(Published 2019; Amended 2023)

To cite this guideline:

Stephenson A, Bass EB, Bixler BR, et al. Diagnosis and treatment of early-stage testicular cancer: AUA Guideline amendment 2023. J Urol. 2023;10.1097/JU.0000000000003694. https://doi.org/10.1097/JU.0000000000003694

Unabridged version of this guideline [pdf]
Amendment Summary [pdf]

Andrew Stephenson, MD; Scott E. Eggener, MD; David M. Chelnick, BS; Siamak Daneshmand, MD; Darren Feldman, MD; Timothy Gilligan, MD; Jose A. Karam, MD; Bradley Leibovich, MD, FACS; Stanley L. Liauw, MD; Timothy A. Masterson, MD; Joshua J. Meeks, MD, PhD; Phillip M. Pierorazio, MD; Joel Sheinfeld, MD

Andrew Stephenson, MD; Siamak Daneshmand, MD; Philippe E Spiess, MD

Staff and Consultants

Brooke R. Bixler, MPH; Erin Kirkby, MS; Eric B. Bass, MD, MPH; Alexis Marianes, PhD; Ritu Sharma

Purpose

Testis cancer is the most common solid malignancy in young males. Testis cancer is a relatively rare malignancy, with outcomes defined by specific cancer- and patient-related factors. The vast majority of men with testis cancer have low-stage disease (limited to the testis and retroperitoneum; clinical stages I-IIB); survival rates are high with standard therapy. A priority for those patients with low-stage disease is limiting the burden of therapy and treatment-related toxicity without compromising cancer control. Thus, surveillance has assumed an increasing role among those with cancer clinically confined to the testis.  Likewise, paradigms for management have undergone substantial changes in recent years as evidence regarding risk stratification, recurrence, survival, and treatment-related toxicity has emerged.

Methodology

The systematic review utilized to inform this guideline was conducted by a methodology team at the Johns Hopkins University Evidence-based Practice Center. Scoping of the report and review of the final systematic review to inform guideline statements was conducted in conjunction with the Testicular Cancer expert panel. The methodology team searched using PubMed®, Embase®, and the Cochrane Central Register of Controlled Trials (CENTRAL) from January 1980 through August 2018. The team developed a search strategy by using medical subject heading (MeSH) terms and key words relevant to the diagnosis and treatment of early-stage testicular cancer. The evidence review team also reviewed relevant systematic reviews and references provided by the panel to identify articles that may have been missed by the database searches. Searches were updated using the same methodological protocol to capture literature published through March 2023.

GUIDELINE STATEMENTS

Initial Management

Diagnosis and Initial Consultation

1. A solid mass in the testis identified by physical exam or imaging should be managed as a malignant neoplasm until proven otherwise. (Clinical Principle)

2. In a man with a solid mass in the testis suspicious for malignant neoplasm, serum tumor markers (AFP, hCG, and LDH) should be drawn and measured prior to any treatment, including orchiectomy. (Moderate Recommendation; Evidence Level: Grade C)

3. Prior to definitive management, patients should be counseled about the risks of hypogonadism and infertility (Moderate Recommendation; Evidence Level: Grade C) and should be offered sperm banking, when appropriate. In patients without a normal contralateral testis or with known subfertility, this should be considered prior to orchiectomy. (Clinical Principle)

4. Scrotal ultrasound with Doppler should be obtained in patients with a unilateral or bilateral scrotal mass suspicious for neoplasm. (Strong Recommendation; Evidence Level: Grade B)

5. Testicular microlithiasis in the absence of solid mass and risk factors for developing a germ cell tumor (GCT) does not confer an increased risk of malignant neoplasm and does not require further evaluation. (Moderate Recommendation; Evidence Level: Grade C)

6. Patients with normal serum tumor markers (hCG and AFP) and indeterminate findings on physical exam or testicular ultrasound for testicular neoplasm should undergo repeat imaging in six to eight weeks. (Clinical Principle)

7. Magnetic Resonance Imaging (MRI) should not be used in the initial evaluation and diagnosis of a testicular lesion suspicious for neoplasm. (Moderate Recommendation; Evidence Level: Grade C)

Orchiectomy

8. Patients with a testicular lesion suspicious for malignant neoplasm and a normal contralateral testis should undergo a radical inguinal orchiectomy; testis-sparing surgery (TSS) is not recommended. Transscrotal orchiectomy is discouraged. (Strong Recommendation; Evidence Level: Grade B)

9. Testicular prosthesis should be discussed prior to orchiectomy. (Expert Opinion)

10. Patients who have undergone scrotal orchiectomy for malignant neoplasm should be counseled regarding the increased risk of local recurrence and may rarely be considered for adjunctive therapy (excision of scrotal scar or radiotherapy) for local control. (Moderate Recommendation; Evidence Level: Grade C)

Testis-Sparing Surgery

11a. TSS through an inguinal incision may be offered as an alternative to radical inguinal orchiectomy in highly selected patients wishing to preserve gonadal function with masses <2cm and (1) equivocal ultrasound/physical exam findings and negative tumor markers (hCG and AFP), (2) congenital, acquired or functionally solitary testis, or (3) bilateral synchronous tumors. (Conditional Recommendation; Evidence Level: Grade C)

11b. Patients considering TSS should be counseled regarding (1) higher risk of local recurrence, (2) need for monitoring with physical examination and ultrasound, (3) role of adjuvant radiotherapy to the testicle to reduce local recurrence, (4) impact of radiotherapy on sperm and testosterone production, and (5) the risk of testicular atrophy and need for testosterone replacement therapy, and/or subfertility/infertility. (Moderate Recommendation; Evidence Level: Grade C)

11c. When TSS is performed, in addition to the suspicious mass, multiple biopsies of the ipsilateral testicle normal parenchyma should be obtained for evaluation by an experienced genitourinary pathologist. (Moderate Recommendation; Evidence Level: Grade C)

GCNIS Counseling and Management

12. Clinicians should inform patients with a history of GCT or GCNIS of risks of a second primary tumor while rare is significantly increased in the contralateral testis. (Moderate Recommendation; Evidence Level: Grade B)

13a. In patients with GCNIS on testis biopsy or malignant neoplasm after TSS, clinicians should inform patients of the risks/benefits of surveillance, radiation, and orchiectomy. (Moderate Recommendation; Evidence Level: Grade C)

13b. Clinicians should recommend surveillance in patients with GCNIS or malignant neoplasm after TSS who prioritize preservation of fertility and testicular androgen production. (Moderate Recommendation; Evidence Level: Grade C)

