3. Epidemiology
• The peak incidence of invasive epithelial ovarian cancer is at about 60 years of
age.
• About 30% of ovarian neoplasm in postmenopausal are malignant and 7% in
premenopausal.
• Epithelial cancers are most common ovarian/fallopian malignancies.
• It has highest fatality to case ratio of all gynecological malignancies.
• Fifth most common cause of death from malignancy in women.
• Second most common gynaecologic carcinoma.
• A woman’s lifetime risk of being diagnosed with ovarian cancer is 1-1.5% and of
dying from ovarian cancer is almost 0.5%.
4. Hereditary ovarian cancer
• Most hereditary ovarian cancers are associated with mutation in BRCA1
located on chromosome 17 and small proportion has BRCA 2 mutation
located on chr 13.
• 5-10 % of EOC have hereditary predisposition.
• The mutation are inherited in an autosomal dominant pattern.
• Life time risk of having ovarian cancer
BRCA 1 54%
BRCA 2 23 %
HNPCC 15 %
• BRCA 1 is more carcinogenic than BRCA 2.
6. Risk Factors
• Age –between 45 and 60 years.
• Nulliparity
• Woman with previous PCOS, or on tamoxifen.
• High calories ,high fat diet.
• Genetic predisposition BRCA-1 and BRCA-2 gene mutation.
• Early menarche and Late menopause
• Family history of breast and gastrointestinal cancers.
• Multiple cycles of ovulation induction.
• Endometriosis
• Talc use
7. Protective factors
• Parity- having atleast one child is protective for ovarian cancer.
• OCP use- reduces the risk of epithelial ovarian cancer. There is 50%
reduction in the likelihood of development of ovarian cancer.
• The OCP is the only documented method of chemoprevention for
ovarian cancer. This is important for women with a strong family
history of ovarian cancer.
• Prophylactic salpingo-oophorectomy- significantly reduces, but does
not totally eliminate the risk because, peritoneal carcinomas can
occur in 2-3% of women even after prophylactic bilateral salpingo-
oophorectomy.
8. Epithelial ovarian carcinoma
• Previously thought to be derived from the
coelomic epithelium on the surface of the
ovary or from ovarian inclusion cysts.
• It is now apparent from multiple studies
that most serous carcinomas originate
from the fallopian tube, while other
subtypes( clear cell, endometrioid) are
derived from endometriosis.
• Neoplastic transformation occur when
genetically predisposed to oncogenesis or
oncogenic factors or both.
Type of EOC Cellular type
Serous 80% Endosalpigeal
Endometroid 10% Endometrial
Mucinous 5% Intestinal, endocervical
Clear cell 5% Mullerian
Brenner’s <1% Transitional
Mixed epithelial <1% mixed
Undifferentiated <1% May be anaplastic
9. Serous tumors
• Serous tumors are so classified
because they resembles tubal
secretory cells.
• Serous epithelial cancers are
divided into two groups as they
differ considerably in the cell of
origin ,molecular pathogenesis
and biological behavior.
Type 1 Type 2
Serous borderline
tumor
Rapid growing and
highly aggressive
Low grade serous
carcinoma
Appear to arise from
fimbrial end of
fallopian tube
Genetically stable Genetically unstable
Mutation of KRAS and
BRAF
Almost universally
have P53 mutation
10. • Psammoma bodies are frequently found in the serous tumors ,made up of
concentric ring of calcification.
• Hypothesis Development of psammoma bodies are ,including apoptosis of tumor
cells and osteo inductive cytokines produced by macrophages, which result in
calcification that can be extensive.
• Borderline tumours-
low malignant potential,
remain confined to ovary for long periods
occur predominantly in premenopausal women(30-50years
very good prognosis
11. • Borderline serous tumors
• approx.10% of all ovarian serous tumors.
• Criteria for diagnosis include:
• Epithelial hyperplasia in the form of pseudo stratification, tufting,
cribriform and micropapillary architecture.
• Mild nuclear atypia and mild mitotic activity.
• Detached cell clusters
• Absence of destructive stromal invasion.
• Extraovarian implants may occur with serous borderline tumours which can be
either noninvasive or invasive. Invasive implants has a higher likelihood of
progression, which can ultimately lead to intestinal obstruction caused by
associated fibrosis and death.
12. • Serous carcinoma :
• In malignant serous tumors , stromal invasion is present.
