OQ: GC/SCS Ovarian Cancer

Question 1

19 yo with solid adnexal mass is referred. What labs and imaging do you get?

Answer 1

AFP, LDH, betaHCG, Inhibin A/B, AMH

CA125, CEA, CA19-9

Androgens if virulized

Pelvic US

CXR

Question 2

What do you see in these slides from an ovarian mass, and what is the diagnosis?

Answer 2

Coffee bean nuclei, Call exner bodies. GCT.

Question 3

What pathologic findings suggest a better or worse prognosis for GCT?

Answer 3

Patients with high risk stage I disease associated with large tumor size (≥10-15 cm), stage IC, poorly differentiated tumor, high mitotic index, or tumor rupture might be considered for adjuvant chemotherapy in view of increased risk of relapse

• Absence of call exner bodies and high mitotic index are BAD prognostic findings
• Juvenile GCT worse prognosis than adult GCT
• FOXL2 homozygous genotype more aggressive- higher risk of recurrence
• KMT2D/MLL2 mutations & TERT promoter mutations associated with recurrence

Question 4

What tumor markers are associated with GCT?

Answer 4

+/- LDH, betaHCG, AFP

1. Inhibin A and B (peptide hormone produced by ovarian granulosa cells that plays a role in regulation of FSH secretion by the pituitary. inhibin B level is usually elevated in a higher proportion of these tumors.)
2. AMH (only produced by granulosa and sertoli cells)
3. testosterone (if hirsutism, mostly in sertoli leydig), if testosterone high, check adrenal hormones

Question 5

What is the difference between inhibin A/B?

Answer 5

Inhibin A and B share an alpha subunit but have a distinct beta subunit (betaA vs beta B)

Both can be increased in GCT but inhibin B is more frequently elevated (A: 67% vs B: 89% were elevated)

Inhibin A: corpus luteum and dominant follicle, B: non-dominant follicles

Question 6

What staging do you do for GCT? What if cystectomy had been done at OSH at the time of referral?

Answer 6

What staging do you do?

Fertility sparing Surgery: USO, omentectomy, staging biopsies, preserve uterus and contralateral ovary if normal, endometrial sampling if abnl bleeding or thickened EMS or preserving uterus, then completion surgery after childbearing

Risk of endometrial hyperplasia 30%, risk of cancer 2-27%

Standard surgery: Hyst/BSO/omentectomy +/- nodes

Can omit LND bc retrospective data (thrall et al…and Goff, 87 pts retrospective, Gyn Onc, 47% with LND, 0% LN mets. Risk of recurrence only correlated with tumor size. Even when they recur in lymph nodes, the LND originally was negative

Palpate LN and remove enlarged ones.

Tumor ruptures intraop = high risk → obs or plat based chemo (carbo/taxol)

What if cystectomy had been done at OSH at the time of referral?

Would recommend oophorectomy

Reoperate if 1) fertility is not desired or 2) concern for inadequate abdominopelvic assessment or 3) imaging showed other gross disease

Question 7

What genetic mutations are associated with Adult granulosa cell tumor, Sertoli leydig tumor, SCTAT?

Answer 7

Adult granulosa cell tumor - FOXL2 in 97% of pts, higher risk of recurrence

Sertoli leydig tumor - DICER1 in 60% of pts (pleuropulmonary blastoma, cystic nephroma, thyroid nodules, ciliiary body medulloepitheloma, botryoid type embryonal rhabdomyosarcoma, nasal chondromesenchymal hamartoma, pineoblastoma, pituitary blastoma) screen with cxr, ct, renal u/s, pelvic u/s, thyroid u/s

SCTAT - peutz jegher (STK11 - also associated with breast, colorectal, pancreas, cervix adenoma malignum, ovary cancers)

Question 8

What genetic testing do you recommend for ovarian cancers?

Answer 8

ASCO guidelines: All women diagnosed with epithelial ovarian cancer should have germline genetic testing for BRCA1/2 and other ovarian cancer susceptibility genes. Women diagnosed with clear cell, endometrioid, or mucinous ovarian cancer should be offered somatic tumor testing for mismatch repair deficiency (dMMR).

Question 9

What are the histologic differences between juvenile and adult granulosa cell tumors?

Answer 9

Mutations:

Adult GCT: FOXL2

Juvenile GCT (<5% of all granulosa): GNAS mutation

Question 10

What IHC is seen for granulosa cell tumor?

Answer 10

Inhibin+, FOXL2 mutation in >95% adult type
EMA negative
Vimentin+, desmin-, SMA+, S100 +/-
Calretinin 90%+

Question 11

What chemotherapy would you treat granulosa cell tumor? Does treatment vary by stage?

