Testicular germ cell neoplasia in situ

INTRODUCTION — Testicular germ cell neoplasia in situ (GCNIS; formerly known as intratubular germ cell neoplasia of the unclassified type [1]) is typically a precursor of testicular germ cell tumors (GCTs) in adult males (except for spermatocytic tumors [ie, spermatocytic seminomas]) as well as yolk sac tumors and mature teratomas in infants. However, GCNIS is not an epithelial lesion, and thus, the term "germ cell carcinoma in situ" is not used. GCNIS is noninvasive because the neoplastic cells are confined within the seminiferous tubules. (See "Anatomy and pathology of testicular tumors", section on 'Germ cell neoplasia in situ'.)

The epidemiology and risk factors, clinical presentation, diagnosis, and management of GCNIS is discussed here. Other related topics include:

●(See "Epidemiology and risk factors for testicular cancer".)

●(See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors".)

PATHOGENESIS — GCNIS is found in the testicular tissue adjacent to testicular germ cell tumors (GCTs) in more than 90 percent of adults with testicular cancer [2,3]. It can also be found in individuals at high risk for testicular cancer, including males with cryptorchid testes [4-6], prior testicular cancer development [7-9], and in individuals with abnormal sexual differentiation [4,10]. However, GCNIS is not found in patients with childhood forms of testicular GCT [11,12], and there is no clear association between GCNIS and testicular GCTs in prepubertal males.

The prevalence of GCNIS in these populations mirrors that of GCTs; this reproducible observation has contributed significantly to the theory that GCNIS is the precursor of GCTs [13,14]. These observations also suggest there is a field defect in which genetic or developmental events that produce gonadal dysfunction predispose both gonads to malignancy [15].

GCNIS cells are derived from primordial germ cells and are believed to be present at birth [16,17]. As an example, testicular GCNIS has been found in infants as young as one month old [16,18]. Although the exact developmental stage that GCNIS arises is controversial, the 8th through 12th weeks of gestation are the focus of much attention. Two proteins, the c-kit receptor (KIT) and placental-like alkaline phosphatase (PLAP), are overexpressed by GCNIS cells; these and other markers are expressed by fetal germ cells only between the 8th and 12th week of development [19-21]. Furthermore, prolonged expression of c-kit has been found in the fetal testes of intersex individuals who are at high risk of developing early testis tumors [22]. (See 'Immunohistochemistry' below and 'Androgen insensitivity syndromes or mixed gonadal dysgenesis' below.)

The high incidence of testis cancer in males with cryptorchidism and other congenital errors of gonadal development points to intrauterine factors as playing an important role in the transformation of germ cells to GCNIS. During this period, which may be a crucial step in germ cell differentiation, either genetic factors (eg, gonadal dysgenesis) or environmental influences (eg, the estrogenic milieu) may lead germ cells to acquire malignant potential [18].

The altered hormonal environment during puberty may cause GCNIS cells to begin to replicate [16]. Initially, GCNIS spreads longitudinally in a noninvasive fashion along the seminiferous tubules. Upon reaching the rete testis, GCNIS cells spread to other tubules.

At some point following puberty, GCNIS becomes "invasive" (penetrating the basement membrane); however, invasion of the basement membrane is not synonymous with either seminomatous or nonseminomatous GCTs. The specific factors that lead to initiation and promotion of invasiveness have not been elucidated.

The GCNIS cell appears to be the precursor of all of the different phenotypic varieties of testicular GCTs, except spermatocytic tumors (also known as spermatocytic seminomas) in older adult males as well as yolk sac tumors and mature teratomas in young children [14,16,23]. Morphologically, GCNIS cells resemble seminomas more closely than nonseminomatous GCT. Although it was originally thought that the GCNIS cell progressively differentiated into seminoma and then into a nonseminomatous GCT, most now believe that GCNIS can progress along two different pathways, either from seminoma to nonseminomatous GCT [24] or from GCNIS into a nonseminomatous GCT directly [23,25]. This may result from the gradual loss of stem cell potential of the GCNIS cell with increasing age [18]. The infrequently termed "intratubular seminoma" (characterized by a GCNIS appearance without interspersed Sertoli cells) may not usefully be discriminated from GCNIS and should not be included in classifications of in situ disease, as both entities may be associated with either category of GCT [26].

