:
    • Pelvic examination
    • Rectovaginal examination
  • Detection of a mass is not indicative of malignant cancer, but should prompt imaging.

Imaging

Imaging is typically ordered 1st if signs/symptoms suggestive of a pelvic mass are present. Discovery of concerning masses is often 1st identified on imaging and can help narrow differential diagnoses, assess the extent of disease, and assist in treatment planning. Modalities include:

  • Transvaginal ultrasound: initial imaging modality of choice
  • Pelvic MRI: ↑ specificity when ultrasound findings are indeterminate
  • CT of the abdomen and pelvis Pelvis The pelvis consists of the bony pelvic girdle, the muscular and ligamentous pelvic floor, and the pelvic cavity, which contains viscera, vessels, and multiple nerves and muscles. The pelvic girdle, composed of 2 "hip" bones and the sacrum, is a ring-like bony structure of the axial skeleton that links the vertebral column with the lower extremities. Pelvis:
    • May be helpful in treatment planning
    • Generally not sensitive enough to pick up small intraperitoneal disease
  • Imaging findings that are a cause of concern for malignancy include:
    • Thick septa, especially if vascularized
    • Solid components
    • Wall nodularity/papillary excrescences
    • 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
  • Additional imaging:
    • Chest X-ray: to detect an effusion and evaluate for metastases in 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
    • Mammogram: should be up to date, especially in women with 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-producing tumors

Laboratory

Tumor markers are generally nonspecific but can aid in diagnosis and assessing treatment response if imaging is suggestive of ovarian cancer. Commonly obtained serum tumor markers Serum Tumor Markers Serum tumor markers are proteins or carbohydrates produced by cancer cells that are associated with a malignancy of a specific origin (e.g., thyroglobulin in thyroid cancer). Genetic changes in a malignancy, such as gene mutations or patterns of gene expression, are also being used as tumor markers, and are often referred to as "cellular tumor markers." Serum Tumor Markers include:

  • CA-125:
    • Associated with several ovarian tumors, especially epithelial tumors
    • Only ↑ in 50% of early-stage EOCs
    • Also ↑ in benign conditions, including endometriosis, 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 cysts
  • CA19-9
  • Carcinoembryonic antigen (CEA)
  • α-Fetoprotein (AFP): associated with germ cell tumors
  • LDH
  • Inhibins A and B: associated with granulosa tumors
  • β-hCG: ↑ in 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 choriocarcinomas
  • Human epididymis protein 4 (HE4): a new marker associated with epithelial tumors

Histopathology and cytology

Histopathologic evaluation is ultimately required for diagnosis (gold standard).

  • Histopathology determines the subtype of ovarian cancer.
  • Recommended:
    • Specimen is generally obtained during the surgical excision of a concerning mass.
    • Laparotomy Laparotomy Laparotomy is an open surgical exploration of the abdomen, usually through a single large incision. Laparotomy and Laparoscopy or laparoscopy Laparoscopy Laparoscopy is surgical exploration and interventions performed through small incisions with a camera and long instruments. Laparotomy and Laparoscopy are both acceptable surgical techniques.
  • Not recommended:
    • Fine-needle aspiration (FNA)
    • Percutaneous biopsy
  • Pelvic washings:
    • Fill the pelvic cavity with fluid, then suction fluid → send for cytology
    • Helps identify dissemination within the cavity

Staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis

Ovarian cancer is staged surgically. There are 4 primary stages (each also contains several substages, which are beyond the scope required for medical school).

Staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis procedures:

Since staging depends on the extent of disease and presence of metastasis, staging procedures involve evaluation of:

  • Peritoneal cytology
  • Multiple peritoneal biopsies
  • Omental biopsies
  • Pelvic and para-aortic lymph node sampling

Ovarian cancer stages:

Individuals are staged based on their “highest” findings. For example, an individual with a tumor confined to the ovary but with positive para-aortic lymph nodes is classified as stage III.

Table: Summary of ovarian cancer staging
Stage Extent of tumor invasion into surrounding tissue Distant metastasis
I Tumor is confined 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 (may be bilateral). None
II Direct tumor invasion into other tissues within the pelvic cavity (i.e., below the pelvic brim), which typically includes:
  • Uterus
  • Fallopian tubes
  • Peritoneum
None
III Tumor invades outside the pelvis Pelvis The pelvis consists of the bony pelvic girdle, the muscular and ligamentous pelvic floor, and the pelvic cavity, which contains viscera, vessels, and multiple nerves and muscles. The pelvic girdle, composed of 2 "hip" bones and the sacrum, is a ring-like bony structure of the axial skeleton that links the vertebral column with the lower extremities. Pelvis/peritoneal cavity, potentially including:
  • Omentum
  • Intestines
  • Capsule 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/ 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
Metastasis to regional lymph nodes: para-aortic or pelvic nodes
IV Tumor invasion into the hepatic or splenic parenchyma
  • Metastasis to lymph nodes beyond the regional nodes
  • Metastasis to extraabdominal organs (e.g., 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)

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.

Table: Prognosis in ovarian cancer
Stage Epithelial ovarian carcinomas Ovarian germ cell tumors Sex cord-stromal tumors
Stage I Approximately 85% Approximately 100% Approximately 90%‒100%
Stage II Approximately 70% Approximately 85% Approximately 55%‒75%
Stage III Approximately 40% Approximately 80% Approximately 25%‒50% (combined data)
Stage IV Approximately 20% Approximately 70%

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.

References

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  2. Salani, R., Cosgrove, C.M. (2021). Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Surgical staging. UpToDate. Retrieved September 10, 2021, from https://www.uptodate.com/contents/epithelial-carcinoma-of-the-ovary-fallopian-tube-and-peritoneum-surgical-staging 
  3. Chen, L. Berek, J. (2021). Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Clinical features and diagnosis. UpToDate. Retrieved September 10, 2021, from https://www.uptodate.com/contents/epithelial-carcinoma-of-the-ovary-fallopian-tube-and-peritoneum-clinical-features-and-diagnosis 
  4. Rendi, M. (2021). Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Histopathology. UpToDate. Retrieved September 10, 2021, from https://www.uptodate.com/contents/epithelial-carcinoma-of-the-ovary-fallopian-tube-and-peritoneum-histopathology 
  5. Chen, L., Berek, J. (2021). Overview of epithelial carcinoma of the ovary, fallopian tube, and peritoneum. UpToDate. Retrieved September 10, 2021, from https://www.uptodate.com/contents/overview-of-epithelial-carcinoma-of-the-ovary-fallopian-tube-and-peritoneum 
  6. Gershenson, D. (2020). Sex cord-stromal tumors of the ovary: Management in adults. UpToDate. Retrieved September 10, 2021, from https://www.uptodate.com/contents/sex-cord-stromal-tumors-of-the-ovary-management-in-adults
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  9. Gershenson, D. (2020). Treatment of malignant germ cell tumors of the ovary. UpToDate Retrieved September 10, 2021, from https://www.uptodate.com/contents/treatment-of-malignant-germ-cell-tumors-of-the-ovary 
  10. Hochberg, L., Hoffman, M. (2021). Types of adnexal masses. UpToDate. Retrieved Sep 10, 2021, from https://www.uptodate.com/contents/types-of-adnexal-masses 
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