ovarian and uterine tumors -- Oncology

1. Ovarian and Uterine Cancer
Lara Masri

2. Ovaries histology
• Surface epithelium also called
germinal epithelium covers the
ovaries.
• Stroma: comprises bulk of
ovarian connective tissue that
binds structures together an
enriched with blood vessels,
cells, and several hundred
thousand follicles.
• Follicles: small sacs filled with
fluid that are found inside a
woman's ovaries. They secrete
the hormones. Each has the
potential to release an egg for
fertilization

3. Ovarian Cancer
Epidemiology:
• Ovarian tumors are the most common ovarian mass in women > 55 years of age. ( In
young women, follicular cysts are the most common ovarian mass)
• Ovarian cancer is the second most common gynecological cancer (after endometrial
cancer) but causes the most deaths (with endometrial cancer causing the second most).
• Median age at diagnosis of ovarian cancer: 63 years
• Metastases to the Ovaries mostly from endometrium, breast, Colon, Stomach and cervix

4. Risk factors
 General
o Age
o Asbestos
 Genetic predisposition
o BRCA1/BRCA2 mutation: The lifetime risk of developing ovarian cancer is up to
44% for BRCA1-positive women and 17% for BRCA2-positive women.
o HNPCC syndrome: The lifetime risk of developing ovarian cancer is ∼ 10%.
o Family history
o Peutz-Jeghers syndrome
o Cowdens Disease
o Lynch syndrome
 Hormonal factors
o Elevated number of lifetime ovulations
 Infertility/low number of pregnancies
 Early menarche and late menopause
o Endometriosis
o Polycystic Ovarian Syndrome (PCOS)

5. Protective Factors:
These are conditions that decrease the total number of lifetime ovulations
• OCP
• Chronic anovulation
• Breast feeding
• Short reproductive life
• Bilateral Salpingo-oophorectomy
• Hysterectomy
• Tubal Ligation

6. Types of ovarian cancer
The ovaries contain 3 main kinds of cells:
1. Epithelial
2. Germ cells
3. Stromal cells
Each of these cells can develop into different types of tumors.
Subsequently, there are 3 types of ovarian tumors:
• Epithelial ovarian tumors
 Most commonly benign
• Germ cell ovarian tumors
 Can be benign or malignant
 Subtypes are determined by structural differentiation
1. Extraembryonic differentiation: yolk sac tumor
2. Somatic differentiation: teratoma
3. No differentiation: dysgerminoma
• Sex cord and stromal ovarian tumors

8. Epithelial Ovarian tumors:
• Most common ovarian cancer – 90%
• Derive from ovarian epithelial lining
• Often spread directly into peritoneum
• Classic presentation is adnexal mass
• May cause vague abdominal symptoms
o Bloating
o Early satiety
o Pelvic/abdominal pain
• Average age at diagnosis: 63 years old

9. CA-125
Cancer Antigen 125
 Biomarker for epithelial ovarian cancer ( increase only in epithelial cell carcinoma)
 Poor performance for screening
 Useful in evaluating adnexal mass
 Over 35 units/mL is abnormal
 Over 200 units/mL concerning for malignancy
 Useful in monitoring response to treatment
 Serial measurement for follow-up
 CA-125 is used as a tumor marker for epithelial ovarian cancer but can also be
elevated in endometriosis, cirrhosis, and malignancies (e.g., uterine leiomyoma).

10. •Histological classification
• Benign
• Borderline ovarian tumors
• Malignant
•Clinicopathological classification [20]
• Type I ovarian tumors: low-grade, indolent tumors that typically manifest as
large, unilateral, cystic neoplasms
• Histologic subtypes include low-grade serous, endometrioid, clear
cell, mucinous carcinomas, and malignant Brenner tumors
• Account for ∼ 10% of ovarian cancer deaths
• Associated with low levels of chromosomal instability
• p53 mutations are uncommon.
• Type II ovarian tumors: high-grade, aggressive tumors that typically involve
both ovaries and are diagnosed at an advanced stage
• Histologic subtypes include high-grade serous, carcinosarcoma, and
undifferentiated carcinoma
• Account for ∼ 90% of ovarian cancer deaths
• Associated with high levels of chromosomal instability
• p53 mutations are common

