1.Ovarian CA

8/12/2019 1.Ovarian CA

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Tumor markerslimited values because of

difficulties with sensitivity and specificitys

AFPHCC: chorioca

HCG- hydatidiform mole: chorioca

Co 125endometriosis; non mucinous

epith. Tumor CEAmucinous cystadenocrvinoma, ca

colon


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DIFFERENTIAL DIAGNOSIS

full bladder

pregnancy (6-10wk)

uterine fibromyomata chronic salpingitis

endometriosis

leiomyoma

PIDwith hydrosalpinx/tuboovarian complex/ abscess.

Faeces

Pelvic kidneys


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INVESTIGATION:

Abominal / pelvic ultrasound

Tumour markers

hCG + alfafetoprotein: functional germ cell tumour

Ca 125: non mucinous epithelia tumour/ endometriosis

CEA : mucinous custadenocarcinoma.

Chest radiograph.

IVU/ barium enema.


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MANAGEMENT:

Surgery

benign tumour and reproductive age: conservative surgery

malignant and young , family not completed , stage 1 confined to single ovary

unilateral salpingo- oophorectomy

others: TAHBSO + omentectomy

Chemotherapy:

Epithelial ovarian cancer- one of the solid tumors that response to chemo.

Adjuvant following surgical resection or cystoreductive surgery -^ survival

Cisplatin or carboplatin.

Aggressive surgery and intensive chemotherapy have increased the median survival

rate, but 5 yrs survival , barely change.

Radiotherapy:

very little part to play.

Not very helpful.

Dysgerminoma- uniquely radiosensitive.


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CLINICAL FEATURES:

Usually no sx

Lost of weight and general malaise , feel ill ,

paradoxically think that they are not really losing weightbecause their waist line is the same or even increasing

(ascites)

Pain: tersion , rupture , haemorrhage , infection.

Pressure; urinary retention , ^freq. Endocrine effect: precocious puberty, irregular menses,

PM bleeding,

Malignant: indigestion , anorexia, malaise , abdomen

discomfortbowel symptoms, late stage: weight loss,ascites, very ill.


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SURFACE EPITHELIAL CELL TUMOR

Serous Cystadenoma:

General: - common benign, reproductive yrs, age: 30-40

. 25% bilateral, Gross: any size, serosa covering, smooth + glistering,

small cystic- single cavity, larger one multilocular, divide

by septa,

HPE: - single layer of cuboidal epithelial, cell ciliated withsecretory cell- resemble epithe. Of fallopion tube.

Contain psammoma bodies, concentrically lamilated

Serous cystadeno carcinoma: commonest 10

Ca. 66%bilateral, rapid spread


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Mucinous cystadenoma;

Gen: commonest large. 3rd-4thdecade

Gross: multilocular, cyst separated by fibrous septa,

mucin glycoprotein, burst spontaneously, secrete mucininto pelvic cavity + pseudomyxoma peritonei~ extensive

adhesion with bowel obstruction.

HPE: cyst wass cinsists of fibrous septa, loculi- lined by

tall columnar epith.resemble endocervical epith. Epith.

Layer 1 cell thick may assoc. with branner tumour +

benign teratoma.

Endometroid: mostly malignant


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GERM CELL TUMOR

Benign cystic teratoma:

Gen:

Commonest germ cell T. 20% bilateral, age: 20-

30 years, 80%?, derived from >2 primitive germ

cell layers, Gross: usually unilocular , diameter


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SEX CORD STROMAL TUMOUR: Granulosa + theca cell:

Majority of functioning tumor ate potentially malignant, usually late

reproductive age/ early menoP

Path: granulosa cells vary gem microscopic, foci to large, solid + cysticencapsilated mass, yellow on cut surface

Thecoma: firmsolid, contain lipid droplet , closely resemble fibroma,

Clinical feature:

Occur before puberty , breasts grow , endometrial bleeding

reproductive life, small oest, period regular . discovered when torsion,oest^^- period irregular , very ^^ oest- amenorrhoea, oest, fallwithdrawal

bleeding,

post menopausal period , - post meno /aural bleeding associated with cystic

endometrial hyperplasia , Ca endometrium. Enlarge breasts,


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OV RI N C RCINOMClinical Staging

Diagnosis

Treatment

Prognosis

Haslin Ramli

Year 5(Group 6)

6 Sept 2005


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CLINICAL

STAGING


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FIGO staging for primary ovarian carcinoma.

Stage FIGO definition (simplified)

I Growth limited to ovaries

Ia Growth limited to one ovaryno ascites, no tumour on external surfaces, capsule intact

Ib Growth limited to both ovaries

no ascites, no tumour on external surfaces, capsule intact

Ic Tumour either stage Ia or Ib but tumour on surface of one

or both ovaries / with ascites present containingmalignant cells

II Growth involving one / both ovaries with pelvic extension

III Growth involving one / both ovaries with peritoneal

implants outside the pelvis or positive retroperitoneal /

inguinal nodes.Superficial liver metastases.

IV Growth involving one / both ovaries with distant

metastases

Positive cytology of pleural effusion

Parenchymal liver metastases.


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DIAGNOSIS


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DIAGNOSISSymptoms :

Abdominal pain / discomfort

Abdominal distension / feeling a lump

Indigestion, urinary frequency, weight loss Abnormal menses / post-menopausal bleeding

Signs :

Abdominal mass arising from pelvic

A fixed, irregular, hard pelvic mass -by VE, PR

Ascites, enlarged nodes (neck & groin)

Investigation :

FBC, BUSE, LFT

CXR

Barium enema / colonoscopy (to differentiated between colonic u

tumour and ovarian tumour & assess bowel involvement) Intravenous pyelogram (ds in adjacent pelvis structures)

Ultrasound (confirm mass, detect ascites), CT-scan.

