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Deep Learning Technology: Sebastian Arnold, Betty van Aken, Paul Grundmann, Felix A. Gers and Alexander Löser. Learning Contextualized Document Representations for Healthcare Answer Retrieval. The Web Conference 2020 (WWW'20)
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There is no simple and reliable way to test for ovarian cancer in women who do not have any signs or symptoms. The Pap test does not screen for ovarian cancer.
Screening is not recommended in women who are at average risk, as evidence does not support a reduction in death and the high rate of false positive tests may lead to unneeded surgery, which is accompanied by its own risks.
Ovarian cancer is usually only palpable in advanced stages. Screening is not recommended using CA-125 measurements, HE4 levels, ultrasound, or adnexal palpation in women who are at average risk. Risk of developing ovarian cancer in those with genetic factors can be reduced. Those with a genetic predisposition may benefit from screening. This high risk group has benefited with earlier detection.
Ovarian cancer has low prevalence, even in the high-risk group of women from the ages of 50 to 60 (about one in 2000), and screening of women with average risk is more likely to give ambiguous results than detect a problem which requires treatment. Because ambiguous results are more likely than detection of a treatable problem, and because the usual response to ambiguous results is invasive interventions, in women of average risk, the potential harms of having screening without an indication outweigh the potential benefits. The purpose of screening is to diagnose ovarian cancer at an early stage, when it is more likely to be treated successfully.
Screening with transvaginal ultrasound, pelvic examination, and CA-125 levels can be used instead of preventative surgery in women who have BRCA1 or BRCA2 mutations. This strategy has shown some success.
For surface epithelial-stromal tumors, the most common sites of metastasis are the pleural cavity (33%), the liver (26%), and the lungs (3%).
Diagnosis of ovarian cancer starts with a physical examination (including a pelvic examination), a blood test (for CA-125 and sometimes other markers), and transvaginal ultrasound. Sometimes a rectovaginal examination is used to help plan a surgery. The diagnosis must be confirmed with surgery to inspect the abdominal cavity, take biopsies (tissue samples for microscopic analysis), and look for cancer cells in the abdominal fluid. This helps to determine if an ovarian mass is benign or malignant.
Ovarian cancer's early stages (I/II) are difficult to diagnose because most symptoms are nonspecific and thus of little use in diagnosis; as a result, it is rarely diagnosed until it spreads and advances to later stages (III/IV). Additionally, symptoms of ovarian cancer may appear similar to irritable bowel syndrome. In patients in whom pregnancy is a possibility, BHCG level can be measured during the diagnosis process. Serum alpha-fetoprotein, neuron-specific enolase, and lactate dehydrogenase can be measured in young girls and adolescents with suspected ovarian tumors as younger patients are more likely to have malignant germ cell tumors.
A physical examination, including a pelvic examination, and a pelvic ultrasound (transvaginal or otherwise) are both essential for diagnosis: physical examination may reveal increased abdominal girth and/or ascites (fluid within the abdominal cavity), while pelvic examination may reveal an ovarian or abdominal mass. An adnexal mass is a significant finding that often indicates ovarian cancer, especially if it is fixed, nodular, irregular, solid, and/or bilateral. 13–21% of adnexal masses are caused by malignancy; however, there are other benign causes of adnexal masses, including ovarian follicular cyst, leiomyoma, endometriosis, ectopic pregnancy, hydrosalpinx, tuboovarian abscess, ovarian torsion, dermoid cyst, cystadenoma (serous or mucinous), diverticular or appendiceal abscess, nerve sheath tumor, pelvic kidney, ureteral or bladder diverticulum, benign cystic mesothelioma of the peritoneum, peritoneal tuberculosis, or paraovarian cyst. Ovaries that can be felt are also a sign of ovarian cancer in postmenopausal women. Other parts of a physical examination for suspected ovarian cancer can include a breast examination and a digital rectal exam. Palpation of the supraclavicular, axillary, and inguinal lymph nodes may reveal lymphadenopathy, which can be indicative of metastasis. Another indicator may be the presence of a pleural effusion, which can be noted on auscultation.
