10- MALIGNANT TUMORS OF OVARY AND TUBES Quiz

Ovarian and Tubal Tumors

• Asena Ayar Madenli, MD, Asst. Prof.
• ISU Medical School (2024-2025)
• Liv Hospital Vadi Istanbul
• Department of Obstetrics and Gynecology

Ovarian Cancers

• Epithelial (90%):
  • Serous (HGSOC, LGSOC)
  • Mucinous
  • Brenner
  • Endometrioid
  • Clear cell
• Germ Cell:
  • Dysgerminoma
  • Yolk sac
  • Choriocarcinoma
  • Teratoma
  • Embryonal carcinoma
• Sex Cord Stromal:
  • Granulosa cell
  • Sertoli-Leydig cell
  • Thecoma
  • Fibroma
• Metastatic:
  • Krukenberg

Epidemiology

• Epithelial ovarian cancers are a significant cause of mortality worldwide.
• In developed countries, there are ~190,000 new cases and ~114,000 deaths annually.
• They account for ~3% of all cancers.
• They rank 5th among cancer-related deaths (after lung, breast, colorectal, and pancreatic).
• Ovarian cancer is the second most common gynecological malignancy (~23% of gynecological cancers).
• Estimated lifetime risk of a woman developing ovarian cancer is between 1.4% and 1.7%. (1/70)
• Average age of diagnosis is 63.

Epidemiology- Continued

• Tumors may occur at any age, with variations in histologic subtypes by age.
• Germ cell tumors predominate in women under 20.
• Borderline tumors typically occur in women in their 30s and 40s.
• Invasive epithelial ovarian cancers mostly occur after the age of 50.

Epithelial Ovarian Cancer (EOC)

• Originate from the coelomic epithelium
• Account for 90% of ovarian cancer cases.
• Subtypes:
  • Serous (high-grade serous ovarian cancer, low-grade serous ovarian cancer)
  • Mucinous
  • Brenner
  • Endometrioid
  • Clear cell
• Classification: Benign, borderline (low malignant potential), malignant.

Carcinogenesis

• Surface epithelium
• Inclusion cysts
• Metaplasia occurring in inclusion cysts
• Genetic predisposition in ~5-10% of cases.

Risk Factors

• Age (>40 years)
• Reproductive history: nulliparity, infertility, fertility medications (HRT >10 years)
• Personal history of breast cancer
• Race
• Family history (hereditary nonpolyposis colorectal cancer (HNPCC)-Lynch 2 syndrome)
• Early menarche-late menopause
• Environmental factors
• Genetic predisposition (BRCA mutations)
• For epithelial ovarian tumors:
  • Reproductive risk factors: women who have never had children are twice as likely to develop the disease.
  • First pregnancy at an early age, early menopause, and the use of oral contraceptives have been associated with lower risks.
  • No clear relationship to fallopian tube cancer.

BRCA 1 and 2

• These are two tumor-suppressor genes.
• BRCA1 is located on chromosome 17q21. Patients with a mutation have a dramatically elevated risk of developing ovarian cancer (39-46%).
• BRCA2 is located on chromosome 13q12 and generally leads to a less likely risk of ovarian cancer (12-20%).
• Mutations can skip generations.
• Prophylactic bilateral salpingo-oophorectomy (BSO) is recommended in BRCA1 or BRCA2 carriers. BSO may be performed upon completion of childbearing or by age 40.
• Prophylactic BSO reduces the risk of developing breast cancer by ~50%.

Protective Factors

• Multiparity
• Oral contraceptives
• Lactation
• Hysterectomy
• Tubal ligation
• BSO (bilateral salpingo-oophorectomy)

Staging Ovarian, Fallopian Tube, and Peritoneum

• Stage I: Tumor confined to the ovaries or fallopian tubes (T1-No-Mo)
  • IA: Tumor limited to 1 ovary, no tumor on ovarian or fallopian tube surface, no malignant cells in ascities or peritoneal washings
  • IB: Tumor limited to both ovaries, no tumor on ovarian or fallopian tube surface, no malignant cells in ascities or peritoneal washings
  • IC: Tumor limited to 1 or both ovaries or fallopian tubes with the following:
    • IC1: Surgical spill
    • IC2: Capsule ruptured before surgery or tumor on ovarian or fallopian tube surface -IC3: Malignant cells in the ascities or peritoneal washings
• Stage II: Tumor involves one or both ovaries or fallopian tubes with pelvic or extra pelvic extension
• Stage III: Involvement of peritoneum
• Stage IV: Distant metastases (excluding peritoneal metastases)

Symptoms

• Irregular bleeding in premenopause
• Pressure symptoms
• Lower abdominal distension
• Dyspareunia
• Acute pain
• Distension due to ascites
• Distension related to omental and intestinal metastasis
• Postmenopausal bleeding

