Neuroblastoma with Dr. Meera Kotagal

Hi, everyone. I'm M. Gaudy, a research fellow at Cincinnati Children's Hospital Medical Center. Today, we will hear from Dr. Mira Coragal, a pediatric surgeon at Cincinnati Children's, about neuroblastoma diagnosis, staging, and management with three cases. Neuroblastoma makes up about 8 to 10% of all pediatric cancers, and about 15% of cancer-related deaths. It is basically made up of low risk, intermediate risk, and high-risk disease. And the course for each of those is completely different. When we think about low-risk disease, those patients are often have a fairly benign course. The high-risk patients often have metastatic disease or the disseminated disease, and is often fatal. For folks who have relapsed high-risk neuroblastoma, the survival rate is zero. So, high-risk disease and low-risk disease are very different, and we are going to walk through some cases. This is a three-year-old girl. She has no past medical history. She has a some recent intermittent abdominal pain, no fever, weight loss, uh, no subcutaneous nodules, no proptosis. And we get the ultrasound that shows an abdominal mass, and we order a CT. CT shows a lobulated soft tissue mass just below the diaphragm, 5.8 by 4.9 by 7.9 cm, and has some calcifications. It encases the abdominal aorta, proximal to the level of the renal arteries, and includes the celiac and its branches, as well as the SMA. It pushes the IVC laterally, and it elevates the porta hepatis. What do you want to do when you get a cancer patient? Name it, stage it, treat it, right? So, we're going to start with diagnosis and staging. What labs do you want? We'll start with a simple blood panel, including blood cell counts, liver and kidney function, coagulation panel, and electrolytes. For this patient, we'll move to the specific labs. Neuroblastoma cells often make catecholamines, like epinephrine and norepinephrine. So you're going to get, you're in spot catecholamine serum levels. And then, we can check for epinephrine and norepinephrine metabolites, which are homovanillic acid, HVA, and vanillylmandelic acid, VMA. So, this patient's uh, HVMA and VMA are normal. How many neuroblastomas have elevated HVA and VMA? 10% chance. 90% of them do have elevated function, but for the neuroblastomas, we don't think of them as causing blood pressure. And after diagnosis, the next step is staging. What imaging would you want to get for staging? So, CT of the chest, abdomen, pelvis, and maybe an MRI to rule out retroperitoneal liposarcoma. So, you got abdominal imaging, you get a chest imaging that's negative, anything else. So, in our institution, we tend to get both MIBG and PET. It also to help you understand the metastatic disease. How much bony disease do they have? Do they have calvarial lesions? And then, you can track that Vidacure score over time in order to be able to see whether or not they have regression with treatment. The cure score is specifically used to assess the extent of metastasis in neuroblastoma patients based on MIBG scans. The body is divided into 10 regions. Each region is scored from zero to three based on the degree of cancer involvement. Zero, no involvement, to three, extensive involvement. The scores from each region are summed to produce a total Q score. The maximum possible score is 30. This score helps determine the extent of metastatic disease in neuroblastoma, which is critical for staging the disease, evaluating treatment response, and guiding therapeutic decisions. So, this is this patient went on to get a biopsy, and the biopsy showed ganglioneuroblastoma intermixed with favorable histology, non amplified, and then they got bone marrow aspirate. The bone marrow was negative for metastatic tumor, and the biopsy was also negative. So, no evidence of disease in the bone marrow. When thinking about neuroblastomas, there are two staging systems that are the most common ones people talk about. There's the INSS. INSS stands for International Neuroblastoma Staging System. The INSS takes into account the results of surgery to remove the tumor. It cannot help doctors determine a stage before any treatment has started. So, it doesn't work as well for children who don't need or can't have surgery. This is obviously not so useful for us in thinking about patients pre-operatively. So, there's been a sort of progression in staging to think about INRG, which stands for the International Neuroblastoma Risk Group, which is a pre-operative staging system. And it's designed to allow you to think about how difficult patients may be to resect and how we can compare patients pre-operatively across. Of course, INRG does not replace INSS. Providers