Transcript malignant disorders of the ovaries - University of Yeditepe Faculty of

MALIGNANT
DISORDERS OF THE
OVARIES
Assoc. Prof. Gazi YILDIRIM, M.D.
Yeditepe University, Medical Faculty
Dept of Ob&Gyn

The 5. most common
cancer in women

The 5. most frequent
cause of cancer death

Lifetime risk 1/70
•5-year survival rate
<35%
•Mortality has
decreased only
slightly in 30 years
•Most diagnosis
made at advanced
disease
RISK FACTORS
Cause of Ovarian Cancer
is unknown

Risk Factors
 High socio-economic status
 Early menarche
 Late menopause
 Few children
 Never used oral contraceptive
 Genetic (10%)
 Environment???



Dietary factors
Exposure to talc
Exposure to asbestos
>90% of ovarian cancer
develops sporadically.
~10% of epithelial ovarian
cancers are based on genetic
predisposition.
GENETIC PREDISPOSITION

Chromosomal abnormalities
Turner syndrome
Dysgerminoma, gonadoblastoma
 Hereditary ovarian cancer
BOC (breast and ovarian cancer syndrome)

BRCA-1
mutations on chromosome 17 and less
commonly BRCA-2 mutations on chromosome 13.
Lynch
II syndrome (HNPCC syndrome)
DNA
mismatch repair gene mutations
Colon ca, ovarian-endometrial-breast cancer
Acquired
P53
genetic abnormalities
tumor supressor gene mutations, HER2/neu proto-oncogene
activation
Genetic Predisposition: 5-10% 0f
Ovarian Cancer

Carriers of BRCA1 or
BRCA2:


40% risk of ovarian
cancer
BRCA1 and 2 Germ line
mutations:
10% of all ovarian
cancers
 1-2% of all breast
cancers

HISTOPATHOLOGY OF
OVARIAN CANCER
OVARIAN CANCER
EPITHELIAL
GERM CELL
Serous
Mucinous
Endometrioid
Clear cell
Transitional cell
Undifferentiated
Dysgerminoma
Endodermal sinus tm
Teratoma
Embryonal carcinoma
Choriocarcinoma
Gonadoblastoma
Polyembryoma
Mixed germ cell
SEX CORD
AND STROMAL
Granulosa cell tm
Fibroma
Thecoma
Sertoli-leydig cell
gynandroblastoma
5% of ovarian cancer arises from metastases!!
(breast, colon, stomach, endometrium, lymphoma)
EPITHELIAL NEOPLASMS

Derived from the ovarian surface
mesothelial cells.
Serous
 Mucinous
 Endometrioid
 Clear cell
 Transitional cell
 Undifferentiated


Account >60% of all ovarian neoplasms
and >90% of malignant ovarian tumors.
Serous Neoplasms

Most common malignant tumor
of the ovary.




35-50% of all epithelial tumors.
Bilateral in 40-60 of cases.
Extraovarian spread at the time
of diagnosis in 85% of cases.
Cut section: solid areas,areas
of hemorrhage,necrosis, cyst
wall invasion and adhesions to
adjacent structures.
Histology- serous carcinoma



Mild to moderate nuclear
atypia
Psammoma body
(irregular calcifications)
The grade of
differentiation is based on
the degree of
preservation of the
papillary architecture.
Mucinous Neoplasms



Account for 10-20% of
all epithelial ovarian
neoplasms
The second most
common type of
epithelial ovarian
cancer.
Bilateral in <10% of
cases (in contrast to
serous tumors!!!!)
Large size
(~16 cm)
 Cut sections:
multilocular
cysts filled with
viscous mucin.

