Current use of testicular biomarkers for screening, diagnosis, and follow-up is reviewed in the context of potential clinical utility of these tests. This information will be of value to clinicians to determine patient suitability for certain treatments and will also assist in reviewing current literature regarding potential biomarkers that may be used for testicular cancer.
Key points
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Aside from classic serum tumor markers for testicular cancer (human chorionic gonadotropin, alpha fetoprotein, lactate dehydrogenase), limited data on additional molecular biomarkers have been published or validated.
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Larger series with consistent results from independent groups are required to validate new testicular cancer biomarkers.
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microRNA-371-3 has potential utility as a molecular biomarker for germ cell tumor detection and prognosis.
Introduction
Most germ cell tumors (GCTs) originate in the testes and account for approximately 95% of testicular cancers. Occasionally, GCTs originate in extragonadal sites, such as the mediastinum or retroperitoneum. Clinical and pathologic heterogeneity is an important feature of GCTs. Benign forms demonstrate extensive somatic differentiation (teratoma), whereas malignant GCTs are divided into seminoma and nonseminomatous GCTs (NSGCT).
Serum tumor markers (STMs) are prognostic factors and are important for diagnosis and staging. STM should be determined before and following orchiectomy. The 3 classic STMs for testicular cancer diagnosis and staging are alpha fetoprotein (AFP), which is produced by yolk sac cells; human chorionic gonadotropin (HCG), which is expressed by trophoblasts; and lactate dehydrogenase (LDH).
STMs are increased in approximately 60% of testicular cancer cases. AFP and HCG are increased in 50% to 70% and in 40% to 60% of patients with NSGCTs, respectively. Approximately 90% of NSGCTs present with an increase in one or 2 of these markers. Up to 30% of seminomas can present with or develop an elevated HCG level during the course of the disease.
LDH is a less specific marker with its concentration being proportional to tumor volume. Its level may be elevated in up to 80% of patients with advanced testicular cancer. Negative marker levels do not exclude the diagnosis of a GCT. Placental alkaline phosphatase (PLAP) is an optional marker for monitoring patients with pure seminoma but may have limited value in smokers.
Traditional STMs are not only specific for testicular cancer. Elevations in HCG are commonly seen in a wide variety of carcinomas (gastric, pancreatic, neuroendocrine, lung, head and neck, lymphoma, leukemia). Similarly, elevations of AFP can be observed in hepatocellular carcinoma and benign liver disease.
A biomarker has been defined as “any substance, structure, or process that can be measured in the body or its products and influence or predict the incidence of outcome or disease” by the World Health Organization. An ideal biomarker for testicular cancer would be an easily detectable molecule that would be unique for GCTs.
Limited contemporary data have been published regarding the use of biomarkers for testicular cancer diagnosis and prognosis in addition to traditional STMs (AFP, HCG, LDH). Cytogenetic and molecular markers based on microRNA (miRNA), cell-circulating mitochondrial DNA, or DNA methylation are available at limited centers but at present are not commonly used in clinical practice ( Table 1 ).
| Molecular Marker | Target | Characteristics | Able to Differentiate GCT from Healthy Controls | Correlation with GCT Stage |
|---|---|---|---|---|
| miRNA | miRNA367-3p, 371a-3p, 372-3p, 373-3p | Noncoding RNA; very stable; interfere in the translation of mRNA to protein | Y | Y |
| mtDNA | mtDNA-79; mtDNA-220 | Short length, simple structure | Y | N |
| CircDNA | — | Same methylation pattern as tumor cells | Y | N |
| CpG island hypermethylation | Gene silencing (APC, GSTP1, p14, p16, PTGS2, RASSF1A) | Easy to detect methylation; techniques already established | Y | N |
| CTC | — | Easy to detect; molecular techniques | Y | Y |
Introduction
Most germ cell tumors (GCTs) originate in the testes and account for approximately 95% of testicular cancers. Occasionally, GCTs originate in extragonadal sites, such as the mediastinum or retroperitoneum. Clinical and pathologic heterogeneity is an important feature of GCTs. Benign forms demonstrate extensive somatic differentiation (teratoma), whereas malignant GCTs are divided into seminoma and nonseminomatous GCTs (NSGCT).
