Uterine myoma and sarcoma Fudan University Weiwei Feng, MD,Ph Uterine myoma and sarcoma Fudan University Weiwei Feng, MD,Ph.D Email:jingsakura@gmail.com

Terms: Myoma Leiomyoma Fibroid The commonest benign conditions of the uterus

an exceedingly frequent event Incidence True incidence--- uncertain Common in women between 20~50y Clinically evident in 20%~30% of the women over 30 years old. an exceedingly frequent event

Etiology Related to hormones ( estrogen and progesterone) Elevated ER expression in myoma Abnormal cytogenetics Arise during the period of menstrual activity, shrink after menopause

Classification Location Corpus ( 90%) Cervix ( 10%) Growth pattern Intramural( 60~70%) Subserosal (20%) Submucosal (10~15%) Multiple (>=2)

Pathology- grossly examination Pseudo capsule Margins : blunt, non-infiltrating, pushing Cut surface Whorled, spiral patterns of fibers

Microscopic features Elongated smooth muscle cells and fibrous tissue. No nuclear atypia, mitotic figures are absent or sparse.

Sarcomatous degeneration ( 0.4~0.8%) Degenerations Cause: gradually inadequacy of blood supply Hyaline degeneration : commonest Cystic degeneration Red degeneration Degeneration with calcification Benign Malignant Sarcomatous degeneration ( 0.4~0.8%)

Hyaline degeneration Cause: inadequacy of the blood supply Uniform, eosinophilic, ground-glass appearance Cystic degenration: secondly to hyaline degeneration

Red degeneration Frequent during pregnancy or puerperium A deep pink or red, softer The ghosts of the muscle cells and their nuclear remain

Sarcomatous change 1.Margin not well defined, blurred, merging, irregular 2. Loss of whorled pattern 3. Yellow, tan, or gray color 4. Heterogeneity 5. Softer, less rubbery 6. Absence of a bulging surface

Symptoms and physical signs 40~50% asymptomatic, discovered incidentally after routine examination

Menorrhagia Menostaxis Irregular mense Change of mense Menorrhagia Menostaxis Irregular mense Intramural myoma Anemia Shortness of breath Palpitations Weakness Submucosal myoma

Pelvic mass and physical signs Depend on the size, location, number and degeneration type Asymmetric enlargement of uterus Consistency Firm or rubbery Hard or stony ( calcification) Soft ( cystic)

Pelvic mass and Physical signs A firm mass extruded from the cervical OS (submucosal) Distortion and elongation of the cervical canal (cervical )

Compressive symptoms Different location of the myoma Cervical or lower segment Cervical or broad ligment Posterior Urethral obstruction Ureteral obstruction Recto-sigmoid compression Frequency and retention of urine Nephrohydrosis Hydroureter Constipation Discomfort

Increasing of discharge Intramural myoma—increased uterus cavity area Submucosal myoma— purulent discharge ( infection) lower abdominal discomfort

Pain Red degeneration Torsion of pendunculated myoma Extrusion of submucosal myoma from the cervix

Myoma and infertility infrequent primary cause of infertility 27% of women who received myomectomy had a history of infertility Usually caused by submucosal and intramural myoma

Myoma and pregnancy Pregnancy loss , abortion Increased cesarean section ( Obstruction of labor) Question: Can myoma be removed during cesarean section? Postpartum hemorrhage Red degeneration Growth of myoma Most patients have uncomplicated pregnancies and deliveries.

Diagnostic methods History Physical signs Ultrasound/ MRI 4. Cervical cytology 5. Dilation &Curretage 4,5 : To rule out cervical cancer and endometrial cancer 23

6. Hysterosalpingography 7. Hysteroscopy 8. Laparoscopy 9. Other lab tests ( HCG, Hb)

Differential diagnosis Pregnant uterus Ovarian tumor Uterine adenomyosis Malignant uterine neoplasms

Pregnant uterus VS. Myoma History Amenorrhoea Regular period, menorrhagia Signs Symmetric enlarged uterus Asymmetric enlarged uterus Ultra-sound Sac or fetus in cavity Low-echoed mass Lab. test HCG + HCG -

Ovarian tumor VS. Myoma Solid ovarian tumor VS. Subserous leiomyoma Ovarian cyst VS. Cystic /hyaline degenerative myoma

