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Epithelial Ovarian Cancer

Ovarian cancer is the leading cause of death from gynecological cancers. Ovarian neoplasms most commonly originate from epithelial cells and thus, about 90% of affected women are diagnosed with epithelial ovarian cancer (EOC). EOC is generally treated by surgery and chemotherapy, but this approach lacks efficacy in case of advanced-stage disease. Unfortunately, non-specific symptoms as well as false-negative serological and imaging findings complicate the early diagnosis of EOC. Mean five-year survival rates are therefore below 50%.


Presentation

Ovarian cancer is sometimes referred to as "silent killer" and has the reputation of not causing illness or discomfort until advanced stages of the disease. Retrospective surveys, however, have shown that up to 80% of all patients do experience cancer-related symptoms [1]. Unfortunately though, EOC-associated symptoms are frequently seen in the general population, they are explained by common gastrointestinal, genitourinary, and gynecological disorders, and are thus often ignored by patients and physicians [2]. Characteristic yet unspecific symptoms of EOC comprise abdominal or pelvic pain, early satiety, bloating, urinary urgency and pollakisuria [3]. Women may also present with a palpable abdominal mass.

Both hematogenic and lymphogenic spread are regularly observed in EOC patients, but it is even more likely that tumor cells are shed into the peritoneal cavity and implant on the omentum, visceral or parietal peritoneum. Depending on their location, metastases may cause additional symptoms. Advanced-stage EOC may also be associated with constitutional symptoms like fever, night sweats and chills, loss of appetite and weight.