11. epithelial ovarian tumors
1- Cystadenoma
1. Ovarian Serous Cystadenoma
2. Ovarian mucinous Cystadenoma
• Benign
• Most (serous) and second most common (mucinous) benign ovarian tumor
• Typically asymptomatic
• Symptoms of abdominal displacement may be present (e.g., pain, ↑ urinary frequency)
• Ultrasound appearance:
 Serous  unilocular cystic mass
 Mucinous  Large multilocular cystic tumor
• Gross Examination
 Serous  cysts with watery fluid
 Mucinous  smooth with gelatinous material
• Histology
 Serous  May contain small papillary projections, Psammoma bodies, Cyst is lined
by serous epithelial cells
 Mucinous  Cyst is lined by columnar epithelium that secretes thick mucus
(similar to the epithelium of cervix)

13. 2- Brenner Tumor
• Benign
• Rare
• Ultrasound appearance:
 Mostly small tumors with a solid component and
calcifications
• Gross Examination
 Encapsulated, Pale yellow solid tumor
• Histology
 Similar to transitional cells of the bladder
(urothelium)
 Circular patches of cells with coffee bean nuclei

14. 3- Cystadenocarcinoma
1. Ovarian Serous Cystadenocarcinoma
 High grade ( Most aggressive)
 Low Grade
2. Ovarian mucinous Cystadenocarcinoma
• Malignant
• Often Bilateral
• Serous Cystadenocarcinoma is the most common malignant
ovarian tumor
• mucinous Cystadenocarcinoma is rare and can be metastatic
from GI cancer
• Acute abdominal pain
• Pseudomyxoma peritonei

15. Pseudomyxoma Peritonei
• Rupture of a mucinous cystadenoma or cystadenocarcinoma leading to the spread of
tumor cells throughout the peritoneum.
• Mucinous cells cause gelatinous ascites and intraabdominal adhesions.
• Mucinous appendiceal tumor

16. 4- Endometrioid Carcinoma
• Malignant
• 10% of epithelial tumors
• Concomitant endometrial carcinoma in 10–15% of cases
• Associated with endometriosis
• Good prognosis  Sensitive to chemotherapy
• Pelvic pain
• Symptoms of abdominal displacement may be present (e.g., pain, ↑ urinary frequency)
• Abnormal vaginal bleeding
• Gross Examination
 Smooth surface with cystic spaces filled with blood-stained fluid (
 Completely solid with necrosis/hemorrhage
Any Para-umbilical mass become painful, increased in size and bleeding during menstrual
period is endometriosis until proven otherwise.

17. 4- Clear Cell Tumor
• Malignant
• 5-10% of epithelial tumors
• Most commonly occur in perimenopausal women.
• Associated with endometriosis
• Pelvic pain
• Symptoms of abdominal displacement may be present (e.g., pain, ↑
urinary frequency)
• Abnormal vaginal bleeding
• Gross Examination
 Endometriosis associated tumors are filled with chocolate colored
fluid.

18. Germ cell tumors  5%  Predominantly occurs in Teenagers
1- Teratoma
1. Dermoid Cyst ( mature cystic teratoma)
2. Struma Ovarii ( mature teratoma)
3. Immature teratoma
Dermoid Cyst
• Benign
• Most common of all germ cell tumors
• Most common ovarian tumor in women < 30 yr
• Asymptomatic
• Contain hair, squamous cells, sebaceous (oily) material
• Walls may contain calcification, tooth-like material
• Up to 20% bilateral
• High fat content makes tumors mobile
• Commonly lead to ovarian torsion
• May also rupture → peritonitis
• Small risk (< 1%) of malignant transformation( Squamous cell carcinoma most
common )
• Usually removed surgically to avoid complications
• No tumor marker

19. Struma Ovarii
• Benign
• 5% of all ovarian teratomas
• Mostly Asymptomatic
• Symptoms of hyperthyroidism ( <10%)
• Endodermal differentiation into thyroid tissue
• No tumor marker
Immature Teratoma
• Malignant, aggressive
• Rare
• Women <20 yr.
• Unspecific symptoms  amenorrhea
• Composed of immature neuroectodermal tissue
• Tumor markers ( rare)  LDH, AFP

20. 2- Dysgerminoma
• Most common MALIGNANT ovarian germ cell tumor
• Rapid growth
• Acute onset of symptoms
• Microscopic exam show central neuclei surrrounde by clear cytoplasm arrange
lobule separate by fibrovascular septa ( Fried egg cells)
• Tumor marker  LDH
3- Yolk sac tumor ( endodermal sinus tumor)
• Malignant
• Rapid growth
• Acute onset of symptoms
• Occurs mainly in children and adolescents
• Macroscopic appearance: yellow, friable mass (due to hemorrhage), Schiller-Duval
bodies (resemble glomeruli on microscopy)
• Tumor marker  LDH
4- Nongestational Choriocarcinoma
• Malignant
• Made of germ cells that turn into syncytiotrophoblast which are the ones that help form
the placenta Small, highly vascular tumer so it bleed easily and mets early
• hCG

