MALIGNANT MALIGNANT DISORDERS OF DISORDERS OF THE OVARIESTHE OVARIES

Assoc. Prof. Gazi YILDIRIM, M.D.

Yeditepe University, Medical Faculty Dept of Ob&Gyn

To defineTo define Ovarian cancerOvarian cancer

To learnTo learn Risk factors for ovarian cancerRisk factors for ovarian cancer Prognostic factor for ovarian cancerPrognostic factor for ovarian cancer Diagnosis of ovarian cancerDiagnosis of ovarian cancer

To manage To manage A woman with ovarian cancer A woman with ovarian cancer

Objectives Objectives

The 5. most common The 5. most common cancer in womencancer in women

The 5. most frequent The 5. most frequent cause of cancer deathcause of cancer death

Lifetime risk 1/70Lifetime risk 1/70

•5-year survival rate <35%

•Mortality has decreased only

slightly in 30 years

•Most diagnosismade at advanced

disease

RISK FACTORSRISK FACTORS Cause of Ovarian Canceris unknown

Risk Factors High socio-economic status Early menarche Late menopause Few children Never used oral contraceptive Genetic (10%) Environment???

Dietary factors Exposure to talc Exposure to asbestos

>90% of ovarian cancer develops sporadically.

~10% of epithelial ovarian cancers are based on genetic

predisposition.

GENETIC PREDISPOSITIONGENETIC PREDISPOSITION

Chromosomal abnormalitiesChromosomal abnormalities Turner syndromeTurner syndrome Dysgerminoma, gonadoblastoma

Hereditary ovarian cancerHereditary ovarian cancerBOC (breast and ovarian cancer syndrome)BOC (breast and ovarian cancer syndrome)

BRCA-1 mutations on chromosome 17 and less BRCA-1 mutations on chromosome 17 and less commonly BRCA-2 mutations on chromosome 13.commonly BRCA-2 mutations on chromosome 13.

Lynch II syndrome (HNPCC syndrome)Lynch II syndrome (HNPCC syndrome)DNA mismatch repair gene mutationsDNA mismatch repair gene mutationsColon ca, ovarian-endometrial-breast cancerColon ca, ovarian-endometrial-breast cancer

Acquired genetic abnormalitiesAcquired genetic abnormalitiesP53 tumor supressor gene mutations, HER2/neu proto-oncogene P53 tumor supressor gene mutations, HER2/neu proto-oncogene activationactivation

Genetic Predisposition: 5-10% 0f Ovarian Cancer

Carriers of BRCA1 or BRCA2: 40% risk of ovarian

cancer BRCA1 and 2 Germ line

mutations: 10% of all ovarian

cancers 1-2% of all breast

cancers

HISTOPATHOLOGY OF HISTOPATHOLOGY OF OVARIAN CANCEROVARIAN CANCER

OVARIAN CANCER

EPITHELIALSerous

MucinousEndometrioid

Clear cellTransitional cellUndifferentiated

GERM CELLDysgerminoma

Endodermal sinus tmTeratoma

Embryonal carcinomaChoriocarcinomaGonadoblastomaPolyembryomaMixed germ cell

SEX CORD AND STROMAL

Granulosa cell tmFibromaThecoma

Sertoli-leydig cellgynandroblastoma

5% of ovarian cancer arises from metastases!! (breast, colon, stomach, endometrium, lymphoma)

EPITHELIAL NEOPLASMSEPITHELIAL NEOPLASMS Derived from the ovarian Derived from the ovarian surface surface

mesothelial cells.mesothelial cells. SerousSerous MucinousMucinous EndometrioidEndometrioid Clear cellClear cell Transitional cellTransitional cell UndifferentiatedUndifferentiated

Account Account >60% of all>60% of all ovarian neoplasms ovarian neoplasms and and >90% of malignant>90% of malignant ovarian tumors. ovarian tumors.

Serous Neoplasms Serous Neoplasms

Most commonMost common malignant tumor malignant tumor of the ovary.of the ovary. 35-50% of all epithelial tumors.35-50% of all epithelial tumors.

