Cryptorchidism (Undescended Testes)

Columbia Urology Grand Rounds 11/11/15 - Cryptorchidism: Evaluation, consequences and contemporary management

1. Columbia University Dept. of Urology Pediatric Urology Grand rounds Cryptorchidism: Evaluation, consequences and contemporary management

2. Overview Case Background and History Testicular development and pathophysiology Evaluation and Diagnosis Associated pathology Management Conclusions

3. Overview Case Background and History Testicular development and pathophysiology Evaluation and Diagnosis Associated pathology Management Conclusions

4. Case Presentation CC: Undescended testicle HPI: 3 month old otherwise healthy boy referred from PCP with left undescended testicle since birth.

5. Case Presentation Prenatal Hx : normal antenatal imaging; normal AFI, full term, NSVD PMH : None PSH : None Meds : None All : NKDA SH : lives with mom and dad in WaHi FH : No GU hx

6. Physical Exam Vitals : 98.7 F, HR 101, BP 95/60, 99% on RA Gen : NAD, well appearing baby boy Lungs : breathing comfortably on RA Abd : soft, nt / nd Back : no sacral dimple GU : circumcised phallus, R testicle descended and palpable, L testicle non- palpable, scrotum rugated and normal appearing

7. Case: Assessment 3 month old otherwise healthy boy with left non-palpable testicle since birth. How would you proceed? Where’s the testicle? Why should we care? W hat do we do about it?

8. Overview Case Background and History Testicular development and pathophysiology Evaluation and Diagnosis Associated pathology Management Conclusions Pope Innocent X, 1644 “ Habet duos testiculos et bene pendentes !” (He has two testicles and they hang well)

9. Cryptorchidism “Hidden testis ” One or both testicles are not appropriately positioned in the scrotum at birth M ost common GU congenital abnormality

10. Definitions Cryptorchidism – a testis that is not within the scrotum and does not descend spontaneously by 4 mo Undescended testis (UDT) – stopped short on normal path Ectopic testis – descend normally through the external ring but then are diverted to an aberrant position Absent testis – no testis due to agenesis or atrophy (Boys who have bilaterally absent testes have anorchia ) Retractile testis – normal testis that has been pulled into a suprascrotal position by the cremasteric reflex Ascending testis – noted to be in a scrotal position in childhood and then to become undescended

11. Surgical History of Undescended Testes 1755 – von Haller Tackett et al. “A history of cryptorchidism.” J Ped Urol. 2007

12. Surgical History of Undescended Testes 1755 – von Haller 1786 – Hunter Tackett et al. “A history of cryptorchidism.” J Ped Urol. 2007

13. Surgical History of Undescended Testes 1755 – von Haller 1786 – Hunter 1871 – Adams Tackett et al. “A history of cryptorchidism.” J Ped Urol. 2007

14. Surgical History of Undescended Testes 1755 – von Haller 1786 – Hunter 1871 – Adams 1877 - Annandale Tackett et al. “A history of cryptorchidism.” J Ped Urol. 2007

15. Surgical History of Undescended Testes 1755 – von Haller 1786 – Hunter 1871 – Adams 1877 - Annandale 1957 – Lattimer Tackett et al. “A history of cryptorchidism.” J Ped Urol. 2007

16. Surgical History of Undescended Testes 1755 – von Haller 1786 – Hunter 1871 – Adams 1877 - Annandale 1957 – Lattimer 1976 - Corseti Tackett et al. “A history of cryptorchidism.” J Ped Urol. 2007

17. Overview Case Background and History Testicular development and pathophysiology Evaluation and Diagnosis Associated pathology Management Conclusions

18. Regulation of testicular descent Mechanical factors Intra-abdominal Pressure Gubernaculum tension Processus vaginalis patency Growth factors Insulin-like 3 (INSL3) growth factor (Abdominal phase) Calcitonin gene related peptide Hormonal factors Testosterone ( Inguinoscrotal Phase)

19. Testicular descent Intra-abdominal Phase “Undescended testes cryptorchidism in children Clinical features and evaluation.” UpToDate . April, 2015.

20. Testicular descent Inguinoscrotal Phase “Undescended testes cryptorchidism in children Clinical features and evaluation.” UpToDate . April, 2015.

