Uterine Malignancies

Gynecology Gynecologic lesions of the uterus & its malignancies dra. Bautista (sshhh! Quiet!) 4th shifting (Dec 2008) Eryka, Amyra, Rain, Allain Benign Lesions of the Uterus  Leiomyomas  Endometrial Polyps  Hematometra

Etiology of myomas • Incompletely understood

Leiomyomas • Also called myomas, fibroids, fibromyomas

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Highest prevalence during the 5 decade of life Benign tumors of smooth muscle origin Mostly arise in any part of the body of smooth muscle origin Believed to be due to the degeneration of some smooth muscles Majority is found in the corpus of the uterus Some women may develop myomas, some may not May appear singly but are most often multiple Varies in size from microscopic (5mm) to multinodular, weighing more than 50 lbs. Small, round, firm, solid More prone to grow & become symptomatic in nullliparous woman With continued growth, the myometrium at the edge of the tumor forms a pseudocapsule (valuable in surgical plane myomectomy) Rare before menarche Diminish in size following menopause due to reduction of the significant amounts of circulating estrogen. Occasionally enlarge due to oral contraceptives Enlarges during pregnancy

Most Common Types of Myomas Based on the relative anatomic relationship and position to the layers of the uterus

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Intramural • within the muscle layer • Initially, most myomas develop in the myometrium Submucous • 5-10% of myomas

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“humps & bumps” on D&C Most troublesome clinically Associated with vaginal bleeding

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Distortion of the uterine cavity → infertility or abortion • Rarely enlarges & becomes pedunculated → uterus will try to expel it → prolapsed fibrous myoma Subserous

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Gross appearance • Lighter color than the normal myometrium • Cur surface: glistening, pearl white with smooth muscle arranged in a trabeculated or whorled configuration, no capsule, tumor rounded and well demarcated Histologic Features • Tumor is rounded & well demarcated from the muscle coat of the uterus • No capsule • Consist of interlacing bundles of smooth muscles & small amounts of fibrous tissue Fate of Myomas • Determined by a relatively poor blood supply • Arterial supply of myoma of significantly less than that of the similar sized area of the normal myometrium

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May cause hydroureter as they enlarge

Growth of myoma →outgrow its blood supply → degeneration

Degrees of Degeneration 1. Hyaline – mildest form 2. Myxomatous 3. Calcific 4. Cystic 5. Red/Carneous or infarction • Most acute form of degeneration • Causes severe pain and localized irritation 6. 7. 8.

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• Occurs during pregnancy, approximately 5-10% Necrosis Fatty Malignant degeneration • Incidence: 0.3-0.7% • Term is ambiguous and may be incorrect •

Gives the uterus a knobby contour during pelvic exam Further growth may lead into the pedunculated myoma wandering into the peritoneal cavity → may outgrow its uterine blood supply → parasitic myoma

Broad Ligament Myoma • Growth of myoma in a lateral direction from the uterus • Difficult to differentiate from a solid ovarian tumor on pelvic exam

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Pathogenesis • Neoplastic transformation is probably a somatic mutation of a normal myometrium to leiomyoma that is influenced by estrogen, progesterone and local growth factors such as insulin-like growth factor 1 and platelet-derived growth factor • Exact mechanism of stimulus is unclear

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Unknown whether myoma degenerate into sarcoma or if sarcoma arise spontaneously in myomatous uterus Incidence increases with age Possibility of uterine tumor being leiomyosarcoma is 10 times greater among women in their 60’s than their 40’s

Symptomatology • Majority of women with intrauterine myomas are asymptomatic

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Rapid growth of uterine myoma after menopause is a disturbing symptom and is suggestive of leiomyosarcoma

MARY YVETTE ALLAIN TINA RALPH SHERYL BART HEINRICH PIPOY KC JAM CECILLE DENESSE VINCE HOOPS CES XTIAN LAINEY RIZ KIX EZRA GOLDIE BUFF MONA AM MAAN ADI KC PENG KARLA ALPHE AARON KYTH ANNE EISA KRING CANDY ISAY MARCO JOSHUA FARS RAIN JASSIE MIKA SHAR ERIKA MACKY VIKI JOAN PREI KATE BAM AMS HANNAH MEMAY PAU RACHE ESTHER JOEL GLENN TONI

