Of all gynecologic malignancies, ovarian cancer continues to have thehighest mortality and is the most difficult to diagnose. In the United Statesfemale 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 significantsymptoms 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 beenassociated with aberrant, dysfunctional expression and/or mutation ofvarious 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 andclassified 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 distincthistologic entity in the World Health Organization (WHO) classification of ovariantumors since 1973 and is the most lethal ovarian neoplasm with an overall five yearsurvival of only 34% (Kennedy, 342). Clear cell adenocarcinoma, like most ovariancancers, originates from the ovarian epithelium which is a single layer of cells found onthe surface of the ovary.
Patients with ovarian clear cell adenocarcinoma are typicallyabove the age of 30 with a median of 54 which is similar to that of ovarian epithelialcancer in general. OCCA represents approximately 6% of ovarian cancers and bilateralovarian 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. Transformationfrom endometriosis to clear cell adenocarcinoma has been previously demonstrated insporadic cases but was not observed by Kennedy et al. Hypercalcemia occurs in asignificant percentage of patients with OCCA.
Patients with advanced disease are moretypically affected than patients with nonmetastatic disease. Patients with OCCA are alsomore likely to have Stage I disease than are patients with ovarian epithelial cancer ingeneral (Kennedy, 348). Histologic grade has been useful as an initial prognostic determinant in some studiesof epithelial cancers of the ovary. The grading of ovarian clear cell adenocarcinoma hasbeen problematic and is complicated by the multiplicity of histologic patterns found inthe same tumor. Similar problems have been found in attempted grading of clear celladenocarcinoma of the endometrium (Disaia, 176).
Despite these problems, tumorgrading has been attempted but has failed to demonstrate prognostic significance. However, collected data suggest that low mitotic activity and a predominance of clearcells may be favorable histologic features (Piver, 136). Risk factors for OCCA and ovarian cancer in general are much less clear than forother genital tumors with general agreement on two risk factors: nulliparity and familyhistory. There is a higher frequency of carcinoma in unmarried women and in marriedwomen with low parity. Gonadal dysgenesis in children is associated with a higher riskof developing ovarian cancer while oral contraceptives are associated with a decreasedrisk. Genetic and candidate host genes may be altered in susceptible families.
Amongthose currently under investigation is BRCA1 which has been associated with anincreased 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 celladenocarcinomas and they are generally indistinguishable from other epithelial ovariancarcinomas.
They could be cystic, solid, soft, or rubbery, and may also containhemorrhagic and mucinous areas (O’Donnell, 250). Microscopically, clear cellcarcinomas are characterized by the presence of variable proportions of clear and hobnailcells. The former contain abundant clear cytoplasm with often centrally located nuclei,while the latter show clear or pink cytoplasm and bizarre basal nuclei with atypicalcytoplasmic intraluminal projections. The cellular arrangement may be tubulo acinar,papillary, or solid, with the great majority displaying a mixture of these patterns. Thehobnail and clear cells predominate with tubular and solid forms, respectively (Barber,214).
Clear cell adenocarcinoma tissue fixed with alcohol shows a high cytoplasmicglycogen content which can be shown by means of special staining techniques. Abundant extracellular and rare intracellular neutral mucin mixed with sulfate andcarboxyl group is usually present. The clear cells are recognized histochemically andultrastructurally (short and blunt microvilli, intercellular tight junctions and desmosomes,free ribosomes, and lamellar endoplasmic reticulum). The ultrastructure of hobnail andclear cells resemble those of the similar cells seen in clear cell carcinomas of theremainder of the female genital tract (O’Brien, 254). A variation in patterns of histologyis seen among these tumors and frequently within the same one.
Whether both tubular components with hobnail cells and the solid part with clear cellsare required to establish a diagnosis or the presence of just one of the patterns issufficient has not been clearly established. Fortunately, most tumors exhibit a mixture ofthese components. Benign and borderline counterparts of clear cell ovarianadenocarcinomas are theoretical possibilities. Yoonessi et al reported that nodalmetastases could be found even when the disease appears to be grossly limited to thepelvis (Yoonessi, 296). Examination of retroperitoneal nodes is essential to allow formore factual staging and carefully planned adjuvant therapy. Surgery remains the backbone of treatment and generally consists of removal of theuterus, tubes and ovaries, possible partial omentectomy, and nodal biopsies.