Ca125 estimationto calculate a risk of malignancy score


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MARKERS FOR EPITHELIAL TUMOURS

Ca125- Marker commonly use

- Detect the antibody of the ovarian tumour cells

- Assess response to chemotherapy

- Can be normal in presence of small tumour deposits.

- Can also be raised in benign conditions such as endometriosis.


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TREATMENT


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SURGERY

-mainstay for both diagnosis &

treatment-vertical incision: facilitate removal of

neoplasm & permit adequatevisualization of entire abdominal

cavity-sample of ascitic fluid / peritoneal

washings with normal saline: forcytology

-therapeutic objective: removal of alltumour (achieved in majority stage I& II)

+ additional therapy (stage II); d/tmicroscopic deposits still persist.


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Surgery for epithelial ovarian cancer

Primary surgery (determine diagnosis &

remove tumour)

total abdominal hysterectomy

bilateral salpingo-oophorectomy

infracolic omentectomy


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Conservative primary surgery (unilateralsalpingo-oophorectomy)

young, nulliparous women, stage Ia disease

no evidence of synchronous endometrial ca(currettage uterine cavity)

no metastatic (carefulexploration)

Borderline tumours

Young women: ovarian cystectomy /

oophorectomy Older women: hysterectomy & bilateral

salpingo-oophorectomy


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Interval debulking surgery (2ndlaparotomy)

Women with bulky disease after primary

surgery

Must respond after 2-4 courses ofchemotherapy

Chemo resumed after surgery

Second-look surgery

planned laparotomy at the end ofchemotherapy

(to determine response to previous therapy,to plan subsequent management & excise any

residual disease)


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Selecting patients with post-op treatment

- Women with stage Ia or Ib & well-moderately-

differentiated tumours may not require further

treatment

-Others (stage Ic) require adjuvant therapy


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RADIOTHERAPY

-Almost never used in routine management

- A potential exception is radio-immunotherapy,

intraperineally in which radioactive Ytrium is

linked to a monoclonal antibody whichrecognizes an antigen found on most ovarian

cancer. Given intraperitoneallyremains an

experimental Rx


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CHEMOTHERAPY

Chemotherapy for epithelial ovarian ca :

stages II-IV - possibly stage Ic;

carboplatin / cisplatin & taxol

- To prolong clinical remission n survival & for

palliation in advanced n recurrent disease

- Commenced ASAP after surgery, usually givenfor 5/6 cycles at 3-4 weekly intervals


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Cisplatin

very toxic, severe nausea n vomiting, permanentrenal damage (give with adequate hydration-IV

fluids), peripheral neuropathy n hearing loss,electrolyte disturbances, anaemia

Carboplatin

less nausea n vomiting, no significant renal toxicity

Paclitaxel (taxol)

given as a 4 hour infusion after a premedicationregime of dexamethasone 20mg, diphenhydramine50mg and ranitidine/cimetidine to preventhypersensitivity reactions

S/E : sensory neuropathy n neutropenia, myalgia narthralgia, loss of body hair, bradycardia nhypotension, nausea n vomiting


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PROGNOSIS


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PROGNOSIS

Borderline ovarian epithelial tumours confined to

the ovaries: good long term prognosis

15-year survival for serous type is around 90%

(even with extra-ovarian spread)

stage III mucinous tumours, 15 year survival rate isonly 44%

Invasive epithelial ovarian cancer

depend on stage, size of residual tumour at the end

of initial surgery & grade of tumour

5 year survival rate ranges: 60-70% (stage I) to 10%

(stages III-IV)


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NONEPITHELIAL TUMOURS

SEX CORD STROMAL

Granulosa cell tumour

Theca cell tumour

Sertoli-Leydig tumour

GERM CELL

Dysgerminoma

Yolk Sac tumour

Teratoma


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Treatment of non-epithelial tumours

SEX CORD STROMAL TUMOURS

Mainly treated by surgery

hysterectomy and bilateral

salpingo-oophorectomy

Unilateral salphingo-oophorectomy

only in young women with Stage Ia

disease

Chemotherapy (when required)

same regimens as used for

epithelial tumours

GERM CELL TUMOURS

Mainly conservative

surgery because thepatients are usually young

Combination chemo. Is

highly effective when

required


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DR AMIR

O&G DEPARTMENT

HUSM


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INTRODUCTIONAccounts for 25 % of gynae malignancy but 50 % of death

of gynae malignancy.Rates varies between countriesrelate to reproductive

pattern.HighestScandinavian & UK

Lowest : Africa, India, Far east

In UK :4thcommonestafter breast, colorectal & lungs cancer.

6 % of all ca death ( > all gynae ca combine together )

In general :

90 % - benign10 % - malignant :

90 % - epithelial

10 % - non epithelial

80 % present in advanced stage : 5 yr survival30 %


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RISK FACTORS1. Non epitheliallittle is known

Malignant germ cellsmaternal use of hormones in 1sttrimester.

2. Epithelial : Reproductive & genetics

Reproductive :Nulliparity

Low parity

Infertility treatmentovulation inductionEarly menarche & late menopause.

Genetics : 5 %a. Inherited mutation in :

BRCA 1 genes :

Breast ca60 %Ovarian ca50 %

BRCA 2 genes :Breast ca80 %

Ovarian ca25 %

b. Type 2 Lynch Syndrome : colon, breast, ovary, endometrial ( maleprostate )


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CLASSIFICATION

a. Morphological classification : WHO 99- Most widely used

b. Histological classification : Shaw pg 679

Morphological classification :

Based on type of cells

1. Epithelial

2. Germ cells3. Sex cord stromal


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DIAGNOSIS

1. Detail Hx :High index of suspicion required

Asymptomatic in early stages.

a. In those with symptomsnon specificVague abdominal discomfort - commonest

Indigestion

Feeling of abdominal lump

Pressure symptoms

Menstrual irregularities

b. Age :Older women ( 5070 yrs )EOCYounger ( 2nd& 3rddecade )germ cells

( sex cord stromalany age )

c. Risk factors: reproductive & family Hx


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DIAGNOSIS.

