ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Serum tumor markers in testicular germ cell tumors

Serum tumor markers in testicular germ cell tumors
Literature review current through: Jan 2024.
This topic last updated: Jun 13, 2023.

INTRODUCTION — Testicular germ cell tumors (GCTs) are one of the most curable solid neoplasms due to remarkable treatment advances that began in the late 1970s. Prior to that time, testicular cancer accounted for 11 percent of cancer deaths in men between the ages of 25 and 34, and the five-year survival rate was 64 percent [1]. Currently, the five-year survival rate is over 95 percent, largely due to a better understanding of the natural history of testicular tumors, improved staging and surgical techniques, the use of effective platinum-based combination chemotherapy, and the availability of highly sensitive serum tumor markers to detect minimal residual disease. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

Three serum tumor markers have established roles in the management of men with testicular GCTs:

The beta subunit of human chorionic gonadotropin (beta-hCG)

Alpha-fetoprotein (AFP)

Lactate dehydrogenase (LDH)

Serum concentrations of AFP and/or beta-hCG are elevated in 80 to 85 percent of men with nonseminomatous GCTs. By contrast, serum beta-hCG is elevated in fewer than 25 percent of seminomas, and AFP is not elevated in pure seminomas (table 1).

Although these markers can provide supportive evidence for the initial diagnosis of a testicular cancer and are useful for prognosis and risk stratification, their main utility is for monitoring response to treatment and detecting recurrence. The role of these serum tumor markers in the management of men with testicular GCTs will be reviewed here. The integration of serum tumor markers into the overall follow-up plan for patients who have completed their initial treatment for a GCT is discussed separately. (See "Posttreatment follow-up for testicular germ cell tumors".)

HUMAN CHORIONIC GONADOTROPIN — Testicular GCTs produce the intact human chorionic gonadotropin (hCG) molecule. Most serum assays measure the beta subunit since the alpha subunit is common to several pituitary hormones. Guidelines from the American Society of Clinical Oncology (ASCO) [2], which follow the recommendations made by the National Academy of Clinical Biochemistry (NACB) [3], suggest use of a double-antibody immunometric assay that measures total beta-hCG (both intact alpha/beta dimer plus free beta monomer).

Beta-hCG is the most commonly elevated tumor marker in testicular cancer. The normal value in men is less than 5 to 10 international units/L.

The production of hCG by testicular nonseminomatous GCTs (NSGCTs) varies depending upon the tumor burden and the histologic subtypes.

Nonseminomatous germ cell tumors — Serum levels of beta-hCG are elevated in 10 to 20 percent of clinical stage I NSGCTs and up to 40 percent of those with advanced disease [2]. Serum hCG elevations are typically seen in tumors that comprise pure or mixed embryonal carcinoma or choriocarcinoma.

Seminomas — Among patients with pure seminomas, an elevated serum beta-hCG is seen in 15 to 20 percent of those with advanced disease [2]. An increase in serum beta-hCG primarily reflects higher tumor burden, but not necessarily a greater metastatic potential [4]. Thus, an elevated serum beta-hCG that returns to normal after orchiectomy in a patient with stage I seminoma does not indicate advanced disease. (See "Treatment of stage I seminoma".)

Half-life of hCG — The serum half-life of beta human chorionic gonadotropin (hCG) is 1.5 to 3 days, which is an important consideration in determining the response to therapy [2]. Rapid normalization after orchiectomy for stage I disease suggests elimination of the tumor, while persistence of an increased beta-hCG level after treatment may be the only evidence of occult disease. (See 'Monitoring response to therapy' below.)

False-positive hCG — Although persistent elevation of serum beta human chorionic gonadotropin (hCG) implies the presence of residual disease, it should be interpreted with caution since false-positive elevation of hCG can be due to a number of factors [2]:

Hypogonadal states lead to a compensatory increase in pituitary production of hCG as well as the secretion of luteinizing hormone, which crossreacts with the immunoassay used to measure beta-hCG. (See "Clinical features and diagnosis of male hypogonadism" and "Causes of secondary hypogonadism in males".)

Tumor lysis can result in a transient release of hCG during the first cycle of chemotherapy.