BilateralBilateral in 40-60 of cases. in 40-60 of cases. Extraovarian spreadExtraovarian spread at the time at the time

of diagnosis in 85% of cases.of diagnosis in 85% of cases. Cut sectionCut section: solid areas,areas : solid areas,areas

of hemorrhage,necrosis, cyst of hemorrhage,necrosis, cyst wall invasion and adhesions to wall invasion and adhesions to adjacent structures.adjacent structures.

Histology- serous carcinomaHistology- serous carcinoma

Mild to moderate nuclear Mild to moderate nuclear atypiaatypia

Psammoma bodyPsammoma body (irregular calcifications)(irregular calcifications)

The The grade of grade of differentiationdifferentiation is based on is based on the the degree of degree of preservation of the preservation of the papillary architecture.papillary architecture.

Mucinous NeoplasmsMucinous Neoplasms

Account for Account for 10-20% of 10-20% of allall epithelial ovarian epithelial ovarian neoplasmsneoplasms

The The second most second most commoncommon type of type of epithelial ovarian epithelial ovarian cancer.cancer.

Bilateral in <10%Bilateral in <10% of of cases cases (in contrast to (in contrast to serous tumors!!!!)serous tumors!!!!)

Large sizeLarge size

((~~16 cm)16 cm) Cut sections:Cut sections:

multilocular multilocular cysts filled with cysts filled with viscous mucin.viscous mucin.

Histology- mucinous carcinomaHistology- mucinous carcinoma

Composed predominantly of Composed predominantly of intestinal-like intestinal-like cellscells that invade surrounding stroma. that invade surrounding stroma.

Invasive tumors exhibit Invasive tumors exhibit marked histologic marked histologic variabilityvariability from area to area within the from area to area within the tumortumor..

The differentiation is based on the The differentiation is based on the preservation of the preservation of the glandlike architectureglandlike architecture of the tumor. of the tumor.

Extensive sampling required !!

Pseudomyxoma peritoneiPseudomyxoma peritonei Resulting from the Resulting from the

progressive progressive accumulation of mucin in accumulation of mucin in the abdominal cavitythe abdominal cavity..

Most commonly in Most commonly in association with association with low low malignant potentialmalignant potential..

Also with Also with cystadenocarcinoma of cystadenocarcinoma of the ovary and appendix, the ovary and appendix, mucocelemucocele of the of the appendix.appendix.

*potentially morbid secondary to repeated bowel obstruction.

Endometrioid NeoplasmEndometrioid Neoplasm

Exhibits an Exhibits an adenomatoid patternadenomatoid pattern that resembles that resembles endometrial adenocarcinoma.endometrial adenocarcinoma.

Bilateral in 30-50%Bilateral in 30-50% of cases. of cases. Arises rarely in Arises rarely in foci of endometriosisfoci of endometriosis (<10% of (<10% of

cases).cases). The degree of The degree of differentiationdifferentiation is based on the is based on the

extent to which the extent to which the glandular architectureglandular architecture is is retained.retained.

In In 30%30% of cases, there is a of cases, there is a synchronous synchronous endometrial carcinomaendometrial carcinoma of the uterus of the uterus

A second primary rather than a metastatic focus !!!

Clear Cell CarcinomaClear Cell Carcinoma

Also referred to as Also referred to as mesonephroid carcinomamesonephroid carcinoma Biologically aggressiveBiologically aggressive hypercalcemia hypercalcemia

and hyperpyrexiaand hyperpyrexia Difficult to differentiate from mucinous Difficult to differentiate from mucinous

neoplasms the neoplasms the periodic acid-Schiff periodic acid-Schiff reactionreaction only only weakly (+) in clear cellweakly (+) in clear cell carcinoma; carcinoma; strikingly (+) in mucinous tumorsstrikingly (+) in mucinous tumors..

Transitional Cell (Brenner) CarcinomaTransitional Cell (Brenner) Carcinoma

Composed of cells that resemble Composed of cells that resemble low-low-grade transitional cell carcinoma of the grade transitional cell carcinoma of the urinary bladder.urinary bladder.

Typically diagnosed at Typically diagnosed at advanced stageadvanced stage diseasedisease

Poorer prognosisPoorer prognosis when compared with when compared with that of other histologic types of epithelial that of other histologic types of epithelial ovarian cancer.ovarian cancer.

