INTRODUCTION — Germ cell tumors (GCTs) account for 95 percent of testicular cancers and include both seminomas and nonseminomatous germ cell tumors (NSGCTs). Testicular sex cord-stromal tumors are the other predominant type of primary testicular malignancy (table 1). (See "Anatomy and pathology of testicular tumors".)
The epidemiology and risk factors for the development of testicular germ cell tumors are discussed here. The clinical presentation and diagnosis of testicular germ cell tumors are discussed separately. (See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors" and "Clinical features, diagnosis, and evaluation of gynecomastia in adults".)
EPIDEMIOLOGY
Incidence — Testicular cancer is the most common solid malignancy affecting males between the ages of 15 and 35. In the United States, approximately 9800 males are diagnosed with testicular cancer each year. Due to effective multimodality therapy, there are fewer than 500 deaths annually due to testicular cancer [1]. Most patients with testicular cancer present with disease confined to the testicle (stage I disease) [2]. (See "Treatment of stage I seminoma" and "Management of stage I nonseminomatous germ cell tumors".)
Worldwide, there are approximately 75,000 cases of testicular cancer and over 9000 deaths per year [3]. Geographic areas with the lowest incidence of testicular GCT in 2020 include Africa and Asia (age standardized incidence rate [ASIR] of 0 to 1.7), areas with an intermediate incidence include North America and Eastern Europe (ASIR of 1.7 to 5.8), and areas with the highest incidence include the Scandinavian countries, Western Europe, parts of South America, and Australia-New Zealand (ASIR of 5.8 to 13.2) [3].
The incidence of testicular cancer has been increasing globally [4-7], but the cause is unclear. As examples:
●In the United States, the overall incidence of testicular germ cell tumors (GCTs) among males rose 44 percent (from 3.35 per 100,000 males in the period from 1973 to 1978 to 4.84 per 100,000 males in the period from 1994 to 1998) [5]. The incidence of seminoma rose 62 percent, while the incidence of nonseminomatous germ cell tumors (NSGCTs) rose 24 percent. More patients with GCTs are also being diagnosed with localized disease over time (68 versus 55 percent in the 1970s) [8].
●In observational data from 12 European countries, the incidence of GCTs increased by 1 to 6 percent per year [4]. By contrast, mortality rates decreased or were stable in most regions, reflecting improvements in treatment.
Ethnicity — Testicular cancer is less common among Black Americans, as the incidence in this population is estimated to be one-fourth that of White Americans [9]. However, the incidence of testicular cancer in Black Americans may be increasing. In one observational study, the incidence of testicular cancer among Black Americans doubled between 1988 and 1992 and from 1998 to 2001 [10]. In this population, the increase in incidence was higher for seminoma than for NSGCT (124 versus 64 percent).
The incidence of testicular cancer is rising the fastest within the Hispanic American population [11]. There also appears to be a higher risk of death among Black Americans, Native Americans, Filipinos, Hawaiians, and Hispanic Americans with testicular cancer [12]. In an observational study of 16,086 cases of primary testicular cancer diagnosed from 1973 to 1999, these groups were initially diagnosed at more advanced disease stages. Even after adjustment for stage, histology, and period of diagnosis, the relative risk of dying from testicular cancer was higher for these groups when compared with non-Hispanic White Americans (1.4 to 3.6).
RISK FACTORS — Several risk factors are associated with the development of testicular cancer. Some risk factors predispose to the development of carcinoma in situ (CIS) and testicular germ cell tumors (GCTs), while others predispose to the development of other types of primary testicular malignancies (eg, certain genetic disorders are associated with increased incidence of sex cord stromal tumors).
Testicular and other genitourinary conditions
Germ cell neoplasia in situ — In adults, both seminomas and nonseminomatous germ cell tumors (NSGCTs) are preceded by a premalignant condition called germ cell neoplasia in situ (GCNIS). GCNIS has been identified in 0.4 to 1.1 percent of males undergoing testicular biopsy because of infertility but appears to be less common in the general population. (See "Testicular germ cell neoplasia in situ".)
GCNIS is found in testicular tissue adjacent to GCTs (except spermatocytic seminoma) in approximately 90 percent of adult cases [13]. It also is observed in all patient groups at risk for testicular cancer, including males with cryptorchid testicles (up to 5 percent) [13-15], prior or contralateral testicular GCTs (5 percent) [16-18], and syndromes of abnormal sex differentiation [13,19]. Although GCNIS can be present from birth, it typically does not become malignant until after puberty. These observations suggest the possibility of a field defect, in which genetic or developmental events that produce gonadal dysfunction confer a predisposition to malignancy over a wide area [20]. (See 'Contralateral testicular cancer' below and "Pathogenesis and clinical features of disorders of androgen action".)
