Testicular seminoma and non-seminoma: ESMO-EURACAN Clinical Practice Guideline for diagnosis, treatment and follow-up
•This ESMO Clinical Practice Guideline provides key recommendations on the management of testicular seminoma and non-seminoma.•Authorship includes a multidisciplinary group of experts from different institutions and countries in Europe.•Key treatment recommendations are provided.•Recommendations are based on available scientific data and the authors’ collective expert opinion. Germ-cell tumours (GCTs) affect predominantly younger males aged between 15 and 40 years, with nearly 74 500 new cases estimated globally in 2020.1Sung H. Ferlay J. Siegel R.L. et al.Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2021; 71: 209-249Google Scholar About one-third of all GCT cases worldwide are diagnosed in Europe. Testicular GCT (TGCT) is the most common malignant GCT, with noted geographic variations.2Znaor A. Skakkebaek N.E. Rajpert-De Meyts E. et al.Testicular cancer incidence predictions in Europe 2010-2035: a rising burden despite population ageing.Int J Cancer. 2020; 147: 820-828Google Scholar The highest incidence rates in 2010 (per 100 000) were observed in Denmark with 10.2 and Norway with 11.5 and are currently declining in these two countries. TGCT incidence rates (per 100 000) will probably increase particularly in areas with low incidences, e.g. Eastern Europe exemplified by Belarus and Ukraine with 2010 rates of 2.3 and 2.2, respectively.2Znaor A. Skakkebaek N.E. Rajpert-De Meyts E. et al.Testicular cancer incidence predictions in Europe 2010-2035: a rising burden despite population ageing.Int J Cancer. 2020; 147: 820-828Google Scholar Although exposure to endocrine-disrupting chemicals has been hypothesised, the aetiology of GCTs remains elusive.2Znaor A. Skakkebaek N.E. Rajpert-De Meyts E. et al.Testicular cancer incidence predictions in Europe 2010-2035: a rising burden despite population ageing.Int J Cancer. 2020; 147: 820-828Google Scholar Also, in ageing European populations with relatively fewer younger men aged 15-40 years, unconfirmed factors are believed to increase the number of future GCT patients. TGCT is associated with cryptorchidism, hypospadias and decreased fertility, often referred to as the testicular dysgenesis syndrome.3Skakkebaek N.E. Rajpert-De Meyts E. Buck Louis G.M. et al.Male reproductive disorders and fertility trends: influences of environment and genetic susceptibility.Physiol Rev. 2016; 96: 55-97Google Scholar In utero exposure to endocrine disruption chemicals might increase the likelihood of this syndrome. Among these chemicals, organochlorine insecticides have been demonstrated to increase the risk of GCT.4Rajpert-De Meyts E. McGlynn K.A. Okamoto K. et al.Testicular germ cell tumours.Lancet. 2016; 387: 1762-1774Google Scholar Furthermore, GCT seems to be more frequent in certain families,5Del Risco Kollerud R. Ruud E. Haugnes H.S. et al.Family history of cancer and risk of paediatric and young adult's testicular cancer: a Norwegian cohort study.Br J Cancer. 2019; 120: 1007-1014Google Scholar with higher risks among brothers [relative risk (RR) 6.3] than for sons or fathers (RR 4.4-4.7) of affected family members. So far, no highly penetrant GCT genes have been identified. Genome-wide association studies have identified several low-risk and moderate-risk single nucleotide polymorphisms associated with the risk of GCT, estimated to account for ∼37% of the familial GCT risk.6Wang Z. McGlynn K.A. Rajpert-De Meyts E. et al.Meta-analysis of five genome-wide association studies identifies multiple new loci associated with testicular germ cell tumor.Nat Genet. 2017; 49: 1141-1147Google Scholar,7Loveday C. Law P. Litchfield K. et al.Large-scale analysis demonstrates familial testicular cancer to have polygenic aetiology.Eur Urol. 2018; 74: 248-252Google Scholar A recent study found pathogenic germline DNA repair gene variants among 10% of TGCT cases, of which CHEK2 was suggested to be a potential novel moderate-penetrance susceptibility gene for GCT.8AlDubayan S.H. Pyle L.C. Gamulin M. et al.Association of inherited pathogenic variants in checkpoint kinase 2 (CHEK2) with susceptibility to testicular germ cell tumors.JAMA Oncol. 