Adenomyosis VS. Myoma adenomyosis leiomyoma

Endometrial cancer / Cervical Cancer VS. Submucous myoma

Management

principle Factors should be taken into consideration Age Desire of childbearing Symptoms Location, size and number Malignant change

observation Observation with close follow-up Indications: small and asymptomatic myoma especially for peri-menopausal women

Medications Indications: Size <= 2 months pregnant uterus Mild symptoms Peri-menopausal With contraindications for operation

Gonadotropin-releasing hormone agonist (GnRH-a) Mechanism: Inhibit FSH, LH and Estrogen Efficacy : 40~60% decrease in uterine volume Side effects: hypoestrogenism reversible bone loss and hot flashes obvious for long use (>6 months) estrogen add-back therapy Regrowth : within a few months after stopping therapy. .

Indications of GnRH-a Preservation of fertility before attempting conception Treatment of anemia to allow recovery of Hb before surgery, minimizing the need for blood transfusion Preoperative treatment of large leiomyomas to make surgery more feasible. Treatment of women in menopausal period .

GnRH-a gesorelin ( 3.6mg q28d× 6) , leuprorelin: ( 3.75mg q28d × 6) Mifepristone ( Ru486) : 12.5mg P.O. progesterone receptor antagonist

Surgery Indications: Menorrhagia with anemia, resistant to medication Markedly enlarged uterus with compression symptoms Chronic pain, dyspareunia, Acute pain, as in torsion of a pedunculated myoma, or prolapsing submucosal fibroid 4. Rapid enlargement of uterus-sarcomatous change? 5. Infertility or spontaneous abortion with myoma as the only abnormal finding

Surgical procedures Myomectomy Hysterectomy Abdominal / laparoscopic / hysteroscopic or vaginal Myomectomy Hysterectomy 38

Myomectomy Indications: young patients who desire for childbearing Recurrence risk: as high as 50%, and up to 1/3 requiring repeat surgery

Hysterectomy Indications: no requirement of uterine preservation Note: : Cervical or endometrial cancer must be excluded before operation

Other treatments: Uterine artery embolization, UAE Endometrium ablation by hysteroscopy

Video 1: Laparoscopic myomectomy Advantages : Minimizes incision, quicker recovery Disadvantages: Risks of convertion to a laparotomy Immature suture technique: uterine rupture during pregnancy Video 2: Laparoscopic hysterectomy

Uterine sarcoma

General information Rare tumors of mesodermal origin (myometrium, connective tissue, stroma of endometrium, or secondly to myoma) 2~4% of uterine malignancies Poor prognosis ( death occurring within 1 to 2 years after diagnosis, except ESS)

Three commonest types Leiomyosarcoma (~45%) Endometrial stromal sarcoma (ESS) Undifferentiated endometrial sarcoma (15~25%) Mixed epithelial and mesenchymal tumors Adenosarcoma Carcinosarcoma , or malignant mesodermal mixed tumor, MMMT

leiomyosarcoma Age: 45-55 yr, Usually arise de novo from uterine smooth muscle, rarely arise in a preexisting myoma Diagnosis usually is not made before surgery. D&C are diagnostic only for ~10% of tumors that are submucous. Poor prognosis

leiomyosarcoma mitotic figures>5/10HPF severe cytologic atypia , . mitotic figures>5/10HPF severe cytologic atypia coagulative tumor necrosis

Endometrial stromal sarcoma Before 2003, low grade ESS, low grade (低度恶性子宫内膜间质肉瘤） Most ESS involve endometrium, infiltrate muscles, sometimes protrude from the OS. D&C lead to diagnosis (about half). The only uterine sarcoma related to hormone, ER, PR (+), response to hormone treatment Behaviour : indolent, late recurrence and metastasis may occur. 5-yr survival >80%

ESS, low grade Originated from endometrial stromal cells, similar to proliferative phase ESS with invasive border

Undifferentiated endometrial sarcoma ( UES) UES: behave aggressively, with 5-year survival < 40% UES with severe atypia Mitosis>10/10HPF

Mixed epithelial and mesenchymal tumors Adenosarcoma : Benign epithelial element Malignant mesenchymal element

Carcinosarcoma Malignant mesodermal mixed tumor, MMMT Both epithelial and mesenchymal elements are malignant In FIGO 2009, carcinosarcoma was regarded as type II endometrial carcinoma, because the prognosis is mainly determined by epithelial elements.

