Nonseminomatous Testicular Tumors 

Updated: Sep 20, 2019
Author: Alexander D Tapper, MD; Chief Editor: Bradley Fields Schwartz, DO, FACS 

Overview

Practice Essentials

Testicular cancer is relatively uncommon in the United States, with an estimated 9560 new cases in 2019, accounting for 0.5% of all new cancer diagnoses in the United States. Rates for new testicular cancer cases have been rising on average 0.8% each year over the last 10 years. Death rates have been stable over 2006-2016, with a 5-year survival rate of 95.2%.[1]  

Testicular tumors may arise in males of nearly any age but are most often seen in men 20-34 years old. There are three main types of primary testicular neoplasms: germ cell tumors, sex cord–stromal tumors, and extragonadal tumors. Germ cell tumors, which are the most common, are classified histologically as either seminoma or nonseminoma. Of the three main types of testicular cancer, nonseminomatous germ cell tumors (NSGCTs) are second only to seminomas in terms of frequency. A small percentage are sex cord/stromal tumors. Tumor histology (see Histologic Findings) and tumor stage (see Staging) are of primary importance in determining the prognosis for patients with testicular tumors.

The classic presentation of a testicular tumor is as a painless testicular mass 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. Roughly one third of patients diagnosed with NSGCT will present with disseminated disease.[2]

Radical orchiectomy is the gold standard in management of suspected testicular neoplasms, as it has both diagnostic and therapeutic benefits. Trans-scrotal biopsy or a scrotal approach to orchiectomy should never be performed in cases of suspected neoplasm, as it can cause contamination of the scrotum and alter patterns of lymphatic spread of tumor as well as complicate subsequent management.

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.

For patient education information, see the Testicular Cancer Directory and Testicular Self-Exam.

Relevant Anatomy

Testicular lymphatics relate to the embryonic origin of the testis. The male gonad forms near the kidney and descends through the inguinal canal to the scrotal sac. The right and left gonadal arteries arise from the abdominal aorta at approximately the level of the second lumbar vertebra. Additional blood supply derives from the deferential and cremasteric arteries. The right gonadal vein derives from the inferior cava, while the left gonadal vein derives from the left renal vein.

Testicular lymphatics follow the vessels of the spermatic cord through the inguinal canal and into the retroperitoneum. Testicular cancer spreads predominantly and initially through lymphatic routes. On the right, lymphatic drainage is between the aorta and the inferior vena cava. On the left, it is on top of and lateral to the aorta. Within the retroperitoneum, there can be a crossover from the lymphatics draining the right toward those of the left.

Scrotal skin lymphatics are different from testicular lymphatics and drain into the inguinal nodes. As such, a radical orchiectomy should be performed through an inguinal route to avoid tumor spillage into the inguinal drainage basin. If a patient undergoes scrotal exploration, subsequent therapy may necessitate hemiscrotectomy and radiation treatment of the ipsilateral inguinal nodes.

In patients who have undergone prior herniorrhaphy, orchiopexy, or other alteration in lymphatic drainage, radiation treatment, if indicated, should include the contralateral inguinal region with contralateral testis shielding.

Lastly, while these cancers spread predominantly through lymphatic pathways, choriocarcinoma is known to metastasize hematogenously.

 

Pathophysiology

As many as 90% of germ cell tumors are associated with intratubular germ cell neoplasia (ITGCN). ITGCN appears to result from arrested maturation of gonocytes. These cells fail to differentiate into spermatogonia, and maintain their ability to differentiate into both germinal and somatic tissues.[3, 2]

NSGCTs are germ cell tumors that contain embryonal stem cells. These may be differentiated into extraembryonic tissues or somatic elements. Most NSGCTs are composed of a mixture of these elements, though they can be present in pure forms.

The four histologic classifications of NSGCTs are as follows:

Mixed histology tumors have some combination of the above tumors and may have a component of seminomatous tumor present as well.  As such, tumors with both seminomatous and nonseminomatous elements are classified as NSGCTs because the NSGCT component most accurately reflects the response to treatment and overall prognosis.

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 cryptorchidism (undescended testis), personal history of testicular cancer, family history of testicular cancer, intratubular germ cell neoplasia (ITGCN), and gonadal dysgenesis. Other risk factors may include childhood inguinal hernias and any other cause of testicular atrophy.

