Ovarian Cancer Essay, Research Paper
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). 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