21. Epidemiology & Risk factors Incidence 2-5% of full-term infants 30% of premature infants 10% of cases bilateral Prevalence reported to be (possibly) increasing Risk factors Prematurity SGA at birth or birth weight <2.5 kg Associated endocrine, genetic, and developmental disorders ?Prenatal exposure to endocrine disruptors

22. Geographic variation 9% cryptorchidism 2.4% cryptorchidism

23. Genetics of cryptorchidism Most common genetic findings: 8 cases of Klinefelter syndrome 5 cases of mutations in INSL3 receptor gene (RXFP2) Ferlin A , et al. Genetic alterations associated with cryptorchidism. JAMA 2008; 300:2271.

24. Genetics: INSL3 and RXFP2 receptor Role in gubernaculum development Insl3 and Rxfp2 knockouts B/L cryptorchidism at birth + absent spermatogenesis in adulthood Normal if surgically corrected early 4.7% mutation frequency in men with cryptorchidism Foresta et al . Hormones and Genes in Cryptorchidism. Endocrine Rev, 2008.

25. Associated conditions Abdominal wall defects ( eg , prune belly) Neural tube defects ( eg , myelomeningocele ) Cerebral palsy ~50% Disorders of sexual development Genetic disorders Diminished testosterone secretion ( eg , Klinefelter ) Diminished testosterone action ( eg , Androgen insens .) Primary hypogonadism ( eg , Noonan) Chromosomal disorders ( eg , trisomy 18, trisomy 13)

26. Associated conditions X-linked syndromes and aneuploidies

27. Associated conditions Autosomal syndromes a/w cryptorchidism Component of more than 390 syndromes!

28. Environmental influences Testicular dysgenesis hypothesis Skakkebaek (2001) theorized that cryptorchidism, hypospadias, poor semen quality and testicular cancer could all be linked to one origin of hormonal disruption during fetal development Environmental endocrine disruptors Eg , pesticides, DES, polyaromatic hydrocarbons, phthalates Maternal exposures Smoking (OR 1.13) Alcohol (OR 3.10) H.E. Virtanen, A. Adamsson / Molecular and Cellular Endocrinology 355 (2012) 208–220

29. Overview Case Background and History Testicular development and pathophysiology Evaluation and Diagnosis Associated pathology Management Conclusions

30. Clinical features Empty, hypoplastic or poorly rugated scrotum / hemiscrotum Inguinal fullness Left side predominant if unilateral (58%) Bilateral with associated conditions (10%) Clark DA. Atlas of Neonatology - A companion to Disease of the Newborn, 1st ed. 

31. Testis locations abdomen (1) inguinal canal (2 ) suprascrotal regions (3) suprapubic region (4) femoral region (5) perineal region (6) contralateral hemiscrotum (7)

32. Examination PCP should palpate testes for quality and position at each recommended well-child visit (AUA standard; Grade B) Full GU exam of phallus, meatus, scrotum, and inguinal canals for hernias Maneuvers for retractile testis “ Criss -cross apple-sauce” Warm compress Valsalva Cremasteric fatigue

33. Imaging Imaging with US, CT or MRI Providers should not perform ultrasound or other imaging modalities in the evaluation of boys with cryptorchidism prior to referral as these studies rarely assist in decision making (AUA Standard; Grade B) Cases courtesy of Radiopaedia.org

34. Meta-analysis 18 studies addressing the performance of imaging in identifying and localizing nonpalpable UDT Mostly poor-quality studies Using surgery as the reference standard, the sensitivity, specificity, and overall accuracy rates at identifying testes were determined Penson DF, Krishnaswami S, Jules A, et al. AHRQ Comparative Effectiveness Review No. 88 . December 2012 Available at www.effectivehealthcare.ahrq.gov /undescended- testicle.cfm .

35. Imaging Technique Number and Quality of Studies Performance Characteristic Measures Good Fair Poor Sensitivity Specificity PPV* * NPV † † Overall Accuracy Rate § US 1 2 6 15 – 80 67 – 100 67 – 100 – 80 21 – 76 MRI 3 7 33 – 91 56 – 100 83 – 100 – 75 42 – 92 CT 1 57 100 100 14 60 MRA ¶ 1 1 100 NA – 100 100 NA – 100 100 MRV ¶ 1 100 100 100 100 100

36. * Assess the possibility of DSD when there is increasing severity of hypospadias with cryptorchidism (AUA Recommendation; Grade C) *

37. Overview Case Background and History Testicular development and pathophysiology Evaluation and Diagnosis Associated pathology Management Conclusions

