Management of residual masses in advanced testicular germ cell tumors following initial systemic therapy

INTRODUCTION — 

Testicular cancers, 95 percent of which are germ cell tumors (GCTs), are one of the most curable solid neoplasms. Patients with advanced testicular GCTs are treated with initial cisplatin-based chemotherapy. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

However, despite receiving initial systemic therapy, some patients may still have residual masses present on posttreatment imaging. This topic will discuss the role of management of residual masses following initial systemic therapy in males with advanced testicular GCT. Other topics related to the initial management of testicular GCT are discussed separately.

●(See "Overview of the treatment of testicular germ cell tumors".)

●(See "Treatment of stage I seminoma".)

●(See "Treatment of stage II seminoma".)

●(See "Treatment of stage I nonseminomatous germ cell tumors".)

●(See "Treatment of stage II nonseminomatous germ cell tumors".)

●(See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

TYPES OF RESIDUAL MASSES — 

In patients with advanced testicular germ cell tumors (GCT), the types of residual masses that are present at the completion of initial chemotherapy includes [1-4]:

●Necrosis or fibrosis (40 to 50 percent of retroperitoneal masses).

●Mature or immature teratoma (30 to 40 percent).

●Residual nonteratomatous GCT (10 to 20 percent), although the percentage of patients with viable GCT may be higher in those who have received multiple chemotherapy regimens [5,6].

It is generally not possible to distinguish these possibilities without a tissue diagnosis. For example, multiple factors may predict the histology of residual retroperitoneal masses in males with nonseminomatous germ cell tumor (NSGCT), including the presence of teratomatous elements in the primary tumor, levels of serum tumor markers prior to chemotherapy, and the degree of reduction in mass size during chemotherapy [1-3,7-10]. However, none have sufficient accuracy to negate the role of tissue in identifying the final pathology [11-13].

DIAGNOSTIC EVALUATION OF RESIDUAL MASSES

Selection of imaging studies — For all patients with advanced germ cell tumors (GCTs; either seminoma or nonseminomatous germ cell tumor [NSGCT]) who complete systemic therapy, we obtain imaging to assess for residual disease. Imaging options include either contrast-enhanced computed tomography (CT) abdomen and pelvis or gadolinium-enhanced magnetic resonance imaging (MRI) abdomen and pelvis. Patients who had disease outside of the retroperitoneum are also imaged with a contrast-enhanced CT chest.

Seminoma

Radiographic patterns of residual masses — Residual retroperitoneal masses can be seen after chemotherapy for seminoma. Two radiologic patterns are usually described on initial CT imaging [14-19]:

●The retroperitoneal mass may have the appearance of a sheet of tissue around the great vessels, obliterating radiographic planes [20]. Such a mass tends to merge with the great vessels, psoas muscles, and other retroperitoneal structures. This appearance usually represents fibrosis and is often unresectable [21].

●Retroperitoneal masses may appear delineated and distinct from surrounding structures. Compared with the above pattern of radiographic abnormality, these masses are more likely to be resectable and often represent residual seminoma [21,22].

Approach to posttreatment residual masses — For patients with seminomas whose initial posttreatment imaging (CT or MRI) shows a residual retroperitoneal mass, our approach is based on the size of the mass.

Progressive disease — Patients with evidence of progressive disease (growing masses on comparative imaging studies or rising tumor markers) are treated with second-line systemic therapy for relapsed or refractory disease. (See "Diagnosis and treatment of relapsed and refractory testicular germ cell tumors", section on 'Management'.)

Residual masses ≤3 cm — For residual masses ≤3 cm after therapy with normal serum tumor markers, we suggest observation rather than further treatment. These masses often do not contain viable tumor, and approximately one-half will resolve without intervention [23,24]. Such patients may proceed to routine surveillance for treated seminoma. (See "Posttreatment follow-up for testicular germ cell tumors", section on 'Seminoma'.)

Residual masses >3 cm — For one or more residual masses >3 cm with normal serum tumor markers, we obtain fluorodeoxyglucose (FDG) positron emission tomography (PET)-CT imaging from skull base to midthigh at six weeks or longer after treatment completion to determine further management. However, surveillance for treated seminoma is also an option, given the possibility of a false-positive PET-CT for detecting residual disease. (See "Posttreatment follow-up for testicular germ cell tumors", section on 'Seminoma'.)

