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Germ-cell tumours of the testis – 2016

UPDATED JANUARY 2016

1. GENERAL INFORMATION

1.1 Epidemiology

1.1.1 Incidence and mortality

Although testicular cancers are rare, accounting for 0.7% of all cancers in males (Globocan 2012), in many countries they are the most common malignancy in young men (15-35 years) (Chia 2010). Approximately 98% of testicular cancers are germ cell tumours (GCTs) (CI5); the remaining 2% include sex cord tumours (including Leydig cell and Sertoli cell cancers), rhabdomyosarcoma, and lymphoma.
The age-standardised incidence rate (ASR) for testicular cancers ranges widely across the world. In 2012, white males living in Western industrialised countries, particularly in Northern and Western Europe showed the highest annual incidence rates of testicular tumours (12 per 100,000 in Denmark, Norway, and Switzerland), whereas black males in Africa showed the lowest (<0.5 per 100.000 in the majority of African countries) (Globocan 2012b). The occurrence of the disease is also high in Australia and New Zeeland, and in North America (USA and Canada), with the ASR of 7 and 5 per 100,000, respectively. Even in Central and South America we found large differences among countries, from 7 (Chile) to less than 1 per 100,000 (Guatemala, Nicaragua).
In many high-risk areas, such as Europe and North America, white men have experienced the greatest increases in incidence throughout the late 20th century and it is still increasing in the majority of European countries (Znaor 2015). By contrast, mortality, which is very low, has declined since the mid Seventies, attributable to the development of effective treatments, centred around platinum-based chemotherapy. The recent mortality trend analyses (1980-2010) observed a levelling off in the rates in the most recent calendar years, suggesting that a plateau in mortality has been reached (Bosetti 2013).
According to the RARECAREnet project (RARECAREnet), about 16,000 of these cancers were estimated to be diagnosed in 2013 in the 28 European member states. For the period 2000-2007, the total crude incidence of testicular and paratesticular cancers was 3.3 per 100,000/year, 55% of which were seminomatous and 38% were non-seminomatous forms. The age-adjusted incidence of these cancers in the male population was 6.4 per 100,000/year. During the period 1995-2007, incidence rates – age-adjusted and calculated on all the population (male+female) – slightly increased from 2.8 to 3.4. Among five European regions, incidence was highest in the North and Centre (3.7 and 3.8, respectively) and lowest in the South of Europe (2.5) (RARECAREnet).
Germ-cell tumours have an early incidence peak in the age group 0-4 years followed by a second peak in adolescents and young adults (15-19 and 25-29 and 30-34 years) (Trama 2013). The first peak is mainly due to non-seminomas, mostly due to yolk sac tumour and teratoma, which have an annual incidence of 0.1/100,000 and 0.03/100,000, respectively.
Non-seminomatous forms are more common than the seminomatous until the age of 30 years; however, the histologic types of those between 15 and 30 years are mainly embryonal carcinoma and mixed germ cell tumours and only to a lower extent teratoma and yolk sac tumour (Trama 2013).
In people aged >30 years, seminomas are predominant. Overall, seminomas presented an incidence peak 10 years later than non-seminomas (Trama 2013).

1.1.2 Survival

Survival from testicular and paratesticular cancers for men diagnosed in Europe (RARECAREnet) during 2000-2007 was 97% at one year and 95% at five years, the highest survival rate for any malignant tumour in men (De Angelis 2014). Among these cancer types, seminomatous forms had the highest 5-year survival rate (98%; 95%CI 97-98) followed by spermatocytic seminomas (95%; 95%CI 92-98), and non-seminomatous forms (93%; 95%CI 93-93). Survival was consistently lower for patients aged 65 years or more (73% at 5 years, based on 1,308 cases) than for younger patients (RARECAREnet). There have been improvements in survival since the early 1980s (Trama 2015). In Europe, during 1999-2007 survival remain stable (RARECAREnet). Even if testicular cancer is curable, still in 2000-2007 there were disparities in 5-year survival across European regions: survival was lowest in the Eastern countries (88%) and highest in Northern Europe (97%); in the other regions 5-year survival was between 96% and 94%. Differences in the age distribution or biology of testicular cancers cannot account for the international variability in testicular cancer survival, which is more probably attributable to differences in the accessibility of effective treatment (Coleman 2003). An association between deprivation and survival has been found for testis cancer (Coleman 1999). Survival is higher for men in affluent groups (94% for most affluent patients diagnosed in 1986-1990). The deprivation gap between affluent and deprived groups was about -6% at 5 years after diagnosis. For the subsequent period (1991-2001) survival improved more in the deprived group, thus the discrepancy was -1.5 and 1.2 at 5 and 10 years, respectively. This narrowing of the deprivation gap appears to reflect a “ceiling effect”, as there is little room for any further increase in survival among most affluent group.
Survival data reported in these notes derived from information collected by population-based cancer registries. They provide the means by which we can measure progress against cancer.

1.1.3 Prevalence

In Europe, at the beginning of 2008 about 476,000 persons were living with a diagnosis of testicular cancer (RARECAREnet). The proportion was 93 per 100,000. The 5-year prevalence, that is the number of living people with a diagnosis of testicular cancer made 5 or less years before the index date, was only 16 per 100,000 (80,000 people). The last figure provides an indication of the need for clinical follow-up and treatment for recurrences. Of the total population with testicular cancer, 55% people are long-term survivors, that is people living with a diagnosis made 15 or more years before the index date. The early age of diagnosis and the very good prognosis of testicular cancer are the most important contributor to prevalence of survivors.

1.2 Aetiology and risk factors

1.2.1 Aetiological factors and risk factors

Undescended testis, or cryptorchidism, is the most recognised risk factor for testicular cancer (Cook 2010). The risk of cancer is increased by two- to eight-fold in men who have had undescended testis and 5% to 10% of all men with testicular cancer have a history of cryptorchidism (Toppari 1999; Dieckmann 2004). Treatment for undescended testis before puberty can prevent testicular cancer. 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 in boys with an undescended testicle. Treated people aged 13 years or more had a relative risk of 5.4 compared to the general population, about twice the risk of those treated at younger ages (Pettersson 2007).
Family history of testicular cancer is associated with risk of testicular cancer: from the Swedish Family Cancer Database, the incidence ratios for familiar risk were almost 4 and 8 fold when the father or the brother had testicular cancer, respectively (Hemminki 2006).
Several studies show that a previous history of testicular cancer is strongly associated to a second cancer in the contralateral testis. Two studies, from Netherlands and New Zealand, reported an increased risk of a contralateral tumour in patients who previously had testicular cancer, with very high relative risks of 25-28 (Henderson 1979; Li 1972). A large population-based cohort study involving about 30,000 US men estimated a lower risk: testis cancer patients had a 12 times greater risk of developing a metachronous contralateral testicular cancer than the general population (Fossa 2005).
A systematic review of pre- and perinatal variables focus on maternal characteristics (Cook 2009) revealed evidence for associations with maternal bleeding (odds ratio – OR: 1.33), birth order (first vs. the others OR: 1.08), and sibship size (OR from 0.93 to 0.75 for 2, 3, 4 vs. first). Bleeding is generally the result of a developmental aberration, like abnormal placental differentiation or aggressive implantation, which may be hypothesized to disrupt foetal development and increase risk for a prenatal, stem-cell progenitor of testicular cancer.
Exposure to endocrine disrupting chemicals (EDCs) during the foetal period has been postulated to be a risk factor (Wuttke 2010) to testicular cancer. EDCs 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 known EDCs to which humans are exposed to via the environment. In a Swedish study the concentrations of chlorinatedbiphenyls (PCBs), p,p’-dichlorodiphenyl-dichloroethylene (pp’-DDE), hexachlorobenzene (HCB), chlordanes, and polybrominated diphenylethers (PBDEs) were assessed higher in blood from mothers of people with testicular cancer compared with control mothers (Hardell 2003). A risk of about 4 was estimated for the exposition of a sum of PCBs. Most of the cases were born during a period with the highest concentrations of persistent organic pollutants (POPs), such as PCBs, in the ecological system. Since then, the concentrations have fallen substantially. In Sweden, the large difference in increase in incidence between 1984-1993 and 1994-2003 supports the hypothesis that exposure to certain POPs during foetal period is of aetiologic significance in testicular carcinogenesis.
Another systematic review and meta-analysis of perinatal variables, with a specific focus upon characteristics of the son (Cook 2010), provides evidence that low birth weight, gestational age, inguinal hernia, cryptorchidism, and twinning are associated with a higher risk of testicular cancer. Their ORs ranged between 1.63 and 1.22, excluding cryptorchidism carrying the highest risk of 4.3. Another subsequent Swedish study confirmed that genital malformations were associated with increased risk of testicular cancer, in addition to cryptorkidism and inguinal hernia, also hypospadias (OR: 2.4) was reported. It should be considered that some of these factors are related between them and could arguably be proxies of the maternal in utero environment. There is evidence that exposure to maternal hormones, particularly oestrogens, is associated with testicular germ-cell cancer risk (OR: 4.9) (Weir 2000).
The average height and the incidence of testicular cancer have both been increasing over several generations with strong cohort effects (Cook 2011). A systematic review and meta-analysis analysed the body size and confirmed the association with height only, with OR of 1.13 per 5 cm increase in height. Mechanisms to explain this association include childhood nutrition (Diekmann 2002), increased levels of insulin-like growth factor (Juul 1994; Khandwala 2000) or an earlier age at puberty in those with a greater height (Hagg 1992; Karlberg 2002). Adult height is largely determined in the period between birth and age 2 years (Karlberg 2002), therefore nutrition at this age may be particularly relevant to testicular cancer risk (McGlynn 2007).
Several occupational exposures have been suggested to be associated with testicular cancers, such as polychlorinated biphenyls, EMF exposure, and pesticides. In addition, several occupations have been linked to firemen, policemen, military personnel, agricultural workers and industrial workers (paper, plastic or metal) (Charbotel 2013; McGlynn 2012). Since testicular cancer occurs mainly in young adults, the potential impact of occupational exposure of mothers to endocrine disruptors during intrauterine development have to be considered (McGlynn 2012; Skakkebaek 2001).
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 (McGlynn 2012).

1.3 Early diagnosis

1.3.1 Screening and case finding

For testicular cancer there are no reliable screening tests. Due to low occurrence and a high cure rate, testicular self-examination and the impact of self-assessment are controversial (Stewart 2003).

2. PATHOLOGY AND BIOLOGY

2.1 Biological data

2.1.1 Histogenesis of testicular germ cell tumours

Testicular germ cell tumours (TGCTs) derive from the transformation of cells in the germ-cell lineage that are blocked in their maturation process. TGCTs in adults are thought to initiate during fetal development and involve changes to primordial germ cells either during migration to the embryonic genital ridges or after cells have arrived at the gonads. The pluripotentiality of the tumour germ cells manifests as histologic differentiation into germ cell-like undifferentiated (seminoma), primitive zygotic (embryonal carcinoma), embryonal-like somatically differentiated (teratoma), extraembryonically differentiated phenotypes (choriocarcinoma and yolk sac tumour).
The precursor lesion of almost all TGCTs is intratubular germ cell neoplasia unclassified (IGCNU) or carcinoma in situ (CIS), defined as malignant germ cells confined to the seminiferous tubules. The incidence of IGCNU in the overall population is 0.9%. IGCNU gives no symptoms, but precedes invasive testicular germ cell tumour in all cases of seminoma, except spermatocytic seminoma, and non-seminomatous histologies, with a median time for progression of CIS to invasive disease of 5 years (Boublikova 2014). Tumour growth of invasive GCT varies in accordance with histological type. Seminomas grow slowly with successive involvement of lymphatic vessels and retroperitoneal lymph nodes. Non-seminoma tumours grow quickly with rapid involvement of blood vessels (choriocarcinoma often shows lung and brain metastases at diagnosis).

