Ovarian Cancer Essay Example
Ovarian Cancer Essay Example

Ovarian Cancer Essay Example

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  • Pages: 16 (4211 words)
  • Published: February 1, 2019
  • Type: Case Analysis
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Diagnosing ovarian cancer is the most challenging and has the highest fatality rate among all gynecologic malignancies. In the United States, it ranks fifth in cancer-related deaths for women, with an annual mortality rate of 13,000 (Barber, 3). The majority of cases are detected at stages III or IV, posing treatment complications for about 60 to 70% of patients.

The lack of effective tumor markers hinders early detection of ovarian cancer, as patients typically do not exhibit noticeable symptoms until the disease has advanced. Extensive research on primary tumors and established ovarian tumor cell lines has provided a dependable source of tumor material. Ovarian cancer presents considerable clinical challenges, such as malignant progression, rapid development of drug resistance, and associated cross-resistance. While this form of cancer frequently metastasizes to other body regions, it primarily remains confined within the peritoneal ca


vity. Abnormal gene expression or mutation has been linked to tumor formation.

This can involve oncogene overexpression, amplification, or mutation, abnormal tumor suppressor expression or mutation. In addition, the subversion of the host's antitumor immune responses may contribute to the development of cancer (Sharp, 77). Ovarian clear cell adenocarcinoma was initially identified by Peham in 1899 as "hypernephroma of the ovary" due to its resemblance to renal cell carcinoma. By 1939, Schiller observed a histological similarity to mesonephric tubules and classified these tumors as "mesonephros." In 1944, Saphir and Lackner reported two cases of "hypernephroid carcinoma of the ovary" and suggested using "clear cell" adenocarcinoma as an alternative term.

Clear cell tumors of the ovary are believed to have originated from the mullerian and genital tract of mullerian origin. Clear cell adenocarcinoma has been known to develop from th

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epithelium of an endometriotic cyst (Yoonessi, 289). Occasionally, a primary clear cell adenocarcinoma may be mistaken for metastasized renal cell carcinoma in the ovary. Ovarian clear cell adenocarcinoma (OCCA) has been classified as a separate histologic entity by the World Health Organization (WHO) since 1973 and is extremely lethal, with only a 34% five-year survival rate (Kennedy, 342). Similar to other ovarian cancers, clear cell adenocarcinoma originates from the ovarian epithelium - a single layer of cells on the surface of the ovary.

Patients with ovarian clear cell adenocarcinoma (OCCA) typically have a median age of 54, which is similar to the age range of ovarian epithelial cancer in general. OCCA accounts for approximately 6% of all ovarian cancers. In less than 50% of cases, even in advanced stages, patients with OCCA have bilateral ovarian involvement. The connection between OCCA and endometriosis has been firmly established, as confirmed by De La Cuesta (243) and Kennedy et al. According to Kennedy et al's study, 45% of patients showed histologic or intraoperative evidence of endometriosis.Although sporadic cases have demonstrated a transformation from endometriosis to clear cell adenocarcinoma, this transformation was not observed by Kennedy et al.Furthermore, a significant proportion of OCCA patients experience hypercalcemia.
Kennedy et al discovered that 45% of patients in their study showed signs suggesting a connection to endometriosis. However, there were no instances of endometriosis transforming into clear cell adenocarcinoma during their investigation. It is worth noting that a significant percentage of individuals diagnosed with OCCA also experience hypercalcemia.

Patients with advanced disease are more commonly affected compared to patients with nonmetastatic disease. OCCA patients are also more likely to have Stage I disease compared to

patients with ovarian epithelial cancer in general (Kennedy, 348).

Histologic grade has been useful in determining prognosis in some studies of ovarian epithelial cancers. Grading clear cell adenocarcinoma of the ovary and endometrium has been challenging due to the multiple histologic patterns present in the same tumor (Disaia, 176). Despite these challenges, attempts have been made to grade tumors but have not yielded significant prognostic value.

