Undescended Testes and Testicular Tumors

J. Joy Lee and Linda M. Dairiki Shortliffe

Undescended Testes

Normal testicular descent relies on a complex interplay of numerous factors. Any deviation from the normal process can result in a cryptorchid or undescended testis (UDT) (Fig. 51-1). UDT is a common abnormality that carries fertility and malignancy implications.

FIGURE 51-1 Testicular descent in males: 1, 90 mm crown–rump length (CRL) (12–24 weeks of gestational age); 2, 125 mm CRL (15–17 weeks); 3, 230 mm CRL (24–26 weeks); 4, 280 mm CRL (28-30 weeks); 5, at term. The convoluted structure is the epididymis. (Adapted from Hadziselimovic F. Embryology of testicular descent and maldescent. In: Hadziselimovic F, editor. Cryptorchidism: Management and Implications. New York: Springer-Verlag; 1983. p. 23.)

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 all 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, while 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.¹ In humans, the frequency of UDT is increased in boys with diseases that affect androgen secretion or function.^2,3 When anti-androgens are given to pregnant rats, the rate of UDT in male offspring is 50%.^4,5 Estradiol downregulates INSL3 in experimental models, and maternal exposure to estrogens such as diethystilbesterol (DES) has also been associated with cryptorchidism.^6,7

Under the influence of INSL3, the gubernaculum undergoes two phases: outgrowth and regression.8,9 Outgrowth refers to rapid swelling by 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.¹⁰ Next, during regression, the gubernaculum undergoes cellular remodeling and becomes a fibrous structure.¹¹ 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 initiating testicular descent. However, the gubernaculum is not directly attached to the scrotum during inguinal passage, and does not act as a pulley. Transit through the inguinal canal is relatively rapid, starting around week 22 and typically completed after week 27.^12,13

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).⁹ While research in rats has implicated CGRP in contraction of cremasteric muscle fibers and subsequent gubernacular and testicular descent,^14,15 in humans the cremaster is distinct from the gubernaculum.^12,16 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.⁸

Epididymal anomalies are found in up to 50% of men with UDT.17,18 Some investigators postulate that the gubernaculum facilitates epididymal descent, indirectly guiding the testis into the scrotum.¹⁹ Others believe that an abnormality of paracrine function is responsible for both epididymal anomalies and UDT, but that epididymal abnormalities are not causal.¹

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.²⁰ The distinction can be blurred, however, as when a previously palpable testis falls back into the abdomen through the open ring, or an intra-abdominal ‘peeping’ testis can be felt at 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 difficult diagnosis or suboptimal attachment within the scrotum that changes position of the testis with growth of the child.²¹

A true UDT has halted somewhere along the normal path of descent from 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. Ascending or acquired UDT refers to a testis that was previously descended on examination, but at a later time can no longer be brought down into the scrotum. While an association between retractile testes and secondary testicular ascent has been identified, a link between rate of height growth and ascended testes suggests that the ability to reach the scrotum changes with a child’s growth.22,23 Acquired UDT may also be iatrogenic, as 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 birth weight <2.5 kg male infants.²⁴ The majority of testes descend within the first 6 to 12 months such that at 1 year, the incidence is down to 1%. Testicular descent after 1 year is unlikely.²⁵ However, 2–3% of boys in the USA, and up to 5.3% in some European series, undergo orchiopexy for UDT.^26,27 This discrepancy between higher orchiopexy rates and actual incidence of the disease is thought to lie partially in misdiagnosis between retractile testes, but also from acquired UDT. The overall rate of secondary testicular ascent has been reported between 2–45%.^28,29

Series documenting the location of a UDT find that two-thirds to three-quarters of cases are palpable, usually within the inguinal canal or distal to the external ring.30,31 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.²²

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 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 be compensatorily hypertrophied. 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. Approximately 18% of nonpalpable testes are subsequently palpated when examined under anesthesia in the operating room.30,31

On examination, both retractile testes and low UDTs may be manipulated into the scrotum. Once in scrotal position, the retractile testis appears to remain in place, whereas the low UDT does not. The ipsilateral hemiscrotum is fully developed with a retractile testis, whereas it may be underdeveloped in a UDT.

