Risk Factors of Intratubular Germ Cell Neoplasia

The prevalence of ITGCN has been reported to be less than 1% in the normal male population, and 0.43% to 0.8% in autopsy studies, with most cases being unilateral. Because ITGCN leads to the development of TGCT, they have similar risk factors, including familial susceptibility. Table 1 lists the various risk factors of ITGCN and its associated prevalence rate.

One of the strongest risk factors for ITGCN is a history of contralateral testicular cancer. Patients who have testicular cancer with an atrophic contralateral testis who present before the age of 31 years are considered to be high risk for ITGCN. Heterogeneous parenchyma of the contralateral testis on ultrasonography in a patient with testicular cancer is also suggestive of ITGCN, with a positive predictive value of 22.2% and negative predictive value of 97.6%. Rud and colleagues reported that lower sperm concentration, small contralateral testis volume, irregular ultrasonic echo pattern of the contralateral testis, and younger age can be used to predict those patients with unilateral TGCT more likely to harbor a contralateral ITGCN lesion with a prevalence rate as high as 8%. Because ITGCN is associated with poor spermatogenesis and with testicular atrophy, the National Comprehensive Cancer Network (NCCN) and European Association of Urology (EAU) guidelines recommend investigation with contralateral testicular biopsy in patients with testicular cancer with a contralateral testicular volume less than 12 mL, poor spermatogenesis, and age less than 40 years.

Infertility is another major risk factor for the development of ITGCN. Older literature initially reported no increased risk of ITGCN in infertile men with a sperm density lower than 10 million/mL or lower than 20 million/mL associated with testicular atrophy (<15 mL). However, in a subsequent study 10 years later, Olesen and colleagues reported a 3-fold increased prevalence of ITGCN in men with severe oligozoospermia (sperm density ≤2.06 million/mL) compared with an age-matched cohort of normal men.

Cryptorchidism carries an increased risk of ITGCN. The NCCN and the EAU, therefore, recommend biopsy of the contralateral undescended testis in a patient with unilateral TGCT. However, immunohistochemical markers have failed to detect ITGCN in prepubertal boys with cryptorchidism.

ITGCN has also been noted in children with disorders of sexual differentiation. Ramani and colleagues reviewed more than 100 cases of children with various intersex states and reported a 10-fold increased frequency of ITGCN in the testis. No evidence of ITGCN was seen in cases of androgen insensitivity syndrome (testicular feminization), but previous reports have shown higher prevalence rates associated with this disease.

Testicular microlithiasis (TM) has not been associated with an increased prevalence of ITGCN in healthy, asymptomatic men, but in those with risk factors such as a unilateral TGCT, infertility, testicular atrophy, or sonographic heterogeneity, it can signify an increased occurrence of ITGCN. Although TM is seen in approximately 5% of healthy patients, the prevalence of TM is higher in those with these significant risk factors. It has also been suggested that bilateral TM may harbor an increased risk of ITGCN. Guidelines advocate the consideration of testicular biopsy in young men with TM and at least 1 risk factor for TGCT, and self-examination is recommended for all other patients, including asymptomatic men with TM.

Pathogenesis of Intratubular Germ Cell Neoplasia

There are 2 proposed mechanisms for the development of ITGCN. The first suggests the abnormal persistence of primordial gonocytes beyond the neonatal period that fail to differentiate into spermatogonia, and the second mechanism involves the regression of spermatogonia toward a precursor germ cell phenotype. These fetal gonocytes are pluripotent, with the ability to accumulate mutations and develop into various germinal and somatic tissues. Gondos and colleagues noted morphologic similarities between ITGCN and germ cells at early stages of differentiation under the microscope ( Fig. 1 ). This link was further reinforced by the discovery of many similar markers as well as gene expression profiles in ITGCN and fetal gonocytes. Modulation of protein expression in ITGCN also occurs with similar mechanisms as in primordial germ cells, strengthening evidence to its origin from persistent fetal gonocytes.