Cryptorchidism is one of the most significant risk factors for testicular cancer. Almost 10% of men with testicular cancer have a history of undescended testicle.[3]  

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 in those who underwent orchidopexy at age 13 years or older was 5.40.[4] Therefore, orchidopexy performed before puberty appears to reduce the likelihood of testicular cancer later in life.

Additionally, ITGCN is thought to be a common precursor of most testicular germ cell neoplasms. Roughly 90% of testicular tumors are associated with adjacent ITGCN. Furthermore, men with known ITGCN have an approximately 50% risk of cancer developement in 5 years.[3]

 

Epidemiology

Frequency

United States incidence

Testicular cancer is relatively uncommon, with approximately 9560 new cases predicted to occur in 2019 in the United States.[5] 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.

Between 1973 and 1995, the incidence of testicular cancer in the US increased 51%, from 3.61 to 5.44 per 100,000 men. Birth cohort was strongly associated with relative risk of testicular cancer, and peak age at diagnosis decreased for each successive birth cohort.[6] The incidence of testicular cancer has continued to increase over the past 10 years, rising on average 0.8% each year. Based on 2012-2016 data, the incidence is approximately 5.9 cases per 100,000 men.[1]

Testicular cancer is most frequently seen in non-Hispanic white men. The lowest incidence is in African-American men. 

International incidence

Worldwide, testicular cancer has the highest incidence in northern Europe, with the highest rates in Norway and Denmark. Rates continue to increase in most countries worldwide, particularly southern Europe and Latin America. In contrast, the increase in rates has begun to slow in countries such as Australia and the US.[7]

Prognosis

The prognosis for patients with NSGCT is ultimately dependent on clinical staging and subsequent risk stratification using histology, primary tumor site, post-orchiectomy tumor marker nadir, and imaging including a minimum or chest x-ray and CT scan of the abdomen and pelvis.  

Using the risk stratification system established by the International Germ Cell Cancer Collaborative Group (IGCCCG) in 1997, patients are categorized into good, intermediate, or poor prognostic categories.[8] Rates of disease-free survival at 5  years are roughly 90%, 75%, and 50% for good-, intermediate-, and poor-risk groups, respectively. 

Disease-free survival varies by stage and risk, as follows:

  • 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

In a study from Norway, Mykletun et al 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.[9]  Overall, only minimal differences were seen in quality of life among recipients of 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 facing the diagnosis and treatment of testicular cancer.

 

Presentation

History

The classic presentation of a testicular tumor is a painless testicular mass 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. Roughly one-third of patients diagnosed with a nonseminomatous germ cell tumor (NSGCT) will present with metastatic disease.

Some patients present with a swollen painful mass in the scrotum that may be misdiagnosed as infectious or inflammatory in nature, potentially resulting in a detrimental delay in starting treatment for NSGCT. In all patients in whom testicular tumors are suspected, obtain a complete history and perform a complete physical examination. Questions about how and when the mass was noted and by whom are useful. The history should also include specific questions regarding possible risk factors for testicular cancer, including a history of cryptorchidism and in such cases, the timing of orchidopexy.

Similarly, questions regarding prior urologic history should be asked to idenitify additional risk factors or prior procedures that may alter the typical presentation or natural history of the disease. Questions about trauma and mumps orchitis are useful. Likewise, the patient's occupational, chemical exposure, and smoking history should be obtained. A full family history should be obtained as well, as there is increased risk in those who have a first-degree relative with testicular cancer.

 

 

Physical Examination

In the physical exam, both testicles should be carefully evaluated. 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 two testicles should be assessed and noted. Any palpable firmness within the testicular parenchyma should raise suspiscion for malignancy and prompt further workup. 

Differentiation of the scrotal contents should be found with careful palpation. The epididymis, attached to the posterolateral aspect of the testicle, is frequently the site of induration or cysts. These conditions should be identifiable during the physical examination. Additionally, testis tumors can cause hydrocele, limiting the ability to perform complete exam. 

Whenever the physical examination reveals any deviation from a palpably normal testicle, scrotal ultrasonography should be performed. Scrotal ultrasonography is also necessary if inability to perform an adequate evaluation is a concern.

In 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, or these patients may present with hemoptysis, dyspnea, or cough. Abdominal examination should be performed to assess for visceral or bulky lymphatic involvement. In patients with risk factors for altered lymphatic drainage (see Relevant Anatomy), careful examination of the inguinal lymph nodes should be performed.

