© Springer-Verlag Berlin Heidelberg 2015Vincenzo Mirone (ed.)Clinical Uro-Andrology10.1007/978-3-662-45018-5_15
15. Testicular Cancer
Department of Urology, University Federico II of Naples, Naples, Italy
15.1 Germ Cell Tumors
15.1.2 Risk Factors
15.1.5 Clinical Presentation
15.1.6 Clinical Examination
15.1.7 Differential Diagnosis
15.1.10 Clinical Staging
15.1.11 Prognosis in Advanced GCT
15.1.13 Treatment-Related Adverse Events
15.2.1 Leydig Cell Tumors
15.2.2 Sertoli Cell Tumor
15.2.3 Granulosa Cell Tumors
15.3.1 Epidermoid Cyst
15.4.2 Leukemic Infiltration
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Testicular cancer includes diverse groups of tumors, 95 % of which are germ cell tumors (GCTs). GCTs are generally categorized as seminoma and nonseminoma (NSGCT) due to differences in natural history and treatment.
GCTs are moderately rare malignancies, accounting for 1–2 % of cancers among men in the United States, with an incidence in the order of five cases per 100,000. Approximately 90 % of GCTs take place in the testis and 2–5 % are extragonadal (the retroperitoneum and mediastinum are the most common sites). With the advancement of cisplatin-based chemotherapy and the combination with surgery, GCTs have become a model of a curable neoplasm and supply as a paradigm for the multidisciplinary management of cancer (Einhorn 1981). Prior to the introduction of treatment with cisplatin, the cure rate for patients with advanced GCT was 5–10 %. At present the long-term survival for men with metastatic GCT is 80–90 %. Mortality from GCT is due to resistance to platin chemotherapy and to the not successful eradication of residual disease elements in the early course of therapy. Non-GCTs of the testis are rare and include sex cord/stromal tumors, lymphoid and hematopoietic tumors, tumors of the collecting duct and rete testis, and tumors of the testicular adnexa.
15.1 Germ Cell Tumors
In the United States, it was estimated that 8,400 men developed a testicular cancer in United States, and 380 would die of this disease (Jemal et al. 2010).
Testicular cancer is the most frequent tumor among men aged 20–40 years and the second most frequent cancer after leukemia among males aged 15–19 years (Horner et al. 2009). Testicular tumors are distributed in three peaks: infancy, ages 30–34 years, and approximately age 60. The incidence of bilateral GCT is approximately 2 % (Fossa et al. 2005).
Testicular lymphoma is less frequent than GCT but represents the greater part of testicular tumors in men older than 50 years and is more likely to have a synchronous bilateral presentation. The incidence of testicular cancer varies drastically according to geographic region: rates are highest in Scandinavia, Germany, Switzerland, and New Zealand; intermediate in the United States and Great Britain; and lowest in Africa and Asia. The incidence of testicular tumor in the United States in non-Hispanic whites is five times higher than the incidence in African-Americans, four times higher than the incidence in Asians, and 78 % higher than in Hispanics (Horner et al. 2009).
The incidence of GCT is increased worldwide (McKiernan et al. 1999; McGlynn et al. 2005; Purdue et al. 2005). In the United States, the age-adjusted incidence rate for males aged 15–49 years increased from 2.9 per 100,000 in 1975 to 5.1 per 100,000 in 2004 (Holmes et al. 2008). Over this time period incidence rates have increased substantially more for seminoma than NSGCT (McGlynn et al. 2005; Powles et al. 2005). A change of GCT stage has been viewed in several countries owing, in part, to augmented attentiveness and earlier diagnosis. The percentage of tumors diagnosed at a localized stage increased from 55 to 73 %, between 1973 and 2001 among white males. The stage distribution for African-American males remained stable during this time (McGlynn et al. 2005). Only 10–30 % of men will present with distant metastatic disease.
In the United Kingdom the change in stage distribution over time is largely restricted to an increase in localized seminoma and a decrease in metastatic NSGCT; rates of localized NSGCT and metastatic seminoma are largely unchanged (McGlynn et al. 2005). Currently, localized seminoma is the most common presentation of GCT, representing approximately 50 % of all men with GCT (Powles et al. 2005). Thus, contemporary testicular germ cell tumors have more favorable prognostic features on average compared with those diagnosed in the 1970s and 1980s.
15.1.2 Risk Factors
There are four well-known risk factors for testicular tumor: cryptorchidism, family history of testicular cancer, a personal history of testicular cancer, and intratubular germ cell neoplasia (ITGCN). Infertility also is a cause of a higher incidence of testicular cancer. Numerous studies have showed that current increases in the incidence of testicular cancer can be mostly attributed to birth cohort effects, according to whom diet and other environmental factors have a key role in GCT carcinogenesis (Liu et al. 1999; Huyghe et al. 2003; McGlynn et al. 2003; Richiardi et al. 2004; Bray et al. 2006; Verhoeven et al. 2008).
Males with cryptorchidism are four to six times more likely to be diagnosed with testicular cancer, but the relative risk (RR) falls to 2.0–3.0 if orchidopexy is performed before puberty (Dieckmann and Pichlmeier 2004; Wood and Elder 2009). A lot of studies support the thesis that most of the increased risk reflects an increased risk of cancer in the undescended testis, but a recent meta-analysis of cryptorchidism studies reported that the contralateral descended testis is at slightly increased risk (RR 1.74 [95 % CI, 1.01–2.98]) (Akre et al. 2009).
Men with a relative with testicular cancer have a considerably increased risk, and the median age at diagnosis in these men is 2–3 years younger than in the general population (Mai et al. 2009). An individual’s RR for testicular cancer is 8.0–12.0 with an affected brother compared with 2.0–4.0 in those with an affected father (Westergaard et al. 1996; Sonneveld et al. 1999; Hemminki and Chen 2006).
Men with a history of testicular cancer are at a 12-fold increased risk of developing GCT in the contralateral testis, but the 15-year cumulative incidence is only 2 %. The risk is higher in patients who are younger when testicular cancer is diagnosed and in men whose initial GCT is seminoma (Theodore et al. 2004; Fossa et al. 2005). A study showed that a man younger than the age of 30 with a testicular seminoma has a 3.1 % risk of developing a contralateral testicular cancer (Fossa et al. 2005) and reported also that the 10-year overall survival after diagnosis with a second primary (i.e., contralateral) testicular cancer was 93 %. Most GCTs arise from a precursor lesion called intratubular germ cell neoplasia (ITGCN) (which is also referred to as carcinoma in situ). There is a significantly increased risk of developing invasive GCT in men with ITGCN. Different studies have demonstrated that ITGCN is present in adjacent testicular parenchyma in 80–90 % cases of invasive GCT and is associated with a 50 % risk of GCT within 5 years and a 70 % risk within 7 years (Skakkebaek et al. 1982; Dieckmann and Skakkebaek 1999; Montironi 2002).
Other studies showed that from 5 to 9 % patients with GCT, there is ITGCN within the unaffected contralateral testis, and the incidence of contralateral ITGCN increases to about 36 % in men with testicular atrophy or cryptorchidism (Dieckmann and Loy 1996; Dieckmann and Skakkebaek 1999).
With a gene expression profile analysis, it has been found that ITGCN develops before birth from an arrested gonocyte (Hussain et al. 2008; Sonne et al. 2009). In men with a history of GCT, the finding of testicular microlithiasis on ultrasound evaluation of the contralateral testis is associated with an increased risk of ITGCN (Karellas et al. 2007). Though the meaning of microlithiasis in the general population is not completely clear, a study of 1,500 army volunteers found a 5.6 % prevalence of microlithiasis, yet fewer than 2 % of those with microlithiasis developed cancer within the subsequent 5 years (DeCastro et al. 2008).
There are a lot of steps to make clear the carcinogenesis of GCTs. As described before, a precursor lesion, ITGCN, is necessary to testicular GCT development. ITGCN probably develops from arrested primordial germ cells or gonocytes that failed to differentiate into prespermatogonia (Rajpert-de Meyts and Hoei-Hansen 2007; Hussain et al. 2008). These cells are thought to lie dormant until after puberty when they are stimulated by augmented testosterone levels. The augmented incidence of testicular cancer, initiated in the first half of the twentieth century, has been gone together with an increased incidence of other male reproductive disorders, such as hypospadias, cryptorchidism, and subfertility (Rajpert-de Meyts and Hoei-Hansen 2007; Sonne et al. 2008). Testicular cancer and these other disorders are all consequences of a testicular dysgenesis syndrome, which in turn resulted from environmental and/or lifestyle factors and genetic susceptibility. The specific environmental or lifestyle factors have not been defined.
The first hypothesis about the risk factors referred to prenatal estrogen exposure, but this is controversial (Martin et al. 2008). Meanwhile there are stronger evidences that testicular dysgenesis syndrome can be caused by reduction in androgen activity. At same time this deficiency might be the cause also of cryptorchidism, hypospadias, and impaired spermatogenesis, but a direct link between reduced androgen signaling and ITGCN or GCTs remains hypothetical (Sonne et al. 2008; Hu et al. 2009). Another evidence for the contribution given by the environmental and lifestyle factors to testicular cancer includes the rapid increase in its incidence as well as findings that the risk in second-generation immigrants is similar to that in their country of birth. Some studies founded that mothers of children with testicular cancer (but not the testicular cancer patients themselves) have been found to have higher blood levels of certain organic pollutants compared with other mothers (Sonne et al. 2008).