13c.  Clinicians should recommend testicular radiation (18-20 Gy) or orchiectomy in patients with GCNIS or malignant neoplasm after TSS who prioritize reduction of cancer risk taking into consideration that radiation reduces the risk of hypogonadism compared to orchiectomy. (Moderate Recommendation; Evidence Level: Grade C)

Staging

Serum Tumor Markers

14. Nadir serum tumor markers (AFP, hCG, and LDH) should be repeated at appropriate T1/2 time intervals after orchiectomy for staging and risk stratification. (Moderate Recommendation; Evidence Level: Grade B)

15. For patients with elevated AFP or hCG post-orchiectomy, clinicians should monitor serum tumor markers to establish nadir levels before treatment only if marker nadir levels would influence treatment. (Clinical Principle)

16. For patients with metastatic GCT (Stage IIC or III) requiring chemotherapy, clinicians must base chemotherapy regimen and number of cycles on the IGCCCG risk stratification. IGCCCG risk stratification is based on nadir serum tumor marker (hCG, AFP and LDH) levels obtained prior to the initiation of chemotherapy, staging imaging studies, and tumor histology following radical orchiectomy. (Strong Recommendation; Evidence Level: Grade A) Any post-pubertal male, regardless of age, should be treated according to adult treatment guidelines. (Moderate Recommendation; Evidence Level: Grade B)

17. For patients in whom serum tumor marker (AFP and hCG) levels are borderline elevated (within 3x upper limit of normal) post-orchiectomy, a rising trend should be confirmed before management decisions are made as false-positive elevations may occur. (Clinical Principle)

Imaging

18. In patients with newly diagnosed GCT, clinicians should obtain cross-sectional imaging of the abdomen and pelvis with IV contrast or MRI if CT is contraindicated. (Strong Recommendation; Evidence Level: Grade B)

19a. In patients with newly diagnosed GCT, clinicians must obtain chest imaging. (Clinical Principle)

19b. In the presence of elevated and rising post-orchiectomy markers (hCG and AFP) or evidence of metastases on abdominal/pelvic imaging, chest x-ray or physical exam, a CT chest should be obtained. (Strong Recommendation; Evidence Level: Grade C)

19c. In patients with clinical stage I seminoma, clinicians should preferentially obtain a chest x-ray over a CT scan. (Moderate Recommendation; Evidence Level: Grade B)

19d. In patients with non-seminomatous germ cell tumors (NSGCT), clinicians may preferentially obtain a CT scan of the chest over a chest x-ray and should prioritize CT chest for those patients recommended to receive adjuvant therapy. (Conditional Recommendation; Evidence Level: Grade C)

20. In patients with newly diagnosed GCT, clinicians should not obtain a positron emission tomography (PET) scan for staging. (Strong Recommendation; Evidence Level: Grade B)

21. Patients should be assigned a TNM-s category to guide management decisions. (Strong Recommendation; Evidence Level: Grade B)

Management

Principles of Management

22. Management decisions should be based on imaging obtained within the preceding 4 weeks and serum tumor markers (hCG and AFP) within the preceding 10 days. (Expert Opinion)

23. Management decisions should be made in a multidisciplinary setting involving experienced clinicians in urology, medical oncology, radiation oncology, pathology, and radiology. (Clinical Principle)

24. Expert review of pathologic specimens should be considered in clinical scenarios where treatment decisions will be impacted. (Moderate Recommendation; Evidence Level: Grade C)

25. In patients with normal serum tumor markers (hCG and AFP) and equivocal imaging findings for metastasis, clinicians may consider repeat imaging in six to eight weeks to clarify the extent of disease prior to making a treatment recommendation. (Clinical Principle)

Seminoma Management – Surveillance/RPLND/Chemotherapy/Radiation

26. Clinicians should recommend surveillance after orchiectomy for patients with stage I seminoma. Adjuvant radiotherapy and carboplatin-based chemotherapy are less preferred alternatives. (Strong Recommendation; Evidence Level: Grade B)

27a. For patients with stage IIA or IIB seminoma with a lymph node ≤3cm, clinicians should recommend RT or multi-agent cisplatin-based chemotherapy based on shared decision-making. (Moderate Recommendation; Evidence Level: Grade B)

27b. For patients with stage IIA or IIB seminoma with a lymph node ≤3cm who wish to avoid the long-term toxicities associated with chemotherapy or radiation therapy, RPLND may be offered as an appropriate and effective treatment option. (Moderate Recommendation; Evidence Level: Grade B)

27c. For patients with IIB seminoma with a lymph node >3 cm, chemotherapy is recommended. (Moderate Recommendation; Evidence Level: Grade B)

Non Seminoma Management – Surveillance/RPLND/Chemotherapy/Radiation

28. Clinicians should recommend risk-appropriate, multi-agent chemotherapy for patients with NSGCT with elevated and rising post-orchiectomy serum AFP or hCG (i.e. stage TanyN1-2S1). (Strong Recommendation; Evidence Level: Grade B)

29. Clinicians should recommend surveillance for patients with stage IA NSGCT. RPLND or one cycle of bleomycin, etoposide, and cisplatin chemotherapy are effective and appropriate alternative treatment options for patients who decline surveillance or are at risk for non-compliance. (Moderate Recommendation; Evidence Level: Grade B)

30. For patients with stage IB NSGCT, clinicians should recommend surveillance, RPLND, or one or two cycles of bleomycin, etoposide, and cisplatin chemotherapy based on shared decision-making. (Strong Recommendation; Evidence Level: Grade B) 

31. Patients with stage I NSGCT and any secondary somatic malignancy (also known as teratoma with malignant transformation) in the primary tumor at orchiectomy should undergo RPLND. (Expert Opinion)

32. Clinicians should recommend RPLND or chemotherapy for patients with stage IIA NSGCT with normal post-orchiectomy serum (S0) AFP and hCG. (Moderate Recommendation; Evidence Level: Grade B)

33. In patients with clinical stage IIB NSGCT and normal post-orchiectomy serum AFP and hCG, clinicians should recommend risk-appropriate, multi-agent chemotherapy. (Moderate Recommendation; Evidence Level: Grade B). Clinicians may offer RPLND as an alternative to chemotherapy to select patients with clinical stage IIB NSGCT with normal post-orchiectomy serum AFP and hCG. (Conditional Recommendation; Evidence Level: Grade C)

34. Among patients who are candidates for RPLND, it is recommended clinicians consider referral to an experienced surgeon at a high-volume center. (Moderate Recommendation; Evidence Level: Grade C)

