Ovarian Cancer

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.

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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 …