2019; 5: 514-522Google Scholar About 5% of men with GCT are diagnosed with contralateral TGCT, further suggesting a genetic disposition.9Andreassen K.E. Grotmol T. Cvancarova M.S. et al.Risk of metachronous contralateral testicular germ cell tumors: a population-based study of 7,102 Norwegian patients (1953–2007).Int J Cancer. 2011; 129: 2867-2874Google Scholar Regardless of whether GCT has genetic and/or environmental causes, the interindividual risk is remarkable as patients diagnosed with seminoma and non-seminoma have standardised incidence ratios of 13 and 29, respectively, of developing a contralateral TGCT as compared with the incidence of first GCT in the general population.10Hemminki K. Liu H. Sundquist J. Second cancers after testicular cancer diagnosed after 1980 in Sweden.Ann Oncol. 2010; 21: 1546-1551Google Scholar Approximately 55%-60% of the GCTs are pure seminomas and 40%-45% are non-seminomas.4Rajpert-De Meyts E. McGlynn K.A. Okamoto K. et al.Testicular germ cell tumours.Lancet. 2016; 387: 1762-1774Google Scholar Probably due to a slower progression, ∼85% of seminomas are diagnosed as clinical stage I disease as compared with 60% among non-seminomas. Approximately 95% of GCTs arise in the testicles, with 5% developing outside the gonads, i.e. extragonadal GCT (EGGCT). EGGCTs are usually found in the body’s midline, e.g. retroperitoneum, mediastinum or cerebrum, sometimes posing diagnostic difficulties. Testicular cancer is usually diagnosed as a unilateral testicular mass detected by the patient or identified incidentally during an ultrasound (US). Together with an incidental or palpable mass, patients may have scrotal pain (27%) or back or flank pain (11%), and 1% might present with gynaecomastia (germ-cell or sex cord/gonadal tumour of the testes).11Germa-Lluch J.R. Garcia del Muro X. Maroto P. et al.Clinical pattern and therapeutic results achieved in 1490 patients with germ-cell tumours of the testis: the experience of the Spanish Germ-Cell Cancer Group (GG).Eur Urol. 2002; 42 (discussion 562-553): 553-562Google Scholar, 12Baird D.C. Meyers G.J. Hu J.S. Testicular cancer: diagnosis and treatment.Am Fam Physician. 2018; 97: 261-268Google Scholar, 13Honecker F. Aparicio J. Berney D. et al.ESMO Consensus Conference on testicular germ cell cancer: diagnosis, treatment and follow-up.Ann Oncol. 2018; 29: 1658-1686Google Scholar Diagnosis of a GCT is based on histology of the testicular mass [II, A]. In patients with a testicular lesion (even when palpable), however, testicular US should be carried out with a high-frequency (>10 MHz) probe with colour Doppler assessment.14Auer T. De Zordo T. Dejaco C. et al.Value of multiparametric US in the assessment of intratesticular lesions.Radiology. 2017; 285: 640-649Google Scholar In addition to confirming the presence of an intratesticular mass, US permits evaluation of the contralateral testicular volume, presence of synchronous tumours and microcalcifications. US may also reveal an impalpable testicular lesion in patients assessed for fertility problems, metastatic disease or elevated serum tumour markers.15Stephenson A. Eggener S.E. Bass E.B. et al.Diagnosis and treatment of early stage testicular cancer: AUA guideline.J Urol. 2019; 202: 272-281Google Scholar, 16Laguna MP, Albers P, Algaba F, et al. EAU Guidelines on testicular cancer EAU guidelines 2020. Available at https://uroweb.org/guideline/testicular-cancer. Accessed January 25, 2022.Google Scholar, 17Richie J.P. Birnholz J. Garnick M.B. Ultrasonography as a diagnostic adjunct for the evaluation of masses in the scrotum.Surg Gynecol Obstet. 1982; 154: 695-698Google Scholar, 18Angulo J.C. Gonzalez J. Rodriguez N. et al.Clinicopathological study of regressed testicular tumors (apparent extragonadal germ cell neoplasms).J Urol. 2009; 182: 2303-2310Google Scholar The broadening use of testicular US is detecting increasing numbers of impalpable tumours of which many turn out to be of no significance, such as small Leydig-cell tumours.19Scandura G. Verrill C. Protheroe A. et al.Incidentally detected testicular lesions <10 mm in diameter: can orchidectomy be avoided?.BJU Int. 2018; 121: 575-582Google Scholar The role of scrotal magnetic resonance imaging (MRI) is limited and it may be used to distinguish between an intra- and extra-testicular mass when this cannot be confirmed clinically or with US.20Tsili A.C. Bertolotto M. Turgut A.T. et al.MRI of the scrotum: recommendations of the ESUR scrotal and penile imaging working group.Eur Radiol. 