Management of stage II nonseminomatous germ cell tumors

INTRODUCTION — Testicular cancers, 95 percent of which are germ cell tumors (GCTs), are one of the most curable solid tumors. Testicular GCTs are more sensitive to systemic chemotherapy than most adult solid tumors. Chemotherapy is routinely administered with curative intent for men with metastatic seminomas or nonseminomatous germ cell tumors (NSGCTs; ie, stage III disease (table 1A-B)) and for those with persistently elevated serum tumor markers following orchiectomy (stage Is).

The management of stage II NSGCTs requires an understanding of the appropriate roles of chemotherapy and retroperitoneal lymph node dissection. In addition to chemotherapy, a curative approach to testicular cancer often requires surgery, in part because primary and metastatic tumors may contain teratoma, which is less prone to dissemination but more resistant to chemotherapy than other GCT histologies. (See "Serum tumor markers in testicular germ cell tumors".)

The management of stage II NSGCTs following orchiectomy will be reviewed here. An overview of the management of testicular cancer and the management of other stages of testicular cancer are discussed separately. (See "Management of stage I nonseminomatous germ cell tumors" and "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

CLASSIFICATION — Stage II disease refers to cancers that have spread to the regional (ie, retroperitoneal) lymph nodes without distant metastases or marked elevation of serum tumor markers (S0 or S1) (table 1A-B) [1]. (See 'Serum tumor markers' below.)

Stage II disease can be defined based on either imaging criteria combined with clinical judgment (clinical stage II) or a histopathologic analysis showing germ cell tumor (GCT) in lymph nodes resected during a retroperitoneal lymph node dissection (RPLND; pathologic stage II). (See 'Clinical stage II NSGCT' below and 'Pathologic stage II NSGCT' below.)

It is important to recognize that there are two competing frameworks that come into play in clinical staging: the radiologic framework and the staging framework. The radiologic framework is focused on whether or not lymph nodes are enlarged, while the staging framework is focused on the clinician's judgment of whether or not lymph node metastases are present.

Lymph node imaging criteria — Distinguishing stage I from stage II testis cancer is not always straightforward [2]. Imaging may detect mildly enlarged lymph nodes (measuring 1 to 2 cm in greatest dimension), but this does not necessarily indicate the presence of active 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 disease, up to 40 percent will be diagnosed with pathologic stage I disease [6].

Thus, the radiographic framework focuses on the definition of normal. Importantly, it is the length of the short axis in the transverse plane that is used to determine whether or not a lymph node is enlarged on cross-sectional imaging. All measurement criteria in this section refer to measurements in the transverse plane.

Although one observational study demonstrated that craniocaudal lymph node length (measured on coronal or sagittal plane images) was associated with increased relapse risk, this particular measurement has not been definitively associated with adverse outcomes [7].

Clinical framework — From a radiologic perspective, lymph nodes are considered enlarged if the short axis is ≥10 mm. Therefore, lymph nodes will generally be reported as normal unless the short axis is ≥10 mm.

However, for staging purposes, the clinician must make a judgement as to whether or not lymph node metastases are present. If the clinician judges that lymph node metastases are present, then it is the long axis measurement in the transverse plane that determines whether an enlarged node (ie, a node with a short axis at least 10 mm) is stage IIA, IIB, or IIC.

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 this is clinical stage I. Similarly, a patient with five lymph nodes measuring 9 by 9 mm could appropriately be staged clinical stage IIA if the clinician thought the nodes represented metastases, even though all these nodes fall within normal limits with regard to size.

In other words, a patient is clinical stage II because they are judged to have lymph node metastases, not simply because they have nodes of a certain size. However, nodal size clearly and strongly influences clinical judgement. It is essential for clinicians caring for testis cancer patients to carefully evaluate the patient's cross-sectional imaging and other clinical data in order to form a well-considered judgement about proper staging. A reflexive response to radiology reports is strongly inappropriate in this disease.

Subcategories of clinical stage II — The criteria for the different subcategories of clinical stage II are based on the greatest dimension of nodal metastases in the transverse plane: stage IIA refers to retroperitoneal nodal metastases measuring ≤2 cm, stage IIB refers to metastatic nodes measuring >2 and ≤5 cm, and stage IIC refers to retroperitoneal nodes >5 cm.