2.1.2 Genetic abnormalities

Molecular mechanisms underlying development and progression of TGCT are still not clear. Chromosome 12p alterations are the hallmark of TGCT, identified in nearly all invasive TGCT, as well as intratubular embryonic carcinoma and intratubular seminoma. Specifically, isochromosome 12p is the most common alteration (~80%), with duplication of 12p and amplification of shorter stretches of 12p being much less common. The typical chromosomal abnormality in GCT is hyperdiploidy (triploidy and tetraploidy). Mutations in single genes are uncommon in TGCT. The top five genes mutated in TGCT are KIT, TP53, KRAS /NRAS, and BRAF. Among these genes, KIT, TP53, and KRAS /NRAS were found to be more frequently mutated in seminomas (6-19%) compared to NSGCT (0-2%). Other mutated genes associated with TGCT were FGFR3, HRAS, PTEN, SIK1, SMAD4, STK10, and STK11, but they were detected in very few cases each (Sheikine 2012).

2.2 Histological types

2.2.1 Incidence of histological types
Germ cell tumour is classified into two major groups: seminoma and non-seminoma tumours, which differ in biological and clinical characteristics and therapeutical approach. Seminoma accounts for approximately 45-50% of GCT and non-seminomatous histology for 50-55%. Frequently, mixed germ cell tumours are found and the percentage of each component must be specified (Hanna 2014).

2.2.2 WHO classification

The recommended pathological classification (modified from the 2004 version of the World Health Organization guidance) is shown below (Eble 2004):

Germ cell tumours

  • Intratubular germ cell neoplasia, unclassified (IGCNU)
  • Seminoma (including cases with syncytiotrophoblastic cells)
  • Spermatocytic seminoma (mention if there is sarcomatous component)
  • Embryonal carcinoma
  • Yolk sac tumour
  • Choriocarcinoma
  • Teratoma (Mature, Immature, With malignant component)
  • Tumours with more than on histological type (specify percentage of individual components)

Sex cord/gonadal stromal tumours

  • Leydig cell tumour
  • Malignant Leydig cell tumour
  • Sertoli cell tumour
    • lipid-rich variant
    • sclerosing
    • large cell calcifying
  • Malignant Sertoli cell tumour
  • Granulosa cell tumour
    • adult type
    • juvenile type
  • Thecoma/fibroma group of tumours
  • Other sex cord/gonadal stromal tumours
    • incompletely differentiated
    • mixed
  • Tumours containing germ cell and sex cord/gonadal stromal (gonadoblastoma)

Miscellaneous non-specific stromal tumours

  • Ovarian epithelial tumours
  • Tumours of the collecting ducts and rete testis
  • Tumours (benign and malignant) of non-specific stroma
2.2.3 Seminoma

Seminoma accounts for 40-50% of all GCTs of the testis and frequently appears in the fourth decade of life. The typical form consists of large cells with abundant cytoplasm and round, hyperchromatic nuclei with prominent nucleoli. A lymphocytic infiltrate, granulomatous reaction with Langerhans-like giant cells, or both are frequently present. Approximately 7% of classic seminomas contain true syncytial trophoblastic giant cells (as distinct from Langerhans cells) that stain positively for human chorionic gonadotropin (HCG) and that may account for the low level elevation of serum HCG in some patients with seminoma (5%-10%) (variant: seminoma with syncytiotrophoblastic cells). The “anaplastic form” is an old term used when three or more mitotic figures are seen per high-power field; it has no clinical or prognostic importance. In the atypical form the cells are cytologically similar to classical seminoma, but lymphocytic infiltrate and necrosis are absent. Spermatocytic seminoma is a rare histological variant (4%-7% of all seminomas) that occurs in an older population than classic seminoma, with a median age of 65 years.

2.2.4 Non-seminoma

Non-seminomatous germ cell tumours represent about 50-55% of all GCTs and frequently appear in the third decade of life. Embryonal carcinoma (20% of all testicular cancers) frequently presents with areas of necrosis and hemorrhage. Microscopically, the appearance is extremely variable due to ability of embryonal carcinoma to differentiate into other pathological variants. Teratoma contains somatic cells derived from endoderm, mesoderm, and ectoderm, with varying degrees of differentiation. Although technically no malignant tissue exists in these terminally differentiated (histologically benign) tumours, metastases can occur and death can result from slowly progressive, unresectable disease. Teratoma does not secrete human chorionic gonadotrophin (HCG) or alpha-fetoprotein (AFP) and not responsive to chemotherapy: surgical excision represents the only therapeutic option. Mature teratoma presents as epithelial-lined structures, as mature cartilage, or as striated or smooth muscle. In immature teratoma the presence of a highly cellular stroma exhibiting mitotic figures is sufficient to make the diagnosis. Areas of primitive mesoderm, endoderm or ectoderm mixed with the more mature elements are present. Teratoma with malignant transformation contains malignant nongerm cell elements. It is unclear whether these elements represent partial differentiation along somatic lines of the malignant totipotent germ cell, or malignant degeneration of mature somatic elements of the teratoma. Teratoma with malignant transformation may include areas of adenosquamous carcinoma, rhabdomyosarcoma, neuroblastoma or nephroblastoma. The presence of these malignant somatic tissues at the time of diagnosis or following chemotherapy indicates a poor prognosis. Choriocarcinoma shows on microscopical examination, close proximity of cytotrophoblasts (ovoid cells with well-defined borders, and with hyperchromatic or vacuolated nuclei) with the more easily recognizable syncytiotrophoblasts (larger, multinucleated cells with indistinct borders and a large amount of eosinophilic cytoplam). Stroma is sparse, but tends to be highly vascular. Choriocarcinoma represents the most aggressive pathologic variant of the GCT in adults, and early haematogenous spread and visceral metastases may be observed at first diagnosis. In these patients extreme elevations of serum levels of HCG have been reported, with a normal serum level of AFP. The form of pure choriocarcinoma is rare in the adult testis. Yolk sac tumour shows a great variety of patterns, but commonly the lesions contain cystic areas lined by ovoid or flattened cells that protrude into the lumen of the cyst. The appearance of the endodermal sinus is pathognomonic. Serologically, patients with pure yolk sac tumours have elevated serum levels of alpha-fetoprotein, with a normal serum level of HCG.

2.2.5 Co-existence of different histological types

Frequently mixed histological types are found. Mixed seminomatous-non-seminomatous forms must be treated as non-seminomatous cancers due to the worst prognosis of this histological type. If an increasing value of AFP is found in seminoma, the tumour must be considered and treated as non-seminomatous tumour.

2.2.6 Immunohistochemical markers

Immunohistochemical markers can be useful in the pathological diagnosis. Seminomas exhibit positivity for placental alkaline phosphatase (PLAP) (Manivel 1987) and ckit/CD117 (Izquierdo 1995), but are generally negative for keratin. Embryonal carcinomas express keratins on the cell surface (Battifora 1984). Vimentine can be found in mesenchymal parts of mature teratomas.

2.3 Accuracy and reliability of pathological diagnosis

2.3.1 The pathological report

The pathological report should include the following pathological requirements:

  • Macroscopic features: side, testis size, maximum tumour size and macroscopic features of epididymis, spermatic cord and tunica vaginalis.
  • Sampling: a 1 cm2 section for every centimeter of maximum tumour diameter, including normal macroscopic parenchyma (if present), albuginea and epididymis, with selection of suspected areas. At least one proximal and one distal section of spermatic cord plus any suspected area.
  • Microscopic features and diagnosis: histological type (specify individual components and estimate amount as percentage) according to WHO 2004:
    • presence or absence of peri-tumoural venous and/or lymphatic invasion
    • presence or absence of albuginea, tunica vaginalis, rete testis, epididymis or spermatic cord invasion
    • presence or absence of IGCNU
  • pT category according to Tumour Node Metastasis (TNM) 2002.
  • Immunohistochemical studies: in seminoma and mixed germ cell tumour, AFP and hCG.

3. DIAGNOSIS

3.1 Diagnostic clues

3.1.1 Presentation

The majority of TGCTs are clinically detectable at initial examination. The usual presentation of testicular cancer is a painless unilateral testicular mass; 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 epidydimitis or develops bleeding within the testis, since expansion of the tunica albuginea produces pain. Gynaecomastia is sometimes present if HCG is increased. 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 to the brain). Only 5% of all germ cell tumours (GCT) present as extragonadal and the remaining 95% of GCT are purely gonadal in origin and presentation.

3.2 Diagnostic strategy

3.2.1 Clinical assessment and imaging

A complete history should be taken, including information about previous inguinal or scrotal surgery, maldescent, retractile testis, and orchiopexy. The physical examination of the testis should be performed by carefully palpating the organ between the thumb and the first two fingers. The normal testis is homogenous in consistency and freely moveable. Any nodular, hard, or fixed area discovered in the testis, must be considered neoplastic until proved otherwise. The contralateral testis provides a comparative model for examiner. The physical examination should pay attention to possible sites of lymph node metastases (abdomen, supraclavicular regions). The presence or absence of gynaecomastia is an important observation. If a testicular tumour is suspected, testicular ultrasound should be performed.
Currently, diagnostic ultrasound serves to confirm the presence of a testicular mass and to explore the contralateral testis. Its sensitivity in detecting a testicular tumour is almost 100%, and it has an important role in determining whether a mass is intra- or extratesticular. Ultrasound is an inexpensive test, but it is unnecessary when the presence of a testicular tumour is clinically evident. Magnetic resonance imaging (MRI) offers higher sensitivity and specificity than ultrasound for diagnosing tumours, but its high cost does not justify its use for diagnosis (Dieckmann 2013).

3.2.2 Pathological diagnosis

Pathological diagnosis and staging represent the cornerstone on which treatment decisions are based. A radical orchiectomy, using an inguinal incision with early high ligation of the spermatic cord at the deep inguinal ring, is the only acceptable therapeutic and diagnostic procedure. The testicle and spermatic cord are removed en bloc. A transscrotal orchiectomy is contraindicated, because it permits the development of alternate lymphatic drainage pathways to the inguinal and pelvic lymph nodes. In the rare situation in which the diagnosis of a testicular tumour is in question, frozen section analysis should be considered intra-operatively.

4. STAGING

4.1 Staging Classification

4.1.1 Formal stage classification

The American Joint Committee on Cancer (AJCC) and International Union Against Cancer (UICC) have designated staging by TNM classification (UICC 2002). In 1997 for the first time an S category for the serum concentration of LDH, HCG, and AFP was incorporated because of its independent prognostic significance.