Undifferentiated CarcinomaUndifferentiated Carcinoma

<10%<10% of epithelial neoplasms. of epithelial neoplasms. Characterized by the Characterized by the absence of any absence of any

distinguishing microscopic featuresdistinguishing microscopic features that that permit its placement in one of the other permit its placement in one of the other histologic categories.histologic categories.

GERM CELL NEOPLASMSGERM CELL NEOPLASMS Arise from the Arise from the germ cell elementsgerm cell elements of the ovary. of the ovary.

DysgerminomaDysgerminoma Endodermal sinus tumorEndodermal sinus tumor Embryonal cell carcinomaEmbryonal cell carcinoma ChoriocarcinomaChoriocarcinoma TeratomaTeratoma PolyembryomaPolyembryoma Mixed germ cell tumorsMixed germ cell tumors

Occur during the Occur during the second and third decadessecond and third decades of of life.life.

Produce Produce biologic markersbiologic markers which can be which can be monitored to assess monitored to assess response to therapyresponse to therapy..

Tumor Markers that may be elevated in Tumor Markers that may be elevated in the presence of Germ Cell Neoplasmsthe presence of Germ Cell Neoplasms

NeoplasmNeoplasm AFPAFP hCGhCG

DysgerminomaDysgerminoma -- +/-+/-

Endodermal sinus tmEndodermal sinus tm ++ --

Immature teratoma Immature teratoma +/-+/- --

Mixed germ cell tmMixed germ cell tm +/-+/- +/-+/-

Choriocarcinoma Choriocarcinoma -- ++

Embryonal Embryonal carcinoma carcinoma

-- ++

DysgerminomaDysgerminoma The female counterpart of the The female counterpart of the seminoma seminoma

in the male.in the male. Young femalesYoung females 30-40% of germ cell tumors30-40% of germ cell tumors.. Unilateral in 85-90%Unilateral in 85-90% of cases. of cases.

Endodermal Sinus TumorEndodermal Sinus Tumor

Second most commonSecond most common germ cell tumor germ cell tumor (20%).(20%).

Bilateral in <5%Bilateral in <5% of cases. of cases. The The most rapidly growingmost rapidly growing neoplasm !! neoplasm !! Commonly present with an Commonly present with an acute acute

abdomen.abdomen. Pathognomic finding: Pathognomic finding: Schiller-Duval bodySchiller-Duval body AFP(+)AFP(+)

Immature TeratomaImmature Teratoma

The The malignant counterpart of the mature malignant counterpart of the mature cystic teratoma or dermoidcystic teratoma or dermoid..

20%20% of germ cell tumors. of germ cell tumors. Bilateral in <5%Bilateral in <5% of cases, although the of cases, although the

contralateral ovarycontralateral ovary commonly commonly contains a contains a dermoid cystdermoid cyst

ImmatureImmature elements: commonly elements: commonly neuroectodermalneuroectodermal

Mature Teratoma (Dermoid)Mature Teratoma (Dermoid)

CommonCommon 20-30 years20-30 years The The most common tumormost common tumor diagnosed diagnosed

during pregnancyduring pregnancy.. Rarely, the squamous component Rarely, the squamous component

undergoes malignant transformation over undergoes malignant transformation over the age 40. (<2%)the age 40. (<2%)

Embryonal CarcinomaEmbryonal Carcinoma

YoungerYounger patients (mean age of 14 years) patients (mean age of 14 years) Epithelial cells resembling those of the Epithelial cells resembling those of the

embryonic disc.embryonic disc. Typically produce Typically produce hCGhCG 75% also secrete 75% also secrete AFP.AFP.

ChoriocarcinomaChoriocarcinoma

Primary ovarian choriocarcinoma arises Primary ovarian choriocarcinoma arises from a germ cell similar in appearance to from a germ cell similar in appearance to gestational choriocarcinoma.gestational choriocarcinoma.

Nongestational tumors: poorer prognosisNongestational tumors: poorer prognosis

* * The The detection of other germ cell detection of other germ cell componentscomponents indicates nongestational indicates nongestational tumors!tumors!

GonadoblastomaGonadoblastoma

Rare tumor composed of nests of germ Rare tumor composed of nests of germ cells and sex cord derivativescells and sex cord derivatives..

More common in the More common in the right ovaryright ovary.. Usually during the second decade of life.Usually during the second decade of life. Found in patients with Found in patients with abnormal gonadal abnormal gonadal

development in the presence of a Y development in the presence of a Y chromosome.chromosome.