The presence of heterophile antibodies or other factors can interfere with the immunoassay for beta-hCG [5]. Of note, repeating the measurement of hCG with a different assay system generally will solve this problem [6].

Marijuana use has been reported to result in a false-positive elevation of beta-hCG in at least one report [7], but this has not been observed in a more extensive series [8].

Other cancers have been associated with elevations in serum hCG levels, including neuroendocrine, bladder, kidney, prostate, lung, head and neck, gastrointestinal, cervix, uterus, and vulvar cancers, lymphoma, and leukemia [9].

Marked elevations (above 10,000 international units/L) in serum beta-hCG concentrations occur only in GCTs, the rare patient with trophoblastic differentiation of a primary lung or gastric cancer, or pregnancy or gestational trophoblastic disease in women.

Hyperthyroidism and hCG — Clinical hyperthyroidism can develop in men with NSGCTs who have markedly elevated serum beta human chorionic gonadotropin (hCG) levels due to ligand-receptor crossreactivity between hCG and thyroid-stimulating hormone (TSH). The frequency of this complication was illustrated by a series of 144 patients with GCTs in which five cases (3.5 percent) of hyperthyroidism were identified. All were in patients with markedly elevated beta-hCG levels (ie, >50,000 international units/L) [10]. The symptoms and biochemical evidence of hyperthyroidism abated with treatment of the GCT. (See "Disorders that cause hyperthyroidism", section on 'Trophoblastic disease and germ cell tumors'.)

ALPHA-FETOPROTEIN — Alpha-fetoprotein (AFP) is normally produced by the fetal yolk sac and other organs and is essentially undetectable in the serum in normal men [2]. The upper limit of normal for serum AFP is less than 10 to 15 micrograms/L.

Many tissues regain the ability to produce this oncofetal protein if they undergo malignant degeneration; however, serum AFP concentrations greater than 10,000 micrograms/L are found almost exclusively in patients with nonseminomatous GCTs (NSGCTs) or hepatocellular carcinoma. (See 'Diagnosis' below.)

Nonseminomatous germ cell tumors — In men with NSGCTs, AFP is produced by yolk sac (endodermal sinus) tumors and, less often, embryonal carcinomas. As with beta human chorionic gonadotropin, the frequency of an elevated serum AFP increases with advancing clinical stage, from 10 to 20 percent of men with stage I tumors to 40 to 60 percent of those with disseminated NSGCTs [2].

Seminomas — By definition, pure seminomas do not cause an elevated serum AFP. However, molecular studies have demonstrated AFP messenger RNA in minute quantities in pure seminoma [11], and several case reports have described pure seminoma with borderline elevations in serum AFP (10.4 to 16 ng/mL) [12]. Higher serum AFP concentrations are considered diagnostic of a nonseminomatous component of the tumor or hepatic metastases [13]. If the presence of elevated serum AFP is confirmed, patients should be treated as if they had an NSGCT [14].

Half-life of AFP — The half-life of alpha-fetoprotein (AFP) is approximately five to seven days [2]. Following effective therapy, normalization of the serum AFP concentration over 25 to 30 days is indicative of an appropriate decline. (See 'Monitoring response to therapy' below.)

False-positive AFP — False-positive elevations of serum alpha-fetoprotein (AFP) can occur from tumors of the gastrointestinal tract, particularly hepatocellular carcinoma, or from liver damage (eg, cirrhosis, hepatitis, or drug or alcohol abuse) [2]. Lysis of tumor cells during the initiation of chemotherapy may result in a transient increase in serum AFP.

LACTATE DEHYDROGENASE — Serum lactate dehydrogenase (LDH) concentrations are elevated in 40 to 60 percent of men with testicular GCTs [2]. LDH is a less sensitive and less specific tumor marker than beta human chorionic gonadotropin or alpha-fetoprotein for men with nonseminomatous GCTs, but it may be the only marker that is elevated in some seminomas. The degree of elevation in the serum LDH has prognostic value in men with advanced GCTs and is incorporated into the International Germ Cell Cancer Collaborative Group (IGCCCG) risk stratification system [15]. (See 'Prognostic value and risk stratification' below and "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'Definition of risk'.)

