The Washington Manual of Oncology, 3 Ed.

Testicular Cancer and Germ Cell Tumors

Daniel Morgensztern • Bruce Roth

 I. PRESENTATION

1. Subjective. Patients with testicular cancer most commonly present with a painless solid testicular mass. Less frequently, the testicular mass may become painful as the result of bleeding or infarction in the tumor. Symptoms from metastatic disease may be present in up to 25% of patients, including lower back pain from bulky retroperitoneal disease, bone pain, and pulmonary symptoms such as cough, dyspnea, and chest pain.
2. Objective. A thorough physical examination is essential in patients with suspected testicular cancer. This examination should include evaluation of the external genitalia and scrotum, palpation of each testis by bimanual technique, examination of lymph nodes, with particular attention to the supraclavicular areas, and breast examination for evidence of gynecomastia. If the examination reveals a suggestive scrotal mass, the next step in the workup is ultrasonography. A hypoechoic mass within the testicular parenchyma should be considered a neoplasm until proven otherwise.
3. WORKUP AND STAGING
4. Practical approach to a new testicular mass. The differential diagnosis for patients presenting with a testicular mass includes malignancy, hydrocele, varicocele, testicular torsion, and epididymitis. For suspicious testicular masses, further evaluation includes chest x-ray and serum concentrations of α-fetoprotein (AFP), beta-human chorionic gonadotropin (β-hCG), and lactate dehydrogenase (LDH). These tumor markers are useful for diagnosis, prognosis, and assessment of treatment outcome. Referral to urology for suspected testicular malignancy is indicated for radical inguinal orchiectomy, which should be performed before any further therapy in patients with high clinical suspicion for germ cell tumor (GCT). Both testicular biopsy and trans-scrotal surgical approach are contraindicated due to concerns of tumor seeding. If testicular GCT is confirmed pathologically, patients should have computed tomography (CT) of the chest, abdomen, and pelvis. Additional imaging such as bone scan may be obtained in individuals with pure seminoma histologically or the presence of an elevated serum alkaline phosphatase. CNS imaging with either CT or MRI is indicated in those with CNS symptoms, or those with pure choriocarcinoma histologically, large volume pulmonary metastases, or a baseline hCG of >100,000. Sperm banking should be considered before any therapeutic intervention that may compromise fertility, including surgery, radiation therapy, and chemotherapy. At least 70% of GCT patients are oligospermic prior to any intervention.
5. Pathologic classification of testicular tumors
6. GCT. Approximately (95%) of primary testicular tumors originate from germ cells. GCTs carry an excellent prognosis with more than 90% of patients cured, including 50% to 90% of those with advanced disease. GCTs are classified for clinical purposes into two major groups: seminomas or nonseminomas. Nonseminomas include embryonal carcinoma, teratoma, choriocarcinoma, and yolk sac tumor, and frequently contain more than one cell type. Approximately 50% of GCTs are of pure seminoma histology, 35% are nonseminomas, and 15% have features of both. Patients with mixed histology or elevated AFP should be treated as nonseminomas. Pathology reports should also include the presence or absence of vascular/lymphatic invasion (VI) of the primary tumor, which carries prognostic significance in early stage tumors.
7. Testicular intratubular germ cell neoplasia carcinoma (TIGCN). TICGN, also known as testicular intraepithelial neoplasm (TIN) or carcinoma in situ (CIS) is a premalignant germ cell lesion with a 70% probability of progression to GTC within 7 years. It is often found in a normal-appearing testis biopsied for indications such as infertility evaluation, undescended testis, extragonadal germ cell tumors (EGGCTs), or when a contralateral testis contains a malignant GCT.
8. Seminomas. Pure seminoma is the most common testicular tumor, representing approximately 50% of GCTs. They generally have a more favorable prognosis, being more likely confined to the testicle at presentation, and having a higher response rate to both first-line and salvage chemotherapy regimens than nonseminomas. Only tumors with pure seminoma histology, and without elevated AFP, are considered seminoma for management purposes. Syncytiotrophoblasts capable of producing hCG are present in roughly 20% of these tumors. Seminoma typically presents in patients approximately 10 years older than their nonseminoma counterparts.
9. Nonseminomas. These are present in approximately 35% of all testicular tumors, and an additional 15% of GCTs with mixed histology are classified as nonseminoma. The peak age of incidence in is the 15- to 35-year range, where it represents the most common male malignancy. Nonseminomas often consist of mixed histology in any combination, and may also include histologic features of seminoma.