Histology- mucinous carcinoma



Composed predominantly of intestinal-like
cells that invade surrounding stroma.
Invasive tumors exhibit marked histologic
variability from area to area within the
Extensive sampling required !!
tumor.
The differentiation is based on the
preservation of the glandlike architecture
of the tumor.
Pseudomyxoma peritonei



Resulting from the
progressive
accumulation of mucin in
the abdominal cavity.
Most commonly in
association with low
malignant potential.
Also with
cystadenocarcinoma of
the ovary and appendix,
mucocele of the
appendix.
*potentially
morbid
secondary to repeated
bowel obstruction.
Endometrioid Neoplasm





Exhibits an adenomatoid pattern that resembles
endometrial adenocarcinoma.
Bilateral in 30-50% of cases.
Arises rarely in foci of endometriosis (<10% of
cases).
The degree of differentiation is based on the
extent to which the glandular architecture is
retained.
In 30% of cases, there is a synchronous
endometrial carcinoma of the uterus
A second primary rather than a metastatic focus !!!
Clear Cell Carcinoma



Also referred to as mesonephroid carcinoma
Biologically aggressive
hypercalcemia
and hyperpyrexia
Difficult to differentiate from mucinous
neoplasms
the periodic acid-Schiff
reaction
only weakly (+) in clear cell
carcinoma; strikingly (+) in mucinous tumors.
Transitional Cell (Brenner) Carcinoma



Composed of cells that resemble lowgrade transitional cell carcinoma of the
urinary bladder.
Typically diagnosed at advanced stage
disease
Poorer prognosis when compared with
that of other histologic types of epithelial
ovarian cancer.
Undifferentiated Carcinoma


<10% of epithelial neoplasms.
Characterized by the absence of any
distinguishing microscopic features that
permit its placement in one of the other
histologic categories.
GERM CELL NEOPLASMS

Arise from the germ cell elements of the ovary.









Dysgerminoma
Endodermal sinus tumor
Embryonal cell carcinoma
Choriocarcinoma
Teratoma
Polyembryoma
Mixed germ cell tumors
Occur during the second and third decades of
life.
Produce biologic markers which can be
monitored to assess response to therapy.
Tumor Markers that may be elevated in
the presence of Germ Cell Neoplasms
Neoplasm
AFP
hCG
Dysgerminoma
-
+/-
Endodermal sinus tm
+
-
Immature teratoma
+/-
-
Mixed germ cell tm
+/-
+/-
Choriocarcinoma
-
+
Embryonal
carcinoma
-
+
Dysgerminoma




The female counterpart of the seminoma
in the male.
Young females
30-40% of germ cell tumors.
Unilateral in 85-90% of cases.
Endodermal Sinus Tumor






Second most common germ cell tumor
(20%).
Bilateral in <5% of cases.
The most rapidly growing neoplasm !!
Commonly present with an acute
abdomen.
Pathognomic finding: Schiller-Duval body
AFP(+)
Immature Teratoma




The malignant counterpart of the mature
cystic teratoma or dermoid.
20% of germ cell tumors.
Bilateral in <5% of cases, although the
contralateral ovary commonly contains a
dermoid cyst
Immature elements: commonly
neuroectodermal
Mature Teratoma (Dermoid)




Common
20-30 years
The most common tumor diagnosed
during pregnancy.
Rarely, the squamous component
undergoes malignant transformation over
the age 40. (<2%)
Embryonal Carcinoma




Younger patients (mean age of 14 years)
Epithelial cells resembling those of the
embryonic disc.
Typically produce hCG
75% also secrete AFP.
Choriocarcinoma
Primary ovarian choriocarcinoma arises
from a germ cell similar in appearance to
gestational choriocarcinoma.
Nongestational tumors: poorer prognosis
* The detection of other germ cell
components indicates nongestational
tumors!

Gonadoblastoma




Rare tumor composed of nests of germ
cells and sex cord derivatives.
More common in the right ovary.
Usually during the second decade of life.
Found in patients with abnormal gonadal
development in the presence of a Y
chromosome.
Mixed Germ Cell Tumors



10% of germ cell neoplasms.
Contain ≥2 germ cell elements.
Dysgerminoma and endodermal sinus
tumor occur together most frequently.
SEX CORD-STROMAL TUMORS
Heterogeneus group of rare neoplasms
originating from the ovarian matrix.
cells within matrix have potential
for hormon production.
Signs and symptoms of
estrogen or androgen excess.

