Contemporary surgical management of testicular seminoma
Introduction
Background
Testis cancer is the most common solid malignancy in young males aged 15 to 44 years, with approximately 9,760 predicted new diagnoses and 500 deaths estimated in the United States in 2024 (1). Testicular germ cell tumors (GCTs) are divided into two distinct histologic categories with differing managements strategies: seminomas, which encompasses about 60% of all GCTs and non-seminomas, which comprise the remaining 40% (2). Management following radical orchiectomy is dictated by histologic diagnosis, pathologic stage of the primary tumor, and clinical staging of the retroperitoneum and beyond to exclude regional and/or metastatic disease. Testicular cancers are staged according to the American Joint Committee on Cancer (AJCC) staging system, which is derived from the TNMS (tumor, node, metastasis, serum markers) Staging Classification (Tables 1,2) (3). Broadly, tumors that are confined to the testicle are considered AJCC stage I, those with regional lymph node involvement are classified as AJCC stage II, and those with distant metastasis or non-regional lymph node involvement are categorized as AJCC stage III (4). The International Germ Cell Cancer Collaborative Group (IGCCCG) originally devised a classification system in 1997 that incorporates disease extent and serum tumor marker levels post-orchiectomy that classifies patients with GCTs into good-, intermediate- and poor-risk groups (Table 3). This model, which was updated in 2021 to include contemporary patients with metastatic GCTs, provides prognostic information and guides therapy for patients, particularly with advanced disease (5). In general, patients with seminoma are classified as either good-risk or intermediate-risk.
Table 1
Stage | Criteria |
---|---|
Clinical T | Primary tumor |
cTX | Primary tumor cannot be assessed |
cT0 | No evidence of primary tumor |
cTis | Germ cell neoplasia in situ |
cT4 | Tumor invades scrotum with or without vascular/lymphatic invasion |
Pathological T | Primary tumor |
pTX | Primary tumor cannot be assessed |
pT0 | No evidence of primary tumor |
pTis | Germ cell neoplasia in situ |
pT1 | Tumor limited to testis (including rete testis invasion) without lymphovascular invasion |
pT1a | Tumor smaller than 3 cm in size |
pT1b | Tumor 3 cm or larger in size |
pT2 | Tumor limited to testis (including rete testis invasion) with lymphovascular invasion |
OR | |
Tumor invading hilar soft tissue or epididymis or penetrating visceral mesothelial layer, covering the external surface of tunica albuginea with or without lymphovascular invasion | |
pT3 | Tumor directly invades spermatic cord soft tissue with or without lymphovascular invasion |
pT4 | Tumor invades scrotum with or without lymphovascular invasion |
Clinical N | Regional lymph nodes |
cNX | Regional lymph nodes cannot be assessed |
cN0 | No regional lymph node metastasis |
cN1 | Metastasis with a lymph node mass 2 cm or smaller in greatest dimension |
OR | |
Multiple lymph nodes, none larger than 2 cm in greatest dimension | |
cN2 | Metastasis with a lymph node mass larger than 2 cm but not larger than 5 cm in greatest dimension |
OR | |
Multiple lymph nodes, any one mass larger than 2 cm but not larger than 5 cm in greatest dimension | |
cN3 | Metastasis with a lymph node mass larger than 5 cm in greatest dimension |
Pathological N | Regional lymph nodes |
pNX | Regional lymph nodes cannot be assessed |
pN0 | No regional lymph node metastasis |
pN1 | Metastasis with a lymph node mass 2 cm or smaller in greatest dimension and less than or equal to five nodes positive, none larger than 2 cm in greatest dimension |
pN2 | Metastasis with a lymph node mass larger than 2 cm but not larger than 5 cm in greatest dimension; or more than five nodes positive, none larger than 5 cm; or evidence of extra nodal extension of tumor |
pN3 | Metastasis with a lymph node mass larger than 5 cm in greatest dimension |
M | Distant metastasis |
M0 | No distant metastases |
M1 | Distant metastases |
M1a | Non-retroperitoneal nodal or pulmonary metastases |
M1b | Non-pulmonary visceral metastases |
S | Serum markers |
SX | Marker studies not available or not performed |
S0 | Marker study levels within normal limits |
S1 | LDH <1.5 × normal and hCG (mIU/mL) <5,000 and AFP (ng/mL) <1,000 |
S2 | LDH 1.5–10 × normal or hCG (mIU/mL) 5,000–50,000 or AFP (ng/mL) 1,000–10,000 |
S3 | LDH >10 × normal or hCG (mIU/mL) >50,000 or AFP (ng/mL) >10,000 |
TNMS, tumor, node, metastasis, serum markers; LDH, lactate dehydrogenase; hCG, human chorionic gonadotropin; AFP, alpha-fetoprotein.
