Testes Neoplasm

Testes Neoplasm

Michelle Carey1, Omar M. Aboumarzouk2,3, and Johannes Alfred Witjes4

1 Department of Urology, Cheltenham General Hospital, Cheltenham, UK

2 Glasgow Urological Research Unit, Department of Urology, Queen Elizabeth University Hospital, Glasgow, UK

3 University of Glasgow, School of Medicine, Dentistry & Nursing, Glasgow, UK

4 Department of Urology, Radboud University Medical Center, Nijmegen, Netherlands


Primary testicular neoplasms are the most common solid tumour affecting men ages 20–45, representing 5% of urological tumours and 1–1.5% of male neoplasms in the western world. The widespread use of serum tumour markers, sensitive ultrasound, and accurate computed tomography staging has meant that patients can undergo a radical orchiectomy in a timely manner, which is a curative procedure in up to 75% of cases. Adjuvant chemotherapy, radiotherapy, and radical lymph node dissection forms the basis of management following radical orchiectomy and techniques are improving year on year. With such advances in knowledge and accuracy of relapse prediction testicular neoplasms have become one of the most curative cancers if managed early. This chapter outlines the diagnosis, management options, and prognosis for germ cell and non‐germ cell testicular neoplasms.

Keywordstesticular cancer; germ cell tumours; seminoma; non‐seminoma; orchiectomy; retroperitoneal lymph node dissection (RPLND); paratesticular cancer; epididymal cancer

39.1 History

The distinction between solid tumours of the testicle (lethal) and cystic (innocent) ones was known to the Romans. William Harvey advised ligature of the testicular artery as a safer alternative to castration, and Astley Cooper researched the lymphatic drainage of the testicle and the method of tumour spread [1]. The crucial biological difference between the two main histological types of testicular tumours was discovered by Chevassu who coined the terms ‘seminoma’ and ‘teratoma’ [2].

Kocher was the first to attempt to cure testicular cancer by radical node dissection; however both his patients had advanced disease and died [2]. In 1926, Cairns reviewed these attempts and concluded that they were futile [3]. Within a few years, radiotherapy replaced surgery for lymph node disease in some centres, but in others, the morbidity caused by overdoses of radiation discredited it. For the next 50 years, a contest began between radical node dissection and radiation [1]. The conflict became meaningless because advocates of either method were always comparing tumours that were classified by different systems and staged by different criteria. Eventually, the argument was overtaken by the introduction of tumour markers, combination chemotherapy, and a better understanding of the natural history of these tumours.

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 [47]. 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).

2 Diagrams of the scrotum with lines marking secondary hydrocele (left) and deforming the epididymis (right).

Figure 39.1 It is difficult to feel a lump in the testicle when it is surrounded by healthy tissue or situated near the epididymis.

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.

Image described by caption.

Figure 39.2 Ultrasound images of the testicle (a) large solid lesion representing a testicular tumour (b) Doppler showing a well‐perfused testicular tumour (c) multiple hypoechoic areas consistent with multiple testicular tumours, microlithiasis present throughout testicle, secondary hydrocele (d) a scrotal lump indistinguishable clinical from the testicle found to be a large epididymal lipoma. (e and f) Testicular microlithiasis.

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.

Image described by caption.

Figure 39.3 Computed tomography (CT) scans (a‐e) showing large para‐aortic lymph node metastases.

Source: Photographs courtesy of Dr. Neil Collins Southmead Hospital.

Image described by caption.

Figure 39.4 Magnetic resonance imaging (MRI) scans showing large para‐aortic lymph node metastases.

Source: Photographs courtesy of Dr. Neil Collins Southmead Hospital.

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).

Table 39.1 Table of the common onco‐foetal proteins detected in the serum of patients with a testicular neoplasm.

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. 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.

Image described by caption and surrounding text.

Figure 39.5 Orchiectomy for testicular tumour. A clamp is placed on the cord before delivering the testis.

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.

Image described by caption.

Figure 39.6 The cord is transfixed and ligated above the clamp.

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. 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].

Table 39.2 The World Health Organisation histopathological classification of the more common testicular tumours.

Germ cell tumours:

  • 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
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
Diagram displaying the cellular origin of germ cell tumours with lines marking Leydig cells, Sertoli cells, teratoma, seminoma, and germinal cells.

Figure 39.7 Cellular origin of germ cell tumours.

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. 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. 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.

