eMedicine Specialties > Urology > Cancer, Testicle

Nonseminomatous Testicular Tumors

David M Hoenig, MD, Associate Professor, Department of Urology, Albert Einstein College of Medicine; Chief of Weiler Division, Director of Laparoscopy and Endourology, Co-Director of Fellowship in Laparoscopy and Endourology, Residency Program Director, Department of Urology, Montefiore Medical Center
Janice Angela Santos-Cortes, MD, Chief Resident, Department of Urology, Albert Einstein Program, Montefiore Medical Center; Thomas H Rechtschaffen, MD, Consulting Staff, Department of Urology, A Family Urology Practice, PC

Updated: Sep 28, 2009

Introduction

Testicular cancer is relatively uncommon in the United States, with approximately 5500 cases per year. The overall incidence of testicular tumors worldwide ranges from 0.2-10.3 cases per 100,000 persons. Such tumors may arise in males of nearly any age and may be of germ cell or non–germ cell origin. Tumor histology (see Histologic Findings) and tumor stage (see Staging) are of primary importance in determining the prognosis of testicular tumors. This article addresses the demographics, histology, prognosis, and treatment of nonseminomatous germ cell tumors (NSGCTs).

History of the Procedure

The treatment of testicular cancer has developed in earnest over the past half century. Before 1970, testicular tumors carried a mortality rate that approached 50%, whereas recent studies have reported that the cure rate using multimodal therapy exceeds 90%. Improved understanding of the histology, mechanisms of tumor spread, and tumor markers, combined with the improved quality of radiographic imaging for accurate staging, have greatly contributed to the management of testicular cancer. The combination of refinements in surgical intervention and the application of effective combination chemotherapy has emerged as a paradigm for the successful use of multimodal therapy for solid tumors.

Problem

Testicular cancer has 3 main types—(1) germ cell tumors, (2) non–germ cell tumors, and (3) extragonadal tumors. Germ cell tumors, which are the most common, are classified as either seminoma or nonseminoma, based on histology. Of the 3 main types of testicular cancer, NSGCTs are behind only seminoma in terms of frequency. This discussion explores the incidence, risk factors, diagnosis, treatment options, and prognosis of NSGCTs.

Frequency

US incidence

Testicular cancer is relatively uncommon, with approximately 5500 new cases per year in the United States. The peak incidence is in men aged 20-34 years. Testicular cancer is the most common solid tumor in this otherwise young, healthy, and productive age group. Furthermore, despite improvements in survival rates since the introduction of platinum-based chemotherapy in the United States in the 1970s and 1980s, from 1975-2001, the incidence of testicular cancer among white males in the United States rose by 46%. Currently, the incidence is approximately 5.44 cases per 100,000 persons.¹

The rate of NSGCTs specifically also appears to have increased. In addition, the incidence of NSGCTs among active servicemen in the military almost doubled from 1988-1996.² NSGCTs are less common in African American males than in white males.

International incidence

Worldwide, testicular cancer has the highest incidence in Norway, Denmark, Germany, and Switzerland. The incidence in Switzerland in 1997 was 10.3 cases per 100,000 persons, with NSGCTs accounting for 45%-50% of cases. The incidence in this population has increased alarmingly (>300%) since 1955. The risk for the disease has increased in all birth cohorts except for those born during World War II.

Etiology

Factors that alter the differentiation of the primordial germ cell, resulting in the presence of an embryonal stem cell, can increase the risk of NSGCT. Risk factors include a history of testicular cancer in the contralateral testis, cryptorchidism (undescended testis), gonadal dysgenesis, prenatal exposure to high estradiol levels, exposure to chemical carcinogens, trauma, and orchitis. Other risk factors may include childhood inguinal hernias and any cause of testicular atrophy.

In 2005, a 25-year follow-up study of 44,864 Swedish men suggested that elevated serum cholesterol levels may increase the risk of testicular cancer.³ Further validation studies are required to evaluate these findings in other populations.

One of the most significant risk factors for testicular cancer is cryptorchidism. In addition, the age at which orchidopexy (an operation to bring the testicle down into the scrotum) is performed appears to play a significant role. A 2007 study reported a 2.23 relative risk (in comparison with the general Swedish population) of testicular cancer in patients who underwent orchidopexy before age 13 years, while the relative risk among those who underwent orchidopexy at age 13 years or older was 5.40.⁴ Therefore, among boys with cryptorchidism, orchidopexy performed before puberty appears to reduce the likelihood of testicular cancer later in life.

Pathophysiology

NSGCTs refer to the germ cell tumors that contain embryonal stem cells. These may be differentiated into extraembryonic tissues or somatic elements. Most tumors are composed of a mixture of these elements.

The 4 histologic classifications of NSGCTs include (1) embryonal carcinoma, (2) teratoma, (3) choriocarcinoma, and (4) yolk sac tumor.

Mixed tumors are those with a mixture of these histologies. Tumors with both seminomatous and nonseminomatous elements are considered NSGCTs because the NSGCT component most accurately reflects the response to treatment and overall prognosis.

