Ovarian Cancer
CHAP. 33 Ovarian Cancer
December 9 1997
1st year resident OB & GY
Sung Hee Oh. M.D
EPITHELIAL OVARIAN CANCER
90 % of ovarian cancer
from the coelomic epithelium or mesothelium
1. PATHOLOGY
*borderline tumors
"tumor of low malignant potential"
tend to remain confined to the ovary for long periods, occur predominantly in premenopausal
women and are associated with a very good prognosis
uncommon, metastatic implants may occur
The criteria for the diagnosis of borderline tumors
Epithelial proliferation with papillary formation and pseudostratification
Nuclear atypia and increased mitotic activity
Absence of true stromal invasion (without tissue destruction)
20-25% of borderline malignant tumors spread beyond the ovary
based on the histologic features of the primary tumors
1) Serous tumors
invagination of the surface ovarian epithelium
secrete serous fluid
Psammoma body
papillary ingrowths
a . borderline serous tumors
10% of all avarian serous tumors
50% occur before the age of 40 years
40% of women with ovarian serous bordeline tumors have extraovarian implants
40% of theses women eventually die of disease
non-invasive group (only three of 50)/invasive group (four of six), Bell et all
b . malignant serous carcinomas
well differentiated
: papillary and glandular structures
nuclei are uniformly round to oval with 0-2 mitoses per high powered field
poorly differentiated
: solid sheets of cells
nuclear pleomorphism, high mitotic activity usually 2-3 mitoses per HPF
2) mucinous tumors
8-10%
they may reach an enormous size, filling the entire abdominal cavity
a . bordeline mucinous tumors
enigma
b . malignant mucinous carcinomas
papillary proliferations -less common
bilateral tumors occur in 8-10% of cases
intraovarian in 95-98% of cases
malignant develops in 5-10% of benign mucinous cysts
c . pseudomyxoma peritonei
neoplastic epithelium secretes large amouts of gelatinous mucinous material
3) Endometrioid tumors
6-8%
malignant potential of endometriosis is very low, although a transition from benign to malignant epithelium may be demonstrated (hemorrhagic foci)
a . borderline endometrioid tumors
wide morphologic spectrum
endometrial polyp or complex endometrial hyperplasia with crowding of glands
some bordeline malignant tumors have a prominent fibromatous component (adenofibroma)
b . malignant endometrioid carcinomas
adenomatous pattern with all the potential variations of epithelia fond in the uterus
adenocarcinoma with benign- appearing squamous metaplasia gas an excellent prognosis
patients with mixed adenosquamous carcinomas have a very low survival rate
c . multifocal disease
Endometrioid tumors of the ovary are often saaociated with similar lesions
in the endometrium
metastatic from uterus to ovaries have a 30-40% 5-year survival
synchronous multifocal disease have a 75-80% 5-year survival
4) Clear cell (mesonephroid) tumors
3%
hypercalcemia or hyperpyrexia and most such cases are associated with metastatic disease
* malignant clear cell carcinomas
clear cells and hobnails cells
: the tall clear cells have abundant clear or vacuolated cytoplasm, hyperchromatic,
irregular nuclei, and nucleoli of various sizes
hobnails cells project their nuclei to the atypical cytoplasm
focal areas of endometriosis and endometrioid carcinoma sometimes occur
histologically identical to that seen in the uterus or vagina of the young patient who has
been who has exposed to DES in uterus
5) Brenner tumors
a. borderline Brenner tumors
the epithelium dose not invade the stroma
low-grade papillary transitional cell carcinoma of the urinary bladder
complete surgical removal usually results in cure
b . malignant Brenner tumors
rare
benign Brenner tumors coexisting with invasive transitional cells or another type of
carcinoma
c . transitional cell tumors
a primary ovarian carcinoma resembling transitional cell carcinoma of the urinary
bladder without a recognizable Brenner tumor
more than 50% of TCC are more sensitive to chemotherapy and have a more favorable
prognosis than other pool differentiated ovarian carcinomas of comparable stage
more frequently diagnosed in an advanced stage---- poorer survival rate
6) Undifferentiated carcinomas
a . large cell types
large round to oval nuclei, prominent nucleoli , a moderate amount of cytoplasm and
high mitotic activity are arranged in solid without glandular or squamous differentation
b . small cell types
small, hyperchromatic nuclei, scanty cytoplasm and high mitotic activity
in young women (hypercalcemia)
immunohistochemical stains - lymphoma, leukemia or sarcoma
7) Mesotheliomas
fibrosarcomatous/tubopapillary/carcinomatous/mixed
multiple intraperitoneal masses
develop after hysterectomy and bilateral salpingo-oophorectomy for benign disease
8) peritoneal carcinomas
primary malignant transformation of the peritoneum
simulates ovarian cancer clinically
the overall prognosis for borderline serous peritoneal tumors is excellent
appearance of a moderately to poorly differentiated serous ovarian carcinoma
primary peritoneal endometrioid carcinoma less common
2. Clinical features
more than 80% of epithelial ovarian cancers are fond in postmenopausal women
62 years
about 30% of ovarian neoplasms in postmenopausal women are malignant whereas only about
7% of ovarian epithelial tumors in premenopausal patients are frankly malignant
1) screening
transvaginal ultrasonography
: a very high (>95%) sensitivity for the detection of early-stage ovarian cancer, although
this test alone might require as many as 10-15 laparotomy procedures for each case of per
ovarian cancer detected
CA 125
: Sweden and the U.K.