For patients who are imaged with PET-CT, further management is based on the extent of FDG uptake by the residual mass:

●Negative FDG uptake – For residual masses with negative FDG uptake, we offer posttreatment surveillance. (See "Posttreatment follow-up for testicular germ cell tumors", section on 'Seminoma'.)

●Indeterminant FDG uptake – For residual masses with indeterminant FDG uptake, we repeat imaging with either PET-CT or contrast-enhanced CT in six to eight weeks. Based on our clinical experience, most PET-CT scans with borderline FDG avidity represent posttreatment necrosis. If subsequent imaging of the residual mass reveals a decrease in size, a decrease (or resolution) in FDG uptake on PET-CT, or both, such patients may be observed. (See "Posttreatment follow-up for testicular germ cell tumors", section on 'Seminoma'.)

However, a residual mass that increases in size (regardless of FDG uptake on PET-CT) indicates progressive disease and should be treated with second-line systemic therapy for relapsed or refractory disease. (See "Diagnosis and treatment of relapsed and refractory testicular germ cell tumors", section on 'Management'.)

●Positive FDG uptake – For residual masses with positive FDG uptake, clinical practice is variable amongst UpToDate experts. Some experts offer surgical resection, due to concerns about residual disease and the possibility of a false-negative result/sampling error with biopsy alone [25]. Other experts offer interventional radiology (IR)-guided biopsy of the mass, due to the possibility of a false-positive finding on the PET-CT and because many such masses are unresectable.

•Management after surgical resection of residual mass – Patients who undergo complete surgical resection and whose postoperative tissue sample demonstrates no evidence of residual malignancy on histopathology may proceed to routine posttreatment surveillance. (See "Posttreatment follow-up for testicular germ cell tumors", section on 'Seminoma'.)

•If a complete surgical resection reveals viable seminoma and no residual masses remain on imaging, we administer two additional courses of adjuvant chemotherapy with either etoposide plus cisplatin (EP) (table 1) or paclitaxel, ifosfamide, and cisplatin (TIP) (table 2), followed by routine posttreatment surveillance. However, if surgical resection reveals viable seminoma, but is incomplete or residual masses remain on imaging, then systemic therapy for relapsed or refractory disease is warranted. (See "Diagnosis and treatment of relapsed and refractory testicular germ cell tumors", section on 'Management'.)

•Management after biopsy of residual mass – Patients who undergo a biopsy of the residual mass that reveals no evidence of viable seminoma may proceed with surveillance; however, the frequency and type of surveillance imaging can be intensified depending on the level of suspicion of viable seminoma. For example, in patients with a high level of suspicion due to the possibility of a false-negative biopsy from sampling error, some experts may prefer to follow with conventional imaging (CT or MRI) at more frequent intervals, or with additional PET-CT studies.

•If a biopsy reveals viable seminoma, options include either complete surgical resection or second-line chemotherapy for relapsed or refractory disease, depending upon the practice of the treating clinician and the resectability of the tumor. For patients who underwent a biopsy due to unresectable disease, we offer second-line chemotherapy for relapsed or refractory disease. (See 'Surgical approaches' below and "Diagnosis and treatment of relapsed and refractory testicular germ cell tumors".)

•No role for radiation therapy (RT) – We do not offer RT to patients with seminoma and residual retroperitoneal masses after initial systemic therapy, as this approach is not associated with improved progression-free survival [26].

Rationale — In patients with seminoma and posttreatment residual masses >3 cm on initial CT imaging, studies suggest a higher incidence of viable seminoma or local disease progression [24,27]. However, size criteria alone do not detect all cases of residual disease; viable tumor can be present in smaller nodes while larger nodes may be exclusively comprised of necrotic, nonmalignant tissue.

FDG PET-CT imaging can reliably indicate the presence of viable residual tumor tissue using both the size and the degree of FDG avidity within the residual mass [28-30]. As an example, in a prospective multicenter trial (SEMPET), 51 patients with seminoma who received chemotherapy and had CT-documented residual masses (ranging from 1 to 11 cm) were imaged using 56 PET-CT scans [29].

●The sensitivity, specificity, positive predictive value, and negative predictive value of PET imaging to detect residual disease was 80, 100, 100, and 96 percent, respectively.

●The overall sensitivity of PET imaging was superior to CT discrimination by size (>3 cm/≤3 cm) (80 versus 70 percent), as was the specificity (100 versus 74 percent).