4.1.2 TNM Staging classification

Primary Tumour (T)
The extent of primary tumour is classified after radical orchiectomy
pTx Primary tumour cannot be assessed (if no radical orchiectomy has been performed,Tx is used)
pT0 No evidence of primary tumour (e.g, histological scar in testis)
pTis Intratubular germ cell neoplasia (carcinoma in situ)
pT1 Tumour limited to testis and epididymis without lymphatic/vascular invasion; tumour may invade into the tunica albuginea but not the tunica vaginalis
pT2 Tumour limited to testis and epididymis with lymphatic/vascular invasion, or tumour extending through the tunica albuginea with involvement of the tunica vaginalis
pT3 Tumour invades the spermatic cord with or without lymphatic/vascular invasion
pT4 Tumour invades the scrotum with or without lymphatic/vascular invasion

Regional lymph nodes (N)

CLINICAL
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in a single lymph node, 2 cm or less in greatest dimension; or multiple lymph nodes, none more than 2 cm in greatest dimension
N2 Metastasis in a single lymph node, more than 2 cm but non more than 5 cm in greatest dimension; or multiple lymph nodes, none more than 5 cm in greatest dimension
N3 Metastasis in a lymph node more than 5 cm in greatest dimension

PATHOLOGIC
N0 No evidence of tumour in regional lymph nodes
N1 Metastasis in 1-5 lymph nodes, none more than 2 cm in greatest dimension
N2 Metastasis in 1-5 lymph nodes, more than 2 cm but non more than 5 cm in greatest dimension; or evidence of extranodal extension tumour
N3 Lymph node mass more than 5 cm in greatest dimension

Distant metastases (M)

CLINICAL
Mx Presence of distant metastases cannot be assessed
M0 No distant metastases
M1 Distant metastases
M1a: Non-regional nodal or pulmonary metastases
M1b: Distant metastases other than to non-regional nodes and lungs

PATHOLOGIC: pM category correspondes to cM category

Serum tumour markers (S)
SX Markers studies not available or not performed
S0 Marker study levels within normal limits
S1 LDH < 1.5 x N AND HCG (mIU/ml) < 5000 AND AFP (ng/ml) < 1000
S2 LDH 1.5-10 X N OR HCG (mIU/ml) 5000- 50,000 OR AFP (ng/ml) 1000 – 10,000
S3 LDH 10 X N OR HCG (mIU/ml) > 50,000 OR AFP (ng/ml) > 10,000
N : indicates the upper limit of normal for the LDH assay

UICC Stage Grouping
Stage 0 pTis N0 M0 S0 SX
Stage I pT1-4 N0 M0 SX
Stage IA pT1 N0 M0 S0
Stage 1B pT2 N0 M0 S0
pT3 N0 M0 S0
pT4 N0 M0 S0
Stage IS any pT/TX N0 M0 S1-3
Stage II any pT/TX N1-3 M0 SX
Stage IIA any pT/TX N1 M0 S0
any pT/TX N1 M0 S1
Stage IIB any pT/TX N2 M0 S0
any pT/TX N2 M0 S1
Stage IIC any pT/TX N3 M0 S3
any pT/TX N3 M0 S1
Stage III any pT/TX any N M1 SX
Stage IIIA any pT/TX any N M1a S0
any pT/TX any N M1a S1
Stage IIIB any pT/TX N1-3 M0 S2
any pT/TX any N M1a S2
Stage IIIC any pT/TX N3 M0 S3
any pT/TX any N M1a S3
any pT/TX any N M1b any S
4.1.3 Classifications for metastatic germ-cell tumours

Since there is a possibility of cure for most patients with advanced disease, it has become necessary to stratify patients according to the likelihood of treatment success. Histology, primary site, metastatic site, and serum concentrations of tumour markers are independent prognostic variables and have been shown to predict the likelihood of cure. Several classifications have been used to categorize good and poor risk status [the Memorial Sloan Kettering Cancer Center and the Indiana University (Birch 1986) classifications in the USA, and the Medical Research Council and the EORTC (de Wit 1995) classifications in Europe], but a comparison of risk criteria used in these classifications in advanced non-seminomatous germ cell tumours demonstrated marked differences and showed that the allocation to good- or poor-risk categories was in agreement in only 56% of patients (Bajorin 1988). Due to these differences, in 1997 a prognostic factor-based classification for the metastatic germ cell tumours was developed by the International Germ Cell Cancer Collaborative Group (IGCCCG 1997). This classification, based on a retrospective analysis of 5,202 patients with metastatic non-seminomatous and 660 patients with metastatic seminomatous germ cell tumours (all treated with cisplatinum, or carboplatinum, containing therapy as first-line chemotherapy), was agreed by all major clinical trial groups active worldwide. Median follow up time was 5 years. For non-seminomatous germ cell cancers the following independent adverse factors were identified: mediastinal primary site; degree of elevation of AFP, HCG, and LDH; and presence of nonpulmonary visceral metastases, such as liver, bone, and brain. For seminoma, the predominant adverse feature was the presence of nonpulmonary visceral metastases. Integration of these factors produced the following grouping: 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; and poor prognosis, comprising 14% of germ cell cancers with a 48% 5-year survival rate. This classification should be used in clinical practice and in the design and reporting of clinical trials results for patients with metastatic germ cell cancers.

1. Good Prognosis (5-year survival rate of 91%) non-seminoma:
Testis/retroperitoneal primary
And
No non-pulmonary visceral metastases
And
Good marker leves – all of
AFP < 1000 ng/ml and
HCG < 5000 mIU/ml and
LDH < 1.5 x upper limit of normal

56% of non-seminomas
5-year PFS: 89%
5-year overall survival: 92%

Seminoma:
Any primary site
And
No non-pulmonary visceral metastases
And
Normal AFP, any HCG, any LDH
90% of seminomas
5-year PFS: 82%
5-year overall survival: 86%

2. Intermediate Prognosis (5-year survival rate of 79%) non-seminoma:
Testis/retroperitoneal primary
And
No non-pulmonary visceral metastases
And
Intermediate marker levels – any of :
AFP >/=1000 ng/ml and HCG >/=5000 mIU/ml and LDH >/= 1.5 x upper limit of normal and
20% of non-seminomas
5-year PFS: 75%
5-year overall survival: 80%

Seminoma:
Any primary site
And
Non-pulmonary visceral metastases
And
Normal AFP, any HCG, any LDH

10% of seminomas
5-year PFS 67%
5-year overall survival 72%

3. Poor Prognosis (5-year survival rate of 48%) non-seminoma:
Mediastinal primary
or
Non-pulmonary visceral metastases
or
Poor marker levels – any of :
AFP >/=10,000 ng/ml or
HCG >/=50,000 mIU/ml or
LDH >/=10 x upper limit of normal

10% of non-seminomas
5-year PFS 41%
5-year overall survival 48%

Seminoma:
No patients classified as poor prognosis

4.2 Staging procedures

4.2.1 Imaging

Computer tomography (CT) scan of the abdomen and pelvis is mandatory. Thoracic CT should be carried out in case of non-seminoma, but can be omitted in seminoma patients without infradiaphragmatic metastases. Magnetic resonance imaging (MRI) produces similar results to CT scanning in the detection of retroperitoneal nodal enlargement. The main objections to its routine use are its high cost and limited access to it. Nevertheless, MRI can be helpful when abdominopelvic CT or ultrasound are inconclusive, when CT scan is contraindicated because of allergy to contrast media, or when the physician or the patient are concerned about radiation dose. There is not enough evidence to support the use of the fluorodeoxyglucose-PET (FDG-PET) scan in the staging of testis cancer. A bone scan is indicated in patients with suspected bone metastases. A brain CT or MRI is performed in case of cerebral symptoms and in patients with multiple (>20) lung metastases and choriocarcinoma/high HCG levels (>10,000 IU/L) (Oldenburg J 2013).

4.2.2 Serum tumour markers

Many testicular cancers produce tumour markers, alpha-fetoprotein (AFP), human chorionic gonadotropin (HCG), lactate dehydrogenase (LDH). These markers are useful in the following settings:

  • diagnosis and staging of disease;
  • monitor the therapeutic response;
  • detect of tumour recurrence.

Increasing levels of tumour markers during follow-up, is an indication that therapy should be initiated, even if no evident disease is found. The half-life of markers must be taken into consideration when evaluating therapeutic responses. Marker monitoring has been introduced in GCT staging.

Alpha-fetoprotein (AFP) is a glycoprotein normally produced by fetal yolk sac, the liver and the gastroenteric tract. It is increased not only in yolk sac tumours and embryonal carcinoma, but also in hepatocarcinoma, in infective-degenerative liver diseases, and in regenerative liver after toxic damage. Temporary increases are found in week-end drinkers. If an increasing value of AFP is found in pure seminoma, the tumour must be considered as, and treated as if it were, a non-seminomatous tumour. The half-life of AFP is 5-7 days.

Human chorionic gonadotropin (HCG) is a glycoprotein produced by syncytiotrophoblastic cells and it consists of two subunits, alpha and beta. The alpha subunit is common to three pituitary trophic hormones: FSH, LH, TSH. The beta subunit makes HCG enzymatically and immunologically distinct. Only the beta subunit (betaHCG) is measured. It is highly specific for testicular cancer: it is produced specifically by choriocarcinoma cells, but it can be found in 5% to 10% of pure seminomas. The half-life of betaHCG is 18-36 hours.

Lactate dehydrogenase (LDH) is a less specific marker. Its concentration reflects the “tumour burden”, growth rate and cellular proliferation. It has an independent prognostic significance. LDH is increased in about 80% of advanced seminomas and in about 60% of advanced non-seminomatous GCTs. The LDH isoenzyme 1 appears to be more specific and sensitive for GCT than the other four isoenzymes (2-5) (von Eyben 1983).

5. PROGNOSIS

5.1 Natural history

5.1.1 General considerations

Germ cell tumour of the testis is a highly treatable, often curable, cancer. More than 90% of patients with newly diagnosed TGCT are cured. Delay in diagnosis correlates with a higher stage at presentation for treatment (Scher 1983; Bosl 1981). Seminoma (all stages combined) has a cure rate of greater than 90%. For patients with low-stage disease, the cure approaches 100%. For patients with non-seminoma tumours, the cure rate is >95% in stage I and II; it is ~ 70% with standard chemotherapy and resection of residual disease, if necessary, in stage III and IV.

6. TREATMENT

6.1 Treatment strategy

6.1.1 General considerations

TGCTs are divided into seminoma and non-seminoma types for treatment planning because seminomatous testicular cancers are sensitive either radiotherapy than chemotherapy, and non-seminomatous tumours to chemotherapy alone. Tumours that appear to have a seminoma histology but that are accompanied by elevated serum levels of AFP should be treated as non-seminomas. Non-seminomatous testicular tumours include embryonal carcinoma, teratoma, yolk sac carcinoma, chorioncarcinoma, 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 those with brain metastases, may still be curable and should be treated with this intent (Spears 1992).

6.1.2 Surgical therapy

Radical inguinal orchiectomy, using an inguinal incision with initial ligation of the spermatic cord at the deep inguinal ring, minimizes local tumour recurrence and aberrant lymphatic spread. This is the only acceptable therapeutic and diagnostic procedure on a type C basis. A prosthesis can be inserted (Dieckmann 2015). Trans-scrotal orchiectomy is not recommended, because it leaves intact the inguinal portion of spermatic cord (from the external to the internal ring) and predisposes the patient to scrotal skin and inguinal and pelvic nodal metastases (due to the development of alterate lymphatic drainage pathways to the inguinal and pelvic lymph nodes). In a systematic review of all published studies between 1958 and 1993, it was reported that 206 of 1128 patients underwent scrotal violation (scrotal orchiectomy, open testicular biopsy, and fine needle aspiration) (Capelouto 1995). In this review no search strategy or further information about the selection of articles was provided. The results showed, in contrast to traditionally held beliefs, that the overall distant recurrence rate was not significantly different between inguinal surgery (11.5%) and scrotal violation (12.7%), although the overall local recurrence rates were statistically significant higher (0.4% vs. 2.9%; p<0.001). At a median follow up of 22.6-116 months, the overall survival rates were similar (91.5% for inguinal surgery and 92.7% for scrotal violation). However, further prospective evaluation is needed before firm conclusions can be made on the safety of scrotal violation. For retroperitoneal lymph node dissection (RPLND) see 6.7.2.

6.2 Carcinoma in situ (CIS) of the testis

6.2.1 Treatment strategy

The diagnosis of CIS is based on biopsy of the testis. The management of CIS of the testis may be:

  • orchiectomy;
  • surveillance with orchiectomy when an invasive tumour develops;
  • low-dose testicular irradiation (20 Gy in 10 fractions of 2 Gy , given as 5 fractions per week) on a type 3 level of evidence (von der Maase 1987; Giwercman 1991).

6.3 Pure seminoma

6.3.1 Treatment strategy

Pure seminomas are characterized by high radiosensitivity, relatively slow growth of micrometastases, and patients’ mean age of 36 years at diagnosis. The initial standard treatment of unilateral seminoma of testis is radical inguinal orchiectomy on type C basis. In patients with small-sized primary tumours without a functioning contralateral testis, gonad-conserving treatment may be considered (tumour resection followed by testicular irradiation) (Heidenreich 2001). After testicular surgery, the management depends on stage of disease. Pure seminonas also include seminomas with a high mitotic index (previously called anaplastic seminomas). Production of HCG, demonstrated by immunohistochemistry or by elevated preorchiectomy serum levels, does not alter the stage-related clinical course of pure seminoma and its treatment (Weissbach 1999). Patients whose tumour appears to be pure seminoma histologically but who have elevated serum levels of AFP, should be treated with a strategy for non-seminoma. Spermatocytic seminomas, that are usually diagnosed in men older than 60 years and almost never metastasize, can be treated by orchiectomy alone. For patients with seminoma (all stages combined), the cure rate exceedes 90%.