If neither testis is palpable, anorchia, androgen insensitivity syndrome, or a chromosomal abnormality must be differentiated from bilateral UDT. If the baseline follicle-stimulating hormone (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 luteinizing hormone (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 the testosterone level does not increase appropriately, nonfunctional testicular tissue may still be present and exploration should still be performed. The hCG stimulation test does not distinguish between normal nonpalpable testes and functioning testicular remnants.³²

Radiographic imaging is rarely helpful in locating a UDT and is not recommended routinely. 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 detection of soft tissue masses less than 1 cm.³³ 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.^34,35

While easy to perform with minimal risk, ultrasound has low accuracy with a sensitivity of 45% and specificity of 78%, and adds unnecessary cost.36,37 In one series, ultrasound incorrectly indicated UDT for 48% of patients when the testis was retractile.³⁸ In summary, negative imaging is not diagnostic of testicular absence.

Fertility

A UDT and, to a lesser degree, its contralateral descended mate have been demonstrated to be histologically abnormal by investigators who performed bilateral testes biopsies at the time of orchiopexy.39,40 Clinically, patients with a history of UDT exhibit subnormal semen analyses.⁴¹ 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%).^42,43 Despite these findings, the infertility rate of men with a history of unilateral UDT is equivalent to that of the normal population (10%).^43,44,45 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 counterparts.^46,47

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.²² Elevated testicular temperature in a UDT results in immaturity of Sertoli cells in monkeys.²² A blunted normal testosterone surge at 60 to 90 days postnatally results in a lack of Leydig cell proliferation and delay in transformation of gonocytes to adult dark spermatogonia on histopathology.⁴⁸ 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.⁴⁹ Furthermore, delayed orchiopexy at 3 years versus 9 months resulted in impaired testicular catch-up growth in boys.⁵⁰

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.⁵¹ A similar prospective randomized trial on neoadjuvant gonadotropin-releasing hormone therapy prior to orchiopexy also found an improvement in the mean fertility index compared to the untreated group.⁵² Neoadjuvant therapy prior to 24 months achieved the best results.

Risk of Malignancy

UDT appears to be associated with a two- to eightfold increased risk of malignancy.25,53 The risk of malignancy arising from a UDT varies with location, e.g., 1% with inguinal and 5% with abdominal testes.^54,55 Cancers arising in testes that remain in the abdomen are most frequently seminomas (74%).^56,57 In contrast, malignancies arising after successful orchiopexy, regardless of original location, are most frequently nonseminomatous germ cell tumors (63%).^58,59

Among men with testicular cancer, up to 10% have a history of UDT.⁶⁰ There are two competing theories regarding this increased risk. First, the ‘position theory’ implicates the carcinogenic potential of the altered micro- and macro-environment 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 a UDT showed that those having orchiopexy before age 13 had a 2.23 relative risk of developing cancer.⁶¹ 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 10 was associated with six times the risk of malignancy.⁶² The association of orchiopexy with a decrease in cancer risk has not been demonstrated prospectively. Nevertheless, orchiopexy facilitates subsequent testicular examination and 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.⁶³ In patients with a 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 1.7.⁶⁴ The incidence of carcinoma in situ (CIS) is 2–4% in men with cryptorchidism compared with less than 1% in non-affected men. In the postpubertal male, CIS progresses to invasive germ cell tumors in 50% of cases within 5 years.⁶⁵ However, the natural history of CIS diagnosed in a young child at the time of orchiopexy is less clear. It has been recommended that these patients undergo repeated biopsies after puberty.⁶⁶

Management and Treatment

Indications and Timing

Guidelines (AAP 1996 and EAU 2012) recommend that orchiopexy in otherwise healthy males be performed by 12–18 months of age, as the UDT is unlikely to descend after 12 months of age.67,68 Despite this recommendation, many children are referred after age 2 years. In one review of over 28,000 children with UDT in the Pediatric Health Information System database, only 18% underwent operation by 1 year of age, and 43% by 2 years of age. Black and Hispanic boys less commonly underwent orchiopexy by age 2 years, regardless of payer group and socioeconomic status.⁶⁹ Repair may be undertaken even earlier if a symptomatic hernia is present. The risk of general anesthesia after 6 months is acceptably low in hospitals with dedicated pediatric anesthesiologists. In addition to the evidence that early scrotal placement may affect the risk of malignancy and infertility, treatment of a UDT also reduces the risk of torsion, facilitates testicular examination, improves the endocrine function of the testis, and creates a normal-appearing scrotum.