2018; 28: 31-43Google Scholar Serum tumour markers are part of the initial work-up and diagnosis for patients with suspected testicular cancer, see Table 1.11Germa-Lluch J.R. Garcia del Muro X. Maroto P. et al.Clinical pattern and therapeutic results achieved in 1490 patients with germ-cell tumours of the testis: the experience of the Spanish Germ-Cell Cancer Group (GG).Eur Urol. 2002; 42 (discussion 562-553): 553-562Google Scholar,16Laguna MP, Albers P, Algaba F, et al. EAU Guidelines on testicular cancer EAU guidelines 2020. Available at https://uroweb.org/guideline/testicular-cancer. Accessed January 25, 2022.Google Scholar α-Fetoprotein (AFP), beta subunit of human chorionic gonadotropin (β-hCG) and lactate dehydrogenase (LDH) levels should be determined before carrying out orchiectomy, as they are associated with germ-cell cancer histology and support the diagnosis of testicular cancer.16Laguna MP, Albers P, Algaba F, et al. EAU Guidelines on testicular cancer EAU guidelines 2020. Available at https://uroweb.org/guideline/testicular-cancer. Accessed January 25, 2022.Google Scholar,21Gilligan T.D. Seidenfeld J. Basch E.M. et al.American Society of Clinical Oncology Clinical Practice Guideline on uses of serum tumor markers in adult males with germ cell tumors.J Clin Oncol. 2010; 28: 3388-3404Google Scholar Overall, serum tumour markers have a low sensitivity (especially in seminoma) such that normal marker levels do not exclude GCTs. LDH has a low specificity since it may be elevated due to a number of reasons.21Gilligan T.D. Seidenfeld J. Basch E.M. et al.American Society of Clinical Oncology Clinical Practice Guideline on uses of serum tumor markers in adult males with germ cell tumors.J Clin Oncol. 2010; 28: 3388-3404Google Scholar,22Barlow L.J. Badalato G.M. McKiernan J.M. Serum tumor markers in the evaluation of male germ cell tumors.Nat Rev Urol. 2010; 7: 610-617Google Scholar Post-orchiectomy levels of serum tumour markers are nevertheless important for prognostic stratification and should be followed in patients with initially elevated markers (AFP half-life is 5-7 days and β-hCG half-life is 1-3 days) until normalisation.21Gilligan T.D. Seidenfeld J. Basch E.M. et al.American Society of Clinical Oncology Clinical Practice Guideline on uses of serum tumor markers in adult males with germ cell tumors.J Clin Oncol. 2010; 28: 3388-3404Google Scholar Persistent or increasing tumour markers after orchiectomy usually indicate metastatic disease. Circulating serum microRNAs (miRNAs) are reported to have a high sensitivity and specificity and are discussed in the section on personalised medicine.Table 1Serum tumour markers for non-seminoma testicular cancerLDH (U/l)β-hCG (IU/l)AFP (ng/ml)SXMarker studies not available or not carried outMarker studies not available or not carried outMarker studies not available or not carried outS0NormalNormalNormalS1<1.5 × ULN<5000<1000S21.5-10 × ULN5000-50 0001000-10 000S3>10 × ULN>50 000>10 000AFP, α-fetoprotein; β-hCG, beta subunit of human chorionic gonadotropin; LDH, lactate dehydrogenase; ULN, upper limit of normal. Open table in a new tab AFP, α-fetoprotein; β-hCG, beta subunit of human chorionic gonadotropin; LDH, lactate dehydrogenase; ULN, upper limit of normal. Testicular neoplasia is a complex and challenging area of pathology due to the large range of entities and relative rarity of diagnosis. More than 95% of malignant testicular tumours arise from germ cells. While immediate treatment may be based on classic clinical presentation of life-threatening GCT and elevated serum markers only, the vast majority of tumours are diagnosed on primary orchiectomy specimen. The rarity of these tumours, combined with their complex morphology, means that, in non-expert hands, there is a significant risk of misdiagnosis of both type and staging of these neoplasms.23Shamash J. Ansell W. Alifrangis C. et al.The impact of a supranetwork multidisciplinary team (SMDT) on decision-making in testicular cancers: a 10-year overview of the Anglian Germ Cell Cancer Collaborative Group (AGCCCG).Br J Cancer. 