Finally, a neurologic examination should be conducted. This is important to evaluate for possible brain metastasis.

 

DDx

Diagnostic Considerations

In any patient with a palpable abnormality on testicular exam, or in whom the exam is limited, testicular ultrasound is indicated to rule out a testicular mass.

Differential Diagnoses

 

Workup

Laboratory Studies

Basic lab tests that should be obtained as part of the initial workup of a patient with suspected testicular malignancy, include a complete blood cell count, creatinine level to check renal function, and a liver function panel. A liver function panel has the utility of both assessing for abnormalities that may be indicative of hepatic metastasis as well as any underlying liver disease that may alter tumor marker levels (see below).

Serum tumor markers must be assessed during the initial evaluation of a patient with a testis tumor. Since 1997, the American Joint Committee on Cancer (AJCC) has included human chorionic gonadotropin (hCG), alpha-fetoprotein (AFP), and lactate dehydrogenase (LDH) in the classification system for nonseminomatous germ cell tumors (NSGCTs).

Tumor marker nadir following orchiectomy is used in the initial staging, and further, monitoring 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.

Serum hCG and AFP are the most important tumor markers. AFP levels are elevated in 50-70% of patients with NSGTs, and hCG levels are elevated in 40%-60%. AFP has a half-life of 5-7 days, and hCG has a half-life of 24-48 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, after radical inguinal orchiectomy , at least 1 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 20%-60% of patients with NSGCT; however, this is considered a nonspecific marker and is most useful in measuring tumor burden.

Tumor marker levels that are considered abnormal are as follows:

  • AFP > 9 ng/mL (Note that the AFP value may be elevated in patients with liver dysfunction.)
  • hCG > 4 mIU/mL (Note that the hCG value may be elevated in hypogonadotrophic patients.)
  • LDH > 1.5 times the reference range (LDH is present in skeletal, smooth, and cardiac muscle; it is a nonspecific marker that can be elevated for a variety of reasons and as a result of a wide range of conditions.)

Monitoring the values of these markers is vital in assessing the success of treatment of a testis tumor. The degree of elevation in pretreatment marker levels has not been shown to reliably predict treatment outcomes. A 2007 study 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, but the same study found that neither preorchiectomy tumor size nor hCG levels correlated with the presence of retroperitoneal metastases.[10]

Elevated AFP levels in a patient with a pathologically diagnosed seminoma indicate the presence of NSGCT elements that were not observed by the pathologist, as pure seminomas do not produce AFP. These tumors are therefore treated as NSGCT because the NSGCT components of the histologically mixed tumor better predicts treatment response.

 

Imaging Studies

Ultrasonography

In the diagnosis and staging of NSGCT, imaging studies are of primary importance. Although most tumors are diagnosed on the basis of physical examination findings, scrotal ultrasonography is typically performed to confirm the 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.  Conversely, seminomas tend to have a more homogeneous echotexture on sonography.

When the tumor contains teratoma elements, sonograms may demonstrate well-defined structures of ectodermal derivation.

Computed tomography

CT scan of the abdomen and pelvis with IV and oral contrast is integral to the staging of a testis tumor and is typically performed after pathological confirmation of a testis tumor following orchiectomy. 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.This imaging is also crucial in providing an assessment of the retroperitoneal anatomy for retroperitoneal lymph node dissection (RPLND), should that be indicated in the future.

Left-sided NSGCTs typically spread first to the left para-aortic and then the preaortic lymph nodes inferior to the renal vessels. Right-sided tumors spread to the paracaval and interaortocaval nodes inferior to the renal vessels. Lymphatic drainage in the retroperitoneum travels in the right-to-left direction. 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.

Radiography

Chest radiography is usually obtained to help identify any possible pulmonary metastases. CT of the chest may also be used and increases the sensitivity of the diagnosis; it is indicated if any suspicious lesions are identified on initial chest x-ray. 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.

Magnetic resonance imaging

MRI appears to be equally accurate as CT 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 the following:

  • Brain metastases
  • Neurologic involvement
  • Musculoskeletal metastases
  • Involvement of the large vessels and bones.