38. Spermatogenesis Spermatagonium (Ad and Ap )

39. Testicular maldevelopment & infertility In 1965 Mancini, et. al. observed UDT: decreased germ cell counts arrested development of spermatogonia progressive loss of spermatogonia

40. Purpose : explore abnormalities in germ cell maturation in UDTs and in descended contralateral testes. Methods : 737 boys with unilateral cryptorchidism Between birth and 9 years old H ad orchiopexy and bilateral testicular biopsies Total and differential germ cell counts performed on sections

41. Findings: Gonocytes failed to disappear and adult dark spermatogonia failed to appear D efect in the first step in maturation  failure to establish an adequate adult stem cell pool. Primary spermatocytes failed to appear in UDT and appeared in only 19% of contralateral descended testes at 4–5 years NORMAL UDT

42. UDT

43. UDT

44. Impact on fertility Strong evidence that abnormal germ cell development is present after infancy in UDT Men with a history of undescended testes have an subfertility in about 10% Lower sperm counts Sperm of poorer quality L ower fertility rates van Brakel et al. Fertility potential in a cohort of 65 men with previously acquired undescended testes. J Pediatric Surg. 2013.

45. Testis Cancer I ncreased risk of testicular cancer General population 5.4 in 100,000 Cryptorchid testes have an ~3x increased cancer risk (more risk when intrabdominal) 10-25% of tumors occur in the contralateral normal descended testicle

46. Purpose : Significant variability exists for the relative risk (RR) of testicular malignancy in isolated cryptorchidism. M eta -analysis to clarify the true magnitude of this risk. Methods : meta-analysis of 9 case -control studies (including a total of 2281 cases) and 3 cohort studies (including more than 2 million boys)

47. Purpose : study the relationship between the age at treatment for undescended testis and the risk of testicular cancer . Methods : Sweden, 1964-1999 population database with 16,983 men who underwent orchiopexy and followed for a total of 209,984 person-years

48. Testicular torsion 10x higher risk in undescended testes Decreased salvage rate due to diagnostic delay Singal AK, et al. Undescended testis and torsion: is the risk understated? Arch Dis Child 2013; 98:77.

49. Overview Case Background and History Testicular development and pathophysiology Evaluation and Diagnosis Associated pathology Management Conclusions

50. Treatment strategies Observation Medical hormonal therapy Surgery Exploratory laparoscopy Primary orchiopexy Single stage Fowler-Stephens o rchiopexy Two stage Fowler-Stephens orchiopexy

51. Observation Variable rates of spontaneous descent 7-88% reported in literature Testes complete descent within 3-4 months old and spontaneous descent is rare after six months of age

52. >6 mo

53. Medical Hormonal Therapy Rational Administration of gonadotropins (either hCG or LHRH) may stimulate testicular descent Evidence Highly variable success rates reported from 0% to 75 % C onfounding variables in available studies including: inclusion /exclusion of retractile testes variable age/duration of treatment different dosing and regimens small cohorts

54. Medical Hormonal Therapy Penson DF, Krishnaswami S, Jules A, et al. AHRQ Comparative Effectiveness Review No. 88. Available at www.effectivehealthcare.ahrq.gov /undescended- testicle.cfm .

55. Medical Hormonal Therapy AHRQ Evidence Review hCG vs. placebo (AHRQ Evidence Rating: Low ) LHRH vs. placebo (AHRQ Evidence Rating: Moderate ) hCG vs. LHRH (AHRQ Evidence Rating: Low ) “ Providers should not use hormonal therapy to induce testicular descent as evidence shows low response rates and lack of evidence for long-term efficacy. ” (AUA Standard ; Grade B)

56. Exploratory Surgery Diagnostic and potentially therapeutic In boys with nonpalpable testes, specialists should perform EUA to reassess for palpability. If non-palpable , surgical exploration and, if indicated, abdominal orchido-pexy should be performed (AUA Standard; Grade B) B lind ending vessels and vas Intraabdominal testis

57. Primary Orchiopexy Outcomes S uccess rate for testicular descent 96.4% ( range 89.1 – 100% ) O verall testicular atrophy rate for 1.8% ( range 0 – 4% ) In prepubertal boys with palpable, cryptorchid testes, surgical specialists should perform scrotal or inguinal orchidopexy (AUA Standard; Grade B)

