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). Mutations in host tumor suppresser gene
p53 are found in 50% of ovarian carcinomas. There also appears to be a racial
predilection, as the vast majority of cases are seen in Caucasians (Yoonessi,
295). Considerable variation exists in the gross appearance of ovarian clear
cell adenocarcinomas and they are generally indistinguishable from other
epithelial ovarian carcinomas. They could be cystic, solid, soft, or rubbery,
and may also contain hemorrhagic and mucinous areas (O'Donnell, 250).
Microscopically, clear cell carcinomas are characterized by the presence of
variable proportions of clear and hobnail cells. The former contain abundant
clear cytoplasm with often centrally located nuclei, while the latter show clear
or pink cytoplasm and bizarre basal nuclei with atypical cytoplasmic
intraluminal projections. The cellular arrangement may be tubulo acinar,
papillary, or solid, with the great majority displaying a mixture of these
patterns. The hobnail and clear cells predominate with tubular and solid forms,
respectively (Barber, 214). Clear cell adenocarcinoma tissue fixed with alcohol
shows a high cytoplasmic glycogen content which can be shown by means of special
staining techniques. Abundant extracellular and rare intracellular neutral mucin
mixed with sulfate and carboxyl group is usually present. The clear cells are
recognized histochemically and ultrastructurally (short and blunt microvilli,
intercellular tight junctions and desmosomes, free ribosomes, and lamellar
endoplasmic reticulum). The ultrastructure of hobnail and clear cells resemble
those of the similar cells seen in clear cell carcinomas of the remainder of the
female genital tract (O'Brien, 254). A variation in patterns of histology is
seen among these tumors and frequently within the same one. Whether both tubular
components with hobnail cells and the solid part with clear cells are required
to establish a diagnosis or the presence of just one of the patterns is
sufficient has not been clearly established. Fortunately, most tumors exhibit a
mixture of these components. Benign and borderline counterparts of clear cell
ovarian adenocarcinomas are theoretical possibilities. Yoonessi et al reported
that nodal metastases could be found even when the disease appears to be grossly
limited to the pelvis (Yoonessi, 296). Examination of retroperitoneal nodes is
essential to allow for more factual staging and carefully planned adjuvant
therapy. Surgery remains the backbone of treatment and generally consists of
removal of the uterus, tubes and ovaries, possible partial omentectomy, and
nodal biopsies. The effectiveness and value of adjuvant radiotherapy and
chemotherapy has not been clearly demonstrated. Therefore, in patients with
unilateral encapsulated lesions and histologically proven uninvolvement of the
contralateral ovary, omentum, and biopsied nodes, a case can be made for (a)no
adjuvant therapy after complete surgical removal and (b) removal of only the
diseased ovary in an occasional patient who may be young and desirous of
preserving her reproductive capacity (Altchek, 97). In the more adv- anced
stages, removal of the uterus, ovaries, omentum, and as much tumor as possible
followed by pelvic radiotherapy (if residual disease is limited to the pelvis)
or chemotherapy must be considered. The chemotherapeutic regimens generally
involve adriamycin, alkylating agents, and cisPlatinum containing combinations
(Barber, 442). OCCA is of epithelial origin and often contains mixtures of other
epithelial tumors such as serous, mucinous, and endometrioid. Clear cell
adenocarcinoma is characterized by large epithelial cells with abundant
cytoplasm. Because these tumors sometimes occur in association with
endometriosis or endometrioid carcinoma of the ovary and resemble clear cell
carcinoma of the endometrium, they are now thought to be of mullerian duct
origin and variants of endometrioid adenocarcinoma. Clear cell tumors of the
ovary can be predominantly solid or cystic. In the solid neoplasm, the clear
cells are arranged in sheets or tubules. In the cystic form, the neoplastic
cells line the spaces. Five-year survival is approximately 50% when these tumors
are confined to the ovaries, but these tumors tend to be aggressive and spread
beyond the ovary which tends to make 5-year survival highly unlikely (Altchek,
416). Some debate continues as to whether clear cell or mesonephroid carcinoma
is a separate clinicopathological entity with its own distinctive biologic
behavior and natural history or a histologic variant of endometrioid carcinoma.
