Ovarian cancer

Overview

In the United States, ovarian cancer is the leading cause of cancer mortality from gynecologic malignancies. Malignant ovarian lesions include both primary lesions developing from normal ovarian tissues and secondary lesions arising from malignancies elsewhere in the body. Primary lesions include epithelial ovarian carcinoma.

The existing screening tests have a low predictive value, which adds to the misery. The major early detection techniques include detailed gynecological assessment, transvaginal ultrasound, and laboratory markers such as cancer antigen-125 (CA-125) test, which have demonstrated no substantial benefit in the morbidity or death of this malignancy.

Surgery and platinum-based chemotherapy are the mainstay treatments; however, anti-angiogenic bevacizumab and Poly(ADP-ribose) polymerase (PARP) inhibitors have gained traction in the management of this gynecological cancer in the last decade.

 

Ovarian cancer definition

Ovarian cancer is one of the leading causes of cancer-related mortality among women in industrialized countries. They should be detected early in order to have a greater chance of healing it and avoiding the high morbidity and fatality rates. It is also the sixth leading cause of mortality among women overall. The majority of cases are discovered at an advanced stage, resulting in poor illness outcomes.

 

Epidemiology

In 2020, there will be roughly 21,750 new instances of ovarian cancer, accounting for 1.2 percent of all cancer cases. It is estimated that 13,940 people died as a result of it. The projected 5-year relative survival rate is 48.6 percent. Around 15.7 percent of ovarian cancer cases are found at the local stage, and around 58 percent are diagnosed at the metastasized stage, when the 5-year survival rate drops to 30.2 percent instead of 92.6 percent if detected early in the local phase.

In 2012-2016, the average incidence rate per 100,000, age-adjusted to the US standard population of 2000, was 11.1. Non-Hispanic whites had the highest incidence (11.6 per 100,000), followed by American Indians and Alaska Natives (10.3 per 100,000), Hispanics (10.1 per 100,000), non-Hispanic blacks, and Asian and Pacific Islanders.

Ovarian malignancies are 90% epithelial, with the serous subtype being the most frequent. According to statistical methods of analysis, age-adjusted rates of new ovarian cancer cases are on the decline. 

 

Etiology

Ovarian cancer is connected with a number of risk factors. It mostly affects postmenopausal women, with increasing age related with greater incidence, advanced stage of the illness, and poorer reported survival rates.

According to a few case-control studies, parity has a protective function, with older age at delivery associated with a lower incidence of ovarian cancer. A positive family history of breast or ovarian cancer is the most important risk factor for ovarian cancer, although a personal history of breast cancer also increases the risk. Several studies have found that smoking increases the incidence of mucinous epithelial cancers.

 

Histopathology

Serous, endometrioid, clear cell, and mucinous tumor are the four most prevalent histological forms of epithelial ovarian cancer. They are further classified into subgroups based on their unique biology and therapeutic responses. Brenner and seromucinous are rare subtypes.

Ovarian cancer is further subdivided into two subtypes: Type I and Type II tumors, with the latter being a more lethal variety considered to be produced by continuous ovarian cycles, resulting in inflammation and endometriosis. Low-grade serous, endometrioid, clear-cell, and mucinous carcinomas are all kinds I tumors, with seromucinous and Brenner tumors being rare subtypes.

Atypical proliferative (borderline) tumors are the most common cause of type I cancers. High-grade serous carcinoma, carcinosarcoma, and undifferentiated carcinoma are examples of type II tumors, which are mostly derived from serous tubal intraepithelial carcinoma. Type I cancers often occur at an early stage and are low grade, with the exception of clear cell tumors, which are considered high grade.

Typically, their proliferative activity is minimal. They are diagnosed early and have a favorable prognosis. Type II tumors, on the other hand, are high-grade and virtually invariably advanced-stage cancers. When compared to type I, they have a high proliferative activity, quick and aggressive growth, and a high degree of chromosomal instability, with the presence of p53 mutations in the majority of cases.

The most prevalent subtype of ovarian cancer is ovarian serous carcinoma. It manifests as either low-grade (10% of all serous subtype tumors) or high-grade carcinoma (90 percent of all the serous subtype tumors). The low-grade subtype (LGSC) has less nuclear atypia, just a few mitoses, and fewer molecular abnormalities. In contrast, the high-grade subtype (HGSC) has more copies of molecular abnormalities and considerable nuclear atypia and mitosis (>12 per 10 high-power fields).