According to collected data, certain histologic features such as a low number of dividing cells and predominance of clear cells may be considered favorable (Piver, 136). Risk factors for ovarian clear cell adenocarcinoma (OCCA) and ovarian cancer in general are not as well-defined compared to other genital tumors. However, there is widespread agreement on two common risk factors: nulliparity and family history.

Carcinoma occurs more frequently in women who have never given birth and married women with few children. Children with gonadal dysgenesis have a higher chance of developing ovarian cancer, while the use of oral contraceptives is associated with reduced risk. In susceptible families, genetic and candidate host genes may undergo alterations.

The investigation of BRCA1 is currently underway due to its association with an increased risk of breast cancer. Around 30% of ovarian adenocarcinomas express high levels of the HER-2/neu oncogene, which is connected to a poor prognosis (Altcheck, 375-376). Mutations in the p53 tumor suppressor gene are present in half of ovarian carcinomas. Ovarian clear cell adenocarcinomas have various appearances and can be challenging to differentiate from other types of epithelial ovarian carcinomas. Interestingly, this specific type of cancer predominantly affects Caucasians, suggesting a racial predisposition (Yoonessi, 295).

They have different characteristics such as cystic, solid, soft, or rubbery texture, and

can also contain areas with hemorrhagic and mucinous components (O'Donnell, 250). Under a microscope, clear cell carcinomas are identified by the presence of a combination of clear and hobnail cells. Clear cells have abundant clear cytoplasm with centrally located nuclei, while hobnail cells have clear or pink cytoplasm and abnormal basal nuclei with unusual cytoplasmic projections. The arrangement of cells can be tubular acinar, papillary, or solid, with most cases showing a mix of these patterns. The tubular forms are predominantly composed of hobnail and clear cells, while the solid forms are mainly made up of clear cells (Barber, 214).

The cytoplasm of clear cell adenocarcinoma tissue, fixed with alcohol, contains a high amount of glycogen that can be observed using special staining techniques. There is also typically an abundance of extracellular neutral mucin mixed with sulfate and carboxyl groups, as well as a small amount of intracellular mucin. Histochemically and ultrastructurally, the clear cells have short and blunt microvilli, tight junctions between cells, desmosomes, free ribosomes, and lamellar endoplasmic reticulum. The hobnail and clear cells have a similar ultrastructure to those found in clear cell carcinomas elsewhere in the female genital tract (O'Brien, 254). These tumors exhibit various histological patterns that may even vary within the same tumor.

It is not clear whether both tubular components with hobnail cells and the solid part with clear cells are needed for a diagnosis or if just one pattern is sufficient. Luckily, most tumors contain a mix of these components. There is a theoretical chance of benign and borderline clear cell ovarian adenocarcinomas. Yoonessi et al discovered that nodal metastases can be present even when the disease seems to

be limited to the pelvis (Yoonessi, 296). It is crucial to examine retroperitoneal nodes for accurate staging and well-thought-out adjuvant therapy.

Surgery is the primary treatment for ovarian clear cell adenocarcinoma (OCCA) and involves removing the uterus, tubes, ovaries, partial omentectomy, and nodal biopsies. The effectiveness of adjuvant radiotherapy and chemotherapy remains uncertain. However, if there is a unilateral encapsulated lesion without involvement of the contralateral ovary, omentum, or biopsied nodes, complete surgical removal may not require additional therapy. In some cases where a young patient wishes to preserve their reproductive capacity, only the affected ovary can be removed. For advanced stages of OCCA, complete surgical removal of the uterus, ovaries, omentum and as much tumor as possible should be followed by pelvic radiotherapy or chemotherapy if there is limited residual disease in the pelvis. Common chemotherapeutic regimens typically combine adriamycin, alkylating agents and cisPlatinum. OCCA is an epithelial cancer that often consists of various other types such as serous, mucinous and endometrioid tumors (Altchek 97) (Barber 442).

