Ovarian tumors

The ovaries consist of different kinds of tissue (epithelial, germ cells, and sex cord tissue), which may give rise to benign or malignant tumors. Symptoms depend on the type of tissue affected and range from local abdominal discomfort to endocrinological phenomena caused by hormone-producing tumors. Metastases of other tumors and lymphomas may also affect the ovaries. The most common malignant tumor of the ovaries is serous ovarian cancer, which (with the exception of those who are genetically predisposed) mostly affects older women. The lack of early symptoms of ovarian cancers often delays diagnosis, resulting in an unfavorable prognosis. Ovarian cancers primarily metastasize intraperitoneally and later become noticeable mostly due to increasing abdominal girth caused by malignancy-related ascites. Treatment generally involves radical surgical removal of the tumor and chemotherapy.

• Lifetime prevalence of malignant ovarian cancer: 1–2%
• Peak incidence: 60–70 years
• Genetic predisposition may play a role in familial incidence and in younger patients (< 30 years) developing tumors.
• Epithelial ovarian carcinomas account for 70% of all ovarian malignancies.

References:^[1][2][3]

Epidemiological data refers to the US, unless otherwise specified.

Risk factors

• Genetic predisposition
  • BRCA1/BRCA2 mutation
  • HNPCC syndrome
  • Peutz-Jeghers syndrome
• Hormonal imbalance and menstrual cycle
  • Elevated number of lifetime ovulations (the contraceptive pill appears to have a protective effect)
  • Infertility/low number of pregnancies
  • Early menarche and late menopause
  • PCOS

References:^[4][2][3]

Epithelial Tumors

• 65–75% of all ovarian tumors; ∼ 70% of all malignant ovarian tumors
• Cystadenoma/cystadenocarcinoma
  • Serous
    • Most common ovarian tumor
    • Serous cystadenocarcinoma; is the most aggressive ovarian cancer
    • Frequently bilateral (65% of cases)
    • Histology:
      • Tumor cells with papillary structures; and small cytoplasm
      • Psammoma bodies are a typical feature.
  • Mucinous
    • Second most common ovarian tumor
    • Up to 75% of cases are benign.
• Endometrioid carcinoma
  • Frequently associated with endometrial cancer and endometriosis
  • Commonly malignant
• Borderline ovarian tumors
  • Characterized by increased epithelial proliferation and cellular atypia, without the invasive characteristics typical of malignant tumors
  • About 10–15% recur, often in the form of invasive tumors
  • Peak incidence: 35–45 years
• Clear cell carcinoma
• Undifferentiated carcinoma
• Brenner tumor (mostly benign, derived from embryonic coelomic epithelium)

Epithelial ovarian tumors may be benign, malignant, or borderline!

Germ cell tumors

• 15–25% of all ovarian tumors
• Teratoma
  • Mature
    • Dermoid cysts: most common of all germ cell tumors (90% of cases)
      • Malignant transformation in 2% of cases
      • Can theoretically contain any type of tissue, e.g., hair, teeth, and sebaceous glands, but mostly include parts of ectodermal origin
      • Differentiated, mostly benign tumor
    • Struma ovarii: teratoma with endodermal differentiation into thyroid tissue
      • Very rare: malignant transformation into a thyroid carcinoma
      • May produce thyroxine and cause hyperthyroidism symptoms
      • Differentiated, mostly benign tumor
  • Immature:
    • Rare, undifferentiated
    • May contain tissue of embryonic/fetal period
    • High risk of malignancy
• Dysgerminoma; : most common malignant ovarian tumor in young women (20–30 years); female histological equivalent to the male seminoma
• Yolk sac tumor of the ovary: : often malignant; occurs mainly in childhood and adolescence
• Non-gestational choriocarcinoma; : rare and extremely malignant; normally accompanied by beta hCG production

Sex cord-stromal tumors of the ovary

• 5–10% of all ovarian tumors
• Estrogen producing: granulosa cell tumor and theca cell tumor
  • ∼ 75% of cases affect postmenopausal women.
• Androgen producing: Sertoli-Leydig cell tumor
  • Occurs very rarely; ∼ 20% malignant transformation
  • Production of androgens → virilization
  • Primarily affects women aged 30–40 years
• Ovarian fibroma
  • Benign, although may cause Meigs' syndrome