Table 39.3 The international TNM staging for testicular neoplasm.

T (Primary Tumour) pTx‐ Primary tumour cannot be assessed
T0‐ no evidence of primary tumour
Tis‐ intratubular germ cell neoplasia
T1‐ tumour limited to testis and epididymis without vascular/lymphatic invasion. May invade albuginea but not vaginalis
T2‐ tumour limited to testis and epididymis with vascular/lymphatic invasion or extending through tunica albuginea with involvement of tunica vaginalis
T3‐ tumour invades spermatic cord with or without vascular/lymph invasion
T4‐ tumour invades scrotum with or without vascular/lymph invasion.
N (Regional lymph nodes clinical) NX‐ regional lymph nodes cannot be assessed
N0‐ No regional lymph nodes affected
N1‐ Metastasis with a lymph node <2 cm or multiple lymph nodes none more than 2 cm in greatest diameter
N2‐ metastasis with lymph node >2 cm but not more than 5 cm or multiple lymph nodes
N3‐ Metastasis with lymph node mass more than 5 cm in greatest diameter
pN (pathological‐RPLND staging) pNX‐ regional lump node cannot be assessed
PN0‐ no regional lymph node affected
pN1‐ metastasis with lymph node mass <2 cm and 5 or fewer positive nodes, none of which are greater than 2 cm
pN2‐ metastasis with lymph node mass of >2 cm but not more than 5 cm or more than 5 nodes positive, none more than 5 cm. Or evidence of extranodal extension of tumour.
pN3‐ metastasis with lymph node mass more than 5 cm in greatest dimension.
M (Distant Metastasis) Mx‐ distant metastasis cannot be assessed
M0‐ no distant metastasis
M1‐ distant metastasis
M1a‐ non‐regional lymph nodes or lung
M1b‐ other sites
S (Serum Tumour Markers) Sx‐ serum marker studies not performed/not available
S0‐ serum markers study level within normal limits
S1‐ LDH <1.5 X N AND hCG <5000 AND AFP <1000
S2‐ LDH 1.5–10 X N OR hCG 5000–50 000 OR AFP 1000–10 000
S2‐ LDH >10 X N OR hCG >50 000 OR AFP >10 000

LDH measured in U l−1, hCG in mIU ml−1 and AFP measured in ng ml−1.

AFP, alpha fetoprotein; LDH, lactate dehydrogenase; hCG, human chorionic gonadotropin; RLPND, retroperitoneal lymph node dissection; TNM, tumour, node, metastasis.

Table 39.4 Stage grouping for testicular cancer.

Stage T N M S
Stage 0 pTis N0 M0 S0, SX
Stage I
Any patient/TX
N0 M0 SX
Stage II
Any patient/TX N1–3
M0 S0–1, SX
Stage III

Any patient/TX Any N
Any N
Any N
Any N
Any N

Any S

Table 39.5 The Royal Marsden staging system.

I Disease confined to testis
IM Rising tumour markers post orchiectomy
II Abdominal lymphadenopathy

  1. A‐ <2 cm

  2. B‐ 2–5 cm

  3. C‐ 5 cm
III Supra‐diaphragmatic disease No abdominal disease
A–C Abdominal nodal disease as above
IV Extra‐lymphatic metastasis
L1 <3 lung metastasis
L2 >3 lung metastasis
L3 >3 lung metastasis with 1 or more >2 cm
H+ Liver involvement

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).

Table 39.6 Prognostic‐based staging system for metastatic germ cell cancer.

Source: From International Germ Cell Cancer Collaborative Group.

Good prognosis group Intermediate prognosis group Poor prognosis group
Non‐seminomas (56%) Seminomas (90%) Non‐seminomas (28%) Seminomas (10%) Non‐seminomas (16%) Seminomas
a5 y‐ PFS 89%
a5 y‐ S 92%
a5 y‐PFS 82%
a5 y‐S 86%
a5 y‐PFS 75%
a5 y‐S 80%
a5 y‐PFS 67%
a5 y‐S 72%
a5 y‐PFS 41%
a5 y‐S 48%
No patients classified as poor prognosis
Plus all of the following criteria:
‐Testis or retroperitoneal primary
‐no non‐pulmonary visceral metastasis
‐hCG <5000 IU l−1
‐LDH <1.5 × ULN
‐AFP < 1000 ng ml−1
Plus all of the following criteria:
‐any primary site
‐no non‐pulmonary visceral metastases
‐Normal AFP
‐Any LDH
‐Any hCG
‐testis or retroperitoneal primary
‐AFP 1000–10 000 ng ml −1or hCG 5000–50 000 IU l−1 or LDH 1.5–10 X ULN
Plus all of the following criteria:
‐any primary site
‐non‐pulmonary visceral metastases
‐normal AFP
‐ any hCG
‐any LDH
Plus any of the following criteria:
‐mediastinal primary
‐non‐pulmonary visceral metastases
AFP >10 000 ng ml−1 or hCG >50 000 IU l−1 or LDH >10 xULN

a y‐PFS year progression free survival. Y‐S year survival.