●Stages IIB and IIC are straightforward to diagnose clinically; such nodal involvement almost always represents metastatic disease.

●An accurate diagnosis of stage IIA is more complicated. A significant number of men with normal-size retroperitoneal nodes (clinical stage I) will have cancer discovered if RPLND is performed, and a significant number of men with mild adenopathy (stage IIA) will be found to have benign nodes (pathological stage I) if RPLND is performed. CT scans thus have substantial false negative and false positive rates.

For instance, in one series of 122 men with clinical stage IIA testis 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 study of men 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) in the primary landing zone for testis cancer (ie, the interaortocaval, 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 threshold was used out of the primary landing zone. However, specificity and positive predictive values declined to 52 and 53 percent [8]. Although this model is not used in practice, it is a reminder of the importance of using clinical judgment when reading retroperitoneal images of men 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 disease. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

Serum tumor markers — Serum tumor markers are also used in staging testicular GCTs (table 1A-B). In order to be classified as stage II, 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 of the following:

●Lactic dehydrogenase (LDH) <3 times ULN. The cutoff for LDH by American Joint Committee on Cancer (AJCC) staging criteria is 1.5 times ULN, but we recommend a higher cutoff of 3 times ULN due to the high rate of false positive LDH elevations.

●Alpha-fetoprotein (AFP) <1000 ng/mL.

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

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

The treatment approach to clinical stage II and pathologic stage II nonseminomatous GCTs is reviewed below; this is largely consistent with guidelines from the National Comprehensive Cancer Network (NCCN) [9]. (See 'Clinical stage II NSGCT' below and 'Pathologic stage II NSGCT' below.)

CLINICAL STAGE II NSGCT — Men with clinical stage II nonseminomatous germ cell tumors (NSGCTs) have a high likelihood of cure. Our approach depends on the size and imaging characteristics of retroperitoneal lymph nodes and the serum tumor markers obtained postorchiectomy (algorithm 1).

Normal tumor markers — For men with normal tumor markers postorchiectomy, our approach depends on whether they have stage IIA, IIB, or IIC disease.

Clinical stage IIA — For men with lymph nodes ≤2 cm and normal (S0) tumor markers (stage IIA disease), we prefer retroperitoneal lymph node dissection (RPLND) rather than chemotherapy. RPLND provides more accurate staging and cures 80 to 90 percent of men with stage IIA nodal disease. In addition, it spares a substantial number of patients (who would be pathologically downstaged to stage I) from unnecessary chemotherapy. (See "Retroperitoneal lymph node dissection for early-stage testicular germ cell tumors".)

Alternatively, for men with stage IIA disease who do not wish to proceed with RPLND for whatever reason, we advocate chemotherapy with three cycles of bleomycin, etoposide, and cisplatin (BEP) or four cycles of etoposide and cisplatin (EP). If men treated with chemotherapy have residual adenopathy after completion of chemotherapy, then a postchemotherapy RPLND should be performed by a highly experienced surgeon.

However, if the staging is ambiguous (ie, if in the clinician's judgement there is significant uncertainty over whether the patient should be staged as clinical stage I or IIA), then surveillance is the preferred alternative to RPLND. The goal of surveillance is to avoid treating the minority of men whose mild adenopathy turns out to be benign. If surveillance is chosen, strict attention to assuring close follow-up is essential since these men 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.

Stage IIA testis cancer is a heterogeneous entity. In patients who are borderline between stage I and stage IIA, the following factors are suggestive of lymph node metastases: location in the primary landing zone for the cancer testicle, multiple enlarged or borderline-enlarged nodes, and round rather than elliptical nodes (ie, nodes with little difference between the long and short diameter).

Clinical stage IIB to IIC — Men with retroperitoneal lymph node metastases >2 cm and normal (S0) tumor markers (clinical stage IIB or IIC disease) should receive chemotherapy rather than proceed with RPLND. The cure rate for these men is 65 percent if managed only with RPLND [3,10].

