Ovarian Malignancies
The Ovarian tumor is a silent pathology able to involve one or both ovaries. This is the result of abnormal cells with the ability to invade or spread to other parts of the pelvis and through the entire body. Generally, there may be no symptoms or simply can be manifested in mild symptoms. The signs become more noticeable as the tumor increases in size
Mild signs of bloating or pelvic discomfort, constipation and loss of appetite can represent some early signs of an ovarian tumor. These tumors have a tendency in spreading along the lining of the abdomen to reach the lymph nodes of the groin, and later, the lungs and the liver.
The risk of ovarian cancer increases with the lack of ovulation over a lifetime of a woman especially for the one who have never bore any children, or those who have started their menstrual period very early as well as the one who reached menopause at an older age. There are other risk factors related to hormonal therapy around the menopause, or obesity and women receiving fertility medication.
Others factors may decrease the risk especially with hormonal birth control pill. Tubal ligation and breast feeding. 10% of cases are inherited genetical risks like with the BRCA1 or the BRCA2 who share 50% of the chances in developing the disease.
There are 5 main subtypes of ovarian carcinomas originating from the cells covering the ovaries from the fallopian tubes to the gem stem. The carcinomas are the most prevalent ovarian cancers comprising more than 95 % of the cases. The less common forms are the germ cell tumors and the sex cord stromal tumors. Screening is generally not recommended in women at risk because of the high rate of false positivity which may lead to unnecessary surgical procedures.
A diagnosis can easily be obtained through a biopsy of the tissue. Women at high risk may have their ovaries removed as a preventive measure. If caught and treated at an early stage, ovarian cancer is often curable with a combination of surgery, radiation therapy and chemotherapy. The subtype of cancer may dictate variations in the treatment but the overall five-year survival rate is almost 50% in the United States. The outcomes are worse in other countries around the world.
240,00 women were diagnosed with ovarian carcinomas in 2012 and the number increased to 1.2 million and resulting in more than 160,000 deaths in the world.
Ovarian carcinomas are the seventh-most-common cancer in women and count for the eight-most-common cause of death. Generally diagnosed in the mid-sixties, death is more common among women from North America and Europe than woman from Africa and Asia.
What are the early symptoms of ovarian carcinomas?
The early signs or symptoms of such malignancy can be completely absent or present subtle signs of pain for months before being recognized or diagnosed. Gastrointestinal symptoms reminding an irritable bowel syndrome can be observed. At the beginning, the process is painless and the symptoms can be related to the subtype or borderline tumor with low-malignant potential not yet identifiable by ultrasound and unable to increase the level of CA-125. There may be abdominal distension or pelvic pain as typical symptoms with this pathology. The mass is not generally large although a large mass has a tendency of being benign un nature.
Any woman with an ovarian cancer may present with early bloating, abdominal or pelvic discomfort, even back pain possibly. Pre- or post-menopausal bleeding is a common finding. Irregular menstruation, bleeding and/or pain after or during sexual intercourse. General fatigue, loss of appetite, diarrhea, heartburn, constipation, nausea, frequent urination or urinary urgency can also be seen as symptoms. Later, the growing mass can torsion or cause more pelvic pain by simply placing pressure over the abdominopelvic organs. The tumor may be aggressive enough to have already spread with metastasis causing a “Sister Mary Joseph nodule”. If it is a teratoma, the spreading of the teratoma through the abdomen or the pelvis can create a teratoma syndrome or “peritoneal gliomatosis”.
Patient may experience menorrhagia or metrorrhagia with abnormal vaginal bleeding especially after menopause. Other symptoms like hirsutism, abdominal pain, virilization with an adnexal mass may follow with the seeding through the abdomen. In young adolescents or in children, more abdominal pain and bleeding can be encountered especially when these tumors are sex-cord-stromal tumors. They generally impose an early puberty, abdominal pain and distention. In the process, an accumulation of fluid can be seen in the peritoneal cavity with or without the presence of lymph nodes and even a pleural effusion can be noted.
It is believed that ovarian cancer is related to the amount of time spent ovulating. A woman who has never has children becomes a risk factor for ovarian cancer. The ovulation is suppressed during pregnancy and it is shown that women who have never been pregnant, have twice the risk of having ovarian cancer. The one with a longer period of ovulation may have presented with an early first menstruation or maybe a late menopause, placing them as well as a risk factor to develop ovarian cancer. More, obesity and hormonal replacement may raise also the risk.