35. Surgeons with experience in the management of GCT and expertise in minimally invasive surgery may offer a minimally-invasive RPLND, acknowledging the lack of long-term data on oncologic outcomes. (Expert Opinion)

36. Primary RPLND should be performed with curative intent in all patients. RPLND should be performed with adherence to the following anatomical principles, regardless of the intent to administer adjuvant chemotherapy. These principles are applied to both open and minimally-invasive approaches. (Moderate Recommendation; Evidence Level: Grade B)

• A full bilateral template dissection should be performed in patients with suspicious lymph nodes based on CT imaging or intraoperative assessment and in those with somatic-type malignancy in the primary tumor.
• A full bilateral template or modified template dissection may be performed in patients with clinically negative lymph nodes.
• A right modified template dissection may omit the para-aortic lymph nodes below the inferior mesenteric artery. Omission of para-aortic lymph nodes above the inferior mesenteric artery is controversial.
• A left modified template dissection may omit paracaval, precaval, and retrocaval lymph nodes. Omission of interaortocaval lymph nodes is controversial.
• Nerve-sparing should be offered in select patients desiring preservation of ejaculatory function.
• Nerve-sparing attempts should not compromise the quality of the lymph node dissection.
• A complete retroaortic and/or retrocaval lymph node dissection with division of lumbar vessels should be performed when within the planned template.
• The ipsilateral gonadal vessels should be removed in all patients.
• The cephalad extent of the dissection is the crus of the diaphragm to the level of the renal arteries. The caudad extent of disease is the crossing of the ureter over the ipsilateral common iliac artery.

37.  After primary RPLND, clinicians should recommend surveillance or adjuvant chemotherapy in patients with NSGCT who have pathological stage II disease that is not pure teratoma. (Moderate Recommendation; Evidence Level: Grade B)

• For patients with pN1 and/or pN1-3 pure teratoma, surveillance is preferred.
• For patients with pN2-3 at RPLND, multi-agent cisplatin-based chemotherapy is preferred.

Surveillance for Stage I Testicular Cancer

38. For patients with clinical stage I seminoma choosing surveillance, clinicians should obtain a history and physical examination and perform cross-sectional imaging of the abdomen with or without the pelvis, every 6 months for the first 2 years, and then every 6-12 months in years 3-5. Routine surveillance imaging of the chest and serum tumor marker assessment can be obtained as clinically indicated. (Strong Recommendation; Evidence Level: Grade B)

39. In patients with stage I NSGCT undergoing surveillance after orchiectomy, clinicians should perform a physical examination and obtain serum tumor markers (AFP, hCG +/- LDH) every 2-3 months in year 1, every 2-4 months in year 2, every 4-6 months in year 3, and every 6-12 months for years 4 and 5. (Moderate Recommendation; Evidence Level: Grade C)

40. In patients with stage I NSGCT undergoing surveillance after orchiectomy, radiologic assessment (chest x-ray and imaging of the abdomen with or without the pelvis) should be obtained every 3-6 months in year 1 starting at 3 months, every 4-12 months in year 2, once in year 3, and once in year 4 or 5. (Moderate Recommendation; Evidence Level: Grade B) Men at higher risk of relapse (e.g., lymphovascular invasion) should be imaged with shorter intervals. (Expert Opinion)

41. Patients who relapse on surveillance should be fully restaged and treated based on their TNM-s status. (Moderate Recommendation; Evidence Level: Grade C)

42. Clinicians should inform patients with stage I GCT on surveillance of the ≤1% risk of late relapse after 5 years. (Moderate Recommendation; Evidence Level: Grade B) Annual serologic and radiographic assessment may be performed thereafter as indicated based upon clinical concerns. (Clinical Principle)

Additional Survivorship

43. Clinicians should refer patients to a survivorship clinic appreciating the long-term risks and potential sequelae of prior treatment among patients with GCT, with the integration of screening and monitoring for potential medical issues which may arise (Expert Opinion) including:

• Monitoring for signs and symptoms of hypogonadism. If present, serum AM testosterone and luteinizing hormone (LH) levels should be measured.
• Patients with a history of GCT whose treatment has included radiation therapy, chemotherapy, or both should be advised of the elevated risk of cardiovascular disease and should establish regular care with a primary care physician so that modifiable risk factors for cardiovascular disease (e.g., diet, exercise, smoking, serum lipid levels, blood pressure, serum glucose) can be monitored.
• Patients with a history of GCT whose treatment has included radiation therapy, chemotherapy, or both should be advised of the elevated risk of secondary malignancy and should establish regular care with a primary care physician for appropriate health care maintenance and cancer screening as appropriate.

Purpose

Testis cancer is the most common solid malignancy in young males. The vast majority of men with testis cancer have low-stage disease (limited to the testis and retroperitoneum; clinical stages I-IIB); survival rates are high with standard therapy. A priority for those patients with low-stage disease is limiting the burden of therapy and treatment-related toxicity without compromising cancer control. Thus, surveillance has assumed an increasing role among those with cancer clinically confined to the testis. Testis cancer is a relatively rare malignancy, with outcomes defined by specific cancer- and patient-related factors. Likewise, paradigms for management have undergone substantial change in recent years as evidence regarding risk stratification, recurrence, survival, and treatment-related toxicity has emerged.

Urologists are frequently the initial treating clinician for men with newly diagnosed testis cancer and thus play a crucial role in counseling and treatment decision making. This clinical practice guideline provides evidence-based recommendations for clinicians regarding the diagnosis, staging, treatment selection, and post-treatment surveillance of patients with clinical stages I, IIA, and IIB seminoma and nonseminomatous germ cell tumor (NSGCT). Please also refer to the associated Low-Stage Testis Cancer Treatment Algorithm.

Methodology

Panel Formation and Process

The Testicular Cancer Panel was created in 2017 by the American Urological Association Education and Research, Inc. (AUAER). The Practice Guidelines Committee (PGC) of the AUA selected the Panel Chairs who in turn appointed the additional panel members based on specific expertise in this area. The Panel included specialties from urology, oncology, and radiology. In 2023, an update review assessing abstracts from new studies published since the publication of the 2019 Guideline was completed.

Peer Review and Document Approval

An integral part of the guideline development process at the AUA is external peer review. The AUA conducted a thorough peer review process to ensure that the document was reviewed by experts in the diagnosis and treatment of testicular cancer. In addition to reviewers from the AUA PGC, Science and Quality Council (SQC), and Board of Directors (BOD), the document was reviewed by representatives from American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Urologic Oncology as well as external content experts. Additionally, a call for reviewers was placed on the AUA website from December 14-28, 2018 to allow any additional interested parties to request a copy of the document for review. The guideline was also sent to the Urology Care Foundation to open the document further to the patient perspective. The draft guideline document was distributed to 105 peer reviewers. All peer review comments were blinded and sent to the Panel for review. In total, 45 reviewers provided comments, including 30 external reviewers.  At the end of the peer review process, a total of 530 comments were received. Following comment discussion, the Panel revised the draft as needed. Once finalized, the guideline was submitted for approval to the AUA PGC, SQC and BOD for final approval.

