1. MALIGNANT DISORDERS OF THE OVARIES
Assoc. Prof. Gazi YILDIRIM, M.D.
Yeditepe University, Medical Faculty
Dept of Ob&Gyn

2. Objectives To define To learn To manage Ovarian cancer
Risk factors for ovarian cancer
Prognostic factor for ovarian cancer
Diagnosis of ovarian cancer
To manage
A woman with ovarian cancer

3. The 5. most common cancer in women
The 5. most frequent cause of cancer death
Lifetime risk 1/70

8. 5-year survival rate
<35%
Mortality has
decreased only
slightly in 30 years
Most diagnosis
made at advanced
disease

9. >90% of ovarian cancer develops sporadically.
RISK FACTORS
Cause of Ovarian Cancer
is unknown
Risk Factors
High socio-economic status
Early menarche
Late menopause
Few children
Never used oral contraceptive
Genetic (10%)
Environment???
Dietary factors
Exposure to talc
Exposure to asbestos
>90% of ovarian cancer develops sporadically.
~10% of epithelial ovarian cancers are based on genetic predisposition.

10. GENETIC PREDISPOSITION
Chromosomal abnormalities
Turner syndrome
Dysgerminoma, gonadoblastoma
Hereditary ovarian cancer
BOC (breast and ovarian cancer syndrome)
BRCA-1 mutations on chromosome 17 and less commonly BRCA-2 mutations on chromosome 13.
Lynch II syndrome (HNPCC syndrome)
DNA mismatch repair gene mutations
Colon ca, ovarian-endometrial-breast cancer
Acquired genetic abnormalities
P53 tumor supressor gene mutations, HER2/neu proto-oncogene activation

11. Genetic Predisposition: 5-10% 0f Ovarian Cancer
Carriers of BRCA1 or BRCA2:
40% risk of ovarian cancer
BRCA1 and 2 Germ line mutations:
10% of all ovarian cancers
1-2% of all breast cancers

12. HISTOPATHOLOGY OF OVARIAN CANCER
5% of ovarian cancer arises from metastases!!
(breast, colon, stomach, endometrium, lymphoma)

13. EPITHELIAL NEOPLASMS
Derived from the ovarian surface mesothelial cells.
Serous
Mucinous
Endometrioid
Clear cell
Transitional cell
Undifferentiated
Account >60% of all ovarian neoplasms and >90% of malignant ovarian tumors.

14. Serous Neoplasms Most common malignant tumor of the ovary.
35-50% of all epithelial tumors.
Bilateral in of cases.
Extraovarian spread at the time of diagnosis in 85% of cases.
Cut section: solid areas,areas of hemorrhage,necrosis, cyst wall invasion and adhesions to adjacent structures.

15. Histology- serous carcinoma
Mild to moderate nuclear atypia
Psammoma body (irregular calcifications)
The grade of differentiation is based on the degree of preservation of the papillary architecture.

16. Mucinous Neoplasms
Account for 10-20% of all epithelial ovarian neoplasms
The second most common type of epithelial ovarian cancer.
Bilateral in <10% of cases (in contrast to serous tumors!!!!)

17. Large size
(~16 cm)
Cut sections: multilocular cysts filled with viscous mucin.

18. Histology- mucinous carcinoma
Composed predominantly of intestinal-like cells that invade surrounding stroma.
Invasive tumors exhibit marked histologic variability from area to area within the tumor.
The differentiation is based on the preservation of the glandlike architecture of the tumor.
Extensive sampling required !!

19. Pseudomyxoma peritonei
Resulting from the progressive accumulation of mucin in the abdominal cavity.
Most commonly in association with low malignant potential.
Also with cystadenocarcinoma of the ovary and appendix, mucocele of the appendix.
*potentially morbid secondary to repeated bowel obstruction.

20. Endometrioid Neoplasm
Exhibits an adenomatoid pattern that resembles endometrial adenocarcinoma.
Bilateral in 30-50% of cases.
Arises rarely in foci of endometriosis (<10% of cases).
The degree of differentiation is based on the extent to which the glandular architecture is retained.
In 30% of cases, there is a synchronous endometrial carcinoma of the uterus
A second primary rather than a metastatic focus !!!

21. Clear Cell Carcinoma Also referred to as mesonephroid carcinoma
Biologically aggressive hypercalcemia and hyperpyrexia
Difficult to differentiate from mucinous neoplasms the periodic acid-Schiff reaction only weakly (+) in clear cell carcinoma; strikingly (+) in mucinous tumors.

22. Transitional Cell (Brenner) Carcinoma
Composed of cells that resemble low-grade transitional cell carcinoma of the urinary bladder.
Typically diagnosed at advanced stage disease
Poorer prognosis when compared with that of other histologic types of epithelial ovarian cancer.

23. Undifferentiated Carcinoma
<10% of epithelial neoplasms.
Characterized by the absence of any distinguishing microscopic features that permit its placement in one of the other histologic categories.

24. GERM CELL NEOPLASMS Arise from the germ cell elements of the ovary.
Dysgerminoma
Endodermal sinus tumor
Embryonal cell carcinoma
Choriocarcinoma
Teratoma
Polyembryoma
Mixed germ cell tumors
Occur during the second and third decades of life.
Produce biologic markers which can be monitored to assess response to therapy.

