Testicular Germ-Cell Tumours (TGCT)

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Edurne Alonso	--	1750	2022-05-23 11:30:45	\|
2	Reference format revised.	Lindsay Dong	-6 word(s)	1744	2022-05-24 03:35:04	\|

This entry is adapted from the peer-reviewed paper 10.3390/cancers14071633

Testicular Germ Cell Tumors (TGCTs) are the second most common form of Germ Cell Tumour after benign ovarian teratomas. They are considered a “curable cancer” due to their exceptionally high survival rate of their patients: young caucasian men mostly. A better stratification of those patients would mean an improvement in their quality of life, which is currently diminished by the aggressiveness of prognostic treatments. The knowledge about the relation between TGCTs and the immune system could give keys to improve prognosis, diagnosis and treatment of this cancer.

testicular cancer Testicular Germ Cell Tumours (TGCT)

1. Testicular Germ-Cell Tumours (TGCT)

Germ Cell Tumours (GCTs) originate from germ cells, usually in the gonads (testes and ovaries), but they can also be found elsewhere in the central nervous system, pelvis, thorax, abdomen and mediastinum ^[1]. TGCTs are the second most common form of Germ Cell Tumour after benign ovarian teratomas and account for more than 90% of neoplasms found in testicles ^[1]^[2]. Their incidence has been on the rise since the 1970s, and even though they have an extremely high survival rate, it shrinks considerably by 30 years after the diagnosis, due to metastases and relapses (15–30% of patients) ^[3]^[4]^[5]^[6].

The different types of TGCTs have usually been classified following morphological criteria into two categories: seminomas and non-seminomatous Germ Cell Tumours (NSGCTs). Of those two, NSGCTs are less common but more aggressive and heterogeneous. They are categorised into four histological types: embryonal carcinoma, yolk-sac carcinoma, choriocarcinoma and teratoma; most tumours present more than one cell category, making them harder to treat.

2. Tumour Classification

An early problem in the study of TGCTs was the different terminology used for their classification by different research groups. Until recently, their classification was morphology-based but it was updated in 2016 by the World Health Organisation (WHO) to reflect the latest studies and the epidemiological similarities or differences between certain types of tumours ^[7] (Table 1). According to this nomenclature, Testicular Germ Cell Tumours are classified based on their relationship with the germ cell neoplasia In Situ (GCNIS): a group of malignant intratubular germ cells with seminoma-like morphology that appear in the spermatogenic niche and precede most TGCTs. Then, GCTs are classified in two main groups: GCNIS-derived tumours and not GCNIS-derived tumours ^[7].

Table 1. World Health Organization (WHO) classification of TGCT, adapted ^[7].

Germ Cell Tumors Derived from Germ Cell Neoplasia In Situ

Non-invasive germ cell neoplasia

Germ cell neoplasia in situ (GCNIS)

Specific forms of intratubular germ cell neoplasia

Tumors of single histological type (pure forms)

Seminoma

Seminoma with scyncytiotrophoblast cells

Non-seminomatous germ cell tumors

Embryonal carcinoma

Yolk sac tumor, postpubertal-type

Trophoblastic tumors

Choriocarcinoma

Non-choriocarcinomatous trophoblastic tumors

Placental site trophoblastic tumor

Epithelioid trophoblastic tumor

Cystic trophoblastic tumor

Teratoma, postpubertal-type

Teratoma with somatic-type malignancy

Non-seminomatous germ cell tumors of more than one histologycal type

Mixed germ cell tumors

Germ cell tumors of unknown type

Regressed germ cell tumors

Germ Cell Tumors Unrelated to GCNIS

Spermatocytic tumor

Teratoma, prepubertal-type

Dermoid cyst

Epidermoid cyst

Well-differentiated neuroendocrine tumor (monodermal teratoma)

Mixed teratoma and yolk sac tumor, prepubertal-type

Yolk sac tumor, prepubertal-type

The most closely related to GCNIS would be pure seminomas, which maintain the same histology. From there, another type of classification that is often used in clinics arises, which divides tumours into seminomatous or non-seminomatous. This is especially important for treatments because seminoma cells are sensitive to chemotherapy and radiotherapy ^[8]^[9]^[10].

