Dr. Bartley G. Cilento, Jr. - Cryptorchidism: The "Almond Joy" Disease

The OK. OK, I guess we better get started, everybody. Good morning. Um. We'll, uh, start here with the introduction. I'm sure a few more will, uh, start trickling in. But, uh, today is our pleasure to uh welcome Doctor uh Bartley Cilento, um, from our urology group. He's gonna address, uh, the topic of cryptorchidism. Uh, Doctor Cilento currently serves as a program director, uh, in our urology program. He's had, he's held this role since 2009. Uh, he completed his medical degree at Tufts University and did his residency in urology, as well as his fellowship in San Diego. He serves as an assistant clinical professor at UCSD prior to joining our faculty at this institution. Here he has completed a master's in Public Health at Harvard, a public health school, and he continues to be actively engaged in clinical research, having authored over 40 papers, as well as a number of other chapters and reviews. Since 1998 to 2008, he was also an active member of the United States Naval Reserve, where he retired as a captain. Under his stewardship, the Urology Fellowship at uh our uh Hospital has continued the tradition of training the future leaders in pediatric urology. Please join me in welcoming Doctor Cento to, to the podium, please. Thank you for that kind introduction. Um, so, um, thank you for inviting me to talk to you today about, uh, crypto orchidism. Um, it is a large topic, uh, but, um, I will do my best to cover some of the salient points about this. Um, I will tell you personally that the operative, uh, treatment of crypt orchidism is fairly straightforward. It's a highly successful procedure. Uh, it takes about 30 minutes in the operating room. Some of the more interesting aspects of crypto organism are going to be more along the lines of what's been discovered with some of the basic science research, which hopefully will lead to better treatment and diagnosis and even preservation of fertility and reduction in malignancy, which we'll talk about. So I've, I've fondly. coined this topic, the almond joy disease, and then we'll talk to you about why that is. So if you recall, Peter Paul, uh uh candy company had uh almond joy and mounds, and their kind of limerick was sometimes you feel like a nut and sometimes you don't. So really with crypt orchidism, it's sometimes you feel a nut and sometimes you don't. Sometimes you feel like a Sometimes I don't. So for those of you that are old enough in this audience to remember, uh, that was uh a very common uh refrain you would hear on these uh commercials. So we'll talk a little bit about the embryology of testicular development. We'll talk about, uh, the, the, um, embryology of testicular descent, and then we'll get into the more clinical aspects which are, you know, the, um, um. Things like how do we treat this, how do we diagnose it, um, the issues with malignancy and fertility. So obviously everything derives from the Greek and so cryptos means hidden and oros means testes. So this starts the embryology portion of the testes, and the human gonadal ridge contains both somatic and germ cells, and these are located on the medial urogenital ridge at about 32 days after conception. And at this point these cells are indistinguishable from male and female. Um, you can see here we have the indifferent gonad, um, here and under certain gene activations and their associated proteins, they will either develop into the testes or the ovary. These primordial germ cells actually originate in the yolk sac and then will migrate up at about the 5th week of gestation. We see that there's the earliest expression of some of these genetic markers that begin between about 41 and 44 days, and again, SRY SOX 9. The SRY is considered the master gene for masculinization of the fetus. So this is a micrograph that shows the early embryonic development, and what I want you to appreciate is that there is very close proximity of the of the kidney developing with the sex cords, which are really at this point the undifferentiated gonad. And then you have the mesonephris and pronephros. These two structures are really interesting because during the time of surgery, we'll see that there is either an appendix testis or an appendix epididymis, all of which I think you've seen in the operating room, and these are really originating from these structures. These are sort of the embryologic remnants of those structures. So this is just a cartoon depicting early development and basically at the time of conception we can be both male or female, and which one develops is based on the expression of certain genes and hormones. So here you have the indifferent gonad, you have the Wolffian system, which is destined to be the male system, and then you have the Millerian system, which is destined to be the female system. And you can see these corresponding structures, for example, fallopian tubes, uterus, in the male, we're talking about the epididymis, the vas deferens, and the seminal vesicles. So, uh, continuing on histologically, uh, we, we can find that there's evidence of Sertoli cells and testicular cords at 9 weeks. Well, what are Sertoli cells? Sertoli cells are these structures that you see down here that sort of, if you will, envelope or encase this spermatogonia, and they allow for the maturation of ultimately of maturation of spermatogonia up into actually sperm. And they produce a substance called anti-mullerian hormone, which I want you to remember because this will be important in the process of differentiation of the of the embryo. With regards to um lydig cells, they can be identified at about 9 weeks of gestation, and lydig cells are, um, and I'll show you a micrograph later, but these are outside the seminiferous tubules. These are the cells that are basically responsible for the production of testosterone. Which has the feedback onto the anterior pituitary. Um, with regards to the actual germ cells, which are the spermatogonia, we can see, um, um, cell markers, which is C kit at about 7 weeks of gestation. So, you know, this whole process, this is a very simplistic and brief overview, but gonadal determination without question is very complex. And highly orchestrated. So we talked, we just spoke about spermatogonia and lying cells, and this is just a micrograph showing that these outside of the seminiferous tubules, which is the structure here, you can see the lying cells. And again, these are the cells that actually produce the testosterone. Within the seminiferous tubules, we can see