Mixed Germ Cell TumorsMixed Germ Cell Tumors

10%10% of germ cell neoplasms. of germ cell neoplasms. Contain Contain ≥2 germ cell≥2 germ cell elements. elements. Dysgerminoma and endodermal sinusDysgerminoma and endodermal sinus

tumor occur together most frequentlytumor occur together most frequently..

SEX CORD-STROMAL TUMORSSEX CORD-STROMAL TUMORS

Heterogeneus group of rare neoplasms Heterogeneus group of rare neoplasms originating from the originating from the ovarian matrixovarian matrix..

cells within matrix have potentialcells within matrix have potential

for hormon production.for hormon production.

Signs and symptoms of Signs and symptoms of

estrogen or androgen excessestrogen or androgen excess..

Granulosa Cell TumorsGranulosa Cell Tumors

1-2% of all ovarian tumors.1-2% of all ovarian tumors. The The most commonmost common malignant tumors of malignant tumors of

the the sex cord-stromal tumorssex cord-stromal tumors.. HyperestrogenismHyperestrogenism

Call-exner bodiesCall-exner bodies

Precocious puberty in young girls

Endometrial hyperplasia and vaginal bleeding in postmenopausal women

ThecomaThecoma

BenignBenign HyperestrogenismHyperestrogenism Lipid-laden stromalLipid-laden stromal cells cells

Typically develop in Typically develop in postmenopausalpostmenopausal women in their women in their mid-60smid-60s..

Yellow color on cut section

FibromaFibroma

BenignBenign Meigs’ SyndromeMeigs’ Syndrome

Ovarian fibromaOvarian fibroma AscitesAscites Pleural effusionPleural effusion

Hormonally inactiveHormonally inactive

Mimic the presentation of

ovarian cancer.

Sertoli-Leydig Cell TumorsSertoli-Leydig Cell Tumors

RareRare Consist of Consist of testicular structurestesticular structures at different at different

stages of development.stages of development. Usually Usually virilizingvirilizing During the During the third decadethird decade of life of life Rarely bilateralRarely bilateral

Tumors metastatic to the ovaryTumors metastatic to the ovary

25% of all ovarian malignancies.25% of all ovarian malignancies. Clinically Clinically mimic the primary ovarian cancermimic the primary ovarian cancer Usually present as Usually present as bilateral adnexal bilateral adnexal

massesmasses 25% of cases unilateral25% of cases unilateral

Most common primary cancers: Most common primary cancers: breast, breast, stomach, colon and endometrium.stomach, colon and endometrium.

SYMPTOMSSYMPTOMS

Vague and non-specific !!

Abdominal bloating Indigestion, dyspepsia Altered bowel habits Menstruel abnormalities Pelvic fullness Pain

Evaluation of the patient with a Evaluation of the patient with a suspected ovarian neoplasmsuspected ovarian neoplasmDifferential diagnosis

of a pelvic mass

Age of the patient??

The characteristics of the mass on pelvic examination

The radiographic appearance of the mass

The prepubertal child and

the postmenopausal woman are at greatest risk

for developing a pelvic mass that subsequently provesto be a malignant ovarian tumor.

The reproductive age woman is more likely to have

a functional ovarian cyst orendometrioma.

Physical ExaminationPhysical Examination Perform a Perform a comprehensive examination.comprehensive examination. Attention to the Attention to the lymph-node-bearing areaslymph-node-bearing areas

Particularly the Particularly the supraclavicular and inguinalsupraclavicular and inguinal areas. areas. Examination of the abdomenExamination of the abdomen

Abdominal distentionAbdominal distention The presence of The presence of flank fullness and shifting dullnessflank fullness and shifting dullness Tympanitic Tympanitic percussion note over the percussion note over the lateral abdomenlateral abdomen a a large mass displacing the bowel to large mass displacing the bowel to

the periphery.the periphery.

central tympaniticcentral tympanitic percussion note percussion note ascitesascites

Characteristics of a pelvic mass Characteristics of a pelvic mass on physical examinationon physical examination

BENIGN !!MobileCystic

UnilateralCul-de-sac: smooth

MALIGNANT !!Fixed

Solid or formBilateral

Cul-de-sac:nodular

Radiographic Evaluation-IRadiographic Evaluation-I

UltrasonographyUltrasonography TransabdominalTransabdominal TransvaginalTransvaginal Color flow doppler studiesColor flow doppler studies

CT retroperitoneal structures,pelvic CT retroperitoneal structures,pelvic organsorgans

MRI more information regarding the MRI more information regarding the nature of the ovarian tumor.nature of the ovarian tumor.