Mesenchymal tumors

• ∼ 4% of all ovarian tumors
• Malignant fibrosarcoma
  • Very rare but extremely malignant tumor

Metastasis

• 10–15% of all ovarian tumors
• Primary tumors are most often found in the gastrointestinal tract, breast, or endometrial cancer
• Krukenberg tumor: bilateral ovarian metastases; from an undifferentiated gastric carcinoma (mucin-secreting, signet ring cell carcinoma)

References:^{[4][2][3][5][6][7]}

General symptoms

• In most cases, there are no early symptoms.
• In advanced stages, the size and growth of the tumor can lead to:
  • Abdominal pain and ascites
  • Cancer cachexia
  • Possible disruption of menstrual cycle
  • Dyspnea due to malignant pleural effusion
  • Abdominal or pelvic mass
• Complication: tumor can cause ovarian torsion→ tissue infarction → surgical emergency

The first symptom is often increasing abdominal girth (clothes no longer fit at the waist)!

Specific symptoms

• Granulosa cell tumor: Granulosa cells express aromatase (estrogen synthesis occurs in 25% of tumors).
  • Menstrual irregularities such as postmenopausal bleeding and metrorrhagia
  • Increased risk of endometrial cancer
  • Precocious puberty
• Sertoli-Leydig cell tumor: can produce either estrogen or testosterone
  • Virilization due to tumor-induced testosterone production:
    • Symptoms in females: Amenorrhea, hirsutism, decreased fertility, and acne
    • Symptoms in males: Precocious puberty in boys and gynecomastia in men, feminization in males if estrogen is produced
• Yolk sac tumor, dysgerminoma: rapid growth, acute onset of symptoms (pelvic mass and pain)
• Struma ovarii: symptoms of hyperthyroidism
• Extra-ovarian primary peritoneal carcinoma
  • Frequency: up to 10% of all ovarian cancers!
  • Mostly mucinous, serous, or seropapillary ovarian carcinoma, with predominantly extraovarian involvement
  • Criteria
    • Both ovaries are either of normal size or only enlarged by a benign process
    • Invasion of max. 5 x 5 mm of the ovary surface/periphery
• Pseudomyxoma peritonei
  • Bursting of a mucinous cystadenoma/carcinoma may spread tumor cells throughout the peritoneum.
  • Mucinous cells cause gelatinous ascites and intra-abdominal adhesions.
  • May require several surgical treatments and, in the long term, usually leads to cachexia and death.
• Meigs syndrome
  • Ascites and pleural effusion in association with an ovarian tumor (e.g., ovarian fibroma)
  • In 90% of cases, the ovarian tumor is unilateral.
  • The cause is unknown.
  • Surgical removal of the tumor leads to a complete resolution of symptoms.

Metastatic dissemination

• Lymphatic spread: especially along the pelvic and para-aortic lymph nodes; less often along the inguinal lymph nodes
• Hematogenous spread: rare; metastases can occur in the lungs, liver, bones, and CNS
• Spread by continuity: peritoneal carcinomatosis with intraperitoneal spread and superficial metastases.; commonly spreads to to the omentum (omental caking)

References:^{[1][2][3][5][6][8]}

• Hypercalcemia due to paraneoplastic synthesis of PTHrP
• Tumor markers
  • Epithelial ovarian tumor: CA-125, CA 72‑4 , CA 15-3, CEA
  • Yolk sack tumor: alpha-fetoprotein
  • Non-gestational choriocarcinoma: beta hCG
  • Granulosa cell tumor: inhibin B
• Imaging: Transvaginal ultrasound is the gold standard, but abdominal or rectal ultrasound may also be conducted.
  • CT/MRI for staging
• Histology:
  • Granulosa cell tumor: Call-Exner bodies (granulosa cells arranged in clusters surrounding a central cavity with eosinophilic secretions, resembling primordial follicles)
  • Sertoli-Leydig cell tumor: contain Reinke crystals
  • Ovarian fibroma: clusters of spindle-shaped cells (fibroblasts)

Fine needle aspiration cytology is absolutely contraindicated in ovarian tumors because it increases the risk of spreading tumor cells to the peritoneum!

Call your Ex and Grandparents! – Call-Exner bodies are characteristic of Granulosa cell tumors.