Physical Findings

• Pelvic examination reveals a solid, irregular fixed mass
• Upper abdominal mass
• Ascites
• Palpable ovaries in postmenopausal patients
• Pleural effusion

Diagnostic Evaluation

• Physical examination
• Ultrasound, MRI, CT
• Tumor markers (CA 125, CA 15-3, CA 19-9)
• Cervical cytology
• Endometrial sampling(for patients with irregular menstruation and postmenopausal bleeding complaints)
• Investigation of liver and pancreatic pathologies (in patients without pelvic masses with ascites)
• Laparotomy/Laparoscopy for definitive diagnosis

Why a Successful Screening is Difficult?

• Anatomical localization of ovaries
• No well-defined precursor lesion
• No specific validated diagnostic method that would reduce unnecessary intervention.

CA 125

• Malignant: Increases in endometrial, fallopian tube, germ cell, cervical, pancreatic, breast, and colon cancers.
• Benign: Increases in endometriosis, fibroids, PID, adenomyosis, functional ovarian cysts, and pregnancy
• Also increases in other diseases (kidney, heart, liver)
• High in ~1% of normal women
• Normal value <35. In very few benign conditions >100-200.

Treatment

• Surgery
• Chemotherapy
• Radiotherapy
• Immunotherapy
• Hormone therapy

Treatment-Specific to particular Tumors

• Borderline tumors: Resection of the primary tumor
• Stages IA and IB G1 tumors: Surgery alone is sufficient(Fertility-sparing surgery can be performed)
• Stages IA and IB G2-3 and Stage IC tumors: Surgery plus chemotherapy is required
• Advanced stages: Cytoreductive surgery (debulking) plus chemotherapy is indicated.
• Germ cell tumors: Optimal surgical staging, unilateral salpingo-oophorectomy, Chemotherapy.

Cytoreductive Surgery

• The goal is to achieve a state where there are no residual tumors larger than 1 cm, as this is the best indicator of survival in advanced-stage disease.
• It is not the volume of the remaining tumor cells that determines prognosis, but rather the diameter of the largest residual tumor.

Favorable Prognostic Factors

• Younger age
• Good performance status
• Cell type other than mucinous and clear cell
• Well-differentiated tumor
• Smaller disease volume prior to surgical debulking
• No ascites
• Smaller residual tumor after primary cytoreductive surgery

Non-Epithelial Ovarian Tumors

• Germ cell tumors
  • Mature teratoma
  • Immature teratoma
  • Dysgerminoma
  • Embryonal carcinoma
  • Endodermal sinus tumor
  • Choriocarcinoma
  • Gonadoblastoma
  • Koruyokarsinom

Germ Cell Ovarian Tumors

• The most important feature is that they originate from primitive germ cells and account for ~70% of ovarian tumors seen before the age of 20.
• After the third decade, it is very rare.
• The most commonly seen malignant germ cell tumor is dysgerminoma (~40% of all germ cell tumors).
• When diagnosed, ~60-75% are in stage I.

Dysgerminoma

• Accounts for 1-3% of ovarian cancers and 30-45% of all germ cell tumors.
• Observed in individuals between the ages of 10 and 30, and constitute 20-30% observed during pregnancy.
• Along with dysgerminoma, other germ cell tumors are observed.
• Immature teratoma is the most common.
• 5% of dysgerminomas are associated with abnormal gonads.
• Seen in patients with gonadal dysgenesis and androgen insensitivity.
• 10-15% is bilateral.
• 75% of cases are stage I when diagnosed.

Tumor Markers in Germ Cell Tumors

• Dysgerminoma: AFP (-) β-hCG (-/+) CA 19-9 (-) LDH (-)
• Chorionic carcinoma: AFP (-) β-hCG (+) CA 19-9 (-) LDH (+)
• Immature teratoma: AFP (-) β-hCG (-) CA 19-9 (+) LDH (+)
• Endodermal sinus tumor: AFP (+) β-hCG (-) CA 19-9 (+) LDH (-)
• Embryonal carcinoma: AFP (+) β-hCG (-) CA 19-9 (-) LDH (+)

Treatment of Germ Cell Tumors

• The most commonly encountered germ cell ovarian cancer occurs in 75% of cases between the ages of 10 and 30, with 75% being in stage I
• Treatment outlines that preserve the patient's fertility as much as possible and provide the longest survival include:
  • Optimal surgical staging
  • Unilateral salpingo-oophorectomy
  • Chemotherapy

