Undescended Testes and Testicular Tumors

Embryology

Testicular development and descent depend on a coordinated interaction among endocrine, paracrine, growth, and mechanical factors. Bipotential gonadal tissue located on the embryo’s genital ridge begins differentiation into a testis during weeks 6 and 7 under the effects of the testis-determining SRY gene. Sertoli cells begin to produce Müllerian inhibitory factor (MIF) soon thereafter, causing regression of most Müllerian duct structures except for the remnant appendix testis and prostatic utricle. By week 9, Leydig cells produce testosterone and stimulate development of Wolffian structures, including the epididymis and vas deferens. The testis resides in the abdomen near the internal ring until descent through the inguinal canal at the beginning of the third trimester.

Two important hormones in testicular descent are insulin-like factor 3 (INSL3) and testosterone, both secreted by the testis. Two important anatomic players are the gubernaculum testis and the cranial suspensory ligament (CSL). The gubernaculum is thought to help anchor the testis near the internal inguinal ring as the kidney migrates cephalad. Androgens prompt the involution of the CSL, allowing for eventual downward migration of the testicle. In humans, the frequency of UDT is increased in boys with diseases that affect androgen secretion or function. When antiandrogens are given to pregnant rats, the rate of UDT in male offspring is 50%. Estradiol downregulates INSL3 in experimental models, and maternal exposure to estrogens such as diethylstilbestrol (DES) has also been associated with cryptorchidism.

Under the influence of INSL3, the gubernaculum undergoes two phases: outgrowth and regression. Outgrowth refers to rapid swelling of the gubernaculum, thereby dilating the inguinal canal and creating a pathway for descent. Mice with homozygous mutant INSL3 have been found to have poorly developed gubernacula and intra-abdominal testes. Next, during regression, the gubernaculum undergoes cellular remodeling and becomes a fibrous structure. It is believed that intra-abdominal pressure then causes protrusion of the processus vaginalis through the internal inguinal ring, transmitting pressure to the gubernaculum and fostering testicular descent. However, the gubernaculum is not directly attached to the scrotum during inguinal passage, and does not appear to act as a pulley. Transit through the inguinal canal is relatively rapid, starting around week 22, and is typically completed after week 27.

Other potential mediators of descent include MIF, by causing resorption of Müllerian structures and clearing anatomic roadblocks to descent, and calcitonin gene–related peptide (CGRP). While research in rats has implicated CGRP in contraction of cremasteric muscle fibers and subsequent gubernacular and testicular descent, in humans the cremaster is distinct from the gubernaculum. In addition, growth factors such as epidermal growth factor act on the placenta to enhance gonadotropin release, which stimulates secretion of descendin, a growth factor for gubernacular development.

Epididymal anomalies are found in up to 50% of men with UDT. Some investigators postulate that the gubernaculum facilitates epididymal descent, indirectly guiding the testis into the scrotum. Others believe that an abnormality of paracrine function is responsible for both epididymal anomalies and UDT, but the epididymal abnormalities are not causative in the failure of testicular descent.

Classification

Variability in nomenclature regarding UDT has led to ambiguity in the literature and difficulty comparing treatment results. The clearest classification divides testes into palpable and nonpalpable, with the obvious limitation that a nonpalpable gonad may not represent an undescended but an absent testis. The distinction can also be blurred, as when a previously palpable testis falls back into the abdomen through an open internal ring, or an intra-abdominal “peeping” testis can be intermittently felt in the upper inguinal canal. A retractile testis is a normally descended testis that retracts into the inguinal canal as a result of cremasteric contraction; it is not an UDT. Though retractile testes do not require operative repair, in some series as many as one-third become ascending UDTs, suggesting either an initial incorrect diagnosis or suboptimal attachment within the scrotum that changes the position of the testis with growth of the child.

A true UDT has halted somewhere along the normal path of descent from the abdomen to distal to the inguinal ring. An ectopic UDT is one that has deviated from the path of normal descent and can be found in the inguinal region, perineum, femoral canal, penopubic area, or even contralateral hemiscrotum. An ascending or acquired UDT refers to a testis that was previously descended on examination, but cannot be brought down into the scrotum at a later time. While an association between retractile testes and secondary testicular ascent has been identified, a link between the rate of height growth and ascended testes suggests that the ability to reach the scrotum changes with a child’s growth. Thus, a significant growth spurt may be a factor in a retractile testis becoming an undescended testis. An acquired UDT may also be iatrogenic, which can occur when a previously descended testis becomes trapped in scar tissue cephalad to the scrotum after inguinal surgery. A nonpalpable testis may be simply intra-abdominal some of the time, or truly vanished due to intrauterine or perinatal torsion. This condition is known as monorchia, or anorchia if both testes are absent.