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Pressure symptoms from an enlarging pelvic mass • Anterior myoma → pressing the bladder → urinary frequency & urgency • Posterior myoma → constipation • Urinary symptoms more common than rectal symptoms • Extremely large myomas and broad ligament myomas → unilateral or bilateral hydroureter • Digestive disturbance • Edema Edema • Acquired dysmenorrheal: most common, frequent complaint, associated with increased myometrial activity

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Milder pelvic discomfort: pelvic heaviness, dull aching sensation, may be due to edematous swelling of the myoma • Severe: vascular compromise → acute degeneration or torsion of the pedicle Abnormal Uterine Bleeding • 30% of women with myoma • Menorrhagia – most common

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Intermenstrual spotting or disruption of the normal pattern Most popular theory o Myomas may result in an abnormal microvascular growth pattern & function of vessels in adjacent endometrium o Theory that amount of menorrhagia is directly related to increased endometrial surface has been disproved

Diagnosis of Myoma 1. Pelvic Exam • Enlarged, firm, irregular uterus • Differential diagnosis: o Pregnancy o Adenomyosis o Ovarian neoplasm • After excluding pregnancy, place a metal sound in the uterine cavity to help establish the clinical diagnosis • Sounding – hysterometer is used to measure the uterine depth 2. Ultrasound • Transvaginal, transabdominal 3. Hysteroscopy • Diagnostic & therapeutic 4. Hysteropsalpingography • Contrast media, xray guided, to see the outline of the uterus 5. Hysterosonography 6. CT/MRI Management 1. Judicious observation • Observe & reevaluate at 6 months interval to determine the rate of growth • Small asymptomatic myoma • Myoma with AUB thorough investigation 2. Medical 3. Surgical o Myomectomy vs. Hysterectomy o Consider age, parity, future reproductive plans Classic Indications for Myomectomy • Rapidly expanding pelvis mass • Persistent abdominal uterine bleeding

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Enlargement of an asymptomatic myoma to greater than 8 cm in women who has not completed child bearing

Contraindications • Pregnancy • Advanced adnexal disease • Malignancy • Situation in which enucleation of myoma would result in a severe reduction of endometrial surface so that the uterus would be functional Myomectomy can be done through: • Laparotomy • Laparoscopic technique • Resection via cervical canal using hysteroscope Indications for Hysteroscopy • Indications for myomectomy • Asymptomatic myomas when the uterine size is like 14-26 weeks of gestation • Rapid growth of myoma after menopause • Consider age, future reproductive plans Prolapsed Myoma of the Cervix Management: • Vaginal removal & ligation of the base of the myoma – hysteroscopic resection • Antibiotic coverage Medical Treatment • To reduce the levels of estrogen and progesterone o GnRH agonist o Medroxyprogesterone acetate o Danazol o Antiprogesterone RU 486 Advantages & Disadvantages of Pre-OP Treatment • Advantages of shrinkage of uterine fibroid o May allow vaginal hysterectomy o May decrease intraoperative blood loss o May allow Pfannenstiel incision – “bikini type cut” o May facilitate endoscopic momectomy • Advantages gained by induction of amenorrhea o May correct hypermenorrhea – menorrhagia associated with anemia o May improve ability to donate blood

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May decrease need for non-autologous blood transfusion May atrophy endometrium, facilitating hysteroscopic resection

Disadvantages of Pre-OP GnRH Tx • Delay final tissue diagnosis • Degeneration of some leiomyomas necessitating piece – meal enucleation at myomectomy • Hypoestrogenic effects (eg. Trabecular bones, vasomotor flushes) • Cost • Need to self administer or receive injection in many cases • Vaginal hemorrhage in approximately 2% Transcatheter Uterine Artery Embolization • Newest modality • Ambulatory non-surgical technique • 4 deaths in 4000 cases • Large-scale randomized clinical trial is desperately needed • Promising success rate in decreasing menorrhagia

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Insert catheter to femoral artery, gel/foam/silicon pushed and will obstruct uterine artery and myoma will decrease in size

Associated Rare Disease 1. Intravenous Leiomyomatosis • Rare disease • Benign smooth muscle fibers severely invade the venous channels of the pelvis • Tumor grows by direct extension • Spaghetti tumor (gross)