• In low grade serous adenocarcinoma, papillary and glandular
structure predominate
• High grade neoplasms are characterized by solid sheets of cells,
nuclear pleomorphism, and high mitotic activity
• Serous psammomacarcinoma is a rare variant of serous carcinoma
characterized by massive psammoma body formation and low
grade cytological features. Relatively favourable prognosis.
13. Mucinous tumors
• Cystic ovarian tumors have multiple
loculi lined with the mucin secreting
epithelium- honey comb appearance
on cut surface.
• Lining epithelium consist of mucin
and resembles the endocervix, gastric
pylorus or intestine.
• 8-10% of epithelial ovarian
carcinoma.
• They may reach enormous size, filling
the entire abdominal cavity.
14. Mucinous tumors
Borderline mucinous tumors
• Low malignant potential
• Important to take multiple sections from many areas to identify
the most malignant alteration
• Well differentiated mucinous epithelium may be seen
immediately adjacent to a poorly differentiated focus.
15. Mucinous carcinoma
• Bilateral tumour occurs in 8-10% of cases
• Confined to ovary in 95 to 98 %
• Mostly contain enteric type cells, therefore cannot be distinguished
from metastatic ca of GIT on the basis of histology alone.
• Primary ovarian neoplasms rarely metastasize to the mucosa of the
bowel, whereas gastrointestinal lesions frequently involve the ovary by
direct extension or lymphatic spread.
16. Pseudomyxoma peritonei
• Abundant mucoid or gelatinous material in the pelvis and abdominal
cavity surrounded by fibrous tissue.
• Most commonly secondary to well differentiated appendiceal mucinous
neoplasm, also occurs with mucinous cystadenoma of ovary.
• Findings at laparotomy resemble a boiled sago pudding.
• Recurrence is common
• Prognosis of pseudomyxoma peritonei is bad due to incomplete removal
and recurrence.
17. Endometrioid tumors
• 6-8% of Epithelial Ovarian Carcinoma.
• The malignant potential is very low.
Borderline endometroid tumours
• Low malignant potential.
• Resembles endometrial polyp or
complex endometrial hyperplasia with
glandular crowding .
• Some have prominent fibromatous
component.(adenofibroma)
18. Endometroid carcinoma
• Markedly complex glandular pattern with all the potential variation of epithelia of
uterus
• Multifocal disease-
Endometrioid carcinoma of ovary is associated in 15-20% of the cases with ca
endometrium.
Identification of multifocal disease is important because
5 year survival-
• Disease metastatic from the uterus to the ovaries- 30-40% survival.
• with synchronous multifocal disease - 75-80%.
19. CLEAR CELL CARCINOMAS
• Tumors are made up of clear and
hobnail cell that project their nuclei
into the apical cytoplasm.
• Clear cell have abundant clear or
vacuolated cytoplasm,
hyperchromatic irregular nuclei, and
nucleoli of various sizes.
• Almost invariably high grade (grade 3)
nuclei are identified. Hence, clear cell
carcinoma is not graded.
20. BRENNERS TUMORS
Borderline Brenner tumor Malignant Brenner
tumor
Transitional cell carcinoma
Subclassified as
• Proliferating tumor-
resemble low grade
papillary urothelial
carcinoma of urinary
bladder and
• Borderline tumor-
resemble high grade
papillary urothelial
carcinoma of urinary
bladder.
• Cure is surgical removal
These rare tumor are
defined as benign or
borderline brenner
tumors coexisting
with invasive
transitional cell
carcinoma.
• Primary ovarian carcinoma
resembling transitional cell
carcinoma of urinary
bladder without a
recognizable brenner
tumour.
• Unlike malignant brenner
tumours, these are
diagnosed in an advanced
stage.
21. BRENNERS TUMORS
• Histologically, the tumor shows a
background of fibrous tissue-
interspersed with in it are nests of
transitional epithelium – Walthard cell
nests.
• May cause postmenopausal bleeding
• Occasionally, associated with ascites and
hydrothorax- pseudomeig’s syndrome.
22. CLINICAL FEATURES
• Asymptomatic
• Anorexia, wt loss
• Abdominal –pain/
distension/bloating
• Irregular mass
• Dyspnoea
• Nausea/constipation
• Urinary frequency
• Ascites
• Lower abdominal/ pelvic mass
• Omental cake
• Nodules in pouch of douglas
• Menstrual irregularities/
postmenopausal bleeding
Symptoms Advanced disease
Silent killer- that did not produce symptoms until far advanced.