with elevated CA 125 levels (>30u/ml) have undergone abdominal ultrasonography and
14 ovarian cancers have been discovered among 27,000 women screened
about four laparotomies were performed for each case of cancer detected
considering the false-positive results for both CA 125 and transvaginal ultrasonography,
particularly for premenopausal women, these tests are not cost-effective and should not be
used routinely to screen for ovarian cancer
2) genetic risk for epithelial ovarian cancer
familial or hereditary patterns account for fewer than 5% of all malignancies
a . site- specific familial ovarian cancer
the risk of developing epithelial ovarian cancer is higher in the presence of a positive
family history
hereditary ovarian cancers generally occur in women about 10 years younger than those with
nonhereditary tumors (before 50 years)
b . Breast/ovarian familial cancer syndrome
combination of epithelial ocarina and breast cancers, affecting a mixture of first and
second degree relatives
a young age, and the breast cancers may be bilateral
autosomal dominant mode of inheritance
two-to four fold greater than the general population
17q chromosome, the BRCA1 gene
prospect of screening of women at risk
individuals who have a mutation in the BRCA1 have a cumulative lifetime risk of
85-90% of developing breast cancer and 50% risk of ovarian cancer
c . Lynch II syndrome
the Lynch II syndrome (hereditary nonpolyposis colon cancer) which includes multiple
adenocarcinomas involves a combination of familial colon cancer and a high rate of
ovarian , endometrial, and breast cancers and other malignancies of the gastrointestinal
and genitourinary systems
The current recommendations of the Committee on Gynecologic Practice of the
American College of Obstetricians and Gynecologists are summarized below
Women who wish to preserve their reproductive capacity should undergo periodic
screening by transvaginal ultrasonography every 6 months and should consider
prophylatic oophorctomy when childbearing has been completed.
Oral contraceptives may be given to a young woman before she has children,
although the protective effect for women at high risk has not been evaluated.
Women with familial ovarian or hereditary breast/ovarian cancer syndrome who do
not wish to maintain their fertility should be offered prophylactic bilateral
saopingo-oophorectomy. The risk should be clearly documented, preferably
satablished by pedigree analysis, before oophorectomy. These women should be
counseled that this operation does not offer absolute protection because
perotomenal carcinomas oc asionally can occur after bilateral oophorectomy.
The role of BRCA1 testing in these women in being evaluated
Women with a documented Lynch II syndrome should be treated in the same
manner as women with familial breast/ovarian cancer syndrome , but in addition,
they should undergo periodic screening mammography, colonoscopy, and
endometrial biopsy
3) Symptoms
no symptoms for long periods of time
urinary frequency or constipation
lower abdominal distention, pressure, or pain (dyspareunia)
acute symptoms, such as pain secondary to rupture or torsion are unsual
in advanced stage disease : symptoms related to the presence of ascites omental metastsis, or
bowel metastasis
--- abdominal distention, bloating , constipation, nausea, anorexia ,early satiety
4) Signs
solid, irregular, fixed pelvic mass is highly suggestive of an ovarian malignancy
upper abdominal mass or ascites is present
ovaries-not palpable (at least 1 year)
: postmenopausal ovary syndrome ? only about 3 % of palpable masses measuring <5cm
in postmenopausal women are malignant
5) Diagnosis
serum CA125
useful in distinguishing malignant from benign pelvic masses
postmenopausal patients- >95U/ml : malignancy
premenopausal patient- observation : mobile, mostly cystic, unilateral and of regular contour
no more than 2 months , hormonal suppression
with the oral contraceptive ----> regress
not regress or increases in size---> must be removed surgically
>8cm in diameter , solid, relatively fixed , or irregularly shaped---> laparotomy
Exploratory laparotomy
routine hematologic and biochemical assessments
x-ray of the chest , IVP, barium enema or colonoscopy (over the 45years),
bilateral mammography
Cervical cytologic study
Endometrial biopy and an endocervical curretage ? irregular menses or
postmenopausal vaginal bleeding
6) Patterns of spread
a . transcoelomic
by exfoliation of cells that implant along the surfaces of the peritoneal cavity
tend to follow the circulatory path of the peritoneal fluid
up the paracolic gutters, especially on the right , along the intestinal mesenteries,
to the right hemidiaphragm