NATURAL HISTORY — The natural history of GCNIS may or may not be progression to invasive germ cell tumor (GCT) including seminoma or nonseminomatous GCT, although rare reports exist of "burned out" GCNIS [14]. The frequency and rate of progression are variable. Studies performed in infertile males and in those with unilateral testicular tumors undergoing contralateral testis biopsy suggest that 50 percent of such individuals, if untreated, develop "invasive" tumors within five years [5,7] and 70 percent within seven years. However, "invasion" is defined as invasion of the basement membrane, which is distinctly different from actual testicular cancers.

EPIDEMIOLOGY AND RISK FACTORS — The incidence of GCNIS varies significantly between the general population and other populations at increased risk for testicular cancer. (See "Epidemiology and risk factors for testicular cancer", section on 'Risk factors'.)

Identified risk factors for GCNIS include:

●Contralateral testicular germ cell tumor (GCT) – (See 'Contralateral germ cell tumor' below.)

●Extragonadal GCT – (See 'Extragonadal germ cell tumor' below.)

●Cryptorchid testis (regardless of orchidopexy) – (See 'Cryptorchidism' below.)

●Infertility – (See 'Infertility' below.)

●Androgen insensitivity or mixed gonadal dysgenesis – (See 'Androgen insensitivity syndromes or mixed gonadal dysgenesis' below.)

General population

●Incidence of GCNIS – Based on available data, the incidence of GCNIS in the general population ranges between 0.4 and 0.8 percent [13,27-29].

•In a pathological study of 1388 otherwise-healthy males from Germany who died unexpectedly and underwent bilateral testicular biopsy at autopsy, the rate of GCNIS was 0.4 percent [13]. This rate of GCNIS was also comparable with the lifetime risk of GCT in the male population of Germany.

•In another pathological study of 399 Danish males who died unexpectedly between ages 18 and 50, there were no cases of GCNIS on testicular biopsy at autopsy [29]. However, three individuals had been previously treated for testicular tumor or GCNIS. Thus, the overall prevalence of testicular GCNIS was 0.8 percent, comparable with the lifetime risk of testicular cancer in the male population of Denmark.

●Impact of testicular cancer incidence on diagnosis and management of GCNIS – However, the incidence of testicular GCT in the patient's treatment area often influences the diagnosis and management of GCNIS, since it impacts the level of concern about the progression of GCNIS to invasive testicular cancer. (See 'Indications for testicular biopsy' below and 'Management' below.)

Geographic areas with the lowest incidence of testicular GCT include Africa and Asia (age-standardized incidence rate [ASIR] of 0 to 1.7), areas with 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) [30]. (See "Epidemiology and risk factors for testicular cancer", section on 'Incidence'.)

Contralateral germ cell tumor — Individuals with testicular GCT are at risk of having GCNIS in the contralateral testis. In an observational series from Denmark and Germany of males with unilateral testicular GCT who underwent contralateral testis biopsy, the frequency of detecting GCNIS was 5 to 6 percent [7,8,31]. Other systematic reviews suggest an incidence of GCNIS in the contralateral testicle that ranges between 4 and 8 percent [32].

However, the incidence of GCNIS in the contralateral testis of males with unilateral testis cancer substantially exceeds the lifetime risk of contralateral testis cancer. This suggests that GCNIS may be necessary but by itself is insufficient for the development of contralateral testicular cancer. Among patients with unilateral testicular cancer, the estimated incidence of bilateral testis cancer is approximately 1 to 2 percent in American males [33] and 2 to 4 percent in European males [34-36]. (See "Epidemiology and risk factors for testicular cancer", section on 'Germ cell neoplasia in situ'.)