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Leiomyomatosis Peritoneal Disseminata (LPD) • Benign disease with multiple small nodules over the surface of the pelvic & abdominal peritoneum

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Mimics disseminated carcinoma Histologic exam: benign appearing myomas Associated with recent pregnancy ENDOMETRIAL POLYPS • Localized overgrowths of endometrial glands and stroma that project beyond the surface of the endometrium • Soft, palliable; single or multiple • Few millimeters to several centimeters

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Endometrial polyps may be; sessile (broad-based) pedunculated (with slender pedicle) Prevalence: 20-25% in reproductive age group Unknown etiology

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Majority are asymptomatic If symptomatic: wide range f abdnornal uterine bleeding patterns No single abnormal bleeding pattern is diagnostic of polyps Pedunculated endometrial polyp with long pedicle may protrude to the external os Large polyps contribute to infertility Succulent & velvety with large central core Usually gray to tan, occasionally red or brown

3 histologic components of Endometrial Polyps • Endometrial glands • Endometrial stroma • Central vascular channel ***malignant transformation – 0.5%*** Differential Diagnosis for Endometrial Polyps • Submucous Leiomyomas • Actenomyomas • Retained products of conception • Endometrial hyperplasia • Carcinoma • Uterine Ca Management • Removal (polypectomy) – curettage hysteroscope • Specimen for biopsy HEMATOMETRA • Uterus is distended with blood & secondary to gynatresia – partial or incomplete obstruction of any portion of the lower genital tract • Obstruction of the isthmus of the uterus , cervix or vagina may be congenital or acquired 2 most common causes of Hematometra • Imperforate hymen • Transverse vaginal septum Causes of acquired lower tract stenosis

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Senile atrophy of endocervical canal & endometrium Scarring of isthmus or synechiae (intrauterine adhesion) Cervical stenosis associated with surgery Radiation therapy Cryotherapy or electrocautery Malignant disease of the endocervical canal Cervical obstruction by tissue following suction curettage

Symptomatology • Depends on the age of the patient • Menstrual history

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Rapidity of accumulation of blood in the uterine cavity → secondary bacterial infection → pyometra Early age → primary amenorrhea, cyclic lower abdominal pain Incomplete obstruction – spotting of dark brown blood Post menopausal o Asymptomatic o Pelvic exam – mildly tender, globular uterus

Diagnosis

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History of amenorrhea, cyclic abdominal pain Ultrasound Probing (perforate/puncture) of cervix with narrow metal dilator – release of dark brownish discharge

Management • Dependent on operative relief of the lower tract obstruction. UTERINE CANCER 1. Cancer of the endometrium or endometrial cancer 2. Sarcoma of the uterus ENDOMETRIAL CANCER • Most common malignancy of the female genital tract

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3rd in Philippines Almost all endometrial cancers are adenocarcinoma (from glands) Occurs primarily in postmenstrual women and is increasing virulent with advancing age Role of Estrogen – clearly understood, any factor that increases exposure to unopposed estrogen increases the risk of endometrial cancer

Pathognomonic Type of Endometrial Cancer 1. Estrogen dependent • Younger perimenopausal women with history of exposure to unopposed estrogen either endogenous (eg Estrogen-secreting ovarian tumors) or exogenous (eg pills) • Tumor begins as hyperplastic endometrium and progresses to carcinoma • Better differentiated – more favorable prognosis 2. Estrogen independent • Older, postmenopausal, thin women • Less differentiated – poorer prognosis • Not associated pathologically with endometrial hyperplasia • May arise even in atrophic endometrium Risk factors in Endometrial Cancer • Unopposed estrogen stimulus • Unopposed menopausal estrogen-replacement therapy • Menopause after 52 years of age -2.4x • Obesity (21-50lbs overweight -2.3x; >50 lbs – 10x) • Nulliparity – 2-3x • Diabetes – 2.8x • Feminizing ovarian tumors – secretes estrogen

Gynecology Gynecologic lesions of the uterus & its malignancies Page 4 of 6 • •

Polycystic ovarian syndrome Tamoxifen therapy for breast CA (>2 years)