AFP alpha‐fetoprotein; hCG human chorionic gonadotrophin; LDH lactate dehydrogenase.

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).

Diagram displaying the T staging of tumour of the testis depicted by shaded areas labeled T4b into scrotal skin, T2 through tunica albuginea, T1 confined to testis, T4a into cord, T3 into epididymis, etc.

Figure 39.8 T staging of tumour of the testis.

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).

Image described by caption.

Figure 39.9 Spread of testis tumours. (a) By lymphatics to the ipsilateral para‐aortic lymph nodes (b) Secondary lymphatic spread to the mediastinum and pelvic nodes (c) Haematogenous spread to lungs, etc.

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.

39.9 Prognosis

If a patient presents early and adequate measures ensure he proceeds to orchiectomy in a timely manner, the prognosis for these patients is very good. Those who present late or have a delay in their treatment do not have such a good prognosis [24]. The International Germ Cell Cancer Collaborative Group have provided a prognostic‐based system for metastatic germ cell cancer (Table 39.6).

High risk for relapse of seminomas stage I are patients with tumours >4 cm or rete testis invasion, whereas those with <4 cm and no rete testis invasion are low‐risk group patients.

High‐risk group for NSGCT stage I include lymphovascular invasion of primary tumour (most important factor), a proliferation rate >70%, and the presence of >50% embryonal carcinoma [2527]. For those with metastatic disease, relapse rates depend on elevated tumour marker levels, the presence of nonpulmonary visceral metastasis, and the primary location.

39.10 Treatment

The role of the surgeon is usually limited to the radical orchiectomy and, if needed, lymph node dissection. However, it is important to understand the subsequent management options to ensure better counselling of patients.

39.10.1 Localised Disease (Stage I: T1‐4N0M0) Seminomas

Radical orchiectomy cures approximately 75–80% of patients. Continual management options include surveillance, adjuvant radiotherapy, or adjuvant chemotherapy.

Tumours ≤4 cm and no rete testis invasion have a low risk of relapse (<6%), hence regular close long‐term surveillance is feasible in these patients [7, 28]. Surveillance is only possible in a well‐equipped unit with ready access to CT scanning and prompt measurement of tumour markers. The patient must be compliant and understand the need for strict cooperation and repeated follow‐up to allow timely treatment of any tumour that appears during surveillance.

Nearly 15–20% have subclinical metastatic disease, not detectable with current radiological modalities, which will relapse within five years. The remaining 5% will present with distant metastatic disease. Use of adjuvant carboplatin or radiotherapy reduces relapse to <1% [29, 30]. With no difference between disease relapse with use of single course carboplatin therapy or radiotherapy treatment, recommendations are for adjuvant carboplatin use because it avoids toxic complications of radiotherapy [7]. Carboplatin treatment of patients who have high risk of disease relapse (tumour >4 cm or rete testis invasion) reduces recurrence to 1.4% [31].

To summarise, low risk should be observed, and high risk should be observed or be treated with chemotherapy instead of radiotherapy. How Chemotherapy Works

A simplistic explanation for the sensitivity of CGTs to chemotherapy is that there is a high level of p53 tumour suppressor gene in normal germ cells, located on chromosome 17p. It has a key role in the control of DNA replications, regulation of apoptosis, and inhibits angiogenesis. Therefore, it can suppress cell proliferation and transformation. In tumour cells, there is an absence of p53 mutations and p53 is overexpressed when exposed to chemotherapy, leading to apoptosis of the tumour cells [32]. Furthermore, possibly under p53 control, TCa express high levels of the apoptosis‐promoting protein Bax and have little or no expression of the suppressor of apoptosis Bcl‐2. Bcl‐2 is important in determining if the cellular damage to chemotherapy undergoes repair or apoptosis [32]. NSCGTs

Radical orchiectomy cures approximately 70–75% of patients. Continual management options include surveillance, chemotherapy, or RPLND.