LGSCs are typically diagnosed at a young age and have a better prognosis than HGSCs, which typically appear at a later age and have a 10-year death rate of 70%. Further investigation demonstrated that low-grade serous carcinoma has a high frequency of KRAS and BRAF mutations, whereas high-grade serous carcinoma has a high frequency of p53 and BRCA 1 and 2 gene alterations.

Endometriosis is thought to be the origin of ovarian endometrioid carcinomas. Their sliced sections exhibit cystic regions with soft masses and bloody fluid, as well as less common solid portions with severe bleeding and necrosis. Although no important molecular indicators have been identified in this subtype, the beta-catenin gene mutation is one of the most prevalent molecular abnormalities.

Endometrioid carcinomas emerging from the ovaries and the uterus may be distinguished using molecular research, despite their physical similarities. Microsatellite instability and PTEN mutations are more common in ovarian endometrioid malignancies than in uterine cavity cancers. When compared to synchronous tumors, single ovarian cancer had a lower prevalence of beta-catenin mutation. They are frequently discovered at an earlier stage, giving women with this histological subtype of ovarian cancer a better prognosis.

Ovarian mucinous carcinoma (MOC) is frequently heterogeneous, with a mix of benign and malignant tumors identified in a single specimen. Mutations in KRAS are frequent in these cancers. The intestinal subtype, which is usually linked with metastases from the gastrointestinal tract (GI), will demonstrate the existence of glands with architectural and cytology clinical characteristics of adenocarcinoma; however, it may lack stromal invasion.

Due to the difficulty in distinguishing original ovarian mucinous carcinomas from metastatic mucinous appendix tumors, many gynecologic oncologists perform standard appendectomy in all MOC patients. Microinvasion evidence is less prevalent in intestinal subtype borderline cancers.

Invasive mucinous carcinoma is infrequent, and the prognosis is found to be better than that of the serous subtype, owing to the fact that it is generally discovered at stage I, around 80% of the time. The molecular changes responsible for the benign mucinous tumor's malignant transformation are yet unclear.

 

Ovarian cancer symptoms

Because the symptoms of ovarian cancer are non-specific, they can be easily ignored at an early stage because they might be attributed to other probable disease processes. Symptoms frequently appear late in the disease's progression (stage III or stage IV)

Symptoms include stomach fullness, bloating, nausea, abdominal distention, early satiety, fatigue, change in bowel motions, urinary symptoms, back pain, dyspareunia, and weight loss. The symptoms appear months before an ovarian cancer diagnosis.

In clinical situations of high suspicion, a comprehensive physical examination should be performed, including rectovaginal examination on an empty bladder to search for pelvic and abdominal tumors. A palpable pelvic mass or ascites, as well as reduced breath sounds due to the presence of pleural effusions, can be seen in advanced instances. A sister Mary Joseph nodule is infrequently found as a consequence of metastases to the umbilicus. Leser-Trelat sign, which refers to a rapid rise in the presence of seborrheic keratosis, also provides a clinical signal suggesting the existence of concealed cancer.

Ovarian cancer is only occasionally related with paraneoplastic disorders. Subacute cerebellar degeneration caused by tumor-induced autoimmune response to cerebellar antigens can cause ataxia, dysarthria, nystagmus vertigo, and diplopia. This syndrome frequently occurs months or years before the underlying ovarian tumor. Trousseau's condition has been linked to ovarian cancer.

Hypercalcemia can result from elevated amounts of circulating parathyroid hormone-releasing protein, which can present as altered mental state, weariness, constipation, stomach discomfort, increased thirst, and urine frequency. Such early warning signals of different paraneoplastic syndromes should be examined far in advance in order to avoid a straight diagnosis of ovarian cancer at an advanced stage where the patient may be unresponsive to curative therapy.

 

How to diagnose Ovarian cancer?

Radiological imaging, particularly transvaginal ultrasound (TVUS, which is extremely sensitive and recommended) and/or abdominal and pelvic ultrasonography, is performed in patients with a high degree of clinical suspicion. It offers a good picture of the ovarian mass's size, location, and complexity. Further imaging using chest and abdominal pelvis CT scan, pelvic MRI, and/or PET scan can be done to define tumor extension.

CA-125 levels are typically measured in conjunction with imaging. CA-125 levels are increased in the majority of epithelial ovarian malignancies, but only half of the early stage epithelial ovarian tumors. Postmenopausal women had better specificity and positive predictive value than premenopausal women. Endometriosis, pregnancy, ovarian cysts, and inflammatory peritoneal disorders all have elevated CA-125 values.