 i. Yolk sac tumor. Pure yolk sac tumors (formerly referred to as endodermal sinus tumors) are uncommon, and frequently associated with significantly elevated levels of AFP, and a tendency to develop hepatic metastases.

  ii. Choriocarcinoma. Pure choriocarcinoma may present with very elevated levels of hCG, frequently in the hundreds of thousands. These tumors, while rare, may have significant metastatic burden, possibly even with an occult primary lesion, and have a propensity to develop CNS metastases, where the lesions are at an increased risk of associated bleeding.

iii. Embryonal carcinoma. There is no definitive tumor marker pattern seen in pure embryonal carcinoma, as these tumors may be associated with elevated levels of either hCG, AFP, or both.

1. Teratomas. These tumors have elements from one or more germ layers in various stages of maturation. Histologically, teratomas are divided into three subgroups: mature teratoma, immature teratoma, and teratoma with malignant transformation (TMT). Both immature and mature teratomas may contain primitive or mature elements of ectodermal, endodermal, or mesodermal origin, but clinically there are no significant differences between them. However, the presence of teratoma with malignant transformation (which contains malignant degeneration along somatic lines) has negative prognostic significance.

 v. Other testicular tumors. Approximately 5% of testicular tumors are not of germ cell origin. Sex cord stroma tumors account for approximately 5% of all testicular tumors and include interstitial tumors (Leydig cell tumors and Sertoli cell tumors), granulosa cell tumors, and sarcomas. Embryonal rhabdomyosarcomas of the paratesticular tissues, mesothelioma of the tunica vaginalis, and adenocarcinoma of the rete testis are extremely rare. Non-GCT testicular malignancies in men older than 50 years are most commonly lymphomas.

  vi. Occult testicular tumor presenting as carcinoma of unknown primary. Metastatic disease alone may be the initial presentation in 5% to 10% of testicular GCTs. The testis may have a small asymptomatic tumor, CIS, scar, or residual testicular tumor detected only on ultrasonograph. Given the favorable prognosis of testicular cancer, serum tumor markers for GCTs should be part of the diagnostic workup in patients presenting with carcinoma of unknown primary, particularly in cases with midline distribution including retroperitoneal and mediastinal lymphadenopathy.

