ARRO Case: Early-stage Endometrial

Ankit Modh, MD (PGY-4) Faculty Advisor: Mohamed A Elshaikh, MD Department of Radiation Henry Ford Cancer Institute Case Presentation

• 70 y/o African American female presenting with an episode of post-menopausal .

March 20, 2018 Relevant Past Medical History

• PMH: – – History of sarcoidosis (in remission) – Glaucoma – Osteoarthritis – – 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

March 20, 2018 Physical Exam

• Pelvic: – External genitalia is normal including normal , and . Perineum and anal area without erythema or lesions.

– Speculum exam reveals normal appearing and vagina without erythema, inflammation or lesions.

– Bimanual exam reveals palpably normal and cervix without lesions or nodularity. No masses appreciated.

March 20, 2018 Imaging

Pelvic ultrasound: “The endometrial stripe is thickened. The endometrial stripe measures 16.6 mm. Heterogeneous.”

March 20, 2018 Differential Diagnosis by Imaging Findings • Endometrial – Risk of carcinoma is ~7% if the 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): 558-65.

March 20, 2018 Pathology • : – Endometrioid , FIGO grade 2

- Webpathology: http://www.webpathology.com/image.asp?case=569&n=13

March 20, 2018 Epidemiology

• In 2017, >61K new cases estimate, >10k deaths

• Most (67%) diagnosed at early stage due to post-menopausal bleeding

• 4th most common in females (lung, breast, colorectal); ~6% of in women.

• In USA: 1st MC GYN cancer; 2nd MC GYN cancer death (ovarian is #1). Worldwide MC GYN Ca is cervical.

• age at diagnosis: 62

• 5- and 10-year survival rate 82% and 79%

- Miller, K.D., et al., Cancer treatment and survivorship 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

•

• Bowel or bladder symptoms

• + pap smear

March 20, 2018 Risk Factors

• Endogenous and exogenous

– Obesity

– Early age at

– Nulliparity

– Late on-set of

– Older age

–

– HNPCC

March 20, 2018 Work Up

• H&P (including bimanual pelvic exam)

• Ultrasound to measure endometrial stripe then Endometrial biopsy or fractional D&C &/or

• CT C/A/P

• Role for MRI to investigate depth of invasion pre- operatively and PET-CT for evaluation, however not standard at our institution

March 20, 2018 Staging

• 2009 FIGO staging for carcinoma of the endometrium: – stage 0: – 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 – 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 • IVa: bladder or rectal mucosal involvement • IVb: distant metastases, malignant ascites, peritoneal involvement

March 20, 2018 Prognostic Factors

• Age • Grade • Depth of invasion • LVSI • Non-endometriod histology • Lymph node evaluation • Race • Comorbidities

March 20, 2018 Pathology

• Epithelial - Arise within the of the uterine lining - 90% of uterine – 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 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

• – – 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: https://www.uptodate.com/contents/endometrial-carcinoma-histopathology-and-pathogenesis

March 20, 2018 Bokhman subtypes

Characteristic Type 1 Type 2

Unopposed (+) (-)

Racial Predilection White Black

Growth Slow Fast

Precursor Atypical 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 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, 2016. 387(10023): p. 1094-108.

March 20, 2018 Genetic subtypes

• TCGA - However, currently does not change – POLE-mutant (best management. prognosis) – MSI-high – Copy number low MSS - Levine, D.A. and C.G.A.R. Network, Integrated genomic characterization of – Copy number high endometrial carcinoma. Nature, 2013. 497(7447): p. 67.

March 20, 2018 Management

• Surgical staging, which includes: – and salpingo-ophorectomy, – Lymph node evaluation (controversial - institution/ surgeon dependent) – Peritoneal cytology

• Adjuvant Treatment, which, dependent on prognostic factors, could include: – External beam – – – Or combination of the above

March 20, 2018 NCCN 1.2018

- 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.

March 20, 2018 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 control group

• Conclusions – VBT has limited impact on low- risk patients

- 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

March 20, 2018 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 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 with or without adjunctive external pelvic in intermediate risk endometrial adenocarcinoma: a 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.

March 20, 2018 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 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 randomized PORTEC-2 trial. Journal of Clinical Oncology, 2009. 27(21): p. 3547-3556.

March 20, 2018 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 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. , right – 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

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

• 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 . A case report. Journal of contemporary brachytherapy, 2013. 5(3): p. 164 - 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, 2014. 88(4): p. 866-871

March 20, 2018 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

March 20, 2018