these, the spermatogonia in various stages of development, which is spermatogonia to spermatocytes, spermatozoa. And this is just a higher picture of the thing, and you can see this progression. This is the most basic cell, the spermatogonium, and then you get the spermatocyte, and then you get spermatids, and then out in here you can actually see the formation of a fully formed sperm. Um So, one of the, I put this up because I wanted to show you that um we're gonna see some micrographs of a crypt orchid testis, and I'm gonna, I want you to appreciate the difference. But you can see the seminiferous tubule has a very thin layer. Um, and again, there's these supporting cells, which are the sertoli cells, which will produce anti-mullerian substance, and then the various progression of the spermato spermatogonia. So again, the SRY gene is sort of the master gene in this entire process of development, but there are certainly others that are involved, and testicular determination is really directly dependent upon the activation of other things like SOX 9 and fiberglass growth factor 9, whereas ovarian development results in obviously other activation of other genes and their proteins, RSPO1. And WNT4. And again, you can see that depicted here and here. So, um, you know, this is all stuff that, you know, 10 years ago, 15 years ago, we didn't know anything about. So there has been a lot of work in sort of looking at what causes testicular differentiation and what, why does it result, where does it go wrong and why does this result in either infertility, cancer, and or um uh mal descent. So the hormonal function of the fetal testes is also critical for masculinization and for ultimately for testicular descent. In the beginning, there are a series of fetal lytic cells which I pointed out early, but it's interesting that these fetal lytic cells will undergo a series of 3 phases of development, but ultimately, they will totally involute. So, you have a proliferation differentiation phase. It goes for about 7 to 14 weeks. They will mature all the way up to 18 weeks, and then all of a sudden they spontaneously go involution. But then what happens is that there's a re-emergence of a different population of lighting cells, which we call the neonatal lying cells, and this happens in about 2 to 3 months. No one really understands why there has to be a precursor lighting cell and then a final lying cell that's still being looked at, but this emergence of the neonatal lighting cells actually corresponds to a sudden peak in testosterone and insulin-like growth factor 3. And what it appears to do is it appears to take the gonocyte, which I'll show you a picture of, and actually cause a differentiation of that to what we call an AD spermatogonia, where everything just freezes in time from that 2 to 3 month period, and then it waits until puberty, and then there's further development. And I'll, I'll show you a picture of that so you'll, you'll understand that. The synthesis of testosterone embryologically will start at about 6 to 7 weeks. Initially, this whole process is independent of gonadotropin stimulation and probably is orchestrated by the placental HCG, which stimulates this androgen activity production, um, but then eventually the testis becomes responsive to central responses from the pituitary like LH and FSH. Um, It's important to note that the Sertoli cells, which were those supporting structures, actually produce a substance called the anti-mullerian hormone, and this is, or it's also known as MIS, but this substance actually causes the regression of the Mullerian system. Otherwise, if it didn't produce that, basically we would we would have both female and male internal systems. So, um, the, the fetal, um, mullerian duct system, which you can see over here, actually becomes responsive to this anti-mullerian hormone, uh, before 8 weeks and then causes regression between 9 and 10 weeks. Um, There are androgen receptors and estrogen receptors. They're both expressed in the undifferentiated gonad at about 7 weeks. It's interesting that the androgen receptors are found on the myoid, lydig, and interstitial cells of the testes, but of all the cells contained within the testes, they're absent um on the Sertoli cells. The reason for that is that the androgens will inhibit anti-mullerian production by the Sertoli cells. So therefore, their absence is really logical because if there were androgen receptors on the Sertoli cells, you wouldn't have anti-melian production, and you would have both internal and external or internal and female and male systems. Um, sort of another interesting fact is that there's a lot of estrogen receptors that seem to be expressed on all of the male cells within the testes. It's really uncertain what these are, but it's postulated that these really play a role in testicular development, but it's really not well understood. So as I stated, the fetal lytic cells will regress after birth, and they're replaced by this new neonatal population of lytic cells at about 2 to 3 months, and you get the subsequent peak in testosterone and insulin-like factor II, and this results in a central surge of the gonadotropins, and this causes sort of this development in the first few months of life of the intratubular gonadocytes to migrate from the basement membrane and become spermatogonia. And this is important because if this process doesn't happen, there's a thinking that if this population of neonatal gonocytes do not develop, these may be the precursors for inchesticular germ cell neoplasia and subsequent germ cell tumors. So here's that depiction. So here's the, the fetal gonadocyte, and under the 1st 23 months, 2 to 3 months of hormonal stimulation, these will then sort of evolve into these AD spermatagonia. And this is where everything sort of will stay quiescent. Until puberty, and then once puberty hits, there's a further progression from the Aedes spermatogonia to the primary spermatocytes, and then this whole process then begins. So it's interesting that the Sertoli cells undergo continue to go under proliferation all the way through the first year of life, and this seems to be a major determinant for testicular size, and you can see a 2.6 fold increase in testicular size between ages 1 and 10 years of age, and this is primarily due to the proliferation of Sertoli cells. So this slide is to remind me that we're finally done with the embryology section, so you can breathe a sigh of relief and move on to uh testicular descent. Um, testicular descent, is becoming fairly well