Treatment of stage II nonseminomatous germ cell tumors

INTRODUCTION — 

Germ cell tumors (GCTs) account for most testicular cancers. The most common histologic subtypes of GCTs are seminomatous (ie, seminomas) and nonseminomatous germ cell tumors (NSGCTs). Stage II NSGCT is a highly curable malignancy.

The management of stage II NSGCTs following orchiectomy will be presented here. An overview of the treatment of testicular GCTs, the treatment of stage I NSGCT, and the treatment of advanced NSGCT are discussed separately. (See "Overview of the treatment of testicular germ cell tumors" and "Treatment of stage I nonseminomatous germ cell tumors" and "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

DEFINITION OF STAGE II NSGCT — 

Stage II NSGCT refers to nonseminomatous testicular germ cell tumors that have spread to the regional (ie, retroperitoneal) lymph nodes without distant metastases and with normal (S0) or mild elevation of serum tumor markers (S1) following orchiectomy (table 1A-B) [1]. (See 'Serum tumor markers' below.)

Stage II NSGCT can be defined either as a clinical stage II NSGCT based on imaging criteria combined with clinical judgment, or as a pathologic stage II NSGCT based on histopathologic analysis showing germ cell tumor (GCT) in lymph nodes resected during a retroperitoneal lymph node dissection (RPLND). Each has a separate staging system (table 1A-B).

Clinical stage II NSGCT — Imaging studies and the clinician's judgment of lymph nodes are both important criteria for the clinical staging of stage II NSGCT. Imaging studies are focused on whether lymph nodes are enlarged or not, while the clinician's judgment focuses on whether lymph node metastases are clinically present or not.

Lymph node imaging criteria — Distinguishing stage I from stage II testicular cancer is not always straightforward [2]. Imaging studies may detect mildly enlarged lymph nodes (measuring 1 to 2 cm in greatest dimension), but this does not necessarily indicate the presence of disease. The positive predictive value of a computed tomography (CT) scan ranges from 64 to 88 percent, and the negative predictive value is approximately 62 percent [3-5]. For those who ultimately undergo RPLND for clinical stage IIA NSGCT, up to 40 percent will be diagnosed with pathologic stage I NSGCT [6].

Thus, imaging studies focus on the definition of normal lymph nodes. Importantly, it is the diameter of the short axis in the transverse plane that is used to determine whether a lymph node is enlarged or not on cross-sectional imaging. All measurement criteria in this section refer to measurements in the transverse plane. In one observational study of patients with stage I testicular GCT, craniocaudal lymph node length (measured on coronal or sagittal plane images) was associated with increased relapse risk, but this particular measurement has not been definitively associated with adverse outcomes [7].

Clinician judgment of lymph nodes — From a radiologic perspective, lymph nodes are classified as enlarged if the maximum diameter of the short axis is ≥10 mm. Therefore, lymph nodes will generally be reported on radiology studies as normal unless the short axis is ≥10 mm.

However, a patient can be classified as having clinical stage II disease if the clinician judges them to have lymph node metastases clinically, and not simply because they have nodes of a certain size. It is essential for clinicians to carefully evaluate the patient's cross-sectional imaging and other clinical data to properly judge the disease stage. A reflexive response to radiology reports is inappropriate in this disease. Some clinical guidance on how to distinguish malignant from benign lymph nodes are as follows:

●If the clinician judges that lymph node metastases are present, then it is the long axis measurement in the transverse plane that determines whether the tumor is a clinical stage IIA or IIB disease, based on tumor, node, metastasis (TNM) staging criteria (table 1A-B). For example, a lymph node that is 0.5 by 1.5 cm is not enlarged by radiographic criteria. But, if the clinician believes the lymph node represents a metastasis, then the clinical stage is IIA; if the clinician believes the lymph node is benign, then the clinical stage is I. Similarly, a patient with five lymph nodes measuring 0.9 by 0.9 cm could appropriately be staged as having clinical stage IIA disease if the clinician thought the lymph nodes represented metastases, even though all these nodes fall within radiographic normal limits for size. By contrast, patients with stage IIC disease typically have lymph nodes that are enlarged by radiographic criteria.

●Stage IIA testis cancer is a heterogeneous entity. In patients whose disease is borderline between stage I and stage IIA, the following clinical factors are suggestive of lymph node metastases: location in the primary landing zone corresponding to the laterality of the affected testicle, multiple enlarged or borderline-enlarged nodes, and round lymph nodes (ie, nodes with little difference between the long and short diameter) rather than elliptical nodes (which are more likely to be benign).