Also the genetic factors have been evaluated, and the evidences include the clustering of testicular cancer in some families, the big disparity in the rate of testicular cancer in black and white Americans, and the finding of susceptibility loci on chromosomes 5, 6, and 12 in case-control studies (Mai et al. 2009). Furthermore, specific polymorphisms of certain genes, including the gene encoding c-KIT ligand, have been associated with an increased risk of testicular cancer (Blomberg Jensen et al. 2008; Kanetsky et al. 2009). Gonocytes depend on c-KIT ligand for survival, and the gene for this protein is located on the short arm of chromosome 12. Approximately 70 % of GCTs have an extra copy of chromosome 12 in the form of an isochromosome 12p (i[12p]) (Bosl et al. 1989). Thus, a connection between mutations or polymorphisms in this gene and GCT has biologic plausibility.
The most important characteristic of GCTs is their sensitivity to cisplatin-based chemotherapy, which allows cure in almost all of patients with widely metastatic disease. The specific biologic basis of this acute vulnerability to chemotherapy is still not completely clear, but probably it derives from the low threshold for undergoing apoptosis in response to DNA damage due to the close relationship between GCTs and embryonal stem cells and gonocytes (Mayer et al. 2003; Schmelz et al. 2010).
GCTs have elevated intrinsic levels of wild-type TP53 protein (acting a role in cell cycle arrest and apoptosis), and TP53 mutations in GCTs are uncommon, yet differences have not been consistently found in TP53 status when comparing chemosensitive and chemoresistant germ cell tumors (Burger et al. 1998; Houldsworth et al. 1998). Likewise, in germ cell tumors, the expression of the antiapoptotic protein BCL2 is low, but BCL2 levels do not discriminate chemosensitive and chemoresistant cell lines (Mayer et al. 2003).
With gene expression analysis has been demonstrated an upregulation of numerous genes that facilitate apoptosis, including FASLG, TNFSF10, and BAX, whereas BCL2 is downregulated (Schmelz et al. 2010). Expression patterns of genes controlling the G1/S-phase checkpoint in GCTs seem to promote induction of apoptosis (Schmelz et al. 2010). Furthermore, GCTs do not have transporters to export cisplatin from the cell and have a diminished capability to repair cisplatin-induced DNA damage (Mayer et al. 2003).
Nevertheless, a few of GCTs are resistant to chemotherapy, and the origin of that resistance remains obscure, although DNA mismatch repair deficiency, microsatellite instability, and BRAF mutations have been associated with treatment failure (Honecker et al. 2009).
Up to 10 % of GCTs are extragonadal developing in midline anatomic locations. There are proposed two main theories concerning the pathogenesis of extragonadal GCTs. The first one proposes that the extragonadal GCTs originate from germ cells that had an unusual migration along the genital ridge and were able to survive in an extragonadal environment. The second hypothesis sustains a reverse migration from the testis to extragonadal locations (Chaganti and Houldsworth 2000). Primary mediastinal NSGCTs differ in numerous ways from those originating in the testis or retroperitoneum. Primarily they are less sensitive to chemotherapy and have a poor prognosis with a 5-year overall survival of about 45 % (Bokemeyer et al. 2002b). In mediastinal NSGCTs, there are often yolk sac tumor components; for this there is a correlation with elevations in serum α-fetoprotein (AFP) (Kesler et al. 2008). They are also associated with Klinefelter syndrome and with hematologic malignancies that carry extra copies of the short arm of chromosome 12, as seen in adult GCTs (Bokemeyer et al. 2002a; McKenney et al. 2007). In contrast, mediastinal seminomas carry a similar prognosis to testicular seminomas. Primary retroperitoneal GCTs are impossible to differentiate biologically from testicular GCTs and have the same prognosis.
GCTs are generally cataloged as seminoma and NSGCT, and the relative distribution of each is 52–56 % and 44–48 %, respectively (McGlynn et al. 2005; Powles et al. 2005). NSGCTs comprise embryonal carcinoma (EC), yolk sac tumor, teratoma, and choriocarcinoma subtypes, either alone as pure forms or in combination as mixed GCT with or without seminoma (Ulbright 2005). Most NSGCTs are mixed tumors formed by two or more GCT subtypes. GCTs that contain both NSGCT subtypes and seminoma are classified as NSGCT.
Intratubular Germ Cell Neoplasia
Except the spermatocytic seminoma, all invasive GCTs developed by the adult arise from ITGCN. ITGCN is made of undifferentiated germ cells that seem like seminoma, located basally within the seminiferous tubules. In the tubule typically there is absent or decreased spermatogenesis, and normal cells are replaced by ITGCN. When a specimen obtained performing orchiectomy in men with testicular cancer shows presence of ITGCN, there is not any prognostic implications about risk of relapse of the cancer (von Eyben et al. 2004).
Seminoma is the most frequent category of GCT. Normally, seminomas arise at an older average age than NSGCTs, and the diagnosis is most common during the fourth or fifth decade of life (Rayson et al. 1998). The seminoma is a soft tan to white diffuse or multinodular mass. Necrosis could be present but is frequently focal and not prominent. Seminomas are a sheetlike collection of cells with polygonal nuclei and clear cytoplasm, with the cells that are collected into nests by fibrovascular septa containing lymphocytes (Ulbright 2005). Syncytiotrophoblasts, which are positive for human chorionic gonadotropin (hCG) marker, can be recognized in about 15 % of cases of pure seminoma, but there is not any clear prognostic significance (Cheville 1999). Lymphocytic infiltrates and granulomas are often seen and seminomas seem to be related with an increased incidence of sarcoidosis (Rayson et al. 1998; Tjan-Heijnen et al. 1998). Seminomas could be mystified with solid-pattern EC, yolk sac tumor, or Sertoli cell tumors (Ulbright and Young 2008). Even if immunohistochemical staining has no big role in the diagnosis of GCTs, seminomas are typically negative for CD30, positive for CD117, and strongly positive for placental alkaline phosphatase (PLAP). Anaplastic seminoma was a previously recognized subtype of seminoma, but this difference is of no clear biologic or clinical meaning and is no longer documented. Seminoma occurs from ITGCN and is believed to be the common precursor for the other NSGCT subtypes (Ulbright 2004). This aptitude of seminoma to transform into NSGCT elements has significant therapeutic implications for the managing of seminoma (Ulbright 2004).
Spermatocytic seminoma represents less than 1 % of GCTs. It is a distinct clinicopathologic entity from other GCTs, but it is classified as a variant of seminoma. Spermatocytic seminoma does not develop from ITGCN, is not connected with cryptorchidism or bilaterality, does not arise as part of mixed GCTs, and does not express PLAP or i(12p) (Ulbright 2005). Histopathologically, it varies from seminoma in that the nuclei are round, it has minimal lymphocytic infiltration, and three distinct cell types are present, including small lymphocyte-like cells, medium-sized cells with dense eosinophilic cytoplasm and a round nucleus, and large mononucleated or multinucleated cells (Aggarwal and Parwani 2009). The sixth decade of life is the most involved (Eble 1994; Chung et al. 2004a). It is a benign tumor (only one documented case having metastasized) and is almost always cured with orchiectomy (Chung et al. 2004a).
EC shows undifferentiated malignant cells similar to primitive epithelial cells from early-stage embryos with packed pleomorphic nuclei (Ulbright 2005). Grossly, EC is a tan to yellow neoplasm that often displays large areas of hemorrhage and necrosis. At microscopic observation, these tumors appear significantly different, and they may grow in solid sheets or in papillary, glandular alveolar, or tubular patterns. At times, syncytiotrophoblasts can be recognized. EC is related with a high rate of metastasis, frequently in patients with regular serum tumor markers. EC is the most undifferentiated cell type of NSGCT and has a totipotential capacity to differentiate to other NSGCT cell types (including teratoma) both within the primary tumor or metastases. EC typically stains for AE1/AE3, PLAP, and OCT3/4 and does not stain for c-KIT.
Choriocarcinoma is an aggressive tumor that classically shows with high serum hCG levels and disseminated disease. It is rare and usually spreads by hematogenous routes, and common sites of metastases comprise the lungs and brain, but eye and skin metastases have also been reported (Tinkle et al. 2001; Osada et al. 2004). Microscopically the tumor is composed of syncytiotrophoblasts and cytotrophoblasts, and specimen stains positively for hCG (Cheville 1999). Seminoma and EC may also contain syncytiotrophoblasts. Usually there are huge areas of necrosis and hemorrhage, so testicular choriocarcinoma is prone to serious hemorrhage, and such bleeding can be catastrophic, predominantly when it happens in the lungs or brain (Motzer et al. 1987).
