Gynecologic Tumor Markers

[Extracted from Emedicine.medscape.com]

Tumor markers are glycoproteins that are usually detected by monoclonal antibodies. Each tumor marker has a variable profile of usefulness for screening, determining diagnosis and prognosis, assessing response to therapy, and monitoring for cancer recurrence. They are produced by tumor cells in response to cancer or certain benign conditions and indicate biological changes that signal the existence of malignancy. These soluble molecules can usually be detected in elevated quantities in the blood, urine, or body tissues of patients with certain types of cancer. They are produced by the tumor itself or by the body in response to the presence of cancer or certain benign conditions. The levels of tumor marker are not altered in all cancer patients, especially in early stage cancer. The level of some tumor markers can be elevated in patients with noncancerous conditions. Following the development of monoclonal antibodies, many new tumor markers have been discovered during the past 2 decades.

Gynecologic malignancies include ovarian cancer, uterine cervical cancer, endometrial cancer, and trophoblastic neoplasms.

Due to the location of ovarian tumors within the abdominal cavity, making a preoperative pathological diagnosis of cancer is difficult without laparotomy. From this point of view, the use of tumor markers that consist of carbohydrate antigens, such as CA-125, in addition to diagnostic imaging are useful in the diagnosis of ovarian cancer. SCC antigen, a marker for squamous cell carcinoma, is clinically useful in the management of advanced cervical cancer. At present, no useful tumor markers exist for endometrial cancer that exhibit both high sensitivity and specificity, although CA-125 is often used in clinical practice. Finally, human chorionic gonadotropin (hCG) serves as an ideal tumor marker for trophoblastic disease; however, the incidence of trophoblastic neoplasms has decreased dramatically with the incorporation of strict clinical management of postmolar disease as well as with the overall decrease in the number of pregnancies.

The use of a tumor marker not only depends on its sensitivity and specificity, but also on its ability to influence decisions between alternative plans for patient management. Use of beta human chorionic gonadotropin (beta-hCG) for monitoring gestational trophoblastic neoplasia has set the standard to which other assays must be compared. Beta-hCG and alpha-fetoprotein have provided useful markers for ovarian germ cell tumors.

Recently, a monoclonal antibody-based immunoassay for CA-125 has been used to monitor the treatment of epithelial ovarian carcinomas. Persistent elevation of CA-125 in serum has generally reflected persistence of disease at second look surveillance procedures. However, CA-125 levels can return to within normal limits and residual disease can be found at laparoscopy or laparotomy. CA-125 shows promise for distinguishing benign from malignant pelvic masses. Several trials are ongoing to determine the potential of CA-125 in combination with other markers to increase earlier detection of occult ovarian cancer.

Tumor markers are glycoproteins that are usually detected by monoclonal antibodies. Each tumor marker has a variable profile of usefulness for screening, determining diagnosis and prognosis, assessing response to therapy, and monitoring for cancer recurrence. They are produced by tumor cells in response to cancer or certain benign conditions and indicate biological changes that signal the existence of malignancy. These soluble molecules can usually be detected in elevated quantities in the blood, urine, or body tissues of patients with certain types of cancer. They are produced by the tumor itself or by the body in response to the presence of cancer or certain benign conditions. The levels of tumor marker are not altered in all cancer patients, especially in early stage cancer. The level of some tumor markers can be elevated in patients with noncancerous conditions. Following the development of monoclonal antibodies, many new tumor markers have been discovered during the past 2 decades.

Gynecologic malignancies include ovarian cancer, uterine cervical cancer, endometrial cancer, and trophoblastic neoplasms.

Due to the location of ovarian tumors within the abdominal cavity, making a preoperative pathological diagnosis of cancer is difficult without laparotomy. From this point of view, the use of tumor markers that consist of carbohydrate antigens, such as CA-125, in addition to diagnostic imaging are useful in the diagnosis of ovarian cancer. SCC antigen, a marker for squamous cell carcinoma, is clinically useful in the management of advanced cervical cancer. At present, no useful tumor markers exist for endometrial cancer that exhibit both high sensitivity and specificity, although CA-125 is often used in clinical practice. Finally, human chorionic gonadotropin (hCG) serves as an ideal tumor marker for trophoblastic disease; however, the incidence of trophoblastic neoplasms has decreased dramatically with the incorporation of strict clinical management of postmolar disease as well as with the overall decrease in the number of pregnancies.