understood, but not completely so. There appears to be 5 major determinants of testicular descent. There's this caudal mesonephros that contacts the gubernaculum, and it happens very early in embryogenesis, where it's occurring at the internal ring. Uh, the genital femoral nerve seems to be a player in this process, and it seems to accompany the the gubernaculum at about 7 to 10 weeks of age. Following this, there's a large growth of the testes. There's regression of the mallerian ducts, which we just talked about, and then the testes actually contacts the gubernaculum. Um, the gubernaculum, by the way, means rudder in Latin. So, it's thought that this is guiding the process of testicular, uh, uh, development. Uh, or descent. So there's in the gubernaculum, what happens is there's this mesenchy mesenchymal tissue that begins to sort of enlarge and proliferate and swell, and it's actually causing this sort of this almost kind of paving the way for this path down the internal inguinal ring. So the swelling continues, the cremasteric muscle starts to develop, and we get the migration of the prosthesis vaginalis. Interestingly, and no one really understands this, there seems at this point there's a release of the gubernaculum from the testes, so they're not in continuity with one another yet. The gubernaculum seems critical to testicular descent. This trans inguinal passage of the testes occurs at about 20 to 28 weeks, and then subsequent to that, there's fertile caudal movement of the testes into the scrotum with regression of the gubernaculum, and this occurs at 7 months and beyond. So it's not until about 7 months that you start to see the testes sort of in the scrotum. And here's this picture, you know, kind of depicting this process. You can see obviously that this is the gubernacular mesenchyme, and this is the thing that begins to proliferate and expand, causing the testes to descend through the inguinal canal. So the process there are really, and then to break this down into a sort of a 30,000 view, there are kind of two major processes the transabdominal descent and the and the and the inguinal descent. The transabdominal descent occurs very early in embryogenesis. It's about 75 to 7 weeks, um, and it does not appear to be androgen, male specific. More importantly, it doesn't appear to be androgen sensitive, so this just happens. Without hormonal stimulation, but the trans inguinal descent is definitely androgen dependent. So there's subsequent swelling of the gubernaculum, which again is is critical to the descent, resulting from proliferation of the extracellular matrix. Um, again, the gubernaculum is unattached distally during and after transangal passage, which is really a surprise, but no one really understands why. Um. So the passage of the testes into the inguinal canal really begins prior to 22 weeks of gestation, but the majority of the testes are actually in the scrotal position by about 27 to 28 weeks of gestation. So I think the thing to take away is that insulin-like growth factor 3, testosterone are key in gubernacular development and and in the process of testicular descent, primarily of the trans inguinal descent. These androgens and insulin-like factor 3 work synergistically to promote cellular proliferation, growth of gubernaculum, and descent. The role of the gubernaculum, the genital femoral nerve is really unclear, but there's been speculation that this is that there's a release of a calcitonin gene related peptide that causes stimulation of the gubernaculum and subsequent contraction of the gubernaculum, aiding in descent of the testes. So finally, uh, key points, SRY is the master gene that's uh um that derepresses the critical test is determining factors like SOX 9 and fibrogloss growth factor. The differentiation of gonocytes, sotoli cells, and lytic cells occur at about 5 to 9 weeks of gestation. Um, testosterone and insullike growth factor 3 peak. Um, and then at 14 to 17 weeks of gestation are critical for testicular descent, and the gubernain clearly is, is, uh, involved in the process of testicular descent. And this process of gubernaculum is really the result of just stimulation of the extracellular matrix and perhaps maybe the genitofemoral nerve, and ultimately the testes will be in this testicular position at about 28 weeks. So that brings us to more of the more clinical aspect of crypto orchidism, which is really the classification and treatment. So this is a picture of an intraabdominal testes, as you can see where there's the internal ring here and the testes and the epididymis. So again, as we said, the gubernaculum really is actually the rudder. Crypt orchidism refers to the absence of the testes within the scrotum. Some of the subtleties of this is that there can be not all undescended testes are equal. We think of a crypt orchid testis as a testes that's following the normal course of descent from the intraabdominal position to the scrotal position. So for example, you can see here, this is the inguinal ring or intraabdominal. This is high inguinal. Uh, lowering it all and then the scrotal position. So this is the normal path of descent. So this would be what we would call an undescended testes, whereas this is not along the normal course of descent. This is a baby that has a testes that's located in the perineum. Um, and this is what we would consider an ectopic testes. So, interestingly, um, surgically what we see is that an ectopic testis is really a fully descended testes, so we don't usually see a patent processis vaginalis with these ectopic positions because the process of descent has completed and the tunica vaginalisis subsequently closed, whereas in in distinction in an undescended testes, that process of normal descent hasn't occurred, so. It stops and so there isn't subsequent closure of the tunica vaginalis. So we'll see a patent, we always find, you know, a patents processes vaginalis with a truly undescended testes, whereas commonly with an ectopic testes, we do not. Um, and then of course, we also have the possibility that the test has never developed either at the because of some. Catastrophic event at the Gnado Ridge or perhaps it's at the inguinal canal, and there's a vascular event and we end up with a vanishing testes. So crypto organism is certainly one of the most common congenital anomalies. From a pediatric neurologist's perspective, this is probably the 2nd, 3rd most common procedure that we end up seeing and treating. Um, in terms of its incidence, I always remember 44 and 40. So, in 4% of term infants, you will