2021; 124: 368-374Google Scholar, 24Delaney R.J. Sayers C.D. Walker M.A. et al.The continued value of central histopathological review of testicular tumours.Histopathology. 2005; 47: 166-169Google Scholar, 25Purshouse K. Watson R.A. Church D.N. et al.Value of supraregional multidisciplinary review for the contemporary management of testicular tumors.Clin Genitourin Cancer. 2017; 15: 152-156Google Scholar It has been recommended by ESMO that expert pathologists should see a minimum of 30 cases a year.13Honecker F. Aparicio J. Berney D. et al.ESMO Consensus Conference on testicular germ cell cancer: diagnosis, treatment and follow-up.Ann Oncol. 2018; 29: 1658-1686Google Scholar Testicular tumours should be typed in line with the World Health Organization (WHO) 2016 classification.26Williamson S.R. Delahunt B. Magi-Galluzzi C. et al.The World Health Organization 2016 classification of testicular germ cell tumours: a review and update from the International Society of Urological Pathology Testis Consultation Panel.Histopathology. 2017; 70: 335-346Google Scholar This is a modified nomenclature from previous iterations to align morphology with molecular and outcome data. The major pre-neoplastic lesion of GCTs is germ-cell neoplasia in situ (GCNIS).27Berney D.M. Looijenga L.H. Idrees M. et al.Germ cell neoplasia in situ (GCNIS): evolution of the current nomenclature for testicular pre-invasive germ cell malignancy.Histopathology. 2016; 69: 7-10Google Scholar GCTs may be simply divided into those derived from GCNIS (most adult GCTs) and those not derived from GCNIS. The latter is a heterogeneous group including spermatocytic tumour and most prepubertal GCTs. A new classification was published by the WHO during the writing of this guideline; modifications are minor.28WHO Classification of Tumours Editorial BoardGenitourinary Tumours.5th ed. International Agency for Research on Cancer, Lyon (France)2021Google Scholar Histopathologically, seminomas are characterised by cells analogous to the primordial germ cells/gonocytes present during early embryonic development, while non-seminomas show a variety of differentiation patterns from embryonic and extra-embryonic tissues. Around 5% of testicular cancer patients have GCNIS in the contralateral testis with the highest risk (∼30%) in men with testicular atrophy (volume <12 ml) and age <40 years. Approximately 30%-40% of patients with retroperitoneal EGGCT harbour testicular GCNIS.29Gupta M. Cheaib J.G. Patel H.D. et al.Diagnosis and management of intratubular germ cell neoplasia in situ: a systematic review.J Urol. 2020; 204: 33-41Google Scholar, 30Kristianslund S. Fossa S.D. Kjellevold K. Bilateral malignant testicular germ cell cancer.Br J Urol. 1986; 58: 60-63Google Scholar, 31Oldenburg J. Hypogonadism and fertility issues following primary treatment for testicular cancer.Urol Oncol. 2015; 33: 407-412Google Scholar In 2%-5% of TGCT patients a GCT is diagnosed in the contralateral testicle, either metachronously or synchronously. A recent population-based study reported a 20-year crude cumulative incidence rate of a metachronous contralateral GCT of 5.4% [95% confidence interval (CI) 4.2-6.8] after surgery only. Treatment with three or more cycles of cisplatin-based chemotherapy (ChT) was associated with significantly reduced risks of 3.2% (95% CI 2.5-4.0) for a second GCT.32Hellesnes R. Myklebust T.Å. Bremnes R.M. et al.Metachronous contralateral testicular cancer in the cisplatin era: a population-based cohort study.J Clin Oncol. 2021; 39: 308-318Google Scholar Radiotherapy (RT) is the standard treatment of GCNIS with 9-10 fractions of 2 Gy corresponding to a total dose of 18-20 Gy. As this treatment renders the patient infertile and also weakens testosterone production, the indication for, and timing of this treatment has to be discussed carefully with the patient.29Gupta M. Cheaib J.G. Patel H.D. et al.Diagnosis and management of intratubular germ cell neoplasia in situ: a systematic review.J Urol. 2020; 204: 33-41Google Scholar The majority of European testicular cancer consensus experts do not consider a routine biopsy of the contralateral testis as indicated [V, C].13Honecker F. Aparicio J. Berney D. et al.ESMO Consensus Conference on testicular germ cell cancer: diagnosis, treatment and follow-up.Ann Oncol. 