most patients being postmenopausal Enlarged or irregular uterus Tumor protrudes through the cervical OS like a polyp (50%) Behaviour: aggressive Recurrence rate: 53% 5 year survival 11~35% Carcinosarcoma

Patterns of spread Directly spread (to myometrium, pelvic structures) pelvic vessels lymphatics

Symptoms and signs Uterine Bleeding ( 75%~95%) Pelvic pain (33%) Pelvic mass Enlarged uterus ( 15%~50%) Prolapsed necrotic tissue through cervical OS Other : Compressive symptoms Discharge

Diagnosis Symptoms ( Uterine bleeding ) and signs Ultrasound / MRI D & C Pathological diagnosis

Staging New staging systems ( FIGO 2009) Three different staging systems for 1. Leiomyosarcoma 2. ESS and adenosarcoma 3. Carcinosarcoma

Staging FIGO 2009 leiomyosarcoma I Tumor limited to uterus IA<5CM IB ≥ 5CM II Tumor grows outside of uterus but not outside the pelvis IIA tumor is growing into adnexa IIB tumor is growing to the tissue of pelvis other than adnexa III tumor grows into tissue of abdomen ( not just intruding into abdomen) IIIA in one place IIIB in 2 or more places IIIC tumor has spread to pelvic/ para-aortic lymph nodes IV The tumorr has spread to the urinary bladder or the rectum, and/or to distant organs, such as the bones or lung IVA spread to bladder or the rectum IVB distant metastasis

Staging FIGO 2009 ESS and adenosarcoma I Tumor limited to uterus IA limited to endometrium IB <1/2 myometrium IC ≥ 1/2 myometrium II Tumor grows outside of uterus but not outside the pelvis IIA tumor is growing into adnexa IIB tumor is growing to the tissue of pelvis other than adnexa III tumor grows into tissue of abdomen ( not just intruding into abdomen) IIIA in one place IIIB in 2 or more places IIIC tumor has spread to pelvic/ parpaotic lymphnodes IV The tumor has spread to the urinary bladder or the rectum, and/or to distant organs, such as the bones or lung IVA spread to bladder or the rectum IVB distant metastasis

Carcinosarcoma the same as FIGO Staging for endometrial cancer

Treatment 1. Surgery: only treatment of proven curative value Stage I and II : hysterectomy + bilateral oorphorectomy Pelvic and or para-aortic lymphnectomy: ESS/UES and Carcinosarcoma: required Leiomyosarcoma: not certain

cytoreductive surgery for advanced stage ( III or IV) patients 2. Adjunvant therapy: Chemotherapy +/- radiotherapy Radiotherapy improves tumor control in the pelvis without influencing final outcome chemotherapy : response rate (~20%) Drugs: doxorubicin, cisplatin, ifosfamide, palitaxel

3. Hormone therapy ( only used in ESS, low grade) progesterone, letrozol GnRH antagonist

Prognosis Generally poor, 5-year survival 20%~30% Stage is the most important prognostic factor. Cell type, grade, metastasis, and treatment If the leiomyosarcoma arises in a benign myoma, the prognosis is improved ESS: 5-yr survival >80%.

Case discussion History : A 33 year old woman complains heavy bleeding during period for 1 year. The duration of bleeding usually lasts 9 days. Sometimes she has blotting. Physical examination : shows pale and short of breath. Pelvic examination revealed enlarged uterus with a size of two-month pregnancy.

Case discussion Ultrasound: A 65/55/50 mm low-echoes mass with clear margin in myometrium was seen by ultrasound. In addition, a 23/20/19mm low echoes mass protrudes from uterus cavity. Lab test: Hb: 80g/L.

Questions What ‘s the diagnosis ? ( give the evidence) Which diseases should be excluded? What is the suitable treatment? Does this treatment affect fertility?

Take home message About the myoma The symptoms are related to the types of location and degenerations. Half of the patients are asymptomatic. The commonest symptom is change of mense. Ultrasound is the common and accurate diagnostic tool.

Take home message About the myoma No treatment is required for asymptomatic patients. Medications are suitable for peri-menopausal patients with mild symptoms. Surgery is the effective way to treat symptomatic patients or suspicious for sarcomatous change.

Take home message About the sarcoma Rare tumors with poor prognosis The commonest symptom is irregular vaginal bleeding with pain. Diagnosis is by pathology results. Surgical treatment is the main option. Adjunvant therapy depends on stage and type.

Thank You !