23. signs
• Pelvic mass- a solid, irregular, fixed pelvic mass is an important sign of
EOC.
• Ascites
• Postmenopausal palpable ovary syndrome- any palpable pelvic mass
in women 1 year past menopause should be considered potentially
malignant.
• Atypical glandular cells on PAP test- signals upper genital tract
malignancy and should prompt further evaluation.
• Paraneoplastic syndromes- rare, include DIC, polyneuritis,
dermatomyositis, hemolytic anemia and cerebellar degeneration.
24. Screening
• Unfortunately, till date no specific method of screening for early
detection of OC are available.
Various methods available :
• Tumor markers CA125, HE4
• TVS and color doppler
• Screening is done in patient with strong family history of ovarian or
breast carcinoma , or woman having above sign and symptoms.
25. CA125
• It is a high molecular glycoprotein.
• Only proven biomarker to detect the ovarian malignancy before any
clinical symptoms develop.
• Elevated serum level (>35U/ml) is seen in 80% of advanced ovarian
cancer but raised in only 25-50%in early cancers.
• CA-125 has overall sensitivity of 84.4% and a specificity 0f 66.3%.
• Lack of sensitivity in detecting early stage ovarian cancer limits the
CA-125 as a valuable screening tool
26. HE4
• HE-4 is a protein first discovered in the distal epithelium of the epididymis.
• Its levels are found to be elevated in ovarian cancer being higher in serous
and endometrioid type than in other types.
• sensitivity of 90%
• specificity of 77.6%
• Combined with CA 125 sensitivity increased to 94%.
• FDA approved tumour marker for ovarian cancer where CA 125 level is
normal.
• HE4 is less affected by other benign pelvic condition like endometriosis.
27. Risk of malignancy index(RMI)
• The product of the serum CA 125 level (U/ml), The ultrasound scan result
and the menopausal status.
• Sensitivity- 85%
• Specificity- 97%
• Serum level of CA125 >35 U/ml was considered abnormal.
• Ultrasound findings (U) were scored with one point for each of the
following:
Multi-locular cyst,
Evidence of solid areas,
Evidence of metastases,
Presence of ascites,
Bilateral Lesions.
28. Based on the data obtained RMI-1, RM1-2, RMI-3 and RMI-4 were calculated as described
below.
RMI calculation Usg score
RMI-1 U X M X CA125 value Score 0 made U=0.
Score1 made U=1
a score of > 2 made U=3
Premenopausal status made
M=1
post-menopausal status M=3.
RMI-2 U X M X CA –125 total USG score of 0 or 1 made U= 1
score ≥ 2 made U=4
Premenopausal status M–1
post-menopausal status M=4.
RMI-3 U X M X CA 125 USG score of 0 or 1 made U=1
a score of ≥ 2 made U=3
Premenopausal status made
M=1
postmenopausal status M=3
RMI-4 U X M X Size(cm) X CA –125 total USG score 0 or 1 made U=1
score of ≥2 made U=4
Premenopausal status made
M=1 postmenopausal M = 4
When.. Tumour size (single greatest diameter) of ≤7 cm made S=1
≥7 cm made S=2.
The serum level of CA-125 was applied directly to the calculation.
berek and novak 15 e
29. Interpretation of risk malignancy index (RMI)
• If the score < 25, it was considered as low risk,
• If the score 25-250, it was considered as, moderate risk
• If the score > 250, it was considered as high risk.
Most accurate diagnostic preoperative method which could
differentiate benign from malignant ovarian masses is RMI 1 with
sensitivity 92.4% and specificity of 83.3%
30. Risk of ovarian malignancy algorithm (ROMA)
• Calculated on the combined result of CA125 and the HE4 .
• The index classifies women either in low risk and high risk malignant
disease.
It has sensitivity of 89% and specificity of 74.5%
Premenopausal women
• ROMA value> 11.4% =high risk of finding epithelial ovarian cancer
• ROMA value < 11.4%= low risk of finding epithelial ovarian cancer
Post menopausal women
• ROMA value >29.9% =high risk of finding epithelial ovarian cancer
• ROMA value <29.9% =low risk of finding epithelial ovarian cancer
31. Diagnosis
• Ultrasonographic signs :
• Adnexal mass with areas of complexity, such as irregular borders, multiple
echogenic patterns within the mass, and dense multiple irregular septae.