In 2023, as a part of the amendment process, the AUA conducted a thorough peer review process. A call for peer reviewers was posted in April 2023 and the draft guideline document was distributed to 62 peer reviewers, 16 of which submitted comments. The Amendment Panel reviewed and discussed all submitted comments and revised the draft as needed. Once finalized, the guideline was submitted for approval to the original guideline panel, the PGC and SQC. It was then submitted to AUA BODs for final approval. Panel members received no renumeration for their work.

Search Strategy

The Johns Hopkins University Evidence-based Practice Center team searched PubMed®, Embase®, and the Cochrane Central Register of Controlled Trials (CENTRAL) from January 1980 through August 2018. Searches were updated using the same methodological protocol to capture literature published through March 2023. The team developed a search strategy by using medical subject headings terms and key words relevant to the diagnosis and treatment of early-stage testicular cancer. The evidence review team also reviewed relevant systematic reviews and references provided by the Panel to identify articles that may have been missed by the database searches.

Study Selection and Data Abstraction

Study selection was based on predefined eligibility criteria for the patient populations, interventions, outcomes, and study designs of interest. Two reviewers independently screened titles, abstracts, and full text for inclusion. Differences between reviewers regarding eligibility were resolved through consensus.

Reviewers extracted information on study characteristics, participants, interventions, and outcomes. One reviewer completed data abstraction, and a second reviewer checked for accuracy.

Assessment of Risk of Bias (ROB) and Data Extraction

Two reviewers independently assessed risk of bias for individual studies. The Cochrane Collaboration’s tool was used for assessing the risk of bias of randomized controlled trials (RCTs).¹ For non-randomized studies of treatment interventions, the reviewers used the Cochrane Risk of Bias Assessment Tool for Non-Randomized Studies of Interventions (ACROBAT-NRSI). For diagnostic studies, reviewers used the quality assessment tool for diagnostic accuracy studies (QUADAS -2).² Differences between reviewers were resolved through consensus. The evidence review team graded strength of evidence on outcomes by adapting the AUA’s three predefined levels of strength of evidence.

Determination of Evidence Strength

The categorization of evidence strength is conceptually distinct from the quality of individual studies. Evidence strength refers to the body of evidence available for a particular question and includes not only the quality of individual studies but consideration of study design; consistency of findings across studies; adequacy of sample sizes; and generalizability of study populations, settings, and interventions for the purposes of the guideline. The AUA categorizes body of evidence strength as Grade A (well-conducted and highly-generalizable RCTs or exceptionally strong observational studies with consistent findings), Grade B (RCTs with some weaknesses of procedure or generalizability or moderately strong observational studies with consistent findings), or Grade C (RCTs with serious deficiencies of procedure or generalizability or extremely small sample sizes or observational studies that are inconsistent, have small sample sizes, or have other problems that potentially confound interpretation of data). By definition, Grade A evidence has a high level of certainty, Grade B evidence has a moderate level of certainty, and Grade C evidence has a low level of certainty (Table 1).³

AUA Nomenclature: Linking Statement Type to Evidence Strength

The AUA nomenclature system explicitly links statement type to body of evidence strength, level of certainty, magnitude of benefit or risk/burdens, and the Panel’s judgment regarding the balance between benefits and risks/burdens (Table 2). Strong Recommendations are directive statements that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be undertaken because net benefit or net harm is substantial. Moderate Recommendations are directive statements that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be undertaken because net benefit or net harm is moderate. Conditional Recommendations are non-directive statements used when the evidence indicates there is no apparent net benefit or harm or when the balance between benefits and risks/burden is unclear. All three statement types may be supported by any body of evidence strength grade. Body of evidence strength Grade A in support of a Strong or Moderate Recommendation indicates the statement can be applied to most patients in most circumstances and that future research is unlikely to change confidence. Body of evidence strength Grade B in support of a Strong or Moderate Recommendation indicates the statement can be applied to most patients in most circumstances, but better evidence could change confidence. Body of evidence strength Grade C in support of a Strong or Moderate Recommendation indicates the statement can be applied to most patients in most circumstances, but better evidence is likely to change confidence. Body of evidence strength Grade C is only rarely used in support of a Strong Recommendation. Conditional Recommendations can also be supported by any evidence strength. When body of evidence strength is Grade A, the statement indicates benefits and risks/burdens appear balanced, the best action depends on patient circumstances, and future research is unlikely to change confidence. When body of evidence strength Grade B is used, benefits and risks/burdens appear balanced, the best action also depends on individual patient circumstances, and better evidence could change confidence. When body of evidence strength Grade C is used, there is uncertainty regarding the balance between benefits and risks/burdens, alternative strategies may be equally reasonable, and better evidence is likely to change confidence.

Where gaps in the evidence existed, Clinical Principles or Expert Opinions are provided via consensus of the Panel. A Clinical Principle is a statement about a component of clinical care widely agreed upon by urologists or other clinicians for which there may or may not be evidence in the medical literature. Expert Opinion refers to a statement based on members' clinical training, experience, knowledge, and judgment for which there may or may not be evidence in the medical literature.

Table 1: Strength of Evidence Definitions

Table 2: AUA Nomenclature Linking Statement Type to Level of Certainty, Magnitude of Benefit or Risk/Burden, and Body of Evidence Strength

Epidemiology

In 2019, an estimated 9,500 men will be diagnosed with testis cancer in the United States, and 400 will die from the disease.⁴ Testis cancer is the most common solid malignancy among men aged 20 to 40 years. The incidence rate is highest among Caucasians, lowest among African-Americans, and most rapidly increasing in Hispanic populations.^5,6  Age-adjusted incidence has nearly doubled over the last 4 decades for unknown reasons, from 3.7 per 100,000 in 1975 to 6.4 per 100,000 in 2014.⁵ A stage migration of GCT has been observed, presumably due to increased awareness and earlier diagnosis. Between 1973 and 2014, the percentage of tumors diagnosed at a localized stage increased from 55% to 68% in the United States. Currently, less than 15% of men present with stage III disease (to the lungs, viscera, or non-regional lymph nodes).