Fatigue
  • Grade 3 fatigue occurred in both patients, resulting in a dose reduction of thalidomide, with toxicity otherwise acceptable. One patient had a partial response, while the second patient had stable disease.[ncbi.nlm.nih.gov]
  • NACT provided better QOL in terms of fatigue (weight mean difference [WMD], -3.28; [95% CI: -3.99 to -2.57]), role functioning (WMD: 5.29 [95% CI: 4.44 to 6.14]), emotional functioning (WMD: 6.19 [95% CI: 5.57 to 6.82]), and cognitive functioning (WMD[ncbi.nlm.nih.gov]
  • ), low levels of white blood cells (neutropenia or leukopenia), heart palpitations, nausea, constipation, vomiting, abdominal pain/swelling (distention), inflammation of the mucous membranes (mucositis), diarrhea, indigestion (dyspepsia), dry mouth, fatigue[fda.gov]
  • The most common adverse events were diarrhea, nausea, and fatigue [ 43 ].[intechopen.com]
  • Alopecia and fatigue were probably more common with treosulfan than leuprorelin (alopecia RR 0.32, 95% CI 0.12 to 0.91 (very low-quality evidence) ).[cochrane.org]
Virilization
  • A common symptom is known as virilism, which can include: infrequent menstrual periods menstrual periods after menopause appearance of facial hair a hoarse voice[ovariancanada.org]
Chills
  • Advanced-stage EOC may also be associated with constitutional symptoms like fever, night sweats and chills, loss of appetite and weight.[symptoma.com]
Constitutional Symptom
  • Advanced-stage EOC may also be associated with constitutional symptoms like fever, night sweats and chills, loss of appetite and weight.[symptoma.com]
Pleural Effusion
  • Verheul et al. in their study, observed that malignant ascites and pleural effusion in cancer patients contained high levels of active VEGF-A and hypothesized that blocking VEGF-A expression may benefit patients with recurrent ascites or pleural effusion[omicsonline.org]
  • effusion or EOC with distant metastasis other than peritoneal metastasis In order to realize a complete tumor staging, all features considered in the FIGO staging system have to be checked.[symptoma.com]
Dyspnea
  • […] urinary tract infection, liver problems (AST/ALT elevation), muscle pain (myalgia), back pain, joint pain (arthralgia), headache, dizziness, unusual taste sensation (dysgeusia), insomnia, anxiety, cold-like symptoms (nasopharyngitis), trouble breathing (dyspnea[fda.gov]
  • There was more toxicity in the form of dyspnea (20% vs. 8%) in the aflibercept arm and also intestinal perforation (3 patients vs. 1). However, there was more fatigue or asthenia (13% vs. 44%) and more dehydration (10% vs. 12%) with placebo [ 47 ].[intechopen.com]
Nausea
  • A 60-year-old woman with stage Illc epithelial ovarian cancer developed neutropenic fever, abdominal pain, severe diarrhoea, nausea, vomiting and oral mucositis one week after the first postoperative cycle of paclitaxel (175 mg/m2 3-hour infusion) plus[ncbi.nlm.nih.gov]
  • The most common treatment-related adverse events (AEs) were hand-foot syndrome (51.7%), hypertension (34.6%), nausea and vomiting (31.0%). 3 patients had no significant toxicity. 9 patients experienced grade 3 treatment-related AEs.[ncbi.nlm.nih.gov]
  • Common side effects of Zejula include low levels of red blood cells (anemia), low levels of blood platelets (thrombocytopenia), low levels of white blood cells (neutropenia or leukopenia), heart palpitations, nausea, constipation, vomiting, abdominal[fda.gov]
  • There may be little or no difference in other Grade 3/4 side effects: nausea and vomiting ( RR 0.65, 95% CI 0.12 to 3.66 ( very low-quality evidence )); neurotoxicity ( RR 0.32, 95% CI 0.01 to 7.71 ( very low-quality evidence )) and neutropenia ( RR 0.97[cochrane.org]
Constipation
  • A case of strumal carcinoid of the ovary with contralateral clear cell adenocarcinoma of the ovary discovered with a complaint of constipation is described. Constipation was dramatically improved by resectioning the tumor.[ncbi.nlm.nih.gov]
  • By spring, episodes of constipation, an expanding waistline and serious fatigue were emerging, but I rationalized them away. Everyone is constipated sometimes, I must have gained weight and women in my family tend to have bellies.[sharecancersupport.org]
  • Common side effects of Zejula include low levels of red blood cells (anemia), low levels of blood platelets (thrombocytopenia), low levels of white blood cells (neutropenia or leukopenia), heart palpitations, nausea, constipation, vomiting, abdominal[fda.gov]
  • […] early symptoms include: abdominal bloating , pressure, and pain abnormal fullness after eating difficulty eating an increase in urination an increased urge to urinate Ovarian cancer can also cause other symptoms, such as: fatigue indigestion heartburn constipation[healthline.com]
Diarrhea