2.Complete physical examination:Including breast, pelvic & PR examination

Majorities will have findings :

Palpable abdominal massMetastasis :

ascites,

pleural effusion,

enlarged inguinal / supraclavicular nodes,

leg edema,

cachexia.

G OS S


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DIAGNOSIS.3. Investigationsa. Tumour marker:

Older : Ca 125 & CEAYoung : hCG & AFPmandatory ( germ cells tumor )

b. Radiological imaging :1. U/S:

confirm the mass

Liver metastasis , sometimes pelvic/paraaortic LNTVS > sensitive than TAS

2. CXRmetastasis

3. CT scan abdomen & pelvisshould be done to delineate extendof disease.

4. Ba enema: bowel symptoms

5. Mammogram

c. Haematological: FBC , BUSE, RFT/LFT

d. Cytology: pleural effusion

e. FNAC: clinically suspicious nodesneck or groin


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Tumor Markers

Epithelial tumor markers

Main1. Ca 125

Elevated in 80 % of EOC

Limitations :

Elevated in only 50 % of intact stage 1 disease.

Also elevated in :Other malignancies : endometrial , pancreatic, lungs, breast,

colon ca.

Benign conditions: adenomyosis, PID, Diverticulitis,inflammatory bowel disease, endometriosis, menstruation.

Other epithelial markers

2. CEA

May be raised in mucinous cystadeno ca

Usually reflect intestinal pathology.


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Tumor Markers.

3. MCSF , Ca 15-3, Ca 19-9, OVX 1, OVX 2, & GAT

- when used with Ca 125 : increased sensitivity &

specificity- Non specific when used alone.

4. Inhibin : mucinous ca


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Tumor Markers.

Specific tumor markers :

1. AFP: Yolk sac / Endodermal sinus tumor

2. B-HCG: Chorio ca

Dysgerminoma ( 3 % ) occasionally

3. LDHDysgerminoma ( metastasis )

4. Estrogen: Granulosa cell tumor

5. Androgen: Sertoli Leydig cell tumor

S G G


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STAGINGI Confined to ovariesIA

Confined to 1 ovary,intact capsule,

no tumor on ovarian surface,

no malignant cells in ascites/peritoneal washing.

IB

Limited to both ovariesCapsule intact

No tumor on ovarian surface

no malignant cells in ascites/peritoneal washing.

ICLimited to one or both ovariesWith any of the followings :

Capsule rupture,

tumor on ovarian surface,

malignant cells in ascites/peritoneal washing.


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II Involvement of 1 or both ovaries with pelvicextension

IIAExtension and/or in uterus and/or tubes

No malignant cells in ascites/peritonealwashing.

IIBExtension to other pelvic organ

No malignant cells in ascites/peritonealwashing.

IIC

IIa/IIB with positive malignant cells inascites/peritoneal washing.


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III Involvement of 1 or both ovaries withmicroscopically confirmed peritonealmetastasis outside the pelvis and/or regional

LN metastasis.IIIA

Microscopic peritoneal metastasis beyond the pelvis

IIIB

Microscopic peritoneal metastasis beyond the pelvis, 2cm or less in greatest dimension

IIIC

Peritoneal metastasis beyond pelvis, > 2 cm in greatest

dimension and/or regional LN metastasis

IV Distant metastasis beyond peritoneal cavity.


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Management - EOC

1. Staging Laparotomy

Accurate staging is vital for :Prognostic

Adjuvant therapy

Procedure :Midline incision

Peritoneal fluidcytology

No peritoneal fluidirrigation with NS

- Washing sent for cytologyExamination of all peritoneal surfaces

Biopsy of suspicious areas

Ovarycheck for capsular rupture.


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2. Treatment :

Surgery

Chemotherapy

Early stages : I or II

Stage Ia & Ib, grade I :

Surgery alone is curative

TAHBSO + infracol ic omentectom y

Stage Ic, higher grade stage Ia & Ib :Should consider adjuvant chemo

Controversial

Stage IIshould receive adjuvant chemo

LEVEL A EVIDENCE


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Fertility sparing :

Unilateral oopherectomy can be performed

Criteria :

Adequate staging : staging laparotomy

Intraoperative finding of unilateral ovarian tumor

with intact capsule ( stage Ia )

Normal contralateral ovary

Ad St III & IV


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Advance Stages : III & IV

Usually symptomatic

All patient who are fit for surgerySHOULDundergo laparotomy & optimal cytoreduction.# Those initially not fit for surgery or primary

cytoreduction was suboptimal - Interval debulking

may be considered after 3 chemo cycles.

After cytoreduction : ALLSHOULDreceiveadjuvant chemotherapy :

1st

choice :paclitaxel or docetaxel ( less neurotoxic )

+

carboplatin


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Chemotherapy For EOC

Recommended regimes :

Paclitaxel 175 mg/m2over 3 H +

Carboplatin AUC 6 over 1 H

or

Docetaxel 75mg/m2over 1 H +

Carboplatin AUC 5 over 1 H

* Dose of carboplatinbased on Calverts formulausing creatinineclearance calculated with mathematical formula, not using EDTA method.


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Chemotherapy For EOC..

Other regimes :

Paclitaxel 135 mg/m2 over 24 H +

Cisplatin 75 mg/m2 over 6 H

orPaclitaxel 175 mg/m2 over 3 H +

Cisplatin 75 mg/m2 over 6 H


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Prognosis :Stage at diagnosis

Volume of residual disease

Histology subtype & grading

* Most importantstage & residual disease


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Follow upMalignant EOC

In general :

1styearevery 3/121st5thyear : 4 - 6 monthly

5thyearannually

Each f/u :

Detail HxComplete physical examination : including breast, pelvic & rectal

Ca 125at regular interval

Radiological testU/S , CT scan, MRIwhen clinical findings ortumor marker suggest recurrence

Intact Cxpap smear

MammogramAbove 40 yrsyearly

Younger patient with strong family Hx


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Mx of Relapse EOC

Majorities will relapseMainstay : chemotherapyDrug of choicedepends on previous regime

Efficacy :

Depends on dis ease free intervalafter 1stlinechemo.