In an effort to characterize clear cell adenocarcinoma, Jenison et al compared
these tumors to the most common of the epithelial malignancies, the serous
adenocarcinoma (SA). Histologically determined endometriosis was strikingly more
common among patients with OCCA than with SA. Other observations by Jenison et
al suggest that the biologic behavior of clear cell adenocarcinoma differs from
that of SA. They found Stage I tumors in 50% of the observed patient population
as well as a lower incidence of bilaterality in OCCA (Jenison, 67-69).
Additionally, it appears that OCCA is characteristically larger than SA,
possibly explaining the greater frequency of symptoms and signs at presentation.
Risk Factors There is controversy regarding talc use causing ovarian cancer.
Until recently, most talc powders were contaminated with asbestos. Conceptually,
talcum powder on the perineum could reach the ovaries by absorption through the
cervix or vagina. Since talcum powders are no longer contaminated with asbestos,
the risk is probably no longer important (Barber, 200). The high fat content of
whole milk, butter, and meat products has been implicated with an increased risk
for ovarian cancer in general. The Centers for Disease Control compared 546
women with ovarian cancer to 4,228 controls and reported that for women 20 to 54
years of age, the use of oral contraceptives reduced the risk of ovarian cancer
by 40% and the risk of ovarian cancer decreased as the duration of oral
contraceptive use increased. Even the use of oral contraceptives for three
months decreased the risk. The protective effect of oral contraceptives is to
reduce the relative risk to 0.6 or to decrease the incidence of disease by 40%.
There is a decreased risk as high as 40% for women who have had four or more
children as compared to nulliparous women. There is an increase in the incidence
of ovarian cancer among nulliparous women and a decrease with increasing parity.
The "incessant ovulation theory" proposes that continuous ovulation
causes repeated trauma to the ovary leading to the development of ovarian
cancer. Incidentally, having two or more abortions compared to never having had
an abortion decreases one's risk of developing ovarian cancer by 30% (Coppleson,
25-28). Etiology It is commonly accepted that cancer results from a series of
genetic alterations that disrupt normal cellular growth and differentiation. It
has been proposed that genetic changes causing cancer occur in two categories of
normal cellular genes, proto- oncogenes and tumor suppressor genes. Genetic
changes in proto-oncogenes facilitate the transformation of a normal cell to a
malignant cell by production of an altered or overexpressed gene product. Such
genetic changes include mutation, translocation, or amplification of proto-oncogenes
Tumor suppressor genes are proposed to prevent cancer. Inactivation or loss of
these genes contributes to development of cancer by the lack of a functional
gene product. This may require mutations in both alleles of a tumor suppressor
gene. These genes function as regulatory inhibitors of cell proliferation, such
as a DNA transcription factor, or a cell adhesion molecule. Loss of these
functions could result in abnormal cell division or gene expression, or
increased ability of cells in tissues to detach. Cancer such as OCCA most likely
results from the dynamic interaction of several genetically altered proto-oncogenes
and tumor suppressor genes (Piver, 64- 67). Until recently, there was little
evidence that the origin of ovarian was genetic. Before 1970, familial ovarian
cancer had been reported in only five families. A familial cancer registry was
established at Roswell Park Cancer Institute in 1981 to document the number of
cases occurring in the United States and to study the mode of inheritance. If a
genetic autosomal dominant transmission of the disease can be established,
counseling for prophylactic oophorectomy at an appropriate age may lead to a
decrease in the death rate from ovarian cancer in such families. The registry at
Roswell Park reported 201 cases of ovarian cancer in 94 families in 1984. From
1981 through 1991, 820 families and 2946 cases had been observed. Familial
ovarian cancer is not a rare occurrence and may account for 2 to 5% of all cases
of ovarian cancer. Three conditions that are associated with familial ovarian
cancer are (1) site specific, the most common form, which is restricted to
ovarian cancer, and (2) breast/ovarian cancer with clustering of ovarian and
breast cases in extended pedigrees (Altchek, 229-230). One characteristic of
inherited ovarian cancer is that it occurs at a significantly younger age than
the non-inherited form. Cytogenetic investigations of sporadic (non-inherited)
ovarian tumors have revealed frequent alterations of chromosomes 1,3,6, and 11.
