Testicular cancer (TCa) mostly affects younger males (between the ages of 15- and 40-years). The good news is that survival rates range from 99% for localised disease. If there is local involvement of nearby structures or lymph nodes, survival rates drop to 96%.1

According to data published by the International Agency for Research on Cancer (IARC), 74 458 new cases of TCa were reported globally in 2020. Prevalence shows significant global variation, with rates ranging from three to 12 new cases per 100 000 males per year in Western societies.¹

In contrast, the prevalence of cases in African countries is notably lower (0.3-0.6 cases per 100 000) but this may be due to underreporting. In 2020, the IARC recorded 3302 cases on the African continent, constituting 4.4% of the global total. Mortality due to TCa on the continent is higher, which may be due to a lack of resources and advanced stage diagnosis.¹

How common in TCa in South Africa?

The latest report on cancer incidence published by Stats South Africa, shows that 51.3% of diagnosed cancers in the country were among women, compared to 48.6% among men.²

The median age at cancer diagnosis was 59-years for women and 64-years for men. Notably, the median age at death attributable to cancer was 62- for women and 64-years for men. This observation suggests that cancer in men may often be diagnosed at more advanced stages compared to women.²

In the age group of 20- to 29-years, the predominant malignancy was Kaposi sarcoma, a disease in which cancer cells are found in the skin or mucous membranes that line the gastrointestinal tract, from mouth to anus, including the stomach and intestines (16.7% of cases), followed by non-Hodgkin lymphoma (12.2%) and TCa (10%). For males aged 30- to 39-years, Kaposi sarcoma remained the most prevalent malignancy (18.4%), with TCa ranked sixth (4.6%).²

What causes TCa?

Studies show that risk factors for the development of TCa include cryptorchidism (undescended testis) as well as genetic and environmental factors.^1,3,4

The most widely accepted hypothesis regarding the development of TCa suggests that the risk is primarily or exclusively determined during prenatal or in utero development. Cryptorchidism increases the risk of developing TCa by 3.7–7.5 times. One of the main causes of cryptorchidism is Klinefelter syndrome, a genetic condition that results when a boy is born with an extra copy of the X chromosome, which affect ~1 in every 700 men.^1,3

According to a recent study by Grobler et al, the predominant risk factor for TCa in South Africa is cryptorchidism (14.1%), although the majority of participants  (82.4%) in this study reported no identifiable risk factors.⁴

Other factors linked to an increased risk include a history and greater adult height. The highest risk is associated with having a brother with TCa, which increases an individual's risk by  ~10-fold.¹

Numerous genomic studies have been conducted to identify genetic loci potentially linked to TCa. These studies have pinpointed six loci on four chromosomes with potential correlations to TCa: 9q24 (double-sex and Mab-3 related transcription factor 1), 5q31 (sprouty homologue 4), 12p13 (activating transcription factor 7 interacting protein), 6p21 (BCL2 antagonist/killer 1), 5p15 (telomerase reverse transcriptase and cleft lip and palate transmembrane 1-like), and 12q21 (KIT ligand).¹

The most robust association has been identified in single-nucleotide polymorphisms in the 12q21 locus, which confer a three-fold increase in the risk of cancer per affected allele. However, even among first-degree relatives of men with TCa, these risk loci are estimated to contribute minimally, accounting for only 11% of the risk in brothers and 16% of the risk in sons.¹

Environmental risk factors for TCa can be classified into four main categories:³

1. Microbiological factors: Viral infections have been explored, with Epstein-Barr virus showing associations through serological markers.
2. Mechanical factors: Traumatic events on the testis, are considered a potential causal factor, supported by studies linking testicular trauma to a doubled TCa risk.
3. Chemical exposures: Studied in occupational settings, include heavy metals like cadmium, although associations with TCa remain uncertain. Pesticides, particularly in agricultural settings, have shown mixed evidence.
4. Physical factors: Notably heat stress, have been investigated, revealing potential associations with increased TC risk, especially in occupations involving elevated temperatures.