  • Surveillance: Suitable for compliant patients with low risk of relapse (pT1 with no lymphovascular invasion). Risk of relapse is quoted at 80% in the first year, 12% in second year, 6% in third year, and 1% in fourth and fifth years, necessitating close regular follow‐up for at least five years.
  • Patients who are unwilling or unable to be managed with surveillance or have high risk of relapse (pT2‐pT4 or pT1 with lymphovascular invasion), can receive two courses of chemotherapy with bleomycin (B), etoposide (E), and cisplatin (P) (PEB). Reducing recurrence rates to as low as 2.7% [7].
  • RPLND: The oncologist will often manage the patient after radical orchiectomy, but the urologist may be involved in the RPLND. Nearly 30% of patients are found to have lymph node metastasis on RPLND (upgrading their staging to stage II disease), and if no lymph nodes are found, nearly 10% will relapse with distant metastasis [7].
  • Patients with low‐risk disease who are not willing or suitable for surveillance can either have chemotherapy or nerve‐sparing RPLND; however, if lymph nodes metastasis was found, two course BEP should be considered. Nearly 30% (pathologically stage I) and 50% (clinically stage I) of patients with vascular invasion relapse; however, two courses of BEP reduce the incidence to <2% [7].
  • RPLND involves taking para‐aortic nodes, and one must be cautious of damage to the sympathetic chain, which will lead to ejaculatory failure. Careful preservation of the sympathetic chain (at least one and its preaortic fibres) can reduce the chances of ejaculatory failure. In the US, RPLND is the gold standard for staging investigation following radical orchiectomy, whereas in the UK it is only performed on select cases for debulking post‐chemotherapy.

39.10.2 Metastatic Disease (Stages II and III) Seminomas

  • Stage IIa (any pTN1M0S0–1): Radiotherapy; long‐term relapse‐free survival 92–95% [33, 34].
  • Stage IIb (any pTN2M0S0–1): Radiotherapy (only in small volume stage 2b because of the toxicity to the bowel); long‐term relapse‐free survival 89–90% [33, 34]. Chemotherapy with four cycles of EP (indications to leave out B: smoking, age older than 50, chronic obstructive pulmonary disease, and top athletes) or three cycles of BEP achieve similar long‐term relapse free rates (87%) to radiotherapy [35].
  • Stage ≥III: Chemotherapy with BEP with or without RPLND if residual lymph nodes >3 cm NSGCTs

  • Dependent on the prognostic grouping (Table 39.6).

    • Chemotherapy with three cycles of BEP or four cycles of EP if bleomycin indicated for the good prognosis group and four cycles of BEP for intermediate and poor prognostic group [7]. Nerve‐sparing RPLND for residual or recurrent mass or for patients unwilling to undergo primary chemotherapy. Cure rate for either is nearly 98% [7]. Residual or Refractory Disease or Relapse after Primary Treatment

For seminomas: if HCG is elevated, the patient must undergo salvage chemotherapy. Salvage radiotherapy in small volume disease is an alternative. If HCG is negative, patients should undergo histological verification with either biopsy or surgical excision or positron emission tomography (PET) scanning before salvage chemotherapy [7].

NSGCTs: Residual disease (masses >1 cm) should be completely resected within four to six weeks of completion of chemotherapy [7]. After chemotherapy, only 10% of residual masses will contain viable cancer, 50% will contain mature teratoma, and 40% will contain necrotic‐fibrotic tissue [7].

Salvage chemotherapy after first‐line chemotherapy can give up to 54% of patients long‐term remission [36]. The recommended regime is four cycles of etoposide, ifosfamide, and cisplatin (PEI/VIP), our cycles of paclitaxel, ifosfamide, cisplatin (TIP), or four cycles of vinblastine, ifosfamide, and cisplatin (VeIP) [7].

Late relapse, occurring >2 years after chemotherapy for metastatic disease of NSGCTs, should undergo immediate radical surgery and excision of all lesions [7]. If it is not possible to resect all the lesions, then salvage chemotherapy should be given.

Postprimary chemotherapy surgical excision should be carried out in specialised centres with appropriate interdisciplinary specialities in case hepatic resection, vessel replacement, spinal neurosurgery, or thoracic surgery are needed. These centres are capable of reducing perioperative mortality from 6 to <1%, in addition to reducing local recurrence rates from 16 to 3% [7]. If completely excised, no further treatment is required, otherwise two cycles of chemotherapy should be given [7].