The use of a tumor marker not only depends on its sensitivity and specificity, but also on its ability to influence decisions between alternative plans for patient management. Use of beta human chorionic gonadotropin (beta-hCG) for monitoring gestational trophoblastic neoplasia has set the standard to which other assays must be compared. Beta-hCG and alpha-fetoprotein have provided useful markers for ovarian germ cell tumors.

Recently, a monoclonal antibody-based immunoassay for CA-125 has been used to monitor the treatment of epithelial ovarian carcinomas. Persistent elevation of CA-125 in serum has generally reflected persistence of disease at second look surveillance procedures. However, CA-125 levels can return to within normal limits and residual disease can be found at laparoscopy or laparotomy. CA-125 shows promise for distinguishing benign from malignant pelvic masses. Several trials are ongoing to determine the potential of CA-125 in combination with other markers to increase earlier detection of occult ovarian cancer.1

Tumor markers are glycoproteins that are usually detected by monoclonal antibodies. Each tumor marker has a variable profile of usefulness for screening, determining diagnosis and prognosis, assessing response to therapy, and monitoring for cancer recurrence. They are produced by tumor cells in response to cancer or certain benign conditions and indicate biological changes that signal the existence of malignancy. These soluble molecules can usually be detected in elevated quantities in the blood, urine, or body tissues of patients with certain types of cancer. They are produced by the tumor itself or by the body in response to the presence of cancer or certain benign conditions. The levels of tumor marker are not altered in all cancer patients, especially in early stage cancer. The level of some tumor markers can be elevated in patients with noncancerous conditions. Following the development of monoclonal antibodies, many new tumor markers have been discovered during the past 2 decades.

Gynecologic malignancies include ovarian cancer, uterine cervical cancer, endometrial cancer, and trophoblastic neoplasms.

Due to the location of ovarian tumors within the abdominal cavity, making a preoperative pathological diagnosis of cancer is difficult without laparotomy. From this point of view, the use of tumor markers that consist of carbohydrate antigens, such as CA-125, in addition to diagnostic imaging are useful in the diagnosis of ovarian cancer. SCC antigen, a marker for squamous cell carcinoma, is clinically useful in the management of advanced cervical cancer. At present, no useful tumor markers exist for endometrial cancer that exhibit both high sensitivity and specificity, although CA-125 is often used in clinical practice. Finally, human chorionic gonadotropin (hCG) serves as an ideal tumor marker for trophoblastic disease; however, the incidence of trophoblastic neoplasms has decreased dramatically with the incorporation of strict clinical management of postmolar disease as well as with the overall decrease in the number of pregnancies.

The use of a tumor marker not only depends on its sensitivity and specificity, but also on its ability to influence decisions between alternative plans for patient management. Use of beta human chorionic gonadotropin (beta-hCG) for monitoring gestational trophoblastic neoplasia has set the standard to which other assays must be compared. Beta-hCG and alpha-fetoprotein have provided useful markers for ovarian germ cell tumors.

Recently, a monoclonal antibody-based immunoassay for CA-125 has been used to monitor the treatment of epithelial ovarian carcinomas. Persistent elevation of CA-125 in serum has generally reflected persistence of disease at second look surveillance procedures. However, CA-125 levels can return to within normal limits and residual disease can be found at laparoscopy or laparotomy. CA-125 shows promise for distinguishing benign from malignant pelvic masses. Several trials are ongoing to determine the potential of CA-125 in combination with other markers to increase earlier detection of occult ovarian cancer.1

Some tumor markers can be used for screening, diagnosis, management, determining response, and recurrence. Some markers show promise as prognostic indicators.

The following are important gynecologic tumor markers :

a) Cancer antigen 125 (CA-125)

b) Beta chorionic gonadotropin (beta-hCG)

c) Alpha-fetoprotein (AFP)

d) Inhibin

e) Estradiol

f) Müllerian inhibiting substance (MIS)

g) Carbohydrate antigen 19-9

h) Ferritin

i) Topoisomerase II

j) Urinary gonadotropin fragment

k) Carcinoembryonic antigen (CEA)

m) Human telomerase reverse transcriptase (hTERT)

n) Others :

1) Tumor-associated trypsin inhibitor

2) Cyclin E

3) Lysophosphatidic acid (a lipid found to be elevated in serum and ascites fluid)

4) Mesothelin

5) HE4

6) Osteopontin

7) Vascular endothelial growth factor (VEGF)

8) Interleukin 8

9) Macrophage colony-stimulating factor

10) Insulinlike growth factor–binding protein-3

11) OVX1

No marker is completely specific; therefore, diagnostic immunohistochemistry testing must be used in conjunction with morphologic and clinical findings.

