1 00:00:00,000 --> 00:00:08,920 Hi everyone, I'm Em Gootee, a research fellow at Cincinnati Children's Hospital Medical 2 00:00:08,920 --> 00:00:09,920 Center. 3 00:00:09,920 --> 00:00:15,280 Today, we will hear from Dr. Meera Kodagal, a pediatric surgeon at Cincinnati Children's, 4 00:00:15,280 --> 00:00:23,760 about neuroblastoma diagnosis, staging, and management with three cases. 5 00:00:23,760 --> 00:00:27,600 Neuroblastoma makes up about 8 to 10 percent of all pediatric cancers and about 15 percent 6 00:00:27,600 --> 00:00:29,060 of cancer-related deaths. 7 00:00:29,060 --> 00:00:37,160 That is basically made up of low-risk, intermediate-risk, and high-risk disease. 8 00:00:37,160 --> 00:00:43,180 When we think about low-risk disease, those patients often have a fairly benign course. 9 00:00:43,180 --> 00:00:48,240 The high-risk patients often have metastatic disease or the disseminated disease and it's 10 00:00:48,240 --> 00:00:54,200 often fatal. 11 00:00:54,200 --> 00:00:57,720 So high-risk disease and low-risk disease are very different. 12 00:00:57,720 --> 00:00:59,720 And we are going to walk through some cases. 13 00:00:59,720 --> 00:01:01,400 This is a three-year-old girl. 14 00:01:01,400 --> 00:01:03,240 She has no past medical history. 15 00:01:03,240 --> 00:01:08,440 She has some recent intermittent abdominal pain, no fever, weight loss, no subcutaneous 16 00:01:08,440 --> 00:01:10,100 nodules, no proptosis. 17 00:01:10,100 --> 00:01:14,720 And we get the ultrasound that shows an abdominal mass and we order a CT. 18 00:01:14,720 --> 00:01:23,480 CT shows a lobulated soft tissue mass just below the diaphragm, 5.8 by 4.9 by 7.9 centimeters, 19 00:01:23,480 --> 00:01:25,540 and has some calcifications. 20 00:01:25,540 --> 00:01:30,720 It encases the abdominal aorta proximal to the level of the renal arteries and includes 21 00:01:30,720 --> 00:01:34,280 the celiac and its branches as well as the SMA. 22 00:01:34,280 --> 00:01:38,440 It pushes the IVC laterally and it elevates the portahepitis. 23 00:01:38,440 --> 00:01:40,920 What do you want to do when you get a cancer patient? 24 00:01:40,920 --> 00:01:43,360 Name it, stage it, treat it, right? 25 00:01:43,360 --> 00:01:46,360 So we're going to start with diagnosis and staging. 26 00:01:46,360 --> 00:01:47,360 What labs do you want? 27 00:01:47,360 --> 00:01:52,320 We'll start with a simple blood panel, including blood cell counts, liver and kidney function, 28 00:01:52,320 --> 00:01:54,800 coagulation panel, and electrolytes. 29 00:01:54,800 --> 00:01:58,560 For this patient, we'll move to the specific labs. 30 00:01:58,560 --> 00:02:02,080 Neuroblastoma cells often make catecholamines like epinephrine and norepinephrine. 31 00:02:02,080 --> 00:02:05,960 So you're going to get the urine spot catacolamine serum levels. 32 00:02:05,960 --> 00:02:10,880 And then we can check for epinephrine and norepinephrine metabolites, which are homovenilic 33 00:02:10,880 --> 00:02:14,800 acid, HVA, and vanilla mandelic acid, VMA. 34 00:02:14,800 --> 00:02:17,560 So this patient's HVMA and VMA are normal. 35 00:02:17,560 --> 00:02:21,600 How many neuroblastomas have elevated HVA and VMA? 36 00:02:21,600 --> 00:02:22,600 10% chance. 37 00:02:22,600 --> 00:02:24,520 90% of them do have elevated. 38 00:02:24,520 --> 00:02:28,480 But for the neuroblastomas, we don't think of them as causing blood pressure. 39 00:02:28,480 --> 00:02:31,200 And after diagnosis, the next step is staging. 40 00:02:31,200 --> 00:02:33,860 What imaging would you want to get for staging? 41 00:02:33,860 --> 00:02:42,080 So CD of the chest, abdomen, pelvis, and maybe an MRI to rule out retroperitoneal liposarcoma. 42 00:02:42,080 --> 00:02:45,920 So you got abdominal imaging, you get a chest imaging that's negative, anything else. 43 00:02:45,920 --> 00:02:49,720 So in our institution, we tend to get both MIVG and PET. 44 00:02:49,720 --> 00:02:52,440 It also to help you understand the metastatic disease. 45 00:02:52,440 --> 00:02:54,680 How much bony disease do they have? 46 00:02:54,680 --> 00:02:56,120 Do they have calvarian lesions? 