Many proto-oncogenes have been mapped to these chromosomes, and deletions of
segments of chromosomes (particularly 3p and 6q) in some tumors is consistent
with a role for loss of tumor suppressor genes. Recently, a genetic linkage
study of familial breast/ovary cancer suggested linkage of disease
susceptibility with the RH blood group locus on chromosome 1p. Allele loss
involving chromosomes 3p and 6q as well as chromosomes 11p, 13q, and 17 have
been frequently observed in ovarian cancers. Besides allele loss, point
mutations have been identified in the tumor suppressor gene p53 located on
chromosome17p13. Deletions of chromosome 17q have been reported in sporadic
ovarian tumors suggesting a general involvement of this region in ovarian tumor
biology. Allelic loss of MYB and ESR genes map on chromosome 6q near the
provisional locus for FUCA2, the locus for a-L-fucosidase in serum. Low activity
of a-L-fucosidase in serum is more prevalent in ovarian cancer patients. This
suggests that deficiency of a-L-fucosidase activity in serum may be a hereditary
condition associated with increased risk for developing ovarian cancer. This
together with cytogenetic data of losses of 6q and the allelic losses at 6q
point to the potential importance of chromosome 6q in hereditary ovarian cancer
(Altchek, 208-212). Activation of normal proto-oncogenes by either mutation,
translocation, or gene amplification to produce altered or overexpressed
products is believed to play an important role in the development of ovarian
tumors. Activation of several proto- oncogenes (particularly K-RAS, H-RAS, c-MYC,
and HER-2/neu) occurs in ovarian tumors. However, the significance remains to be
determined. It is controversial as to whether overexpression of the HER-2/neu
gene in ovarian cancer is associated with poor prognosis. In addition to
studying proto-oncogenes in tumors, it may be beneficial to investigate proto-oncogenes
in germ-line DNA from members of families with histories of ovarian cancer
(Barber, 323-324). It is questionable whether inheritance or rare alleles of the
H-RAS proto-oncogene may be linked to susceptibility to ovarian cancers.
Diagnosis and Treatment The early diagnosis of ovarian cancer is a matter of
chance and not a triumph of scientific approach. In most cases, the finding of a
pelvic mass is the only available method of diagnosis, with the exception of
functioning tumors which may manifest endocrine even with minimal ovarian
enlargement. Symptomatology includes vague abdominal discomfort, dyspepsia,
increased flatulence, sense of bloating, particularly after ingesting food, mild
digestive disturbances, and pelvic unrest which may be present for several
months before diagnosis (Sharp, 161-163). There are a great number of imaging
techniques that are available. Ultrasounds, particularly vaginal ultrasound, has
increased the rate of pick-up of early lesions, particularly when the color
Doppler method is used. Unfortunately, vaginal sonography and CA 125 have had an
increasing number of false positive examinations. Pelvic findings are often
minimal and not helpful in making a diagnosis. However, combined with a high
index of suspicion, this may alert the physician to the diagnosis. These pelvic
signs include: Mass in the ovarian area Relative immobility due to fixation of
adhesions Irregularity of the tumor Shotty consistency with increased firmness
Tumors in the cul-de-sac described as a handful of knuckles Relative
insensitivity of the mass Increasing size under observation Bilaterality (70%
for ovarian carcinoma versus 5% for benign cases) (Barber, 136) Tumor markers
have been particularly useful in monitoring treatment, however, the markers have
and will probably always have a disadvantage in identifying an early tumor. To
date, only two, human gonadotropin (HCG) and alpha fetoprotein, are known to be
sensitive and specific. The problem with tumor markers as a means of making a
diagnosis is that a tumor marker is developed from a certain volume of tumor. By
that time it is no longer an early but rather a biologically late tumor (Altchek,
292). Many reports have described murine monoclonal antibodies (MAbs) as
potential tools for diagnosing malignant ovarian tumors. Yamada et al attempted
to develop a MAb that can differentiate cells with early malignant change from
adjacent benign tumor cells in cases of borderline malignancy. They developed
MAb 12C3 by immunizing mice with a cell line derived from a human ovarian tumor.