●In the 19 patients with a residual lesion >3 cm, PET imaging detected all seven cases that either had tumor documented at resection or subsequently relapsed, while accurately predicting the absence of tumor in the remaining 12 cases.

●In the 37 patients with a residual lesion ≤3 cm, PET imaging detected one of three cases that contained tumor and accurately predicted the absence of tumor in 34 of 36 cases without disease. There were no false positives in any of the cases where tumor was not documented.

For those with residual masses ≥3 cm, we wait six weeks or longer following chemotherapy prior to obtaining the PET-CT imaging to reduce the risk of a false-positive result (eg, due to posttreatment inflammation or necrosis). In a subsequent retrospective validation study of the SEMPET trial in a larger group of patients with seminoma and postchemotherapy residual masses, the overall false-positive rate was estimated at 15 percent [31]. Among patients with a residual mass ≥3 cm, waiting six weeks or longer to obtain a PET-CT study was associated with a lower false-positive rate versus obtaining earlier imaging (6 versus 23 percent). However, a false-positive result can still occur even if a PET-CT is performed after six weeks [32]. Many of these false positives are borderline positive due to posttreatment inflammation or necrosis rather than true positive results due to residual disease.

Nonseminomatous germ cell tumor — In contrast to seminoma, there is no role for FDG-PET scans in the work-up of residual disease seen on CT or MRI of males with NSGCT. A retroperitoneal lymph node dissection (RPLND) is indicated if there are one or more residual retroperitoneal lymph nodes larger than 1 cm present postchemotherapy on cross-sectional imaging.

Unlike in seminoma, imaging cannot reliably exclude the presence of active disease based on size. For example, in one series of 87 patients [11]:

●Teratoma or viable malignant GCT was identified in 30 and 8 percent of males who had a residual retroperitoneal mass <2 cm, respectively.

●When the cut-off for residual mass size was reduced to <1 cm, 11 percent (6 of 54 males) had viable malignant GCTs. Despite this, the final pathology identified in subcentimeter disease does not appear to have any relevance to the prognosis of the patient. Therefore, surgical resection is not necessarily required in this specific subgroup of patients. (See 'Indications for surgical intervention' below.)

In contrast to the situation in seminoma, there is no role for FDG-PET scans in the work-up of residual disease seen on CT or MRI of males with NSGCT. PET is not sufficiently sensitive in detecting nodes that contain viable tumor [33,34], nor can it reliably differentiate teratoma from fibrosis. This was shown in a multicenter study of 121 males who underwent RPLND for residual masses greater than 1 cm after cisplatin-based chemotherapy [33]:

●PET scans were positive in only 47 of 67 cases (70 percent) with pathologically confirmed tumor.

●Among 54 cases that were pathologically negative, PET imaging was positive in 33.

RATIONALE FOR RESECTION OF RESIDUAL MASSES IN PATIENTS WITH NSGCT — 

The goal of resecting residual masses is to remove any residual teratoma or viable germ cell tumor (GCT). In addition, the presence of residual cancer is necessary to guide decisions about whether to administer additional chemotherapy.

There are multiple reasons to resect residual teratoma even though most teratomas behave in an indolent manner:

●Teratomas are relatively resistant to the chemotherapy and radiation therapy (RT) regimens for testicular GCTs because they are relatively slow growing tumors. Therefore, surgery is the only reliable way to eliminate them.

●Viable GCT may coexist with teratoma, which can lead to clinical recurrence if not resected [35,36].

●Teratoma can differentiate into a somatic-type malignancy (formerly called teratoma with malignant transformation) [37]. Sarcomas or carcinomas arising from a teratoma are resistant to chemotherapy and are associated with a poor prognosis [37-39]. (See "Anatomy and pathology of testicular tumors", section on 'Teratoma with somatic-type malignancy'.)

●Indolent growth of a teratoma may compromise vital organ function and/or cause pain and other symptoms [40].

INDICATIONS FOR SURGICAL INTERVENTION — 

For males who are treated with primary chemotherapy for advanced germ cell tumor (GCT), surgery may be indicated in males who exhibit either of the following scenarios:

Persistent elevation of the tumor markers following chemotherapy

●Nonseminomatous germ cell tumor (NSGCT) – In males with NSGCT, serum tumor markers that remain unchanged or sluggishly decline at the end of treatment without normalizing represent a cohort of males at high risk of relapse, with or without the presence of residual masses. Postchemotherapy resection of residual masses or retroperitoneal lymph node dissection (RPLND) is often followed by normalization of tumor markers and durable long-term survival [41-43]. As an example, of 114 patients with persistently elevated markers after first-line (n = 50) or second-line (n = 64) chemotherapy, postchemotherapy RPLND was associated with an overall five-year survival rate of 54 percent [43]. When stratified by final pathologic findings, the five-year survival rate for males with residual malignant GCT, teratoma, or fibrosis was 31, 78, and 86 percent, respectively.