It is beneficial for women to breastfeed because in breast feeding, the re-appearance of the menstruations will be delayed, and the same can be achieved in taking any oral contraceptive. The risk of ovarian cancer is also reduced when tubal ligation with bilateral ovariectomies is performed or if a total hysterectomy is performed with the removal of the ovaries. Age is definitely a risk factor as well.
The period of Fertility contributes to the formation of the ovarian tumors although the link has been disputed in many studies. The drugs used also may be associated to a higher risk for borderline tumors formation especially among women who have never been pregnant. It seems that the epithelial form of ovarian cancer is seen more frequently among this group. The cause remains unclear. Others think that the fact that a woman is infertile, may raise the incidence.
In women with Polycystic Ovary Disease and Endometriosis, there is a strong association with ovarian cancer which may need in time to be confirmed. The postmenopausal hormone replacement (HRT) has a high chance to increase the risk of ovarian cancer especially when combined Estrogen and Progesterone are known to increase the risk of mucinous tumors as well as clear cell and endometrioid tumors of the uterus while such patient suffers also of endometriosis. We have already discussed the fact that menopause, with obesity increase the risk of ovarian cancer. Another study has demonstrated an association between taller women and ovary cancer.
There is a family history of ovarian cancer in people with hereditary non-polyposis colon cancer (Lynch syndrome) and those with BRCA-1 and BRCA-2 gene mutations. The major genetic risk factor for ovarian cancer is a mutation in the BRCA1 and BRCA2 or in the DNA mismatch repair (10%). Only one allele needs to mutate in order to have a person at risk but the gene can be inherited from the father or the mother with variable penetrance. Mutations in BRCA1 have a lifetime risk (45%) while the one from BRCA2 are less risky (10%). The BRCA associated ovarian cancers can develop 15 years prior to any other ovarian cancer because the individual who inherit the allele need only one mutation to start the process of carcinogenesis while people with two normal genes will need to acquire two mutations.
In the USA, 5 % of women with a first-degree relative living with an ovarian cancer, will develop also an ovarian cancer placing the other affected members of the family at a triple risk. 5-10% of ovarian cancers have a genetic cause but the BRCA are more associated to the high-grade serous non-mucinous epithelial type.
A family history of endometrial cancer, colon cancer or gastro-intestinal cancers may indicate the presence of a syndrome” Hereditary nonpolyposis colorectal cancer” (Lynch Syndrome) with high chances in developing different cancers. Many genetic mutations are associated to this syndrome including MSH2, MLH1, MLH6, PMS1, PMS2 and carry a 12% risk of developing ovarian cancer. European Jewish descents, Icelandic descents. Hungarian descents are at a high risk for epithelial ovarian cancer. Estrogen receptor beta gene (ESR2) seems to provide an answer to the pathogenesis and the therapy. Many other genes were found to be associated with ovarian cancer like BRIP1, CHD1, PalB2, RADS1C etc.
Some rare genetic disorders have been found to be associated with ovarian cancer like Peutz-Jeghers syndrome, Ollier’s disease, Maffucci’s syndrome even benign fibroma have been implicated in the formation of a nevoid basal cell carcinoma syndrome.
In the industrialized nations with the exception of Japan, there is a higher rate of epithelial ovarian cancers. Caucasians have a 40% rate higher than black and Hispanics because of their socioeconomic conditions and the fact that white women have a tendency in having fewer children. Studies have found a correlation between dairy consumption and ovarian cancer but it is not well confirmed. Red meat or processed meat may have as well a relation to a higher rate of ovarian cancer.
Pesticides, perineal talc and herbicides are also implicated in the risk of ovarian cancer although controversial and not really proven. Alcohol or smoking or low vitamin D have not been also investigated for possibly be responsible of inclusion ovarian cysts while smoking tobacco may be associated with a higher risk of mucinous ovarian cancer but a lower risk for sex cord stromal tumors. Human papilloma virus which is known to cause some cervical cancer. Has been disproven to be a risk factor ovarian cancer. Prolonged sitting and older age maybe associated with a higher mortality rate from epithelial ovarian cancer.