58. Fowler-Stephens Orchiopexy Outcomes Success rate for testicular descent was 78.7% ( range 33 – 94.3%) for one-stage and 86% ( range 67 – 98 %) for two - stage T esticular atrophy rate 28.1% ( range 22 – 67%) for one-stage and 8.2%( range 0 – 12% ) for two- stage

59. Laparoscopic Repair Outcomes Success rate for testicular descent was 74% (65-100%) for orchiopexy and 63% (60-97%) for Fowler-Stephens Testicular atrophy rate 2-22%

60. Timing of surgery Purpose : compare the growth of congenital, unilaterally UDT following orchiopexy at age 9 months or 3 years. Methods : Karolinska University Hospital, 1998. A total of 164 boys with unilateral palpable undescended testis were randomized to orchiopexy at 9 months (n=72) or 3 years (n=83) J Urol 2007; 178 : 1589.

61. UDT

62. Descended testis

63. Timing of surgery The growth of unilateral undescended testes may be impaired compared with the normally descended contralateral testes Treatment before one year of age may be associated with partial catch-up growth In the absence of spontaneous testicular descent by six months (corrected for gestational age), specialists should perform surgery within the next year (AUA Standard; Grade B)

64. AUA Guidelines for Treatment

65. AUA Guidelines for Treatment (cont.)

66. Overview Case Background and History Testicular development and pathophysiology Evaluation and Diagnosis Associated pathology Management Conclusions

67. Future Directions Genetic and environmental factors that contribute to cryptorchidism Define role of cross sectional imaging with CT, MRV, or MRA in locating undescended testes Long term outcome data on fertility Comparative effectiveness of surgical interventions based on location of testes One vs. two stage Fowler Stephens Open vs. Laparoscopic orchiopexy

68. Conclusions Cryptorchidism is extremely common Imaging for cryptorchidism is not recommended prior to referral, which should occur by 6 months of age. O rchiopexy is the most successful therapy to relocate the testis into the scrotum, while hormonal therapy is not recommended. Successful scrotal repositioning of the testis may reduce but does not prevent the potential long-term issues of infertility and testis cancer . Appropriate counseling and follow-up of the patient is essential.

69. Case: Clinical Course 3 month old otherwise healthy boy with left non-palpable testicle since birth. Testes intraabdominal at laparoscopy Repaired by one-stage Fowler-Stephens orchiopexy at 7 mo. Doing well

70. References Campbell MF, Wein AJ, Kavoussi LR. Campbell-Walsh Urology. 9th ed. Philadelphia: W.B. Saunders; 2007. Cooper , C., et al. ( 2015, April 17). Undescended testes (cryptorchidism) in Children : Clinical features and evaluation. Retrieved November 9, 2015, from UpToDate . Huff, et al. (2001). Abnormal germ cell development in cryptorchidism. Hormone Research , 55 (1), 11–17. Janus, et al. (2014). American Urological Association (AUA) Guideline on Cryptorchidism, 1–38. Kollin , et al . (2007). Surgical Treatment of Unilaterally Undescended Testes: Testicular Growth After Randomization to Orchiopexy at Age 9 Months or 3 Years. The Journal of Urology , 178 (4), 1589–1593. http:// doi.org /10.1016/j.juro.2007.03.173 Lip, et al. (2012). A meta-analysis of the risk of boys with isolated cryptorchidism developing testicular cancer in later life. Archives of Disease in Childhood , 98 (1), 20–26. http:// doi.org /10.1136/archdischild-2012-302051 Penson , et al . (2012). Evaluation and Treatment of Cryptorchidism . EHRQ Report. Pettersson , et al. (2007). Age at surgery for undescended testis and risk of testicular cancer. The New England Journal of Medicine , 356 (18), 1835–1841. http:// doi.org /10.1056/NEJMoa067588 Singal , et al . (2012). Undescended testis and torsion: is the risk understated? Archives of Disease in Childhood , 98 (1), 77–79. http:// doi.org /10.1136/archdischild-2012-302373 Thorup , et al . (2013). The Relation between Adult Dark Spermatogonia andOther Parameters of Fertility Potential in Cryptorchid Testes. Journal of Urology , 190 (S), 1566–1571. http:// doi.org /10.1016/j.juro.2013.01.058 van Brakel , et al . (2014a). Journal of Pediatric Surgery. Journal of Pediatric Surgery , 49 (4), 599–605. http:// doi.org /10.1016/j.jpedsurg. 2013.09.020