Extragonadal germ cell tumor — Among males with extragonadal GCTs, up to 50 percent have GCNIS in one or both testes [37]. These findings suggest that some extragonadal GCTs and testicular GCTs may have a common cell origin, or there may be a common stimulus for malignant transformation of primordial germ cells in both locations. However, it is known that extragonadal GCTs, particularly mediastinal nonseminomatous GCTs, usually have poorer prognosis than those with testicular GCT. (See "Extragonadal germ cell tumors involving the mediastinum and retroperitoneum".)

Cryptorchidism — Cryptorchidism (ie, undescended testis) refers to a testis that is not within the scrotum and cannot be manipulated manually to be within the scrotum by the age of one year. A history of cryptorchidism is the best-established risk factor for GCNIS and invasive testicular cancer. (See "Undescended testes (cryptorchidism) in children: Clinical features and evaluation" and "Undescended testes (cryptorchidism) in children: Management".)

The prevalence of GCNIS in cryptorchid testes is age-dependent and is approximately 5 percent [28]. The diagnosis of GCNIS is usually established in postpubertal testes. It is difficult to establish in prepubertal testes because GCNIS cells resemble normal infantile gonocytes. (See 'Diagnosis' below.)

A history of cryptorchidism increases the risk of testicular cancer; it is highest in those with an intra-abdominal undescended testicle. Early surgical correction may reduce the incidence of testicular cancer. Twenty-five percent of such GCT cases occur in the contralateral, normally descended testicle. (See "Epidemiology and risk factors for testicular cancer", section on 'Cryptorchidism'.)

It is unclear whether all cases of GCNIS in an undescended testicle progress to cancer. In one Swiss study, placental-like alkaline phosphatase (PLAP)-positive germ cells morphologically identical to adult GCNIS cells were found in 5 percent of prepubertal males with cryptorchidism undergoing orchidopexy [38]. After two decades of follow-up, none of these males developed testicular cancer, strongly suggesting that GCNIS does not inevitably progress, at least during this time period.

Because of the possible bleeding and other complications, a biopsy of the contralateral normal testicle at the time of orchidopexy is not performed. Instead, most experts in testicular cancer and pediatric urologists advocate patient education and self-examination to monitor for malignancy in the undescended testis.

Infertility — Testicular GCNIS is commonly associated with abnormalities in spermatogenesis and Leydig cell dysfunction [39], and males with impaired fertility are more likely to develop testicular cancer than other males with normal fertility [40,41]. In one series of 32,442 males undergoing semen analysis, 89 cases of testicular cancer were diagnosed; the standardized incidence ratio was 1.6 (95% CI 1.3 to 1.9) compared with the expected number of testicular cancers in the Danish male population [40]. (See "Epidemiology and risk factors for testicular cancer".)

Although systematic screening has not been performed, the incidence of GCNIS in males undergoing fertility evaluation has been approximately 1 percent or less [42-44].

Androgen insensitivity syndromes or mixed gonadal dysgenesis — Individuals with androgen insensitivity syndrome (individuals with 46XY chromosomes and mutations of the androgen receptors) or mixed gonadal dysgenesis are at risk for GCNIS as well as germinal and nongerminal neoplasms in cryptorchid gonads [45-48]. In this population, the frequency of GCNIS is approximately 5 to 10 percent [49,50]. (See "Pathogenesis and clinical features of disorders of androgen action" and "Diagnosis and treatment of disorders of the androgen receptor".)

CLINICAL PRESENTATION — For patients without an associated germ cell tumor (GCT), GCNIS is asymptomatic since GCNIS does not form a mass lesion in the affected testis. The testis harboring GCNIS is palpably normal on physical examination and typically appears normal on imaging studies.

Serum markers for GCTs, such as alpha-fetoprotein (AFP), beta subunit of human chorionic gonadotropin (beta-hCG), and lactate dehydrogenase (LDH), are not elevated in patients with GCNIS unless an invasive GCT is also present. (See "Serum tumor markers in testicular germ cell tumors".)