The distinction between morphology and epidemiology-based classifications is most notably seen in the case of teratomas and yolk sac tumours. There is no significant morphological difference between the pre- and post-pubertal types, but the tumours seen in children more often lack the markers associated with GCNIS that are prevalent in tumours seen after puberty. Therefore, although they were previously considered to be a single disorder, scholars now know that there are considerable epidemiological and molecular differences ^[7].

In fact, the most prominent theory on the origin of GCNIS states that there is some kind of tumorigenic event in utero during embryogenesis, which impairs the maturation of primordial stem cells into spermatogonia ^[11]. Those cells are identified as GCNIS and remain unchanged until puberty, when alterations in their molecular environment lead to malignancy. GCNIS could be considered as the precursor of most post-pubertal TGCTs and is usually treated as a stage 0 cancer.

The seminomatous/non-seminomatous nomenclature is still used today and normally differentiates between pure seminoma (seminomatous tumours) and every other type of TGCT (non-seminomatous) ^[12]. For the treatment of mixed tumours the non-seminomatous approach has a better prognosis, as these types of cancer present more aggressive characteristics ^[12].

3. Risk Factors

The main risk factor identified, especially in the case of seminoma, is cryptorchidism (problem with the descent of the testes, leaving one or both of them outside the scrotum). The prevalence of TGCT increases between 3.7- and 7.5-fold in these patients; in fact, between 5% and 10% of testicular cancer patients have a history of cryptorchidism ^[13]^[14].

Other prominent risk factors include a previous tumour in the contralateral testicle, especially in the preceding 5 years (24.5- to 27.5-fold increase) with a family history of TGCT, which has been linked to various candidate genes, some of which are also related to cryptorchidism ^[2]^[15]^[16]^[17].

It has been observed that the cells from GCNIS are really hard to distinguish from germ cells in intersex gonads, which present a delay in their maturation. One theory suggests that these abnormal cells become GCNIS, which would explain why between 25% and 30% of people with gonadal dysgenesis and a Y chromosome develop a GCT ^[7]^[18].

Lastly, an increased risk of developing a TGCT has also been linked to abnormalities of the germ cell lines that lead to hypofertility and infertility ^[19]^[20]. Nevertheless, it is not yet clear whether there is a direct causal relationship or a third element that leads to both impaired fertility and an increased risk of TGCT ^[21].

4. Diagnosis, Prognosis and Treatment

When a suspicious testicular mass is discovered, the first step is to analyse certain tumoral biomarkers and carry out a trans-scrotal ultrasonography. If the imaging shows a mass that is suspected of being malignant, an inguinal orchiectomy would be carried out for further diagnosis. It is usually recommended not to damage the scrotum during the procedure, as it can lead to complications during treatment, but recent meta-analyses discard these negative effects at least for short-term survival ^[22]^[23].

The most common primary therapeutic approach, a radical orchiectomy, is performed when the affected testicle is completely extracted ^[12]. That leads to the loss of the entire organ, which is problematic if the contralateral testicle has already been removed or in young patients. Therefore, in certain cases, research groups have proposed partial orchiectomies or testis-sparing surgery (TSS) to minimise endocrine and psychological negative effects and preserve fertility ^[24].

If the initial diagnosis was stage I cancer, the same biomarkers investigated at the start of the diagnosis are followed up until normalisation. If levels do not return to normal, some kind of metastasis is confirmed, and the diagnosis shifts to a later stage. Adjuvant therapies are considered depending on the diagnosis and evolution of the serum biomarker. All of the information is taken together, and patients are classified into three main categories of prognosis: good, intermediate or poor. This classification (Table 2) was developed by the International Germ Cell Cancer Collaborative Group (IGCCCG) in 1997 ^[25].

Table 2. TGCT prognosis classification guidelines by the IGCCCG ^[25]. The IGCCCG stratifies stage III patients according to three groups: good prognosis, intermediate prognosis, and poor prognosis. AFP: alpha-fetoprotein, hCG: human chorionic gonadotropin, LDH: lactic dehydrogenase and PFS: progression-free survival.