Chemotherapy provides earlier treatment of micrometastatic disease and spares men from the morbidity of RPLND if they have a complete response to chemotherapy [4,11]. However, a substantial proportion of men with stage IIB and IIC disease will have residual masses requiring postchemotherapy RPLND. Our preferred regimen is three cycles of chemotherapy with BEP (table 2), although four cycles of chemotherapy with EP is a reasonable alternative. This approach is based on the results of treatment using this regimen in patients with disseminated germ cell tumors (GCTs). (See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

There are no randomized trials that compare systemic chemotherapy with RPLND for patients in this clinical setting. The available data suggest that chemotherapy results in similar survival outcomes compared with RPLND for men with stage IIA disease and that it is probably superior for men with stage IIB to IIC disease [4-6,12,13]. For example, a study of 252 men with clinical stage IIA and IIB NSGCT found that relapse-free survival was significantly greater with chemotherapy than with RPLND (98 versus 79 percent) [5]. Observational studies provide little guidance on which patients are suited for one treatment or the other [4-6].

Elevated tumor markers — For patients with clinical stage II disease (inclusive of stages IIA to IIC) whose serum beta human chorionic gonadotropin (hCG) or alpha-fetoprotein (AFP) is mildly elevated (S1) after orchiectomy, we administer chemotherapy rather than perform RPLND.

Mild elevations of lactic dehydrogenase (LDH) are of no known significance in this setting. The concern is that patients with an elevated beta-hCG or AFP are more likely to have distant micrometastases, and treating with chemotherapy first prevents such metastases from progressing. In addition, these men have a substantial chance of being cured with chemotherapy alone, and this potentially spares them from undergoing both RPLND and chemotherapy, with all the potential toxicities associated with combined modality treatment. However, a substantial proportion of clinical stage II patients have residual adenopathy requiring postchemotherapy RPLND, and many patients require dual modality treatment regardless of whether RPLND or chemotherapy is done first.

Patients with more marked elevations of serum tumor markers (S2 or S3) have stage III disease and are treated accordingly. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

Our preferred regimen is three cycles of chemotherapy with BEP (table 2), although four cycles of chemotherapy with EP is a reasonable alternative. This is based on the results of treatment using this regimen in disseminated GCTs. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

The prognosis of these patients is shown in the following studies, which also highlight the excess risk of recurrence in the absence of systemic therapy:

●In one study that included 95 men with pathologic stage II GCTs, RPLND followed by observation was associated with a recurrence rate of 51 percent [10]. When stratified by marker status, 18 of 33 (55 percent) and 19 of 34 (56 percent) had a relapse associated with an isolated elevation of hCG or AFP, respectively. Among the 22 men who had elevation of both markers, 13 (59 percent) had a recurrence.

●A separate study enrolled 50 patients who underwent RPLND for pathological stage IIA disease, and reported that four of five men with elevated AFP or beta-hCG relapsed [14]. Among 45 men with normal tumor markers prior to RPLND, only seven men relapsed.

Treatment of residual masses — In general, we suggest RPLND rather than observation for all men who have residual masses ≥1 cm in the long axis following chemotherapy. For men with small residual masses that measure <1 cm in the long axis, surveillance is a reasonable alternative, provided that men are willing and able to follow a surveillance protocol. (See "Posttreatment follow-up for testicular germ cell tumors".)

The evidence to support surveillance in men with residual masses that measure <1 cm comes from a 2014 meta-analysis that included six studies of men with subcentimeter residual masses who underwent a postchemotherapy RPLND (n = 558) and four surveillance studies (n = 455) [15]. The main results were as follows:

●Among men who underwent RPLND, the pooled incidence of necrosis, teratoma, and active cancer were 71, 24, and 4 percent, respectively.

●Among men who underwent surveillance, disease recurred in 5 percent.

●Despite the lack of randomized data, survival appears to be comparable between those who underwent RPLND and those who chose surveillance (over 90 percent among men with stage II or good-risk stage III disease).

The role of RPLND after chemotherapy in men with clinical stage II NSGCTs is discussed separately. (See "Approach to surgery following chemotherapy for advanced testicular germ cell tumors", section on 'Retroperitoneal lymph node dissection'.)

PATHOLOGIC STAGE II NSGCT — Pathologic stage II disease (table 1A-B) refers to histologically confirmed retroperitoneal lymph node involvement. Most often it represents an upstaging of men felt to have clinical stage I disease who are diagnosed with nodal involvement when they undergo a retroperitoneal lymph node dissection (RPLND). (See "Management of stage I nonseminomatous germ cell tumors", section on 'Retroperitoneal lymph node dissection'.)

