Precancer, benign and malignant tumors of the uterus and ovary Eduard Kučera

Uterine fibroids

Risk factors They are many risk factors1 associated with the development of uterine fibroids Check smoking 1.Flake GP et al, Environmental Health Perspectives 2003; 111(8):1037-54

What are the symptoms? Not all fibroids are symptomatic However, for the 50% of women with symptomatic fibroids, the condition is debilitating.1 Symptoms can include: Abnormal or heavy menstrual bleeding1, 2 Pain,1,2 pressure symptoms1,2 and urinary symptoms2 Impairment of Quality of Life 2 Mass effects related to the size and location of fibroids Pregnancy complications Bleeding complaints These symptoms and consequences have been shown to diminish quality of life3 When symptomatic, fibroids can be linked to at least three major problems3 Tropeano G, Amoroso S, Scambia G. Hum. Reprod. Update (2008) 14 (3): 259-274. Downes E, Sikirica V, Gilabert-Estelles J. et al. Eur J Obstet Gynecol Reprod Biol. 2010; 152(1): 96-102. Viswanathan M, Hartmann K, McKoy N. et al. Evid Rep Technol Assess (Full Rep). 2007 Jul;(154):1-122. Review.

Mechanisms FOR FERTILITY IMPACT Mechanistic: space; abnormal contractions Local inflammation for sperm and embryo Inadequate blood supply

DIAGNOSIS - When and how? Physical examination may be the first signal that a woman might have uterine fibroids.1 Imaging methods to evaluate these benign tumours:1 Ultrasonography Hysteroscopy Magnetic resonance imaging (MRI) Evans P, Brunsell S. Am Fam Physician. 2007 May 15;75(10):1503-1508.ian

Uterine Fibroids TREATMENT

Therapeutic approach Currently, therapies are intended to reduce or eliminate uterine fibroid symptoms through one of the following options1 Reduction of the size of tumours Reduction of the amount of bleeding Removal of the uterine fibroids or uterus Miller CE, Journal of Minimally Invasive Gynecology 2009; 16:11–21

Therapeutic approach The choice of therapy is influenced by the patient’s Symptom severity Tumour characteristics (e.g. volume, localisation) Age Uterine preservation wishes Fertility preservation wishes

Endometrial cancer Endometrial cancer – most common gynecological malignancy 4th most frequent malignancy in women In Czech Rep. incidence 32/100 000 year 1500 new cases diagnosed per year (e.g. in UK 6,430) Maximum around 60 - 70 years Obesity of women – typical phenotype

Etiology so called „endometrial carcinoma syndrome“: obesity, (DM, hypertension) - peripheral transformation of androgens - insufficiency of ShBG recently often used so celled.: postmenopausal syndrome age: 6. - 7. decade nulliparity (RR=2,8) Infertility (RR=8) late menopause (RR= 2,4) estrogen producing ovarian cancers high intake of animal proteins and fats exogenous estrogens - unopposed gestagens (RR=2,3) tamoxifen (RR=2,4)

Carcinogenesis in peri- and postmenopausal women younger women older women complex hyperplasia de novo hyperplasia with atypia endometrial carcinoma ( Type I usually well diff. ) ( Type II usually poorly diff. ) endometroid carcinoma papillary serous clear cell carcinoma

Histological types Carcinoma (98%) endometroid adenocarcinoma adenocarcinoma with squamous cells clear cell carcinoma papillary serous spinocellular Sarcoma (2%) leiomyosarcoma endometrial stromal sarcoma mixed mesodermal cancers

Hyperplasia of endometrium Complex atypical hyperplasia = precancerosis of endometrial carcinoma ( especially endometroid type) - cell polymorphism, mitosis, nucleoplasmic index, hyperchromatosis - creation is independent on estrogen stimulation in atrophic endometrium Motlík,K, Živný,J.:Patologie v ženském lékařství,Grada,2001.

