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OK. Uh Yeah, shoulda shall we start now? Yes. OK. Um OK. Uh Good afternoon, everybody. Uh Thank you for waiting patiently and soon you will realize that this wait was really worth it because uh today, uh Doctor Jua who is our register is going to talk about rhabdomyosarcoma. He has been mentored by our consultant, Doctor Ya Manic. And we really have uh the honor and pleasure of having Professor Larry Headley as our invited guest. Um uh I don't think there is anybody in this uh audience in the participants who doesn't know Professor Headley. Um So I really won't say much about his professional achievements. Um And, and all the research activities. I just very briefly mention his strong uh connection to our department of pediatric Surgery in East London. And it, it goes uh as far back as uh the time uh when the department was in absolute infancy. And I think it was exactly uh 25 years ago when Professor Headley was the first consultant from outside East London to visit our department. And I still remember the day when we had presented him cases in the old ward, 25 at hospital and since then, pro has always been um available for guiding. Um I remember fondly uh two weeks which I spent with him in Durban in 2004 when I was preparing for my exam. And uh all our registrars have the honor and privilege of, of uh being trained uh under his til. And we also thank him for giving us Doctor Yoda manic and we are not ready to release her. I don't prof uh uh Professor Colin Lazarus Col fly sends his regards and his apologies. Unfortunately, he is still coming back from his leave so he can't be with us. And uh our format will be Professor Doctor Julie will present initially. Uh then I will invite pro to share his thoughts. He has a few slides and after that, I will invite later, Doctor Moni and Doctor Mataya uh to come in all the other participants. If you have any questions for Doctor Juna or hardly or Doctor Moni, please just type them into the chat box and we will try and, and uh address to them at the end. Um ok. So John de la, I will stop sharing my screen and I will let you share your screen. All right, prof thanks. Ok, you can go ahead. All right. Um Good evening. I'm Doctor Jua, um pediatric surgery, Registrar in East London and Water Sisulu University. Today, I'm going to be talking about the rhabdomyosarcoma in Children. Ok. I'm just gonna start off um by talking about the definition. So um it is just describing what it is. It is a primary malignant in Children and adolescent. It is a fast growing and highly malignant tumor and it arise from the primitive um muscle cells. Um You need a high index of suspicion and early diagnosis is a key factor in the prognosis of this disease. So, um demographics and rhabdomyosarcoma, they form 50% of all soft tissue sarcomas. Uh They account for about um 5% 4.5 of all childhood cancers. And it is the third most common extracranial solid tumor. Um after worm's tumor and neuroblastomas, its distribution is bimodal. Uh You, you have a peak at age between two and six and you have another peak in um late teenagers uh between the age of 15 and 19. It has a slightly higher uh preference for male than female at the ratio of three is um is to two and it is also um more common in Caucasians and uh Noncaucasian just to mention. Ok. Um So, histology uh it is described as a small uh round blue cells. Like most of our pediatric um um tumors, there are small round blue cells but what really um demonstrate that it's a rhabdomyosarcoma is the immunochemistry where you want to see if the there are desmin and um actin and the myogenin. Those are the specific markers that you can pick up on your immuno. Uh chemical results added into two broad uh types, embryonal and um alveolar uh embryonal being the most uh common um which has its own subtype, which is a uh spin cell um subtype. And uh and you have your um but uh subtype as well, your alveolar is the one that is, has um poorer prognosis and it is common more on the extremities and trunk. It just um so this is just a histological um picture uh which basically represents um your embryonal uh histology. This just showing a dense um spindle areas. And you can see also with a loose uh strong how these tumors are actually described. They've got a loose uh stroma and you can see them and then you have your alveolar type which this one shows dense trauma with um pseudoalveolar um space. So um this, this light uh actually under the microscope, I can show you this uh and these lines and the, it looks like um alveolar of the lung and it's a name. OK. So um tumor biology, which um actually also forms part of uh prognosis and it also determines uh what type of treatment that the patient is going to get. So, it's also uh important uh in these rhabdomyosarcomas. So, for your embryonal type, there is um there is a loss of heterozygosity at um 11 p and 15 locals. That is where the insulin like. Um I do my, there are frequencies tetraploid and um translocation on your FK HR gene. And from chromosome 13, with, with either PEX three on chromosome two or pe seven on chromosome. Um one, this is associated with a poorer uh prognosis and 25% of them, they can be translocation um negative and those ones, they behave more like um embryonal um Neuromyo sarcomeres. I mean, there are a couple of associated uh condition with breast cancer with neurofibromatosis. Uh This patient, they have up to 7% chances of getting um malignancies. So they are also at a high risk of getting uh rhabdom, um myo myosarcoma. There is other syndromes that are not uh so common like your liver syndrome, which is an autosomal um g mutation, which basically increases uh the risk for leukemia brain tumors and breast cancer, including the including the rhabdomyosarcomas. And then you have your back with vitamin syndrome, which we see mostly these kids they present with um omphalocele. They can have um they can have microglossia and uh are in the high risk also of um hypoglycemia. But they are also high risk for development of rhabdomyosarcoma. The picture here and what we have is actually uh Rubenstein syndrome, which these kids, they present with a short stature and they have these broad thumbs on them, on, on their toes and, and, and, and, and their femur. So when you see some of these conditions, you need to think about um the risk of, of, of uh rhabdomyosarcomas uh some of the environmental factors that have been mentioned at the and um cocaine can be intrauterine exposure to X ray or previous exposure to alkylating agents. These are common sites of origin uh for the tumors. So, by sarcomas, they've got specific areas that they grow into, they can actually go anywhere where there is um mu muscles and these um sites of origin, they're actually divided into favorable sites and unfavorable sites Uh depending on how the tumor in that area um does in prognosis, but we're still gonna go um into that on ne next coming slides. So, um clinical presentation. So this this patient, they may present with an expanding mass. Uh it can be painless or they can have um pain or they can even present with um metastatic related um symptoms can present with bone pain if they've had um metastatic on the brain as well or in the lungs, they can present with the, the lesion in the chest, uh x-ray or sometimes it can be picked up uh hematologically when they've had a bone, um marrow spread as well. But most of the symptoms, they actually depend on the location of the tumor itself. So, in, in the pi this patient, they will present with um things like um proptosis and uh sicula, it will be a painless scrotal mass with uh prostate. You will have your bladder and your bowel difficulties. It could be um also bladder outlet obstruction or urinary retention