1. CA OVARY
DR. VARUN
MEDICAL ONCOLOGIST
RGCI DELHI

2. • Epidemiology
• Risk factors
• Pathology and pathogenesis
• Diagnosis
• Screening
• Staging

3. INTRODUCTION
• Ovarian cancer is one of the most treatable solid
tumors, as the majority will respond temporarily
to surgery and cytotoxic agents.
• Tumors of epithelial, germ cell, or sex cord–
stromal origin.
– Epithelial - in postmenopausal women,
– Germ cell tumors - in younger women, and
– Sex cord–stromal tumors - at any age.
• 80- 90% of ovarian cancer is epithelial in origin.

4. Burden of suffering
• 5th most frequent cancer in women worldwide.
• 5th leading cause of cancer death in women in
U.S. (after breast, lung, colon and pancreas)
• MC cause of death arising from a female pelvic
malignancy.
• each year, in the US
– 22,000 new cases of epithelial ovarian cancer
– 15,460 deaths

5. FEMALE—LEADING SITE
Name of Registry Leading Site 2nd Leading site 3rd leading site
Bangalore Breast Cervix Ovary
Barshi Expanded Cervix Breast Ovary
Bhopal Breast Cervix Ovary
Chennai Breast Cervix Ovary
Delhi Breast Cervix Ovary
Mumbai Breast Cervix Ovary
Barshi Rural Cervix Breast Esophagus
Cachar District Breast Cervix Gall bladder
Dibrugarh District Breast ESophagus Gall bladder
Kamrup District Breast Cervix Esophagus

6. INDIAN DATA-- DELHI

7. Trends in Cancer incidence-Female
Registry Leading site in 1982 Now(2006-2008)
Banglore Cervix Breast, Ovary(↑)
Bhopal Cervix Breast, Ovary(↑)
Chennai Cervix Breast, Ovary(↑)
Barshi Cervix Cervix, Lung(↑)
Delhi Cervix Breast, Ovary(3rd)
GB(4th)
Mumbai Breast Breast, Lung(↑)
Ovary(↑)

8. • Overall 5-year survival rate is 45%
• The “silent killer”: asymptomatic in early
stages
– 75% diagnosed with advanced stage disease; 5-
year survival only 10-28%
• Woman’s lifetime risk of
– developing sporadic epithelial ovarian cancer
• 1.7% in developed nations and 0.75% in India.
– dying from ovarian cancer is1.1%

9. • ̴ 25% of ovarian tumors are malignant.
• Approximately 80％ of them are primary
growths of the ovary.
• The remainder being secondary.

10. • Median age at diagnosis
– for sporadic - 60 years,
– With a genetic predisposition (5-10%) - fifth
decade.
• only 10% to 15% - in premenopausal
women

11. Risk Factors

14. BRCA Mutations
• Greater risk of developing ovarian cancer,
• Overall they have superior outcomes
compared with patients who do not possess
these mutations.
• Rubin 1996; Boyd 2000
• The theory behind this observation - same genetic
defect that increases the risk of cancer prevents
already-malignant cells from repairing the damage
induced by agents such as platinum.

15. HNPCC or Lynch Syndrome
• ~7% of hereditary ovarian cancer cases
• Responsible genes: Mismatch repair genes
(MMR) including MLH1, MSH2, and MSH6
• Increased incidence of other
adenocarcinomas, including stomach, small
bowel, and bile duct malignancies (not breast)

16. Protective factors
• Multiparity: First pregnancy before age 30
• Oral contraceptives: 5 years of use cuts risk
nearly in half
• Tubal ligation
• Hysterectomy
• Bilateral oopherectomy -↓ risk by 80% to 95%
• Lactation
• Epidemiologic and laboratory evidence suggest a
potential role for retinoids, vitamin D, NSAIDs as
preventive agents for ovarian cancer

17. PATHOGENESIS
• Role of ovulation (repetitive process of DNA damage,
inflammation, and repair of the surface epithelium) in the
pathogenesis of the malignancy
• Epithelial ovarian neoplasms are thought to
arise from the surface epithelium covering the
ovary.
• As repair follows multiple ovulations, the surface
epithelium of the ovary often extends into the ovarian
stroma to form inclusion glands and cysts.