DIAGNOSIS

Testicular biopsy — The diagnosis of GCNIS is based on the identification of neoplastic germ cells in a testicular tissue specimen (either a testicular biopsy or orchiectomy specimen) [51]. Because other benign conditions can mimic GCNIS, the pathological diagnosis of GCNIS should be stringently confirmed based on histology as well as positive immunohistochemistry (IHC) markers. Imaging studies are not specific or diagnostic for GCNIS, although they may suggest the need for biopsy.

Indications for testicular biopsy

Patients without testicular GCT — In individuals without testicular germ cell tumor (GCT), testicular biopsy is rarely performed to diagnose GCNIS. Possible indications for a testicular biopsy include conditions that significantly increase the risk for testicular GCT, such as gonadal dysgenesis. (See 'Androgen insensitivity syndromes or mixed gonadal dysgenesis' above.)

More commonly, GCNIS is identified as an incidental finding on testicular needle core biopsy performed for infertility evaluation. However, the incidence of GCNIS in this population is extremely low (1 percent). (See 'Infertility' above.)

Testicular biopsies are typically not performed for patients with a testicular mass. The evaluation of a testicular mass concerning for testicular cancer or other nonacute scrotal conditions is discussed separately. (See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors", section on 'Diagnostic evaluation' and "Nonacute scrotal conditions in adults".)

Patients with testicular GCT — In patients who present with a unilateral testicular GCT, it is controversial whether (or not) to perform a diagnostic contralateral testicular biopsy for GCNIS. (See 'General population' above.)

●Surveillance of the contralateral testicle (no biopsy) – In most patients, an immediate contralateral testicular biopsy to detect GCNIS is not offered, particularly in areas with a lower incidence of testicular GCT (eg, North America). For such patients, the standard of care is surveillance of the contralateral testicle as part of routine posttreatment follow-up for testicular GCT. (See "Posttreatment follow-up for testicular germ cell tumors".)

The rationale for surveillance is that the risk of progression from GCNIS to GCT is variable among those who do not undergo contralateral testicular biopsy (see 'Natural history' above). In addition, the risk of developing a contralateral testicular cancer is extremely low (1 to 4 percent) [33-36]. The rare patient who develops a metachronous primary GCT in the contralateral testicle also has an extremely favorable prognosis using available treatments, with five-year overall survival (OS) of 95 percent or more. It is also unclear whether patients with GCNIS require treatment, and there are concerns about the impact of such treatment on survival and quality of life. In particular, biopsy and subsequent treatment of GCNIS in the contralateral testis are associated with hypogonadism and infertility [32].

●Immediate contralateral testicular biopsy – In areas with a higher incidence of testicular GCT (eg, Scandinavian countries and some European countries), a contralateral testicular biopsy to detect GCNIS may sometimes be offered at the time of primary orchiectomy, especially to patients at high risk of developing a second GCT. In these areas, studies report a higher incidence of GCNIS in the contralateral testes of individuals with a unilateral testicular GCT (5 to 6 percent) [7,31].

The rationale for biopsy is to potentially avoid more extensive therapy for advanced cancer should a contralateral testicular GCT arise, rather than an improvement in OS [52]. However, at a 2018 European Society for Medical Oncology (ESMO) consensus conference on testicular cancer, there was no consensus amongst experts in Europe as to whether a contralateral biopsy should be carried out due to lack of data demonstrating that this diagnostic approach confers an OS benefit [53]. They recommended to discuss this diagnostic strategy with patients at high risk of developing a second GCT (eg, those less than 40 years old with small atrophic testis and/or microlithiasis).

Contralateral testicular biopsy, if obtained, may be performed by a urologist at the same time as the primary orchiectomy for the testicular GCT, once a frozen section has demonstrated testicular cancer within the orchiectomy specimen. All patients who undergo testicular biopsy should be offered sperm banking.

Management based on the results of the testicular biopsy is discussed below. (See 'Testicular GCT and GCNIS in the contralateral testicle' below.)