1. Serum tumor markers. Serum tumor markers are frequently elevated in GCTs. The three tumor markers that have been established in testicular GCTs are AFP, hCG, and LDH. Any elevation of AFP implies the presence of nonseminomatous elements, even if the pathology of the testicle is read as pure seminoma. Serum tumor markers are useful in patients with suspicious testicular lesions, providing both diagnostic and prognostic information. Patients with nonseminoma histology should have serum tumor markers, before retroperitoneal lymph node dissection (RPLND) in stages I and II, immediately before chemotherapy for stages II and III, before each chemotherapy cycle, at the end of treatment, and during surveillance.
2. hCG is produced by syncytiotrophoblasts. Levels less than 200 may be seen in patients with pure seminoma, but higher levels generally indicate the presence of nonseminomatous elements. Extremely high levels (perhaps in the hundreds of thousands to 1 million or greater) suggest choriocarcinoma. The half-life of hCG is 1 to 3 days. Because of the potential cross-reactivity of diagnostic tests for luteinizing hormone (LH) and hCG, a hypogonadal state (occasionally seen in patients post-orchiectomy and/or post-chemotherapy), elevated levels of LH may produce a “false-positive” hCG, although generally not in excess of a level of 20. Levels greater than this, particularly if they continue to rise, are indicative of recurrent testicular cancer.
3. AFP is produced exclusively in nonseminoma. It is elevated in approximately 50% of nonseminomas. The half-life of AFP is 5 to 7 days. AFP may also be elevated in hepatocellular disease of any etiology.
4. LDH is a relatively nonspecific tumor marker, but may be particularly helpful in the follow-up of patients with no elevations of hCG or AFP, such as in pure seminoma on marker-negative nonseminoma. Several large multivariate analyses have found it to be an independent prognostic variable.
5. Staging. In addition to traditional TNM (Tumor, Node, Metastasis) classification that assesses the primary tumor, lymph node involvement, and metastatic disease, the American Joint Committee on Cancer (AJCC) guidelines include measurement of serum tumor markers (S) in testicular GCT staging. Stage I is defined as disease limited to the testis; stage II, disease limited to retroperitoneal lymph nodes, and stage III is characterized by involvement of non-regional lymph nodes or distant metastases. T stage may be further subdivided into T1 (invasion of the tunica albuginea and no vascular or lymphatic invasion), T2 (vascular or lymphatic invasion, or involvement of the tunica vaginalis), T3 (invasion of the spermatic cord), or T4 (invasion of the scrotum). N stage may be subdivided into N0 (no regional lymph node metastases), N1 (metastasis to one or more lymph node measuring 2 cm or less), N2 (metastases to one or more lymph nodes measuring more than 2 cm and less than 5 cm), or N3 (lymph node measuring more than 5 cm). M stage can be further subdivided into M0 (no distant metastases), M1a (non-regional lymph nodes or pulmonary metastases), and M1b (distant metastases other than non-regional lymph nodes or pulmonary). The serum tumor marker (S) stage is divided into S0 (normal tumor markers), S1 (hCG <5,000 mIu/ml, AFP <1,000 ng/ml, and LDH <1.5 times the upper limit of normal [ULN]), S2 (hCG 5,000 to 50,000, AFP 1,000 to 10,000, or LDH 1.5 to 10 times ULN), and S3 (hCT >50,000, AFP >10,000, or LDH >10 times ULN). Stage IA is defined by T1N0M0, whereas IB is defined as T2–4N0M0. Stages IIA, IIB, and IIC are defined by the presence of N1, N2, or N3, respectively, without distant metastases. Stage III is defined by the presence of M1 or lymph node positive plus S2 or S3.

AFP, α -fetoprotein; hCG, human chorionic gonadotropin; LDH, lactate dehydrogenase.

^aNo patients with seminomas are considered to have poor risk.

 All patients with advanced disease requiring chemotherapy as initial treatment should be risk-stratified using the International Germ Cell Cancer Consensus Group (IGCCCG) classification system (Table 22-1). Patients with seminoma or nonseminoma are stratified into risk prognostic groups based on the primary site of tumor, presence of non-pulmonary metastatic disease, and serum tumor markers. Risk status is used to predict prognosis and to determine the appropriate first-line chemotherapy. Cure rates for patients with good risk, intermediate risk, and poor risk are 90%, 75%, and 45%, respectively.

1. Fertility issues and sperm banking. Infertility is associated both with disease and treatment. Approximately 70% of newly diagnosed patients are oligospermic at presentation prior to any therapy, and certainly treatments such as combination chemotherapy and abdominal/pelvic radiotherapy can compromise sperm counts to an even greater degree. Any patient considering active therapy of either of these two modalities should be counseled regarding sperm cryopreservation, as sterility following therapy may be permanent. It should also be recommended that patients use an approved form of contraception during chemotherapy and for a full year following its completion.