The longer disease free intervalthe betterresponse to treatment

Disease free interval of :> 6 monthplatinum sensitive

< 6 monthplatinum refractory


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A. Platinum Sensitive:

2 options :1. Single agent platinum : carboplatin /

cisplatin

2. Clinical trial : carboplatin + othercytotoxic/non cytotoxic

Localized recurrence : may benefit from 20

cytoreduction ( controversial )( GOG trial onthis, just completed : result awaited )


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Relapsed based on tumor marker :

AsymptomaticOptions :

1. Close observation

2. Hormonal therapy :Drugs : tamoxifen, GnRH analogue, combined

Estrogen & Progesterone or progestogen.

Less side effect as compare to chemo

Response rate : 814 %Response usually in wellmod differentiated or in

endometriod type.

N E ith li l T


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Non Epithelial Tumors1. Germ Cell Tumor

Among the most high ly curable cadue to itschemosensitivity.

Unilateral, except dysgerminoma ( bilateral in 10-15 % )

Age peak2nd& 3rddecade.

# because of all these reasons, fert i l i ty sparing su rgery

shou ld be the rule, even in th e presence of

metastasis.

Most aggressive : yolk sac & chorio ca

Chemo can cure majority of even patient, even with

advanced disease.


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Classification: histologicallyImportant for prognostication & chemotherapy.

1. Dysgerminoma2. Non Dysgerminoma ( embroyonal ca )

Embryonal differentiation :

Mixed

Mature

Immature

Extraembryonal differentiation :

Chorio ca

Yolc sac / endodermal sinus

Extraembryonic ca


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TreatmentStagingsimilar with EOC

Conservative surgery :

Standard in al l stages

Staging laparotomy + limited cytoreduction (contralateral ovary & uterus are kept )

a. Dysgerminoma ( radio & chemosensitive )Stage Iano chemo required

Beyond Stage Iachemotherapy

Chemo regime : BEP

Radiotherapy :

As effective as chemo in early stages.

However it causes ovarian failure

If chemo is contraindicated, radiotherapy is an option.


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F ll ( ll t )


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Follow up ( germ cell tumor ) :Relapse usually occur within 2 yrs

Frequency1styear1-2 monthly

2ndyr2/12

3rdyr3/12

4thyr4/12

5thyr5/12

6thyr onwardannually

During f/uDetail Hx

Physical examination

Tumor markers

Tumor markers :DysgerminomaLDH + bHCG

Non dysgerminomaLDH, AFP & HCG

2 Gran losa Cells T mor


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2. Granulosa Cells Tumor

3-5 % of ovarian ca

Commonest sex cord stromal tumor

Secretes estrogen ( 75 %) & rarely androgen.

Type :Juvenilepresent with precocious puberty ( high estrogen )

Adultmore common

Predominantly in post menopause.

Present with post menopausal bleeding

Majority present in stage I

Bilateral in 5 % only

Nature : slow growing with tendency for late recurrence.


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Treatment :Stagingas in EOC

Mainstay : Adequate cytoreductionConservative surgery : can be considered in stage I

Adjuvant chemo :

No evidence of its benefit ( as it is a rare tumor )

Based on small studies :Stage Ino need chemo

Stage II & IIIsome advocate chemo.

Recurrence :

Surgically treated if possibleChemo :

Palliative

Platinum based + other agent

Any centers : BEP regime


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Management Of Ovarian

CancerDr Dayang Marshitah Mohammad


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Introduction..

Leading cause of death in female gynaecological cancerin UK and USA

Annual death in UK4000 cases , exceed figure ofcarcinoma of endometrium and cervix combined

In Malaysia ,2nd

leading cause of death after cancer ofcervix

Life time risk1.7 %

Incidence is 4050 / 100 000

3 / 4 of cases presented with advanced stage

Despite the introduction of new chemotherapeutic agentthe poor survival rates have changed little over the past30 years

T t f t i f l


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Ten most frequent cancers in female

Peninsular Malaysia 2003 ( NCR )

Breast cancer - 35 %

Cervix uteri - 12.6 %

Colon - 6.0%

Corpus uterus - 4.3%

Rectum - 4.1% Ovary - 4.1 %

Leukaemias - 4.0 %

Lung - 3.8 %

Stomach - 2.9 %

Skin - 2.7 %


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Aetiology..

Incessant ovulation theory high risk to developovarian cancer in nulliparous women or women with low

parity.Risk is lower in high parity ,breastfeeding and oral

contraceptive userreduction of risk of having ovarian

cancer with regular use of OCP is 36 % and up to 70%after 6 years of use

Family history of ovarian cancer :

- Up to 10 % of ovarian cancer are hereditary

- 5.8% related to mutation in BRCA 1 ( lead to 4060 %)

- 3.7 % related to mutation in BRCA 2 ( lead to 10

20%)


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Aetiology..

- 1% related to Hereditary Non Polyposis colorectal cancerLynch type II variant of HNPCC has 510 % life timerisk to develop ovarian cancer and 30 % risk ofdeveloping endometrial cancer

Environmental Factors :- Asbestos and talc containing hydrous magnesiumsilicates have been implicated

-Dietary factorshigh fat , low fibre diet has beenassociated with ovarian cancer

- No clear association found in high caffeine intake ,exposure to radiation or certain viral infectionsmumps, rubella , influenza


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Histogenetic Classification of Ovarian Neoplasm

Derived from coelomic epithelium

- Serous

-Mucinous

-Endometrioid

-Clear cell ( mesonephroid )

- Brenner

-Mixed epithelial

-Undifferentiated-Carcinosarcoma and mixed mesodermal tumour


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Histogenetic Classification of ovarian neoplasms

Sex CordStromal tumours- Granulosa cell tumour

- thecoma

- androblastoma ( Sertoli Leydig cell tumour )

Germ cell tumour- dysgerminoma

- yolk sac tumourendodermal sinus tumour

- choriocarcinoma

- immature teratomas-embryonal cell carcinoma

- mixed germ cell tumour


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Histogenetic classification..

