Gynecologic Malignancies

OVARIAN CANCER

Juliana Eng

Roisin O’Cearbhaill

Epidemiology

Ovarian CA is the leading cause of death from gyn CA in the United States
5th most common cause of CA mortality in ♀, ˜22240 new cases/y
Incidence ↑ w/age; incidence rate of 57/100000 ♀ in the 8th decade
Median age at dx is 63 y; >70% present w/advanced disease
Fallopian tube & 1° peritoneal CA: Similar entities to ovarian CA

Risk Factors

Advancing age, early menarche, late menopause, obesity, PCOS, nulliparity, involuntary infertility, older age at first birth (>35 y)
˜10% of cases are “familial”; may present earlier than sporadic cases
Conversely, a 30-60% ↓ risk of CA associated w/younger age at pregnancy & first birth (≤25 y), OCPs, and/or breast-feeding

Etiology

HGS CA may originate in fallopian tube fimbria as STIC (J Clin Oncol 2008;26:4160-4165)
Clear cell & endometrioid histologies assoc w/endometriosis (ARID1A)

Genetics

BRCA 1 or 2 Mt: AD inheritance. Most definable cause of hereditary ovarian CA

esp. in AJ pop. 16-21% HGS are BRCA+. BRCA1: Lifetime risk of breast CA 85% & ovarian CA 40-60%. BRCA 2: Ovarian CA in 16-27% by age 70. Possible better prognosis: ↑ Sn to platinum-based chemo (J Clin Oncol 2012;30(21):2654-2663)
Lynch type II: AD inheritance. Nonpolyposis colorectal CA, uterine CA, & ovarian CA; germline Mt of MMR genes (MLH1, MSH2, MLH6, PMS2). Lifetime risk of ovarian CA 5-15%.

Pathology Subtypes

Epithelial (EOC) (95%): Serous (most common ˜75%, majority WT1+ &/or PAX 8+), mucinous, endometrioid, clear cell, transitional cell
Germ cell (<3%, often <30 y): Dysgerminoma (like seminoma in ♂), endodermal sinus tumors, embryonal CA (like NSGCT in ♂), teratoma. Surgery + (except stage I immature teratoma/dysgerminoma) BEP × 3-4
Sex cord stromal (<2%) heterogeneous, often early-stage, can produce androgens, estrogen: Granulosa (inhibin B as tumor marker, 5-10% assoc w/early-stage uterine CA), theca, sertoli, leydig (DICER1). Mainly surgery ± chemo (BEP or T/C). Consider RT if pelvic recur.

Clinical Manifestations

70% EOC tumors have spread beyond true pelvis (≥stage III) at dx
Localized disease often asx
Persistent, non-specific: Abd/pelvic pain/mass/bloating, urinary urgency or frequency, constipation, early satiety, dyspnea, VTE (↑ in clear cell), torsion (germ cell), rarely vaginal bleeding or paraneoplastic syndrome: Cerebellar degen, polyneuritis, DM, ↑ CA²⁺ (small cell)

Screening and Prevention

Asx ♀ at avg risk should NOT undergo ovarian CA screening
PLCO trial: Screening w/annual transvaginal U/S (TVUS) × 4 y & CA 125 × 6 y did not ↓ ovarian CA mortality (JAMA 2011;305:2295-2303)
In high-risk ♀ (hereditary syndrome, BRCA1/2+) can consider multimodality screening (TVUS & CA125 q6mos starting at age 30-35 or 5-10 y earlier than earliest age of 1st ovarian CA in family), but rrBSO is most effective way to ↓ risk of ovarian/fallopian tube CA. rrBSO is recommended as soon as childbearing is complete or by age 35-40. In premenopausal BRCA+ ♀ can also ↓ breast CA risk
OCP use in BRCA+ ♀ assoc. w/↓ ovarian CA risk (˜5%/y of OCP use)

Staging and Workup of EOC

Laparotomy w/TAH/BSO w/comprehensive staging (inspection of all peritoneal surfaces, bx of suspicious areas/adhesions, omentectomy, pelvic & para-aortic LND & effort to achieve maximal cytoreduction) is the 1° procedure to establish dx, accurate disease extent & for maximal tumor cytoreduction
Mucinous tumors: + appendectomy & explore upper & lower GI tract
Optimal debulking → residual tumor <1 cm max diameter or thickness
Ideally performed by gyn oncologist & w/“no gross residual disease”
↑ CA125 in 20% early-stage & 80% of advanced-stage EOC

Stage	Definition	5-y Survival^**
Stage I	Confined to ovary or ovaries. A: One ovary; B: Both ovaries; C: Surface involvement or malig cells in peritoneal washings or ascites	85-95% (90-95% for IA or IB)
Stage II	Pelvic extension. A: +uterus &/or tubes w/neg. washings; B: +another pelvic organ w/neg. washings; C: +malig cells in washings/ascites	70-80%
Stage III	Spread into but confined to abd. A: Abd mets microscopic; B: Abd mets macroscopic but ≤2 cm; C: Abd mets >2 cm &/or +regional LNs	25-50%
Stage IV	Spread outside abd &/or liver parenchyma	5-19%
^**Prognosis also depends on age, extent of residual disease & histology