Answer 11

MITO9 - retrospective study of 35 pts with stage 1-4 recurrent granulosa cell tumors - receipt of adjuvant chemo originally was associated with improved PFS but not OS

Still, NCCN says:

Stage 1A,B - ok to obs

Stage 1C - consider chemo if higher risk, ok to obs

Stage 2-4 - chemo

carbo/taxol is preferred regimen for age >40yo due to toxicity

Per Gershenson, BEP preferred for young fit pts

GOG264 stage2-4 granulosa cell tumor OR recurrent, chemo naive – BEP vs carbo/taxol; CLOSED poor accrual

Stage 1 to consider treatment: ruptured/ 1C, mitotic rate, atypia

for other SCST: heterologous elements (intermediate risk), high grade SCST

Juvenile type granulosa cell tumors have higher mitotic range and are more aggressive - chemo may help contribute to long lasting complete remission.

Question 12

What is dosing of BEP? What are dose limits for BEP? What are anticipated toxicities? What is clearance of BEP?

Answer 12

Sex cord stromal- 4 cycles, q 21 days. max lifetime bleo dose 120 units

Bleo 20 units/m2 Day 1

Etoposide 75mg/m2 D1-5

Cisplatin 20mg/m2 D1-5

Toxicity

• Bleomycin - < 400 units due to pulmonary fibrosis
• It is recommended that the DLCO be monitored monthly if it is to be employed to detect pulmonary toxicities, and thus the drug should be discontinued when the DLCO falls below 30% to 35% of the pretreatment value.
• No bleo if cr> 2.0
• Cisplatin - nephrotoxicity – need 2 liters hydration to achieve 100mL/hr UOP for 2 hrs before and 2 hrs after cisplatin
• ototoxicity
• Highly emetogenic

Clearance:

Bleomycin – metabolized by bleomycin hydrolase (present in normal tissues, but decreased in lung), 65% cleared in urine

Etoposide - 98% protein bound. Hepatic metabolism via CYP3A4 and 3A5

Cisplatin - inactivated by GSSH, excreted in urine

Question 13

When is typical recurrence for granulosa cell tumor and how is it treated?

Answer 13

Long duration median 4-6 years until relapse, recurrences reported as long as 40 years out

-Surgery if possible

Karalok et al, Tumori 2016 - 18 pts with adult GCT. 13/18 optimally debulked – all unifocals and 37% multifocal recurrences debulked optimally. Residual disease decreased PFS 31 vs 207 mo, and OS 22 vs 220mo

• Hormonal therapy - no studies comparing efficacy of hormonal therapy to chemo
• Radiation - studies show efficacy in for granulosa cell
• Possible chemo:

carbo/taxol if carbo/taxol naive, Bevacizumab, taxol, adriamycin, carbo/etoposide, PVB, epithelial ovarian cancer regimens

• Study for Bev: Phase II- bev in recurrent sex cord - response rate 17%, 78% stable disease
• Trial

Question 14

A: what is that arrow pointing to?

B: What is that arrow?

Answer 14

A Sertoli cells - charcot-bottcher filament bundles (cytoplasmic inclusions)

B Leydig cells - may have crystals of Reinke

Question 15

For sertoli Leydig tumor, is staging, decision to operate, chemo any different than granulosa cell that we just reviewed?

Answer 15

Sertoli leydig -

Presentation: adrogen excess in form of virilization

Staging and intraoper decision making same as granulosa cell above

Decision to re-operate same

Decision for chemo:

Well differentiated - no adjuvant treatment for stage 1

Well differentiated but with heterologous elements or retiform pattern - consider chemo for 20% relapse rate

Poorly differentiated - relapse rate 60%, give chemo for all stages

What is recurrence pattern of sertoli leydig?

***???

Question 16

What are tumor markers for SLT?

Answer 16

Testosterone, AMH, inhibin, AFP q2-4mo x 2 years, then q6mo. Monitoring multiple markers appears superior for detection of macroscopic disease.

Question 17

Therapy for recurrent sertoli leydig?