have crypto orchidism or undescended testes. However, in upwards of 40% or 45% of premature infants, you can see an undescended testes. Excuse me. The pathogenesis is really, uh, it's fair to say it's unknown. But it appears to be multifactorial. There are probably genetic components, and there may also be environmental factors due to exposure to um androgens, or androgen, I should say, um, antagonists. The genetic component is thought to be polygenic and multifactorial. The most cited mode of inheritance is autosomal dominant with reduced penetrance. There is a relative risk of crypto orchidism. It's 10 to 1 in twins, 3.5% in brothers, and about 2 2.3% of offspring. This is helpful because some parents will ask, is there a risk of subsequent or undescended testes in subsequent pregnancies. Um, crypt orchidism can be both, uh, syndromic and non-syndromic. So in a non-syndromic crypto orchidism, the, the risk factors include prematurity, low birth weight, a breach presentation, and maternal diabetes. There's also this concept of ascent of the testes, which is thought to be an acquired phenomenon. This really is a group or a small population of patients where the testes was previously thought to be descended through birth, and then as they undergo somatic growth at the ages of somewhere between 8 and 12 in boys, it becomes clear that the testes is no longer in a scrotal position and is at the scrotal inlet. And the explanation for this is that, you know, when babies are born they're about 21 inches, so that area is very compact and the testes is very mobile, so a low lying testes could easily be construed as being in a satisfactory position within the scrotum, but as these kids begin to grow and they get to be 4 and 5 ft, that whole area sort of spreads out and it becomes clear on a subsequent exam that the testes is really at the scrotal inlet. It was probably in that position all along, but just not really recognized, and this has been coined ascent of the testes. The ratio of syndromic to non-syndromic to syndromic crypt orchidism is 6 to 1, so by far and away the most common cause is uh non-syndromic. Uh, with related to the syndromes, they can be related to diseases that result in reduced androgen production and or action, either because of androgen biosynthesis defects or androgen insensitivity or receptor issues. There can be lying cell agenesis or gonadotropin disorders. With regards to the musculoskeletal and CNS and abdominal wall defects, which, which you are all familiar, they include things like prune belly, spageian hernia, cerebral palsy, arthrogyposis, meningomyocele, phalocele, gastroschisis, and perfanus, postureurethral valves, and umbilical hernia. So this is a photograph of a baby with Eagle-Barrett's syndrome or prunebelly, and 100% of these children's children have crypto orchidism that need treating. Um, As far as the diagnosis and classification in a large clinical series, about 80% of these testes are palpable on examination. 60 to 70% are unilateral crypt orchid patients. In the European studies, they've had similar results where 8% are abdominal, 63% are canalicular, which is inguinal. Uh, 24% prescrotal and 11% would be superficial inguinal pouch, which is another one of those ectopic positions. So they're, they're fairly comparable findings. Um, the non-palpable testes, this is probably of all the ones that we deal with is the most challenging one. the, uh, possible clinical findings at the time of uh laparoscopy include that in 50% of these cases, you'll find that it's located in the abdomen, generally right at the, at the internal ring. Peeping means that there's a large hernia sac and sometimes these testes can slide in and out of the internal inguinal ring. Uh, and upwards of 40%, you can find that they're atrophied or vanishing, but that I would say would be high. I would say that the rate of atrophy really is quite low in my experience, probably in the range of about 15%. And then, of course, you might not find the test is in the abdomen at all, and there can be a couple of reasons for that. One can be that there, it's actually in the inguinal canal. And in today's environment we have a lot of obesity, so sometimes a small prepubertal testes really can't be palpable on exam, and you might be surprised that it's actually located in the inguinal canal, even though you cannot feel it on a good examination either in the office or under general anesthesia. Um, So, with regards to the vanishing testes, um, this diagnosis can be made, but it has to be made after documentation of blind ending spermatic vessels. You have to see those to be certain that this is a vanishing testes. Um, in boys that have bilateral non palpable testes and or laparoscopy or bilateral non palpable testes, um, you can either perform laparoscopy, you're sure they're not intraabdominal, but if there's a suspicion that these may be an orchid boys, you can make this diagnosis medically. You can usually these boys will have a high FSH and LH, and they will have a non-etectable anti antimullerian. A hormone and inhibit, and that has been used. What has also been used in the past, but isn't recommended is you could stimulate these boys with HCG and then subsequently test for testosterone. So if there's testicular tissue, of course, you would then cause this sort of sudden bump in testosterone. But it doesn't appear to be as sensitive as testing for um inhibit an immuran hormone. A lot of pediatricians will refer patients with an undescended testes and obtain an ultrasound. Um, basically, ultrasound really is not helpful in the diagnosis or management of the undescended testes by and large, because if you diagnose. Uh, an undescended testes by ultrasound. You're still relegated to doing an orchiopexy. Um, if you're using it to try to find an intraabdominal test, this ultrasound is very poor at making that diagnosis. They've also done head to head studies with ultrasound, and pediatric urologist Jack Elder did that study a long time ago and showed that a good examination is actually more sensitive than an ultrasound. So in this era of cost containment and um Conserving medical dollars, we really uh discourage the use of uh adult ultrasound and diagnosis, diagnosing the undescended testes. So after having said that, I will say that there's probably one scenario where it may be beneficial. In a boy who is obese and you cannot examine them well enough, if you do an ultrasound and you can diagnose an inguinal testis, that would obviate, it doesn't obviate the need for surgery, but it does