or constipation. And with your uterus at your cervix, you can have menorrhea or menorrhagia. And in the vagina, you can get a protruding uh polypoid mass which looks like a bunch of grapes and it can uh easily can somehow be um missed uh for, for HPV. Uh warts. So you just need to watch out if you have um, young babies that have uh what you think might be um genital warts. It might be something more sinister in the extremities. They can present with the painlessness or sometimes it, it it can have um you can have uh some pain with your parameningeal. They actually affect mostly your sinuses. So you present mostly with your upper respiratory um symptoms and they can also present with your rhinitis and then that will point you towards that. It's more um on your sinuses, your paramenia. So, um imaging uh for the for investigation. So you can have a plain X ray for a primary area of consent or a chest X ray. So, this is helpful in determining uh the presence of calcification and the involvement of bone in the primary uh tissue. And also you can look for metastatic disease in the lungs just from the plain chest X ray. The role from ultra sound um can be used in um also as an investigative to look out for the masses which mostly in the abdomen. It's mostly useful there to identify the mass, but also even uh for ultrasound, guided biopsy. And you can also be able to pick up uh metastatic um disease on the ultrasound. Um And then you have uh the CT scan which basically shows you the extent of the lesion. And then it shows you also uh if there are metastatic um lesions already. And then we also have our MRI. So, MRI is a gold standard for soft tissue uh tumors cause you're actually able to see the tissue uh very well with uh little radiation as well. Um So it it forms part of, of oo oo of, of, of the gold standard for being very um you are able to appreciate soft tissue much better than the rest of the of, of other investigation. And uh bone scanning is mostly um for looking for bone mets and you can also do a pet scan as well, which can be useful in uh looking for recurrent um recurring disease. Ok. Um So this uh it just shows us an alveolar rhabdomyosarcoma of um of the calf you can see on uh frame a then it just shows you that there is a soft tissue looks like soft tissue swelling, you know, you are unable to, you can't really appreciate if there is um a mass them or not on just a plain X ray. But if you do your further imaging, your MRI, you will be able to appreciate that there is actually um a mass growing the as you can see on Frame B and on Frame C there, um you can see the inguinal um lymph nodes, they are lighting up the there which shows the extent of, of, of, of, of, of, of the disease. So, um biopsy is part of our um investigation. So um what you can use from the tissue uh that you biopsy, you can use it for histology for cytogenetic and molecular testing. So you can either use a co um needle biopsy. It's also um depends on where the mass is that you would like to biopsy and how accessible it is because you can also do excisional biopsy. Those that's for superficial uh masses that are small, that are uh that are accessible, that you can um completely take them out with um clear margins. But if you can't, then you will have uh to do an incisional um biopsy. This is mostly uh for mass that you can't really exercise um completely or you because of the size of the mass or because of the area where the, the mass is. So you can do um incisional um biopsy there. OK. And so there is high risk group um risk. So this is an intergroup, Rhabdomyosarcoma study uh group which basically started um in the sixties which basically look at how to improve the management of uh this uh condition. And if you look at the progress that they have that has been made in management of this um condition. It's great because it started early in 1960 where actually the survival was around um the five-year survival was around uh 30%. But now uh five year survival is above um 83% with the introduction of uh the new uh protocol that come out uh from this group. So this group, what it does, it uh stratifies the risk to determine um how you're going to manage this um this patient. So the groups are divided into a low risk, intermediate risk and higher risk. It includes the TNM staging, the site, the clinical grouping and the histology. So it puts everything into uh context before they determine um the risk. And this is determined by the fact that with the studies that were ongoing, they're able to determine that people who have this TNM staging and this on the side with this histology, they behave um a certain way. So they are grouped in the, in the same uh group for that because their management is also the same. So um this is uh just a schematic representation to show um how the survival based on this um group. So your low risk has got um up to 85% survival and your intermediate is about 50% and, and your high risk is about 15% survive. This also comes from the IRS um study. So um this is your TNM um staging according to site So your T is for the tumor, which basically your T one is the tumor confined uh to the original site. And T two is where the tumor extend beyond uh that side with your nodes. Your N zero is there is no nodes involvement. N one is um there is N nodal involvement and NX is, is when there is unknown uh involvement of, of the nodes. And me for metastatic disease, M not is from nomads and M one is for the metastatic uh are present. OK. So now we're looking at the preclinical um staging. So this treatment starts from stage one to stage four. So it's based mostly on the, on, on the site of, of the tumor. So um your stage one is your tumor which are on the orbit, head and neck. But that exclude uh your, your parameningeal and also your your genital urinary system. But it, it, it exclude the bladder and prostate. Since the preening uh bladder and prostate, they actually form part of the non uh favorable side. So they're not part of the stage one. And, and in stage two, it, it's um it's the bladder and the prostate, ex extremities and the cranial. So this is also uh as per stage, it increases um with the stage, the prognosis is worse as the stage um go up. So with your stage four, it's basically all the sites but with uh metastatic disease. So stage four is just metastatic um um uh disease. But yeah, that's yeah. OK. So here we have our clinical grouping which also form part of that um stratification of the risk for these tumors. So in your group one, basically your group one to group three, those are a localized disease. And group four being your distant metastatic disease. So group one is basically for your for the tumor that has been uh completely uh removed. Whereas group two is when there is microscopic residual of the tumor or there's involvement of the nodes or you have them both or one of the two. In group three, you have gross uh residual um uh uh tumor o on the side. And then group four is a distant um disease. OK. So this, this now here it's putting into context all those um grouping and staging. We were looking at your pretreatment stage, your clinical group, your site and your histology. So you have your low, low to your intermediate and your high. So um things to uh highlight here is that all your, all your four, all your, all your stage four and glinka stage four. So your metastatic disease, they are all um they all form your, your high risk and each of these, the site histology, they also important in determining the risk group. Because if you can see on the histology side, the alveolar um histology risk group, it's basically upgrade um it, it, it, it upgrades the risk regardless of the clinical uh group or the pretreatment uh stage as, as long as it's an alveolar um histology, it's, it, it, it