Cancer Antigen 125

After its initial discovery in the early 1980s, the serum CA-125 level has been widely used as a marker for a possible epithelial ovarian cancer in the primary assessment of a pelvic mass. In this setting, false-positive results may derive from several conditions, especially those associated with peritoneal inflammation, such as endometriosis, adenomyosis, pelvic inflammatory disease, menstruation, uterine fibroids, or benign cysts. Malignancies other than ovarian cancer can also increase CA-125 levels, but the most marked elevations (>1500 U/mL) are generally seen with ovarian cancer.

The primary use of CA-125 measurement is to monitor the disease status of patients with ovarian cancer, such as detecting early recurrence or assessing chemoresponse during chemotherapy. Serum CA-125 levels are also included in the American College of Obstetricians and Gynecologists and Society of Gynecologic Oncologists guidelines for referring patients to a gynecologic oncologist.

Postmenopausal women with serum levels of CA-125 higher than 35 U/mL or premenopausal women with CA-125 levels higher than 200 U/mL should be referred to a gynecologic oncologist. In an attempt to improve CA-125 measurement for the detection of epithelial ovarian cancers, especially at an early stage, recent studies have identified several new candidates for markers. Examples include lysophosphatidic acid (a lipid found to be elevated in serum and ascites fluid), mesothelin, HE4, osteopontin, vascular endothelial growth factor (VEGF) and interleukin 8, macrophage colony-stimulating factor, and different kallikreins. Interestingly, among these potential markers, HE4 has sensitivity similar to CA-125 in detecting late-stage disease but greater specificity than CA-125 in diagnosing early ovarian cancer. Validation of HE4 as a diagnostic biomarker in detecting ovarian cancer at early stages is currently ongoing.

Approximately 90% of ovarian cancers are celomic epithelial carcinomas and contain a celomic epithelium–related glycoprotein-designated CA-125. CA-125 can be localized in most serous, endometrioid, and clear cell ovarian carcinomas; mucinous tumors express this antigen less frequently. CA-125 is also found in the epithelium of the fallopian tubes, endometrium, and uterine cervix.

Ovarian carcinoma is the leading cause of death from gynecologic malignancies. CA-125 is an important tumor marker for the diagnosis, treatment, and follow-up care of patients with epithelial ovarian cancer and has been recommended for screening; however, CA-125 may not lead to early diagnosis because it is not perfectly sensitive or specific for ovarian cancer. CA-125 can be used clinically to determine response to treatment, relapse, and survival.

Although CA-125 is most consistently elevated in patients with epithelial ovarian cancer, it can be expressed in a number of gynecologic (eg, endometrium, fallopian tube) and nongynecologic (eg, pancreas, breast, colon, lung) cancers. CA-125 levels are frequently elevated with tumor spread beyond the uterus and have been found highly sensitive in detecting extrauterine disease.

Serum CA-125 markers are primarily used to monitor the progress of ovarian cancer. An increase in CA-125 levels during or after treatment is a strong predictor of future disease progression. A rapid decrease in CA-125 levels during initial treatment correlates with longer progression-free intervals and survival. A CA-125 level less than 15 U/mL after a standard 6-course treatment generally correlates with longer progression-free intervals, although it does not predict whether microscopic disease is present. A CA-125 value greater than 35 U/mL after a standard 6-course chemotherapy treatment predicts the presence of disease. Disease progression may also occur when CA-125 values are stable.

Standardized CA-125 definitions have the potential of complementing or, in some cases, replacing current response definitions in a cost-effective way. The rate of CA-125 decline during primary chemotherapy is an important independent prognostic factor. Persistent elevation of CA-125 levels at the time of a second-look surgical surveillance procedure predicts residual disease with at least a 95% specificity. Rising CA-125 values have preceded clinical detection of recurrent disease by at least 3 months. Given the modest activity of salvage chemotherapy, this information has not yet influenced survival rates. Rising CA-125 level during subsequent chemotherapy is associated with progressive disease in at least 90% of cases. CA-125 may serve as an effective surrogate marker for clinical response in clinical trials of new drugs.