18. • The epithelium, via neoplastic
transformation, may exhibit
differentiation toward a
variety of müllerian-type cells
– serous  fallopian tubal lining
– mucinous
• Intestinal  gastrointestinal
mucosa
• Müllerian  endocervix
– Endometrioid  endometrial
glands
– Brenner/transitional  bladder
– clear cell  mesonephric (renal
cell)

19. • Ovarian carcinogenesis can be divided
into two broad phases:
– malignant transformation
• Benign borderline  malignant ovarian
tumors.
– peritoneal dissemination.
• Now do not appear to be valid for the
majority of ovarian cancers

20. New model of ovarian
carcinogenesis
• Surface epithelial tumors divides into two
broad categories: Type I and Type II
– based on their clinicopathologic features and
characteristic molecular genetic changes

21. Type I Type II
• Low grade • High grade
• Arise from precursor lesion • Arise “de novo”
in a stepwise fashion
– Cystadenoma
– Borderline tumor
• Typically present in stage I • Typically present in
• Slow growing, indolent advanced stage
• Often remains low grade • Rapid growing, aggressive
• E.g. • E.g.
– Low grade micropapillary – High grade serous
– Mucinous – MMMT
– Clear cell
– endometroid

22. • Molecular biologic evidence  supports dualistic
model of ovarian carcinogenesis.
– High-grade serous carcinomas  p53 mutations
– low grade serous carcinomas mutations in K-ras
and BRAF genes.
• Pten mutations in endometrioid tumors and K-ras in
mucinous tumors also supports the stepwise
progression model.

23. • Very recently, Lee et al. have proposed
– many high-grade serous carcinomas actually arise
in the mucosa of the fimbriated end of the
fallopian tube.

24. Pathologic Classification
• Surface epithelial –
65-70%
• Germ cell tumors –
15-20%
• Stromal– 5-10%
• Metastatic tumors –
5%

25. World Health Organization Histologic Classification of Ovarian Neoplasms
1.Surface epithelial tumors 3. Germ cell tumors
1. Serous tumors 1. Dysgerminoma
2. Mucinous tumors 2. Yolk sac tumor (endodermal sinus tumor)
1. Endocervical-like 3. Embryonal carcinoma
2. Intestinal type 4. Polyembryoma
3. Endometrioid tumors 5. Choriocarcinoma
4. Clear cell tumors 6. Teratoma
5. Transitional cell tumors 1. Immature
6. Squamous cell tumors 2. Mature
7. Mixed epithelial tumors 3. Struma ovarii
8. Undifferentiated and unclassified carcinoma 4. Carcinoid tumors
2.Sex cord-stromal tumors 7. Mixed germ cell tumors
1. Granulosa-stromal cell tumors 4. Gonadoblastoma
1. Granulosa cell tumors (adult and juvenile) 5. Miscellaneous
2. Tumors in the thecoma—fibroma group 1. Small cell carcinoma
1. Thecoma 2. Malignant lymphomas, leukemias,
2. Fibroma plasmacytomas
3. Cellular fibroma 3. Unclassified
4. Fibrosarcoma 4. Metastatic tumors
5. Sclerosing stromal tumor
2. Sertoli/stromal-cell tumors
1. Sertoli cell tumors
2. Sertoli-Leydig cell tumors
3. Sex cord tumors with annular tubules
4. Gynandroblastoma
5. Unclassified
6. Steroid (lipid) cell tumors
1. Stromal luteoma
2. Leydig cell tumor
3. Steroid cell tumor, not otherwise specified

26. Surface Epithelial tumors
• Serous (tubal)
• Mucinous (endocx & intestinal)
• Endometrioid
• Transitional cell - Brenners.
• Clear cell

27. Surface Epithelial tumors
All types can be benign, borderline , or malignant, depending
upon;
• Benign ;-
– gross: mostly cystic
– microscopic; fine papillae, single layer covering (no stratification), no
nuclear atypia, no stromal invasion)
• Borderline ; -
– gross; cystic / solid foci
– microscopic; papillary complexity, stratification, nuclear atypia, no
stromal invasion
• Malignant ; -
– gross; mostly solid & hemorrhage / necrosis
– microscopic; papillary complexity, stratification, nuclear atypia,
stromal invasion

28. Serous Tumors:
• Frequently bilateral
(30-66%).
• 75% benign/bord.,
• 25% malignant.
• Tall columnar ciliated
epithelium.