6.4 Clinical stage I seminoma

Clinical stage I seminoma is characterized by normal post-orchiectomy findings by clinical, radiologic, and biochemical examinations (including abdominal and pelvic CT). Approximately 80% of the patients with seminoma present with stage I disease and most of these patients are cured by orchiectomy alone. The actuarial relapse rate is in the order of 14-20% at 5 years and most of the relapses are first detected in infra-diaphragmatic lymph nodes. In most recent reports, median time to relapse was 14-15 months and approximately 95% of the relapse occurred within 5 years of follow-up. Tumour size >4 cm and invasion of rete testis were associated with an increased risk of relapse in an international retrospective study of 638 men, reporting relapse rates of 31.5%, 15.9% and 12.2% in those with both, one and neither risk factor, respectively (Warde 2002). Some subsequent reports did not confirm these findings (Tandstad 2011; Chung 2015). However, these factors are sometimes used to choose between surveillance or adjuvant treatment. Management options of clinical stage I seminoma include active surveillance, adjuvant chemotherapy and adjuvant radiation therapy. However, overall survival of patients with stage I seminoma is ~99%, independent of the chosen strategy (Tandstad 2011; Kollmannsberger 2011; Leung 2013; Aparicio 2011). Currently, most authors and international guidelines recommended an individualized decision making about management of stage I seminoma patients (Oldenburg 2013; Oldenburg 2015). The most relevant way of personalizing management of stage I patients is the identification of the patient’s individual risk factors, providing unbiased information and involving the patient in a discussion about the potential risks and benefits of each different management strategy and helping the patient in deciding which management to prefer (Oldenburg 2015).

6.4.1 Adjuvant radiotherapy

The traditional management after radical inguinal orchiectomy has been with prophylactic irradiation of the retroperitoneal nodes, that is recommended, on a type I basis, even with a negative computed tomographic scan (CT), because about 15% of such patients will have occult nodal spread that can be cured with irradiation (Fossa 1999). Up to the 1990s, standard radiotherapy was applied to ispilateral iliac and para-aortic lymph nodes (“dog-leg” fields). Treatment was given 5 days/week with daily fractions of 1.8 to 2 Gy up to target doses of 26 to 30 Gy. To reduce the acute and late toxicity, some attempts have been made to reduce the treatment burden, both by reducing the treatment field (Bamberg 1999) and by lowering the target dose. Treatment field- The National Cancer Research Institute (UK) Testis Cancer Clinical Studies Group conducted a phase III trial (1989 to 1993) that compared the outcome of conventional radiotherapy “dog-leg” (DL) (ipsilateral iliac and para-aortic lymph nodes) with para-aortic (PA) field radiotherapy, applying 30 Gy to both fields (Fossa 1999). Patients with previous ipsilateral inguinal or scrotal surgery or with pT4 tumours were not eligible because of the risk of altered lymph drainage. The 3-year relapse-free survival rate (96% vs. 96.6%) and overall survival rate (99.3% vs. 100%) were similar in two groups. Adjuvant radiotherapy confined to the PA lymph nodes was associated with reduced haematologic, gastrointestinal and gonadal toxicity. After PA radiotherapy, 4 patients developed a pelvic recurrence vs. any relapse after DL radiotherapy. Except for one, all relapsing patients were rendered disease-free, mostly by chemotherapy (Fossa 1999). Target dose- Single-center phase II reports in 1990s suggested that target doses below 30 Gy would be sufficient as the adjuvant irradiation for stage I seminomas (Read 1993; Niewald 1995). In a randomised trial of the National Cancer Research Institute (trial TE18), the efficacy and toxicity of a target dose of 30 Gy was compared with a target dose of 20 Gy in 625 patients (Jones 2005). Patients from a subsequent trial comparing radiotherapy at 20 Gy or 30 Gy with carboplatin chemotherapy could also be considered, if they had been allocated to the radiotherapy arm (469 patients). Thus, 1,094 patients were eligible for the comparison of 20 Gy and 30 Gy as the target dose. 20 Gy and 30 Gy are clinically equivalent with respect to relapse rates; 20 Gy produces an improved short-term morbidity profile (Jones 2005). From the results of these trials, it can be concluded that 20 Gy given to a para-aortic lymph-nodes (PA) target field represents the current standard treatment in patients with seminoma stage I and with unaltered lymph drainage and ≥pT3 tumours in whom prophylactic radiotherapy is indicated, on a type 1 level of evidence. Patients with seminoma stage I and previous ipsilateral inguinal or scrotal surgery and patients with pT4 tumours should have a DL field. In the case of orchiectomy via a scrotal incision, the scrotum is only included in the radiotherapy fields if there a high risk of contamination. Adjuvant retroperitoneal radiotherapy is contraindicated in patients with:

  1. a horseshoe kidney;
  2. a second metachronous testicular germ cell tumour;
  3. inflammatory bowel disease.

A horseshoe kidney is a contraindication to retroperitoneal radiotherapy due to the high likelihood of radiation-induced renal failure. Patients who develop a second metachronous testicular germ cell tumour and who have undergone a prior retroperitoneal lymph node dissection or retroperitoneal radiotherapy, should be observed frequently, after orchiectomy, if clinical stage I seminoma is present. For patients with inflammatory disease, observation or adjuvant chemotherapy are preferred options.

6.4.2 Adjuvant chemotherapy

Adjuvant chemotherapy with one course of carboplatin (area under the curve (AUC) x 7) is now recommended on a type I basis. Preliminary phase II trials suggested that radiotherapy could be substituted by chemotherapy, with less toxicity and similar results (Oliver 1994; Dieckmann 1996). To answer this question, the Medical Research Council and EORTC groups conducted a phase III trial, randomizing patients to either radiotherapy or one cycle of carboplatin (AUC x 7).
The aim of the trial was to demonstrate the non-inferiority of carboplatin over irradiation. The primary outcome measure was the relapse-free rate, with the trial powered to exclude a doubling of the relapse rate at 2 years with 90% power at a one-sided significance level of 5%. This corresponds to a hazard ratio (HR) of approximately 2.0; thus for the updated analysis published in 2011 to demonstrate noninferiority with respect to relapse rates in the longer term, the upper confidence limit of a two-sided 90% CI for the HR must be less than 2.0 (Oliver 2011). Between 1996 and 2001, 1477 patients from 70 hospital in 14 countries were randomly assigned to receive radiotherapy (para-aortic strip or dog-leg field; No. 904) or one cycle of carboplatin (AUC x 7; n=573). With a median follow-up of 6.5 years, relapse-free rates at 5 years were 94.7% for carboplatin and 96.0% for radiotherapy (HR 1.25; 90% CI, 0.83 to 1.89; p=0.37). Patients receiving carboplatin relapsed more frequently in the PA nodes than did those receiving radiotherapy (74% vs. 9%). However, mediastinal or supraclavicular relapse and pelvic-node relapse were more common after radiotherapy than after chemotherapy. Ten patients have died in the RT arm: one as a result of seminoma, three as a result of other cancers and six as a result of other noncancer causes. Six patients have died in the carboplatin arm: none as a result of seminoma, two as a result of other cancers and four as a result of other noncancer causes. Contralateral GCT have been reported in two patients in the carboplatin arm and in 15 in the RT arm; the contralateral GCT-free rates at 5 years are 99.8% and 98.8%, respectively, which results in a relative reduction in risk of nearly 80% (HR 0.22; p=0.03). Radiation, however, is associated with more short-term toxicity than carboplatin and is associated with an increased risk of delayed cardiovascular disease and second malignancy (Zagars 2004; Travis 2005; Horwich 2014).

6.4.3 Active surveillance

No randomized trial has compared the surveillance strategy with adjuvant prophylactic treatment (radiotherapy or chemotherapy) in stage I seminoma. Due to the fact that radiotherapy or chemotherapy represent an unnecessary overtreatment in the 80% of the patients who do not have micrometastases, some centres have introduced the surveillance policy for patients with stage I seminoma, to avoid the acute and (although rare) long-term toxicity. After radical inguinal orchiectomy, these patients are followed up with short intervals for long time periods by determination of serum markers, chest x-rays, and CT/MRI abdominal scans. Management of stage I seminoma patients with active surveillance has been validated in a number of large institutional and population-based studies (Warde 1995; von der Maase 1993; Horwich 1992; Tandstad 2011; Kollmannsberger 2011; Leung 2013; Aparicio 2011; Kollmannsberger 2015). From 14% to 20% of these patients have relapsed, predominantly in the retroperitoneal lymph nodes. Median time to relapse was 14-15 months and approximately 95% of the relapse occurred within 5 years of follow-up. Patients who had recurrences, received salvage treatment by radiotherapy, or more often, by chemotherapy: thus, the overall survival rates obtained with surveillance were similar to those observed with adjuvant therapy (~99%).Overall, active surveillance avoids active therapy in 80-85% of stage I seminoma patients, sparing patients unnecessary acute and long-term toxicities. Active surveillance has become the preferred approach in most guidelines for stage I seminoma and based on recent data from the National Cancer Data Base, it is now the most commonly used management option for these patients in the United States (Gray 2015). Currently, surveillance can be a treatment option in stage I seminoma patients on a type 3 level of evidence.

6.5 Clinical stage II seminoma

6.5.1 Treatment strategy

About 15-20% of patients with advanced seminoma presents with retroperitoneal lymphadenopathy as the sole evidence of metastatic disease. The transverse diameter of the largest retroperitoneal lymphadenopathy has been used to subcategorize stage II disease. Stage II seminoma is divided 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. If there is no debate about the indication of chemotherapy in cases with bulky disease, much controversy exists regarding the optimal choice between chemotherapy and radiotherapy for stage IIA and IIB. There have been no prospective, randomized trials involving stage IIA or IIB testicular seminoma due to the rarity of such patients. A few retrospective series from single institutions and prospective noncomparative studies, with small number of patients each, are available 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 differential outcomes between chemotherapy and radiotherapy have been poorly analyzed in depth. Furthermore, toxicities following each treatment modality are still a critical issue, particularly regarding the long-term side-effects and the incidence of second neoplasms (Giannatempo 2015).

6.5.2 Nonbulky disease (stage IIA-IIB)

Standard of care post-orchiectomy for stage IIA and IIB testicular seminoma is radiation therapy (RT) or cisplatin-based combination chemotherapy on a type 1 level of evidence (Oldenburg 2013, Warde 2011). Radiotherapy to para-aortic and ipsilateral iliac lymph nodes (“dog-leg” fields), with a target dose of 30-60 Gy in 3-4 weeks, remains the preferred approach by most investigators for stage IIA testicular seminoma. Relapses occur in 10-15% of the patients. Prophylactic mediastinal/supraclavicular RT is no longer given for stage II testicular seminoma due to its late toxicity. Radiation to inguinal nodes is not standard unless there has been some damage to the scrotum to put inguinal lymph nodes at risk (Hallemeier 2013; Detti 2009; Chung 2003; Classen 2003; Zagars 2001). Retroperitoneal radiotherapy is contraindicated in patients with:

  1. a horseshoe kidney;
  2. a second metachronous testicular germ cell tumour;
  3. inflammatory bowel disease.