has the worst prognosis compared to embryo now. And then the sides there are also put as a favorable and your unfavorable site, your favorable sites here in your, ate, your genital uh urinary tract, your tract and your non um paramenia parameningeal forehead and neck. So these groups, so these patients then are then uh stratified into these groups and they are treated according um to which group they belong in. Ok. So um medical treatment for these uh patients. Well, the mainstay of this treatment, it's a multimodel. So it's a combination of both surgery, chemotherapy and uh radiation. So the treatment itself, it can be prolonged and it, it's quite um complicated. So you need to have as many people involved with different expertise as well. The surgeon, the oncologist, they must all be involved and the early diagnosis is imperative in this um condition. And then, as we've mentioned, the patient, they are categorized according to their group. And then from then you decide um how to treat them just to be iterated. All the patients with the metastatic disease, they are considered uh high risk as I've mentioned before. So, um moving into chemotherapy also, chemotherapy is also based on um the risk uh group of the patient. But the standard um treatment is uh vinCRIStine actin and Saros. But you, you can add other agent based on, on your, on, on, on, on the local protocol or if it's, it's an atypical uh type of uh presentation as well. Um with the radiotherapy, you know, uh so for radiotherapy, they are candidates um that qualify for, for, for radiotherapy. So, and those are your patient in your, your group two with your microscopic residual or your cross residual and also the patient with the recurrent um disease. So, with the recurrence disease, it's always you weigh in whether to for surgical resection or radiotherapy. So which that's when you decide which one is more feasible is the surgery not gonna come with a lot of um lots of uh side effects as well, um uh un unwanted um outcome as well. So if it's gonna bring more unwanted outcome, you rather uh have uh the patient go for radiation instead. OK. And then um surgical care for this patient. So, um the main part about the surgical uh management is that it depends on the site um of the tumor. And if it's feasible to remove the tumor, then and the tumor can be removed without any unacceptable disfigurement or loss of function, then the tumor must be um removed uh completely. So, and with the surgical approach, there has been a move from um from a radical um surgical approach into a more um multimodel um form of, of, of, of, of, of management. And this helps to prevent disfigurement and loss of function because these tumors can invade um lots of tissues that um I still need to be used for function as well that are important for daily life. So, preservation of function is important, complete resection. If it can be achieved, it is uh also very um important with um your primary tumor. You have a couple of options also depending on the size and the size of the tumor uh uh uh as well because um you can have your white uh local excisions with a um adequate margins that at least not 0.5 centimeters. And also for a primary procedure, you might need um to do a re-look procedure. So this RL procedure, it can be a re procedure prior to the start of uh chemotherapy after you've done an accidental biopsy. And it comes back that there's still a tumor left and it can be removed so that patient can uh go back and have um can research just to take the rest of the tumor. Um that is left. And if that's the only tumor present there, that also can be um curative, but sometimes the rook also can be from recurrence or maybe if the initial operation wasn't um adequate and they still, it's still there. You can still um operate on, on, on, on this um on this patient with the recurrent tumor. It's as I mentioned before, you have to weigh in whether you're gonna give um the just radiation and not operate or you're gonna do both or just uh an operation if you can be able to take out the rest of, of, of, of, of the tumor with um the lymph node sampling. So, um regional lymph node sampling is um advocated but not a radical um node dissection. It's not uh allowed anymore with the tumors that are in the extremities. They, they have a high chance of having um involvement of lymph nodes. So your femoral lymph nodes and your arterial lymph node, you might need um to take them with your, when you have your lymph um uh the tumor, but the current recommendation is just uh for, for sentinel lymph node um biopsy. So, um so now I'm just gonna speak about just specific um uh for the site specific management for the site. Um So I'm looking at head and neck. So these um tumors, they, they can be managed uh by chemo and radiation, but they might need um surgery. But in most cases, you, you can be able to manage them with just uh radiation and chemotherapy. But the parameningeal tumors have got a poorer uh prognosis. So, in your extremities and they constitute about 15 to 20% which is mostly um alveolar and these ones, they usually affect older uh Children. MRI is the choice of investigation, as we mentioned before. If the lesion is less than five centimeter, um you can do a complete uh excision with uh clear margin. But if it's in a nonfavorable position and it's a large um mass, then you can do an incisional uh biopsy. So, um with your genital urinary, it constitute about 12% of your rhabdomyosarcoma. So your bladder and prostate, the main thing you want to do there is to salvage uh the bladder and it can be a very difficult um operation with a lot of um structures around there. You have your urethra, your urethra, your, your rectum, uh your bowel that all can be injured during uh this procedure. So it's best to do the operation at the best uh uh time when you, you know, it can be done with uh with safety. But this forms one of the most difficult um uh myosarcoma to manage because in some patients, you might have to take out the whole uh bladder and the lifestyle of the patient already is uh is going to change for life with your vulva and uterus. As I have mentioned, you get mostly your obituary type, which they um they've got a good uh survival of about um 80%. And with them, the involvement of lymph node is really um uncommon and then you have and then you get your para testing, you know, so did so these um they are in a favorable uh site and they usually your embryonal would spin your subtype and, and just a radical um orchidectomy with a, a high ligation of, of, of a spermatic cord. Um So this orchidectomy is done via an inguinal incision. You try and avoid going through um the scrotum even for a biopsy because you can cause um tumor spillage and see of the, of the tumor as well. So, these are other sites um that are also involve um that form part of the rhabdomyosarcoma. You can have them on your Trunkal which is usually high in of uh alveola. But if you can do a complete excision, then um like any other, you have to do a complete excision, then you have your, your paraspinal, which on diagnosis, you might want to differentiate from s um sarcoma and then you have your retroperitoneal, you have your b your bilary and your perineal and with your biliary, they can, with your biliary, rhabdomyosarcoma, they can actually present with um obstructive jaundice they've got with a biliary uh mass. Then you find out that it's a, it's a rhabdomyosarcoma metastatic disease and 15% of the patients they might present already with uh metastatic um disease at the time of presentation already. And the most common area is your lung, your bone marrow lymph nodes, and uh your bones recurrent rate is as high as 30% and it's got quite high um mortality rate. It can either be localized or or widespread. And