When an ovarian malignancy is included in a list of diagnostic possibilities, a limited number of laboratory tests are indicated. A complete blood count and serum electrolyte test is usually obtained; when an ovarian cancer is present, these tests often show a high number of platelets (20–25% of people) and low blood sodium levels due to chemical signals secreted by the tumor. A positive test for inhibin A and inhibin B can indicate a granulosa cell tumor.
A blood test for a marker molecule called CA-125 is useful in differential diagnosis and in follow up of the disease, but it by itself has not been shown to be an effective method to screen for early-stage ovarian cancer due to its unacceptable low sensitivity and specificity. CA-125 levels in premenopausal people over 200 U/mL may indicate ovarian cancer, as may any elevation in CA-125 above 35 U/mL in post-menopausal people. CA-125 levels are not accurate in early stage ovarian cancer, as fully half of stage I ovarian cancer patients have a normal CA-125 level. CA-125 may also be elevated in benign (non-cancerous) conditions, including endometriosis, pregnancy, uterine fibroids, menstruation, ovarian cysts, systemic lupus erythematosus, liver disease, inflammatory bowel disease, pelvic inflammatory disease, and leiomyoma. HE4 is another candidate for ovarian cancer testing, though it has not been extensively tested. Other tumor markers for ovarian cancer include CA19-9, CA72-4, CA15-3, immunosuppressive acidic protein, haptoglobin-alpha, OVX1, mesothelin, lysophosphatidic acid, osteopontin, and fibroblast growth factor 23.
Use of blood test panels may help in diagnosis. The OVA1 panel includes CA-125, beta-2 microglobulin, transferrin, apolipoprotein A1, and transthyretin. OVA1 above 5.0 in premenopausal people and 4.4 in postmenopausal people indicates a high risk for cancer. A different set of laboratory tests is used for detecting sex cord-stromal tumors. High levels of testosterone or dehydroepiandrosterone sulfate, combined with other symptoms and high levels of inhibin A and inhibin B can be indicative of an SCST of any type.
Current research is looking at ways to consider tumor marker proteomics in combination with other indicators of disease (i.e. radiology and/or symptoms) to improve diagnostic accuracy. The challenge in such an approach is that the disparate prevalence of ovarian cancer means that even testing with very high sensitivity and specificity will still lead to a number of false positive results, which in turn may lead to issues such as performing surgical procedures in which cancer is not found intraoperatively. Genomics approaches have not yet been developed for ovarian cancer.
CT scanning is preferred to assess the extent of the tumor in the abdominopelvic cavity, though magnetic resonance imaging can also be used. CT scanning can also be useful for finding omental caking or differentiating fluid from solid tumor in the abdomen, especially in low malignant potential tumors. However, it may not detect smaller tumors. Sometimes, a chest x-ray is used to detect metastases in the chest or pleural effusion. Another test for metastatic disease, though it is infrequently used, is a barium enema, which can show if the rectosigmoid colon is involved in the disease. Positron emission tomography, bone scans, and paracentesis are of limited use; in fact, paracentesis can cause metastases to form at the needle insertion site and may not provide useful results. However, paracentesis can be used in cases where there is no pelvic mass and ascites is still present. A physician suspecting ovarian cancer may also perform mammography or an endometrial biopsy (in the case of abnormal bleeding) to assess the possibility of breast malignancies and endometrial malignancy, respectively. Vaginal ultrasonography is often the first-line imaging study performed when an adnexal mass is found. Several characteristics of an adnexal mass indicate ovarian malignancy; they usually are solid, irregular, multilocular, and/or large; and they typically have papillary features, central vessels, and/or irregular internal septations. However, SCST has no definitive characteristics on radiographic study.
To definitively diagnose ovarian cancer, a surgical procedure to inspect the abdomen is required. This can be an open procedure (laparotomy, incision through the abdominal wall) or keyhole surgery (laparoscopy). During this procedure, suspicious tissue is removed and sent for microscopic analysis. Usually, this includes a unilateral salpingo-oophorectomy, removal of a single affected ovary and Fallopian tube. Fluid from the abdominal cavity can also be analyzed for cancerous cells. If cancer is found, this procedure can also be used to determine the extent of its spread (which is a form of tumor staging).