Hormonal Treatment

The value of hormonal therapy in the treatment of UDT is controversial. Buserelin, an LHRH agonist, is frequently used to treat UDT in Europe.⁷⁰ The highest success rates have been observed in cases where the testis is at or distal to the external inguinal ring.^71,72 Some authors recommend low-dose hCG therapy, regardless of the operative plan to restore a normal endocrine milieu and enhance germ cell maturation, particularly in bilateral UDT.⁷³ Trials combining buserelin and hCG have yielded success rates in the range of 60%, but orchiopexy is still required in 40% of patients.^74,75 Buserelin has not been approved for this use by the USA Food and Drug Administration, but as noted above, clinical trials of LHRH used in a neoadjuvant fashion in young boys undergoing orchiopexy suggest that it may improve fertility.⁵¹

Orchiopexy

The operative approach for UDT depends on whether the testis is palpable (Fig. 51-2). It is important to re-examine the patient under anesthesia because up to 18% of nonpalpable testes may become palpable on examination under anesthesia.⁷⁶ Unilateral and bilateral palpable UDT are managed similarly. Routine biopsy of the testis at the time of surgery is not recommended, but may provide prognostic information regarding fertility.⁷⁷

FIGURE 51-2 Management algorithm for undescended testis. FSH, follicle-stimulating hormone; LH, luteinizing hormone; hCG, human chorionic gonadotropin. (a) If blind-ending vessels are unequivocally identified, then there is no need for further exploration. (b) Baseline FSH and LH levels are elevated if values are 3 SD above the mean. (c) Increased suspicion of anorchia with elevated baseline FSH and LH levels; however, exploration is still warranted. (d) Testicular remnant tissue may be present despite a negative hCG stimulation test; therefore, exploration for testicular remnant tissue should still be performed.

For the unilateral palpable UDT that presents after puberty, orchiopexy is preferred. If orchiopexy is difficult and a normal contralateral testis is present, or if the UDT is abnormally soft and small, then an orchiectomy should be performed. Likewise, orchiectomy is the treatment of choice for the postpubertal, unilateral intra-abdominal UDT because of the increased cancer risk. Laparoscopic orchiectomy is ideal in this setting.⁷⁸ In uncommon cases such as postpubertal males with significant anesthetic risks, or males older than 50, observation is an acceptable alternative to operation.⁵⁶

Palpable Undescended Testes: Unilateral or Bilateral

The mainstay of therapy for the palpable UDT is orchiopexy with creation of a subdartos pouch.79,80 This may be performed through a standard two-incision (inguinal and scrotal) approach, or a single-incision high scrotal approach.^81,82 With the standard inguinal approach, the success rate is as high as 95%.⁸³ Similar success rates have been reported for the high scrotal approach.^81,84 With both techniques, scrotal fixation is achieved by scarring of the everted tunica vaginalis to the surrounding tissues.⁸⁵ Placement of sutures in the tunica albuginea for fixation is generally discouraged because it causes significant testicular inflammation, increases infertility risk, and may damage intratesticular vessels.^86,87 Associated findings such as an open processus vaginalis or hernia should be repaired.

A standard inguinal approach to orchiopexy with a subdartos pouch is depicted in Figure 51-3. The operation is usually performed as an outpatient procedure under general anesthesia. The patient is supine. Intraoperative administration of an ilioinguinal nerve block with bupivacaine provides excellent postoperative analgesia. An incision is made along one of the Langer lines over the internal ring. The external oblique aponeurosis is incised in the direction of its fibers, avoiding injury to the ilioinguinal nerve. Once located, the testis and spermatic cord are freed from the canal and any cremasteric and ectopic gubernacular attachments. The tunica vaginalis is then dissected off the vas deferens and spermatic vessels. The proximal sac is twisted, doubly suture ligated, and amputated. Retroperitoneal dissection through the internal ring may provide additional cord length for the testis to reach the scrotum.