Cancer of the Testis
Lance C. Pagliaro
Christopher J. Logothetis
INTRODUCTION
Testicular cancers are the most common malignant neoplasm affecting men ages 15 to 35 years. Approximately 90% of testicular cancers are germ cell tumors, which can be broadly classified as seminoma or nonseminomatous germ cell tumors (NSGCT). Male extragonadal germ cell tumors are also discussed in this chapter. Analogous germ cell and sex cord stromal tumors in women are not included here, but in many cases the male and female counterparts share a common biology and therapeutic approach.
INCIDENCE AND EPIDEMIOLOGY
In the United States, 8,820 new cases of testicular cancer per year is estimated for 2014.1 This figure greatly underestimates the prevalence of testicular cancer survivors. This is because the cancer-specific survival rate for testicular cancer with standard treatment is >95%.2 The incidence varies among geographic areas, being highest in Scandinavia, Switzerland, and Germany, and lowest in Africa and Asia.3 Although testicular germ cell tumors are most common among adolescent and young adult men, they can potentially occur in males of any age or genetic background. For reasons that have yet to be discovered, the incidence of testicular germ cell tumors has increased over the preceding 30 years in the United States and United Kingdom.4
Risk Factors
Men whose family history includes a first-degree relative with testicular germ cell tumor or who have a personal history of cryptorchidism are at increased risk of developing germ cell tumor.5,6 Testicular cancer survivors are also at increased risk of a second primary cancer in the contralateral testicle.7 These risk factors suggest a genetic or developmental etiology for testicular germ cell tumors. No postnatal environmental risk factors have yet been identified.8
In the United States, testicular cancer is rare among African Americans and most common among Caucasian men.9 This racial disparity in testicular cancer diagnosis and its geographic distribution suggest a genetic linkage with the Caucasian phenotype, but no high penetrance allele has yet been identified.4 Testicular germ cell tumors are commonly accompanied by intratubular germ cell neoplasia (ITGCN). It is thought that all adult germ cell tumors, with the exception of spermatocytic seminoma, arise from ITGCN.10 The widely accepted theory is that ITGCN begins in utero.11 The multifocality of ITGCN suggests a field effect within the testicle and provides a mechanistic explanation for cases of bilateral testicular cancer.
Men without a history of testicular cancer are occasionally found to have ITGCN on testicular biopsy or orchiectomy that was performed for other reasons. The incidental finding of testicular microlithiasis on ultrasound may also provide evidence of ITGCN in an otherwise healthy man.12,13 The risk of testicular cancer for such individuals has not been determined, but they should be counseled regarding a potential increased risk and to report any new testicular symptoms.14
INITIAL PRESENTATION AND MANAGEMENT
Symptoms and Signs
Testicular swelling is the most common presenting complaint and in most cases is detected by the patient himself. Patients may also report a pressure-like sensation, heaviness, or mild-to-moderate testicular pain. This will sometimes be confused with orchitis or epididymitis and treated initially with antibiotics. Acute or severe pain is rarely caused by testicular cancer and suggests a different etiology such as testicular torsion. Testicular ultrasound should be obtained as soon as a neoplasm is suspected, and it will appear as one or more hypoechoic lesions within the testicle. Ultrasound distinguishes a solid from cystic mass, and intratesticular from intrascrotal/extratesticular location. A solid intratesticular mass on ultrasound is presumed to be a neoplasm and is an indication for radical inguinal orchiectomy.15
Approximately half of patients present with a testicular mass and no clinical evidence of metastasis (clinical stage I). Others present with metastatic disease that may also be symptomatic. Primary tumors can be small and asymptomatic, even in the presence of metastatic disease, and occasionally they “burn out” leaving only a fibrotic scar (burned-out primary). Metastases can be the source of clinical symptoms on presentation in such cases, and include back pain, shortness of breath, cough, gynecomastia, hemoptysis, and weight loss.16 Ultrasound of the testicles is helpful in establishing the diagnosis even if there is no palpable testicular mass.15 The detection of elevated serum tumor markers can also be helpful when an occult testicular primary or extragonadal germ cell tumor is suspected.17
