39.2 Incidence

Primary testicular neoplasm is the most common solid tumour affecting men ages 20–45 in the Western world and is increasing in incidence, representing 1–1.5% of all male neoplasms and 5% of urological tumours [4–7]. The incidence has been rising over the last century in Europe and North America with data from the Surveillance Epidemiology and End Results (SEER) programme showing a continuing increased risk of seminoma in Caucasian men in the United States [8, 9]. Nearly all testicular cancers (TCa) (90–95%) are germ cell tumours (GCTs) and have a peak incidences in the third decade for non‐seminomas and fourth decade for seminomas [6, 7].

The introduction of tumour markers and combination chemotherapy has enhanced patient care and increased survival rates. Survival rates are at their highest, and it is now recognised as the most curable cancer. Public health campaigns aimed at young men to encourage them to self‐examine have played a large part in making early diagnosis and treatment possible, leading to a decrease in the average time from diagnosis to treatment [10].

39.3 Basic Embryology

Germ cells from the yolk sac cross the coelom to the gonadal ridge where they differentiate into Leydig, Sertoli, and more germ cells. The germ cells continue to divide to form diploid primary spermatocytes, haploid secondary spermatocytes, and finally spermatozoa from which every cell that may occur in the foetus, yolk sac, or placenta, in benign or malignant variations, may arise.

Germ cells have clear cytoplasm full of glycogen and stain for placental alkaline phosphatase (PLAP). If held up in their journey from yolk sac to gonadal ridge, they may give rise to extragonadal CGTs in the para‐aortic region, mediastinum, or pineal gland. If they arise in streak gonads in intersex, they are called dysgerminomas. The primordial germ cells, the atypical cells found in seminiferous tubules, and seminoma cells are probably identical.

39.4 Aetiology and Risk Factors

• Age: The incidence occurs in any age, increasing post‐puberty with a maximum onset in the 20s and 30s, and rarely occurring in infants, prepubertal boys, and men older than 60 years of age [11].
  
• Race: Caucasians are up to three times more likely to develop testicular cancer than other races [12]. It is rare in non‐European origin populations, except for the Maori population of New Zealand [11].
  
• Genetic: There have been associations found with the human leucocyte antigens (HLAs) and first‐degree relatives (i.e. fathers and brothers) are at a higher risk of being affected [13]. Gene expression analysis and genome‐wide screening studies suggest that cancer‐specific gene mutations are found on chromosomes 4, 5, 6, 12, 18, and X [11, 12]. The isochromosome of the short arm of chromosome 12 (i12p) is described in all GCT types [14]. Patients with Klinefelter syndrome are at a higher risk, but the exact mechanism for this is unclear.
  
• Cryptorchidism or undescended testis: Is associated with three‐ to fivefold increased risk of developing GCTs [11]. One in every 10 cases of testicular tumour occurs in men with an undescended testicle. The higher the undescended testicle, the more likely it is to become malignant [15]. Stilboestrol ingestion during pregnancy has been linked to the increase risk of cryptorchidism, and it is also suggested that high levels of natural oestrogens may be equally important [16]. Cryptorchidism is associated with a 2.2‐fold increased risk of TCa in men who underwent orchidopexy before 13 years of age as opposed to a 5.4‐fold increased risk for those who underwent orchidopexy after 13 years of age, therefore advocating early fixation [17]. Standard practice is to perform the surgery before two years of age.
  
• Intratubular germ cell neoplasia (ITGCN) (testicular intraepithelial neoplasia [TIN]): Incidence of ITGCN is rare but is present in 4% of patients with a history of cryptorchidism, 5% of patients with contralateral TCa, and in 1% of patients with oligospermia. The disease arises from malignant change in spermatogonia where 50% develop invasive germ cell testicular cancer within five years and 90% in seven years [11]. Nearly 66% of cases have chromosomal alteration in p53 locus [18]. The presence of a contralateral TCa or TIN has also been shown to have an increased risk of developing TCa on the nonaffected side [7].
  