25. Tumor Markers that may be elevated in the presence of Germ Cell Neoplasms
AFP
hCG
Dysgerminoma -
+/-
Endodermal sinus tm +
Immature teratoma
Mixed germ cell tm
Choriocarcinoma
Embryonal carcinoma

26. Dysgerminoma The female counterpart of the seminoma in the male.
Young females
30-40% of germ cell tumors.
Unilateral in 85-90% of cases.

27. Endodermal Sinus Tumor
Second most common germ cell tumor (20%).
Bilateral in <5% of cases.
The most rapidly growing neoplasm !!
Commonly present with an acute abdomen.
Pathognomic finding: Schiller-Duval body
AFP(+)

28. Immature Teratoma
The malignant counterpart of the mature cystic teratoma or dermoid.
20% of germ cell tumors.
Bilateral in <5% of cases, although the contralateral ovary commonly contains a dermoid cyst
Immature elements: commonly neuroectodermal

29. Mature Teratoma (Dermoid)
Common
20-30 years
The most common tumor diagnosed during pregnancy.
Rarely, the squamous component undergoes malignant transformation over the age 40. (<2%)

30. Embryonal Carcinoma Younger patients (mean age of 14 years)
Epithelial cells resembling those of the embryonic disc.
Typically produce hCG
75% also secrete AFP.

31. Choriocarcinoma
Primary ovarian choriocarcinoma arises from a germ cell similar in appearance to gestational choriocarcinoma.
Nongestational tumors: poorer prognosis
* The detection of other germ cell components indicates nongestational tumors!

32. Gonadoblastoma
Rare tumor composed of nests of germ cells and sex cord derivatives.
More common in the right ovary.
Usually during the second decade of life.
Found in patients with abnormal gonadal development in the presence of a Y chromosome.

33. Mixed Germ Cell Tumors 10% of germ cell neoplasms.
Contain ≥2 germ cell elements.
Dysgerminoma and endodermal sinus tumor occur together most frequently.

34. SEX CORD-STROMAL TUMORS
Heterogeneus group of rare neoplasms originating from the ovarian matrix.
cells within matrix have potential
for hormon production.
Signs and symptoms of
estrogen or androgen excess.

35. Granulosa Cell Tumors 1-2% of all ovarian tumors.
The most common malignant tumors of the sex cord-stromal tumors.
Hyperestrogenism
Call-exner bodies
Precocious puberty in young girls
Endometrial hyperplasia and vaginal bleeding in postmenopausal women

36. Thecoma Benign Hyperestrogenism Lipid-laden stromal cells
Typically develop in postmenopausal women in their mid-60s.
Yellow color on cut section

37. Mimic the presentation
Fibroma
Benign
Meigs’ Syndrome
Ovarian fibroma
Ascites
Pleural effusion
Hormonally inactive
Mimic the presentation of
ovarian cancer.

38. Sertoli-Leydig Cell Tumors
Rare
Consist of testicular structures at different stages of development.
Usually virilizing
During the third decade of life
Rarely bilateral

39. Tumors metastatic to the ovary
25% of all ovarian malignancies.
Clinically mimic the primary ovarian cancer
Usually present as bilateral adnexal masses
25% of cases unilateral
Most common primary cancers: breast, stomach, colon and endometrium.

40. SYMPTOMS Vague and non-specific !! Abdominal bloating
Indigestion, dyspepsia
Altered bowel habits
Menstruel abnormalities
Pelvic fullness
Pain

41. Evaluation of the patient with a suspected ovarian neoplasm

42. The prepubertal child and the postmenopausal woman
are at greatest risk
for developing a pelvic mass that subsequently proves
to be a malignant ovarian tumor.
The reproductive age woman is
more likely to have
a functional ovarian cyst or
endometrioma.

43. Physical Examination Perform a comprehensive examination.
Attention to the lymph-node-bearing areas
Particularly the supraclavicular and inguinal areas.
Examination of the abdomen
Abdominal distention
The presence of flank fullness and shifting dullness
Tympanitic percussion note over the lateral abdomen
a large mass displacing the bowel to the periphery.
central tympanitic percussion note ascites

44. Characteristics of a pelvic mass on physical examination
BENIGN !!
Mobile
Cystic
Unilateral
Cul-de-sac: smooth
MALIGNANT !!
Fixed
Solid or form
Bilateral
Cul-de-sac:nodular

45. Radiographic Evaluation-I
Ultrasonography
Transabdominal
Transvaginal
Color flow doppler studies
CT retroperitoneal structures,pelvic organs
MRI more information regarding the nature of the ovarian tumor.
High cost and questionable benefit !!!
Particular benefit in the evaluation of pregnant woman.

