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,

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). Mutations in host tumor suppresser gene p53 are