Ovary Part 6

Ovarian Cancer
Written By Sydney Oesch

Episode Notes

Germ Cell tumors

  1. Epidemiology

    1. 5% of all ovarian cancers

    2. Account for 70% of all ovarian neoplasms in patients aged 10-30yo

    3. Most common subtype: benign teratomas

      1. Rare presentation: anti-NMDA receptor encephalitis, can present with both mature and immature teratomas

    4. Risk factors: gonadal dysgenesis (Turner, Swyer syndrome)

  2. Presentation and prognosis: 

    1. Cause ascites in 20% of cases. May have pain/abdominal enlargement

    2. ⅔ confined to one ovary at time of presentation

    3. 5 yr survival >85%

    4. Make sure to differentiate from small cell carcinoma of the ovary

  3. Evaluation

    1. Tumor markers: AFP, hCG, LDH, CA-125

    2. Pregnancy testing

    3. Karyotype (gonadal dysgenesis evaluation)

    4. Imaging: ultrasound vs. pelvic MRI, with CT C/A/P if concerned for malignancy, and brain MRI for choriocarcinoma or dysgerminomas with disease above diaphragm

  4. Treatment

    1. All are candidates for fertility sparing surgery (washings, USO vs. BSO, omentectomy, peritoneal biopsies)

    2. Lymphadenectomy controversial, may vary by institution

      1. No definitive survival advantage with routine lymphadenectomy

      2. Recurrences appear to be higher in incompletely staged patients

      3. Children’s oncology group does not perform lymphadenectomy in pediatric population; outcomes not inferior with this approach

    3. Adjuvant treatment: 

      1. BEP recommended for all germ cell tumors after surgical resection EXCEPT:

        1. Stage 1 dysgerminoma

        2. Stage 1 grade 1 immature teratoma

        3. Observation can be considered for these patients even if incompletely staged, as long as there is negative imaging and tumor markers. 

      2. BEP studied in GOG78: nonrandomized, prospective trial in patients with completely resected germ cell tumors.  3 cycles BEP.  98% disease free survival at follow-up. 

        1. Dose intensity is important: reductions and delays not recommended!!

        2. Crucial to start chemotherapy ASAP after surgery due to rapid progression/regrowth postoperatively

        3. # of cycles: 3 vs. 4. 4 cycles usually given for patients with residual disease after surgery.  Consider omission of bleomycin for the fourth cycle. Consider omission of bleomycin for patients with stage 1 disease. 

        4. Pre-chemo workup?  PFTs with DLCO, Chest xray, lung exam

          1. DLCO most sensitive marker for injury from bleomycin: if decreases by 30%, omit bleomycin

    4. Persistent/residual disease after first line chemo?

      1. Consider repeat surgical resection vs. observation/close monitoring if tumor markers are normal.  If tumor markers are elevated and definitive residual disease, second line chemotherapy with paclitaxel/ifosfamide/cisplatin vs. high dose chemotherapy.

    5. Recurrent disease

      1. Imaging to evaluate extent

      2. If no prior BEP? Give BEP! Associated with nearly 100% cure rate

      3. If prior BEP? Salvage chemotherapy - one option is paclitaxel/ifosfamide/cisplatin.  Best practice is referral to a tertiary care center! 

  5. Subtypes

    1. Dysgerminoma: account for 50% of all germ cell tumors, bilateral in 10-15% of cases

      1. Elevated LDH (may have elevated hCG, E2)

      2. Positive LN in up to 28% of cases, but have excellent prognosis

      3. Chemotherapy in the setting of recurrent disease is typically curative

    2. Immature teratoma

      1. Elevated AFP, LDH, E2, or DHEA (negative hCG!)

      2. Can co-present with mature teratoma in contralateral ovary

      3. Can recur with mature teratoma, immature teratoma, gliosis (recurrence is not necessarily malignant)

      4. Grading: based on % of primitive neuroectodermal tissue in the tumor

    3. Yolk sac/endodermal sinus tumor

      1. Elevated AFP, LDH

      2. Pathology: Schiller Duvall bodies

    4. Rare subtypes: embryonal carcinoma, mixed germ cell tumors, nongestational choriocarcinomas. 

      1. Embryonal: elevated hCG (can also have AFP, LDH, E2)

      2. Choriocarcinomas: hCG (maybe LDH)

  1. Sex Cord Stromal tumors

    1. Epidemiology

      1. 7% of all ovarian cancers

      2. Often present at early stage with good prognosis

      3. Exam findings: may have signs of estrogen or androgen excess

    2. Granulosa cell: most common subtype. 

      1. Estrogen producing frequently!

        1. 20% of the time have hyperplasia or EIN

        2. 5% have concurrent endometrial cancer

        3. Recommend performing endometrial sampling in all granulosa cell tumors

      2. 95% unilateral

      3. Histopath: FOXL2 mutation, Call-exner bodies and coffee bean nuclei on pathology

      4. Classic tumor marker: Inhibin B

      5. Factors associated with worse prognosis: advanced stage, residual disease after primary surgery, rupture, increased nuclear atypia, high mitotic index