If one of these 3 contraindications to RT is present, then cisplatin-based combination chemotherapy is recommended.
The Spanish Germ Cell Cancer Group conducted the first study of cisplatin-based chemotherapy as frontline therapy in stage IIA testicular seminoma patients (Garcia-del-Muro 2008). None of the 19 stage IIA patients relapsed. Also, in the Swedish and Norwegian Testicular Cancer Project (SWENOTECA) study (Tandstad 2011), none of the 6 stage IIA patients who received cisplatin-based chemotherapy relapsed. Based on the impressive progression-free survival in these two studies, the European Society for Medical Oncology recommends cisplatin-based chemotherapy or modified dog-leg RT to 30 Gy in 15 fractions, with no preference for one treatment option over another, for stage IIA testicular seminoma (Oldenburg 2013). Cisplatin-based chemotherapy used to be reserved for stage IIB patients with high-volume disease, e.g., multiple lymph nodes measuring 3.1-5.0 cm (Warde 2011). The Spanish Germ Cell Cancer Group conducted a study that included 54 patients with low-volume, e.g., a solitary retroperitoneal node measuring 2.1-3.0 cm, or high-volume stage IIB disease. Patients were treated with three cycles of cisplatin, etoposide, and bleomycin (PEB) or four cycles of cisplatin and etoposide (PE) (Garcia-del-Muro 2008). Median follow up was 72 months. The 5-year progression-free survival rate for stage IIB patients was 87%. The SWENOTECA study included 67 stage IIB patients with low-volume or high-volume disease who were treated with cisplatin-based chemotherapy (Tandstad 2011). None of them relapsed based on a median follow-up of 5.2 years. Based on the excellent progression-free survival in the SWENOTECA study, most of the international guidelines recommend three cycles of PEB chemotherapy for all stage IIB patients, regardless of tumour burden. If there is a contraindication to bleomycin, such as a reduction in lung capacity, emphysema, current or a history of heavy smoking, or poor renal function, then four cycles of PE may be used (Oldenburg 2013). Modified dog-leg RT to 36 Gy in 18 fractions also constitutes a treatment option for stage IIB patients in whom chemotherapy would be unsuitable (Oldenburg 2013) or who have a solitary retroperitoneal node measuring 2.1-3.0 cm (Motzer 2015) One treatment that has been investigated for stage IIA and IIB testicular seminoma is a single course of neoadjuvant carboplatin chemotherapy followed by para-aortic RT to 30-35 Gy. In a recent single center pilot study involving 51 seminoma patients, neoadjuvant carboplatin before radiotherapy further reduce relapse rates compared with radiotherapy alone (there have been no relapses after a median follow up of 55 months) and permit a smaller radiation field (Horwich 2013). However, this promising strategy needs further investigation.

6.5.3 Bulky disease (stage IIC)

In patientswith bulky disease (stage IIC), after radical inguinal orchiectomy combination chemotherapy is recommended on a type C basis (Mason 1988): cisplatin- and etoposide- based chemotherapy (3 cycles of BEP or 4 cycles of EP) cures nearly 90% of these patients.

6.6 Clinical stage III seminoma

6.6.1 Treatment strategy

Radical inguinal orchiectomy followed by chemotherapy represents the standard of care. Chemotherapy combinations include: BEP (bleomycin, etoposide, cisplatin), and EP (etoposide, cisplatin). Three cycles of BEP (Einhorn 1989; Saxman 1998; de Wit 2001) or 4 cycles of EP (Culine 1999) are recommended on type 1 level of evidence for good prognosis patients according IGCCCG and four cycles for intermediate prognosis patients according IGCCCG (alternatively four cycles of etoposide, ifosfamide and cisplatin (VIP), if there are arguments against bleomycin) (Oldenburg 2013). These approaches should lead to an overall cure rate of about 90%.
A randomised trial comparing 4 cycles of BEP with 4 cycles of VIP showed similar overall survival and time to failure but more haematological toxicity with the VIP regimen (Nichols 1998). Furthermore, a randomised trial comparing 4 cycles of EP to VAB-VI (vinblastine, dactinomycin, bleomycin, cyclophosphamide, cisplatin) showed similar efficacy but less toxicity with EP (Bajorin 1991).

6.7 Post-chemotherapy management

Residual radiologic masses are commonly present after completion of chemotherapy; usually these masses represent fibrotic remnants and regress over a period of months, but could be residual malignancy if the mass is larger than 3 cm. In some studies, surgical resection of residual masses showed residual seminoma in 27% of cases (Puc 1996; Herr 1997). Other authors indicate that the size of the residual mass does not correlate with active residual disease and most residual masses do not grow (Horwich 1997; Culine 1996). The treatment of residual masses is controversial. Surveillance observation is preferred when the residual mass is equal or less than 3 cm; in case of lesions >3 cm a 2-fluor-2-deoxy-D-glucose PET (FDG-PET) scan a minimum of 6 weeks after ending chemotherapy is the recommended approach. Based on the negative predictive value >90%, a negative PET scan warrants follow-up only. In the case of a positive PET scan, the possibility of residual seminoma is high, though a false-positive result cannot be excluded (Decoene 2015; Bachner 2012; De Santis 2004). A biopsy might be carried out before treatment by irradiation or resection. Routine radiotherapy was not associated with significant improvement in progression-free survival after platinum-based combination chemotherapy in a retrospective consecutive series of 174 seminoma patients with post-chemotherapy residual disease seen at 10 treatment centers (Duchesne 1997). However, perioperative complications are more common than in non-seminoma due to desmoplastic reactions of the chemotherapy-exposed seminoma metastases.

6.8 Clinical stage I non-seminoma

6.8.1 Treatment strategy

In 50% of patients, testicular non-seminomatous germ cell tumours (NSCGCT) are confined to the testis at the time of the initial diagnosis. Despite refinement of radiologic imaging, 15% to 40% of patients with clinical stage I non-seminoma are understaged: retroperitoneal metastases are found in approximately 30% of patients judged preoperatively to be clinical stage I. After initial orchiectomy for stage I non-seminoma, without any additional treatment, about 25-30% of patients relapse, usually in the first year of follow-up. In clinical stage I non-seminoma tumours, there is still no consensus on a reproducible objective prognostic model to distinguish between tumours with a high risk and tumours with a low risk of relapse (Heidenreich 1997). Several studies have identified the presence of vascular and lymphatic invasion (VI) as the most important prognostic factor for relapse (Klepp 1990; Freedman 1987). The presence of embryonal carcinoma in the primary tumour (Sweeny 2000), the absence of teratoma and yolk sac tumour, the invasion of rete testis, a normal preoperative AFP level and the expression of Ki67 have also been shown to have a prognostic value in several studies (Heidenreich 1997; Droz 1993). The most important study was performed by the Medical Research Council. A multivariable analysis revealed that four factors were of prognostic importance: VI positivity, lymphatic invasion, the presence of embryonal carcinoma and the absence of yolk sac tumour (Freedman 1987). Subsequently, a prospective study supported the use of a prognostic index on the basis of these factors (Read 1992). In a recent systematic review, the presence of vascular invasion of the primary tumour cells had shown the strongest effect. Intermediate effects were found for embryonal carcinoma in the primary tumour and where the tumour was of an advanced pathologic stage. Size of the primary tumour and age of the patient had weaker, although also statistically significant, associations with occult metastases. Immunohistochemical staining of the primary tumour cells with the MIB-1 monoclonal antibody which showed proliferative activity was a promising predictor (Vergouwe 2003). Most recently, the treatment results in a large cohort with stage I non-seminoma treated in a surveillance program were reported. Presence of vascular invasion, rete testis invasion and presence of embryonal carcinoma resulted independent risk factors for relapse in multivariable analysis. If all risk factors were present, the 5-year relapse rate was 50%; if only VI was present the 5-year risk of relapse was 18%; if none of the risk factors were present, 12% had a relapse (Daugaard 2014).

  • Patients with clinical stage I non-seminoma and with persistently elevated HCG and /or AFP (clinical stage IS) have the presence of metastatic disease and must be treated with chemotherapy (Davis 1994).
  • In patients with clinical stage I non-seminoma and with HCG and AFP levels which are normal or falling appropriately (based on half-lives) after radical inguinal orchidectomy, standard treatment options are:
  1. nerve-sparing retroperitoneal lymph node dissection (NSRPLND);
  2. surveillance;
  3. adjuvant chemotherapy.

Each of these methods of management has advantages and disadvantages, but survival is excellent and independent of management approach, with 98% to 100% of patients alive at 5 years. Therefore, the choice of therapy in an individual patient is based on specific histological features, morbidity of treatment, individual patient desires and options, and long-term side effects of therapy. Non-seminoma germ cell tumours are radioresistant and radiotherapy has no role in their initial treatment. Most of the experts have proposed 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. They propose in low risk patients surveillance as preferred approach. If surveillance is not feasible, e.g. due to difficulties with repeated imaging, low compliance or patient’s preference, adjuvant chemotherapy is given. In addition, adjuvant chemotherapy has a particular indication in high risk patients and in patients with comorbidities that might compromise a full course of treatment for metastases. In patients not suitable for surveillance or adjuvant chemotherapy, nerve-sparing retroperitoneal lymph node dissection in highly experienced centers is an option. Some experts consider NSRPLND the preferred treatment of patients with teratoma and somatic transformation in the primary tumour (Oldenburg 2013; Albers 2011; Oldenburg 2015; Horwich 2015).

6.8.2 Nerve-sparing retroperitoneal lymph node dissection (NSRPLND)

The rational of this approach was to provide more accurate staging of retroperitoneal nodes and to reduce relapse risk in those with subclinical metastases confined to those nodes. Other potential advantages of RPLND are to decrease the amount of chemotherapy needed for patients with retroperitoneal metastases who otherwise would have recurred on surveillance and, in expert hands, eliminate the need for screening of the retroperitoneum. Challenges and risks include the possible lack of surgical expertise in many areas, the lack of uniform RPLND approaches and templates, the acute morbidity of the surgery and the small but significant risk of retrograde ejaculation, particularly in a patient with negative nodes. Retroperitoneal metastases are found in removed lymph nodes in 27-28% of patients judged preoperatively to be clinical stage I (Klepp 1990; Heidenreich 2003). Bilateral RPLDN not only provided prognostic information, but is curative, in 50% to 90% of patients with disease that has metastasized to retroperitoneal lymph nodes (Donohue 1993; Sweeney 2000) on a type 3 level of evidence. In the past, most patients managed by bilateral retroperitoneal lymph node dissection, experienced retrograde or failure of ejaculation and consequently sterility because of the sacrifice of postganglionic sympathetic fibers (Narayan 1982). Modifications of this procedure were developed over the years to spare these nerves: the NSRPLND has reduced the problem of loss of emission/ejaculation and consequently the likelihood of maintaining emission and ejaculation is >90% (Donohue 1993; Fossa 1984; Foster 1994; Pettus 2009; Heidenreich 2003). Moreover, NSRPLND appears to be effective as the standard retroperitoneal dissection (Foster 1992; Donohue 1998). However, the surgery is not trivial and is only proficiently performed in specialised centres. The short- and long-term morbidity is essentially that of a laparotomy (Foster 1992): the most common side effects include about a 1% chance of a small bowel obstruction due to surgical adhesion and a 3% to 5% chance of developing an incisional hernia. . Researchers from high-volume referral centers have demonstrated excellent outcomes with primary RPLND with recurrence rates of 5% to 7% and retroperitoneal recurrence rates of 1% to 3% (Heidenreich 2003, Stephenson 2005). The German Testicular Cancer Study Group has conducted an open-label, randomized phase III trial to compare retroperitoneal lymph node dissection with one course of BEP chemotherapy in the adjuvant treatment of stage I non-seminomatous TGCT in a community-based setting (Albers 2008). Primary endpoint of the study was the rate of recurrence. The study was powered to detect a 7% reduction (from 10% to 3%) of recurrence with chemotherapy compared with surgery. Between 1996 and 2005, 382 patients were randomly assigned to receive either RPLND (n=191) or one cycle of BEP (n=191) after orchiectomy. Pathologic T stage categories including vascular invasion (RPLND, 42.1%; chemotherapy, 41.8%) were evenly distributed between the group. After a median follow-up of 4.7 years, two and 15 recurrences were observed in the intention-to-treat population with chemotherapy and surgery, respectively (p=.0011). The difference in the 2-year recurrence-free survival rate between chemotherapy (99.46%) and surgery (91.87%) was 7.59%. All relapses in the RPLND arm occurred within 17 months after surgery. Contrary to specialized single center experiences, the rate of relapses in the retroperitoneum (7 of 15) was comparatively high in this community-based study. The Germany Group has previously reported the results of RPLND for stage I disease with a 1.2% rate of retroperitoneal recurrence if surgery is performed in tertiary referral centers (Heidenreich 2003). The results of this trial demonstrate the importance of experienced surgeons and quality control if RPLND is used as a treatment option.