Serum LDH can be elevated due to a variety of processes that result in tissue injury, and thus, serum LDH is neither a sensitive nor specific indicator of disease recurrence in men with GCTs [2].

CLINICAL APPLICATIONS — Serum tumor markers (beta human chorionic gonadotropin [beta-hCG], alpha-fetoprotein [AFP], lactate dehydrogenase [LDH]) have a potential role in the diagnosis of men with a suspected testicular GCT, in determining the optimal therapy based upon risk stratification, in assessing the response to treatment, and in surveillance following treatment. Serum tumor markers should not be used to screen asymptomatic men for testicular tumors. The literature supporting the utilization of serum tumor markers for these indications has been reviewed in guidelines from the American Society of Clinical Oncology (ASCO) [2].

Diagnosis — Serum levels of beta-hCG and AFP should be measured prior to orchiectomy to help establish the diagnosis and to provide guidance for postorchiectomy management [2]. The majority of men with a suspected testicular GCT undergo orchiectomy for both histologic confirmation and local tumor control. Postorchiectomy levels of tumor markers are used in risk stratification.

Generally, neither serum beta-hCG nor AFP should be used alone to establish the diagnosis of testicular cancer in the absence of histologic confirmation. However, markedly elevated serum tumor markers can be used to support a presumptive diagnosis of GCT if initial orchiectomy or metastatic biopsy is not feasible because of an urgent need to initiate treatment. Serum tumor markers may also be used to support the diagnosis of GCT if biopsy of a metastatic site reveals a poorly differentiated carcinoma without characteristic histopathologic features. (See "Extragonadal germ cell tumors involving the mediastinum and retroperitoneum" and "Poorly differentiated cancer from an unknown primary site", section on 'Extragonadal germ cell tumors' and "Poorly differentiated cancer from an unknown primary site", section on 'Clinical evaluation'.)

Prognostic value and risk stratification — Pretreatment tumor marker levels (beta-hCG, AFP, LDH) are valuable for staging and prognosis in men with testicular GCTs. Traditional Tumor, Node, Metastasis (TNM) staging is not as useful a prognostic tool as it is in other solid malignancies because even men with disseminated disease have a high likelihood of long-term survival. (See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors".)

The International Germ Cell Cancer Collaborative Group (IGCCCG) has incorporated serum tumor markers as prognostic indicators in GCTs (table 2A-B) [16,17]. In the IGCCCG schema, postorchiectomy levels of serum beta-hCG, AFP, and LDH are used as independent predictors of risk along with the site of primary disease and the presence of nonpulmonary visceral metastases (table 3) [16]. The IGCCCG risk stratification system is described in detail separately. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'Definition of risk'.)

Monitoring response to therapy — Serial measurements of serum tumor markers, especially beta-hCG and AFP, are used to monitor the response to treatment of GCTs, with a fall in marker values signifying an adequate tumor response, and a plateau or rise in marker levels indicating relapse or resistance to therapy. Assessment of response to therapy (orchiectomy for localized disease, systemic therapy for advanced disease) requires a consideration of the serum half-lives of hCG and AFP. (See 'Half-life of hCG' above and 'Half-life of AFP' above.)

Guidelines from ASCO have outlined recommendations for the use of serum tumor markers in men being treated for testicular GCTs [2].

Nonseminomatous germ cell tumor patients — Considerations in the use of serum tumor markers following orchiectomy in patients with nonseminomatous GCT (NSGCT) include the following [2]:

Following orchiectomy, beta-hCG and AFP should be measured prior to chemotherapy. The presence of an elevation in either marker that does not resolve in a manner that is consistent with the tumor marker's half-life signifies the presence of residual disease, even if there is no other evidence of residual disease. The level of the serum markers is also useful in risk stratification and determining the duration of treatment required. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'Definition of risk'.)

For patients with clinical stage I or II disease in whom retroperitoneal lymphadenectomy is being considered, the presence of increasing levels of beta-hCG or AFP indicates the need for systemic therapy similar to that in patients with stage III disease [2]. (See "Management of stage II nonseminomatous germ cell tumors" and "Management of stage I nonseminomatous germ cell tumors".)

