Chapter 21 Female Genital Tumor 6. Ovarian Tumor Women’s Hospital, School of Medicine, Zhejiang university Xing Xie

Ovarian tumor Common gynecologic malignant tumors Occur in females of all ages but different histological types in different age-periods Epithelial ovarian carcinoma with poor prognosis 5-year survival rate about 30-40% the mortality rate ranks first in gynecological malignancies

General Introduction Histological classification very complicated Most histological types in body organs The current classification issued by WHO in 1973

Histologic types of ovarian tumor Ovarain epithelial tumor Germ cell tumor Sex-cord stromal cell tumor Lipid (lipoid) cell tumor Gonadal blastoma Non-specific ovarian soft tissue tumor Unclassified tumor Metastatic tumor Tumor-like lesions

Symptoms and signs Benign tumors No symptoms as tumor is small Abdominal distention or pelvic mass as tumor is medium size Gynecological examinations A spherical mass on one side of the uterus, cystic, smooth surface, movable

Symptoms and signs Ovarian cancer early stage asymptomatic, often found occasionally by gynecological examinations Late stages Abdominal distention, abdominal mass, ascites End-stage Weight loss, severe anemia, cachexia Transvagina-rectnum examination Pelvic masses: bilateral , solid or semi-solid, not movable

Complications pedicel retortion Common gynecological emergency Frequency about 10% Usually occur in mass with a longer pedicle, medium size, good movability, and center deflection Blood flow blocked and tumor necrosis after retortion Symptoms: one side of lower abdomen pain concomitant nausea and vomit, Signs: Mass with high tension and tenderness Treatment emergency surgery once diagnosed

Complications Rupture Frequency about 3% Traumatic and spontaneous Symptom lower abdominal pain related to the size of rupture the quality and quantity of cyst fluid Signs abdominal tenderness muscle intensity ascites Treatment emergency surgery

Complications Infection Malignant change Due to rupture, retorsion or the near organs’ infection Symptoms fever, abdominal pain Signs mass, abdominal tenderness, muscle intensity Treatment anti-infection, surgery Malignant change surgery as soon as possible

Diagnosis Benign tumors Ovarian cancer No specific symptoms A mass found occasionally by physical examination Ovarian cancer Gynecological examination bilateral pelvic mass, solid , poor movability, with ascites, uterus rectum nest nodules

Diagnosis Adjuvant examinations Imaging techniques Ultrasonography ： mainly used to diagnose primary lesion accuracy rate above 90% difficult to measure the diameter <1cm lesion Radiology (X-Ray, CT, MRI) mainly used to diagnose the metastatic lesion

Ultrasound: ovarian cancer

Diagnosis Adjuvant examinations Tumor markers §CA125 rise up in 80% epithelial cancers more used for disease monitoring and prognosis evaluation §AFP rise in endodermal sinus tumor §hCG ovarian choriacarcinoma §Sex hormone sex-cord stromal cell tumor Laparoscopy Ascitic cytology

Metastatic pathway Features pathways Widely disseminated in abdominal cavity Subclinical metastasis pathways spread directly and abdominal cavity plant lymph metastasis blood vessel metastasis

Clinical surgical-pathology staging (2000，FIGO) Stage I Growth limited to ovaries 　 　 　 IA Growth limited to one side ovaries; no ascites. No tumor on external surface; capsules intact IB Growth limited to both ovaries; no ascites. No tumor on external surface; capsules intact IC Tumor either IA or IB but with tumor on surface of one or both ovaries;or with capsule ruptured; or with ascites containing malignant cells, or with positive peritoneal washings II Growth involving one or both ovaries with pelvic extension. IIA Extension and/or metastasis to the uterus and/or tubes. IIB Extension to other pelvic tissues. IIC Tumor either Stage IIA or IIB, but with tumor on surface of one or both ovaries; or with capsule ruptured; or with ascites containing malignant cells, or with positive peritoneal washings. III Tumor involving one or both ovaries with peritoneal implants outside pelvis and/or positive retroperitoneal or inguinal nodes. Superficial liver metastasis equals Stage III. IIIA Tumor grossly limited to true pelvis with negative nodes, but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces. IIIB Tumor of one or both ovaries with histologically confirmed implants to abdominal peritoneal surfaces, none exceeding 2 cm in diameter Nodes are negative. IIIC Abdominal implants >2 cm in diameter and/or positive retroperitoneal or inguinal nodes. IV Growth involving one or both ovaries with distant metastasis. If pleural effusion present, must be positive cytology to assign a case to Stage IV. Parenchymal live metastasis equals Stage IV.