Yolk Sac Tumor
Yolk sac tumors (also called endodermal sinus tumors) are only a small part of adult-type GCTs but are more common in mediastinal and pediatric GCTs. In mixed GCTs frequently some component of yolk sac tumor can be included, which consists of a reticular network of medium-sized cuboidal cells with cytoplasmic and extracytoplasmic eosinophilic, hyaline-like globules (Epstein 2010). Hyaline globules are a typical characteristic and are present in up to 84 % of cases. Yolk sac tumors can grow in a glandular, papillary, or microcystic pattern. The Schiller-Duval body is a distinctive feature, which looks a lot like endodermal sinuses, and is seen in approximately half of cases. Yolk sac tumors almost always produce AFP but not hCG. Among men with CS I NSGCT with standard serum tumor markers, the presence of a yolk sac tumor is related with a minor risk of relapse, but this can merely be a result of serum tumor markers (i.e., AFP) having a higher sensitivity to identify micrometastatic disease in this type of GCT (Read et al. 1992).
Teratoma in the ancient Greek means “monster tumor.” Teratomas include well-differentiated or moderately differentiated elements of at least two of the three germ cell layers of endoderm, mesoderm, and ectoderm. Normally all components are intermixed. Well-differentiated tumors are marked as mature teratomas, and the partially differentiated are called immature teratomas. Mature teratomas may contain elements of mature bone, cartilage, teeth, hair, and squamous epithelium. Their form may depend on the elements within it, with most tumors having solid and cystic areas. Generally this tumor is related with usual serum markers, but mildly elevated serum AFP levels are often reported. Pure teratomas are uncommon but roughly 47 % of adult mixed GCTs contain teratoma (Epstein 2010). In adults, teratomas are histologically benign but are frequently found at metastatic sites in patients with advanced NSGCT. A hypothesis is that nonteratomatous elements (mostly EC) are able to mature into teratoma and that the metastases derive from these elements before their differentiation. Teratoma is resistant to chemotherapy. The intrinsic chemoresistance of teratoma reduces the possible treatment approaches for NSGCT that utilize chemotherapy alone. Sometimes teratomas present genetic abnormalities recurrently found in malignant GCT elements, including aneuploidy, i(12p), and widely variable proliferative capacity (Castedo et al. 1989; Sella et al. 1991). Different studies demonstrated that cystic fluid from teratoma often contains hCG and AFP, corroborating the malignant potential of teratoma (Sella et al. 1991; Beck et al. 2004). The genetic instability of teratoma has significant clinical implications. Teratomas may develop uncontrollably, invade adjacent structures, and become unresectable (growing teratoma syndrome) (Logothetis et al. 1982). Infrequently teratoma may transform into a somatic malignancy such as rhabdomyosarcoma, adenocarcinoma, or primitive neuroectodermal tumor (Little et al. 1994; Comiter et al. 1998; Motzer et al. 1998). In these cases, the literature uses the appellatives “teratoma with somatic-type malignancy” or “teratoma with malignant transformation.” Frequently abnormalities of chromosome 12 or i(12p) are shown, preserving their origin from GCT. These kinds of teratomas are highly aggressive, resistant to conventional chemotherapy, and associated with a poor prognosis. Last but not least, unresected teratoma in patients with advanced NSGCT may result in late relapse (Sheinfeld 2003).
15.1.5 Clinical Presentation
In most cases the presentation of testicular cancer is a painless testicular mass. A less common presentation is represented by acute testicular pain, due to a rapid expansion of the testis caused by intratumor hemorrhage or infarction depending on tumor growth.
Pain is usually associated with NSGCT, because these tumors are inclined to be more vascular and show more fast growth compared with seminomas. Patients commonly report a history of testicular trauma, although incidental trauma is likely responsible of an increased attention of the patients on his testis for the first time. A vague scrotal discomfort or a heaviness can be complained by patients. Regional or distant metastasis at diagnosis is present in about two thirds of NSGCTs and 15 % of pure seminomas, and symptoms related to metastatic disease are the presenting complaint in 10–20 % of patients. Sometimes a palpable mass can be caused by bulky retroperitoneal metastasis, associated with abdominal pain, flank pain due to ureteral obstruction, back pain due to involvement of the psoas muscle or nerve roots, lower extremity swelling due to compression of the inferior vena cava, or gastrointestinal symptoms. If there is pulmonary metastasis, they may cause dyspnea, chest pain, cough, or hemoptysis.
Metastasis to supraclavicular lymph nodes can arise as a neck mass. About 2 % of men have gynecomastia, and this is caused by the combination of different factors as high serum hCG levels, decreased androgen production, or augmented estrogen levels (frequently seen in men with Leydig cell tumors). About two thirds of men with GCT have diminished fertility, but it is not a common initial presentation.
15.1.6 Clinical Examination
A correct physical examination requires cautious inspection of both the affected and the normal contralateral testes, investigating their size and uniformity and palpating for any testicular or extratesticular masses. Atrophy of the involved or contralateral testis is common, predominantly in patients with a history of cryptorchidism. Any solid area within the testis should suggest further investigations cause is indicative of a possible malignancy. Sometimes there is a hydrocele along with testicular cancer and can falsify the physician’s examination of the testis. In this case, to improve the diagnostic capability, a scrotal ultrasonography is warranted. The evaluation of the patient should be carried out for any evidence of palpable abdominal mass or tenderness, inguinal lymphadenopathy (predominantly if he had inguinal or scrotal surgery), gynecomastia, and supraclavicular lymphadenopathy, and the research for intrathoracic disease should be done with the auscultation of the chest.
15.1.7 Differential Diagnosis
There are a lot of diseases that we must consider in the differential diagnosis of testicular mass, including epididymo-orchitis, testicular torsion, hematoma, or paratesticular neoplasm (benign or malignant). Other possible similar diseases which can be distinguished from a testicular mass by physical examination comprise hernia, varicocele, or spermatocele. A solid intratesticular mass should be considered cancer until proved otherwise and it is mandatory investigate this mass with scrotal ultrasonography. In patients which received a diagnosis of epididymo-orchitis, a second evaluation is compulsory within 2–4 weeks of treatment with a proper oral antibiotics administration. If there is a persistent mass or continuous pain, they should be investigated further with scrotal ultrasonography.
15.1.8 Diagnosis: Importance of Timing
Testicular cancer is the tumor most frequent in young adult males and is also famous for the diagnostic delay due to patient and physician’s delay. Patients affected by testicular cancer are usually young and are often less prone to medical examination for symptoms due to denial, ignorance, or limited access. In other cases the delay is due to misunderstanding by physician in the diagnosis. Studies show that more than one third of testicular tumors are diagnosed as epididymitis or hydrocele at first (Bosl et al. 1981). Rarely, in patients with signs or symptoms from metastatic GCT, the physician could focus his/her attention only on the symptomatic metastasis failing to diagnose GCT. These patients may undergo inappropriate treatment, diagnostic tests, and superfluous surgery with consequent delays in best therapy. In the literature, there are reported cases describing patient which underwent exploratory laparotomy, neck dissection, or mastectomy for unsuspected metastatic GCT. The absence of an early diagnosis is associated with advanced clinical stage, suboptimal response to chemotherapy, and reduced survival. Moul and colleagues (1990) described a decrease in survival in GCT patients cured from 1970 to 1987 with a diagnostic delay greater than 16 weeks, even though an important survival difference was not detected among patients treated in the cisplatin era.
In the literature, a higher number of men requiring intensive chemotherapy (multiple regimens, high dose, and salvage chemotherapy) are reported among those with a treatment delay greater than 30 days due to avoidable exploratory laparotomy (Stephenson et al. 2004).
The improvement of physician’s education and patient’s compliance can reduce the diagnostic delay. Any male 15–50 years old with a solid testicular mass, midline retroperitoneal mass, or mass in the left supraclavicular fossa should be investigated for the diagnosis of GCT. A methodical physical examination with proper radiologic (testicular ultrasonography) and serologic evaluations (serum AFP, hCG, lactate dehydrogenase [LDH]) is the correct way to obtain a correct diagnosis.
15.1.9 Disease Determination, Diagnostic, and First Management
220.127.116.11 Scrotal Ultrasonography
Scrotal ultrasonography is a technique capable of differentiating intratesticular masses from extratesticular lesions with high-frequency transducers (5–10 MHz). It is often used because it is widespread, cheap, and noninvasive. Scrotal ultrasonography must be performed, after the physical examination, in patients who show testicular mass, hydrocele, or other unknown scrotal symptoms or signs.
Ultrasonography can distinguish GCT from NSGCT. In fact GCT appears as multiple discrete hypoechoic lesions. Heterogeneous echostructure is typically associated with NSGCT, because seminomas typically have a homogeneous echostructure. The increase of vascularization within the lesion on color Doppler ultrasonography is indicative of malignancy; however, its absence does not exclude GCT. Testicular microlithiasis can be recognized by ultrasonography, but its presence does not require further investigation because the association with GCT has not been well defined (DeCastro et al. 2008). Although the incidence (2 %) and diagnosis (0.5 % of all GCTs) of bilateral tumors are low, both testes should be evaluated ultrasonographically, while metachronous presentation is more frequent (Fossa et al. 2005). In men with advanced GCT and a normal testicular examination, scrotal ultrasonography should be executed to rule out the presence of a small, impalpable scar or calcification, indicating a “burned-out” primary testicular tumor. The diagnosis of small (<10 mm), impalpable intratesticular lesions in the absence of disseminated GCT or elevated serum tumor markers is very difficult because they could be benign (testicular cysts, small infarcts, Leydig cell nodules, or small Leydig cell or Sertoli cell tumors) or even malignant (usually seminoma) (Hindley et al. 2003; Connolly et al. 2006; Muller et al. 2006).