generally use both, but INRG is often used pre-op. The INRG staging system includes L1, which are local tumors, L2, which are local tumors that also have an IDRF, or an image defined risk factor. M for metastatic tumors and MS for metastatic special, which is similar to 4S. There are lots and lots of IDRFs. The best way to think about IDRFs are things that touch things that are important. Touching the vessels, touching the brachial plexus, touching the trachea, all of those things. Counts as IDRF. Radiologists at Cincinnati Children's use a standard template to go through and be able to tell you this is IDRF positive or not. And that helps determine whether it's L1 or L2, unless it's in more than one body cavity, in which case it automatically becomes end disease. We then put patients into risk groups, based on their INRG status and a bunch of other things. Age, Nmic status, ploidy, and 11Q aberrations are factors considered for the staging. Also, we have a tree that we use with INRG for staging. You can find the illustrations in the description below. Neuroblastoma tends to fall into aggressive neuroblastoma, benign neuroblastoma, and then that intermediate risk. Aggressive neuroblastoma is high stage, and benign neuroblastoma is low stage disease. High stage disease has very poor survival, and so our goals are to intensify therapy. Low stage disease has really good survival rates, and our goals with that are really to reduce their therapy and try to avoid late effects from therapy. Because we know that for many cancer patients, two thirds of them will have some long-term morbidity from their chemo. Let's go back to our patient. The biopsy came ganglioneuroblastoma, favorable histology, not amplified Nmic. We'll start at the bottom of the tree. L1, L2, MRS. The tumor was localized to the abdomen, but encasing SMA. Does that make her an L2? Yes. Any IDRF, okay. You become an L2. And you know that she has no bone marrow disease. So that helps you to know that she doesn't have M disease. Age is greater than 18 months. She did not have loss of heterozygosity, and she had differentiating neuroblastoma. So she's actually at H. And now we're looking at the table for grouping patients according to their INRG3 result. Again, you can find this table attached in the description below. She's H, she's intermediate risk. In general, the intermediate risk patients are getting chemo. My experience is that the neuroblastoma patients, they will get neoadjuvant chemotherapy, depending on the degree of the chromosomal factors, they'll get two, four, six, or eight cycles. After that, you then make a plan to go to the OR. What is your approach? We have a couple of things to think about with neuroblastoma resections. They're different from other tumors because we divide them into tiny, tiny pieces while we're taking them out. The biggest thing to do with neuroblastoma is stay on the vessels. So, find yourself a normal vessel and work from normal to abnormal. So if you're on the left side, find yourself the aorta and walk your way up the aorta, but you want to stay on vessels and walk up. The closer you are to the vessels, the safer you are. You could use a drap ultrasound, we don't generally. Usually, you start on the vessels, and you just work your way from known to unknown. In this case, they went through and carefully separated the mass from all the vessels. And here, Dr. Coragal shares the pathology findings from this case. Neuroblastic tumor, status post treatment, predominantly viable tumor with minimal therapy related change. So, this was the kid that had not had a significant substantial response to chemo. So classic presentation for this case, right? Management of an intermediate risk, which is going to include upfront and then eventual resection, and then IDRFs really are associated with risk of complications. Let's move on to the second case. 14 month old male with no past medical history who presented with a cough and a respiratory viral illness. And then the patient underwent a chest CT, which revealed a hypointense heterogeneous mass with calcifications originating from the mediastinum. This mass appears to be extending towards the right side, exerting pressure on the right lung and is located adjacent to the aorta. Additional imaging like CT abdomen and pelvis, MIBG and PET scan didn't show any metastatic disease. You want to get some tissue for a biopsy. You could do a percutaneous biopsy through the chest wall, or you could open and do a surgical biopsy, which is better in terms of diagnosis? And here, Dr. Coragal brought us a paper which shows that when corneal biopsies are performed by experienced practitioners who