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Prophylactic oophorectomy (PO) is performed along with
bilateral removal of the fallopian tubes (prophylactic salpingooophorectomy, PBSO) in order to remove potential precursors
of fallopian tube carcinoma. An occasional carcinoma in situ or
overt early carcinoma is discovered in the specimens of PBSO in
women at risk as well as in the control population. Since primary
fallopian tube carcinomas are rare, their precursors are assumed
to be unusual findings. However, atypia of the fallopian tube
mucosal epithelium is not unusual. The progression of such atypical changes reminiscent of dysplasia to overt carcinoma is possibly
hindered by still poorly understood host defense mechanisms in the
fallopian tube.
STAGE I OVARIAN CARCINOMA
Only a minority of ovarian cancers of epithelial origin are diagnosed
in early stages, when confined to one or both ovaries. The prognosis
188 L Deligdisch
Table 3. Prophylactic Oophorectomy
Most effective way to prevent ovarian cancer in women at high risk.
Most commonly found structural alterations: epithelial invaginations, surface
papillations, psammoma bodies, epithelial stratification, ovarian dysplasia
(cancer-prone phenotype) and occasional “silent” carcinoma.
Most common biologic/molecular changes: increased expression of MIB-1,
Ca 125, p53.
Ovarian carcinogenesis requires multiple mutations leading to the loss of cell cycle
control, clonal expansion and invasive growth.
Prophylactic oophorectomy specimens may reveal cancer precursor changes.
Table 4. “High Risk” Ovarian Study
Multiple sections of entire ovarian and fallopian tube specimens necessary.
Occasional occult carcinoma.
Precursor lesions of ovarian carcinoma significantly more common in PO specimens.
Identification of subtle morphologic features of “preneoplastic phenotype”.
Validation by morphometry and metabolic/molecular biology.
changes dramatically for ovarian cancers diagnosed in late stages. In
about 75% of Stage I ovarian carcinomas the prognosis is 80%–90%
five year survival. The prognosis for Stage III/IV ovarian carcinoma
is only 30% five year survival.
The high lethality of ovarian carcinoma diagnosed in late stages is
due to a paucity of symptoms in the majority of cases. Most ovarian carcinomas are classified histologically as serous papillary adenocarcinomas
(OSPC, 46%) and present most commonly as bilateral ovarian cystic
and solid neoplasms with the involvement of the peritoneum by tumor
masses that often exceed the volume of the ovarian tumors. It is amazing how often large masses of tumor contained in the abdominal cavity
are asymptomatic, or are manifested only by vague upper gastrointestinal symptoms such as bloating and nausea. Symptoms often appear with
the advent of ascites that occurs in late stages of the disease.
Ovarian carcinomas histologically diagnosed as non-serous,
include mucinous, endometrioid and clear cell carcinomas. These are
generally less frequent than their serous papillary (OSPC) counterparts. When considered in all stages: they are 20% mucinous, 28%
endometrioid and 6% clear cell carcinomas. These tumors are more
often unilateral and are less often associated with peritoneal tumor
involvement at the time of diagnosis. Their prognosis does not differ
much when diagnosed at the same stage as the OSPC. However, they
are more frequently diagnosed in early stages, due to their association
with pathologic findings that are symptomatic. Endometrioid and clear
cell carcinomas of the ovary are often associated with endometriosis,
especially endometriotic ovarian cysts and pelvic endometriosis. The
patients harboring these non-serous ovarian carcinomas are usually
younger and often present with symptoms of infertility, irregular
vaginal bleeding and hormonal disturbances associated with hyperestrogenism such as endometrial polyps, adenomyosis, and uterine
leiomyomas. Endometrial hyperplasia of various degrees of severity
and endometrial carcinomas are not infrequently diagnosed in
patients with ovarian carcinoma. It is not very uncommon to find an
ovarian neoplasm that has been clinically silent, only to be discovered
at surgery performed for endometrial/uterine pathology that was
manifested clinically by abnormal vaginal bleeding or pelvic pain.
18
Early Diagnosis of Ovarian Cancer 189
Ovarian endometriosis is a very common disorder and fortunately
only rarely associated with ovarian cancer. Patients suffering from
symptoms due to endometriosis are often diagnosed with ovarian
endometriotic cysts, which are occasionally lined by an atypical
endometrioid epithelium. An adjacent overtly neoplastic endometrioid
and/or clear cell carcinoma is identified in some cases which came to
medical attention due to symptomatic endometriosis (Fig. 13).