 III. THERAPY

1. Testicular seminoma
2. Stage I seminoma. Despite normal CT scans, there is a 15% risk of occult metastatic disease in locoregional lymph nodes with subsequent disease progression if no adjuvant treatment is given after orchiectomy in stage I seminoma. However, the cure rate in clinical stage I seminoma patients is greater than 99% regardless of management strategy, and adjuvant radiation, adjuvant chemotherapy, or surveillance with subsequent salvage therapy in the event of relapse representing acceptable standard management options. The main risk factors for relapse in stage I seminoma are tumor size >4 cm and invasion of rete testis (J Clin Oncol2002;20:4448), as well as the presence of lymphovascular invasion.
3. Radiation therapy. Adjuvant radiation therapy with 20 Gy, in 10 fractions of 2 Gy each to the infradiaphragmatic area with or without radiation to the ipsilateral inguinal lymph nodes, is associated with a relapse rate of 3% to 4%. Radiation toxicity includes dose-related gastrointestinal toxicity, impaired fertility, and possibly late malignancies. The few patients who relapse almost always have recurrent disease outside the radiation field, typically within 18 months of diagnosis of the primary tumor, and may still be salvaged with chemotherapy. Contraindications to adjuvant radiation include pelvic or horseshoe kidney, inflammatory bowel disease, or previous radiation, due to risk for excessive toxicity.
4. Surveillance. Since 85% of patients are already cured with an orchiectomy alone, by definition, all of these patients will be overtreated with any additional therapy. The curability of advanced disease makes surveillance the most appropriate treatment option in these patients (J Clin Oncol 2013;31:3490). In a retrospective study including 1,344 patients with stage I seminoma undergoing surveillance after orchiectomy, there were 173 (13%) relapses at a median time of 14 months, with 92% occurring in the first 3 years. After a median follow-up of 52 months, there were no disease-related deaths, with 99% of patients alive without disease, 1 patient dying from treatment-related complications, and 16 (1%) from unrelated causes (J Clin Oncol 2014, in press). Pooled data from several large observational experiences has shown 5-year disease-specific survival of 99.7%.
5. Adjuvant carboplatin chemotherapy. A third alternative is adjuvant chemotherapy with one cycle of carboplatin at area under the curve (AUC) of 7. The MRC TE 19/EORTC 30982 randomized 1,447 patients with resected stage I seminoma to adjuvant radiation therapy with 20 or 30 Gy or one cycle of single-agent carboplatin AUC7. The mature data from the trial showed a relapse-free rate at 5 years of 94.7% and 96% for the carboplatin and radiotherapy arms, respectively (J Clin Oncol 2011;29:957). This intervention, however, will unnecessarily expose 85% of patients not requiring any additional therapy to toxicity.
6. Stage II seminoma. One approach to the treatment of Stage IIA or IIB seminoma following orchiectomy is radiation therapy. The usual course of therapy includes the para-aortic lymph nodes and iliac chain nodes on the same side as the primary tumor (so-called inverted hockey stick field). This results in a relapse-free survival rate of 95% for stage IIA and 89% for stage IIB at 6 years. While some investigators have argued to eliminate the pelvic potion of the field (para-aortic strip only), this approach clearly results in a higher risk of recurrent disease in the pelvis.

The other, more commonly utilized approach in the modern era is the use of combination chemotherapy with either three cycles of cisplatin plus etoposide and bleomycin (BEP), or four cycles of etoposide and cisplatin (EP) alone. See Table 22-2 for the common chemotherapy regimens.