Diminished Risk • Ovulation • Progestin therapy • Combination of oral contraceptive • Menopause prior to 49 year old • Normal weight • Multiparity ENDOMETRIAL HYPERPLASIA • Precancerous • Predominant form: usually present with vaginal bleeding Classification of endometrial hyperplasia 1. Simple hyperplasia • Endometrium with dilated glands that may contain some outpouching and abundant endometrial stroma • Cystic hyperplasia • “Swiss Cheese” hyperplasia • Occurs in hyperplastic endometrium in menopausal or pause menopausal women • Weakly malignant • No atypia 2. Complete hyperplasia

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Uterine enlargement

Endometrial Cancer Diagnosis

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Office endometrial biopsy – out-patient small volume tissue obtained

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Hysteroscopy D&C – get sample from the endocervix

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Fractional D&C – endocervical → endometrium • Diagnostic procedure of choice ( gold standard)

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Hysteroscopy – direct visualization of endometrial surface TVS ( transvaginal ultrasound)

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Endometrial thickness > 5mm Polypid endometrial mass Collection of fluid

Management • Ovulation induction • Cyclic progestin therapy – MPA 10-20 mg • Continuous progestin tx • Periodic endometrial biopsy

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Glands are crowded with very little endometrial stroma and a very complex gland pattern and outpouching formations • Traditional terminology – variant of adenomatous hyperplasia with moderate to severe degree of architectural atypia but no cytological atypia • Low pre-maliganant potential • Architecturally complex (budding & infolding) crowded glands with less intervening stroma, no atypia Atypical Hyperplasia • Contain glands with cytologic atypia (criteria: large nuclei, variation of size & shape, lost of polarization) • Degree of cytologic atypia is the major determinant of pre-malignant potential • Increase N:C ratio with irregularity in size and shape of the nuclei a. Atypical simple hyperplasia b. Atypical complex hyperplasia • Greatest pre malignant potential

Endometrial hyperplasia classification TYPE PROGRESSION TO CA Simple hyperplasia 1% Complex hyperplasia 3% Atypical simple 8% Atypical complex 29% Diagnosis a. Screening a. Endometrial sampling, fractional D&C, hysteroscopy b. Transavaginal sonography • Endometrial thickness (>4mmhyperplasia) c. Progestin challenge d. Pap smear – 30-70% of endometrial hyperplasia b. Symptoms a. Vaginal bleeding (peri- or postmenopausal) – classic b. Watery pus like discharge c. Pain (pelvic pressure or discomfort) – late d. Hematometria or pyometria – on postmenopausal e. Parametrial induration – late findings

ENDOMETRIAL CANCER PATHOLOGY 1. • • • • •

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Endometriod cancer 80% Criteria: presence of invasion Desmoplastic stroma Glands back to back without intervening stroma Extensive papillary pattern Squamous epithelial differentiation Adenocanthomas – benign squamous differentiation Adenosquamous cancer – malignant looking squamous element, endometrial cancer with squamous differentiation

Grading Grade 1 Grade 2 Grade 3 2.

Well-differentiated Moderately differentiated Poorly differentiated Clear cell cancer • Less common • Resembles clear cell carcinoma of the ovary, cervix, vagina • Tends to develop on postmenopausal women • Prognosis much worse than typical endometrial adenocarcinoma

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Cells have hobne configuration arranged in papilla with hyalinized stalk Serous cancer • Uterine papillary serous cancer • Highly virulent and uncommon • Histology: epithelial anaplasia & papillary growth • Resembles papillary serous of the ovary Secretory cancer • Extremely rare • Occurs primarily in perimenopausal women • Diagnosed in the presence of progestational stimulation

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• Good prognosis Mucinous cancer

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Extremely rare • Occurs primarily in postmenopausal women • Can be confused with primary mucinous cancer of the ovary cervix or bowel Squamous cell cancer • Occurs in postmenopausal women