●Seminoma – The only tumor marker of interest in males with a pure seminoma is the serum beta-human chorionic gonadotropin (beta-hCG); lactate dehydrogenase (LDH) is not sufficiently specific posttreatment to be of use, and by definition, these tumors do not produce alpha-fetoprotein (AFP). (See "Serum tumor markers in testicular germ cell tumors".)

For these males, persistently elevated or sluggishly declining serum beta-hCG is rare and the relevance of such a finding is not well defined. Therefore, decisions about management of residual masses in males with pure seminoma are not generally based on serum beta-hCG levels. The management of residual masses in males with pure seminomas is discussed below. (See 'Surgical approaches' below.)

Surveillance as an alternative option — It is important to note that there is no consensus on the best approach to manage males with NSGCT who have persistently elevated serum tumor markers that are either stable or sluggishly declining at the end of treatment. For males who choose not to undergo surgery for whatever reason, surveillance is reasonable and may help determine the most appropriate management. The rationale for surveillance builds on the risk that tumor markers may rise in the immediate postoperative period while the patient is recovering from surgery, which may cause an undesirable delay to the start of second-line chemotherapy.

For males with NSGCT who choose not to proceed with surgery for whatever reason, we base subsequent decisions about surgery on the changes of tumor markers during surveillance:

●If the markers rise, patients have refractory GCT and should be treated with systemic chemotherapy. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

●If the markers normalize over time, males should undergo resection of any residual mass >1 cm. For most males with residual masses ≤1 cm whose tumor markers have normalized, we offer surveillance and do not proceed with surgery. However, some UpToDate experts may offer postchemotherapy RPLND to select patients with a residual subcentimeter or unresolved retroperitoneal mass when there is a yolk sac tumor or teratoma component in the primary testicular tumor, given a higher risk of finding cancer or teratoma in the RPLND specimen.

In the absence of rising markers or evidence of radiologic disease progression, there is no intervention required and males should proceed to posttreatment surveillance. (See "Posttreatment follow-up for testicular germ cell tumors".)

Normalized tumor markers with abnormal imaging findings — For males who normalize their tumor markers but have abnormal imaging findings suggestive of persistent disease, the approach is based on the histologic type of GCT. This is discussed below.

Seminoma — In general, we do not resect or treat residual masses <3 cm in size following treatment for seminoma [23,26,27]. These masses rarely contain viable tumor if resected, and males rarely relapse if they are not resected. In addition, at least one report suggests that approximately one-half of such masses will disappear during surveillance within one year [24]. (See 'Residual masses ≤3 cm' above.)

For males with larger lesions, we routinely will obtain a fluorodeoxyglucose (FDG) positron emission tomography (PET)-CT scan to further assess whether or not to proceed with surgery. (See 'Residual masses >3 cm' above.)

Nonseminomatous germ cell tumor — A residual mass is present in approximately 25 to 30 percent of males with NSGCT following chemotherapy [44]. The majority of these are in the retroperitoneum, although such masses can occur at other sites, including the lung, mediastinum, liver, and brain. Rarely, the residual mass may be increasing in size despite normalized or decreasing tumor marker levels (the so-called "growing teratoma syndrome") [45-47].

For males with NSGCT, an RPLND is indicated if there are one or more residual retroperitoneal lymph nodes larger than 1 cm present postchemotherapy. Centers that are not accustomed to performing RPLNDs should refer the patient to a center of excellence with extensive experience in resecting postchemotherapy residual GCT masses whenever possible. Similarly, residual masses elsewhere, including enlarged lymph nodes in the thorax, neck, or pelvis, and metastatic lesions in the lung, liver, brain, or other organs should be resected if technically feasible. (See 'Surgical approaches' below.)

For most males with NSGCT and residual masses ≤1 cm whose tumor markers have normalized, we offer surveillance, despite the potential risk of GCT in these subcentimeter lesions. The rationale for surveillance is based on observational studies and a meta-analysis that consistently report excellent outcomes without surgical intervention [11,12,48-50]. Data also support surveillance for patients with residual masses measuring <1 cm in the short axis [51]. As an example, a meta-analysis included six studies of patients with NSGCT and subcentimeter residual masses who underwent a postchemotherapy RPLND (n = 558) and four surveillance studies (n = 455) [52].