Diagnosis
Radical inguinal orchiectomy is the standard diagnostic and therapeutic procedure for a solid intratesticular mass.18 Transscrotal orchiectomy or biopsy is specifically contraindicated because of the risk of tumor cell seeding of the inguinal and pelvic lymphatic drainage. Biopsy is also of limited value because testicular germ cell tumors are heterogeneous. Removal of the entire organ is necessary to properly identify the histologic type(s) present and to select the appropriate therapy. It is reasonable to perform needle biopsy of a metastatic site in cases of occult testicular primary, burned-out primary, or extragonadal germ cell tumor; although, the results of needle biopsy must always be interpreted with caution due to sampling error. The pattern of serum tumor marker elevation is also informative about the likely cell types present (seminoma or nonseminoma), as discussed in the next section.17
HISTOLOGY
Male germ cell tumors are broadly classified as seminoma and NSGCT (Table 44.1).19,20 Patients with pure seminoma are
managed differently than patients with NSGCT or mixed histology tumors, although mixed tumors may have a component of seminoma. In that sense, when we refer to seminoma as a clinical diagnosis it is meant as pure seminoma, whereas seminoma as a histologic pattern may also be present in mixed NSGCT.
managed differently than patients with NSGCT or mixed histology tumors, although mixed tumors may have a component of seminoma. In that sense, when we refer to seminoma as a clinical diagnosis it is meant as pure seminoma, whereas seminoma as a histologic pattern may also be present in mixed NSGCT.
TABLE 44.1 World Health Organization Histologic Classification of Testicular Germ Cell Tumors | ||||||||||||||||||||||||||||||||||||||||||
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 Figure 44.1 Seminoma, classic type, with neoplastic cells (arrow) and the typical accompanying lymphocytic infiltrate (arrowhead). (Source: Rao B, Pagliaro LC. Testicular germ cell tumors. In. Silverman PM, ed. Oncologic Imaging: A Multidisciplinary Approach. Philadelphia: Elsevier; 2012:335-357.) |
Seminoma
The microscopic appearance of seminoma is characterized by sheets of neoplastic cells with abundant cytoplasm, round, hyperchromatic nuclei and prominent nucleoli (Fig. 44.1). A prominent lymphocytic infiltrate is common, such that it is sometimes confused with lymphoma until the surface immunophenotype has been determined. Most seminomas do not produce serum tumor markers, but the presence of syncytiotrophoblastic giant cells in a minority of cases accounts for modest elevations of serum human chorionic gonadotropin (hCG).21 Seminomas never produce alpha-fetoprotein (AFP), and patients whose tumors have the histologic appearance of seminoma and whose serum AFP is elevated should be considered to have a mixed NSGCT, even if a nonseminomatous histologic pattern cannot be identified.22 Exceptions are cases in which there is another explanation for the elevated AFP, such as liver disease or a chronic nonspecific elevation.
Immunohistochemistry is usually positive for placental alkaline phosphatase (PLAP), negative for CD30, AFP, and epithelial membrane antigen, and either negative or weak/focally positive for cytokeratin.23
Histologic variations of seminoma such as “anaplastic” or “atypical” seminoma are of no known clinical relevance. Spermatocytic seminoma, however, is the one variant of seminoma that has a different natural history and is even of uncertain relation to other germ cell tumors. Spermatocytic seminoma usually occurs in older individuals and has low metastatic potential.24 Orchiectomy is the only treatment required. Unlike all other germ cell tumors, spermatocytic seminoma is not associated with ITGCN.
Nonseminomatous Histologies
Germ cell tumors may be composed of a single histology or multiple histologic patterns.19 Through poorly understood processes of mutation and differentiation, a single clone beginning as ITGCN can develop into an undifferentiated neoplasm (seminoma), or to a primitive zygotic neoplasm (embryonal carcinoma).25 Further differentiation from embryonal carcinoma results in somatically differentiated tumors (teratoma) or extraembryonal-differentiated tumors (yolk sac and choriocarcinoma).26 Nonseminomatous histologies are found in 55% of germ cell tumors. Male germ cell tumors that contain any histologic cell type other than seminoma or syncytiotrophoblasts are collectively referred to as NSGCT.