In some studies, MRI has shown some ability to differentiate seminomatous tumors from NSGCTs. Heterogenicity on contrast-enhanced and nonenhanced images suggests an NSGCT component.[11]

Positron emission tomography

Positron emission tomography (PET) currently has no role in the initial staging workup of primary testicular malignancies. However, with recently improved technology in PET scanning, evidence supports its utility in identifying viable tumor in residual masses following chemotherapy. Some studies have shown that a PET scan can define relapse sites before they become evident on CT.[12] In addition, some evidence has shown that PET scans may predict mature teratoma more accurately than CT scans. However, note that negative PET findings do not exclude the possibility 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. 

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.

The eighth edition (2017) of the American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging system divides testis cancer into three anatomic stages.[13] Stage I disease is subdivided into stages Ia and Ib, depending on the primary tumor size. 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 more than 5 nodes are involved or one or more of the involved nodes are larger than 2 cm. Stage II subdivisions are as follows:

  • 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
  • p0 - No evidence of primary tumor
  • pTis - Germ cell neoplasia  in situ
  • pT1 - Tumor limited to the testis (including rete testis invasion) without lymphovascular invasion
  • pT2 - Tumor limited to the testis (including rete testis invasion) with lymphovascular invasion or tumor invading hilar soft tissue or epididymis or pentrating visceral mesothelial layer covering the external surface of tunica albuginea with or without lymphovascular invasion
  • pT3 - Tumor invades the spermatic cord with or without lymphovascular invasion
  • pT4 - Tumor invades the scrotum with or without lymphovascular 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

  • pNX - Regional lymph nodes cannot be assessed
  • 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
  • pN2 - Lymph node mass is larger than 2 cm but not larger than 5 cm in greatest dimension or 5 or more nodes positive and none larger than five cm or 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 - Nonretroperitoneal nodal or pulmonary metastases
  • M1b - Nonpulmonary visceral masses

Serum tumor markers (S)

Table 1. Serum Tumor Markers (S) (Open Table in a new window)

S

LDH

HCG (mIU/mL)

AFP (ng/mL)

Sx

Not assessed

Not assessed

Not assessed

S0

Normal

and

Normal

and

Normal

S1

< 1.5 x N

and

< 5000

and

< 1000

S2

1.5-10 x N

or

5000-50,000

or

1000-10,000

S3

> 10 x N

or

> 50,000

or

> 10,000

*N=upper limit of reference range for the LDH assay

Table 2. Stage Grouping (Open Table in a new window)

Stage grouping

T

N

M

S

Stage 0

pTis

N0

M0

S0

Stage I

pT1-T4

N0

M0

Sx

Stage IA

pT1

N0

M0

S0

Stage IB

pT2-4

N0

M0

S0

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

N1-3

M0

S2

Any pT/TX Any N M1a S2
Stage IIIC Any PT/TX

N1-3

M0

S3

Any pT/TX Any N M1a S3

Any pT/TX

Any N

M1b

Any S

See also Nonseminoma Testicular Cancer Staging.

Stage-specific clinical findings and treatment options

Clinical stage I NSGCT

Clinical findings are as follows:

  • 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

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 one study, normal AFP levels prior to orchiectomy correlated with a higher risk of retroperitoneal lymph node metastases.[10]

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 scans 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 (retroperitoneal lymph node dissection [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 cross-sectional imaging, CT scans at 3 months and 12 months may be a reasonable surveillance protocol after orchiectomy in select low-risk patients.[14]

A prospective study explored the use of MRI as an alternative to CT for surveillance of retroperitoneal nodes, in order to reduce radiation exposure with repeat CT scans. The authors concluded that for experienced radiologists, MRI is comparable to CT for detection of  enlarged retroperitoneal nodes.[15]

Alternatively, 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 cure rate of approximately 90% for patients with a pathologic stage I tumor. 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 scans of the retroperitoneum).[16] 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 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 or primary chemotherapy. RPLND affords the certainty of pathologic staging in combination with surgical excision of the disease.

Stage IIB is managed with either primary RPLND or primary chemotherapy, depending on the philosophy of the treating physician. 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 5-year survival rate associated with this treatment combination approaches 95%.

Stage IIC (advanced bulky metastases) is more commonly managed similarly to stage III disease and is discussed below.

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.[17]

Clinical stage IIC and stage III NSGCT

Clinical findings are as follows:

  • Stage IIC disease: lymph nodes larger than 5 cm observed on abdominal and pelvic CT scans
  • Stage III disease: lymph node or viscera involvement above the diaphragm

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 recurrence rate 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-, intermediate-, and high-risk groups, 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

Approach Considerations

Radical (inguinal) orchiectomy is used to determine the histologic type of the cancer and the local tumor stage in testicular cancer. It also provides initial treatment and is the gold standard of care for suspected testicular neoplasms. It 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. 