Table 2
Stage | T | N | M | S |
---|---|---|---|---|
Stage 0 | pTis | N0 | M0 | S0 |
Stage I | pT1–T4 | N0 | M0 | SX |
Stage IA | pT1 | N0 | M0 | S0 |
Stage IB | pT2 | N0 | M0 | S0 |
pT3 | N0 | M0 | S0 | |
pT4 | N0 | M0 | S0 | |
Stage IS | Any pT/TX | N0 | M0 | S1–3 |
Stage II | Any pT/TX | N1–3 | M0 | SX |
Stage IIA | Any pT/TX | N1 | M0 | S0 |
Any pT/TX | N1 | M0 | S1 | |
Stage IIB | Any pT/TX | N2 | M0 | S0 |
Any pT/TX | N2 | M0 | S1 | |
Stage IIC | Any pT/TX | N3 | M0 | S0 |
Any pT/TX | N3 | M0 | S1 | |
Stage III | Any pT/TX | Any N | M1 | SX |
Stage IIIA | Any pT/TX | Any N | M1a | S0 |
Any pT/TX | Any N | M1a | S1 | |
Stage IIIB | Any pT/TX | N1–3 | M0 | S2 |
Any pT/TX | Any N | M1a | S2 | |
Stage IIIC | Any pT/TX | N1–3 | M0 | S3 |
Any pT/TX | Any N | M1a | S3 | |
Any pT/TX | Any N | M1b | Any S |
Table 3
Risk status | Nonseminoma | Seminoma |
---|---|---|
Good risk | Testicular or retroperitoneal primary tumor | Any primary site |
AND | AND | |
No nonpulmonary visceral metastases | No nonpulmonary visceral metastases | |
AND | AND | |
Post-orchiectomy markers—all of: | Normal AFP | |
AFP <1,000 ng/mL | Any hCG | |
hCG <5,000 IU/L | Any LDH† | |
LDH <1.5 × upper limit of normal | ||
Intermediate risk | Testicular or retroperitoneal primary tumor | Any primary site |
AND | AND | |
No nonpulmonary visceral metastases | Nonpulmonary visceral metastases | |
AND | AND | |
Post-orchiectomy markers—any of: | Normal AFP | |
AFP 1,000–10,000 ng/mL | Any hCG | |
hCG 5,000–50,000 IU/L | Any LDH | |
LDH 1.5–10 × upper limit of normal | ||
Poor risk | Mediastinal primary tumor | No patients classified as poor prognosis |
OR | ||
Nonpulmonary visceral metastases | ||
OR | ||
Post-orchiectomy markers—any of: | ||
AFP >10,000 ng/mL | ||
hCG >50,000 IU/L | ||
LDH >10 × upper limit of normal |
†, patients with good-risk disseminated seminoma with LDH >2.5 × upper limit of normal have a worse prognosis than other good-risk patients. However, there are insufficient data to recommend treating these patients differently based on LDH alone and the risk categorization remains the same (5). AFP, alpha-fetoprotein; hCG, human chorionic gonadotropin; LDH, lactate dehydrogenase.
Rationale and knowledge gap
Patterns for disseminated testicular cancer are predictable and reproducible, initially metastasizing to the retroperitoneum before metastasizing to the lungs or other viscera. As seminomas are exquisitely sensitive to radiation therapy and platinum-based chemotherapy, traditional post-orchiectomy treatment strategies are AJCC-stage and IGCCC-risk dependent, and include surveillance, chemotherapy, radiation, or surgery. Though chemotherapy and radiation therapy are well-established options to reduce relapse rates in early-stage seminoma (clinical stage I) and to treat those with low-volume disseminated disease (clinical stage IIA/IIB), these therapies may be associated with long-term toxicities in this distinctively young population. Therefore, management strategies have focused on survivorship.
Objective
In this review, we discuss the contemporary stage- and risk-dependent management for patients with testicular seminomas and outline indications to consider surgery in men with metastatic seminoma.
Management of early-stage seminoma (clinical stage I)
The management of stage I seminoma has evolved over time. Acceptable treatment options following orchiectomy currently include surveillance, adjuvant radiotherapy, or adjuvant single-agent carboplatin chemotherapy. According to the American Urological Association (AUA) and the National Comprehensive Cancer Network (NCCN) clinical practice guidelines on Testicular Cancer, surveillance is the preferred management approach after radical orchiectomy (3,6).