As a result, alternative biomarkers are now being investigated in order to increase specificity for ovarian cancer biomarkers. Human epididymis protein 4 (HE4) is a novel biomarker under investigation. It has been discovered to be more sensitive for ovarian cancer and to be present in nearly all serous and endometrioid subtypes. According to current research, a combination of elevated CA-125 and HE4 levels is considered to be predictive of malignant ovarian tumors and may one day serve as a valuable diagnostic tool.

CA-125 levels can also be used to generate the risk of malignancy index (RMI), which takes TVUS findings and menopausal state into account. RMI more than 200 is related with a significant probability of malignancy, with better than 96% specificity.

To evaluate the risk of malignancy, the malignancy algorithm (ROMA) risk uses a mathematical calculation that integrates HE-4 and CA 125 values adjusted for pre and post-menopausal status. The ROMA is a helpful screening test that uses the high specificity of HE4 and the high sensitivity of CA-125 to detect more ovarian cancer patients overall, particularly in the early stages.

The patient is usually given the risk of malignancy index (RMI), which includes TVUS results, menopausal state, and CA-125 readings. Multimarker longitudinal models are now being developed for the early identification of ovarian cancer.

 

Ovarian cancer staging

Optimal staging is achieved by exploratory laparotomy and careful examination of the abdominal and pelvic regions for disease, including examination of peritoneal surfaces with biopsy and/or pelvic washings. It determines the stage of ovarian cancer using the International Federation of Gynecology and Obstetrics (FIGO) staging system.

Following that, a complete abdominal hysterectomy and bilateral salpingo-oophorectomy (BSO) with para-aortic and pelvic lymph node dissection and omentum are performed. A pathologist's evaluation of tissue samples aids in the ultimate diagnosis of histological type, grade, and staging. 

 

Ovarian cancer treatment

The standard treatment for ovarian cancer in women is severe debulking surgery and chemotherapy. The goal of cytoreductive surgery is to confirm the diagnosis, determine the extent of the illness, and remove any visible tumor. Neoadjuvant chemotherapy is becoming more popular. 

Surgery

The type of operation is determined by whether or not the illness can be seen outside the ovaries. When there is no disease visible outside the ovaries or no lesion larger than 2 cm outside the pelvis, the patient requires formal surgical staging, which includes peritoneal cytology, multiple peritoneal biopsies, omentectomy, pelvic and para-aortic lymph node sampling, and diaphragmatic peritoneum biopsies.

If visible illness is discovered, vigorous surgical debulking with the goal of removing all visible disease should be performed. If the surgeon concludes that adequate debulking is not achievable, neoadjuvant chemotherapy should be explored. Surgery for individuals with stage IV illness should be customized based on their presentation.

Surgical procedures that may be performed in women with ovarian cancer are as follows:

• Surgical staging
• Cytoreductive surgery
• Interval debulking
• Laparoscopic surgery
• Secondary surgery

 

Chemotherapy

Postoperative chemotherapy is recommended for all patients with ovarian cancer, with the exception of those with surgical-pathologic stage I illness with low-risk features. Combination treatment with a platinum component and a taxane is the standard postoperative chemotherapy for ovarian cancer (eg, carboplatin and paclitaxel). The following are additional agents for recurring disease:

• Liposomal doxorubicin
• Etoposide
• Topotecan
• Gemcitabine
• Vinorelbine
• Ifosfamide
• Fluorouracil
• Melphalan
• Altretamine
• Bevacizumab
• Olaparib
• Niraparib
• Rucaparib
• Pazopanib

Adjunctive medications include the following:

• Cytoprotective agents 
• Antiemetics 

 

Recurrent Ovarian Cancer

Tumor progression or recurrence affects around 80% of women with advanced-stage ovarian cancer. The platinum free interval (PFI) is one of the most consistent indicators of recurrent ovarian cancer response to future treatment. The time between the completion of the last platinum-based treatment and the onset of recurrence is referred to as the PFI. However, platinum sensitivity is commonly defined as a period of more than 6 months between the previous platinum-based chemotherapy (PBC) cycle and the start of the next PBC cycle.

Patients with advanced ovarian cancer are treated with initial reductive surgery, followed by platinum-based chemotherapy. However, neoadjuvant chemotherapy is advised for poor surgical candidates or individuals who may not achieve successful cytoreductive surgery.

Around 80% of women with advanced-stage ovarian cancer have tumor progression or recurrence. The platinum free interval (PFI) is one of the most reliable predictors of recurrent ovarian cancer treatment response. The PFI is the period of time between the conclusion of the last platinum-based therapy and the commencement of recurrence. Platinum sensitivity, on the other hand, is typically described as a time of more than 6 months between the last platinum-based chemotherapy (PBC) cycle and the commencement of the following PBC cycle.