Clinical stage II subcategories — The criteria for the different subcategories of clinical stage II NSGCT (IIA, IIB, and IIC) are based on the greatest dimension of nodal metastases in the transverse plane (table 1A and table 1B).

●Clinical stage IIB and IIC – Clinical stage IIB refers to retroperitoneal lymph nodes measuring >2 and ≤5 cm, and stage IIC refers to retroperitoneal lymph nodes measuring >5 cm. Clinical stages IIB and IIC are generally straightforward to diagnose clinically since such nodal involvement almost always represents metastatic disease.

●Clinical stage IIA – Clinical stage IIA disease refers to retroperitoneal lymph node metastases measuring ≤2 cm. An accurate diagnosis of clinical stage IIA disease is more complicated, as CT scans have substantial false-negative and false-positive rates. Many patients with normal-size retroperitoneal nodes (clinical stage I) will have cancer within those nodes if RPLND is performed, and many patients with mild adenopathy (stage IIA) will have benign nodes (pathologic stage I) if RPLND is performed.

As example, in one observational series of 122 patients with clinical stage IIA testicular cancer, only 60 percent had GCT found at lymph node dissection, resulting in a false-positive rate of 40 percent [6]. By contrast, in another observational study of patients undergoing primary RPLND, sensitivity and negative predictive value increased to 91 and 90 percent, respectively, if a 3 mm short axis cutoff was used for the upper limit of normal (ULN) for lymph nodes in the primary landing zone for testicular cancer (ie, the interaortocaval, paracaval, precaval, and preaortic nodes for tumors of the right testis and the para-aortic and preaortic nodes for tumors of the left testis) and a 10 mm cutoff was used for lymph nodes outside of the primary landing zone [8]. However, specificity and positive predictive values declined to 52 and 53 percent. Although this model is not used in practice, it is a reminder of the importance of using clinical judgment when reading retroperitoneal imaging studies of patients with testis cancer and taking into account the different landing zones of left and right testis cancers.

Of note, pelvic and inguinal lymph node metastases are considered distant metastases and represent stage III testicular GCTs. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

Serum tumor markers — Serum tumor markers that are obtained after orchiectomy are also used in staging clinical stage II NSGCT (table 1A-B). The optimal timing to assess tumor markers following orchiectomy is discussed separately. (See "Serum tumor markers in testicular germ cell tumors".)

For tumors to be classified as a stage II NSGCT, metastases must be limited to the retroperitoneal lymph nodes and all the markers must be in the S0 to S1 or "good-risk" range inclusive of all the following:

●Alpha-fetoprotein (AFP) <1000 ng/mL

●Human chorionic gonadotropin (hCG) <5000 milli-international units/mL

●Lactic dehydrogenase (LDH) <3 times ULN

Although published staging tables, such as the American Joint Committee on Cancer staging criteria (table 1A-B), and risk-stratification tables list an LDH cutoff of 1.5 times ULN [9], we use a cutoff of 3 times ULN because LDH is not specific to GCTs or malignancy and can be elevated for many different reasons. Many GCT experts would not intensify a patient's treatment from good risk to intermediate risk if the only adverse prognostic factor was an LDH between 1.5 and 3 times ULN [10,11]. Alternatively, some experts prefer an LDH cutoff of 2.5 times ULN. This is based on data from the International Germ Cell Cancer Collaborative Group update consortium that an LDH of 2.5 times ULN or more is associated with a worse prognosis in metastatic NSGCTs [12].

Patients with one or more moderately- or highly-elevated tumor markers beyond these levels (S2 or S3) are classified as having stage III (advanced) disease, even if metastases are limited to the retroperitoneal nodes. The management approach to patients with stage III (advanced) testicular GCTs is discussed separately. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

Pathologic stage II NSGCT — Patients with pathologic stage II NSGCT (table 1A-B) are those who have undergone RPLND and have histologically confirmed tumor involvement in the retroperitoneal lymph nodes. Such patients typically had either clinical stage I or clinical stage IIA or IIB disease at initial diagnosis, underwent an RPLND as postorchiectomy treatment, and were found to have tumor involvement in the resected lymph nodes. If the pathologic stage of the tumor differs from the previously defined clinical stage, then the pathologic stage should be used. (See "Treatment of stage I nonseminomatous germ cell tumors".)