Salvage surgery, carried out after salvage chemotherapy of all residual masses, can provide up to 25% long‐term survival [7].

39.10.3 Other Considerations in the Treatment of These Patients

It is advised that consideration is given to performing fertility investigations before commencing chemo‐ or radiotherapy. Sperm abnormalities are often found in patients with testis tumours, and subsequent chemo‐ or radiotherapy can further impair fertility. These tests include total testosterone, luteinising hormone (LH), follicle‐stimulating hormone (FSH), and semen analysis. It is important to discuss the use of sperm banking with your patient and their partner if necessary. This should be considered before orchiectomy or if not possible at least before commencement of chemotherapy. Patients should be offered a testicular prosthesis which can occur at time of initial orchiectomy or at a later date. In cases of bilateral orchiectomy, lifelong testosterone treatment may be necessary.

39.10.4 Follow‐Up

As recurrence or relapse can occur at any time, strict follow‐up regimes were recommended by the European Association of Urology to ensure detection and subsequent treatment is carried out promptly, allowing for a higher chance of survival and cure rate (Table 39.7).

Table 39.7 European Association of Urology recommended follow up regimes.

a) Stage I NSGCT under surveillance management
Procedure Year 1 Year 2 Year 3–5 Year 6–10
Physical examination 4 times 4 times Once a year Once a year
Tumour markers 4 times 4 times Once a year Once a year
Chest X‐ray 2 times 2 times
AbdoPelvic CT scan 2 times (at 3 and 12 months)

b) Stage I NSGCT after RPLND
Procedure Year 1 Year 2 Year 3–5 Year 6–10
Physical examination 4 times 4 times Once a year Once a year
Tumour markers 4 times 4 times Once a year Once a year
Chest X‐ray 2 times 2 times
AbdoPelvic CT scan 1 time 1 time
c) Stage I Seminomas
Procedure Year 1 Year 2 Year 3–5 Year 6–10
Physical examination 3 times 3 times Once a year Once a year
Tumour markers 3 times 3 times Once a year Once a year
AbdoPelvic CT scan 2 times 2 times
d) Stage II and Metastatic disease
Procedure Year 1 Year 2 Year 3–5 After 5 years
Physical examination 4 times 4 times Twice a year Once a year
Tumour markers 4 times 4 times Twice a year Once a year
Chest X‐ray 4 times 4 times Twice a year Once a year
AbdoPelvic CT scan a , b 2 times 2 times As Indicated As Indicated
Chest CT scanb , c As Indicated As Indicated As Indicated As Indicated
Brain CT scand As Indicated As Indicated As Indicated As Indicated

a An abdominal CT must be performed at least annually if teratoma is found in the retroperitoneum.

b If the postchemotherapy evaluation in a seminoma patient shows any mass >3 cm, the appropriate CT should be repeated two and four months later to ensure that the mass is continuing to regress. If available, FDG‐PET/CT can be performed.

c A chest CT is indicated if abnormality is detected on a plain radiography chest and after pulmonary resection.

d In patients with headaches, focal neurological findings, or any central nervous system symptoms.

CT, computed tomography; FDG‐PET, fluorodeoxyglucose‐positron emission tomography; NSGCT, nonseminomas germ cell tumour; RLPND, retroperitoneal lymph node dissection.

39.11 Nongerm Cell Tumours

The majority of this chapter is devoted to GCTs because they are by far the most common. Often testicular masses are treated as GCTs until the histology proves otherwise. It is important for the urologist to know the main nongerm cell tumours such as Leydig, Sertoli tumours, and granulosa cell tumours. It is also important to be aware of other tumours such as sarcoma or lymphoma that can affect the testis.

39.11.1 Sex Cord or Gonadal Stromal Tumours

Rare tumours accounting for 2–4% of all testicular tumours.

39.11.2 Leydig Cell Tumours

Incidence: Leydig cell tumours (LCTs) account for 1–3% of all adult testicular tumours, more commonly in the third to sixth decades of life and 3% of infant and children testicular tumours, between three and nine years of age [11]. Nearly 5–10% of patients have a history of cryptorchidism, and there have been occasional cases in patients with Klinefelter syndrome [11]. Nearly 10% are malignant and rarely occurring bilaterally (3%) [7, 11].