In stage IA nonseminomatous germ cell tumors (NSGCTs), surgery may be considered possibly curative; the National Comprehensive Cancer Network (NCCN) recommends surveillance as the preferred primary treatment in those patients, with nerve-sparing retroperitoneal lymph node dissection (RPLND) or single-cycle primary chemotherapy with bleomycin, etoposide, and cisplatin (BEP) as alternatives (eg, when compliance with follow-up examination is in doubt).[18]

Stage IB disease treatment recommendations after orchiectomy are for either nerve-sparing RPLND or adjuvant chemotherapy with 1-2 cycles of BEP. A category 2B recommendation is that stage IB patients with T2-3 disease may be offered surveillance, however, it is important to note that these patients must be extremely reliable for close follow-up. Furthermore, evidence of lymphovascular invasion on pathology specimen indicates high risk for relapse and this should be considered prior to offering surveillance as an option to patients with stage IB disease.[18]

European Association of Urology guidelines support a risk-adapted approach to treatment of stage I NSGCT. Adjuvant chemotherapy with one cycle of BEP is recommended for patients with vascular invasion of the primary tumor in blood or lymphatic vessels, which is the most important predictor of occult metastatic disease. Surveillance is recommended for patients without vascular invasion.[19]

Patients with stage IIA or IIB disease may be offered either chemotherapy or nerve-sparing RPLND permitting post-orchiectomy tumor markers are negative. For patients with stage IIB disease the recommendations generally are for primary chemotherapy, with initial RPLND being a management option in few isolated cases.[18]

Chemotherapy is used as primary therapy in advanced disease (stage IIC and III) and in low-stage disease when risk factors persist or tumor markers are persistently elevated after orchiectomy (stage IS). Recommended primary chemotherapy dose and protocols for advanced disease (stage IIC-III) are based on risk stratification.[18]

A good prognosis can typically be expected in patients with the following:

  • Testicular or retroperitoneal primary tumor
  • No nonpulmonary visceral metastases
  • Alpha-fetoprotein (AFP) level below 1000 ng/mL
  • Human chorionic gonadotropin (hCG) level below 5000 IU/L
  • Lactate dehydrogenase (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 three-cycle regimen of BEP has typically been used as first-line chemotherapy. Alternatively, some centers administer etoposide and platinum alone (ie, the EP regimen) for four cycles. These regimens elicit a response rate that ranges from 81%-92%. In 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 (four cycles of BEP). This approach yields a cure rate and a durable response of less than 60% in most series. Patients who may not tolerate bleomycin may be treated with four cycles of etoposide, cisplatin, and ifosfamide (VIP).[18]

Intermediate prognostic features include (1) a testis or retroperitoneal primary tumor, (2) no nonpulmonary visceral metastases, and (3) one of the following:

  • AFP level of 1000-10,000 ng/mL
  • hCG level of 5000-50,000 IU/L
  • 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
  • AFP level greater than 10,000 ng/mL
  • hCG level greater than 50,000 IU/L
  • 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. Due to the poor response to standard chemotherapy regimens in those patients with advanced stage disease and high risk prognostic indicators. Recommendations for these patients is to consider consultation at higher volume centers. [18]

Second-line chemotherapy regimens included standard-dose TIP or VeIP or high-dose regimens with carboplatin and etoposide or paclitaxel, ifosfamide, carboplatin and etoposide.[18]

Third-line options include high-dose regimens gemcitabine, paclitaxel, oxaliplatin or gemcitabine and oxaliplatin or gemcitabine and paclitaxel or etoposide (oral).[18]   Alternatively, high-dose therapy in combination with autologous bone marrow transplantation has been used with some success for the most refractory cases.[20]

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.[21] Palliative chemotherapy regimens for metastatic NSGCTs include gemcitabine plus oxaliplatin and/or paclitaxel.[18]

For more information, see Nonseminoma Testicular Cancer Treatment Protocols

Toxicities

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 (three cycles of BEP consists of 270 U of bleomycin; four cycles consists of 370 U).[22] 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. Raynaud phenomenon has also been attributed to bleomycin and may be exacerbated by cisplatin and vinblastine.

