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endometrial cancer (carcinoma)

Etiology: 1) risk factors: a) age > 45 years, menopause [2] b infertility or anovulatory cycles - anovulatory bleeding [2] c) obesity d) nulliparity, early menarche, late menopause [2] e) estrogen unopposed by progesterone (see Million Women Study) f) tamoxifen g) family history of cancer: endometrium, breast, or GI tract - Lynch syndrome, Cowden syndrome [2] h) sugar-sweetened beverages increases risk of estrogen-dependent endometrial cancer in postmenopausal women (RR=1.4) [7] 2) protective factors: a) high progesterone levels of pregnancy b) use of oral contraceptive &/or hormone-replacement therapy containing both estrogen & progesterone [9] c) smoking [8] d) low body mass index [8] e) bisphosphonates [8] f) breast feeding > 3 months [12] Epidemiology: 1) most common gynecologic cancer 2) peak incidence if in 6th & 7th decades of life 3) black wonen with increased risk of more aggressive cancers & death from non-endometroid endometrial cancer [15] Pathology: - endometrial hyperplasia progresses to endometrial cancer in 10-30% of patients Microscopic pathology: histopathologic types 1) endometrioid carcinoma (80%) [15] 2) villoglandular adenocarcinoma 3) adenocarcinoma with benign squamous elements, squamous metaplasia, or squamous differentiation (adenoacanthoma) 4) adenosquamous carcinoma (mixed adenocarcinoma and squamous carcinoma) 5) mucinous adenocarcinoma 6) serous adenocarcinoma (papillary serous) 7) clear cell adenocarcinoma 8) squamous cell carcinoma 9) undifferentiated carcinoma 10) malignant mixed mesodermal tumors Genetics: - susceptibility associated with defects in MSH2, MSH3, MSH6, MLH1 - MLH1 & MSH2 gene mutations are assosiated with Lynch syndrome - other implicated genes ANLN, KIAA1324, PELP1, CASC2, VTCN1, CDH1, PTEN Clinical manifestations: 1) abnormal uterine bleeding a) irregular vaginal bleeding in women > 40 years of age b) postmenopausal bleeding 2) vaginal discharge Laboratory: - endometrial cancer genotyping Special laboratory: - Pap smear with atypical glandular cells or endometrial cells - hysteroscopy with endometrial biopsy if endometrial thickness > 5 mm [10] - vaginal cytology after treatment for endometrial cancer of little or no value [11] Radiology: 1) transvaginal ultrasound a) thickened, nodular or irregular endometrium (endometrial stripe) - if endometrial thickness > 5 mm, hysteroscopy with endometrial biopsy [10] b) fluid in the endometrial cavity c) screening for endometrial cancer not been shown to be cost-effective [5] 2) imaging is NOT more effective than physical exam for diagnosing recurrent cancer [2] Complications: - recurrence of gynecologic cancer most often detected by symptoms or physical examination [10,11] Staging: AJCC/TNM/FIGO TNM FIGO Assessment TX - primary tumor cannot be assessed T0 - no evidence of primary tumor Tis 0 carcinoma in situ T1 I tumor confined to corpus uteri T1a IA tumor limited to endometrium T1b IB tumor invades less than 1/2 of myometrium T1c IC tumor invades 1/2 or more of myometrium T2 II tumor invades cervix , does not extend beyond uterus T2a IIA tumor limited to glandular epithelium of endocervix. No evidence of