Presentation

The classic presentation of a testicular tumor is a painless, swollen, hard testis in an otherwise healthy man in the third or fourth decade of life. The presentation can vary depending on the amount of disease, clinical stage, and the presence of metastases at the time of referral. Some patients present with a swollen painful mass in the scrotum that may be dismissed as infectious or inflammatory in nature, potentially resulting in a detrimental delay in starting treatment for NSGCT. Whenever the physical examination reveals any deviation from a palpably normal testicle, scrotal ultrasonography should be performed.

In all patients in whom testicular tumors are suspected, obtain a complete history and perform a complete physical examination. The history should include specific questions regarding possible risk factors for testicular cancer. Questions about cryptorchidism, trauma, and mumps orchitis are useful. Likewise, the occupational, chemical exposure, and smoking history of the patient should be obtained.

During the general physical examination, special attention should be given to the presence of gynecomastia, which is a finding in 5% of testicular cancer cases. Supraclavicular adenopathy may be a finding in advanced disease. Lung examination in patients with widespread lung metastases may reveal areas of decreased breath sounds. Abdominal examination should be performed to assess for visceral or bulky lymphatic involvement. The contralateral testis must be examined for possible abnormalities. Finally, a neurologic examination is also important to evaluate for possible brain metastasis. The testicles should be readily palpable in the scrotum. The contour of each testicle should be smooth and the consistency uniform. Any size discrepancy between the 2 testicles should be assessed and noted.

Differentiation of the scrotal contents should be found with careful palpation. The epididymis, attached to the posterior aspect of the testicle, is frequently the site of induration or cysts. Patients may discover such abnormalities during self-examination, prompting them to seek medical attention. These conditions should be identifiable during the physical examination. If the inability to perform an adequate evaluation is a concern, scrotal ultrasonography must be performed to aid in the diagnosis.

Indications

Surgery is indicated not only for the initial treatment of nonseminomatous germ cell tumors (NSGCTs) but also for diagnosis.

Relevant Anatomy

See Clinical.

Contraindications

Radical (inguinal) orchiectomy has no contraindications, other than potential anesthetic risks and uncontrolled bleeding diathesis. In such high-risk patients, preoperative clearance and preparation may be required, but radical orchiectomy should still be performed at the earliest opportunity.

Workup

Laboratory Studies

• Serum tumor markers: Serum tumor markers must be assessed during the initial evaluation of a patient with a testis tumor. Monitoring the values of these markers is vital in assessing the success of treatment and in observing for the earliest evidence of recurrence. The degree of elevation among tumor markers is a prognostic index, and the post-treatment levels have been shown to be reliable markers of residual disease. Since 1997, the American Joint Committee on Cancer (AJCC) has included human chorionic gonadotrophin (hCG), alpha-fetoprotein (AFP), and lactate dehydrogenase (LDH) in the classification system for nonseminomatous germ cell tumors (NSGCTs).
  • Serum hCG and AFP are the most important tumor markers. AFP levels are elevated in 50%-70% of patients with nonseminomatous tumors, and hCG levels are elevated in 40%-60%. AFP has a half-life of 5-7 days, and hCG has a half-life of 36 hours. The half-lives can be used to calculate when the values of these markers should drop after therapy, hopefully to within the reference ranges. Therefore, in order to ensure reliable values after orchiectomy, at least one week must be allowed to pass before hCG is measured and 5 weeks before AFP is measured.
  • LDH is an indicator of possible tumor burden. LDH levels are elevated in 60% of patients with NSGCT; however, this is considered a nonspecific marker.
  • Monitoring the values of these markers is vital in assessing the success of treatment of a testis tumor. However, the degree of elevation in pretreatment marker levels has not been shown to reliably predict treatment outcomes. Nonetheless, a 2007 study has suggested that, in patients with NSGCT, a pretreatment AFP level within the reference range may indicate a greater likelihood of retroperitoneal nodal metastases in otherwise low-stage disease.⁵ If future clinical experience confirms these findings, more aggressive surgical staging with retroperitoneal lymph node dissection (RPLND) may be warranted in this subset of patients.
  • Elevated AFP levels in a patient with a pathologically diagnosed seminoma indicate the presence of NSGCT elements that were not observed by the pathologist. These tumors should be regarded as NSGCT rather than as pure seminoma because the disease course typically reflects that of the NSGCT component. The only type of NSGCT that does not secrete AFP is pure choriocarcinoma, which is rare.
  • Abnormal tumor marker levels are as follows:
    • An AFP value that exceeds 9 ng/mL is considered abnormal. (Note that the AFP value may be elevated in patients with liver dysfunction.)
    • An hCG level that exceeds 4 mIU/mL is considered abnormal. (Note that the hCG value may be elevated in hypogonadotrophic patients.)
    • An LDH value of more than 1.5 times the reference range is considered abnormal.