obviate the need for diagnostic laparoscopy, so then you can proceed directly to an open orchiopexy. So in that, in that particular instance, it may be beneficial. Um, laparoscopy is now the procedure of choice for evaluating the non-palpable testes. We have now growing evidence that early orchiopexy may be beneficial. This is because there's, there can be abnormal development of the germ cells that occur very early after infancy, upwards of maybe 2 years. We can start to see these changes. So we're thinking that early intervention may be beneficial, although that is yet to be conclusively proven. Um, and again we spoke earlier that the reason why this happens is there may be impaired transformation of these embryologic gonatocytes to the spermatogonia, and this may in the future play a role in sort of predicting fertility potential for these boys. So treatment, what, what are the goals of treatment? Treatment is to optimize testicular function to potentially reduce or to facilitate the diagnosis of testicular cancer. There's the obvious cosmetic case for this, and there's a prevention of hernia and torsion. In my 19 years here, I've had one infant who we diagnosed with undescended testis. We generally wait till they're about 6 months of age due to anesthetic concerns. Also, there is a chance that an undescended testis may descend, and we'll get into that in a second. But in that process of waiting, the child underwent that that inguinal testis underwent torsion. So it is possible, although the probability of that is really quite low. But there's always a hernia there that we find and that needs to be addressed as well. So those are sort of the treatment goals and the reason why we proceed with surgical intervention early. Consensus now supports early surgical treatment at 6 months, and there's there's reasons for that. If you look at term infants, we said that the undescended rate is about 4%. But if you look at 6 and 12 months, it's very low. It's like 9 and 0.7. So the difference between descent, further descent at 6 months and 12 months is 2.1%. But the difference between birth and 6 months is quite large. So what this tells us is that if testicular descent is going to occur, it's going to happen probably within the 1st 3 to 4 months after birth, and the risk of this and the chance of descent beyond 6 months is really minimal. So that's sort of our optimal window to then perform the procedure, and they're sort of cleared from an anesthetic perspective, at least with current thinking. So the surgical treatment of crypto orchidism, um, the key steps involve really making your inguinal incision, identifying the testes. Um, we then sort of transect the gubernaculum. We remove the cremasteric muscles, um, and dissect the testes all the way to the internal ring. We identify the hernia sac and separate away that from the vas deferens and spermatic vasculature and ligate that. And then there's also this other process, which is actually can be very helpful. Is that there are, once you've ligated the hernia sac, there can be these lateral spermatic fascial bands, and these can actually give you an additional 0.5 centimeter of length, um, depending on how high the testes is. So you're really carrying your dissection more proximally or on a retroperitoneal fashion. Um, once that's done, um, We open the tunica vaginalis down towards the testis, and my practice is to remove any of those appendages, whether they be the appendix, testes, or epididymis. This uh sort of removes the possibility that they would present to the emergency room later with torsion of the appendix testis, which is a really a common occurrence and keeps our residents up. So, um, once that's all achieved, then you make a scrotal incision. Um, here you, um, then sort of dissect the pouch, and then you take a hemostat, you grab the gubernaculum and you transpose it down through the scrotal incision, and basically, that should be sufficient because if you've done enough of a dissection, there's no tension on the testes. Um, however, some people do, will fix the testes. They'll take either a suture through the dartos fascia through the tunica alvainia. My preference is not to do that, um, and My personal thinking is that the testes is an imm immunologically privileged site, so I don't want to violate the tunic Albainia. Um, an alternate way to do testicular fixation would be to grab the dartos fascia and put it through the sort of mesonephrosis of the, of the testes, which provides just another area of fixation ultimately. Um, and of course, then you just close your incisions and, and you're off. This can also be done laparoscopically for the intraabdominal testes. Um, this is, again, like I said, the procedure of choice. It can be done in a one-stage or a two-stage, uh, process. One-stage means that we would just mobilize the testes intraabdominally without transecting the spermatic vessels and uh. So here you can see the the issue with the intraabdominal testes is that the vasculature of the testes emanates close to the renal artery. And if you recall when I showed you that black and white micrograph that the the kidney and the sex cords are right in close proximity to each other. So the vas vasculature follows that. So as the kidney ascends, the testes descends. But yet the vasculature remains in close proximity. So this is really our tether to getting this testes from the intraabdominal position all the way into a scrotal position. So that's why these are our most challenging cases. So one technique is to mobilize this testes on a posterior peritoneal window and and try and hope that you have enough length to get into a scrotal position. Alternatively, you can stage this where you, the first laparoscopic stage you would clip. The testicular artery, and the test is within Survive on the deferential cremasteric artery and these undergo hypertrophy. And then 6 to 8 months later you come back, transect between your two clips, and actually take the testes and just flip it down into the scrotum. So this is a photograph of an intraabdominal testes. You can see this has grasped the gubernaculum, and you've pulled it out through the internal ring and you would transect here. You would then begin to mob and the vast deference is now coming from medial to lateral, and you would mobilize this on a posterior peritoneum, either clipping the vessels or having left them intact. Then you make a scrotal incision and you can insert a port site. This is usually medial to the inferior epigastric vessels, but lateral to the bladder. Use a