A diet high in animal fats seems to play a little role in in the genesis of ovarian cancer but the connection is not too clear. A low-fat diet high in carotene, fibers and vitamins and vegetable can be protective. A higher level of C-reacting protein seems to be paired with a higher risk of ovarian cancer while high caffein consummation is associated with a low risk.
There are some protective factors like the suppression of the ovulation and the inflammation can be protective. Breast feeding, Pregnancy, combined with contraceptives intake can become protective factors. Each birth decreases the risks of ovarian cancers and combined with oral contraceptives; ti can reduce the risks of 50%. The use of Aspirin or Acetaminophen medications maybe associated to a lower risk of ovarian cancer. Tubal ligation is also protective for all women especially the one with the BRCA1 mutation but not with the BRCA2 mutation. Hysterectomy reduces the risk and the removal of the Fallopian tubes and the ovaries (salpingo-oophorectomy) will reduce the risk.
The diagnosis of an ovarian cancer starts with the physical examination with a pelvic examination, a lab test for a CA-125 or other markers, a vaginal ultrasound. It is important to know that if surgery is planned, a rectovaginal examination is mandatory. Ovarian cancer at an earlier stage can be difficult to diagnose because of the paucity of the symptoms and often the diagnosis is confirmed through the surgical procedure after inspection of the abdominal cavity examination where biopsies are taken to assure a diagnosis. Other tissue like peritoneal fluids can help also in the diagnosis to determine if the process is benign or malignant. Most often, symptoms are non-specific and it may be difficult to make any diagnosis unless we are dealing with an advanced stage.
The pelvic ultrasound is essential for a proper diagnosis. An ovarian mass or an ascites can be discovered or simply an adnexal mass and one has to remember that in such case, 20% of those masses are malignant, although many benign masses can be also discovered like an ovarian follicular cyst, a leiomyoma, an ectopic pregnancy. Even a state of endometriosis can mimic a mass. Many pathologies can mimic a mass starting with an inflamed appendix to an abscess or any disease of the peritoneum or the bowels like a diverticulum etc. Occasionally an inguinal or supraclavicular lymph node can pinpoint toward the diagnosis.
Laboratory studies should look for a complete blood test with platelets count and serum electrolytes. Near 25% of patient suffering from such problem may present with a high number of platelets and a low sodium level due to the chemicals secreted by the tumors. Inhibin A or B can indicate a granulosa tumor. A blood test to search for a marker molecule called CA-125 is useful in the differential diagnosis and in the follow-up of the disease, but by itself it, has not been shown to be an effective method in screen for early-stage ovarian cancer due to its unacceptable low sensitivity and specificity. If a patient in a stage of menopause is seen with a CA-125 above 200 U/mL, such value may indicate the possibility of an ovarian cancer. Elevation may be also elevated in non-cancerous conditions like endometriosis, pregnancy. Uterine fibroids and even menstruation etc. Other tumors may excrete high level of testosterone. Perhaps, a genomic approach will soon be developed.
The CT-Scan is the preferred diagnostic tool to assess the extension of the tumor in the peritoneal cavity. MRI can supplement the search for metastasis especially with omental seeding. Chest X-rays are useful to detect lesions in the thoracic cavity or in the lungs or a pleural effusion. Barium enema is useful to evaluate the rectosigmoid. Mammograms or endometrial biopsy in patients with vaginal bleeding can help in the diagnosis of an uterine cancer. Vaginal ultrasonography is almost always done to check on adnexal masses which are generally solid or multilocular and irregular.
A surgical approach via a laparotomy will allow a better evaluation of the abdominal cavity or a laparoscopy. Suspicious tissues can be removed and sent to pathology for microscopic analysis. Salpingo-oophorectomies, affecting a diseased ovary or a Fallopian tube with or without fluid from the cavity can help with the diagnosis and allow the surgeon to stage the disease if cancer is discovered and creating a risk of malignancy index (RMI). The higher the RMI, the greater the chances in having an ovarian cancer. Number reaching 200-250 indicate a higher risk in having an ovarian cancer. The RMI is calculated based on the ultrasound score x menopausal score x CA-125 level in U/ml. Others can use the Risk of Ovarian Cancer Algorithm (ROCA) which observe the levels through time. The RMI remains the best technique. Others have used the Q-cancer for ovary… etc. Ovarian Cancers will then be classified by their microscopic appearance and the histology will dictate the clinical treatment, management and prognosis.