Imaging Studies

• Ultrasonography
  • In the diagnosis and staging of NSGCT, imaging studies are of primary importance. Although most tumors are diagnosed based on physical examination findings, scrotal ultrasonography is typically performed to ensure the correct diagnosis or to establish a diagnosis in a patient in whom the scrotal structures cannot be differentiated during testicular examination.
  • In patients with testicular tumors, scrotal sonograms usually demonstrate a mass in the testis, usually confined by the tunica albuginea. This mass may contain microcalcifications and areas of hemorrhage and is typically heterogeneous in appearance.
  • In the setting of teratoma elements, sonograms may demonstrate well-defined structures of ectodermal derivation.
• CT scanning
  • Abdominal and pelvic CT scanning is integral to the staging of a testis tumor and is typically performed after pathological confirmation of a testis tumor following orchiectomy.
  • Left-sided NSGCTs typically spread first to the left para-aortic and then preaortic lymph nodes inferior to the renal vessels. Right-sided tumors spread to the paracaval and interaortocaval nodes inferior to the renal vessels.
  • However, crossover is not uncommon with lymph node metastases of testis tumors and is more typical of right-sided tumors than left-sided ones. In up to 20% of right-sided NSGCTs, lymph node involvement is found on the left side of the retroperitoneum. The location and size of metastases discovered on abdominal and pelvic CT scans are used to clinically stage the testicular tumor, providing a means of defining prognosis and the best course of treatment.
• Radiography
  • Chest radiography is usually obtained to help identify any possible pulmonary metastases.
  • CT scanning of the chest may also be used and increases the sensitivity of the diagnosis. However, small benign granulomas of the lung, if present, are misdiagnosed as metastatic disease in up to 30% of patients with clinically low-stage disease.
• MRI
  • MRI appears to be equally accurate as CT scanning in the detection of retroperitoneal metastases. However, MRI is more expensive and is not as readily available in some institutions.
  • In patients with testicular tumors, MRI may be used to detect brain metastases, neurologic involvement, musculoskeletal metastases, and involvement of the large vessels and bones.
  • In some studies, MRI has shown some ability to differentiate seminomatous tumors from and NSGCTs. Heterogenicity on contrast-enhanced and nonenhanced images suggests an NSGCT component.
• Positron emission tomography
  • With recently improved technology in positron emission tomography (PET) scanning, evidence supports its utility in identifying viable tumor in residual masses following chemotherapy. Some studies have shown that PET scanning can define relapse sites before CT scanning can. In addition, some evidence has shown that PET scanning may predict mature teratoma more accurately than CT scanning.
  • Note that negative PET scanning findings do not exclude the presence of metastatic disease.

Other Tests

Patients with testicular tumors should be offered the opportunity to undergo semen analysis and to bank sperm for future fertility concerns. This can be performed either before or after orchiectomy. See Complications.

Diagnostic Procedures

• Percutaneous biopsy of a testicular mass has no role in patients with possible testicular cancer. This procedure may alter the lymphatic drainage of the tumor, potentially resulting in spillage of tumor cells and metastases to atypical sites.
• If testicular biopsy is considered, it should be performed during inguinal exploration with control of the testicular vessels, with planned radical orchiectomy if the biopsy results are positive for cancer upon frozen-section analysis.

Histologic Findings

NSGCTs encompass several histologic types, including embryonal, teratoma, yolk sac, choriocarcinoma, or a combination. In addition, the finding of any of these histologic types within a seminoma defines the tumor as an NSGCT, primarily because the natural history of these tumors is less favorable than that of pure seminoma.

Staging

The prognosis and optimal treatment of testicular tumors are determined with tumor staging. Tumors are initially staged clinically, using results from a survey of serum tumor markers, abdominal and pelvic CT scanning, and chest radiography to evaluate for any metastases.

• Clinical stage classifications according to the AJCC (1997): The AJCC tumor, node, metastasis (TNM) system subdivides stage I disease into stages Ia, Ib, or Is depending on the T stage. Stage II is subdivided depending on the volume of retroperitoneal lymph node involvement. Stage III is subdivided according to the degree of metastatic involvement and serum tumor marker levels.
  • Stage I is defined as an absence of regional lymph node metastases. The tumor is confined to the testicle. Invasion to the epididymis, tunica albuginea, spermatic cord, or scrotum does not change the T stage but does increase the risk of nodal involvement and risk of recurrence.
  • In stage II disease, the risk of recurrence is increased if (1) more than 5 nodes are involved, one or more of the involved nodes are larger than 2 cm, or if extranodal fat is involved.
    • Stage IIA: Involved lymph nodes are smaller than 2 cm.
    • Stage IIB: Involved lymph nodes are larger than 2 cm but smaller than 5 cm.
    • Stage IIC: Involved lymph nodes are larger than 5 cm.
  • Stage III disease is characterized by supradiaphragmatic lymph nodes, visceral involvement, or persistently elevated marker values.