If GCNIS is left untreated, the risk of progression to invasive malignancy is approximately 50 percent in five years [16]. Whether all cases of GCNIS eventually progress to invasive malignancy is unclear. (See "Testicular germ cell neoplasia in situ".)
Cryptorchidism — Males with cryptorchidism (undescended testicle) are at increased risk for testicular cancer. Approximately 10 percent of all testicular cancers occur in the setting of cryptorchidism. However, testicular malpositioning alone does not explain the increased risk of testicular cancer, as the normally descended testicle is involved in some patients with cryptorchidism and testicular cancer.
Surgical repositioning of the testis (orchiopexy) may decrease the risk of testicular cancer if performed prior to puberty [21]. Further details on cryptorchidism and testicular cancer risk are discussed separately. (See "Undescended testes (cryptorchidism) in children: Management", section on 'Testicular cancer'.)
Hypospadias — The incidence of testicular GCTs appears to be increased in males with a history of hypospadias, a congenital abnormality of the male urethra, foreskin, and penis that results in abnormal ventral placement of the urethral opening. In a health registry study from Denmark that included 5441 males with testicular GCTs, the incidence of cancer was significantly increased (relative risk 2.13, 95% CI 1.26-3.61) [22]. The risk of GCT is even higher for those with proximal hypospadias [23]. (See "Hypospadias: Pathogenesis, diagnosis, and evaluation".)
Contralateral testicular cancer — A small proportion (less than two percent) of males with testicular cancer will have a second (contralateral) testicular cancer, either at presentation or with a subsequent metachronous cancer [24,25].
In one observational study, 29,515 cases of testicular cancer in males under the age of 55 were reported to the United States National Cancer Institute (NCI) Surveillance, Epidemiology and End Results (SEER) program between 1973 and 2001 [24]. In this study, approximately 175 males presented with a synchronous contralateral cancer (0.6 percent). The 15-year cumulative risk of a contralateral (metachronous) testicular cancer was 1.9 percent, which is similar to that reported in other studies with long-term follow-up [26,27]. Observational data also suggest a decreased risk of metachronous contralateral testicular cancer among males whose primary testicular cancer was treated with platinum-based chemotherapy [27,28].
The incidence of second cancers is similar to the incidence of GCNIS seen in patients with unilateral testicular cancer who undergo a biopsy of the contralateral testicle at the time of orchiectomy. Males with contralateral GCNIS appear to be the group at primary risk for the development of contralateral testis cancer [16,18]. This was illustrated in a series of 500 patients with testicular GCTs in whom the contralateral testicle was biopsied at the time of orchiectomy [16]. Seven of 27 males with GCNIS developed later contralateral invasive cancer compared with none of the 473 without GCNIS. (See "Testicular germ cell neoplasia in situ".)
Extragonadal germ cell tumor — Males with extragonadal GCTs are at risk of developing both testicular GCNIS and invasive GCTs. The risk is most pronounced in those with retroperitoneal rather than mediastinal disease, and nonseminomatous histology. (See "Testicular germ cell neoplasia in situ", section on 'Extragonadal germ cell tumor' and "Extragonadal germ cell tumors involving the mediastinum and retroperitoneum".)
Family history of testicular cancer — A family history of testicular cancer is a potential risk factor for developing testicular cancer [29,30].
Among males with testicular GCT, approximately 1 to 3 percent have a family member with the disease, which suggests a potential hereditary predisposition [31-33]. The relative risk of testis cancer is increased 6- to 10-fold in the brothers or sons of a patient with testicular cancer [29,34-37]. Family and twin studies have suggested that the estimated heritability of testicular GCTs is as high as 49 percent [38]. The clinical and pathologic manifestations of testicular GCTs in these families appear to be similar to those seen in nonfamilial cases [39]. A few rare inherited disorders have been associated with an elevated risk of testicular cancer [40]. An increased risk of testicular cancer has also been suggested with certain candidate chromosomal regions [41-43]. As examples:
●Among families with testicular GCTs compatible with X-linked inheritance, a locus has been suggested on chromosome Xq27. This locus may also predispose to undescended testes and bilateral GCTs [42].
●Isochromosome 12p is present in most patients with testicular GCTs [44,45]. In a series of 179 analyzed cases of testicular GCT, abnormal karyotypes were present in 101 (59 percent), and 79 of these had the isochromosome 12p abnormality [45]. However, the role of this abnormality in familial GCTs is undefined. (See "Anatomy and pathology of testicular tumors", section on 'Molecular markers'.)
