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Germ-cell tumours of the testis – 2016

UPDATED JUNE 2016

1. General information

1.1 What is the disease and how is it treated?

What are germ cell tumours of the testis?
They are solid tumours that arise from immature germ cells (the cells that form sperm) in the testicles.

What are the causes of the disease?
The exact causes are not known, but several risk factors have been identified, such as undescended testicles and exposure to certain chemicals.

Is it a frequent disease?
Although testicular cancer is rare, accounting for 0.7% of all cancer in males, in many countries it is the most common malignancy in young men (15-35 years).

How is it treated?
The standard initial treatment is usually removal of the affected testicle. Depending on tumour  features, chemotherapy or radiotherapy may follow, or simple surveillance may be opted for, with regular check-ups to see if the disease recurs.

2. What is it, how does it occur, how is it diagnosed?

2.1 What are germ cell tumours of the testis?

2.1.1 Genesis of testicular germ cell tumours

The testicles (also known as testes or male gonads) are the two male sex glands; they are located inside the scrotum, below the penis. They produce sperm cells and testosterone, the male sex hormone.
Approximately 98% of testicular cancers arise from immature germ cells (the cells that form sperm); that is why they are called testicular germ cell tumours, or germ cell tumours of the testis. The remaining 2% of testicular cancers arise from different cells and include sex cord tumours (such as Leydig and Sertoli cell tumours), rhabdomyosarcoma, and lymphoma.
Testicular germ cell tumours in adults are thought to initiate during foetal development. As germ cells can develop into a wide range of cell types, germ cell tumours can present in several different forms (called histological types). The most important distinction is between seminoma, when tumour cells maintain the appearance of undifferentiated, germ cell-like cells, and non-seminomas, when tumour cells begin to develop into more differentiated cells. Non-seminomas include embryonal carcinoma (tumour cells appear as primitive zygotic cells, the first cells that form when the fertilized egg begins dividing), teratoma (differentiated cells that can resemble various types of body tissues), choriocarcinoma and yolk sac tumour (differentiated cells that resemble the cells of the chorion or of the yolk sack, two of the membranes that grow outside the embryo during development).
Almost all testicular germ cell tumours derive from a precursor tumour called carcinoma in situ (or intratubular germ cell neoplasia unclassified). Carcinoma in situ consists in malignant germ cells that have not yet become invasive, so they are confined to the tissue where they arose, inside the seminiferous tubules. Testicular carcinoma in situ is present in 0.9% of the overall population and gives no symptoms.
Growth of invasive germ cell tumours varies in accordance with histological type: seminomas grow slowly, and only after some time begin spreading through the lymphatic vessels and invading the retroperitoneal lymph nodes; non-seminomas grow quickly, with rapid spread through the blood vessels (in choriocarcinoma patients lung and brain metastases are often already present at diagnosis).

2.1.2 Histological types and classification

Germ cell tumours are classified into two major groups: seminoma and non-seminoma tumours, which differ in biological and clinical characteristics and treatment. Seminomas account for approximately 45%-50% of germ cell tumours and non-seminomas for 50%-55%. Frequently, mixed tumours are found, which behave and are treated as non-seminomas.
The recommended pathological classification for testicular germ cell tumours (modified from the 2004 version of the World Health Organization guidance) is shown below:

  • Intratubular germ cell neoplasia unclassified (IGCNU), also called carcinoma in situ (CIS) of the testis;
  • Seminoma;
  • Spermatocytic seminoma (see below);
  • Embryonal carcinoma;
  • Teratoma;
  • Choriocarcinoma;
  • Yolk sac tumour;
  • Tumours with more than one histological type.

The classification also includes other kinds of testicular, non-germ cell tumours (see Professional area, Paragaph 2.2.2, WHO classification)

2.1.3 Seminoma and spermatocytic seminoma

Seminoma accounts for 40%-50% of all germ cell tumours of the testis and frequently appears between 30 and 40 years of age.
There are a few variants of seminoma, with specific features.
Approximately 5%-10% of classic seminomas contain cells called syncytiotrophoblastic cells: they produce human chorionic gonadotropin (HCG), a hormone which is normally secreted by the foetus and by choriocarcinoma testicular cell tumours, but which is also elevated in germ cell tumour patients (see 4.1).
Another variant is spermatocytic seminoma (4%-7% of all seminomas), which presents cells with specific features. It occurs in an older population than classic seminoma: half of patients are 65 or older.
Other terms are also used to distinguish different forms of seminoma (such as the old term “anaplastic form” for seminomas with rapidly dividing cells, or “atypical form”), but they have no relevance for treatment and prognosis.

2.1.4 Non-seminoma

Non-seminomatous germ cell tumours represent about 50%-55% of all germ cell tumours and frequently appear between 20 and 30 years of age.

  • Embryonal carcinoma represents 20% of all testicular cancer. Microscopically, its appearance is extremely variable due to the ability of its cells to differentiate into other forms of germ cell tumour.
  • Teratoma contains somatic cells, of many possible tissues (e.g., cartilage or muscle), with varying degrees of differentiation. Although technically no malignant tissue exists in these tumours, nevertheless metastases can occur, and death can result if tumour cells reach vital organs, continue to grow (though slowly), and cannot be removed without damaging the vital organs. Teratoma does not secrete human chorionic gonadotropin (HCG) or alpha-fetoprotein (AFP) (HCG and AFP are serum markers, i.e., proteins found in the blood whose levels indicate tumour type or progression, see 4.1) and is not responsive to chemotherapy, so surgical excision is the only option to treat it.

Some teratomas show malignant transformation: they contain malignant cells which are not germ cells, but may include different kinds of tumour tissues (such as kidney, nerve, muscle, or other). If these malignant tissues are present at diagnosis or following chemotherapy, unfortunately the prognosis is poor.

  • Choriocarcinoma is the most aggressive variant of germ cell cancer in adults, and at first diagnosis it may have already spread through the blood vessels and formed visceral metastases. In these patients, extreme elevations of serum levels of HCG have been reported, with a normal serum level of AFP (HCG and AFP are serum markers, i.e., proteins found in the blood whose levels indicate tumour type or progression, see 4.1).
  • Yolk sac tumours show a great variety of cell patterns. Patients with pure yolk sac tumours have elevated levels of AFP in the blood, with normal HCG levels.
2.1.5 Co-existence of different histological types

Frequently mixed histological types are found. Mixed seminomatous/non-seminomatous forms must be treated as non-seminomatous cancers because this histological type has a worse prognosis and requires a more aggressive treatment. If an increasing value of AFP is found in seminoma, the tumour must be considered and treated as a non-seminomatous tumour.

2.1.6 Immunohistochemical markers

Immunohistochemical markers are proteins produced by normal or pathological tissues, which can be visualized staining the tissue with particular treatments and help to distinguish it from other kinds of tissue. They can be useful to diagnose what type of cancer is present, as some forms of testicular germ cell tumour produce different proteins than other forms. Seminomas exhibit two such proteins (placental alkaline phosphatase or PLAP and ckit/CD117), but generally do not show keratin; embryonal carcinomas express keratins, while some parts of mature teratomas produce vimentin.

2.1.7 Genetic abnormalities

It is still unclear what genetic mutations, and consequent anomalies in cell functioning, lead to the development and progression of testicular germ cell tumours.
Alterations in chromosome 12 (such as isochromosome 12p, duplication of 12p, or amplification of shorter stretches of 12p) are found in nearly all invasive testicular germ cell tumours, as well as in some forms of its precursor carcinoma in situ. Another typical abnormality is an excessive number of chromosomes, including triploidy (having 3 sets of chromosomes instead of the normal 2 sets) and tetraploidy (having 4 sets of chromosomes).
Mutations in single genes are uncommon in testicular germ cell tumour. The most frequent are found in five genes (KIT, TP53, KRAS/NRAS, and BRAF), while only in very few cases mutations are found in other genes (FGFR3, HRAS, PTEN, SIK1, SMAD4, STK10, and STK11).
The presence or absence of some of these mutations may help identify men at higher risk of cancer, or patients with a better or worse prognosis, or who can benefit more from certain treatments, but these issues are still being studied.