47 00:02:56,120 --> 00:03:00,360 And then you can track that with a CURE score over time in order to be able to see whether 48 00:03:00,360 --> 00:03:03,280 or not they have regression with treatment. 49 00:03:03,280 --> 00:03:07,800 The CURE score is specifically used to assess the extent of metastasis in neuroblastoma 50 00:03:07,800 --> 00:03:11,620 patients based on MIVG scans. 51 00:03:11,620 --> 00:03:14,080 The body is divided into 10 regions. 52 00:03:14,080 --> 00:03:18,480 Each region is scored from 0 to 3 based on the degree of cancer involvement. 53 00:03:18,480 --> 00:03:23,200 0, no involvement, to 3, extensive involvement. 54 00:03:23,200 --> 00:03:26,880 The scores from each region are summed to produce a total CURE score. 55 00:03:26,880 --> 00:03:30,160 The maximum possible score is 30. 56 00:03:30,160 --> 00:03:34,600 This score helps determine the extent of metastatic disease in neuroblastoma, which is critical 57 00:03:34,600 --> 00:03:39,960 for staging the disease, evaluating treatment response, and guiding therapeutic decisions. 58 00:03:39,960 --> 00:03:42,600 So this is this patient that went on to get a biopsy. 59 00:03:42,600 --> 00:03:48,440 And the biopsy showed ganglion neuroblastoma intermixed with favorable histology, non-amplified 60 00:03:48,440 --> 00:03:50,720 and then they got bone marrow aspirates. 61 00:03:50,720 --> 00:03:55,240 The bone marrow was negative for metastatic tumor and the biopsy was also negative. 62 00:03:55,240 --> 00:03:57,800 So no evidence of disease in the bone marrow. 63 00:03:57,800 --> 00:04:01,880 When thinking about neuroblastomas, there are two staging systems that are the most 64 00:04:01,880 --> 00:04:03,040 common ones people talk about. 65 00:04:03,040 --> 00:04:04,040 There's the INSS. 66 00:04:04,040 --> 00:04:08,760 INSS stands for International Neuroblastoma Staging System. 67 00:04:08,760 --> 00:04:12,900 The INSS takes into account the results of surgery to remove the tumor. 68 00:04:12,900 --> 00:04:17,560 It cannot help doctors determine a stage before any treatment has started. 69 00:04:17,560 --> 00:04:22,200 So it doesn't work as well for children who don't need or can't have surgery. 70 00:04:22,200 --> 00:04:26,640 This is obviously not so useful for us in thinking about patients preoperatively. 71 00:04:26,640 --> 00:04:31,660 So there has been a sort of progression in staging to think about INRG, which stands 72 00:04:31,660 --> 00:04:37,600 for the International Neuroblastoma Risk Group, which is a preoperative staging system. 73 00:04:37,600 --> 00:04:43,720 And it's designed to allow you to think about how difficult patients may be to resect and 74 00:04:43,720 --> 00:04:46,560 how we can compare patients preoperatively across. 75 00:04:46,560 --> 00:04:49,360 Of course, INRG does not replace INSS. 76 00:04:49,360 --> 00:04:53,360 Providers generally use both, but INRG is often used pre-op. 77 00:04:53,360 --> 00:04:58,440 The INRG staging system includes L1, which are local tumors, L2, which are local tumors 78 00:04:58,440 --> 00:05:00,000 that also have an IDRF. 79 00:05:00,000 --> 00:05:02,000 Or an image-defined risk factor. 80 00:05:02,000 --> 00:05:07,280 M for metastatic tumors and MS for metastatic special, which is similar to 4S. 81 00:05:07,280 --> 00:05:08,880 There are lots and lots of IDRFs. 82 00:05:08,880 --> 00:05:13,180 The best way to think about IDRFs are things that touch things that are important. 83 00:05:13,180 --> 00:05:16,880 Touching the vessels, touching the brachial plexus, touching the trachea, all of those 84 00:05:16,880 --> 00:05:18,920 things count as IDRFs. 85 00:05:18,920 --> 00:05:23,720 Radiologists and Cincinnati Children's use a standard template to go through and be able 86 00:05:23,720 --> 00:05:26,720 to tell you this is IDRF positive or not. 87 00:05:26,720 --> 00:05:32,740 And that helps determine whether it's L1 or L2, unless it's in more than one body 88 00:05:32,740 --> 00:05:36,960 cavity, in which case it automatically becomes an disease. 