posterior cul-de-sac, paracolic gutters, right hemidiaphragm, liver capsule, the peritoneal
surfaces of the intestine and their mesenteries
seldom invades the intestinal lumen (carcinomatous ileus)
b . lymphatic
advanced stage disease : supraclavicular lymph node
78% of patients with stage III disease have metastases to the pelvic lymph node
para-aortic lymph nodes was 18% in stage I, 20% in stage II, 42% in stage III, and
67% in stage IV
c . hematogenous
uncommon
3 . Prognostic factors
1) Pathologic factors
: histologic grade --- significant heterogeneity of tumors and observational bias, the value of histologic grade as an independent prognostic factor has not been clearly established
2) biological factors
: low-stage cancers tend to be diploid and high-stage tumors tend to be aneuploid
flow cytometric analysis also provides data on the cell cycle, and the proliferation fraction (S phase) determined by this technique has correlated with prognosis in some studies
30%- HER-s/neu oncogene, poorer prognosis
3) clinical factors
the extent of residual disease after primary surgey, the volume of ascites, patient age, and performance status----- all independent prognosis variables
4 . Staging
: FIGO system --- based on findings at surgical exploration
1) technique for surgical staging
December 9 1997
1st year resident OB & GY
Sung Hee Oh. M.D
EPITHELIAL OVARIAN CANCER
90 % of ovarian cancer
from the coelomic epithelium or mesothelium
1. PATHOLOGY
*borderline tumors
"tumor of low malignant potential"
tend to remain confined to the ovary for long periods, occur predominantly in premenopausal
women and are associated with a very good prognosis
uncommon, metastatic implants may occur
The criteria for the diagnosis of borderline tumors
Epithelial proliferation with papillary formation and pseudostratification
Nuclear atypia and increased mitotic activity
Absence of true stromal invasion (without tissue destruction)
20-25% of borderline malignant tumors spread beyond the ovary
based on the histologic features of the primary tumors
1) Serous tumors
invagination of the surface ovarian epithelium
secrete serous fluid
Psammoma body
papillary ingrowths
a . borderline serous tumors
10% of all avarian serous tumors
50% occur before the age of 40 years
40% of women with ovarian serous bordeline tumors have extraovarian implants
40% of theses women eventually die of disease
non-invasive group (only three of 50)/invasive group (four of six), Bell et all
b . malignant serous carcinomas
well differentiated
: papillary and glandular structures
nuclei are uniformly round to oval with 0-2 mitoses per high powered field
poorly differentiated
: solid sheets of cells
nuclear pleomorphism, high mitotic activity usually 2-3 mitoses per HPF
2) mucinous tumors
8-10%
they may reach an enormous size, filling the entire abdominal cavity
a . bordeline mucinous tumors
enigma
b . malignant mucinous carcinomas
papillary proliferations -less common
bilateral tumors occur in 8-10% of cases
intraovarian in 95-98% of cases
malignant develops in 5-10% of benign mucinous cysts
c . pseudomyxoma peritonei
neoplastic epithelium secretes large amouts of gelatinous mucinous material
3) Endometrioid tumors
6-8%
malignant potential of endometriosis is very low, although a transition from benign to malignant epithelium may be demonstrated (hemorrhagic foci)
a . borderline endometrioid tumors
wide morphologic spectrum
endometrial polyp or complex endometrial hyperplasia with crowding of glands
some bordeline malignant tumors have a prominent fibromatous component (adenofibroma)
b . malignant endometrioid carcinomas
adenomatous pattern with all the potential variations of epithelia fond in the uterus
adenocarcinoma with benign- appearing squamous metaplasia gas an excellent prognosis
patients with mixed adenosquamous carcinomas have a very low survival rate
c . multifocal disease
Endometrioid tumors of the ovary are often saaociated with similar lesions
in the endometrium
metastatic from uterus to ovaries have a 30-40% 5-year survival
synchronous multifocal disease have a 75-80% 5-year survival
4) Clear cell (mesonephroid) tumors
3%
hypercalcemia or hyperpyrexia and most such cases are associated with metastatic disease
* malignant clear cell carcinomas
clear cells and hobnails cells
: the tall clear cells have abundant clear or vacuolated cytoplasm, hyperchromatic,
irregular nuclei, and nucleoli of various sizes
hobnails cells project their nuclei to the atypical cytoplasm
focal areas of endometriosis and endometrioid carcinoma sometimes occur
histologically identical to that seen in the uterus or vagina of the young patient who has
been who has exposed to DES in uterus
5) Brenner tumors
a. borderline Brenner tumors
