Ovarian Cancer

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Ovarian Cancer

Of all gynecologic malignancies, ovarian cancer continues to have the highest
mortality and is the most difficult to diagnose. In the United States female
population, ovarian cancer ranks fifth in absolute mortality among cancer
related deaths (13,000/yr). In most reported cases, ovarian cancer, when first
diagnosed is in stages III or IV in about 60 to 70% of patients which further
complicates treatment of the disease (Barber, 3). Early detection in ovarian
cancer is hampered by the lack of appropriate tumor markers and clinically, most
patients fail to develop significant symptoms until they reach advanced stage
disease. The characteristics of ovarian cancer have been studied in primary
tumors and in established ovarian tumor cell lines which provide a reproducible
source of tumor material. Among the major clinical problems of ovarian cancer,
malignant progression, rapid emergence of drug resistance, and associated
cross-resistance remain unresolved. Ovarian cancer has a high frequency of
metastasis yet generally remains localized within the peritoneal cavity. Tumor
development has been associated with aberrant, dysfunctional expression and/or
mutation of various genes. This can include oncogene overexpression,
amplification or mutation, aberrant tumor suppressor expression or mutation.

Also, subversion of host antitumor immune responses may play a role in the
pathogenesis of cancer (Sharp, 77). Ovarian clear cell adenocarcinoma was first
described by Peham in 1899 as "hypernephroma of the ovary" because of
its resemblance to renal cell carcinoma. By 1939, Schiller noted a histologic
similarity to mesonephric tubules and classified these tumors as "mesonephromas."

In 1944, Saphir and Lackner described two cases of "hypernephroid carcinoma
of the ovary" and proposed "clear cell" adenocarcinoma as an
alternative term. Clear cell tumors of the ovary are now generally considered to
be of mullerian and in the genital tract of mullerian origin. A number of
examples of clear cell adenocarcinoma have been reported to arise from the
epithelium of an endometriotic cyst (Yoonessi, 289). Occasionally, a renal cell
carcinoma metastasizes to the ovary and may be confused with a primary clear
cell adenocarcinoma. Ovarian clear cell adenocarcinoma (OCCA) has been
recognized as a distinct histologic entity in the World Health Organization
(WHO) classification of ovarian tumors since 1973 and is the most lethal ovarian
neoplasm with an overall five year survival of only 34% (Kennedy, 342). Clear
cell adenocarcinoma, like most ovarian cancers, originates from the ovarian
epithelium which is a single layer of cells found on the surface of the ovary.

Patients with ovarian clear cell adenocarcinoma are typically above the age of

30 with a median of 54 which is similar to that of ovarian epithelial cancer in
general. OCCA represents approximately 6% of ovarian cancers and bilateral
ovarian involvement occurs in less that 50% of patients even in advanced cases.

The association of OCCA and endometriosis is well documented (De La Cuesta,

243). This was confirmed by Kennedy et al who encountered histologic or
intraoperative evidence of endometriosis in 45% of their study patients.

Transformation from endometriosis to clear cell adenocarcinoma has been
previously demonstrated in sporadic cases but was not observed by Kennedy et al.

Hypercalcemia occurs in a significant percentage of patients with OCCA. Patients
with advanced disease are more typically affected than patients with
nonmetastatic disease. Patients with OCCA are also more likely to have Stage I
disease than are patients with ovarian epithelial cancer in general (Kennedy,

348). Histologic grade has been useful as an initial prognostic determinant in
some studies of epithelial cancers of the ovary. The grading of ovarian clear
cell adenocarcinoma has been problematic and is complicated by the multiplicity
of histologic patterns found in the same tumor. Similar problems have been found
in attempted grading of clear cell adenocarcinoma of the endometrium (Disaia,

176). Despite these problems, tumor grading has been attempted but has failed to
demonstrate prognostic significance. However, collected data suggest that low
mitotic activity and a predominance of clear cells may be favorable histologic
features (Piver, 136). Risk factors for OCCA and ovarian cancer in general are
much less clear than for other genital tumors with general agreement on two risk
factors: nulliparity and family history. There is a higher frequency of
carcinoma in unmarried women and in married women with low parity. Gonadal
dysgenesis in children is associated with a higher risk of developing ovarian
cancer while oral contraceptives are associated with a decreased risk. Genetic
and candidate host genes may be altered in susceptible families. Among those
currently under investigation is BRCA1 which has been associated with an
increased susceptibility to breast cancer. Approximately 30% of ovarian
adenocarcinomas express high levels of HER-2/neu oncogene which correlates with
a poor prognosis (Altcheck, 375-376).

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