29. Serous Cystadenoma
• Single layer of ciliated
columnar
•Fine papillae
Papillary cystadenoma
(bor)
•Papillary complexity
•Nuclear stratification& atypia
•No stromal invasion

30. Serous cystadenocarcinoma
• Papillary
complexity
• Nuclear
stratification &
atypia
• stromal invasion
• Psammoma bodies
• Often associated
with CA 125
elevation.

31. Mucinous Tumors:
• Less common 25%, very
large.
• Rarely malignant - 15%.
• Multiloculated, many small
cysts.
• Rarely bilateral – 5-20%.
• Tall columnar, apical mucin.
• Pseudomyxoma peritonei.

32. Mucinous cystadenoma
•Multilocular cyst lined by
single layer of columnar cells
with basally placed nuclei and
apical mucin.
Mucinous cystadenoma-
borderline
•Papillary complexity
•Nuclear stratification&
atypia
• No stromal invasion

33. Mucinous cystadenocarcinoma
•Papillary complexity
•Nuclear stratification& atypia
•stromal invasion
•CA 125 levels may not be
markedly elevated.
•Relatively chemoresistant.
•sim. Clear cell ca also.
• Differential diagnosis of a
mucinous ovarian tumor
includes metastatic disease
from an appendiceal primary.

34. Endometrioid tumors
• most are unilateral (40%
are bilateral)
• almost all are malignant
• many are associated
with endometrial cancer
(30%)
• patient may have
concurrent
endometriosis

35. Endometrioid adenocarcinoma
• stromal invasion by
irregular malignant
endometrial glands

37. TNM and FIGO staging for Ovarian Cancer
Primary tumor (T)
TNM FIGO
T1 I Tumor limited to the ovaries (1 or both)
T1a IA Tumor limited to 1 ovary; capsule intact, no tumor on ovarian surface; no malignant cells in
ascites or peritoneal washings
T1b IB Tumor limited to both ovaries; capsules intact, no tumor on ovarian surface; no malignant cells
in ascites or peritoneal washings
T1c IC Tumor limited to 1 or both ovaries with any of the following: capsule ruptured, tumor on
ovarian surface, malignant cells in ascites or peritoneal washings
T2 II Tumor involves 1 or both ovaries with pelvic extension
T2a IIA Extension and/or implants on the uterus and/or tube(s); no malignant cells in ascites or
peritoneal washings
T2b IIB Extension to other pelvic tissues; no malignant cells in ascites or peritoneal washings
T2c IIC Pelvic extension (T2a or T2b) with malignant cells in ascites or peritoneal washings
T3 III Tumor involves 1 or both ovaries with microscopically confirmed peritoneal metastasis outside
the pelvis
T3a IIIA Microscopic peritoneal metastasis beyond the pelvis (no macroscopic tumor)
T3b IIIB Macroscopic peritoneal metastasis beyond the pelvis ≤ 2 cm or less in greatest dimension
T3c IIIC Macroscopic peritoneal metastasis beyond the pelvis > 2 cm in greatest dimension and/or
regional lymph node metastasis

38. Regional lymph nodes (N)
TNM FIGO
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 IIIC Regional lymph node metastasis
Distant metastasis (M)
TNM FIGO
M0 No distant metastasis
M1 IV Distant metastasis (exclude peritoneal metastasis)

39. Stage I ovarian cancer
• limited to the ovaries.
– Stage IA: tumour limited to 1
ovary, the capsule is intact, no
tumour on ovarian surface and
no malignant cells in ascites or
peritoneal washings.
– Stage IB: tumour limited to both
ovaries, capsules intact, no
tumour on ovarian surface and
no malignant cells in ascites or
peritoneal washings.
– Stage IC: tumour is limited to 1
or both ovaries with any of the
following: capsule ruptured,
tumour on ovarian surface,
malignant cells in ascites or
peritoneal washings.