Clear cell adenocarcinoma is a type of ovarian tumor characterized by large epithelial cells with abundant cytoplasm. These tumors can be found alongside endometriosis or endometrioid carcinoma of the ovary and resemble clear cell carcinoma of the endometrium. They are believed to originate from the mullerian duct and are considered variations of endometrioid adenocarcinoma.

Clear cell ovarian tumors can be either primarily solid or cystic. In solid neoplasms, the clear cells form sheets or tubules, while in the cystic form, neoplastic cells line spaces.

If these tumors remain confined to the ovaries, the 5-year survival rate is approximately 50%. However, due to their aggressive behavior and tendency to spread beyond the

ovaries, achieving a 5-year survival becomes highly unlikely (Altchek, 416).

The ongoing debate revolves around whether clear cell or mesonephros carcinoma should be considered its own distinct clinicopathological entity with unique biological behavior and natural history, or if it is simply a variation of endometrioid carcinoma. To address this issue, Jenison et al conducted a study comparing clear cell adenocarcinoma to the more common serous adenocarcinoma (SA). They found that patients diagnosed with clear cell adenocarcinoma had a higher prevalence of histologically confirmed endometriosis compared to those with SA. Additionally, Jenison et al also noted other differences in the biological behavior exhibited by clear cell adenocarcinoma when compared to SA.

They discovered that 50% of the patients observed had Stage I tumors, and OCCA had a lower occurrence of bilaterality compared to SA (Jenison, 67-69). Furthermore, OCCA tends to be larger than SA, potentially accounting for the higher prevalence of symptoms and signs during its presentation. Regarding risk factors, there is ongoing debate about the influence of talc use on ovarian cancer. Historically, most talc powders were contaminated with asbestos, and it is conceivable that talcum powder on the perineum could reach the ovaries through absorption via the cervix or vagina.

According to Barber (200), talcum powders no longer contain asbestos, making the associated risk insignificant. The consumption of whole milk, butter, and high-fat meat products has been linked to an increased risk of ovarian cancer. A study conducted by the Centers for Disease Control compared 546 women diagnosed with ovarian cancer to 4,228 control subjects. The study revealed that women aged 20-54 who used oral contraceptives had a 40% lower risk of developing ovarian cancer. Additionally, the

risk decreased further with longer duration of oral contraceptive use. Even using oral contraceptives for as little as three months was shown to decrease the risk.

Using oral contraceptives can reduce the risk of disease by 40% or lower the relative risk to 0.6. Women who have given birth to four or more children also experience a decreased risk of disease, up to 40%, compared to women who have never given birth. Conversely, nulliparous women have a higher incidence of ovarian cancer, while the incidence decreases as parity increases. According to the "incessant ovulation theory," repeated ovulation may cause damage to the ovary and contribute to the development of ovarian cancer. Interestingly, having two or more abortions instead of never having an abortion is associated with a 30% lower risk of ovarian cancer (Coppleson, 25-28).

The cause of cancer is commonly believed to be a series of genetic alterations that disrupt the normal growth and differentiation of cells. These alterations mainly impact two types of genes: proto-oncogenes and tumor suppressor genes. Changes in proto-oncogenes can convert a healthy cell into a cancerous one by producing an altered or excessively active gene product. Mutations, translocations, or amplifications may be involved in these changes. Conversely, tumor suppressor genes aid in preventing cancer. When these genes are disabled or lost, the absence of functional gene products can lead to the development of cancer. Typically, mutations must occur in both copies of a tumor suppressor gene for this to happen.

The roles of genes within a DNA transcription factor or a cell adhesion molecule are crucial in regulating cell proliferation. Dysfunction of these genes can lead to abnormal cell division, altered gene

expression, or increased detachment of cells from tissues. OCCA, a type of cancer, is believed to be caused by the complex interaction between multiple mutated proto-oncogenes and tumor suppressor genes (Piver, 64-67). Initially, there was limited evidence linking ovarian cancer to genetics. Before 1970, only five families had reported cases of familial ovarian cancer. In 1981, the Roswell Park Cancer Institute established a registry to monitor occurrences in the United States and investigate inheritance patterns.