grasper and you actually just pull the testes down through and into the scrotal position. In this particular case, they've done this as a one stage, and you can see that these are the spermatic vessels, and they're on a little bit of tension, but sometimes you can get them into a satisfactory scrotal position. I, I will say that my preference has been to do this in a two-stage process. Um, it's interesting that even high inguinal testes, we can sometimes have some difficulty getting enough length to get them into the scrotum. So the thinking being is that if it's even proximal to that, why would I have an easier time getting it in a one stage? And I've been in the past unhappy with some of the results of trying to do a one stage. You come back, you see these patients, and it's either high in the scrotal inlet or even above the pubis, and doing a subsequent orchiopexy in a scarred area is very challenging, and, and it has a high rate of testicular loss. I put this in for completeness. There was a time, particularly in Europe, less so in the United States, where hormonal treatment was thought to be the treatment for the undescended testes. However, there's been a lot of rigorous studies that have done that have really shown that there's really marginal effect over placebo, and this is either using HCG as a stimulant, but the other one was buscerelin, which is an LHRH analog and stimulates germ cell development. It was thought also to increase the spermatogonia to the transsection of the tubule ratios to increase fertility. Long story short, uh, they're non-randomized studies. They're not blinded, and so ultimately there's really little, if any, high quality evidence to support hormonal treatment, so we just don't do it. Um, fertility. Both Aedes spermatagonia and germ cell reductions appear as promising measures for fertility in the future, in the future. However, the predictive value really hasn't been confirmed, and this is still a story waiting for a conclusion. Um, Interestingly, studies that have used semen analysis for fertility potential are interesting. They, they show that there's consistent differences in semen density, motility, morphology between controls, both in unilateral and bilateral undescended testes. But the interesting thing is, Fraternity, which is actually the best measure for fertility, shows a better picture. It shows that with bilateral and descended testes, 65% of these men are able to achieve pregnancy. 90% of unilaterals are able to achieve pregnancy, and if you look at the controls, it's 93%. So the counseling that I give is that in unilateral undescended test system, the fertility rates are nearly identical to the general population, and there's very little worry. The big, the, the big drop in fertility is, is with boys that have bilateral undescended testes, and, and you can either further sort of dice this as well because bilateral intraabdominal testes are going to have a higher rate of infertility than bilateral low inguinal testes. So I think the summary is that fertility potential is somewhat compromised in men, particularly with bilateral undescended testes. If you look at, you know, the hormonal and semen parameters, but the relative risk of infertility as measured by paternity data is much better. And this is really just depicting that if you, if you look at these are normal semen analysis in boys that have an undescended testes and bilateral undescended testes, um, you can see that in the unilateral undescended testes, it's between 70% and 95% have normal semen analysis, whereas in the bilateral group it's low, much lower, 40 to perhaps or 20 to 40%. But when you look at the paternity data, it's much better. Even in the bilateral undescended testes, paternity rates range from 33 to 48 to 60%. Malignancy. So that's another big concern when parents come in. In fact, that's usually the one they talk about the most is the risk of malignancy. Um, I think the short story is that testicular cancer is very rare. And although testicular cancer in crypt orchidism is higher, it's still higher than very low, and, and, and that's sort of the message I think you have to give parents in a very simplistic way. If you look at men with a history of undescended testes, they only, they only account for 10% of men that present with testicular germ cell tumors, so a very low percentage. Um, the theory is, again, they get out of sight are the precursors of this process, and they did that their failure to transform normally may be the, may be the cause. However, if you look at the literature, the relative rate of malignancy transformation in undescended testes is about 2.5 to 8 times the general population. However, when you kind of look at this even more closely, the relative rate is only about 2 to 3 when their orchiopexies are done in early in life. Um, we know that if you, uh, untreated, undescended testes, so these men get to adulthood, the more likely tumor that they're going to develop would be seminoma. Seminoma of all the germ cell tumors is the most favorable. It's highly radiosensitive, um, and, and very treatable. Histologically, this is what a crypt orchidestus looks like. Um, you can see um that the There's pertubular fibrosis. There appears to be a paucity of cells within the seminiferous tubules. These are only the supporting cells, which are Sertoli cells. What you do not see here, you do not see any spermatogonia or spermatids or any of that, uh, those cells. Um. This is a, a bigger picture, and here you can see these are these uh what they call intertubular germ cell neoplasia. So this is sort of the precursors of testicular cancer. Again, these are just side by side. You can obviously see the difference between these two. This is a normal testes and this is a crypt orchid testis. And again, you do not see any of the spermatogonia, primary spermatocytes or spermatids. So this would be a patient obviously that would have azospermia. Um, so the relative risk of malignancy in prepubertal boys is about 2 to 3 times the relative risk. Um, it's interesting that it corresponds to a reported risk of CIS of about 2 to 3% in previously crypt orchid boys, um. In testicular cancer, the contralateral testes may have CIS in it, and the general population, it's about 11 to 2%, so it doesn't appear to be any different than the general population. So there was this practice in an undescended testes to biopsy the contralateral testes. The problem is if you biopsy the contralateral testes and you see this. Uh, tubular germ cell neoplasia, what do you do with