40. Stage II ovarian cancer
• tumors involving 1 or both ovaries
with pelvic extension and/or
implants.
– Stage IIA: extension and/or
implants on the uterus and/or
fallopian tubes. No malignant
cells in ascites or peritoneal
washings.
– Stage IIB: extension to and/or
implants on other pelvic tissues.
No malignant cells in ascites or
peritoneal washings.
– Stage IIC: Pelvic extension
and/or implants (stage IIA or
stage IIB) with malignant cells in
ascites or peritoneal washings.

41. Stage III ovarian cancer
• tumours involving 1 or both ovaries
with microscopically confirmed
peritoneal implants outside the
pelvis. Superficial liver metastasis
equals stage III.
•
– Stage IIIA: microscopic
peritoneal metastasis beyond
pelvis (no macroscopic tumour).
– Stage IIIB: macroscopic
peritoneal metastasis beyond
pelvis less than 2 cm in greatest
dimension.
– Stage IIIC: peritoneal metastasis
beyond pelvis greater than 2 cm
in greatest dimension and/or
regional lymph node metastasis.

42. Stage IV ovarian cancer
Tumours involving 1 or both ovaries with distant metastasis.
Parenchymal liver metastasis equals stage IV.

43. Metastasis
• Typical spread– omentum, peritoneal surfaces such as
undersurface of diaphragm, paracolic gutters and bowel
serosa
• Lymphatics– follows bld supply thru infundibulopelvic lig
to nodes in para aortic region
• Drainage thru broad lig and parametrium– involves ext
iliac, obturator and hypogastric regions
• Along round lig– involves inguinal nodes
• Extra abd mets– pleura, liver , spleen, lung, bone and CNS

44. Ovarian Cancer

45. Diagnosis and Clinical Evaluation
• ̴75% to 85% of patients with epithelial
ovarian cancer are diagnosed at the time
when their disease has spread throughout the
peritoneal cavity.

46. Symptoms of ovarian cancer
• Asymptomatic
• Vague new and frequent (>12days/month)
symptoms of
– bloating,
– Abdominal enlargement
– pelvic or abdominal pain,
– difficulty eating, or early satiety,
– Vaginal bleeding
– or urinary urgency or frequency.

47. Diagnostic tools
 History
• Pelvic Exam (including rectal)
• Transvaginal Ultrasound
• Tumor markers
• CT
• MRI

48. Exam
• Physical
– Malignancy: irregular
margins, solid
consistency, is fixed,
nodular, or bilateral, is
associated with ascites

49. Physical examination
In menstruating women only 5-18% of
adnexal masses will prove malignant vs.
postmenopausal women 30-60% of masses
will be malignant.

50. So if you find a mass…what else can it be???
• Endometrioma
• Fibroid
• Functional cyst
• Ectopic pregnancy
• Dermoid tumor (younger women)

51. Ultrasound
• Initial imaging modality of choice
– for benign vs malignant
• Results of screening trials have
consistently demonstrated that US
detects more stage I ovarian
carcinomas than CA125 levels and
physical examination
• very few stage I carcinomas have been
found

52. • near 95% to 99% NPV in excluding
malignancy
• benign :- smooth, thin walls; few, thin
septations; absence of solid components or
mural nodularity.
• mural nodules, mural thickening or
irregularity, solid components, thick
septations (3 mm) and associated findings
such as ascites, peritoneal implants, and/or
hydronephrosis suggest malignancy
• use of color and pulse Doppler in the
evaluation of ovarian masses is
controversial

53. TVS vs Pelvic Exam
Detection TVS PE N=
Overall 85% 44% 289
> 55 yrs 74% 30% 88
> 200 lbs 73% 9% 66
> 200 gram ut 80% 16% 74
TVS is significantly more accurate (p< 0.001)
Ueland, DePriest, DeSimone, Pavlik, Lele, Kryscio, van Nagell JR Jr.
The accuracy of examination under anesthesia and transvaginal sonography in evaluating ovarian size.
Gynecol Oncol. 2005 Nov;99(2):400-3.