For patients with testicular GCT and rising tumor markers following orchiectomy, RPLND is not generally performed as initial therapy due to the concern for distant metastatic disease that may not be adequately treated with surgery alone. (See "Retroperitoneal lymph node dissection for early-stage testicular germ cell tumors", section on 'Overview of treatment options after orchiectomy'.)

CLINICAL STAGE II NSGCT — 

Patients with clinical stage II NSGCTs have a high likelihood of cure. Selection of therapy depends on the tumor stage, the size and imaging characteristics of the retroperitoneal lymph nodes, and the serum tumor markers obtained following orchiectomy (algorithm 1).

Clinical stage IIA disease (S0) — For patients with metastases to lymph nodes ≤2 cm and normal (S0) tumor markers following orchiectomy (clinical stage IIA disease), we suggest retroperitoneal lymph node dissection (RPLND) rather than chemotherapy. Alternative options include chemotherapy or surveillance.

RPLND cures 80 to 90 percent of patients with clinical stage IIA nodal disease, provides more accurate staging, and treats both teratoma and other germ cell tumor (GCT) elements. Patients who undergo RPLND and have tumor involving the lymph nodes confirmed on postoperative pathology are subsequently managed according to their pathologic stage. As a result, RPLND also spares a substantial number of patients whose disease turns out to be pathologic stage I from the late toxicities of chemotherapy. For those who are classified as pathologic stage II disease, RPLND can reduce the amount of chemotherapy the patient receives. (See "Treatment of stage I nonseminomatous germ cell tumors" and 'Pathologic stage II NSGCT' below.)

Alternatives to RPLND for patients with clinical stage IIA (S0) disease include chemotherapy or surveillance. Selecting between these options may be based on the following clinical factors:

●Chemotherapy – Chemotherapy may be offered to those patients whose lymphadenopathy is clinically judged to be almost certainly malignant (eg, adenopathy in the primary landing zone corresponding to the laterality of the affected testicle, multiple enlarged or borderline-enlarged nodes, rounded lymph nodes).

In addition, some clinicians and patients who prefer single modality treatment (ie, chemotherapy or RPLND, but not both) may favor chemotherapy when clinical features are present which suggest an increased likelihood of relapse if the patient were treated with primary RPLND alone in the absence of adjuvant chemotherapy. For example, chemotherapy may be preferred in patients with multiple serial imaging studies that demonstrate rapidly enlarging retroperitoneal lymph nodes, as they may be more likely to demonstrate higher pathologic stage at RPLND than preoperative imaging suggests.

For such patients who select chemotherapy, options include three cycles of bleomycin, etoposide, and cisplatin (BEP) (table 2) or four cycles of etoposide and cisplatin (EP) (table 3). If patients treated with chemotherapy have residual adenopathy after completion of chemotherapy, then an RPLND should subsequently be performed by a highly experienced surgeon.

●Surveillance – Surveillance is preferred if the clinical staging is ambiguous (ie, if in the clinician's judgment, there is significant uncertainty over whether the patient should be staged as clinical stage I or IIA). The goal of surveillance is to avoid treating the minority of patients whose mild lymphadenopathy turns out to be benign. If surveillance is chosen, strict attention to assuring close follow-up is essential since these patients may have early-stage metastatic disease that will progress and require chemotherapy. With close surveillance, the prognosis is excellent; even if a patient experiences progression, cure is still attainable with chemotherapy or, in select cases, RPLND. (See "Posttreatment follow-up for testicular germ cell tumors".)

For patients with stage IIA disease, chemotherapy results in lower rates of relapse but similar disease-free survival compared with RPLND. As an example, in an observational study of 252 males with clinical stage IIA and IIB NSGCT, relative to RPLND alone, chemotherapy (either alone or followed by RPLND) was associated with higher five-year relapse-free survival (98 versus 79 percent) but similar five-year disease-free survival (100 versus 98 percent) [5].

Clinical stage IIB to IIC (S0) — For patients with retroperitoneal lymph node metastases >2 cm and normal (S0) tumor markers (clinical stage IIB or IIC disease), we suggest cisplatin-based chemotherapy rather than RPLND. Options include three cycles of BEP (table 2) or four cycles of EP (table 3). Selecting between these regimens is discussed separately. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'Good-risk disease'.)