High cost and questionable benefit !!!High cost and questionable benefit !!! Particular benefit in the evaluation of pregnant womanParticular benefit in the evaluation of pregnant woman..

Radiographic Evaluation-IIRadiographic Evaluation-II

Radiograph of the chestRadiograph of the chest exclude exclude metastatic parenchymal disease and metastatic parenchymal disease and detect pleural effusion.detect pleural effusion.

Barium enemaBarium enema Screening Screening mammogrammammogram study study

Radiographic characteristics that help to Radiographic characteristics that help to

differentiate benign and malignant adnexal massesdifferentiate benign and malignant adnexal masses BENIGN

*Simple cyst, <10 cm in size*Septations,

<3 mm in thickness*Unilateral

*Calcification,especially teeth

*Gravity-dependent layering of cyst

contents

MALIGNANT

*Solid or cystic+solid*multiple septations

>3mm in size*bilateral*ascites

PROGNOSTIC FACTORSPROGNOSTIC FACTORS

Stage !! Grade Cell-type of tumor Residual disease after surgery Disease volume prior to any surgical

debulking Age of woman >70

Performance status

SCREENING FOR OVARIAN SCREENING FOR OVARIAN CANCERCANCER

Ultrasound Transvaginal Abdominal Color flow

Tumor Markers: Ca 125 Protein patterns

Pelvic exam Genetic screening

NO EVIDENCE THAT SCREENING WORKS!!

SURGICAL TREATMENT of SURGICAL TREATMENT of epithelial overian cancerepithelial overian cancer

Surgery: the cornerstone of therapy debulking: remove as much of the cancer as possible

the less cancer left after primary surgery the better the outcome

the best outcome is when there is no residual disease

..

At the time of diagnosis,At the time of diagnosis, >70% of patients with epithelial ovarian cancer >70% of patients with epithelial ovarian cancer

have metastases beyond the pelvishave metastases beyond the pelvis

The most common locations of metastases:*peritoneum (85%)*omentum (70%)

*liver (35%)*pleura (33%)*lung (25%)*bone (15%)

Lymphatic metastasis occurs frequently, with up to

80% involving pelvic lymph nodes and67% involving para-aortic lymph nodes,

depending on the stage of cancer.

INTRAOPERATIVE DIFFERENTIATION INTRAOPERATIVE DIFFERENTIATION OF BENIGN AND MALIGNANT MASSESOF BENIGN AND MALIGNANT MASSES

BENIGN

•Simple cyst•Unilateral

•No adhesions•Smooth surfaces

•Intact capsule

MALIGNANT*Adhesions

*Rupture*Ascites

*Solid areas*Areas of hemorrhage

or necrosis*papillary excrescences

*multioculated massbilateral

Procedures in the surgical Procedures in the surgical staging of ovarian cancerstaging of ovarian cancer

Sample of Sample of ascites or peritoneal washingsascites or peritoneal washings from the from the paracolic gutters and pelvic and subdiaphragmatic paracolic gutters and pelvic and subdiaphragmatic surface for cytologysurface for cytology

Complete abdominal explorationComplete abdominal exploration Intact removal of tumorIntact removal of tumor HysterectomyHysterectomy Infracolic omentectomyInfracolic omentectomy Biopsies of abdominal peritoneal implantsBiopsies of abdominal peritoneal implants; if present, ; if present,

random biopsies from the paracolic gutter random biopsies from the paracolic gutter peritoneum,pelvic peritoneum,and right peritoneum,pelvic peritoneum,and right subdiaphragmatic peritoneal surfacesubdiaphragmatic peritoneal surface

Pelvic and para-aortic lymph node biopsiesPelvic and para-aortic lymph node biopsies Cytoreductive surgeryCytoreductive surgery to remove all visible disease to remove all visible disease