  • […] low levels of blood platelets (thrombocytopenia), low levels of white blood cells (neutropenia or leukopenia), heart palpitations, nausea, constipation, vomiting, abdominal pain/swelling (distention), inflammation of the mucous membranes (mucositis), diarrhea[fda.gov]
  • The most common adverse events were diarrhea, nausea, and fatigue [ 43 ].[intechopen.com]
  • The safety profile for the overall pooled population was consistent with previously reported data, with the most common adverse events including diarrhea, fatigue, nausea and blurred vision; however, these were low grade and well-managed.[curetoday.com]
  • Topotecan pills had destroyed the lining of my colon, leaving me hospitalized for nine days with bloody diarrhea and in need of four transfusions.[sharecancersupport.org]
Abdominal Pain
  • A 60-year-old woman with stage Illc epithelial ovarian cancer developed neutropenic fever, abdominal pain, severe diarrhoea, nausea, vomiting and oral mucositis one week after the first postoperative cycle of paclitaxel (175 mg/m2 3-hour infusion) plus[ncbi.nlm.nih.gov]
  • Common side effects of Zejula include low levels of red blood cells (anemia), low levels of blood platelets (thrombocytopenia), low levels of white blood cells (neutropenia or leukopenia), heart palpitations, nausea, constipation, vomiting, abdominal[fda.gov]
  • This is called obstruction , and can cause abdominal pain, nausea, and vomiting. Dealing with an intestinal blockage can be difficult.[cancer.org]
  • pain or swelling Elevated levels of the protein CA-125 According to the Ovarian Cancer National Alliance , most patients diagnosed with ovarian cancer develop a recurrence.[cancercenter.com]
  • Of the 68 patients treated with 32 P, 14 (21 percent) reported mild-to-moderate abdominal pain, and 4 (6 percent) had severe pain. One patient had chemical peritonitis, and one had infectious peritonitis.[nejm.org]
Loss of Appetite
  • Advanced-stage EOC may also be associated with constitutional symptoms like fever, night sweats and chills, loss of appetite and weight.[symptoma.com]
  • Signs and symptoms of ovarian cancer recurrence may include: Persistent abdominal bloating, indigestion or nausea Changes in appetite, typically a loss of appetite or feeling full sooner Pressure in the pelvis or lower back Urge to urinate more frequently[cancercenter.com]
  • Other symptoms that may develop include: Loss of appetite. Weight loss. Back pain. Pain in the lower abdomen when having sex. Passing urine frequently (as the bladder is irritated by the nearby tumour).[patient.info]
Night Sweats
  • Advanced-stage EOC may also be associated with constitutional symptoms like fever, night sweats and chills, loss of appetite and weight.[symptoma.com]
Back Pain
  • pain, joint pain (arthralgia), headache, dizziness, unusual taste sensation (dysgeusia), insomnia, anxiety, cold-like symptoms (nasopharyngitis), trouble breathing (dyspnea), cough, rash and high blood pressure (hypertension).[fda.gov]
  • pain menstrual irregularities painful intercourse dermatomyositis (a rare inflammatory disease that can cause skin rash, muscle weakness, and inflamed muscles) These symptoms may occur for any number of reasons.[healthline.com]
  • Back pain. Pain in the lower abdomen when having sex. Passing urine frequently (as the bladder is irritated by the nearby tumour). Change in bowel habit such as constipation or diarrhoea. A more marked swelling of the abdomen.[patient.info]
Pelvic Pain
  • Characteristic yet unspecific symptoms of EOC comprise abdominal or pelvic pain, early satiety, bloating, urinary urgency and pollakisuria. Women may also present with a palpable abdominal mass.[symptoma.com]
  • Other symptoms such as bloating and pelvic pain are often confusing and fail to catch the clinician’s attention Even the increase in CA-125 levels is considered highly non-specific in recent times and is used to assess response to treatment.[omicsonline.org]
Vaginal Bleeding
  • Because sex-cord stromal tumors make an overabundant supply of estrogen, they often cause abnormal vaginal bleeding. Subtypes of sex cord-stromal tumors include granulosa cell tumors, granulosa-theca tumors and Sertoli-Leydig tumors.[cancercenter.com]
Adnexal Mass
  • Clinicians are advised to thoroughly investigate adnexal masses in this patient population.[ncbi.nlm.nih.gov]
Urinary Urgency
  • Characteristic yet unspecific symptoms of EOC comprise abdominal or pelvic pain, early satiety, bloating, urinary urgency and pollakisuria. Women may also present with a palpable abdominal mass.[symptoma.com]
Pollakisuria
  • Characteristic yet unspecific symptoms of EOC comprise abdominal or pelvic pain, early satiety, bloating, urinary urgency and pollakisuria. Women may also present with a palpable abdominal mass.[symptoma.com]

