Hiperplasia and Cancer Endometrium

Definisi Hiperplasia Endometrium Pertumbuhan endometrium abnormal yang melebihi pertumbuhan normal siklus menstruasi dan disertai dengan proliferasi kelenjar dan stroma. M ONTGOMERRY B, D AUM G, D UNTON C. Endometrial hyperplasia : a review. Obstetrical and Gynecological Survey 2004;89:

Normal Endometrium The endometrium consists of o a single layer of columnar epithelium on the stroma  basalis layer o a layer of connective tissue  functionalis layer Simple tubular uterine glands reach from the endometrial surface through to the base of the stroma  carries a blood supply of spiral arteries Blue Histology - Female Reproductive System. School of Anatomy and Human Biology - The University of Western Australia William's Gynecology, McGraw 2008, Chapter 8, Abnormal Uterine Bleeding

Normal Endometrium US o endometrium is of high signal intensity and is therefore visualized as a thin white stripe o inner myometrium is of uniformly low signal intensity, while the outer myometrium is of intermediate signal intensity  regular hypoechoic band or ‘halo’

Normal Endometrium adjacent to the uterine cavity  built up after the end of menstruation during the first part of the previous menstrual cycle. Form 2/3 of endometrial layer To prepare for the implantation  proliferation, secretion, and degeneration Thickness varies ~ hormonal changes The functionalis layer Speroff. Clinical Gynecology Endocrinology and Infertility. 8th ed. Kluwer.

Normal Endometrium Proliferatif phase length varies from days, “ideal” is 14 days glands become more tortuous ~ epithelial proliferation, in response to estrogen production and estrogen receptors on epithelium The functionalis layer Speroff. Clinical Gynecology Endocrinology and Infertility. 8th ed. Kluwer.

Normal Endometrium Secretory phase undulant surface epithelium, tortuous glands with prominent mitotic activity and pseudostratification; dense stroma, subnuclear vacuoles in less than 50% of glands The functionalis layer Speroff. Clinical Gynecology Endocrinology and Infertility. 8th ed. Kluwer.

Normal Endometrium Menstrual Typical fragmentation, stromal collapse and bloody necrotic background The functionalis layer Speroff. Clinical Gynecology Endocrinology and Infertility. 8th ed. Kluwer.

Normal Endometrium Post menopause the inactive endometrium No influence from estrogen / progesteron The functionalis layer Speroff. Clinical Gynecology Endocrinology and Infertility. 8th ed. Kluwer.

Normal Endometrium US The basalis layer, adjacent to the myometrium and below the functional layer, is not shed at any time during the menstrual cycle  the functional layer develops Present as a hypoechoic area on endometrial line Speroff. Clinical Gynecology Endocrinology and Infertility. 8th ed. Kluwer. The basalis layer

Normal Endometrium US William's Gynecology, McGraw 2008, Chapter 8, Abnormal Uterine Bleeding Takasaki A, Tamura H, Miwa I, Taketani T, Shimamura K, Sugino N (April 2010). "Endometrial growth and uterine blood flow: a pilot study for improving endometrial thickness in the patients with a thin endometrium". Fertil. Steril. 93 (6): 1851–8.

Possible Diagnostic Pathway in Postmenopausal & Perimenopausal Bleeding Van Hanegen N, et al. Diagnostic evaluation of the endometrial in postmenopausal bleeding : An Evidence based approach. Maturitas (2010), doi : /j.maturitas Suna et al. Evaluation of endometrial thickness with transvaginal ultrasonography and histopathology in premenopausal women with abnormal vaginal bleeding. Arch Gynecol Obstet (2010) 282:395–399 DOI /s y Premenopausal: Suna et al : cut off ED ≥ 8 mm (ss:83,6%, sp: 56,4%) Postmenopausal: Smith-Bindman : cut-off ED ≥ 3 mm (ss 100% : sp 38 %) Smith-Bindman, Gupta : cut-off ED ≥ 4 mm (ss 96% : sp 53) US guidelines & me-A : cut-off ED ≥ 5 mm (ss 96% : sp 61%)

Klasifikasi dan Histopatologi Klasifikasi oleh International Society of gynecology Pathologist (ISGP) dan WHO. o Hiperplasia simpleks o Hiperplasia kompleks o Hiperplasia atipik B ARAKAT R, M ARKMAN M, ME R. Principle and practice of Gynaecology Oncology. Edisi V. Philadelphia: Lippincott Williams & Wilkins;

Patogenesis Hiperplasia Endometrium Gil Mor et al. Role of the Fas/Fas ligand system in female reproductive organs : survival and apoptosis. Biochemical Pharmacology 64 (2002)

