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Dialogue Archives: Part I: The Children's Hospital of Philadelphia Treatment Approach to Cryptorchidism
(Volume 24, Number 12, December 2001)

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Guest Editor: Douglas A. Canning, MD
Michele R. Clement, MD Howard M. Snyder, III, MD
J. Christopher Austin, MD Dale S. Huff, MD
Susan L. Rusnack, MSIV Hsi-Yang Wu, MD Dale S. Huff, MD Howard M. Snyder, III, MD Michael C. Carr, MD Richard D. Bellah, MD Stephen A. Zderic, MD Douglas A. Canning, MD
In this issue and the one that follows, we plan to update Dialogues readers on our experience with the treatment of boys with undescended testis.
Our approach has evolved during the last 17 years through the guidance of John Duckett and Howard Snyder. Drs. Duckett and Snyder initiated a long and lasting relationship with Faruk Hadziselimovic of Switzerland in the early 1980's. During a sabbatical at Children's Hospital of Philadelphia (CHOP), Dr. Hadziselimovic, working with Dale Huff of our pathology department, helped to establish our testis biopsy program. This program has been an ongoing one since 1985.
In this issue, Michele Clement and Dr. Snyder review a series of our recent discoveries. Next, Dr. Huff and Chris Austin discuss II how to perform and read a testis biopsy. The CHOP method of analysis and reporting of prognosis for fertility is described by the authors. Our hope is that some of the mystery of the pathological assessment and potential impact on fertility will be easier to understand as a result of their contribution. With this background, Susan Rusnack, Hsi-Yang Wu, and others on our team present a preliminary correlation of testicular histopathology and future spermiograms.
In January, Michael Carr shares his thoughts on the assessment of the early hormonal milieu in cryptorchidism and how this is important in the developing testis. Our new CHOP associate, Thomas Kolon, reviews some of the current concepts on the molecular biology of cryptorchidism. I then summarize
Richard M. Ehrlich, MD
Clinical Professor of Surgery/Urology
School of Medicine
University of California, Los Angeles
William J. Miller
my impressions of how these observations have affected my treatment for the child with an undescended testis.
We hope you will find these issues of Dialogues informative and useful.
Douglas A. Canning, MD
Director, Division of Urology, Children's Hospital of Philadelphia
predictive of fertility, the testicular volume was compared with germ cell count. Although there was a generalized trend of smaller testes to correlate with a lower germ cell count, the range was large and thus testicular volume could not accurately predict germ cell count on a case-by-case basis. Testis biopsy has remained a necessary component in the evaluation of the fertility potential in patients with an undescended testis (Noh and colleagues: J Urol, 163:593-6, 2000).
After describing the morphological and histological changes found in the general cryptorchid population, the database has been screened for populations of subtypes of cryptorchidism.
latrogenic undescended testis. latrogenic cryptorchid testes are those which were not noted to be in an undescended position until after surgical manipulation, namely hydrocoele or inguinal hernia repair. There were no significant differences in volume or total and differential germ cell counts in either the affected or contralateral testis in patients with an iatrogenic undescended testis compared with those with a unilateral primary undescended testis. When there is a greater than five-year interval between initial surgery and orchiopexy, the mean number of germ cells per tubule is significantly decreased in comparison to the iatrogenic undescended testes repaired within five years.
The evidence suggests that there is germ cell maturation defect in these testes similar to other boys with undescended testes. They may represent a mild form of undescended testis, unrecognized prior to herniorrhapy. Early surgery to correct iatrogenic testes is advocated (Fenig and associates: J Urol, 165:1258-61,2000).
Ascending testes. Similar comparisons were made between normal testes, ascending testes, and contralateral controls. An ascending testis was defined as one that on initial exam by a competent observer was noted to be in the scrotum, but on subsequent exam is found to reside outside of the scrotum. Patients with an ascending testis without prior surgical procedure also had germ cell counts similar to those with a primary unilateral undescended testis and may represent a low form of true undescended testes which become more clinically evident with time and growth. What are felt to be retractile testes in small boys need careful follow-up.