A retrospective study of 83 women with sex cord–stromal tumours (73 with granulosa cell tumour and 10 with Sertoli-Leydig cell tumour), all diagnosed between 1975 and 2003, reported that survival was higher with age under 50, smaller tumour size, and absence of residual disease. The study found no effect of chemotherapy. A retrospective study of 67 children and adolescents reported some benefit of cisplatin-based chemotherapy.
A prospective study of ovarian sex cord–stromal tumours in children and adolescents began enrolling participants in 2005.
For more general information, see ovarian cancer.
For advanced cancer of this histology, the US National Cancer Institute recommends a method of chemotherapy that combines intravenous (IV) and intraperitoneal (IP) administration. Preferred chemotherapeutic agents include a platinum drug with a taxane.
A pelvic examination may detect an adnexal mass. A CA-125 blood test is a nonspecific test that tends to be elevated in patients with tubal cancer. More specific tests are a gynecologic ultrasound examination, a CT scan, or an MRI of the pelvis.
Occasionally, an early fallopian tube cancer may be detected serendipitously during pelvic surgery.
While cancer is generally considered a disease of old age, children can also develop cancer. In contrast to adults, carcinomas are exceptionally rare in children..
The two biggest risk factors for ovarian carcinoma are age and family history.
10-year survival rates for mucinous tumors is excellent in the absence of invasion.
In the case of borderline tumors confined to the ovary and malignant tumors without invasion, the survival rates are 90% or greater. In invasive mucinous cystadenocarcinomas, the survival is approximately 30%
Prognosis depends to a large degree on the stage of the condition. In 1991 it was reported that about half of the patients with advanced stage disease survived 5 years with a surgical approach followed by cisplatinum-based chemotherapy.
Presence of an ovarian tumour plus hormonal disturbances suggests a Leydig cell tumour, granulosa cell tumour or thecoma. However, hormonal disturbances, in Leydig tumours, is present in only 2/3 of cases. Testicular Leydig cell tumours can be detected sonographically, ultrasound examinations may be ordered in the event of a palpable scrotal lump, however incidental identification of these lesions is also possible.
A conclusive diagnosis is made via histology, as part of a pathology report made during or after surgery. Reinke crystals are classically found in these tumours and help confirm the diagnosis, although they are seen in less than half of all Leydig cell tumours. See also Sex cord-stromal tumour. Immunohistochemical markers of Leydig cell tumours include inhibin-alpha, calretinin, and melan-A.
The 1997 International Germ Cell Consensus Classification is a tool for estimating the risk of relapse after treatment of malignant germ cell tumor.
A small study of ovarian tumors in girls reports a correlation between cystic and benign tumors and, conversely, solid and malignant tumors. Because the cystic extent of a tumor can be estimated by ultrasound, MRI, or CT scan before surgery, this permits selection of the most appropriate surgical plan to minimize risk of spillage of a malignant tumor.
Access to appropriate treatment has a large effect on outcome. A 1993 study of outcomes in Scotland found that for 454 men with non-seminomatous (non-germinomatous) germ cell tumors diagnosed between 1975 and 1989, 5-year survival increased over time and with earlier diagnosis. Adjusting for these and other factors, survival was 60% higher for men treated in a cancer unit that treated the majority of these men, even though the unit treated more men with the worst prognosis.
Choriocarcinoma of the testicles has the worst prognosis of all germ cell cancers
Diagnosis of EIN lesions is of clinical importance because of the increased risk of coexisting (39% of women with EIN will be diagnosed with carcinoma within one year) or future (the long term endometrial cancer risk is 45 times greater for a woman with EIN compared to one with only a benign endometrial histology) endometrial cancer. Diagnostic terminology is that used by pathologists, physicians who diagnose human disease by examination of histologic preparations of excised tissues. Critical distinctions in EIN diagnosis are separation from benign conditions such as benign endometrial hyperplasia (a field effect in endometrial tissue caused by excessive stimulation by the hormone estrogen), and cancer.