Theeffectiveness and value of adjuvant radiotherapy and chemotherapy has not been clearlydemonstrated. Therefore, in patients with unilateral encapsulated lesions andhistologically proven uninvolvement of the contralateral ovary, omentum, and biopsiednodes, a case can be made for (a)no adjuvant therapy after complete surgical removaland (b) removal of only the diseased ovary in an occasional patient who may be youngand 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 possiblefollowed by pelvic radiotherapy (if residual disease is limited to the pelvis) orchemotherapy must be considered. The chemotherapeutic regimens generally involveadriamycin, alkylating agents, and cisPlatinum containing combinations (Barber, 442).
OCCA is of epithelial origin and often contains mixtures of other epithelial tumorssuch as serous, mucinous, and endometrioid. Clear cell adenocarcinoma is characterizedby large epithelial cells with abundant cytoplasm. Because these tumors sometimesoccur in association with endometriosis or endometrioid carcinoma of the ovary andresemble clear cell carcinoma of the endometrium, they are now thought to be ofmullerian duct origin and variants of endometrioid adenocarcinoma. Clear cell tumors ofthe ovary can be predominantly solid or cystic. In the solid neoplasm, the clear cells arearranged 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 make5-year survival highly unlikely (Altchek, 416). Some debate continues as to whether clear cell or mesonephroid carcinoma is aseparate clinicopathological entity with its own distinctive biologic behavior and naturalhistory or a histologic variant of endometrioid carcinoma. In an effort to characterizeclear cell adenocarcinoma, Jenison et al compared these tumors to the most common ofthe epithelial malignancies, the serous adenocarcinoma (SA).
Histologically determinedendometriosis was strikingly more common among patients with OCCA than with SA. Other observations by Jenison et al suggest that the biologic behavior of clear celladenocarcinoma differs from that of SA. They found Stage I tumors in 50% of theobserved patient population as well as a lower incidence of bilaterality in OCCA(Jenison, 67-69). Additionally, it appears that OCCA is characteristically larger thanSA, possibly explaining the greater frequency of symptoms and signs at presentation.
Risk FactorsThere is controversy regarding talc use causing ovarian cancer. Until recently, mosttalc powders were contaminated with asbestos. Conceptually, talcum powder on theperineum could reach the ovaries by absorption through the cervix or vagina. Sincetalcum powders are no longer contaminated with asbestos, the risk is probably no longerimportant (Barber, 200). The high fat content of whole milk, butter, and meat productshas been implicated with an increased risk for ovarian cancer in general.
The Centers for Disease Control compared 546 women with ovarian cancer to 4,228controls and reported that for women 20 to 54 years of age, the use of oralcontraceptives reduced the risk of ovarian cancer by 40% and the risk of ovarian cancerdecreased as the duration of oral contraceptive use increased. Even the use of oralcontraceptives for three months decreased the risk. The protective effect of oralcontraceptives is to reduce the relative risk to 0. 6 or to decrease the incidence of diseaseby 40%.
There is a decreased risk as high as 40% for women who have had four ormore children as compared to nulliparous women. There is an increase in the incidenceof ovarian cancer among nulliparous women and a decrease with increasing parity. The”incessant ovulation theory” proposes that continuous ovulation causes repeated traumato the ovary leading to the development of ovarian cancer. Incidentally, having two ormore abortions compared to never having had an abortion decreases one’s risk ofdeveloping ovarian cancer by 30% (Coppleson, 25-28). EtiologyIt is commonly accepted that cancer results from a series of genetic alterations thatdisrupt normal cellular growth and differentiation.
It has been proposed that geneticchanges causing cancer occur in two categories of normal cellular genes, proto-oncogenes and tumor suppressor genes. Genetic changes in proto-oncogenes facilitatethe transformation of a normal cell to a malignant cell by production of an altered oroverexpressed gene product. Such genetic changes include mutation, translocation, oramplification of proto-oncogenes Tumor suppressor genes are proposed to preventcancer. Inactivation or loss of these genes contributes to development of cancer by thelack of a functional gene product. This may require mutations in both alleles of a tumorsuppressor gene.
These genes function as regulatory inhibitors of cell proliferation, suchas a DNA transcription factor, or a cell adhesion molecule. Loss of these functionscould result in abnormal cell division or gene expression, or increased ability of cells intissues to detach. Cancer such as OCCA most likely results from the dynamic interactionof 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. Before1970, familial ovarian cancer had been reported in only five families. A familial cancerregistry was established at Roswell Park Cancer Institute in 1981 to document thenumber of cases occurring in the United States and to study the mode of inheritance.