54. You found a mass…what next…
It’s reasonable to follow a mass IF…
- The mass is not suspicious on ultrasound
- (ie the mass is mobile, looks like a simple cyst, is less than 8-10cm)
- The mass should resolve over 2 mos or
otherwise patient should have surgery.
- The threshold is lower for post menopausal
women…surgery if their cyst is > 5 cm.

55. • In postmenopausal and asymptomatic, with
unilateral simple cyst <5cm AND normal CA-
125, can follow closely with repeat TVUS
• All other postmenopausal women with
ovarian mass require surgical evaluation

56. Computed Tomography
• Not the study of choice to evaluate a
suspected ovarian lesion.
• the sensitivity, specificity, and accuracy of CT
for characterizing benign versus malignant
lesions are reported to be 89%, 96% to 99%,
and 92% to 94%, respectively.

57. • On CT, ovarian cancer demonstrates varied
morphologic patterns, including a multilocular
cyst with thick internal septations and solid
mural or septal components, a partially cystic
and solid mass, and a lobulated, papillary solid
mass.

58. Magnetic Resonance Imaging
• Complementary to US in the evaluation of a
suspected ovarian lesion.
• As with CT, disease metastatic to the ovary is
often indistinguishable from primary ovarian
cancer on MRI scans
• both the colon and the stomach should be examined as
potential primary tumor sites if an ovarian mass is
detected.

59. • Several studies have compared MRI to CT and
US for characterizing adnexal masses, with
mixed results
• Both TVS and MRI have high sensitivity (97%
and 100%, respectively) in the identification of
solid components within an adnexal mass.
– MRI, however, shows higher specificity (98% vs.
46%)

60. • MRI was shown to be the most efficient
second test when an indeterminate ovarian
mass was detected at gray-scale US.
• high cost of MRI precludes its use as a
screening modality.
• The additional use of FDG-PET has been
shown to be extremely useful and should be
considered as an adjunct to, rather then a
replacement for, conventional imaging.

61. Positron Emission Tomography
• little clinical role in the primary detection of a
pelvic mass
• Appears to be promising for
– its potential to detect tumor prior to significant
morphologic changes.
• Specifically, the sensitivity, specificity,
accuracy, PPV, and NPV of FDG-PET were 83%,
80%, 82%, 86%, and 76%, respectively.

62. • US, CT, MRI, and FDG-PET all have a role to
play in the accurate staging of ovarian cancer.
• These modalities also play a role in the
monitoring of therapy and detection of
recurrent disease.

63. Tumor Markers
• CA125
– an antigenic determinant on a high-molecular-weight
glycoprotein recognized by the murine monoclonal
antibody OC-125.
– upper limit of normal- 35 U/mL.
– In postmenopausal women :- lower cutoffs, 20 U/mL.
– 85% of patients with epithelial ovarian cancer have >35
U/mL.
• in 50% of patients with stage I disease,
• >90% of patients with advanced disease.

64. • CA125 can be elevated
– less frequently elevated in mucinous, clear cell, and
borderline tumors compared to serous tumors.
– in other malignancies (pancreas, breast, colon, and
lung cancer) and
– in benign conditions and physiological states such as
pregnancy, endometriosis, and menstruation.
– Many of these nonmalignant conditions are not
found in postmenopausal women, improving the
diagnostic accuracy of elevated CA125 in this
population.

65. ROCA: Risk of Ovarian Cancer Algorithm
• CA125 was initially
interpreted using a fixed
cutoff.
• Sensitivity and specificity
has been improved by the
development of a statistical
algorithm
• When the ROC algorithm
was applied, the area
under the curve was
significantly improved in
comparison to a fixed
CA125 cutoff (93% vs. 84%)

66. • One of the limitations of CA125 is that 15% to
20% of ovarian cancers do not express the
antigen.
• Several other markers studied
• Human epididymis protein 4
• Mesothelin
• B7-H4
• Decoy receptor 3
• Spondin 2
– Neither of these is useful.
• Though FDA approved, NCCN does not
recommend use of biomarkers including CA-125
for estimating risk of cancer in case of pelvic
mass.