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

●Among males who underwent surveillance, the rate of disease recurrence was 5 percent.

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

Alternatively, some UpToDate experts may offer postchemotherapy RPLND to select patients with a residual subcentimeter or unresolved retroperitoneal mass when there is a yolk sac tumor or teratoma in the primary testicular tumor, given a higher rate of finding cancer or teratoma in the RPLND specimen [11,44,53,54] In one retrospective series, 149 patients with NSGCT who achieved a complete response to first-line chemotherapy were subsequently observed without RPLND [48]. At a median follow-up of 15.5 years, relapses were observed in 12 patients (9 percent) and death in four patients (3 percent), all of whom died from GCT or teratoma with somatic type malignancy. [48]. Although these relapse and death rates are overall low, they are higher than those seen in other observational studies of patients with advanced NSGCT who were managed with initial chemotherapy and RPLND [55]. (See "Posttreatment follow-up for testicular germ cell tumors", section on 'NSGCT'.)

SURGICAL APPROACHES

Retroperitoneal lymph node dissection — The surgical technique and complications of retroperitoneal lymph node dissection (RPLND) are discussed separately. (See "Retroperitoneal lymph node dissection for early-stage testicular germ cell tumors", section on 'Surgical approaches' and "Retroperitoneal lymph node dissection for early-stage testicular germ cell tumors", section on 'Complications following RPLND'.)

The most common findings at RPLND include fibrosis/necrosis, teratoma, and viable germ cell tumor (GCT). As an example of contemporary experience, in a single-institution series of 504 patients with nonseminomatous germ cell tumor (NSGCT) who underwent RPLND, 51 percent of cases had fibrosis/necrosis, 37 percent had teratoma, and 15 percent had viable GCT [56]. Similar proportions have been seen in other series [57].

The outcomes in representative large series are illustrated by the following:

●Necrosis/fibrosis – The five-year disease-free and overall survival rates were 94 and 96 percent, respectively, in a series of 598 males in whom fibrosis/necrosis was identified at RPLND [58]. In the 36 patients who had a relapse, distant metastases were present in 27 (75 percent). Locoregional recurrence occurred in 14, including six with concurrent distant disease; only eight patients had locoregional disease alone at recurrence.

●Teratoma – Long-term follow-up in patients with residual teratoma at RPLND was analyzed in one institutional series of 210 cases [39]. Surgical findings included 178 with mature teratoma, 15 with immature teratoma, and 17 with teratoma with somatic-type malignancy (85, 7, and 8 percent, respectively). The 10-year, disease-free survival after complete resection of residual teratoma was 80 percent. At a median follow-up of 37 months, 30 patients relapsed, including 10 with teratoma, five with teratoma with somatic-type malignancy, and 15 with malignant GCT. Disease-specific survival at 5 and 10 years was 94 and 92 percent, respectively. On multivariate analysis, large size of the residual mass and intermediate or poor pretreatment International Germ Cell Cancer Collaborative Group (IGCCCG) risk status were predictors of a higher likelihood of recurrence (table 3). Similar results were seen in series from M. D. Anderson Cancer Center and Indiana University in patients who had teratoma identified at RPLND [59,60]. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'Risk stratification'.)

●Viable germ cell tumor – In contrast to males with teratoma or necrosis/fibrosis discovered at postchemotherapy RPLND, males with viable malignant GCT have a relatively poor prognosis. This was illustrated by a series of 146 patients with NSGCT who had viable residual disease identified at posttreatment resection, all of whom had normal tumor markers prior to surgery [61]. The five-year, progression-free and overall survival rates were 64 and 73 percent, respectively. Adverse prognostic factors were incomplete resection of residual masses, more than 10 percent viable malignant cells in the resected residual mass, and an intermediate or poor IGCCCG prognostic classification at the start of first-line chemotherapy. A subsequent validation study testing these prognostic variables reported that overall survival rates in patients with zero, one, and two to three risk factors were 90, 86, and 52 percent, respectively [41].