The spectrum of disease which must be distinguished from EIN (Table II) includes benign endometrial hyperplasia and carcinoma:
Table II: Disease classes that need to be distinguished from EIN.
EIN may be diagnosed by a trained pathologist by examination of tissue sections of the endometrium. All of the following diagnostic criteria must be met in a single area of one tissue fragment to make the diagnosis (Table III).
Table III: EIN diagnosis.
Women with benign germ cell tumors such as mature teratomas (dermoid cysts) are cured by ovarian cystectomy or oophorectomy. In general, all patients with malignant germ cell tumors will have the same staging surgery that is done for epithelial ovarian cancer. If the patient is in her reproductive years, an alternative is unilateral salpingoophorectomy, while the uterus, the ovary, and the fallopian tube on the opposite side can be left behind. This isn't an option when the cancer is in both ovaries. If the patient has finished having children, the surgery involves complete staging including salpingoophorectomy on both sides as well as hysterectomy.
Most patients with germ cell cancer will need to be treated with combination chemotherapy for at least 3 cycles. The chemotherapy regimen most commonly used in germ cell tumors is called PEB (or BEP), and consists of bleomycin, etoposide, a platinum-based antineoplastic (cisplatin).
Presence of an ovarian tumour plus hormonal disturbances suggests a Sertoli–Leydig cell tumour. However, hormonal disturbance is present in only 2/3 of cases. A conclusive diagnosis is made via histology, as part of a pathology report made during or after surgery. See also Sex cord-stromal tumour.
PUNLMPs are treated like non-invasive low grade papillary urothelial carcinomas, excision and regular follow-up cystoscopies.
There is a rare occurrence of a pelvic recurrence of a low-grade superficial TCC after cystectomy. Delayed presentation with recurrent low-grade urothelial carcinoma is an unusual entity and potential mechanism of traumatic implantation should be considered. Characteristically low-grade tumors are resistant to systemic chemotherapy and curative-intent surgical resection of the tumor should be considered.
Grading of carcinomas refers to the employment of criteria intended to semi-quantify the degree of cellular and tissue maturity seen in the transformed cells relative to the appearance of the normal parent epithelial tissue from which the carcinoma derives.
Grading of carcinoma is most often done after a treating physician and/or surgeon obtains a sample of suspected tumor tissue using surgical resection, needle or surgical biopsy, direct washing or brushing of tumor tissue, sputum cytopathology, etc. A pathologist then examines the tumor and its stroma, perhaps utilizing staining, immunohistochemistry, flow cytometry, or other methods. Finally, the pathologist classifies the tumor semi-quantitatively into one of three or four grades, including:
- Grade 1, or well differentiated: there is a close, or very close, resemblance to the normal parent tissue, and the tumor cells are easily identified and classified as a particular malignant histological entity;
- Grade 2, or moderately differentiated: there is considerable resemblance to the parent cells and tissues, but abnormalities can commonly be seen and the more complex features are not particularly well-formed;
- Grade 3, or poorly differentiated: there is very little resemblance between the malignant tissue and the normal parent tissue, abnormalities are evident, and the more complex architectural features are usually rudimentary or primitive;
- Grade 4, or undifferentiated carcinoma: these carcinomas bear no significant resemblance to the corresponding parent cells and tissues, with no visible formation of glands, ducts, bridges, stratified layers, keratin pearls, or other notable characteristics consistent with a more highly differentiated neoplasm.
Although there is definite and convincing statistical correlation between carcinoma grade and tumor prognosis for some tumor types and sites of origin, the strength of this association can be highly variable. It may be stated generally, however, that the higher the grade of the lesion, the worse is its prognosis.
PUNLMPs are exophytic lesions that appear friable to the naked eye and when imaged during cystoscopy.
They are definitively diagnosed after removal by microscopic examination by pathologists.
Histologically, they have a papillary architecture with slender fibrovascular cores and rare basal mitoses. The papillae rarely fuse and uncommonly branch. Cytologically, they have uniform nuclear enlargement.
They cannot be reliably differentiated from low grade papillary urothelial carcinomas using cytology, and their diagnosis (vis-a-vis low grade papillary urothelial carcinoma) has a poor inter-rater reliability.