Early Stage Adjuvant Treatment of EOC

Low Risk: Stage IA/B: Grade 1→ no adj tx; grade 2 → consider IV taxane/carboplatin (T/C) × 3-6 cycles; grade 3/clear cell → IV T/C × 3-6
High Risk Stage IC → adj tx w/IV T/C × 3-6 cycles; ↑ DFS & OS

Advanced Stage (II-IV) Adjuvant Treatment

6-8 cycles of taxane/platinum chemo.
Stage II & stage III optimally debulked (<1 cm): IV/IP paclitaxel & IP CIS. In stage III optimally debulked pts, median PFS ↑6 mos (23.8 vs. 18), median OS ↑ 16 mos (65.6 vs. 49.7) compared w/q3wk IV Rx. ↑tox w/IP: Fatigue, pain, neuropathy, renal, IP port complications. Only ˜40% pts completed all 6 IV/IP cycles (GOG 172 NEJM 1996;354:34-43). ↑ benefit w/↑no. of IP cycles. No ↑ OS w/+ 3rd chemo drug (J Clin Oncol 2006;24:18s ASCO#5002). BEV ↑ PFS 1.7-4 mos (NEJM 2011;365:2473-2483; NEJM 2011;365:2484-2496)
Residual disease >1 cm, stage IV, not IP candidate: Dose-dense IV T/C (wkly paclitaxel) may be superior to q3wk IV T/C. In stage II-IV (opt & subop) dose-dense IV T/C vs. q3wk T/C: ↑ PFS 11 mos (28 vs. 17) & ↑ 3-y OS by 7% (72 vs. 65%) (Lancet 2009;374(9698):1331-1338)
Unresectable bulky disease or poor PS: Obtain bsy for dx. Neoadj chemo × 3-6 cycles → interval tumor debulking → adj chemo
Low malignant potential: If invasive implants, consider treating as EOC

Recurrent Disease

Majority of adv-stage recur. Platinum-refractory if <6 mos of 1° platinum
Platinum-sensitive (recurs >6 mos): Platinum-based doublet (gem, liposomal dox, paclitaxel) ± 2° cytoreduction. 1st recurrence → + BEV ↑ PFS 4 mos (12.4 vs. 8.4) (OCEANS J Clin Oncol 2012;30(17):2039-2045); Serial relapses & remission w/chemo until platinum-resistance occurs.
Platinum-resistant (<6 mos): Single-agent lipo dox, gem, topo, tax. + BEV ↑ PFS ˜3 mos (6.7 vs. 3.4) (AURELIA J Clin Oncol 2012;30 LBA5002)
Mek inh (Selumetinib) for recurrent low grade serous (Lancet Oncol 2013;14(2):134-140)

OVARIAN GERM CELL TUMORS

Anya Litvak

Rachel N. Grisham

Epidemiology: 0.41 per 100000 in the USA; 5% of all ovarian malignancies; 20% of all benign ovarian tumors; usu present at early stage in young women between 10 & 30 y of age; ↑ rate in Asian/Pacific islanders/Hispanic population > Caucasians; tumors tend to be large at dx (median size = 16 cm)

Pathology
Benign tumors	Mature cystic teratoma: 5-25% of OGCTs; 10-20% bilateral; 1-2% malignant degeneration; often present w/thickened area from w/c hair & teeth arise (Rokitansky’s protuberance)
Malignant Primitive OGCT	Dysgerminoma (35-50%): Most common malignant OGCT; ovarian counterpart of testicular seminoma; 75% of pts are adolescents & young adults (avg age = 19); can produce estrogen, testosterone, B-HCG, & LDH; can cause menstrual abnormalities; usu diagnosed at stage IA; spreads via lymphatics; highly radiosensitive; 10-15% bilateral; histology w/fried egg appearance; better prognosis than nondysgerminomas Yolk sac/endodermal sinus tumors (14-20%): Usu presents in adolescents (median age = 19); spreads intraperitoneally & hematogenously, usu produces AFP & LDH; histology w/Schiller-Duval bodies Embryonal carcinoma (4%): Most aggressive OGCT; usu produce HCG ± AFP; spreads intraperitoneally; mean age <30 y; histology w/sheets & ribbons Polyembryoma: Rare, treated like nondysgerminomas Nongestational choriocarcinoma (2.1%): Aggressive; mean age 20; produces B-HCG if arise from ovary; can cause precocious puberty; relatively chemoresistant Mixed germ cell tumor: (10-15%): Treated like nondysgerminomas
Malignant Teratomas:	Immature teratoma (˜20%): Graded from well differentiated to poorly differentiated based on portion of tissue in histologic section containing immature neural elements; 75% present in first 2 decades of life; 12-15% bilateral; 60-70% stage I; rarely produce tumor markers Monodermal Teratoma: Teratoma composed predominantly of one tissue element; most common “struma ovarii”: Mature thyroid tissue w/c can causes hyperthyroidism; can be benign. Other types: Carcinoid (1/3 present w/carcinoid syndrome), melanoma, sarcoma, sebaceous tumor, pituitary type, etc.; chemotherapy geared toward transformed component