Serum tumor markers (STMs) are prognostic factors and are important for diagnosis and staging. STM should be determined before and following orchiectomy. The 3 classic STMs for testicular cancer diagnosis and staging are alpha fetoprotein (AFP), which is produced by yolk sac cells; human chorionic gonadotropin (HCG), which is expressed by trophoblasts; and lactate dehydrogenase (LDH).
STMs are increased in approximately 60% of testicular cancer cases. AFP and HCG are increased in 50% to 70% and in 40% to 60% of patients with NSGCTs, respectively. Approximately 90% of NSGCTs present with an increase in one or 2 of these markers. Up to 30% of seminomas can present with or develop an elevated HCG level during the course of the disease.
LDH is a less specific marker with its concentration being proportional to tumor volume. Its level may be elevated in up to 80% of patients with advanced testicular cancer. Negative marker levels do not exclude the diagnosis of a GCT. Placental alkaline phosphatase (PLAP) is an optional marker for monitoring patients with pure seminoma but may have limited value in smokers.
Traditional STMs are not only specific for testicular cancer. Elevations in HCG are commonly seen in a wide variety of carcinomas (gastric, pancreatic, neuroendocrine, lung, head and neck, lymphoma, leukemia). Similarly, elevations of AFP can be observed in hepatocellular carcinoma and benign liver disease.
A biomarker has been defined as “any substance, structure, or process that can be measured in the body or its products and influence or predict the incidence of outcome or disease” by the World Health Organization. An ideal biomarker for testicular cancer would be an easily detectable molecule that would be unique for GCTs.
Limited contemporary data have been published regarding the use of biomarkers for testicular cancer diagnosis and prognosis in addition to traditional STMs (AFP, HCG, LDH). Cytogenetic and molecular markers based on microRNA (miRNA), cell-circulating mitochondrial DNA, or DNA methylation are available at limited centers but at present are not commonly used in clinical practice ( Table 1 ).
| Molecular Marker | Target | Characteristics | Able to Differentiate GCT from Healthy Controls | Correlation with GCT Stage |
|---|---|---|---|---|
| miRNA | miRNA367-3p, 371a-3p, 372-3p, 373-3p | Noncoding RNA; very stable; interfere in the translation of mRNA to protein | Y | Y |
| mtDNA | mtDNA-79; mtDNA-220 | Short length, simple structure | Y | N |
| CircDNA | — | Same methylation pattern as tumor cells | Y | N |
| CpG island hypermethylation | Gene silencing (APC, GSTP1, p14, p16, PTGS2, RASSF1A) | Easy to detect methylation; techniques already established | Y | N |
| CTC | — | Easy to detect; molecular techniques | Y | Y |
Clinical utility of traditional serum tumor markers
Screening Utility of Serum Tumor Markers
In the context of screening for GCTs, no role of STM has been demonstrated because of the low incidence and mortality of testicular cancer. It is very unlikely that STM as a screening tool would decrease mortality because of the natural history of the disease.
Diagnostic Utility of Serum Tumor Markers
STMs have been shown to assist in determining the origin of GCTs and in some clinical scenarios will dictate treatment. For example, if only seminoma is observed in an orchiectomy specimen, but increased AFP is detected, patients will be treated according to NSGCT protocols. Few conditions other than GCTs cause extreme elevation of STM, but moderate elevations are not as uncommon. See Table 2 for conditions that may cause elevation of STMs.