The measurement of CA-125 levels, usually in combination with other modalities (eg, bimanual pelvic examination, transvaginal ultrasonography) is a proposed method of early detection of ovarian cancer, which is the most promising application of this tumor marker. CA-125 levels can help distinguish malignant and benign pelvic masses, which permits effective triage of patients for primary surgery. In addition, an algorithm has been developed that estimates the risk of ovarian cancer based on the level and trend of CA-125 values.

Screening using CA-125

Early-stage ovarian cancer has excellent prognosis after definitive therapy. Therefore, early detection is vital in reducing mortality due to this disease. However, no screening program for ovarian cancer has achieved this goal. Several studies have been launched to identify the best strategy for detecting early-stage disease and reducing mortality by using either CA-125 or ultrasonography as the primary screening test. In a cohort of roughly 15,500 women, the positive predictive value for ultrasonography screening ranged from 1.5% when abdominal ultrasonography was used to close to the screening-recommended 10% when transvaginal ultrasonography was used. This low positive predictive value is due to the commonality of benign pelvic lesions, even in postmenopausal women.

High specificity is important in screening strategies for ovarian cancer because a positive test result generally requires definitive surgical assessment. Given the relatively low prevalence of ovarian cancer, a test with 95% specificity would result in 50 surgical procedures for every ovarian cancer detected. Einhorn and colleagues screened 5550 women with CA-125 alone and this screening approach resulted in an unacceptable 29 surgeries for every cancer detected. Another major limitation of CA-125 screening is that serum levels are elevated in only about 50% of patients with stage I disease.

Because several gynecologic and nongynecologic conditions can elevate CA-125 levels, combination test strategies have been tried to improve the predictive value of CA-125. Jacobs and colleagues randomized 22,000 postmenopausal women to be screened with 3 annual CA-125 measurements or no screening. Those patients with CA-125 levels higher than 30 U/mL underwent transvaginal ultrasonography. Twenty-nine women were referred for surgical exploration, and 6 women were diagnosed as having ovarian cancer (3 of whom had stage I). The positive predictive value was 20.7%. Ten additional women in the screening arm developed ovarian cancer during follow-up. Twenty women in the control arm developed ovarian cancer. The investigators were able to show a median survival benefit (73 months in the screened arm vs 42 months in the control group; P =.01)

Two large randomized studies are currently ongoing. The NIH Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial4 enrolled 75,000 women aged 55-74 years from 1992-2001. The study randomly assigned women to screening (ie, annual pelvic examination, transvaginal ultrasonography, and CA-125 assay) or no screening. The recently published prevalence data from this study revealed familiar findings: 31 women operated on for every invasive cancer detected and a high proportion of advanced-stage cancers. However, these initial results are affected greatly by the benign and malignant conditions prevalent at a woman’s first screening evaluation. The true effectiveness of the screening strategy will now be tested by its ability to detect new cancers during the next several years.

The second study, started in 2001, called the UK Collaborative Trial of Ovarian Cancer Screening, has completed randomization of 200,000 postmenopausal women to transvaginal ultrasonography, multimodality screening, or a control group. These studies will answer the question of whether ultrasonography with or without CA-125–based screening in women with ovarian cancer can reduce mortality due to ovarian cancer.

Currently new screening approaches are being studied including high-throughput techniques using microarray technology and proteomic screening to identify panels of novel markers that may be altered early in the disease.

Ovarian epithelial tumors are histologically classified into serous tumors, mucinous tumors, endometrioid tumors, clear cell tumors, Brenner tumors, undifferentiated tumors, mixed epithelial tumors (composed of ≥2 of the 5 major cell types of common epithelial tumors), and intraperitoneal cancer (the ovaries appear to be incidentally involved and not the primary origin, which should be classified as extraovarian peritoneal cancer).

Serous tumors are the most common type, accounting for almost half of all epithelial ovarian cancers. These cells histologically resemble cells that line the fallopian tube. They tend to be high grade and are the cancers most often seen in BRCA mutation carriers. Endometrioid cancers resemble the cells that line the endometrium. These cancers are sometimes associated with endometriosis. Clear cell tumors are relatively uncommon, occurring most often in women in their 40s. Approximately 50% of women with clear cell tumors have associated endometriosis. Although most clear cell cancers are diagnosed at an early stage, these tumors are aggressive. The cells of mucinous tumors resemble those of the cervix or intestine. Mucinous tumors are more likely to be found in younger women, and 75-80% are benign and develop in only 1 ovary. Cancerous mucinous tumors are more common in older women and do not produce CA-125.