TNM classification

Primary tumor (T)

• pTX - Primary tumor cannot be assessed (If radical orchiectomy has not been performed, the designation TX is used.)
• pT0 - No evidence of primary tumor (eg, histologic scar in testis)
• pTis - Intratubular germ cell neoplasia (carcinoma in situ)
• pT1 - Tumor limited to the testis and epididymis with no vascular or lymphatic invasion
• pT2 - Tumor limited to the testis and epididymis with vascular or lymphatic invasion or tumor extending through the tunica albuginea with involvement of the tunica vaginalis
• pT3 - Tumor invades the spermatic cord with or without vascular or lymphatic invasion
• pT4 - Tumor invades the scrotum with or without vascular or lymphatic invasion

Regional lymph nodes (N) - Clinical versus pathologic

• Clinical
  • NX - Regional lymph nodes cannot be assessed
  • N0 - No regional lymph node metastasis
  • N1 - Lymph node mass is 2 cm or smaller in greatest dimension or multiple lymph node masses, none larger than 2 cm in greatest dimension
  • N2 - Lymph node mass is larger than 2 cm but not more than 5 cm in greatest dimension, or multiple lymph node masses, any one mass larger than 2 cm but not larger than 5 cm in greatest dimension
  • N3 - Lymph node mass is larger than 5 cm in greatest dimension
• Pathologic
  • pN0 - No evidence of tumor in lymph nodes
  • pN1 - Lymph node mass is 2 cm or smaller in greatest dimension and fewer than 6 nodes are positive, with none larger than 2 cm in greatest dimension
  • pN2 - Lymph node mass is larger than 2 cm but not larger than 5 cm in greatest dimension, with more than 5 nodes positive and none larger than five cm (There is evidence of extranodal extension of tumor.)
  • pN3 - Lymph node mass is larger than 5 cm in greatest dimension

Distant metastases (M)

• M0 - No evidence of distant metastases
• M1a - Nonregional nodal or pulmonary metastases
• M1b - Nonpulmonary visceral masses

Serum tumor markers (S)

Staging

• Stage 0 - pTis, N0, M0, S0
• Stage I - pT1-4, N0, M0, SX
• Stage IA - pT1, N0, M0, S0
• Stage IB - pT2-4, N0, M0, S1-S3
• Stage IS - Any pT/Tx, N0, M0, S1-S3
• Stage II - Any pT/Tx, N1-3, M0, SX
• Stage IIA - Any pT/Tx, N1, M0, S0-S1
• Stage IIB - Any pT/Tx, N2, M0, S0-S1
• Stage IIC - Any pT/Tx, N3, M0, S0-S1
• Stage III - Any pT/Tx, any N, M1, SX
• Stage IIIA - Any pT/TX, any N, M1a, S0-S1
• Stage IIIB - Any pT,Tx, any N, M0-M1a, S2
• Stage IIIC - (1) Any pT/Tx, N1-N3, M0, S3; (2) any pT/Tx, any N, M1a, S3; or (3) any pT/Tx, any N, M1b, any S