  • Patients with pathologic stage I disease after RPLND (no metastases in retroperitoneal lymph nodes) will be observed by follow up. The relapse rate in these patients after RPLND is in the order of 10% to 15%; approximately 99% of all recurrences after RPLND will occur within 2 years and will cure by chemotherapy (Klepp 1990).
  • Patients who relapse after RPLND usually present with pulmonary- or serologic-only disease. Retroperitoneal recurrences are rare if surgery is performed in tertiary referral centers and monitoring of the abdomen with CT scan postoperatively could be is not necessary. Therefore, monitoring after RPLND entails physical examination, chest x-ray, and determination of serum markers (AFP and beta HCG) monthly for the first year and 2-monthly for the second year (Lange 1984; Williams 1982). Chemotherapy is employed on first evidence of recurrence.
  • In patients with pathologic stage II after RPLND, the relapse rate is 30% to 40% (Klepp 1990). These patients, after RPLND, should be treated with surveillance or adjuvant chemotherapy (2 cycles of BEP or 2 cycles of EP), based on the pathologic features of involved retroperitoneal nodes.
6.8.3 Laparoscopic retroperitoneal lymph node dissection

Several experienced surgeons have reported that laparoscopic retroperitoneal lymph node dissection (L-RPLND) for clinical stage I non-seminoma testicular cancer is technically feasible (Rassweiler 1996), but a long and steep learning curve for the surgeons involved is necessary. Controversies associated with the procedure include the thoroughness of dissection, the high rate of chemotherapy exposure and the potential deleterious effects of pneumoperitoneum. However, the oncological efficacy of this approach is difficult to assess, since most of the patients with pathologically involved lymph nodes were treated after RPLND with two cycles of chemotherapy (Janetschek 2000) and no prospective, randomized trials respect open RPLND but only small, consecutive series were reported. In 2008, a systematic review of the largest series published in 2000 and later was performed to update the role of L-RPLND in patients with clinical stage I non-seminomatous germ cell tumour compared to open-RPLND (O-RPLND) (Rassweiler 2008). Results of >800 patients treated by L-RPLND reported in 34 articles were analyzed. Lymph node dissection was based on modified templates, removing an average of 16 (5-36) lymph nodes. At experienced centers, complication rates were 15.6%, including 2% retrograde ejaculation and 1.7% reintervention. Operating room times are longer compared to O-RPLND (204 vs. 186min). Five publications with a median follow-up of 63months include 557 patients. One hundred twenty-six of 140 (90%) patients with positive nodes (25%) received adjuvant chemotherapy, resulting in a local relapse rate of 1.4% with no in-field recurrence; rate of distant relapses was 3.3%, including one port-site metastasis; and rate of biochemical failure was 0.9%. Two of 14 patients with positive nodes who did not receive adjuvant chemotherapy relapsed, both 8 months after surgery, and were salvaged by chemotherapy. In conclusion, compared with O-RPLND, there was no difference in relapse rates, percentage of patients receiving chemotherapy (29% vs. 31%), numbers of chemotherapy cycles, rate of salvage surgery (1.2% vs. 1.5%), and patients with no evidence of disease (100% vs. 99.7%). On the basis of the results of this systematic review, L-RPLND offers similar staging accuracy and long-term outcome to O-RPLND and in experienced L-RPLND centers, there was a trend towards fewer complications. More recently, a large retrospective study of patients with a clinical stage I non-seminomatous germ cell tumour undergoing laparoscopic retroperitoneal lymph node dissection was reported. 91 patients underwent extended template laparoscopic retroperitoneal lymph node dissection at the Johns Hopkins from 1995 to 2010. 60 patients (66%) had lymphovascular invasion and 55 (60%) had greater than 40% embryonal carcinoma. Four patients (4.3%) experienced intraoperative complications and there were 4 open conversions (4.3%). Nine patients (9.8%) experienced postoperative complications. 28 patients (31%) had retroperitoneal metastasis. Follow up was available for 55 patients at a median 38.0 months (range 12 to 168). No pN0 case recurred in the retroperitoneum but there were 5 systemic relapses in pN0 cases. Of the 21 patients with pN1 disease 14 elected chemotherapy and 7 elected surveillance. There was no relapse in either group. The authors conclude that laparoscopic retroperitoneal lymph node dissection appears to be safe, viable and effective for stage I non-seminomatous germ cell tumours (Hyams 2012).
To date, laparoscopic retroperitoneal lymph node dissection is not recommended as standard tool in European Association of Urology (EAU) and ESMO guidelines. L-RPLND could be represent a valuable tool for experienced laparoscopic surgeons.

6.8.4 Surveillance

In multiple surveillance series, after inguinal radical orchiectomy, the risk of recurrence in stage I non-seminoma was approximately 30%. The median time to relapse is 5-6 months. The majority of relapses occurred within 2 years (~90%) and late relapses (>5 years after orchidectomy) account for ~1% of relapses. The retroperitoneum is the site of relapse in 60% of patients, and the lung in 20-25% of patients. Elevation of serum tumour markers is seen in about 60% of patients who relapse. The serum tumour marker elevation is the only evidence of recurrence in 20% of cases (Gels 1995; Read 1992; Nicolai 1995; Dunphy 1988; Sogani 1998; Daugaard 2014; Kollmannsberger 2015). The surveillance strategy with close monitoring of clinical stage I non-seminoma patients, makes treating only those patients who show clinical evidence of recurrence feasible at a stage in which the disease would still be highly curable. There are few prospective studies on surveillance. The Medical Research Council trial that randomly assigned 414 patients who were undergoing surveillance for stage I non-seminomas to receive fıve scans at months 3, 6, 9, 12, and 24, or two scans at months 3 and 12, reported similar outcomes (Rustin 2007). Only 10% of patients in this study had LVI, and thus, no conclusions can be made about the appropriateness of this surveillance program for patients with stage IB non-seminoma. The Royal Marsden schedule for the surveillance of patients with non-seminoma involves monthly tumour markers and chest radiographs for the fırst 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 (van As 2008). However, a number of guidelines recommend fewer assessments without clear detriment. The outcomes and long-term follow-up in a population-based cohort in Denmark were recently reported (Daugaard 2014). From 1984 to 2007, 1,226 patients with stage I non-seminoma TGCT were observed in a surveillance program. Only 14% of patients had LVI-positive disease. The number of CT scans was 5 or 6 scans within the first five years after orchiectomy (at 4, 8, 12, 18, 24 and 60 or at 4, 8, 12, 36 and 60 months after orchiectomy). The relapse rate was 30.6% at 5 years. Presence of LVI together with embryonal carcinoma and rete testis invasion in the testicular primary identified a group with a relapse risk of 50%. Without risk factors, the relapse risk was 12%. The median time to relapse was 5 months and 80% of relapses occurred within the first year after orchiectomy. Late relapses after 5 years were seen in 1.6% of relapsing patients equivalent to a relapse rate of 0.5%. The majority of relapses (94.4%) belonged to the good prognostic group according to the IGCCCG. Six patients died as a result from TGCT. Forty-eight patients (3.9%) dropped out of the follow-up program before the final control at 5 years. A recent retrospective report on surveillance outcomes based on more than 1,000 patients with stage I non-seminoma found that only 19% relapsed (Kollmannsberger 2015). Only 16% of patients had LVI-positive disease. The median time to relapse was 6 months, and the relapse risk was 44% in patients with LVI compared with 14% in patients without LVI. Relapsed patients were classified as IGCCCG good, intermediate, or poor risk in 90%, 8% and 2%, respectively. At the time of reporting, there had been only fıve disease- or treatment-related deaths and an additional two patients were alive with disease. In summary, surveillance is a commonly recommended strategy for clinical stage I non-seminoma which appears safe and effective. Compliance with the surveillance program was high in all previously reported studies. Open and honest communication about all aspects of management of the disease may contribute to achieving an effective e satisfactory doctor-patient relationship, which has been shown to predict adherence to follow-up schedules (Moynihan 2009).

6.8.5 Adjuvant chemotherapy

The rationale for considering adjuvant chemotherapy following orchiectomy is based on the avoidance of the risk of toxicities that may occur during a full treatment of relapsed disease, as well as the disappointment and natural anxiety experienced when relapse occurs. Initial studies suggested a benefıt of adjuvant chemotherapy with two cycles of BEP for patients with stage I non-seminomatous tumours considered at high risk of relapse on a type 3 level of evidence (Cullen 1996). A high volume of embryonal carcinoma in the orchiectomy specimen and LVI remain the most widely accepted histological parameters predictive of occult metastatic disease (Moul 1994; Leibovitch 1998). In one trial with 114 patients at high risk (~ 50% predicted relapse rate based on presence of vascular invasion and histologic type), the relapse-free survival at 2 years was 98% with 2 cycles of BEP (cisplatin, bleomycin, etoposide) (Cullen 1996). Another study of high risk patients treated with 2 adjuvant cycles of PEB reported relapse rates after chemotherapy of less than 5% vs. 50% in historical series of high risk patients followed without adjuvant chemotherapy (Pont 1996). However, in the historical series, cure rates have been as high as 95% after chemotherapy for relapse. The adjuvant chemotherapy trials are too small to draw c conclusions about the late toxicity from chemotherapy and about risk of late relapse.
However, more recently there have been persuasive reports suggesting a benefıt with a single cycle. A German Testicular Group trial randomly assigned patients to undergo RPLND and one cycle of BEP (Albers 2008). Of 191 patients treated with BEP, the relapse risk was only 0.5%. Similarly, a community protocol by the SWENOTECA group that included 517 patients who received one course of adjuvant BEP reported relapse rates of 1.6% for patients with LVI-negative and 3.2% for patients with LVI-positive tumours (Tanstad 2014). At a median follow-up of 7.9 years, 12 relapses have occurred, all with IGCCC good prognosis, the latest relapse occurred 3.3 years after adjuvant treatment and five-year cause-specific survival was 100%.

6.9 Clinical stage II non-seminoma

6.9.1 Treatment strategy

Stage II non-seminoma is curable in more than 95% of patients. Nerve-sparing RPLND is an available option in some patients with clinical stage IIA-IIB non-seminomatous tumours. Most of the patients with metastatic non-seminoma can be cured with highly effective chemotherapy and they should be treated according to the IGCCCG’s prognostic group and recommendations.