Obtaining and processing the specimen — An appropriate testicular biopsy should be at least 3 by 3 mm in size and should contain at least 40 tubules on histological cross-section to represent the entire testis [14]. With an appropriate biopsy, the risk of a false-negative result and the development of subsequent cancer have been reported to be less than 0.5 percent [54,55]. GCNIS is a multifocal rather than diffuse process. Therefore, there will be a higher chance of a false negative (ie, missing the lesion) when using a relatively small biopsy.

Given the possibility that small, single biopsies might miss foci of GCNIS, some authors have recommended larger specimens or double biopsies, although this practice has not been widely established. A study of 2318 patients from Germany noted an 18 percent increase in diagnostic yield with a second biopsy as well as a 31 percent discordance among biopsy pairs from the same testicle [56]. Needle core biopsy and fine needle aspiration (FNA) should not substitute for an adequate testicular biopsy [57].

The pathological diagnosis of GCNIS is usually established on light microscopic examination of testicular tissue with or without IHC staining. Proper fixation of the biopsy specimen is crucial. Formalin may not be the best fixative for preservation of the cell morphology, but it is acceptable for the diagnosis of GCNIS. Although other fixatives including Bouin or Stieve solutions may provide better cell morphology, they may interfere with immunoreactivity of some markers [58,59].

Histological appearance — Histologically, testicular GCNIS is characterized by proliferation of enlarged neoplastic germ cells with large hyperchromatic nuclei, often one or two prominent nucleoli, and clear cytoplasm (picture 1A), which gives the appearance of "fried eggs." Sertoli cells are often displaced luminally. Affected seminiferous tubules almost always lack active spermatogenesis and usually have thickened peritubular basement membranes. The interstitium may show hyperplasia of the Leydig cells. It is common for GCNIS to spread into the rete testis in a pagetoid fashion [14].

A negative biopsy performed before puberty does not exclude a subsequent risk of testicular cancer. Although GCNIS can be occasionally seen in the testes of prepubertal individuals, the histological diagnosis can be challenging because normal infantile gonocytes resemble GCNIS cells.

Immunohistochemistry — IHC can help to establish the diagnosis of GCNIS [58]. Immunohistochemically, GCNIS cells share many characteristics of testicular GCT cells. Some of the markers seen in GCNIS can be found in invasive testicular GCTs. Therefore, these markers can only be used to distinguish GCNIS from benign testicular conditions and not from other invasive GCTs.

●Placental-like alkaline phosphatase (PLAP) – PLAP is one of the most sensitive but least specific markers for GCNIS since this enzyme is detected in almost all subtypes of neoplastic germ cells (GCNIS, seminoma, and nonseminomatous GCTs) but usually not in normal germ cells, except at the embryonal stage. Approximately 98 percent of cases of GCNIS can be diagnosed with positive PLAP staining [60]. (See 'Pathogenesis' above.)

●Octamer binding transcription factor 4 (OCT4) – Another useful diagnostic marker is OCT4 (also called POU domain class 5 transcription factor 1, or POU5F1). OCT4 is expressed in embryonic stem and germ cells and is involved in the initiation, maintenance, and differentiation of pluripotent and germline cells during normal development. In the adult testis, positive immunostaining for this marker is a strong indicator of the presence of GCNIS, seminomas (other than spermatocytic tumor [spermatocytic seminoma]), or embryonal carcinoma [61,62]. Other subtypes of GCTs, such as yolk sac tumor, choriocarcinoma, and mature and immature teratomas, do not show OCT4 immunoreactivity.

●C-kit (CD117) – C-kit (CD117), a tyrosine kinase receptor, is another useful marker because its immunoreactivity can be seen in GCNIS and seminoma. Other nonseminomatous GCTs [19] or benign germ cells and sex stromal cells in the adult testis do not show the distinct membranous c-kit immunostaining (picture 1B).

●Other markers – Other monoclonal antibodies, including M2A, 43/9F, and TRA-1-60, that recognize common epitopes shared by GCNIS and GCT have been reported as helpful stains for GCNIS with high sensitivities in the literature [63-65]. However, immunostaining with these antibodies is not used in routine clinical practice, possibly due to heterogeneous or inconsistent staining patterns in GCNIS [23].

