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Novak 33. Ovarian ca Novak 33. Ovarian ca Nonepithelial Ovarian Can Nonepithelial Ovarian Can cers cers 부부부부부 부부부부 부부부부부 부부부부 R2 R2 부부부 부부부

Novak 33. Ovarian ca Nonepithelial Ovarian Cancers 부산백병원 산부인과 R2 박영미

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Text of Novak 33. Ovarian ca Nonepithelial Ovarian Cancers 부산백병원 산부인과 R2 박영미

  • Novak 33. Ovarian caNonepithelial Ovarian Cancers


  • Nonepithelial Ovarian Cancers Compared with epithelial ovarian cancers, other malignant tumors of the ovary are uncommon about 10% of all ovarian cancers 1. malinancies of germ cell origin, sex cord-stromal cell origin, 2. metastatic carcinoma to ovary 3. extremely rare ovarian cancers (sarcoma, lipoid cell tumors)

  • Germ-Cell Malignancies

  • Germ-Cell Malignancies

  • Germ-Cell Malignancies Serum tumor markers in malignant germ cell tumors :can be clinically useful in the diagnosis of a pelvic mass and in monitoring course of patient after surgery

    -fetoprotein(AFP), human chorionic gonadotropin(hCG) : secreted by germ cell malignancy

    Placental alkaline phosphatase (PLAP), lactate dehydrogenase(LDH) : produced by dysgerminoma

  • Germ-Cell Malignancies Symptoms Germ-cell malignancies grow rapidly, in contrast to the relatively slow growing epithelial ovarian tumors : often are characterized by subacute pelvic pain related to capsular distension, hemorrhage, or necrosis : may produce pressure symptoms on the bladder or rectum

  • Germ-Cell MalignanciesIn menarchal patients, menstrual irregularities may also occur Some young patients may misinterpret the early symptoms of a neoplasm as pregnancy --> This can lead to a delay in the diagnosis

    Acute symptoms associated with torsion or rupture of the adnexa

    In more advanced cases, ascites and abdominal distension may develop

  • Germ-Cell Malignancies Diagnosis

    Adnexal masses will usually require surgical exploration 2 cm or larger in premenarchal patient 8 cm or larger in other premennopausal patient

    Predominantly cystic lesions up to 8cm in diameters in postmenarcheal patients : may be observed or given oral contraceptives for two menstrual cycles

  • Germ-Cell MalignanciesFor young patient Blood test - serum hCG and AFP titers, CBC, LFTChest x-ray - evaluation for metastasis to the lung or mediastinum Karyotype - preoperatively for all premenarcheal girl because of the propensity of these tumors to arise in dysgenetic gonads CT or MRI - may document retroperitoneal lymphadenopathy or liver metastases but, such expensive and time- consuming evaluation is unnecessary because the patients require surgical exploration

  • Dysgerminoma Clinical Characteristics

    The most common malignant germ-cell tumor (30-40%) 1-3% of all ovarian cancer 5-10% of ovarian cancers in patients younger than 20 years of age

    * 5% : before the age of 10 years, * 75% : between the ages of 10 and 30 years * rarely occur after 50 years of age

  • Dysgerminoma20-30% of ovarian malignancies associated with pregnancy are dysgerminomas Found in both sexes and may arise in gonadal or extragonadal sites

    Size varies widely, but usually 5-15cm in diameter

    Capsule is slightly bosselated, the cut surface consistency is spongy, the color is gray-brown

  • DysgerminomaThe histologic characteristics

    The large round, ovoid, or polygonal cells

    abundant, clear, very pale staining cytoplasm, large and irregular nuclei, and prominent nucleoli

  • DysgerminomaApproximately 5% of dysgerminomas are discovered in phenotypic females with abnormal gonads.

    pure gonadal dysgenesis (46XY, bilateral streak gonads), mixed gonadal dysgenesis (45X/46XY, unilateral streak gonad, contralateral testis), androgen insensitivity syndrome (46XY, testicular feminization)

    the karyotype should be determined in premenarcheal patients with a pelvic mass

  • DysgerminomaAbout 75% of dysgerminomas are stage I at diagnosis : 85-90 % are confined to one ovary : 10-15% are bilateral