Epithelial tumors of the ovary are also subclassified by grading: Gx, grade cannot be assessed; G1, well differentiated; G2, moderately differentiated; and G3, poorly differentiated. Grade is related to prognosis in ovarian cancer, with patients with low-grade cancers doing better. Grade information is considered in treatment decisions for women with stage I disease.

Borderline ovarian tumors, or tumors of low malignant potential, also develop in the epithelial cells that cover the surface of the ovaries. Although borderline tumors have some malignant features, such as malignant-appearing histologic features and excess proliferation, they generally behave in an indolent manner. One important feature of borderline tumors is that they do not invade the stroma of the ovary. Borderline tumors make up 10-15% of all epithelial ovarian tumors. Approximately 3000 women in the United States are diagnosed with borderline tumors every year. Although these tumors can occur in women of all ages, they commonly occur in younger woman compared to epithelial ovarian cancers, and they have the same risk factors as epithelial ovarian cancer.

At diagnosis, approximately 20% of borderline tumors have spread beyond the ovary via peritoneal implants, but unlike epithelial ovarian cancer implants, these borderline peritoneal implants are noninvasive. However, in less than 5% of borderline tumors, so-called invasive implants can be found that invade below the peritoneal surface layer. A borderline tumor with invasive implants behaves more aggressively than does a borderline tumor with noninvasive implants. Surgery is the mainstay of treatment for women with borderline tumors of the ovary. Chemotherapy can be given to those patients that have more aggressive features, such as invasive implants or rapid recurrence after surgery.

CA-125 can be elevated up to 3% more than normal postmenopausal women. Therefore, screening using the CA-125 test has not been effective enough for widespread use. For ovarian cancer to be detected in 1 additional patient using CA-125 as the primary screening tool, another 100-150 women would have to receive evaluation and approximately 30 diagnostic operations be performed. To enhance the use of CA-125 for ovarian cancer screening, the change in CA-125 concentration in the bloodstream over time is being investigated as compared to just depending upon the absolute value.

Ovarian cancer screening is not recommended for women with no risk factors (RR≤3). For women with increase risk (RR=3-6 times), after evaluating risks and benefits, ovarian cancer screening with CA-125 and/or transvaginal ultrasonography can be done, usually by clinical trials. In women at inherited risk (RR>6 times), usually with mutations in ovarian cancer susceptibility genes, should receive screening by a combination of transvaginal ultrasonography and CA-125. For patients with mutations in BRCA1 or the mismatch repair genes, MLH1, MSH2, and MSH6, screening should begin around 30-35 years of age. For patients with mutations in BRCA2, ovarian cancer screening should be performed around 35-40 years of age.

The Gynecologic Cancer Intergroup uses the Rustin definition to define a rise in CA-125. If the CA-125 level becomes normal after surgery, a subsequent level twice the upper limit of normal is consistent with progression. If the CA-125 level is not normal after surgery, then a subsequent level twice the patient's nadir value signifies progressive disease.

Serum CA-125 level has been widely used as a marker for a possible epithelial ovarian cancer in the primary assessment of a pelvic mass. The predominant use of CA-125 measurement is to monitor disease status of patients with ovarian cancer, such as detecting early recurrence or assessing response during chemotherapy. CA-125 has provided a useful first-generation marker for monitoring ovarian cancer and triaging patients with pelvic masses, despite limitations in sensitivity and specificity. In the next decade, the challenge will be to identify new markers that will complement CA-125 in monitoring ovarian cancer and facilitate screening for occult early-stage disease. The expression of growth factors and their receptors and application of monoclonal antibodies to immunohistochemistry and radionuclide imaging may also provide new areas of diagnostic application for monoclonal antibodies in gynecologic oncology.

Other Gynecologic Tumor Markers

human chorionic gonadotropin

Beta-hCG is expressed in human fetal tissue and cancer cells of various histologic types. It is degraded to the beta-core fragment, which is concentrated in urine and is also known as urinary gonadotropin peptide. Urinary gonadotropin fragment and lipid-associated sialic acid levels are elevated in up to 60% of patients with endometrial cancer.

