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.