Therapy Surgery Objectives To confirm the diagnosis To resect tumor To determine surgical-pathology staging of malignancy Chemotherapy and radiation for malignancy follow-up ovarian cancer is easy to recurrent and should be long-term follow-up

Epithelial tumors The most common histological type accounting for 50-70% of the primary tumor 85-90% of malignant tumor Derived from ovarian germinal epithelium belong to the primitive body cavity epithelium have potential to differentiate into a variety of Mullerian epithelia More common in older women Can be divided into benign, borderline, malignant tumors

Epithelial tumors Borderline tumors low malignant potential tumors pathological features of malignant tumor cells but no stromal invasion clinically slower development, fewer metastasis and more later recurrence

Histological classification Epithelial tumors Serous tumors Mucinous tumors Endometrioid tumor Brenner tumor Mixed epithelial tumors Undifferentiated carcinoma

Pathology Serous tumors cancer cell differentiate into oviduct epithelial Serous cystadenoma Mostly unilateral, spherical, smooth, cystic, serous fluid Microscope: simple columnar epithelium serous cystadenocarcinoma Mostly bilateral, semi-substantive, multiple antrum cystoid, cavity filled with papilla, crisp, bloody cyst fluid Microscope: cubic or columnar epithelium, stratified, arranged in ≥4 layers, cellular atypia, stromal invasion

Serous tumors Serous cancer

Pathology Mucinous tumors cancer cell differentiate into enteric or cervical endometrial Mucinous cystadenoma Mostly unilateral, large size, cystic, and often have more capsules with the jelly-like mucus Microscope: simple columnar epithelium, can see goblet and argyrophil cells If tumor rupture, tumor cells seed in peritoneal to form peritoneal myxoma Mucinous cystadenocarcinoma Mostly unilateral, cystic, cystic see the papilla, bloody cyst fluid Microscope: columnar epithelium, stratified, arranged in ≥ 3 layers, cellular atypia, stromal invasion

Mucinous tumors Mucinous cancer

Pathology Endometrioid tumor Endometrioid carcinoma Benign, borderline tumor is few Endometrioid carcinoma Mostly unilateral, cystic or solid, with papilla, bloody cyst fluid. Microscope: similar to endometrial cancer Often concomitant with endometrial cancer

Endometrioid cancer

Pathology Clear cell tumors Benign tumors are few Clear cell carcinoma Mostly unilateral, cystic or solid Microscope: alveolar tumor cells with abundant cytoplasm , atypia nuclear Easy to lymph node and liver metastasis Often concomitant with endometriosis and hypercalcemia Brenner tumor Differentiate and formate from transitional epithelum Most are benign, unilateral, diameter <5cm, hardware quality

Clear cell tumors

Brenner tumor

Epithelial Tumors Treatment benign tumors Once diagnosed, surgical extension reproductive period women ovarian tumor resection or oophorectomy perimenopausal and postmenopausal women ● adnexectomy ● hysterectomy and bilateral salpingo-oophorectomy Notices in surgery ① differentiate the benign and malignant tumors during surgery (grossly, frozen section ) ② take out the tumor integrally

Epithelial Tumors Treatment malignancy Principle: surgery combined with chemotherapy and radiotherapy surgery Early stage: Staging surgery Cytology for ascites or peritoneal washings Complete pelvic and abdominal exploration Omentectomy Back peritoneum lymph nodes excision Hysterectomy + bilateral salpingoophorectomy Conservative surgery only for eligible young women desiring childbearing

Epithelial Tumors Treatment surgery malignancy Advanced stage: Cytoreductive surgery (debulking surgery) Resect primar and metastatic tuomrs as much as possible , to minimize diameter of residual tumor (<1cm)

Epithelial Tumors Chemotherapy Radiotherapy Prognosis Major adjuvant therapy, post-surgery Commonly used drugs cisplatin, carboplatin, paclitaxel, CTX, others. Preferred to platinum-based combination chemotherapy “Gold standard”: carboplatin and paclitaxel combination Radiotherapy For metastasis and recurrence Others immunotherapy Prognosis 5-year survival rate of Ia stage >90％ 5-year survival rate of advanced stage <30％

Ovarian germ cell tumor Features From primitive germ cells in embryonic gonad Ability to produce diversity organizations Frequency: account for 20~40% in all ovarian tumors More common in young women and girls Sensitive to chemotherapy ，most can be reserved for reproductive function Abnormal tumor markers: AFP, HCG

Histologic classification Germ cell tumors dysgerminoma endodermal sinus tumor embryonal tumor polyembryoma choriocarcinoma teratomas mixed tumor

