Ovarian Cancer

OVARIAN CANCER
Dr. Myat Su Aung

• Fifth leading cause of cancer death in women
• leading cause of gynecologic cancer death.(WHO cancer
statistics,2015)
• Average lifetime risk is 1 in 70
• median age at diagnosis is 63 years.
• 75% present with stage III or IV disease.
• Early diagnosis is frequently difficult because of vague abdominal
symptoms at presentation
Epidemiology
6/23/2016 Ovarian cancer 2

Risk Factors for Ovarian Cancer
Patient Characteristics
• Increasing age
• Personal history of breast cancer
Genetic factor
• Family history of ovarian cancer
• BRCA 1 / 2 mutations
• Hereditary nonpolyposis colorectal cancer
Reproductive factors
• Nulliparity
• Early menarche
• Late menopause
• Infertility
• Polycystic ovarian syndrome
• Endometriosis
• ovulation inducing drugs
• Hormone replacement therapy
Environmental factor
• Obesity and high fat diet
• Talc exposure
• Cigarette smoking (for mucinous ovarian cancer)
Ovarian cancer 3

A higher risk for developing epithelial ovarian cancer is for
nulliparous women
A lower risk for those
• who have had children,
• who have breastfed,
• who have undergone tubal ligation,
• or who have taken oral contraceptives.

• Strongest risk factor is a family history of ovarian cancer
• only 5–10% of tumors result from a known genetic disposition.
• Lifetime risk:
- general population 1.8%,
- one first-degree relative: 5%,
- two first-degree relatives: 25–50%.

World Health Organization Classification of
Ovarian Tumors

World Health Organization Classification
of Ovarian Tumors

Classification of Ovarian tumors

EPITHELIAL OVARIAN CANCER

Histologic types
• serous 50%,
• endometrioid 20%,
• undifferentiated 15%,
• mucinous 10%,
• clear cell <5%
Boderline tumour
Tumors of low malignant potential (LMP, borderline tumors)
• have an excellent prognosis compared with invasive carcinomas
• Lack stromal invasion
• Occur in premenopausal women

• Histologic grade
Grade Percentage of undifferentiated
cells
G1 0-25
G2 25-50
G3 >50

COMMON HISTOLOGIC TYPES OF
EPITHELIAL OVARIAN CANCER
Papillary serous
• most common type of epithelial ovarian cancer.
• May contain psammoma bodies
• Is often associated with CA 125 elevation.
Endometrioid
• associated with endometriosis or an independent uterine cancer of similar histology.
• May occur with early stage disease in younger patients, although advanced disease is also possible.
Mucinous
• rarely be associated with pseudomyxoma peritoneii.
• CA 125 levels may not be markedly elevated.
• Relatively chemoresistant.
• Differential diagnosis of a mucinous ovarian tumor includes metastatic disease from an appendiceal
primary.
Clear cell
• The most chemoresistant type of ovarian cancer.
• Often contains "hobnail" cells with cleared out cytoplasm due to glycogen.
• associated with endometriosis or humorally mediated hypercalcemia6/23/2016 Ovarian cancer 13

• Concentric rings of calcification
called psammoma bodies- in the
papillary serous epithelial ovarian
cancer
• May be seen in breast, lung, and
papillary thyroid cancers
clear cell carcinoma shows prominent hobnail
cells lining the glands. They have bulbous
hyperchromatic nuclei that protrude into the
gland lumen.