  Risk factors for TIN: Older than 30 years of age, <12 ml testes, cryptorchidism, atrophic contralateral testis, previous or contralateral testicular cancer, 45XO, Klineflelter syndrome, and infertility. Biopsy can be offered to high‐risk groups.

  
  

  Treatment, if unilateral involvement and contralateral testis is normal, is either by conservative observation or radical orchiectomy. If contralateral testis is involved or has established TCa, then treatment is by radiotherapy. Infertility counselling should be discussed with potential sperm storage.

  
  
• Trauma: Although not a known risk factor, occasionally a history of trauma can predispose to a testicular mass presenting. It can be difficult to decipher whether the lump was from the trauma or whether the injury has brought an unnoticed lump to the attention of the patient. If there is any doubt an ultrasound should be performed.
  
• Infections: HIV sufferers develop seminomas more frequently than expected; however, HIV in itself has not been proven to cause TCa [11]. In up to 10% of cases, a testicular tumour mimics epididymo‐orchitims so caution is advised particularly in recurrent or refractive epididymo‐orchitis. If there is any doubt of the diagnosis, an ultrasound should be performed.
  
• Others: Men with subfertility or infertile, patients who are immunosuppressed with renal transplants, low birth weight and small‐for‐gestational‐age have been weakly implicated with risk of developing TCa [11]. There is no link between testicular microlithiasis and cancer in healthy men.

39.5 Clinical Features

Often presentation is with a painless isolated scrotal lump incidentally identified. Occasionally patients have with a nonspecific ache in the testicle, and in nearly 20% of cases, the first symptom will be scrotal pain, with 27% of patients with TCa having local pain [6]. TCa can present with physical signs of inflammation with the testicle swollen, red, and warm, suggesting epididymo‐orchitis or possibly neglected torsion. The pathophysiology of this inflammation is unclear, but it is speculated that haemorrhage into the tumour can contribute. Inflammation in an abdominal cryptorchid testicle may present as an acute abdomen.

It is wise to have a low index for suspicion in the young man with vague discomfort in the testicle or the sensation of a lump. Do not be reassured with the finding of a mere varicocele or dismiss discomfort as adolescent neurosis until the testicle has been carefully examined. Similarly, when a young man complains of vague backache, be sure to exclude metastases from a testicular tumour, even when the testes appear normal.

Trauma to the testicles may reveal the presence of a mass. A small secondary hydrocele can be present, and very rarely it may be the presenting feature. Larger tumours may be concealed by a thick‐walled hydrocele containing turbid fluid through which light will not shine. A hydrocele in a young male always calls for confirmation of the diagnosis by ultrasound, tumour markers, and when in doubt, exploration (Figure 39.1).

Gynecomastia from release of chorionic gonadotrophin is reported in up to 7% of cases as the first symptom of a testicular tumour. Therefore, every young man with signs of gynecomastia must have their testicles examined and tumour markers measured [6]. A point‐of‐care pregnancy test can give an instant diagnosis.

Sometimes the tumour erodes through the testis, leaving behind a scar that shrinks as it heals. The patient will often notice that the testicle is getting smaller. A small primary tumour may be entirely replaced by a scar, leaving a normal testicle, even though the tumour has metastasized widely.

Bilateral testicular cancer occurs in 1–2% of cases [14]. Therefore, it is always advisable to examine both the affected and nonaffected side, in addition to a complete general physical examination looking for possible distant metastasis (e.g. supraclavicular lymph nodes), gynaecomastia, or a palpable abdominal mass. Lower limb oedema may suggest lymph node compression obstructing the venous drainage of the limb.

Delayed presentations can lead to symptoms of weight loss, lumps in the neck, chest symptoms, or bone pain; this suggests advanced disease, which is seen in 10% of cases.

39.6 Diagnosis

Imaging and tumour markers should be carried out as a matter of urgency if a testicular neoplasm is suspected. Once confirmed, surgical excision is done to establish a pathological diagnosis.

