CA OVARY

DR. VARUNMEDICAL ONCOLOGIST

RGCI DELHI

• Epidemiology• Risk factors• Pathology and pathogenesis• Diagnosis• Screening• Staging

INTRODUCTION• Ovarian cancer is one of the most treatable solid

tumors, as the majority will respond temporarily to surgery and cytotoxic agents.

• Tumors of epithelial, germ cell, or sex cord–stromal origin.– Epithelial - in postmenopausal women, – Germ cell tumors - in younger women, and – Sex cord–stromal tumors - at any age.

• 80- 90% of ovarian cancer is epithelial in origin.

Burden of suffering• 5th most frequent cancer in women worldwide. • 5th leading cause of cancer death in women in

U.S. (after breast, lung, colon and pancreas)• MC cause of death arising from a female pelvic

malignancy.

• each year, in the US – 22,000 new cases of epithelial ovarian cancer – 15,460 deaths

Name of Registry Leading Site 2nd Leading site 3rd leading site

Bangalore Breast Cervix Ovary

Barshi Expanded Cervix Breast Ovary

Bhopal Breast Cervix Ovary

Chennai Breast Cervix Ovary

Delhi Breast Cervix Ovary

Mumbai Breast Cervix Ovary

Barshi Rural Cervix Breast Esophagus

Cachar District Breast Cervix Gall bladder

Dibrugarh District Breast ESophagus Gall bladder

Kamrup District Breast Cervix Esophagus

FEMALE—LEADING SITE

INDIAN DATA-- DELHI

Trends in Cancer incidence-FemaleRegistry Leading site in 1982 Now(2006-2008)

Banglore Cervix Breast, Ovary(↑)

Bhopal Cervix Breast, Ovary(↑)

Chennai Cervix Breast, Ovary(↑)

Barshi Cervix Cervix, Lung(↑)

Delhi Cervix Breast, Ovary(3rd)GB(4th)

Mumbai Breast Breast, Lung(↑) Ovary(↑)

• Overall 5-year survival rate is 45%

• The “silent killer”: asymptomatic in early stages– 75% diagnosed with advanced stage disease; 5-

year survival only 10-28%

• Woman’s lifetime risk of – developing sporadic epithelial ovarian cancer

• 1.7% in developed nations and 0.75% in India.

– dying from ovarian cancer is1.1%

• ̴� 25% of ovarian tumors are malignant.

• Approximately 80 ％ of them are primary growths of the ovary.

• The remainder being secondary.

• Median age at diagnosis – for sporadic - 60 years, – With a genetic predisposition (5-10%) - fifth

decade.

• only 10% to 15% - in premenopausal women

Risk Factors

BRCA Mutations

• Greater risk of developing ovarian cancer, • Overall they have superior outcomes

compared with patients who do not possess these mutations.

• Rubin 1996; Boyd 2000

• The theory behind this observation - same genetic defect that increases the risk of cancer prevents already-malignant cells from repairing the damage induced by agents such as platinum.

HNPCC or Lynch Syndrome

• ~7% of hereditary ovarian cancer cases

• Responsible genes: Mismatch repair genes (MMR) including MLH1, MSH2, and MSH6

• Increased incidence of other adenocarcinomas, including stomach, small bowel, and bile duct malignancies (not breast)

Protective factors

• Multiparity: First pregnancy before age 30• Oral contraceptives: 5 years of use cuts risk nearly

in half• Tubal ligation• Hysterectomy• Bilateral oopherectomy -↓ risk by 80% to 95%• Lactation• Epidemiologic and laboratory evidence suggest a

potential role for retinoids, vitamin D, NSAIDs as preventive agents for ovarian cancer

• Role of ovulation (repetitive process of DNA damage,

inflammation, and repair of the surface epithelium) in the pathogenesis of the malignancy

• Epithelial ovarian neoplasms are thought to arise from the surface epithelium covering the ovary.