For patients with an isolated GCNIS (ie, GCNIS without a diagnosis of GCT), the diagnosis should be stringently confirmed through histology as well as appropriate IHC markers. As an example, in preliminary results from a cohort of 117 non-neoplastic orchiectomy specimens obtained from patients undergoing gender-affirming surgery, no cases of GCNIS were detected [66]. However, most specimens demonstrated occasional "pseudoneoplastic germ cells," which are part of the differential diagnosis of GCNIS. Pseudoneoplastic germ cells are non-neoplastic germ cells with atypical nuclear features in atrophic tubules. These scattered atypical germ cells exhibit large nuclei ranging from 14 to 18 nm in diameter, histologically mimicking GCNIS. However, these cells were determined to be non-neoplastic due to their distribution patterns and negative IHC staining for CD117 and OCT4.

Cytogenetic abnormalities — Abnormalities involving the short arm of chromosome 12, both isochromosome 12 p [i(12p)] and gain of 12p sequences, are the most common chromosomal changes found in testicular germ cell neoplasia, including GCNIS [67]. (See "Anatomy and pathology of testicular tumors", section on 'Molecular markers'.)

Noninvasive testing — These noninvasive tests are promising for diagnosis of GCNIS in the future, particularly as a diagnostic strategy in prepubertal males and high-risk groups, but their clinical utility remains to be established. The limitation of these nontissue-based tests is the difficulty to distinguish GCNIS from seminoma even with a positive result.

●Imaging studies – Imaging studies have a limited role in the diagnosis of GCNIS. In high-risk populations, an irregular echo pattern on testicular ultrasound is used to exclude a hypoechoic lesion that may represent a GCT [68,69]. In one observational series of 78 males with unilateral testis cancer, testicular ultrasound preceded biopsy of the contralateral testis [70]. Eight of nine males with GCNIS had an irregular or coarse echogenic pattern. However, the predictive value of this imaging finding for GCNIS was only 22 percent.

●Semen evaluation – Semen evaluation for abnormal cells is an evolving technique. Characteristic malignant germ cells can be detected in the semen of males with GCNIS using IHC, deoxyribonucleic acid (DNA) flow cytometry, and DNA in situ hybridization [71,72]. In addition, both i(12p) and overrepresentation of 12p sequences have been demonstrated in the semen of males with GCNIS by fluorescence in situ hybridization [73].

MANAGEMENT — For most patients with a confirmed diagnosis of GCNIS (either with or without a concomitant diagnosis of testicular germ cell tumor [GCT]), we suggest surveillance rather than initiating therapy for GCNIS. However, treating the testicle containing GCNIS with either orchiectomy (only for those with isolated GCNIS and a well-functioning contralateral testicle) or low-dose radiation therapy (RT) is an alternative, particularly in areas with a high incidence of testicular GCT. Since management is controversial and patient preference is also important, clinicians should offer a risk-benefit discussion on available management strategies. All patients with GCNIS should be instructed in testicular self-examination.

Isolated GCNIS (no testicular GCT) — The clinical scenarios where an individual with no concurrent testicular GCT may be diagnosed with isolated GCNIS are discussed separately. (See 'Patients without testicular GCT' above.)

Management is controversial for patients with a confirmed diagnosis of isolated GCNIS. Although concern exists that GCNIS may progress to invasive testicular GCT, the precise risk and latent period are unclear. Therefore, treatment may be influenced by the incidence of testicular GCT in the area and the practice of the treating institution. (See 'General population' above and "Epidemiology and risk factors for testicular cancer", section on 'Incidence'.)

●Unilateral GCNIS – Most patients with an isolated, unilateral diagnosis of GCNIS are offered surveillance alone, particularly in areas with a low incidence of testicular GCT. Few patients with GCNIS will progress to invasive testicular GCT. In addition, therapy for GCNIS has substantial side effects, including possible fertility issues.

