stage Endometrial - PDF document

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 Case Presentation • 70 y/o African American female presenting with an episode of post - menopausal vaginal bleeding. March 20, 2018 Relevant Past Medical History • PMH: – Hypertension – History of sarcoidosis (in remission) – Glaucoma – Osteoarthritis – Obesity – BMI 35 • GYN: â

€“ 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 March 20, 2018 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 appea

ring cervix and vagina without erythema, inflammation or lesions. – Bimanual exam reveals palpably normal uterus and cervix without lesions or nodularity. No masses appreciated. March 20, 2018 Imaging March 20, 2018 Pelvic ultrasound: “The endometrial stripe is thickened. The endometrial stripe measures 16.6 mm. Heterogeneous.” 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 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): 558 - 65 . March 20, 2018 Pathology • Endometrial biopsy: – Endometrioid adenocarcinoma, FIGO grade 2 March 20, 2018 - Webpathology : http ://www.webpathology.com/image.asp?case=569&n=1

3 Epidemiology • In 201�7, 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: 62 • 5 - and 10 - year survival rate 82% and 79% - Miller , K.D., et al., Cancer treatment and sur

vivorship statistics, 2016. CA: a cancer journal for clinicians, 2016. 66(4): p. 271 - 289 . - https ://seer.cancer.gov/statfacts/html/corp.html March 20, 2018 Clinical Presentation • Postmenopausal uterine bleeding • Perimenopausal heavy or prolonged bleeding • Pelvic pressure • Low back pain • Vaginal discharge • Bowel or bladder symptoms • + pap smear March 20, 2018 Risk Factors • Endogenous and exogenous estrogens – Obesity – Early age at mena

rche – Nulliparity – Late on - set of menopause – Older age – Tamoxifen – HNPCC March 20, 2018 Work Up • H&P (including bimanual pelvic exam) • U ltrasound 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 pre - operatively and PET - CT for lymph node evaluation, however not standard at our institution March 20, 2018 Staging • 2009 FIGO staging for car

cinoma 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 March 20, 2018 Prognostic Factors • Age • Grade • Depth of invasion • LVS

I • Non - endometriod histology • Lymph node evaluation • Race • Comorbidities March 20, 2018 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 o

utcomes – 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 epithelia

l and stromal components • Mesenchymal Carcinomas - (outside scope of this presentation) – 0% – Include leimoyosarcoma , stromal sarcoma, r hadomyosarcoma , 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 March 20, 2018 - UpToDate : https://www.uptodate.com/contents/endometrial - carcinoma - histopathology - and

- pathogenesis 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 March 20, 2018 - Morice , P., et al., Endometrial cancer. Lancet, 2016. 387 (10023): p. 1094 - 108 . Genetic subtypes • TCGA - – POLE - mutant (best prognosis) – MSI - high – Copy number low MSS – Copy number high March 20, 2018 However, currently does not change management. - Levine , D.A. and C.G.A.R. Network, Integrated genomic characterization of endometrial carcinoma. Nature, 2013. 497 (7447): p. 67. M

anagement • 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 March 20, 2018 NCCN 1.2018 March 20, 2018 - 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. Low risk • Sorbe et. al 2009 – – 645 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 contr

ol group • Conclusions – VBT has limited impact on low - risk patients March 20, 2018 - Sorbe , B., et al., Intravaginal brachytherapy in FIGO stage I low - risk endometrial cancer: a controlled randomized study. International Journal of Gynecological Cancer, 2009. 19 (5): p. 873 - 878 High - intermediate risk • GOG 99 HIR – 3 risk factors: • LVSI , outer 1/3 myometr invas , gr2 - 3 • Age � 70 with 1 factor • Age 50 – 70 with 2 factors • Any ag

e 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). March 20, 2018 - 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, 2004. 92 (3): p. 744 - 751 . - 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, 2000. 355 (9213): p. 1404 - 11. EBRT vs Vaginal Brachytherapy • PORTEC - 2 – Patients age �60 with % MI G3 orP-4; 50% and G1 - 2 – Randomized to VBT or EBRT – Vaginal recurrences similar, slightly higher pelvic relapses wi

th VBT – QOL improved with VBT (especially GI toxicity) March 20, 2018 - Nout , R., et al., Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high - intermediate risk (P ORTEC - 2): an open - label, non - inferiority, randomised trial. The Lancet, 2010. 375 (9717): p. 816 - 823 . - Nout , R.A., et al., Quality of life after pelvic radiotherapy or vaginal brachytherapy for endometrial cancer: first results of the rand

omized PO RTE C - 2 trial. Journal of Clinical Oncology, 2009. 27 (21): p. 3547 - 3556 . 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 March 20, 2018 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, resec

tion: 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 March 20,

2018 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. March 20, 2018 Treatment - Brachytherapy March 20, 2018 • Treatment ideally 6 - 8 weeks p

ost - 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, 2013. 5 (3): p. 164 - Catta

neo , 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, 2014. 88 (4): p. 866 - 871 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 stenos