Pathology Teratomas Comprised of multi-germ layer , rarely one layer Mostly are mature , few are immature Mature teratomas（dermoid cyst） benign tumor，the most common germ cell tumor frequently single side, cystoid with smooth surface, contains tissues of fat, hair, teeth and bone microscopy： scolex contains three layers malignant transformation: squamocarcinoma in scolex epilithium

Mature Cystic Teratoma Immature ovarian teratoma

Pathology Dysgerminoma Moderate malignant tumor Mostly occurs at puberty and child-bearing perild Single side, solid Microscopy ：rotundity or mostly cornual cells Extraordinary sensitive to radiotherapy

dysgerminoma

Pathology Endodermal sinus tumor Common in children and young women Highly malignant, poor prognosis Single side with large mass, fragile, obvious bleeding and necrosis; Microscopy：loose reticulate and endothelial sinus structure Produce AFP

Endodermal sinus tumor

Treatment Benign tumor Malignant tumor The same as epilithial tumors Surgery Lateral salpingoophorectomy regardless any stage as long as opposite side ovary and uterus are not involved Chemotherapy Sensitive to chemotherapy : BEP BVP VAC Radiotherapy sensitive for Dysgerminoma，seldom used for young ages

Sex cord-stromal tumors From sex cord and stromal tissues of embryonic gonad Frequency: account for 5％ in all ovarian tumors Comprised or uni- or multi-cell components Mostly are benign or low malignant tumor Produce steroid hormones, with endocrine funtion, produce female or male features, also called “functioning ovarian tumor ”

Histologic classification Sex cord-stromal tumors Granulosa cell -stromal cell tumors Sertoli-stromal cell tumors Granudroblastoma

Pathology Granulosa cell tumors Adult form and child form Adult form common low malignant，produce E2，female features solid or partly cystic microscopy: Granulosa cell, Call-Exner body Child form seldom, highly malignant

Granulosa cell tumor Granulosa cell tumor Call–Exner bodies (sex cord-stromal tumors ) Granulosa cell tumor Granulosa cell tumor stromal cell tumors

Pathology Ovarian thecoma (theca cell tumor) Benign，seldom malignant Single side, solid. Microscopy short spindle cells, spiral arrangement Female features

Ovarian thecoma

Pathology Fibroma Benign Single side, solid, hardness Microscopy short spindle cells, knitting arrangement. Meigs syndrome fibroma combination with ascites or hydrothorax, naturally disappear after tumor excision

Fibroma

Treatment Benign tumor Malignant tumor surgery as same as epithelial tumor Malignant tumor Surgery Conservative surgery for young women with stage I, desiring childbearing Radical surgery for others Chemotherapy Combinated Chemotherapy Regimens: as same as germ cell or epilithelial tumors

Ovarian metastatic tumors Origin any organs’ tumors commonly from breast, gastrointestinal and genital tract Krukenberg tumors (signet ring cell tumor) From gastrointestinal Bilateral, solid, median size, without adhension ovary –shape or kidney-shape microscopy：signet ring cells Surgery combined with chemotherapy and radiotherapy Poor prognosis

Krukenberg tumors

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Gestational Trophoblastic Disease Chapter 22 Gestational Trophoblastic Disease Women’s Hospital, School of Medicine Zhejiang University Xing Xie

Gestational trophoblastic disease A group of diseases originated from placental trophoblastic cells Gestational trophoblasitc disease (GTD) Hydatidiform mole (complete and partial) Invasive mole Choriocarcinoma Placental-site trophoblastic tumor (PSTT) Gestational trophoblastic neoplasia (GTN) Non-gestational trophoblastic tumor Uncommon, derived from germ cells in ovarian or testicular   clinically histologically

Development and differentiation of gestational trophoblastic cells gestational trophoblastic cells evolved from extra-embryonic cells At the time of implantation cytotrophoblast outermost layer of the blastocyst 7-8 days after implantation syncytiotrophoblast implantation site Before villi formation previllous trophoblast 2 weeks after pregnancy, primary villi formation Villous surface villous trophoblast Other parts extravillous trophoblast

Development and Differentiation of gestational trophoblastic cells Cytotrophoblast trophoblast stem cells proliferability and differentiability Syncytiotrophoblast differentiated mature cells synthesize pregnancy-related hormones material exchange between the fetus and the mother Two differentiated forms of Cytotrophoblast villous surface area Syncytiotrophoblast extravillous Intermediate trophoblast