Risk factors for developing testis cancer include germ cell neoplasia in situ (GCNIS), history of undescended testis (UDT)/ cryptorchidism, family history, and a personal history of testis cancer. Infertility is associated with the presence of GCT, though this association is thought to arise from inherent testicular dysfunction.^7,8,9 GCNIS is the precursor lesion from which the majority of GCTs arise. Among men with invasive GCT, GCNIS is found in adjacent testicular parenchyma in 80-90%. Among men with GCNIS, the risk of developing invasive GCT is approximately 50% within 5 years.¹⁰ Men with cryptorchidism have a four to six fold increased risk of developing testis cancer in the affected testicle, but the relative risk (RR) falls to two to three fold if orchiopexy is performed before puberty.^11,12 Studies assessing the cancer risk of UDT in the contralateral testis are conflicting, though a meta-analysis of cryptorchidism studies showed the contralateral descended testis is also at slightly increased risk of developing cancer (RR 1.74; 95% Confidence Interval [CI], 1.01 to 2.98).¹³ Men with a first-degree relative with GCT are at an increased risk of developing testis cancer and at an earlier age.¹⁴ Men with a personal history of testis cancer are at a 12-fold increased risk of developing GCT in the contralateral testis, but the 15-year cumulative incidence is only 2%.¹⁵

Etiology

GCNIS arises from transformed primordial germ cells that develop in utero or early infancy that lay dormant until puberty when they are stimulated by increased serum LH and/or testosterone levels.¹⁶ The carcinogenesis of GCNIS and testis cancer is poorly understood. The increase in testis cancer incidence along with other male reproductive disorders (e.g., infertility, hypospadias, UDT) suggests that GCT may arise from ‘testicular dysgenesis,’ which results from a combination of environmental and/or lifestyle factors (possibly from exposure in utero) in combination with genetic susceptibility. The role of genetic factors is supported by the clustering of testis cancer in some families, the extreme difference in the rate of testis cancer in black and white Americans, and the finding of susceptibility loci on chromosomes 5, 6, and 12.¹⁴ Additionally, polymorphisms of certain genes, including the gene encoding c-KIT ligand, have been associated with an increased risk of testis cancer.¹⁷ Gonocytes depend on KIT ligand for survival; the gene for this protein is located on the long arm of chromosome 12, where an increased number of copies is a universal finding in adult GCT.¹⁸ Thus, a connection between mutations or polymorphisms in c-KIT ligand and GCT has biological plausibility. Inherited alterations to susceptibility genes involved in DNA repair may contribute to the development of adult GCT. A multicenter case-control gene-level enrichment analysis of germline pathogenic variants in individuals with GCT relative to cancer-free controls found 22 pathogenic germline DRG variants, one-third of which were in CHEK2. The variant CHEK2 allele was found in 9.8% of cases and associated with a four-fold increased risk of GCT.¹⁹

Histological Classification

The histological classification of post-pubertal GCT is outlined in Table 3.¹⁶ GCT are broadly classified as GCNIS-derived (germ-cell) and non-GCNIS derived (non-germ cell). The vast majority of post-pubertal GCT are GCNIS-derived. GCT are divided into seminoma and NSGCT, with relative distribution of 52-56% and 44-48%, respectively.²⁰ NSGCT includes embryonal carcinoma, yolk sac tumor, teratoma, and choriocarcinoma subtypes, either alone as pure forms or in combination as mixed GCT with or without seminoma. Most NSGCTs are composed of two or more GCT subtypes (mixed tumors). GCTs that contain both NSGCT subtypes and seminoma are classified as NSGCT even if the NSGCT component represents a tiny proportion of the tumor.

The classification of GCT into seminoma and NSGCT has histological, biological, and practical implications. Compared to NSGCT, pure seminomas tend to develop at a later age, are of lower stage at diagnosis, and grow at a slower rate.²¹ The risk of occult systemic disease for stage I disease is lower for seminoma than for NSGCT. Lastly, pure seminomas are even more highly sensitive to chemotherapy relative to NSGCTs and sensitive to radiation therapy. All these differences have important treatment implications. Among NSGCT, embryonal carcinoma is the most undifferentiated cell type and has totipotential capacity to differentiate into other NSGCT cell types (yolk sac, choriocarcinoma, and teratoma) within the primary tumor and at metastatic sites.

Among NSGCT patients, the potential for teratoma to arise within the primary tumor or at metastatic sites has important management implications. Though histologically benign, teratomas contain many genetic abnormalities frequently found in malignant GCT elements.^22,23 Teratoma typically grows slowly or may be indolent. However, their underlying genetic instability may lead to uncontrollable growth and invasion of surrounding structures (growing teratoma syndrome)²⁴ or transformation into somatic-type malignancies such as sarcoma or adenocarcinoma.²⁵ Unlike other GCT subtypes, teratoma is universally resistant to chemotherapy and only curable by surgical resection. This has important implications in treatment selection for all stages of NSGCT. 

Table 3: 2016 World Health Organization Classification of Germ Cell Tumors of the Testis¹⁶

Serum Tumor Markers

Testis cancer is one of the few malignancies with reliable serum tumor markers (alpha-fetoprotein [AFP], human chorionic gonadotropin [hCG], and lactate dehydrogenase [LDH]) that are essential for diagnosis, prognosis, clinical staging, management, response to therapy, and post-treatment surveillance. AFP is produced by yolk sac and embryonal carcinoma and is elevated in 10-40% of low-stage (clinical stages I, IIA, IIB) NSGCT.²⁶ Choriocarcinoma and seminoma do not produce AFP. Patients with pure seminoma in the primary tumor with an elevated serum AFP are considered to have NSGCT. The half-life of AFP is five to seven days. Other malignant sources of AFP include cancers of the stomach, pancreas, biliary tract, liver, and lung. Non-malignant sources of AFP include liver disease (infectious, drug-induced, alcohol-induced, autoimmune), ataxia telangiectasia, hereditary tyrosinemia, and heterophile antibodies.^27,28 Hereditary persistence of AFP (HPAFP), a congenital alteration in the hepatic nuclear factor binding site of the AFP gene leads to increased AFP transcription and is a rare cause of elevated AFP.²⁹  Despite most laboratories considering an AFP level of >8 ng/mL to be abnormally elevated, a proportion of the population may have levels up to 15 or 25 ng/mL in the absence of any pathology.⁷ Treatment decisions soley based on “elevated” AFP levels that are stable and <25 ng/mL are discouraged.