3. Stage IIC and III seminoma. Patients with advanced seminoma require chemotherapy according to the risk stratification based on the IGCCCG classification. Patients with good risks may be treated with four cycles of EP or three cycles of bleomycin plus etoposide and cisplatin (BEP). Approximately 90% of patients have good risk and 10% intermediate risk, with 5-year overall survivals of 86% and 72%, respectively.
4. Management of residual mass. Following chemotherapy for seminoma, reassessment of serum tumor markers and CT scan of the chest, abdomen, and pelvis is recommended. The larger the volume of disease initially, the higher the likelihood that a residual mass will be present at the end of chemotherapy. In the vast majority of cases, post-chemotherapy resection of residual masses should not be undertaken. These masses almost always are comprised of just necrosis/fibrosis, and these patients following either radiation or chemotherapy have dense desmoplastic reactions, vastly increasing the risk of perioperative complications, including vascular or renal injury. Patient who have normal tumor serum markers and either complete response or residual tumors measuring ≤3 cm do not need additional therapy. Patient with residual tumors larger than 3 cm should have a positron emission tomography (PET) scan at approximately 6 weeks after completion of chemotherapy to evaluate for the presence of residual tumor. In case of negative PET scan, no further therapy is required and the patients should undergo surveillance. However, since a positive PET scan usually indicates the presence of residual active disease, patients may require biopsy or resection. If resection is not possible or the serum tumor markers are elevated, the most appropriate treatment is with second-line chemotherapy.

BEP

Bleomycin, 30 units i.v. on days 1, 8, and 15 or on days 2, 9, and 16

Etoposide (VP-16), 100 mtg/m² i.v. days 1–5

Cisplatin, 20 mg/m² i.v. from days 1–5

EP

Etoposide (VP-16), 100 mg/m² on days 1–5

Cisplatin, 20 mg/m² i.v. on days 1–5

VeIP

Vinblastine 0.11 mg/kg i.v. on days 1–2

Ifosfamide 1,200 mg/m² i.v. on days 1–5

Cisplatin 20 mg/m² i.v. on days 1–5

Mesna 400 mg/m² i.v. daily every 8 h on days 1–5

VIP

Etoposide 75 mg/m² on days 1–5

Ifosfamide 1,200 mg/m² on days 1–5

Cisplatin 20 mg/m² on days 1–5

Mesna 400 mg/m² i.v. daily every 8 h on days 1–5

TIP

Paclitaxel, 250 mg/m² i.v. on day 1

Ifosfamide, 1,500 mg/m² i.v. daily on days 2–5

Mesna, 500 mg/m² i.v. before, and then 4 and 8 h after each dose of ifosfamide

Cisplatin, 25 mg/m² i.v. daily on days 2–5

All regimens are given on 21-day cycles

1. Testicular nonseminoma
2. Stage I. For patients with disease confined to the testicle and whose serum tumor markers (if elevated pre-orchiectomy) normalize, 70% of these individuals are already cured of their disease with the orchiectomy and will never relapse. Therefore, any additional therapy (surgery, chemotherapy) will unnecessarily cause toxicity in these individuals. Additionally, in the 30% destined to relapse after orchiectomy, their close follow-up should have assured a relatively small tumor burden at relapse, which is associated with a >95% cure rate with subsequent chemotherapy. For that reason, active surveillance represents the best option for these patients. In a recent multicenter study evaluating 1,139 patients with nonseminoma undergoing surveillance after orchiectomy, there were 221 (19%) relapses, including 81 out of 183 (44%) patients with LVI, 132 out of 934 (14%) without LVI, and 8 out of 21 (38%) with unknown LVI status. The median time to relapse and percentage of relapses within 3 years were 4 months and 98% for patients with LVI and 8 months and 93% for those without LVI. The overall 5-year disease-specific survival was 99.7% (J Clin Oncol 2014, in press). With the patterns of relapse, the authors suggested that the surveillance include physical examination and tumor markers every 2 months on the first year, every 3 months on the second year, and every 6 months from the third to fifth year. Chest radiograph and CT scan of the abdomen was recommended at 4, 8, 12, 18, and 24 months after orchiectomy, with consideration for repeating CT scan at 36 and 60 months.