Ultrasound workup of ovarian masses
	Benign	Malignant
Internal structure	Uniform, thin walls	Irregularly thickened septa
Margins	Smooth	Indistinct borders; papillary projections
Echogenicity	Anechoic	Hypoechoic, anechoic, and hyperechoic components
Content	Cystic	Cystic or solid components
Vascularization	Unremarkable	Possible central vascularization
Pouch of Douglas	Unremarkable	Possible free fluid (ascites)

References:^[5][6][10]

• Ovarian cysts
• Endometriosis
• Tubo-ovarian abscess
• Ectopic pregnancy
• Pelvic inflammatory disease

The differential diagnoses listed here are not exhaustive.

• Surgery
  • Frozen section and histology positive for carcinoma: radical surgical staging
    • Removal of the greater omentum
    • Lymphadenectomy (pelvic and para-aortic)
    • Hysterectomy with bilateral salpingo-oophorectomy (removal of uterus, ovaries, tubes, and supporting structures)
    • The prognosis is directly correlated with the extensiveness of the radical tumor removal.
    • Exception: A fertility-sparing surgery is possible in cases of verified stage FIGO IA and of grade G1 (i.e., tissue is well differentiated)
    • Appendectomy if involvement is suspected during surgery
    • Biopsy from all noticeable locations/adhesions (peritoneal biopsy and washing cytology
  • Frozen section negative for carcinoma: tumor resection, but no surgical staging
  • Second-look surgery
• Chemotherapy
  • Indicated for all patients as adjuvant therapy
  • First-line therapy: carboplatin; polychemotherapy and antimitotics (e.g., paclitaxel)
  • Second-line therapy and platinum-refractory recurrent carcinoma
    • Recurrent, platinum-resistant ovarian cancer: as alternative, monotherapy with, e.g., topotecan, anthracyclines (pegylated liposomal doxorubicin), gemcitabine, paclitaxel, treosulfan
    • Recurrent, platinum-sensitive ovarian cancer: combination therapy (all therapeutic schemes, if necessary, can be combined with anti-VEGF antibody bevacizumab)
      • Carboplatin + pegylated liposomal doxorubicin
      • Carboplatin + paclitaxel
      • Carboplatin + gemcitabine
  • Radiation therapy: rarely used due to the intraperitoneal location and low radiosensitivity of the tumor

Malignant germ cell tumors respond particularly well to polychemotherapy because they are highly aggressive!

References:^[5][6]

• Genetic predisposition
  • Consider a preventive bilateral salpingo-oophorectomy if no future pregnancies are desired
  • If surgery is not pursued, then frequent screening (CA 125 and transvaginal ultrasound) is recommended
• Hormonal contraceptives; , GnRH analogs, breast feeding, and tubal ligation appear to reduce the risk of ovarian carcinoma.

References:^[11]

Pregnant women

• Pregnancy luteoma
  • Definition: : rare benign tumors that develop specifically during pregnancy.
  • Clinical features
    • The majority of patients are asymptomatic.
    • When clinically apparent, it typically manifests with symptoms of virilization during pregnancy.
  • Diagnostics: tumor often diagnosed incidentally (during cesarean delivery)
    • Apparent as solid adnexal masses (unilateral or bilateral; usually nodular)
    • The size of the tumor is usually < 10 cm in diameter.
  • Treatment: observation only; regresses spontaneously post-partum
• Theca lutein cysts
  • Definition: a type of benign enlargement of the ovaries. It is a functional ovarian cyst that is thought to originate due to excessive amounts of circulating gonadotropins such as beta-hCG.
    • Strongly associated with gestational trophoblastic disease and multiple gestations.
  • Diagnostics: Ultrasonography shows bilateral enlarged, multilocular, cystic masses of the ovaries.
  • Treatment
    • No treatment required because they typically regress spontaneously once beta-HCG levels fall
    • Treatment of underlying cause, if present (e.g., gestational trophoblastic disease)

If surgical removal of an ovarian tumor is indicated during pregnancy, surgery should, if possible, be scheduled for after the 10^th week of gestation, as the secretion of progesterone by the corpus luteum is essential for the maintenance of the pregnancy. The placenta takes over this function from approximately the 10^th week of pregnancy onwards.

References:^{[12][13][14][15]}