Primordial germ cells (gonocytes) have a large, round central nucleus with absent or inconspicuous nucleoli and scant cytoplasm. Their persistence on microscopy has been associated with the development of ITGCN. Hematoxylin and eosin stain (H&E stain), 40×.

Diagnosis of Intratubular Germ Cell Neoplasia

ITGCN diagnosis is based on testicular biopsy. Histologically, ITGCN consists of enlarged cells with clear cystoplasm, large hyperchromatic nuclei, and prominent nucleoli ( Fig. 2 ). Tubular basement membranes are thickened, and ITGCN is often interspersed among normal Sertoli cells and seminiferous tubules showing intact spermatogenesis. Immunohistochemical staining also distinguishes ITGCN from nonneoplastic spermatogenic cells, because markers for placentallike alkaline phosphatase and octamer-binding transcription factor 3/4 show high sensitivity and specificity rates on biopsy specimens.

ITGCN is identified on microscopic examination by germ cells with enlarged hyperchromatic nuclei, prominent nucleoli, and clear cytoplasm. These cells are typically arranged along the basement membrane of the seminiferous tubule with frequent mitotic figures. H&E stain, 60×.

Testicular biopsy has an approximately 0.5% false-negative rate for ITGCN. This finding is secondary to the focal nature of the disease, with a certain degree of sampling error. Two-site biopsies have further improved the sensitivity of detection, but subsequent TGCTs in patients with 1 or 2 previous negative biopsies have been described.

Controversy still exists with regards to the type of patient who would benefit from testicular biopsy. Although most of the academic world recommends testicular biopsy in patients with unilateral TGCT and a risk factor for contralateral disease, certain centers in Germany and Denmark perform routine contralateral testicular biopsies on all patients with TGCT at the time of orchiectomy. Proponents of routine biopsies argue that early detection allows treatment with radiation therapy (XRT) and preserves testicular hormone production in contrast to future orchiectomy, whereas opponents claim that many cases of recurrence exist even after XRT, with reports of hypogonadism in these patients as high as 40%.

Prognosis of Intratubular Germ Cell Neoplasia

The relationship between ITGCN and the development of TGCTs is well established, and the malignant potential of ITGCN does not occur until after the hormonal changes of puberty. Longitudinal studies have reported that when ITGCN is present on testicular biopsy, 40% of patients develop a TGCT within 3 years and 50% within 5 years. Loss of PTEN and p18 expression and gain of chromosome 12p have all been associated with progression of ITGCN to TGCT. This process also seems to occur independent of Sertoli cell interaction.

Treatment of Intratubular Germ Cell Neoplasia

Treatment of ITGCN includes surveillance, orchiectomy, or low-dose external beam radiation (XRT) to the affected testis. Chemotherapy for TGCT is not effective in controlling ITGCN in the contralateral testicle.

For patients with unilateral ITGCN and a normal contralateral testis, orchiectomy is the preferred treatment option. Orchiectomy may also be considered in patients with ITGCN in an atrophic, poorly functioning testis or in patients with ITGCN associated with oligospermia who are pursuing assisted reproductive techniques. ITGCN in the solitary testicle is more controversial, with some advocating surveillance with testicular self-examination and others recommending early low-dose XRT to the affected testis. Treatment of ITGCN should be weighed against the consequences of resultant infertility and possible hypogonadism with reliance on long-term testosterone supplementation.

ITGCN responds to XRT most effectively at doses of 18 to 20 Gy. Giwercman and colleagues reported resolution of ITGCN in patients treated with 20 Gy of XRT with up to 2 years follow-up, but 25% of patients required hormone supplementation because of Leydig cell dysfunction. In addition, patients who undergo XRT to a solitary testicle are rendered infertile as a result of destruction of normal spermatogonia. Lower doses ranging from 14 to 16 Gy have been used with varying degrees of success, but an increased risk of recurrence has been reported.

Surveillance remains an option for patients who wish to preserve fertility and endocrine function. However, patients need to be compliant with follow-up and regular testicular self-examination.