Embryonal Carcinoma
Embryonal carcinoma is the most undifferentiated type of germ cell tumor and is thought to be pluripotent. Cells are characterized by indistinct borders and scant cytoplasm, which can be arranged in solid sheets or in glandular or tubular structures (Fig. 44.2). On immunohistochemical staining, embryonal carcinoma can be positive for cytokeratin, CD30, PLAP, AFP, and hCG. Modest elevations of serum AFP and/or hCG can be seen, and frequently it is marker-negative. Lactate dehydrogenase (LDH) concentration in the serum is an important prognostic factor in metastatic embryonal carcinoma that is marker negative.
 Figure 44.2 Mixed nonseminomatous germ cell tumor comprised of teratoma (arrow) and embryonal carcinoma (arrowhead). (Source: Rao B, Pagliaro LC. Testicular germ cell tumors. In. Silverman PM, ed. Oncologic Imaging: A Multidisciplinary Approach. Philadelphia: Elsevier; 2012:335-357.) |
 Figure 44.3 Chest radiograph of a man with primary mediastinal choriocarcinoma and pulmonary metastases. |
Choriocarcinoma
Choriocarcinoma is composed of both cytotrophoblasts and syncytiotrophoblasts.27 The cells strongly express hCG. The clinical presentation of a choriocarcinoma-predominant or pure choriocarcinoma tumor often includes very high serum hCG levels, widespread hematogenous metastases, and tumor hemorrhage (Fig. 44.3). Syncytiotrophoblasts and syncytiotrophoblastic giant cells can be associated with other germ cell histologies, so the presence of cytotophoblasts is required for the diagnosis.
Yolk Sac Tumor
Yolk sac tumor (endodermal sinus tumor) is commonly seen as a component of mixed NSGCT. Pure yolk sac tumors represent a significant proportion of mediastinal germ cell tumors, but are rarely seen in adult testicular cancer. Histologic patterns include papillary, solid, glandular, hepatoid, macrocystic, and microcystic types. Perivascular arrangements of epithelial cells can be seen in yolk sac tumor and are known as glomeruloid or Schiller-Duval bodies. Immunostains are diffusely positive for AFP and may also be positive for cytokeratin, SALL4, glipican-3, PLAP, and CD117. Yolk sac tumor is associated with high serum levels of AFP.
Teratoma
Teratoma arises from a pluripotent malignant precursor (embryonal carcionoma or yolk sac tumor) and contains somatic cells from at least two germ cell layers (ectoderm, endoderm, or mesoderm). Teratoma is commonly seen as a component of adult mixed NSGCT (see Fig. 44.2). A small percentage (2% to 3%) of postpubertal male germ cell tumors appear to have teratoma as the only histologic type, but these are always assumed to harbor a minor component of pluripotent NSGCT and are treated the same as a mixed NSGCT.
Immature teratoma shows partial somatic differentiation, whereas mature teratoma has terminally differentiated tissues such as cartilage, skeletal muscle, or nerve tissue, and frequently forms cystic structures. Although these cells can resemble normal tissues, teratoma is a low-grade malignancy and if untreated will grow until it is unresectable. Moreover, teratomas can give rise to secondary somatic malignancy, such as rhabdomyosarcoma, poorly differentiated carcinoma, or primitive neuroectodermal tumor.28 These typically display the biology of their de novo counterparts and are treated accordingly.29,30
Teratoma does not produce elevated serum AFP or hCG. Patients with elevated serum AFP and/or hCG should be assumed to have a nonteratoma germ cell tumor component, unless the elevation can be otherwise explained.