FIGO staging 2010 The 2010 FIGO staging system is as follows: Carcinoma of the Endometrium IA Tumor confined to the uterus, no or < ½ myometrial invasion IB Tumor confined to the uterus, > ½ myometrial invasion II Cervical stromal invasion, but not beyond uterus IIIA Tumor invades serosa or adnexa IIIB Vaginal and/or parametrial involvement IIIC1 Pelvic lymph node involvement IIIC2 Para-aortic lymph node involvement, with or without pelvic node involvement IVA Tumor invasion bladder mucosa and/or bowel mucosa IVB Distant metastases including abdominal metastases and/or inguinal lymph nodes

5 – year survival year Stage 5 year survival rate I-A 90% I-B 88% I-C 75% II 69% III-A 58% III-B 50% III-C 47% IV-A 17% IV-B 15%

Hysteroscopy and dg. curettage Curettage – frequent false negative results (10-50%) Curettage – in polyps up to 61% Hysteroscopy and targeted biopsy < 2% false negative results (Gimbelson, Loffer 1988, 1989, AJOG) Studies in 1383 histological findings obtained with D&C - 60% inadequate results (Smith, 1985) In 60% patients curetted < 1/2 cavity of the uterus (Stock, Obst.Gyn.,1975)

Diagnostic hysteroscopy - options Panoramatic view – magnified 1x conventional hysteroscopy allows viewing the whole uterine cavity and locate pathologies panoramatic macro-hysteroscopy – 20x magnification in distance < 1 cm Micro-contact hysteroscopy – 80x magnification allows evaluation of endometrial vascularisation, gland characteristic and their openness

Tamoxifen a endometrium Nonsteroidal synthetic anti-estrogen Adjuvant therapy in breast carcinoma Accumulation of effective substance in basal endometrium Endometrial proliferative abnormality (up to 40% postmenopausal women) - polyps, hyperplasia as much as endometrial carcinoma (2-3/1000/year) Higher risk of endometrial carcinoma after using more then 5 (?) years (2-7.5x) Most safe and effective screening is hysteroscopy in yearly intervals

Tamoxifen – endometrium pathology Length of therapy not more then 5 years Metrorrhagia always indication to endometrial examination In asymptomatic women (cca 70%) HSK vs. UZ part of periodic yearly check ups High percentage of false positive results with ultrasound examination– stromal edema (vacuolar degeneration) Tamoxifen - 37 - 71% incidence of polyps – proliferative activity in epithelial and stromal part Incidence of endometrial carcinoma cca in 3%

Tamoxifen and endometrium International agreement – 1997 Bioptical examination of the endometrium before beginning the therapy After 3 years of using observation in yearly intervals Lancet,1698-1711,2000.

Tamoxifen and endometrium Hysteroscopy with biopsy – first choice in patients with Tamoxifen therapy Symptomatic patients and therapy longer then 3 years Positive family history Taponeco,F et al. Indication of hysteroscopy in tamoxifen treated breast cancer patients. J.Exp.Clin.Cancer,21,2002

Ovarian Neoplasms

Ovarian Neoplasms- Introduction Common neoplasms. 80% are benign – young (20-45) 20% are Malignant - older (>40) 6% of all cancers in women. 50% deaths due to late detection.

Ovarian cyst Most ovarian cysts are functional in nature and benign Functional or non functional Functional – folicular, corpus luteal, thecal haemorrhagical c. Non – functional – dermoid, endometriotic, cystadenoma, parovarian etc.

Diagnosis - sonography

Ovarian cancer Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses Ovarian cancer is the second most common gynecologic cancer and the deadliest in terms of absolute number.[57] It caused nearly 14,000 deaths in the United States alone in 2010.

Risk Factors Null parity Gonadal Dysgenesis Family History Ovarian cancer genes BRCA1 (17q12) & BRCA2(13q12) (Cancer suppressor, Breast & ovary)

FIGO staging Stage I — limited to one or both ovaries IA — involves one ovary; capsule intact; no tumor on ovarian surface; no malignant cells in ascites or peritoneal washings IB — involves both ovaries; capsule intact; no tumor on ovarian surface; negative washings IC — tumor limited to ovaries with any of the following: capsule ruptured, tumor on ovarian surface, positive washings Stage II — pelvic extension or implants IIA — extension or implants onto uterus or fallopian tube; negative washings IIB — extension or implants onto other pelvic structures; negative washings IIC — pelvic extension or implants with positive peritoneal washings Stage III — peritoneal implants outside of the pelvis; or limited to the pelvis with extension to the small bowel or omentum IIIA — microscopic peritoneal metastases beyond pelvis IIIB — macroscopic peritoneal metastases beyond pelvis less than 2 cm in size IIIC — peritoneal metastases beyond pelvis > 2 cm or lymph node metastases Stage IV — distant metastases to the liver or outside the peritoneal cavity

