ARRO Case: Early-stage Endometrial Cancer

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1 ARRO Case: Early-stage Endometrial Cancer Ankit Modh, MD (PGY-4) Faculty Advisor: Mohamed A Elshaikh, MD Department of Radiation Oncology Henry Ford Cancer Institute

2 Case Presentation 70 y/o African American female presenting with an episode of post-menopausal vaginal bleeding.

3 Relevant Past Medical History PMH: Hypertension History of sarcoidosis (in remission) Glaucoma Osteoarthritis Obesity BMI 35 GYN: G5P1041 Last Pap smear: 6/22/2012 negative Hormonal contraceptives: none. HRT use: minimal - premarin for 2 months Social: Married, monogamous Never smoker Occasional wine drinker Family: Two brothers with prostate cancer

4 Physical Exam Pelvic: External genitalia is normal including normal vulva, vagina and urethra. Perineum and anal area without erythema or lesions. Speculum exam reveals normal appearing cervix and vagina without erythema, inflammation or lesions. Bimanual exam reveals palpably normal uterus and cervix without lesions or nodularity. No masses appreciated.

5 Imaging Pelvic ultrasound: The endometrial stripe is thickened. The endometrial stripe measures 16.6 mm. Heterogeneous.

6 Differential Diagnosis by Imaging Findings Endometrial carcinoma Risk of carcinoma is ~7% if the endometrium is >5 mm and 0.07% if the endometrium is <5 mm Hyperplasia Polyp Endometritis - Smith-bindman R, Weiss E, Feldstein V. How thick is too thick? When endometrial thickness should prompt biopsy in postmenopausal women without vaginal bleeding. Ultrasound Obstet Gynecol. 2004;24 (5):

7 Endometrial biopsy: Pathology Endometrioid adenocarcinoma, FIGO grade 2 - Webpathology:

8 Epidemiology In 2017, >61K new cases estimate, >10k deaths Most (67%) diagnosed at early stage due to post-menopausal bleeding 4 th most common in females (lung, breast, colorectal); ~6% of cancers in women. In USA: 1st MC GYN cancer; 2nd MC GYN cancer death (ovarian is #1). Worldwide MC GYN Ca is cervical. Median age at diagnosis: and 10-year survival rate 82% and 79% - Miller, K.D., et al., Cancer treatment and survivorship statistics, CA: a cancer journal for clinicians, (4): p

9 Clinical Presentation Postmenopausal uterine bleeding Perimenopausal heavy or prolonged bleeding Pelvic pressure Low back pain Vaginal discharge Bowel or bladder symptoms + pap smear

10 Risk Factors Endogenous and exogenous estrogens Obesity Early age at menarche Nulliparity Late on-set of menopause Older age Tamoxifen HNPCC

11 Work Up H&P (including bimanual pelvic exam) Ultrasound to measure endometrial stripe then Endometrial biopsy or fractional D&C &/or hysteroscopy CT C/A/P Role for MRI to investigate depth of invasion preoperatively and PET-CT for lymph node evaluation, however not standard at our institution

12 Staging 2009 FIGO staging for carcinoma of the endometrium: stage 0: carcinoma in situ stage I: limited to the body of the uterus Ia: no or less than half ( 50%) myometrial invasion Ib: invasion equal to or more than half ( 50%) of the myometrium stage II: cervical stromal involvement (endocervical glandular involvement only is stage I) stage III: local or regional spread of the tumour IIIa: tumour invades the serosa of the body of the uterus and/or adnexa IIIb: vaginal or parametrial involvement IIIc: pelvic or para-aortic lymphadenopathy IIIc1: positive pelvic nodes IIIc2: positive para-aortic nodes with or without pelvic nodes stage IV: involvement of rectum and or bladder mucosa and or distant metastasis IVa: bladder or rectal mucosal involvement IVb: distant metastases, malignant ascites, peritoneal involvement