connective tissue stromal invasion. T2b IIB invasion of stromal connective tissue of cervix T3 III local &/or regional spread T3a IIIA tumor involves serosa &/or adnexa (direct extension or metastasis) &/or cancer cells in ascites or peritoneal washings T3b IIIB vaginal involvement (direct extension or metastasis) T4 IVA tumor invades bladder mucosa &/or bowel mucosa NX - regional lymph nodes cannot be assessed N0 - no regional lymph node metastasis N1 IIIC regional lymph node metastasis to pelvic &/or para-aortic nodes MX - distal metastases cannot be assessed M0 - no distant metastasis M1 IVB distant metastasis (includes abdominal lymph nodes other than para-aortic &/or inguinal lymph nodes; excludes metastasis to vagina, pelvic serosa or adnexa) stage T N M stage 0 Tis N0 M0 stage I T1 N0 M0 stage IA T1a N0 M0 stage IB T1b N0 M0 stage IC T1c N0 M0 stage II T2 N0 M0 stage IIA T2a N0 M0 stage IIB T2b N0 M0 stage III T3 N0 M0 stage IIIA T3a N0 M0 stage IIIB T3b N0 M0 stage IIIC T1 N1 M0 - T2 N1 M0 - T3 N1 M0 stage IVA T4 N_ M0 stage IVB T_ N_ M1 Histologic grading: GX: grade cannot be assessed G1: well differentiated G2: moderately differentiated G3-4: poorly differentiated or undifferentiated G1: 5% or less of a non-squamous or non-morular solid growth pattern G2: 6% - 50% of a non-squamous or non-morular solid growth pattern G3: more than 50% of non-squamous or non-morular solid growth pattern - notable nuclear atypia inappropriate for architectural grade raises grade to 3 - serous, clear cell and mixed mesodermal tumors are high risk & considered grade 3 - adenocarcinomas with benign squamous elements are graded according to the nuclear grade of the glandular component. 1) stage 1: confined to corpus 2) stage 2: involves corpus & cervix 3) stage 3: extends outside the uterus, but not outside the pelvis 4) stage 4: extends outside the pelvis or involves the bladder or rectum Management: 1) surgical resection a) total abdominal hysterectomy with bilateral salpingo-oophorectomy b) radiation therapy &/or chemotherapy may be added in higher risk patients [2] 2) radiation therapy alone in high-risk surgical patients [14] 3) chemotherapy is not very effective a) cisplatin b) carboplatin c) doxorubicin d) epirubicin e) paclitaxel 4) recurrent endometrial cancer a) symptom monitoiring & physical examination as effective as imaging for diagnosis of recurrent endometrial cancer b) treatment of recurrent endometrial cancer is poor - combination of medroxyprogesterone acetate & tamoxifen - median progression-free survival 3.8 months [13] - combination of everolimus & letrozole - 25% response - median progression-free survival 6.3 months [13] 5) prognosis - 5 year survival by stage at presentation 1] stage 1: 89% 2] stage 2: 80% 3] stage 3: 30% 4] stage 4: 9% 6) storing of embryos prior to therapy is an option in women of reproductive age 7) genetic classification of endometrial cancer may better estimate prognosis & facilitate treatment [6] 8) screening: a) not recommended, does not reduce mortality [2] b) atypical endometrial cells reported on Pap Smear should be further evaluated c) carriers of MLH1 gene & MSH2 gene mutations should be screened by endometrial biopsy (Lynch syndrome) [16]

