Transcript Novak 33. Ovarian ca

Novak 33. Ovarian ca
Nonepithelial Ovarian Cancers
부산백병원 산부인과
R2 박영미
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

α-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 Malignancies

In 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 Malignancies

For young patient




Blood test - serum hCG and AFP titers, CBC, LFT
Chest 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
Dysgerminoma

20-30% 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
Dysgerminoma

The histologic
characteristics


The large round,
ovoid, or polygonal
cells
abundant, clear, very
pale staining
cytoplasm, large and
irregular nuclei, and
prominent nucleoli
Dysgerminoma

Approximately 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
Dysgerminoma

About 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
Dysgerminoma

In 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 disease
Metastasis 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
Dysgerminoma

Surgery



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
Dysgerminoma



Karyotype 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
Dysgerminoma

Radiation

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
Dysgerminoma

Chemotherapy

Metastatic dysgerminomas with systemic
chemotherapy
• the treatment of choice
• preservation of fertility

The most frequently used regimens
• BEP (bleomycin, etoposide, cisplatin)
• VBP (vinblastine, bleomycin, cisplatin)
• VAC (vincristine, actinomycin, cyclophosphamide)
Dysgerminoma

Cysplatin-based combination chemoTx
• Advanced stage, incompletely resected dysgerminoma
have an excellent prognosis
• The 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 available
• the 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
Dysgerminoma

If prior chemotharapy with BEP regimen

POMB-ACE may used
• Vincristine, 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


More advanced diseases


the tumor can be removed intact & the pregnancy continued
continuation of the pregnancy depend on gestational age
Chemotherapy



in 2nd & 3rd trimester
in 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
Dysgerminoma

In 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
chemotherapy
 cure 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 tissue



Grade 1 tumor
: <1 LPF contains immature neural elements
Grade 2 tumor
: 1-3 LPFs with immature elements
Grade 3 tumor
: >3 LPFs with these elements
Immature teratomas

The 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 teratomas
 occuring in 1-2% of cases
 usually 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 germcell 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 teratomas

Chemotharapy



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 teratomas

Regimen
: 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 teratomas

Radiation 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 nodes


Only mature elements : chemoTx should be discontinued
Persistent 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 pain



The most frequent initial symptom
about 75%
Asymptomatic pelvic mass

In 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 Tumor

Schill-Duval body



Microscopically, the
characteristic feature
The 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 Tumor

Most 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 Tumor

The tumors tend to be solid and large
• In size from 7 to 28 cm (median 15 cm)

Bilaterality is not seen

Most patients have early stage disease
• Stage I : 71%
• Stage II : 6%
• Stage III : 23%
Endodermal Sinus Tumor

Chemotherapy


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 regimen
• Primary 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 Tumor

Cisplatin-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 lesions
AFP values return to normal
Remain normal for the balance of their treatment
Embryonal Carcinoma

Extremely rare tumor

Distinguished from a choriocarcinoma


The patients are very young


By the absence of syncytiotrophoblastic and
cytotrophoblastic cells
Between 4 and 28 years (median 14yr)
Estrogen secretion


precocious pseudopuberty
Irregular 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 EST

Unilateral 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 hCG

Isosexual precocity in about 50% of patients
before menarche
Choriocarcinoma of the Ovary

MAC regimen
: complete responses have been reported




Methotrexate
Actinomycin D
Cyclophosphamide
The prognosis has been poor

Most patients having metastases to organ
parenchyma at the time of diagnosis
Polyembryoma

Extremely rare tumor

Composed of embryoid bodies

Very young & premenarcheal girls



Pseudopuberty
Elevated AFP & hCG
VAC regimen : effective
Mixed Germ Cell Tumors

The most common component of a mixed
malignancy






The most frequent combination


Dysgerminoma in 80%
EST in 70%
Immature teratoma in 53%
Choriocarcinoma in 20%
Embryonal carcinoma in 16%
Dysgerminoma and EST
Combination chemotherapy BEP
Mixed Germ Cell Tumors

Second look laparotomy


Macroscopic desease was present at initiation of
chemotherapy
The most important prognostic features

The size of the primary tumor
• Stage IA, samller than 10cm : survival is 100%

The relative size of most malignant component
• Less 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, trabeculated
Yelow or gray-yellow
Granulosa-stromal cell tumor

“Coffee bean”
grooved nuclei

Call-Exner bodies

Small clusters or
rosettes around a
central cavity
Granulosa-stromal cell tumor
- Diagnosis 
Of the rare prepubertal patients



For women of reproductive age



75% are associated with sexual pseudoprecocity
because of the estrogen secretion
menstrual irregulartities or secondary amenorrhea
cystic hyperplasia of the endometrium
For postmenopausal women

abnormal uterine bleeding
Granulosa-stromal cell tumor

Endometrial cancer in 5%

Endometrial hyperplasia in 25-50%

Ascites is present in about 10%

Hemorrhagic
: occasionally rupture and produce a
hemoperitoneum
Granulosa-stromal cell tumor

Usually stage I at diagnosis
but may recur 5-30 years after initial
diagnosis

Hematogenously spread

Lungs, 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 tumor
 Surgery

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 performed
• assessment of the contralateral ovary - biopsy
Granulosa-stromal cell tumor

For premenopausal patients in whom the
uterus is left in situ
• Endometrial biopsys should be perfromed
• the 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 tumor
 Chemotherapy



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 rate



10 YSR ; 90 %
20 YSR ; 75 %
The DNA ploidy -> correlated with survival

Residual-negative DNA diploid tumors had a 10year 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 Tumors

Treatment

In reproductive years
• Unilateral salpingo-oophorectomy and evaluation of the
contralateral ovary
• Low-grade lesion are only rarely bilateral (<1%)

Older patients
• TAH c BSO

Prognosis


The 5-year survival rate : 70-90%
Recurrences : uncommon
Fallopian tube cancer

0.3% of all female genital tract

Similar to ovarian cancer


Frequently involved secondarily from other
primary sites


The evaluation and treatment are the same
ovaries, 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
① a prominent watery vaginal discharge
② pelvic pain
③ a pelvic mass
Fallopian tube cancer

Vaginal 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
stage
stage
stage
I : 20-25%
II : 20-25%
III : 40-45%
IV : 5-10%
Fallopian tube cancer
- Treatment  Similar to epithelial ovarian cancer

Exploratory laparotomy is necessary




the most frequently employed treatment


to remove the primary tumor (TAH c BSO)
to stage the disease (No gross tumor spread)
to resect metastases (as much as possible)
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 rate



stage 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