The antibody reacted with human ovarian carcinomas rather than with germ cell
tumors. MAb 12C3 stained 67.7% of ovarian epithelial malignancies, but exhibited
an extremely low reactivity with other malignancies. MAb 12C3 detected a novel
antigen whose distribution in normal tissue is restricted. According to Yamada
et al, MAb 12C3 will serve as a powerful new tool for the histologic detection
of early malignant changes in borderline epithelial neoplasms. MAb 12C3 may also
be useful as a targeting agent for cancer chemotherapy (Yamada, 293-294).
Currently there are several serum markers that are available to help make a
diagnosis. These include CA 125, CEA, DNB/70K, LASA-P, and serum inhibin.
Recently the urinary gonadotropin peptide (UCP) and the collagen-stimulating
factor have been added. Although the tumor markers have a low specificity and
sensitivity, they are often used in screening for ovarian cancer. A new tumor
marker CA125-2 has greater specificity than CA125. In general, tumor markers
have a very limited role in screening for ovarian cancer. The common epithelial
cancer of the ovary is unique in killing the patient while being, in the vast
majority of the cases, enclosed in the anatomical area where it initially
developed: the peritoneal cavity. Even with early localized cancer, lymph node
metastases are not rare in the pelvic or aortic areas. In most of the cases,
death is due to intraperitoneal proliferation, ascites, protein loss and
cachexia. The concept of debulking or cytoreductive surgery is currently the
dominant concept in treatment. The first goal in debulking surgery is inhibition
of debulking surgery is inhibition of the vicious cycle of malnutrition, nausea,
vomiting, and dyspepsia commonly found in patients with mid to advanced stage
disease. Cytoreductive surgery enhances the efficiency of chemotherapy as the
survival curve of the patients whose largest residual mass size was, after
surgery, below the 1.5 cm limit is the same as the curve of the patients whose
largest metastatic lesions were below the 1.5 cm limit at the outset (Altchek,
422-424). The aggressiveness of the debulking surgery is a key question surgeons
must face when treating ovarian cancers. The debulking of very large metastatic
masses makes no sense from the oncologic perspective. As for extrapelvic masses
the debulking, even if more acceptable, remains full of danger and exposes the
patient to a heavy handicap. For these reasons the extra-genital resections have
to be limited to lymphadenectomy, omentectomy, pelvic abdominal peritoneal
resections and rectosigmoid junction resection. That means that stages IIB and
IIC and stages IIIA and IIB are the only true indications for extrapelvic
cytoreductive surgery. Colectomy, ileectomy, splenectomy, segmental hepatectomy
are only exceptionally indicated if they allow one to perform a real optimal
resection. The standard cytoreductive surgery is the total hysterectomy with
bilateral salpingoophorectomy. This surgery may be done with aortic and pelvic
lymph node sampling, omentectomy, and, if necessary, resection of the
rectosigmoidal junction (Barber. 182-183). The concept of administering drugs
directly into the peritoneal cavity as therapy of ovarian cancer was attempted
more than three decades ago. However, it has only been within the last ten years
that a firm basis for this method of drug delivery has become established. The
essential goal is to expose the tumor to higher concentrations of drug for
longer periods of time than is possible with systemic drug delivery. Several
agents have been examined for their efficacy, safety and pharmacokinetic
advantage when administered via the peritoneal route. Cisplatin has undergone
the most extensive evaluation for regional delivery. Cisplatin reaches the
systemic compartment in significant concentrations when it is administered
intraperitoneally. The dose limiting toxicity of intraperitoneally administered
cisplatin is nephrotoxicity, neurotoxicity and emesis. The depth of penetration
of cisplatin into the peritoneal lining and tumor following regional delivery is
only 1 to 2 mm from the surface which limits its efficacy. Thus, the only