GOOD PROGNOSIS
Non-seminoma	Seminoma
Testis/retroperineal primary tumor And No non-pulmonary visceral metastases And Good markers (all of): AFP< 1000 ng/mL hCG< 5000 iu/L (1000 ng/mL) LDH< 1.5 × upper limit of normal 56% of non-seminomas 5 years PFS 89% 5 year survival 92%	Any primary site And No non-pulmonari visceral metastases And Normal AFP, any hCG and any LDH 90% of Seminomas 5 years PFS 82% 5 year survival 86%
INTERMEDIATE PROGNOSIS
Non-seminoma	Seminoma
Testis/retroperitoneal primary And No non-pulmonary visceral metastases And Intermediate markers (any of): AFP ≥ 1000 and ≤ 10,000 ng/mL hCG ≥ 5000 iu/L and ≤ 50,000 iu/L LDH ≥ 1.5 × N and ≤ 10 × N 28% of non-seminomas 5 years PFS 75% 5 year survival 80%	Any primary siite And Non pulmonary visceral metastases And Normal AFP, any hCG, any LDH 10% of seminomas 5 years PFS 67% 5 year survival 72%
POOR PROGNOSIS
Non-seminoma	Seminoma
Mediastinal primary Or Non-pulmonary visceral metastases Or Poor markers (any of): AFP > 10,000 ng/mL hCG > 50,000 iu/L (10,000 ng/mL) LDH > 10 × upper limit of normal 16% of non-seminomas 5 year PFS 41% 5 year survival 48%	No patients classified as poor prognosis

5. TGCT Molecular Markers

Molecular markers are useful to track the progress of the treatments used and distinguish between different types of tumours during the diagnostic process. These can be detected through histological analysis by biopsy and by biochemical tests of blood or urine samples. In the case of TGCT, decisions are made based on the patient’s family history and the presence of a few markers with limited diagnostic and prognostic value which have been the same for decades ^[26]. Further study of this field could lead to a finer sorting of patients according to the potential risks of each treatment. In addition, more precise and less aggressive treatments than cisplatin-based chemotherapy could be developed because this is the treatment that is widely used today, whose risks and side effects are really negative for the patient ^[27]^[28].

6. Immunotherapeutic approaches

In the complex molecular regulation between autoimmunity and immune-escape, the interaction between the programmed death receptor 1 (PD-1) and its ligand (PD-L1) has proven to be an extremely important molecular checkpoint. In fact, some organs like the testicles acquire an immune privileged status by using PD-1L expression to avoid attacks from the immune system, presumably to protect the process of spermatogenesis, where male gametes are formed ^[29] . In some cases of cancer, PD-L1 is used by tumour cells to suppress tumour immunity ^[30].

In recent years, connexions have been drawn between TGCT prognosis, inflammatory molecular environments and in-tumour PD1-L expression ^[31]. This has led to an increased interest in developing immunotherapeutic strategies that target that specific checkpoint, in order to improve the human body’s own defences against the tumors ^[31].

Even if the theoretical reasoning is sound, clinical trials have not proven satisfactory, and there is still an active search to find the missing piece of this equation. Scholars propose the family of proprotein convertases as possible targets to improve the patient’s response to immunotherapy ^[32].

It is also important to consider that, even if clinical trials have not been as successful as expected, the sample of patients eligible to those experimental treatments is comprised of the most aggressive cases of TGCTs, which are definitely not the norm.