Management options include inguinal orchiectomy, which should be performed when there are signs of malignancy (in fact the risk increases with the size of the lesion) (Carmignani et al. 2005); inguinal exploration with intraoperative ultrasonography which can be useful to locate the lesion; excision (with frozen section analysis to rule out GCT); and observation with frequent ultrasonographic evaluation (with exploration of growing lesions).
18.104.22.168 Serum Tumor Markers
High levels of serum tumor markers (LDH, AFP, and hCG) can be found in testicular tumor, especially in NSGT. They are necessary in its diagnosis, prognosis, evaluation of treatment, and monitoring for risks of relapse through evaluation of enzymes before and after orchiectomy. But the serum tumor marker test should not be used to evaluate the use of orchiectomy.
At diagnosis, AFP levels are elevated in 50–70 % of low-stage (CS I, IIA, IIB) NSGCT and 60–80 % of advanced (CS IIC, III) NSGCT. EC and yolk sac tumors secrete AFP. Choriocarcinomas and seminomas do not secrete AFP. The half-life of AFP is 5–7 days. AFP levels are not specific because they also can be found in hepatocellular carcinoma and cancers of the stomach, pancreas, biliary tract, and lung, or in nonmalignant liver disease (autoimmune, drug induced, infectious, alcohol induced), ataxic telangiectasia, and hereditary tyrosinemia.
hCG levels are elevated in 20–40 % of low-stage NSGCT and 40–60 % of advanced NSGCT. About 15 % of seminomas secrete hCG. Also choriocarcinoma and EC secrete hCG. Levels greater than 5,000 IU/L are frequently associated with NSGCT. The half-life of hCG is 24–36 h. hCG levels may be elevated in cancers of the liver, breast, pancreas, stomach, biliary tract, kidney, and bladder.
False positive can be given by cross-reactivity of the hCG assay with luteinizing hormone in patients with primary hypogonadism or by marijuana use. Elevated serum hCG results caused by hypogonadism will normalize within 48–72 h after the administration of testosterone, and this can be done to distinguish between true- and false-positive hCG results.
LDH levels are increased about 20 % of low-stage GCTs and 20–60 % of advanced GCTs. A nonspecific marker for GCT in fact is expressed in tissues such as smooth, cardiac, and skeletal muscles or in diseases like a lymphoma. LDH-1 is commonly the isoenzyme most elevated in GCT. LDH-1 levels are correlated with the chromosome arm 12p copy number, which is frequently amplified in GCT. High levels of LDH are correlated with the mass of disease. The serum half-life of LDH is 24 h.
In rare patients who present a testicular, retroperitoneal, or mediastinal primary tumor and conditions in which the patients require urgent treatment, elevated serum AFP and/or hCG levels may be considered sufficient for diagnosis of GCT. For rare patients with medically unstable disease, treatment must not be delayed until histology results permit a tissue diagnosis. However, these patients should have radical orchiectomy after the completion of chemotherapy, because the testis is a sanctuary site for malignant GCT owing to the blood–testis barrier and because the testis frequently contains residual invasive GCT, teratoma, and/or ITGCN (Geldart et al. 2002).
22.214.171.124 Radical Inguinal Orchiectomy
A removal of the tumor-bearing testis and spermatic cord to the level of the internal inguinal ring should be performed in patients with a suspect testicular neoplasm. A transscrotal orchiectomy or biopsy is contraindicated because it amplifies the risk of local recurrence and pelvic or inguinal lymph node metastasis. Because of the rapid growth of GCT, orchiectomy should be performed quickly, avoiding an unjustified delay. Radical orchiectomy has different important roles: it defines the histologic diagnosis and primary T stage, gives important prognostic information from the tumor histology, and is curative in 80–85 % and 70–80 % of CS I seminoma and CS I NSGCT, respectively. The histopathologic examination of the testis helps to define the histologic type of the tumor, the tumor size, multifocality, local tumor invasion (rete testis, tunica albuginea, tunica vaginalis, epididymis, spermatic cord, scrotum), primary T stage (Sobin and Wittekind 2002; Greene et al. 2002), presence of ITGCN, invasion of blood or lymphatic vessels (termed lymphovascular invasion [LVI]), and the surgical margin status (Sobin and Wittekind 2002). Mixed GCTs have to be evaluated by each individual tumor subtype and its relative proportion. A review of primary tumor specimens by experienced pathologists is necessary, because the treatment of GCT is based on the histopathologic diagnosis.
126.96.36.199 Testis-Sparing Surgery
Patient suspected of having a testicular neoplasm with a normal contralateral testis should not undergo a testis-sparing surgery. However, it may be indicated for organ-confined tumors of less than 2 cm in patients with synchronous bilateral tumors or tumor in a solitary testis with sufficient testicular androgen production. If serum AFP, hCG, and LDH values are normal, suspected benign tumor or indeterminate lesion can be treated with a testis-sparing surgery. This procedure is frequently unsuitable for larger tumors (>2 cm) because a complete excision frequently leaves insufficient residual testicular parenchyma for preservation. When this kind of surgery is performed, biopsies of the adjacent testicular parenchyma should be executed to verify an eventual ITGCN, which is present in adjacent testicular parenchyma in 80–90 % cases of GCT and is associated with a 50 % risk of GCT within 5 years and 70 % within 7 years (Skakkebaek et al. 1982; Dieckmann and Skakkebaek 1999; Montironi 2002). Adjuvant radiotherapy to the residual testis using doses of 20 Gy or greater is usually sufficient to prevent the development of a GCT.
188.8.131.52 Biopsy of the Contralateral Testis
In normal patients with GCT, the risk of ITGCN in the contralateral testis is between 5 and 9 % (Dieckmann and Skakkebaek 1999), while it rises to 36 % in patients with an atrophic testis, history of cryptorchidism, or younger than 40 years (Dieckmann and Loy 1996). In the latter category of patients, an open inguinal biopsy of the contralateral testis may be considered (Motzer et al. 2006).
184.108.40.206 Supposed Extragonadal GCT
Extragonadal GCTs are 2–5 % of GCT (Bokemeyer et al. 2002b). One third of the patients with metastatic GCT without a testicular mass definitively have a primary extragonadal GCT (Scholz et al. 2002). GCT should be considered in any young male with a midline mass. For the diagnosis of GCT, elevated serum AFP and/or hCG and a normal testicular evaluation are enough, while histologic confirmation by biopsy is not necessary before starting therapy. If serum tumor markers are regular, the diagnosis of GCT can be confirmed only by the biopsy of the mass. A biopsy specimen presenting poorly mature carcinoma represents a diagnostic dilemma if a primary tumor site cannot be confirmed. Inguinal orchiectomy is indicated in patients with probable retroperitoneal extragonadal GCT at some point during their treatment course if the pattern of metastasis is consistent with a right- or left-sided testicular primary tumor or if there is ultrasonographic evidence of a “burned-out” primary tumor.
15.1.10 Clinical Staging
The prognosis of GCT and the treatment choices are led by the clinical stage; this is an estimation of how much cancer is based on histopathologic exam results and the pathologic stage of primary tumor, the levels of tumor markers in serum of patients with orchiectomy, and on any metastases and their extension evaluated with imaging techniques. Only in 1997 an international classification of GCT was established by the American Joint Committee on Cancer (AJCC) and Union Internationale Contre le Cancer (UICC); this staging system is unique for the reason that serum tumor marker group(s) centered on postorchiectomy AFP, hCG, and LDH levels is used to improve the prognostic grades as determined by body extension of pathological process.
Nowadays the CS is divided in three stages: the first one is clinically defined as testis-confined disease, the second one by the extension to the retroperitoneal lymph node metastasis, and the third one by the involvement of non-regional lymph node and/or organ metastasis.
220.127.116.11 Staging Imaging Studies
The expectable pattern of metastatic diffusion of GCT has facilitated the successful treatment. Excluding the only choriocarcinoma that spreads via hematogenous vessels, the most important way of cancer diffusion is through lymphatic vessels, from the principal tumor mass to the retroperitoneal lymph nodes (that represents the first metastatic site in 70–80 % of patients), and then to the farthest sites. A series of studies on retroperitoneal lymph node dissection (RPLND) have increased the knowledge of the testicular lymphatic drainage, and they revealed the common sites of metastatic spread (Sheinfeld 1994). The interaortocaval lymph nodes inferior to the renal vessels represent for right testicular tumors the primary drainage site, followed by the paracaval and para-aortic nodes; instead for left testicular tumors, the first “landing zone” is the para-aortic lymph nodes, followed by the interaortocaval nodes (Donohue et al. 1982). Moreover, in the retroperitoneum, the pattern of lymphatic drainage is from right to left; therefore, contralateral dissemination is commonly seen from the primary metastatic site with right-side tumors but is unusual for the left-side one and generally is associated with bulky disease. More caudal “landing zone” of metastatic disease typically reproduces retrograde spread to distal iliac and inguinal lymph nodes, subordinate to seriousness of disease, and very seldom aberrant testicular lymphatic drainage. Retroperitoneal lymphatic vessels drain into the cisterna chyli behind the right renal artery and right crus of the diaphragm, thus making it possible to see, in patients with retroperitoneal disease, the metastasis of retrocrural lymph node that via the thoracic duct spreads to the posterior mediastinum and left supraclavicular fossa.