Derived from nonspecific mesenchyme

- fibroma ,haemangioma,leiomyoma,lipoma

-lymphoma

-sarcoma

Neoplasm metastatic to the ovary

- GIT tract ( krukenberg )

- Breast- Endometrium

- lymphoma


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Epithelial ovarian tumour

In uteroovary first appear as an aggregation of cells covered withprimitive coelomic epithelium.

Germ cells migrate from yolk sac into gonadal area.ceolomic

epithelium that cover the ovarygive rise to variety of epithelium of

mullerian in origin,line genital tract , fallopian tubes, uterus and

cervix

Well diff serous carcinoma resembles epithelium in Fallopian tubes ,

whereas in endometrioid tumourssimilar appearance with cells in

endometrial gland.

Serous tumor4050 %,mucinous12%, endometrioid ca

15%,clear cell ca6% ,undifferentiated ca- 17%

Commonly presented as bilateral in serous carcinoma


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Sex cord tumour

Includes those that contain granulosa cells , theca cells and luteinizedderivatives , sertoli cells , leydig cells and fibroblast cell

Account for 5% of all ovarian tumour

Granulosa cell tumourdivided into 2 subtype adult GCT and juvenile

Adultmore common than juvenile type95%

Commonly in postmenopausal women Oestrogen secreting tumour may lead to endometrial hyperplasia or endometrial

carcinoma

Few can secrete androgen

Juvenilemostly occur in first 3 decade of life

If occur in children a/w sexual precocity

Overalltrue GCT are low grade malignancies , usually confined to the ovary atthe time of diagnosis and has excellent prognosis

Only 5-10% stage 1 will recur and usually rec - > 5 year

Tumour marker - inhibin


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SertoliLeydig Cell tumour

Also known as androblastoma / arrhenoblastoma

Very rareaccount for 0.5% of all ovarian tumour

Most often occur in young womenvirilizing tumour

temporal balding , deepening of voice,hirsutism and

clitoromegaly

Considered as low malignant potential , good prognosis

Five year survival are reported up to 92%


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Germ cell tumour - classification

Germ Cell tumour

Dysgerminoma

Endodermal sinus tumour

Embryonal carcinoma

Polyembryoma

Choriocarcinoma

Teratomaimmature

- mature- monodermal or highly specialized -

struma

ovary


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classification..

Mixed germ cell tumour

Tumour composed of germ cells and sex cord stroma

derivative :

Gynandoblastoma

Mixed germ cell tumoursex cord tumour


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germ cell tumour

Overall , germ cell tumour account for 20% of all ovarianmalignancies

Usually occur in young women

Duration of symptom usually short , presented with rapidly growing

mass associated with abdominal pain

Dysgerminoma : commonest germ cell tumour

majority in young women but also reported to occur

in infancy and old age

bilaterality occur in 1015% ( the only germ cell

tumour)tumour markerLDH , hCG

- highly sensitive to radiotherapy


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germ cell tumour

Yolk sac tumour2ndcommonest germ cell tumour Median age is 19 year old

Extremely rapid growth tumour with intraabdominal spread

Most patient had elevated level of alfa feto protein

Previously , prognosis for patient with endodermal sinus tumourof the ovary has been unfavourable with median survival up to

1218 months of diagnosis

With introduction of multiple chemo regime,improvement in

median survival has been noted

Chemo regime : VAC(vincristine,adriamycin,cyclo),VBP(vinblastine,bleomycin,cisplat),

BEP(bleomycin,etoposide,cisplatin)


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Sign and Symptoms

75 % already in advanced state.

Common symptomabdominal bloatedness ,dyspepsia

,palpable mass per abdomen.

Others due to pressure symptomfrequency ,

constipation or pain

Symptoms of metastasisshortness of breath , gradual

abdominal distention

Rarelyhormone producing tumourandrogenic

manifestation of Sertoli Leydig Cell tumour orpostmenopausal bleeding


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Spread of the disease..

Mainly into peritoneal cavity / direct spread :

- direct spread to adjacent organ eg fallopian tubes ,

uterus

- later on to peritoneal cavity especially the omentum

omental cake

peritoneal surfacesseedlings, diapghram

- lymphaticspelvic and para aortic nodes

- haematogenous spreadoccur in advanced case,

spread to liver parenchyma , lung, bone or CNS


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Investigation

Routine invest. : ultrasound examination of the abdomenand pelvis,full blood count ,biochemical profile , tumourmarker eg CA 125 , CEA , alpha feto protein , LDH , hCG and chest X ray

Other investigation may be appropriate in view ofplanning before operation eg : CT Scan abdomen orpelvisgive information regarding extent of the tumorand delineate ureters or intravenous urographyspecifically to see outline of ureter if clinically pelvic

mass is fixed Investigation to rule out primary sitemetastatic to

ovary can be due to ca breast , colonic ca , stomachcancer and bronchial carcinoma


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Tumour marker

CA 125a glycoprotein , cancer associated antigen- a non specific tumour marker, usually elevated in manybenign gynaecologic condition eg fibroid,pelvicinflammatory disease , endometriosis or functionalovarian cyst. Also elevated in liver disorder , nonmalignant ascites , CCF , pneumonia,connect tissue ds

Usually elevated in epithelial type of ovarian ca ,nonmucinous type.

Role of CA 125 as a screening for ovarian cancer in

general population is not reccomendedlow positivepredictive value

Useful in monitoring progress of patient afterchemotherapy and during follow up


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Management..