Workup

Increased serum concentrations of tumor marker cancer antigen 125 may raise a suspicion of malignancy, but should not be considered an exclusion criterion for ovarian cancer. Indeed, diagnostic imaging is still the most important tool for EOC diagnosis. Imaging studies may either be carried out in symptomatic women or in the scope of surveillance programs, and they may provide valuable hints on the presence of an abdominal neoplasm. Sonography, computed tomography, and magnetic resonance imaging are usually employed to this end. Notwithstanding the usefulness of these techniques, they may lack sensitivity for the detection of early-stage EOC [4]. Concerning characteristic findings, ovarian malignancies often appear as cyst-bearing, heterogeneous lesions [1].

Tissue samples have to be obtained in order to determine cellular origin, grade and histotype of the tumor. There are four main histotypes of EOC, namely serous, endometrioid, mucinous, and clear cell EOC. They differ with regard to their macroscopic and microscopic appearance, their gene expression, growth behavior and response to therapy. It is beyond the scope of this article to describe the histotypes of EOC in detail and the interested reader is referred to excellent literature available on this topic [5] [6]. Briefly, the following features are characteristic of serous, endometrioid, mucinous, and clear cell EOC [5] [6]:

  • Serous carcinoma is the most common histotype of EOC; it resembles the epithelium lining the Fallopian tube. In most cases, both ovaries are affected at the time of diagnosis. The tumor comprises solid parts, cystic lesions, necrotic foci and hemorrhages. Papillary architecture may be observed under the microscope, with papillae being lined by stratified epithelium of the serous type. Ciliated cells are rare. Papillae are separated by slit-like invaginations. Tumor cells frequently contain psammoma bodies. Mitotic figures and nuclear atypia are prominent in high-grade serous carcinomas.
  • Endometrioid tumors account for 10-20% of EOC cases. They consist of epithelial and stromal elements that remind of the endometrium. These tumors usually contain cysts filled with dark brown fluid.
  • Mucinous carcinoma consists of irregular glands and cysts lined by stratified epithelium composed of cells with abundant intracytoplasmic mucin and basal nuclei. There may be goblet cells and different types of endocrine cells, but contrary to benign mucinous cystadenoma, malignancies don't usually resemble the endocervical or intestinal epithelium. Of note, mucinous tumors may consist of benign, borderline, and malignant neoplastic tissue.
  • Clear cell EOC is characterized by polygonal clear cells with abundant cytoplasmic glycogen and eccentric nuclei, and hobnail cells with protruding nuclei. Clear cell EOC is particularly common in women suffering from endometriosis.

With regard to EOC staging, the so-called FIGO staging system is generally applied. This system considers the following tumor stages [7] [8]:

  • Stage 0: carcinoma in situ
  • Stages 1A, 1B, 1C: tumor limited to one or both tubes, possibly penetrating the serosal surface, possibly surgical spill, capsule ruptured before surgery, tumor on ovarian surface, or presence of malignant cells in ascites or peritoneal washings
  • Stages 2A, 2B: EOC with pelvic extension, metastases in ovaries, uterus and/or other pelvic structures
  • Stages 3A, 3B, 3C: EOC with microscopic or macroscopic peritoneal implants outside the pelvis and/or positive regional lymph nodes
  • Stage 4A, 4B: malignant pleural effusion or EOC with distant metastasis other than peritoneal metastasis

In order to realize a complete tumor staging, all features considered in the FIGO staging system have to be checked.

Pleural Effusion
  • Verheul et al. in their study, observed that malignant ascites and pleural effusion in cancer patients contained high levels of active VEGF-A and hypothesized that blocking VEGF-A expression may benefit patients with recurrent ascites or pleural effusion[omicsonline.org]
  • effusion or EOC with distant metastasis other than peritoneal metastasis In order to realize a complete tumor staging, all features considered in the FIGO staging system have to be checked.[symptoma.com]

Treatment

To date, EOC treatment is mainly based on surgery and chemotherapy: Women diagnosed with stage 1 EOC are generally referred for bilateral salpingo-oophorectomy or total abdominal hysterectomy. Those who wish to preserve fertility may possibly opt for unilateral salpingo-oophorectomy, but this approach requires close postoperative monitoring. Cytoreductive surgery is carried out in case of advanced-stage EOC and may be preceded by neoadjuvant chemotherapy. EOC patients should receive chemotherapy after tumor removal or debulking. Standard regimens comprise combination platinum-based chemotherapy with carboplatin and paclitaxel, carboplatin and gemcitabine, or carboplatin and pegylated liposomal doxorubicin. Monotherapy with carboplatin is associated with reduced toxicity and has been proven effective in multiple trials. Finally, monotherapy with paclitaxel, pegylated liposomal doxorubicin, or topotecan is another treatment option [9].

Cytoreductive surgery plus conventional chemotherapy may cure more than 70% of patients diagnosed with stage 1 or 2 EOC, but less than 20% of those suffering from stage 3 or 4 disease. Unfortunately though, only 25% of all tumors are detected in stages 1 and 2 [4]. Additionally, multimorbid patients are often unfit for surgical interventions, but sole chemotherapy is not curative [9]. Treatment options presented so far may be combined with radiation, immunotherapy and molecular targeted therapy. Genetic analyses should precede the decision for adjuvant chemotherapy with biologics since certain mutations may render the tumor more or less susceptible to certain compounds [10]. Women carrying BRCA1 or BRCA2 mutations, for instance, may benefit from PARP inhibitors. Women who don't carry such mutations should rather receive niraparib [9].