Risk Factors and Clinical Manifestations

RF for poor survival: Advanced FIGO stage, nondysgerminoma or grade 2/3 immature teratoma, bulky residual disease after surgery, elevation of both HCG & AFP tumor markers preoperatively (J Clin Oncol 2006;24:4862-4866)
Sx: Abdominal pain & palpable pelvic abdominal mass (85%), abdominal distension (35%), fever (10-25%), vaginal bleeding from B-HCG/estrogen production (10%), precocious puberty 2/2 to B-HCG production (rare), NMDA receptor encephalitis (rare), hyperthyroidism (2/2 struma ovarii). Can be bilateral in benign cystic teratoma, dysgerminoma, & tumors w/components of dysgerminoma
Growing teratoma syndrome: Rare complication of immature teratomas 2/2 enlarging teratoma that becomes mature during chemo; needs prompt surgery

Serum Tumor Markers in MOGCTs
Histology	AFP	B-HCG	LDH
Dysgerminoma	−	±	+
Yolk sac tumor	+	−	+
Immature teratoma	±	−	−
Mixed germ cell tumor	±	±	±
Choriocarcinoma	−	+	−
Embryonal carcinoma	±	+	−
Polyembryoma	±	+	−

Workup and Staging

W/u: Serum tumor markers: AFP, LDH, HCG; CXR, pelvic US or CT abd/pelvis. Karyotype if dysgenetic gonads are suspected. Use tumor markers to monitor response to Rx & recurrence. R/O pregnancy if B-HCG ↑
Fertility preservation: Discuss embryo cryopreservation. If not feasible, cryopreservation of oocytes or ovarian tissue an option (experimental)
Stage I: Confined to ovaries (Stage IA: Single ovary; Stage IB: Both ovaries; Stage IC: Ovarian surface involvement or capsule rupture); Stage II: Extension into other pelvic tissues (Stage IIA: Extension/implants on uterus/tubes; Stage IIB: Extension or implants on other pelvic tissues; Stage IIC other Stage II criteria plus + washings); Stage III: Disease spread beyond pelvis or to lymph nodes but remains in abdomen/pelvis (Stage IIIA: Microscopic peritoneal mets beyond pelvis; Stage IIB: Macroscopic mets beyond pelvis (≤2 cm); Stage IIIC: Peritoneal mets beyond pelvis >2 cm or regional lymph node mets); Stage IV: Distant mets or liver parenchyma involvement

Management: Low Risk Disease (Benign OGCT; Stage IA, Grade 1 Immature Teratoma & Stage IA Dysgerminoma):

Definitive Surgery: Fertility sparing ovarian cystectomy/salpingooophorectomy if fertility is desired or standard surgical staging (TAH, BSO) & optimal cytoreduction if pt has completed childbearing. May want to bx contralateral ovary if dysgerminoma present (controversial).

Management: All Other Malignant OGCT:

1° Surgery: Perform before chemo as pts w/completely resected disease have ↑ oncologic results, although data inconclusive. May be more critical for nondysgerminomas
Adjuvant Chemotherapy: Standard of care w/3-6 cycles of BEP (bleomycin, etoposide, CIS). Ideally give 7-10 d after surgery; give at full dose Rx even w/myelosuppression as ↑ oncologic benefit (N Engl J Med 1987;316:1435-1440; J Clin Oncol 1994;12:701-706)
Debulking Surgery after Chemotherapy: Consider if residual disease present after adjuvant chemotherapy w/negative tumor markers. Can prevent Growing Teratoma Syndrome & dedifferentiation of teratoma into active CA (Gynecol Oncol 1994;55:217-223)
RT: Previously used in dysgerminomas; currently has largely been replaced by platinum-based chemotherapy (J Clin Oncol 1991;9:1950-1955)

Management: Recurrent Malignant OGCT:

90% of pts that will recur, recur in first 2 y after Rx completion; if recurs after 2 y, usu slow growing & chemo resistant
Salvage Chemotherapy: If no prior chemotherapy: BEP; If prior chemotherapy: VIP (etoposide, ifosfamide, CIS), VeIP (Vinblastine, ifosfamide, CIS), TIP (paclitaxel, ifosfamide, CIS). Palliative options: Paclitaxel, GEM ± CIS, epirubicin + CIS
High-Dose Chemotherapy w/Stem Cell Rescue: Consider for persistent, refractory, or platinum-resistant disease (J Clin Oncol 2000;18:1173-1180)

Long Term Side Effects of BEP Chemotherapy:

Renal insufficiency, gonadal dysfunction, neurotoxicity, cardiovascular tox 2/2 to CIS, 2° malignancies 2/2 etoposide (solid tumors, leukemias), & pulm fibrosis 2/2 bleomycin. 80% pts preserve menstrual function after fertility sparing surgery/platinum-based chemotherapy (Obstet Gyn 2003;101(2):251)

ENDOMETRIAL CARCINOMA

Anya Litvak

Martee L. Hensley

Epidemiology