Ectopic testes. Pathologic findings in ectopic and undescended testes were compared. No significant difference was noted in the number of germ cells per tubule, testicular volume, the incidence of patent processus vaginalis, or epididymal abnormalities in these patients. The similar findings suggest that ectopic and undescended testes are variants of the same congenital anomaly (Hutcheson and coauthors: JUrol, 163:961-3,2000).
Division of Urology, The Children's Hospital of Philadelphia
Division of Urology, The Children's Hospital of Philadelphia A Review of Recent Findings at CHOP
Introduction. We would like to review a few of the more recent discoveries that have been made at CHOP. These findings are beginning to help us understand the histopathology of the cryptorchid testis and its impact on fertility as the child ages.
Testis database. From 1985 to the present at Children's Hospital of Philadelphia, a library of more than 3000 testis biopsies in a wide range of genital anomalies from varicocoele to testis torsion to intersex has been compiled. Biopsies were obtained at time of orchiopexy from the affected as well as the contralateral testis. Additionally, the size of both testes, morphology of the epididymis, and the patency of the processus vaginalis were recorded. All of the specimens in the database have been reviewed by a single pathologist.
Histology of the normal testis. The normal surge in gonadotropin and testosterone at 60 to 90 days of life leads to the first postnatal step in the maturation of male germ cells. Gonocytes disappear and dark spermatogonia simultaneously appear at ages three to six months. Primary spermatocytes appear at ages four to five years, marking the onset of meiosis.
Histopathology of the undescended testis. There is a defect in germ cell maturation in the cryptorchid testis. The germ cell to tubule ratio is normal to increased, and the gonocyte to tubule ratio increased in the first year of life, reflecting nontransformed gonocytes. In the second year of life, nontransformed gonocytes undergo apoptosis, resulting in a low total germ cell count per tubule. The adult dark (Ad) spermatogonia per tubule count decreases as a result of failure of maturation. In both the cryptorchid and contralateral/descended testis, there is a failure of meiosis and the transformation of Ad spermatogonia to primary spermatocytes.
Testis volume versus germ cell count/histology. In an attempt to determine if testis size alone would be
Prune Belly Syndrome. The subpopulation of undescended testes in patients with Prune Belly Syndrome (PBS) was compared with other patients who had bilateral abdominal testes. Histopathologic changes were similar between the two groups. Both groups exhibited a maturational defect, manifested as a decreased number of adult dark (Ad) spermatogonia. This study does not support the concept of undescended testes in PBS as resulting from a mechanical cause.
Proximal hypospadias and cryptorchidism. The work generated from the testis database points toward an endocrinopathy as a contributing factor to most cases of cryptorchidism. It follows that cryptorchidism would be more prevalent or severe in those patients with other pathologies possibly due to hypogonadism, such as hypospadias. Patients with hypospadias and cryptorchidism were reviewed. Those with proximal hypospadias had a higher incidence of bilateral undescended testes. In those with unilateral cryptorchidism and hypospadias, the contralateral (descended) testis has a decreased volume and Ad spermatogonium to tubule ratio, suggesting that there is a more severe endocrinopathy and more than one organ system has been affected.
A review of our testis biopsy database has provided new insight into the possible pathophysiology of many different genital conditions. We anticipate there will be further contributions in the future.
portion of tissue to protrude. Once an adequate amount of tissue is exposed, the sample may be obtained. It is extremely important to handle the tissue gently. Any grasping of the tissue with forceps will destroy the architecture of the tubules and germ cells and may make the sample uninterpretable. To remove the tissue, use the scalpel in an oscillating fashion across the surface of the tunica. The back and forth motion of the blade will do the cutting and traumatize the tissue much less than the shearing action of the scissor's blades. The biopsy is lifted up using the scalpel blade as a spatula and then gently placed into a small tube of refrigerated 1 % glutaraldehyde. The small specimen tube is placed in a beaker containing ice and delivered to pathology immediately. Alternatively, Bouins' solution may be used. The tunica albuginea is closed with a running 6-0 polyglyconate suture. The testis is then placed into the dartos pouch and the procedure is completed.