Radical orchiectomy — For males who present with clinically advanced disease, a radical orchiectomy is performed to remove the primary tumor prior to chemotherapy whenever possible. Nonetheless, there are some males who present with life-threatening advanced disease who undergo systemic chemotherapy prior to orchiectomy. In this setting, orchiectomy of the testis that had the primary tumor should be performed upon completion of chemotherapy. (See "Radical inguinal orchiectomy for testicular germ cell tumors", section on 'Delayed orchiectomy'.)

Metastasectomy

Lung lesions — Males with NSGCT and persistent intrathoracic masses following cisplatin-based chemotherapy should undergo resection of disease if technically feasible. Prognosis following resection is favorable; over 80 percent can be expected to achieve long-term survival [62-64].

The outcomes of resection for postchemotherapy intrapulmonary residual masses were illustrated in a single-institution review of 251 males with testicular NSGCT [64]. The following findings were noted:

●Among males undergoing resection after their initial chemotherapy, the histopathology was teratoma, necrosis, persistent NSGCT, and teratoma with somatic-type malignancy in 49, 32, 11, and 8 percent, respectively. In contrast, teratoma was less common and persistent NSGCT more common among those who underwent surgery after salvage chemotherapy (26 and 31 percent of cases, respectively).

●The majority of males with residual NSGCT after first-line chemotherapy were given additional chemotherapy. At long-term follow-up, 88 percent were alive and 79 percent continuously disease-free. The results were worse in patients resected after salvage chemotherapy. At long-term follow-up, 54 percent were alive and 44 percent continuously disease-free.

●There were only three postoperative deaths: one each from sepsis, pneumonia, and respiratory failure with pulmonary fibrosis.

Preoperative considerations — For patients with lung disease in whom a significant volume of pulmonary resection is planned, a non-bleomycin-containing regimen rather than a bleomycin-containing regimen may be a better option due to risks of perioperative bleomycin pulmonary toxicity. If bleomycin is administered, subsequent resection of residual intrathoracic disease may be accompanied by greater morbidity and mortality. The regimens used to treat males with metastatic GCT are reviewed separately. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors" and "Bleomycin-induced lung injury".)

The risks of pulmonary toxicity in patients who had received bleomycin are illustrated by a series of 530 males who presented for resection of residual intrathoracic disease following chemotherapy for either metastatic or primary mediastinal NSGCT [65]. In a subset of 32 males who required pneumonectomy or bilobectomy, the mean total dose of prior bleomycin was 360 units or milligrams, and the mean preoperative diffusing capacity was 66 percent of predicted. Prior treatment with bleomycin was associated with:

●Four operative deaths (13 percent) directly attributable to respiratory complications.

●Major pulmonary postoperative complications in an additional four males, including intubation for longer than 48 hours, a prolonged air leak with empyema, and need for supplemental oxygen at discharge.

●However, 14 of 20 long-term survivors had a satisfactory performance status at follow-up.

Further information on bleomycin-related lung toxicity is discussed separately. (See "Treatment-related toxicity in testicular germ cell tumors", section on 'Pulmonary' and "Bleomycin-induced lung injury".)

Mediastinal disease — In contrast to GCTs that are metastatic to the mediastinum, GCTs that arise in the mediastinum carry a very poor prognosis despite chemotherapy or a multimodality approach. (See "Extragonadal germ cell tumors involving the mediastinum and retroperitoneum".)

Nonetheless, males with a mediastinal primary NSGCT who have one or more residual masses following chemotherapy are treated like other NSGCT patients with residual masses. For males with testicular or retroperitoneal primary NSGCT who have residual disease in both the retroperitoneum and mediastinum, we prefer a combined surgical approach with RPLND and mediastinal surgery [66,67]. In one report of 18 patients who underwent concomitant RPLND and mediastinal surgery, the overall five-year survival rate was 92 percent [67].

Neck disease — Although residual cervical nodal disease is an uncommon site of residual masses or late recurrence (<5 percent in one report [68]), such patients should be evaluated for modified neck dissection [69,70]. In one series of 45 such patients, only four recurred in the treated neck, and 97 percent of those with normal preoperative serum tumor markers remained disease-free. In another observational series of 665 patients with either seminoma or NSGCT, the frequency of cervical lymph node metastases was 4 percent (26 patients), most of whom had a NSGCT as their primary tumor (22 patients) [70].

Liver metastases — Resection of residual hepatic disease following chemotherapy can be performed safely and is as important as resection of residual retroperitoneal or pulmonary masses [71-75]. This was illustrated by a series of 52 patients with NSGCT and normal serum markers after chemotherapy [71]. After resection of residual hepatic disease, 35 (67 percent) were recurrence-free at last follow-up [71].