Treatment: Other considerations

• Examine the other ovary if a suspicious lesion is found.
• Resect the suspicious lesion while preserving normal ovarian tissue.
• If fertility is not desired, consider radical surgery.
• If there are dysgenetic gonads, perform bilateral oophorectomies, while preserving uterus.
• Is pelvic/para aortic lymphadenectomy necessary?
• Dysgerminomas most often spread through the lymphatic system (near the renal vein). Since dysgerminoma is sensitive to chemotherapy, sampling is sufficient.
• How should management be in a pregnant patient?
  • Stage IA: Remove the tumor, pregnancy continues
  • Other stages: Treat based on gestational age. Conservative surgery is performed(followed by chemotherapy)
• Which patients have highest risk of recurrence?
  • Under age 20
  • Mass larger than 15 cm
  • Rupture of mass during surgery
  • Lymphatic involvement

Immature Teratoma

• They account for 20% of germ cell ovarian tumors.
• Ovaries account for 10-20% of cases in women under 20.
• Responsible for over 30% of deaths from ovarian cancer in this age group.
• Average age of onset is 18
• In 70% cases, stage I upon diagnosis.
• Rare in bilateral cases.
• 5% of cases contain benign cystic teratoma in the other ovary, resulting in potential errors regarding metastasis.

The Importance of "Grade" in Immature Teratoma

• Histological classification based on neural tissue maturation
  • Grade I: 0–1 immature cells
  • Grade II: Immature cells in less than 3 areas
  • Grade III: Immature cells in more than 3 areas
• Grade III tumors which contain malignant squamous components have worse prognoses.
• Treatment: Surgical staging & unilateral salpingo-oophorectomy, biopsy of the other ovary not necessary. Chemotherapy for all tumors other than stage I.

Endodermal Sinus Tumor

• Accounts for 20% of germ cell ovarian tumors
• 15% ipsilateral ovary, 5% opposite ovary with dermoid cyst.
• Average age of onset is 18
• 75% of cases involve pelvic pain.
• Treatment: Unilateral salpingo-oophorectomy.
• Total abdominal hysterectomy(TAH) will not affect prognosis.
• AFP is a good tumor marker.

Granulosa Cell Tumors

• They make up 70% of sex cord stromal cell tumors.
• Seen in every period from childhood to senility.
• Two types: adult and juvenile.
• Adult type in 95% all cases, juvenile type in the prepubertal period.
• Tumors with low malignant potential
• 30% associated with endometrial hyperplasia
• 10% associated with endometrial cancer.
• 80-90%- Stage I on diagnosis.
• (2–5%) Bilateral tumors.

Granulosa Cell Tumors (Juvenile Type)

• At the time of diagnosis, approximately 90% are stage IA-IB.
• Childhood brain tumors account for 5-7% of all tumors.
• 5% bilateral.
• Observed before ~90% of puberty.
• Associated with peripheral precocious puberty (pseudo-precocious puberty)
• E2, progesterone, testosterone ↑; FSH-LH↓
• 10% of cases with acid, 10% with tumor rupture.

TM Markers

• E2
• Inhibin
• Follicle regulatory protein (FRP)
• Müllerian inhibiting factor (MIF)

Treatment-Prognosis

• Treatment for granulosa cell tumors is adjusted according to the age at diagnosis and desire for fertility.
• Fractional curettage is essential in perimenopausal and postmenopausal periods.
• If fertility is to be preserved. USO + surgical staging.
• 5-year survival (adult type): Stage I (92–100%), Stage II–III (33–53%).
• 10-year survival (juvenile type): Stage I (97%).
• Prognosis is better in cases with false precocious puberty (early diagnosis).

Fibro-Thecoma

• Considered benign.
• Almost always one-sided
• Conservative surgery performed.
• Associated with endometrial hyperplasia and cancer.
• May cause Meigs syndrome and Gorlin syndrome.

Sertoli-Leydig Cell Tumors

• Very rare (~0.5% of all ovarian tumors)
• Average age of onset is 25; 10% seen after age 50
• 1% bilateral
• Feminization/masculinization in ~75-85% of cases.
• Treatment with USO + surgical staging is sufficient.
• Poor prognosis if tumor contains a "reticular" pattern, or extra-ovarian spread at time of diagnosis or heterologous mesenchymal differentiation.

Metastatic Tumors of the Ovary

• Ovaries are the most frequently metasized organs among genital organs
• Can originate from thyroid, stomach, breast, colon, and gallbladder
• ~10% of all ovarian tumors are metastatic tumors.

Metastatic Tumors of the Ovary (continued)

• ~50% of cases from gastrointestinal system and ~83% of those from breast, are in reproductive period on diagnosis.
• Young patients with ascites, either bilateral or unilateral ovarian lesions, should be evaluated for potential metastatic ovarian involvement.
• Laparoscopy is the method of choice for differential diagnosis.