Surveillance presents the best option for patients to avoid treatment-related morbidity from chemotherapy or radiation and confers an 80% to 85% relapse-free rate after orchiectomy alone. For the 15% to 20% of patients who relapse on initial surveillance, cancer-specific survival after subsequent treatment is similar to those treated with up-front chemotherapy or radiation (7,8).
The factor most associated with increased risk of relapse in patients with stage I seminoma is increased size of the primary tumor. Though there is a size-dependent increase in risk of relapse, a cutoff of 3 cm was arbitrarily chosen to subcategorize stage I seminomas given the wide variation of size reported in the literature (4,9,10). Rete testis invasion is another factor that has been associated with risk of relapse in stage I seminoma in some studies, though its prognostic significance has not been universally corroborated (11). As a result, the NCCN guidelines do not advise risk-adapted management of men with stage I seminoma but instead, strongly recommend surveillance (3). The absence of both factors portend a low risk of recurrence, approximately 6% (12).
The 5-year relapse-free survival rates for patients who receive 1 or 2 cycles of adjuvant single-agent carboplatin is about 95% and 97%, respectively (10,12,13). Though platinum-based chemotherapy is associated with increased risk of secondary malignancies and cardiac toxicity, the intermediate- and long-term risks from single-agent carboplatin are not yet known (14).
Radiation therapy confers excellent oncologic outcomes for stage I seminoma patients. In a large randomized phase III trial comparing carboplatin to radiation therapy for men with stage I seminoma, 4-year relapse rates between chemotherapy versus radiation were similar (97.7% versus 96.7%, respectively) (13). However, the risk of secondary malignancies in patients receiving radiotherapy for stage I seminoma is well documented and the low overall risk of relapse without adjuvant treatment in these patients needs to be considered and weighed against the potential long-term toxicities of radiotherapy (15).
Management of early disseminated seminoma (clinical stage IIA and IIB)
Men with stage II seminoma comprise roughly 15% to 20% of seminoma patients and for patients with low-volume stage II disease (IIA/IIB), radiation therapy or primary chemotherapy [3 cycles of bleomycin, etoposide, cisplatin (BEP) or 4 cycles of etoposide, cisplatin (EP)] have traditionally been the mainstay of treatment (3).
Historically, radiotherapy was the backbone of treatment for patients with low-volume retroperitoneal disease. In a seminal prospective multicenter trial, Classen and co-investigators followed 87 patients with stage II seminoma (66 stage IIA and 21 stage IIB) after radiotherapy and found that at a median follow-up of 70 months, relapse-free survival was 95% and 89% in the IIA and IIB cohorts, respectively. All relapses were managed with salvage platinum-based chemotherapy successfully, leading to disease-specific survivals approaching 100% (16).
Primary induction chemotherapy has been shown to be similarly effective. Garcia-del-Muro et al. prospectively evaluated 72 patients, 18 with stage IIA and 54 with stage IIB disease, to assess response to platinum-based chemotherapy regimens. After a median follow-up of 71.5 months, the 5-year progression-free survival (PFS) rates for men with stage IIA or IIB disease were 100% and 87%, respectively. Five-year PFS and overall survival (OS) rates for the entire cohort were 90% and 95%, respectively (17).
While radiotherapy and chemotherapy have excellent cure rates, they may both be associated with significant long-term toxicities. Multiple studies highlight cardiac toxicity in patients who received radiotherapy, chemotherapy, or a combination. Haugnes and colleagues assessed cardiovascular disease in patients who received chemotherapy, radiation or a combination of chemotherapy and radiation when compared to surgery alone. In their cohort of 990 patients, the risk of atherosclerotic disease was 2.3-, 2.6-, and 4.8-fold higher for radiotherapy, chemotherapy, or combination therapy, respectively, when compared to patients managed with surgery alone. Furthermore, patients treated with BEP alone were shown to have a 5.7 higher risk of cardiovascular disease compared to surgery only patients, and a 3.1-fold higher risk of myocardial infarction compared to controls from the general population (18). Secondary malignancy in the prior radiation field as well as secondary leukemia are also risks in this patient population (19,20). Given these concerns of long-term toxicities in this young population where long-term survival is an expectation, treatment strategies have focused on minimizing morbidity.