For patients with nonbulky stage IIB disease (lymph nodes >2 and ≤3 cm), RPLND is an appropriate alternative for those who wish to avoid the potential long-term toxicities of chemotherapy and are willing to accept a potentially higher risk of recurrence. In observational studies, the cure rate for patients with stage IIB or IIC NSGCT managed with RPLND alone is approximately 65 percent [3,13]. Patients who undergo RPLND and have testicular cancer involving the lymph nodes confirmed on postoperative pathology are subsequently managed according to their pathologic stage. (See 'Pathologic stage II NSGCT' below.)

In patients with stage IIB and IIC disease and normal serum tumor markers, chemotherapy provides treatment of micrometastatic disease and reduces the risk of relapse. It also spares patients with a complete response to chemotherapy from needing a subsequent RPLND [4,14]. However, some patients with stage IIB and IIC disease who initially receive chemotherapy will have residual masses requiring subsequent RPLND. (See "Management of residual masses in advanced testicular germ cell tumors following initial systemic therapy", section on 'Nonseminomatous germ cell tumor'.)

Data comparing chemotherapy with RPLND for patients with clinical stage II NSGCT come mostly from observational studies and prospective nonrandomized clinical trials [4-6,15,16].

●In an observational study of 252 males with clinical stage IIA and IIB NSGCT, relative to RPLND alone, chemotherapy (either alone or followed by RPLND) was associated with higher five-year relapse-free survival (98 versus 79 percent) but similar five-year disease-free survival (100 versus 98 percent) [5].

●In another prospective nonrandomized clinical trial, 187 patients with clinical stage IIA and IIB NSGCT were treated with either RPLND plus two cycles of adjuvant cisplatin-based chemotherapy or three to four cycles of primary cisplatin-based chemotherapy [4]. Among those treated with primary RPLND, the rates of pathologic stage I, IIA/A, and IIC/III disease were 12, 70, and 18 percent, respectively. Among those treated with chemotherapy, the complete response rate was 67 percent, and the remainder (33 percent) required subsequent RPLND due to residual masses. At a median follow-up of three years, RPLND plus adjuvant chemotherapy versus primary chemotherapy resulted in similar relapse rates (7 versus 11 percent). Primary RPLND was associated with fewer surgical complications than RPLND following chemotherapy but higher rates of loss of ejaculation (32 versus 16 percent). Acute toxicity of chemotherapy was higher in those treated with primary chemotherapy, presumably due to the administration of more cycles of chemotherapy.

Clinical stage IIA to IIC (S1) — For patients with clinical stage II disease (inclusive of stages IIA, IIB, and IIC) whose serum beta-human chorionic gonadotropin (hCG) or alpha-fetoprotein (AFP) is mildly elevated (S1) after orchiectomy, we suggest cisplatin-based chemotherapy rather than RPLND. These tumors, which are classified as "good-risk" disease using the International Germ Cell Cancer Collaborative Group criteria (table 4), are treated with either four cycles of EP (table 3) or three cycles of BEP (table 2) using the same approach to those with more advanced testicular GCTs. Further details, including selecting between these regimens, are discussed separately. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'Good-risk disease'.)

Patients with clinical stage II disease and more marked elevations of serum tumor markers (S2 or S3) have stage III (advanced) disease (table 1A-B). The initial management of these patients is discussed separately. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

Mild elevations of lactate dehydrogenase (LDH) are of no known significance in this setting. However, patients with an elevated beta-hCG or AFP are more likely to have distant micrometastases. Studies also suggest a higher risk of recurrence (as high as 80 percent) in patients with stage II NSGCT and elevated tumor markers who are treated with RPLND alone [13,17]. Therefore, RPLND is not generally performed as initial therapy in patients with testicular NSGCT and rising AFP or hCG following orchiectomy due to the concern for distant metastatic disease that may not be adequately treated with surgery alone. Such patients have a substantial likelihood of being cured with chemotherapy alone.

However, clinicians should advise patients in advance that some with clinical stage II NSGCT who are initially treated with chemotherapy will have residual lymphadenopathy and require subsequent RPLND. Many patients require both treatments, regardless of whether initial treatment is with RPLND or chemotherapy. Advising patients of this prior to undergoing either treatment helps lessen the risk that the patient will interpret the need for additional treatment as a sign that the first treatment did not work.