the epithelium dose not invade the stroma
low-grade papillary transitional cell carcinoma of the urinary bladder
complete surgical removal usually results in cure
b . malignant Brenner tumors
rare
benign Brenner tumors coexisting with invasive transitional cells or another type of
carcinoma
c . transitional cell tumors
a primary ovarian carcinoma resembling transitional cell carcinoma of the urinary
bladder without a recognizable Brenner tumor
more than 50% of TCC are more sensitive to chemotherapy and have a more favorable
prognosis than other pool differentiated ovarian carcinomas of comparable stage
more frequently diagnosed in an advanced stage---- poorer survival rate
6) Undifferentiated carcinomas
a . large cell types
large round to oval nuclei, prominent nucleoli , a moderate amount of cytoplasm and
high mitotic activity are arranged in solid without glandular or squamous differentation
b . small cell types
small, hyperchromatic nuclei, scanty cytoplasm and high mitotic activity
in young women (hypercalcemia)
immunohistochemical stains - lymphoma, leukemia or sarcoma
7) Mesotheliomas
fibrosarcomatous/tubopapillary/carcinomatous/mixed
multiple intraperitoneal masses
develop after hysterectomy and bilateral salpingo-oophorectomy for benign disease
8) peritoneal carcinomas
primary malignant transformation of the peritoneum
simulates ovarian cancer clinically
the overall prognosis for borderline serous peritoneal tumors is excellent
appearance of a moderately to poorly differentiated serous ovarian carcinoma
primary peritoneal endometrioid carcinoma less common
2. Clinical features
more than 80% of epithelial ovarian cancers are fond in postmenopausal women
62 years
about 30% of ovarian neoplasms in postmenopausal women are malignant whereas only about
7% of ovarian epithelial tumors in premenopausal patients are frankly malignant
1) screening
transvaginal ultrasonography
: a very high (>95%) sensitivity for the detection of early-stage ovarian cancer, although
this test alone might require as many as 10-15 laparotomy procedures for each case of per
ovarian cancer detected
CA 125
: Sweden and the U.K.
with elevated CA 125 levels (>30u/ml) have undergone abdominal ultrasonography and
14 ovarian cancers have been discovered among 27,000 women screened
about four laparotomies were performed for each case of cancer detected
considering the false-positive results for both CA 125 and transvaginal ultrasonography,
particularly for premenopausal women, these tests are not cost-effective and should not be
used routinely to screen for ovarian cancer
2) genetic risk for epithelial ovarian cancer
familial or hereditary patterns account for fewer than 5% of all malignancies
a . site- specific familial ovarian cancer
the risk of developing epithelial ovarian cancer is higher in the presence of a positive
family history
hereditary ovarian cancers generally occur in women about 10 years younger than those with
nonhereditary tumors (before 50 years)
b . Breast/ovarian familial cancer syndrome
combination of epithelial ocarina and breast cancers, affecting a mixture of first and
second degree relatives
a young age, and the breast cancers may be bilateral
autosomal dominant mode of inheritance
two-to four fold greater than the general population
17q chromosome, the BRCA1 gene
prospect of screening of women at risk
individuals who have a mutation in the BRCA1 have a cumulative lifetime risk of
85-90% of developing breast cancer and 50% risk of ovarian cancer
c . Lynch II syndrome
the Lynch II syndrome (hereditary nonpolyposis colon cancer) which includes multiple
adenocarcinomas involves a combination of familial colon cancer and a high rate of
ovarian , endometrial, and breast cancers and other malignancies of the gastrointestinal
and genitourinary systems
American College of Obstetricians and Gynecologists are summarized below
Women who wish to preserve their reproductive capacity should undergo periodic
screening by transvaginal ultrasonography every 6 months and should consider
prophylatic oophorctomy when childbearing has been completed.
Oral contraceptives may be given to a young woman before she has children,
although the protective effect for women at high risk has not been evaluated.
Women with familial ovarian or hereditary breast/ovarian cancer syndrome who do
not wish to maintain their fertility should be offered prophylactic bilateral
saopingo-oophorectomy. The risk should be clearly documented, preferably
satablished by pedigree analysis, before oophorectomy. These women should be
counseled that this operation does not offer absolute protection because
perotomenal carcinomas oc asionally can occur after bilateral oophorectomy.