It was reported that 30%–40% of ovarian endometrioid and clear
cell carcinomas contain identifiable areas of endometriosis.
19
The
atypical areas of endometriosis adjacent to carcinoma (Fig. 14) share
some immune-phenotypical characteristics with the malignant tissue
such as bcl-2 and p53 altered proteins (Fig. 15).
Bax, MMP-9 and PTEN have been reported as positive in cancer
associated endometriosis along with the high positivity of the cancerous tissue for the same markers.
19
Ovarian endometrioid and clear-cell
adenocarcinomas are not infrequently associated with simultaneous
primary endometrial carcinomas. They are often diagnosed in Stage I,
are unilateral and despite the concomitant primary endometrial carcinoma, their prognosis is generally more favorable than that of ovarian
serous papillary carcinomas.
20
190 L Deligdisch
Fig. 13 Ovarian endometriotic cyst with solid nodule representing a clear cell
carcinoma.
Early Diagnosis of Ovarian Cancer 191
Fig. 14 Endometrioid adenocarcinoma (left) adjacent to atypical endometriosis
(right) Hematoxylin/eosin, orginal magnification 40×.
Fig. 15 Immunoreactivity to PTEN similar in endometrioid adenocarcinoma and
adjacent endometriosis.
These findings are suggestive of biological alterations taking place
in the endometriotic tissue adjacent to malignancy, reminiscent of the
dysplastic ovarian epithelium adjacent to ovarian serous papillary carcinoma, both representing early manifestations of preinvasive ovarian
cancer, involving two different carcinogenetic mechanisms (Table 5).
Indeed, serous papillary ovarian neoplasms are different from
non-serous carcinomas in a number of ways, clinically, histologically
and biologically. The biological markers are different as well, with p53
being the most reliable for OSPC and PTEN for endometrioid and
clear cell carcinomas (Table 6).
192 L Deligdisch
Table 5. Ovarian Carcinoma Adjacent to Endometriosis
Carcinoma arising from ovarian endometriosis is more common than from other
locations of endometriosis.
Clear cell and endometrioid carcinoma associated with endometriosis in 30%–40%.
Atypical epithelial changes at the transition between endometriosis and carcinoma.
Abnormal immunoreactivity: bcl-2, p53 altered proteins, Bax, MMP-9, PTEN in
a typical endometriosis.
Ovarian endometriosis associated with cancer with potentially precancerous
biological activity?
Table 6. Ovarian Carcinoma and Carcinogenesis
Serous papillary Endometrioid, clear cell
Most frequent Less frequent
70%–80% diagnosed Stage III, with Often diagnosed in Stage I, rare
peritoneal involvement peritoneal involvement
Mostly bilateral Mostly unilateral
Older patients Younger patients
Breast Ca hx, BRCA1 and 2 mutations Hyperestrogenism: Endometriosis,
infertility, endometrial pathology
Precursor: ovarian dysplasia, Precursor: Endometriosis, atypical,
precancerous phenotype, often clear cell carcinoma in situ
identified in prophylactic
oophorectomy specimens
Tumor markers: p53, Ca 125, MIB-1 Tumor markers: Bax, MMP-9,
PTEN, Bcl-2
In terms of early diagnosis, ovarian carcinomas diagnosed in
Stage I are, as mentioned, rare, and their histologic distribution is
fundamentally different from that of ovarian carcinomas of all stages.
While in all stages, OSPC are by far the most common, in Stage I,
they represent a minority of cases, which is less than a third as
recently reported.
21
Mucinous carcinomas are rather rare primary
ovarian neoplasms but they are more often diagnosed in Stage I.
Endometrioid carcinomas are the most common ovarian carcinomas
diagnosed in Stage I. This is due to their association with symptomatic pathologic findings such as endometriosis manifested by
pelvic pain, compression of neighboring organs, and endometrial
hyperplasia or neoplasia manifested by abnormal vaginal bleeding
(Table 7).
The OSPC diagnosed early represent uncommon situations when
sonograms performed for various reasons, often in patients with
breast cancer histories who are under close surveillance, reveal clinically silent ovarian tumors. It should be emphasized, however, that
despite the lack of a screening program for ovarian carcinoma and
the lack of adequate tumor markers (CA 125 is neither sensitive
Early Diagnosis of Ovarian Cancer 193
Table 7. Stage I: Ovarian Carcinoma
Different histopathologic distribution of Stage I compared to all stage ovarian
carcinoma: predominant non-serous ovarian carcinomas in stage I versus
predominant serous in all stages.