2.1.8 Disease stats
2.1.8.1 Incidence and mortality

Although testicular cancers are rare, accounting for 0.7% of all cancers in males, in many countries they are the most common malignancy in young men (15-35 years). Approximately 98% of testicular cancers are germ cell tumours.
The age-standardized incidence[number of new cases in a year for each age range] rate for testicular cancers ranges widely across the world. In 2012, white males living in Western industrialized countries, particularly in Northern and Western Europe, showed the highest annual incidence rates (12 per 100,000 males in Denmark, Norway, and Switzerland), whereas black males in Africa showed the lowest rates (less than 0.5 per 100,000 in most African countries). The disease is also relatively frequent in Australia and New Zealand (incidence rate 7 per 100,000), and in the USA and Canada (5 per 100,000). Even in Central and South America we found large differences among countries, from 7 per 100,000 (Chile) to less than 1 per 100,000 (Guatemala, Nicaragua).
According to the RARECAREnet project, a network that follows rare cancers in Europe (http://www.rarecarenet.eu/rarecarenet) among five European regions, incidence was highest in the North and Centre (3.7 and 3.8 cases per 100,000 person per year, respectively) and lowest in the South of Europe (2.5).
Germ cell tumours have an early incidence peak in the 0-4 year age group, followed by a second peak in adolescents and young adults (15-19, 25-29, and 30-34 years).
The most common forms in children are non-seminomas, mostly yolk sac tumour and teratoma. Non-seminomas remain more common than seminomas until 30 years of age, but between 15 and 30 years the most common forms are embryonal carcinoma and mixed germ cell tumour, followed by teratoma and yolk sac tumour. Beyond 30 years of age, seminomas prevail. Overall, seminomas presented an incidence peak 10 years later than non-seminomas.
Incidence has increased in many high-risk areas, such as Europe and North America, where white men have experienced the greatest increases throughout the late 20th century, and it is still increasing in most European countries.
By contrast, mortality, which is very low, has declined since the mid Seventies, thanks to the development of effective treatments centred around platinum-based chemotherapy. The recent mortality trend analyses (1980-2010) show a levelling off in the last years, suggesting that a plateau in mortality has been reached.

2.1.8.2 Prevalence

In Europe, at the beginning of 2008 about 476,000 persons were living with a diagnosis of testicular cancer (93 per 100,000 males). The 5-year prevalence (the number of living people who received a diagnosis of testicular cancer 5 or less years before) was only 16 per 100,000 (80,000 people). Of the total population with testicular cancer, 55% are long-term survivors, who were diagnosed 15 or more years before.

2.1.8.3 Survival

Survival from testicular and paratesticular cancer for men diagnosed in Europe during 2000-2007 was 97% at one year and 95% at five years, the highest survival rate for any malignant tumour in men. Seminomas had the highest 5-year survival rate (98%) followed by spermatocytic seminomas (95%) and non-seminomas (93%). Survival was consistently lower for patients aged 65 years or more (73% at 5 years, based on 1,308 cases) than for younger patients.
Survival has been improving since the early 1980s, though in Europe it remained stable during 1999-2007.
Even though testicular cancer is curable, in 2000-2007 there were disparities in 5-year survival across European regions. Survival was lowest in Eastern Europe (88%) and highest in Northern Europe (97%); in the other regions it was between 96% and 94%. This variability is not explained by differences in the age distribution or biological features of testicular cancers, and it is probably due to differences in accessibility of effective treatment. In fact, it has been found that lower survival is linked to deprivation, with higher survival for men in affluent groups. Survival reached 94% at 5 years after diagnosis for most affluent patients diagnosed in 1986-1990, while for deprived groups it was about 6% lower. In 1991-2001 survival improved more in the deprived group, reducing the gap to 1.5% at 5 and 1.2% at 10 years. This narrowing of the deprivation gap appears to reflect a “ceiling effect”: available treatments are reaching their maximum efficacy, so there is little room for further increase in survival among the most affluent group.
It is important to note that survival data reported here derive from population-based cancer registries, which collect and keep detailed records about cancer patients and their treatments and outcomes, allowing us to evaluate parameters such as incidence and survival, to look for cancer causes and measure progress in its treatments.

2.2 Risk factors

Undescended testis, or cryptorchidism, is the most recognized risk factor for testicular cancer. The risk of cancer is increased by 2-fold to 8-fold in men who have had undescended testis, and 5%-10% of all men with testicular cancer have had cryptorchidism. If undescended testis is treated before puberty, this can prevent testicular cancer. In fact, a cohort of about 20,000 Swedish boys treated for their cryptorchidism with orchiopexy indicates that age at orchiopexy has an effect on the risk of testicular cancer: people treated at the age of 13 or later had a risk increased by 5.4-fold compared to the general population, about twice the risk of those treated at younger ages.
A family history of testicular cancer increases the risk: from the Swedish Family Cancer Database, the incidence ratios for familiar risk were almost 4- and 8-fold, respectively, when the father or brother had testicular cancer.
Several studies show that a previous history of testicular cancer is strongly associated to a second cancer in the other testis. Two studies, from the Netherlands and New Zealand, reported a highly increased risk (25-28 times higher than the general population) of a tumour in the other testis in patients who previously had testicular cancer. A large study involving about 30,000 US men estimated a lower risk increase (12 times) of developing cancer in the other testis.
A systematic review of pre- and perinatal variables focused on maternal characteristics, and revealed that the risk is influenced by birth order (risk increased by 8% for firstborn vs. subsequent children), sibship size (risk decreased from 7% to 25% for 2, 3, or 4 siblings vs. one), and maternal bleeding (risk increased by 33%). Bleeding is generally the result of some aberration occurring during pregnancy, such as an abnormal placenta, which might disrupt foetal development and increase risk for cancer.
Exposure to chemicals that disrupt endocrine functions during the foetal period has been postulated to be a risk factor for testicular cancer. Endocrine disrupting chemicals are substances able to interact with the human endocrine systems such as the system of the sexual hormones testosterone and oestrogen. Pentachlorophenol, bisphenol A, and phthalates are examples of such chemicals to which humans are exposed via the environment. In a Swedish study, higher levels of certain endocrine disrupting chemicals (chlorinatedbiphenyls or PCBs, p,p’-dichlorodiphenyl-dichloroethylene or pp’-DDE, hexachlorobenzene or HCB, chlordanes, and polybrominated diphenylethers or PBDEs) were found in the blood of mothers of testicular cancer patients compared with control mothers. A risk about 4 times higher was estimated for exposure to a combination of PCBs. Most patients were born during a period in which the concentrations of such chemicals in the environment were at their highest levels. Since then, thanks to increased environmental attention and stricter laws, the concentrations of these chemicals have fallen substantially. In Sweden testicular cancer incidence increased much more in the period 1984-1993 than in 1994-2003, when levels of such chemicals had fallen, supporting the hypothesis that exposure to some of these chemicals during the foetal period contributes to promote testicular carcinogenesis.
Another systematic review and meta-analysis of perinatal variables, with specific focus on characteristics of the son, provides evidence that low birth weight, gestational age, inguinal hernia, cryptorchidism, and twinning are associated with a higher risk of testicular cancer. These conditions caused an increase in risk ranging between 22% and 63%, excluding cryptorchidism, which increased risk 4.3 times. A subsequent Swedish study confirmed that genital malformations were associated with increased risk of testicular cancer; in addition to cryptorchidism and inguinal hernia, even hypospadias (2.4 times) was reported. Some of these factors are related and could arguably indicate that problems occurred in the uterine environment during pregnancy. There is evidence that exposure to maternal hormones, particularly oestrogens, increases testicular germ cell cancer risk (4.9 times).
Average height and the incidence of testicular cancer have both been increasing over several generations. A systematic review and meta-analysis confirmed the association between risk and height (a 13% risk increase per 5 cm increase in height). This link may be explained by several mechanisms, including childhood nutrition, increased levels of insulin-like growth factors, or an earlier age at puberty in taller boys. Adult height is largely determined in the period between birth and age 2 years, therefore nutrition at this age may be particularly relevant to testicular cancer risk.
Several occupational exposures have been suggested to be associated with testicular cancers, such as exposure to polychlorinated biphenyls, electromagnetic fields, and pesticides. In addition, several occupations seem to increase risk: firemen, policemen, military personnel, agricultural workers, and industrial (paper, plastic, or metal) workers appear to be at higher risk. Since testicular cancer occurs mainly in young adults, it should be considered that occupational exposure of pregnant women to endocrine disruptors could harm the foetus.
Other exposures – to heat, polyvinyl chloride, non-ionizing radiation, heavy metals, agricultural work, and polychlorinated biphenyls, as well as marijuana use – might have an association with testicular cancer, but this has not yet been definitely proved.

2.3 What are the symptoms?

The usual presentation of testicular cancer is a painless mass in one testicle; in some cases there is only diffuse testicular pain, or hard swelling within the testis. Acute onset of pain is rare, unless the patient has concomitant epididymitis or develops bleeding within the testis.
Gynaecomastia is sometimes present if the HCG hormone is elevated (in choriocarcinoma and some seminomas). Some patients present with abdominal or back pain (if large retroperitoneal lymph node metastases are present) or other symptoms caused by metastases (i.e., to the lung or brain). Only 5% of all germ cell tumours are found outside the testicles.

2.4 Diagnosis

There are no reliable screening tests for testicular cancer. Due to low occurrence and a high cure rate, testicular self-examination and the impact of self-assessment are controversial.
Most testicular germ cell tumours are detected as a painless mass in one testicle at initial examination. To diagnose the tumour, doctors ask patients for a complete history, including information about previous inguinal or scrotal surgery, undescended or maldescended testicles, retractile testes, and orchiopexy. Doctors will also perform a physical examination of the testis, by carefully palpating the organ to look for any nodule or hard or fixed areas, and of other areas where lymph node metastases could be present (abdomen, supraclavicular regions). Furthermore, they will look for the presence or absence of gynaecomastia.
If a testicular tumour is suspected, testicular ultrasound will probably be performed, to confirm the presence of a testicular mass and to explore the contralateral testis. Ultrasound detects almost all testicular tumours and helps to determine whether a mass is inside or outside the testicle. It may be unnecessary when the presence of a testicular tumour is already evident.
The high cost of magnetic resonance imaging (MRI) does not justify its use for diagnosis of testicular tumours, as ultrasound is already very effective.
When a testicular tumour is diagnosed, a radical orchiectomy is performed (the testicle and spermatic cord are removed), both to treat the tumour and to analyze tumour tissue, in order to stage it (see 4., Stages of germ cell tumours of the testis) and decide on further treatment and follow-up.