Granulosa Cell Tumors



1-2% of all ovarian tumors.
The most common malignant tumors of
the sex cord-stromal tumors.
Hyperestrogenism
Precocious puberty
in young girls

Call-exner bodies
Endometrial hyperplasia
and vaginal bleeding in
postmenopausal women
Thecoma



Benign
Hyperestrogenism
Lipid-laden stromal cells
Yellow color on cut section

Typically develop in postmenopausal women in
their mid-60s.
Fibroma


Benign
Meigs’ Syndrome
Ovarian fibroma
 Ascites
 Pleural effusion


Hormonally inactive
Mimic the presentation
of
ovarian cancer.
Sertoli-Leydig Cell Tumors





Rare
Consist of testicular structures at different
stages of development.
Usually virilizing
During the third decade of life
Rarely bilateral
Tumors metastatic to the ovary



25% of all ovarian malignancies.
Clinically mimic the primary ovarian cancer
Usually present as bilateral adnexal
masses


25% of cases unilateral
Most common primary cancers: breast,
stomach, colon and endometrium.
SYMPTOMS

Vague and non-specific !!
Abdominal bloating
 Indigestion, dyspepsia
 Altered bowel habits
 Menstruel abnormalities
 Pelvic fullness
 Pain

Evaluation of the patient with a
suspected ovarian neoplasm
Differential diagnosis
of a pelvic mass
Age of the patient??
The characteristics of the mass
on pelvic examination
The radiographic appearance
of the mass
The prepubertal child and
the postmenopausal woman
are at greatest risk
for developing a pelvic mass that subsequently proves
to be a malignant ovarian tumor.
The reproductive age woman is
more likely to have
a functional ovarian cyst or
endometrioma.
Physical Examination


Perform a comprehensive examination.
Attention to the lymph-node-bearing areas


Particularly the supraclavicular and inguinal areas.
Examination of the abdomen




Abdominal distention
The presence of flank fullness and shifting dullness
Tympanitic percussion note over the lateral abdomen
a large mass displacing the bowel to
the periphery.
central tympanitic percussion note
ascites
Characteristics of a pelvic mass
on physical examination
BENIGN !!
Mobile
Cystic
Unilateral
Cul-de-sac: smooth
MALIGNANT !!
Fixed
Solid or form
Bilateral
Cul-de-sac:nodular
Radiographic Evaluation-I

Ultrasonography







Transabdominal
Transvaginal
Color flow doppler studies
CT
retroperitoneal structures,pelvic
organs
MRI
more information regarding the
nature of the ovarian tumor.
High cost and questionable benefit !!!
Particular benefit in the evaluation of pregnant woman.
Radiographic Evaluation-II



Radiograph of the chest
exclude
metastatic parenchymal disease and
detect pleural effusion.
Barium enema
Screening mammogram study
Radiographic characteristics that help to
differentiate benign and malignant adnexal masses
BENIGN
*Simple cyst,
<10 cm in size
*Septations,
<3 mm in thickness
*Unilateral
*Calcification,
especially teeth
*Gravity-dependent
layering of cyst
contents
MALIGNANT
*Solid or cystic+solid
*multiple septations
>3mm in size
*bilateral
*ascites
PROGNOSTIC FACTORS






Stage !!
Grade
Cell-type of tumor
Residual disease after surgery
Disease volume prior to any surgical
debulking
Age of woman >70

Performance status
SCREENING FOR OVARIAN
CANCER

Ultrasound
Transvaginal
 Abdominal
 Color flow


NO EVIDENCE
THAT SCREENING WORKS!!
Tumor Markers:
Ca 125
 Protein patterns



Pelvic exam
Genetic screening
SURGICAL TREATMENT of
epithelial overian cancer



Surgery: the cornerstone of therapy
debulking:
remove as much of the cancer as possible
the less cancer left after primary surgery the
better the outcome
 the best outcome is when there is no residual
disease

At the time of diagnosis,
>70% of patients with epithelial ovarian cancer
have metastases beyond the pelvis