Staging imaging studies of the abdomen and pelvis are fundamental for patients with GCT; the most operative and noninvasive technique is the computed tomography (CT) after administration of intravenous or oral contrast agents. Moreover, CT procures a more specific anatomic evaluation of the retroperitoneum to detect pathologic anomalies that may complicate successive RPLND, such as a circumaortic or retroaortic left renal vein, lower pole renal artery, or retrocaval right ureter. Lymphangiography has no role where transaxial imaging is available. Inflamed retroperitoneal lymph nodes are found on CT in 10–20 % of seminomas and 60–70 % of NSGCT. The retroperitoneum represents the most difficult area to stage clinically; in fact otherwise the progresses in CT over the past four decades, also in the presence of a “normal” CT scan about 25–35 % pathological retroperitoneal lymph nodes has been reported for CS I NSGCT (Fernandez et al. 1994). There is not unanimous consensus about universal size criteria for retroperitoneal lymph nodes that establish a “normal” CT scan; a size of 10 mm is detected as cutoff for identifying enlarged lymph nodes, but false-negative rates up to 63 % have been described when this size criterion is used. Among patients with CS IIA and IIB disease, clinical overrating by CT (i.e., pathologically negative lymph nodes at RPLND despite enlarged lymph nodes on CT) is reported in 12–40 % of patients.
The knowledge of the primary drainage sites for left- and right-side tumors has led the studies to increase the sensitivity of abdominopelvic CT by reducing the size criteria for clinically positive lymph nodes in the primary “landing zone,” and a size criterion smaller of 4 mm has been proposed. Leibovitch and colleagues (1995) showed that a size cutoff of 4 mm in the primary landing zone and 10 mm outside this region was correlated with a sensitivity and specificity for pathologic stage II disease of 91 and 50 %, respectively. In a similar study, Hilton and associates (1997) described a sensitivity and specificity of 93 and 58 %, respectively, using a cutoff of 4 mm for lymph nodes in the primary “landing zone” that were anterior to a horizontal line bisecting the aorta. Based on this information, retroperitoneal lymph nodes greater than 5–9 mm in the primary “landing zone,” particularly if they are anterior to the great vessels on transaxial CT images, should be viewed with misgiving for regional lymph node metastasis. Due to the rapid growth of GCT, it is suitable to base the management decision on CT studies executed within 4 weeks of the start of treatment. Malignant GCT gathers fluorodeoxyglucose (FDG), and several researches have studied FDG-labeled positron emission tomography (FDG-PET) in the staging of GCT at diagnosis and assessing response after chemotherapy. Numerous small pilot studies proposed that FDG-PET can recognize retroperitoneal metastasis in low-stage seminoma and NSGCT with more accuracy than CT (Albers et al. 1999). In a prospective trial, FDG-PET studies in 111 contemporary patients with CS I NSGCT on surveillance were reviewed; relapse was detected in 33 of 87 patients who were PET negative, with a valued relapse-free rate of 63 % (Huddart et al. 2007). The researcher established that FDG-PET is not sufficiently sensitive to accurately stage CS I NSGCT. De Wit and associates (2008) also recounted that FDG-PET yielded only rather better results than CT as a primary staging technique for low-stage NSGCT. Nowadays there is no part for FDG-PET in the routine valuation of NSGCT and seminoma at the time of diagnosis. CS II disease is categorized into three groups—IIA (enlarged retroperitoneal lymph nodes ≤2 cm), IIB (enlarged retroperitoneal lymph nodes >2 cm but ≤5 cm), and IIC (enlarged lymph nodes >5 cm)—which are based on the size of regional lymph node(s) as determined by abdominopelvic imaging.
18.104.22.168 Chest Imaging
A chest imaging is required before any treatment decisions are taken for every patients with GCT. It is very rare, especially for seminoma, to observe thorax metastasis in the lack of retroperitoneal one and/or high serum tumor markers. Hence, routine chest CT may be correlated with an elevated amount of false-positive findings, which may complicate successive therapy (Horan et al. 2007). Thus, it is suggested to achieve a chest RX at the time of diagnosis as a first imaging technique, and then a CT should be executed only in patients with raised postorchiectomy levels of serum tumor markers, evidence of metastatic disease by physical examination or abdominopelvic CT, and atypical or ambiguous findings on thorax radiography. It could be sensible to effect chest CT in patients with CS I NSGCT with evidence of LVI or EC predominance because some works have reported an important rate of hematogenous metastasis to the lung in the context of a negative CT for retroperitoneal metastasis (Hermans et al. 2000; Sweeney et al. 2000). Mediastinal or hilar lymphadenopathy without retroperitoneal disease suggests a suspicion of non-GCT etiology such as lymphoma or sarcoidosis, and histologic confirmation of GCT by mediastinoscopy and biopsy should be performed before initiating systemic therapy (Hunt et al. 2009). In non-attendance of symptoms or other clinical signs of disease, it is unusual in GCT observing visceral metastasis to bone or brain; for this reason, there is no evidence to execute a bone scintigraphy or brain CT at the time of diagnosis. An exception to this is brain CT for patients with a very high hCG value (>10,000 IU/L) because these levels are often joined with metastatic choriocarcinoma, which has a propensity for brain metastases.
15.1.11 Prognosis in Advanced GCT
An international, retrospective pooled analysis of 5,202 patients with advanced NSGCT treated between 1975 and 1990 with platin-containing chemotherapy regimens (cisplatin or carboplatin) identified AFP, hCG, and LDH levels at the initiation of chemotherapy, the presence of non-pulmonary visceral metastasis, and primary mediastinal NSGCT as significant and independent prognostic factors for progression and survival. In 660 patients with advanced seminoma, only the presence of non-pulmonary visceral metastasis was an important predictor of progression and survival (International Germ Cell Consensus Classification 1997). Based on these evidences, the International Germ Cell Consensus Classification Group (IGCCCG) risk classification for advanced GCT was settled. The IGCCCG risk group should be defined for each patient with metastatic GCT, and this could be led treatment decision making on the selection of chemotherapy (discussed later). This systematization involves only patients with advanced GCT at the time of diagnosis, but not patients with relapsed GCT. The classification is also based on the postorchiectomy serum tumor marker levels at the beginning of chemotherapy, not the preorchiectomy levels. 56, 28, and 16 % of patients with advanced NSGCT are categorized as good, intermediate, and poor risk, respectively, by the IGCCCG criteria, and the 5-year progression-free and overall survival rates for these patients are 89 % and 92 %, 75 % and 80 %, and 41 % and 48 %, respectively. There is no poor-risk category for seminoma. Approximately 90 and 10 % of patients with advanced seminoma are classified as good and intermediate risk, respectively, by the IGCCCG criteria, and the 5-year progression-free and overall survival rates for these patients are 82 % and 86 % and 67 % and 72 %, respectively. Van Dijk and coworkers (2006) published a meta-analysis of ten studies of 1775 NSGCT patients treated after 1989 and reported pooled 5-year survival estimates of 94, 83 and 71 % for good-, intermediate-, and poor-risk patients by the IGCCCG criteria. From these data, the survival results significantly improved, especially if they are compared with those of the original study (particularly for those classified as poor risk), and are ascribed to more efficient treatment strategies and more understanding in treating NSGCT patients. The TNM system does incorporate marker levels (S0-3) and non-pulmonary visceral metastasis in the staging of testicular cancer. However, this system does not recognize the differences in prognosis between seminomas and NSGCT with non-pulmonary visceral metastasis. In the TNM system, these would both be classified as CSIII, but IGCCCG would classify the former as intermediate risk and the latter as poor risk. As such, the IGCCCG system is preferentially used for prognostic assessment and the selection of chemotherapy.
To avoid evitable deaths or pain, a rapid diagnosis and an appropriate treatment for GCT are necessary. After orchiectomy, staging imaging studies, serum tumor marker status, and treatment plans should be performed rapidly. Considering that the cure is possible even in the presence of metastasis, an aggressive chemotherapeutic and postchemotherapeutic approach (postchemotherapeutic surgery) has been developed. Chemotherapy is generally administered regardless of low white blood cell counts or thrombocytopenia, and nephrotoxic chemotherapy (cisplatin) is often administered even in the presence of moderate-to-severe renal insufficiency (Williams et al. 1987a; Einhorn et al. 1989; Bajorin et al. 1993; Loehrer et al. 1995; Bokemeyer et al. 1996b; Nichols et al. 1998; de Wit et al. 2001). After chemotherapy for NSGCT, an aggressive surgical approach is taken to resect all sites of residual disease, even if this involves multiple anatomic sites. The young age and generally good health of GCT patients permit an aggressive treatment approach if needed. Serum tumor markers strongly influence the management of GCTs, particularly NSGCT. An initial approach with chemotherapy is indicated in patients with elevated serum AFP or HCG after orchiectomy: in fact the elevation of these markers in the blood indicates the presence of metastatic disease. For patients receiving chemotherapy, rising serum tumor marker levels during or after therapy generally indicate refractory or relapsed disease, respectively. As discussed, serum AFP, hCG, and LDH levels at the beginning of chemotherapy are important prognostic factors and define the type and duration of chemotherapy regimens (International Germ Cell Consensus Classification 1997). Testicular cancer is a relatively rare disease; the treatment algorithms are relatively complex (Donohue et al. 1993, 1995; Heidenreich et al. 2003; Stephenson et al. 2005b; Williams et al. 2009b). If the treatment is provided at a high-volume institution, the survival rate improves (Aass et al. 1991; Harding et al. 1993; Feuer et al. 1994; Collette et al. 1999; Joudi and Konety 2005; Suzumura et al. 2008). Therefore, whenever possible, GCT patients should be treated at a high-volume centers and RPLND should be performed by experienced surgeons.