The role of BRCA1 testing in these women in being evaluated
Women with a documented Lynch II syndrome should be treated in the same
manner as women with familial breast/ovarian cancer syndrome , but in addition,
they should undergo periodic screening mammography, colonoscopy, and
endometrial biopsy
3) Symptoms
no symptoms for long periods of time
urinary frequency or constipation
lower abdominal distention, pressure, or pain (dyspareunia)
acute symptoms, such as pain secondary to rupture or torsion are unsual
in advanced stage disease : symptoms related to the presence of ascites omental metastsis, or
bowel metastasis
--- abdominal distention, bloating , constipation, nausea, anorexia ,early satiety
4) Signs
solid, irregular, fixed pelvic mass is highly suggestive of an ovarian malignancy
upper abdominal mass or ascites is present
ovaries-not palpable (at least 1 year)
: postmenopausal ovary syndrome ? only about 3 % of palpable masses measuring <5cm
in postmenopausal women are malignant
5) Diagnosis
serum CA125
useful in distinguishing malignant from benign pelvic masses
postmenopausal patients- >95U/ml : malignancy
premenopausal patient- observation : mobile, mostly cystic, unilateral and of regular contour
no more than 2 months , hormonal suppression
with the oral contraceptive ----> regress
not regress or increases in size---> must be removed surgically
>8cm in diameter , solid, relatively fixed , or irregularly shaped---> laparotomy
Exploratory laparotomy
routine hematologic and biochemical assessments
x-ray of the chest , IVP, barium enema or colonoscopy (over the 45years),
bilateral mammography
Cervical cytologic study
Endometrial biopy and an endocervical curretage ? irregular menses or
postmenopausal vaginal bleeding
6) Patterns of spread
a . transcoelomic
by exfoliation of cells that implant along the surfaces of the peritoneal cavity
tend to follow the circulatory path of the peritoneal fluid
up the paracolic gutters, especially on the right , along the intestinal mesenteries,
to the right hemidiaphragm
posterior cul-de-sac, paracolic gutters, right hemidiaphragm, liver capsule, the peritoneal
surfaces of the intestine and their mesenteries
seldom invades the intestinal lumen (carcinomatous ileus)
b . lymphatic
advanced stage disease : supraclavicular lymph node
78% of patients with stage III disease have metastases to the pelvic lymph node
para-aortic lymph nodes was 18% in stage I, 20% in stage II, 42% in stage III, and
67% in stage IV
c . hematogenous
uncommon
3 . Prognostic factors
1) Pathologic factors
: histologic grade --- significant heterogeneity of tumors and observational bias, the value of histologic grade as an independent prognostic factor has not been clearly established
2) biological factors
: low-stage cancers tend to be diploid and high-stage tumors tend to be aneuploid
flow cytometric analysis also provides data on the cell cycle, and the proliferation fraction (S phase) determined by this technique has correlated with prognosis in some studies
30%- HER-s/neu oncogene, poorer prognosis
3) clinical factors
the extent of residual disease after primary surgey, the volume of ascites, patient age, and performance status----- all independent prognosis variables
4 . Staging
: FIGO system --- based on findings at surgical exploration
1) technique for surgical staging
- any free fluid, pelvic cul-de-sac
- peritonea washing (no free fluid), recovering 50-100ml of saline from the pelvic
cul-de-sac , each paracolic gutter, and beneath each hemidiaphragm, with the
use of a rubber cathethe attached to the end of a bulb syringe
- a systematic exploration of all the intra- abdominal surfaces and viscera is performed
: clockwise fashion from the cecum cephalad along the paracolic gutter and the ascending
colon to the right kidney, the liver and gall bladder, the right hemidiaphragm the
entrance to the lessser sac at the paraaortic area across the transverse colon to the left
hemidiaphragm down the left gutter and the descending colon to the rectosigmoid
colon
- any suspicious areas or adhesions on the peritoneal surfaces should be biopsied
No ---- peritoneum of the pelvic cul-de-sac, both paracolic gutters, the peritoneum
over the bladder, and the intestinal mesenteries
- diaphragm --- by biopsy or by scraping with a tongue depressor and obtaining a sample
for cytologic assessment
- the omentum should be resected from the transverse colon "infracolic omentectomy
if the gastrocolic ligament is palpably normal, it does not need to be resected
- to evaluate the pelvic and paraaortic lymph node
2) Results
: stage I and II ---- three in 10 patients whose tumor appears to be confined to the pelvis
have occult metastatic disease in the upper abdomen or the retroperitoneal lymph nodes