hCG levels are elevated in 10-30% of low-stage NSGCT and 10-15% of seminomas.²⁶ hCG is secreted by choriocarcinoma, embryonal carcinoma, and syncytiotrophoblastic cells found in 10-15% of seminomas. The half-life of hCG is 24-36 hours. hCG levels may be elevated in cancers of the liver, biliary tract, pancreas, stomach, lung, breast, kidney and bladder. The alpha-subunit of hCG is common to several pituitary tumors, thus immunoassays for hCG are directed at the beta-subunit. Similarly, heterophile antibodies, hypogonadism, and possibly some medications can lead to false-positive elevations of hCG.^30-34

LDH levels are the least relevant and clinically applicable of the serum tumors markers and elevated in approximately 20% of low-stage GCT.²⁶ LDH is expressed in smooth, cardiac, and skeletal muscle and can be elevated from cancerous (e.g., kidney, lymphoma, GI, breast) or non-cancerous conditions (e.g., heart failure, anemia, HIV). Of the five isoenzymes of LDH, LDH-1 is the most frequently elevated isoenzyme in GCT. The magnitude of LDH elevation correlates with bulk of disease. As a non-specific marker, its main GCT use is in the prognostic assessment at diagnosis. Treatment decisions based solely on LDH elevation in the setting of normal AFP and hCG should be discouraged.

Prognosis and Staging

Prognosis and initial management decisions are dictated by clinical stage, which is based on the pathological stage of the primary tumor, post-orchiectomy serum tumor marker levels, and staging as determined by physical examination and imaging. In 1997, an international consensus for GCT staging was developed by the American Joint Committee on Cancer (AJCC) and Union Internationale Contre le Cancer (UICC) (Table 4).³⁵ The AJCC and UICC staging systems for GCT are unique because, for the first time, a serum tumor marker category (S) based on post-orchiectomy AFP, hCG, and LDH levels was used to supplement the prognostic stages (Table 5). Clinical stage I is defined as disease clinically confined to the testis, clinical stage II indicates regional (retroperitoneal) lymph node metastasis, and clinical stage III represents non-regional lymph node, lung and/or visceral metastasis, although post-orchiectomy serum tumor marker levels can upstage patients from clinical stage II to III.

For patients with low-stage GCT (clinical stage I, IIA, or IIB), long-term survival is 95% or better. As GCT patients are often healthy and young with long estimated life expectancy, reducing the burden of therapy and treatment-related toxicity are particularly important.

Table 4: Stages of Testicular Cancer ³⁵

Table 5: Tumor Marker S Designation Levels³⁵

A solid mass in the testis identified by physical exam or imaging should be managed as a malignant neoplasm until proven otherwise. (Clinical Principle)

In a man with a solid mass in the testis suspicious for malignant neoplasm, serum tumor markers (AFP, hCG, and LDH) should be drawn and measured prior to any treatment, including orchiectomy. (Moderate Recommendation; Evidence Level: Grade C)

Prior to definitive management, patients should be counseled about the risks of hypogonadism and infertility (Moderate Recommendation; Evidence Level: Grade C) and should be offered sperm banking, when appropriate. In patients without a normal contralateral testis or with known subfertility, this should be considered prior to orchiectomy. (Clinical Principle)

Scrotal ultrasound with Doppler should be obtained in patients with a unilateral or bilateral scrotal mass suspicious for neoplasm. (Strong Recommendation; Evidence Level: Grade B)

Testicular microlithiasis in the absence of solid mass and risk factors for developing a germ cell tumor (GCT) does not confer an increased risk of malignant neoplasm and does not require further evaluation. (Moderate Recommendation; Evidence Level: Grade C)

Patients with normal serum tumor markers (hCG and AFP) and indeterminate findings on physical exam or testicular ultrasound for testicular neoplasm should undergo repeat imaging in six to eight weeks. (Clinical Principle)

Magnetic Resonance Imaging (MRI) should not be used in the initial evaluation and diagnosis of a testicular lesion suspicious for neoplasm. (Moderate Recommendation; Evidence Level: Grade C)

Patients with a testicular lesion suspicious for malignant neoplasm and a normal contralateral testis should undergo a radical inguinal orchiectomy; testis-sparing surgery (TSS) is not recommended. Transscrotal orchiectomy is discouraged. (Strong Recommendation; Evidence Level: Grade B)

Testicular prosthesis should be discussed prior to orchiectomy. (Expert Opinion)

Patients who have undergone scrotal orchiectomy for malignant neoplasm should be counseled regarding the increased risk of local recurrence and may rarely be considered for adjunctive therapy (excision of scrotal scar or radiotherapy) for local control. (Moderate Recommendation; Evidence Level: Grade C)

11a. TSS through an inguinal incision may be offered as an alternative to radical inguinal orchiectomy in highly selected patients wishing to preserve gonadal function with masses <2cm and (1) equivocal ultrasound/physical exam findings and negative tumor markers (hCG and AFP), (2) congenital, acquired or functionally solitary testis, or (3) bilateral synchronous tumors. (Conditional Recommendation; Evidence Level: Grade C)

11b.  Patients considering TSS should be counseled regarding (1) higher risk of local recurrence, (2) need for monitoring with physical examination and ultrasound, (3) role of adjuvant radiotherapy to the testicle to reduce local recurrence, (4) impact of radiotherapy on sperm and testosterone production, and (5) the risk of testicular atrophy and need for testosterone replacement therapy, and/or subfertility/infertility. (Moderate Recommendation; Evidence Level: Grade C)

11c. When TSS is performed, in addition to the suspicious mass, multiple biopsies of the ipsilateral testicle normal parenchyma should be obtained for evaluation by an experienced genitourinary pathologist. (Moderate Recommendation; Evidence Level: Grade C)

Clinicians should inform patients with a history of GCT or GCNIS of risks of a second primary tumor while rare is significantly increased in the contralateral testis. (Moderate Recommendation; Evidence Level: Grade B)

13a. In patients with GCNIS on testis biopsy or malignant neoplasm after TSS, clinicians should inform patients of the risks/benefits of surveillance, radiation, and orchiectomy. (Moderate Recommendation; Evidence Level: Grade C)

13b. Clinicians should recommend surveillance in patients with GCNIS or malignant neoplasm after TSS who prioritize preservation of fertility and testicular androgen production. (Moderate Recommendation; Evidence Level: Grade C)

13c. Clinicians should recommend testicular radiation (18-20 Gy) or orchiectomy in patients with GCNIS or malignant neoplasm after TSS who prioritize reduction of cancer risk taking into consideration that radiation reduces the risk of hypogonadism compared to orchiectomy. (Moderate Recommendation; Evidence Level: Grade C)