Other potential adverse effects include the following:

Chemotherapy also carries an increased risk of secondary malignancies. The relative risk of the following cancers 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.[23]

Surgical Therapy

Radical orchiectomy is performed when there is suspicion for testicular malignancy either upon examination or scrotal ultrasound. This procedure is performed via an inguinal incision in order to prevent tumor spread or alteration of the lymphatic drainage pattern of the testicle by violation of the scrotal wall. Radical orchiectomy also allows ligation of the spermatic cord at the level of the internal inguinal ring, which eliminates the need to explore the inguinal canal again if subsequent surgical removal of the spermatic cord is performed, and allows for easy identification of the cord if retroperitoneal lymph node dissection is required (ie, for therapy or staging).

Of note, partial orchiectomy is an option in a select few patients. Patients in whom this may be offered should have an absent or abnormal contralateral testicle with ipsilateral tumor that is less than 2 cm in size and in a polar location.[2] The approach for partial orchiectomy is the same as for radical orchiectomy, with care taken not to violate the scrotum.

After radical orchiectomy is performed and the tumor is identified as a nonseminomatous germ cell tumor (NSGCT), clinical and/or surgical staging is mandatory. In those patients for whom surveillance or primary chemotherapy is not an initial management option, primary RPLND is used to determine pathological staging and, in some patients, provides curative therapy.

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.

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

As mentioned previously, chemotherapy carries multiple acute and late toxicities that should be considered and discussed with the patient prior to treatment. 

In patients with advanced NSGCT in whom RPLND is indicated, a nerve-sparing procedure can be performed, even in the post-chemotherapy setting, with hopes of preserving ejaculatory function. A 2009 study found that ejaculatory function was maintained in the majority of patients without compromising oncologic outcomes.[24]  

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 minimally invasive approach as opposed to the open surgical technique. The advantages of minimally invasive 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 NSGCTs have 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 months) and stage II disease (mean follow-up of 42.7 months) 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 minutes); however, the time improved dramatically with experience.[25]

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 reported on 136 patients who underwent laparoscopic RPLND, with 94% of patients remaining relapse-free after a mean follow-up of 68 months.[26]  Minimally invasive approaches should be offered only if they will not compromise oncologic control of disease.

Postchemotherapy RPLND is a much more complicated procedure and may be critical to achieving cure. Shayegan et al 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.[27, 28]  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 minimally invasive RPLND, while initially fraught with significant intraoperative and postoperative morbidities, continues to be explored, with improving results with continued surgeon experience. A retrospective study of single-surgeon experience demonstrated successful performance of laparoscopic RPLND in 14 of 16 patients and a dramatic decrease in complications as experience was gained.[29]  

For a thorough review of RPLND, see Retroperitoneal Lymph Node Dissection.

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, a roughly 3-5 cm inguinal incision is made. The external oblique is opened sharply. The ilioinguinal nerve should be identified anterior to the cord with attempts made to identify and preserve it. The cord is then isolated and compressed with a vessel loop or penrose drain 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, again with care taken not to violate the scrotal wall.

The cord is then dissected proximally to the level of the internal ring and divided between clamps. The proximal vessels and vas deferens are secured with long nonabsorbable suture in the event subsequent RPLND is to be performed, to permit the proximal end of the cord to be more easily identified.

A prosthesis may be placed in the scrotum at the time of orchiectomy, based on patient preference.

Postoperative Details

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

If serum tumor marker values were elevated prior to orchiectomy, repeat measurements of serum marker levels should be obtained to assess if an appropriate postoperative decrease occurred. Staging is done using the post-orchiectomy tumor marker nadir; appropriate time should be allotted for marker levels to fall, according to their respective half-life. 

Complications

Complications of radical orchiectomy, as with any surgical procedure, include risks of bleeding and infection. Additionally, injury to the ilioinguinal nerve may occur, which can cause hypoesthesia of the ipsilateral groin and lateral aspect of the ipsilateral hemiscrotum. 