Residual masses following chemotherapy — The management of patients with clinical stage II NSGCT who are initially treated with chemotherapy and have residual retroperitoneal masses are discussed separately. (See "Management of residual masses in advanced testicular germ cell tumors following initial systemic therapy", section on 'Nonseminomatous germ cell tumor'.)

PATHOLOGIC STAGE II NSGCT — 

Patients with pathologic stage II NSGCT (table 1A-B) are those who have undergone retroperitoneal lymph node dissection (RPLND) and have histologically confirmed tumor involvement in the retroperitoneal lymph nodes (algorithm 1). Patients with pathologic stage II NSGCT have a high likelihood of cure.

RPLND is not generally performed as primary therapy in patients with testicular germ cell tumors (GCTs) and rising tumor markers following orchiectomy due to the concern for distant metastatic disease that may not be adequately treated with surgery alone. (See 'Pathologic stage II NSGCT' above.)

Lymph nodes with teratoma — Patients with pathologic stage II NSGCTs are divided into either those with or without teratomas within the retroperitoneal lymph nodes, based on the histopathologic findings from the RPLND. (See "Anatomy and pathology of testicular tumors", section on 'Teratoma'.)

●Pure teratoma – For patients with pure teratoma in their retroperitoneal nodes, we suggest surveillance. Teratomas are generally slow-growing tumors that are relatively resistant to chemotherapy [18]. Therefore, teratomas that are found within the retroperitoneal lymph nodes are less likely to benefit from adjuvant chemotherapy and can be closely monitored. (See "Posttreatment follow-up for testicular germ cell tumors".)

There are no randomized trials comparing surveillance versus adjuvant therapy in this population. Since teratoma does not typically metastasize, some studies hypothesize that patients with teratoma in the retroperitoneum may have had a viable nonteratomatous GCT histology (such as embryonal carcinoma or yolk sac tumor) in the testis that metastasized to the lymph nodes and then differentiated into a teratoma. Therefore, potential microscopic nonteratomatous GCT may still be present that is sensitive to chemotherapy [19]. Some clinical trials evaluating adjuvant chemotherapy in pathologic stage II NSGCT also included patients with pure teratoma within the retroperitoneal lymph nodes [20]. However, we generally do not pursue adjuvant chemotherapy given there are limited data supporting this approach.

●Teratoma with secondary somatic type malignancy – For patients with a secondary somatic-type malignancy (ie, a GCT that transforms into a malignant non-germ cell histology) in the retroperitoneum, management is nuanced and based on the specific histology. Referral to a clinical center with expertise in such tumors is advised. For example, patients with primitive neuroectodermal tumor transformation of testicular teratoma noted on RPLND may be candidates for adjuvant multiagent cisplatin-based chemotherapy [21].

Lymph nodes without teratoma — For patients with pathologic stage II NSGCT with GCT elements other than teratoma in the lymph nodes, management is presented below. Of note, extranodal extension as an isolated pathologic finding does not appear to be an additional risk factor beyond the extent of disease in the retroperitoneal lymph nodes [22].

Pathologic stage IIA disease — For patients with pathologic stage IIA NSGCT, we suggest surveillance rather than adjuvant chemotherapy. (See "Posttreatment follow-up for testicular germ cell tumors".)

For patients who are unable or unwilling to comply with surveillance following RPLND or those who strongly desire to reduce relapse risk and willingly accept the risks of late treatment-related toxicity, adjuvant chemotherapy is an appropriate alternative. We typically administer two cycles of etoposide and cisplatin (EP).

Among patients with pathologic stage IIA disease whose tumor markers normalize following orchiectomy and are treated with RPLND alone, the relapse rate is 10 to 20 percent and the cure rate is approximately 85 to 90 percent [17,23]. In a randomized trial, adjuvant chemotherapy reduced the recurrence rate relative to surveillance but did not confer an overall survival advantage [13]. In this study, 195 patients with pathologic stage II NSGCT were randomly assigned to surveillance or adjuvant chemotherapy (two cycles of a cisplatin-based regimen) [13]. Patients whose disease relapsed while on surveillance were treated with three or four cycles of chemotherapy. Results were as follows:

●The recurrence rates for adjuvant chemotherapy versus surveillance were 6 (6 of 97 patients) versus 49 (48 of 98 patients) percent, respectively. Among the six relapses in the patients treated with adjuvant chemotherapy, five occurred in patients who had either refused treatment or relapsed before adjuvant chemotherapy could be initiated.