21. Sex Cord-Stromal Tumors
1- Ovarian fibroma
• Benign
• Postmenopausal
• Lower abdominal discomfort and/or a pulling-sensation in the inguinal area
• May be associated with Meigs syndrome: ascites and pleural effusion in association
with a benign ovarian tumor.
• Usually unilateral
• Fibroblasts ( Histology)
2- Theca Cell Tumor (Thecoma)
• Benign
• Postmenopausal
• Abnormal postmenstrual bleeding due to estrogen production

22. 3- Sertoli – Leydig cell tumor
• Usually Benign ( 20% higher grade )
• Rare
• 30-40 yr.
• Symptoms of excessive androgens and/or estrogen production
 ↑ Testosterone
o Virilization, hirsutism, acne, temporal balding (male pattern)
o Amenorrhea, clitoromegaly, ↓ fertility
 ↑ Estrogen
o Menstrual bleeding abnormalities
o Endometrial polyps and hyperplasia
• Small, Yellow-brown
• Histology  Seminiferous-like tubules lined by Sertoli cells and Reinke crystals

23. 4- Granulosa Cell Tumor
• Malignant
• Most common type of sex cord malignancies ( 90%)
• 50 – 55 yr.
• Symptoms caused by estrogen and/or progesterone secretion
 Adult subtype: menstrual irregularities (e.g., postmenopausal bleeding, endometrial
hyperplasia)
 Juvenile subtype: precocious puberty
• Breast tenderness
• Associated with increased risk of endometrial cancer
• Histology  Call-Exner bodies: granulosa cells arranged in clusters surrounding a central
cavity with eosinophilic secretions, resembling primordial follicles
• Tumor Marker  Inhibin A,B
• Increased incidence of endometrial tumors, Breast CA
• Endometrial Biopsy is gold standard test to rule out endometrial malignancy

24. Krukenberg tumor
• secondary ovarian tumor that most commonly arises
from metastatic spread of gastric carcinoma
• Often bilateral
• Characteristic mucin-secreting signet ring cells on
histology

25. Diagnosis
Pelvic ultrasound  Imaging test of choice for evaluation of adnexal masses and suspected
ovarian cancer
Tumor Markers:
• Premenopausal women: Elevated CA-125 points to a benign process.
• Postmenopausal women: Elevated CA-125 > 35 units should raise concern for malignancy.
• Should only be used to monitor disease progression or recurrence after treatment
Tissue Diagnosis
• Noninvasive biopsy: not recommended due to the risk of tumor seeding and, as a result,
advancing the stage of disease [62]
• Surgical evaluation
• Recommended method for diagnosing ovarian cancer [63]
• Should only be utilized in patients with a high probability of a malignant ovarian mas
Fine needle aspiration is absolutely contraindicated in ovarian tumors because it may directly
spread tumor cells to the peritoneum!

26. FIGO Staging

28. Treatment
• Surgery
 Surgery is often the initial treatment of choice for ovarian cancer, provided
patients are medically fit.
 The aim of surgery is to confirm the diagnosis, define the extent of disease, and
resect all visible tumor.
 If the patient does not desire future fertility, perform a total abdominal
hysterectomy and excise the opposite ovary. Appendectomy can be performed if a
mucinous tumor is present.
 Surgical staging: used to obtain pathologic specimens and evaluate the extension
of cancer spread
1. Peritoneal cytology
2. Hysterectomy with bilateral salpingo-oophorectomy
3. Pelvic and paraaortic lymph node dissection
4. Omentectomy
 Surgical debulking: Whenever possible, maximal cytoreduction (i.e., removal of
visible tumor) should be completed to improve long-term outcomes.

29. • Chemotherapy
 Carboplatin/paclitaxel  Carbo-Taxol
 Higher-risk early-stage disease includes all histologic subtypes with
stage IA and stage IB grade 3 or IC any grade These patients are
usually treated with front-line chemotherapy with a
taxane/platinum combination for a minimum of three courses

30. Recurrent Disease
platinum refractory  Progression of the disease during chemotherapy treatment.
Platinum-sensitive  Complete response to chemotherapy but recurrence occur after 6
months
platinum-resistant  Complete response to chemotherapy but recurrence occur before 6
months