3. How are germ cell tumours of the testis treated?

3.1 Treatment strategy

3.1.1 General considerations

Testicular germ cell tumours are divided into seminoma and non-seminoma types for treatment, because seminomatous testicular cancers are sensitive to both radiotherapy and chemotherapy, while non-seminomatous tumours are sensitive to chemotherapy alone. Tumours that appear as seminomas but are accompanied by elevated serum levels of alpha-fetoprotein (AFP) should be treated as non-seminomas. Non-seminomatous testicular tumours include embryonal carcinoma, teratoma, yolk sac carcinoma, choriocarcinoma, and various combinations of these cell types. Tumours which have a mixture of seminoma and non-seminoma components should be managed as a non-seminoma.
It is important to note that even patients with widespread metastases at presentation, including brain metastases, may still be curable.

3.1.2 Surgical therapy

The standard initial treatment is removal of the affected testicle with an operation called radical inguinal orchiectomy (the testicle and spermatic cord are removed through an inguinal incision). This procedure serves both for diagnosis and staging, providing tumour tissue for analysis, as well as treatment, removing the primary tumour and minimizing the risks of local recurrence and tumour spread.
A prosthesis can be inserted to replace the removed testicle.
Other surgical procedures that cut into the scrotum have been used to reach the testicle both for diagnosis and treatment, including trans-scrotal orchiectomy (testicle removal cutting through the scrotum), open testicular biopsy (a biopsy performed cutting through the scrotum), and fine needle aspiration (a biopsy performed inserting a needle into the lump under the skin).
However, trans-scrotal orchiectomy is not recommended because it leaves the inguinal (upper) portion of the spermatic cord intact and increases the risk of metastases to scrotal skin and nearby lymph nodes.
Furthermore, it was thought that the incision of the scrotum (known as scrotal violation) increased the risk of tumour dissemination and distant metastases. However, a systematic review of all published studies between 1958 and 1993, including more than 200 patients who underwent scrotal violation, found that, in contrast to traditional beliefs, the overall distant recurrence rate was not significantly different between inguinal surgery (11.5%) and scrotal violation (12.7%) and the survival rates were similar; the local recurrence rates were higher for scrotal violation, but still low (0.4% vs. 2.9%). So, it is still debatable whether scrotal violation leads to a worse outcome, or if it requires stronger local therapies (with potential adverse consequences) to prevent recurrences, and further evaluation is needed before firm conclusions can be made regarding its safety.
Besides testicle removal, another kind of operation, retroperitoneal lymph node dissection (RPLND), is used in patients with lymph node metastases (see 3.8.2)

3.2 Carcinoma in situ (CIS) of the testis

Diagnosis of carcinoma in situ is based on testicular biopsy. The management of carcinoma in situ of the testis may involve:

  • orchiectomy;
  • simple surveillance (also called wait-and-see; waiting and checking how the disease evolves before deciding if treatment is necessary), proceeding to orchiectomy only when an invasive tumour develops;
  • low-dose testicular irradiation (delivered over 10 sessions, 5 sessions per week).

3.3 Seminoma, general information

Pure seminomas (not mixed with other types of testicular cancer cells) are characterized by high sensitivity to radiation and relatively slow growth of micrometastases.
The initial standard treatment of unilateral seminoma of the testis is radical inguinal orchiectomy (see 3.1.2).
If a patient has a small-sized primary tumour, and the other testis has already been removed or is not functioning, a testicle-conserving treatment may be considered (only the tumour and not the whole testis is removed, and testicular radiotherapy follows).
After testicular surgery, the management depends on disease stage, as detailed below (see 3.4 to 3.7) (for staging see: 4., Stages of germ cell tumours of the testis).
If pure seminoma cells are rapidly dividing (what is known as anaplastic seminoma), or the tumour is producing the HCG hormone, this does not alter the course of the disease nor its treatment. Whereas, if the tumour appears to be a pure seminoma but serum levels of AFP are elevated, it should be treated as a non-seminoma.
Spermatocytic seminomas (see 2.1.3), which are usually diagnosed in men older than 60 years and almost never metastasize, can be treated by orchiectomy alone.
For patients with seminoma, of all stages combined, the cure rate exceeds 90%.

3.4 Clinical stage I seminoma

In clinical stage I seminoma, the clinical, radiologic, and biochemical (blood) examinations performed after orchiectomy find no anomaly (no spread of cancer cells or abnormal blood levels of tumour markers, see 4.). Approximately 80% of patients with seminoma present with stage I disease and most of them are cured by orchiectomy alone.
The relapse rate is 14%-20% at 5 years and most relapses are first detected in infra-diaphragmatic lymph nodes. In most recent reports, half of the relapses occurred within 14-15 months and approximately 95% of the relapses occurred within 5 years.
According to an international study of more than 600 men, if the tumour is greater than 4 cm or if it invades the rete testis the risk of relapse increases; reported relapse rates were of 31.5%, 15.9%, and 12.2% in patients with both, one, and neither of these two risk factors, respectively. However, some subsequent reports did not confirm these findings. Nevertheless, these factors are sometimes used to choose between simple surveillance or adjuvant treatment.
Management options after surgery include active surveillance, adjuvant chemotherapy, and adjuvant radiotherapy. However, overall survival of patients with stage I seminoma is around 99%, regardless of the chosen strategy. Currently, most authors and international guidelines recommend an individualized decision: patient’s individual risk factors are identified, he is informed about them and is involved in a discussion about the potential risks and benefits of each of the various management strategies, helping him decide which management to choose.

3.4.1 Adjuvant radiotherapy

The traditional management after radical inguinal orchiectomy has been with preventive irradiation of the retroperitoneal nodes, which is recommended even when CT does not show metastases, because about 15% of patients have small groups of cancer cells not seen in imaging exams (occult metastases or micrometastases) in some lymph nodes, that can be cured with irradiation.
Up to the 1990s, standard radiotherapy was applied to a large group of lymph nodes: ipsilateral iliac and para-aortic lymph nodes (“dog-leg” fields). Treatment was given 5 days per week, up to total doses of 26-30 Gy. To reduce acute and late toxicity, attempts have been made to decrease the treatment burden, both by reducing the irradiated area and lowering the dose of radiation.
A trial carried out from 1989 to 1993 by the UK’s National Cancer Research Institute Testis Cancer Clinical Studies Group, compared conventional “dog-leg” radiotherapy with the same amount of irradiation given only to the para-aortic lymph nodes, but not to the iliac ones (except in some patients with more advanced disease). The two treatments were nearly equally effective in controlling cancer (3-year overall survival rate 99.3% vs. 100%), but the reduced irradiation caused fewer side effects.
Furthermore, in the 1990s some small studies had suggested that a lower radiation dose might be equally effective. So The National Cancer Research Institute performed another large trial, on more than 1,000 patients, to check if the dose could be reduced without losing efficacy. Again, the trial showed that irradiation with only 20 Gy is as effective as the classical 30 Gy in reducing relapses, but causes fewer short-term side effects.
From these trials, the following can be concluded:

  • if preventive radiotherapy is indicated, a reduced dose given to a limited area (20 Gy to a para-aortic lymph node area) represents the current standard treatment in patients with not too advanced stage I seminoma (stage pT1, pT2, or pT3) who did not receive a previous inguinal or scrotal surgery on the affected side (because this surgery can alter local lymph vessels, allowing cancer cells to spread to a wider area);
  • patients with pT4 tumours or who received previous inguinal or scrotal surgery on the affected side should have dog-leg field irradiation;
  • if orchiectomy was performed with a scrotal incision, the scrotum should be included in the irradiated area, but only if there is a high risk that it has been contaminated by tumour cells during the surgery.

Adjuvant retroperitoneal radiotherapy is contraindicated:

  1. in patients with a horseshoe kidney, because in these kidneys there is a high risk of renal failure induced by radiation;
  2. in patients who are being treated for a second testicular germ cell tumour which developed after the first one; if these patients have already undergone a prior retroperitoneal lymph node dissection or retroperitoneal radiotherapy, they should be followed with active surveillance at short intervals;
  3. in patients with inflammatory bowel disease; observation or adjuvant chemotherapy are preferred options in these patients.