• As repair follows multiple ovulations, the surface epithelium of the ovary often extends into the ovarian stroma to form inclusion glands and cysts.

PATHOGENESIS

• The epithelium, via neoplastic transformation, may exhibit differentiation toward a variety of müllerian-type cells– serous fallopian tubal lining– mucinous

• Intestinal gastrointestinal mucosa

• Müllerian endocervix

– Endometrioid endometrial glands

– Brenner/transitional bladder– clear cell mesonephric (renal

cell)

• Ovarian carcinogenesis can be divided into two broad phases:

– malignant transformation• Benign borderline malignant ovarian tumors.

– peritoneal dissemination.

• Now do not appear to be valid for the majority of ovarian cancers

New model of ovariancarcinogenesis

• Surface epithelial tumors divides into two broad categories: Type I and Type II

– based on their clinicopathologic features and characteristic molecular genetic changes

Type I

• Low grade• Arise from precursor lesion

in a stepwise fashion– Cystadenoma– Borderline tumor

• Typically present in stage I• Slow growing, indolent• Often remains low grade• E.g.

– Low grade micropapillary– Mucinous– Clear cell– endometroid

Type II

• High grade• Arise “de novo”

• Typically present in advanced stage

• Rapid growing, aggressive• E.g.

– High grade serous – MMMT

• Molecular biologic evidence supports dualistic

model of ovarian carcinogenesis.

– High-grade serous carcinomas p53 mutations

– low grade serous carcinomas mutations in K-ras

and BRAF genes.

• Pten mutations in endometrioid tumors and K-ras in

mucinous tumors also supports the stepwise

progression model.

• Very recently, Lee et al. have proposed – many high-grade serous carcinomas actually arise

in the mucosa of the fimbriated end of the fallopian tube.

Pathologic Classification

• Surface epithelial – 65-70%

• Germ cell tumors – 15-20%

• Stromal– 5-10%• Metastatic tumors –

5%

1.Surface epithelial tumors1. Serous tumors2. Mucinous tumors

1. Endocervical-like2. Intestinal type

3. Endometrioid tumors4. Clear cell tumors5. Transitional cell tumors6. Squamous cell tumors7. Mixed epithelial tumors8. Undifferentiated and unclassified carcinoma

2.Sex cord-stromal tumors1. Granulosa-stromal cell tumors

1. Granulosa cell tumors (adult and juvenile)2. Tumors in the thecoma—fibroma group

1. Thecoma2. Fibroma3. Cellular fibroma4. Fibrosarcoma5. Sclerosing stromal tumor

2. Sertoli/stromal-cell tumors1. Sertoli cell tumors2. Sertoli-Leydig cell tumors

3. Sex cord tumors with annular tubules4. Gynandroblastoma5. Unclassified6. Steroid (lipid) cell tumors

1. Stromal luteoma2. Leydig cell tumor3. Steroid cell tumor, not otherwise specified

3. Germ cell tumors1. Dysgerminoma2. Yolk sac tumor (endodermal sinus tumor)3. Embryonal carcinoma4. Polyembryoma5. Choriocarcinoma6. Teratoma

1. Immature2. Mature3. Struma ovarii4. Carcinoid tumors

7. Mixed germ cell tumors4. Gonadoblastoma5. Miscellaneous

8. Small cell carcinoma9. Malignant lymphomas, leukemias,

plasmacytomas10. Unclassified11. Metastatic tumors

World Health Organization Histologic Classification of Ovarian Neoplasms

Surface Epithelial tumors

• Serous (tubal) • Mucinous (endocx & intestinal)• Endometrioid• Transitional cell - Brenners.• Clear cell

Surface Epithelial tumors

All types can be benign, borderline , or malignant, depending upon;

• Benign ;- – gross: mostly cystic – microscopic; fine papillae, single layer covering (no stratification), no

nuclear atypia, no stromal invasion)• Borderline ; -

– gross; cystic / solid foci – microscopic; papillary complexity, stratification, nuclear atypia, no

stromal invasion• Malignant ; -

– gross; mostly solid & hemorrhage / necrosis– microscopic; papillary complexity, stratification, nuclear atypia,

stromal invasion

Serous Tumors:

• Frequently bilateral (30-66%).

