Nonseminomatous Testicular Tumors Workup

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 gonadotropin (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 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 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 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 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. The degree of elevation in pretreatment marker levels has not been shown to reliably predict treatment outcomes. Nonetheless, 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. ^[8]

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.

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

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.

Computed tomography

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.

Magnetic resonance imaging

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. ^[9]

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. ^[10] In addition, some evidence has shown that PET scanning may predict mature teratoma more accurately than CT scanning. However, note that negative PET scanning findings do not exclude the presence of metastatic disease.

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.

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.

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.

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 (2010) ^[11] : 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 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 (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)

Table. Serum tumor markers (Open Table in a new window)

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

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 a recent study, normal AFP levels prior to orchiectomy were found to correlate with a higher risk of retroperitoneal lymph node metastases. ^[8]

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. ^[12]

In a 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. ^[13]

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). ^[14] 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. 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 cure rate using this treatment combination approaches 95% for 5-year survival.

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. ^[15]

Clinical stage IIC and stage III NSGCT

Clinical findings are as follows:

• 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.

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.