The decision to undertake hepatic resection should take into account the size of the hepatic lesions [74]. Lesions ≤10 mm in greatest dimension have a high probability of necrosis and can be closely monitored. In contrast, larger lesions have a higher risk of containing viable cancer and should be resected.

Brain metastases — Brain metastases may be present in males with testicular GCTs at the initial diagnosis, in conjunction with systemic relapse, or as an isolated relapse after control of systemic disease [76]. Multidisciplinary evaluation is necessary between neurosurgery, radiation oncology, and medical oncology. The management of patients with brain metastases in patients with testicular GCTs is discussed separately. (See "Diagnosis and treatment of relapsed and refractory testicular germ cell tumors", section on 'Brain metastases'.)

Multisite disease — For males with NSGCT, residual retroperitoneal disease, and disease at other sites, we suggest resection of retroperitoneal disease as the initial surgical treatment. Decisions about resection of other disease sites should be individualized based on patient and provider preferences.

For males who do undergo resection of retroperitoneal disease, we base subsequent decisions regarding the resection of residual disease on pathologic findings:

●If teratoma is found in the final pathology, we suggest resection of all other sites of disease.

●If viable GCT is found, patients have chemorefractory disease. Therefore, patients should be counseled about the role of further chemotherapy (with or without further disease resection), preferably in the context of a specialty multidisciplinary discussion. (See "Diagnosis and treatment of relapsed and refractory testicular germ cell tumors".)

●For most patients with only necrosis and fibrosis identified with no viable tumor seen, we suggest surveillance. However, resection is an appropriate alternative, particularly for larger residual lesions outside the retroperitoneum.

For males with multiple residual masses following cisplatin-based chemotherapy, up to 33 percent can have a complete response following resection of disease [77]. However, 50 percent of those that undergo surgery once tumor markers have normalized will have evidence only of necrosis at final pathology and will have undertaken surgery unnecessarily [77-80]. In one of the largest series, 159 males with NSGCT underwent simultaneous RPLND and thoracotomy following cisplatin-based chemotherapy [79]. The finding of necrosis in the retroperitoneal specimen was associated with an 89 percent probability of necrosis in the lung.

Despite these data, resection remains an appropriate alternative, particularly for larger residual lesions outside of the retroperitoneum. Other studies report discordant histologies in up to 50 percent of males undergoing resections at different anatomic sites and advocate the need for resection of all areas of residual disease [81-84].

ROLE OF ADJUVANT CHEMOTHERAPY — 

Following resection of residual masses that contain viable germ cell tumors (GCTs), at least two further cycles of adjuvant chemotherapy are advised, although retrospective studies have reported conflicting results with regard to whether adjuvant chemotherapy is associated with improved outcomes [41,61,85,86].

Successful outcomes have been reported in males who refuse further chemotherapy following surgery alone, even if tumor markers are elevated preoperatively, although this is not the preferred approach [87]. However, it may be possible to identify patients for whom the prognosis is favorable enough to forego chemotherapy. Among patients with viable tumor at resection following chemotherapy, factors associated with a favorable outcome include [41,61,86,88]:

●Complete resection

●Less than 10 percent viable tumor cells on final pathology

●Good risk disease according to the International Germ Cell Consensus Classification (for males who presented with advanced disease)

Males who meet all these criteria have been reported to have a 90 and 92 percent five-year overall and progression-free survival rate, respectively.

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

●Types of residual masses – In patients with advanced testicular germ cell tumors (GCTs), residual masses that are present following initial chemotherapy can be due to necrosis/fibrosis, teratoma, or viable residual GCT. It is generally not possible to distinguish between these possibilities without a tissue diagnosis. (See 'Types of residual masses' above.)

●Selection of imaging studies – For all patients with advanced GCTs (either seminoma or nonseminomatous germ cell tumor [NSGCT]) who complete systemic therapy, we obtain imaging to assess for residual disease. Imaging options include either contrast-enhanced CT abdomen and pelvis or gadolinium-enhanced MRI abdomen and pelvis. Patients who had disease outside the retroperitoneum are also imaged with a contrast-enhanced CT chest. (See 'Selection of imaging studies' above.)

●NSGCT

•Normal serum tumor markers – For patients with nonseminomatous GCTs and normal serum tumor markers, we suggest surgery to resect all residual masses >1 cm throughout the body (Grade 2C).