Pathogenesis and Patterns of
Metastases
Patterns of Spread
• Local spread: intraperitoneally
• Peritoneal carcinosis: intraperitoneal spread after rupture of the
ovarian capsule
• Lymphatic metastasis: para-aortic lymph nodes, in rare cases
retrograde invasion of inguinal / femoral lymph nodes
• Hematogenous metastasis - liver, lung, CNS, in rare cases bone
involvement

Pathogenesis and Patterns of Metastases
Molecular abnormalities identified in patients with epithelial
ovarian cancer
• Mutation in the p53 protooncogene
• mutations in B-raf, K-ras, PTEN, or ,8-catenin
• Amplification of the HER2/neu
• Overexpression of pro-apoptotic genes such as BAX
• Expression of angiogenic cytokines such as the vascular
endothelial growth factor (VEGF)

Diagnosis
• abdominal
discomfort/pain,
• increasing girth,
• change in bowel
habits,
• early satiety,
• dyspepsia, nausea,
• ascites,
• adnexal mass,
• pleural effusion,
• Sister Mary Joseph’s
nodule,
H&P with complete gynecologic exam
No signs or symptoms until it spreads to the upper abdomen

H&P with complete gynecologic exam
Other Associated Paraneoplastic syndrome
• Neurological syndrome: peripheral neuropathy,
cerebellar ataxia
• Cushing syndrome
• Hypercalcemia
• Thrombophelebitis
Diagnosis

Diagnosis
Serum tumor marker
CA 125
• Elevated in 80% of epithelial ovarian tumors
• Also increased in endometrial, pancreatic & breast cancer and
benign condition; endometriosis, inflammatory bowel disease,
hepatitis
• valuable as an early marker for disease recurrence, treatment
response and early treatment failure
• False positive possible, especially in premenopauseal women

Diagnosis
Serum tumor marker
CA 19-9
• Low sensitivity
CEA – elevated in 58% with stage III disease
AFP and βHCG - measure if <30 yrs old to help rule out germ
cell tumor

Diagnosis
Imaging
Ultrasound abdomen
Transvaginal Ultrasound (TVU)
• TVU is an important diagnostic tool in the evaluation of
patients with a pelvic mass.
• The classic sonographic finding of malignancy is a "complex“
cyst, defined as containing both solid and cystic components,
sometimes with septations and internal echogenicity
• Simple cyst <3 cm can be followed by serial US.

Diagnosis
Imaging
CT/MRI abdomen/pelvis
• especially helpful preoperatively if advanced disease.
• Useful in assessment of retroperitoneal LN involvement
Cystoscopy, sigmoidoscopy, barium enema, upper GI series, or
endoscopy as clinically indicated.

Diagnosis
Imaging
Chest radiographs
• to evaluate the presence of pleural effusions, which occur in 1
0 % of patients with epithelial ovarian cancer at diagnosis
A definite histological diagnosis requires surgery
It is best to avoid percutaneous biopsy during the initial
evaluation, which can result in cyst rupture and spillage of
malignant cells into the peritoneal cavity

STAGING
2014 FIGO ovarian cancer staging system
Stage I – Tumor confirmed to ovaries
IA Tumor limited to one ovary (capsule intact) no tumor on ovarian surface;
no malignant cells in the ascites or peritoneal washings
IB Tumor limited to both ovaries (capsules intact) no tumor on ovarian
surface; no malignant cells in the ascites or peritoneal washings
IC Tumor limited to one or both with any of the following
IC 1 Surgical spill
IC 2 Capsule ruptured before surgery or tumor on ovarian surface
IC 3 Malignant cells in the ascites or peritoneal washing

STAGING
Stage I

STAGING
Stage II – Tumor involves one or both ovaries with pelvic extension (below pelvic brim)
or primary peritoneal cancer
IIA Extension and/or implants on uterus and/or fallopian tubes
IIB Extension to other pelvic intraperitoneal tissues

STAGING
Stage III. Tumor involves one or both ovaries with cytologically of histologically confirmed
spread to the peritoneum outside the pelvis and /or metastasis to the retroperitoneal LN
IIIA Positive retroperitoneal lymph nodes and /or microscopic metastasis beyond
the pelvis)
IIIA 1 Positive retroperitoneal lymph nodes only
IIIA 1 (i) Metastasis up to 10mm in greatest dimension
IIIA 1 (ii) Metastasis more than 10mm in greatest dimension
IIIA 2 Microscopic, extrapelvic (above the brim) peritoneal involvement ± positive
retroperitoneal lymph nodes
IIIB Macroscopic, extrapelvic, peritoneal metastasis ≤ 2 cm ± positive
retroperitoneal lymph nodes. Includes extension to capsule of liver/spleen
IIIC Macroscopic, extrapelvic, peritoneal metastasis > 2 cm ± positive
retroperitoneal lymph nodes. Includes extension to capsule of liver/spleen