    Dysgerminoama is the only germ-cell malignancy that has this significant rate of bilaterality Other germ-cell tumor are rarely bilateral

    Contralateral ovary has been preserved : diseases can develop in 5-10% of the retained gonads over next 2 years

  • DysgerminomaIn the 25% of patients who present with metastatic disease

    the tumor most commonly spreads via lymphatic system Metastases to the lungs, liver, brain : with long standing or recurrent diseaseMetastasis to the mediastinum and supraclavicular lymph nodes : a late manifestation of disease

  • Dysgerminoma Treatment

    The treatment of early dysgerminoma : primarily surgical, including resection of the primary lesion and proper surgical staging

    Chemotherapy or radiation is administered to patients with metastatic disease Special consideration must be given to the preservation of fertility because the disease principally affects girls and young women

  • DysgerminomaSurgery

    Minimum operation : unilateral oophorectomy

    If there is a desire to preserve fertility, even in the presence of metastatic disease : contralateral ovary, fallopian tube, and uterus should be left in situ : because of the sensitivity of the tumor to chemotherapy

    If fertility need not be preserved : TAH and BSO with advanced disease

  • DysgerminomaKaryotype analysis reveals a Y chromosome --> both ovaries should be removed

    Dysgerminoma is the only germ-cell tumor that tends to be bilateral --> bisection of the contralateral ovary and excisional biopsy of any suspicious lesion

    If a small contralateral tumor is found --> resect it and preserve some normal ovay

  • DysgerminomaRadiation

    Dysgerminoma are very sensitive to radiation therapy

    Doses of 2500-3500cGy may be curative

    Loss of fertility is a problem radiation should rarely be used as first-line treatment

  • DysgerminomaChemotherapy

    Metastatic dysgerminomas with systemic chemotherapythe treatment of choicepreservation of fertility

    The most frequently used regimens BEP (bleomycin, etoposide, cisplatin) VBP (vinblastine, bleomycin, cisplatin) VAC (vincristine, actinomycin, cyclophosphamide)

  • DysgerminomaCysplatin-based combination chemoTx Advanced stage, incompletely resected dysgerminoma have an excellent prognosisThe best regimen : Four cycles of BEP

    Macroscopic disease has all been resected at the primary operation -> No need to perform a second-look laparotomy

    Extensive macorscopic residual disease at the start of chemotherapy -> a second-look operation could be used effective second-line therapy is availablethe earlier persistent disease is identified, the better the prognosis

  • Dysgerminoma

  • Dysgerminoma Recurrent Disease

    About 75% of recurrences occur within the first year after initial treatment

    most common site : peritoneal cavity, retroperitoneal LN

    Patients with recurrent disease who have had no therapy other than surgery -> should be treated with chemotherapy

  • DysgerminomaIf prior chemotharapy with BEP regimen

    POMB-ACE may usedVincristine, bleomycin, cisplatin, etoposide, actinomycin D, cyclophosphamide

    The use of high-dose chemotherapy Carboplatin, etoposide

    Radiation therapy is effective for this disease ; major disadvantage is loss of fertility

  • Dysgerminoma Pregnancy

    Dysgerminomas tend to occur in young patient -> may coexist with pregnancy

    Stage Ia the tumor can be removed intact & the pregnancy continued

    More advanced diseases continuation of the pregnancy depend on gestational age

    Chemotherapy in 2nd & 3rd trimesterin the same dosages as given for the nonpregnant patients without apparent detriment to the fetus

  • Dysgerminoma Prognosis

    Stage Ia (unilateral encapsulated dysgerminoma) -> unilateral oophorectomy alone : 5yr disease-free survival rate of greater than 95%

    Higher tendency to recurrence lesions larger than 10-15 cm in diameter age younger than 20 years a microscopic pattern that includes numerous mitoses, anaplasia, medullary pattern

  • DysgerminomaIn the past, Surgery for advanced disease followed by pelvic and abdominal radiation resulted in a 5-year survival rate of 63-83%,

    Now With the use of VBP or BEP combination chemotherapycure rates of 85-90% for this same group