that? Do you recommend an orchiectomy, and so now you're making this boy an orchid? Um, and so this practice has really fallen by the wayside because We don't know whether this intertumor germ cell neoplasia guarantees that the individual will go on to develop testicular tumor, so the practice is not to biopsy the contralateral side. All right, so for fun, uh, crypto-organism increases the risk of all the following except Um, sporadic cord torsion, clinical hernia, reactive hydrocele, infertility, and testicular malignancy. Well, the answer is reactive hydrocele. Everything else does occur in crypto orchidism. The risk of crypto-organism is higher in all of the except cerebral palsy, cystic fibrosis, arthroglyposis, prune belly, and poster urethral valves. Answer is cystic fibrosis. Interestingly though, cystic fibrosis. Um, the, the thing that's associated with cystic fibrosis is absence of the vass, so. Something to keep in mind. And the percentage of uh undescended testes that are non-palpable at presentation. It's 20%. So, in conclusion, um, testicular descent is very complex. Germ cell development is important, may be impaired, and may be the precursor for testicular cancer ultimately. The long-term effects appear to be really unclear. There's a strong role for surgical management, and I would insert early surgical management, and there appears to be little role. Uh, for hormonal manipulation. Now, uh, given our recent, uh, weather, uh, in Boston, I, I have some good news for you that we have evidence that hell has finally frozen over. So that concludes any questions or comments, you'll be welcome. Thank you. Great, uh, presentation of the, the topic and particularly, uh, reviewing the new, uh, Newer information about the genetics. So, uh, so two questions, um. One is obviously the, the early timing of. Uh, archiopexy before 6 months, it doesn't affect the risk of, of, of, of uh tumors. What is, what is the, the driving force to recommend that, that it be done now at 6 months rather than a year, which used to be the The classic teaching because I, I don't think there are really studies that show that there's differences in fertility between those two times. No, no, no, there, there, there is, we, we, we don't have that kind of granular data about fertility potential, um. So you're asking between 6 and 12 months. Really, the issue is that the that there is no expect, there is little or no expectation that further descent will occur beyond 6 months of age. Um, so, you know, the other, the other factor is that when you do an archiopexy on an older child and you do it in a younger child, it's definitely easier on a younger child. At 6 months, the tissues are so elastic, the vascularity of the spermatic cord is, and the distance that you have to gain between getting it in the inguinal position to the scrotal position is, is shorter, um, so that the more the child grows and expands, the more you have to have a length to get that into the scrotum. So, Since the, the, since the feeling is that there's no increased anesthetic risk between 6 and 12 months, and there's little expectation that the testes would descend and the child is at 6 months immobile and not walking. That it seems to be an ideal time to do the procedure with no added risk. And unless, until we find evidence from our anesthetic colleagues that, you know, an anesthetic at 6 months is different than an anesthetic at 12 months. There doesn't seem to be any real benefit to waiting till 12 months. So it's really the technical performance of the procedure and not any effects on the fertility. The, the, the studies that we do know is looking at um the change in, you know, spermatogonia, the density of the spermatogonia within its tubules. They've shown that um there starts, there, there are changes that begin. Up to or at around 2 years of age. So now he's now gone back and done further biopsies and studies to show that those changes are really beginning at say 6 months or 12 months. I think the, the supposition is, is that this is probably a kind of a spectrum that just, that the loss of spermatogonia doesn't really happen suddenly at 2 years, that it's probably an ongoing process. So again, The thinking being that earlier orchiopexy may be beneficial. So it, but there's no hard evidence, so you're right. But you know, no one could be, no one could be faulted for doing it at 12 months either for other reasons. In fact, it's interesting we just did our indications. It's, it's You know, you would think that in today's environment we'd be seeing all these kids at birth or shortly at birth and doing all of our orchiopexies at 6 months of age. It's not true. We, we're seeing kids that are on our surgical schedule that are 4567, and 8. I just saw a kid who was 18. Someone just made the diagnosis. So, um, The the age of our archopexes is really all over the map. Additional questions for Doctor Solando. Hey Burt, thanks very much. I, I just to follow up on that, I remember as a medical student that, that, uh, children, they, they were, the idea was that you do them just prior to puberty. So you had these 10 and 12 year old kids who are coming in and getting their orchiopexy. So, and obviously at that point you, it was clear that there were changes in the, in the, uh, uh, maturation of the, uh, of the testicles. So that was important that, uh, the timing is, it continues to be. A bit of an issue because in fact the AAP right now, if you look on their website on very poor data is saying that we shouldn't be doing elective operations before 3 years of age. Now, to be honest with you, none of us have taken that very seriously, but it's out there and it's something that the public sees and, and perhaps is unduly conservative, but it certainly weighs in this timing sort of issue. The one specific question I wanted to ask you was that you mentioned that about 40%. Of premature babies will have or up to 40% of premature babies will have undescended testes. I wonder if that changes your, your time frame in terms of the six months. If you're dealing with a premature baby, do you, do you want to give longer, or is it, uh, doesn't really impact? No. So when we, when we recommend surgery, they have to be, to be an outpatient. Procedure. They have to be 60 weeks post conceptual age. So we end up doing all the math, um, they end up being much older than sort of 6 months to get to that period of time. So, yes, the answer is really yes, we are waiting a little bit longer on those babies. Yeah. I've certainly always taught the or instructed the parents