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Key Points

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  • Disease summary:

    • Testicular germ cell tumor (TGCT) is the most common cancer diagnosed among young Caucasian men, and is relatively rare in African-American men. Most affected individuals are diagnosed with seminomas or nonseminomas; however, mixed germ cell tumors also occur. Intratubular germ cell neoplasia (carcinoma in situ) precedes most invasive cancers. Affected men have a good prognosis if managed according to modern treatment strategies.

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  • Differential diagnosis:

    • Gonadal stromal tumors, various other rare histologies such as hematopoietic tumors, tumors of ducts or the paratesticular structures, spermatocytic seminoma, and others.

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  • Monogenic forms:

    • Monogenic forms are not known. TGCT can occur in individuals with disorders of sex determination. Men with Klinefelter syndrome are at increased risk of mediastinal germ cell tumors.

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  • Family history:

    • 1% to 2% of all cases of TGCT have a positive family history (familial TGCT). Linkage analysis has failed to identify statistically significant genomic regions which might harbor a highly penetrant gene. Familial cases are significantly younger than sporadic cases, a difference which is not clinically useful. Otherwise, the clinical features of familial and sporadic TGCT are remarkably similar. The most common number of affected persons in multiple-case families is two, and families with greater than or equal to three affected individuals are quite rare. It has been suggested that the combined effect of multiple, common, low penetrance alleles is responsible for the familial aggregation of TGCT. Testicular microlithiasis has been implicated in the pathogenesis of familial TGCT.

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  • Twin studies:

    • The risk of TGCT has been reported to be higher among twins than nontwins. Moreover, a 37-fold or 76.5-fold elevated risk of TGCT in dizygotic or monozygotic twin brothers of men with TGCT has been reported.

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  • Environmental factors:

    • Epidemiologic data strongly support the notion that TGCT has a strong environmental component; however, specific exposures associated with an increased TGCT risk remain unknown.

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  • Genome-wide associations:

    • Multiple genomic loci in which TGCT risk-modifying variants might reside have been identified recently. Disease-associated genetic variants (single-nucleotide polymorphisms [SNPs]) provide insight into disease pathogenesis, in that most are part of biologic pathways involved in testicular development or fertility. Testing for SNPs is not yet clinically validated to diagnose or guide management of TGCT.

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  • Pharmacogenomics:

    • The homozygous variant G/G of the BLMH gene SNP A1450G has been associated with reduced survival and higher prevalence of early relapses in patients treated with the chemotherapeutic agent bleomycin, one of the cornerstones of modern multidrug therapy for TGCT.

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Diagnostic Criteria and Clinical Characteristics

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Diagnostic evaluation often includes the following:

  • Serum markers: alpha-fetoprotein (AFP); beta-human chorionic gonadotrophic (β-HCG); and lactate dehydrogenase (LDH).

  • Imaging: testicular ultrasound, chest x-ray, computed tomographic (CT) scan or magnetic resonance imaging (MRI) of abdomen and pelvis, and chest CT scan.

  • MRI or CT of central nervous system (CNS) in advanced disease or in the presence of symptoms.

  • Radionuclide bone ...

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