  • Immature teratomas

    Fewer than 1% of all ovarian cancer

    2nd most common germ-cell malignancy

    10-20% of all ovarian malignancy in younger than 20 years ago of age

    30% of deaths from ovarian cancer in younger than 20 years ago of age

    About 50% of pure immature teratoma in women between 10 and 20 years

    Rarely occur postmenopausal women

  • Immature teratomas- Pathology Neural tissues : demonstrate most clearly the importance of the ability to mature

    Immature teratomas are classified : according to a grading system based on the degree of differentiation and the quantity of immature neural tissueGrade 1 tumor : 3 LPFs with these elements

  • Immature teratomasThe prognosis can be correlated with the grade of these immature neural elements

    With a higher grade, there is a poorer prognosis

    Malignant change in benign cystic teratomasoccuring in 1-2% of casesusually after the 40 years of age

  • Immature teratomas- Diagnosis -

    Some of these lesions will contain calcification similar to mature teratomas

    Calcification can be detected by an x-ray of the abdomen or by ultrasonography

    Tumor markers are negative unless a mixed germ-cell tumor is present

  • Immature teratomas- Treatment - Surgery

    For premenopausal patient, confined to a single ovary : unilateral ooporectomy and surgical staging

    For postmenopausal patients : TAH and BSO

    Contralateral involvement is rare and routine resection or wedge biopsy of the contralateral ovary is unnecessary

  • Immature teratomasChemotharapy

    Stage Ia, grade 1 : an excellent prognosis : no adjuvant therapy is required

    Stage Ia, grade 2 or 3 : adjuvant chemotherapy should be used

    Ascites : Chemotherapy is also indicated regardless of tumor grade

  • Immature teratomasRegimen : VAC (most frequently used in the past) :BEP, VBP(the newer approach)the BEP regimen is superior to the VAC regimen in the treatment of completely resected nondysgerminomatous germ cells tumors of the ovary

    The switch from VBP to BEP replacement of vinblastine with etoposide a better therapeutic index, especially less neurologic and gastrointestinal toxicity

  • Immature teratomasRadiation therapy

    Generally not used in the primary treatment

    No evidence that the combination of chemotherapy and radiation has a higher rate of disease control than chemotherapy alone

    For patients with localized persistent disease after chemotherapy

  • Immature teratomas- Second-Look Laparotomy -

    The need for second-look operation has been questioned

    It seems not to be justified in patient who have received chemotherapy in an adjuvant setting, because chemotherapy in these patients is so effective

    Sampling of any peritoneal lesions and the retroperitoneal lymph nodesOnly mature elements : chemoTx should be discontinuedPersistent immature elements : alternative chemoTx

  • Immature teratomas- Prognosis -

    The most important prognostic feature : the grade of the lesion

    the stage of disease and the extent of tumor at the initiation of treatment -> have an impact on the curability

    the 5-year survival rate all stage : 70-80%surgical stage I : 90-95 %

    The 5yr survival rates for all stages with grade 1, 2, 3 : 82%, 62%, 30%

  • Endodermal Sinus Tumor

    Yolk sac carcinoma

    3rd most frequent malignant germ-cell tumor

    Median age ; 16-18 year

    Abdominal or pelvic painThe most frequent initial symptom about 75%

    Asymptomatic pelvic massIn 10%

  • Endodermal Sinus Tumor

    - Pathology -

    The gross : soft grayish-brown

    Cystic areas : degeneration of the rapidly growing lesions

    The capsule is intact

    Unilateral in 100%Biopsy of the opposite ovary in such young patients is contraindicated

  • Endodermal Sinus TumorSchill-Duval body

    Microscopically, the characteristic featureThe cystic space is lined with a layer of flattened or irregular endothelium into which projects a glomerulus-like tuft with a central vascular core

  • Endodermal Sinus TumorMost EST secrete AFP

    There is a good correlation between the extent of disease and the level of AFP

    AFP is useful in monitoring the patient's response to treatment

  • Endodermal Sinus Tumor- Treatment -Surgery

    Unilateral salpingo-oophorectomy and a frozen section for diagnosis

    Any gross metastases should be removed

    Surgical staging is not indicated All patients need chemotherapy

  • Endodermal Sinus TumorThe tumors tend to be solid and largeIn size from 7 to 28 cm (median 15 cm)