Classification Surface epithelial – 65-70% stromal – 15-20% Germ cell tumors – 5-10% Metastatic tumors – 5%

5- year survival rate

Surface Epithelial tumors: Coelomic mesothelium. Serous(tubal), Mucinous (Cx) & endo Most common primary neoplasms 90% of malignant tumors of ovary Morphologically Cystic – Cystadenomas Solid/cystic – Cystadenofibromas Solid - adenofibromas

Surface Epithelial tumors Serous (tubal) Mucinous (endocx & intestinal) Endometrioid Transitional cell - Brenners. Clear cell

Surface Epithelial tumors all types can be benign, borderline , or malignant, depending upon; Benign ; - gross: mostly cystic - microscopic; fine papillae, single layer covering (no stratification), no nuclear atypia, no stromal invasion) Borderline ; - gross; cystic / solid foci - microscopic; papillary complexity, stratification, nuclear atypia, no stromal invasion Malignant ; - gross; mostly solid & hemorrhage / necrosis - microscopic; papillary complexity, stratification, nuclear atypia, stromal invasion

Serous Tumors: Frequently bilateral (30-66%). 75% benign/bord., 25% malignant. One unilocular cysts, papillary/less solid- benign/borderline Tall columnar ciliated epithelium. Papillary, solid, hemorrhage, necrosis or adhesions – malignancy. Extension to peritoneum – bad prognosis.

Mucinous Tumors: Less common 25%, very large. Rarely malignant - 15%. Multiloculated, many small cysts. Rarely bilateral – 5-20%. Tall columnar, apical mucin. Pseudomyxoma peritonei.

Endometrioid tumors most are unilateral (40% are bilateral) cells look like endometrium even though they are coming from the coelum of the ovary. almost all are malignant about 20% of all ovarian tumors many are associated with endometrial cancer (30%) patient may have concurrent endometriosis

Clinical course of coelomic surface epithelial tumors low abdominal pain abdominal enlargement GI tract complaints urinary tract complaints malignant ones produce ascites serosal surfaces are seeded with cancer in metastasis grow slowly and get very large

Germ cell Tumors Teratoma – Dysgerminoma Benign cystic (dermoid cysts) Solid immature Monodermal – struma ovarii, carcinoid Dysgerminoma Yolk sac tumor (Endodermal sinus tumor ) Choricarcinoma Mixed germ cell tumor

Endodermal sinus tumor (Yolk sac carcinoma) Tumor is a highly malignant and clinically aggressive neoplasm Most frequently in children and young females 20% of malignant germ cell tumors. fatal within 2 years of diagnosis

Sex Cord - Stromal Tumors Granulosa-cell tumor Thecoma Fibroma Sertoli-Leydig cell tumors

Granulosa Cell Tumor Hormonally active tumor The most common estrogenic ovarian neoplasm. The adult form occurs mainly in postmenopausal women, associated with endometrial hyperplasia and carcinoma The juvenile type occurs in the first two decades, cause precocious sexual development.

Granulosa Cell Tumor Sheets of granulosa cells containing spaces lined by the cells to give a follicle-like appearance (Call-Exner bodies).

Thecoma Functional tumors producing estrogen It occur in postmenopausal women Endometrial hyperplasia or carcinoma may develop

Sertoli-Leydig cell tumors 1% of ovarian neoplasms It occur predominantly in young women. Commonly androgenic, cause defeminization of women manifested as breast atrophy, amenorrhea, and loss of hair and hip fat , to virilization with hirsutism

Metastases to ovary About 3% of malignant tumors in the ovary are metastatic The most common primary site is the breast followed by the large intestine, stomach, and other genital tract organs.

Krukenberg tumor It is applied to the uniform enlargement of the ovaries (usually bilaterally) due to diffuse infiltration of the ovarian stroma by metastatic signet-ring cell carcinoma . The commonest primary site is the stomach followed by the colon.

Therapy Surgery Chemotherapy Biological therapy