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

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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