6.9.2 Clinical stage IIA-IIB non-seminoma

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

  • Patients with elevated serum markers should be treated with cisplatin-based chemotherapy (Stephenson 2007; Donohue 1980) according to the IGCCCG’s recommendations: BEP (bleomycin, etoposide, cisplatin) for 3 cycles, or EP (etoposide, cisplatin) for 4 cycles if bleomycin is contraindicated in patients with good prognosis; four cycles of BEP or VIP in patients with intermediate or poor prognosis. In case of contraindication against bleomycin, four cycles of VIP are used. First-line high-dose chemotherapy has not been proven superior to standard dose chemotherapy in three randomized trials (Daugaard 2011; Motzer 2007; Droz 2007).
  • Patients with stage IIA-IIB and normal markers might be treated by retroperitoneal lymph node dissection (RPLND) on a type 3 level of evidence. After RPLND, the treatment should be based on the pathological features of involved retroperitoneal nodes and adjuvant chemotherapy with two cycles BEP may be considered in case of vital tumour in the specimen. Completely resected teratoma warrants follow-up only.
  • Patients who have less than 6 positive lymph nodes at retroperitoneal dissection and no extracapsular lymph node invasion (pN1), should be followed by regular follow-up (physical examination, chest x-ray, and serum marker tests) (Baniel 1995). These patients have a relapse rate, after surgery, of 20% to 30% and most patients are curable with chemotherapy administered at relapse (Richie 1991). Presence of microscopic vascular (lymphatic or venous) invasion in the primary tumour can also help to predict which patients may relapse: after RPLND the relapse rate is higher in patients with vascular invasion (64%) than in patients without vascular invasion (24%) (Sesterhenn 1992).
  • In patients treated by RPLND who have 6 or more positive nodes involved, or any node greater than 2 cm, or extranodal extension (pN2), adjuvant chemotherapy should be considered. Two courses of adjuvant cisplatin-based chemotherapy are effective on basis 3 level of evidence, with a relapse-free survival of nearly 100% (Vogelzang 1983; Vugrin 1981; Vugrin 1983; Williams 1987a; Motzer 1995).

The Testicular Cancer Intergroup Study randomised 195 pathologic stage II patients to no further therapy after RPLND (with standard chemotherapy at relapse) or to two courses of adjuvant chemotherapy with PVB (cisplatin, vinblastine, bleomycin) or VAB-VI (vinblastine, dactinomycin, bleomycin, cyclophosphamide, cisplatin) (Williams 1987a). With a median follow up of 4 years, there was a significant difference in relapse-free survival, with 49% of the observation group relapsing as compared to 6% of patients assigned to receive adjuvant chemotherapy on type 2 level of evidence. In terms of survival, there was no significant difference between the two groups, indicating that either approach should result in a greater than 90% cure rate, provided that an adequate RPLND is undertaken and meticulous follow up observed, if adjuvant chemotherapy is not used (Williams 1987a). Etoposide has replaced vinblastine in adjuvant regimens and a more recent trial showed that 2 cycles of etoposide and cisplatin (EP) is adequate and that bleomycin is not necessary as part of adjuvant therapy (Motzer 1995; Kondagunta 2004).

6.9.3 Clinical stage IIC non-seminoma

In patients with clinical stage IIC non-seminoma, with clinical and/or radiologic large retroperitoneal masses which would be difficult to resect, chemotherapy is recommended on a type 3 level of evidence. Patients with good prognosis should receive 3 cycles of BEP (bleomycin, etoposide, cisplatin) (Williams 1987a; Saxman 1998) or 4 cycles of EP (etoposide, cisplatin) if contraindications against bleomycin exist (Culine 2007; Kondagunta 2005). Bleomycin is an essential component of the BEP regimen when only 3 cycles are administered (Loehrer 1995). Other regimes (PVB, VAB-VI) have equivalent anticancer activity but more toxicity. Four cycles of BEP represents standard treatment of patients with intermediate or poor prognosis. In case of contraindication against bleomycin, four cycles of VIP are used. Four (to eight) weeks after the last cycle of chemotherapy, determination of tumour markers as well as imaging should be carried out. In case of complete response (normal markers, no retroperitoneal lymph nodes ≥10mm), no further treatment is necessary. In patients who do not achieve a complete response after chemotherapy (retroperitoneal lymph nodes ≥10mm) but who obtain normalization of serum markers, nerve-sparing RPLND should be performed (Toner 1990a). Residual masses may contain only fibrosis and necrosis (45%-50% of resected residual masses), teratoma (35%) or viable germ cancer cells (15%-20%) (Toner 1990a; Fossa 1992; Tait 1984; Gelderman 1988; Harding 1989; Steyerberg 1996). Resection is necessary to diagnose a complete pathological response, to prevent regrowth of teratoma (Loehrer 1986), to prevent growth of non-germ cell elements present; and to determine the presence of viable tumour cells. The presence of persistent viable malignant cells in the resected masses might be an indication for further chemotherapy (Fox 1993). In a retrospective analysis in patients with disseminated non-seminomatous germ-cell tumours (NSGCTs) and viable residual disease after first-line cisplatin-based chemotherapy, three factors were independently associated with both PFS and OS: complete resection (p<0.001), <10% of viable malignant cells (p=0.001) and a good International Germ Cell Consensus Classification (IGCCC) group (p=0.01). Patients were assigned to one of the three risk groups: those with no risk factors (favourable group), those with one risk factor (intermediate group), and those with two or three risk factors (poor-risk group). Postoperative chemotherapy appeared beneficial in both PFS (p<0.001) and OS (p=0.02) in the intermediate-risk group but was not statistically beneficial in the poor-risk group. A complete resection may be more critical than the recourse to postoperative chemotherapy in the setting of postchemotherapy viable malignant NSGCT. Immediate postoperative chemotherapy or surveillance alone with chemotherapy at relapse may be reasonable options depending on the completeness of resection, IGCCC group, and percent of viable cells (Fizazi 2001, Fizazi 2008).

6.10 Stage III non-seminoma

6.10.1 Treatment strategy
  • Prognostic factor-based classification (IGCCCG 1997) for metastatic gem cell tumours should be used in clinical practice.
  • In good prognosis non-seminoma metastatic tumours (5-year PFS:89%; 5-year OS suvivall: 92%), the treatment is based, after orchidectomy, on chemotherapy 3 BEP (or 4 EP) followed by surgical resection of residual masses.
    In intermediate (5-year PFS: 75%; 5-year OS: 80%) or poor prognosis (5-year PFR: 41%; 5-year OS: 48%) non-seminoma metastatic tumours the standard treatment is, after orchiectomy, four cycles of BEP chemotherapy followed by resection of residual disease. In case of contraindication against bleomycin, four cycles of VIP can be used.
  • High-dose chemotherapy and autologous bone marrow transplantation (ABMT) failed to demonstrate any advantage as first line treatment for intermediate and poor prognosis patients in several randomised, phase III trials (Necchi 2015; Daugaard 2011; Motzer 2007; Droz 2007; Chevreau 1993).
  • Many poor risk patients with non-seminomatous germ cell cancer of testis who have elevated levels of HCG at the start of cisplatin-based chemotherapy, may still have an elevated level at the completion of chemotherapy, when an initial rapid decrease is followed by a plateau (Zon 1998). In the absence of other signs of progressive disease, monthly evaluation with the initiation of salvage therapy if and when there is serological progression may be indicated. However, some patients will remain disease-free without further therapy (Zon 1998) on a type 3 level of evidence.
6.10.2 Chemotherapy
6.10.2.1 Good prognosis metastatic non-seminomatous germ-cell tumours

In good prognosis metastatic non-seminomatous germ cell tumours, chemotherapy is recommended: 3 cycles of BEP (bleomycin, etoposide, cisplatin) are strongly recommended; in the recent past this regimen was considered equivalent to 4 cycles of EP (etoposide, cisplatin) on a type 1 level of evidence (Einhorn 1989; Saxman 1998; de Wit 1999). Randomized trials have shown that bleomycin is an essential component of the BEP regimen when only 3 cycles are administered (Loehrer 1995; de Wit 2001) on a type 1 level of evidence. The maximum total dose of bleomycin should not exceed 270 mg/m2 to avoid any clinically significant pulmonary toxicity. Mature data from a randomized phase III study show that 3 cycles of BEP are equivalent to four cycles of EP (etoposide and cisplatin) with 500 mg/m2 per cycle of etoposide (Culine 2007) on a type 1 level of evidence. A prospective trial of the EORTC showed that BEP chemotherapy administered over 5 days produced less toxicity compared with BEP administered over 3 days (de Wit 2001). Substitution of carboplatin for cisplatin to reduce toxicity is inappropriate on a type 3 level of evidence (Horwich 1997; Bajorin 1993a).

6.10.2.2 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 (bleomycin, etoposide, cisplatin) and this is recommended on type 1 level of evidence. A randomized trial, performed to compare BEP and PVB, showed higher complete responses with BEP (63% vs. 38%) and less toxicity (Williams 1987b). The BEP was compared with a VIP regimen (etoposide, ifosfamide, cisplatin) in another trial and no advantage was found for the ifosfamide-containing arm, which was also more toxic (Nichols 1995).

  • No advantage was found for 4 alternating cycles of BEP+PVB versus 4 cycles of BEP (de Wit 1995), nor for BOP-VIP (bleomycin, vincristine, cisplatin+VIP) when compared with BEP (Kaye 1998).
  • The superiority of the higher dose of cisplatin (200 mg/m2) in a PVB (Ozols 1988) or in a PEB combination (Nichols 1991) was associated with greater toxicity (ototoxicity, neurotoxicity and myelosuppression) without improvement in survival and is not recommended on type 1 level of evidence.
  • High-dose chemotherapy and autologous bone marrow transplantation (ABMT) failed to demonstrate any advantage as first line treatment for intermediate and poor prognosis risk patients in several randomised, phase III trials (Necchi 2015; Daugaard 2011; Motzer 2007; Droz 2007; Chevreau 1993).
  • Even patients with widespread metastases at diagnosis, including patients with brain metastases, may still be curable and should be treated with this intent (Spears 1992).
6.10.3 Surgery after chemotherapy

In patients responding to chemotherapy, who do not achieve a complete response but obtain normalization of serum markers, surgical resection of all residual masses should be performed (Toner 1990a). Resection is necessary:

  1. to diagnose a complete response by pathological criteria;
  2. to prevent regrowth of teratomas (Loehrer 1986): mature teratoma may grow rapidly, become unresectable or cause vascular or ureteral obstruction (Morgentaler 1988); however, the risk of dysfunction and sterility is higher with RPLND (no nerve-sparing) after chemotherapy;
  3. to prevent malignant trasformation of teratomas (Little 1994);
  4. to determine the presence of viable tumour cells (Einhorn 1981): the presence of persistent viable malignant cells in the resected masses is an indication for further chemotherapy (Fox 1993).

Residual thoracic masses should always be removed (Tiffany 1986).
In some patients chemotherapy is initiated prior to orchidectomy because of life-threatening metastatic disease. In these patients orchidectomy after initiation or completion of chemotherapy is advisable, due to the high incidence of residual cancer in the testis after chemotherapy with platinum-based regimens (Leibovitch 1996). In a retrospective analysis in patients with disseminated non-seminomatous germ-cell tumours (NSGCTs) and viable residual disease after first-line cisplatin-based chemotherapy, three factors were independently associated with both PFS and OS: complete resection (p<0.001), <10% of viable malignant cells (p=0.001) and a good International Germ Cell Consensus Classification (IGCCC) group (p=0.01). Patients were assigned to one of the three risk groups: those with no risk factors (favourable group), those with one risk factor (intermediate group), and those with two or three risk factors (poor-risk group). Postoperative chemotherapy appeared beneficial in both PFS (p<0.001) and OS (p=0.02) in the intermediate-risk group but was not statistically beneficial in the poor-risk group. A complete resection may be more critical than the recourse to postoperative chemotherapy in the setting of postchemotherapy viable malignant NSGCT. Immediate postoperative chemotherapy or surveillance alone with chemotherapy at relapse may be reasonable option depending on the completeness of resection, IGCCC group, and percent of viable cells. (Fizazi 2001).