3.4.2 Adjuvant chemotherapy

If adjuvant chemotherapy is chosen, one course of the drug carboplatin is now recommended.
Preliminary small trials suggested that chemotherapy could substitute radiotherapy as an adjuvant treatment to prevent recurrences after tumour removal, with less toxicity and similar effectiveness. To answer this question, between 1996 and 2001 the UK Medical Research Council and the European Organisation for Research and Treatment of Cancer (EORTC) groups conducted a trial on almost 1,500 patients from 70 hospital in 14 countries, randomly assigned to receive either radiotherapy or one cycle of carboplatin. However, neither treatment showed a clear superiority over the other. Therefore, as previously mentioned, patients can discuss the pros and cons of the various available choices with their doctor, considering that overall survival of patients with stage I seminoma is, in any case, around 99%, regardless of the chosen strategy.

3.4.3 Active surveillance

After surgery, some centres prefer not to immediately treat patients with preventive radiotherapy or chemotherapy, but to choose active surveillance: at first, they do not schedule any treatment, but only regular visits and exams, to check how the disease evolves, and proceed to treatment only if there are signs of disease progression or relapse.
The reason for this choice is that 80% of patients with stage I seminoma do not have occult metastases, so for them radiotherapy or chemotherapy, with their short-term and (although rare) long-term toxicity, would be unnecessary overtreatment. After surgery, patients are followed up at short intervals for a long time, with monitoring of serum markers, chest x-rays, and CT/MRI abdominal scans.
No randomized trial has compared the surveillance strategy with adjuvant radiotherapy or chemotherapy in stage I seminoma, but the strategy has been validated in a number of large studies. Between 14% and 20% of these patients have relapsed, predominantly in the retroperitoneal lymph nodes. Half of the relapses occurred within 14-15 months and approximately 95% within 5 years. Patients who had recurrences received radiotherapy or, more often, chemotherapy, and the overall survival rates were similar to those observed with adjuvant therapy (around 99%). So, overall, active surveillance avoids unnecessary treatment and toxicity in 80%-85% of stage I seminoma patients.
Therefore, it has become the preferred approach in most guidelines for stage I seminoma and it is now the most common management option for these patients in the United States.

3.5 Clinical stage II seminoma

3.5.1 Treatment strategy

While in stage I seminoma the tumour is still confined to the testis, in more advanced stages it has spread. In stage II the tumour has spread to retroperitoneal lymph nodes, but not to other organs. About 15%-20% of patients with advanced seminoma present with enlarged retroperitoneal lymph nodes because of tumour cells, but no signs of metastases elsewhere, and thus have stage II disease (see 4., Stages of germ cell tumours of the testis).
The size of the largest enlarged lymph node has been used to subcategorize stage II seminoma into nonbulky disease (stage IIA and IIB) and bulky disease (stage IIC) for treatment planning and prognosis: bulky disease is defined as a tumour greater than 5 cm on a CT scan.
While chemotherapy is doubtless indicated for bulky disease, much controversy exists regarding the optimal choice between chemotherapy and radiotherapy for nonbulky disease. As patients with disease at this stage are rare, only a few studies with small numbers of patients have been performed, and no definitive recommendations exist regarding the superiority of one option over the other. While overall survival is almost 100% irrespective of treatment, relapse-free survival approximates 90%, and it is not known if chemotherapy and radiotherapy lead to the same results regarding relapse-free survival, long-term side effects, or the risk of developing a second cancer.

3.5.2 Nonbulky disease (stage IIA and IIB)

Standard of post-surgery care for stage IIA and IIB testicular seminoma is radiotherapy or cisplatin-based combination chemotherapy.
For stage IIA, the preferred approach by most investigators is radiotherapy to the para-aortic and ipsilateral iliac lymph nodes (“dog-leg” fields), the same as for stage I seminoma (see 3.4.1) but with a higher dose, delivered over 3-4 weeks. Relapses occur in 10%-15% of the patients.
Prophylactic irradiation to other areas (mediastinal/supraclavicular radiotherapy) was used in the past, but today is no longer given for stage II testicular seminoma, due to its late toxicity.
Radiation to inguinal nodes is used only in selected cases, such as when there has been some damage to the scrotum, so that cancer could have spread to inguinal lymph nodes.
Retroperitoneal radiotherapy is contraindicated in patients with:

  • a horseshoe kidney;
  • a second testicular germ cell tumour appearing after the first one;
  • inflammatory bowel disease.

If one of these three contraindications to radiotherapy is present, then chemotherapy is recommended.
For stage IIA seminoma – based on two studies (by the Spanish Germ Cell Cancer Group and the Swedish and Norwegian Testicular Cancer Project – SWENOTECA – study) which got excellent progression-free survival – the European Society for Medical Oncology recommends cisplatin-based chemotherapy (BEP or PE) or modified dog-leg radiotherapy, with no preference for one option over another.
For stage IIB disease, in the past a distinction was made between patients with low- and high-volume disease (thus called according to the number and size of lymph nodes affected by the tumour), but now, based on the excellent progression-free survival in the SWENOTECA study, most international guidelines recommend three cycles of cisplatin, etoposide, and bleomycin (BEP) chemotherapy, regardless of tumour burden. Bleomycin may be contraindicated in some patients, e.g., those with lung or renal problems; in these cases, four cycles of cisplatin and etoposide (PE) may be used. In stage IIB patients in whom chemotherapy would be unsuitable, or who have a low-volume disease (a solitary retroperitoneal node measuring 2.1-3.0 cm), modified dog-leg radiotherapy may be employed.
A combined treatment, with a single course of carboplatin chemotherapy followed by para-aortic radiotherapy, has been investigated for stage IIA and IIB seminoma to further reduce the risk of relapses. Recently, it gave promising results in a small pilot study, reducing relapse rates compared with radiotherapy alone and allowing to reduce the irradiated area, but it still needs further investigation.

3.5.3 Bulky disease (stage IIC)

In patients with bulky disease (stage IIC), after surgery combination chemotherapy is recommended: BEP or PE chemotherapy cures nearly 90% of these patients.

3.6 Clinical stage III seminoma

When distant metastases are present, seminoma is in stage III and the standard of care is radical inguinal orchiectomy followed by chemotherapy.
According to the International Germ Cell Cancer Collaborative Group (IGCCCG), the chemotherapy regimen for metastatic patients depends on their prognosis (evaluated according to several parameters: see 4.2, Classifications for metastatic germ cell tumours). Three cycles of BEP (cisplatin, etoposide, and bleomycin) or 4 cycles of PE (etoposide, cisplatin) are recommended for good prognosis patients. For intermediate prognosis patients, 4 cycles of BEP are recommended; alternatively, if there are reasons to avoid bleomycin (e.g., because of lung or renal problems), 4 cycles of VIP (etoposide, ifosfamide, cisplatin) can be used, which in a randomized trial showed similar efficacy but more toxicity. These approaches should lead to an overall cure rate of about 90%.

3.7 Post-chemotherapy management

After completion of chemotherapy, it is common to see residual masses in radiological images. Usually you should not be worried because these masses are often scar tissue, remnants of dead tumour, and regress spontaneously over a few months. Sometimes, however, a mass could be a residual malignancy. Some studies have shown that there is residual seminoma in 27% of cases, and that a mass is more likely to be a residual tumour if it is large (more than 3 cm), but other authors indicate that most residual masses do not grow, regardless of their size, so the treatment of residual masses is still controversial.
Simple surveillance is usually preferred when the residual mass is equal to or less than 3 cm. For lesions larger than 3 cm, an imaging exam called FDG-PET (2-fluor-2-deoxy-D-glucose PET scan) is recommended, at least 6 weeks after ending chemotherapy. If the FDG-PET shows no residual cancer tissue, only follow-up is needed. If it shows residual cancer, a biopsy might be carried out to confirm that the tumour is present, followed by irradiation or removal of the mass, as determined by the doctor.

3.8 Clinical stage I non-seminoma

3.8.1 Treatment strategy

In 50% of patients with testicular non-seminomatous germ cell tumours, the tumours are confined to the testis at the time of the initial diagnosis, so they are classified in clinical stage I. However, despite refinement of radiologic imaging, 15% to 40% of these patients are understaged: retroperitoneal metastases are found in approximately 30% of patients judged preoperatively to be clinical stage I.
After initial orchiectomy without any additional treatment, about 25%-30% of patients relapse, usually in the first year of follow-up, and there is still no reliable way to definitely distinguish between tumours with a high or low risk of relapse. However, several studies identified a few factors that influence the risk. The following are among the most important factors: whether the primary tumour cells have invaded blood vessels (this appears to be the strongest predictive factor), whether they have invaded lymphatic vessels, whether the primary tumour cells appear as an embryonal carcinoma, and whether they do not appear as a yolk sac tumour. Other relevant factors seem to be: the absence of teratoma cells; whether the tumour has invaded the rete testis; preoperative blood levels of alpha-fetoprotein (AFP) and the presence of Ki67; if the tumour is large or at an advanced pathologic stage; and age of patient. Still other factors are being investigated as promising predictors. Recently, a large study showed that in patients with vascular invasion, rete testis invasion, and presence of embryonal carcinoma, the 5-year relapse rate was 50%; if only vascular invasion was present the 5-year risk of relapse was 18%; if none of the risk factors were present, 12% had a relapse.
Regarding treatment choices after orchiectomy, the first distinction to be made is between 2 situations:

  • If patients with clinical stage I non-seminoma have elevated HCG and/or AFP levels which persist after surgery (classified as clinical stage IS), this means that they have metastatic disease and must be treated with chemotherapy.
  • In patients with clinical stage I non-seminoma and with HCG and AFP levels which are normal or falling as expected after surgery, there are three standard treatment options:
    • nerve-sparing retroperitoneal lymph node dissection (NSRPLND);
    • surveillance;
    • adjuvant chemotherapy.