89 00:05:36,960 --> 00:05:43,400 We then put patients into risk groups based on their INRG status and a bunch of other 90 00:05:43,400 --> 00:05:44,400 things. 91 00:05:44,400 --> 00:05:50,000 H, NMIC status, Ploidi, and 11Q aberrations are factors considered for the staging. 92 00:05:50,000 --> 00:05:53,280 Also, we have a tree that we use with INRG for staging. 93 00:05:53,280 --> 00:05:56,240 You can find the illustrations in the description below. 94 00:05:56,240 --> 00:05:59,840 Neuroblastoma tends to fall into aggressive neuroblastoma, benign neuroblastoma, and then 95 00:05:59,840 --> 00:06:01,920 that intermediate risk is in the middle. 96 00:06:01,920 --> 00:06:06,800 Aggressive neuroblastoma is high-stage, and benign neuroblastoma is low-stage disease. 97 00:06:06,800 --> 00:06:08,840 High-stage disease has very poor survival. 98 00:06:08,840 --> 00:06:11,320 And so our goals are to intensify therapy. 99 00:06:11,320 --> 00:06:14,360 Low-stage disease has really good survival rates. 100 00:06:14,360 --> 00:06:19,760 And our goals with that are really to reduce their therapy and try to avoid late effects 101 00:06:19,760 --> 00:06:20,760 from therapy. 102 00:06:20,760 --> 00:06:25,100 Because we know that for many cancer patients, two-thirds of them will have some long-term 103 00:06:25,100 --> 00:06:26,760 morbidity from their chemo. 104 00:06:26,760 --> 00:06:28,080 Let's go back to our patient. 105 00:06:28,080 --> 00:06:34,480 The biopsy came, ganglion neuroblastoma, favorable histology, not amplified NMIC. 106 00:06:34,480 --> 00:06:38,080 We'll start at the bottom of the tree. 107 00:06:38,080 --> 00:06:41,440 The tumor was localized to the abdomen, but encasing SMA. 108 00:06:41,440 --> 00:06:43,680 Does that make her an L2? 109 00:06:43,680 --> 00:06:44,680 Any IDRF. 110 00:06:44,680 --> 00:06:45,680 You can come in L2. 111 00:06:45,680 --> 00:06:47,680 And you know that she has no bone marrow disease. 112 00:06:47,680 --> 00:06:50,480 So that helps you to know that she doesn't have M disease. 113 00:06:50,480 --> 00:06:52,120 Age is greater than 18 months. 114 00:06:52,120 --> 00:06:55,800 She did not have loss of heterozygosity. 115 00:06:55,800 --> 00:06:58,200 And she had differentiating neuroblastoma. 116 00:06:58,200 --> 00:07:00,440 So she's actually at age. 117 00:07:00,440 --> 00:07:06,560 And now we're looking at the table for grouping patients according to their INRG3 result. 118 00:07:06,560 --> 00:07:10,280 Again, you can find this table attached in the description below. 119 00:07:10,280 --> 00:07:11,280 She's eight. 120 00:07:11,280 --> 00:07:12,280 She's intermediate risk. 121 00:07:12,280 --> 00:07:15,560 In general, the intermediate risk patients are getting chemo. 122 00:07:15,560 --> 00:07:19,200 My experience is that the neuroblastoma patients, they will get neoadjuvant chemotherapy. 123 00:07:19,200 --> 00:07:25,000 Depending on the degree of the chromosomal factors, they'll get two, four, six, or eight 124 00:07:25,000 --> 00:07:26,000 cycles. 125 00:07:26,000 --> 00:07:28,220 After that, you then make a plan to go to the OR. 126 00:07:28,220 --> 00:07:29,220 What is your approach? 127 00:07:29,220 --> 00:07:33,320 We have a couple of things to think about with neuroblastoma resections. 128 00:07:33,320 --> 00:07:37,200 They're different from other tumors because we divide them into tiny, tiny pieces while 129 00:07:37,200 --> 00:07:38,320 we're taking them out. 130 00:07:38,320 --> 00:07:42,120 The biggest thing to do with neuroblastoma is stay on the vessels. 131 00:07:42,120 --> 00:07:46,440 So find yourself a normal vessel and work from normal to abnormal. 132 00:07:46,440 --> 00:07:50,280 So if you're on the left side, find yourself the aorta and walk your way up the aorta. 133 00:07:50,280 --> 00:07:52,320 Because you want to stay on vessel and walk up. 134 00:07:52,320 --> 00:07:54,640 The closer you are to the vessels, the safer you are. 135 00:07:54,640 --> 00:07:55,720 You could use a drip ultrasound. 136 00:07:55,720 --> 00:07:57,520 We don't generally. 137 00:07:57,520 --> 00:08:02,960 Usually you start on the vessels and you just work your way from known to unknown. 