Staging LaparotomyA full and complete staging laparotomyshould be done for every patient diagnosed to have ovarian cancer

Steps in staging laparotomy :

- midline longitudinal incisionfacilitate removal of neoplasm ,permit visualisation of entire abdominal cavity , palpation of under

surface of diapghram- Take peritoneal fluid for cytologyat least must take from 4 place:subdiagphramatic , right and left paracolic spaces and pelvic region

-careful inspection and palpation of peritoneal surfaces

-Biopsy of all suspicious lesion

-Random biopsy of normal appearing peritoneal surfaces-TAHBSO

-Selected pelvic or paraaortic lymphadenopathy

-Infracolic omentectomy


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FIGO Staging of Ovarian Carcinoma

Stage 1 Growth limited to the ovaries

Stage 1a Limited to one ovary , no ascites , no

tumour on capsule , capsule intact

Stage 1b Limited to both ovaries ,no ascites ,no

tumour on external surfaces , capsuleintact

Stage 1c 1a or 1b with tumour on surfaces ,

capsule rupture , positive

malignant cells by ascites Stage 2 Growth involving one or both ovaries

with pelvic extension

FIGO St i


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FIGO Staging..

Stage 2a Extension and /or metastases to theuterus and/or tubes

Stage 2b Extension to other pelvic tissue

Stage 2c 2a or 2b with tumour on surface ,

ruptured capsule,positive ascites

Stage 3 tumour involv . One or both ovaries

with peritoneal implants outside the

pelvis and /or positive retroperitoneal or inguinal

nodes Stage 3a limited to true pelvis , with

histologically confirmed microscopic seedling

FIGO S i


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FIGO Staging..

Stage 3b Tumour of one or both ovaries withabdominal implants less than 2

cm , nodes negative

Stage 3c Abdominal implants > 2cm , positive

retroperitoneal nodes or inguinalnodes

Stage 4 growth involving one or two ovaries

with distant metastasis , if

pleural effusion is present , theremust be positive malignant

cells,liver parenchymal mets

five year survival rate ( FIGO annual


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five year survival rate ( FIGO annual

report 1994 )

Stage 1a 83 % Stage 1b 79 %

Stage 1c 73 %

Stage 2a 64 %

Stage 2b 54 % Stage 3a 51 %

Stage 3b 29 %

Stage 3c 17 %

Stage 4 14 %

St 1 1b 1


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Stage 1a ,1b, 1c

TAHBSOthe best therapeutic management

Omentectomy is also done - as it harbour microscopic

disease and if adjunctive intraperitoneal therapy with

radioactive colloidal phosphorus is to be done

All clinically stage 1c will be given post operativeadjuvant chemotherapy

In stage 1a or 1b additional features such as grade of

tumour , histological type need to be considered

In stage 1a or 1b with grade 2 or grade 3 tumour, risk ofrelapse is highit is recommended to give adjuvant

chemo

St 2 2b d 2


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Stage 2a ,2b and 2c

TAHBSO with omentectomy is the treatment of choice inmany centres

Adjuvant therapy include systemic chemotherapy

Some centre prefer to use post operative abdominal and

pelvic radiotherapy as adjuvant or instillation ofintraperitoneal Phosphorus.

St 3 d t 4


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Stage 3 and stage 4

Debulking surgery is done to remove the tumour as much aspossible together with TAHBSO

As tumour mass usually big and fixed to other pelvic or abdominal

viscera,proper planning of surgery should be done by doing CT

Scan and bowel preparation.

Those who had maximal surgical debulking ( less than 2cm residual) had 5 year survival rate up to 28% compared to 9% if surgery done

with bigger residual disease ( Munnell )

Advantage of debulking surgerybulky solid tumour as ovarian

cancer had large number of cells in resting phase ( G0 ) ,by

removing it the residual cells can be propel to cell cycle.

Adjuvant chemotherapy using multiple agent is mandatory

postoperatively

l f h h


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role of chemotherapy..

Date Drug 5 year survival

1946 none < 3

1950 - 1960 Alkylatingagents

10%

1960 - 1970 Combination

chemotherapy

520%

1974 Cisplatin 2030%

1990 Taxol 15-20%

R l f h th


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Role of chemotherapy

Recommended in early stage ovarian carcinoma ; stage 1a or 1bgrade 2, clear cell histology

In early stage ovarian cancerACTION and ICON 1 study shown

that increase median free survival with adjuvant chemotherapy

absolute difference of 11% recurrence free survival at 5 years

Most centres would recommend treatment with platinum basedagent alone or in combination with paclitaxel following primary

surgery

NICE guidelines1stline therapy after surgery should be given

platinum based ( cisplatin or carboplatin ) alone or in combination

with paclitaxelNICE 2003 /2004

Advanced ovarian carcinomamost important are the amount of

residual disease left .

In advanced ovarian carcinomacombination chemo recommended



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Stage 1A-B; Grade 2-3, Stage 1C & 2A and all clear

cell cancer ICON-1(1991):

ACTION (1990):

Platinum based chemotherapy

Pooled data: Overall 5 year survival of 82% with

chemo versus 70% without chemo

Trimbos JB (2003), J Natl Cancer Inst 95(2):105-12

Stage 1A G1 do not need chemotherapy National Cancer Institute (2005)



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Commonly used regimes after primary surgery areCisplatin 75mg /m2 and Paclitaxel or carboplatin and

paclitaxel

Relapse ovarian caif platinum sensitive , can

rechallenge with similar agent . In platinum refractorymay benefit from paclitaxel if the agent was not a

component of primary therapy .