Histological methods. The biopsies are fixed in glutaraldehyde overnight and then transferred into buffer until they can be further processed. They are then embedded in Epon, sectioned at 0.4 microns, stained with toluidine blue, mounted on microscopic slides, and histologically examined with a high quality light microscope at 60X magnification. The biopsies range from less than 1mm to 2mm in greatest dimension. An adequate biopsy contains complete cross sections of a minimum of 50 uncrushed tubules. A biopsy less than 1 mm in diameter is likely to be inadequate for evaluation. A biopsy which is 2mm in diameter may contain 200 or more tubules. Common sense and good judgment must be used in interpreting biopsies with fewer than 50 uncrushed tubules.
Morphometric analysis. A histologic data sheet is set up to record the morphometric data for each biopsy. Each horizontal line of the data sheet represents one tubule. Vertical columns are established, one for each subtype of germ celi-gonocyte, fetal spermatogonia, adult dark spermatogonia, adult pale spermatogonia, B spermatogonia, primary spermatocyte, secondary spermatocyte, early spermatid, late spermatid, sperm, and not classifiable (NOS), and finally, a column for the total number of all germ cells.
Morphometric analyses are performed on both the undescended and contralateral descended testes, including total and differential germ cell counts. Using a mechanical stage, the left edge of the microscopic field is placed at the left edge of the tissue section, and the field is moved to the most inferior point of the tissue. The number of each subtype of germ cell and the total number of all germ cells are recorded separately for each complete tubular section one tubule at a time. After all the tubules in the field of view have been examined and the number of germ cells recorded for each, the field of view is moved vertically up to the next field and the process
The Children's Hospital of Philadelphia
Division of Urology and Department of Pathology, The Children's Hospital of Philadelphia
How to Perform a Testis Biopsy and How to Interpret It
Performing the testis biopsy. The biopsy is not performed until the testis has been brought down to the scrotum and just prior to its placement into the dartos pouch. This ensures that the testicular vessels have adequate length for the testis to remain in its new scrotal position. Using a fresh #20 scalpel blade, a vertical incision is made through the tunica albuginea at the superior pole of the testis. The length of the incision is approximately 4-5mm. Gently squeezing the testis at its posterior aspect will cause the testis tissue to protrude through the incision. Our aim is to sample a piece of tissue which measures 1mm x 1mm x 1mm. If there is poor protrusion of the testis tissue, then undermining the tunica albuginea on either side with a scalpel blade will free the attachments of the surrounding tubules to the tunica and allow a larger
repeated, one tubule at a time, and one field of view at a time. When the top edge of the tissue is reached, the field of view is moved horizontally to the next lateral field of view and the process is repeated, moving the field of view vertically downward to the bottom of the tissue. The analysis is continued until all tubules have been examined and all germ cells recorded. Then, the number of total germ cells per tubule, the total germ cell count, and the number of each subtype of germ cell per tubule, the differential germ cell count, are calculated.
A system to insure that no tubules are counted more than once and that none are missed should be developed. To accomplish this for each field of view, all tubules completely within the field and all those that extend beyond the left and upper edges of the field are analyzed but those that extend beyond the right and lower borders of the field are not counted. They will be included with subsequent fields. Also, when the field of view is moved vertically or horizontally, the edge of the new field should just touch but not overlap the edge of the last. This process is more precise if an eyepiece reticle with an engraved square is used.
After the germ cells have been evaluated, the process is repeated for the Leydig cells. First, all the tubules in a field are counted and then all of the Leydig cells in the field are counted and recorded. The process is repeated for each field of view until at least 20 tubules have been counted. The number of Leydig cells per tubule is then calculated. The type of Leydig cells — fetal, juvenile, or adult—should be recorded. Finally, the presence or absence of tubular atrophy, interstitial fibrosis, carcinoma-in-situ, or other unusual features should be recorded.
The surgical report. The final report records the data from both the undescended and contralateral descended testes. It should include the total germ cell counts and indicate whether they are normal; mildly, moderately or severely reduced, or elevated for age. The prognosis for future fertility is determined by the total germ cell counts of the undescended and contralateral descended testes, and the quality of the contralateral descended testis determines future fertility more often than that of the undescended testis. The degree of maturation is determined by the differential germ cell count and is recorded in the final report. Various subtypes of germ cells appear or disappear with successive maturational steps at certain ages. Failure to attain the normal developmental landmarks at the proper ages constitutes abnormal maturation. Recent studies suggest that failure of maturation of gonocytes into adult dark spermatogonia at three months of age may be the best indicator of future subfertility, and the maturation in the descended testis is almost always more important than that in the undescended testis.