FIGO staging of ovarian cancerFIGO staging of ovarian cancer

Stage 1: growth limited to ovaries 1a: one ovary involved 1b: both ovaries involved 1c: 1a or 1b and ovarian surface tm, ruptured capsule, malignant

ascites, or peritoneal cytology (+) for malignant cells

Stage 2: extension of the tm from the ovary to the pelvis 2a: extension to the uterus or fallopian tube 2b: extension to other pelvic tissues 2c: 2a or 2b and ovarian surface tm, ruptured capsule,

malignant ascites, or peritoneal cytology (+) for malignant cells

Stage 3: Stage 3: disease extension to the abdominal disease extension to the abdominal cavitycavity 3a: 3a: abdominal peritoneal surfaces with microscopic metastasesabdominal peritoneal surfaces with microscopic metastases 3b: 3b: tm metastases < 2 cm in sizetm metastases < 2 cm in size 3c: 3c: tm metastases > 2 cm in size or metastatic disease in the tm metastases > 2 cm in size or metastatic disease in the

pelvic, paraaortic or inguinal lymph nodespelvic, paraaortic or inguinal lymph nodes

Stage 4: Stage 4: distant metastatic diseasedistant metastatic disease Malignant pleural effusionMalignant pleural effusion Pulmonary parenchymal metastasesPulmonary parenchymal metastases Liver or splenic parenchymal metastases (not surface implants)Liver or splenic parenchymal metastases (not surface implants) Metastases to the supraclavicular lymph nodes or skinMetastases to the supraclavicular lymph nodes or skin

SURGICAL TREATMENT SURGICAL TREATMENT of germ cell neoplasmsof germ cell neoplasms

Early stage at the time of diagnosisEarly stage at the time of diagnosis Low incidence of bilateralityLow incidence of bilaterality Young age of patientsYoung age of patients

Fertility sparing surgery by removal the involved adnexa

CHEMOTHERAPY CHEMOTHERAPY of epithelial ovarian cancerof epithelial ovarian cancer

All other All other patients,except stage Ia and patients,except stage Ia and grade I tumorsgrade I tumors, should undergo systemic , should undergo systemic chemotherapy.chemotherapy.

Agents against epithelial ovarian cancer:Agents against epithelial ovarian cancer: CisplatinCisplatin CarboplatinCarboplatin CyclophosphamideCyclophosphamide PaclitaxelPaclitaxel

Combination therapies !!

Assessment of response to combination chemotherapy is based on

physical examination,changes in size of palpable or

radiographically measurable lesions andchanges in the CA-125 level.

*an elevated CA-125 level (>35IU/mL)predicts persistent disease at second look

in >97% of patients.

*a normal CA-125 level does NOT completely exclude the possibility of residual, subclinical disease.

Chemotherapy-associated toxicitiesChemotherapy-associated toxicities

Cisplatin:Cisplatin: nephrotoxicity, neurotoxicity, ototoxicity nephrotoxicity, neurotoxicity, ototoxicity Carboplatin:Carboplatin: thrombocytopenia, neutropenia thrombocytopenia, neutropenia Cyclophosphamide: Cyclophosphamide: hemorrhagic cystitis, pulmonary hemorrhagic cystitis, pulmonary

fibrosis fibrosis Paclitaxel:Paclitaxel: myelosupression myelosupression Altretamine:Altretamine: peripheral neuropathy peripheral neuropathy Etoposide:Etoposide: myelosupression myelosupression Bleomycine:Bleomycine: pulmonary fibrosis pulmonary fibrosis DoxorubicinDoxorubicin: : cardiac toxicitycardiac toxicity VincristineVincristine: : neuropathyneuropathy IfosfamideIfosfamide: : hemorrhagic cystitis, central neurotoxicityhemorrhagic cystitis, central neurotoxicity

RADIATION THERAPYRADIATION THERAPY

Limited roleLimited role in the treatment of in the treatment of epithelialepithelial ovarian cancer.ovarian cancer.

Intraperitoneal PIntraperitoneal P³²³² For For stage 1cstage 1c disease disease For For microscopically (+) second-lookmicroscopically (+) second-look

operationsoperations.. Succesfull in the treatment of Succesfull in the treatment of dysgerminomadysgerminoma

Dysgermioma: most radiation-sensitive Dysgermioma: most radiation-sensitive tumortumor identified. identified.