BIOLOGY
Mechanism of Germ Cell Transformation
ITGCN is thought to derive from malignant transformation of primordial germ cells or gonocytes during fetal development.31 Primordial germ cells migrate from the proximal epiblast (yolk sac) through the hindgut and mesentery to the genital ridge, and become gonocytes. The precise molecular events underlying transformation to ITGCN are not well understood. The most consistent genetic finding in germ cell tumors is a gain of material from chromosome 12p. The majority of NSGCT and seminomas contain i(12p), an isochromosome comprised of two fused short arms of chromosome 12. The remaining i(12p)-negative germ cell tumors also have a gain of 12p sequences in the form of tandem duplications that may be transposed elsewhere in the genome.
Gain of 12p sequences has been found in ITGCN, indicating that it is an early event in testicular cancer pathogenesis. The acquisition of i(12p) is not thought to be the initiating event, however, because it is preceded by polyploidization.32 Overexpressed genes on 12p are likely to be important, and there are candidate genes on 12p including several that confer growth advantage (KRAS2, CCND2 [cyclin D2]), and others that establish or maintain the stem cell phenotype (NANOG, DPPA3, GDF3). The exact genes that are critical to this step have not yet been identified.
Seminomas are usually hypertriploid, whereas NSGCT is more commonly hypotriploid.33 Other chromosome regions were found to have nonrandom gains or losses in germ cell tumors with less frequency than 12p. Single gene mutations are uncommon in germ cell tumors. The most commonly mutated genes are BRAF, KIT, KRAS, NRAS, and TP53.11 The KIT/kit ligand (KITLG) pathway
has special relevance for gonadal development. The biologic function of this pathway is broad and includes development of hematopoietic cells, melanocytes, and germ cells.34 KITLG is essential for primordial germ cell survival and motility, as are the chemokine SDF-1 (CXCL12) and its receptor CXCR4.11 Immunohistochemical markers found on primordial germ cells and gonocytes (PLAP, CD117 [KIT], OCT3/4 [POU5F1]) are also found on ITGCN, suggesting a transformation from these cells during fetal development (Fig. 44.4). The biallelic expression of imprinted genes in germ cell tumors has been reported, showing that they likely arose from primordial germ cells where the genomic imprinting is temporarily erased.31
has special relevance for gonadal development. The biologic function of this pathway is broad and includes development of hematopoietic cells, melanocytes, and germ cells.34 KITLG is essential for primordial germ cell survival and motility, as are the chemokine SDF-1 (CXCL12) and its receptor CXCR4.11 Immunohistochemical markers found on primordial germ cells and gonocytes (PLAP, CD117 [KIT], OCT3/4 [POU5F1]) are also found on ITGCN, suggesting a transformation from these cells during fetal development (Fig. 44.4). The biallelic expression of imprinted genes in germ cell tumors has been reported, showing that they likely arose from primordial germ cells where the genomic imprinting is temporarily erased.31
 Figure 44.4 Pathogenesis of testicular germ cell tumors. (Adapted from Sheikine Y, Genega E, Melamed J, et al. Molecular genetics of testicular germ cell tumors. Am J Cancer Res 2012;2:153-167.) |
Somatic mutations in KIT as well as increased copy number have been described in 9% of testicular germ cell tumors and 20% of seminomas.4 The somatic alterations in KIT found in germ cell tumors are predicted to upregulate pathway activity. KITLG plays a role in determining skin pigmentation and has undergone strong selection in European and Asian populations. Difference in the frequency of risk alleles for KITLG between European and African populations may provide an explanation for the difference in germ cell tumor incidence between Caucasian and African Americans.
There is evidence that epigenetic regulation of gene expression plays a role in the pathogenesis of germ cell tumors. The DNA methylation patterns are different among histologic types. Global hypomethylation is more common in seminomas than in NSGCT.31 In a study of 16 germ cell tumors, the methylation of CpG islands in NSGCT was similar to that observed in other tumor types, whereas it was virtually absent in seminomas.35 Aberrant promoter methylation is generally associated with absent or downregulated expression of the methylated genes. This can result, for example, in the silencing of tumor suppressor genes.31 Methylation has also been correlated with germ cell tumor differentiation. The more differentiated tumors (yolk sac tumor, choriocarcinoma, teratoma) were consistently hypermethylated, whereas seminoma and ITGCN were hypomethylated.36 Some of the observed methylation patterns may reflect normal development rather than germ cell tumor pathogenesis.