STAGING
Stage III

STAGING
Stage IV – Distant metastasis excluding peritoneal metastasis
Stage IVA Pleural effusion with positive cytology
Stage IVB Parenchymal metastases and metastases to extra-abdominal
organs (including inguinal lymph nodes and lymph nodes
outside of the abdominal cavity

STAGING
5-year survival rate according to stage
Stage 5-year survival rate (%)
Stage I 80
Stage II 60
Stage III 30
IIIA 40
IIIB 25
IIIC 23
Stage IV 10

Prognostic Factors for Epithelial
Ovarian Cancer
Most important negative prognostic factors:
• stage,
• grade,
• Residual volume of disease.
Other negative factors:
• age>65,
• pre-op ascites,
• CA125 elevated after 3c chemo or nadir >20 U/mL after first-line
therapy.
The extent to which the disease can be surgically debulked also
affects prognosis.

Algorithm for management of ovarian cancer
6/23/2016

Management
Stage IA and IB, grade1
(1) Premenopausal patients
• After staging laparotomy , undergo unilateral oophretomy to
preserve fertility
• Follow up regular pelvic examination and monitor CA125
levels
• The other ovary and uterus are removed when child bearing is
completed
(2) Postmenopausal patients
• Should undergo TAH and BSO and staging

Stage IA and IB (grade2 and 3)
• Treated with TAH/BSO and staging followed by chemotherapy
Stage II, III, and IV
• Surgery – cytoreductive surgery
• chemotherapy
Management

Full staging laparotomy
• a total abdominal hysterectomy (TAH),
• bilateral salpingo-oophorectomy (BSO),
• omentectomy,
• biopsies of suspicious areas, and
• Peritoneal lavage or ascitic fluid sampling.
• Blind peritoneal, paraaortic/ pelvic lymph node biopsies should
be performed to exclude the possibility of microscopic Stage III
disease,
Surgery

Primary Cytoreductive surgery
• removal of large, necrotic tumors with poor blood supply that
might lead to impaired chemotherapy delivery
• permit residual tumor to proliferate more rapidly and
• thereby enhance sensitivity to postoperative chemotherapy

Primary cytoreduction
• refers to performance of debulking surgery prior to
administration of first-line chemotherapy and
• is the standard approach for managing most patients with
suspected epithelial ovarian cancer.

Interval Cytoreductive Surgery
Interval cytoreduction is defined as a debulking procedure
performed
• after several cycles of chemotherapy have been administered,
• typically in those patients who had a suboptimal cytoreduction
at the time of initial surgery

Postoperative Chemotherapy
• Platinum agents have proven to be a critical component of the
treatment of epithelial ovarian cancer.
• Carboplatin has less ototoxicity, neuropathy, renal impairment,
and emetogenesis than cisplatin
• However, carboplatin causes myelosuppression particularly if
combined with other agents.
• Carboplatin is now the standard platinum agent for treating
ovarian carcinoma
Chemotherapy

• The current standard first-line therapy for ovarian carcinoma is
six cycles of carboplatin AUC 5-7 over one hour with paclitaxel
(175 mg/m 2 ) as a three-hour infusion every 21 days.
• Chemotherapy should begin within four to six weeks of
surgery.
• The platinum–paclitaxel combination is superior to single
agent platinum
• In patients who are poorly tolerated combination treatment,
single agent carboplatin is a satisfactory alternative

Role of other agents
• Liposomal doxorubicin, topotecan, gemcitabine, and
epirubicin have been evaluated as first-line therapy in
addition to the carboplatin and paclitaxel combination
• The carboplatin–docetaxel combination was associated with
less neurotoxicity and greater myelosuppression than
carboplatin-paclitaxel