31. There is no current screening test for ovarian cancer

32. Endometrial Cancer
• Endometrial cancer is the most common cancer of the female genital tract in the
US.
• 4th most common cancer in women
• Peak incidence between 65 and 74 years of age ( Disease of Postmenopausal
women)
• Two types based on histological characteristics
1. Type I endometrial cancer 80%: endometrioid adenocarcinomas
(grade 1 and 2) derived from atypical endometrial hyperplasia.
2. Type II endometrial cancer 20% : endometrioid adenocarcinomas
(grade 3) and tumors of nonendometrioid histology (serous, clear cell,
mucinous, squamous, transitional, and undifferentiated cells)

34. Etiology
 Type I endometrial cancer
• Directly related to long-term exposure to increased estrogen levels
• Some genetic mutations (e.g., in the PTEN gene or mismatch repair genes)
 Type II endometrial cancer
• Mostly estrogen-independent
• Associated with endometrial atrophy (especially in postmenopausal women)
• Strongly associated with a genetic predisposition ( p53 mutation)
Risk factors for estrogen-dependent tumors
1. Nulliparity
2. Early menarche and late menopause
3. Polycystic ovary syndrome
4. Metabolic syndrome (esp. obesity and diabetes mellitus type 2 )
5. Hypertension
6. Unopposed estrogen replacement therapy (e.g., for menopausal symptoms)
7. History of breast cancer and tamoxifen treatment
8. Lynch syndrome

36. Related to mutations in genes :
1. PTEN : tumor suppressor gene
2. PIK3CA : oncogene
3. ARID1A: regulate chromatin structure
4. CTNNB1
5. KRAS
6. No Tp53 mutation except in grade III .
All these mutations increase the signaling in the PI3K/AKT pathway.
• PI3K/AKT pathway promote growth and replication of endometrial cells.
• More signaling increases the expression of genes linked to estrogen receptors , so
having high levels of estrogen will cause endometrial hyperplasia , leading to increase risk
of developing endometrial intraepithelial neoplasia (EIN) then adenocarcinoma .

37. Clinical Features
• Abnormal uterine bleeding is the main symptom.
o Postmenopausal: any amount of vaginal
bleeding, including spotting or staining
o Perimenopausal/premenopausal:
metrorrhagia, menometrorrhagia
o Vaginal bleeding usually does not occur in
type II cancer.
• Later stages may present with pelvic pain,
palpable abdominal mass, and/or weight loss.
• Pelvic exam is often normal. Possible findings
include:
o Abnormal cervix
o Enlarged uterus
o Evidence of local metastases
The majority of endometrial cancers are diagnosed
at an early stage and have a good prognosis.

38. Types
Endometrioid adenocarcinoma  Well differentiated
 Type I endometrial carcinoma
 Type II endometrial carcinoma
Tumors of nonendometrioid  poorly differentiated
 Serous adenocarcinoma (contains psammoma bodies and papillary structure with
tufts)  Always High Grade
 Clear cell adenocarcinoma  High Grade always
 Mucinous adenocarcinoma
 Squamous cell carcinoma; rare with poor prognosis
 Undifferentiated carcinoma

39. Diagnosis
Laboratory tests
• CBC: anemia
• Coagulation studies: assessing other possible causes of heavy uterine bleeding
Imaging
Transvaginal ultrasonography
• Considered to be the first diagnostic step by some experts since it is noninvasive and
enables initial assessment
• Findings
 Thickening of the endometrium
 Cystic changes, variable echogenicity
 Possibly visible tumor infiltration into neighboring organs
Abdominal ultrasonography: A complete abdominal ultrasound is indicated to exclude
metastasis.
Chest x-ray, CT, MRI: assessment of metastatic spread (lungs, pelvis)

40. Endometrial biopsy with histology
Procedures
• Endometrial sampling: most commonly performed as part of a pelvic exam
• Hysteroscopy-guided biopsy
• Dilatation and curettage
Results
• Endometrial hyperplasia, with or without atypia
• Pronounced proliferation of disorganized glandular tissue (characteristic of
endometrial adenocarcinoma)
• If there is no detectable pathology on biopsy and if no further symptoms occur,
endometrial cancer can be ruled out.

41. FIGO Staging of Endometrial Carcinoma

43. Management
Surgical management
Indication: women with endometrial cancer who are postmenopausal, perimenopausal, or do
not intend to become pregnant
Procedures
• Total hysterectomy with bilateral salpingo-oophorectomy (TAH/BSO) with or without
lymph node removal
• Advanced radical hysterectomy and removal of the upper vagina according to
Wertheim-Meigs additional
Nonsurgical management
Progestins: Indicated for women with early stage endometrial carcinoma (well-differentiated
and progesterone and estrogen receptor positive) , who would prefer to avoid TAH-BSO and
preserve fertility, or as adjuvant therapy
Radiotherapy and/or chemotherapy (adjuvant or palliative)