As with white blood cell counts, the total germ cell count may be normal in the face of an abnormal differential germ cell count of clinical significance. The Leydig cell count should be recorded in the final report and an interpretation of whether it is normal; mildly, moderately or severely reduced, or increased, should be recorded. The final diagnosis should also indicate the presence or absence of tubular atrophy, interstitial fibrosis, and carcinoma-in-situ.
This analysis of the undescended and contralateral descended testes may take an hour or more. The time required can be shortened by having an assistant record the findings while the pathologist calls out the counts allowing the pathologist to keep his or her eyes constantly fixed on the microscopic section. Even more time can be saved if the counts are entered directly into a computer program which can save every data point, compute the germ cell counts, and generate the final report.
Division of Urology and Departments of Pathology* and Radiology** The Children's Hospital of Philadelphia
Testis Histopathology in Cryptorchid Boys Correlates with Future Spermiograms
In 1998, we began a long-term follow-up study to assess the fertility of patients who had previously undergone orchiopexy and bilateral testis biopsy for cryptorchidism. Patients were eligible for the study after reaching age 18. To date, 24 patients with unilateral undescended testes (UUDT) and eight patients with bilateral undescended testes (BUDT) have been evaluated. The mean age at surgery was 9.8 years {range 3-19 years). Patients underwent physical exam, scrotal ultrasound, semen analysis, and serum determinations of luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone, and inhibin B. Previously obtained biopsy results were stratified into mild, intermediate, and severe groups based on total germ cell counts in each testis (Table 1). For patients with BUDT, the more severely affected testis was considered undescended and the less affected testis was considered the contralateral descended testis. The normal counts were obtained from Huff's and Hadziselimovic's previously published data.15
Results. UUDT patients in the severe histology category were more likely to have a sperm density less than 20 million/cc compared with patients with intermediate histology (8/14 vs. 0/10, p=0.0064 Fisher's exact) (Figure 1). The patients with severe histology also had a significantly lower total sperm count than their intermediate counterparts (55.3 million vs. 147.3 million, p=0.0042, analysis of variance) (Figure 2) and 3/9 intermediate and 10/14 severe patients had total motile counts less than 40 million sperm (p=0.102, Fisher's exact). There were no statistically significant differences between the severe and intermediate categories when comparing FSH, LH, testosterone, inhibin B, and testicular volumes. There are currently no UUDT patients in the mild histology category.
Patients with BUDT did not demonstrate any significant differences between histological categories. Six of eight (75%) had a sperm density less than 20 million/cc (Figure 3). Six of eight also had a total motile count of less than 40 million sperm. There were three intermediate histology and five severe histology patients. Again, there were no biopsy specimens that qualified for the mild category for BUDT.
Discussion. This is the first American study to correlate testis biopsy histopathology and fertility potential in the cryptorchid male. It is also the only study to correlate bilateral testis biopsy with fertility potential. Hadziselimovic found that cryptorchid boys with fewer than 0.2 germ cells per tubular cross section in the undescended testis had a high likelihood of infertility in adulthood. This applies to both UUDT and BUDT, despite successful orchiopexy.20 In another study, he found that 50% of UUDT patients had germ cell counts of less than 0.1 per tubule, which correlated on spermiogram with 41 % who were severely oligospermic or
azoopermic.17 In contrast to Cortes, who found no difference in fertility potential for orchiopexy performed between the ages of two and twelve, we found that including the pathology of the contralateral descended testis allowed us to select the high risk patients.16
We found no correlation between adult hormonal levels and testis histopathology and spermiograms. Inhibin B appears to be the most sensitive indicator of the integrity of the seminiferous tubules.1 A correlation has also been demonstrated between increased FSH levels and lower sperm counts in cryptorchid men. Higher FSH levels were found particularly when investigating a subset of men who reported unsuccessful attempts at paternity as compared to those who were successful.7 Another study demonstrated more normal serum levels of inhibin B and FSH in men who underwent orchiopexy by age two years.8 This indicates there is further damage incurred in the testis when left in the cryptorchid position, typically from exposure to a higher temperature. Our study did not reproduce such findings, but the patient population was small, especially when compared with other papers regarding hormone levels.