6.11 Recurrent or refractory disease

About 10% to 30% of patients with advanced germ cell tumours relapse or fail to achieve a complete response to first-line cisplatin-base therapy (Hanna 2014). Even when given second or subsequent salvage treatment, approximately 10% to 20% of patients may still be cured. Conclusive recommendations as to an optimal salvage approach in patients relapsing after cisplatin-based first-line treatment cannot be made at present. Options include salvage surgery for patients with anatomically confined relapse, standard dose cisplatin combination chemotherapy, or high-dose chemotherapy with carboplatin plus etoposide with peripheral blood stem cell transplantation. The standard-dose salvage regimens are VeIP (vinblastine, ifosfamide, cisplatin), VIP (etoposide, ifosfamide, cisplatin) or TIP (paclitaxel plus ifosfamide plus cisplatin) (Loehrer 1998; Motzer 2000; Loehrer 1988; Kondagunta 2005). These regimens can induce a complete response in 25% to 35% of refractory and recurrent patients after first-line cisplatin-based chemotherapy (Loehrer 1998; Motzer 1990). There have been no randomized phase III studies suggesting or proving superiority of one form of standard-dose salvage chemotherapy. Today either of these standard-dose salvage chemotherapy regimens are appropriate as second-line chemotherapy.
Several phase II trials and retrospective series have shown a possible benefit for patients with relapsed or refractory GCT of high-dose chemotherapy (HDC) and autologous bone marrow transplantation or autologous hemapoietic stem cell support (Beyer 2002, Einhorn 2007). Despite these results, data derived from randomized phase III studies failed to demonstrate any survival advantage for HDCT over conventional chemotherapy. The role of HDCT in TGCT remains controversial, also in view of the most recent, published data.
The German Testicular Cancer Study Group compared two commonly used high-dose regimens in a prospective, randomized, phase II trial. 211 patients with relapsed or refractory GCT were randomly assigned to treatment with either one cycle of VIP plus three cycles of high-dose carboplatin 1,500 mg/m2 and etoposide 1,500 mg/m2 (arm A) or three cycles of VIP plus one cycle of high-dose carboplatin 2,200 mg/m2, etoposide 1,800 mg/m2, and cyclophosphamide 6,400 mg/m2 (arm B) followed by autologous stem-cell reinfusion. Overall, 108 and 103 patients were randomly assigned to arms A and B, respectively. The study was stopped prematurely because of excess treatment-related mortality in arm B (14%) compared with that in arm A (4%; p=0.01). No differences in five-year progression free (47% in arm A and 45% in arm B; hazard ratio [HR], 1.16; 95% CI, 0.79 to 1.70; p=0.454) and in five-year OS (49% in arm A and 39% in arm B (HR, 1.42; 95% CI, 0.99 to 2.05; p=0.057) were reported (Lorch 2012). Memorial Sloan Kettering Cancer Center has pioneered an innovative approach with two cycle of paclitaxel and ifosfamide (TI) followed by three courses of high-dose carboplatin plus etoposide, each with autologous stem cell support . This study show encouraging results including a 52% 5-year OS and 47% 5-year DFS (Feldman 2010). However, there are no randomized studies suggesting any specifıc strategy of high dose chemotherapy is preferred.
After salvage chemotherapy (standard-dose or high-dose), complete residual tumour resection, if feasible, is recommended on type 3 level of evidence (Motzer 1996).
Patients who relapse with brain metastases after complete response to first line chemotherapy require further chemotherapy, and surgical excision of solitary lesions should be considered (Spears 1992). The role of radiotherapy remains unclear.

6.12 Late relapse

A small proportion of patients (~3%) experience germ cell tumour recurrences more than 2 years after the end of primary treatment. Late relapses are characterized by the presence of predominantly teratoma and yolk sac tumour histologies and refractoriness to platinum-based chemotherapy. In late relapses the surgical management is very important (Baniel 1995). The possibility of late relapse in patients treated for GCT means that long term annual follow up is required, including determination of serum markers and, probably, CT scans when teratoma is a major component of the primary tumour.

6.13 Contralateral tumour

Approximately 80% to 85% of contralateral testicular tumours are metachronous germ cell tumours. Metachronous germ cell tumours appearing in the contralateral testis occur in 2% to 3% of all patients (Wanderas 1997). The treatment should not differ from the usual treatment applied for unilateral tumours. Since contralateral tumours can occur as long as 25 years after the primary cancer, long term follow up is required. After the second orchidectomy, replacement testosterone is required to maintain normal serum testosterone levels, secondary sexual characteristics and sexual function.

7. LATE SEQUELAE

7.1 Late sequelae related to surgery

The major potential adverse effect of classic bilateral RPLND is the infertility due to the sacrifice of post-ganglionic sympathetic fibers and the hypogastric plexus that are in close proximity to the nodes and that control ejaculation. Patients undergoing bilateral RPLND have normal potency and the subjective sensation of orgasm but a 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.

7.2 Late sequelae related to radiotherapy

The impact of adjuvant retroperitoneal radiotherapy on subsequent fertility depends upon the extent of the radiation field and the consequent scattered dose to the contralateral testis. With the standard technique the contralateral testis should receive less than 100 cGy; 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. Coronary artery disease resulting from mediastinal radiation therapy is well recognized. Radiotherapy has been linked to the development of secondary cancers, especially solid tumours in the radiation portal (stomach, bladder, colon, rectum), usually after 10 years or more. Overall risk of radiation-induced secondary cancers is 1.4 to 1.6 after more than 10 years (Van Leeuwen 1993; Bokemeyer 1995; Travis 2005).

7.3 Late sequelae related to chemotherapy

Some adverse effects of chemotherapy develop during treatment and may persist during follow-up (e.g, peripheral neuropathy). These adverse effects are referred to as long-term effects, whereas late effects become manifest months to years after completion of treatment (Haugnes 2012).
The long-term toxicities of chemotherapy are:

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

Examples of late effects of chemotherapy are:

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

Nephrotoxicity is a well-recognized acute and long-term effect of cisplatin, associated with damage of the proximal and distal tubular epithelium and collecting ducts. The severity of renal damage during cisplatin treatment can be limited by adequate hydration during treatment but it cannot be completely avoided. Minor decreases in creatinine clearance occur (~15% decrease, on average) during platinum-based therapy, but these appear to remain stable in the long term, without significant deterioration (Osanto 1992).
Long-term cisplatin neurotoxicity has been reported in 20% to 40% of patients treated for testicular cancer. Cisplatin-induced neuropathy is typically sensory neuropathy of the distal limbs, with paresthesias being the core symptom. This neurotoxicity causes peripheral numbness, which is especially severe in the soles of the feet and is associated with loss of vibration sense (Hansen 1989). The cumulative dose of cisplatin is a risk factor implicated in the development of peripheral neuropathy.
Another specific problem with cisplatin administration is ototoxicity, presumably caused by selective damage to the outer hair cells of the cochlea. A high-tone frequency loss is found in about 30% of patients. However, this toxicity is often subclinical and due to the fact that it generally occurs at sound frequencies outside the range of conversational tones, hearing aids are rarely required after standard doses of cisplatin. Less frequently, ototoxicity is associated with tinnitus. The ototoxicity is irreversible and its grade is related to the cumulative dose of cisplatin (Pollera 1988).
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. The long-term prevalence of patients with nonfatal bleomycin pulmonary toxicity varies between 7% and 21%. Fatal pulmonary toxicity has been reported in 1-3% of patients treated with bleomycin. Cumulative dose below 300 units was associated with increased risk of pulmonary toxicity (Haugnes 2012).

7.3.2 Gonadal toxicity

One of long-term effects of cisplatin-base chemotherapy is the toxicity on spermatogenesis (Petersen 1998). However, impaired spermatogenesis (azoospermia or oligospermia) and high FSH levels are frequently observed in patients at diagnosis, before any treatment (Petersen 1999). The pretreatment sperm count and the cumulative dose of cisplatin have been shown to be correlated with subsequent gonadal function. The cumulative dose of cisplatin may also influence persistent dysfunction of Leydig cells, with increased serum LH levels (in 85% of patients) despite normal testosterone levels (Howell 1999). This compensated insufficiency is observed up to 60 months after chemotherapy. In long-term follow-up of cohorts of testicular cancer survivors with known intentions to conceive a child, overall post-treatment conception and paternity rates vary from 49% to 82%. In a retrospective review of 680 patients treated with cisplatin-base chemotherapy, 145 (21%) were reported to have achieve paternity. There is no evidence of an elevated risk of malformations for children fathered by GCT patients (Senturia 1990). Patients with GCTC should be informed that recovery from chemotherapy-induced azoospermia may take several years. Furthermore, offering cryopreservation is obligatory before chemotherapy.

7.3.3 Secondary malignancies

Secondary non-germ cell malignancies in chemotherapy treated patients for GCT are rare. In a series of 40,576 testicular cancer survivors, the overall post-TC observed/expected ratio for developing a solid second cancer was 1.55 (95%CI, 1.48-1.62) in 10-year survivors (Travis 2005). However, the relative risk of secondary leukaemia is significantly elevated (2.4-5.2) for these patients (Bokemeyer 1995; Travis 1997). In some cases, these leukaemias (usually non-lymphocytic) are associated with the prolonged use of alkylating agents or with the use of radiation: they occur more frequently after 5-7 years, are preceded by a preleukaemic myelodysplastic phase and have common cytogenetic abnormalities of chromosome 5 and 7. Etoposide-containing regimens are also associated with a risk of a secondary acute leukaemias, with a characteristic 11q23 translocation and a shorter latent period (2-4 years) in contrast to alkylating-associated leukaemias. The secondary leukaemia incidence is related to etoposide total dose: it is 0.1% to 0.5% in patients receiving a total dose of 2000 mg/m2 (Nichols 1993; Boshoff 1995; Bajorin 1993b) and 6% in patients receiving a total dose >3000 mg/m2 (Pedersen-Bjergaard 1991). Acute leukaemia develops in 1.3% of all patients receiving median cumulative etoposide dose greater than 2400 mg/m2 (Kollmannsberger 1998). However, the risk of secondary leukaemias do not out weigh the high cure rate induced by etoposide-containing regimens and does not change current standard strategy. Sarcoidosis appears frequently in GCT patients (Toner 1990b): it is not a sequela of therapy because it occurs before or after diagnosis of germ cell cancers. It must be considered when pulmonary nodules, pulmonary infiltrates or paratracheal adenopathy occur in the absence of elevated concentrations of serum markers or in cases of seminoma without retroperitoneal disease. In these patients a biopsy should be performed.

7.3.4 Cardiovascular disease

Cardiovascular toxicity has been reported in patients treated for GCT: increased frequency of diastolic hypertension (Hansen 1988), pulmonary emboli (Bosl 1986), angina, and myocardial infarction (Vogelzang 1980; Meinardi 2000). Some reports suggested that hypercholesterolemia and overweight might be long-term cardiovascular risk factors (Raghavan 1992). Early-onset metabolic syndrome occurs in about 20%-30% of long-term survivors (de Haas 2013). Compared with 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 TGCT survivors (Haugnes 2012). 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) (Strumberg 2002). Erectile dysfunction may be associated with Raynaud’s phenomenon as a sign of microvascular angiopathy (van Basten 1997).

8. FOLLOW-UP

The aims of follow up in patients treated for GCT of the testis are:

  1. early detection and treatment of relapse. The relapses are more frequent within 2 years, but late relapses have been reported in a small proportion of patients: long term follow up with marker, radiologic and physical examination is recommended (Gerl 1997);
  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 randomised data regarding the follow up regimens most effective in identifying relapsed disease; optimal means of imaging, frequency of physician visits and serum marker level measurements need to be further addressed.

INDEX

 

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Dr. Ugo De Giorgi (Author)
Ospedale S. Maria delle Croci, Ravenna (Italy)
mail: ugo_degiorgi@yahoo.com

Dr. Gemma Gatta (Consultant)
Istituto Nazionale Tumori – Milan (Italy)
mail: gatta@istitutotumoti.mi.it

Dr. Stefania Gori (Author)
Ospedale Policlinico Monteluce, Perugia (Italy)
mail: stefania.gori@tin.it

Dr. Maurizio Marangolo (Reviewer)
Ospedale S. Maria delle Croci, Ravenna (Italy)
mail: m.marangolo@ausl.ra.it

Dr. Stella Porrozzi (Author)
Ospedale Policlinico Monteluce, Perugia (Italy)

Dr. Caserta Claudia (Author)
Azienda Ospedaliera Santa Maria, Terni (Italy)
mail: caserta_claudia@libero.it

Dr. Fausto Roila (Associate Editor)
Azienda Ospedaliera Santa Maria, Terni (Italy)
mail: faroila@unipg.it