13 Prognostic Factors Age Grade Depth of invasion LVSI Non-endometriod histology Lymph node evaluation Race Comorbidities

14 Pathology Epithelial Carcinomas - Arise within the epithelium of the uterine lining - 90% of uterine neoplasms Endometrial Adenocarcinoma / Endometrioid (90% of epithelial carcinomas) Papillary Serous Carcinoma (< 10% of epithelial carcinomas) account for ~40% of endometrial cancer deaths) -Associated with more aggressive disease and worse outcomes Clear Cell Carcinoma (< 5% of epithelial carcinomas). Associated with older women; Seen in ovarian, cervical and vaginal cancers. Very aggressive, especially if mixed with PSC. Mucinous Carcinoma Tend to be well-differentiated; 50% clinical course is similar to endometrioid adenocarcinoma. Mixed cell tumors - > 5% but < 50% non-endometrioid histology Squamous Cell Carcinoma Carcinosarcoma contain both epithelial and stromal components Mesenchymal Carcinomas - (outside scope of this presentation) <10% Include leimoyosarcoma, stromal sarcoma, rhadomyosarcoma, adenosarcoma Grading Grade 1 Less than 5 percent solid growth patterns Grade 2 6 to 50 percent solid growth patterns Grade 3 Greater than 50 percent solid growth - UpToDate:

15 Bokhman subtypes Characteristic Type 1 Type 2 Unopposed Estrogen (+) (-) Racial Predilection White Black Growth Slow Fast Precursor Atypical hyperplasia Endometrial intraepithelial carcinoma Histology Endometrioid Serous, Clear cell Grade Low High Depth of Invasion Superficial Deep Molecular genetic changes Diploid; Low allelic instability; Aneuploid; High allelic instability; Associated gene mutations 1) K-Ras, 2) MLH1 methyl, 3) PTEN 1) TP53, 2) ERBB2 (HER2) Outcomes Favorable Poor clinical outcomes - Morice, P., et al., Endometrial cancer. Lancet, (10023): p

16 Genetic subtypes TCGA - POLE-mutant (best prognosis) MSI-high Copy number low MSS Copy number high However, currently does not change management. - Levine, D.A. and C.G.A.R. Network, Integrated genomic characterization of endometrial carcinoma. Nature, (7447): p. 67.

17 Management Surgical staging, which includes: Hysterectomy and salpingo-ophorectomy, Lymph node evaluation (controversial - institution/ surgeon dependent) Peritoneal cytology Adjuvant Treatment, which, dependent on prognostic factors, could include: External beam Brachytherapy Chemotherapy Or combination of the above

18 NCCN Adverse risk factors include: age, LVSI, tumor size, lower uterine segment or surface cervical glandular involvement. - Aside from stage IA, grade 1 without other risk factors (which there is general agreement to observe) there is a high degree of variability in treatment options.

19 Low risk Sorbe et. al pts treated wit TH/BSO, pelvic cytology, LN sampling - having no MI or < 50 %, Grade 1-2 Randomized to observation or VBT Rate of vaginal recurrences:1.2% in the treatment group versus 3.1% in the control group Conclusions VBT has limited impact on lowrisk patients - Sorbe, B., et al., Intravaginal brachytherapy in FIGO stage I low-risk endometrial cancer: a controlled randomized study. International Journal of Gynecological Cancer, (5): p

20 High-intermediate risk GOG 99 HIR 3 risk factors: LVSI, outer 1/3 myometr invas, gr2-3 Age > 70 with 1 factor Age with 2 factors Any age with all 3 factors PORTEC-1 HIR 2 of 3 required Age > 60, gr 3, 50% myo invasion No IC + grade 3 (= high risk) EBRT reduced LR in both studies (but not OS). - Keys, H.M., et al., A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study. Gynecologic oncology, (3): p Creutzberg, C.L., et al., Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma. Lancet, (9213): p