Testicular volume did not serve as an accurate indicator for fertility potential in our patient population. Noh attempted to use testicular volume as a possible replacement for testicular biopsy. Although testis volume correlated to germ cell count, the confidence interval was too wide to accurately select those patients with poor histology.18 We found no correlation between testis volume and testicular histology, nor was there a correlation between the testicular volume and the results of the semen analysis.
We found that using the total germ cell count per tubule
TABLE 1. Criteria
for Classification of Testicular
GC/T within 1 standard deviation of age-matched normal
GC/T>= mean GC/T for age-matched normal
GC/T <= mean age-matched UDT GC/T
GC/T at least 1 standard deviation below the mean for age-matched normal
All others
All others
FIGURE 1. Sperm Density in UUDT
FIGURE 2. Total Sperm Count in UUDT
FIGURE 3. Sperm Density in BUDT
Number of bilaterally cryptorchid men
for both testes served as a fairly accurate indicator of fertility potential in UUDT males when examining semen analyses. Hadziselimovic states that at birth all cryptorchid boys have germ cells that are in the normal range. However, after the second year of life, 25% to 40% of all cryptorchid testes have completely lost their germ cells. Fertility potential is clearly dependent on the number of testes affected (unilateral or bilateral cryptorchid ism) and the total number of germ cells present at the time of orchiopexy.11
The intermediate group uniformly had densities greater than the W.H.O. standard of 20 million/cc, whereas 62% of the severe UUDT group fell below this standard. In men with a sperm density of less than 20 million/cc, it is statistically more difficult to achieve pregnancy.2 There was also a significant difference in the total sperm counts between these two groups. Even more striking is the total motile count (TMC) calculated by multiplying the total number of sperm by the motility percentile. This measurement is important because motility is a key factor in the ability of a
sperm to fertilize an egg. For fertility treatment, 40 million motile sperm is used as a dividing point for those patients considered to be normal.2 Thirty-three percent of the intermediate group had TMC below this point, but 71 % of the severe group fell below this standard. Based on these results, total germ cell count seems to be a fairly good indicator of UUDT fertility potential, using our method of stratification.
When examining BUDT, we found that the total germ cell count was not an accurate indicator of fertility potential. Seventy-five percent of participants had sperm densities below 20 million/cc and the highest sperm densities occurred in men with severe histology. Also, 75% had a TMC less than 40 million. The low sperm densities and TMCs bode poorly for the fertility potential in BUDT.
A weakness of our study is that the patients had only one semen analysis. Infertility evaluation usually requires three separate samples in order to eliminate any anomalous counts. We also had a small patient population of 32 total cryptorchid men and all had
their orchiopexy after the age of two years. In a study by McAleer, no significant differences were found between fertility index measurements (spermatogonia per tubule) in undescended testes and those previously reported in normal testes for patients younger than one year of age. However, there were significant differences in all the other age groups.5 Fenig found that even within the first year of life, testicular histopathology demonstrates a defective maturational process in the undescended testis.21 This idea was taken one step further by Huff when examining testicular histology in children. He found that at age five years, undescended testes and the contralateral descended partners failed to progress to more mature forms of spermatocytes.22 Based on the studies cited above, our results may not be applicable to patients who had orchiopexy before the age of two. It is known that orchiopexy alone does not cause improvement in the testicular histology, but it can prevent further thermal damage. Lee found no correlation between paternity and patient age at orchiopexy.1 This is important since our patient population was three years or older at the time of orchiopexy. Our study population consists of the first patients to reach the age of 18. Soon, we hope to extend our study population to include men who had orchiopexy before the age of two years.
In order to elucidate the presumed endocrinopathy of cryptorchidism (hypogonadotropic hypogonadism), the testis biopsy of the contralateral descended testis is critical. Determining the total germ cell count per tubule is a fairly accurate way to discern which patients may be best suited for GnRH analogue stimulation therapy in an attempt to increase the germ cell number and stimulate the maturation of these germ cells.20 For patients with BUDT, perhaps all of the intermediate and severe patients should receive GnRH therapy, considering the generally poor results of the semen analyses. References
1.    Lee PA, Coughlin, MT, Bellinger MF: Paternity and hormone levels after unilateral cryptorchidism: association with pretreatment testicular location. J Urol, 164:1697, 2000.