46. Radiographic Evaluation-II
Radiograph of the chest exclude metastatic parenchymal disease and detect pleural effusion.
Barium enema
Screening mammogram study

47. *Solid or cystic+solid
Radiographic characteristics that help to differentiate benign and malignant adnexal masses
BENIGN
*Simple cyst,
<10 cm in size
*Septations,
<3 mm in thickness
*Unilateral
*Calcification,
especially teeth
*Gravity-dependent
layering of cyst
contents
MALIGNANT
*Solid or cystic+solid
*multiple septations
>3mm in size
*bilateral
*ascites

48. PROGNOSTIC FACTORS Stage !! Grade Cell-type of tumor
Residual disease after surgery
Disease volume prior to any surgical debulking
Age of woman >70
Performance status

49. SCREENING FOR OVARIAN CANCER
NO EVIDENCE
THAT SCREENING WORKS!!
Ultrasound
Transvaginal
Abdominal
Color flow
Tumor Markers:
Ca 125
Protein patterns
Pelvic exam
Genetic screening

50. SURGICAL TREATMENT of epithelial overian cancer
Surgery: the cornerstone of therapy
debulking:
remove as much of the cancer as possible
the less cancer left after primary surgery the better the outcome
the best outcome is when there is no residual disease

51. The most common locations of metastases:
At the time of diagnosis,
>70% of patients with epithelial ovarian cancer
have metastases beyond the pelvis
The most common locations of metastases:
*peritoneum (85%)
*omentum (70%)
*liver (35%)
*pleura (33%)
*lung (25%)
*bone (15%) .
Lymphatic metastasis occurs frequently,
with up to
80% involving pelvic lymph nodes and
67% involving para-aortic lymph nodes,
depending on the stage of cancer.

52. INTRAOPERATIVE DIFFERENTIATION OF BENIGN AND MALIGNANT MASSES
Simple cyst
Unilateral
No adhesions
Smooth surfaces
Intact capsule
MALIGNANT
*Adhesions
*Rupture
*Ascites
*Solid areas
*Areas of hemorrhage
or necrosis
*papillary excrescences
*multioculated mass
bilateral

53. Procedures in the surgical staging of ovarian cancer
Sample of ascites or peritoneal washings from the paracolic gutters and pelvic and subdiaphragmatic surface for cytology
Complete abdominal exploration
Intact removal of tumor
Hysterectomy
Infracolic omentectomy
Biopsies of abdominal peritoneal implants; if present, random biopsies from the paracolic gutter peritoneum,pelvic peritoneum,and right subdiaphragmatic peritoneal surface
Pelvic and para-aortic lymph node biopsies
Cytoreductive surgery to remove all visible disease

54. FIGO staging of ovarian cancer
Stage 1: growth limited to ovaries
1a: one ovary involved
1b: both ovaries involved
1c: 1a or 1b and ovarian surface tm, ruptured capsule, malignant ascites, or peritoneal cytology (+) for malignant cells
Stage 2: extension of the tm from the ovary to the pelvis
2a: extension to the uterus or fallopian tube
2b: extension to other pelvic tissues
2c: 2a or 2b and ovarian surface tm, ruptured capsule, malignant ascites, or peritoneal cytology (+) for malignant cells

55. Stage 3: disease extension to the abdominal cavity
3a: abdominal peritoneal surfaces with microscopic metastases
3b: tm metastases < 2 cm in size
3c: tm metastases > 2 cm in size or metastatic disease in the pelvic, paraaortic or inguinal lymph nodes
Stage 4: distant metastatic disease
Malignant pleural effusion
Pulmonary parenchymal metastases
Liver or splenic parenchymal metastases (not surface implants)
Metastases to the supraclavicular lymph nodes or skin

56. SURGICAL TREATMENT of germ cell neoplasms
Early stage at the time of diagnosis
Low incidence of bilaterality
Young age of patients
Fertility sparing surgery
by removal the involved adnexa

57. CHEMOTHERAPY of epithelial ovarian cancer
All other patients,except stage Ia and grade I tumors, should undergo systemic chemotherapy.
Agents against epithelial ovarian cancer:
Cisplatin
Carboplatin
Cyclophosphamide
Paclitaxel
Combination
therapies !!

58. changes in the CA-125 level.
Assessment of response
to combination chemotherapy is based on
physical examination,
changes in size of palpable or
radiographically measurable lesions and
changes in the CA-125 level.
*an elevated CA-125 level (>35IU/mL)
predicts persistent disease at second look
in >97% of patients.
*a normal CA-125 level does NOT completely exclude
the possibility of residual, subclinical disease.

59. Chemotherapy-associated toxicities
Cisplatin: nephrotoxicity, neurotoxicity, ototoxicity
Carboplatin: thrombocytopenia, neutropenia
Cyclophosphamide: hemorrhagic cystitis, pulmonary fibrosis
Paclitaxel: myelosupression
Altretamine: peripheral neuropathy
Etoposide: myelosupression
Bleomycine: pulmonary fibrosis
Doxorubicin: cardiac toxicity
Vincristine: neuropathy
Ifosfamide: hemorrhagic cystitis, central neurotoxicity

60. RADIATION THERAPY
Limited role in the treatment of epithelial ovarian cancer.
Intraperitoneal P³²
For stage 1c disease
For microscopically (+) second-look operations.
Succesfull in the treatment of dysgerminoma
Dysgermioma: most radiation-sensitive tumor identified.