Pluripotency of Embryonal-Like Differentiation in Germ Cell Tumors
Embryonal carcinoma has a six-gene signature (DNMT3B, DPPA4, GAL, GPC4, POU5F1, TERF1), which was detected in three of five independent studies.11 All six of these genes are involved in establishing and maintaining pluripotency. SOX2 encodes a transcription factor essential for maintaining self-renewal of embryonic stem cells and is upregulated in embryonal carcinoma. Two additional genes that encode transcription factors associated with stem cell pluripotency, NANOG and POU5F1, are upregulated in both seminoma and embyronal carcinoma.26 Lineage differentiation takes place in NSGCT, mimicking the development of a normal zygote. Thus, embryonal carcinoma can be thought of as the transformed counterpart of embryonic stem cells, displaying self-renewal, pluripotency, and lineage differentiation.
Familial Predisposition to Germ Cell Tumors
Approximately 1.4% of patients with newly diagnosed germ cell tumor report a family history of germ cell tumor.34 First-degree male relatives of patients with testicular cancer have a 6- to 10-fold increased risk of developing testicular cancer. These observations point to the likely existence of a hereditary germ cell tumor subset. The inheritable effect is mild, and the most common number of affected relatives in a family is two. The age at diagnosis among familial cases is 2 to 3 years younger than sporadic cases, and there is a higher incidence of bilateral tumors.
The gr/gr deletion on chromosome Y, common among infertility patients and associated with a two- to threefold increased risk of testicular cancer, was studied as a candidate region for hereditary risk.4 The frequency of gr/gr variant is low, however, such that it could only account for a small component of hereditary risk. Genome-wide association studies (GWAS) for testicular cancer have been hampered by relatively small sample sizes. Nevertheless, five loci of interest were identified in a GWAS study from the
United Kingdom, on chromosomes 1, 4, 5q31.3, 6, and 12p22, including confirmatory data for the chromosome 6 locus. The single nucleotide polymorphism (SNP) associations on chromosomes 1 and 4 were not convincingly replicated in an independent US study, whereas the associations on chromosomes 5 and 12 were confirmed. The strongest associated SNPs were at 12q22 within the KITLG gene, for which there is a >2.5 risk of disease per major allele. For the chromosome 5 and 6 loci, a 1.5-fold increased risk was identified per major allele. The loci on chromosome 5 implicate the gene SPRY4, which encodes an inhibitor of the mitogen-activated protein kinase pathway. The locus on chromosome 6 falls within the intron of BAK1, which promotes apoptosis. The location of a disease-associated SNP near or within a gene does not definitively implicate that gene, yet all three of the genes identified in GWASs are directly or indirectly associated with the KIT/KITLG pathway.11 These genes may be responsible for an estimated 15% of genetic predisposition to germ cell tumors, whereas the genetic basis of the other 85% of familial aggregations remains unexplained.
United Kingdom, on chromosomes 1, 4, 5q31.3, 6, and 12p22, including confirmatory data for the chromosome 6 locus. The single nucleotide polymorphism (SNP) associations on chromosomes 1 and 4 were not convincingly replicated in an independent US study, whereas the associations on chromosomes 5 and 12 were confirmed. The strongest associated SNPs were at 12q22 within the KITLG gene, for which there is a >2.5 risk of disease per major allele. For the chromosome 5 and 6 loci, a 1.5-fold increased risk was identified per major allele. The loci on chromosome 5 implicate the gene SPRY4, which encodes an inhibitor of the mitogen-activated protein kinase pathway. The locus on chromosome 6 falls within the intron of BAK1, which promotes apoptosis. The location of a disease-associated SNP near or within a gene does not definitively implicate that gene, yet all three of the genes identified in GWASs are directly or indirectly associated with the KIT/KITLG pathway.11 These genes may be responsible for an estimated 15% of genetic predisposition to germ cell tumors, whereas the genetic basis of the other 85% of familial aggregations remains unexplained.