References

Trama, A.; Berrino, F. The Epidemiology of Malignant Germ Cell Tumors: The EUROCARE Study. In Pathology and Biology of Human Germ Cell Tumors; Springer: Berlin/Heidelberg, Germany, 2017; pp. 11–21.
Jimenez, R.E.; Gupta, S.; Herrera-Hernandez, L.P.; Sebo, T.J. Testicular Germ Cell Tumors. In Pathology and Biology of Human Germ Cell Tumors; Springer: Berlin/Heidelberg, Germany, 2017; pp. 267–325.
Huyghe, E.; Matsuda, T.; Thonneau, P. Increasing Incidence of Testicular Cancer Worldwide: A Review. J. Urol. 2003, 170, 5–11.
Kvammen, Ø.; Myklebust, T.Å.; Solberg, A.; Møller, B.; Klepp, O.H.; Fosså, S.D.; Tandstad, T. Long-term Relative Survival after Diagnosis of Testicular Germ Cell Tumor. Cancer Epidemiol. Biomarkers Prev. 2016, 25, 773–779.
Boujelbene, N.; Cosinschi, A.; Boujelbene, N.; Khanfir, K.; Bhagwati, S.; Herrmann, E.; Mirimanoff, R.-O.; Ozsahin, M.; Zouhair, A. Pure seminoma: A review and update. Radiat. Oncol. 2011, 6, 90.
Albers, P.; Albrecht, W.; Algaba, F.; Bokemeyer, C.; Cohn-Cedermark, G.; Fizazi, K.; Horwich, A.; Laguna, M.P.; Nicolai, N.; Oldenburg, J. Guidelines on Testicular Cancer: 2015 Update. Eur. Urol. 2015, 68, 1054–1068.
Moch, H.; Cubilla, A.L.; Humphrey, P.A.; Reuter, V.E.; Ulbright, T.M. The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs—Part A: Renal, Penile, and Testicular Tumours. Eur. Urol. 2016, 70, 93–105.
Krege, S.; Beyer, J.; Souchon, R.; Albers, P.; Albrecht, W.; Algaba, F.; Bamberg, M.; Bodrogi, I.; Bokemeyer, C.; Cavallin-Ståhl, E.; et al. European Consensus Conference on Diagnosis and Treatment of Germ Cell Cancer: A Report of the Second Meeting of the European Germ Cell Cancer Consensus group (EGCCCG): Part, I. Eur. Urol. 2008, 53, 478–496.
Jones, W.G.; Fosså, S.D.; Mead, G.M.; Roberts, J.T.; Sokal, M.; Horwich, A.; Stenning, S.P. Randomized Trial of 30 Versus 20 Gy in the Adjuvant Treatment of Stage I Testicular Seminoma: A Report on Medical Research Council Trial TE18, European Organisation for the Research and Treatment of Cancer Trial 30942 (ISRCTN18525328). J. Clin. Oncol. 2005, 23, 1200–1208.
Oosterhuis, J.W.; Looijenga, L. Testicular germ-cell tumours in a broader perspective. Nat. Cancer 2005, 5, 210–222.
Meyts, E.R.-D. Developmental model for the pathogenesis of testicular carcinoma in situ: Genetic and environmental aspects. Hum. Reprod. Updat. 2006, 12, 303–323.
Gilligan, T.; Lin, D.W.; Aggarwal, R.; Chism, D.; Cost, N.; Derweesh, I.H.; Emamekhoo, H.; Feldman, D.R.; Geynisman, D.M.; Hancock, S.L.; et al. Testicular Cancer, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology. J. Natl. Compr. Cancer Netw. 2019, 17, 1529–1554.
Taran, I.; Elder, J.S. Results of orchiopexy for the undescended testis. World J. Urol. 2006, 24, 231–239.
Thorup, J.; McLachlan, R.; Cortes, D.; Nation, T.R.; Balic, A.; Southwell, B.R.; Hutson, J.M. What is new in cryptorchidism and hypospadias—a critical review on the testicular dysgenesis hypothesis. J. Pediatr. Surg. 2010, 45, 2074–2086.
Colls, B.M.; Harvey, V.J.; Skelton, L.; Thompson, I.P.; Frampton, C.M. Bilateral germ cell testicular tumors in New Zealand: Experience in Auckland and Christchurch 1978-1994. J. Clin. Oncol. 1996, 14, 2061–2065.
Østerlind, A.; Berthelsen, J.G.; Abildgaard, N.; Hansen, S.O.; Jensen, H.; Johansen, B.; Munck-Hansen, J.; Rasmussen, L.H.; Hansen, O. Incidence of bilateral testicular germ cell cancer in Denmark, 1960–1984: Preliminary findings. Int. J. Androl. 1987, 10, 203–208.