2018; 29: 1658-1686Google Scholar •Diagnosis of GCT should generally be based on histology [II, A] except when urgent ChT is required.•Symptomatic patients with high tumour burden and elevated tumour markers should receive ChT without delay caused by attempts to achieve a biopsy when the clinical picture is clear [III, A].•Serum tumour markers (AFP, β-hCG and LDH) should be determined before and after orchiectomy and throughout follow-up. They are used for accurate staging and risk stratification to monitor treatment and to detect relapse [II, A].•Approximately 5% of GCT patients harbour GCNIS in the contralateral testis, requiring physical and/or US examinations during follow-up [III, A].•As RT for GCNIS prevents fatherhood by natural means, upfront versus delayed RT should be carefully discussed with patients [III, A]. Post-orchiectomy management should be the responsibility of clinicians with experience in the classification and treatment of TGCT [III, A]. Staging and risk group categorisation are carried out according to the Union for International Cancer Control (UICC) and the International Germ Cell Cancer Collaborative Group (IGCCCG), comprising the original publication from 1997 as well as updates with contemporary outcomes and refined risk categorisations for metastatic seminoma and non-seminoma, respectively, reflecting the extent of the disease based on clinical and radiological examinations and the results of serum tumour markers after orchiectomy, including LDH.33International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group.J Clin Oncol. 1997; 15: 594-603Google Scholar, 34Gillessen S. Sauve N. Collette L. et al.Predicting outcomes in men with metastatic nonseminomatous germ cell tumors (NSGCT): results from the IGCCCG update consortium.J Clin Oncol. 2021; 39: 1563-1574Google Scholar, 35Beyer J. Collette L. Sauve N. et al.Survival and new prognosticators in metastatic seminoma: results from the IGCCCG-update consortium.J Clin Oncol. 2021; 39: 1553-1562Google Scholar Risk factors for recurrence in clinical stage I GCTs include tumour (T) stage comprising vascular invasion by the primary tumour as well as size, rete testis invasion and the amount of embryonal carcinoma in non-seminomas. Unfortunately, at present there is disparity between American Joint Committee on Cancer (AJCC) and UICC versions of the TGCT TNM (tumour–node–metastasis) staging such that the applied staging system should always be specified.36Delahunt B. Egevad L. Samaratunga H. et al.UICC drops the ball in the 8th edition TNM staging of urological cancers.Histopathology. 2017; 71: 5-11Google Scholar Tumour markers (AFP, β-hCG, LDH) are determined preferably before and after orchiectomy and followed until normalisation or lack of further decrease. The half-life for β-hCG is 1-3 days and 5-7 days for AFP. For stage I disease, different risk factors have been identified for seminoma and non-seminoma based on histological features in the primary tumour and the 5-year survival rate of adequately managed patients approaches 100%.37Daugaard G. Gundgaard M.G. Mortensen M.S. et al.Surveillance for stage I nonseminoma testicular cancer: outcomes and long-term follow-up in a population-based cohort.J Clin Oncol. 2014; 32: 3817-3823Google Scholar In non-seminoma stage I tumours, vascular invasion of blood or lymphatic vessels is most often caused by embryonal carcinoma. Although the presence of embryonal carcinoma might represent an individual risk factor, most experts recommend considering the presence of vascular invasion as the single and most important predictor of micrometastases and subsequent recurrence. In seminoma clinical stage I, tumour size and possibly rete testis infiltration represent weaker risk factors identifying ‘higher-risk’ patients.38Aparicio J. Germà J.R. García del Muro X. et al.Risk-adapted management for patients with clinical stage I seminoma: the Second Spanish Germ Cell Cancer Cooperative Group study.J Clin Oncol. 