Answer 17

Same as granulosa cell above EXCEPT no hormonal therapy

Radiation data only extrapolated from granulosa cell tumor. No actual data on radiation

Question 18

Who gets chemo for other SCST? Non sertoli leydig and non granulosa cell

Answer 18

For other SCST, unspecified, chemo is given for stage 1C optional, stage 2-4

Question 19

Some example clinical scenarios we didn’t answer for GCT/SLT:

Answer 19

• 39 yo with a beard and moustache (no kidding). How do you work this woman up? Any pre-operative tests that you want to get? Why? Let’s assume a normal Adrenal test, and she has an ovary with a large cystic mass, how do you proceed? Frozen c/w 12cm mass with ascites, intra-op rupture, and an adult granulosa cell tumor with sarcomatoid features. Do you treat? If so with what? What is the natural course of this disease? Let’s assume you treat and three years later she as a 6cm pelvic mass and a 2 cm pulmonary lesion. What next? Why won’t you do an exploratory surgery first? Any role for thoracic surgery? If you treated her at first, how do you treat her now?
• 45 yo with vaginal bleeding and pelvic mass. Slide of granulosa cell tumor. What next-staging. Showed picture of IVC/aorta, how high LND, name some vessels etc. Adjuvant chemo with BEP. Comes back with pelvic mass on CT (showed picture). I reresect and give more BEP. 3 years later mass in same place, resect, maybe some XRT. What do you follow (inhibin).
• Had a 19 year old with a large pelvic mass. What’s your differential diagnosis. It was a sertoli Leydig tumor. How would you treat? Stage IC? Would you give adjuvant chemo? What kind? What doses? How many cycles? What’s the toxicity of bleo and etoposide?
• 12 yo adnexal mass and precocious puberty: What is DDX. What labs to get. Surgery? Treatment?

​80% of juvenile granulosa cell tumors present with precocious puberty; 50% can have acute abdomen, tumor rupture

Question 20

Young patient, primary amenorrhea and pelvic mass, what should you be thinking?

Answer 20

• Benign germ cell tumor: gonadoblastoma can turn into dysgerminoma or seminoma
• 5% risk of germ cell tumors with dysgenetic gondads- consider karyotype for premenarchal girls with pelvic mass >2cm. (46 XY)

Question 21

What are the characteristic findings on these slides?

A:

B:

B:

C.

D:

Answer 21

A: Schiller duval bodies - yolk sac tumor

B: Neuroepithelial rosettes - immature teratoma

C: Cells growing in cords - dysgerminoma

D: Syncytiotrophoblasts - dysgerminoma (rare)

Question 22

What staging procedures do you do for dysgerminoma?

Answer 22

Fertility sparing - washings, USO, PPALND, omentectomy

Not fertility sparing - same as epithelial ovary

Risk of LN mets

• Dysgerminoma 28%
• Malignant teratoma 8%
• Mixed germ cell tumor 16%

Second operation for staging procedure? Obtain imaging first- very chemosensitive; if already candidate for chemo, would not re-operate if no residual disease

No comprehensive surgical staging for pediatric patients

Question 23

Slide of dysgerminoma

1. What if frozen on a 28 year old says dysgerminoma? When do I stage? Why? What if there is a “ditzel” on the other ovary? Besides chemo, what else could I give ? What is disadvantage of RT?

Answer 23

I would perform fertility sparing staging if 28 yo was found to have dysgerminoma

Ditzel? Biopsy ditzel? Ditzelectomy

Not sure what you would give other than chemo. Stage 1 dysgerminoma does not require chemotherapy.

Results of GOG 45 and 90 found a complete response in 91%, 100% and 95% disease free after either BEP or VAC therefore radiation is not necessary if residual disease

Question 24

What are adjuvant chemo options for MOGCT?

Answer 24

BEP vs carbo/etoposide for dysgerminoma

BEP For non-dysgerminomas

Question 25

How does chemo for MOGCT impact fertility?

Answer 25

>95% pts have resumption of menses after chemo and are 75% able to achieve pregnancy.

And this was off of GNRH agonists

Question 26

What is regimen for recurrent MOGCT?

Answer 26

TIP, VeIP, high dose chemotherapy + stem cell rescue

TIP: Taxol 250mg/m2 D1, ifos 1500 mg/m2 D2-5, cisplatin 25 mgm/2 D2-5

VeIP: vinblastine 0.11mg/kg on D1-2,, ifos 1200 mg/m2 IV. cisplatin

High dose chemo with stem cell rescue - carbo 700 mg/m2, etoposide 750mg/m2 D3,4,5 and stem cell support D14-21 x 3 cycles

Question 27

Do you do LND for MOGCT?

Answer 27

MITO9- no change in survival with LND

SEER retrospective study (Mahdi, British J Cancer 2011) lymphadenectomy upstaged 10% of patients but no change in survival for MOGCT.

Can omit, but since dysgerminoma has lymphatic spread in up to 20% and is practice changing (no chemo for stage 1), then I would do lymphadenectomy for staging in clinical stage 1 dysgerminomas

Pediatric patients with clinical stage 1 MOGCT - NCCN says ok to omit

Question 28

19 yo with immature teratoma on frozen, do you do nodes? Do you do anything else (uterus, contralateral ovary). Final path stage 1A grade 2, do you give adjuvant chemo. What if pt is 11?