●MicroRNA 371a-3p (miR-371a-3p) is a universal molecular hallmark of GCTs regardless of age, site of origin, or sex. The role of miR-371a-3p in GCT tumorigenesis is unknown [46]. (See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors", section on 'Serum tumor markers'.)
●Moderate-risk and low-risk single nucleotide polymorphisms, identified through genome-wide association studies, are thought to explain approximately one-third of father-to-son familial risk for testicular GCT [38,47-49].
●DNA damage with deficient repair may be important in the development of testicular GCTs. Testicular GCTs are enriched for reciprocal loss of heterozygosity, a DNA double-strand break-enriched genomic signature. One observational study evaluated inherited DNA repair gene alterations in 205 unselected males with a testicular GCT. In this group, 20 males with 22 pathogenic germline DNA repair gene variants were identified, one-third of which were in the checkpoint kinase 2 (CHEK2) gene [50,51]. Furthermore, those individuals with the loss-of-function CHEK2 variants developed testicular GCT six years earlier than those with CHEK2 wild-type alleles.
Genetic disorders
Klinefelter syndrome — Klinefelter syndrome is associated with mediastinal extragonadal GCTs [52-54] and Leydig cell tumors. (See "Extragonadal germ cell tumors involving the mediastinum and retroperitoneum" and "Causes of primary hypogonadism in males", section on 'Klinefelter syndrome' and "Down syndrome: Clinical features and diagnosis", section on 'Urologic abnormalities'.)
Down syndrome — Down syndrome has been associated with testicular cancer [54,55]. (See "Extragonadal germ cell tumors involving the mediastinum and retroperitoneum" and "Causes of primary hypogonadism in males", section on 'Klinefelter syndrome' and "Down syndrome: Clinical features and diagnosis", section on 'Urologic abnormalities'.)
Peutz-Jeghers syndrome — Males with Peutz-Jeghers syndrome have an increased incidence of Sertoli cell testicular tumors. (See "Peutz-Jeghers syndrome: Clinical manifestations, diagnosis, and management" and "Testicular sex cord stromal tumors", section on 'Additional diagnostic evaluations'.)
Carney complex — Patients with Carney complex are at increased risk for developing Sertoli cell tumors [56]. Carney complex is an autosomal dominant disorder characterized by two major types of findings: pigmented lentigines and blue nevi on the face, neck, and trunk; and multiple tumors, both endocrine (testicular Sertoli cells and occasionally adrenal, pituitary, or thyroid) and nonendocrine (cutaneous, mammary, and atrial myxomas, and psammomatous melanotic schwannomas). Sex cord stromal tumors in Carney complex are often bilateral and multifocal [57]. (See "Carney complex" and "Testicular sex cord stromal tumors", section on 'Additional diagnostic evaluations'.)
Hormonal factors
Androgen insensitivity syndromes and mixed gonadal dysgenesis — Intersex individuals with androgen insensitivity syndrome or mixed gonadal dysgenesis are at high risk of GCNIS, and germinal and nongerminal neoplasms in cryptorchid gonads [58-60]. (See "Pathogenesis and clinical features of disorders of androgen action" and "Diagnosis and treatment of disorders of the androgen receptor" and "Testicular germ cell neoplasia in situ".)
In utero estrogenic effects — Studies suggest that higher exposure to estrogenic compounds in utero increases the risk of testicular GCT. In one case-control study, exposure to exogenous estrogens in utero was associated with a 4.9-fold increase in the risk of testicular GCT [61]. However, a similar association was not observed for malignant GCTs arising in children younger than 15 years [62].
Additional, indirect evidence supporting a role for hormonal influences comes from a case-control study that found increased blood levels of organochlorine pesticides in males with testicular GCTs compared with matched controls [63]. These persistent pesticides are known to bind to estrogen receptors, and exposure in utero or early in life may contribute to the risk of testicular GCTs.
The role of diethylstilbestrol in the development of testicular cancer is controversial. Further details are discussed separately. (See "Outcome and follow-up of diethylstilbestrol (DES) exposed individuals", section on 'Testicular and prostate cancers'.)
Lifestyle factors
Marijuana (cannabis) — Studies suggest an association between marijuana (cannabis) and the risk of testicular GCTs. In several meta-analyses, the risk of testicular GCT was twice as high among those using marijuana on a regular basis (either frequently [ie, at least weekly] or chronically [ie, for more than 10 years]) versus those who never used marijuana [64,65]. Another study in Swedish military conscription recruits found a similar increase among those with heavy marijuana use [66].