Hydatidiform mole

Hydatidiform mole Complete moles Partial moles Hydropic degeneration of all villi Villous edema, trophoblastic hyperplasia, fetal-derived blood vessels disappear in stroma Partial moles combine embryo or fetus Villous edema partially, trophoblastic proliferation lighterly, fetal-derived blood vessels present stroma

Partial moles Complete moles

Hydatidiform mole Related Factors Complete moles Area common in Latin America, Asia uncommon in North America and Europe Race differences of the same race in different regions Nutrition and Economy lack of Vit A Age < 20 or >35 years The fertilization of an empty egg the fertilization of an empty egg by a haploid sperm Diploid genome 90% of the time (usually 46,XX) Genomic imprinting disorder

Hydatidiform mole Partial moles high-risk factors are still unknown "Haploid egg" fertilization usually two sperm fertilize a normal egg a triploid karyotype (69 chromosomes ), with the extra haploid set of chromosomes derived from father

Comparison of complete and partial hydatidiform moles Karyotype 46, XX(90%) 46, XY(10%) Triploid (69XXY, 69XXX) Embryo Absent Present Villi Hydropic Few hydropic Trophoblasts Diffuse hyperplasia Mild focal hyperplasia Villus outline regular irregular Blood vessel absence presence

Hydatidiform mole Partial moles Clinical Presentation Complete moles Abnormal vaginal bleeding during early pregnancy( 8-12week) most common symptom Uterine enlargement exceeding normal pregnant uterus Others Abdominal pain Pregnancy-induced hypertension Theca lutein ovarian cyst Hyperthyroidism (CHM) Partial moles Mild symptoms, Confused with abortion easily

Hydatidiform mole hCG regression pattern after hydatidiform Mean time of the hCG regressed to normal — 9 weeks no more than 14 weeks Abnormal hCG regression pattern after hydatidiform signifies the presence of GTN Complete mole 15% local invasion and 4% distant metastasis High –risk : ①HCG>100,000U/L ② Enlargement of Uterine ③ Theca lutein ovarian cyst >6cm Partial mole 4%local invasion and almost no distant metastasis High –risk :unclear

Hydatidiform mole Diagnosis Abnormal bleeding after amenorrhea Inappropriately enlarged uterus Absence of fetal heart sounds not palpate fetus between 16-20th week Vaginal discharge hydatidiform-like tissue Hydatidiform mole should be considered

Hydatidiform mole Diagnosis Ultrasound HCG DNA karyotype Complete moles produce a characteristic vesicular sonographic pattern, usually referred to as a “snowstorm” pattern HCG Elevated above expected for gestational age Dynamic observation for 8-10 weeks, continued to rise HCG-related molecules Hyperglycosylated HCG free β-HCG subunit DNA karyotype Complete moles — usually diploid Partial moles — usually triploid

a “snowstorm” pattern

Hydatidiform mole Treatment Suction curettage Molar pregnancy should be terminated as soon as possible when diagnosis has been confirmed Suction curettage is a first choice, must be fully done in operating room tissue from curettage should be submitted to pathology

Hydatidiform mole Treatment Theca lutein cysts of the ovary do not need special treatment Prophylactic chemotherapy: A controversial topic only be offered to patients with high-risk factor or impossible follow-up Hysterectomy Only remove local invasion, but not distant metastasis Only for old women without childbearing desire

Hydatidiform mole Follow-up necessary for diagnosis of early GTN Methods: HCG Symptom: Abnormal uterine bleeding Pelvic examination Ultrasound, chest X-ray and CT Contraception: Condom and oral contraceptives, not IUD Duration for contraceptiom — 1 year

Gestational Trophoblastic Neoplasia

General Consideration Antecedent gestation 60% hydatidiform mole 30% follow abortion 10% term pregnancy or ectopic pregnancy from mole — invasive mole or choriocarcinoma from Non-mole — choriocarcinoma

Gestational Trophoblastic Neoplasia Pathogenesis Invasive mole Invasive mole is a hydatidiform mole that invades the myometrium and may produce distant metastases. Microscopic finding are the same as in hydatidiform mole Choriocarcinoma Gloss：invades the myometrium , penetrate the serosa and may produce distant metastases Microscopy：no villi, but instead sheets or foci of trophoblasts on a background of hemorrhage and necrosis

Invasive mole Choriocarcinoma Invasive mole Choriocarcinoma Invasive mole Choriocarcinoma

invades the myometrium Lung metastases Brain metastases cervical metastases

Gestational Trophoblastic Neoplasia Clinical Manifestation Nonmetastatic GTN the antecedent gestational event is usually HM Abnormal vaginal bleeding after mole Others: Enlarged uterus Theca lutein cysts of the ovary Abdominal pain Fake pregnancy symptoms

