Novak 33. Ovarian caNonepithelial Ovarian Cancers

R2

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