138 00:08:02,960 --> 00:08:07,280 In this case, they went through and carefully separated the mass from all the vessels. 139 00:08:07,280 --> 00:08:11,160 And here Dr. Kodagal shares the pathology findings from this case. 140 00:08:11,160 --> 00:08:14,600 Neuroblastic tumor status post treatment, predominantly viable tumor with minimal therapy 141 00:08:14,600 --> 00:08:15,600 related to this. 142 00:08:15,600 --> 00:08:19,440 So this was a kid that had not had a substantial response to chemo. 143 00:08:19,440 --> 00:08:22,640 So classic presentation for this case, right? 144 00:08:22,640 --> 00:08:25,560 Management of intermediate risk, which is going to include upfront and then eventual 145 00:08:25,560 --> 00:08:33,160 resection and then IDRFs really are associated with risk of complications. 146 00:08:33,160 --> 00:08:34,560 Let's move on to the second case. 147 00:08:34,560 --> 00:08:39,120 14 month old male with no past medical history who presented with a cough and a respiratory 148 00:08:39,120 --> 00:08:40,460 viral illness. 149 00:08:40,460 --> 00:08:45,680 And then the patient underwent a chest CT, which revealed a hypo intense heterogeneous 150 00:08:45,680 --> 00:08:49,840 mass with calcifications originating from the mediastinum. 151 00:08:49,840 --> 00:08:54,400 This mass appears to be extending towards the right side, exerting pressure on the right 152 00:08:54,400 --> 00:08:58,000 lung and is located adjacent to the aorta. 153 00:08:58,000 --> 00:09:02,840 Additional imaging like CT abdomen and pelvis, MIBG and PET scan didn't show any metastatic 154 00:09:02,840 --> 00:09:13,840 disease. 155 00:09:13,840 --> 00:09:18,380 And here Dr. Kodagal brought us a paper which shows that when corneal biopsies are performed 156 00:09:18,380 --> 00:09:23,760 by experienced practitioners who ensure to obtain multiple cores, the adequacy of these 157 00:09:23,760 --> 00:09:26,360 biopsies significantly improves. 158 00:09:26,360 --> 00:09:31,960 We as our standard here will get percutaneous corneal biopsies for patients unless there 159 00:09:31,960 --> 00:09:33,280 is no window. 160 00:09:33,280 --> 00:09:36,960 Our radiologists usually get 25 cores from different parts of the tumor. 161 00:09:36,960 --> 00:09:42,240 All this to say percutaneous biopsy is not inferior to open surgical biopsy. 162 00:09:42,240 --> 00:09:46,960 So when you can, spare the patient an open surgical procedure and give them their percutaneous 163 00:09:46,960 --> 00:09:50,560 biopsy so that they can get on with their treatment. 164 00:09:50,560 --> 00:09:51,560 Let's get back to our case. 165 00:09:51,560 --> 00:10:04,160 We did the biopsy and what did the results show? 166 00:10:04,160 --> 00:10:05,960 Now we're back to our 3. 167 00:10:05,960 --> 00:10:09,240 You can check this 3 illustration attached in the description below. 168 00:10:09,240 --> 00:10:14,600 Here we're starting from the trunk and following branches until we reach the end and see which 169 00:10:14,600 --> 00:10:16,400 group the patient is in. 170 00:10:16,400 --> 00:10:22,880 Since the tumor is encasing the aorta, for IDRF classification we can tell it's L2. 171 00:10:22,880 --> 00:10:27,620 Tumor is N-Mc- and the patient is younger than 18 months old. 172 00:10:27,620 --> 00:10:30,040 So we are at G, intermediate risk. 173 00:10:30,040 --> 00:10:31,840 So we have another intermediate risk here. 174 00:10:31,840 --> 00:10:33,120 What do you want to do? 175 00:10:33,120 --> 00:10:39,000 We would start off with neoadjuvant chemotherapy, follow up the patient and then decide on operative 176 00:10:39,000 --> 00:10:40,000 resection. 177 00:10:40,000 --> 00:10:42,480 Do neuroblastoma resections have to be done open? 178 00:10:42,480 --> 00:10:44,680 Well, not necessarily. 179 00:10:44,680 --> 00:10:49,660 For neuroblastoma, unlike most tumors that we resect, we would like to get as much as 180 00:10:49,660 --> 00:10:51,200 of it we can. 181 00:10:51,200 --> 00:11:01,120 But we would expect that we're not possibly getting every single ounce of tumor. 