 Traditionally these patients were treated surgically with a full, bilateral retroperitoneal lymph node dissection, developed at a time when systemic curative chemotherapy had not been yet developed. Despite modifications to this approach over the past several decades (modified template dissections, nerve-sparing approaches, etc.), this procedure is being offered much less frequently. As a result, with the exception of high volume testicular cancer centers, fewer urologists are being trained in this technique and its utilization will continue to fade in the clinical stage I patient.

2. Stage II. Patients with stage IIA and negative serum tumor markers should be treated with NS-RPLND, whereas four cycles of EP or three cycles of BEP remains an alternative option. For patients with stage IIB and negative serum tumor markers, the primary option is chemotherapy with four cycles of EP or three cycles of BEP. In case of complete response or residual tumor less than 1 cm after chemotherapy, there is no need for additional therapy. However, tumors measuring 1 cm or more after chemotherapy should be treated with NS-RPLND. Patient with persistently elevated serum tumor markers should be treated with chemotherapy.
3. Stages IIC and III. Patients with advanced nonseminoma, similar to those with seminoma, should be classified according to the IGCCCG criteria as having either good, intermediate, or poor-prognosis disease.
4. Good-risk patients. This category includes 56% of patients and is associated with a 5-year overall survival of 92%. The recommended treatment is four cycles of EP or three cycles of BEP, which have been shown to have similar efficacy. The substitution of carboplatin for cisplatin in either EP or BEP has been associated with inferior outcomes.
5. Intermediate- and poor-risk patients. Intermediate- and poor-risk nonseminomas are present in 28% and 16% of patients, respectively, with 5-year overall survivals of 80% in the intermediate-risk group and 48% in the poor-risk group. Patients should be treated with four cycles of BEP chemotherapy. Clinical trials, if available, should be considered for poor-risk patients. If brain metastases are present, cranial irradiation should be offered prior to chemotherapy.
6. Management of post-chemotherapy masses. Patients with advanced nonseminoma treated with chemotherapy should have a repeated CT scan between 4 and 8 weeks following completion of chemotherapy. In the setting of normalized tumor markers, maximum shrinkage of disease in response to chemotherapy may not occur for up to a year following completion of chemotherapy, and no decision regarding subsequent resection of residual disease should be made until maximum shrinkage has occurred. At that time, if <90% volumetric reduction (compared to pre-therapy scans) has occurred, consideration should be given to resection of residual radiographic disease, because of the possible presence of teratoma. Teratoma is unresponsive to chemotherapy, does not secrete tumor markers, and is only surgically curable. There is no diagnostic study (including PET scan) that can differentiate between teratoma and scar tissue. At the time of resection, if only necrosis/fibrosis or teratoma are found, no other therapy is required. If viable germ cell tumor is resected, additional chemotherapy (generally two additional cycles of EP) is warranted.
7. Management of recurrent disease after initial therapy. Patients with early stage disease who develop recurrent disease or those with advanced stage who have relapse following first-line chemotherapy can still be cured with additional chemotherapy, with the survival depending on several factors including primary site of disease, response to first-line therapy, progression-free survival, tumor markers, and presence of liver, bone, or brain metastases. The standard salvage chemotherapy regimens include vinblastine plus ifosfamide and cisplatin (VeIP) and paclitaxel plus ifosfamide and cisplatin (TIP). High-dose chemotherapy, usually with carboplatin plus etoposide, followed by auto-SCT is another option for patients with relapsed or recurrent GCTs. The large multicenter phase 3 IT-94 trial randomized 280 patients to chemotherapy alone of followed by auto-SCT and showed no significant differences in survival (Ann Oncol 2005;16:1152). In a retrospective analysis of 1,984 patients with GTC progressing after first-line chemotherapy, 604 patients (38%) achieved a 2-year progression-free survival using either conventional chemotherapy or high-dose salvage regimens followed by autologous stem cell transplant (auto-SCT). The 2-year progression-free survival ranged from 75% in patients with very low risk to 5.6% in those with high risk (Table 22-3) (J Clin Oncol 2010;28:4906). In a subset analysis of the study according to salvage treatment, the 2-year progression-free survival was significantly higher for the auto-SCT compared to standard chemotherapy for all patients (49.6 vs. 27.8%, p <0.001) and for each prognostic risk category. The 5-year overall survival also favored the auto-SCT group (53.2 vs. 40.8%, p <0.001), although it did not reach statistical significance for patients with low risk (J Clin Oncol 2011;29:2178).