2005; 23: 8717-8723Google Scholar, 39Aparicio J. Maroto P. García del Muro X. et al.Prognostic factors for relapse in stage I seminoma: a new nomogram derived from three consecutive, risk-adapted studies from the Spanish Germ Cell Cancer Group (SGCCG).Ann Oncol. 2014; 25: 2173-2178Google Scholar, 40Tandstad T. Ståhl O. Dahl O. et al.Treatment of stage I seminoma, with one course of adjuvant carboplatin or surveillance, risk-adapted recommendations implementing patient autonomy: a report from the Swedish and Norwegian Testicular Cancer Group (SWENOTECA).Ann Oncol. 2016; 27: 1299-1304Google Scholar, 41Boormans J.L. Mayor de Castro J. Marconi L. et al.Testicular tumour size and rete testis invasion as prognostic factors for the risk of relapse of clinical stage I seminoma testis patients under surveillance: a systematic review by the testicular cancer guidelines panel.Eur Urol. 2018; 73: 394-405Google Scholar The ESMO consensus conference voting resulted in >90% majority voting in favour of applying both rete testis infiltration and tumour size as continuous variables for risk categorisation.13Honecker F. Aparicio J. Berney D. et al.ESMO Consensus Conference on testicular germ cell cancer: diagnosis, treatment and follow-up.Ann Oncol. 2018; 29: 1658-1686Google Scholar In the following text, this definition of ‘higher-risk’ seminoma, which is in line with the view of the European Association of Urology (EAU) testis panel as well, will be used when discussing the indication of adjuvant treatment.16Laguna MP, Albers P, Algaba F, et al. EAU Guidelines on testicular cancer EAU guidelines 2020. Available at https://uroweb.org/guideline/testicular-cancer. Accessed January 25, 2022.Google Scholar In patients without visible radiological metastatic lesions, a slower than expected decline of increased pre-orchiectomy β-hCG and AFP might indicate systemic disease. In some rare patients, β-hCG or AFP are elevated without GCT activity, e.g. liver disease, hypogonadism, hereditary AFP elevation. These patients should be referred to and at least discussed with GCT experts, before considering initiation of systemic treatment. Increasing serum markers without identification of metastases indicate the need of systemic treatment of (stage IS) testicular cancer (i.e. serum marker-positive without radiological evidence of metastases). In patients with metastatic disease, serum marker values are integrated into the IGCCCG risk classification.33International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group.J Clin Oncol. 1997; 15: 594-603Google Scholar, 34Gillessen S. Sauve N. Collette L. et al.Predicting outcomes in men with metastatic nonseminomatous germ cell tumors (NSGCT): results from the IGCCCG update consortium.J Clin Oncol. 2021; 39: 1563-1574Google Scholar, 35Beyer J. Collette L. Sauve N. et al.Survival and new prognosticators in metastatic seminoma: results from the IGCCCG-update consortium.J Clin Oncol. 2021; 39: 1553-1562Google Scholar To rule out the presence of nodal or distant metastases, contrast-enhanced computed tomography (CT) of the chest, abdomen and pelvis should be carried out [III, A]. MRI has been established as a substitute for CT in the follow-up, but its role in staging is less clear. Accuracy of abdominal–pelvic staging should be similar between MRI and CT, but for the chest and lungs, CT is superior. Therefore, and due to the lack of evidence for MRI-based staging, contrast-enhanced CT of chest, abdomen and pelvis is recommended as the standardised, robust, reproducible, widely available technique. An MRI of the central nervous system (CNS) is advisable in non-seminoma patients with high β-hCG values or multiple lung metastases belonging to the poor-prognostic group. There is no evidence to support the routine use of [18F]2-fluoro-2-deoxy-d-glucose-positron emission tomography (FDG-PET) in the staging of GCT [III, D]. Serum levels of total testosterone, sex hormone-binding globulin, luteinizing hormone and follicle-stimulating hormone should be determined. IGCCCG identified three prognostic groups for patients with metastatic GCTs (MGCTs) with a disease-specific survival rate of 95%, 85% and 64% for good, intermediate and poor