• 75% benign/bord., • 25% malignant.• Tall columnar ciliated

epithelium.

Serous Cystadenoma

• Single layer of ciliated columnar

•Fine papillae

Papillary cystadenoma (bor) •Papillary complexity

•Nuclear stratification& atypia

•No stromal invasion

Serous cystadenocarcinoma

• Papillary complexity• Nuclear stratification & atypia• stromal invasion• Psammoma bodies• Often associated with CA 125 elevation.

Mucinous Tumors:

• Less common 25%, very large.

• Rarely malignant - 15%.• Multiloculated, many small

cysts.• Rarely bilateral – 5-20%.• Tall columnar, apical mucin.• Pseudomyxoma peritonei.

Mucinous cystadenoma

•Multilocular cyst lined by single layer of columnar cells with basally placed nuclei and apical mucin.

Mucinous cystadenoma-borderline•Papillary complexity•Nuclear stratification& atypia• No stromal invasion

Mucinous cystadenocarcinoma •Papillary complexity•Nuclear stratification& atypia•stromal invasion

•CA 125 levels may not be markedly elevated. •Relatively chemoresistant.• sim. Clear cell ca also.

• Differential diagnosis of a mucinous ovarian tumor includes metastatic disease from an appendiceal primary.

Endometrioid tumors

• most are unilateral (40% are bilateral)

• almost all are malignant• many are associated

with endometrial cancer (30%)

• patient may have concurrent endometriosis

Endometrioid adenocarcinoma

• stromal invasion by irregular malignant endometrial glands

Primary tumor (T)TNM FIGO

T1 I Tumor limited to the ovaries (1 or both)T1a IA Tumor limited to 1 ovary; capsule intact, no tumor on ovarian surface; no malignant cells in

ascites or peritoneal washings

T1b IB Tumor limited to both ovaries; capsules intact, no tumor on ovarian surface; no malignant cells in ascites or peritoneal washings

T1c IC Tumor limited to 1 or both ovaries with any of the following: capsule ruptured, tumor on ovarian surface, malignant cells in ascites or peritoneal washings

T2 II Tumor involves 1 or both ovaries with pelvic extensionT2a IIA Extension and/or implants on the uterus and/or tube(s); no malignant cells in ascites or

peritoneal washings

T2b IIB Extension to other pelvic tissues; no malignant cells in ascites or peritoneal washings

T2c IIC Pelvic extension (T2a or T2b) with malignant cells in ascites or peritoneal washingsT3 III Tumor involves 1 or both ovaries with microscopically confirmed peritoneal metastasis outside

the pelvis

T3a IIIA Microscopic peritoneal metastasis beyond the pelvis (no macroscopic tumor)T3b IIIB Macroscopic peritoneal metastasis beyond the pelvis ≤ 2 cm or less in greatest dimension

T3c IIIC Macroscopic peritoneal metastasis beyond the pelvis > 2 cm in greatest dimension and/or regional lymph node metastasis

TNM and FIGO staging for Ovarian Cancer

Regional lymph nodes (N)TNM FIGO

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N1 IIIC Regional lymph node metastasisDistant metastasis (M)TNM FIGO

M0 No distant metastasis

M1 IV Distant metastasis (exclude peritoneal metastasis)

Stage I ovarian cancer• limited to the ovaries.

– Stage IA: tumour limited to 1 ovary, the capsule is intact, no tumour on ovarian surface and no malignant cells in ascites or peritoneal washings.

– Stage IB: tumour limited to both ovaries, capsules intact, no tumour on ovarian surface and no malignant cells in ascites or peritoneal washings.