Gestational Trophoblastic Neoplasia Metastatic GTN Usually chroriocarcinoma Primary symptoms Metastatic symptoms Lung metastases are frequently common vaginal metastases are the second common liver and brain metastases usually death cause other metastastic sites spleen, kidney, bladder, gastrointestinal system, and bone Simultateously occur or not

Gestational Trophoblastic Neoplasia Diagnosis Symptoms and signs: ◆ Abnormal vaginal bleeding after post-evacuation, abortion, term pregnancy or ectopic pregnancy, ◆ Metastatic symptoms GTT should be considered

Gestational Trophoblastic Neoplasia HCG assay Most important and sometimes only diagnostic evidence Diagnostic criteria for post- HM GTN (FIGO2000) hCG plateau for >4 values （±10％）， over 3 weeks hCG increase of ≥10% over 2 weeks hCG persistence after evacuation of mole for 6 months Diagnostic criteria for non post-HM GTN HCG elevated at 4w after abortion, term or ectopic pregnancy Re-rising HCG titer after reaching normal levels

Gestational Trophoblastic Neoplasia Chest X-ray lung metastases CT small lung metastases and brain metastases MRI Liver and brain metastases Ultrasound primary lesions of uterus and pevical metastases Imaging supports diagnosis, but not necessary

Gestational Trophoblastic Neoplasia Histological diagnosis villus shape can be found in primary or metastatical lesions Presence of villus shape Invasive mole Absence of villus shape Choriocarcinoma Histology is not necessary for diagnosis of GTN

Anatomy staging of GTN (FIGO, 2000) Gestational Trophoblastic Neoplasia Anatomy staging of GTN (FIGO, 2000) StageI Localized to the uterus StageII Lesion diffused, but Localized to the genitalia (accessory,vagina,broad ligament) StageIII Lung metastasis, with or without genitalia change StageⅣ Other metastasis Stage III Stage I Stage II Stage IV

Prognostic scoring system for GTT (FIGO,2000) score 1 2 4 Age(y) ＜40 ≥40 - Antecedent mole abortion term Interval (mo) ＜4 4～6 7～12 ≥13 Pretreatment b-hCG (mIU/ml) ＜10３ 10３～10４ ＞ 10４～10５ ＞ 10５ Largest tumor (cm) － 3～4 cm ≥5cm Site of metastases Lung Spleen, Kidney Gastrointestinal Liver, brain Number of metastases 1～4 5～8 ＞8 Prior chemotherapy failed single ＞2 * Total score≤6 low risk, ≥7 high risk

Gestational Trophoblastic Neoplasia Treatment Chemotherapy combining surgery, radiotherapy and other treatment Base on the assessment and stage, therapy stratified Chemotherapy : Single-agent chemotherapy is applied in low-risk gestational trophoblastic disease (MTX, Act-D, 5-Fu) High-risk patients commonly use combined chemotherapy (EMA-CO)

Single agent chemotherapy DAY Therapy Interval 1-5 MTX 0.4mg/kg im qd 14d 1、3、5、7 MTX1mg/kg im 14d 2、4、6、8 FA 0.1mg/kg im or po 1-5 Act-D10-12ug/kg ivgtt qd 14d 1-8 5-Fu 28-30mg/kg ivgtt qd 12－14d

Combined chemotherapy Drugs Dose ,pathway,periods Interval 5-Fu+KSM 3weeks 5-Fu 26-28mg/kg·d，ivgtt for 8days KSM 6g/kg·d， ivgtt for 8days

Combined chemotherapy EMA-CO Interval 2weeks the first part EMA 1st day VP16 100mg/m2 ivgtt Act-D 0.5mg ivgtt MTX 100 mg/m2 ivgtt MTX 200mg/m2 ivgtt for 12hours 2nd day VP16 100mg/m2，ivgtt Act-D 0.5mg ivgtt CF15mg，im （after 24hours from the use of MTX， once every 12hours，twice） 3rd CF15mg，im，once every 12hours，twice。 4th to 7th rest（no drug） the second part CO 8th day VCR1.0mg/m2， ivgtt CTX600mg/m2， ivgtt

PSTT A special type, more rarely in clinic Most of them have a good prognosis Form the intermediate trophoblast cells Clinical manifestations More common occur at reproductive period women More common occur following term or ectopic pregnancy Abnormal bleeding after amenorrhea

PSTT Diagnosis Treatment Surgery is the preferred treatment HCG was negative HPL mildly elevated  Confirmed by histology Treatment Surgery is the preferred treatment Chemotherapy is adjuvant therapy

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