Ovarian cancers are histologically and genetically divided in two types mainly with low histologic grade (mucinous, endometrioid, and clear-cell carcinomas) and high histologic grade (serous carcinoma and carcinosarcoma). We will not be able to discuss the characteristics of all tumors of the ovaries and their treatments but we wanted to bring to the lectors the most recent diagnostic tools a physician has in his armamentarium to diagnose and approach women with ovarian tumors. I would not like to conclude without mentioning the germ cell tumors with isochromosome 12 with one arm deleted. Cancer markers are used for choriocarcinomas which are monitored by the Beta HCG or the endodermal sinus tumors with Alpha-fetoprotein.
The germ-cell tumors are generally discovered late while they become a palpable mass but the sex cord tumors can cause ovarian torsion with hemorrhage and be discovered earlier. They frequently metastasized to the nearby lymph nodes. If the tumor ruptures, or causes significant bleeding or the ovaries torses, it can cause significant abdominal pain. They can also secrete hormones which change the menstrual cycle. In 25% of the time, these tumors are discovered during a routine examination. A germ cell tumor can be difficult to discover because of the puberty and the normal menstrual cycles causing pain and pelvic symptoms. It can also mimic a teen pregnancy or an ovarian cyst. This is why blood tests like alpha-fetoprotein, karyotype and Human Chorionic gonadotrophin and liver function test are looked for to diagnose a germ cell tumor.
Dysgerminoma accounts for 35% of the ovarian cancer in young women and this is the most likely gem cell to metastasize to the lymph nodes. Some of these tumors may have mutations in relation to gastrointestinal stromal tumor and others may have a XY karyotype and gonadal dysgenesis or even an X0 karyotype like Turner syndrome (Gonadoblastoma). Most of the time both ovaries are removed because of their high malignity in 40% of the cases.
Teratomas present with disorganized tissue arising from all three embryonic germ layers (ectoderm, mesoderm and endoderm). Immature teratomas have also undifferentiated stem cells making them more malignant than a mature teratoma (dermoid Cyst) in which we can discover all kind of tissue like bone and cartilage, hair, mucus, sebum etc. They affect one ovary and generally metastasize in the peritoneum where they can cause mature teratoma implants (Teratoma syndrome) which are generally benign. They may form adhesions. The most common malignancy from a mature teratoma is a squamous cell carcinoma or rarely some other type of carcinoma like adenocarcinoma, carcinoid tumors etc. At this point they need to be treated with surgical ablation with adjuvant chemotherapy and/or radiation therapy.
The Yolk sac tumor (endodermal sinus tumors) represents 20% of all ovarian malignancies and carry the worst prognosis of the germ tumors. They occur before the menarches (1/3 of cases) or after the menarches (2/3 cases) or after the menarche (1/3 of cases). They are often discovered at a stage 1 but they are generally unilateral until they metastasize and then they seed the peritoneal cavity and spread through the blood stream and the lungs. They grow quickly and recur easily. They are not easy treatable. They are solid but friable, yellow and friable with areas of hemorrhage. They are characterized by the presence of Schiller-Duval bodies which are pathognomonic of such lesion. These lesions secrete alpha-fetoproteins as a marker in the blood.
Embryonal cell carcinoma are rare tumors generally found in mixed tumors. They may also develop in the gonads and change into choriocarcinomas or yolk sac tumors or even teratomas. They occur in the younger persons as early as 14-year-old and secrets as well alpha-fetoproteins and Beta HCG. They are similar to the embryonal cell carcinoma.
Other rarer tumors like the Polyembryomas, the squamous cell carcinomas, the mixed tumors, the secondary tumors from metastasis, and finally borderline tumors etc can be mentioned in the variety of the malignant lesions of the Ovary.
They will demonstrate different level of aggressivity but the FIGO Staging of an ovarian tumor will be determine after surgical approaches, including a formal abdominopelvic laparotomy to perform a Hysterectomy with removal of ovaries and Fallopian tubes and Omentum and lymph nodes (pelvic para-aortic) and even an appendectomy when a mucinous lesion is suspected.