Stage-specific clinical findings and treatment options

• Clinical stage I NSGCT
  • Clinical findings
    • Serum marker values, if elevated, return to normal following orchiectomy.
    • Abdominal and pelvic CT scans demonstrate no evidence of solid organ or lymphatic spread.
    • Chest radiograph demonstrates no lesions.
  • Treatment options
    • The designation of clinical stage I NSGCT is accurate in approximately 70% of cases. However, nearly 30% of patients have microscopic metastases to the retroperitoneal lymph nodes at the time of orchiectomy. The percentage of patients with metastases increases with the presence of vascular or local invasion of the tumor on the orchiectomy specimen and the presence of embryonal carcinoma as a predominant component of the tumor. In a recent study, normal AFP levels prior to orchiectomy were found to correlate with a higher risk of retroperitoneal lymph node metastases.⁵
    • The first treatment option is an aggressive surveillance regimen consisting of monthly office visits with (1) tumor marker measurements and chest radiography for the first year and (2) abdominal and pelvic CT scanning every 3-4 months. In the second year, a similar evaluation is performed every 2 months, and office visits are less frequent for the next 3 years. With this approach, approximately 35% of patients develop metastatic spread of their tumor during surveillance, with an excellent subsequent cure rate (>90%) using surgery (RPLND) and/or chemotherapy in those who experience recurrence. Patients placed on surveillance must be willing to maintain a close follow-up schedule faithfully. According to findings from a 2007 study using randomized protocols to evaluate less frequent CT scanning, CT scanning at 3 months and 12 months may be a reasonable surveillance protocol after orchiectomy in select low-risk patients.⁶
    • In a recent prospective study, MRI has been explored as an alternative to CT scanning for surveillance of retroperitoneal nodes in order to reduce radiation exposure with repeat CT scans, with promising initial results.⁷
    • For the second option, initial treatment with primary RPLND may be used to provide both pathologic staging and cure of any metastatic disease. Primary RPLND is regarded as the standard method for optimal tumor staging, and it affords a patient with a pathologic stage I tumor a cure rate of approximately 90%. This approach is often preferred in patients with high-risk features on orchiectomy specimens because these patients are at higher risk for subsequent retroperitoneal metastases.
    • A 2005 study by Stephenson et al reported on the use of RPLND for clinical stage I and IIA disease (negative serum tumor markers and no enlarged lymph nodes on CT scanning of the retroperitoneum).⁸ This study suggests that using RPLND as solitary therapy in these patients is associated with a 96% 4-year disease-free rate and indicates that RPLND is not only diagnostic but also significantly therapeutic.
    • A third option, particularly in patients with high-risk disease, is primary platinum-based chemotherapy. This has been reported to achieve a cure rate of 90%-100%.
• Clinical stage II NSGCT
  • Clinical findings
    • Clinical stage IIA tumors are those in which abdominal and pelvic CT scans demonstrate retroperitoneal lymph nodes smaller than 2 cm. When any retroperitoneal lymph nodes larger than 2 cm but smaller than 5 cm are demonstrated on CT scans, clinical stage IIB is assigned.
    • Stage IIA disease is usually managed with primary RPLND. Stage IIB is managed with either primary RPLND or primary chemotherapy, depending on the philosophy of the treating physician. Stage IIC (advanced bulky metastases) is more commonly managed similarly to stage III disease and is discussed below.
  • Treatment options
    • For clinical stages IIA and IIB NSGCT, primary RPLND, with or without adjuvant chemotherapy, is recommended most often in the United States. Once again, RPLND affords the certainty of pathologic staging in combination with surgical excision of the disease. A high relapse rate in patients with a greater volume of disease, namely pathological stage IIB or C, argues for the addition of adjuvant chemotherapy. The cure rate using this treatment combination approaches 95% for 5-year survival.
    • Alternatively, patients with clinical stage IIA or IIB disease may be advised to undergo primary chemotherapy. In a study of patients with clinical stage IIA or IIB by Horwich et al, 68% of patients had evidence of resolution of lymphadenopathy on subsequent CT scans and 32% of patients required adjuvant RPLND for persistent lymphadenopathy. Overall, the authors reported a 92% cure rate, with 98.5% cause-specific survival at a median follow-up of 5.5 years.⁹
• [#target1]Clinical stage IIC and stage III NSGCT
  • Clinical findings
    • Patients with stage IIC disease have lymph nodes larger than 5 cm observed on abdominal and pelvic CT scans.
    • Patients with stage III disease have lymph node or viscera involvement above the diaphragm.
  • Treatment options
    • Patients with stage IIC disease have a very high relapse rate when treated with primary RPLND alone. When considering treatment choices, these patients should be viewed as patients with stage III disease who have a good prognosis. Because of the high disease recurrence associated with RPLND, patients with stage IIC disease appear to benefit most from primary chemotherapy, with RPLND reserved for persistent or recurrent retroperitoneal masses following chemotherapy.
    • When patients with stage III disease are stratified into low-risk, intermediate-risk, and high-risk patients, their overall 5-year survival is 92%, 80%, and 48%, respectively, when treated with primary chemotherapy. This risk assessment is based on factors such as the degree of elevation of tumor marker values, the size of mediastinal metastases, the presence or absence of cervical nodes, and the number and size of pulmonary metastases.
    • In the most recent disease classification, patients in whom tumor markers fail to normalize following orchiectomy and who have no radiologic evidence of disease are considered to be in clinical stage III.

Treatment

Medical Therapy

Testicular cancer is treated primarily with surgery, in the form of radical (inguinal) orchiectomy, to determine the histologic type of the cancer and the local tumor stage. Chemotherapy is used as primary therapy in advanced disease (stage IIC and III) or as adjuvant therapy in low-stage disease. In some cases, chemotherapy is used as primary therapy in low-stage disease when risk factors persist or tumor markers are persistently elevated (stage IS) after orchiectomy. The increase in survival and cure rate in the last decades has been due mainly to effective chemotherapy.

For stage-specific treatment recommendations, also see Staging.

Recommended primary chemotherapy dose and protocols for advanced disease (stage IIc-III) are based on risk stratification.

• A good prognosis can typically be expected in patients with a testicular or retroperitoneal primary tumor, no nonpulmonary visceral metastases, and an AFP level below 1000 ng/mL, an hCG level below 5000 IU/L, and an LDH level less than 1.5 times the upper limit of the reference range. In patients with disseminated disease who have a good prognosis, a 3-cycle regimen of bleomycin, etoposide, and cisplatin (BEP) has typically been used as first-line chemotherapy. Alternatively, some centers administer etoposide and platinum alone (ie, the EP regimen) in a 4-course cycle. These regimens elicit a response rate that ranges from 81%-92%. Among patients with a good prognosis, the 5-year progression-free survival rate is 89%, and the 5-year overall survival rate is 92%.
• High-risk patients and those with an intermediate prognosis are managed with the same initial regimen (4 cycles of BEP. This approach yields a cure rate and a durable response of less than 60% in most series. Intermediate prognostic features include (1) testis or retroperitoneal primary tumor; (2) no nonpulmonary visceral metastases; and (3) one of the following: an AFP level of 1000-10,000 ng/mL, an hCG level of 5000-50,000 IU/L, or an LDH level 1.5-10 times the upper limit of the reference range. High-risk prognostic features include any of the following: mediastinal primary tumor, nonpulmonary visceral metastases, an AFP level greater than 10,000 ng/mL, an hCG level greater than 50,000 IU/L, or an LDH level greater than 10 times the upper limit of the reference range. The 5-year overall survival rate is 80% in the intermediate group and only 48% in the high-risk group.
• Standard 3-dose regimens using vinblastine/etoposide/paclitaxel, ifosfamide, and cisplatin have been described as salvage therapy for primary treatment failures. Alternatively, high-dose therapy in combination with autologous bone marrow transplantation has been used with success for the most refractory cases.
• Preliminary results of a phase II trial of paclitaxel plus gemcitabine salvage chemotherapy after progression following high-dose chemotherapy with tandem transplantation show promise, even in these extremely high-risk patients. An objective response was achieved in 31% of patients, with 6 complete responses (19%).¹⁰