Increased levels of beta-hCG occur in patients with choriocarcinoma of the uterus, embryonal carcinomas, polyembryomas, mixed cell tumors, and, less commonly, dysgerminomas. Both beta-hCG and human placental lactogen (hPL) are the most useful markers for trophoblastic disease and can be localized in syncytiotrophoblasts of partial and complete hydatidiform moles. The intensity and pattern of reactivity for these antigens differ in partial and complete moles. Gestational choriocarcinomas demonstrate variable but positive staining results for beta-hCG and hPL. The hPL immunostaining differentiates placental-site trophoblastic tumors from choriocarcinomas. The use of beta-hCG is not limited to trophoblastic diseases because it has been localized in a wide array of nontrophoblastic gynecologic neoplasms.

The following diagnostic criteria is commonly used for malignant gestational trophoblastic disease :

a) lateauing of beta-hCG levels over at least 3 weeks
b) 10% or greater rise in beta-hCG for 3 or more values over at least 2 weeks
c) Persistence of beta-hCG 6 months after molar evacuation
d) Histologic identification of choriocarcinoma

Patients who have undergone molar pregnancy evacuation should undergo weekly beta-hCG monitoring until normal levels are achieved, then monthly monitoring until 6-12 months of normal values have been achieved. About 20% patients undergoing evacuation of molar pregnancy will develop postmolar gestational trophoblastic disease, usually manifesting as failure to normalize the postevacuation beta-hCG levels. A 10% rise in beta-hCG over 3 or more weekly titers or a beta-hCG titer of 40,000 mIU/L 4-5 months after uterine evacuation constitutes a serological diagnosis of postmolar trophoblastic disease.

For metastatic malignant trophoblastic disease, beta-hCG monitoring is recommended every 6 months for an indefinite period of time because late recurrence is a possibility.

The beta subunit of human chorionic gonadotropin (beta-hCG) is normally produced by the placenta. Elevated b-hCG levels are most commonly associated with pregnancy, germ cell tumors, and gestational trophoblastic disease. False-positive levels occur in hypogonadal states and with marijuana use.

Both AFP and beta-hCG play crucial roles in the management of patients with nonseminomatous germ cell tumors. The AFP or beta-hCG level is elevated in 85% of patients with these tumors but in only 20% of patients with stage I disease. Hence, these markers have no role in screening.

In patients with extragonadal disease or metastasis at the time of diagnosis, highly elevated AFP or beta-hCG values can be used in place of biopsy to establish a diagnosis of nonseminomatous germ cell tumor. AFP values in excess of 10,000 ng/mL or beta-hCG levels above 50,000 mIU/mL at initial diagnosis portend a poor prognosis, with a 5-year survival rate of 50%. Similarly staged patients with lower AFP and beta-hCG levels have a cure rate above 90%.

Following AFP and beta-hCG levels is imperative in monitoring response to treatment in patients who have nonseminomatous germ cell tumors. Patients with AFP and beta-hCG levels that do not decline as expected after treatment have a significantly worse prognosis, and changes in therapy should be considered. Because curative salvage therapy is possible, the tumor markers are followed every 1-2 months for 1 year after treatment, then quarterly for 1 year, and less frequently thereafter. AFP or beta-hCG level elevation is frequently the first evidence of germ cell tumor recurrence; a confirmed elevation should prompt reinstitution of therapy.

In spite of complete clinical response after chemotherapy, almost 50% of patients with stage III/IV disease have residual tumor. Among patients with persistent elevation of CA-125, about 90-95% will have residual tumor. The beta-hCG level is used for monitoring response to therapy and detecting early relapse. Testing for the beta-hCG is an integral part of the diagnosis, management, and response to treatment for gestational trophoblastic disease and in selected patients with epithelial carcinomas of the ovary. Combined AFP and beta-hCG testing is an essential adjunct in the evaluation and treatment of nonseminomatous germ cell tumors, and in monitoring the response to therapy. AFP and beta-hCG may also be useful in evaluating potential origins of poorly differentiated metastatic cancer.

Human telomerase reverse transcriptase (hTERT)

Human telomerase reverse transcriptase (hTERT) is a novel and newly available biomarker for patients with ovarian and uterine cancers. The hTERT mRNA level has a significant correlation with CA-125 and with histological findings in ovarian cancer. Serum hTERT mRNA is useful for diagnosing gynecologic cancer and is superior to conventional tumor markers. Upregulation of hTERT may play an important role in the development of cervical intraepithelial neoplasia (CIN) and cervical cancer; hTERT could be used as an early diagnostic biomarker for cervical cancer in the future.