4. Faktor Risiko Terapi estrogen tanpa progesteron siklik Tumor ovarium produksi estrogen Tamosifen  kanker payudara Sindroma ovarium polikistik HNPCC (hereditary non-polyposis colorectal carcinoma) Obesitas dengan DM D I S AIA P, C REASMAN W. Clinical Gynecologyc Oncology. Edisi VII. California: Elsevier B EREK J, H ACKER N. Practical gynecologic oncology. Edisi IV. China: Lippincott Williams & Wilkins Estrogen Testosteron

Possible Diagnostic Pathway in Postmenopausal & Perimenopausal Bleeding Van Hanegen N, et al. Diagnostic evaluation of the endometrial in postmenopausal bleeding : An Evidence based approach. Maturitas (2010), doi : /j.maturitas Suna et al. Evaluation of endometrial thickness with transvaginal ultrasonography and histopathology in premenopausal women with abnormal vaginal bleeding. Arch Gynecol Obstet (2010) 282:395–399 DOI /s y Premenopausal : o Suna et all : cut off ED ≥ 8 mm (ss:83,6%, sp: 56,4%) Postmenopausal: Smith-Bindman : cut-off ED ≥ 3 mm (ss 100% : sp 38 %) Smith-Bindman, Gupta : cut-off ED ≥ 4 mm (ss 96% : sp 53%) US guidelines & me-A : cut-off ED ≥ 5 mm (ss 96% : sp 61%)

TVS (Trans-Vaginal Sonography) Take endometrial sampling o Pipelle o Endometrial cytology o Dilation and Curretage (D & C) o office hysteroscopy targeted biopsy Diagnostic Precancer lession and Endometrial Cancer

2.Modalitas Tatalaksana Tidak Respon Berulang Usia Paritas Fungsi Reproduksi - Fungsi Reproduksi + D I S AIA P, C REASMAN W. Clinical Gynecologyc Oncology. Edisi VII. California: Elsevier

Ozlem O dkk.Comparison of the Efficacy of Three Progestins in the Treatment of Simple Endometrial Hyperplasia without Atypia. Gynecol Obstet Invest 2011;72:10–14 DOI: /

Progestin Ovulation inhibition dose mg per day p.o. Transformation dose mg per cycle Transformation dose mg per day p.o. Progesterone Dydrogesterone> Medrogestone Medroxyprogesterone acetate Chlormadinone acetate Cyproterone acetate Norethisterone / Norethisterone acetate / Lynestrenol / Ethynodiol / Levonogestrel Desogestrel Gestodene / Norgestimate0.27.0/ Dienogest1.06.0/ Drospirenone2.050/ Promegestone Nomegestrol acetate Trimegestone0.5// Progestogenic effectivity on the level of the endometrium and gonadotropic effects (dose for ovulation inhibition) of the different progestine Donald OM dkk. The classification, diagnosis and management of endometrial hyperplasia. Reviews in Gynaecological Practice 3 (2003) 89–97

Donal EM. Review The classification, diagnosis and management of endometrial hyperplasia. Reviews in Gynaecological Practice 3 (2003) 89–97

alex.j ch. conservative management of endometrial hyperplasia: new strategies and experimental options. obg management september

Ioannis dkk. LNG-IUS versus oral progestogen treatment for endometrial hyperplasia: a long-term comparative cohort study. Human Reproduction, Vol.28, No.11 pp. 2966– 2971, 2013 Iaonis dkk. LNG-IUS versus oral progestogen treatment for endometrial hyperplasia: a long-term comparative cohort study. Human Reproduction, Vol.28, No.11 pp. 2966–2971, 2013

2.Modalitas Tatalaksana Tidak Respon Berulang Usia Paritas Fungsi Reproduksi - Fungsi Reproduksi + D I S AIA P, C REASMAN W. Clinical Gynecologyc Oncology. Edisi VII. California: Elsevier

2. Terapi Konservatif Operatif Generasi Pertama Membutuhkan Learning curve Komplikasi TCRE Laser

TCRE (Trans Cervical Resection of Endometrium) Efektivitas TCRE Neha dkk. Treatment analysis of transcervical resecrion of endometrium (TCRE) in heavy menstrual bleeding (HMB): A prospective multicentre theurapetic study in india scenario Indian Journal of Obstetrics and Gynaecology, January-March 2015;2(1):28-35

Epidemiology and Risk Factor In the United States, endometrial cancer is the most common gynecologic malignancy Most patients are diagnosed early and are subsequently cured Obesity is the most common cause of endogenous overproduction of estrogen Unopposed estrogen therapy is the next most important potential inciting factor