Cisplatin Sensitivity and Acquired Resistance in Adult Germ Cell Tumors
Exquisite sensitivity to chemotherapy distinguishes germ cell tumors from most other cancers. Levels of p53 protein are elevated in all germ cell tumors except teratoma.31 To maintain genomic integrity, embryonic stem cells have a high sensitivity to DNA damage, suggesting that the high levels of wild-type p53 seen in germ cell tumors may be intrinsic to their germ cell nature. TP53 gene mutations are uncommon in germ cell tumors, however, and the role of acquired TP53 mutations in the emergence of chemotherapy resistance has not been established.11 Moreover, levels of p53 protein assessed by immunohistochemistry were not associated with outcome. While mutations in TP53 have been observed in about 7% of seminomas, its significance in germ cell tumors remains unclear.
Mutations of BRAF including V600E mutations have been detected in a small percentage of NSGCT. BRAF mutations were most prevalent in mediastinal primary tumors, late relapse, and cisplatin-resistant NSGCT, suggesting a role in chemoresistance. Further study is needed to define the prognostic significance of BRAF mutation and whether the V600E mutation can be therapeutically targeted. A high ratio of proapoptotic Bax to antiapoptotic Bcl-2 was found in invasive germ cell tumors and may explain the rapid apoptotic response to DNA-damaging drugs; however, the Bax:Bcl-2 ratio was not associated with treatment outcome.31 Finally, the emergence of cisplatin resistance may be intimately associated with the expression of genes and pathways responsible for lineage differentiation in NSGCT, in other words, intrinsic to the germ cell biology rather than the result of specific mutations.
IMMUNOHISTOCHEMICAL MARKERS
SALL4 is expressed in almost all germ cell tumors and has been reported to be positive in ITGCN, classic seminoma, spermatocytic seminoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma.37,38 OCT3/4 is variably expressed in ITGCN, classic seminoma, embryonal carcinoma, and yolk sac tumor. Spermatocytic seminoma, choriocarcinoma, and teratoma are usually negative for OCT3/4. CD117 (KIT) helps highlight ITGCN and classic seminoma. CD30, SOX2, and keratin are helpful in the diagnosis of embryonal carcinoma, whereas SALL4 and Glypican-3 are often positive in yolk sac tumor.39 In tumors of unknown primary or those presenting as a retroperitoneal or mediastinal mass, SALL4, OCT3/4, CD117, SOX2, CD30, and low-molecular-weight keratins all may be useful in distinguishing germ cell tumors from non-germ cell tumors.
STAGING
The most widely used system for staging testicular cancer is the tumor, node, metastasis classification endorsed by the American Joint Commission on Cancer and the International Union Against Cancer (Tables 44.2 and 44.3).40 An important distinction for germ cell tumors is the inclusion of “S” classification (S0 to S3), signifying serum tumor marker elevation. There are three stage groupings of tumor, node, metastasis/serum tumor marker elevation classifications whereby, in general, stage I disease is confined to the testis, stage II is confined to the retroperitoneal lymph nodes with serum tumor markers in the good-prognosis range (S0 to S1), and stage III includes metastases that extend beyond the retroperitoneum or are extranodal in location. Stage III NSGCT also includes any patient with serum tumor markers in the intermediate- or poor-prognosis range (S2 to S3).