Selected patients who do not achieve a complete medical response and who present with residual masses after treatment may be candidates for adjuvant surgery (RPLND) if certain criteria are met.

Chemotherapy for testicular cancer carries perioperative and postoperative implications. Acute and late toxicities are well recognized.

• Myelosuppression is caused by the commonly used agents.
• These agents increase the risk of cardiovascular disease and myocardial infarction. Proposed mechanisms include direct endothelial damage, vasospasm, and increased cardiac risk factors such as hypertension, hyperlipidemia, increased body mass index (BMI), and renal insufficiency.
• Cisplatin may cause nephrotoxicity, ototoxicity, hypomagnesemia, neuropathy, and infertility. In some cases, the adverse effects are persistent. Cisplatin has also been associated with myocardial infarction, angina pectoris, and thromboembolic events.
• Bleomycin is known to cause pulmonary toxicity. This adverse effect is dose related and develops in approximately 6.8%-8.5% of patients treated with more than 300 U of bleomycin (3 cycles of BEP consists of 270 U of bleomycin; 4 cycles consists of 370 U).
  • Interstitial pneumonitis is the most common pulmonary manifestation and leads to fibrosis and death in 1% of patients. The toxic effects of bleomycin are thought to be partly due to induction of free radicals.
  • Perioperative pulmonary complications were once attributed to high inspired oxygen fractions during surgery, although this theory has been abandoned.
  • A study by Donat and Levy (1998) found that the amount of blood transfused, preoperative forced vital capacity, and length of surgery were the only predictors of postoperative problems with oxygen saturation.¹¹ Therefore, management with intravenous fluids is the mainstay of perioperative therapy.
  • Raynaud phenomenon has also been attributed to bleomycin and may be exacerbated by cisplatin and vinblastine.
• Other potential adverse effects include the following:
  • Etoposide - Secondary leukemia
  • Ifosfamide - Nephrotoxicity, hemorrhagic cystitis, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), CNS toxicity
  • Paclitaxel - Neuropathy, hypersensitivity reaction, diarrhea
  • Vinblastine - Constipation, ileus, SIADH
• Chemotherapy also carries an increased risk of secondary malignancies. The relative risk of leukemia, lymphoma, sarcoma, melanoma, colon cancer, stomach cancer, kidney cancer, prostate cancer, bladder cancer, thyroid cancer, rectal cancer, pancreatic cancer, and connective soft-tissue cancer is increased by a factor of 1.7-8.8. In a study by the Netherlands Cancer Institute, radiation and chemotherapy were found to increase the risk of secondary malignancies or cardiovascular disease to a degree similar to that of smoking.
• Infertility is a well-known, commonly recognized adverse effect (see Complications).

Surgical Therapy

Radical orchiectomy is performed when a testis tumor is appreciated upon examination or preoperative imaging studies. This is performed via an inguinal incision in order to prevent alteration of the lymphatic drainage pattern of the testicle (ie, drainage to the retroperitoneal lymph nodes) by violating the scrotal wall (ie, drainage to the superficial inguinal lymph nodes). Radical orchiectomy also allows ligation of the vas deferens and testicular vessels at the internal inguinal ring, which eliminates the need to explore the inguinal canal again if subsequent surgical removal of the spermatic cord and retroperitoneal lymph nodes is required (ie, for therapy or staging).

After radical orchiectomy is performed and the tumor is identified as a nonseminomatous germ cell tumor (NSGCT), clinical and/or surgical staging is mandatory. Primary RPLND is used to determine pathological staging and, in most of these patients, to provide curative therapy.

A thorough review of RPLND can be found in the eMedicine article Lymph Node Dissection, Retroperitoneal.

For stage-specific treatment recommendations, also see Staging.

Preoperative Details

Prior to radical orchiectomy, routine preoperative preparations should be performed and laboratory studies obtained, as described above.

Prior to planned RPLND, some surgeons advocate that patients should start a low-fat diet 2 weeks before the operation to reduce the risk of chylous ascites, and they should continue this in the immediate postoperative period.

On the day before RPLND, the patient should start a clear liquid diet and take a mechanical bowel preparation at home.

Intraoperative Details

For radical orchiectomy, an inguinal incision is made and the cord isolated and compressed with a vessel loop for vessel control prior to manipulation of the testis. The testicle is maneuvered from the scrotum up into the inguinal canal to expose it in the inguinal incision. The gubernaculum is divided to free the testicle from the inner wall of the scrotum.