Each of these methods has advantages and disadvantages, but survival is excellent with all of them, with 98%-100% of patients alive at 5 years. Therefore, the choice of therapy in an individual patient is based on the cancer’s specific histological features, short-term and long-term side effects expected by treatment, and individual patient preferences and options.
Non-seminomatous germ cell tumours are resistant to irradiation, so radiotherapy has no role in their initial treatment.
Most experts propose a risk-adapted strategy based on the classification of stage I non-seminoma patients into “low risk” (20% relapse rate) and “high risk” (40%-50% relapse rate) by absence or presence of vascular invasion.
In low-risk patients they propose surveillance as the preferred approach. If surveillance is not feasible, e.g., if the patient has difficulties in undergoing repeated imaging, if he is unable to adequately follow the schedule of visits and exams, or if he has other preferences, then adjuvant chemotherapy is given.
Adjuvant chemotherapy is also indicated in high-risk patients, and in patients with other diseases that might compromise the full course of treatment needed if cancer recurred.
In patients not suitable for surveillance nor for adjuvant chemotherapy, a surgery called “nerve-sparing retroperitoneal lymph node dissection” is an option (see below, 3.8.2). Some experts also consider this type of surgery to be the best treatment for the rare patients whose primary tumour is a teratoma containing malignant transformed cells. This surgery should be performed in highly experienced centres.

3.8.2 Nerve-sparing retroperitoneal lymph node dissection (NSRPLND)

This surgery is performed to remove retroperitoneal lymph nodes, which could contain microscopic metastases not seen in radiologic images, in order to provide more accurate staging of retroperitoneal nodes and reduce relapse risk. Other potential advantages are to decrease the amount of chemotherapy needed and eliminate the need for screening of the retroperitoneum after primary tumour removal. Challenges and risks include the possible lack of surgical expertise, the lack of a uniform approach to the surgery, its possible short-term undesired effects, and the small but significant risk that it may cause retrograde ejaculation.
When the surgery is performed in patients who were classified as clinical stage I, retroperitoneal metastases are found in lymph nodes in 27%-28% of them. Bilateral NSRPLND not only is useful to get a more accurate prognosis, but cures 50%-90% of patients whose disease has metastasized to retroperitoneal lymph nodes.
In the past, a less accurate surgical procedure was performed, which often damaged local nerves, causing most patients to experience retrograde or lack of ejaculation and consequent sterility. Over the years this procedure (called simply “bilateral retroperitoneal lymph node dissection”, or RPLND) has been modified to spare these nerves, leading to nerve-sparing retroperitoneal lymph node dissection (NSRPLND), which is as effective as the standard procedure, but makes it possible to maintain ejaculation in more than 90% of patients.
However, the surgery is not simple and studies show that it gives better results if performed in a specialized centre where a great many of these procedures are performed. The most common side effects include about a 1% chance of a small bowel obstruction due to surgical adhesion and a 3%-5% chance of developing a hernia.
After NSRPLND there are several possible treatments:

  • if no metastases are found in the removed lymph nodes, confirming pathologic stage I disease, a simple follow-up will be performed. Around 10%-15% of these patients will relapse, almost always within 2 years, but almost all of them will be cured by chemotherapy;
  • patients who relapse after RPLND usually present with pulmonary- or serologic-only disease. If surgery is performed in specialized centres, retroperitoneal recurrences are rare and postoperative CT scan of the abdomen to monitor for these relapses could be unnecessary. Therefore, monitoring entails physical examination, chest x-ray, and determination of serum markers (AFP and HCG), monthly for the first year and every other month for the second year. Chemotherapy is employed as soon as a recurrence is detected;
  • if metastases are found in the removed lymph nodes, this means that the disease had been understaged: unfortunately, it is not in pathologic stage I but in stage II. In these patients the relapse rate is 30% to 40%. These patients should be treated with surveillance or adjuvant chemotherapy (2 cycles of BEP or 2 cycles of EP), based on the number and size of the affected retroperitoneal lymph nodes and on tumour extension.
3.8.2.1 Laparoscopic retroperitoneal lymph node dissection

Retroperitoneal lymph node dissection can be performed in the standard way (open-RPLND or O-RPLND) or using a less invasive procedure called laparoscopy (L-RPLND). Several experienced surgeons have reported that laparoscopic dissection for stage I non-seminoma testicular cancer is technically feasible, but it requires a long, demanding learning process for the surgeons involved. It should reduce patient discomfort and recovery time, but can have a few disadvantages, and it has been difficult to assess its efficacy compared to the standard procedure.
In 2008, a systematic review of the largest studies concluded that, compared with standard open surgery, laparoscopic surgery shows no difference in relapse rates, use of chemotherapy, or need for subsequent salvage surgery, and in either approach almost no patients show evidence of disease after surgery. Laparoscopic dissection offers similar staging accuracy and long-term outcome and in experienced centres it might reduce complications. A more recent study also concluded that laparoscopic surgery appears to be safe, viable, and effective.
To date, laparoscopic retroperitoneal lymph node dissection is not recommended as a standard approach by European Association of Urology (EAU) and European Society for Medical Oncology (ESMO) guidelines, but in some cases it might be a good choice if performed by experienced laparoscopic surgeons.

3.8.3 Surveillance

In multiple series of patients who, after inguinal radical orchiectomy, underwent only close surveillance until any signs of disease relapse emerged, the risk of recurrence in stage I non-seminoma was approximately 30%.
Half of the relapses occurred within 5-6 months after orchiectomy, 90% occurred within 2 years, and only 1% occurred after more than 5 years. In 60% of patients, relapse occurred in the retroperitoneum, and in 20%-25% of patients in the lung. Elevation of serum tumour markers (see 4., Staging) is seen in about 60% of patients who relapse, and it is the only evidence of recurrence in 20% of cases.
The surveillance strategy aims to treat only those patients where a recurrence is detected, beginning treatment at a stage in which the disease is still highly curable. There are few prospective studies on surveillance and the best approach is still debated.
One surveillance schedule, the Royal Marsden schedule, involves monthly tumour markers and chest radiographs for the first year, chest radiographs every 3 months for the second year, and chest radiographs every 4 months in the third year, as well as CT scans of the abdomen at 3, 12, and 24 months. However, a number of guidelines recommend fewer assessments, which does not seem to cause clear detriment.
In summary, surveillance is a commonly recommended strategy for clinical stage I non-seminoma and it appears safe and effective. Open, honest communication about all aspects of management of the disease between doctor and patient is important, and may contribute to a satisfactory doctor-patient relationship and good adherence to follow-up schedules.

3.8.4 Adjuvant chemotherapy

Adjuvant chemotherapy following orchiectomy aims to reduce the risk of recurrences, so it may be used to avoid the risk of toxicities that may occur during the (stronger) full treatment necessary if disease relapses, and the disappointment and anxiety experienced when relapse occurs.
Initial studies suggested a benefit of adjuvant chemotherapy with two cycles of BEP for patients with stage I non-seminomatous tumours at high risk of occult metastatic disease and therefore at high risk of relapse (patients with a high volume of embryonal carcinoma in the orchiectomy specimen and vascular and lymphatic invasion, see above, 3.8.1). In two studies with patients at high risk who received adjuvant chemotherapy, the 2-year relapse rate was 2%-5% (compared to 50% predicted without chemotherapy).
However, even when patients have relapse, as many as 95% are cured with chemotherapy for recurrence.
The adjuvant chemotherapy trials are too small to draw conclusions about the late toxicity or risk of late relapse.
Recently, there have been compelling reports suggesting that even a single cycle of chemotherapy might provide similar benefits, so this could become an option.

3.9 Clinical stage II non-seminoma

3.9.1 Treatment strategy

In clinical stage II the tumour has spread to retroperitoneal lymph nodes, but not to other organs. Stage II non-seminoma is curable in more than 95% of patients.
The size of the largest enlarged lymph node has been used to subcategorize stage II tumour into nonbulky disease (stage IIA and IIB) and bulky disease (stage IIC) for treatment and prognosis: bulky disease is defined as a tumour greater than 5 cm on a CT scan.
In some patients with stage IIA-IIB non-seminoma, nerve-sparing retroperitoneal lymph node dissection (NSRPLND, see above, 3.8.2) is an option.
Most patients with stage II non-seminoma can be cured with chemotherapy and should be treated according to the International Germ Cell Cancer Collaborative Group (IGCCCG) prognostic group classification and recommendations (see below, 4.2).

