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