of when we're doing the orchidopexy as far as the, the neoplasia, you really aren't changing the, the frequency of neoplasia unless you're, you know, doing it way after puberty, but then it puts a testicle where, you know, it's gonna be palpable and masses can be identified by the patient rather than. Still having an intraabdominal where, yeah, you know that's that is, that's a very nuanced discussion because um I, I, I would, I was taught the same thing, um. Part of the risk of testicular cancer development really has to, you, you can't have the conversation without discussing the position of the testes, the initial position of the testes. So for example, a boy that presents with intraabdominal testes, I would say is at higher risk for developing testicular cancer than a boy that presents with a testes that's located at the scrotal inlet. Um, but, but I do believe, and I think it will eventually come out that the longer you wait, Uh, and the longer that testes is in an abnormal position, the higher the risk for, for malignant transformation. Uh. You know, I think, I think that's probably I think eventually we'll probably be born out cause we, we seem to see, for example, if you look at the, the data that the relative risk of cancer in kids that have had early orchiopexies versus late orchiopexes, as best as we can tell by the available literature seems to be better, as well as the the fertility potential to get to them early. So, you know, the testes needs to be in the scrotum because it's 5 degrees cooler than core body temperature, which is needed for normal development of all the cellular tissues. So, the longer that testes remains in a higher heat environment, the likely, so the presumption is that that's causing some of this uh either malignant potential or the, the diminishment of the spermatagonia. So Excellento, thank you. Uh, are there circumstances then when you, uh, for these late presenters, you know, teenagers or, or so that, that you proceed with orchiectomy straight away or what leads you to that? I was waiting for that. Comment that is, uh, it's very controversial, um, and we have debates within our department all the time about this. Um. Cause we, we tend to be reconstructive-minded versus uh uh extirpative, you know, and removing a gonad is something that we really don't wanna do. Um, there is literature that would make the case that in a post pubertal boy, orchiectomy is probably the way to go. But again, it's a nuanced discussion. If, if I, if I saw a teenage boy postpubertal who had intraabdominal testis. That's easy. I would do an orchiectomy. Because uh. The struggle that you're going to have to get that testes in a postpubertal boy all the way into the scrotum in a satisfactory position and likely have Uh, exocrine function or probably have endocrine function, meaning production of testosterone, but probably not participate in fertility or sperm, is very low. So what are you achieving one, so in that case, just removing the testis is the way to go. This 18 year old boy that I saw last week, who has a testes that's sitting right at the scrotal inlet. I am more likely, I, I, I'm proposing that we bring that testes into the scrotum. Just for the psychological effect, it's gonna be in the scrotum. He'll be able to examine it, um, and But what I will probably do is do a testicular biopsy at the time of his orchiopexy, just to make sure to one, either to document that the testis has fertility potential one, but to make sure that there's no evidence of intertesticular germ cell in the equation, if there is, we'd have to have that conversation about subsequent orchiopexy orchiectomy, excuse me. So, but it's, it's not clear cut and a lot of people would try to preserve the testes and bring it down. Bert, I wanted to ask you 11 more question, that is, what do you quote with, with your stage Fowler Siemens procedure? What do you quote parents as the likelihood that that testicle will, will atrophy or not? Yeah, so you, you know that the historical rates of the open. Um, one stage Fowler Stevens, and just to remind some of the others in the audience, the one stage procedure is where you mobilize the testes, transect the vessels because you don't have enough length, and you put it into the scrotum. That risk is probably in the old literature, it's like it was a 50/50 proposition of testicular survival. With the laparoscopic approach, we've done much better. And so I would, I, I usually will tell parents that the rate of atrophy with a sec with a two-stage laparoscopic orchiopexy. The rate of atrophy is probably in the range of 10 to upwards of 15%. Much better than our, our former open procedure, but still not, not insignificant. All right, it's terrific review. How do you approach timing of bilateral intraabdominals? You do them simultaneously. You do one, then the other. You do one and a stage 2 on the other. Um, so 3 procedures, 3 anesthetics. Um, the first anesthetic is, um. Making the diagnosis. Clipping the first vessel. Right. Then coming back 6 to 8 months later. The 2nd procedure involves the 2nd stage orchiopexy on that side where I've clipped the vessels, and if that goes really well, I will then at the end of the procedure, clip the contralateral vessels. Wait an additional 6 to 8 months and come back and do the second stage on the last side. The argument being that if you lose one, you got to think a lot about what you want to do with the second one. Yeah, well, yes, and It, it's there's no reason, no, no, right, but it's a time to pause and tell the parents, OK, this is what's happened, you know, I, I, I really want to prepare them for the possibility that this second stage might not go well, and it may be an orchid, and what does that mean, um, that type of thing. So yeah, I, I've done the same thing, and, and, and I, I unfortunately I haven't had the situation where I've had to like where I've lost the testicle and not. Not on the other side, but I, I probably would have that long discussion about actually if I lost the first one, leaving the second one until after puberty, so they went through full development and, and the fertility is already pretty compromised and be willing to potentially lose fertility and have that discussion. Yeah, I also think that it It's sort of you're in your last stage. It depends on, you can be somewhat aggressive or you can be more conservative in your mobilization and your dissection and stuff, so I think it it helps doing it in that fashion. Well, thanks a lot. Great presentation, thank you very much for having me.