Pathologic grading and staging tumors are:
graded by the degree of cellular atypia (G1->G3), and
staged:
The usual chemotherapy regimen has limited efficacy in tumours of this type, although Imatinib has shown some promise. There is no current role for radiotherapy.
The usual treatment is surgery. The surgery for females usually is a fertility-sparing unilateral salpingo-oophorectomy. For malignant tumours, the surgery may be radical and usually is followed by adjuvant chemotherapy, sometimes by radiation therapy. In all cases, initial treatment is followed by surveillance. Because in many cases Leydig cell tumour does not produce elevated tumour markers, the focus of surveillance is on repeated physical examination and imaging.
In males, a radical inguinal orchiectomy is typically performed. However, testes-sparing surgery can be used to maintain fertility in children and young adults. This approach involves an inguinal or scrotal incision and ultrasound guidance if the tumour is non-palpable. This can be done because the tumour is typically unifocal, not associated with precancerous lesions, and is unlikely to recur.
The prognosis is generally good as the tumour tends to grow slowly and usually is benign: 10% are malignant. For malignant tumours with undifferentiated histology, prognosis is poor.
The usual treatment is surgery. The surgery usually is a fertility-sparing unilateral salpingo-oophorectomy. For malignant tumours, the surgery may be radical and usually is followed by adjuvant chemotherapy, sometimes by radiation therapy. In all cases, initial treatment is followed by surveillance. Because in many cases Sertoli–Leydig cell tumour does not produce elevated tumour markers, the focus of surveillance is on repeated physical examination and imaging. Given that many cases of Sertoli–Leydig cell tumor of the ovary are hereditary, referral to a clinical genetics service should be considered.
The prognosis is generally good as the tumour tends to grow slowly and usually is benign: 25% are malignant. For malignant tumours with undifferentiated histology, prognosis is poor.
Appearance and location of the tumor is enough to identify it as a mammary tumor. Biopsy will give type and invasiveness of the tumor. In addition, newer studies showed that certain gene expression patterns are associated with malignant behaviour of canine mammary tumors.
Surgical removal is the treatment of choice, but chest x-rays should be taken first to rule out metastasis. Removal should be with wide margins to prevent recurrence, taking the whole mammary gland if necessary. Because 40 to 50 percent of dog mammary tumors have estrogen receptors, spaying is recommended by many veterinarians. A recent study showed a better prognosis in dogs that are spayed at the time of surgery or that had been recently spayed. However, several other studies found no improvement of disease outcome when spaying was performed after the tumor had developed. Chemotherapy is rarely used.
Since Krukenberg tumors are secondary (metastatic), management might logically be driven by identifying and treating the primary cancer. The optimal treatment of Krukenberg tumors is unclear. The role of surgical resection has not been adequately addressed but if metastasis is limited to the ovaries, surgery may improve survival. The role of chemotherapy and/or radiotherapy is uncertain but may sometimes be beneficial.
"Malignant" serous tumours are solid, may be cystic and often show haemorrhage and necrosis. They are lined by a complex papillary pattern with presence of nuclear anaplasia.
Serous carcinomas often have bulky peritoneal and omental metastases, and spread to the lymph nodes is frequent.
Unsurprisingly, 5-year survival decreases as the stage increases.
There is a 25% survival rate with a stage III serous carcinoma.
Staging:
- Stage I - Tumour growth limited to ovaries.
- Stage II - Growth involving one or both ovaries with pelvic extension.
- Stage III - Tumour involving one or both ovaries with implants outside pelvis.
- Stage IV- Tumour involving one or both ovaries with presence of distant metastasis.
"Benign" serous tumours are unilocular (have one lobe); however if very large may be multilocular, contain clear fluid and have a smooth lining composed of columnar epithelial cells with cilia. On gross examination, the serous tumor may present as either a cystic lesion in which the papillary epithelium is contained within a few fibrous walled cysts, or the papillary projections may be away from the surface epithelium. Surgery is curative.
These tumours do better than other types of epithelial tumours of the ovary.