• Bilateral tumors are more likely to be malignant,
• In postmenopausal women with unilocular cysts 8 to 10 cm or less and
normal serial CA125 levels, expectant management is acceptable.
The diagnosis of an ovarian cancer requires an exploratory laparotomy
Doppler study
• The vessels supplying benign ovarian tumors generally were peripheral in
location, had high systolic flow, and a high PI (>1.0) and RI (>0.4).
• In contrast, vessels supplying ovarian malignancies generally had significant
diastolic flow, were centrally located, and had a low PI (<1.0) and RI (<0.4).
32. International ovarian tumour analysis classification(IOTA)
• Risk of malignancy can be predicted preoperatively by various methods of IOTA group.
• IOTA classification for Benign and Malignant Mass using simple rules
Rule 1:>1 M- features +0 B-feature-malignant
Rule 2:> 1B-features +0 M feature-Benign
Rule 3: if both M features and B-features are present , or if no B or M-features are present .result is
inconclusive.
33.
34. Other investigations
• Pap smear to be performed
• Patient with irregular bleeding endometrial sampling is done and
endocervical curettage
• b/l mammography is any breast mass detected.
35. Differential diagnosis
• Ovarian epithelial cancers must be differentiated from benign
neoplasms and functional cysts of the ovaries.
• A variety of benign conditions of the reproductive tract, such as
pelvic inflammatory disease, endometriosis, and pedunculated
uterine leiomyomas, can simulate ovarian cancer.
• Non-gynecologic causes of a pelvic tumor, such as an inflammatory
(e.g., diverticular) disease or neoplastic colonic mass, must be
excluded . A pelvic kidney can simulate ovarian cancer.
36. Patterns of spread
• Ovarian epithelial cancers spread primarily by exfoliation of cells into the peritoneal cavity, by
lymphatic dissemination, and by hematogenous spread.
• Transcoelomic spread :
• Most common and earliest mode of dissemination of ovarian epithelial cancer is by exfoliation of cells that
implant along the surfaces of the peritoneal cavity.
• Typically to posterior cul-de-sac, paracolic gutters, right hemidiaphragm, liver capsule, the peritoneal surfaces
of the intestines and their mesenteries, and the omentum. The disease seldom invades the intestinal lumen
but progressively agglutinates loops of bowel, leading to a functional intestinal obstruction. This condition is
known as carcinomatous ileus
• Lymphatic:
• Lymphatic dissemination to the pelvic and para-aortic lymph nodes is common, particularly in advanced-
stage disease.
• Spread from lymphatic channels of diaphragm + retroperitoneal lymph node to supraclavicular lymph nodes.
Hematogenous
• Hematogenous dissemination at the time of diagnosis is uncommon.
• Spread to vital organ parenchyma, such as the lungs and liver, occurs in only about 2% to 3% of patients.
37. Prognostic factors
Prognostic factors
Pathologic factor Clinical factor Biological factor
Morphology and histologic pattern
Architecture and grade of the
lesion,
The extent of residual disease after
primary surgery,
The volume of ascites, patient age,
and Performance status are all
independent prognostic variables
Ploidy is an independent prognostic
variable
38.
39.
40.
41. Current Recommendations for management of
women at high risk for ovarian cancer
• Women who appear to be at high risk for ovarian or breast cancer
should undergo genetic counseling and, if the risk appears to be
substantial (i.e., a calculated risk of at least 10% in having a mutation
in BRCA1 or BRCA2), may be offered genetic testing for BRCA1 and
BRCA2.
• Women who wish to preserve their reproductive capacity can
undergo screening by transvaginal ultrasonography every 6 months,
although the efficacy of this approach is not established.
• Oral contraceptives should be recommended
42. • Women who do not want fertility or who have completed their families
should be recommended to undergo prophylactic bilateral salpingo-
oophorectomy after the age of 35, but by age 40 years.
• In women who have a strong family history of breast or ovarian cancer,
annual breast screening should be performed beginning at age 30 years
using a combination of magnetic resonance imaging (MRI), mammograms,
and ultrasound. Ideally, these women should be followed in clinics that
manage women at high risk for cancer.
• Women with a documented HNPCC syndrome should be treated as
mentioned above, and they should undergo periodic colonoscopy,
endometrial biopsy, or prophylactic hysterectomy after the completion of
childbearing
43. Staging laparotomy
• A thorough staging laparotomy is an important part of early management. If the
preoperative suspicion is malignancy, a laparotomy should be performed.