Treatment for Endometrial hyperplasia without atypia Progestin therapy continuous or cyclical Childbearing age: Progestin dominant OCP’s or Depo-Provera 150mg IM for 3 consequtive months or Provera 10mg po for 10 days/month in 3-6 cycles and May follow with ovulation induction after normal biopsy if pregnancy desired Peri- or Post-menopausal: Provera 20mg po 10 days/month or Depo-Provera 200mg IM for 2 months Repeat biopsy in 3-4 months

Treatment Endometrial Hyperplasia Without atypia Regression (Reff) o MPA 1x10mg/d for days in 3-6 tx cycles 80% (Ferenczy, 1989) o MPA 1x10 mg/d D16-d25 for 3-6 tx cycles 95% (Affinito, 1994) o GnR- analog 3.75mg/month for 3-6 consecutive cycles o Levonorgestrel-IUS for 6-12 months Repeat biopsy in 3-4 months

Treatment Endometrial Hyperplasia Progestin therapy continuous or cyclical Without atypia Regression o MPA 1x10 – 20 mg/d for days in 3-6 tx cycles 80% Repeat biopsy in 3-4 months

Alur penatalaksanaan hiperplasia endometrium

Treatment for Atypical Endometrial Hyperplasia 27-62% risk of progression to carcinoma (over 10 years) if untreated (Jadoul et al, 2003) Standard treatment when childbearing is complete is total hysterectomy (abdominal or vagina) Conservative medical therapy can be attempted in younger patients who request preservation of fertility.

Treatment Endometrial Hyperplasia With atypia o Hysterectomy Because:- 25% risk underlying adeno- carcinoma - 29% risk progression - Poor response to progestin therapy Progestin therapy: o Only about 50% show histological regression o 25% develop adeno-carcinoma

Postmenopausa l bleeding TVS ED > cut - off ED – sampling (pre) malignancy ruled out Insufficient/inadeq uate sample SIS Diagnostic/theurapeut ic hysteroscopy (pre) malignancy treatment ED ≤ cut – off Expectant management Recurrent bleeding Alur Penegakan Diagnosis Perdarahan Uterus pasca Menopause Van Hanegen N, et al. Diagnostic evaluation of the endometrial in postmenopausal bleeding : An Evidence based approach. Maturitas (2010), doi : /j.maturitas Smith-Bindman : cut-off ED ≥ 3 mm (ss 100% : sp 38 %) Smith-Bindman, Gupta : cut- off ED ≥ 4 mm (ss 96% : sp 53%) US guidelines & me-A : cut- off ED ≥ 5 mm (ss 96% : sp 61%) Ada fasilitas USG TV/transrectal tidak Ada fasilitas USG TV/transrectal D/C

Endometrial hyperplasia

Endometrial cancer - Pathogenesis Biologically and histologically diverse group of neoplasms characterized by a dualistic model of pathogenesis. Type I endometrioid  They are estrogen-dependent, low grade, and derived from atypical endometrial hyperplasia. Type II cancers usually have serous or clear cell histology, no precursor lesion, and a more aggressive clinical course

Endometrial cancer - Histopathology There is a broad spectrum of aggressiveness within the histopathologic types of endometrial cancer Some will have an unfavorable histology that portends a much more aggressive tumor.

Endometrial cancer - Histopathology The most widely used grading system for endometrial carcinoma is the three-tiered FIGO system : Grade 1 lesions typically are indolent with little propensity to spread outside the uterus or recur. Grade 2 tumors have an intermediate prognosis. Grade 3 cancers are associated with an increased potential for myometrial invasion and nodal metastasis.

Pattern of Spread Edometrial cancers have several different potential ways to spread beyond the uterus Type I endometrioid tumors and their variants most commonly spread by: (1) direct extension, (2) lymphatic metastasis, (3) hematogenous dissemination, and (4) intraperitoneal exfoliation. Type II serous and clear cell carcinomas have a particular propensity for extrauterine disease, in a pattern that closely resembles epithelial ovarian cancer. In general, the various patterns of spread are interrelated and often develop simultaneously.

Endometrial cancer - Staging

Multiple factors have been identified for high risk of recurrence in apparent early-stage disease: histological subtype, grade 3 histology, myometrial invasion ≥50%, lymphovascular space invasion (LVSI), lymph node metastases and tumour diameter >2 cm. Stage I can be subdivided into three risk categories Endometrial cancer - Staging

Follow Up Target: 1. Detect recurrence and late adverse effects of treatment; 2 Prevent or screen for secondary cancer; and 3 provide social assistance and help in returning to work Gynecological examination inculde investigation of the whole vagina, pelvic examination, and lymph node palpation. Routine imaging, biologic tests, and vaginal smears are not indicated Follow-up should be done every 4 to 6 months during the first 3 years and then annually for early stages (I and II) and every 4 to 6 months during the first 5 years and then annually for advanced stages (III and IV).

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