For patients receiving chemotherapy either as an adjuvant or for advanced disease, beta-hCG and AFP should be measured prior to each treatment cycle and upon completion of chemotherapy to assess response to therapy and for evidence of relapse or resistance to treatment. An initial increase in tumor markers, particularly during the first cycle of chemotherapy, is not unusual and may reflect lysis of tumor cells. However, unfavorable tumor marker decline after one cycle of standard chemotherapy may suggest the need for subsequent dose-dense treatment [18]. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

As an example, a randomized phase III trial suggested that tumor marker response following one cycle of bleomycin, etoposide, and platinum (BEP) in men with poor-risk disease may have important prognostic value [18]. In this study, 263 men with NSGCTs were treated with BEP using a risk-stratified approach driven by tumor marker response. Patients with an insufficient tumor marker decline after one cycle of BEP were randomly assigned to either dose-dense or standard-dose BEP for the remainder of their treatment. Among this cohort, patients treated with dose-dense BEP experienced higher three-year progression-free survival (59 versus 48 percent) compared with those who continued with standard BEP.

After completion of definitive therapy (orchiectomy with or without chemotherapy), beta-hCG and AFP should be measured at each follow-up visit. Elevation in serum tumor markers may provide the first evidence of relapse, and this approach allows initiation of salvage therapy while the tumor burden is relatively small; it also minimizes exposure to radiation from unnecessary diagnostic studies [19]. The frequency and duration of posttreatment follow-up are discussed separately. (See "Posttreatment follow-up for testicular germ cell tumors".)

Seminoma patients — Considerations in the use of serum tumor markers following orchiectomy in patients with pure testicular seminoma include the following [2]:

For patients who had an elevation in either serum beta-hCG or LDH prior to orchiectomy, these markers should be repeated following orchiectomy. If postoperative therapy (chemotherapy or radiation therapy) is required, serum tumor markers should be repeated upon completion of that therapy. (See "Treatment of stage I seminoma" and "Treatment of stage II seminoma" and "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

After completion of definitive therapy (orchiectomy with or without further treatment), beta-hCG and LDH should be measured at each follow-up visit. Elevation in serum tumor markers may provide the first evidence of relapse, and this approach allows initiation of salvage therapy while the tumor burden is relatively small. The frequency and duration of posttreatment follow-up are discussed separately. (See "Posttreatment follow-up for testicular germ cell tumors".)

EXTRAGONADAL GERM CELL TUMORS — Serum beta human chorionic gonadotropin and alpha-fetoprotein levels are also frequently elevated in patients with retroperitoneal and mediastinal GCTs. The role of tumor markers in these patients is discussed separately. (See "Extragonadal germ cell tumors involving the mediastinum and retroperitoneum", section on 'Tumor markers'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Testicular cancer".)

SUMMARY AND RECOMMENDATIONS

Serum tumor markers in testicular germ cell tumors (GCTs) – Serum levels of the beta subunit of human chorionic gonadotropin (beta-hCG), alpha-fetoprotein (AFP), and lactate dehydrogenase (LDH) are reliable markers for the presence of testicular GCTs.

Beta-hCG – Beta-hCG is produced by embryonal carcinoma and choriocarcinoma and is the most commonly elevated tumor marker in patients with nonseminomatous GCTs (NSGCTs). Beta-hCG is also elevated in 15 to 25 percent of patients with seminomas. (See 'Human chorionic gonadotropin' above.)

AFP – AFP is absent in the serum of normal adults but is detectable in patients with NSGCTs and hepatocellular carcinoma. AFP is not elevated in patients with pure seminomas. (See 'Alpha-fetoprotein' above.)

LDH – LDH is a less sensitive and less specific tumor marker than beta-hCG or AFP for men with NSGCTs but is elevated in 40 to 60 percent of men with testicular GCTs.