the risk factor are actually determined about the uh by the size of the, about the margins of resection. The actual tumor histology and biology, which was uh also determine uh how bad or how good the patient is going to do with recurrence. As I mentioned before, you always have to weigh in your surgery and your radiotherapy. So this is the IRS um graph which shows uh how the survival has the your five year survival has improved since uh from the sixties. With um what's important here is that initially in the sixties, uh the approach was more of um radical surgery to remove the tumor. And it was high mortality and also probably high also uh disfigurement and function loss. But now you can see that's gone up from around, from just below 30% in the 19 sixties. Uh by the nineties already, it was um over 70%. So the IRS group has really revolutionized the management of this uh rhabdomyosarcomas. So with this patient monitoring is quite um important. You want to monitor for recurrence, you want to monitor for long term um effect and the late uh effect as well. So in general, uh they said that the patient um should be examined every three months for the first six year for the first year and every six months for the second and the third year. And then from that, it can be done or yearly or it can be or for your late um side effect, you can follow them up um at five years af after the end of, of, of, of therapy and then you can just keep following them up. You need to ask about how they're doing also uh psychologically and neurological evaluation as well and also how they're doing in school and all those things because they, these are some of the effects that, that this tumor can have in the long run. So I come down to my summary is um basically highlighting that the rhabdomyosarcoma is a fairly common malignant uh tumor of the Children. They have excellent response to chemotherapy. The best treatment uh achieved with the multi modal treatment. There isn't just one way to treat them. Surgical treatment can still be uh curative with uh when you have gotten local um clearance and there is an improvement in our five-year um survival since the disease was um um discovered, which is um great for us. That's going to be the end of my presentation. And these are my references. Thank you very much. Um cough. Yeah, which prompted this. Uh Thank you for the talk. I think it was very thorough. Sorry about the initial technolog technical difficulties. Um I think you covered. Yeah, covered it well, but let's let pro Hadley take over uh prop you can start with your comments on his uh presentation and then we'll load up your slides. OK. Well, I um the my first responsibility is not to comment on it presentation but to apologize to him and to all of you for uh the delay caused by my technical ineptitude. Um uh I sincerely apologize but also to thank Professor Chit and uh doctor Management for uh inviting me to be part of this discussion. It's um it's a, a less frequent um privilege these days. But could I have that uh first slide? Uh Can you go to full screen? Well done. Can we make that full screen me? Yeah. One second. Oh, sorry. Mhm. Yeah. Mhm Yeah. OK. Probably. Yeah. OK. Thanks very much that, that, that'll do beautifully um for you to tell me to change the slide when you want me to. I, I'll, I'll just say slide. OK. And then you can, then you can move on. OK. OK. But um yeah, II think we just had a, a first class um exposition of why uh rhabdomyosarcoma is confusing. Squeeze. Here we go. Slide. Let's try it. There we go. Um As professor said in the introduction, it seems as though I've been around forever um having first visited East London a quarter of a century I gather. Um but I'd like to introduce you to this chap to put things into context. Uh This is a gentleman whose name is probably even known to our pediatric oncological colleagues. Uh This is Antonio Scpa uh and his fascia is probably the, the first eponymous structure that uh surgical trainees encounter. Could you just press again to, to just get the uh um he died at the age of 80 in 1832. And I don't think he was very popular in his department because as soon as he died, his colleagues cut his head off um and put it into a jar of absolute alcohol, they also cut off his thumbs and his penis. But the, that, that, that's a story for another day, but he's still there in his uh glass jar in a cupboard in the Department of Surgery at the University of Pavia in Italy, near, near Milan. Um And so he's been the head in the Department of surgery now for 100 and 80 odd years. So it makes my tenure in Durban look positively improve. We'll have the next slide, please. So why is rhabdomyosarcoma confusing? We've got favorable and unfavorable sites favorable and unfavorable histology. We've got at least five stages, six groups, 44 or five risk groups. And so you have to put together a matrix for each patient in order to decide how to optimally treat the patient. And, and the reason for this confusion is, is historical, although rhabdomyosarcoma was first described in the mid 19th century, in fact, just a year or two after um scar was died, it didn't actually attract serious attention until the late 19 forties, early 19 fifties. Uh when it, it it became a an object of interest to re researchers. Now, in those days, the only research in instrument available to those scientists was a light microscope. And so that's the um that's the instrument they use it. It all you've got is a hammer. Then every problem becomes a nail. And when you look down the microscope, you can see the morphology of the cell, you can see the arrangement of the cells within the tissue. You can look at um some subcellular uh bodies. You can see the nucleus, perhaps a nucleoli and some intracellular structures and relevant to rhabdomyosarcoma. You can see cross striations. And so everything with the cross striation became a rhabdomyosarcoma. Uh And that was plain simple. Then they noticed that some patients were doing rather better than other patients with this disease. And so they went back to their microscopes and they identified growth patterns and they saw that there was an alveolar growth pattern. There was an embryonal growth, pat botryoid growth pattern. And there's a very rare sclerotic growth pattern and they assigned to these um prognostic significance. And that would be, that would be great. That's where we are. And that, that's uh that's very useful and even more usefully, we would at least be interested in morphology, but we're not, we're not interested in what a cell looks like, we're interested in how a cell behaves. And and in fact, what we're trying to do is predict how a tumor is going to behave by looking at the cells within that tumor. And of course, the, the way a cell behaves is governed by the genome within the cell. Um, of course, there are some epigenetic criteria and that cell behavior is modified to some extent by the microenvironment in which the cell exists. But by and large, the, the gene is the important. Well, the genes themselves are not very important because genes don't do very much what they do is simply act as a template for a protein. So it is the gene product. That is the thing that influences um the human behavior of it. The thesis being that an abnormal gene will lead to an abnormal gene product and an abnormal gene product can't fulfill its physiological role. And it will have an impact on all downstream functions, all downstream biochemistry uh within the cells. And it's also important to understand that uh what we're talking about is a tumor that occurs in the developing myoblasts. So, somewhere between it being a primitive mesenchymal cell to it becoming a myocyte somewhere on that journey, a genetic injury occurs which alters the cells behavior. And that of course, can could happen at the beginning of the developmental process or at the end of the developmental process and where it happens will influence the outcome. So go to the next slide. So thank you. I spoke so long. Professor Ness has fallen asleep. Sorry. Yeah, there we go. Now, when, when I was a lad, uh rhabdomyosarcoma was the uh the tumor of thirds a third occur in the head and neck third appear in the genital urinary tract and third occur of elsewhere. And the favorable sites were the orbital and nonparameningeal head and neck parasa and the female urogenital tract. Everything else is unfavorable. Mm. It was also a a tumor first because you required three treatment modalities. In order to get survival, you had to have surgery, you had to have chemotherapy and you had to have uh radiotherapy. Next one. Oh, they, today they, what the pathologist look for are cost variations and myogenin positivity. All that have those features will be described as rhabdom of family. 