The majority of testicular tumours arise from a type of cell in the testicle called a germ cell. There are two main groups of testicular tumours: seminomas and nonseminomatous germ cell tumours (NGCST). Rare tumours of the testis include sex cord stromal tumours, lymphoma and metastases.
The only well recognised predisposing factor is testicular maldescent. There is a history of maldescent in approximately 10% of UK cases of this disease. If either testis fails to descend, then the risk of the disease rises five-fold whereas it is tenfold increased if both fail to descend. Surgical orchidopexy (the correct positioning of the testis down into the scrotum) at an early age protects.
The other factors that predispose a testicle to this disease are a previous history of the disease afflicting the other testis and s positive family history of the disease (father or brother).
Although a rare cause of cancer (1% of the total cancer cases in UK), testicular cancer is important because it is a disease of young men and is the commonest malignancy in this age group (most common age of presentation being 25-35 years) affecting one in six hundred men. The disease is also important because it is nowadays so curable in the vast majority of cases.
Symptoms & diagnosis: Testis cancer
The vast majority of men present because of a lump in the testis
All patients with a suspected diagnosis of testicular cancer should undergo a general examination with assessment of the abdomen (to assess for lymph glands and organs) and an examination of the scrotum. All patients will have a testicular ultrasound to demonstrate that they do indeed have a solid testicular swelling. Further imaging including a CT scan would be considered if there is a concern of spread of the testicular cancer beyond the testis. In addition they will have blood tests to see if blood levels of two marker proteins are elevated: HCG (Human Chorionic Gonadotrophin) and AFP (alpha foetoprotein).
The majority of patients will undergo a surgical removal of the testicle via an inguinal orchidectomy to confirm the diagnosis of a testicular cancer.
Staging, usually in the form of blood tests and CT scans of the body, is used to identify if there is cancer beyond the testicle. Stage I testicular cancer is defined as cancer that is limited to the testis only. Stage II testicular cancer has spread (metastasized) to the abdominal lymph nodes. Stage III testicular cancer has spread to other organs
For testicular cancer a prognostic classification system has been developed to identify good, intermediate and poor prognosis patients. This is largely based on the extent of tumour seen, the levels of AFP marker expressed in the blood. Men with stage I testicular cancers have an excellent prognosis.
Treatment & outcomes: Testis cancer
Seminoma: For patients with stage 1 seminoma (seminoma confined to the testis), and this accounts for approximately three quarters of all men with testicular seminoma presenting in the UK, approximately 20% will harbour microscopic disease in the abdominal lymph nodes. A short course of chemotherapy (usually two high doses of carboplatin – usually suffices to sterilise any microscopic disease outside the testis and brings the cure rate up to 95%+. An alternative therapy with a similar high chance of cure is radiotherapy (low dose as the seminoma is very radiosensitive) to the para-aortic nodes – as these are almost always the first site of spread).
‘Watch and wait’ policies are an acceptable alternative in place of this pro-active therapy policy for stage 1 disease (on the basis that one is over-treating the 80% who would never relapse). If the patient is reliable in follow-up, attending for follow-up scans, then this watchful waiting policy is safe, as early relapse will be detected and is almost always curable in the minority who develop this.
In early stage 2 seminoma, (Stage 2B-C) primary chemotherapy is indicated, with a high expectation of cure – more chemotherapy than stage one (e.g. 4 cycles of etoposide and cis-platin chemotherapy) with a very high chance of cure.
Teratoma: For stage 1 teratoma patients, watchful waiting with serial serum marker tests (HCG and AFP) and CT scanning regularly is performed. It is important to perform the HCG/AFP markers pre-operatively such that (if raised) the Oncologist knows that these will be useful markers in detecting relapse
Approximately 20% of patients who are stage 1 at presentation subsequently relapse and, so long as the relapse is picked up early, their longevity/cure chance is not prejudiced by the watchful waiting policy.
For stage 2 NSGCT disease and all other higher risk groupings, full courses of chemotherapy are advised. The regimen ‘BEP’ (bleomycin, etoposide and cisplatin) remains the number one regime, although the use of high cumulative doses of Bleomycin is nowadays restricted. the cure chance is very high
The response to chemotherapy is monitored by serial assessment of serum markers (HCG and AFP) and by serial scanning. Even after curative doses of chemotherapy have been delivered, a residual mass may remain in the region of the abdominal lymph nodes; a PET (positron emission tomogram) will predict whether this still contains viable tumour cells, as this scans for metabolically active lesions. Many doctors prefer to surgically remove any residual masses; a proportion of these may be inert cells.
Following completion of the chemotherapy programme, the patient must be assiduously watched for at least three years. If relapse of any testicular tumour occurs it is likely to be in the first three years, although the literature does contain instances of later relapses.
The problem patients are those who have already received chemotherapy in full dose and relapse soon afterwards. These are clearly a higher risk group who are much more difficult to cure, but some good response can be obtained with other drugs combinations. In patients who achieve a remission after this second line therapy some consideration should be given to high dose chemotherapy and a peripheral stem cell auto-transplant.
What to do if the patient relapses despite all the foregoing therapies?
If the patient has relapsed after all the first and second line chemotherapy options and perhaps the high dose chemotherapy plus autograft, then the genomic profile of the cancer should be assessed at that time buy a fresh cancer biopsy or from cell-free DNA (cfDNA) from a blood draw. Next generation sequencing (NGS) should be performed in search of driving oncogenes (i.e. those that are driving the cancer forwards).
Testicular germ cell cancers have frequent chromosomal anomalies. In addition to the characteristic gain of isochromosome 12p, NGS has confirmed mutations of previously described genes (i.e., KIT and KRAS) amongst other new mutations. Analysis of cisplatin-resistant cases has identified TP53-MDM2 axis mutations and PI3 kinase, and MAPK signaling pathway mutations that are potentially targetable (‘druggable’).
Whilst there have been reports of good responses to immunotherapy in refractory germ cell tumours, particularly in choriocarcinoma subtype, there is no established role for immunotherapy in this disease as yet (possibly because the cure rate is so high before one needs to consider this option).
Dr. P. N. Plowman. MD. The Oncology Clinic, 20 Harley Street, London W1G 9PH. (Advanced Genomics). Tel: +44-207-631-1632
More than 95% of men with testicular cancer are cured with treatment.
Whilst routine screening for testis cancer is not indicated, nevertheless, patients with (unoperated) undescended testes or delayed orchidopexy, or a past history of one testicular cancer should be surveyed.