Nadir serum tumor markers (AFP, hCG, and LDH) should be repeated at appropriate T1/2 time intervals after orchiectomy for staging and risk stratification. (Moderate Recommendation; Evidence Level: Grade B)

For patients with elevated AFP or hCG post-orchiectomy, clinicians should monitor serum tumor markers to establish nadir levels before treatment only if marker nadir levels would influence treatment. (Clinical Principle)

For patients with metastatic GCT (Stage IIC or III) requiring chemotherapy, clinicians must base chemotherapy regimen and number of cycles on the IGCCCG risk stratification. IGCCCG risk stratification is based on nadir serum tumor marker (hCG, AFP and LDH) levels obtained prior to the initiation of chemotherapy, staging imaging studies, and tumor histology following radical orchiectomy (Strong Recommendation; Evidence Level: Grade A). Any post-pubertal male, regardless of age, should be treated according to adult treatment guidelines. (Moderate Recommendation; Evidence Level: Grade B)

For patients in whom serum tumor marker (AFP and hCG) levels are borderline elevated (within 3x upper limit of normal) post-orchiectomy, a rising trend should be confirmed before management decisions are made as false-positive elevations may occur. (Clinical Principle)

In patients with newly diagnosed GCT, clinicians should obtain cross-sectional imaging of the abdomen and pelvis with IV contrast or MRI if CT is contraindicated. (Strong Recommendation; Evidence Level: Grade B)

19a. In patients with newly diagnosed GCT, clinicians must obtain chest imaging. (Clinical Principle)

19b. In the presence of elevated and rising post-orchiectomy markers (hCG and AFP) or evidence of metastases on abdominal/pelvic imaging, chest x-ray or physical exam, a CT chest should be obtained. (Strong Recommendation; Evidence Level: Grade C)

19c. In patients with clinical stage I seminoma, clinicians should preferentially obtain a chest x-ray over a CT scan. (Moderate Recommendation; Evidence Level: Grade B)

19d. In patients with non-seminomatous germ cell tumors (NSGCT), clinicians may preferentially obtain a CT scan of the chest over a chest x-ray and should prioritize CT chest for those patients recommended to receive adjuvant therapy. (Conditional Recommendation; Evidence Level: Grade C)

In patients with newly diagnosed GCT, clinicians should not obtain a positron emission tomography (PET) scan for staging. (Strong Recommendation; Evidence Level: Grade B)

Patients should be assigned a TNM-s category to guide management decisions. (Strong Recommendation; Evidence Level: Grade B)

Management decisions should be based on imaging obtained within the preceding 4 weeks and serum tumor markers (hCG and AFP) within the preceding 10 days. (Expert Opinion)

Management decisions should be made in a multidisciplinary setting involving experienced clinicians in urology, medical oncology, radiation oncology, pathology, and radiology. (Clinical Principle)

Expert review of pathologic specimens should be considered in clinical scenarios where treatment decisions will be impacted. (Moderate Recommendation; Evidence Level: Grade C)

In patients with normal serum tumor markers (hCG and AFP) and equivocal imaging findings for metastasis, clinicians may consider repeat imaging in six to eight weeks to clarify the extent of disease prior to making a treatment recommendation. (Clinical Principle)

Clinicians should recommend surveillance after orchiectomy for patients with stage I seminoma. Adjuvant radiotherapy and carboplatin-based chemotherapy are less preferred alternatives. (Strong Recommendation; Evidence Level: Grade B)

27a. For patients with stage IIA or IIB seminoma with a lymph node ≤3cm, clinicians should recommend RT or multi-agent cisplatin-based chemotherapy based on shared decision-making. (Moderate Recommendation; Evidence Level: Grade B)

27b. For patients with stage IIA or IIB seminoma with a lymph node ≤3cm who wish to avoid the long-term toxicities associated with chemotherapy or radiation therapy, RPLND may be offered as an appropriate and effective treatment option. (Moderate Recommendation; Evidence Level: Grade B)

27c. For patients with IIB seminoma with a lymph node >3 cm, chemotherapy is recommended. (Moderate Recommendation; Evidence Level: Grade B)

Clinicians should recommend risk-appropriate, multi-agent chemotherapy for patients with NSGCT with elevated and rising post-orchiectomy serum AFP or hCG (i.e. stage TanyN1-2S1). (Strong Recommendation; Evidence Level: Grade B)

Clinicians should recommend surveillance for patients with stage IA NSGCT. RPLND or one cycle of bleomycin, etoposide, and cisplatin chemotherapy are effective and appropriate alternative treatment options for patients who decline surveillance or are at risk for non-compliance. (Moderate Recommendation; Evidence Level: Grade B)

For patients with stage IB NSGCT, clinicians should recommend surveillance, RPLND, or one or two cycles of bleomycin, etoposide, and cisplatin chemotherapy based on shared decision-making. (Strong Recommendation; Evidence Level: Grade B) 

Patients with stage I NSGCT and any secondary somatic malignancy (also known as teratoma with malignant transformation) in the primary tumor at orchiectomy should undergo RPLND. (Expert Opinion)

Clinicians should recommend RPLND or chemotherapy for patients with stage IIA NSGCT with normal post-orchiectomy serum (S0) AFP and hCG. (Moderate Recommendation; Evidence Level: Grade B)

In patients with clinical stage IIB NSGCT and normal post-orchiectomy serum AFP and hCG, clinicians should recommend risk-appropriate, multi-agent chemotherapy. (Moderate Recommendation; Evidence Level: Grade B). Clinicians may offer RPLND as an alternative to chemotherapy to select patients with clinical stage IIB NSGCT with normal post-orchiectomy serum AFP and hCG. (Conditional Recommendation; Evidence Level: Grade C)

Among patients who are candidates for RPLND, it is recommended clinicians consider referral to an experienced surgeon at a high-volume center. (Moderate Recommendation; Evidence Level: Grade C)

Surgeons with experience in the management of GCT and expertise in minimally invasive surgery may offer a minimally-invasive RPLND, acknowledging the lack of long-term data on oncologic outcomes. (Expert Opinion)

Primary RPLND should be performed with curative intent in all patients. RPLND should be performed with adherence to the following anatomical principles, regardless of the intent to administer adjuvant chemotherapy. These principles are applied to both open and minimally-invasive approaches. (Moderate Recommendation; Evidence Level: Grade B)

• A full bilateral template dissection should be performed in patients with suspicious lymph nodes based on CT imaging or intraoperative assessment and in those with somatic-type malignancy in the primary tumor.
• A full bilateral template or modified template dissection may be performed in patients with clinically negative lymph nodes.
• A right modified template dissection may omit the para-aortic lymph nodes below the inferior mesenteric artery. Omission of para-aortic lymph nodes above the inferior mesenteric artery is controversial.
• A left modified template dissection may omit paracaval, precaval, and retrocaval lymph nodes. Omission of interaortocaval lymph nodes is controversial.
• Nerve-sparing should be offered in select patients desiring preservation of ejaculatory function.
• Nerve-sparing attempts should not compromise the quality of the lymph node dissection.
• A complete retroaortic and/or retrocaval lymph node dissection with division of lumbar vessels should be performed when within the planned template.
• The ipsilateral gonadal vessels should be removed in all patients.
• The cephalad extent of the dissection is the crus of the diaphragm to the level of the renal arteries. The caudad extent of disease is the crossing of the ureter over the ipsilateral common iliac artery.