prognosis, respectively (Table 2).42Kier M.G. Lauritsen J. Mortensen M.S. et al.Prognostic factors and treatment results after bleomycin, etoposide, and cisplatin in germ cell cancer: a population-based study.Eur Urol. 2017; 71: 290-298Google Scholar A more recent update has shown that both progression-free survival (PFS) and overall survival (OS) have improved since the original IGCCCG publication. In the updated IGCCCG analysis, age, presence of lung metastases and an LDH value higher than 2.5 × the upper limit of normal (ULN) have been identified as additional prognostic factors.34Gillessen S. Sauve N. Collette L. et al.Predicting outcomes in men with metastatic nonseminomatous germ cell tumors (NSGCT): results from the IGCCCG update consortium.J Clin Oncol. 2021; 39: 1563-1574Google Scholar More precise risk categorisation should yield more homogenous groups of patients, thus facilitating more specific hypotheses and trials. For non-seminoma, use of the online calculator allowing incorporation of age, presence of lung metastases as well as ULN of LDH may be helpful: https://www.eortc.org/IGCCCG-Update.Table 2The IGCCCG prognostic classification for metastatic germ cell cancersAdapted with permission from Beyer et al.35Beyer J. Collette L. Sauve N. et al.Survival and new prognosticators in metastatic seminoma: results from the IGCCCG-update consortium.J Clin Oncol. 2021; 39: 1553-1562Google Scholarand Gillessen et al.34Gillessen S. Sauve N. Collette L. et al.Predicting outcomes in men with metastatic nonseminomatous germ cell tumors (NSGCT): results from the IGCCCG update consortium.J Clin Oncol. 2021; 39: 1563-1574Google Scholar Published by Walters Kluwer Health, Inc. on behalf of the American Society of Clinical Oncology.Prognostic group and survivalPrognostic factorsGoodNon-seminomaAll of the following criteria:5-Year PFS 92%5-Year OS 96%Testicular/retroperitoneal primaryNo non-pulmonary visceral metastasesAFP <1000 ng/ml hCG <5000 IU/l (1000 ng/ml)LDH <1.5 × ULNSeminoma with LDH <2.5 × ULNAll of the following criteria:3-Year PFS 92% and 93%, in training and validation set, respectively3-Year OS 97% and 99%, in training and validation set, respectivelyAny primary siteNo non-pulmonary visceral metastasesNormal AFPAny hCGLDH within 2.5 × ULNSeminoma with LDH >2.5 × ULNAll of the following criteria:3-Year PFS 80% and 75%, in training and validation set, respectively3-Year OS 92% and 96%, in training and validation set, respectivelyAny primary siteNo non-pulmonary visceral metastasesNormal AFPAny hCGLDH >2.5 × ULNIntermediateNon-seminomaCriteria for patients not belonging to good/poor prognosis5-Year PFS 78%5-Year OS 89%Testicular/retroperitoneal primaryNo non-pulmonary visceral metastasesAnd any of the following criteria:AFP 1000-10 000 ng/ml, hCG 5000-50 000 IU/l or LDH 1.5-10 × ULNSeminomaAll of the following criteria:3-Year PFS 78% and 61%, in training and validation set, respectively3-Year OS 93% and 80%, in training and validation set, respectivelyAny primary siteNon-pulmonary visceral metastasesNormal AFPAny hCGAny LDHPoorNon-seminomaAny of the following criteria:5-Year PFS 54%5-Year OS 67%Mediastinal primaryNon-pulmonary visceral metastasesAFP >10 000 ng/ml or hCG >50 000 IU/l (10 000 ng/ml) or LDH >10 × ULNSeminomaNo patients classified as poor prognosisPre-ChT serum tumour markers should be assessed after orchiectomy and immediately before the administration of ChT (same day).AFP, α-fetoprotein; ChT, chemotherapy; hCG, human chorionic gonadotropin; IGCCCG, International Germ Cell Cancer Collaborative Group; LDH, lactate dehydrogenase; OS, overall survival; PFS, progression-free survival; ULN, upper limit of normal. Open table in a new tab Pre-ChT serum tumour markers should be assessed after orchiectomy and immediately before the administration of ChT (same day). AFP, α-fetoprotein; ChT, chemotherapy; hCG, human chorionic gonadotropin; IGCCCG, International Germ Cell Cancer Collaborative Group; LDH, lactate dehydrogenase; OS, overall survival; PFS, progression-free survival; ULN, upper limit of normal. •Post-orchiectomy management should only be carried out by highly experienced clinicians [III, A].•CT scan with contrast enhancement of the thorax, abdomen and pel