70% of them will be embryonal with loss of heterozygosity at 11 P 13. As uh Doctor Julo described it's a very busy place, the short arm of chromosome 11, that's where the wt one gene, the Wilms tumor gene is situated. It's where the um the insulin like growth factor that is responsible for the Becker syndrome exists as well. The alveolar group will have this uh fusion protein, the um P three or pa 7 L1 fusion which gives a a gene product which affects the biology of the, of the cells. However, in describing these typical findings, it is not likely that you get malignant transformation of a benign cell through a single gene alteration. What you need is a constellation of genes to change the behavior of a cell towards a malignancy to be able to invade, to rapidly divide, et cetera and all the features we regard as typical of malignant cells. All right. So you need a constellation, for example, all rhabdomyosarcomas have an abnormality of the gene for uh p 53 on chromosome 17 and P 53 as I'm sure, you know, is a keeper of the genome. Any genomic damage, p 53 will cause a cell to commit suicide. Um But if that gene, if the gene on uh chromosome 17 is abnormal and the P 53 protein is abnormal, it won't be able to do that function. And so the cell will be uh gifted immortality. Uh which is again, one of the features that we associate uh with malignant tumors. So it's not a single gene problem. And as we investigate this, more and more, we'll come up with probably 100s of genes that are altered in a rhabdomyosarcoma. And we need to tease out which ones are important and which ones have uh uh prognostic significance. But we are where we are and we're in the middle of a revolution as we move away from light microscopy to genetics as the prognostic uh uh determinant. And um and, and, and of course, when you, whenever you're in a transition, things become messy, then I have the next slide and II find this staging singularly unhelpful. Um because every everybody's stage three basically. Um And I just wanted to comment on stage four because I think it's important to move away from this HTE and concept that we have a primary tumor that grows and when it reaches a certain size, it sends out emissaries to establish colonies elsewhere in the body. I think it's probably wiser to think of pediatric solid tumors as having a multicentric origin and the primary tumor is dominant simply because the the local um microenvironment is conducive to growth of that particular genetic type. And it's important to remember this so that we acknowledge that rhabdom rhabdomyosarcoma even stage one, rhabdomyosarcoma is a systemic disease and it requires uh systemic treatment. Next slide please. And then there's all from time to time. It's important to be reminded of one's insignificance. Um As surgeons, we are not prime movers in the management of rhabdomyosarcomas. As uh Doctor Juli clearly explained for many tumors. It doesn't matter whether you operate on them or not, you're gonna get survivors and nobody operates on uh tumors invading the base of the brain. But the radiotherapists can get there and the chemotherapist can get there and there are survivors from uh the combination therapy in those areas and it matters very little whether you do a complete resection or whether you have microscopic er positive margins, um complete resection. It's, it's, it's kind of nice and uh it satisfies the surgical libido but it doesn't significantly um uh alter the treatment or the prognosis. Next one and then we come to risk factors. Um Everybody is intermediate risk, right? Everybody that we see is intermediate risk. You do occasionally find a low risk stage, one easily resectable group, one completely resected tumor in a favorable site with embryonal histology. And the, the overall survival is 85%. But what that means is that still 15% of these patients are dying. So it's not just as uh straightforward as it would appear. The uh intermediate risk is, which is what we all see is an unfavorable site group three within stages two or three. And if you've got metastatic embryonal tumor, that's intermediate risk. If you've got alveolar tumor or, but even if it's non metastatic, that is uh intermediate risk and your chances of survival are a coin flip. And I, if, if you've got a, a coin flip, determining your future, I think i it's compelling to provide as much treatment as you can upfront. So this includes chemotherapy surgery and then radiotherapy. The high risk uh patients are basically an experimental group. You can do what you like with them. They are unlikely to survive. And it's worth trying uh even experimental vision in this, in this group of patients. And it's important to note also that age is a significant factor and that if you've got this uh uh um over the age of 10, your prognosis is considerably poorer than, than, than the younger Children. Slightness diagnostic test. I do have emphasized the need for a biopsy. You can't move without a biopsy. No surgeon on planet Earth. Is going to remove uh do a radical excision of something that might be a rhabdomyosarcoma. So he's going to need information to confirm that it's a rhabdomyosarcoma before he operates. So, a biopsy and, and in our practice needle biopsy was overwhelmingly the most common uh form of initial biopsy. The pa pathologists will see a small round blue cell tumor with uh striation and myogenin positivity. We've got to remember to do the bone marrow as uh as was pointed out about a third of patients will have positive bone marrows and imaging. You did whatever you've got. I mean, if, if what you've got is an MRI. Great. If you haven't got AAA an MRI, then do an ultrasound. What we're trying to determine is how operable is the is the tumor, what would need to be removed to clear the tumor completely. And then we must do the genetic studies. If we don't have the facilities for doing genetic studies at our center, then we should cooperate with another center. Uh that does have the facilities and that we should uh we should share the information. The very least that we should be doing is storing our specimens. So that when the facilities do become available, we'll be able to retrospectively analyze the genetic lesions, as I say, because not all of the gene abnormalities are going to have prognostic significance. And it's important for us to be able to tease out the ones that do next slightly. Yeah. So treatment as it excisional biopsy, the very, very occasional small pasic tumor can be excised primarily because surgeons believe that there is no benign solid tumor of the testis. So you, you take it out and then you find out what it was. Um but needle biopsies are common and the treatment is neoadjuvant chemotherapy, neoadjuvant chemotherapy and neoadjuvant chemotherapy, uh just like all other