67. Tumor Markers
• LDH (lactate dehydrogenase)—dysgerminoma
• HCG (human chorionic gonadotropin)–
choriocarcinoma.
• AFP (alpha fetal protein)-- endodermal sinus
tumors

68. • FNA should be avoided.
• May be necessary, if bulky disease not
surgical candidates.
• CBC, LFT, KFT
• Chest X-ray

69. Screening
• 5-year survival rates for
– stage I and stage II ovarian cancer are 80% to 90%
and 70%, respectively ;
– for stages III and IV ranges from 5% to 30%.
• Only 25% diagnosed in Stage I

70. • In 1994, a NIH consensus conference
recommended that screening be offered to
women with ≥2 first-degree relatives with
ovarian carcinoma.
• In practice, many women with a single first-
degree relative are enrolled in screening
programs.

71. • Unfortunately, there are no good screening methods
for ovarian cancer at present;
– most use a combination of physical exam, CA125 levels,
and TVS.
• PLCO Cancer Screening Trial demonstrated that the
PPV value for invasive cancer was
– 1.0% for an abnormal TVS,
– 3.7% for an abnormal CA125, and
– 23.5% if both tests (CA125 and TVS) were abnormal.
– But screening with TVS and CA-125 did not dec. mortality
• Only one study has demonstrated ovarian cancer
screening trials to have a survival benefit.
» Van Nagell JR Jr, et al.. Cancer 2007;109(9):1887–1896.

72. • No role of routine screening in general
population
• Some follow women with high risk factors
(e.g., family history, BRCA mutation) using CA-
125 and TVS.

73. Risk of Malignancy Index (RMI)
• Most valuable clinical tool by combining serum
CA125 values with ultrasound findings and
menopausal status to calculate a Risk of
Malignancy Index (RMI).
• RMI = U x M x CA125
– ultrasound result is scored 1 point for each of the following
characteristics: multilocular cysts, solid areas, metastases, ascites
and bilateral lesions.
– menopausal status is scored as 1 = pre-menopausal and 3 = post-
menopausal
– Serum CA125 in IU/ml and can vary between 0 and hundreds or
even thousands of units.
• It yielded a sensitivity of 85% and a specificity of
97%.

74. • OVA1 is an FDA-cleared blood test that uses
results of 5 biomarkers (transthyretin, apolipoprotien
A1, transferrin, beta-2 microglobin and CA-125), with an
algorithm to indicate the probability of
malignancy of an ovarian mass.
• OvaSure screening test- 6 biomarkers
• Leptin, prolactin, osteopontin, IGFII, MIF and CA-125.
• not recommended.

75. Management

76. Treatment for
Newly Diagnosed Ovarian Cancer
• Complete surgical staging
• Optimal reductive surgery
• Chemotherapy
• Clinical Trials

77. • Complete surgical staging
– Full assessment of abdomen and pelvis
– Random biopsy of visually negative areas
– Lymph node dissection (except Stage I)
• Optimal reductive surgery
• Chemotherapy
• Clinical Trials

78. Surgical Staging of Ovarian Cancer
 Vertical incision
 Multiple cytologic washings
 Random peritoneal biopsies,
including diaphragm
 TAH and BSO
USO in stage IA or IC
 Intact tumor removal
Omentectomy
 Complete abdominal exploration
 Lymph node sampling

79. The State of Treatment for
Newly Diagnosed Ovarian Cancer
• Complete surgical staging
• Optimal reductive surgery
– Stage I, II - Complete removal of all disease
– Stage III, IV - Residual disease < 1 cm
• Chemotherapy
• Clinical Trials

80. Optimal Cytoreduction
Proportion surviving
0 cm
0-1 cm
1-2 cm
>2 cm
Time since initial surgery (years)

81. • Procedures that may be considered for
optimal surgical cytoreduction :-
– Radical pelvic dissection
– Bowel resection
– Diaphragm or other peritoneal surface stripping
– Splenectomy
– Partial hepatectomy
– Cholecystectomy
– Partial gastrectomy or cystectomy
– Or distal pancreatectomy

82. THANK YOU…