Other newer agent that can be used in advanced ovarian

cancer if first line therapy is failtopotecan , pegylatedliposomal doxorubicin , gemcitabine and vinorelbine

Treatment of Advanced


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Treatment of Advanced

Ovarian Cancer

ResponseClinical CR

Progression-Free Survival

Overall Survival

60%

31%

13 mth

24 mth

735118 mth36 mth

Mc Guire WP (1996) NEJM 334: 1-6

Piccart MJ (2000) J Natl Cancer Inst 92:699-708

Parameter

663612 mth25 mth

775016.6 mth35 mth

GOG 111 OV 10Cyclo/Cis vs Pac/Cis Cyclo/Cis vs Pac/Cis

Cisplatin/ Paclitacel vs


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p

Carboplatin/ Paclitaxel

Cis/Pac Carbo/Pac

Recurrence Free Survival21.7 mths 22 mths

Negative second look

laparatomy42.5% 55.5%

GOG 158


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ICON - 3

2074 patients (132 hospitals, 8 countries)

Carbo or CAP versus Carbo/Paclitaxel

No difference in progression free survival or overall

survival Problems

Cross over

Quality control (surgery, pathology)

Harper (1998) MRC Clinical Trials Unit

St & C


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Stage & Crossover

FIGO Stage (%)

1C

23,4optimal

3,4 - suboptimal

-

--

100

-

730

63

9

1134

48

Early crossover (%) none 4 20-25%

GOG 111 OV-10 ICON 3

Mc Guire WP (1996) NEJM 334: 1-6

Piccart MJ (2000) J Natl Cancer Inst 92:699-708

Harper (1998) MRC Clinical Trials Unit

Role of neoadjuvant chemotherapy (NACT )


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Role of neoadjuvant chemotherapy (NACT )

In advanced ovarian carcinomaonly 35 % - 50 % ableto do optimal surgical cytoreduction ( Ozols et al 1996 )

NACT is indicated:

In selected patient who are poor operative risk

In massive ascites or massive pleural effusions

Randomised trial by EORTC ( Van de Burg 1995 )

shown that patient whom had NACT followed by

interval debulking surgery had longer progression free

interval and overall survival

NACT and interval debulking surgery


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NACT and interval debulking surgery..

Disadvantagelimited experience with this approach- higher morbidity to patients2 major

surgery done in shorter period of time

Role of second look laparotomy


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Role of second look laparotomy..

Previously a standard treatment in 1970 s and 1980s Mainly to evaluate patient who are free of disease after

primary surgery and chemotherapy given in order to

decide whether they still needed prolonged course of

chemotherapy or not No longer use as part of evaluation as 4050 %

negative 2ndlook laparotomy will have recurrence

disease

Second line chemotherapy


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Second line chemotherapy

Indicated in cases of recurrent or progressive disease Response rate are much lower1535 % versus 80 %

Better response in women with longer disease free

interval

Maintenance therapy : Extended treatment withchemotherapy up to 812 cycles :

- cisplatin has been usedincrease toxicity

- paclitaxelstill in research , not recommended for

outside clinical trialno benefit to overall survival

2nd line chemotherapy


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2 dline chemotherapy

NICE guidance recommendation for those notresponding to 1stline treatment in patient with advanced

ovarian cancertopotecan , pegylated liposomal

doxorubicin and gemcitabine

All have response rate of 20 % only Choice of drug depends on side effects and scheduling

that acceptable to patient

Oral etoposide also can be given with response rate up

to 26 %

Role of hormonal treatment


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Role of hormonal treatment

Oestrogen and progesterone receptor present in about40% in cytoplasma of malignant cell of ovary

Based on GOG trial only a modest response rate noted

to tamoxifen ( up to 18 % )

Often used in advanced , end stage ovarian tumourpalliative intent

Conclusion : no relationship between presence of

hormone receptors and efficacy of receptor antagonist in

ovarian cancer

Role of radiotherapy


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Role of radiotherapy

Include intraperitoneal radioactive chromium phosphateand EBRT to abdomen and pelvis.

Not suitable for bulky residual disease after laparotomy

Special problem with ovarian cancer :

- limits of tumour spread is often unknown

- variability of radiosensitivity

- total tumour burden usually very large

- dose restriction of other organs

-infrequent detection of early disease


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Newer therapies


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Newer therapies

Still under clinical research , expensive Examples :

- immunotherapyusing antibody to CA 125 antigen ,

murine monoclonal anti idiotypic antibody ACA

125,HMFG1phase 2 trial- gene therapy - using attenuated adenovirus that will

replicate and destroy tumour cells with the mutated p53

geneONYX015phase 1 trial

- signal transduction inhibitorsspecific inhibitors ofepidermal growth factor receptor tyrosine kinase eg

ZD1839 ( Iressa )still in phase 2 trial

Newer therapies


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Newer therapies

Angiogenesis inhibitorvascular endothelial growthfactor is an important target for anti angiogenic drugs in

solid tumours egBevacizumab ( Avastin )currently in

GOG trial phase 2

Thalidomidecurrent on going trial along with tamoxifenin a phase 3 GOG trialmainly for asymptomatic

ovarian cancer with rising CA 125 level after 1stline

therapy

Follow up technique and treatment of


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recurrence

No optimal follow up strategy after primary treatment completed Some centres still practice 2ndlook laparotomy , and following this,

follow up of 3 monthly within the first 2 year of diagnosis reccom

Parameters to be monitorhistory and physical examination

including speculum and v/e , radiological investigation and serum

CA 125 Radiological investigationCT Scan abdomen and pelvis after

finish chemotherapyto look at improvement and once a year

At 2 year anniversaryfrequency of follow up can be reduced to 6

monthly

CA 125should be done at every visit

Rapid regression of CA 125 value after commencement chemo

a/w favourable outcome

Follow up


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Follow up..

After debulking surgery, CA 125 can be elevated due tosurgical procedure itself and the effect can last forseveral week

Role of CA 125 in predicting recurrentnon specific

A rising CA 125 level occur before clinically detectedrelapse by a median of 4 month, but no evidence thatsuggested early treatment based on rising CA 125 orpositive imaging in asymptomatic patient improve longterm survival

Currently EORTC trial looking at whether to institutetreatment based on rising CA 125 only or delaying tillclinical relapse

treatment of recurrent


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treatment of recurrent..