22.214.171.124 Differences Between Seminoma and NSGCT
It is very important to distinguish between seminoma and NSGCT for treatment purposes. In comparison with NSGCT, seminoma has a more favorable natural history. In fact seminoma is less aggressive, is usually diagnosed at an earlier stage, and spreads predictably along lymphatic channels to the retroperitoneum before spreading hematogenously to the lungs or other organs. At diagnosis the proportion of patients with CS I, II, and III disease is 85, 10, and 5 %, respectively, for seminoma and approximately 33, 33, and 33 % for NSGCT (Powles et al. 2005). The proportion of patients with CS I are 85 % for seminoma while that of patients with CS I for NSGCT are just 33 %. Occult metastasis occurs less frequently in patients with CS I for seminoma. Seminoma also has a lower risk of systemic relapse after treatment of the retroperitoneum (1–4 % after radiotherapy for seminoma vs. 10 % after RPLND for NSGCT). Serum tumor markers do not reach high levels in seminoma and are not used in the evaluation of risk in the IGCCCG risk classification. Compared with NSGCT, seminoma is exquisitely sensitive to radiation therapy and platin–based chemotherapy. Regarding the former aspect, substantially lower radiation doses are required to eradicate seminoma compared with other solid tumors. As such, radiation therapy is a standard treatment option for CS I and IIA–B seminoma but has no role in NSGCT, with the exception of treatment for brain metastases. Seminoma is sensitive to lower radiation doses, while radiation therapy does not have a role in NSGCT. Seminoma is also very sensitive to platin-based chemotherapy. It is very important to consider the potentiality of seminoma to transform into NSGCT after a failure of chemotherapy or a radiation therapy. This eventuality influences the management of the treatment. In fact, an eventual NSGCT at metastatic sites can require both chemotherapy and surgery. It is widely accepted that the successful integration of systemic therapy and PCS is a major contributing factor to the improved cure rates for metastatic GCT seen over the past several decades. Although minimizing unnecessary treatment is an important goal, chemotherapy, radiation therapy, and CT imaging are associated with an increased lifetime risk of secondary malignant neoplasms and/or cardiovascular disease (Meinardi et al. 2000; Zagars et al. 2004; Hinz et al. 2008; van den Belt-Dusebout et al. 2007; Tarin et al. 2009). In contrast, RPLND is associated with a substantially more favorable long-term toxicity profile when performed by experienced surgeons.
Clinical Stage I NSGCT
Approximately 33 % of NSGCT patients have CS I with normal postorchiectomy levels of serum tumor markers. Although the controversy about the optimal management of these patients, surveillance is the preferred approach in select centers because it is not associated with morbidity such as RPLND and primary chemotherapy approach after orchiectomy. In fact, occult metastasis occurs in only 20–30 % of patients overall so radiotherapy or chemotherapy represents overtreatment in most cases.
For occult metastasis, LVI and a predominant component of EC are commonly identified as histopathologic risk factors (Heidenreich et al. 1998; Sogani et al. 1998; Hermans et al. 2000; Sweeney et al. 2000; Alexandre et al. 2001; Roeleveld et al. 2001; Vergouwe et al. 2003; Nicolai et al. 2004; Stephenson et al. 2005a; de Wit et al. 2008). The risk of occult metastasis is less than 20 % if these two risk factors are absent. Other identified risk factors include advanced pT stage, absence of mature teratoma, absence of yolk sac tumor, presence of EC (regardless of the percent composition), percentage of MIB-1 staining, tumor size, and patient age. In a pooled analysis of 23 studies assessing predictors of occult metastasis in CS I NSGCT, LVI (odds ratio [OR] 5.2), MIB-1 staining greater than 70 % (OR 4.7), and EC predominance (OR 2.8) were identified as the strongest predictors. Moreover, the results of abdominopelvic CT should be considered when defining treatment recommendations because a size cutoff of 1 cm is associated with a high false-negative rate. Retroperitoneal lymph nodes greater than 5–9 mm in the primary “landing zone” should be viewed with suspicion of regional lymph node metastasis (Freedman et al. 1987; Read et al. 1992; Heidenreich et al. 1998; Sogani et al. 1998; Hermans et al. 2000; Alexandre et al. 2001; Albers et al. 2003; Nicolai et al. 2004; Stephenson et al. 2005a). Three recent prospective studies suggest that LVI and EC predominance may be associated with a lower risk of metastasis, in particular between 35 and 45 %, not 50–70 % as has been reported in most older studies.
Surveillance cures 70–80 % of patients with CS I NSGCT after orchiectomy with identical survival rates of RPLND and primary chemotherapy (International Germ Cell Consensus Classification 1997). As a result, initial surveillance is regarded as a standard treatment option for CS I NSGCT. On the other hand, surveillance is associated with the highest risk of relapse and the potential for secondary malignant neoplasm due to the number of CT (Brenner and Hall 2007; Tarin et al. 2009). Published surveillance series have reported results on more than 2,500 men, with a mean relapse risk of 28 % and a 1.2 % cancer–specific mortality. More than 90 % of relapses occur within the first 2 years, but late relapses (>5 years) are found in up to 1 % of patients (as many as 5 % in some reports) (Daugaard et al. 2003). Induction chemotherapy is indicated as the common treatment in patients with bulky (>3 cm) retroperitoneal lymphadenopathy, elevated serum tumor marker levels, or distant metastasis, while RPLND is commonly indicated if the lymphadenopathy is not bulky and the serum markers are normal (Stephenson et al. 2007). The surveillance schedule employed in published series is highly variable and no schedule has been demonstrated to be superior to another in terms of survival. Surveillance imaging and testing is intense in years 0–2, with less frequent testing in years 3–5 because the relapses occur more frequently within the first 2 years. The risk of late relapse mandates surveillance beyond 5 years.
Retroperitoneal Lymph Node Dissection
The rationale for RPLND for CS I NSGCT is based on several factors: (1) the retroperitoneum is the most common site of occult metastatic disease and the risk of associated systemic disease is low; (2) 15–25 % incidence of retroperitoneal teratoma (which is resistant to chemotherapy) in those with occult metastasis; (3) low risk of abdominopelvic recurrence after full, bilateral template RPLND thereby obviating the need for routine surveillance CT; (4) high cure rates after RPLND alone for patients with low-volume (pN1) retroperitoneal malignancy and teratoma (pN1-3); (5) avoidance of chemotherapy in more than 75 % or more of patients if adjuvant chemotherapy is restricted to those with extensive retroperitoneal malignancy (pN2-3); (6) high salvage rate of relapses with good-risk induction chemotherapy; and (7) low short- and long-term morbidity when a nerve-sparing RPLND is performed by experienced surgeons. In low–stage NSGCT the therapeutic focus is the retroperitoneum, for which RPLND provides most the effective control with the lowest rates of serious long–term morbidity. The disadvantages of RPLND are that all patients undergo major abdominal surgery, it requires the availability of experienced surgeons and thus may not be deliverable to all patients, and it is associated with the highest rate of double therapy. The rate of pathologic stage II in these series ranges from 19 to 28 %, and an estimated 66–81 % of these patients were cured after RPLND alone (where adjuvant chemotherapy was not dictated by protocol) (Donohue et al. 1993; Hermans et al. 2000; Sweeney et al. 2000; Rabbani et al. 2001; Nicolai et al. 2004; Stephenson et al. 2005b). The long-term cancer-specific survival with RPLND (±adjuvant chemotherapy) approaches 100 %, and the risk of late relapse is negligible. Most RPLND series have reported retroperitoneal recurrences in less than 2 % of patients, demonstrating its efficacy for control of the retroperitoneum (Donohue et al. 1993; Hermans et al. 2000; Stephenson et al. 2005b). A full, bilateral template dissection is associated with the lowest risk of abdominopelvic recurrence (<2 %) and the highest rate of antegrade ejaculation (>90 %) when nerve-sparing techniques are employed (Jewett 1990; Donohue et al. 1998; Stephenson et al. 2005b; Eggener et al. 2007b; Subramanian et al. 2010). For this reason it is now considered by many to be the standard of care for primary RPLND (Risk et al. 2011). Thus, patients who opt for RPLND should have this procedure performed by an experienced surgeon with a full, bilateral template dissection. Otherwise, patients should go on surveillance or receive primary chemotherapy. RPLND is a curative procedure in 60–90 % of patients with pN1 disease and up to 100 % of patients with teratoma only (regardless of the extent of lymph node involvement) (Pizzocaro and Monfardini 1984; Williams et al. 1987b; Richie and Kantoff 1991; Rabbani et al. 2001; Sheinfeld et al. 2003; Stephenson et al. 2005b). The risk of relapse in patients with pN2-3 disease is greater than 50 % (Vogelzang et al. 1983; Williams et al. 1987b; Socinski et al. 1988; Stephenson et al. 2005b). With two cycles of adjuvant chemotherapy (most commonly BEP 2 or EP 2), relapses are reduced to 1 % or less (Behnia et al. 2000; Albers et al. 2003; Kondagunta et al. 2004). A randomized trial of adjuvant chemotherapy versus observation after RPLND for pathologic stage II showed a significant reduction in the risk of relapse (6 % vs. 49 %) but no difference in overall survival (Williams et al. 1987b). Adjuvant chemotherapy and observation are acceptable treatment options for patients with pathologic stage II disease, and patients should be informed of the risk of relapse after RPLND and the potential benefits and risks of these approaches.