Cytopathology examination will set the staging and impose treatment. In 30% of the cases, ovarian lesions appeared to be confined. 22% have already metastasized to the lymph nodes and the AJCC staging deals with these metastases in describing the extend of the primary tumor (T), the absence or presence of metastasis to the lymph nodes (N) and the absence or the presence of distant metastasis (M). In the FIGO staging, a Grade 1 has the best prognosis because it has well differentiated cell. A grade 2 has moderately differentiated cells and a grade 3 with the worst prognosis, with poorly differentiate cells.
Metastasis in Ovarian cancers are commonly seen in the abdomen because they cell bust through the ovarian capsule into the peritoneal cavity. They generally grow on the surface of organs commonly the peritoneal lining or the omentum to travel to the lymphatic system. They metastasize first to the lymph nodes along the ligaments (broad, round, infundibulopelvic) and second to the other lymph nodes (paraaortic, hypogastric, external Iliac, obturator, inguinal. Ovarian cancer do not metastasize generally to the liver, brain, lungs or kidneys unless dealing with recurrent disease.
Is there a way to prevent such malignancy?
Indeed, individuals with strong genetic risk for ovarian cancer may consider to have a surgical removal earlier as a measure of prevention especially after childbearing consideration. This will reduce as well the risk of developing breast cancer at least to 50% and (6% for ovarian cancer. If you carry the BRCA gene, it is suggested to have the fallopian tubes removed earlier to avoid cancer in the tubes. It may be beneficial to consult a genetic counselor to know if testing for BRCA mutations may be beneficial. Research papers have established possibly a relation between ovarian stimulation during infertility and ovarian cancer.
There is no simple way to screen for ovarian cancer especially when the women are asymptomatic. A Pap smear does not screen for it. Ovarian cancer is only palpable in advanced stages. There is a low prevalence even in high-risk groups. In women above the age of 55, one per 2000. Screening is ambiguous and it is used more to diagnose ovarian cancer at an earlier stage. Transvaginal ultrasound, pelvic examination and CA-125 levels can be used especially in women with BRCA-1 or BRCA-2 mutations.
Once the diagnosis is made and the location to the ovary, the fallopian tubes or the peritoneal seeding is assumed, a gynecologist-oncologist well trained in the specialty can perform surgical treatment or initiate chemotherapy or even radiation therapy. Surgery depends on the extend of the nearby invasion and the extend of the invasion is based on the staging of the tumor. A unilateral or a bilateral ovariectomy and oophorectomy and salpingectomy is a decision taken by the surgeon in the operating room after observation of the extension of the tumoral cell through the omentum, peritoneum and other ovary and tissue, I will hope that one of our specialists can find time to enlighten us on the decision making and on the prognosis in the treatment of such tumor.
Often when extensive bleeding is expected, Tranexamic acid may be administered prior to the surgical procedure to minimize bleeding during the procedure especially if extensive metastasis is encountered. Often a second surgery may become necessary because of the extension of the lesions. The younger the patient, the more chance that a preservation of one ovary will be attempted. In postmenopausal women with a low malignant potential, a hysterectomy and a bilateral salpingo-oophorectomy is generally the preferred option. During staging, the appendix can be also removed especially if the ovarian tumor is a mucinous tumor.
In advanced tumors, a procedure called “debulking” is offered because of extensive metastasis. This procedure is generally done once and is often considered as the stage IV of the disease where tumoral cells are encountered in the transverse fissure of the liver, mesentery, diaphragm with large area of ascites. Tomography (CT of the abdomen) is then used with MRI to assess the functionality of a debulking procedure. Then Chemotherapy can be used to destroy the remaining cancerous cells. I will invite you to invite an oncologist -gynecologist to the discussion to find his point of view and his approach to such a problem. His may also use repeated ‘debulking” or recurrent surgical treatment. It will depend of the extent of the tumor.
During my years of residency, at Howard University hospital, when a surgical approach was mandated, the procedure was done in a specialized operating room where intra-operative radiation therapy will be planned after the “debulking”. The effectiveness of such surgical treatment will depend on the technique used, the completeness of cytoreduction and the extent of the disease. Hormone replacement therapy may be safe in young women but do not change the outcome.