Inhibin

Inhibin is a peptide hormone normally produced by ovarian granulosa cells. It inhibits the secretion of follicle-stimulating hormone (FSH) by the anterior pituitary gland. It reaches a peak of 772 +/- 38 U/L in the follicular phase of the menstrual cycle and is normally undetectable in the serum of menopausal women. Granulosa-cell tumors produce inhibin and its serum levels reflect the the tumor burden. Measurement of inhibin can be used as a marker for primary as well as recurrent granulosa cell tumor.

The recent availability of markers of ovarian stroma, including melan-A and inhibin-alpha, has provided a means for the positive identification of ovarian stromal tumors, which can manifest in a myriad of histological appearances.

The hormonal activity of granulosa cell tumors permits the use of a variety of serum tumor markers in the diagnostic evaluation. Clinically, the most useful serum marker for granulosa cell tumors is inhibin. Inhibin exists in 2 different isoforms, inhibin A and inhibin B. Both isoforms consist of a dimer of 2 subunits, the alpha and beta subunits. The alpha subunit is the same for both isoforms, while the beta subunits differ (beta A and beta B) and show about 64% homology. The 3 subunits (alpha, beta A, beta B) are produced on separate genes located on chromosomes 2 (alpha and beta B) and 7 (beta A).

Inhibin usually becomes nondetectable after menopause. However, certain ovarian tumors, mostly mucinous epithelial ovarian carcinomas and granulosa cell tumors, produce inhibin. An elevated inhibin level in a postmenopausal woman or a premenopausal woman presenting with amenorrhea and infertility is suggestive of the presence of a granulosa cell tumor, but not specific. Inhibin levels can also be used for tumor surveillance after treatment to assess for residual or recurrent disease. Although most commercial laboratories only provide assays for inhibin A, serum levels of inhibin B seem to be more frequently elevated. Whenever available, the use of assays is suggested that detect both isoforms. The free alpha subunit can also be measured.

Estradiol

Estradiol was one of the first markers identified in the serum of patients with granulosa cell tumors. In general, estradiol is not a sensitive marker for the presence of a granulosa cell tumor. About 30% of tumors do not produce estradiol due to lack of theca cells, which produce androstendione, a necessary precursor for estradiol synthesis. However, following serum estradiol levels postoperatively may be useful for detecting recurrence of an estradiol-secreting tumor.

Müllerian inhibiting substance

Müllerian inhibiting substance (MIS) is produced by granulosa cells in the developing follicles. It has emerged as a potential tumor marker for granulosa cell tumors. As with inhibin, MIS is typically undetectable in postmenopausal women. The elevated MIS level is highly specific for ovarian granulosa cell tumors; however, this test is not commercially available for clinical use.

Topoisomerase II

Topoisomerase II expression is detected in tumor samples by immunohistochemistry and has emerged as a promising, clinically relevant biomarker for survival in patients with advanced epithelial ovarian cancer.

Carbohydrate antigen 19-9

Serum carbohydrate antigen 19-9 levels are elevated in up to 35% of patients with endometrial cancer and can be used in a follow-up evaluation of patients with mucinous borderline ovarian tumors. Measurement of serum tumor markers in the follow-up care of these patients may lead to earlier detection of recurrence in only a very small proportion of patients; the clinical value of earlier detection of recurrence remains to be established. Carbohydrate antigen is not specific for ovarian cancer.

Cancer antigen 27-29

Elevated cancer antigen 27-29 levels are associated with cancers of the colon, stomach, kidney, lung, ovary, pancreas, uterus, and liver. First-trimester pregnancy, endometriosis, ovarian cysts, benign breast disease, kidney disease, and liver disease are noncancerous conditions that are also associated with increased cancer antigen 27-29 levels.

Markers for Response to Therapy and Relapse

The following tumor markers are helpful in assessing response to chemotherapy and in determining relapse when monitoring patients with complete remission.

Squamous cell carcinoma antigen

The squamous cell carcinoma antigen level can be increased in patients with epidermoid carcinoma of the cervix, benign tumors of epithelial origin, and benign skin disorders.