– Stage IC: tumour is limited to 1 or both ovaries with any of the following: capsule ruptured, tumour on ovarian surface, malignant cells in ascites or peritoneal washings.

Stage II ovarian cancer• tumors involving 1 or both ovaries

with pelvic extension and/or implants. – Stage IIA: extension and/or

implants on the uterus and/or fallopian tubes. No malignant cells in ascites or peritoneal washings.

– Stage IIB: extension to and/or implants on other pelvic tissues. No malignant cells in ascites or peritoneal washings.

– Stage IIC: Pelvic extension and/or implants (stage IIA or stage IIB) with malignant cells in ascites or peritoneal washings.

Stage III ovarian cancer• tumours involving 1 or both ovaries

with microscopically confirmed peritoneal implants outside the pelvis. Superficial liver metastasis equals stage III.

• – Stage IIIA: microscopic

peritoneal metastasis beyond pelvis (no macroscopic tumour).

– Stage IIIB: macroscopic peritoneal metastasis beyond pelvis less than 2 cm in greatest dimension.

– Stage IIIC: peritoneal metastasis beyond pelvis greater than 2 cm in greatest dimension and/or regional lymph node metastasis.

Stage IV ovarian cancer Tumours involving 1 or both ovaries with distant metastasis.

Parenchymal liver metastasis equals stage IV.

Metastasis • Typical spread– omentum, peritoneal surfaces such as

undersurface of diaphragm, paracolic gutters and bowel serosa

• Lymphatics– follows bld supply thru infundibulopelvic lig to nodes in para aortic region

• Drainage thru broad lig and parametrium– involves ext iliac, obturator and hypogastric regions

• Along round lig– involves inguinal nodes

• Extra abd mets– pleura, liver , spleen, lung, bone and CNS

Ovarian Cancer

Diagnosis and Clinical Evaluation

• ̴��75% to 85% of patients with epithelial ovarian cancer are diagnosed at the time when their disease has spread throughout the peritoneal cavity.

Symptoms of ovarian cancer

• Asymptomatic• Vague new and frequent (>12days/month)

symptoms of – bloating, – Abdominal enlargement– pelvic or abdominal pain, – difficulty eating, or early satiety, – Vaginal bleeding– or urinary urgency or frequency.

Diagnostic tools

History• Pelvic Exam (including rectal)• Transvaginal Ultrasound • Tumor markers• CT • MRI

Exam

• Physical– Malignancy: irregular

margins, solid consistency, is fixed, nodular, or bilateral, is associated with ascites

Physical examination

In menstruating women only 5-18% of adnexal masses will prove malignant vs. postmenopausal women 30-60% of masses will be malignant.

So if you find a mass…what else can it be???

• Endometrioma• Fibroid• Functional cyst • Ectopic pregnancy• Dermoid tumor (younger women)

Ultrasound

• Initial imaging modality of choice – for benign vs malignant

• Results of screening trials have consistently demonstrated that US detects more stage I ovarian carcinomas than CA125 levels and physical examination

• very few stage I carcinomas have been found

• near 95% to 99% NPV in excluding malignancy

• benign :- smooth, thin walls; few, thin septations; absence of solid components or mural nodularity.

• mural nodules, mural thickening or irregularity, solid components, thick septations (3 mm) and associated findings such as ascites, peritoneal implants, and/or hydronephrosis suggest malignancy

• use of color and pulse Doppler in the evaluation of ovarian masses is controversial

TVS vs Pelvic Exam

Ueland, DePriest, DeSimone, Pavlik, Lele, Kryscio, van Nagell JR Jr. The accuracy of examination under anesthesia and transvaginal sonography in evaluating ovarian size. Gynecol Oncol. 2005 Nov;99(2):400-3.