Patterns of Metastasis
Testicular cancers can undergo both lymphatic and hematogenous dissemination. The lymphatics arising from the testicle accompany the gonadal vessels in the spermatic cord. Some follow the gonadal vessels to their origin while others diverge and drain into the retroperitoneum. The landing zone for metastasis from the right testicle is in the interaortocaval lymph nodes just inferior to the renal vessels (Fig. 44.5). The landing zone from the left testicle is in the para-aortic lymph nodes just inferior to the left renal vessels (Fig. 44.6). Large volume disease tends to progress in retrograde fashion to the aortic bifurcation and below, along the iliac vessels.41
Seminoma
Seminoma can spread extensively through the lymphatic system to include retroperitoneal, retrocrural, mediastinal, supraclavicular, and cervical lymph nodes, often in the absence of hematogenous metastasis.42 Metastasis to lungs (stage IIIA) is common; metastasis to nonpulmonary organs (stage IIIB) is less common.43 Serum tumor markers do not affect the stage (except in stage IS) or prognosis in seminoma. Hematogenous metastasis to extrapulmonary organs (e.g., bone) in seminoma carries an intermediate prognosis. There is no stage IIIC or poor-prognosis designation in seminoma.44
Nonseminomatous Germ Cell Tumors
Similar to seminoma, lymphatic spread is the most common and usually the earliest type of dissemination in NSGCT. Stage groupings depend on both the anatomic extent of disease and serum tumor markers.40 Stage IIIB is distinguished from stage II or IIIA on the basis of tumor markers being in the intermediate-prognosis range (S2). Stage IIIC NSGCT carries a poor prognosis, and more often than seminoma it involves multiple organs such as liver and brain.44
Embryonal carcinoma, in some cases, exhibits hematogenous metastasis to lungs or nonpulmonary viscera without clinical involvement of retroperitoneal lymph nodes.45 Computed tomography (CT) of the chest is necessary for complete staging workup of tumors that have a high percentage of embryonal carcinoma.
Serum Tumor Markers
Serum tumor markers are an important part of the staging system for germ cell tumors. Three markers, namely AFP, hCG, and total LDH, are considered for establishing the correct prognostic classification (good, intermediate, or poor prognosis).44 Markers should be assessed after orchiectomy and before the start of chemotherapy. Markers that are elevated prior to orchiectomy and then normalize appropriately have no prognostic significance. Markers that do not normalize in a patient without any other clinical evidence of metastatic disease are considered stage IS.40 In the absence of residual disease, the expected half-life of postoperative serum tumor marker decline is 2 to 3 days for hCG and 5 to 7 days for AFP.
TABLE 44.2 Definition of TNM | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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TABLE 44.3 Stage Grouping | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 Figure 44.5 Lymph node metastasis from nonseminomatous germ cell tumor of the right testicle. Postchemotherapy resection showed metastatic teratoma. |
 Figure 44.6 Lymph node metastasis from nonseminomatous germ cell tumor of the left testicle (A) at diagnosis, and (B) upon completion of chemotherapy. Postchemotherapy resection showed metastatic teratoma with somatic transformation to primitive neuroectodermal tumor. |
TABLE 44.4 Germ Cell Tumor Risk Classification | ||||||||||||||||||
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Elevated AFP has special significance in seminoma because it is only produced by NSGCT. Germ cell tumors that histologically appear to be pure seminoma with elevated serum AFP are given the clinical diagnosis of NSGCT, and are treated as such.22 HCG can be elevated in either seminoma or NSGCT, but has prognostic significance only for NSCGT.
Total LDH concentration prior to chemotherapy functions as a prognostic factor in NSGCT and helps to determine stage. In seminoma with bulky metastases, LDH can be markedly elevated but has no prognostic significance.
There are several potential causes of spurious elevation of tumor markers. AFP is not cancer specific; it may be elevated in the presence of liver disease or as a nonspecific chronic elevation. Stability of AFP over time suggests a benign etiology. HCG is cancer specific in men, but it is not specific to germ cell tumors. It can be associated with other neoplasms and with exposure to cannabis products. Patients should be questioned about the use of marijuana. A positive hCG test can also occur as a laboratory artifact in patients with low serum testosterone, owing to the increased secretion of luteinizing hormone and its sequence similarity to hCG.46,47
Clinical Staging
The most commonly used methods for detecting metastatic disease are serum tumor markers and CT scan.15 Positron emission tomography (PET) scan can be helpful in the staging evaluation of a seminoma patient by distinguishing hypermetabolic lymph node metastases from reactive lymph nodes. PET is not as useful in NSGCT, where CT scan with oral and intravenous contrast is the preferred technique for detecting retroperitoneal adenopathy.
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