Related

Breast Cancer Detection Demonstration Project endometrial cancer genotyping Million Women Study

General

uterine cancer carcinoma

References

  1. Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 29-30
  2. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 18, 19 American College of Physicians, Philadelphia 1998, 2006, 2009, 2018, 2022. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  3. Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 607-608
  4. AJCC Cancer Staging Manual 6th ed. Springer 2002
  5. Jacobs I et al Sensitivity of transvaginal ultrasound screening for endometrial cancer in postmenopausal women: a case-control study within the UKCTOCS cohort Lancet Oncol. 2011 Jan;12(1):38-48. Epub 2010 Dec 10. PMID: 21147030 http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2810%2970268-0/abstract - Vergote I et al Should we screen for endometrial cancer? The Lancet Oncology, Early Online Publication, 13 December 2010 Lancet Oncol. 2011 Jan;12(1):4-5. Epub 2010 Dec 10. No abstract available. PMID: 21147031 http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2810%2970280-1/fulltext
  6. The Cancer Genome Atlas Research Network Integrated genomic characterization of endometrial carcinoma. Nature 497, 67-73 (02 May 2013) PMID: 23636398 http://www.nature.com/nature/journal/v497/n7447/full/nature12113.html
  7. Inoue-Choi M et al Sugar-Sweetened Beverage Intake and the Risk of Type I and Type II Endometrial Cancer among Postmenopausal Women. Cancer Epidemiol Biomarkers Prev. Nov 22, 2013. 1-11 PMID: 24273064 http://cebp.aacrjournals.org/content/early/2013/11/13/1055-9965.EPI-13-0636.abstract
  8. Kaunitz AM Do Oral Bisphosphonates Affect Endometrial Cancer Risk? NEJM Journal Watch. March 5 2015 Massachusetts Medical Society (subscription needed) http://www.jwatch.org - Newcomb PA et al. Oral bisphosphonate use and risk of postmenopausal endometrial cancer. J Clin Oncol 2015 Feb 23 PMID: 25713431 http://jco.ascopubs.org/content/33/10/1186
  9. Collaborative Group on Epidemiological Studies on Endometrial Cancer. Endometrial cancer and oral contraceptives: an individual participant meta-analysis of 27,276 women with endometrial cancer from 36 epidemiological studies. The Lancet Oncology. Aug 5, 2015 PMID: 26254030 http://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045%2815%2900212-0.pdf
  10. Geriatric Review Syllabus, 9th edition (GRS9) Medinal-Walpole A, Pacala JT, Porter JF (eds) American Geriatrics Society, 2016 - Geriatric Review Syllabus, 11th edition (GRS11) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2022
  11. Novetsky AP, Kuroki LM, Massad LS et al The utility and management of vaginal cytology after treatment for endometrial cancer. Obstet Gynecol. 2013 Jan;121(1):129-35. PMID: 23262937 Free PMC Article
  12. Barbieri RL Endometrial Cancer and Breast-Feeding: Add Another Benefit to the Inventory. NEJM Journal Watch. May 18, 2017 Massachusetts Medical Society (subscription needed) http://www.jwatch.org - Jordan SJ, Na R, Johnatty SE et al. Breastfeeding and endometrial cancer risk: An analysis from the Epidemiology of Endometrial Cancer Consortium. Obstet Gynecol 2017 Jun; 129:1059 PMID: 28486362
  13. Bankhead C. Recurrent Endometrial Ca Responds to mTOR Drug. Responses in half of patients with no prior chemotherapy. MedPage Today. March 25, 2018 https://www.medpagetoday.com/meetingcoverage/sgo/71982 - Slomovitz B, et al GOG 3007, a randomized phase II trial of everolimus and letrozole or hormonal therapy (medroxyprogesterone/tamoxifen) in women with advanced, persistent, or recurrent endometrial carcinoma: A GOG Foundation study. Society of Gynecologic Oncology (SGO) 2018;Abstract 1.
  14. Hoffmann C with Expert Critique from Reddy AB Pelvic RT Remains Standard of Care for High-Risk, Early-Stage Endometrial Cancer. Recent research finds neither vaginal cuff brachytherapy plus chemotherapy nor adjuvant chemotherapy offers more benefit. MedPage Today. ASCO Reading Room 05.21.2018 https://www.medpagetoday.com/reading-room/asco/gynecological-cancers/73003
  15. Lu KH, Broaddus RR Endometrial Cancer. N Engl J Med 2020; 383:2053-2064, Nov 19. PMID: 33207095 https://www.nejm.org/doi/full/10.1056/NEJMra1514010 - Rothaus C Endometrial Cancer. NEJM Resident 360. Nov 18, 2020 https://resident360.nejm.org/clinical-pearls/endometrial-cancer
  16. Carter JS Endometrial Carcinoma Guidelines. Medscape. April 4, 2022 https://emedicine.medscape.com/article/254083-guidelines
  17. Endometrial Cancer (PDQ): Prevention http://www.nci.nih.gov/cancertopics/pdq/prevention/endometrial/HealthProfessional - Endometrial Cancer (PDQ): Screening http://www.nci.nih.gov/cancertopics/pdq/screening/endometrial/HealthProfessional - Endometrial Cancer (PDQ): Treatment http://www.nci.nih.gov/cancertopics/pdq/treatment/endometrial/HealthProfessional

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OMIM 608089 image related to endometrial cancer (carcinoma)