By contrast, in some areas with a higher incidence of testicular GCT, patients with unilateral GCNIS and a well-functioning contralateral testicle are more likely to be offered orchiectomy or low-dose RT [54]. In these areas, it is routine practice to treat GCNIS because of the concern for the development of an invasive testicular GCT [34-36,52].

●Bilateral GCNIS or GCNIS in a solitary testis – For patients with bilateral GCNIS or those with only one testicle who are diagnosed with GCNIS (ie, GCNIS in a solitary testis), options include surveillance or low-dose RT to the affected testicle(s).

Low-dose RT (18 to 20 Gy) can eradicate GCNIS [28], as evidenced by postradiation biopsies revealing only Sertoli cells [74,75]. However, approximately one-third of patients will develop hypogonadism after RT and require hormone replacement therapy [76]. Although lowering the radiation dose to 14 or 16 Gy decreases the incidence of infertility and may preserve testosterone production [77,78], studies have reported relapse of GCNIS with these doses [32,79,80]. (See "Testosterone treatment of male hypogonadism".)

Surveillance is an option as well, but requires patient compliance with follow-up visits (including history, physical examination, and testicular examination by their clinician) and periodic self-testicular examination [28].

Testicular GCT and GCNIS in the contralateral testicle — In patients with testicular GCT, there are divergent approaches to managing GCNIS in the contralateral testicle, which is often based upon the incidence of testicular GCT in the treatment area and the practice of the treating institution.

The divergence in management begins at the decision to perform a diagnostic biopsy for GCNIS. In most patients with testicular GCT, a diagnostic contralateral testicular biopsy to detect GCNIS is not offered, and surveillance of the contralateral testicle is standard of care, particularly in areas where the incidence of testicular GCT is generally low. By contrast, in some areas where the incidence of testicular GCT is higher, diagnostic contralateral testicular biopsy to detect GCNIS may sometimes be performed. Further details are discussed separately. (See 'Patients with testicular GCT' above.)

For those who undergo a testicular biopsy, further management is as follows:

●Negative biopsy – The absence of GCNIS should provide assurance that the patient's cancer risk is not elevated above that of the general population, as the false-negative rate is less than 0.5 percent. Such patients may undergo routine posttreatment follow-up for testicular GCT. (See 'Obtaining and processing the specimen' above and "Posttreatment follow-up for testicular germ cell tumors".)

●Positive biopsy – If GCNIS is identified in the contralateral biopsy specimen, options include surveillance or low-dose RT (18 to 20 Gy) to the contralateral testicle with GCNIS.

Surveillance is one appropriate management strategy for managing GCNIS in the contralateral testicle of patients with testicular GCT. The overall risk of developing a contralateral testicular cancer is extremely low (between 1 to 4 percent, depending upon the region [33-36]). Patients who develop a metachronous second primary testicular cancer in the contralateral testicle have an extremely favorable prognosis using available treatments. Additionally, treatment of GCNIS with low-dose RT the contralateral testicle is associated with higher rates of hypogonadism and infertility than platinum-based chemotherapy [32,81].

By contrast, low-dose RT may be preferred in areas/institutions with a higher incidence of testicular GCT, since it is associated with higher rates of eradicating GCNIS compared with platinum-based chemotherapy and presumably reduces the risk of developing a subsequent testicular malignancy [32,81]. A systematic review of 11 studies (including nine retrospective studies and two multicenter clinical trials) evaluated various treatment approaches for GCNIS in patients with primary testicular GCT of varying stages, histologies, and treatment approaches [32]. Management for GCNIS in the contralateral testicle included surveillance, low-dose RT (18 to 20 Gy), and platinum-based chemotherapy. Outcomes by management strategy for GCNIS were as follows:

●Low-dose RT was associated with improved eradication of GCNIS on follow-up biopsies (0 to 2.5 percent) relative to chemotherapy (median of 30 percent) and surveillance (50 percent) [32,81].