182 00:11:01,120 --> 00:11:05,600 So basically your goal is to get as much of tumor as you can without causing harm. 183 00:11:05,600 --> 00:11:08,400 This was an intermediate risk kid with the right chest mass. 184 00:11:08,400 --> 00:11:12,040 We called it a subtotal resection because it was extending down beyond the diaphragm. 185 00:11:12,040 --> 00:11:16,040 So we chased it a little ways down into the abdomen behind the diaphragm. 186 00:11:16,040 --> 00:11:21,080 But then there was a point where it was right on the renal vein and Dr. Kottigal and her 187 00:11:21,080 --> 00:11:23,300 team chose to stay there. 188 00:11:23,300 --> 00:11:27,720 This patient responded very well to the chemo before the operation and there was a great 189 00:11:27,720 --> 00:11:30,120 treatment response for the remaining tumor. 190 00:11:30,120 --> 00:11:35,040 So percutaneous biopsy can be safely used for the diagnosis of neuroblastoma and minimally 191 00:11:35,040 --> 00:11:40,560 invasive approaches can be used when you pick the patients. 192 00:11:40,560 --> 00:11:52,240 And here's our third and final case of the day. 193 00:11:52,240 --> 00:11:56,280 On the chest CT, this mass looks like it's behind the diaphragm. 194 00:11:56,280 --> 00:11:58,760 And it's a very common place for these tumors. 195 00:11:58,760 --> 00:12:02,000 We see them sneaking into the space right behind the diaphragm. 196 00:12:02,000 --> 00:12:05,200 We know that the patient had no IDRFs. 197 00:12:05,200 --> 00:12:07,560 There's no evidence of metastatic disease. 198 00:12:07,560 --> 00:12:10,840 All we have is a four-month-old with an L1 tumor. 199 00:12:10,840 --> 00:12:12,840 You get a biopsy and it says it's neuroblastoma. 200 00:12:12,840 --> 00:12:15,360 So this patient is going to get an observation as their treatment. 201 00:12:15,360 --> 00:12:21,200 Dr. Kottigal brought us a study from the Children's Oncology Group, or COG, that looked at expected 202 00:12:21,200 --> 00:12:23,240 observations for young infants. 203 00:12:23,240 --> 00:12:28,960 So it was 87 patients less than six months of age with a small adrenal mass and no evidence. 204 00:12:28,960 --> 00:12:33,760 And they observed these patients with serial ultrasounds, intermittent CT, MRI, and then 205 00:12:33,760 --> 00:12:34,760 labs. 206 00:12:34,760 --> 00:12:39,480 In the study, there were four patients that had immediate surgery based on the qualifications. 207 00:12:39,480 --> 00:12:44,520 Sixteen patients were in the observation arm and eventually had surgery, and the remainder 208 00:12:44,520 --> 00:12:46,000 did not. 209 00:12:46,000 --> 00:12:51,280 The four-year event-free survival for patients with neuroblastoma was 97%. 210 00:12:51,280 --> 00:12:55,880 This was obviously studied primary adrenal, but we've expanded that and used that really 211 00:12:55,880 --> 00:13:00,280 for L1 tumors in kids under six months. 212 00:13:00,280 --> 00:13:07,160 So infants with small masses that are not metastatic can be safely observed. 213 00:13:07,160 --> 00:13:09,080 Well that was all for today. 214 00:13:09,080 --> 00:13:14,920 In summary, neuroblastoma is divided into low, intermediate, and high-risk groups, with 215 00:13:14,920 --> 00:13:20,800 high-risk cases having poor survival rates, especially after relapse. 216 00:13:20,800 --> 00:13:26,920 Diagnosis involves imaging and specific blood and urine tests, while staging uses CT, MRI, 217 00:13:26,920 --> 00:13:30,560 MIBG, and PET scans to determine disease extent. 218 00:13:30,560 --> 00:13:38,440 INSS is used postoperatively and INRG preoperatively to assess surgical risks and classify neuroblastoma 219 00:13:38,440 --> 00:13:40,640 stages. 220 00:13:40,640 --> 00:13:45,600 Intermediate-risk patients receive neoadjuvant chemotherapy and careful surgical resection 221 00:13:45,600 --> 00:13:49,720 to maximize tumor removal and minimize harm. 222 00:13:49,720 --> 00:13:54,520 Percutaneous biopsy is effective for diagnosis, and infants with small, non-metastatic tumors 223 00:13:54,520 --> 00:13:58,520 can often be safely observed without immediate surgery. 224 00:13:58,520 --> 00:14:28,440 Thank you for listening to this episode.