Asymptomatic or painless testicular mass or lump is the most common presentation. Gynecomastia is seen in about 30% of patients [11]. Other features such as loss of libido and potency in adults or precocious puberty in adolescents are not uncommon.

Investigations: Comprise of hormone levels, tumour markers, and imaging.

  • Hormone levels: these tumours produce steroids, particularly testosterone, androstenedione, and dehydroepiandrosterone [11]. Serum oestrogen and estradiol levels can be elevated and may be associated with low testosterone and high LH and FSH levels.
  • Tumour markers: to distinguish between LCT (negative) and GCTs.
  • Ultrasound: as this will provide a diagnosis of a mass in the body of the testis but might not distinguish between LCTs and GCTs.

Malignant LCT are large sized (>5 cm), cytological atypia, have increased mitotic activity (>3 per 10 high‐power field), have increased MIB‐1 expression (18.6% vs 1.2% in benign), necrosis, vascular invasion, infiltrative margins, extension beyond the testicular parenchyma, and DNA aneuploidy [7, 11].

It is likely that these tumours will be treated as GCTs and radical orchiectomy performed. Organ‐sparing procedures in small intraparenchymal lesions are sent of pathological confirmation sometimes. Immediate orchiectomy can be avoided in patients with gynecomastia and hormonal imbalances as suspicion will lie with a LCT instead of a GCT [7]. Fresh‐frozen sections can be carried out if any doubt, and if CGT is confirmed the surgeon can proceed to orchiectomy.

Malignant LCT are managed by radical orchiectomy followed by retroperitoneal lymphadenectomy [7]. These tumours respond poorly to radiotherapy or chemotherapy and metastases invariably leads to death [11].

39.11.3 Sertoli Cell Tumours (SCT)

Account for <1% of testicular tumours with a mean age of presentation of 45 years [11]. SCTs can be associated with genetic disorders such as androgen insensitivity syndrome, Carney syndrome, and Peutz‐Jeghers syndrome [11].

Clinical features: A slowly enlarging testicular mass; it can be bilateral in 44% of patients [7].

Pathological classification:

  • Classic SCTs
  • Large cell calcifying form
  • Sclerosing form

Ultrasound cannot safely distinguish between SCTs and GCTs. However, large cell calcifying form SCTs have a characteristic brightly echogenic foci due to calcification [11]. Tumour markers are negative.

Malignant SCTs range from 10 to 22% and typically are large (>5 cm), pleomorphic nuclei with nucleoli, increased mitotic activity (>5 per 10 high power field), necrosis, and vascular invasion [7, 11].

Similar to LCTs where small masses are misdiagnosed as GCTs and radical orchiectomy performed. For small lesions, organ‐sparing surgery is performed, or fresh‐frozen section, and only on histological confirmation of GCT, is orchiectomy performed.

Malignant SCT are managed by radical orchiectomy followed by retroperitoneal lymphadenectomy [7]. These tumours respond poorly to radiotherapy or chemotherapy and metastases invariably leads to death [11].

39.11.4 Granulosa Cell Tumours (GrCT)

There are two types of GrCT, an adult and a juvenile form. Adult GrCTs are rare and are limited to case reports in the literature. The average age of presentation is 44 years [11]. A quarter present with gynecomastia. Patients have a high serum inhibin and müllerian‐inhibiting hormone levels. Nearly 20% of GrCTs are malignant and are large (>7 cm) with vascular invasion and necrosis [7].

Juvenile GrCTs are benign and represent 6.6% of prepubertal testicular tumours [11]. Clinical features are of an asymptomatic scrotal or abdominal mass and 30% are associated with an abdominally located cryptorchidism [11]. Nearly 20% of patients have ambiguous genitalia (with 45X/46XY mosaicism or structural anomalies of Y chromosome), with mixed gonadal dysgensis being most frequent followed by hypospadias [11]. These tumours are cystic on ultrasonography. Treatment is conservative.

39.12 Tumours Containing Both Germ Cell and Sex Cord or Gonadal Stromal Elements: Gonadoblastoma

Composed of large germ cells (seminomas) and small cells (Sertoli and granulosa), most commonly seen in 15–25% of mixed gonadal dysgenesis associated with ambiguous genitalia and 45,X karyotype and Y chromosome material [11]. Bilateral in 40% of cases. Prognosis is based on the germ cell component [7].