●Among patients treated with chemotherapy, cisplatin-based chemotherapy was associated with improved eradication rates versus carboplatin-based chemotherapy, and three cycles of cisplatin-based chemotherapy were associated with improved eradication rates versus two cycles. This is in contrast to other studies, which suggest that the effect of chemotherapy on GCNIS is unpredictable and usually temporary [82-84].

●Among the studies that reported treatment-related hypogonadism, platinum-based chemotherapy was associated with lower rates of hypogonadism (13 to 20 percent) than low-dose RT (30.8 to 38.5 percent) [32,81].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Testicular cancer".)

SUMMARY AND RECOMMENDATIONS

●Definition – Germ cell neoplasia in situ (GCNIS) is typically a precursor of testicular germ cell tumors (GCTs) in adults (except for spermatocytic tumors [ie, spermatocytic seminomas]) and yolk sac tumors and mature teratomas in prepubertal children. GCNIS is found in the testicular tissue adjacent to a testicular GCT in more than 90 percent of adults with testicular cancer. (See 'Introduction' above and 'Pathogenesis' above.)

●Epidemiology – The incidence of GCNIS in the general population ranges between 0.4 and 0.8 percent. However, the incidence of testicular GCT varies by geographic location, which may impact the management of GCNIS. (See 'General population' above.)

●Risk factors – Risk factors for GCNIS include a contralateral or extragonadal GCT, cryptorchidism, infertility, and androgen insensitivity syndrome or mixed gonadal dysgenesis. (See 'Epidemiology and risk factors' above.)

●Clinical presentation – For patients without an associated GCT, GCNIS is asymptomatic. The testis harboring GCNIS is palpably normal on physical examination and typically appears normal on imaging studies. Serum tumor markers for GCTs are also not elevated. (See 'Clinical presentation' above.)

●Diagnosis – The diagnosis of GCNIS is based upon the identification of neoplastic germ cells within the seminiferous tubules of a testicular tissue specimen (either a testicular biopsy or an orchiectomy specimen) (picture 1A-B). Because other benign conditions can mimic GCNIS, the histological diagnosis of GCNIS should be stringently confirmed based on histology as well as positive immunohistochemistry (IHC) markers. (See 'Diagnosis' above.)

●Indications for testicular biopsy

•Patients without testicular GCT – In individuals without testicular GCT, testicular biopsy is rarely performed to detect GCNIS. Possible indications for a testicular biopsy include conditions that significantly increase the risk for testicular GCT, such as gonadal dysgenesis, or as part of an infertility evaluation. (See 'Patients without testicular GCT' above.)

•Patients with testicular GCT – In patients who present with unilateral testicular GCT, it is controversial whether (or not) to perform a diagnostic contralateral testicular biopsy for GCNIS. (See 'Patients with testicular GCT' above.)

-In most patients with testicular GCT, a contralateral testicular biopsy is not offered, particularly in areas with a lower incidence of testicular GCT. The standard of care is surveillance of the contralateral testicle as part of routine posttreatment follow-up for testicular GCT. (See "Posttreatment follow-up for testicular germ cell tumors".)

-In areas with a higher incidence of GCT, contralateral testicular biopsy may sometimes be offered at the time of primary orchiectomy, especially to patients at a high risk of developing a second testicular GCT. (See 'Patients with testicular GCT' above.)

Patients with a negative testicular biopsy result have the same risk for GCNIS as the general population and may undergo routine posttreatment follow-up for testicular GCT. (See 'Testicular GCT and GCNIS in the contralateral testicle' above.)

●Management – For most patients with a confirmed diagnosis of GCNIS (either with or without a concomitant diagnosis of testicular GCT), we suggest surveillance rather than initiating therapy for the GCNIS (Grade 2C). However, treating the testicle containing GCNIS with either orchiectomy (only for those with isolated GCNIS and a well-functioning contralateral testicle) or low-dose radiation therapy (RT) is an alternative, particularly in areas with a high incidence of testicular GCT. Since management is controversial and patient preference is also important, clinicians should offer a risk-benefit discussion on available management strategies. (See 'Management' above.)