Typically, the cord is dissected proximally to the level of the internal ring and divided between clamps. The proximal vessels and vas deferens are secured with nonabsorbable sutures in the event subsequent RPLND is to be performed.

A prosthesis may be placed in the scrotum at the time of orchiectomy.

Postoperative Details

Limitations on physical activity are typically instituted to decrease the risks of pain, bleeding, and/or wound complications.

Follow-up

The median time to recurrence is 7 months, and 90% of patients who experience recurrence do so within 2 years. Hence, an intensive schedule of follow-up and imaging is required for the first 2 years. Surveillance schedules vary but should include, at a minimum, serum marker evaluations, chest radiography, and contralateral testis examination every 1 month for the first year, every 2 months for the second year, every 3 months for the third year, and every 4-6 months for the fourth and fifth years. Abdominal and pelvic CT scanning should be performed every 3 months for the first year, every 3-4 months for the second year, and every 6 months for the third through fifth years.

Physicians who treat patients through the surveillance period have a responsibility to ensure patients are not lost to follow-up and that they comply with the regimen.

If findings are negative after RPLND, follow-up may be less stringent. This should include serum marker evaluations, chest radiography, and physical examinations every 3-4 months for the first 2 years and every 6 months for the third through fifth years. Recurrence in the retroperitoneum is rare in these patients. CT scanning is warranted periodically, at least 6 months postoperatively and annually for the next few years, particularly if the patient was considered high risk.

A recent randomized study suggests that a more liberal surveillance protocol can be considered for low-risk patients with clinical stage I disease.⁶ Such surveillance would consist of follow-up imaging with CT scanning at 3 and 12 months (rather than with 5 follow-up sessions required by traditional surveillance protocols). This protocol offers an excellent ability to rule out disease progression. However, confirmatory studies will likely be required before such a protocol will be widely accepted.

Finally, 2%-4% of patients with NSGCT experience a late relapse (after 2 y),¹² so individualized long-term follow-up is likely prudent.

For excellent patient education resources, visit eMedicine's Men's Health Center and Cancer and Tumors Center. Also, see eMedicine's patient education articles Cancer of the Testicle and Testicular Self-Exam.

Complications

The long-term adverse effects of RPLND and chemotherapy must be considered and discussed with the patient, especially when either modality can be considered primary therapy. In the hands of an experienced surgeon, RPLND should carry a mortality rate of approximately 0%. Significant recovery time is required before patients can return to work, primarily because of the length of the incision. The most commonly described long-term complication is the loss of antegrade ejaculation.

When the patient has low-volume disease and a nerve-sparing procedure can be performed, ejaculation can be maintained in virtually all patients. However, in a patient with stage IIB cancer, a nerve-sparing procedure may compromise surgical cure, and a patient who wishes to preserve ejaculatory function may elect for primary chemotherapy.

In contrast, primary chemotherapy results in azoospermia in most patients for up to 24-36 months, and a persistent absence of sperm in the semen occurs in approximately 25% of patients at 2-5 years of follow-up.

With respect to concerns regarding postoperative sexual function (ie, libido), erectile function, and the potential for orgasm, sacrifice of the sympathetic nerves in the non–nerve-sparing RPLND does not appear to be contributory.

Chemotherapy also carries an increased risk of secondary malignancies. The relative risk of leukemia, lymphoma, sarcoma, melanoma, and gastrointestinal tumors is increased by a factor of 1.7-8.8.

A study on quality of life by Stava et al (2005) among individuals who survived cancer (including testicular cancer) revealed a 6.8% rate of hearing loss (although this was not specific to patients with testicular cancer).¹³

In a study from Norway, Mykletun et al (2005) reported that, at a mean of 11 years of follow-up, men who survived testicular cancer had no clinically significant difference in quality of life compared with age-matched controls.¹⁴ Overall, only minimal differences were seen in quality of life between different testicular cancer treatment modalities. The apparently excellent quality-of-life results of this study may offer some reassurance regarding the potential for complications and challenges to patients who must face the diagnosis and treatment of testicular cancer.

Infertility

Outcome and Prognosis

Patients with stage I disease typically achieve a 98% disease-free survival rate at 5 years.

Patients with stage IIA and IIB disease typically achieve a 92% disease-free survival rate at 5.5 years.

Patients with stage IIC disease can expect an approximately 92% overall survival rate at 5 years.

Patients with stage III disease classified as low-risk have a 92% overall survival rate at 5 years. Intermediate-risk patients have an 80% overall survival rate at 5 years. High-risk patients have a 48% overall survival rate at 5 years.

Future and Controversies

Laparoscopic retroperitoneal lymph node dissection

The long-term adverse effects of RPLND can be diminished by limiting the dissection in appropriate patients. The short-term adverse effects associated with an extensive dissection include a long postoperative hospital stay, significant pain, and a protracted period before the patient can resume normal work and leisure activities.

Some of these disadvantages can be mitigated with a relatively new surgical approach that involves making several small incisions to admit an operative telescope and miniature surgical instruments to accomplish the same surgery as in the traditional, large, single-incision procedure. The advantages of laparoscopic surgery are observed primarily in the postoperative setting, with a shorter hospital stay, decreased pain, and faster convalescence.