childhood uh solid tumors because we're going to have to operate and the smaller the operation we have to do the better. And so uh chemotherapy has a potential to um make the surgeon's life easier and happier. And I'm all for happy surgeons and we use standard facility to provide brachytherapy. Uh in Durban, we used to use it for uh peripheral er rhabdomyosarcomas and for install, installing seeds and wires into the prostate for the bladder prostate. Um uh rhabdomyosarcomas. Uh we've lost that facility now and we are reduced to conformal external be irradiation, but it's high dose radiotherapy. It's, it's not your 15 gray, it's more likely to be 5055 or 60 grade next month. And if you don't know, biopsy, just touch it again. Uh Milan think um because this is a rhabdomyosarcoma of the liver and you don't actually have to have striated muscle in an organ in order to have um a rhabdomyosarcoma there because the myoblasts are distributed throughout the body. Um And uh if they undergo malignant transformation, then you can have this tumor anywhere next slightly. There are some special situations which uh doctor Ju didn't mention. And the first is if you've got a paras tumor in an old boy in a, a Trump boy over the age of 10 years, you must do an orchidectomy and you must do a paraaortic lymph node dissection. That's not a cherry picking lymph node. That's a, a periaortic lymph node dissection, it improves the survival significantly. Secondly, if we're giving ra ra pelvic radiotherapy to girls, then it's important to get the other gonads out of the way. And if we're getting scrotal radiotherapy, get the other gonad out of the way and we surgically move them up into the uh lateral wall of the pelvis. Always biopsying nodes at the knee and the elbow. We tend to forget about uh nodes at the er knee and elbow and they can be positive while the uh um the nodes at the root of the limb are still negative. Um And II would take issue with doctor's statement that, that the primary goal in bladder prostate is is to save the bladder. And what centers that uh um subscribe to this philosophy end up doing is providing the child with a fibrotic hemorrhagic nonexpansile uh bladder with a capacity sometimes of under 10 mils so that the patient is constantly seeking toilet facilities or is becoming incontinent. Um They often have pain in the bladder. After this irradiating, the bladder is not nice for the bladder. So, organ preservation is to me not as important as like preservation. And if we've got residual tumor or recurrent tumor in the bladder, I have absolutely no compunction in taking out the bladder and the prostate and the proximal urethra. And what we would do at that stage is to reimplant the ureters into the sigmoid colon as a ureterosigmoidostomy for the duration of the oncotherapy. Once the patient has shown himself to be a survivor, then we would uh take the, the ureters out of the sigmoid because of the risk of colon cancer. And we put, put it into the conduit of our choice. Next Friday. So this is what it looks like. There's a botryoid tumor. You can see the bladder is full of soap bubbles with the bulb of the foley catheter uh showing very clearly uh on the screen next slide and this is what they look like in real life. You can see that there's been an element of strut of obstruction. The bladder is thickened and uh and uh inflamed. But you could understand why it's called a bunch of grades. And this is what you see on cystoscopy. And that is probably the commonest way in which biopsies are gained for this particular uh anatomical site. Xy. Now, uh there isn't a surge in the world. He's gonna do a primary um anterior compartectomy of the thigh uh for something like this, that might be a rhabdomyosarcoma, but it might not be. So this child has an incisional biopsy. Uh And then when Rhabdomyosarcoma was confirmed, he went back and had uh definitive surgery after neoadjuvant chemotherapy excitement. This is what paratesticular rhabdomyosarcoma looks like in Durban. I um yeah, the thought of doing primary surgery on this is um is visable. This child um simply had a biopsy and was started on neoadjuvant chemotherapy. We added uh epiadriamycin to the vinCRIStine actinomycin and cyclophosphamide, which was our standard therapy. Next five, please. Mm And after four cycles of chemotherapy, this is what it looked like. And we were able to do a um hemisectomy, an orchidectomy inguinal node biopsies. And um and he had the paraortic uh irradiated as an inverted Y and, and we moved his other testis out of the way. Next slide, please. So you don't have to have muscle in the in the situation. In order to have a rhabdomyosarcoma. There's a rhabdomyosarcoma arising in the liver next slide. And II particularly wanted to show you this slide because this, this um little girl had a uh a cervical wrapped about her camera and it was all internal until she coughed and then the whole thing prolapsed. But what we have seen on a number of occasions is little girls presenting to pediatricians with uh vaginal bleeding and your pedia pediatricians uh intuitively feel the need to exclude child abuse and they feel that the need to exclude child abuse is so dominant that they don't have to examine the patient. Um because if, if the pediatrician had done even an abdominal examination on this child, she would, he would have felt the uh this tumor mass. Ok. We've had Children delayed up to five months while social workers run around. Um social workers are not known for doing things as emergencies. Uh but they, they run around and, and, and make sure that the family environment is safe if Children have vaginal bleeding, examine them. Um If there's no injury to the external genitalia, do a rectal examination and palpate the the mass because like all childhood solid tumors in, do we treat these as emergencies and waiting five months is simply an unacceptable uh delay. Thank you. Other than to say, I truly am sorry for holding you up everybody and I thank you for your patience. That's my, my take on rhabdomyosarcoma. Oh, th thank you very much. Uh That was uh each and every word was actually uh it was worth absorbing. Um I will just hand over to Yashoda. Uh Yashoda, please uh take over and comment uh or ask questions to please. OK, thanks. Uh prof and thank you, Prof Hadley for joining us. Um We really appreciate your, your presence eventually. Yes, we got there. Um Yes, thank you for your invaluable wisdom and experience. You don't find this in textbooks. So I hope all our journeys are appreciating this. Um Yeah, so I think Xana has covered most of it. The only uh thing was to differentiate between the pretreatment uh excision and the second look excision uh with the rhabdo. So often uh we get a, a pasar mass or a scrotal mass rather. And the choice is whether to do a biopsy uh or to do an excision biopsy, which uh obviously includes the tunica and it's a radical orchidectomy. But uh so with a solid mass, we would do that. Um But we had a recent um patient who had microscopic residual um and the, the question would be whether to do a pretreatment reexcision to clear the the local um bed tumor bed. Uh because as we know, uh local spread is a prognostic factor for, for rhabdo. Um or would you treat, which is what we did, we treated with chemotherapy and then we did a posttreatment uh CT scan and imaging um to assess whether there was any residual or um further growth. So there is, there is a, a question about that and I don't know if has uh any comments or, or thoughts on that. Um Yeah, I can I ask? Yeah, can I just ask you so that I'm thinking while you're going to be talking uh where was the positive margins in the scrotum or at the transection of the cord uh in the scrotum? It wasn't very well um described on our histology report, but