patients with ovarian cancer who would likely benefit would be those with very
small residual tumor volumes. Overall, approximately 30 to 40% of patients with
small volume residual ovarian cancer have been shown to demonstrate an objective
clinical response to cisplatin-based locally administered therapy with 20 to 30%
of patients achieving a surgically documented complete response. As a general
rule, patients whose tumors have demonstrated an inherent resistance to
cisplatin following systemic therapy are not considered for treatment with
platinum-based intraperitoneal therapy (Altchek, 444-446). In patients with
small volume residual disease at the time of second look laparotomy, who have
demonstrated inherent resistance to platinum-based regimens, alternative
intraperitoneal treatment programs can be considered. Other agents include
mitoxantrone, and recombinant alpha-interpheron. Intraperitoneal mitoxanthone
has been shown to have definite activity in small volume residual
platinum-refractory ovarian cancer. Unfortunately, the dose limiting toxicity of
the agent is abdominal pain and adhesion formation, possibly leading to bowel
obstruction. Recent data suggests the local toxicity of mitoxanthone can be
decreased considerably by delivering the agent in microdoses. Ovarian tumors may
have either intrinsic or acquired drug resistance. Many mechanisms of drug
resistance have been described. Expression of the MDR1 gene that encodes the
drug efflux protein known as p-glycoprotein, has been shown to confer the
characteristic multi-drug resistance to clones of some cancers. The most widely
considered definition of platinum response is response to first-line platinum
treatment and disease free interval. Primary platinum resistance may be defined
as any progression on treatment. Secondary platinum resistance is the absence of
progression on primary platinum-based therapy but progression at the time of
platinum retreatment for relapse (Sharp, 205-207). Second-line chemotherapy for
recurrent ovarian cancer is dependent on preferences of both the patient and
physician. Retreatment with platinum therapy appears to offer significant
opportunity for clinical response and palliation but relatively little hope for
long-term cure. Paclitaxel (trade name: Taxol), a prototype of the taxanes, is
cytotoxic to ovarian cancer. Approximately 20% of platinum failures respond to
standard doses of paclitaxel. Studies are in progress of dose intensification
and intraperitoneal administration (Barber, 227-228). This class of drugs is now
thought to represent an active addition to the platinum analogs, either as
primary therapy, in combination with platinum, or as salvage therapy after
failure of platinum. In advanced stages, there is suggestive evidence of partial
responsiveness of OCCA to radiation as well as cchemotherapy, adriamycin,
cytoxan, and cisPlatinum-containing combinations (Yoonessi, 295). Radiation
techniques include intraperitoneal radioactive gold or chromium phosphate and
external beam therapy to the abdomen and pelvis. The role of radiation therapy
in treatment of ovarian canver has diminished in prominence as the spread
pattern of ovarian cancer and the normal tissue bed involved in the treatment of
this neoplasm make effective radiation therapy difficult. When the residual
disease after laparotomy is bulky, radiation therapy is particularly
ineffective. If postoperative radiation is prescribed for a patient, it is
important that theentire abdomen and pelvis are optimally treated to elicit a
response from the tumor (Sharp, 278-280). In the last few decades, the
aggressive attempt to optimize the treatment of ovarian clear cell
adenocarcinoma and ovarian cancer in general has seen remarkable improvements in
the response rates of patients with advanced stage cancer without dramatically
improving long-term survival. The promises of new drugs with activity when
platinum agents fail is encouraging and fosters hope that, in the decades to
come, the endeavors of surgical and pharmacoogical research will make ovarian
cancer an easily treatable disease.

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