Ifa genetic autosomal dominant transmission of the disease can be established, counselingfor prophylactic oophorectomy at an appropriate age may lead to a decrease in the deathrate from ovarian cancer in such families. The registry at Roswell Park reported 201 cases of ovarian cancer in 94 families in1984. 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 casesof 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 asignificantly younger age than the non-inherited form. Cytogenetic investigations of sporadic (non-inherited) ovarian tumors have revealedfrequent alterations of chromosomes 1,3,6, and 11. Many proto-oncogenes have beenmapped to these chromosomes, and deletions of segments of chromosomes (particularly3p 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 ofdisease 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 mutationshave been identified in the tumor suppressor gene p53 located on chromosome17p13. Deletions of chromosome 17q have been reported in sporadic ovarian tumors suggestinga general involvement of this region in ovarian tumor biology. Allelic loss of MYB andESR genes map on chromosome 6q near the provisional locus for FUCA2, the locus fora-L-fucosidase in serum. Low activity of a-L-fucosidase in serum is more prevalent inovarian cancer patients.
This suggests that deficiency of a-L-fucosidase activity in serummay be a hereditary condition associated with increased risk for developing ovariancancer. This together with cytogenetic data of losses of 6q and the allelic losses at 6qpoint to the potential importance of chromosome 6q in hereditary ovarian cancer(Altchek, 208-212). Activation of normal proto-oncogenes by either mutation, translocation, or geneamplification to produce altered or overexpressed products is believed to play animportant 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 ovariantumors. However, the significance remains to be determined.
It is controversial as towhether overexpression of the HER-2/neu gene in ovarian cancer is associated with poorprognosis. In addition to studying proto-oncogenes in tumors, it may be beneficial toinvestigate proto-oncogenes in germ-line DNA from members of families with historiesof ovarian cancer (Barber, 323-324). It is questionable whether inheritance or rarealleles of the H-RAS proto-oncogene may be linked to susceptibility to ovarian cancers. Diagnosis and TreatmentThe early diagnosis of ovarian cancer is a matter of chance and not a triumph ofscientific approach.
In most cases, the finding of a pelvic mass is the only availablemethod of diagnosis, with the exception of functioning tumors which may manifestendocrine even with minimal ovarian enlargement. Symptomatology includes vagueabdominal discomfort, dyspepsia, increased flatulence, sense of bloating, particularlyafter ingesting food, mild digestive disturbances, and pelvic unrest which may be presentfor 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 sonographyand CA 125 have had an increasing number of false positive examinations. Pelvicfindings are often minimal and not helpful in making a diagnosis.
However, combinedwith a high index of suspicion, this may alert the physician to the diagnosis. These pelvic signs include:Mass in the ovarian areaRelative immobility due to fixation of adhesionsIrregularity of the tumorShotty consistency with increased firmnessTumors in the cul-de-sac described as a handful of knucklesRelative insensitivity of the massIncreasing size under observationBilaterality (70% for ovarian carcinoma versus 5% for benign cases) (Barber, 136)Tumor markers have been particularly useful in monitoring treatment, however, themarkers have and will probably always have a disadvantage in identifying an earlytumor. To date, only two, human gonadotropin (HCG) and alpha fetoprotein, areknown to be sensitive and specific. The problem with tumor markers as a means ofmaking 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 toolsfor diagnosing malignant ovarian tumors. Yamada et al attempted to develop a MAbthat can differentiate cells with early malignant change from adjacent benign tumor cellsin cases of borderline malignancy. They developed MAb 12C3 by immunizing mice witha cell line derived from a human ovarian tumor. The antibody reacted with humanovarian carcinomas rather than with germ cell tumors.
MAb 12C3 stained 67. 7% ofovarian epithelial malignancies, but exhibited an extremely low reactivity with othermalignancies. MAb 12C3 detected a novel antigen whose distribution in normal tissue isrestricted. According to Yamada et al, MAb 12C3 will serve as a powerful new tool forthe 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 theurinary gonadotropin peptide (UCP) and the collagen-stimulating factor have beenadded. Although the tumor markers have a low specificity and sensitivity, they are oftenused in screening for ovarian cancer.
A new tumor marker CA125-2 has greaterspecificity than CA125. In general, tumor markers have a very limited role in screeningfor 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 initiallydeveloped: the peritoneal cavity. Even with early localized cancer, lymph nodemetastases are not rare in the pelvic or aortic areas. In most of the cases, death is due tointraperitoneal proliferation, ascites, protein loss and cachexia.