If it is determined that the disease is transmitted through genetic autosomal dominance, suggesting prophylactic oophorectomy at the appropriate age may result in a reduction in the mortality rate caused by ovarian cancer in affected families. In 1984, Roswell Park's registry documented 201 instances of ovarian cancer in 94 families. From 1981 to 1991, a total of 820 families and 2946 cases were observed. Familial ovarian cancer is fairly prevalent and might make up around 2 to 5% of all cases.

There are three conditions associated with familial ovarian cancer. The first condition, which is called site-specific familial ovarian cancer, is the most common form and only affects the ovaries. The second condition is breast/ovarian cancer, in which cases of ovarian and breast cancer cluster together in extended pedigrees (Altchek, 229-230).

An important characteristic of inherited ovarian cancer is that it tends to occur at a younger age compared to non-inherited forms. Cytogenetic investigations have shown frequent alterations of chromosomes 1, 3, 6, and 11 in sporadic ovarian tumors that are not inherited. These chromosomes contain many proto-oncogenes, and deletions of segments (especially 3p and 6q) in some tumors suggest the involvement of tumor suppressor genes.

A recent genetic linkage study on familial breast/ovary

cancer has found evidence indicating a link between disease susceptibility and the RH blood group locus located on chromosome 1p.

Frequent observations in ovarian cancers include allele loss on chromosomes 3p, 6q, 11p, 13q, and 17. The tumor suppressor gene p53, located on chromosome 17p13, has been found to have point mutations. Additionally, deletions of chromosome 17q have been reported in sporadic ovarian tumors, indicating its involvement in ovarian tumor biology. On chromosome 6q, there is allelic loss of the MYB and ESR genes near the provisional locus for FUCA2, the locus for a-L-fucosidase in serum. Ovarian cancer patients often exhibit low activity of a-L-fucosidase in serum.

The text indicates that having a deficiency in serum a-L-fucosidase activity could be a hereditary condition linked to a higher risk of developing ovarian cancer. This, along with cytogenetic data showing losses at 6q and allelic losses at 6q, suggests the potential importance of chromosome 6q in hereditary ovarian cancer (Altchek, 208-212). The activation of normal proto-oncogenes, through mutation, translocation, or gene amplification, leading to altered or overexpressed products, is believed to play a significant role in ovarian tumor development. Ovarian tumors often exhibit activation of several proto-oncogenes, including K-RAS, H-RAS, c-MYC, and HER-2/neu. However, the significance of this activation is still to be determined. Whether the overexpression of the HER-2/neu gene in ovarian cancer correlates with a poor prognosis remains a subject of controversy.

Investigating proto-oncogenes in germ-line DNA from individuals with familial histories of ovarian cancer (Barber, 323-324) is a valuable addition to studying these genes in tumors. There is uncertainty surrounding whether the inheritance or rare alleles of the H-RAS proto-oncogene are related to ovarian cancer susceptibility. The

diagnosis and treatment of ovarian cancer are currently reliant on chance rather than a scientific approach. Typically, the presence of a pelvic mass is the primary method of diagnosis, except for functioning tumors that may exhibit endocrine symptoms even with minimal ovarian enlargement. Symptoms include nonspecific discomfort in the abdomen, dyspepsia, increased flatulence, a sensation of bloating (particularly after eating), mild digestive issues, and pelvic unrest that may persist for several months before a diagnosis is made (Sharp, 161-163). Numerous imaging techniques are available for diagnostic purposes.

The use of ultrasounds, specifically vaginal ultrasound with the color Doppler method, has improved the detection of early lesions. However, there has been a rise in false-positive results with vaginal sonography and CA 125 testing. Pelvic findings are usually not significant and do not contribute to making a diagnosis. However, when combined with a strong suspicion, they can help alert the physician to the possible diagnosis.