Incidence

UDT occurs in approximately 3% of term male infants and in up to 33–45% of premature and/or low birth weight (<2.5 kg) male infants. The majority of testes descend within the first 6–12 months such that at 1 year, the incidence is down to 1%. Testicular descent after 1 year is unlikely. However, 2–3% of boys in the United States, and up to 5% in some European series, undergo orchiopexy for UDT. This discrepancy between higher orchiopexy rates and the actual incidence of the disease is thought to lie partially in the misdiagnosis of retractile testes, but also likely related to acquired UDT from testicular ascent. The overall rate of secondary testicular ascent has been reported between 2% and 45%.

Series documenting the location of an UDT find that two-thirds to three-quarters of cases are palpable, usually within the inguinal canal or distal to the external ring. Anomalies associated with UDT include a patent processus vaginalis and epididymal abnormalities. Specific syndromes with higher rates of UDT include prune-belly syndrome, gastroschisis, bladder exstrophy, Prader–Willi, Kallman, Noonan, testicular dysgenesis, and androgen insensitivity syndromes.

Diagnosis

Given the historic variability in the definition of what constitutes an UDT, it is not surprising that confusion exists in the primary care setting as well. A careful history and physical examination is thus paramount.

The patient should be examined in a warm room in both the supine and frog-legged sitting position. The scrotum is observed for hypoplasia and examined for the presence of either testis. In cases of monorchia, the solitary testis may show compensatory hypertrophy. The first maneuver to locate the testis is to walk the fingers from the iliac crest along the inguinal canal towards the scrotum, pushing subcutaneous structures toward the scrotum. The scrotum should not be palpated prior to this maneuver as it may activate the cremasteric reflex, thus retracting the testis. Lubricating gel or soap may help reduce friction. Gentle mid-abdominal pressure may help push the testis into the inguinal canal. A cross-legged sitting or squatting position may also help identify the testis. It can be particularly challenging to obtain an accurate exam on a ticklish or obese boy. Due to challenges during physical exam, it is accepted that up to 20% of nonpalpable testes will be subsequently palpated when examined under anesthesia in the operating room.

On examination, both retractile testes and low UDTs may be manipulated into the scrotum. Once in the scrotum, the retractile testes remain in place until displaced by a cremasteric reflex, whereas the low UDT retracts back up to its abnormal location once released. The ipsilateral hemiscrotum is fully developed with a retractile testis, whereas it may be underdeveloped with an UDT.

If neither testis is palpable, anorchia, androgen insensitivity syndrome, or a chromosomal abnormality must be differentiated from bilateral nonpalpable UDT. Moreover, a rare (but potentially a life-threatening condition) should also be considered. A phenotypically male newborn with bilateral nonpalpable gonads, even in the presence of an otherwise normal-appearing penis, could represent a masculinized 46,XX baby with congenital adrenal hyperplasia (CAH). If the diagnosis is delayed, the salt-wasting form of CAH can lead to severe electrolyte imbalance and cardiovascular compromise. In such cases, a karyotype is warranted.

To avoid unnecessary surgical exploration in a 46XY patient with anorchia, studies to determine the presence of viable testicular tissue should include serum MIF, inhibin B, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone. If the child is <9–12 months of age, in the absence of viable testes, serum MIS and inhibin B should be undetectable. If the baseline FSH level is elevated (three standard deviations above the mean) in a boy younger than 9 years, anorchia is likely and no further evaluation is recommended. If baseline LH and FSH levels are normal and human chorionic gonadotropic (hCG) stimulation results in an appropriate elevation of testosterone, functioning testicular tissue is likely to be present and the patient should undergo exploration. However, if testosterone levels do not increase appropriately, nonfunctional testicular tissue may still be present and exploration should still be considered. The hCG stimulation test does not distinguish between normal nonpalpable testes and functioning testicular remnants.

Imaging studies are rarely helpful in determine the presence or location of an UDT and may delay timely referral for surgical treatment. Therefore, their routine use is not recommended. Multiple studies have shown that the experienced surgeon/examiner has a higher sensitivity in locating the UDT than does ultrasonography (US), computed tomography (CT), or magnetic resonance imaging (MRI), especially because the sensitivity of imaging is poor in detecting soft tissue masses <1 cm. In unusual situations of bilateral nonpalpable testes, MRI with gadolinium may be useful for detecting abdominal testes because testicular tissue is particularly bright on MRI. However, these cases can be better evaluated with serum hormones and markers, and MRI tends to add little to the diagnosis while incurring costs and exposure to contrasts agent and anesthesia.