Answer 28

• For IT, can omit LND as it does not impact survival but does upstage. Would leave uterus/ contralateral ovary if grossly normal.
• Chemo for all gr2 IT in the adult literature – BEP x 3-4 cycles
• If pt is 11, pediatric literature supports observation for all stages and grades of IT

Question 29

24yo is referred with gr3 IT after USO, what do you recommend?

Answer 29

• If fertility not desired then fully stage
• If fertility desired – CT CAP and tumor markers, if no gross residual disease, BEP x 3. If gross residual disease, either surgery OR chemo acceptable per NCCN

Question 30

Early stage left ovarian immature teratoma with 4 cm cyst on left ovary what do you do? what if it were a dysgerminoma?

Answer 30

USO, omentectomy, palpate nodal spaces, inspect peritoneum, washings if IT

For dysgerminoma, add PPALND

Question 31

Picture of Big Dysgerminoma. Surgical approach, differential diagnosis, what preop labs/scans do you order, etc. Adjuvant treatment of dysgerminoma

Answer 31

• MIS if i felt i could get an adequate abdominopelvic assessment
• Ddx GCT, SCST, epithelial cancer, borderline tumor, other benign ovarian masses, metastasis
• Pre op CT AP, CXR, full panel of tumor markers listed above
• Adjuvant therapy -stage 1A/B gr1 obs. All other stages, consider BEP or carbo etoposide x 3-4

Question 32

Young girl with a cyst, do I freeze. What if endodermal sinus tumor?, immature teratoma? Dysgerminoma? Does the histology change who you would stage? what are tumor markers. What to do with benign teratoma implants.

Answer 32

• Histology doesn’t change who I would stage
• Endodermal sinus tumor (yolk sac) - LDH, AFP.
• IT - AFP, LDH,HCG
• Dysgerminoma - LDH
• Can remove initially to confirm no MOGCT but if confirmed benign teratoma implants - resect PRN symptoms or early to reduce the risk of needing radical surgery subsequently.

Question 33

Anti NMDA Receptor encephalitis. Wanted to know the natural progression of disease, what was responsible for the syndrome. Treatment options available. How do you treat this patient and the likely outcomes.

Answer 33

• Autoantibodies against NMDA receptor are responsible
• Associated with benign ovarian teratoma
• Is potentially reversible but potentially permanent encephalitis related to autoantibodies
• Tx - remove tumor (decrease disease burden) ,steroids, plasmapheresis, IVIG and cellcept OR rituximab OR cytoxan

Question 34

What is first line chemo for stage 1 epithelial ovarian cancer vs MOGCT ?

Answer 34

• Stage 1 LGSOC and gr1-2 endometrioid - obs, other histologies - carbo/taxol x 3-6 cycles
• Stage 1 dysgerminoma or 1A/B gr1 IT - obs
• Otherwise dysgerminoma etoposide/carbo vs BEP, other MOGCT BEP

Question 35

How many cycles of chemo for yolk sac tumor? Dysgerminoma?

Answer 35

• Yolk sac tumor behaves more aggressively, would favor 4 if higher stage
• For dysgerminoma since better prognosis, 3 sounds acceptable
• No specific data to guide # of cycles.
• For COG poor prognosis (>11 yo and stage 4) i would favor 4 cycles

Question 36

Case: A 19 yo is taken to the OR for an adnexal mass, for which you have intra-operative evaluation which reveals the following:

What is that structure, what is pathology and what is your staging. and treatment recommendation?

Answer 36

Schiller Duval bodies, yolk sac tumor.

Fertility sparing staging – USO, inspection of nodes, omentectomy, pelvic washings

Final stage comes back as 1A, what therapy do you recommend

Stage 1A yolk sac tumor warrants 3-4 cycles of BEP although in pediatric literature for stage 1A/Bs they are observed.

3 or 4 cycles? Either

Question 37

BEP- fertility and long term concerns

Answer 37

• All had menstruation within 1 yr of completion of chemotherapy
• Premature menopause after chemo only in 3-6% of pts with platinum based regimen
• Chronic SAE: hypertension, hypercholesterolemia, loss of hearing (cisplatin), AML chromosome 5 and 7 deletions (etoposide)- 5-7 yrs after etoposide exposure, dose dependent,

Question 38

Describe the IGCCC risk groups for germ cell ovarian cancer and respective post op management pediatric and adult.

Answer 38

Veneris et al Gyn Onc 2020

Pediatric group- can observe most Stage IA tumors- 4 yr PFS was 52% but salvaged after BEP in recurrence

Question 39

Describe tumor marker patterns for germ cell and SCS tumors.