These pelvic signs include: a mass in the ovarian area, relative immobility due to adhesions that fixate it, irregularity of the tumor, a 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, and bilaterality (70% for ovarian carcinoma versus 5% for benign cases) (Barber, 136).
Tumor markers have been particularly useful in monitoring treatment. However, these markers have a disadvantage in identifying an early tumor. Currently, only two tumor markers, human gonadotropin (HCG) and alpha fetoprotein, are known to be sensitive and specific. The problem with using tumor markers for diagnosis is that they are developed from a certain volume of tumor. By the time a tumor marker is present,

it indicates a biologically late tumor rather than an early one (Altchek, 292). Several reports have mentioned murine monoclonal antibodies (MAbs) as potential tools for diagnosing malignant ovarian tumors.

Yamada et al sought to create a monoclonal antibody (MAb) that could distinguish between cells with early malignant changes and adjacent benign tumor cells in cases of borderline malignancy. They developed MAb 12C3 by immunizing mice with a cell line taken from a human ovarian tumor. This antibody reacted specifically with human ovarian carcinomas and not with germ cell tumors. MAb 12C3 stained 67.7% of ovarian epithelial malignancies, but showed very low reactivity with other types of malignancies. MAb 12C3 identified a novel antigen that is found in limited amounts in normal tissue. The authors believe that MAb 12C3 will be a valuable tool for detecting early malignant changes in borderline epithelial neoplasms using histology.

MAbs 12C3 can be utilized as an effective targeting agent in cancer chemotherapy (Yamada, 293-294). Presently, there are multiple serum markers accessible for aiding in diagnosis. These comprise CA 125, CEA, DNB/70K, LASA-P, and serum inhibin. Recently, urinary gonadotropin peptide (UCP) and collagen-stimulating factor have also been integrated. Despite the limited specificity and sensitivity of tumor markers, they are frequently employed in ovarian cancer screening.

A new tumor marker, CA125-2, offers greater specificity compared to CA125. Generally, tumor markers have a limited role in ovarian cancer screening. The ovarian epithelial cancer is unique as it typically remains contained within the peritoneal cavity, where it initially develops, but still has the potential to spread to lymph nodes in the pelvic or aortic areas even in cases of early localized cancer. Death in most

cases is caused by intraperitoneal proliferation, ascites, protein loss, and cachexia. The current dominant treatment concept is debulking or cytoreductive surgery.

The primary objective of debulking surgery is to stop the cycle of malnutrition, nausea, vomiting, and dyspepsia that is commonly observed in patients with mid to advanced-stage disease. By reducing the size of tumors, cytoreductive surgery improves the effectiveness of chemotherapy. Patients with a residual mass size smaller than 1.5 cm after surgery have the same survival rate as those with metastatic lesions smaller than 1.5 cm initially (Altchek, 422-424). Surgeons must consider the aggressiveness of debulking surgery when treating ovarian cancers. Removing very large metastatic masses does not provide any oncological benefits. While debulking extrapelvic masses may be more acceptable, it is still risky and can lead to significant impairments for the patient. Therefore, extra-genital resections should be limited to lymphadenectomy, omentectomy, pelvic abdominal peritoneal resections, and rectosigmoid junction resection.

The only true indications for extrapelvic cytoreductive surgery are stages IIB, IIC, IIIA, and IIB. Colectomy, ileectomy, splenectomy, and segmental hepatectomy are only occasionally recommended if they enable an optimal resection. The standard cytoreductive surgery includes total hysterectomy with bilateral salpingo-oophorectomy. This surgery may also involve aortic and pelvic lymph node sampling, omentectomy, and resection of the rectosigmoidal junction if needed (Barber).

182-183). The administration of drugs directly into the peritoneal cavity as a treatment for ovarian cancer was tried over 30 years ago. However, it is only in the past decade that this method of drug delivery has gained a solid foundation. The main objective is to expose the tumor to higher drug concentrations for longer durations compared to systemic delivery. Various substances have

been studied for their effectiveness, safety, and pharmacokinetic benefits when injected into the peritoneal route. Among them, cisplatin has undergone the most thorough evaluation for regional administration.