For most patients with residual masses ≤1 cm, we offer surveillance due to excellent outcomes without surgical intervention. Alternatively, some UpToDate experts may offer retroperitoneal lymph node dissection (RPLND) to select patients with a residual subcentimeter or unresolved retroperitoneal mass when there is a yolk sac tumor or teratoma in the primary testicular tumor, given the higher risk of finding cancer or teratoma in the RPLND specimen. (See 'Nonseminomatous germ cell tumor' above.)

•Stable or elevated tumor markers – Patients with nonseminomatous GCTs and stable or persistently elevated serum tumor markers should undergo either close surveillance or resection of all residual masses. In the absence of a clear survival benefit to surgery, either approach is reasonable. For patients who opt for surveillance in the presence of slowly declining markers, we suggest surgery once their markers normalize (Grade 2C). (See 'Persistent elevation of the tumor markers following chemotherapy' above.)

●Seminoma – For patients with treated seminoma and residual masses, our approach is based on the size of the mass (see 'Approach to posttreatment residual masses' above):

•Masses ≤3 cm – For residual masses ≤3 cm detected on contrast-enhanced imaging with CT or MRI, we suggest posttreatment surveillance rather than treatment (Grade 2C). (See 'Residual masses ≤3 cm' above.)

•Masses >3 cm – For one or more residual mass >3 cm detected on CT or MRI, we obtain fluorodeoxyglucose (FDG) positron emission tomography (PET)-CT imaging from skull base to midthigh at six weeks or longer after treatment completion to reduce false-positive results from treatment-related inflammation or necrosis. However, surveillance for treated seminoma is also an option, given the possibility of a false-positive PET-CT for detecting residual disease. (See 'Residual masses >3 cm' above.)

For patients who are imaged with PET-CT, further management is based on the extent of FDG uptake by the residual mass:

-For residual masses with negative FDG uptake, we offer posttreatment surveillance.

-For residual masses with indeterminant FDG uptake, we repeat imaging with either a PET-CT or contrast-enhanced CT in six to eight weeks. Further management is based on changes in tumor size and/or FDG avidity.

-For residual masses with positive FDG uptake, clinical practice is variable. Some UpToDate experts offer surgical resection due to concerns about residual disease and the possibility of a false-negative result/sampling error with biopsy alone. Other experts offer interventional radiology (IR)-guided biopsy of the mass due to the possibility of a false-positive finding on PET-CT and because many such masses are unresectable. Further management is based upon the presence or absence of viable seminoma on histopathology.

●Retroperitoneal lymph node dissection – RPLND is an important component of a multidisciplinary approach in these patients, but surgery demands a high level of expertise with respect to both the surgery itself and postoperative care. Thus, these males should be managed in centers of excellence where a high volume of testicular cancer patients is seen. (See 'Retroperitoneal lymph node dissection' above.)

●Supradiaphragmatic disease without retroperitoneal involvement – For patients with NSGCT who have residual lesions at supradiaphragmatic sites but no involvement of the retroperitoneum, we suggest surgical resection rather than observation (Grade 2C). The most common sites of such involvement include the lungs and mediastinum; neck involvement is less common. (See 'Metastasectomy' above.)

●Liver metastases – For patients with NSGCT and residual lesions in the liver following chemotherapy, we suggest resection of lesions that are greater than 10 mm in greatest diameter (Grade 2C). Smaller lesions can be carefully observed, with resection if there is any evidence of growth. (See 'Liver metastases' above.)

●Brain metastases – The management of brain metastases is discussed separately. (See "Diagnosis and treatment of relapsed and refractory testicular germ cell tumors", section on 'Brain metastases'.)

●Supradiaphragmatic and retroperitoneal disease – For males with NSGCT and residual lesions at both supradiaphragmatic and retroperitoneal sites, we suggest a bilateral RPLND as the initial intervention (Grade 2C). Further treatment should be based on the histopathological results (see 'Multisite disease' above):

•For males with residual teratoma, we suggest resection of all other sites of disease (Grade 2C).

•For males with viable GCT, we suggest postoperative chemotherapy (Grade 2C).

•For most patients with only necrosis and fibrosis identified with no viable tumor seen, we suggest surveillance (Grade 2C). However, resection is an appropriate alternative, particularly for larger residual lesions outside of the retroperitoneum.

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Timothy D Gilligan, MD, who contributed to earlier versions of this topic review.