| AFP | HCG | LDH | |
|---|---|---|---|
| Normal limits | 1 mg/L to 10–15 mg/L of serum or plasma | 1 U/L to 5–10 U/L | Depends on assay method used |
| Half-life (d) | 5–7 | 1.5–3.0 | Not reported |
| Seminoma GCT | Never elevated in pure seminoma | Yes (15%–20%) | Yes (40%–60%) |
| Nonseminoma GCT | Yes (10%–20% localized disease; 40%–60% advanced disease) | Yes (10%–20% localized disease; 40%–60% advanced disease) | Yes (40%–60%) |
| Other malignancies | Hepatocellular carcinoma, gastric, lung, colon, pancreatic | Neuroendocrine, bladder, kidney, lung, head and neck, gastrointestinal, cervix, uterus, vulva, lymphoma, leukemia | Lymphoma, small-cell lung, Ewing sarcoma, osteogenic sarcoma |
| Nonmalignant conditions | Alcohol abuse, hepatitis, cirrhosis, biliary tract obstruction, hereditary persistence | Marijuana, hypogonadism | Several |
Ataxia-telangiectasia is a hereditary from of ataxia associated with various skin conditions. More than 95% of affected patients have elevated AFP. Hereditary tyrosinemia is caused by various enzyme deficiencies in the tyrosine degradation pathway. This condition progresses to liver and kidney failure. Because of liver dysfunction, extreme elevations of AFP are present in affected individuals. Similarly, in patients with cirrhotic liver disease and hepatocellular carcinoma, AFP can be elevated but is not always diagnostic of disease (40% of cirrhotic patients have elevation of AFP due to hepatomas).
In primary hypogonadism, a decline in testosterone may cause increased levels of LH. LH is known to have cross reactivity with HCG in some immunoassays. Marijuana use may also result in elevation of HCG.
Staging Utility of Serum Tumor Markers
STMs cannot only help to establish a diagnosis, but the degree of elevation at diagnosis has prognostic significance.
According to NCCN guidelines, the role of STM in preorchiectomy and postorchiectomy is for staging purposes. Before initiation of any treatment (surgical, chemotherapy, or radiotherapy), STMs should be measured. The magnitude of STM variability (International Germ Cell Cancer Collaborative Group [IGCCCG] classification) is used to determine chemotherapy regimens as well as for evaluation of response to chemotherapy.
Measurement of Response to Treatment by Serum Tumor Markers
The use of STMs to monitor the response to chemotherapy is encouraged as increasing concentrations of markers in seminoma may imply disease progression and the need for salvage therapy.
For patients that undergo radical orchiectomy, the rate of decline of STM should coincide with the half-lives of the STMs. If the STMs remain elevated or decline slower than the expected half-life, this may indicate slowly growing metastatic disease. If STMs are elevated and there is no evidence of retroperitoneal disease on imaging, this is considered clinical stage IS disease. Use of STMs may also allow patients with residual disease to be differentiated from cancer-free patients.
Decline after Treatment of Metastatic Disease
The standard chemotherapy regimen for testicular cancer includes bleomycin, etoposide, and cisplatin (BEP) or etoposide and cisplatin (EP). The number of cycles administered depends on the disease risk classification. Salvage chemotherapy is indicated for men who relapse or progress through primary chemotherapy. Finally, high-dose chemotherapy with autologous bone marrow transplant is indicated in poor-prognosis patients in whom standard chemotherapy regimens and/or salvage therapies have failed.
STMs should be measured the day before starting chemotherapy in order to accurately stratify patients according to IGCCCG classification. Thereafter, STMs should be obtained at the beginning of each cycle. Serial measurements are encouraged as it correlates with the amount of viable tumor tissue remaining. Some studies have demonstrated a correlation between STM decline in the first 2 cycles of chemotherapy and oncologic outcomes (complete response, overall survival). The results of a prospective randomized trial in patients with poor-prognosis according to IGCCCG criteria were recently published. Patients were classified according to their response to the first cycle of BEP chemotherapy. Classification was established by the decline in STMs (normalized after first cycle). The group of patients with unfavorable decline received dose-dense chemotherapy that was associated with an improvement in progression-free and overall survival.
Despite these findings, a return to normal STMs does not always indicate a complete response. Up to 20% of patients who receive systemic chemotherapy for retroperitoneal disease demonstrate viable tumor at pathologic examination of lymph nodes.
Related posts:
Biomarkers in Urologic Cancer
Urinary Biomarkers for Prostate Cancer
Current Status of Urinary Biomarkers for Detection and Surveillance of Bladder Cancer
Emerging Bladder Cancer Biomarkers and Targets of Therapy
MicroRNAs in Testicular Cancer Diagnosis and Prognosis
The Emerging Role and Promise of Biomarkers in Penile Cancer
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