In distinction to adjuvant chemotherapy given for pathologic stage II disease after RPLND, primary chemotherapy refers to treatment administered to men with CS I NSGCT after orchiectomy. The goal of primary chemotherapy is to minimize the risk of relapse and to allow men to avoid RPLND and induction chemotherapy (for those who experience relapse on surveillance). The rationale for primary chemotherapy is based on the efficacy of two cycles of chemotherapy to eradicate micrometastatic disease when given as adjuvant therapy after RPLND and the 20–25 % need for chemotherapy despite RPLND (either as adjuvant or for treatment of relapse) (Donohue et al. 1993; Hermans et al. 2000; Nicolai et al. 2004; Stephenson et al. 2005a). Primary chemotherapy offers patients the greatest chance of being relapse-free with any single treatment modality, and it can be delivered at community-based institutions (Tandstad et al. 2009). The disadvantages of primary chemotherapy are that (1) it does not treat retroperitoneal teratoma and thus exposes patients to the potential for chemoresistant and/or late relapse (see later), (2) long-term surveillance CT of the retroperitoneum is required, and (3) all patients are exposed to chemotherapy and the potential risk of late toxicity (cardiovascular disease and secondary malignant neoplasms among others). The risk of late toxicity from two cycles of chemotherapy is poorly defined, although there appears to be no safe lower limit. Primary chemotherapy has been investigated in 11 published series, the majority of which have used BEP 2 (Abratt et al. 1994; Cullen et al. 1996; Pont et al. 1996; Ondrus et al. 1998; Bohlen et al. 1999; Amato et al. 2004; Chevreau et al. 2004; Oliver et al. 2004; Dearnaley et al. 2005; Albers et al. 2008; Tandstad et al. 2009). In men with LVI and/or EC predominance, it is possible to reduce the recurrence rate to 2–3 % with BEP 2 chemotherapy. In 7 of the 11 series, no deaths from GCT have been observed over an average median follow-up of 5 years. In the other four studies totaling 406 patients, 13 relapses (3 %) have been observed and 6 (46 %) of these relapsing patients have died of GCT. Thus, although primary chemotherapy is associated with the lowest risk of relapse, these relapses are less amenable to salvage therapy because they are chemoresistant. In contrast, patients who experience relapse after RPLND or on surveillance are chemotherapy naïve and are cured with chemotherapy in virtually all cases. Although relapses are uncommon with primary chemotherapy, virtually all occur in the retroperitoneum. This mandates the use of surveillance abdominopelvic CT in the follow-up of these patients. Many European institutions prefer BEP 2 to RPLND, because the RPLND is primarily used as a staging procedure and performed without curative intent (Krege et al. 2008a; Schmoll et al. 2009a). A recent randomized trial and a population-based study have investigated the use of BEP 1 as primary chemotherapy for CS I NSGCT (Albers et al. 2008; Tandstad et al. 2009). Over a median follow-up of less than 5 years in both studies, the risk of relapse after BEP 1 ranged from 1 to 3 % and the cancer-specific survival approached 100 % in both studies. BEP 1 needs to be compared with BEP 2 in a randomized trial to verify its safety and efficacy.
Treatment Selection for Clinical Stage I NSGCT
There are no randomized trials that compare the standard treatment approaches for CS I NSGCT. A recent phase III, randomized trial compared BEP 1 versus unilateral, modified-template RPLND (with BEP 2 for patients with pathologic stage II disease) (Albers et al. 2008). Although a statistically significantly reduced risk of relapse was reported with BEP 1, no cancer-specific deaths were reported in either arm. This trial has been criticized because it compared two nonstandard treatment approaches for CS I NSGCT (Sheinfeld and Motzer 2008). Given the excellent long-term survival with surveillance, RPLND, and primary chemotherapy, it is inappropriate to recommend any specific treatment option because there are relative advantages and disadvantages of each approach in terms of treatment-related toxicity, the need for subsequent treatment, and intensity of surveillance testing and imaging. Likewise, patient preferences may vary and should be considered. Several clinical practice guidelines for CS I NSGCT have been published, and surveillance is generally recommended to low–risk patients and either surveillance, RPLND, or primary chemotherapy to those at high risk (Albers et al. 2005; Motzer et al. 2006; Hotte et al. 2008; Krege et al. 2008a; Schmoll et al. 2009a; Stephenson et al. 2011).
Clinical Stage IS NSGCT
CS IS is defined as the presence of elevated postorchiectomy serum tumor markers without clinical or radiographic evidence of metastatic disease. Studies of primary RPLND for CS IS NSGCT have reported that 37–100 % of patients subsequently required chemotherapy for retroperitoneal metastasis, persistently elevated serum tumor markers, or relapse (Davis et al. 1994; Saxman et al. 1996). There is consensus that these patients should be treated similar to those with CS IIC–III and receive induction chemotherapy. The cancer-specific survival after chemotherapy for CS IS is greater than 90 % (Culine et al. 1996; International Germ Cell Consensus Classification 1997). Slightly elevated and stable serum tumor marker levels after orchiectomy in patients without clinical evidence of disease should be interpreted cautiously because they may represent false-positive results for disseminated NSGCT.
Clinical Stage IIA and IIB NSGCT
The optimal management of CS IIA-B NSGCT is controversial. RPLND (± adjuvant chemotherapy) and induction chemotherapy (± postchemotherapy RPLND) are accepted treatment options, with survival rates exceeding 95 %. There are no randomized trials comparing these treatment approaches. In a prospective, multicenter, nonrandomized trial of RPLND and two cycles of adjuvant chemotherapy versus induction chemotherapy, no significant differences in recurrence (7 % for RPLND vs. 11 % for chemotherapy) or overall survival were observed (Weissbach et al. 2000). A single institution, nonrandomized, retrospective comparison of RPLND (and two cycles of adjuvant chemotherapy for pathologic stage II) and induction chemotherapy reported a significant reduction in the risk of recurrence with induction chemotherapy (98 % vs. 79 %), but cancer-specific survival approached 100 % with both modalities (100 % vs. 98 %), RPLND patients received fewer cycles of chemotherapy (mean 4.2 vs. 1.4), and 51 % of RPLND patients avoided chemotherapy (Stephenson et al. 2007). The arguments in favor of RPLND for CS IIA–B are that (1) 13–35 % of patients have pathologically negative lymph nodes and thus avoid chemotherapy (Pizzocaro 1987; Donohue et al. 1995; Weissbach et al. 2000; Stephenson et al. 2007); (2) approximately 30 % have retroperitoneal teratoma that is resistant to chemotherapy (Foster et al. 1996; Stephenson et al. 2007); (3) long-term cancer-specific survival is 98–100 % with RPLND adjuvant chemotherapy (Pizzocaro 1987; Donohue et al. 1995; Weissbach et al. 2000; Stephenson et al. 2007); (4) 10–52 % avoid any chemotherapy (Pizzocaro 1987; Donohue et al. 1995; Weissbach et al. 2000; Stephenson et al. 2007); and (5) ejaculatory function is preserved in 70–90 % of patients (Richie and Kantoff 1991; Donohue et al. 1995; Weissbach et al. 2000). The disadvantages of RPLND are that (1) additional therapy is required in 48 % or more of patients, (2) 13–15 % have persistence of disease after RPLND and require a full induction chemotherapy regimen, and (3) high-quality RPLND may not be deliverable at all institutions (Weissbach et al. 2000; Stephenson et al. 2007). The arguments in favor of induction chemotherapy are that (1) 60–78 % of patients achieve a complete response and avoid PCS, (2) treatment can be delivered at community-based institutions, and (3) cancer-specific survival is 96–100 % (Peckham and Hendry 1985; Logothetis et al. 1987; Socinski et al. 1988; Ondrus et al. 1992; Horwich et al. 1994; Lerner et al. 1995; Culine et al. 1997; Debono et al. 1997; Weissbach et al. 2000; Stephenson et al. 2007). The disadvantages of chemotherapy are that (1) all patients are exposed to the risk of long-term toxicity of chemotherapy and (2) those who do not undergo postchemotherapy RPNLD are at risk of relapse with chemorefractory GCT. Given that 13–35 % of patients with CS IIA NSGCT have pathologically negative lymph nodes (thus, a false-positive CT result), patients with indeterminate lesions on staging abdominopelvic CT who are at otherwise low risk for metastatic disease may be observed closely initially to clarify subsequent treatment decisions. Treatment considerations for CS IIA–B NSGCT include the risk of occult systemic disease, risk of retroperitoneal teratoma, short– and long–term treatment-related morbidity, and need for double therapy. As with CS IS NSGCT, the presence of elevated postorchiectomy AFP and hCG is associated with an increased risk of systemic relapse after RPLND. Rabbani and associates (2001) reported relapses after RPLND in four of five patients (80 %) with elevated postorchiectomy AFP or hCG compared with 7 of 45 (16 %) patients with normal serum tumor markers. Stephenson and coworkers (2005b) identified the presence of elevated serum tumor markers (hazard ratio [HR] 5.6, P < .001) and retroperitoneal lymphadenopathy greater than 3 cm (hazard ratio [HR] 12.3, P < .001) as significant predictors of systemic relapse after RPLND in multivariable analysis adjusting for treatment year and the use of adjuvant chemotherapy. Thus, there is consensus that CS IIA–B NSGCT patients with elevated AFP or hCG or bulky lymph nodes (>3 cm) should receive induction chemotherapy.