Several series on the application of laparoscopic RPLND in patients with clinical stage I nonseminomatous germ cell tumors (NSGCTs) have already been reported in the literature, with promising results.

One such series reported on 73 laparoscopic RPLNDs for clinical stage I NSGCT. Twenty-six percent of the patients had pathological stage II disease, and they all received 2 cycles of adjuvant chemotherapy. All patients with stage I disease (mean follow-up of 43.3 mo) and stage II disease (mean follow-up of 42.7 mo) were free of disease. Ejaculation was preserved in all 70 patients after an adequate follow-up period. The conversion rate from laparoscopic to open RPLND was only 2.7% (2 of 73 cases). The mean operative time was prolonged (297 min); however, the time improved dramatically with experience.²¹

The laparoscopic approach to RPLND has been further refined in recent years, and longer-term follow-up studies have suggested that this approach may be an acceptable alternative to traditional RPLND in select patients. Neyer et al (2007) reported on 136 patients who underwent laparoscopic RPLND, with 94% of patients remaining relapse-free after a mean follow-up of 68 months.²²

The role of RPLND following chemotherapy is controversial. In general, all patients with a residual retroperitoneal mass require RPLND. However, virtually all patients in whom the mass resolves completely or reduces in volume by more than 90% will develop necrosis and fibrosis only, conceivably eliminating the need for RPLND.

Postchemotherapy RPLND is a much more complicated procedure and may be critical to achieving cure. Shayegan et al (2007) reported that, even in high-risk patients, long-term freedom from disease progression is best achieved with a combination of chemotherapy and resection of residual masses, with an 81% disease-specific survival rate and a 70% likelihood of no progression.²³ In this study, multivariate analyses suggest that residual tumor mass, incomplete surgical resection, and the presence of teratoma and viable tumor all independently predicted disease progression after RPLND.

Postchemotherapy laparoscopic RPLND, while initially fraught with significant intraoperative and postoperative morbidities, continues to be explored, with improving results. In a single-surgeon experience, a recent retrospective study of 16 patients showed successful performance of the laparoscopic RPLND in 14 of 16 patients and a dramatic decrease in complications as experience was gained.²⁴ However, further experience is needed before this procedure can be considered routine.

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Keywords

testicular tumor, nonseminomatous testicular tumor, testis cancer, testicular cancer, testis mass, testicular mass, nonseminomatous germ cell tumor, non-seminomatous germ cell tumor, non-seminoma germ cell tumor, nonseminoma germ cell tumor, NSGCT, nonseminomatous germ cell testicular tumor, nonseminomatous testicular germ cell tumor, NSGCTT, NSTGCT, seminoma, nonseminoma, embryonal carcinoma, teratoma, choriocarcinoma, yolk sac tumor, cryptorchidism, testicular trauma, mumps orchitis, gynecomastia, orchiectomy

Contributor Information and Disclosures

Author

David M Hoenig, MD, Associate Professor, Department of Urology, Albert Einstein College of Medicine; Chief of Weiler Division, Director of Laparoscopy and Endourology, Co-Director of Fellowship in Laparoscopy and Endourology, Residency Program Director, Department of Urology, Montefiore Medical Center
David M Hoenig, MD is a member of the following medical societies: American Urological Association and Endourological Society
Disclosure: Boston Scientific Grant/research funds Consulting; Endocare Consulting fee Speaking and teaching; Applied Medical Consulting fee Speaking and teaching

Coauthor(s)

Janice Angela Santos-Cortes, MD, Chief Resident, Department of Urology, Albert Einstein Program, Montefiore Medical Center
Janice Angela Santos-Cortes, MD is a member of the following medical societies: Alpha Omega Alpha
Disclosure: Nothing to disclose.

Thomas H Rechtschaffen, MD, Consulting Staff, Department of Urology, A Family Urology Practice, PC
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

CME Editor

J Stuart Wolf Jr, MD, FACS, David A Bloom Professor of Urology, Director of Division of Minimally Invasive Urology, Department of Urology, University of Michigan
J Stuart Wolf Jr, MD, FACS is a member of the following medical societies: American College of Surgeons, American Urological Association, Catholic Medical Association, Endourological Society, Society for Urology and Engineering, Society of Laparoendoscopic Surgeons, Society of University Urologists, and Society of Urologic Oncology
Disclosure: Terumo Corporation Consulting fee Consulting; Gyrus-ACMI Honoraria Speaking and teaching

Chief Editor

Bradley Fields Schwartz, DO, FACS, Professor of Urology, Director, Center for Laparoscopy and Endourology, Department of Surgery, Southern Illinois University School of Medicine
Bradley Fields Schwartz, DO, FACS is a member of the following medical societies: American College of Surgeons, American Urological Association, Association of Military Osteopathic Physicians and Surgeons, Endourological Society, Society of Laparoendoscopic Surgeons, and Society of University Urologists
Disclosure: Nothing to disclose.

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