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.
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 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][26,27].
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][9,28,29,30]. 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][14,31]. 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][32,33]. 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][34].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 |
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 [291] . In some cases of cancer, PD-L1 is used by tumour cells to suppress tumour immunity [302].
In recent years, connexions have been drawn between TGCT prognosis, inflammatory molecular environments and in-tumour PD1-L expression [313]. 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 [313].
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. ScIn tholarse published review linked below, we propose the family of proprotein convertases as possible targets to improve the patient’s response to immunotherapy [324].
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.