3.9.2 Clinical stage IIA-IIB non-seminoma

The choice of treatment should be made according to the levels of serum markers and the IGCCCG prognostic group:

  • patients with elevated serum markers should be treated with cisplatin-based chemotherapy: in patients with good prognosis, BEP for 3 cycles, or EP (etoposide, cisplatin) for 4 cycles if bleomycin is contraindicated; in patients with intermediate or poor prognosis, four cycles of BEP or VIP. Higher doses did not prove superior to standard therapy in three randomized trials;
  • patients with normal serum markers might be treated by nerve-sparing retroperitoneal lymph node dissection. After surgery, the treatment should be based on the pathological features of the involved retroperitoneal lymph nodes: adjuvant chemotherapy with 2 cycles of BEP may be considered if viable cancer cells are found in the lymph nodes. If the tumour is a teratoma and it is completely resected, only follow-up is necessary;
  • among patients who undergo retroperitoneal dissection, those who have less than 6 lymph nodes with cancer cells, and no tumour invasion outside the lymph node capsule (pN1), should undergo regular follow-up (physical examination, chest x-ray, and serum marker tests). These patients have a relapse rate after retroperitoneal dissection of 20% to 30% and most are curable with chemotherapy at relapse. Presence of microscopic vascular (lymphatic or venous) invasion in the primary tumour can also help to predict which patients may relapse: after retroperitoneal dissection the relapse rate is higher in patients with vascular invasion (64%) than in patients without vascular invasion (24%);
  • in patients treated by retroperitoneal dissection who have 6 or more lymph nodes with tumour cells, or any node greater than 2 cm, or tumour invasion outside the lymph node (pN2), adjuvant chemotherapy should be considered. Two courses of adjuvant cisplatin-based chemotherapy are effective, curing almost all patients.

In general, for patients who have undergone retroperitoneal dissection, there is no clear superiority of an option over the other between surveillance and chemotherapy. A study performed by the Testicular Cancer Intergroup Study on 195 such patients showed that, after a median follow-up of 4 years, relapse-free survival was 49% in patients assigned to simple surveillance (with standard chemotherapy if a relapse was detected), as compared to 6% for patients who received 2 courses of adjuvant chemotherapy. But this did not change survival, as more than 90% of patients were cured in both groups, provided that an adequate NSRPLND was performed and meticulous follow-up observed if adjuvant chemotherapy was not used.

3.9.3 Clinical stage IIC non-seminoma

In patients with clinical stage IIC non-seminoma, who have large retroperitoneal masses which would be difficult to resect, chemotherapy is recommended.
Patients with good prognosis (see below, 4.2) should receive 3 cycles of BEP, or 4 cycles of EP if contraindications against bleomycin exist. Other regimes (such as PVB or VAB-VI) have equivalent anticancer activity but more toxicity.
Patients with intermediate or poor prognosis should usually receive 4 cycles of BEP. In case of contraindication to bleomycin, four cycles of VIP are used.
Four (to eight) weeks after the last cycle of chemotherapy, tumour marker tests as well as imaging should be carried out.
In case of complete response (normal markers, no retroperitoneal lymph nodes larger than 10 mm), no further treatment is necessary.
In patients who do not achieve a complete response after chemotherapy (they still have retroperitoneal lymph nodes larger than 10 mm) but who obtain normalization of serum markers, nerve-sparing RPLND should be performed to evaluate the enlarged lymph nodes. Residual masses in enlarged lymph nodes may contain only scar tissue (called fibrosis and necrosis, found in 45%-50% of resected residual masses), teratoma (35%) or viable germ cancer cells (15%-20%). Resection is necessary to check if only scar tissue is present (meaning that the treatment eliminated tumour masses); or to prevent regrowth of teratoma or growth of other non-germ cell elements that might be present; or to determine if viable tumour cells are present.
If viable malignant cells are still present in the resected masses, further chemotherapy might be necessary. In an analysis of these patients, three factors prognosticated both a higher progression-free survival and a higher overall survival: complete resection, a low number (less than 10%) of viable malignant cells, and a good International Germ Cell Consensus Classification (IGCCC) group (see below, 4.2). The analysis showed that immediate postoperative chemotherapy or surveillance alone with chemotherapy at relapse may both be reasonable options in these patients, depending on the completeness of resection, percentage of viable cells, and IGCCC group.

3.10 Clinical stage III non-seminoma

3.10.1 Treatment strategy

When metastasis beyond retroperitoneal lymph nodes is present, the disease is in stage III. Treatment should be decided according to the IGCCCG prognostic factor-based classification for metastatic gem cell tumours (see below, 4.2).

  • In good prognosis tumours (5-year progression-free survival: 89%; 5-year overall survival: 92%), after orchiectomy the treatment is based on chemotherapy (3 cycles of BEP or 4 cycles of EP; see 3.10.2.1), followed by surgical resection of residual masses (see 3.10.3).
  • In intermediate (5-year progression-free survival: 75%; 5-year overall survival: 80%) or poor prognosis (5-year progression-free survival: 41%; 5-year overall survival: 48%) tumours, after orchiectomy the standard treatment is 4 cycles of BEP chemotherapy (see 3.10.2.2), followed by surgical resection of residual masses (see 3.10.3). If bleomycin is contraindicated, 4 cycles of VIP can be used.

High-dose chemotherapy and autologous bone marrow transplantation failed to demonstrate any advantage as first-line treatment for intermediate and poor prognosis patients in several trials.
Many poor-risk patients who have elevated levels of HCG at the start of chemotherapy may still have an elevated level at the completion of chemotherapy. In the absence of other signs of progressive disease, monthly evaluation may be indicated, with the initiation of salvage therapy only if levels of serum markers increase further. However, some patients will remain disease-free without further therapy.

3.10.2 Chemotherapy
3.10.2.1 Good prognosis metastatic non-seminomatous germ cell tumours

In good prognosis metastatic non-seminomatous germ cell tumours, chemotherapy is recommended. Three cycles of BEP (bleomycin, etoposide, cisplatin) are strongly recommended. A recent study has shown that this regimen is equivalent to 4 cycles of EP (etoposide, cisplatin), which can be chosen if there are reasons to avoid bleomycin (e.g., there is a maximum total dose of bleomycin –  270 mg/m2 – that should not be exceeded to avoid pulmonary toxicity).

3.10.2.2 Intermediate and poor prognosis metastatic non-seminomatous germ cell tumours

The standard chemotherapy for intermediate and poor prognosis metastatic non-seminomatous tumours is 4 cycles of BEP. Trials showed that BEP is less toxic than VIP[etoposide, ifosfamide, cisplatin], and it is more effective and less toxic than PVB. Other regimes have been tried as well, e.g., using higher doses of some drugs, or alternating different combinations, or high-dose chemotherapy and autologous bone marrow transplantation, but no advantages and sometimes higher toxicities have been found.
It is important to remember that even patients with widespread metastases at diagnosis, including brain metastases, may still be curable and should be treated with this intent.

3.10.3 Surgery after chemotherapy

In patients responding to chemotherapy who do not achieve a complete response because there are residual masses, but obtain normalization of serum markers, surgical resection of all residual masses should be performed. Resection is necessary:

  • to diagnose if the masses contain only scar tissue, meaning that response to chemotherapy was complete;
  • to check if the masses contain teratomas and prevent their regrowth: mature teratoma may grow rapidly, may become unresectable or may cause vascular or ureteral obstruction;
  • teratomas may also become malignant, so resection prevents their malignant transformation;
  • to determine if the resected masses contain viable tumour cells: the presence of persistent viable malignant cells indicates that further chemotherapy is needed.
    Residual thoracic masses should always be removed.

In some patients, chemotherapy is initiated prior to orchiectomy because metastases are life-threatening. After initiation or completion of chemotherapy, orchiectomy is in any case advisable in these patients, due to the high incidence of residual cancer in the testis after chemotherapy with platinum-based regimens.
If viable malignant cells are still present in the resected masses, further chemotherapy might be necessary. In a study of these patients, three factors prognosticated both a higher progression-free and a higher overall survival rate: complete resection, a low number (less than 10%) of viable malignant cells, and a good International Germ Cell Consensus Classification (IGCCC) group (see below, 4.2). The analysis showed that immediate postoperative chemotherapy or surveillance alone with chemotherapy at relapse may both be reasonable options in these patients, depending on the completeness of resection, percentage of viable cells, and IGCCC group.

3.11 Recurrent or refractory disease

About 10% to 30% of patients with advanced germ cell tumours relapse (recurrent patients) or fail to achieve a complete response to first-line cisplatin-based therapy (refractory patients), so they need a second or subsequent treatment, which is called salvage treatment.
It is still not clear what the best salvage approaches are in these patients. Options include surgery if the relapsed tumour is confined to a defined location; standard-dose salvage chemotherapy; or high-dose chemotherapy (with carboplatin plus etoposide) and peripheral blood stem cell transplantation.
The standard-dose salvage regimens are VeIP, VIP or TIP. These regimens can induce a complete response in 25% to 35% of these patients; there have been no studies suggesting superiority of one of them over the others and any of them can be used as salvage chemotherapy.
Though some preliminary studies have shown a possible benefit of high-dose chemotherapy and autologous bone marrow transplantation or autologous hematopoietic stem cell support, the latest most rigorous studies (randomized phase III trials) failed to confirm any survival advantage over conventional chemotherapy, so this approach remains controversial.
After salvage chemotherapy, any residual tumour should be completely removed, if possible.
Patients who relapse with brain metastases after complete response to first-line chemotherapy require further chemotherapy; if there are solitary lesions, surgical excision can be considered. The role of radiotherapy remains unclear.