it was in the scrotum. There was no more detail than that. Ok, thanks. Um Yeah. So we opted to do give chemotherapy and then to reimage. And uh the other thing was that his imaging showed uh in uh periodic node. Uh but we opted not to do any biopsies of that at the time of diagnosis. So all we did was that excision biopsy and treated and then did the, the following scans which showed that uh there wasn't any residual in the scrotum and uh that the paraortic nodes actually had resolved uh the lymphadenopathy. So he only had an inguinal um clearance which um I don't know if it's, you know, academically sound but uh maybe from scrotal spread or something. So that's how we manage that patient in particular. But it just brings into question whether we should be doing um pretreatment reexcision to get um negative margins or um you know, or we should uh like you're saying biopsy is needed for chemotherapy and then a proper excision thereafter. But uh is there a role of reexcision before the chemotherapy is started? Yeah, II think it very much depends where you are. Um I if you're in the thigh and, and it's uh uh you know, sort of quadriceps, femoris, uh you know, I've got no problem about going, doing a primary reexcision. Um It, of course, it's a conundrum in the, in the scrotum because primary reexcision would mean a heavy scrotectomy. Um And you know, that's not something that you would uh choose to do the child who's going to have chemotherapy. So, II think you've, you've, you've actually made the right decisions. I think you, you give chemotherapy and you have made all the tumor that is there subradiological. It doesn't mean it's disappeared. It means that it's uh now beyond the resolution of the tools we have available to look for it. Um And it would worry me that he's a candidate for a recurrence. And if those nodes were positive, I think I would still have been positive. I would still irradiate that uh paraortic chain. So would you, would you irradiate him now that uh it seems to have uh it seems to have with? Yes. Yes. OK. Yes. Yeah. I mean, uh 11 of the, one of the things about surgery in rhabdomyosarcoma is it gives the pediatric oncologist a better chance of getting a good chemotherapy effect because we know that chemotherapy is more effective on small tumor volumes. So if you remove and you get microscopic residual in the uh in the wound and then um yes, II think that that doesn't matter because the, the chemotherapy will be um mop it up. But if you've got positive lymph nodes um and they shrunk on chemotherapy, I still think that um you need to apply radiotherapy to them because they will recur as sure as eggs or eggs. Ok. No, that's, that's useful. II will discuss with the oncologist and see if they agree, they tend to use the cog protocols. So, yeah. Uh yeah. Well, there's no accounting for taste. Yeah. Um So yes, we uh well, I didn't want to get into it but you, you did mention that stage one, you, you consider a systemic disease anyway and yet our C OD protocols uh considered that as a curative. So, yeah, II mean, ii mean, I don't think that's the case. I mean, there's, there's still an a 15% mortality for stage one tumors. Uh You know, I mean, if, if anything else, I mean, if appendicitis had a 15% mortality, everybody was throwing their arms in the air and crying. Whoa, whoa and thrice. Whoa. Um No, I think uh it's, it's still a very significant disease and I think that we've got to accept that all childhood solid tumors are systemic diseases. Uh and they need systemic treatment, I think to do otherwise is short changing your patient. Yeah, I would agree. Um Yeah, yeah, I was talking more about rhabdo but um just solid tumors in general, I think I agree with you. Stage one malignancies are systemic and chemotherapy is necessary. Um Yeah, and then I just want to mention for the juniors that II do uh for, for rhabdomyosarcomas even though we don't have uh pathologists in uh public here. Uh We have utilized our private pathologist to come in for, for frozen sections for these cases. Um Specifically uh most tumors we don't um we don't uh you know, stress too much about this, but for rhabdo s and as we are having this discussion, I think they can appreciate that local clear clearance is very important. So if you can frozen section would be ideal in these situations, you're right. Fair enough that comment. Um OK, so I think that's it for me. If anyone else has any questions for me, I will uh invite in a minute. I just want to reemphasize a few things which as you correctly said are not given in the textbook, only probably can teach such things is is that uh for the juniors uh just remember the metrics. So, so it is not linear, it is not only to access X and Y, there are actually four things to consider when you consider uh risk stratification for rhabdomyosarcoma. And if everybody heard, well, when pro discussed uh about neoadjuvant chemotherapy, he said those two words three times. So just remember that new a joint chemotherapy is absolutely critical for these patients. Um And I also want to agree with you so that, that uh these are very useful concepts for all of us to understand that all s malignancy, solid tumors even stage one is a systemic disease. And in fact, that concept of malignancy being metachronous and uh because at the host, at the primary site, it just gets better environment. So it becomes larger. I think that's also very, very useful concept. My only question to prove Hadley is uh prof uh is it one tumor or are we not gathering together spectrum of tumors in rhabdomyosarcoma? Because as you said, they can come anywhere and everywhere and there are so many variables. So are they not different tumors which we are trying to lump them together under one? Yeah, II II mean, I think that is the key issue. I mean, I think in, in, in any other, any other planet apart from ours, all the other rhabdomyosarcoma would not be called rhabdomyosarcoma at all. When, when you guys are my age, you will not be using the word rhabdomys. I came out except if you're except if you're giving a historical lecture, you will, you, you, you will say that I've got um uh a myoblastic tumor with a fusion protein here and a deletion there and an exon extravaganza over there and that, that, that gene lesion will define your treatment plan. Yes, you will look at it and you will say, well, that's a, that's a, that's a very aggressive um uh gene product there. So we're gonna have to give aggressive treatment. Now, this says nothing at all about the, the treatment modalities which are also changing now because we're identifying the gene products and we can inhibit their function. So uh yeah, there's, there's, we're in the middle of a revolution and it's very exciting. Um and uh the prognosis of patients can only get better from here on in because I don't think we should ever be satisfied with an 85% survival rate. Yes. Yes. No, that, that's, that's uh so nicely said. Prof thank you very much. Uh sell Doctor Mataya you still around, please. Uh You can make a comment. Uh Yes, I'm I'm here. Um Thanks Nandi, um Very Concisus Talk and thanks prodi for joining us for our weekly Fun um Here. Um I just wanted to find out something for you prodi um regarding the retroperitoneal rhabdo. Um What, what's your thought about debulking? Um You because as much as you emphasizing neoadjuvant chemo again and again, um do you think it plays a role um in uh debulking the tumor then proceeding with uh chemotherapy or we should just go on ahead and do chemotherapy? Obviously, this is um once you've biopsied the lesion and know uh its characteristics, should we um go ahead just chemotherapy only or do you suggest debulking? Um I would not suggest uh debulking for, to get the retroperitoneal tumor to debulk it, you'd uh