      6. Can recur decades after treatment

      7. Adult vs. Juvenile: Juvenile very rare, more aggressive. Higher mitotic index. Infrequent call-exner bodies. Juvenile tumors should be tested for SMARCA4 deficiency to distinguish from small cell carcinoma of the ovary hypercalcemic type. Prognosis still good with primary complete resection

    3. Sertoli-Leydig: second most common subtype

      1. Most commonly present in teenagers, young adults. Almost always unilateral, stage 1 at presentation with good prognosis. Can often have virilization/hormonal signs/sx

      2. 60% associated with DICER1 mutations, which carry risk for additional malignancies; if DICER1 mutation is present, need to do germline genetic testing

      3. 50% have FOXL2 mutation

      4. Classified by well, intermediate, or poor differentiation. Poorly differentiated are the “true malignant” subtypes.

    4. Rare subtypes

      1. Sex cord tumors with annular tubules: associated with Peutz-Jegher syndrome and mutations in STK11 gene

      2. Fibrosarcoma NOA

      3. Steroid cell tumor (malignant)

      4. Benign: Ovarian fibromas can present with ascites/pleural effusion (aka Meigs syndrome) > this can mimic presentation of ovarian cancer!

    5. Treatment

      1. Surgery! Consider fertility sparing surgery for apparent stage I disease. Can omit lymphadenectomy for tumors grossly limited to the ovary. 

        1. If undergoing fertility sparing surgery, completion surgery after childbearing is finished is generally recommended.

      2. Adjuvant therapy: consider for high risk stage I disease (ruptured or poorly differentiated) and recommended for stage II-IV disease

        1. Chemotherapy regimen: no great data, BEP was historically used regimen

          1. Carbo/taxol preferred regimen in NCCN

          2. GOG264: BEP vs. carbo/taxol for SCST.  No improvement in PFS with carbo/taxol. Carbo/taxol had a favorable side effect profile. Closed early due to interim futility analysis.

          3. GOG115: BEP for SCST; in advanced disease, 70% disease-free at three years. 61% of patients had grade IV myelotoxicity with therapy. 

          4. For younger patients who can tolerate BEP, it *may* be a better option, while for older patients, the side effect profile may favor carbo/taxol

    6. Recurrent disease

      1. Secondary cytoreductive surgery can be considered

      2. Recurrence therapy: carbo/taxol, BEP, other options can be considered

      3. Bevacizumab: consider based on GOG 251 (ORR 17%)

      4. Responses to hormonal therapy very low

References

1. Slayton RE, Park RC, Silverberg SG, Shingleton H, Creasman WT, Blessing JA. Vincristine, Dactinomycin, and Cyclophosphamide in the Treatment of Malignant Germ Cell Tumors of the Ovary A Gynecologic Oncology Group Study (A Final Report). doi:10.1002/1097-0142

2.       Williams SD, Blessing JA, Moore DH, Homesley HD, Adcock L. Cisplatin, vinblastine, and bleomycin in advanced and recurrent ovarian germ-cell tumors. A trial of the Gynecologic Oncology Group. Ann Intern Med. 1989;111(1):22-27. doi:10.7326/0003-4819-111-1-22

3.       Williams S, Blessing JA, Liao SY, Ball H, Hanjani P. Adjuvant therapy of ovarian germ cell tumors with cisplatin, etoposide, and bleomycin: a trial of the Gynecologic Oncology Group. https://doi.org/101200/JCO1994124701. 2016;12(4):701-706. doi:10.1200/JCO.1994.12.4.701

4.       Banerjee SN, Tang M, O’Connell RL, et al. A phase 2 study of anastrozole in patients with oestrogen receptor and/progesterone receptor positive recurrent/metastatic granulosa cell tumours/sex-cord stromal tumours of the ovary: The PARAGON/ANZGOG 0903 trial. Gynecol Oncol. 2021;163(1):72-78. doi:10.1016/j.ygyno.2021.07.024

5.       Homesley HD, Bundy BN, Hurteau JA, Roth LM. Bleomycin, etoposide, and cisplatin combination therapy of ovarian granulosa cell tumors and other stromal malignancies: A Gynecologic Oncology Group Study. Gynecol Oncol. 1999;72(2):131-137. doi:10.1006/gyno.1998.5304

6.       Brown J, Brady WE, Schink J, et al. Efficacy and safety of bevacizumab in recurrent sex cord-stromal ovarian tumors: Results of a phase 2 trial of the Gynecologic Oncology Group. Cancer. 2014;120(3):344-351. doi:10.1002/CNCR.28421

7.       Nasioudis D, Ko EM, Haggerty AF, et al. Performance of lymphadenectomy for apparent early stage malignant ovarian germ cell tumors in the era of platinum-based chemotherapy. Gynecol Oncol. 2020;157(3):613-618. doi:10.1016/J.YGYNO.2020.04.047

8.       Kumar S, Shah JP, Bryant CS, et al. The prevalence and prognostic impact of lymph node metastasis in malignant germ cell tumors of the ovary. Gynecol Oncol. 2008;110(2):125-132. doi:10.1016/J.YGYNO.2008.04.022

9.       Beiner ME, Gotlieb WH, Korach Y, et al. Cystectomy for immature teratoma of the ovary. Gynecol Oncol. 2004;93(2):381-384. doi:10.1016/j.ygyno.2004.01.034

Sydney Oesch
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