For patients with more advanced disease that requires retroperitoneal lymph node dissection, complications of that procedure can include the following:

  • Bleeding, which may result in retroperitoneal hematoma
  • Wound infection
  • Anejaculation from damage to nearby sympathetic nerves
  • Chylous leak secondary to lymphatic system injury

Finally, patients requiring chemotherapy may be susceptible to both the acute and delayed toxicity associated with the chemotherapeutic agents; those effects depend on the agents used. Acute complications seen with cisplatin-based therapy include but are not limited to myelosuppression, fatigue, peripheral neuropathy, diminished renal function, and—in a small percentage—death. Later sequelae can include the following[2] :

  • Hearing loss
  • Peripheral neuropathy
  • Cardiovascular disease
  • Hypogonadism

Infertility

Infertility can result from multiple factors in patients with cancer and is an important consideration in patients with testicular cancer. A systematic review by Djaladat et al found that even before orchiectomy, many men with testicular GCTs have reduced sperm count and sperm motility, as well as increased abnormal sperm morphology[30] This is attributed to deficiencies or defects in spermatogenesis and has been reported in 10-35% of patients.

Philips and Jequier reported an incidence of 0.7% of testicular malignancy in men seeking an evaluation or treatment from an infertility clinic.[31] Raman et al reported the risk of malignancy in men with infertility and abnormal semen analysis findings to be as much as 20-fold higher than in controls.[32]

Abnormalities in spermatogenesis have been described, but the mechanism is not well understood. Causes are likely multifactorial and include cryptorchidism, local effect of the tumor, and disruption of the blood-testis barrier, causing the development of antibodies. In addition, the production of hCG by the testicular tumor can disrupt the normal endocrine axis. Other mechanisms, such as stress and certain inflammatory products, can exert negative effects on the semen quality. In some cases, spermatogenesis normalizes after successful cancer treatment.

Testicular cancer treatment represents the most deleterious effect upon spermatogenesis, including a dose-dependent effect of both chemotherapy and radiation. Spermon et al reported that, in men with testicular germ cell tumors, the rate of successfully achieving pregnancy decreased from 66% to 43% after treatment for the tumors.[33]

Radiation and chemotherapy can also affect fertility, by different mechanisms. Radiation induces irreparable fragmentation of double-stranded DNA. Sertoli cells are extremely radiosensitive, as are the spermatogonia, while Leydig cells are generally somewhat more resistant to radiation. In addition, in patients who receive radiation to the skull, damage to the pituitary gland can manifest as low follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels post-therapy, which can contribute to infertility concerns.

Chemotherapy can cause azoospermia. This is drug and dose related. Alkylating agents (ie, cisplatin) are the most damaging. Sertoli cells are generally susceptible to chemotherapy, while Leydig cells are more resistant to chemotherapy-induced damage. In addition, chemotherapy may cause mutations, causing more abnormalities in spermatogenesis.[34]

Overall, post-treatment fertility issues can be significant following any cancer treatment. Huyghe et al reported that fertility among patients with testicular cancer decreased by 30% after treatment and that radiotherapy appeared to have the most deleterious effect on fertility.[35]

Psychosocial consultation may be beneficial in patients who have distress about infertility, as emotional stress can also affect the potential to father a child.

Sperm cryopreservation is a well-established technique for fertility preservation. Using various techniques, the pregnancy success rate following cryopreservation ranges from 18-50%. Men with post-treatment azoospermia or ejaculatory failure who did not preserve semen prior to treatment may benefit from testicular sperm aspiration (TESA) followed by intracytoplasmic sperm injection (ICSI). This technique resulted in pregnancy success rates of 23% and 31% in two studies.[36, 37]

Long-Term Monitoring

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 depending on initial tumor staging but should include, at a minimum, serum marker evaluations, chest radiography, and contralateral testis examination. Physical exam should be performed and tumor markers measured at least every 2 months for all NSGCT patients, except those with stage IB disease and those with stage IIA/B disease managed with adjuvant chemotherapy and primary RPLND; these patients should have physical exam and tumor markers drawn at 3 and 6 months respectively for the first 2 years of follow up. Abdominal and pelvic CT scans should be performed as well, with the timing and frequency of imaging varying depending on initial staging and management. Full surveillance recommendations can be found in the NCCN Guideline for Testicular Cancer.[18]

Physicians who treat patients through the surveillance period have a responsibility to ensure that 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. It 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 scans are warranted periodically, at least 6 months postoperatively and annually for the next few years, particularly if the patient was considered at high risk.

A randomized study suggests that a more liberal surveillance protocol can be considered for low-risk patients with clinical stage I disease.[14]  Such surveillance would consist of follow-up imaging with CT scans at 3 and 12 months (rather than with five 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 years). The retroperitoneum is the primary site of relapse.[38]