21 EBRT vs Vaginal Brachytherapy PORTEC-2 Patients age >60 with <50% MI G3 or > 50% and G1-2 Randomized to VBT or EBRT Vaginal recurrences similar, slightly higher pelvic relapses with VBT QOL improved with VBT (especially GI toxicity) - Nout, R., et al., Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an openlabel, non-inferiority, randomised trial. The Lancet, (9717): p Nout, R.A., et al., Quality of life after pelvic radiotherapy or vaginal brachytherapy for endometrial cancer: first results of the randomized PORTEC-2 trial. Journal of Clinical Oncology, (21): p

22 Other literature Other highly relevant studies on this topic: Norwegian study (historical) ASTEC/ EN 5 Sorbe IJROBP 2012 Japanese GOG 2033 High risk: PORTEC-3 and GOG 249 PORTEC-4

23 Back to our patient - Surgery Our patient was taken for a Robot-assisted total laparoscopic hysterectomy with bilateral salpingo-oophorectomy and removal of pelvic and para-aortic lymph nodes. Pathology: Pelvic Washings: Negative Uterus, cervix, bilateral ovaries and fallopian tubes, resection: 1. FIGO 2 Endometrioid adenocarcinoma with invasion of greater than one-half of myometrium (3.9/4.0 cm) with lymphovascular involvement 2. Unremarkable cervix and bilateral fallopian tubes 3. Endometriosis, right ovary 4. Unremarkable left ovary C. Right pelvic lymph nodes, resection: Negative for malignancy, four lymph nodes D. Right pelvic lymph nodes, resection: Negative for malignancy, four lymph nodes E. Right para-aortic lymph nodes, resection: Negative for malignancy, one lymph node F. Left para-aortic lymph nodes, resection: Negative for malignancy, one lymph node Summary: 70 y/o F with Stage IB, grade 2, endometrioid adenocarcinoma of the uterus with LVSI Recommendation: Vaginal cuff brachytherapy

24 Brachytherapy Most patients the postoperative vagina can be treated by a cylinder. Use the largest size that fits comfortably in the vagina to avoid air gaps and folds. Cylinder sizes range from 1.5 cm to 4 cm. When fitting patient evaluate vaginal cuff for dehiscence. The proximal 3-4 cm (active length) of the vagina should be treated.

Treatment - Brachytherapy Treatment ideally 6-8 weeks post-op Post placement CT scan: - Verify proper placement - Vaginal cuff dehiscence - Minimize air gaps Dose/ fx: - 7 Gy x 3 fx to 0.

25 Treatment - Brachytherapy Treatment ideally 6-8 weeks post-op Post placement CT scan: - Verify proper placement - Vaginal cuff dehiscence - Minimize air gaps Dose/ fx: - 7 Gy x 3 fx to 0.5 cm depth - 6 Gy x 5 fx to surface our preference - Account for anisotrophy to avoid under dosage at apex - Richard Cattaneo, I., M. Bellon, and M.A. Elshaikh, Vaginal cuff dehiscence after vaginal cuff brachytherapy for uterine cancer. A case report. Journal of contemporary brachytherapy, (3): p Cattaneo, R., et al., Interval between hysterectomy and start of radiation treatment is predictive of recurrence in patients with endometrial carcinoma. International Journal of Radiation Oncology Biology Physics, (4): p

26 Follow-up H/P + pelvic exam 3-6 months x 2-3 years, then then 6 months or annually CA-125 if initially elevated Imaging as clinically indicated Vaginal dilators (or sexually activity) to prevent stenosis

Endometrial Cancer. Incidence. Types 3/25/2019

Endometrial Cancer. Incidence. Types 3/25/2019 Endometrial Cancer J. Anthony Rakowski DO, FACOOG MSU SCS Board Review Coarse Incidence 53,630 new cases yearly 8,590 deaths yearly 4 th most common malignancy in women worldwide Most common GYN malignancy