Prognosis

Prognosis largely depends on tumor grade and stage at the time of diagnosis. For EOC in stages 1 to 4, five-year survival rates have been estimated to 85, 65, 30, and 15% respectively. Stage-independent five-year survival rates range between 35 and 45%, which is due to the fact that most women are diagnosed in advanced stages of the disease [3].

Etiology

The etiology of ovarian cancer remains largely unknown. Slight differences regarding epidemiological parameters have been observed between different ethnicities, but few of them allow to infer possible causes of the disease:

  • Women with a family history of breast and female genital cancer may be predisposed to develop EOC, independent of their country of origin and ethnicity. Their predisposition is generally due to germline mutations in genes BRCA1 and BRCA2: BRCA1 mutations are associated with a lifetime risk of 46%-87% for breast cancer and 39%-63% for malignancies of the ovaries; carriers of BRCA2 mutations have a lifetime risk of 38%-84% for breast cancer and 17%-27% for ovarian cancer [11]. Serous adenocarcinoma is particularly common in patients with BRCA1 or BRCA2 mutations [11].
  • With regard to ovarian tumors due to hereditary susceptibility, 65–85% of all patients carry BRCA1 or BRCA2 mutations. The remainder of cases is explained by mutations in genes encoding for DNA mismatch repair proteins, in tumor suppressor gene TP53, and other genes implicated in the double-strand break repair system, such as BRIP1, CHEK2, PALB2, and RAD51. Some of these mutations are associated with hereditary cancer susceptibility syndromes, e.g., Li-Fraumeni syndrome and Lynch syndrome [12].
  • Excessive gonadotropin secretion, estrogen and progestogen imbalance, and exposure to carcinogens have also been discussed as possible triggers of EOC, but confirmatory data are scarce [2].

Epidemiology

The overall incidence of ovarian cancer is approximately 11-12 per 100.000 women in Europe and North America, with 85-90% of all tumors being classified as EOC. The individual risk of EOC increases with age and postmenopausal women account for the majority of patients [2].

Sex distribution
Age distribution

Pathophysiology

Multiple genetic and epigenetic abnormalities have been detected in EOC. Both the activation of proto-oncogenes as well as the inactivation of tumor suppressor genes may contribute to cancer development, but the latter seems to be more common in EOC. TP53 and PTEN are among the best known tumor suppressor genes involved in EOC pathogenesis, but mutations have also been found in genes OPCML and WWOX, among others. The expression of other genes is altered due to promoter hypermethylation or transcription downregulation. High-grade advanced-stage EOC is characterized by a myriad of gene and chromosomal aberrations, and this fact highlights that genetic stability is decreasing over the course of the disease [1]. There are no universal abnormalities to be found in the majority of EOC - their genetics are as heterogeneous as their radiological and histological appearance.

Prevention

Few recommendations can be given to prevent the onset of EOC, and none can be provided to avoid sporadic disease. However, members of families affected by ovarian cancer due to hereditary cancer susceptibility may benefit from a personalized risk management. They should be tested for mutations predisposing to EOC and other malignancies. Women who test positive for BRCA1 or BRCA2 mutations, or other genetic defects predisposing to ovarian cancer, should be referred for clinical and radiological surveillance. However, no consensus has been reached about the optimum design of surveillance: Tumors may metastasize before reaching a minimum size for sonographic detection and the serum level of cancer antigen 125 has not been proven to be a reliable marker either. A combined approach based on more sensitive imaging techniques, the inclusion of additional serum biomarkers may yield better results [4].

Even in the absence of pathological findings, carriers may undergo prophylactic salpingo-oophorectomy, but infertility and premature menopause argue against such an intervention [11]. Maintenance of the ovaries until the age of natural menopause may at least alleviate the symptoms of premature menopause. In this context, recent studies point out that high-grade ovarian cancers often originate from the Fallopian tubes and that sole salpingectomy may pose a valuable alternative to salpingo-oophorectomy: The risk of life-threatening ovary cancer would be reduced, but women wouldn't have to suffer the complications of estrogen deficiency [11].