The concept ofdebulking or cytoreductive surgery is currently the dominant concept in treatment. The first goal in debulking surgery is inhibition of debulking surgery is inhibition ofthe vicious cycle of malnutrition, nausea, vomiting, and dyspepsia commonly found inpatients with mid to advanced stage disease. Cytoreductive surgery enhances theefficiency of chemotherapy as the survival curve of the patients whose largest residualmass size was, after surgery, below the 1. 5 cm limit is the same as the curve of thepatients 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 facewhen treating ovarian cancers. The debulking of very large metastatic masses makes nosense from the oncologic perspective. As for extrapelvic masses the debulking, even ifmore 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 junctionresection. That means that stages IIB and IIC and stages IIIA and IIB are the only trueindications for extrapelvic cytoreductive surgery. Colectomy, ileectomy, splenectomy,segmental hepatectomy are only exceptionally indicated if they allow one to perform areal optimal resection.
The standard cytoreductive surgery is the total hysterectomy withbilateral salpingoophorectomy. This surgery may be done with aortic and pelvic lymphnode 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 ofovarian cancer was attempted more than three decades ago. However, it has only beenwithin the last ten years that a firm basis for this method of drug delivery has becomeestablished. The essential goal is to expose the tumor to higher concentrations of drugfor longer periods of time than is possible with systemic drug delivery.
Several agentshave been examined for their efficacy, safety and pharmacokinetic advantage whenadministered via the peritoneal route. Cisplatin has undergone the most extensive evaluation for regional delivery. Cisplatinreaches the systemic compartment in significant concentrations when it is administeredintraperitoneally. The dose limiting toxicity of intraperitoneally administered cisplatin isnephrotoxicity, neurotoxicity and emesis.
The depth of penetration of cisplatin into theperitoneal lining and tumor following regional delivery is only 1 to 2 mm from thesurface which limits its efficacy. Thus, the only patients with ovarian cancer who wouldlikely benefit would be those with very small residual tumor volumes. Overall,approximately 30 to 40% of patients with small volume residual ovarian cancer havebeen shown to demonstrate an objective clinical response to cisplatin-based locallyadministered therapy with 20 to 30% of patients achieving a surgically documentedcomplete response. As a general rule, patients whose tumors have demonstrated aninherent resistance to cisplatin following systemic therapy are not considered fortreatment 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, alternativeintraperitoneal treatment programs can be considered.
Other agents includemitoxantrone, and recombinant alpha-interpheron. Intraperitoneal mitoxanthone hasbeen shown to have definite activity in small volume residual platinum-refractory ovariancancer. Unfortunately, the dose limiting toxicity of the agent is abdominal pain andadhesion formation, possibly leading to bowel obstruction. Recent data suggests thelocal toxicity of mitoxanthone can be decreased considerably by delivering the agent inmicrodoses.
Ovarian tumors may have either intrinsic or acquired drug resistance. Manymechanisms of drug resistance have been described. Expression of the MDR1 gene thatencodes the drug efflux protein known as p-glycoprotein, has been shown to confer thecharacteristic multi-drug resistance to clones of some cancers. The most widelyconsidered definition of platinum response is response to first-line platinum treatmentand disease free interval. Primary platinum resistance may be defined as any progressionon treatment. Secondary platinum resistance is the absence of progression on primaryplatinum-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 ofboth the patient and physician. Retreatment with platinum therapy appears to offersignificant opportunity for clinical response and palliation but relatively little hope forlong-term cure. Paclitaxel (trade name: Taxol), a prototype of the taxanes, is cytotoxicto ovarian cancer. Approximately 20% of platinum failures respond to standard doses ofpaclitaxel.
Studies are in progress of dose intensification and intraperitonealadministration (Barber, 227-228). This class of drugs is now thought to represent anactive addition to the platinum analogs, either as primary therapy, in combination withplatinum, or as salvage therapy after failure of platinum. In advanced stages, there is suggestive evidence of partial responsiveness of OCCA toradiation as well as cchemotherapy, adriamycin, cytoxan, and cisPlatinum-containingcombinations (Yoonessi, 295). Radiation techniques include intraperitoneal radioactivegold or chromium phosphate and external beam therapy to the abdomen and pelvis. Therole of radiation therapy in treatment of ovarian canver has diminished in prominence asthe spread pattern of ovarian cancer and the normal tissue bed involved in the treatmentof this neoplasm make effective radiation therapy difficult.
When the residual diseaseafter laparotomy is bulky, radiation therapy is particularly ineffective. If postoperativeradiation is prescribed for a patient, it is important that theentire abdomen and pelvis areoptimally treated to elicit a response from the tumor (Sharp, 278-280). In the last few decades, the aggressive attempt to optimize the treatment ofovarian clear cell adenocarcinoma and ovarian cancer in general has seen remarkableimprovements in the response rates of patients with advanced stage cancer withoutdramatically improving long-term survival. The promises of new drugs with activitywhen 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 aneasily treatable disease. BibliographyAltchek, A.
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