Carcinoembryonic antigen

Most sweat gland tumors of the vulva stain positively for carcinoembryonic antigen (CEA). In most instances, the reaction for CEA occurs in cells that line cysts, form glands, or are arranged around a lumen. The reaction for CEA does not differentiate eccrine from apocrine adnexal tumors. In patients with vaginal adenosis, both surface columnar epithelium and glands may show focal cytoplasmic membrane staining for CEA. As the columnar cells are gradually replaced by the process of squamous metaplasia, CEA positivity may be observed in the cytoplasm of metaplastic cells. Malignant vulvar tumors of sweat gland origin stain positively for CEA. Both in situ and invasive adenocarcinomas underlying extramammary Paget disease of the anogenital area express CEA. CEA is also demonstrable in Paget cells at metastatic sites such as lymph nodes. CEA is present in most urothelial adenocarcinomas of the female urethra.

CEA levels are elevated in up to 35% of patients with endometrial cancer. CEA immunohistochemistry cannot distinguish between benign and malignant glandular proliferations of the uterine cervix; therefore, CEA staining is of no value in the differential diagnosis of endocervical and endometrial adenocarcinomas.

Most epithelial neoplasms of the ovary also express CEA. The neoplasms include, with decreasing intensity and frequency, Brenner, endometrioid, clear cell, and serous tumors. CEA is frequently present in patients with cancer that has metastasized to the ovary because the primary cancer is generally mammary or gastrointestinal in origin and these tumors frequently contain CEA.

Alpha-fetoprotein

Alpha-fetoprotein (AFP) is a normal fetal serum protein synthesized by the liver, yolk sac, and gastrointestinal tract that shares sequence homology with albumin. AFP is a major component of fetal plasma, reaching a peak concentration of 3 mg/mL at 12 weeks of gestation. Following birth, AFP rapidly clears from the circulation because its half-life is 3.5 days. AFP concentration in adult serum is less than 20 ng/mL.

Most endodermal sinus tumors of the ovary express AFP. AFP is present within the cytoplasm of tumor cells and in the characteristic hyalin globules observed in the endodermal sinus tumor. AFP is also expressed by ovarian embryonal cell carcinoma, immature teratomas, and polyembryomas.

Lysophosphatidic acid

Lysophosphatidic acid stimulates cancer cell proliferation, intracellular calcium release, and tyrosine phosphorylation, including mitogen-activated protein kinase activation. Lysophosphatidic acid has been shown to be a multifunctional signaling molecule in fibroblasts and other cells. It has been found in the ascitic fluid of patients with ovarian cancer and is associated with ovarian cancer cell proliferation. Further studies are needed to determine the role of these markers.

MIB1-determined tumor growth fraction has recently been studied as an additional tool for the decision of adjuvant therapy in patients with very early stages of ovarian carcinomas. In one study, MIB1 predicted tumor recurrences in 84% of the ovarian cancers.

L1 (CAM)

According to Daponte et al, L1 (CAM) immunoreactivity correlates with stage and grade of ovarian cancer. It increases from benign tumors to early carcinomas and to advanced stage carcinomas progressively and significantly. L1 (CAM) expression represents a novel diagnostic marker in serous ovarian neoplasms that shows characteristics of tumor progression. L1 expression is associated with chemotherapy response.6

Normalization of tumor markers

Normalization of tumor marker values may indicate cure despite radiographic evidence of persistent disease. In this situation, the residual tumor is frequently nonviable. Sometimes, tumor marker levels may rise after effective treatment (due to cell lysis), but the increase may not portend treatment failure. A consistent increase in tumor marker levels, combined with lack of clinical improvement, may indicate treatment failure. Residual elevation after definitive treatment usually indicates persistent disease.

Screening

Screening tests require high sensitivity to detect early-stage disease. These tests also must have sufficient specificity to protect patients with false-positive results from unnecessary diagnostic work up.

So far, no tumor marker has demonstrated a survival benefit in randomized controlled trials of screening in the general population. However, these tumor markers can play a crucial role in detecting disease, assessing response to therapy, and monitoring for disease recurrence.

The NCI is currently conducting the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) screening trial to determine if certain screening tests, including CA-125 to screen for ovarian cancer, reduce the number of deaths from these cancers.

Proteomics are being investigated for developing better cancer screening and treatment options. Proteomics may also help to identify new proteins that serve as tumor markers in early stages and to predict the effectiveness of treatment and probability of recurrence.