AFP, α -fetoprotein; hCG, human chorionic gonadotropin; CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.

Final score and 2-year progression-free survival.

Very low (score = −1): 75.1%; low (0): 51%; intermediate (1): 40.1%; High (2): 25.9%; very high (3): 5.6%.

 Late relapses are defined as recurrences occurring 2 years or longer after the initial successful chemotherapy. These relapses occur in approximately 3% of patients, are more common in nonseminomas, and are typically associated with less responsiveness to chemotherapy and worse outcomes. Surgery is recommended for all lesions if technically feasible, with chemotherapy alone or followed by auto-SCT used in unresectable disease (Hematol Oncol Clin North Am 2011;25:615).

 IV. BACKGROUND AND EPIDEMIOLOGY. While testicular GCTs account for only 2% of all cancers overall, they are the most common solid tumors in men between the ages of 15 and 34 years. The incidence worldwide has more than doubled in the last 40 years. The incidence of testicular GCTs is lower in African American and Asian populations than in Caucasians. A recent study has reported an increasing frequency of the disease in Hispanic adolescents and young adults in the United States for unclear reasons. Incidence rates climb rapidly and peak in young adults, followed by a decline and leveling off in the elderly. The median age at diagnosis of seminoma is approximately 10 years older than that of nonseminoma.

 Several factors have been associated with the development of testicular cancer, including prior testicular cancer, family history, cryptorchidism, and Klinefelter’s syndrome. Approximately one-third of testicular cancers developing in patients with a history of cryptorchidism l arise in the normally descended testicle. Additionally, first-degree relatives of testicular cancer patients have a higher incidence of nonmalignant urogenital abnormalities, such as hypospadias. These data suggest that what is inherited is a urogenital field defect, one outcome of which may be the malignant degeneration of germinal epithelium. The lifetime risk of a patient with testicular cancer developing a contralateral primary tumor is approximately 1.5%.

1. EGGCT. An extragonadal germ cell tumor can arise from residual germinal epithelium left behind during gonadal migration during embryogenesis, and can arise in the pineal gland, the mediastinum, or the retroperitoneum without evidence of a testicular primary lesion. These lesions characteristically develop in the midline. Primary mediastinal and primary retroperitoneal nonseminomas are associated with an inferior prognosis compared to testicular primaries.

SUGGESTED READINGS

Einhorn LH, Williams SD, Loeher PJ, et al. Evaluation of optimal duration of chemotherapy in favorable-prognosis disseminated germ cell tumors: a Southwestern Cancer Study Group protocol. J Clin Oncol 1989;7:387–391.

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-–3404.

International Germ Cell Cancer Collaborative Group (IGCCCG). International germ cell consensus classification: prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol 1997;15:594–603.

Kollmannsberger C, Tandstad T, Bedard PL. Patterns of relapse in patients with clinical stage I testicular cancer managed with active surveillance. J Clin Oncol 2014;e-pub ahead of print 8/18/2014.

Motzer RJ, Agarwal N, Beard C, et al. Testicular cancer. J Natl Compr Canc Netw 2009;7:672-–693.

Nichols CR, Roth B, Albers P, et al. Active surveillance is the preferred approach to clinical stage I testicular cancer. J Clin Oncol 2013;31:3490-–3493.

Oldenburg J, Fossa SD, Nuver J, et al. Testicular seminoma and non-seminoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;24(Suppl 6):125-–132.