Although easy to perform with minimal risk, US has low accuracy, with a sensitivity of 45% and specificity of 78%, and adds unnecessary cost. In one series, US incorrectly indicated UDT for 48% of patients when the testis was retractile. The 2014 American Urological Association (AUA) update on cryptorchidism does not advocate for the routine use of US in the evaluation of UDT. The high false-positive (identifying a structure thought to represent a testis when a testis is not present) and low true-negative (confirming the absence of a testicle anywhere in the abdomen, inguinal canal, or scrotum) rates negate the utility of this exam for almost all children with UDT. In summary, negative imaging is not diagnostic of testicular absence. It is critical to not “miss” an intra-abdominal testicle. If an imaging test existed that could definitively prove that the testicle was absent (as opposed to undescended), this would be a valuable tool. Currently, however, no such imaging study exists.

Fertility

An UDT and, to a lesser degree, its contralateral descended mate (if present) have been demonstrated to be histologically abnormal by investigators who performed bilateral testes biopsies at the time of orchiopexy. Clinically, patients with a history of UDT exhibit subnormal semen analyses. Early studies showed fertility to be related to the position of the UDT. Men with abdominal or canalicular testes had lower fertility than those with inguinal testes (83.3% vs 90%). Despite these findings, the infertility rate of men with a history of unilateral UDT is equivalent to that of the normal population (∼10%). However, men with bilateral UDT have paternity rates of 50–65% even if corrected early, and thus are six times more likely to be infertile relative to their normal male counterparts.

Mechanisms of infertility in UDT appear to be associated with effects on Sertoli and Leydig cells, as well as Wolffian duct abnormalities (vasal and epididymal), which may further inhibit transport of already insufficient sperm. Elevated testicular temperature in an UDT results in immaturity of Sertoli cells in monkeys. A blunted normal testosterone surge at 60–90 days postnatally results in a lack of Leydig cell proliferation and delay in transformation of gonocytes to adult dark spermatogonia on histopathology. An experimental rat model has demonstrated preservation of germ cell number and spermatogenesis in rats undergoing early orchiopexy for UDT versus germ cell apoptosis in untreated rats. Furthermore, delayed orchiopexy at 3 years versus 9 months resulted in impaired testicular catch-up growth in boys.

A clinical trial of neoadjuvant LH-releasing hormone (LHRH) in young boys undergoing orchiopexy appeared to improve the fertility index (spermatogonia/tubule) in treated versus untreated boys, though these results need confirmation. A similar prospective randomized trial on neoadjuvant gonadotropin-releasing hormone therapy prior to orchiopexy also found an improvement in the mean fertility index compared with the untreated group. Neoadjuvant therapy prior to 24 months achieved the best results. The long-term benefits (or risk) of hormonal stimulation for these purposes remains largely unknown, and it is not commonly practiced in many settings.

Risk of Malignancy

UDT appears to be associated with a two- to eightfold increased risk of malignancy. This risk appears to vary with the gonad’s location: 1% with inguinal and 5% with abdominal testes. Cancers arising in testes that remain in the abdomen are most frequently seminomas (74%). In contrast, malignancies arising after successful orchiopexy, regardless of original location, are most frequently nonseminomatous germ cell tumors (63%).

Among men with testicular cancer, up to 10% have a history of UDT. There are two competing theories regarding this increased risk. First, the “position theory” implicates the carcinogenic potential of the altered micro- and macroenvironment of the UDT. If true, then the timing of correction could potentially lessen or negate the development of malignancy. A 2007 epidemiologic study examining 16,983 Swedish men who underwent correction of an UDT showed that those having orchiopexy before age 13 had a 2.23 relative risk of developing cancer. Those boys having surgery at 13 years or older had a relative risk of 5.40 (compared with normal men). An additional meta-analysis showed that orchiopexy after 10 years of age compared with before age 10 was associated with six times the risk of malignancy. These associations between age of orchiopexy with a decrease in cancer risk need further verification, yet provide compelling evidence for early surgical intervention. Moreover, by placing the gonad in an accessible location, orchiopexy facilitates subsequent testicular examination and can potentially help with early cancer detection.

The alternate “common cause” or “testicular dysgenesis” theory posits that the malignancy risk may be due to an underlying genetic or hormonal etiology that predisposes to both cryptorchidism and testicular cancer. In patients with an UDT, 15–20% of testicular tumors arise in the normally descended contralateral testis. In other words, the normally descended testis still carries an increased relative risk of malignancy of 1.7. The incidence of carcinoma in situ (CIS) is 2–4% in men with cryptorchidism compared with <1% in non-affected men. In the postpubertal male, CIS progresses to invasive germ cell tumors in 50% of cases within 5 years. However, the natural history of CIS diagnosed in a young child at the time of orchiopexy is less clear. Although it has been recommended that patients undergo repeated biopsies after puberty, it is unclear it this intervention leads to benefits in terms of cancer prevention.

Management and Treatment