Recurrent usually incurable and the main objectives of treatment inrecurrent is symptom control and improvement in quality of life

Chemotherapyprimary treatment in recurrent ( use of 2ndline

chemo

Surgery indicated in cases of intestinal obstructionsymptom

relieved Role of secondary cytoreductive surgerydepends on single site

recurrent , resectability , longer treatment free interval and likelihood

of relieving symptomsdifficult to establish whether 2ndary

debulking has any role in improving survival.

Familial ovarian cancer


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Familial ovarian cancer

Three type of familial ovarian cancer: 1. Site specific ovarian cancer syndromewomen at high risk to

develop ovarian cancer only

2. Breast ovarian cancer syndrome ( BRCA 1 & BRCA 2 )

3. Cancer family syndromeboth male and female member are

at increased risk of colonic ca and other type of cancer-gastricca, thyroid ca, and sarcoma. Female member are at high risk to

develop ca endometrium,ovary and breast ca

familial ovarian cancer


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familial ovarian cancer

Mode of inheritanceautosomal dominant , 50% risk can be predicted in allsiblings or offspring

BRCA 1 gene mutation4060% risk of developing ovarian ca

BRCA 2 gene mutation1520 % risk of developing ovarian carcinoma

Significant of family historymust include 3 generation , at what ageaffected and type of tumour ( if possible) , outcome of treatment

Implication of genetic testing that must be considered : Associated cancer risk

Available option for early detection

Option for prevention

Implication to other family member

Insurance Cost of the test , sensitivity , specificity

Interpretation of negative /equivocal test

BRCA 1 & BRCA 2


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BRCA 1 & BRCA 2

Management option :1. chemoprophylaxis with OCP

- based on population studyit is well known that use of OCP > 5years had reduced risk to develop ovarian cancer ( odd ratio 0.5 )

- it is also proven to reduce dev ovarian ca in BRCA 1 and BRCA 2

carrierCanadian study ( Narod et al 1998)- But study in Israel ( larger randomised ) found that OCP use onlydecrease incidence in non BRCA carrier

- how about breast cancer risk ?

- Evidence from Collaborative group studyslightly elevated risk ofbreast ca with current pill user

- study from National Institute of Child Health Human Development(multicentre US study )current user had relative risk of 1.0 andprevious user 0.9

-

chemoprophylaxis in BRCA 1 & 2


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chemoprophylaxis in BRCA 1 & 2

From NICHHDconcluded that current or former user of OCPamong women aged 3564 years does not significantly increase

the risk of breast ca

Evidence link to dev of breast ca with use of OCPage factor ,

duration of usethe effect of using OCP in BRCA gene mutation

carrier still no firm guideline2. Prophylactic surgery

- the only definitive treatment available is prophylactic

salpingoophorectomy ( PO )96 % reduction in BRCA carrier

prophylactic surgery..


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prophylactic surgery..

- Benefit of POif done before menopause , 50% reduction of indevelopment of breast ca

- what age to offer ?controversial issue

- US guidelinesuggest at 35 year old or after childbearing

completed

- risk of surgical menopausecardiovascular risk , osteoporosis andrisk of long term use of HRT to be discussed

- UKno guideline yet , decision is individualised

- timing of surgery depend on when balance of dev. Of ovarian

ca and breast ca in the family

- reasonable to offer at the age of 45 years or 5 years before

the index case in the family , whichever the earlier.

- post operationreasonable to offer HRT for short term relief of

menopausal symptom

Issues of screening in ovarian cancer


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g

Effective population screening toolBENEFITS SHOULDOUTWEIGH THE COSTS

The goal of screening for ovarian cancerable to detect early stage

asymptomatic disease and if test positive should proceed with

surgical investigation eglaparotomy or laparoscopy

Methods of detecting ovarian cancer :1. Physical examinationinsensitive , non specificit has been

calculated that 10,000 routine pelvic examination would be required

to detect one early stage ca in asymptomatic population.

2. Tumour markersuse of CA 125

- in premenopausal womenrelatively low specificity and sensitivity

- 50 % of stage 1 ovarian ca can have normal level CA 125

- if value of 35U /mlsensitivity varies from 71100% , specificity -

Methods of screening


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g

- 35 U / mlspecificity range from 6093%- improved specificity if combined with other additional marker egOVX 1 , LPA

- specificity also improved in postmenopausal women and also ifrising CA 125 level observed .

3. Role of ultrasound- depends on detecting subtle changes in ovarian volume andmorphology a/w early neoplasia

- In US study16 296 women undergone screening with USG, 18out of 524 that undergone surgery had ovarian caspecificity 96%but PPV only 3.4 %

- not suitable for population screening

- specificity improved to 99%using ovarian volume change at repeatscan , morphologic index and adding colour flow doppler


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In general , screening for ovarian cancer in general population is notreccomended and routine screening result in increase in

unnecessary surgical intervention.

On going trial, UK Collaborative Trial of Ovarian Cancer Screening (

UKCTOCS) currently recruiting 200 000 postmenopausal women

into 3 arm : CA 125 & TVS group , annual TVS alone and controlgroup.

Screening is indicated in high risk women that fulfill criteria for

hereditary ovarian cancer syndrome or UK National Familial Ovarian

Cancer Screening Study

UKNFOCSS


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Must be over 25 year old and a first degree relative of an affectedmember of a high risk family as defined by one of the

following:

1. Two or more first degree relative with ovarian cancer

2. One first degree relative with ovarian ca and one with breast

ca at age < 50 year old3. One first degree relative with ovarian ca and 2 first or second

degree relative with breast ca at age < 60 year old

4. Known to have predisposing genes

5. Three fisrt degree relative with colorectal cancer and at least

one first degree relative with ovarian cancer


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Reccomended screening for high risk group as above are annualmammography , transvaginal colour flow doppler study and serum

level of CA 125 starting at age of 35 year oldstill no evidence that

this method reduce mortality from ovarian cancer

1.Ovarian CA

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