39.6.1 Imaging

Ultrasound is the gold standard for exploring a testicular mass because its detection rate for picking up testicular masses is nearly 100%. It can differentiate between an intra‐ or extratesticular mass and allows assessment of the contralateral testis (Figure 39.2) [19]. It is also an inexpensive test that can be carried out readily to avoid delays in management.

An abdominopelvic computed tomography (CT) should be performed on all patients for staging the disease (Figure 39.3). Its sensitivity for detecting enlarged lymph nodes is 70–80%, but the accuracy depends on the size of the nodes [20]. Be aware that at lower stages, there can be a degree of understaging. Magnetic resonance imaging (MRI) produces similar results in detecting nodal disease in the retroperitoneum (Figure 39.4). It can be helpful in those patients who have a contraindication to contrast use or where there is concern about radiation dose. However, its high cost, lack of availability, and similar sensitivity rate mean that CT remains the first‐line imaging modality for staging.

A chest CT is recommended in all patients because of its high sensitivity for mediastinal and thorax lymph nodes. Up to 10% of patients with TCa have small subpleural nodes that will only be diagnosed on chest CT [21]. Other imaging modalities (such as bone scanning, CT of the head or spine, and abdominal ultrasound) should only be used if there is strong clinical suspicion of metastasis or if the patient is in a high‐risk category (see later).

39.6.2 Serum Tumour Markers

Tumour markers contribute to the diagnosis and risk classification of testicular neoplasms and are an important prognostic factors [22]. Tumour markers that should be measured at presentation are the oncofoetal proteins: alpha‐fetoprotein (AFP) and human chorionic gonadotrophin (HCG); and cellular enzymes: lactate dehydrogenase (LDH) and PLAP (Table 39.1).

Marker	Detail	Seminoma	Non‐seminomas	Serum half‐life	Normal value
AFP	Produced by trophoblastic elements In foetal life, AFP is the second‐most common protein after albumen	Not usually but if present strongly suggests a non‐seminomatous element	Present in 50–70%	3–5 days	<10 ng ml−1
hCG	Produced by Syncytiotrophoblastic element	Elevated in 10–30%	40–60% teratoma, 100% choriocarcinomas	24–36 hours	<5 ml U ml−1
LDH	Enzyme marker of cellular turnover therefore non‐specific, but its concentration is proportional to tumour volume and can be elevated in up to 80% of advanced disease.	Elevated in 10–20% most useful to monitor treatment response
PLAP	Foetal isoenzyme. May be elevated in smokers It is non‐specific so not widely used. Its measurement is considered more optional as opposed to the other three.	Up to 40% with advanced disease

AFP, alpha fetoprotein; hCG, human chorionic gonadotropin; LDH, lactate dehydrogenase; PLAP, placental alkaline phosphatase.

It is estimated that 90% of patients with non‐seminomas (i.e. AFP or HCG mainly) and up to 30% of seminomas (i.e. HCG and LDH) will have an elevated tumour markers. Baseline levels of tumour markers should be taken at presentation, one to two weeks after radical orchiectomy, then as monitoring during follow‐up to assess treatment response. A negative tumour marker does not exclude the diagnosis of a TCa or the presence of metastatic disease; however, their persistence after radical orchiectomy may indicate the presence of metastases.

39.6.3 Surgical Excision

Radical inguinal orchiectomy is the gold standard because it is not only part of the initial pathological diagnosis and staging, but it can be curative in nearly 75% of patients. The testis, spermatic cord, and epididymis and their coverings should be excised through a groin incision.

39.6.3.1 The Surgical Approach to Radical Orchiectomy

Through an inguinal incision, open the external oblique and place a vascular clamp across the cord at the internal ring to prevent tumour cells escaping as the testicle is separated from the scrotum (Figure 39.5). If a patient has a large tumour, it is better to carry the inguinal incision into the neck of the scrotum rather than risk bursting the tumour. If there is doubt in the diagnosis, an excisional biopsy by complete enucleation of the intraparenchymal mass is taken for a fresh‐frozen section pathological examination. If the lump proves benign, the tunica albuginea may be closed. After six months, it will be impossible to tell which side has been operated on.