After primary RPLND, clinicians should recommend surveillance or adjuvant chemotherapy in patients with NSGCT who have pathological stage II disease that is not pure teratoma. (Moderate Recommendation; Evidence Level: Grade B)

• For patients with pN1 and/or pN1-3 pure teratoma, surveillance is preferred.
• For patients with pN2-3 at RPLND, multi-agent cisplatin-based chemotherapy is preferred.

For patients with clinical stage I seminoma choosing surveillance, clinicians should obtain a history and physical examination and perform cross-sectional imaging of the abdomen with or without the pelvis, every 6 months for the first 2 years, and then every 6-12 months in years 3-5. Routine surveillance imaging of the chest and serum tumor marker assessment can be obtained as clinically indicated. (Strong Recommendation; Evidence Level: Grade B)

In patients with stage I NSGCT undergoing surveillance after orchiectomy, clinicians should perform a physical examination and obtain serum tumor markers (AFP, hCG +/- LDH) every 2-3 months in year 1, every 2-4 months in year 2, every 4-6 months in year 3, and every 6-12 months for years 4 and 5. (Moderate Recommendation; Evidence Level: Grade C)

In patients with stage I NSGCT undergoing surveillance after orchiectomy, radiologic assessment (chest x-ray and imaging of the abdomen with or without the pelvis) should be obtained every 3-6 months in year 1 starting at 3 months, every 4-12 months in year 2, once in year 3, and once in year 4 or 5. (Moderate Recommendation; Evidence Level: Grade B) Men at higher risk of relapse (e.g., lymphovascular invasion) should be imaged with shorter intervals. (Expert Opinion)

Patients who relapse on surveillance should be fully restaged and treated based on their TNM-s status. (Moderate Recommendation; Evidence Level: Grade C)

Clinicians should inform patients with stage I GCT on surveillance of the ≤1% risk of late relapse after 5 years. (Moderate Recommendation; Evidence Level: Grade B) Annual serologic and radiographic assessment may be performed thereafter as indicated based upon clinical concerns. (Clinical Principle)

Clinicians should refer patients to a survivorship clinic appreciating the long-term risks and potential sequelae of prior treatment among patients with GCT, with the integration of screening and monitoring for potential medical issues which may arise (Expert Opinion) including:

• Monitoring for signs and symptoms of hypogonadism. If present, serum AM testosterone and luteinizing hormone (LH) levels should be measured.
• Patients with a history of GCT whose treatment has included radiation therapy, chemotherapy, or both should be advised of the elevated risk of cardiovascular disease and should establish regular care with a primary care physician so that modifiable risk factors for cardiovascular disease (e.g., diet, exercise, smoking, serum lipid levels, blood pressure, serum glucose) can be monitored.
• Patients with a history of GCT whose treatment has included radiation therapy, chemotherapy, or both should be advised of the elevated risk of secondary malignancy and should establish regular care with a primary care physician for appropriate health care maintenance and cancer screening as appropriate.

Biomarkers for Micrometastases in Low-Stage GCT

Practice patterns of patients with clinical stage I seminoma and NSGCT indicate a substantial shift towards surveillance, even among those with risk factors.²²⁹ Lymphovascular invasion is the only parameter that reliably identifies patients at risk for relapse among patients with clinical stage I NSGCT, and the risk of lymphovascular invasion varies from 35-55%.^230,211 Thus, patients who relapse following surveillance are exposed to treatment intensification. Likewise, adjuvant therapy exposes a substantial proportion of patients to treatment and its associated toxicity who were otherwise cured by orchiectomy. Lastly, despite changes to surveillance protocols, patients on surveillance are subject to intensive monitoring. Circulating biomarkers that reliably identify the presence of residual disease may be helpful in selecting clinical stage I patients for adjuvant therapy, identifying which patients with residual masses after chemotherapy benefit from surgical resection, and modifying surveillance schedules.

In early clinical studies, serum microRNA (miRNA) has demonstrated substantial promise as a biomarker. miRNA are small, non-coding RNA molecules that interact with messenger RNA (mRNA) to regulate gene expression at the post-transcriptional stage. In several cancer types, miRNA plays a role in malignant transformation and exhibits aberrant expression.^231,232 In malignant GCT, expression analysis has demonstrated increased expression of several miRNA clusters, specifically miR-371-373 (chromosome 19q13), and miR-302-367 (chromosome 4q25).^233,234 Both of these are specific to GCT and elevated in patients with both seminoma and NSGCT. Of the miRNA clusters, miR-371a-3p has the best performance characteristics as a biomarker in terms of sensitivity, specificity, and accuracy. Serum levels of miR-371a-3p have been shown to correlate with the extent of disease, response to therapy, relapse, and presence of residual malignant GCT elements.^235-237 Serum levels of miR-371a-3p are not elevated in patients with teratoma. On the basis of the accumulating evidence in support of miR-371a-3p, two large intergroup trials are under development to define the role of miR371a-3p as a circulating biomarker in low-stage and advanced GCT to guide subsequent therapy.

Primary Surgical Management of Low-Volume Metastatic Seminoma

Primary RPLND has previously not been considered in the treatment of low-stage seminoma. Favorable outcomes with primary radiotherapy and primary chemotherapy are associated with acceptable acute toxicity and have been considered the standard-of-care for decades. However, concerns about late toxicity of these modalities has stimulated renewed interest in RPLND for clinical stage IIA and IIB seminoma. Primary RPLND has been a standard option for low-stage NSGCT with proven oncological efficacy and favorable short- and long-term morbidity. In comparison with NSGCT, seminoma is well-suited to treatment by RPLND as it is more likely to spread via lymphatic routes and has lower risks of occult systemic disease. RPLND for IIA and IIB seminoma has been evaluated in small studies, and low relapse rates with surgery alone have been reported.^238-240

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