Primary retroperitoneal lymph node dissection (RPLND) has been proposed as an alternate treatment option for patients with low-volume metastatic seminoma given its well-established efficacy, safety, and few long-term complications in the treatment of men with nonseminomatous GCTs (NSGCTs). Similar to NSGCTs, dissemination patterns for testicular seminoma are very predictable, reliably metastasizing via the lymphatic system to the retroperitoneum before systemic metastasis to the lung, non-regional lymph nodes or other viscera. In men with low-volume clinical stage II NSGCT, RPLND is curative in a substantial proportion of patients, with relapses successfully salvaged by chemotherapy in most instances, resulting in OS rates nearing 100%. Primary RPLND in this setting provides the most accurate staging and can direct the need and consideration for additional adjuvant therapies. Additionally, the incidence of short-term complications after primary RPLND is relatively low, and RPLND is associated with very few long-term complications when compared to chemotherapy or radiation (21,22). The main long-term complication after RPLND is ejaculatory dysfunction (23). However, with contemporary nerve-sparing techniques and performance of RPLND at high-volume centers, immediate morbidity associated with surgery is low and antegrade ejaculation can be preserved in approximately 90% of patients (24,25). Though the data is emerging, RPLND may offer similar efficacy for men with low-volume metastatic seminoma similar to men with low-volume metastatic NSGCT.
A retrospective study in 1997 by Warszawski and Schmucking evaluated 63 patients with clinical stage I or II seminoma who underwent RPLND (26). At a median follow-up of 79 months, they found that RPLND provided relatively similar disease control compared to radiation therapy with respect to in-field, retroperitoneal recurrences. However, relapse rates after RPLND in this setting increased with larger nodal burden, with relapse rates of 4.1% in clinical stage I disease compared to relapse rates of 58.3% for clinical stage IIC disease (26).
Other retrospective studies report encouraging oncologic efficacy for RPLND as primary treatment for low-volume metastatic seminoma. Mezvrishvili and Managadze evaluated 14 patients with pure seminoma (10 high-risk stage I and 4 with stage IIA disease) who underwent primary RPLND. At a mean follow-up of 56 months, all patients were disease free with preservation of antegrade ejaculation (27). Hu and colleagues reported on 4 patients who underwent primary RPLND (3 for IIA seminoma and 1 for IIB seminoma) with no evidence of disease recurrence or complications at 25-month follow-up and maintenance of antegrade ejaculation (28).
The role of primary RPLND for patients with low-volume metastatic seminoma has been clarified recently through data from several prospective clinical trials. The SEMS (Surgery in Early Metastatic Seminoma) Trial is a multi-institutional phase 2 clinical trial that assessed 55 patients from 12 institutions with low volume (<3 cm) metastatic seminoma who received open primary RPLND as treatment. Two-year recurrence-free survival (RFS) of 81% and OS of 100% was observed at a median follow-up 33 months. Only 4 patients (7%) experienced long-term complications, which included incisional hernia or anejaculation. Men who recurred in this trial were successfully treated with additional surgery or chemotherapy (29). The PRIMETEST trial is a phase 2 single-arm, single-center trial evaluating the oncologic efficacy and safety of primary RPLND (open or robotic) for patients with seminoma and unilateral retroperitoneal lymph node metastasis (<5 cm). A total of 33 patients with low volume (<5 cm) disease undergoing primary RPLND or RPLND for recurrence after surveillance or after one dose of carboplatin therapy were included. Though the primary end point of PFS after 36 months was not met,a PFS of 70% after a median follow-up of 32 months was observed. All recurrences were effectively treated with systemic therapy (30). Finally, the COTRIMS (Cologne Trial of Retroperitoneal Lymphadenectomy In Metastatic Seminoma) trial is a prospective, single-arm, clinical phase 2 trial including clinical stage IIA/B seminoma patients evaluating RFS and OS as well as complications after open or robotic RPLND. Thirty patients underwent primary RPLND for stage IIA (n=19) or IIB (n=11) seminoma. At 20-month follow-up, RFS was 90%, with 13% (4 patients) experiencing a Clavien 3a or higher complication (31).
Although inclusion criteria such as extent of disease (size and number of lymph nodes), surgical approach (open or robotic) and template of node dissection varied among these trials, the data collectively demonstrate that primary RPLND can be performed safely, effectively, and with minimal morbidity in patients with low-volume metastatic seminoma. Furthermore, the low percentage of patients who relapse after primary RPLND can be successfully salvaged with chemotherapy or additional surgery. Primary RPLND should be considered as another viable treatment option for patients with low-volume metastatic disease (stage IIA seminoma and select patients with stage IIB seminoma).