Different clinical settings in Stage I ovarian carcinoma: frequent hyperestrogenic,
younger patients with history of endometriosis, infertility, endometrial
pathology.
Non-serous ovarian cancers more often diagnosed early due to symptomatic pelvic
masses and/or vaginal bleeding.
Endometriosis: A potential cancer precursor?
Serous carcinomas mostly asymptomatic; early diagnosis in patients closely followed
for breast cancer history.
Occasional early diagnosis of asymptomatic ovarian cancer at hysterectomy for
symptomatic associated neoplasm.
Essential clinical pathological and biological (immunological, genetical) differences
between serous and non-serous ovarian carcinomas.
Different natural history.
nor specific enough for an early ovarian carcinoma diagnosis) a
combination of vaginal ultrasound, serum tumor markers and especially a thorough clinical examination and history including the
search for paraneoplastic syndromes may disclose the presence of
early stage OSPC, especially in the group of genetically high-risk
patients.
22,23
A separate group of ovarian neoplasms often diagnosed in Stage I
are the so called borderline ovarian tumors which are still the
object of controversial opinions in terms of diagnostic criteria, biological behavior and clinical management. They are generally seen
in patients younger than those with invasive carcinomas.
Histologically, they are most often serous papillary, followed in frequency by mucinous, endometrioid and rare clear cell carcinomas
of borderline malignancy (or low malignant potential). Their biological behavior is less aggressive than that of invasive tumors and
the survival is markedly higher. Histologically, these tumors are
characterized by lack of invasion of the ovarian parenchyma and
mild to moderate nuclear atypia with a relative low mitotic activity.
Their biological characteristics, as demonstrated by molecular
biology studies, are different from those of the invasive ovarian
carcinomas.
24
These tumors are often associated with implants of
the peritoneum, non-invasive or invasive, the latter having a more
ominous prognosis.
25
The five-year survival of borderline ovarian
tumors is generally good, especially for those diagnosed in Stage I,
which is close to 95%. Borderline ovarian tumors recur often at
variable time intervals and the recurrent tumors are histologically
similar to the primary. Recurrences of tumors with a frank invasive
histological pattern probably represent invasive ovarian carcinomas
that were not diagnosed initially as such. Borderline ovarian serous
tumors are presently classified into atypical proliferative and
micropapillary variants, the latter being more often associated with
peritoneal implants and having a more ominous prognosis.
26
While
most borderline ovarian tumors recur as borderline, some may
progress to a low-grade serous papillary adenocarcinoma with
micropapillary features.
27,28
Their long time survival is more favorable than that of the common variety of invasive ovarian serous
papillary carcinomas.
29–31
While the precursor of the low-grade
194 L Deligdisch
serous papillary carcinoma seems to be the serous borderline ovarian
tumor, the precursor of the more common high grade ovarian serous
carcinoma is to be searched in the subtle changes of the ovarian surface epithelium described as ovarian dysplasia.
CONCLUSIONS
The present knowledge of early ovarian carcinogenesis is quite limited as compared to that of other gynecologic malignancies. Despite
numerous ongoing studies, not much progress has been obtained in
the past decades in terms of early diagnosis of this highly lethal cancer. No prevention and no screening program are presently implemented. Only a minority of women are known to be at risk because
of genetic mutations while the majority of ovarian cancer patients
represent sporadic cases. Chemotherapy regimens offer longer
remission periods and are presently better tolerated than in the past.
However, the main task for the future is the discovery of preventive
measures and of diagnostic tools for early stage diagnosis.
Diagnosing and removing precursors of cancer by identifying dysplastic tissues obtained by biopsies and by cytologic screening for
cervical neoplasms, or by endometrial curettings for endometrial
hyperplasia, resulted in spectacular decreases in the morbidity and
mortality due to these cancers. Unfortunately, these models could
hardly be applied to ovarian cancer at the present time.
The progress made in the laparoscopic technology, the discovery
of reliable tumor markers, the identification of patients with genetic
risk, as well as patients with past histories of breast cancer, endometriosis, endometrial hyperplasia and neoplasia may contribute to
the early diagnosis and possibly to a systematic detection of precancerous changes of the ovaries.
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