2.    Turek P, Department of Urology, University of California, San Francisco: email correspondence, 10/25/2000.
3.    Nistal M, Riestra ML, Paniagua R: Correlation between testicular biopsies (prepubertal and postpubertal) and spermiogram in cryptorchid men. Human Pathology, 31:1022, 2000.
4.    Friedman RM, Lopez FJ, Tucker JA, et al: Fertility after cryptorchidism: a comparative analysis of early orchidopexy with and without concomitant hormonal therapy in the young male rat. JUro/, 151:227, 1994.
5.    McAleer IM, Packer MG, Kaplan GW, et al: Fertility index analysis in cryptorchidism. J Urol, 153:1255, 1995.
6.    Leissner J, Filipas D, Wolf HK, Fisch M: The undescended testis: consideration and impact on fertility. BJU, 83:885, 1999.
7.    Lee PA, Bellinger MF, Coughlin MT: Correlations among
hormone levels, sperm parameters and paternity in formerly unilaterally cryptorchid men. J Urol, 160:1155,1998.
8.    Coughlin MT, Bellinger MF, Lee PA: Age at unilateral orchiopexy: effect on hormone and sperm count in adulthood. J Urol, 162:986, 1999.
9.    Swerdlow AJ, Higgins CD, Pike MC: Risk of testicular cancer in cohort of boys wfth cryptorchidism. BMJ, 314:1507, 1997.
10.  MoMer H, Cortes D, Engholm G, Thorup J: Risk of testicular cancer with cryptorchidism and with testicular biopsy: cohort study. BMJ, 317:729, 1998.
11.  Hadziselimovic F: Cryptorchidism. In RetHc AB, Cukeir J (eds): Pediatric Urology. BaJtfmore, WUiams and Wifkins, pp 271-281.
12.  Gracia J, Sanchez Zalabard J, Sanchez Garcia J, et al: Clinical, physical, sperm and hormonal data in 251 adults operated on for cryptorchidfsn in childhood. BJU, 85:1100, 2000.
13.  Engeler DS, Hosli PG, John H, et al: Early orchiopexy: prepubertal mtratubular germ cell neoplasia and fertility outcome. (Urofogy, 56:144, 2000.
114. Hadziseliimovic F, Herzog B, Buser M: Development of cny-ptorchid testes. Eur J Pediatr, 146;S8,1987.
HE Hiiff DS, Hadziselimovic F, Snyder HM, et al: Postnatal testicular maldevelopme nt in unilateral cryptorchidism. J Urol, 142:546,1989.
163 Cortes D, Thorup JM, Linden berg S: Fertility potential after unilateral orchiopexy: an age independent risk of subsequent infertility when ksiopsies at surgery lack germ cells. J Urol, 156:217, 198B;
M*..Hadziselimovic F, Herzog B, Hocht B, et al: Screening for crjptorchid boys; risking sterility and results of tong-term buserelin treatment after s uccessful orchiopexy. Eur J Pediatr, 146:59, 1987.
18.  Noh PH, Cooper CS, Snyder HM, et al: Testicular volume does not predict germ cell count in patients with cryptorchidism. J Urol, 163:593,2000.
19.  Hadziselimovic F, Thommen L, Girard J, Herzog B: The significance of postnatal gomadotropin surge for testicular development in normal and cryptorchid testes. J Urol, 136:274, 1986.
20.  Hadziselimovic F, Herzog B: Treatment with a luteinizing hormone-releasing hormon e analogue after successful orchiopexy markedly improves the chfince of fertility later in life. J Urol, 153:11193,1997;
21.. Fenig DM, Htutcheson JC, Cannimg DA, et at: Histopathology of unilateral cryptorchid test:es during the first year of life. Presentation at the AmericamAcademy of Pediatrics 2000 national meeting.
22. Huff DS, Rsraig DM, Canning DA,, Snyder HM: Normal onset of meiosis at fiveayears of age fails in both undescended testes and their contralateral descended partners. Presentation at the American Academy of Ptediatrics 3800 national meeting.
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Copyright © 2001 by William J. Miller Associates, Inc.
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