1988 FIGO STAGING FOR ENDOMETRIAL CANCER Stage 1 IA Tumor limited to endometrium (lining) IB Invasion <1/2 of myometirium IC Invasion >1/2 of myometrium Stage 2 2A Endocervical glandular involvement only 2B Cervical stroma invasion Stage 3 3A Tumor invades serosa &/or adnexa (&/or peritoneum) &/or positive cytology 3B Vaginal metastasis 3C Metastasis to pelvic &/or para-aortic lymph node Stage 4 4A Invasion of bladder &/or bowel mucosa 4B Distant metastasis including intraabdominal &/or inguinal lymph nodes Prognostic factors 1. Clinical factors • Patient’s age at diagnosis • Race – white Pxs have higher survival rates than blacks • Clinical tumor stage: when recognized prognostic factor for endometrial Ca 2. Pathologic factors • Tumor stage • Histologic type • Uterine size • Death of myometrial invasion • Microscopic involvement of vascular spaces in the uterus by tumor • Spread of lymph nodes, peritoneal cavity, or uterine adnexa Histologic grade G1 G2 G3 Best prognosis Typical adenocarcinoma Better differentiated tumors with or w/o sqaumous element

Treatment 1. Surgery • TAHBSO (total abdominal hysterectomy with bilateral salpinghoopherectomy) + BLND (bilateral lymph node dissection

• Inspect diaphragm, liver, omentum, pelvic

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Uterine sarcoma • Less than 5% of uterine malignancy • Classification is based on determination of resemblance of sarcomatous elements in mesenchymal tissue normally found in the uterus (homologous sarcoma) and from tissues foreign to the uterus (heterologous sarcoma) Modified classification of uterine sarcoma

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Poor prognosis Papillary serous carcinoma Clear cell carcinoma

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Pattern of spread • By lymphatics Pretreatment evaluation 1. History 2. PE 3. Chest Xray, ECG, CBC, Platelet count, blood chemistry 4. Ultrasound, MRI, CT scan 5. Cytoscopy, proctosigmoidoscopy, IVP, barium enema 6. Serum CA 125 Indications for selective pelvic & para aortic lymph node dissection • Tumor histology – clear cell, serous, sqamous, or grade 3 endometriod • Endometrial invasion, >1/2 • Isthmus – cervical invasion • Tumor size >2cm

& aortic lymph node, peritoneal washing, omental biopsy/partial omentectomy • Radical hysterectomy with BLND • Hysterectomy – remove the uterus & may also remove the cervix (total) and vaginal (radical) Radiotherapy – in the early stages of endometrial cancer or in patients with inoperable cancer Chemotherapy – Doxorubicin, Platinum compounds, cisplatin & carboplatin Hormone therapy – progestational agents in the tx of metastatic ca

Sarcoma of the uterus

Mildly differentiated Moderately differentiated Poorly differentiated

Poorly differentiated w/ or w/o squamous element

Extra uterine diseases

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Pure sarcoma a. Homologous (normal/same tissue) i. Smooth muscle tumors • Leiomyosarcoma • Leiomyoblastoma • Metastasizing tumors with benign histologic appearance o Intravenous leiomyomatosis (spaghetti tumor) o Metastasizing uterine leiomyoma o Leiomyomatosis Peritonealis Myosis ii. Endometrial stroma sarcoma b. Heterologous (foreign tissue) i. Rhabdomyosarcoma ii. Chondrosarcoma iii. Osteosarcoma iv. Liposarcoma c. Other sarcoma Carcinoma a. Homologous carcinoma (carcinoma + homologous sarcoma) b. Heterologous carcinoma (carcinoma + heterologous sarcoma) Mullerian Lymphoma

Leiomyosarcoma o Most common Determination of malignancy o # of mitosis/10HPO field o Cytologic atypia, abnormal mitotic figures o nuclear polymorphism

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4 mitosis per 10 HPO field – benign clinical stage >5 mitosis per 10 HPO field with cytological atypia – diagnosis of leiomyosarcoma

Gynecology Gynecologic lesions of the uterus & its malignancies Page 6 of 6

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>10 mitosis per 10 HPO field - worst prognosis

Occur in age 50, occasionally with conjunction of leiomyoma Development of leiomyosarcoma from leomyoma (sumera???) is rare

Signs & symptoms o Rapid uterine enlargement in peri & post menopausal age group o Enlarge pelvic mass, pain, vaginal bleeding Treatment o Surgery - TAHBSO o Exploration laparotomy – special attention to pelvic & para aortic lymph node o Radiotherapy – pre & post operative radiotherapy decreases recurrences o Chemotherapy o Doxorubicin – most active single agent in leiomyosarcoma