Intraperitoneal Chemotherapy
• Epithelial ovarian cancer is largely confined to the peritoneal
space during most of its natural history
• Given this relatively localized distribution, instillation of
chemotherapy directly into the peritoneal cavity is used
• An option in patient with microscopic residual disease after
cytoreductive surgery
• cisplatin and paclitaxel have favorable peritoneal-to-plasma
concentrations

Antiangiogenic Agents
Bevacizumab
• a monoclonal antibody
• against Vascular Endothelial Growth Factor (VEGF-A),
• the first targeted agent to show significant single agent activity
in ovarian carcinoma.
• Used during adjuvant carboplatin /paclitaxel and for
maintenance therapy

• the value of radiation therapy as consolidation therapy following
chemotherapy for patients with ovarian cancer is uncertain.
Adjuvant Whole Abdominal Radiation Therapy (WART)
Used in stage III ovarian cancer,
• If not suitable for chemotherapy and
• >2cm residual
Complication of WART
• Acute – diarrhea, nausea/vomiting, leukopenia,
thrombocytopenia
• Chronic - transient LFT elevation, chronic diarrhea, basal
pneumonitis, serious bowel obstruction
Radiotherapy

• Once epithelial ovarian cancer has recurred, treatment with
curative intent is no longer feasible
• However, the judicious use of palliative chemotherapy can
improve both survival and quality of life for patients with
recurrent disease
Management of Recurrent Disease

Treatment is aimed
• to relieve cancer-related symptoms,
• optimize quality of life,
• delay the time to symptomatic disease
progression, and
• prolong OS.

Chemotherapy
The management of recurrent EOC takes into account the duration
of the platinum-free interval and the response to first-line platinum
therapy.
Indication Treatment
Platinum sensitive disease Platinum based combination therapy( with
gemcitabine or taxane)
Platinum resistant /refractory disease Single agent chemotherapy: Liposomal
doxorubicin, topotecan, gemcitabine, and oral
etoposide
Maintinance in recurrence disease Bevacizumab, concurrent with
carboplatin/gemcitabine for 10 cycles maximum,
followed by bevacizumab alone

Hormonal therapy
• tamoxifen or an aromatase inhibitor – 10% to 20% efficacy
Antiangiogenic Agents
• Bevacizumab used alone or in combinaion with other
cytotoxic drugs

Surgery
• secondary cytoreductionisolated residual disease at relapse
with no gross residual disease greater than 1 cm in diameter
Palliative surgery
• colostomy for relief of a large bowel bstruction,
• lysis of adhesions, and
• management of small bowel obstruction

Radiotherapy
• Symptoms from a growing pelvic mass can cause pain,
bleeding, and rectal narrowing.
• Palliative pelvic radiotherapy can provide rapid relief and, in
some cases, may prevent or delay the need for diverting
colostomy.
• Doses of 8 to 10 Gy in a single fraction, 20 Gy in five fractions,
30 Gy in ten fractions were given
• cerebral or bone metastases can be palliated with
radiotherapy.

GERM CELL TUMORS OF THE OVARY

Germ cell tumor Natural History Serum marker Treatment
1.Dysgerminoma -secrete LDH
-spread earlier through
lymphatic
LDH -primary surgery
-adjuvant chemo for metastatic disease,
BEP(Bleomycin,etoposide,cisplatin)
-RT used in metastatic disease if fertility
is not an issue
2.Immature teratoma Most common metastatic
site is peritoneum
- Normal AFP,β-
HCG
- Only ↑ in 30%
-premenopauseunilateral later
oophorectomy
-postmenopauseTAH & BSO
-stage IA, grade 2 or 3chemotherapy
(BEP)
3. Endodermal sinus
tumors(yolk sac
carcinoma)
-median age at diagnosis –
18 yrs
-secrete AFP
- AFP is useful - Surgical staging, unilateral
oophorectomy
- All patients are given adjuvant or
therapeutic chemotherapy
BEP – most effective