Management of advanced-stage seminoma (clinical stage IIC and III)
Patients with advanced-stage seminoma (stage IIC or stage III) are categorized as either good- or intermediate-risk according to IGCCCG risk stratification. For patients with good-risk disease, 3 cycles of BEP or 4 cycles of EP are appropriate primary induction chemotherapy regimens. Patients with intermediate-risk disease should receive 4 cycles of BEP or 4 cycles of cisplatin, etoposide, ifosfamide (VIP) in patients who cannot tolerate bleomycin. There is currently minimal to no role for upfront primary surgery in men with advanced-stage seminoma (3,32).
Following induction chemotherapy for large volume metastatic seminoma, all patients should undergo serum tumor marker measurements and computed tomography (CT) imaging of the chest, abdomen, and pelvis to assess for residual masses. Residual mass can be detected in at least 40% of patients, however, with surveillance alone 50% will spontaneously resolve in the following year (33). Surveillance should be considered post chemotherapy for patients with no residual mass or a residual mass less than or equal to 3 cm and serum tumor marker normalization. For patients with a residual mass greater than 3 cm, a fludeoxyglucose (FDG)-positron emission tomography (PET) scan should be performed at least 6 to 8 weeks after the last cycle of chemotherapy was completed. A cutoff of 3 cm was determined based on data showing that in patients with masses <3 cm, viable tumor was present in 3%, compared to 27% in masses >3 cm (34).
Historically FDG-PET scans were the imaging of choice for post chemotherapy monitoring as a result of the SEMPET trial, which demonstrated an 80% sensitivity, 100% specificity, 100% positive predictive value (PPV) and 96% negative predictive value (NPV) with increasing sensitivity in post chemotherapy residual masses >3 cm (35). However, more recent studies have found FDG-PET imaging to have a low PPV for vital tumor in residual masses post chemotherapy in those with metastatic seminoma, with PPVs ranging from 23% to 67%, despite a high sensitivity and NPV (36,37).
The management for residual masses deemed concerning on imaging for viable tumor is either surgical treatment with RPLND, if feasible, or salvage chemotherapy. Typically, 90% of residual masses in this setting are histologically necrosis with only 10% composed of viable GCT. Post chemotherapy RPLND in the seminoma population is technically challenging secondary to chemotherapy-induced desmoplasia that results in an operating field with intense fibrosis and altered tissue planes, which can result in incomplete resection or microscopic disease at the resection margin (38). Complete resections in this setting are reported in only up to 75% of patients (33,39,40). Of patients undergoing post chemotherapy RPLND, 38% have been shown to require adjunctive procedures such as nephrectomy, inferior vena cava resection, arterial grafts, small bowel resections and hepatic resections with post operative complications reaching as high as 25% (38). Prognosis for these patients is unfavorable even after surgical resection. A retrospective single institution database review suggested 5-year cancer-specific survival in this patient population was only 54% with a mean post RPNLD time to death of only 6.8 months. Only 25% of patients remained recurrence free, of which 44% required additional chemotherapy (41). Salvage chemotherapy is the alternative treatment to patients who do not undergo post chemotherapy RPLND. In patients receiving second-line vinblastine, ifosfamide, cisplatin (VeIP), 83% achieved complete remission with 40% subsequently relapsing and only 54% surviving long term (42). As the prognosis is guarded in all patients with persistent disease following chemotherapy regardless of subsequent treatment pathway, patient-specific factors are important considerations and a multidisciplinary approach is critical to reaching a consensus on a therapeutic plan.
Discussion
Overall, we provide a comprehensive review of stage and risk dependent management of testicular seminoma with attention to considerations for surgical intervention. We include both a discussion of all the currently available prospective clinical trial data in this space, as well as the relevant and best available quality retrospective data on this topic. A limitation is that the prospective trial data presented included different inclusion criteria, surgical templates (bilateral template versus modified template), and surgical approach (open versus robotic). Additionally, secondary to the relative rarity of the disease, the retrospective data presented in this review included fairly small samples without comparative arms.
Conclusions
Men with low-volume metastatic testicular seminoma have historically been treated with primary induction chemotherapy or radiation therapy. Because of the long-term toxicities related to these traditional therapies, primary RPLND has been proposed for well selected patients with low-volume metastatic seminoma and its efficacy and safety have been confirmed in several prospective clinical trials (SEMS, COTRIMS, PRIMETEST). Finally, though the role of surgical resection of a residual mass post-chemotherapy in men with advanced-stage seminoma is limited, a subset of men with viable tumor suggested on imaging may benefit from resection if technically feasible.
Acknowledgments
Funding: The work from the Cancer Institute of New Jersey was supported by a grant from
Footnote
Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-241/prf
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-241/coif). The authors have no conflicts of interest to declare.
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