    Bilaterality is not seen

    Most patients have early stage diseaseStage I : 71%Stage II : 6%Stage III : 23%

  • Endodermal Sinus TumorChemotherapy

    All patients with EST are treated with either adjuvant or therapeutic chemotherapy

    VBP regimen more effective regimen in the treatment of measurable of incompletely resected tumor

    POMB-ACE regimenPrimary therapy for patients with liver or brain metastases Moderately myelosuppressive the intervals between each course can be kept to a maximum of 14days (usually 9 to 11 days)

  • Endodermal Sinus TumorCisplatin-containing combination chemotherapy, BEP or POMB-ACE

    primary chemotherapy for EST

    3 cycles : stage I & completely resected disease

    2 further cycles after negative tumor marker status : macroscopic residual disease before chemotherapy

  • Endodermal Sinus Tumor- Second-Look Laparotomy -

    The value of a second-look operation has yet to be established in patients with EST

    It seems reasonable to omit the operation Pure low stage lesionsAFP values return to normalRemain normal for the balance of their treatment

  • Embryonal Carcinoma Extremely rare tumor

    Distinguished from a choriocarcinomaBy the absence of syncytiotrophoblastic and cytotrophoblastic cells

    The patients are very youngBetween 4 and 28 years (median 14yr)

    Estrogen secretion precocious pseudopubertyIrregular bleeding

  • Embryonal Carcinoma

    The primary lesions tend to be large

    About two-thirds are confined to one ovary at the time of diagnosis

    The treatment of embryonal carcinoma is the same as for the ESTUnilateral oophorectomy followed by combination chemotherapy with BEP

  • Choriocarcinoma of the Ovary Extremely rare tumor

    The same appearance as gestational choriocarcinoma metastatic to the ovaries

    Most patients are younger than 20 years

    High hCGIsosexual precocity in about 50% of patients before menarche

  • Choriocarcinoma of the Ovary

    MAC regimen : complete responses have been reportedMethotrexateActinomycin DCyclophosphamide

    The prognosis has been poorMost patients having metastases to organ parenchyma at the time of diagnosis

  • Polyembryoma Extremely rare tumor

    Composed of embryoid bodies

    Very young & premenarcheal girls PseudopubertyElevated AFP & hCG

    VAC regimen : effective

  • Mixed Germ Cell TumorsThe most common component of a mixed malignancyDysgerminoma in 80%EST in 70%Immature teratoma in 53%Choriocarcinoma in 20%Embryonal carcinoma in 16%

    The most frequent combination Dysgerminoma and EST

    Combination chemotherapy BEP

  • Mixed Germ Cell TumorsSecond look laparotomy Macroscopic desease was present at initiation of chemotherapy

    The most important prognostic featuresThe size of the primary tumorStage IA, samller than 10cm : survival is 100%

    The relative size of most malignant componentLess than one-third EST, choriocarcinoma, grade 3 immature teratoma : excellent prognosis

  • Sex Cord-Stromal Tumors

  • Sex Cord-Stromal Tumors 5-8 % of all ovarian malignancies derived from the sex cords and the ovarian stroma or mesenchyme

  • Granulosa-stromal cell tumor - granulosa cell tumor -

    low-grade malignancy

    secrete estrogen

    seen in womon of all ages

    bilateral in only 2% of patients

  • Granulosa-stromal cell tumor- Pathology -

    range from a few millimeters to 20cm or more in diameter

    Smooth, lobulated surface

    Solid portion granular, trabeculatedYelow or gray-yellow

  • Granulosa-stromal cell tumor

    Coffee bean grooved nuclei

    Call-Exner bodiesSmall clusters or rosettes around a central cavity

  • Granulosa-stromal cell tumor- Diagnosis -

    Of the rare prepubertal patients75% are associated with sexual pseudoprecocitybecause of the estrogen secretion For women of reproductive age menstrual irregulartities or secondary amenorrhea cystic hyperplasia of the endometrium

    For postmenopausal women abnormal uterine bleeding

  • Granulosa-stromal cell tumorEndometrial cancer in 5%

    Endometrial hyperplasia in 25-50%

    Ascites is present in about 10%

    Hemorrhagic : occasionally rupture and produce a hemoperitoneum

  • Granulosa-stromal cell tumorUsually stage I at diagnosis but may recur 5-30 years after initial diagnosis