When cisplatin is given intraperitoneally, it can reach significant concentrations in the systemic compartment. However, this method of administration can cause dose limiting toxicity such as nephrotoxicity, neurotoxicity, and emesis. The effectiveness of cisplatin is limited because it only penetrates the peritoneal lining and tumor by 1 to 2 mm from the surface. As a result, only patients with very small residual tumor volumes are likely to benefit from this treatment for ovarian cancer.

Approximately 30 to 40% of patients with small-volume residual ovarian cancer have shown a clinical response to cisplatin-based locally administered therapy. Around 20 to 30% of these patients have achieved a complete response as confirmed by surgery. However, patients whose tumors are resistant to cisplatin after systemic therapy are generally not considered for intraperitoneal therapy with platinum-based drugs (Altchek, 444-446).

If a patient with small-volume residual disease and resistance to platinum-based regimens undergoes a second look laparotomy, alternative intraperitoneal treatment options may be considered. Some of these options include mitoxantrone and recombinant alpha-interferon. Intraperitoneal mitoxanthone has demonstrated significant activity in treating small volume residual ovarian cancer that is refractory to platinum.

Unfortunately, the agent has a dose limiting toxicity that causes abdominal pain and adhesion formation, which could result in bowel obstruction. However, recent data indicates that the local toxicity of mitoxanthone can be significantly reduced by administering microdoses of the agent. Ovarian tumors can develop drug resistance either intrinsically or through acquisition. Several mechanisms of drug resistance have been identified. One of these is the expression of

the MDR1 gene, which produces the drug efflux protein known as p-glycoprotein and is responsible for the multi-drug resistance characteristic observed in certain cancer clones.

According to the most commonly accepted definition, platinum response refers to the response to initial treatment with platinum and the disease-free period. Primary platinum resistance is defined as any progression of the disease during treatment. Secondary platinum resistance is when there is no progression during the first platinum-based therapy, but there is progression when platinum is used again for relapse treatment (Sharp, 205-207). The choice of second-line chemotherapy for recurrent ovarian cancer depends on the preferences of both the patient and the physician.

Retreatment with platinum therapy appears to offer significant opportunity for clinical response and palliation but relatively little hope for long-term cure. Paclitaxel, also known as Taxol, is a cytotoxic drug that shows effectiveness in treating ovarian cancer. About 20% of patients who have previously failed platinum therapy respond to standard doses of paclitaxel. Ongoing studies are investigating higher doses and intraperitoneal administration of paclitaxel. This drug class is now considered a valuable addition to platinum analogs, whether used as primary therapy, in combination with platinum, or as a salvage treatment after platinum failure. In advanced stages of ovarian cancer, there is suggestive evidence that OCCA (ovarian clear cell adenocarcinoma) may respond partially to radiation, as well as chemotherapy regimens involving adriamycin, cytoxan, and cisplatinum combinations.

Radiation techniques for ovarian cancer treatment include intraperitoneal radioactive gold or chromium phosphate, as well as external beam therapy for the abdomen and pelvis. However, the role of radiation therapy in treating ovarian cancer has become less important due to the challenges it presents in

effectively targeting the spread pattern of the disease and the surrounding normal tissue. In cases where there is bulky residual disease after laparotomy, radiation therapy is particularly ineffective. If a patient is prescribed postoperative radiation, it is crucial to ensure that the entire abdomen and pelvis receive optimal treatment for a response from the tumor (Sharp, 278-280). Despite significant advancements in response rates for advanced stage ovarian clear cell adenocarcinoma and ovarian cancer in general, long-term survival rates have not seen dramatic improvements over the past few decades.

The encouraging promises of new drugs with activity when platinum agents fail fosters hope that, in the decades to come, surgical and pharmacological research endeavors will make ovarian cancer an easily treatable disease.


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