Rowland, R.G. Risk of contralateral testicular cancer: A population-based study of 29,515 U.S. men: Fossa SD, Chen J, Schonfeld SJ, McGlynn KA, McMaster ML, Gail MH, Travis LB, Department of Clinical Cancer Research, The Norwegian Radium Hospital, University of Oslo, Oslo, Norway. Urol. Oncol. Semin. Orig. Investig. 2006, 24, 173.
Cools, M.; Drop, S.L.; Wolffenbuttel, K.P.; Oosterhuis, J.W.; Looijenga, L.H. Germ Cell Tumors in the Intersex Gonad: Old Paths, New Directions, Moving Frontiers. Endocr. Rev. 2006, 27, 468–484.
Mancini, M.; Carmignani, L.; Gazzano, G.; Sagone, P.; Gadda, F.; Bosari, S.; Rocco, F.; Colpi, G. High prevalence of testicular cancer in azoospermic men without spermatogenesis. Hum. Reprod. 2007, 22, 1042–1046.
Raman, J.; Nobert, C.F.; Goldstein, M. Increased incidence of testicular cancer in men presenting with infertility and abnormal semen analysis. J. Urol. 2005, 174, 1819–1822.
Skakkebæk, N.E.; Jørgensen, N. Testicular dysgenesis and fertility. Andrology 2005, 37, 217–218.
Schmoll, H.-J.; Jordan, K.; Huddart, R.; Pes, M.P.L.; Horwich, A.; Fizazi, K.; Kataja, V. Testicular seminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2010, 21, v140–v146.
Patel, H.D.; Gupta, M.; Cheaib, J.G.; Sharma, R.; Zhang, A.; Bass, E.B.; Pierorazio, P.M. Testis-sparing surgery and scrotal violation for testicular masses suspicious for malignancy: A systematic review and meta-analysis. Urol. Oncol. Semin. Orig. Investig. 2020, 38, 344–353.
Foster, R.S. Organ sparing surgery for malignant germ cell tumor of the testis: Editorial comment. J. Urol. 2001, 166, 2165.
Mead, G.M. International Germ Cell Consensus Classification: A prognostic factor-based staging system for metastatic germ cell cancers. J. Clin. Oncol. 1997, 15, 594–603.
Leão, R.; Ahmad, A.E.; Hamilton, R.J. Testicular Cancer Biomarkers: A Role for Precision Medicine in Testicular Cancer. Clin. Genitourin. Cancer 2019, 17, e176–e183.
Qi, L.; Luo, Q.; Zhang, Y.; Jia, F.; Zhao, Y.; Wang, F. Advances in Toxicological Research of the Anticancer Drug Cisplatin. Chem. Res. Toxicol. 2019, 32, 1469–1486.
Terbuch, A.; Posch, F.; Annerer, L.M.; Bauernhofer, T.; Pichler, M.; Szkandera, J.; Hutterer, G.C.; Pummer, K.; Partl, R.; Kapp, K.S.; et al. Long-term cardiovascular complications in stage I seminoma patients. Clin. Transl. Oncol. 2017, 19, 1400–1408.
Birbrair, A. . Tumor Microenvironments in Organs: From the Brain to the Skin—Part A. In Advances in Experimental Medicine and Biology; Springer, Eds.; Springer: Berlin/Heidelberg, Germany, 2020; pp. 111-121.
Kalavska, K.; Schmidtova, S.; Chovanec, M.; Mego, M; Immunotherapy in Testicular Germ Cell Tumors. ONCOLOGY 2020, 10, 1-9, https://doi.org/10.3389/fonc.2020.573977.
Olcucu, M.T.; Karamik, K.; Yilmaz, K.; Okuducu, Y.; Cakir, S.; Ates, M; Preoperative Inflammation Markers and De Ritis Ratio in Predicting Clinical Presentation and Prognosis of Patients with Testicular Germ Cell Tumors. Journal of College of Physicians and Surgeons Pakistan 2020, 30, 1041–1046, https://doi.org/10.29271/jcpsp.2020.10.1041.
Velado-Eguskiza, A.; Gomez-Santos, L.; Badiola, I.; Sáez, F.J.; Alonso, E. Testicular Germ Cell Tumours and Proprotein Convertases. Cancers 2022, 14, 1633. https://doi.org/10.3390/cancers14071633

© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.

Upload a video for this entry

Information

Subjects: Oncology; Cell Biology

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Edurne Alonso

Aitziber Velado-Eguskiza

Iker Badiola

Francisco Sáez

View Times: 329

Update Date: 24 May 2022

Table of Contents

Video Upload Options

Confirm