●The risk of relapse during surveillance varied only marginally according to the volume of disease identified in the lymph nodes. For patients with nodes >2 cm, nodes ≤2 cm, and microscopically involved nodes, the recurrence rates were 60, 53, and 40 percent, respectively. This difference was not statistically significant. While the relapse rate of 40 to 53 percent for pathologic stage IIA disease was higher in this study than in subsequent observational studies (which range between 10 and 20 percent) [17,23], patients were randomly assigned to surveillance in this study rather than chosen for surveillance based on an expected low risk of relapse.

●At a median follow-up of four years, there was no statistically significant difference in the overall survival rates between the two groups, with three deaths from testicular cancer in the surveillance arm and one in the chemotherapy arm.

However, it is reasonable to administer adjuvant chemotherapy to patients who desire to reduce the risk of relapse (from approximately 10 to 15 percent to 1 percent [23,24]), provided they are advised that adjuvant chemotherapy has not been shown to improve overall survival. For some patients, the peace of mind derived from having a lower risk of relapse is worth the risks of undergoing chemotherapy and its potential late toxicities. (See "Treatment-related toxicity in testicular germ cell tumors".)

Pathologic stage IIB or IIC disease — For patients with pathologic stage IIB or IIC disease, we suggest adjuvant cisplatin-based chemotherapy rather than surveillance. Such patients, who have bulkier retroperitoneal disease than pathologic stage IIA disease, have a higher risk of relapse following RPLND alone [6,17,23,25-31]. For patients who are ineligible for or decline cisplatin-based chemotherapy, close surveillance is an appropriate alternative [32].

●Pathologic stage IIB disease – For pathologic stage IIB disease treated with RPLND alone, the risk of relapse is 50 percent or higher [23,33]. Therefore, we offer two cycles of EP in the adjuvant setting to reduce the risk of relapse [13,20,23,24,26,34]. No comparative trials have been performed comparing EP to BEP as adjuvant therapy. In separate studies, two cycles of EP [20,23] and two cycles of bleomycin, etoposide, and cisplatin (BEP) [24] in the adjuvant setting both result in a relapse rate of approximately 1 percent. We prefer to use two cycles of EP because there is no evidence that adding a third drug (bleomycin) improves outcomes in this setting. In addition, bleomycin is associated with a small risk of pulmonary and other toxicities. The role of chemotherapy for patients with pathologic stage IIA disease, the benefit of chemotherapy in reducing the risk of recurrence was confirmed in a randomized controlled trial comparing surveillance with two cycles of cisplatin-based chemotherapy. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

●Pathologic stage IIC disease – For patients with pathologic stage IIC disease, we offer adjuvant chemotherapy with either three cycles of BEP or four cycles of EP, extrapolating from data in more advanced testicular cancer. Selecting between these two regimens is discussed separately. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'Good-risk disease'.)

Patients with pathologic stage IIC NSGCT are uncommon since those with bulky retroperitoneal disease that are clinically identified on imaging studies typically receive chemotherapy [35]. Such patients also have a particularly poor prognosis without chemotherapy [27,36,37]. As an example, in one observational series of 18 males with pathologic stage IIC NSGCT on RPLND, adjuvant chemotherapy was associated with improved overall survival relative to surveillance (100 versus 29 percent) [27].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Testicular cancer".)

SUMMARY AND RECOMMENDATIONS

●Definition – Stage II nonseminomatous germ cell tumor (NSGCT) refers to nonseminomatous testicular germ cell tumors (GCTs) that have spread to the regional (ie, retroperitoneal) lymph nodes without distant metastases and with normal (S0) or mild elevation of serum tumor markers (S1) following orchiectomy (table 1A-B). Stage II NSGCT is a highly curable malignancy. (See 'Definition of Stage II NSGCT' above and 'Serum tumor markers' above.)

●Clinical versus pathologic stage II NSGCT – Stage II NSGCTs are classified as either clinical stage II NSGCT or pathologic stage II NSGCT. Each has a separate staging system (table 1A-B):

•Clinical stage II disease – For patients with clinical stage II NSGCT, imaging studies focus on whether lymph nodes are enlarged or not, and clinical judgment focuses on whether lymph node metastases are clinically present or not. (See 'Clinical stage II NSGCT' above.)

•Pathologic stage II disease – Patients with pathologic stage II NSGCT are those who have undergone retroperitoneal lymph node dissection (RPLND) and have histopathologically confirmed tumor involvement in the retroperitoneal lymph nodes. (See 'Pathologic stage II NSGCT' above.)