Summary

There are distinct types of ovarian cancer and they are classified according to the type of cell from which they originate. In this context, ovarian cancer includes epithelial, germ cell, and stromal tumors, among others [2]. Epithelial malignancies are most common and account for about 90% of all cases. They derive from cells on the surface of the ovary. In clinical practice, however, the differentiation of EOC and epithelial tumors arising from the Fallopian tube, foci of endometriosis, or the peritoneum may pose a major challenge [12].

Although EOC patients are far from asymptomatic, they aren't usually diagnosed with ovarian cancer until advanced stages of the disease [2]. EOC-associated symptoms often resemble those of common gastrointestinal and gynecological disorders, and early-stage EOC is difficult to identify by means of sonography. Still, every effort should be made to identify ovarian neoplasms as early as possible: The tumor stage at the time of diagnosis is the most important prognostic factor. Women who are diagnosed with stage 1 or 2 EOC are likely to survive for more than five years, but mortality is high among those diagnosed with advanced-stage disease [3]. Therapy mainly relies on surgery and adjuvant chemotherapy.

Patient Information

Malignant neoplasms of the ovary may originate from distinct types of cells. Tumors that arise from cells on the surface of the ovary are classified as epithelial ovarian cancer. It is the most common type of ovarian cancer. Affected women may suffer from abdominal or pelvic pain, a premature feeling of fullness, bloating, urinary urgency and frequency for prolonged periods of time before the disease is diagnosed. It is important not to ignore these symptoms although they may just be caused by common gastrointestinal or gynecological disorders. Women who are diagnosed in early stages of the disease have a much better prognosis than those presenting with advanced-stage ovarian cancer.

References

Article

  1. Bast RC, Jr., Hennessy B, Mills GB. The biology of ovarian cancer: new opportunities for translation. Nat Rev Cancer. 2009; 9(6):415-428.
  2. Rooth C. Ovarian cancer: risk factors, treatment and management. Br J Nurs. 2013; 22(17):S23-30.
  3. Jessmon P, Boulanger T, Zhou W, Patwardhan P. Epidemiology and treatment patterns of epithelial ovarian cancer. Expert Rev Anticancer Ther. 2017; 17(5):427-437.
  4. Mathieu KB, Bedi DG, Thrower SL, Qayyum A, Bast RC, Jr. Screening for ovarian cancer: imaging challenges and opportunities for improvement. Ultrasound Obstet Gynecol. 2017.
  5. Kaku T, Ogawa S, Kawano Y, et al. Histological classification of ovarian cancer. Med Electron Microsc. 2003; 36(1):9-17.
  6. Rosen DG, Yang G, Liu G, et al. Ovarian cancer: pathology, biology, and disease models. Front Biosci (Landmark Ed). 2009; 14:2089-2102.
  7. Tavassoli F, Devilee P., eds. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Breast and Female Genital Organs. Lyon, France: IARC Press; 2003.
  8. Zeppernick F, Meinhold-Heerlein I. The new FIGO staging system for ovarian, fallopian tube, and primary peritoneal cancer. Arch Gynecol Obstet. 2014; 290(5):839-842.
  9. Francis J, Coakley N, Elit L, Mackay H. Systemic therapy for recurrent epithelial ovarian cancer: a clinical practice guideline. Curr Oncol. 2017; 24(6):e540-e546.
  10. Rojas V, Hirshfield KM, Ganesan S, Rodriguez-Rodriguez L. Molecular Characterization of Epithelial Ovarian Cancer: Implications for Diagnosis and Treatment. Int J Mol Sci. 2016; 17(12).
  11. Petrucelli N, Daly MB, Pal T. BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.
  12. Toss A, Tomasello C, Razzaboni E, et al. Hereditary ovarian cancer: not only BRCA 1 and 2 genes. Biomed Res Int. 2015; 2015:341723.

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Last updated: 2019-07-11 20:30