    Hematogenously spreadLungs, liver, brain metastasis years after initial diagnosis

    Recur -> progress rapidly

    Inhibin : useful marker

  • Granulosa-stromal cell tumor- Treatment -

    The treatment depends on the age of the patient and the extent of disease

    For most patients, surgery alone is sufficient primary therapy

    Radiation and chemotherapy recurrent or metastatic disease

  • Granulosa-stromal cell tumorSurgery

    A unilateral salpingo-oophorectomy stage Ia tumors in children or in women of reproductive age bilateral in only about 2% of patients

    If a granulosa-cell tumor is identified by frozen section a staging operation is performedassessment of the contralateral ovary - biopsy

  • Granulosa-stromal cell tumorFor premenopausal patients in whom the uterus is left in situEndometrial biopsys should be perfromedthe possibiltiy of coexistent adenocarcinoma of the endometrium

    Radiation No evidence to support the use of adjuvant radiation therapy for granulosa-cell tumors

  • Granulosa-stromal cell tumorChemotherapy

    No evidence that adjuvant chemotherapy will prevent recurrence of disease

    Metastatic lesions and recurrences have been treated

    The most effective regimen : BEP

  • Granulosa-stromal cell tumor- Prognosis -

    Prolonged natural history, tendency toward late relapse

    Survival rate10 YSR ; 90 % 20 YSR ; 75 %

    The DNA ploidy -> correlated with survival Residual-negative DNA diploid tumors had a 10-year progression-free survival of 96 %

  • Sertoli-Leydig Tumors Extremely rare : less than 0.2% of ovarian cancer

    Most frequently in the third and fourth decades : 75% in younger than 40years

    Low grade malignancies

    Androgen : clinical virilization in 70%-85%Oligomenorrhea, amenorrhea, breast atrophy, acne, hirsutism, clitoromegaly, deepening of the voice, receding hairline

  • Sertoli-Leydig TumorsTreatmentIn reproductive years Unilateral salpingo-oophorectomy and evaluation of the contralateral ovaryLow-grade lesion are only rarely bilateral (
  • Fallopian tube cancer0.3% of all female genital tract

    Similar to ovarian cancerThe evaluation and treatment are the same

    Frequently involved secondarily from other primary sitesovaries, endometrium, GI tract, or breast

    Most frequently in the fifth and sixth decade mean age : 55-60 years

  • Fallopian tube cancer- Symptoms and Signs -

    Classic triad a prominent watery vaginal discharge pelvic pain a pelvic mass

  • Fallopian tube cancerVaginal discharge or bleeding The most common symptom (more than 50%) For perimenopausal and postmenopausal women with an unusual, unexplained,or persistent vaginal discharge -> the clinician should be concerned about the possibility of an occult tubal cancer Often found incidentally in asymptomatic women at the time of TAH and BSO

    Pelvic mass : about 60%

    Ascites : advanced disease

  • Fallopian tube cancer - Spread pattern -

    The same manner as epithelial ovarian malignancies by the transcoelomic exfoliation of cells -> implant throughout the peritoneal cavity

    Permeated with lymphatic channels spread to the para-aortic and pelvic lymph nodes is common(33%)

  • Fallopian tube cancer- Staging -

    Based on the surgical findings at laparotomy

    stage I : 20-25% stage II : 20-25% stage III : 40-45% stage IV : 5-10%

  • Fallopian tube cancer- Treatment -Similar to epithelial ovarian cancer

    Exploratory laparotomy is necessary to remove the primary tumor (TAH c BSO) to stage the disease (No gross tumor spread)to resect metastases (as much as possible)

    the most frequently employed treatment combination chemotherapy (PC or PAC)

    radiation also used in selected cases

  • Fallopian tube cancer- Prognosis -

    Overall 5-year survival : about 40% higher than for patients with ovarian cancer higher proportion of early-stage disease

    5-year survival ratestage I - 65% stage II - 50-60% stage III and IV - 10-20%

  • Tubal Sarcomas Malignant mixed mesodermal tumors

    In the sixth decade

    Advanced at the time of diagnosis

    Platinum based combination chemotherapy (if all gross disease can be resected)

    Survival is generally poor

    Most patients die of their disease within 2 years