39.13 Other Tumours of the Testis

39.13.1 Sarcomas

Testicular and paratesticular adnexal sarcomas are the most common urinary tract sarcomas.

Liposarcoma is the most common in adults with rabdomyosarcoma occurring more commonly in the younger (<30 years of age) age groups. Others include leiomyoma, malignant fibrous histiocystoma, and fibrosarcoma.

Clinical features include an asymptomatic scrotal swelling or lump which can be large (>5 cm).

Ultrasound demonstrate a solid mass, however cannot distinguish between benign and malignant tumours. An MRI scan can be useful. Otherwise, surgical exploration and biopsy is advocated.

Radical orchiectomy with or without RPLND is the treatment of choice. Chemotherapy reserved for patients with regional or distant metastasis.

39.13.2 Lymphoma

Testicular lymphoma (TL) comprises of 2% of TCa, 2% of all high ‐grade lymphomas and 5% of all extranodal lymphomas [11]. Primary TL comprises of 40–60% of TLs and most patients are between 60 and 80 years of age, whereas in children TL is rare, occurring between 3 and 10 years of age. Paratesticular lymphoma (PTL) alone is rare and usually present with TL, with 25–60% of TL showing local spread to paratesticular tissue [11].

Scrotal swelling, with bilateral involvement is rare. However, lymphoma recurrence in the contralateral side is more common (10–40%) [11].

Ultrasound of TL is often indistinguishable from GCTs; those of PTL, appear as multiple nodules or as a diffuse infiltration of the epididymis or spermatic cord with or without testicular involvement. Lymphoma should be suspected when these features are seen and involve both testicular and paratesticular tissue.

Prognosis tends to be poor, with a median survival 32–53 months, with a 5‐ and 10‐year overall survival rates of 37–48% and 19–27%, respectively [11]. In children with primary TL, prognosis is excellent with orchiectomy and chemotherapy, whereas in secondary TL, chemotherapy alone can be curative without the need for orchiectomy [11].

39.14 Tumours of the Paratesticular Structures

These are extremely rare and limited to case reports or series in the literature (Table 39.8).

Table 39.8 Tumours of the paratesticular structures.

Incidence Investigations Treatment
Adenomatoid tumour Comprising 60% of all benign tumours of the paratesticular tumours [11]. Ultrasound‐smooth, round, well circumscribed hyperechoic homogeneous mass that arises from the epididymis, spermatic cord, or tunica albuginea all of which extra‐testicular. Conservative management, however if become symptomatic surgical excision can be offered.
Cystadenoma Benign papillary epithelial hyperplasia of the epididymal ducts,
Seen in one‐third of patients with Hippel‐Lindau syndrome.
They are usually small, asymptomatic nodules, however some have been implicated as causing azoospermic infertility. Conservative with reassurance or of azoospermic infertility.
Nodular mesothelial hyperplasia Benign nodules found either attached or unattached in hernia sacs, caused by reaction of the hernia sac during incarceration and inflammation.
Patient presents with an inguinal hernia.
Clinically defined hernia Surgical hernia repair
Malignant mesothelioma Arise from the tunica vaginalis or albuginea
Peak incidence between 55 and 75 years of age.

Strong associated risk factor is asbestos exposure with incidences ranging from 23 to 50% [37, 38].
Ultrasound‐multiple nodular masses within a hydrocele, which raises the suspicion. Radical orchiectomy with or without RPLND.
Adenocarcinoma of the epididymis Rare malignant condition occurring in men from 27 to 82 years of age. Clinical features are of a painful or painless scrotal mass, can present with testicular pain or a hydrocele. Radical orchiectomy with or without RPLND. Prognosis is poor.
Melanotic neuroectodermal tumour of the epididymis Children ages 1–8 years
Rare tumour
Clinically presents with firm scrotal mass often with a hydrocele Radical orchiectomy with or without RPLND.
Desmoplastic small round cell tumour Rare; patients from 5 to 37 years of age.
These tumours have been implicated with specific genetic abnormalities in the Ewing sarcoma gene on 22q12 and the Wilms’ tumour gene, WT1 on 11p13.

Radical orchiectomy with or without RPLND.
Prognosis is poor with majority of patients developing metastatic disease within 2 years and dying within 3–4 years.

RLPND, retroperitoneal lymph node dissection.

Aug 6, 2020 | Posted by in UROLOGY | Comments Off on Testes Neoplasm
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