Germ cell tumor Natural History Serum marker Treatment
4. Embryonal
carcinoma
-median age at diagnosis –
14 yrs
-secrete estrogen, AFP,β-
HCG
- AFP,β-HCG Unilateral or bilateral oophorotomy
followed by chemotherapy BEP
5.Choriocarcinoma of
ovary
-rare
- Most are younger than
20yrs
-β-HCG Chemotherapy with combination of
methotrexate,actinomycin
D,cyclphosasphmide
6.Mixed germ cell
tumor
Commonly have
dysgerminoma or
endodermal sinus
component
β-HCG and AFP
depend on
component part
Unilateral or bilateral oophorotomy
followed by chemotherapy BEP

SEX CORD-STROMAL TUMORS

Granulosa cell tumors
• Include granulosa cell tumors, thecomas and fibromas
• Cells of granulosa cell tumors produce estrogenic or, less
commonly, androgenic steroids
• May secrete other factors such as inhibin and mullerian inhibitory
substance, useful as tumor markers during follow up
• Surgery alone is sufficient therapy

Sertoli-Leydig cell tumors
• Most produce androgens
• present with symptoms of virilization
• Treatment – unilateral salpingo-oophorectomy with evaluation of
contralateral ovary
- TAH and BSO in older patients

OTHER TUMORS
Lipoid cell tumors
• Rare
• Arise from adrenal cortical rests near ovary
• Treatment – surgical
Ovarian sarcoma
• Extremely rare
• Most occur in postmenopausal women
• Aggressive and die within 2 years
Lipoma of ovary
• Usually bilateral, especially with Burkitt lymphoma
• Treatment is as for lymphomas else in the body

Pregnancy with Ovarian Cancer
• All pregnant patients have luteal cysts, which should be <5 to 6
cm in diameter
• Masses that are larger or continue to enlarge over several
weeks should be examined by laproscopy at 16 wks of
gestation
• Management is the same as for non-pregnant patients who
desire childbearing

Screening and Early Detection
• The potential benefit of screening is its ability to identify ovarian
cancer at a more localized and curable stage, leading to
reduced mortality from the disease
• Risk reduction bilateral salpingo-oophorectomy (RRSO) is
currently the most effective preventative strategy to reduce
ovarian cancer risk in patients with B R CA mutations.

• Other risk-reducing strategies such as tubal ligation and
hysterectomy have also been associated with a reduced
incidence of ovarian cancer among high-risk women.
• Women with a family history of breast/ovarian cancer should be
offered genetic counseling

• Familial ovarian cancer syndrome patients and known
BRCA1/2mut carriers who have not undergone (RRSO) may be
offered screening consisting of
 a pelvic examination,
 TVU, and
 a CA-125 blood test
every 6 months beginning between the ages of 30 to 35 years, or
5 to 10 years earlier than the earliest age of first Epithelial ovarian
cancer (EOC) diagnosis in the family.

The lifetime risk of ovarian cancer
• BRCA 1 mutations - 20% to 40%
• BRCA 2 mutations - 1 0 % to 20
The majority of BRCA 1-associated cancers
• Serous adenocarcinomas,
• with an average age at diagnosis of 48 years
The mean age for BRCA 2-associated ovarian cancers is 60 years.

Reference
• DeVita, Hellman, and Rosenberg’s Cancer. Principle and
Practice of Oncology. 2011. 9th edition.
• Handbook of Evidence-Based Radiation Oncology. 2010. 2nd
edition
• Manual of Clinical Oncology. 2012.
• Seventh EditionMahmood I. Shafi, Helena M. Earl and Li Tee
Tan. Gynecological oncology. Cambridge University press.2009.
• NCCN guidelines. Ovarian version 2.2015.
• Textbook of Medical Oncology. 2009. 4th edition.

Ovarian Cancer

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