Patients with pelvic and inguinal lymph node metastases (which are distant metastases) and those with higher elevations in tumor markers following orchiectomy (S2 or S3) are classified as having stage III (advanced) disease and are treated as such. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

●Clinical stage II NSGCT – For patients with clinical stage II NSGCTs, selection of therapy depends on the tumor stage, the size and imaging characteristics of the retroperitoneal lymph nodes, and the serum tumor markers obtained following orchiectomy (algorithm 1).

•Clinical stage IIA NSGCT (S0) – For patients with clinical stage IIA NSGCT and normal tumor markers following orchiectomy (S0), we suggest RPLND rather than chemotherapy (Grade 2C). RPLND results in high rates of cure, provides more accurate pathologic staging, and may spare some patients from chemotherapy or reduce the amount of adjuvant chemotherapy necessary. Alternative options include chemotherapy or surveillance. (See 'Clinical stage IIA disease (S0)' above.)

•Clinical stage IIB and IIC NSGCT (S0) – For patients with clinical stage IIB (S0) or IIC NSGCT (S0), we suggest cisplatin-based chemotherapy rather than RPLND (Grade 2C). Options include three cycles of bleomycin, etoposide, and cisplatin (BEP) (table 2) or four cycles of etoposide and cisplatin (EP) (table 3). For patients with nonbulky stage IIB disease (lymph nodes >2 and ≤3 cm), RPLND is an appropriate alternative for those who wish to avoid the potential long-term toxicities of chemotherapy and are willing to accept a potentially higher risk of recurrence. (See 'Clinical stage IIB to IIC (S0)' above.)

•Clinical stage IIA to IIC NSGCT (S1) – For patients with clinical stage II NSGCTs and persistently elevated or rising serum alpha-fetoprotein (AFP) and/or beta-human chorionic gonadotropin (hCG) following orchiectomy (S1), we suggest cisplatin-based chemotherapy rather than RPLND (Grade 2C), extrapolating from data in more advanced testicular GCTs. In addition, RPLND is not generally performed as initial therapy in patients with testicular NSGCT and rising tumor markers following orchiectomy due to the concern for distant metastatic disease that may not be adequately treated with surgery alone. Chemotherapy options include three cycles of BEP (table 2) or four cycles of EP (table 3). (See 'Clinical stage IIA to IIC (S1)' above and "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'Good-risk disease'.)

•Residual masses following chemotherapy – The management of patients with clinical stage II NSGCT who receive chemotherapy and have residual retroperitoneal masses is discussed separately. (See "Management of residual masses in advanced testicular germ cell tumors following initial systemic therapy".)

●Pathologic stage II NSGCT – Patients with pathologic stage II NSGCT are divided into those with or without teratoma within the retroperitoneal lymph nodes, based on the histopathologic findings from the RPLND. (See 'Pathologic stage II NSGCT' above.)

•Lymph nodes with teratoma – For patients with pure teratoma in the retroperitoneal lymph nodes, we suggest surveillance (Grade 2C), as such tumors are less likely to benefit from adjuvant chemotherapy.

•Lymph nodes without teratoma – For patients with GCT elements other than teratoma in the lymph nodes, management is as follows:

-Pathologic stage IIA NSGCT – For those with pathologic stage IIA NSGCT, we suggest surveillance rather than adjuvant chemotherapy (Grade 2C). For patients who are unable or unwilling to comply with surveillance following RPLND or those who strongly desire to reduce relapse risk and willingly accept the risks of late treatment-related toxicity, adjuvant chemotherapy with two cycles of EP is an appropriate alternative. (See 'Pathologic stage IIA disease' above.)

-Pathologic stage IIB and IIC NSGCT – For patients with pathologic stage IIB or IIC NSGCT, we suggest adjuvant cisplatin-based chemotherapy rather than surveillance (Grade 2C). Such patients, who have bulkier retroperitoneal disease than pathologic stage IIA disease, have a higher risk of relapse following RPLND alone. For patients with stage IIB disease, we offer two cycles of EP. For those with stage IIC disease, options include three cycles of BEP (table 2) or four cycles of EP (table 3). (See 'Pathologic stage IIB or IIC disease' above.)

ACKNOWLEDGMENT — 

The editorial staff at UpToDate would like to acknowledge Philip W Kantoff, MD, who contributed to an earlier version of this topic review.