Patients with pathologic stage II nonseminomatous germ cell tumors (NSGCTs) are divided into two groups based on pathologic findings within the nodes retrieved surgically.

●Men with pure teratoma – Men with pure teratoma in their retroperitoneal nodes would not be expected to benefit from adjuvant chemotherapy. Therefore, these patients should receive active surveillance after RPLND.

●Men with tumors containing elements of embryonal carcinoma, seminoma, yolk sac tumor, and/or choriocarcinoma – Reasonable options following RPLND include either adjuvant chemotherapy or careful surveillance. If recurrence is detected during surveillance, systemic chemotherapy should be administered.

In addition, decisions regarding treatment for men with nonteratoma pathologic stage II germ cell tumors should consider the volume of disease and patient preference. However, 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 [16].

What follows reflects our approach to men with pathologic stage II disease with nodal disease showing histologic disease other than pure teratoma.

Pathologic stage IIA disease — Approximately 85 to 90 percent of men with pathologic stage IIA disease are cured with RPLND, provided their tumor markers normalized following orchiectomy. We suggest active surveillance for these men rather than adjuvant chemotherapy. (See "Surveillance for stage I testicular germ cell tumors following orchiectomy", section on 'Surveillance protocols'.)

The equivalence between surveillance and adjuvant chemotherapy was shown in a trial involving 195 men with pathologic stage II disease who were randomly assigned to surveillance or adjuvant chemotherapy (two cycles of a cisplatin-based regimen) [10]. Patients who relapsed while on surveillance were treated with three or four cycles of chemotherapy. The main results were the following:

●The recurrence rate was 6 (6 of 97 men) and 49 (48 of 98 men) percent following adjuvant chemotherapy or surveillance, respectively. However, of the six relapses in the group randomly assigned to adjuvant chemotherapy, five occurred in men 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 men 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 pathological stage IIA disease was higher in this study than in subsequent retrospective single-institution analyses, it is worth remembering that in this study, patients were randomly assigned to surveillance 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 survival rates between the two groups, with three deaths from testicular cancer in the surveillance arm and one in the chemotherapy arm.

For patients who are unlikely to comply with a surveillance schedule following RPLND, chemotherapy is advised. Typically, we administer two cycles of adjuvant chemotherapy using either bleomycin, etoposide, and cisplatin (BEP) or just etoposide and cisplatin (EP). In addition, it is reasonable to administer chemotherapy to men who wish to be aggressive with treatment in order to reduce the risk of relapse from 10 to 15 percent down to 1 percent, provided they are aware that there is no clinically significant improvement in overall survival associated with adjuvant chemotherapy. Despite this, for some men the peace of mind this provides is worth undergoing six weeks of chemotherapy.

Pathologic stage IIB or IIC disease — Men with nodal disease >2 cm (stage IIB or IIC disease, otherwise known as "bulky" disease) have a higher risk of relapse following RPLND alone [6,14,17-23]. Therefore, we administer adjuvant chemotherapy rather than offer active surveillance. However, for men with a contraindication to cisplatin-based chemotherapy, surveillance is a reasonable alternative [24] in view of the randomized controlled trial discussed above. (See 'Pathologic stage IIA disease' above.)

For pathologic stage IIB disease, two cycles of EP or BEP (table 2) represent standard adjuvant chemotherapy in the post-RPLND setting for men who undergo chemotherapy for stage II disease [10,18,25-29]. No comparative trials have been performed comparing the two regimens, but each has been associated with 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 improves outcomes in this setting. As described above, regarding the role of chemotherapy for men with clinical 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".)

Patients with bulky disease identified by imaging should not undergo primary RPLND since these patients have a particularly poor prognosis without chemotherapy [30,31]. Thus, classification of patients as having pathologic stage IIC disease is extremely rare. For example, in one older series that included 18 men who had undergone RPLND and had pathologic stage IIC disease, and either did not receive (n = 7) or were treated with chemotherapy (n = 11), the rates of overall survival at five years were 28.5 and 100 percent, respectively [19]. In this situation, there is uncertainty about the optimal approach to chemotherapy, and we favor a full course of cisplatin-based chemotherapy, using three cycles of BEP or four cycles of EP, for disseminated disease.