Finally, Chemotherapy has been the standard of care in the treatment of ovarian tumors to treat residual disease. It can be used prior to surgery (neoadjuvant chemotherapy) or in the post operative especially when a tumor has been debulked through surgical resection (adjuvant chemotherapy). Bevacizumab is used when the tumor is partially removed or at a stage IV lesion. Chemotherapy may be curative in 20% of advanced cases. Adjuvant therapy has been found to improve survival rate in the earlier stages. Other drugs are the “Platins” like Cisplatin, Topotecan, Carboplatin etc can be used alone or in combination as an intravenous medication or in the intra peritoneal cavity. These drugs can cause anemia by iron deficiency. In BRCA mutation, Cisplatin has been found effective while Bleomycin used in the Germ-cell malignancies has not shown much effectiveness. Cisplatin is the drug of choice for recurrent disease but if a tumor is determined to be resistant to Cisplatin, Vincristine or Dactinomycin is then used.
Dysgerminomas are effectively treated by radiation therapy although it causes infertility. Radiation does not improve the survival rate in well-dedifferentiated ovarian tumors. Side effects consist in constipation, diarrhea, frequent urination.
60% of ovarian tumors have estrogen receptors and this is a why ovarian cancers rarely respond to hormonal manipulation. Estrogen and Tamoxifen have no effect on the ovarian tumors. An antibody drug (Bevacizumab) is used in the treatment of advanced cancer along with chemotherapy in Europe but has not been approved in the USA. CA-125 was found to be a good marker in the epithelial ovarian cancers and when the marker doubles, there may be a recurrent disease. The alpha-fetoproteins (AFP) and Human Chorionic Gonadotrophin (HCG) are markers for the germ-cells tumors and the Sertoli-Leydig tumors. In women with stromal cancers, Inhibin, Testosterone or Estrogen levels can help in the monitoring. Other tumor markers in the dysgerminomas like Lactate Dehydrogenase, Isozymes LDH-1 and LDH-2 can be looked for in case of recurrency.
Palliative care aims at relieving symptoms to better the quality of life and rendering the patient more comfortable while living with an intractable cancer. The symptoms and the complications can be treated like the pain or the pleural effusion, bowel obstruction etc. Some surgical treatment can be needed like colostomy, Gastrostomy, nephrostomy, Urethral stents, Paracentesis, thoracentesis even Radiation therapy can be added.
Psychological care may be needed when the quality of life is significantly affected. Often, such patient will experience social isolation and may benefit from having social meeting with other survivors. Self-esteem or body images changes, Depression, anxiety, emotional distress can complicate the picture. Sexual issues can also develop like loss of libido, vaginal dryness and the younger the patient, the lesser problems they may have.
Ovarian cancer has a poor outcome generally and it is disproportionally deadly because most of the cases are discovered late and metastasizes early in their development. High-grade tumors metastasizes faster than low-grade tumors in the peritoneal cavity. Diagnosis is generally done when the ovarian tumor has already spread to the other ovary and the peritoneal cavity. 70% of women with advanced disease will respond to treatment and even have complete remission. Brain metastasis is generally seen in stage III/IV although patients may survive more than 8 months after surgical treatment while chemotherapy and radiation therapy can better the outcome.
Ovarian cancers frequently recur after treatment. 20% of stage I and stage II tumors recurs in the abdomen within the 18 months following treatment. Germ-cell tumors and dysgerminomas have a poor prognosis. Ovarian cancer is most often diagnosed after menopause. More advanced tumors may take up to 20-year to relapse. Recurrent sex-cord stromal tumors are typically unresponsive to treatment but apparently not aggressive. Ovarian cancer, remains the most-deadly gynecologic cancer. Black women have twice the risk for sex cord stromal tumors compared to non-black women.
I wanted to write these pages for my daughter Carolyn Lara to extend her knowledge in the field of gynecology while she is attending medical school and for my niece and little cousin Dominique living in Canada who is about ready to undergo pelvic surgery. At the end, I would like to dedicate this article to all the women in the world knowing well how this organ play an important role in the life of everybody.
Maxime Coles MD (Boca Raton FL)
References:
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