.
The most common locations of metastases:
*peritoneum (85%)
*omentum (70%)
*liver (35%)
*pleura (33%)
*lung (25%)
*bone (15%)
Lymphatic metastasis occurs frequently,
with up to
80% involving pelvic lymph nodes and
67% involving para-aortic lymph nodes,
depending on the stage of cancer.
INTRAOPERATIVE DIFFERENTIATION OF
BENIGN AND MALIGNANT MASSES
MALIGNANT
BENIGN
•Simple cyst
•Unilateral
•No adhesions
•Smooth surfaces
•Intact capsule
*Adhesions
*Rupture
*Ascites
*Solid areas
*Areas of hemorrhage
or necrosis
*papillary excrescences
*multioculated mass
bilateral
Procedures in the surgical
staging of ovarian cancer








Sample of ascites or peritoneal washings from the
paracolic gutters and pelvic and subdiaphragmatic
surface for cytology
Complete abdominal exploration
Intact removal of tumor
Hysterectomy
Infracolic omentectomy
Biopsies of abdominal peritoneal implants; if present,
random biopsies from the paracolic gutter
peritoneum,pelvic peritoneum,and right
subdiaphragmatic peritoneal surface
Pelvic and para-aortic lymph node biopsies
Cytoreductive surgery to remove all visible disease
FIGO staging of ovarian cancer

Stage 1: growth limited to ovaries




1a: one ovary involved
1b: both ovaries involved
1c: 1a or 1b and ovarian surface tm, ruptured capsule, malignant
ascites, or peritoneal cytology (+) for malignant cells
Stage 2: extension of the tm from the ovary
to the pelvis



2a: extension to the uterus or fallopian tube
2b: extension to other pelvic tissues
2c: 2a or 2b and ovarian surface tm, ruptured capsule,
malignant ascites, or peritoneal cytology (+) for malignant
cells

Stage 3: disease extension to the abdominal
cavity




3a: abdominal peritoneal surfaces with microscopic metastases
3b: tm metastases < 2 cm in size
3c: tm metastases > 2 cm in size or metastatic disease in the
pelvic, paraaortic or inguinal lymph nodes
Stage 4: distant metastatic disease




Malignant pleural effusion
Pulmonary parenchymal metastases
Liver or splenic parenchymal metastases (not surface implants)
Metastases to the supraclavicular lymph nodes or skin
SURGICAL TREATMENT
of germ cell neoplasms



Early stage at the time of diagnosis
Low incidence of bilaterality
Young age of patients
Fertility sparing surgery
by removal the involved adnexa
CHEMOTHERAPY
of epithelial ovarian cancer


All other patients,except stage Ia and
grade I tumors, should undergo systemic
chemotherapy.
Agents against epithelial ovarian cancer:
Cisplatin
 Carboplatin
 Cyclophosphamide
 Paclitaxel

Combination
therapies !!
Assessment of response
to combination chemotherapy is based on
physical examination,
changes in size of palpable or
radiographically measurable lesions and
changes in the CA-125 level.
*an elevated CA-125 level (>35IU/mL)
predicts persistent disease at second look
in >97% of patients.
*a normal CA-125 level does NOT completely exclude
the possibility of residual, subclinical disease.
Chemotherapy-associated toxicities










Cisplatin: nephrotoxicity, neurotoxicity, ototoxicity
Carboplatin: thrombocytopenia, neutropenia
Cyclophosphamide: hemorrhagic cystitis, pulmonary
fibrosis
Paclitaxel: myelosupression
Altretamine: peripheral neuropathy
Etoposide: myelosupression
Bleomycine: pulmonary fibrosis
Doxorubicin: cardiac toxicity
Vincristine: neuropathy
Ifosfamide: hemorrhagic cystitis, central neurotoxicity
RADIATION THERAPY


Limited role in the treatment of epithelial
ovarian cancer.
Intraperitoneal P³²
For stage 1c disease
 For microscopically (+) second-look
operations.


Succesfull in the treatment of dysgerminoma

Dysgermioma: most radiation-sensitive
tumor identified.