If the testicle is obviously the seat of a cancer, transfix and ligate the cord above the clamp (Figure 39.6). Haemostasis must be perfect before closing the wound because infection in a haematoma may postpone adjuvant radiotherapy or chemotherapy.

In select patients where there is synchronous bilateral TCa, metachronous contralateral TCa, or TCa in a solitary testis, organ‐sparing surgery can be performed if the tumour is less than 30% of the testicular volume. Surgery should be done in a centre with experience in treating these patients. All must have adjuvant radiotherapy [7, 23]. There is a higher risk of infertility in these cases as well as a risk of long‐term Leydig cell insufficiency.

39.6.4 Retroperitoneal Lymph Node Dissection

Retroperitoneal lymph node dissection (RPLND) is an accurate method of staging the tumour because it can detect microscopic metastases in lymph nodes that are less than 1 cm in diameter. Staging node dissection is not only diagnostic, but it will suffice to cure patients who only have microscopic metastases without the need for chemotherapy, but at the risks of major abdominal surgery.

When comparing different methods of treatment, it is necessary to take account of the way the tumour was staged. Where retroperitoneal node dissection is the routine practice, then lymph node metastases will be detected that would have been missed in the CT scan and so invalidate the comparison. However, with improved imaging, the frequency of primary RPLND to confirm the presence or absence of metastasis in normal sized nodes, is decreasing gradually.

39.6.4.1 Pathological Classification

In 2004, the World Health Organisation (WHO) split testicular neoplasms into GCTs, sex cord/gonadal stromal tumours, and miscellaneous nonspecific stromal tumours (Table 39.2) [11]. Any tissue in the testicle may undergo malignant change, but most neoplasms arise from germ cells (i.e. gonadocytes) and as a group are referred to as germ‐cell tumours (Figure 39.7). There may be only one kind of tissue in the tumour or a mixture, and therefore, the prognosis depends on the level of malignancy of each type of tissue present and the overall percentage composition of each type of tissue [19].

Germ cell tumours: Seminomas Spermatocytic Classical Anaplastic Mixed with nonseminomatous germ cell tumours Nonseminomatous germ cell tumours Teratoma Yolk sac tumours Choriocarcinoma Mixed Mixed germ cell tumours Sex cord or gonadal stromal tumours Leydig cell tumours Sertoli cell tumours Granulosa cell tumours Thecoma or fibroma group tumours Mixed germ cell and sex cord or gonadal stromal tumours

Others: Carcinoid Haematopoietic (lymphoma) Adenomatoid tumour Mesothelioma (benign and malignant types) Adenocarcinoma of the epididymis Papillary cystadenoma of the epididymis Melanotic neuroectodermal tumour Metastatic from other sites

It is vital that the surgeon has an understanding of the requirements for the pathological specimen. Mandatory pathological requirements for diagnosis are a sample of 1 cm² section for every centimetre of maximum tumour diameter, including normal parenchyma if present. At least one distal and one proximal section of the spermatic cord should be analysed. Microscopic features and diagnosis should include the presence or absence of peritumoural venous or lymphatic invasion, albuginea, rete testis, epididymis, or spermatic cord invasion and presence or absence of intratubular germ cell neoplasia in nontumour parenchyma intratubular germ cell neoplasia. Immunochemical markers can be useful in cases of doubt.