TVS is significantly more accurate (p< 0.001)

Detection TVS PE N =

Overall 85% 44% 289

> 55 yrs 74% 30% 88

> 200 lbs 73% 9% 66

> 200 gram ut 80% 16% 74

You found a mass…what next…

It’s reasonable to follow a mass IF… The mass is not suspicious on ultrasound

- (ie the mass is mobile, looks like a simple cyst, is less than 8-10cm)

- The mass should resolve over 2 mos or otherwise patient should have surgery.

- The threshold is lower for post menopausal women…surgery if their cyst is > 5 cm.

• In postmenopausal and asymptomatic, with unilateral simple cyst <5cm AND normal CA- 125, can follow closely with repeat TVUS

• All other postmenopausal women with ovarian mass require surgical evaluation

Computed Tomography

• Not the study of choice to evaluate a suspected ovarian lesion.

• the sensitivity, specificity, and accuracy of CT for characterizing benign versus malignant lesions are reported to be 89%, 96% to 99%, and 92% to 94%, respectively.

• On CT, ovarian cancer demonstrates varied morphologic patterns, including a multilocular cyst with thick internal septations and solid mural or septal components, a partially cystic and solid mass, and a lobulated, papillary solid mass.

Magnetic Resonance Imaging

• Complementary to US in the evaluation of a suspected ovarian lesion.

• As with CT, disease metastatic to the ovary is often indistinguishable from primary ovarian cancer on MRI scans

• both the colon and the stomach should be examined as potential primary tumor sites if an ovarian mass is detected.

• Several studies have compared MRI to CT and US for characterizing adnexal masses, with mixed results

• Both TVS and MRI have high sensitivity (97% and 100%, respectively) in the identification of solid components within an adnexal mass. – MRI, however, shows higher specificity (98% vs.

46%)

• MRI was shown to be the most efficient second test when an indeterminate ovarian mass was detected at gray-scale US.

• high cost of MRI precludes its use as a screening modality.

• The additional use of FDG-PET has been

shown to be extremely useful and should be considered as an adjunct to, rather then a replacement for, conventional imaging.

Positron Emission Tomography

• little clinical role in the primary detection of a pelvic mass

• Appears to be promising for – its potential to detect tumor prior to significant

morphologic changes.

• Specifically, the sensitivity, specificity, accuracy, PPV, and NPV of FDG-PET were 83%, 80%, 82%, 86%, and 76%, respectively.

• US, CT, MRI, and FDG-PET all have a role to play in the accurate staging of ovarian cancer.

• These modalities also play a role in the monitoring of therapy and detection of recurrent disease.

Tumor Markers

• CA125– an antigenic determinant on a high-molecular-weight

glycoprotein recognized by the murine monoclonal antibody OC-125.

– upper limit of normal- 35 U/mL.– In postmenopausal women :- lower cutoffs, 20 U/mL.

– 85% of patients with epithelial ovarian cancer have >35 U/mL.

• in 50% of patients with stage I disease,• >90% of patients with advanced disease.

• CA125 can be elevated – less frequently elevated in mucinous, clear cell, and

borderline tumors compared to serous tumors.

– in other malignancies (pancreas, breast, colon, and lung cancer) and

– in benign conditions and physiological states such as pregnancy, endometriosis, and menstruation.

– Many of these nonmalignant conditions are not found in postmenopausal women, improving the diagnostic accuracy of elevated CA125 in this population.

ROCA: Risk of Ovarian Cancer Algorithm

• CA125 was initially interpreted using a fixed cutoff. • Sensitivity and specificity has been improved by the development of a statistical algorithm• When the ROC algorithm was applied, the area under the curve was significantly improved in comparison to a fixed CA125 cutoff (93% vs. 84%)

• One of the limitations of CA125 is that 15% to 20% of ovarian cancers do not express the antigen.

• Several other markers studied• Human epididymis protein 4• Mesothelin• B7-H4• Decoy receptor 3• Spondin 2

– Neither of these is useful.

• Though FDA approved, NCCN does not recommend use of biomarkers including CA-125 for estimating risk of cancer in case of pelvic mass.