Clinical Stage IIC and III NSGCT
Induction chemotherapy with cisplatin–based multiagent regimens is the initial approach used for the treatment of CS IIC and CS III NSGCT. As discussed previously, induction chemotherapy is also the preferred approach for CS IS and CS IIA-B with elevated postorchiectomy AFP and hCG. The specific regimen and number of cycles are based on the IGCCCG risk stratification (International Germ Cell Consensus Classification 1997). The development of cisplatin-based chemotherapy represents the most important advancement in the treatment of GCT. Before the identification of cisplatin, complete responses to chemotherapy were achieved in 10–20 % of patients and the cure rate was only 5–10 % (Einhorn 1990). Long-term cure is now anticipated in 80–90 % of patients with metastatic GCT. Randomized trials have evaluated the efficacy and safety of various drug combinations to determine the optimal regimen based on the IGCCCG risk (International Germ Cell Consensus Classification 1997). The initial landmark study was conducted at Indiana University using cisplatin–vinblastine–bleomycin (PVB 4) in the 1970s and reported complete responses in 74 % of patients and over 70 % long-term survivors (Einhorn 1990). When it was demonstrated that etoposide could cure some patients with relapse after PVB chemotherapy, PVB 4 was compared with bleomycin–etoposide–cisplatin (BEP 4) in a multicenter randomized trial. No significant difference in overall survival was seen between the two regimens (2-year survival 80 %, P = .11), but BEP 4 was associated with less neuromuscular toxicity and was subsequently adopted as the standard regimen (Williams et al. 1987a).
The treatment of relapsing NSGCTs depends on what treatment the patient has previously received and, in certain cases, the location of the relapse. Patients who have never received chemotherapy have a much more favorable prognosis than patients who have already been treated with chemotherapy for disseminated disease.
Clinical Stage I Seminoma
Generally, testicular cancer in the 80 % of patients with seminoma could be classified as CS I disease. During the last two decades, the treatment of these patients has changed a lot, and as regards surveillance, in particular radiotherapy and chemotherapy with single–agent carboplatin are now accepted among treatment options.
New studies have tried to reduce the burden’s therapy. Platin–based chemotherapy and infradiaphragmatic radiotherapy are connected to an increased danger of late cardiovascular toxicity and secondary malignant neoplasms (Zagars et al. 2004; Travis et al. 2005; van den Belt-Dusebout et al. 2007). Reducing target volume and dose has been investigated to decrease the toxicity of radiotherapy. Carboplatin is less neurotoxic, ototoxic, and nephrotoxic matched with cisplatin, but the risks of cardiovascular disease and secondary malignant neoplasms are widely unknown. In many cases, the short-term efficacy and safety of these approaches have been authenticated by randomized tests. With each of these modalities, the long–term cancer check approaches 100 %.
Until a short time ago, the pivot of therapy for CS I seminoma in the last 40 years had been primary radiotherapy to the retroperitoneum and ipsilateral pelvis, called dog-leg configuration. Published. The optimal radiation dose has not been determined, and most centers use 25–35 Gy in 15–20 daily fractions (Fossa et al. 1989a, 1999b; Warde et al. 1995). Long-term cancer-specific survival approaches 100 %, and progression-free chance between 95 and 97 % is reported (Fossa et al. 1989a, 1999b; Warde et al. 1995, 2005). In–field recurrence after dog–leg radiotherapy is less than 1 %, solving the need for daily/routine monitoring abdominopelvic CT imaging. Inguinal metastases are unusual in those without prior inguinal or scrotal surgery. The most usual/ordinary sites of recurrence are the thorax and left supraclavicular fossa. Practically all recurrences are cured with first–line chemotherapy. Select patients with isolated inguinal relapse may be saved with radiotherapy or surgical resection. The surveillance of patients after dog–leg radiotherapy is characterized by standard clinical assessment, chest radiography, and serum tumor markers. Most patients show some acute side effects with adjuvant radiotherapy, which generally include transient nausea, vomiting, and diarrhea that are regularly mild and self-limited. Acute grade II–IV hematologic toxicity happens in 5–15 % (Fossa et al. 1999b). Moderate and severe late gastrointestinal toxicity (usually chronic dyspepsia or peptic ulcer disease) is announced/indicated in 5 % and less than 2 % of patients, respectively. The testicular germinal epithelium is highly sensitive to ionizing radiation, and scatter dose to the contralateral testis may be very significative in spite of protective shielding. After dog-leg radiotherapy, persistent oligospermia is reported in 8 % (Fossa et al. 1999b). Given the long anticipated life expectance, the problem of late cardiac toxicity and secondary malignant neoplasms as regards these patients is principally germane. The actuarial risk of developing secondary malignant neoplasms is estimated to be 18 % at 25 years after radiotherapy for seminoma (Travis et al. 2005). The small but at the same time very important risk of pelvic recurrence requires the use of routine surveillance pelvic CT with the associated increased cost and radiation exposure (Brenner and Hall 2007). The MRC and the European Organisation for the Research and Treatment of Cancer (EORTC) also conducted a randomized test of 20-Gy versus 30-Gy PA radiotherapy for CS I seminoma (Jones et al. 2005). The 5-year relapse-free survival (96 % vs. 97 %) and total survival (99.6 % vs. 100 %) were alike, but patients receiving 20 Gy experienced less acute gastrointestinal toxicity, leukopenia, and lethargy (though outcomes were similar at 12 weeks). Further follow-up is necessary to estimate the durability/reliability of these results.
Given the potential for late toxicity with dog-leg radiotherapy, the 80–85 % cure rate after orchiectomy, and the more than 90 % cure rates achieved with platin-based chemotherapy for advanced seminoma, surveillance has been evaluated at several centers. In comparison with NSGCT, surveillance for CS I seminoma is much more difficult because of the inadequate role of serum tumor markers to identify relapse and the need for long–term surveillance CT because 10–20 % of relapses occur 4 years or more after diagnosis (Chung et al. 2002). The 5–year relapse–free survival ranges from 80 to 86 %, and cancer–specific survival approaches 100 %. Eighty–four to 100 % of patients experience relapse in the retroperitoneum, and 18–24 % of patients have bulky retroperitoneal disease and/or distant metastases at the time of recurrence (Horwich et al. 1992; von der Maase et al. 1993; Warde et al. 1995; Aparicio et al. 2003). Dog-leg radiotherapy is used for cure of relapse in 73–88 % of patients, and cure rates of 70–90 % are announced. Basically all patients who feel/test relapse of disease outside the retroperitoneum are cured with first-line chemotherapy. To locate and cure recurrences, in the initial phase patients on surveillance should be followed with clinical assessment, chest radiography, serum tumor marker evaluation, and abdominopelvic CT. Surveillance schedules employ rating every 2–4 months in years 1–3, every 6 months in years 4–7, and then annually therefore. The required frequency of CT is poorly defined, and centers perform this every 4–6 months in years 1–3, every 6 months in years 4–7, and then annually therefore. A recent MRC trial proposed that the frequency of surveillance CT in low-risk CS I NSGCT in years 0–2 may be safely decreased from 5 to 2 without affecting survival or burden of treatment (Rustin et al. 2007). It is not clear if these results can be safely enforced to surveillance for seminoma. Long-term follow-up is obligatory given the higher incidence of relapse after 5 years compared with NSGCT (Chung et al. 2002). In a pooled analysis of three large surveillance series from the 1980s, tumor size greater than 4 cm and invasion of the rete testis were significant predictors of relapse in multivariable analysis (Warde et al. 2002). Otherwise in NSGCT, LVI has not been acknowledged as a very important predictor of relapse for CS I seminoma. The 5-year relapse rate for patients with 0, 1, and 2 risk factors was 12, 16, and 32 %, respectively.
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