Advanced ovarian cancer patients are treated with reductive surgery followed by platinum-based chemotherapy. Neoadjuvant chemotherapy, on the other hand, is recommended for poor surgical candidates or patients who may not have effective cytoreductive surgery. 

 

Radiation Oncology

Historically, entire abdomen radiation was used in the past; however, due to the rising incidence of toxicity and problems, its usage has dwindled. Radiation is now used only for palliation in ovarian cancer, either for symptom management or to treat a localized spread of illness. Adjuvant radiation has not even been found to improve survival in the early stages of clear cell carcinoma in a high-risk population of patients.

Because of the development of superior systemic medicines, radiation has taken a back seat in the treatment of ovarian cancer, with very limited use. SBRT (stereotactic body radiotherapy) is a relatively recent palliative radiation treatment. Even when local control is established, there is evidence of significant rates of distant progression of lesions with its usage.

With the advent of novel treatments such as SBRT, intensity-modulated radiotherapy, and low dose hypofractionation, the function of radiation in locally recurrent ovarian cancer, particularly in chemotherapy-resistant lesions, is becoming increasingly important. 

 

Differential Diagnosis

The differential diagnosis for ovarian cancer includes:

• Colon cancer
• Embryologic remnants
• Gastric adenocarcinoma
• Metastatic gastrointestinal carcinoma
• Ovarian torsion
• Peritoneal cyst
• Retroperitoneal mass
• Uterine fibroids
• Endometriosis
• Papillary adenocarcinoma
• Serous adenocarcinomas
• Undifferentiated adenocarcinomas
• Small-cell adenocarcinomas
• Brenner tumors

 

Ovarian cancer survival rate

The prognosis of ovarian cancer is closely related to the stage of the illness at the time of diagnosis. It is also linked to baseline performance status, FIGO stage, and the amount of remaining disease after initial cytoreductive surgery. At 10 years, the median survival rate for ovarian cancer is roughly 40% to 50%, with stage-related survival for stage I ranging from 70% to 92 percent and stage IV being less than 6%.

Women with cancer that has progressed to surrounding tissues have a 5-year survival rate of 80%, whereas those with metastatic disease have a 5-year survival rate of 25%. Patients suffering from recurring illness can be treated. They are, however, frequently incurable. The median survival time for recurrent platinum-sensitive ovarian cancer is around 3 years; however, it is only about 1 year for platinum-resistant patients.

The majority of these ovarian cancer patients develop malignant intestinal obstruction in the late stages, which is extremely difficult to manage. In such cases, palliative symptom care is the mainstay. The amount of remaining disease post-surgery is closely connected to overall survival and PFS, making debulking surgery the best predictor of prognosis.

 

Complications

Women who died from ovarian cancer had a variety of issues in the last 6 months of their lives, the most prevalent of which were:

• Fatigue or weakness (75%)
• Nausea or vomiting (71%)
• Constipation (49%)
• Pedal edema (44%)
• Anemia (34%) 

Women who were unable to receive therapy typically had major problems such as ascites, intestinal blockage, pleural effusion, and bladder obstruction, in addition to nutritional deficiencies.

 

Conclusion 

Despite leading continuing research trials and the development of novel treatment lines in recent decades, ovarian cancer remains one of the most fatal tumors in women. The poor clinical result is largely attributable to the lack of effective early detection measures for ovarian cancer. There is also evidence of care divergence from established recommendations, which might be attributed to clinical diversity encountered in ovarian cancer care.

With the objective of detecting ovarian cancer at an earlier and more treatable stage, we still need to develop effective techniques. The amount of remaining disease after cytoreduction surgery is a significant predictor of patient survival. As a result, it should only be performed by an experienced gynecologic oncologist who handles a high volume of patients in a major busy hospital (>20 cases per year).

One of the main parts is shared decision-making in terms of patient care about newly available treatment options or clinical trials by going through advantages, safety profile, symptom control, and a discussion about the prognosis. A tight interprofessional collaboration, with substantial responsibilities performed by medical oncologists and surgical oncologists, contributes to the seamless and successful care of patients. Early involvement in palliative care aids in fully optimizing the treatment course and improving quality of life.

Patients in clinical remission should be provided cost-effective techniques for close surveillance follow-ups, as well as education about signs signaling disease return and encouragement for genetic risk counseling if not done before in the early illness phase.