39.6.4.1.1 Main CGTs

• Seminoma
  

  There is a peak age incidence at about ages 30–40, which is a decade later than other GCTs. Macroscopically, it forms a pinky‐grey lobulated swelling. Microscopically, sheets of glycogen‐filled cells, staining for PLAP, are interspersed with lymphocytes. Seminomas are part of a continuum. At one extreme is the well‐differentiated spermatocytic seminoma of older men, whose cells resemble spermatocytes. They rarely metastasize and are highly chemosensitive. At the other extreme is the anaplastic seminoma with nuclear pleomorphism, scanty lymphocytes and giant cells resembling syncytiotrophoblast which stain for beta‐HCG and raise the serum HCG, verging with embryonal carcinoma.

  
  
• Nonseminomatous germ cell tumour (NSGCT)
  

  These tumours are often made up of more than one type of cell and are therefore identified according to the cell types seen.

  
  
  
  
  • Embryonal carcinoma
  
  

  In embryonal carcinoma, the macroscopic appearance is even blotchier. Microscopically, amongst sheets of cells and embryoid bodies there are areas with papillary and pseudoglandular patterns arranged in single or double layers of cells which stain for AFP, betraying their yolk sac origin.

  
  
  
  
  • Yolk sac tumours
  
  

  Pure yolk sac tumours are found in infants. In adults, yolk sac tissue is often found in mixed tumours. AFP can be detected in the tissue by immunoperoxidase staining and in the serum is a useful marker of response to treatment.

  
  
  
  
  • Teratocarcinoma
  
  

  In teratoma, the tissues are similar to those of the developing foetus and can be benign or malignant. When only mature tissue is present, the tumour is referred to as ‘mature teratoma’. Of the malignant tissues the worst is choriocarcinoma; it may be the only tissue present, but it is more often present as part of a mixture.

39.6.4.1.2 Nongerm Cell Tumours

In addition to CGTs, benign and malignant tumours can arise in any of the other tissues present in the testis, epididymis, or their coverings.

• Leydig cell tumours
  

  These are composed of normal‐looking interstitial cells and secrete testosterone. Before puberty, they give rise to precocious sexual development, and after puberty, they cause feminization with gynaecomastia.

  
  
• Sertoli cell tumours
  

  These are rare. They occasionally metastasize and occasionally cause gynaecomastia.

  
  
• Connective tissue tumours
  

  Connective tissue tumours from the tissues in and around the testis can give rise to various tumours, (e.g. tunica albuginea often forms benign fibromatous nodules) and rarely it may form mesothelioma or even fibrosarcoma, most often in children.

39.7 Staging

The staging is based on the tumour, node, and metastasis (TNM) classification (Table 39.3) and grouped according to stage (Table 39.4). It is the predominant system used for testicular neoplasm staging in the US and UK. However, the Royal Marsden system (Table 39.5) is used in many European countries.

The Royal Marsden system stage I equates to T1N0M0 because it is disease confined to the testis. Stage II is subdivided into IIa where the nodes detected by CT below the diaphragm are less than 2 cm in diameter, IIb where they are more between 2 and 5 cm, and IIc more than 5 cm in diameter. Stage III includes those in the mediastinum (N2) and stage IV haematogenous metastases. For metastatic CGTs in particular, it is important that patients are staged in accordance with the International Germ Cell Consensus Classification (IGCCC) which gives prognostic grouping (Table 39.6).

39.8 Method of Spread

GCTs spread by direct invasion from the testicular tubules into the surrounding interstitial spaces, through the rete testis into the epididymis, and finally through the tunica albuginea into the scrotum. They invade the connective tissue and veins of the spermatic cord (Figure 39.8).

The lymphatics of the testis arise between the tubules and drain along the spermatic cord to the primary regional lymph nodes around the origin of the testicular arteries, the renal hilus, the first lymph nodes to be involved in TCa. Secondary lymph node spread occurs upwards from the para‐aortic nodes to the mediastinum and enters the systemic circulation via the thoracic duct. There may also be secondary spread downwards to the lymph nodes of the pelvis (Figure 39.9).

TCa with trophoblastic elements erode veins and spread via the bloodstream at an early stage. Choriocarcinoma is notorious for this with haemoptysis from lung metastases being a classic presenting symptom.