Common Metastatic Sites

• Gastric
• Primary colorectal
• Breast
• Gynecologic carcinomas
• Krukenberg tumor

Screening

• Effective screening strategies for the early detection of ovarian cancer do not exist.
• Women with high risk of developing ovarian cancer (germline mutations in BRCA1 or BRCA2) may undergo risk-reducing surgery (bilateral salpingo-oophorectomy).
• Screening strategies in women with average risk use CA125, and transvaginal ultrasonography. These methods may detect early stage cancers, but don't improve patient mortality.

Primary Fallopian Tube Carcinoma (FTC)

• Tumors primarily located in the fallopian tube, arising from endosalpinx.
• Papillary pattern of tubal mucosal involvement, with identifiable transition from benign to malignant epithelium.
• Can be concurrent in ovaries or endometrium, but should be smaller than those in the fallopian tube.
• Approached and managed similarly to ovarian cancers due to similar clinical and histologic features.

Fallopian Tube Carcinoma (continued)

• Two-thirds of cases occur in the postmenopausal period.
• Average age is 60-69.
• Histological types:
  • Serous
  • Mucinous
  • Endometrioid
  • Undifferentiated
  • Transitional carcinomas

Diagnostic Criteria

• Diagnosis in advanced stages, mostly postoperatively.
• The main tumor arises from the endosalpinx.
• The histologic pattern resembles tubal mucosa.
• Transition from benign to malignant tubal epithelium is demonstrable.
• If both tube and ovary affected, larger part of tumor is in the tube.

Incidence

• Fallopian tube carcinomas have clinical and histopathologic features similar to primary peritoneal and high-grade serous carcinomas.
• They represent 1-2% of all gynecologic malignancies.
• Incidence is reported at 0.41 per 100,000 annually.

Epidemiology and Risk Factors

• Primary fallopian tube cancer thought to emerge from chronic tubal inflammation.
• Data on risk factors are limited.
• Postmenopausal progestin-based hormonal therapies (estradiol combined with levonorgestrel-releasing intrauterine system) and sequential estradiol-progestin therapy are associated with higher risk.
• Demographic risk factors: age and race (majority of cases in white women aged 50-60).
• Family history of fallopian tube cancer, BRCA 1 mutations, and Lynch syndrome are also associated with increased risk.
• Use of birth control pills and an increased number of pregnancies are likely protective factors.

Risk Factors (continued)

• BRCA1 and BRCA2 mutations in primary FTC (11% and 5% of cases respectively)
• Chronic tubal inflammation
• Infertility
• Tubal endometriosis
• Tuberculous salpingitis
• Families with high risk of breast and ovarian cancer
• Ethnicity (Ashkenazi Jews)

Signs and Symptoms

• Presenting symptoms are vague but can include: abdominal bloating, fullness, difficulty eating, bowel or bladder changes, pelvic/abdominal pain, and bleeding or watery vaginal discharge (Latzko triad)
• Postmenopausal vaginal bleeding, which may suggest fallopian tube or endometrial carcinoma.
• Watery vaginal discharge (hydros tubae profluens) in ~5% of cases.

Diagnosis

• Imaging, blood work (CA-125), and biopsy confirm.
• Sausage-shaped or cog-and-wheel appearance on imaging.
• Diagnosis can be delayed up to 48 months.
• Ovaian malignancy algorithm(ROMA) to assist in distinguishing malignant from benign masses(assesses CA-125, human epididymis protein 4 (HE4), and menopausal status.)

Staging and Grading

• Shows similarity to ovarian carcinoma, using FIGO staging system (most recently updated in 2014).
• Categorized as low-grade or high-grade serous carcinoma.
• High-grade types are associated with advanced stage and TP53 and BRCA mutations..
• Low-grade types are less common and associated with KRAS and BRAF mutations.

Treatment

• Surgical resection is the primary treatment, with adjuvant therapy required in some cases
• TAH + BSO + omentectomy + pelvic and paraaortic lymphadenectomy

Keynotes for FTC

• Triad of pain, metrorrhagia and leukorrhea are considered pathognomonic for FTC.
• BRCA1 and BRCA2 carriers should undergo extensive fallopian tube-sectioning during risk-reducing surgery.
• Serous Tubal Intraepithelial Carcinoma is a precursor lesion to high-grade serous carcinoma.
• Early salpingectomy with delayed oophorectomy currently being studied for potential high-risk women.

Genetic Screening

• American Cancer Society recommends genetic testing for:
  • Individuals with known familial history of BRCA mutations.
  • Individuals with ovarian, pancreatic, or a family history of breast cancer at a younger age.
  • Those with more than one family member with breast cancer
  • Individuals with male breast cancer.