3.12 Late relapse

A small proportion of patients (around 3%) experiences germ cell tumour recurrences more than 2 years after the end of primary treatment. Late relapses often present predominantly as teratomas and yolk sac tumours and do not respond to platinum-based chemotherapy, so their surgical management is very important. The possibility of late relapse means that long term annual follow-up is required, including monitoring of serum markers and, probably, CT scans when teratoma is a major component of the primary tumour.

3.13 Contralateral tumour

Contralateral testicular tumours occur in 2%-3% of all patients; approximately 80%-85% are subsequent germ cell tumours, appearing later than the first tumour. The treatment is the same as for the primary tumour. Since new tumours can appear in the other testicle as long as 25 years after the primary cancer, long-term follow-up is required. After the second orchiectomy, as there are no more testicles left to produce sex hormones, replacement testosterone is required to maintain normal hormone levels, secondary sexual characteristics, and sexual function.

4. Stages of germ cell tumours of the testis

4.1 Staging classification

4.1.1 TNM Staging classification

Staging of a disease is the determination of distinct phases in its course, to help decide what exams and treatment the patient should undergo.

Germ cell tumours of the testis, like most solid tumours, are staged according to a system created by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC). It is called the TNM Classification of Malignant Tumours (TNM stands for Tumour, Node, Metastasis):

  • T describes the size of the original (primary) tumour and whether it has spread into nearby tissue.
    The extent of the primary tumour is classified after radical orchiectomy. It can range from pT0 (no evidence of primary tumour; e.g., if surgery shows that the mass detected was not cancer but only a scar) to pT1, pT2, pT3, and pT4 (when tumour invades the scrotum), depending on the extent to which the primary tumour penetrated nearby structures. If no radical orchiectomy has been performed and the tumour cannot be measured, it is classified as pTX. If surgery shows that the mass detected was only an intratubular germ cell neoplasia (carcinoma in situ, see 2.1), it is classified as pTis.
  • N describes spread of cancer to nearby lymph nodes.
    N can range from N0 (no regional lymph node metastasis) to N1, N2, or N3 (metastasis in a lymph node more than 5 cm in greatest dimension), according to how many regional lymph nodes show metastases and their sizes. Nx is used if regional lymph nodes cannot be assessed.
    N can be evaluated before surgery based on physical and imaging exams (clinical staging, see below, 4.3, Staging procedures), and after surgery considering also what doctors find during surgery (pathologic staging). Pathologic staging, if available, can be different from clinical staging, e.g., it may show that metastases are present in areas where they had not been detected previously, or instead that some masses are not metastases; so it gives more precise information than clinical staging.
  • M describes whether distant metastases are present.
    M can be either M0 (no distant metastases), M1a (distant metastases only to lymph nodes or lungs), or M1b (distant metastases to other organs). Mx is used if the presence of distant metastases cannot be assessed.
4.1.2 Serum tumour markers

In 1997, an S category was added for germ cell tumours of the testis. It describes the blood concentration of three proteins produced by many testicular cancers, called serum tumour markers (hence the S). These markers are useful in diagnosis and staging (their levels contribute to determine prognosis independently of the other TNM factors); to monitor the therapeutic response; and to detect tumour recurrence (increasing levels during follow-up are an indication that therapy should be initiated, even if no evident tumour is found).
These marker proteins are:

  • Alpha-fetoprotein (AFP), a protein normally produced by the foetus. Its levels are usually low in adults, but increase in certain liver diseases and types of cancer, including testicular cancer.
    The S value can range from S0 (normal levels) to S1, S2, and S3 for growing marker levels, or SX if markers levels are not measured.
  • Human chorionic gonadotropin (HCG), a hormone which is normally secreted by the foetus and by choriocarcinoma testicular cell tumour, but which is elevated specifically in some forms of testicular cancer (choriocarcinoma and certain seminomas). HCG consists of two subunits, alpha and beta, and only the beta subunit is measured in blood exams, so you can find it indicated as betaHCG.
  • Lactate dehydrogenase (LDH), an enzyme involved in cell metabolism. It can be elevated in several conditions, including some cancers, so it is a less specific marker. Its concentration reflects the “tumour burden”, i.e., growth rate and proliferation of tumour cells.
4.1.3 Stages

According to the TNM and S values, a patient can be staged as:

  • Stage 0: no germ cell tumour of the testis but only carcinoma in situ;
  • Stage I: primary tumour has not spread;
  • Stage II: tumour has spread to nearby lymph nodes only;
  • Stage III: distant metastases or high levels of serum markers are detected.

Each stage is subdivided into more detailed stages (e.g., IA and IB) according to the exact TNM-S classification.
For more details about the TNM-S classification and Stages 0-4, see Professional area, 4.2, TNM Staging classification.

4.2 Classifications for metastatic germ cell tumours

Since most patients with advanced disease may be cured, it has become necessary to further distinguish these patients according to the likelihood of treatment success. Histology (seminoma or non-seminoma), primary tumour site, metastatic site, and serum concentrations of tumour markers have been shown to predict the likelihood of cure.
Several classifications have been used in the past to categorize good and poor risk status (the Memorial Sloan Kettering Cancer Center and the Indiana University classifications in the USA, and the Medical Research Council and the EORTC classifications in Europe), but a comparison of these classifications demonstrated marked differences and showed that the allocation to good- or poor-risk categories was often in disagreement. Due to these differences, in 1997 a prognostic factor-based classification for metastatic germ cell tumours was developed by the International Germ Cell Cancer Collaborative Group (IGCCCG). This classification, based on an analysis of almost 6,000 patients, was approved by all major groups worldwide, so it is called the International Germ Cell Consensus Classification (IGCCC).
For non-seminomatous germ cell cancers, the following independent adverse factors were identified: mediastinal[in the mediastinum, the central area of the thorax, containing the heart and all the other organs of the thorax except the lungs] primary site of metastasis; degree of elevation of AFP, HCG, and LDH; and presence of nonpulmonary visceral metastases , such as metastases in the liver, bone, and brain.
For seminoma, the predominant adverse feature was the presence of nonpulmonary visceral metastases.
Considering these factors, the following grouping for patients with metastatic germ cell cancers was produced:

  • good prognosis, comprising 60% of germ cell cancers, with a 91% 5-year survival rate;
  • intermediate prognosis, comprising 26% of germ cell cancers, with a 79% 5-year survival rate;
  • poor prognosis, comprising 14% of germ cell cancers, with a 48% 5-year survival rate.

(For further details on this classification see Professional area, 4.1.3, Classifications for metastatic germ-cell tumours)

4.3 Imaging procedures

To stage the disease, a computer tomography (CT) scan of the abdomen and pelvis is performed. Thoracic CT is usually carried out for non-seminoma, but can be omitted in some seminoma patients. Magnetic resonance imaging (MRI) can be helpful when other imaging exams are not performed because of allergy to contrast media, or because of concerns about radiation dose, or if their results are not clear.
A bone scan is usually performed in patients with suspected bone metastases.
A brain CT or MRI is performed in case of cerebral symptoms and in patients with multiple (more than 20) lung metastases and choriocarcinoma or high HCG levels.

5. Prognosis

5.1 General information

Prognosis indicates the likelihood that treatment will be successful. It is a statistical measure obtained from different studies that observe the progress of the disease in a high number of patients. It is important to remember that these statistics merely provide an indication: no doctor is able to predict exactly what the outcome of treatment in an individual patient will be, nor how long the patient will live, as prognosis depends on several factors, in relation with the individual patient.

5.2 Prognosis of germ cell tumours of the testis

Germ cell tumour of the testis is a highly treatable, often curable, cancer. More than 90% of patients with newly diagnosed testicular germ cell tumour are cured. Delay in diagnosis leads to a higher stage at presentation for treatment and can worsen the prognosis, but even advanced tumours can often be cured. Seminoma (all stages combined) has a cure rate of greater than 90%. For patients with low-stage disease, the cure rate approaches 100%. For patients with non-seminoma tumours, the cure rate is more than 95% in stages I and II; it is around 70% with standard chemotherapy and resection of residual disease, if necessary, in stages III and IV. (See also 2.1.8, Disease stats, Survival).

6. What to do after treatment

6.1 Late sequelae

6.1.1 Late sequelae related to surgery

The major potential adverse effect of classic bilateral RPLND is infertility due to damage to nerves that are in close proximity to the lymph nodes and control ejaculation. Patients undergoing bilateral RPLND have normal potency and the subjective sensation of orgasm but dry ejaculation (retrograde ejaculation). Modifications of this procedure were developed to spare these nerves: if a nerve-sparing RPLND is used, the probability of maintaining ejaculation is 60% to 90%. However, preoperative sperm banking is recommended.