ensure to obtain multiple cores, the adequacy of these biopsies significantly improves. We, as our standard here, will get percutaneous corneal biopsies for patients unless there is no window. Our radiologist usually get 25 cores from different parts of the tumor, all this to say, percutaneous biopsy is not inferior to open surgical biopsy. So, then you can spare the patient an open surgical procedure and give them their percutaneous biopsy so that they can get on with their treatment. Let's get back to our case. We did the biopsy, and what did the results show? It shows poorly differentiated neuroblastoma with favorable histology. The bone marrow biopsy shows no evidence of metastatic disease. Now we're back to our three. You can check this three illustration attached in the description below. Here, we are starting from the trunk and following branches until we reach the end and see which group the patient is in. Since the tumor is encasing the aorta, for IDRF classification, we can tell it's L2. Tumor is Nmic negative and the patient is younger than 18 months old. So we are at G, intermediate risk. So, we have another intermediate risk kid. What do you want to do? We would start off with neoadjuvant chemotherapy, follow up the patient, and then decide on operative resection. Do neuroblastoma resections have to be done open? Well, not necessarily. For neuroblastoma, unlike most tumors that we resect, we would like to get as much as of it we can, but we would expect that we're not possibly getting every single ounce of tumor. There's tumor that extends into the neural foramina or that extends into other places, you're not going to go chasing it. So basically your goal is to get as much of tumor as you can without causing harm. This was an intermediate risk kid with the right chest mass that we called it a subtotal resection because it was extending down beyond the diaphragm. So we chased it a little ways down into the abdomen behind the diaphragm. But then there was a point where it was right on the renal vein, and Dr. Coragal and her team chose to stay there. This patient responded very well to the chemo before the operation, and there was a great treatment response for the remaining tumor. So, percutaneous biopsy can be safely used for the diagnosis of neuroblastoma, and minimally invasive approaches can be used when you pick the patients. And here's our third and final case of the day. Four month old boy with no past medical history who presented with a cough and a respiratory viral illness and got a chest X-ray that showed a 4 cm left paraspinal mass. On the chest CT, this mass looks like it's behind the diaphragm, and it's a very common place for these tumors. We see them sneaking into the space right behind the diaphragm. We know that the patient had no IDRFs. There's no evidence of metastatic disease. All we have is a four month old with an L1 tumor. You get a biopsy and it says it's neuroblastoma. So, this patient's going to get an observation as their treatment. Dr. Coragal brought us a study from the Children's Oncology Group, or COG, that looked at expected observations for young infants. So, it was 87 patients less than six months of age with a small adrenal mass and no evidence. And they observed these patients with serial ultrasounds, intermittent CTs, MRI, and then labs. In that study, there were four patients that had immediate surgery based on the qualifications. 16 patients were in the observation arm and eventually had surgery, and the remainder did not. The four year event free survival for patients with neuroblastoma was 97%. This was obviously studied primary adrenal, but we've expanded that and used that really for L L1 tumors in kids under six months. So, infants with small masses that are not metastatic can be safely observed. Well, that was all for today. In summary, neuroblastoma is divided into low, intermediate, and high-risk groups, with high-risk cases having poor survival rates, especially after relapse. Diagnosis involves imaging and specific blood and urine tests, while staging uses CT, MRI, MIBG, and PET scans to determine disease extent. INSS is used post-operatively, and INRG pre-operatively to assess surgical risks and classify neuroblastoma stages. Intermediate risk patients receive neoadjuvant chemotherapy and careful surgical resection to maximize tumor removal and minimize harm. Percutaneous biopsy is effective for diagnosis, and infants with small non-metastatic tumors can often be safely observed without immediate surgery. Thank you for listening to this episode. Global Cast MD, along with Cincinnati Children's Hospital, sharing knowledge to improve child health around the globe.