TGCT the most common type of TCa

Testicular germ cell tumour (TGCT) account for the majority of TCa cases (90%-95%). Histologically, TGCT can be categorised into seminomas (56% of cases), non-seminomas (43% of cases), spermatocytic seminomas, and mixed forms. The remaining 2% of TCa, which are not GCTs, consist of stromal tumours such as Leydig cell and Sertoli, along with other rare or poorly defined histologic subtypes.¹

Non-seminomas typically present between the ages of 25- to 29-years, while seminomas typically present between the ages of 35- to 39-years. In African countries, the estimated ratio of seminoma to non-seminoma is 1:1.3.^1,5

The study by Grobler et al show an overall five-year survival rate of 91% in South Africa for seminomas, compared with 78% for non-seminomas. Over a 15-year period, patients in the seminoma group are expected to survive 16% longer. Stage 3 patients face a higher risk of mortality compared to stage 1 and 2 patients with no discernible difference between seminomas and non-seminomas. Unfortunately, the majority of patients from African descent are diagnosed at stage 3.^4,5

Signs and symptoms

The most common sign of TCa is a painless, firm mass within the scrotum, typically located in one of the testicles, with occasional occurrence in both. When the cancer spreads to other areas, such as the lungs, brain, abdomen, or neck, various symptoms may manifest, including nausea, vomiting, stomach upset, cough, shortness of breath, weakness, sensory disturbances, abdominal pain, lumps in the neck or groin areas, and back pain.⁶

Diagnostic process and management

Swift evaluation is crucial for early diagnosis and treatment. The diagnostic process involves medical assessment, physical examination, and testicular ultrasound.⁶

Serum tumour markers and cross-sectional imaging are used for further evaluation. In cases where metastatic disease is suspected, additional staging may involve computed tomography scans of the chest and abdomen.⁶

Definitive diagnosis and initial management often involve the removal of the mass along with the affected testicle. Subsequent treatment, whether through additional surgery, radiotherapy, or chemotherapy (ChT), depends on the disease stage and response to initial intervention.⁶

Relapse risk

According to the European Association of Urology, risk factors associated with metastatic relapse in TCa stage 1 vary depending on the histological type. In stage I seminoma, an analysis of retrospective data has identified primary testicular tumour size and stromal invasion of the rete testis, a network of small tubes in the testicle that helps move sperm cells from the testicle to the epididymis, as predictors for relapse. The absence of both factors indicates a low risk of recurrence (6%). ⁷

For non-seminoma stage 1, the invasion of the primary tumour into blood or lymphatic vessels, known as lymphovascular invasion (LVI), is the most reliable single predictor of occult metastatic disease. The risk of relapse at five years with LVI is higher at 50%, compared to 15% without LVI.⁷

Management of relapsed or refractory disease in patients following initial ChT, refractory conditions, or tumour progression during or shortly after ChT involves a standard approach. This typically includes salvage ChT followed by the surgical removal of any remaining disease.⁶

Resection of any residual disease, regardless of size, is crucial as it has been shown to be more effective than salvage therapy in preventing relapse. In cases where disease is deemed unresectable, salvage ChT becomes the primary course of action.⁶

Late relapses (defined as recurrence more than two years after completing first-line therapy) are often associated with chemoresistant tumours. For patients with resectable late relapse, surgery is the preferred initial treatment. Salvage ChT should be reserved for unresectable tumours in these cases.⁶

Patients living with tumours that have progressed after cisplatin-based combination ChT for TGCTs, may be considered for high-dose ChT or peripheral blood stem cell transplantation (PBSCT). High-dose ChT and PBSCT have demonstrated two-year progression-free and overall survival rates of 60% and 66%, respectively.⁶

Conclusion

TCa affects younger men, with a high overall survival rate of 99% for localised disease. The global incidence of TCa varies, with lower rates reported in African countries, due to underreporting. Cryptorchidism is a significant risk factor. Environmental and genetic factors, as well as late-stage diagnosis contribute to the complexity of the disease. Early diagnosis and comprehensive management are crucial for improved outcomes.

 References 

1. Giona S. The Epidemiology of Testicular Cancer. Ovarian Cancer, 2022.
2. Stats SA. Cancer in South Africa (2008 – 2019). 2023. [Internet]. Available at: https://www.statssa.gov.za/publications/03-08-00/03-08-002023.pdf
3. De Toni L, Šabovic I, Cosci I, et al. Testicular Cancer: Genes, Environment, Hormones. Front Endocrinol, 2019.
4. Grobler G, Spies PV, Burger H, et al. Testicular germ cell tumours: Outcomes at a tertiary hospital in the Western Cape, South Africa. South African Journal of Oncology, 2023.
5. Burger H, Rick T, Spies PV, et al. Testicular germ cell cancer in Africa: A survey on patterns of practice. South African Journal of Oncology, 2022.
6. Gaddam SJ, Chesnut GT. Testicle Cancer. [Updated 2023 May 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK563159/
7. Nicol D, Berney D, Boormans JL, et al. EAU guidelines on testicular cancer. 2023. [Internet]. Available at: https://d56bochluxqnz.cloudfront.net/documents/full-guideline/EAU-Guidelines-on-Testicular-Cancer-2023_2023-04-12-091409_hqrv.pdf