6.1.2 Late sequelae related to radiotherapy

The impact of radiotherapy on subsequent fertility depends on the extent of the irradiated area and the consequent dose that scatters to the other testis. With the standard technique the other testis should receive a limited dose, and though temporary suppression of spermatogenesis may occur, in most patients this recovers within 2 years of treatment. Because of the theoretical risk of genetic damage, patients are counselled to avoid conception for 1 to 2 years following treatment.
Mediastinal radiation therapy may cause coronary artery disease.
Radiotherapy has been linked to the development of secondary cancers, especially solid tumours of the stomach, bladder, colon, or rectum, usually after 10 years or more. Overall risk of radiation-induced secondary cancers is increased by 40%-60% compared to the standard/baseline risk for the same cancers after more than 10 years.

6.1.3 Late sequelae related to chemotherapy

Some adverse effects of chemotherapy develop during treatment and may persist during follow-up (e.g., peripheral neuropathy); these consequences are called long-term effects. Other adverse consequences appear months to years after completion of treatment, and are called late effects.
The long-term toxicities of chemotherapy are:

  • a summation of the late toxicities of the drugs (cisplatin, bleomycin, etoposide, vinblastine);
  • gonadal toxicity.

Examples of late effects of chemotherapy are:

  • non-germ cell secondary tumours;
  • cardiovascular disease.
6.1.3.1 Late toxicities of the more frequently employed antiblastic drugs

Nephrotoxicity is a well-recognized acute and long-term effect of cisplatin. The severity of renal damage can be limited by adequate hydration (drinking) during treatment but it cannot be completely avoided. Minor decreases in creatinine clearance occur (around 15% decrease, on average) during platinum-based therapy, but these appear to remain stable in the long term, without significant deterioration.
Long-term cisplatin neurotoxicity affects 20%-40% of patients treated for testicular cancer. Cisplatin-induced neuropathy typically affects sensory nerves of the hands and feet, with paresthesias being the main symptom. This neurotoxicity causes peripheral numbness, which is especially severe in the soles of the feet and leads to loss of vibration sense. The risk of peripheral neuropathy increases with the cumulative dose of cisplatin received.
Another specific problem with cisplatin is ototoxicity. A high-tone frequency loss is found in about 30% of patients. However, this hearing loss is often subclinical and it generally affects sound frequencies outside the range of conversational tones, so hearing aids are rarely required after standard doses of cisplatin. Less frequently, ototoxicity is associated with tinnitus. The ototoxicity is irreversible and its grade increases with the cumulative dose of cisplatin.
Pulmonary toxicity is the major dose-limiting adverse effect of bleomycin treatment. Bleomycin may cause pneumonitis, occasionally progressing to pulmonary fibrosis during or shortly after administration. Nonfatal long-term bleomycin pulmonary toxicity affects between 7% and 21% of patients, while fatal pulmonary toxicity has been reported in 1%-3% of patients.

6.1.3.2 Gonadal toxicity

A long-term effect of cisplatin-based chemotherapy is the toxicity on spermatogenesis. However, impaired spermatogenesis (azoospermia or oligospermia) and high FSH levels are frequently observed in patients at diagnosis, before any treatment. The pre-treatment sperm count and the cumulative dose of cisplatin have been shown to affect subsequent gonadal function. The cumulative dose of cisplatin may also influence persistent dysfunction of Leydig cells (the cells that produce testosterone in the presence of luteinizing hormone, LH); 85% of patients show increased serum LH levels but normal testosterone levels up to 60 months after chemotherapy, because the body produces more LH to keep normal testosterone levels despite less functional Leydig cells.
In long-term follow-up of testicular cancer survivors who wanted to conceive a child, 49% to 82% of treated patients succeeded in having a child. In a retrospective review of 680 patients treated with cisplatin-based chemotherapy, 145 (21%) were reported to have achieved paternity. There is no evidence of an elevated risk of malformations for these children.
Patients with germ cell tumours should be informed that recovery from chemotherapy-induced azoospermia may take several years, so if a patient wants to have children after treatment, he may undergo sperm cryopreservation before chemotherapy.

6.1.3.3 Secondary malignancies

Secondary non-germ cell malignancies in chemotherapy-treated patients for germ cell cancer are rare, especially for solid tumours. However, the risk of secondary leukaemia is significantly elevated (by 2.4-5.2 times).
In some cases, these leukaemias are associated with the use of radiation or with the prolonged use of a category of anticancer drugs (alkylating agents). They occur more frequently after 5-7 years and are preceded by non-cancerous anomalies of white blood cells (known as a preleukaemic myelodysplastic phase).
Etoposide-containing regimens also increase the risk of secondary acute leukaemias, with a characteristic chromosome anomaly (11q23 translocation); they occur after 2-4 years, earlier than alkylating-associated leukaemias. The risk is related to etoposide total dose: secondary leukaemia occurs in 0.1% to 0.5% of patients receiving a limited total dose (2,000 mg/m2) but in 6% of patients receiving a high total dose (more than 3,000 mg/m2). However, as etoposide-containing regimens are very effective and achieve a high cure rate, the risk of leukaemias is justified and is not a reason to change the current standard strategy.
Sarcoidosis appears frequently in germ cell tumour patients: it is not a consequence of therapy because it occurs before treatment. It must be suspected when pulmonary nodules, pulmonary infiltrates or paratracheal adenopathy occur in patients without elevated concentrations of serum tumour markers, or in seminoma patients with no retroperitoneal disease. In these patients a biopsy should be performed to check for sarcoidosis.

6.1.3.4 Cardiovascular disease

Cardiovascular toxicity has been reported in patients treated for germ cell tumour, with increased frequency of diastolic hypertension, pulmonary emboli, angina, and myocardial infarction. Some reports suggested that hypercholesterolemia and overweight might also be long-term consequences of treatment. Early-onset metabolic syndrome occurs in about 20%-30% of long-term survivors. Compared with the general population, there is about a twofold-increased risk of late post-chemotherapy cardiovascular disease (coronary heart disease, myocardial infarction, congestive heart failure, and stroke) among testicular germ cell tumour survivors. Vascular toxicity, most frequently in the form of Raynaud’s phenomenon , was observed as a late effect of treatment with bleomycin (10%-35% of patients). Erectile dysfunction may be associated with Raynaud’s phenomenon as a sign of microvascular damage.

6.2 Follow-up

The aims of follow-up in patients treated for germ cell tumour of the testis are:

  1. early detection and treatment of relapse. Relapses are more frequent within 2 years, but since late relapses do occur in a small proportion of patients, long-term follow-up with markers, radiologic and physical examination is recommended;
  2. monitoring and treating late-toxicities related to therapy;
  3. diagnosis of contralateral germ cell tumour;
  4. detection of secondary malignancies.

Follow-up is based on the pattern and probability of recurrence following primary treatment, according to staging and histology. There is a paucity of rigorous studies regarding the follow-up regimens that are most effective in identifying relapsed disease: frequency of physician visits and serum marker level measurements, and optimal means of imaging need to be further addressed.

7. What to ask doctors

Here is a list of questions that you might wish to ask your doctor or any specialists you may consult. To avoid unnecessary concern, it is useful to ask about any doubts you might have, no matter how small they may appear.

General questions

• May I phone you? What is the best time? If you are not available, may I ask for other specialists? Whom specifically?
• What leaflets, books, or websites could I read to learn more about testicular germ cell tumour?
• How will the disease and treatments interfere with normal life (work or school, playing and holidays, nutrition, having pets, etc.)?
• Does testicular germ cell tumour run in families? Are my relatives at risk of getting testicular germ cell tumour?

Diagnosis and exams

• What type of tumour is it?
• What tests are you going to do?
• What are you looking for?
• How long will the exam take?
• Are ultrasound, CT, or other imaging exams dangerous because of radiation exposure?
• Is biopsy painful? Is it performed under general or local anaesthesia?
• How long will it take to confirm diagnosis?

Treatment

• What should I do to be ready for treatment?
• Do I need a highly specialized centre?
• What other doctors will I see?
• What is the cancer stage, and what does it mean?
• What type of treatment is needed?
• Is there any choice of treatments?
• What is the outlook for cure?
• Should I participate in a clinical trial? If so, in which trial?
• What are the risks and benefits of treatments?
• How long will treatment last? Where will it be done?
• Will treatment reduce symptoms and discomfort?
• What are the possible side effects of therapy? Will I lose my hair, or have nausea and vomiting?
• How can I help to reduce the side effects?
• During treatment should I take special precautions or change any habits?
• Which supportive therapy is suggested during treatment?
• How will treatment affect me?
• How long will it take to recover?
• What follow-up will be needed after treatment?
• What late effects could treatment have?
• Will treatment increase the risk of other cancer in the future?
• Will treatment affect my future sex life or ability to have children?
• Should I take any measures if I want to preserve my future ability to have children?
• Could the cancer recur?
• Will I pay for treatment? What is it likely to cost?