• If there is no visible or palpable evidence of metastasis, the
following should be performed for adequate staging
• Careful evaluation of all peritoneal surfaces.
• Retrieval of any peritoneal fluid or ascites. If there is none, washings of the peritoneal
cavity should be performed.
• Infracolic omentectomy.
• Selective lymphadenectomy of the pelvic and para-aortic lymph nodes, at least ipsilateral if
the malignancy is unilateral.
• Random peritoneal biopsies of normal surfaces, including from the undersurface of
the right hemidiaphragm, bladder reflection, cul de-sac, right and
left paracolic recesses, and both pelvic sidewalls.
• Total abdominal hysterectomy and bilateral salpingo-oophorectomy in most cases.
• Appendectomy for mucinous tumors.
44.
45.
46.
47.
48.
49. • Early stage ,low risk : no adjuvant chemotherapy is recommended for these
patients.
• Early stage ,high risk : The recommendations for therapy follow:
• Patients with high-grade, high-risk stage I epithelial ovarian cancer should be given adjuvant
chemotherapy. The type depends on the patient’s overall health and status.
• Treatment with carboplatin and paclitaxel chemotherapy for three to six cycles seems
desirable in these patients, whereas a short course of a single agent, either carboplatin or
paclitaxel, may be preferable for older women.
50. Chemotherapeutic Recommendation in
Advanced Epithelial Ovarian Cancer
• For the treatment of advanced-stage epithelial ovarian cancer, the following is
recommended
• Combination chemotherapy with intraperitoneal cisplatin and paclitaxel or
intravenous carboplatin and paclitaxel are the treatments of choice for patients
with advanced disease.
• The recommended doses and schedule for intraperitoneal chemotherapy are
paclitaxel 135 mg/m2 intravenous on day 1, followed by cisplatin 50-100 mg/m2
intraperitoneal on day 2, followed by paclitaxel 60 mg/m2 intraperitoneal on day
8, every 3 weeks for 6 cycles, as tolerated.
51. • The recommended doses and schedule for intravenous chemotherapy are:
carboplatin (starting dose AUC 5–6), and paclitaxel (175 mg/m2 ), every 3 weeks
for 6-8 cycles.
• In patients who cannot tolerate combination chemotherapy, single-agent,
intravenously administered carboplatin (AUC 5–6) or paclitaxel 175 mg/m2 can
be given.
• In patients who have a hypersensitivity to paclitaxel or carboplatin, either
desensitization can be performed, or an alternative active drug can be
substituted (e.g., docetaxel, liposomal doxorubicin, topotecan, etoposide).
Etoposide can be given orally.
52.
53. PARP INHIBITORS
• Three parp (poly ADP ribose polymerase)inhibitor have been
approved by FDA for treating ovarian cancer
• Lynparza (also known as olaparib)
• Rubraca (also known as rucaparib)
• Zejula(also known as niraparib)
• These are approved for women who carry germline mutation in
BRCA1 and BRCA 2
54. Treatment assessment
• Serum CA125 levels can be used during chemotherapy to follow those
patients whose levels were positive at the initiation of therapy . The
change in level generally correlates with response
• Positron-emission tomography (PET) alone or with CT imaging may
help in the detection of relapse, although the relative value of adding
PET has not been established. There appears to be a higher false-
positive rate with PET compared with CT.
55. Chemotherapy for persistent –recurrent
ovarian carcinoma
• Platinum sensitive – who
relapse after 6 months of
primary chemotherapy.
• Platinum resistant - who relapse
before 6 months of primary
chemotherapy.
• Platinum refractory –who
progress while on treatment.
Platinum
sensitive
27 to 65 %
response
Median
survival 12
to 24
months
Platinum
resistant
10 to 30 % 6 to 9 months
Platinum
refractory
<20 %
56.
57.
58.
59. Radiation therapy
• Whole-abdominal radiation therapy given as a salvage treatment has
been shown to be associated with a relatively high morbidity.
• The principal problem associated with this approach is the
development of acute and chronic intestinal morbidity.
• As many as 30% of patients treated with this approach develop
intestinal obstruction, which necessitated exploratory surgery with
potential morbidity
60. Survival
5 year survival
• Stage1 94%
• Stage 2 73%
• Stage 3 A 41%
• Stage 3 B 25%
• Stage 3 C 23%
• Stage 4 11 %
• Survival of borderline tumor is very good. When all the stages of
borderline are included 5 year survival rate is 86% to 90%.