Other factors
Testicular microlithiasis — The relationship between testicular microlithiasis (microcalcifications) and testicular malignancy is controversial, in part because microlithiasis is most frequently identified in males who are assessed because of testicular symptoms. Microlithiasis is usually found by scrotal ultrasonography, as diffuse echogenic foci within the seminiferous tubules [67]. (See "Screening for testicular cancer" and "Screening for testicular cancer", section on 'Risk factors'.)
The relationship between testicular microlithiasis and testicular malignancy was evaluated in a systematic review and meta-analysis of 33 reports in which males had been referred for testicular ultrasound [68]. Among the 1347 males with testicular microlithiasis, the incidence of testicular GCTs or GCNIS was higher than those without testicular microlithiasis (risk ratio 8.5, 95% CI 4.5-16.1).
Other data suggest that patients with testicular microlithiasis as well as features of testicular dysgenesis syndrome (cryptorchidism, infertility, contralateral GCT, disorder of sex development) are at the highest risk of developing testicular cancer [69,70].
However, the utility of this observation is limited, since the relatively high frequency of microlithiasis in healthy young males precludes using this finding as a screening tool for testicular cancer. In population-based screening studies, the incidence of microlithiasis ranges between 2.4 and 5.6 percent, which exceeds the incidence of testicular cancer in healthy young males by approximately 1000-fold [71,72]. Furthermore, the incidence of microlithiasis appears to be higher when more sensitive equipment is used to perform the examinations [73].
HIV infection — An increased incidence of testicular GCTs, particularly seminomas, has been described in males living with human immunodeficiency virus (HIV) compared with males living without HIV infection. In a meta-analysis of seven studies with over 440,000 males with acquired immunodeficiency syndrome (AIDS) or HIV infection, there was a modest increase in the incidence of testicular cancer compared with the general population (standardized incidence ratio of 0.7 to 1.8) [74]. The increase was limited to seminomas and did not impact the incidence of nonseminomatous GCTs [75-77]. (See "HIV infection and malignancy: Management considerations", section on 'Testicular neoplasms'.)
Infertility — Data suggest that male infertility is a potential risk factor for the development of testicular cancer, even in the absence of conditions such as cryptorchidism that are associated with both infertility and testicular cancer. Further details are discussed separately. (See "Causes of male infertility", section on 'Association with testicular cancer'.)
Lack of risk with vasectomy — Vasectomy is not a risk factor for testicular cancer. This is discussed separately. (See "Vasectomy", section on 'Testicular cancer'.)
SUMMARY
●Epidemiology – Testicular cancer is the most common solid malignancy affecting males between the ages of 15 and 35. The incidence of testicular cancer has been increasing globally, but the cause is unclear. (See 'Epidemiology' above.)
●Risk factors – Risk factors that are associated with the development of testicular cancer include (see 'Risk factors' above):
•Germ cell neoplasia in situ – In adults, both seminomas and nonseminomatous germ cell tumors (GCTs) are preceded by a premalignant condition called germ cell neoplasia in situ (GCNIS). If GCNIS is left untreated, the risk of progression to invasive malignancy is approximately 50 percent in five years. Whether all cases of GCNIS eventually progress to invasive malignancy is unclear. (See 'Germ cell neoplasia in situ' above.)
•Cryptorchidism – Males with cryptorchidism are at increased risk for testicular cancer. Surgical repositioning of the testis (orchiopexy) may decrease the risk of testicular cancer. (See 'Cryptorchidism' above and "Undescended testes (cryptorchidism) in children: Management", section on 'Testicular cancer'.)
•Contralateral testicular cancer – Less than two percent of males with testicular cancer will have a second (contralateral) testicular cancer, either at presentation or with a subsequent metachronous cancer. (See 'Contralateral testicular cancer' above.)
•Family history of testicular cancer – A family history of testicular cancer is a potential risk factor for developing testicular cancer. (See 'Family history of testicular cancer' above.)
•Genetic disorders – Klinefelter syndrome is associated with the development of testicular GCTs and Leydig cell tumors (a testicular sex cord stromal tumor). Down syndrome is associated with increased risk of testicular tumors. Peutz-Jeghers syndrome and Carney complex are associated with the development of Leydig cell tumors. (See 'Genetic disorders' above and "Testicular sex cord stromal tumors".)
•Other factors – Other conditions potentially associated with an increased risk of testicular cancer include testicular microlithiasis, HIV infection, infertility, hormonal, and lifestyle factors, among others. However, these factors generally have a limited impact on the total incidence of testicular cancer. (See 'HIV infection' above and 'Hormonal factors' above and 'Genetic disorders' above and 'Lifestyle factors' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges William K Oh, MD, who contributed to earlier versions of this topic review.
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