SPECIAL CONSIDERATIONS — Although tumor burden (denoted by stage) is used to make treatment recommendations, the histology of the primary tumor should also be taken into consideration. As an example, men with lymphovascular invasion and a high proportion of embryonal carcinoma in their primary tumor are at higher risk of relapse following retroperitoneal lymph node dissection (RPLND) compared with those without these features. For patients who are borderline between stage IIA and stage IIB, such features would lead us to favor chemotherapy as the initial treatment. By contrast, men with pure teratomas are less likely to benefit from chemotherapy, and we tend to prefer RPLND over chemotherapy.

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

●Stage II nonseminomatous germ cell tumors (NSGCTs) of the testis consist of two distinct entities: clinical stage II disease, in which radiological studies show enlarged retroperitoneal lymph nodes, and pathological stage II disease, in which retroperitoneal lymph node dissection (RPLND) has resulted in histopathological documentation of retroperitoneal lymph node metastases (table 1A-B). Of note, pelvic lymph node metastases are considered distant metastases and represent stage III disease. (See 'Classification' above.)

●For men with clinical stage II NSGCTs and normal serum tumor markers following orchiectomy, the size of the lymph nodes is used to determine whether to proceed with RPLND or administer primary chemotherapy (algorithm 1). Size criteria are used to determine stage IIA versus stage IIB or IIC disease using the greatest dimension of lymph nodes (≤2 cm, 2 to 5 cm, or >5 cm, respectively). (See 'Classification' above and 'Normal tumor markers' above.)

•For men with clinical stage IIA NSGCT, we suggest RPLND rather than primary chemotherapy (Grade 2C). These men have a significant likelihood of having pathologic stage I disease. Patients with evidence of metastatic testicular cancer confirmed at surgery are managed according to their pathologic stage. An alternative to RPLND is close surveillance to monitor for progressive lymph node enlargement or the appearance of distant metastatic disease. Chemotherapy for stage IIA disease should be reserved for those men whose lymphadenopathy is judged to be almost certainly malignant based on adenopathy in the primary landing zone of the cancer and the presence of multiple enlarged nodes. (See 'Clinical stage IIA' above.)

•For men with clinical stage IIB and IIC NSGCT, we suggest primary chemotherapy rather than RPLND (Grade 2C). We use three cycles of bleomycin, etoposide, and cisplatin (BEP) (table 2). Four cycles of etoposide and cisplatin (EP) is a reasonable alternative and should be used with patients who have a contraindication to bleomycin. (See 'Clinical stage IIB to IIC' above.)

●For men with clinical stage II NSGCTs and persistently elevated or rising serum alpha-fetoprotein (AFP) and/or beta human chorionic gonadotropin (hCG) following orchiectomy, we recommend primary chemotherapy (algorithm 1). We use three cycles of BEP. Four cycles of EP is a reasonable alternative. (See 'Elevated tumor markers' above.)

●Men who have residual masses following chemotherapy should undergo a postchemotherapy RPLND. (See 'Treatment of residual masses' above and "Initial risk-stratified treatment for advanced testicular germ cell tumors" and "Approach to surgery following chemotherapy for advanced testicular germ cell tumors".)

●For men with pathologic stage II NSGCT, pathologic information is used to determine whether or not adjuvant chemotherapy should be recommended following RPLND. (See 'Classification' above and 'Pathologic stage II NSGCT' above.)

•For men whose lymph nodes reveal only teratoma, we suggest surveillance (Grade 2C).

•For men with germ cell tumor elements other than teratoma, the options include surveillance or adjuvant chemotherapy:

-For men with pathologic stage IIA NSGCT, we suggest surveillance rather than adjuvant chemotherapy (Grade 2C). However, patient preference should be taken into account in the formulation of the treatment plan. (See 'Pathologic stage IIA disease' above.)

-For patients with pathologic stage IIB disease, we suggest two cycles of adjuvant chemotherapy rather than observation (Grade 2C). We use EP. However, BEP is a reasonable alternative. (See 'Pathologic stage IIB or IIC disease' above.)

-For patients with pathologic stage IIC disease, we suggest three cycles of BEP or four cycles of EP chemotherapy rather than fewer cycles or observation (Grade 2C). (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.