certainly contaminate the peritoneal cavity with uh with viable malignant cells. So, I don't think I would go that route. I think what I would do is I would give neoadjuvant chemotherapy up to say four cycles of, of uh V Asia. And then I would reimage and see whether that uh hadn't now become completely resectable rather than going in and, and uh trying to remove half of it. Um There's a, there's a difference just so that everybody's aware uh between debulking and leaving a microscopic residual debulking is, in fact leaving you with gross residual disease. Um And the, the question is, is there any advantage of having gross residual disease rather than slightly grosser residual disease? And I would say, you know, I would go ahead and give the neo chemotherapy and monitor the response radiologically and you can usually do this with ultrasound on the retro knee. Mm. Ok. Ok. Uh No, that, yeah, that came out because I was like getting slightly um confused in this sense because when you were looking at the, the IRS uh specifically for stage four, back in the days in the, in the late eighties, early nineties, um, they had shown some uh event free survival or increase survival over a five-year period after you've debulked um a tumor, um specifically the embryonal type um versus the ones without debulking. So if obviously this does not bear um any benefit um to the patient, then I think this kind of that notion was, was most likely then, um more old school way of doing things, um, than the modern way, I think. So, um, up until up until the end of IRS two and in the beginning of IRS three, upfront surgery was the treatment of choice. Um So if you had, for example, a bladder, um, prostate rhabdo you, the first thing that would happen to you is you'd have your bladder and prostate removed. Um, and obviously, uh, there were some survivors but there was an awful lot of morbidity and an awful lot of, uh, mortality potential. With that approach. I think it's become very well established over the last certainly 25 years that neo urgent chemotherapy makes sometimes, makes surgery possible and it always makes surgery uh, easier and safer. And uh it part of our responsibility is also for us to reduce surgical morbidity and surgical mortality and by reducing the the magnitude of an operation that needs to be done, we assist in that ambition as well. So, fr fr from my perspective, I can't think of any um childhood solitary, possibly one or two skin lesions. Um I don't benefit from the neoadjuvant chemotherapy added to which you can monitor your tumor response. If you take it out, you have no idea whether your, your uh chemotherapy is working. True. True. True. So, yeah. Ok. Thanks Bob. Ok. Thank you for, I think those uh of the participants who haven't read your articles, which you published about 3035 years ago, uh They need to just revisit those articles and all these uh things which prof is advising now uh about uh giving you a joint chemotherapy to make uh tumors shrink and, and to reduce the, the extent of the operation and the morbidity of the operation. And obviously all the chances of complications during operation much less likely in addition to making surgery easier. Uh So that, that is very good. Prof just uh I also uh like uh your, your advice to us surgeons that in exceptional circumstances, there are still indications for radical operations like total cystectomy in, in uh in a child with bladder, abdomen, sarcoma with a very small capacity, bladder, I think it is something uh uh uh just, just uh additional uh surgeons. Yeah, you, you it's very easy to end up. Yeah, putting in a lot of effort to save, to salvage an organ. There is no use to the patient. Yeah. Yeah, absolutely. And uh as you correctly mentioned, um about 25 years ago, just before we started a radical surgery, uh cystectomy was the procedure of choice because urologist used to do those operations in East London and uh some of those patients did quite well. So, in fact, when calling and I started, we introduced the concept of joint pediatric oncology clinic round and uh then obviously the chemotherapy started and the the new era of uh the current era of uh ca cancer treatment started in this leg. Um Yeah, I'm, I'm pleased to hear it. Uh I see there are two other specialists from other centers. One is uh Professor Nevele. Are you still around? You want to make any comment? I think he left. Uh he has he left? Ok. And is uh doctor man around Doctor Hansen, man. I see you want to make. Uh Yes, I uh thanks. Uh yeah, thanks to the team and uh for uh hi, how are you, man? Uh So, uh the uh firstly, I just want to congratulate uh Melinda on extending this invite to all the other trainees and uh um pediatric surgeons in South Africa because I think it's a wonderful effort to sort of share our knowledge and uh lo local sort of platform and uh share our experiences and learn from that. So I just have two comments. Uh One is uh you know, regarding that uh Pericar Rhabdo and um just for the trainees to note that you're dealing with two lymphatic fields. So you're dealing with the sort of para aortic lymphatic fields that's draining from the testicle and then you're dealing with the inguinal lymphatic field that's draining your scrotum. So, in making your assessment and staging, depending on the sides of the nodes involved, you need to biopsy both sides and that's gonna be impact on that, your sort of staging and then your treatment thereafter. And then the other thing is that uh you know, we often sort of write off uh sort of uh uh what can I say uh uh warts in kids. And I know not so long ago, the guys in Durban did get a caught of guard by having uh treated sort of like recurrent warts and which eventually was biopsied and presented was found to be a rhabdomyosarcoma. So, so just so that the junior guys don't get caught off guard with treating these as, as warts and then later on to find a metastatic tumor. Thanks. Uh and thank for your insightful leg chest. Thank you. See, those are very practical comments. Uh Yeah, so that, do you have any concluding remarks? Uh No pro I think um I think we've, we've covered everything. Uh just to reiterate again to all our juniors that early diagnosis, high index of suspicion is key and to all our district level hos uh hospital doctors that are here that are joining us that um uh solid tumors in Children grow fast and they need to be addressed quickly and uh prompt investigation and management is lifesaving. So the child with that leg pain and you do a, you know, an X ray and it's just, it looks like swelling. Um you must have a high index of suspicion. So, um yeah, that's my last comment and then uh to pro next time, I'm in Durban, I will, I owe you a beer. I just, just one that's so I look forward to it. Yes, pro perfectly. Thank you very much. Uh Yeah, we, we ultimately as a team effort, we managed to uh to overcome the problems and uh I must tell you that you had great help from two women. One is your Children and second is your wife. Without that, you couldn't have participated. Yeah, I'm a, I'm a, I'm afraid that you're absolutely right. Without uh without the women tonight, life would have been very difficult. Indeed. So th thank you very much. Uh It was really nice having you on virtual platform and we will try our best to get you physically in East London. As soon as the travel restrictions are, are lifted and we look forward to welcoming you once again, at least in 2021 in East London. I look forward to it. Me and thanks very much for inviting me and uh I think you've got a great program going well done. Ok. Thank you pro Thank you all for participating and waiting patiently, we appreciate your presence and we will see most of you next week. Have a good night pro. All right. Goodbye. Yes, definitely.