Role of tumor markers in risk stratification and staging – The extent of elevation of these tumor markers is an important prognostic marker for patients with GCTs, and this information is incorporated into the International Germ Cell Cancer Collaborative Group (IGCCCG) risk stratification system and the Tumor, Node, Metastasis (TNM) staging system (table 1 and table 2A-B). (See 'Prognostic value and risk stratification' above and "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors".)

Timing of measurements – Serum tumor markers should be measured prior to orchiectomy and following orchiectomy prior to any planned systemic therapy. Tumor markers should then be monitored during any additional therapy to document the adequacy of treatment. (See 'Monitoring response to therapy' above.)

Surveillance – Serum tumor markers should be measured regularly following treatment to detect any evidence of residual or recurrent disease. (See "Posttreatment follow-up for testicular germ cell tumors".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges William K Oh, MD, who contributed to earlier versions of this topic review.

  1. Einhorn LH. Treatment of testicular cancer: a new and improved model. J Clin Oncol 1990; 8:1777.
  2. Gilligan TD, Seidenfeld J, Basch EM, et al. American Society of Clinical Oncology Clinical Practice Guideline on uses of serum tumor markers in adult males with germ cell tumors. J Clin Oncol 2010; 28:3388.
  3. Sturgeon CM, Duffy MJ, Stenman UH, et al. National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers. Clin Chem 2008; 54:e11.
  4. Hori K, Uematsu K, Yasoshima H, et al. Testicular seminoma with human chorionic gonadotropin production. Pathol Int 1997; 47:592.
  5. Kricka LJ. Human anti-animal antibody interferences in immunological assays. Clin Chem 1999; 45:942.
  6. http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/TipsandArticlesonDeviceSafety/ucm109390.htm (Accessed on July 02, 2013).
  7. Garnick MB. Spurious rise in human chorionic gonadotropin induced by marihuana in patients with testicular cancer. N Engl J Med 1980; 303:1177.
  8. Braunstein GD, Thompson R, Gross S, Soares JR. Marijuana use does not spuriously elevate serum human chorionic gonadotropin levels. Urology 1985; 25:605.
  9. Stenman UH, Alfthan H, Hotakainen K. Human chorionic gonadotropin in cancer. Clin Biochem 2004; 37:549.
  10. Oosting SF, de Haas EC, Links TP, et al. Prevalence of paraneoplastic hyperthyroidism in patients with metastatic non-seminomatous germ-cell tumors. Ann Oncol 2010; 21:104.
  11. Yuasa T, Yoshiki T, Ogawa O, et al. Detection of alpha-fetoprotein mRNA in seminoma. J Androl 1999; 20:336.
  12. Nazeer T, Ro JY, Amato RJ, et al. Histologically pure seminoma with elevated alpha-fetoprotein: a clinicopathologic study of ten cases. Oncol Rep 1998; 5:1425.
  13. Javadpour N. Significance of elevated serum alphafetoprotein (AFP) in seminoma. Cancer 1980; 45:2166.
  14. Fero KE, Lec PM, Sharma V, et al. When is a Seminoma not a Seminoma? The Incidence, Risk Factors and Management of Patients With Testicular Seminoma With Discordant Elevated Serum Alpha-fetoprotein. Urology 2021; 157:188.
  15. Mencel PJ, Motzer RJ, Mazumdar M, et al. Advanced seminoma: treatment results, survival, and prognostic factors in 142 patients. J Clin Oncol 1994; 12:120.
  16. International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin Oncol 1997; 15:594.
  17. Brimo F, Srigley JR, Ryan CJ, et al. Testis. In: AJCC Cancer Staging Manual, 8th ed, Amin MB (Ed), Springer, New York 2017. p.727.
  18. Fizazi K, Pagliaro L, Laplanche A, et al. Personalised chemotherapy based on tumour marker decline in poor prognosis germ-cell tumours (GETUG 13): a phase 3, multicentre, randomised trial. Lancet Oncol 2014; 15:1442.
  19. Fonseca A, Xia C, Lorenzo AJ, et al. Detection of Relapse by Tumor Markers Versus Imaging in Children and Adolescents With Nongerminomatous Malignant Germ Cell Tumors: A Report From the Children's Oncology Group. J Clin Oncol 2019; 37:396.
Topic 2995 Version 31.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