Tumor Markers

• LDH (lactate dehydrogenase)—dysgerminoma

• HCG (human chorionic gonadotropin)– choriocarcinoma.

• AFP (alpha fetal protein)-- endodermal sinus tumors

• FNA should be avoided.

• May be necessary, if bulky disease not surgical candidates.

• CBC, LFT, KFT• Chest X-ray

Screening

• 5-year survival rates for – stage I and stage II ovarian cancer are 80% to 90%

and 70%, respectively ; – for stages III and IV ranges from 5% to 30%.

• Only 25% diagnosed in Stage I

• In 1994, a NIH consensus conference recommended that screening be offered to women with ≥2 first-degree relatives with ovarian carcinoma.

• In practice, many women with a single first-degree relative are enrolled in screening programs.

• Unfortunately, there are no good screening methods for ovarian cancer at present; – most use a combination of physical exam, CA125 levels, and

TVS.

• PLCO Cancer Screening Trial demonstrated that the PPV value for invasive cancer was – 1.0% for an abnormal TVS, – 3.7% for an abnormal CA125, and – 23.5% if both tests (CA125 and TVS) were abnormal.– But screening with TVS and CA-125 did not dec. mortality

• Only one study has demonstrated ovarian cancer screening trials to have a survival benefit.

» Van Nagell JR Jr, et al.. Cancer 2007;109(9):1887–1896.

• No role of routine screening in general population

• Some follow women with high risk factors (e.g., family history, BRCA mutation) using CA-125 and TVS.

Risk of Malignancy Index (RMI)

• Most valuable clinical tool by combining serum CA125 values with ultrasound findings and menopausal status to calculate a Risk of Malignancy Index (RMI).

• RMI = U x M x CA125– ultrasound result is scored 1 point for each of the following

characteristics: multilocular cysts, solid areas, metastases, ascites and bilateral lesions.

– menopausal status is scored as 1 = pre-menopausal and 3 = post-menopausal

– Serum CA125 in IU/ml and can vary between 0 and hundreds or even thousands of units.

• It yielded a sensitivity of 85% and a specificity of 97%.

• OVA1 is an FDA-cleared blood test that uses results of 5 biomarkers (transthyretin, apolipoprotien

A1, transferrin, beta-2 microglobin and CA-125), with an algorithm to indicate the probability of malignancy of an ovarian mass.

• OvaSure screening test- 6 biomarkers• Leptin, prolactin, osteopontin, IGFII, MIF and CA-125.

• not recommended.

Management

Treatment for Newly Diagnosed Ovarian Cancer

• Complete surgical staging

• Optimal reductive surgery

• Chemotherapy

• Clinical Trials

• Complete surgical staging– Full assessment of abdomen and pelvis– Random biopsy of visually negative areas– Lymph node dissection (except Stage I)

• Optimal reductive surgery• Chemotherapy• Clinical Trials

Vertical incision Multiple cytologic washings Random peritoneal biopsies, including diaphragm TAH and BSO

USO in stage IA or IC Intact tumor removalOmentectomy Complete abdominal exploration Lymph node sampling

Surgical Staging of Ovarian Cancer

The State of Treatment for Newly Diagnosed Ovarian Cancer

• Complete surgical staging• Optimal reductive surgery

– Stage I, II - Complete removal of all disease– Stage III, IV - Residual disease < 1 cm

• Chemotherapy• Clinical Trials

Optimal Cytoreduction

0 cm

0-1 cm1-2 cm>2 cm

Time since initial surgery (years)

Prop

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ing

• Procedures that may be considered for optimal surgical cytoreduction :-– Radical pelvic dissection– Bowel resection– Diaphragm or other peritoneal surface stripping– Splenectomy– Partial hepatectomy– Cholecystectomy– Partial gastrectomy or cystectomy– Or distal pancreatectomy

THANK YOU…