We discuss the presentation, diagnosis, and management of congenital neuroblastoma. We are joined by Tanya Watt, MD, Associate Professor of Pediatric Hematology and Oncology at the University of Texas Southwestern Medical Center.
Dr. Neeta Goli:
Welcome to Newborn News, a podcast where we discuss educational topics for medical professionals who care for newborns. I'm your host, Dr. Neeta Goli, a pediatrician in the UT Southwestern Newborn Nursery. Welcome back to the podcast. In today's episode, we'll be discussing congenital neuroblastoma. We are recording remotely due to the ongoing COVID pandemic. We are joined today by Dr. Tanya Watt, Associate Professor of Pediatric Hematology and Oncology at UT Southwestern. Dr. Watt, thanks for joining us today.
Dr. Tanya Watt:
Thanks so much for having me.
Dr. Neeta Goli:
Childhood cancer is fortunately relatively uncommon, with approximately 14,000 cases diagnosed annually. This includes both hematologic and solid malignancies. Neuroblastoma is the most common cancer diagnosed in infancy. To begin, please can you review for us which cell type is abnormal in neuroblastoma?
Dr. Tanya Watt:
Neuroblastoma involves the primordial neural crest cells that normally would develop into the sympathetic ganglia and adrenal medulla. So as a result, neuroblastomas can develop anywhere along the sympathetic chain or most commonly in the adrenal glands.
Dr. Neeta Goli:
How common is neuroblastoma?
Dr. Tanya Watt:
It's the most common extracranial solid tumor; that still results in a relatively low incidence. So approximately 600 to 800 cases are diagnosed in the United States every year.
Dr. Neeta Goli:
Of those 600-800, how many are diagnosed in the neonatal period?
Dr. Tanya Watt:
About 100.
Dr. Neeta Goli:
Okay. Are there any risk factors we should be aware of?
Dr. Tanya Watt:
There are. So we've found that Congenital Central Hypoventilation Syndrome that's associated with PHOX2b mutation results in an increased risk of the development of neuroblastoma. So in pediatrics, there are not a lot of syndromes that require screening for oncologic processes, but CCHS is one of those. And typically for that screening, we'll do abdominal ultrasounds and chest x-rays in addition to screening urine catecholamines every few months for the first six or seven years of life of these patients. There are also occasional reports of children with a slight increased risk if they have neurofibromatosis or Noonan syndrome, but the correlation is not nearly as good as with CCHS.
Dr. Neeta Goli:
How is the diagnosis of CCHS made? Is that typically made on screening or symptomatic?
Dr. Tanya Watt:
It's usually symptomatic. So most of the patients will be in the NICU actually for three or four months, and just unable to come off the ventilator and eventually will get genetic evaluation for CCHS. There is a pretty strong family history, and so some patients are screened for it, but most it's diagnosed in the NICU.
Dr. Neeta Goli:
And what are the subtypes of congenital neuroblastoma?
Dr. Tanya Watt:
So about 1 to 2% are familial, but almost all of them are sporadic in nature. And as we talked about, the ones that tend to be hereditary or familial are either associated with CCHS or can have an ALK mutation.
Dr. Neeta Goli:
Where does neuroblastoma typically occur?
Dr. Tanya Watt:
So most common spot is in the adrenal gland, but can really occur anywhere along the sympathetic chain. So often posterior mediastinal masses or they can develop retroperitoneal masses. Again, most commonly in the adrenal gland.
Dr. Neeta Goli:
Is there any difference between congenital neuroblastoma presentation and childhood neuroblastoma presentation?
Dr. Tanya Watt:
There's much less likely to be metastatic disease (in congenital neuroblastoma), and so usually most of the congenital neuroblastomas are found incidentally. Whereas most of the neuroblastomas diagnosed later in life are found because of symptoms.
Dr. Neeta Goli:
Do you feel like they are found incidentally as abdominal masses or found on imaging?
Dr. Tanya Watt:
Exactly. So often some of them are prenatally diagnosed on routine ultrasounds that are obtained for prenatal care. And then if an infant happens to be in the NICU and has a chest x-ray done for some reason, then occasionally we'll find a posterior mediastinal mass, so it will be detected incidentally.
Dr. Neeta Goli:
You mentioned childhood neuroblastoma is more often diagnosed symptomatically. What kind of symptoms might we see?
Dr. Tanya Watt:
In young children, especially in the neonatal period or the infant period, they can occasionally present with hepatomegaly that leads to respiratory distress. And so big distended bellies with associated respiratory distress makes us actually want to treat them immediately before even doing the biopsy, just because those infants have a higher risk of death from disease. Other things that we see not so severely are you can sometimes see blue skin nodules or discolorations. They tend to be dermal, but occasionally can be subcutaneous also. And then often as the children get older, big abdominal masses that are diagnosed either on well-child check or when the child comes in frequently, if they have metastatic disease complaining of fever or leg pain, not wanting to walk, sometimes constipation. Those are the main things that we'll see as far as symptomatic disease.
Dr. Neeta Goli:
What do the blue nodules represent?
Dr. Tanya Watt:
It's actually tumor deposits in the skin. And so neuroblastoma is a small round blue cell histologically. And so the blue discoloration is just tumor nodules that are found right under the skin. And those, they don't cause any harm. They'll go away when we start treating with chemotherapy. Interestingly, some of them in the children with MS disease, that bizarre metastatic disease that you can have under a year of age, those can just regress on their own without any treatment at all.
Dr. Neeta Goli:
And how about those periorbital ecchymoses (raccoon eyes) that we always learn about?
Dr. Tanya Watt:
Yes. And so those are more typically diagnosed in the symptomatic children, usually over 18 months of age, is typically when we see that. And that represents metastatic disease that's spread to the orbits and because the skin of the orbital wall is so close to the actual orbital bone, you're actually just seeing the metastatic disease deposited in the orbits. And so that's why, again, you get kind of that blue-purplish discoloration.
Dr. Neeta Goli:
How's the diagnosis confirmed?
Dr. Tanya Watt:
We'll often do a biopsy. Some of the children in the neonatal period that have small adrenal masses, and elevated urine catecholamines, we will just monitor very closely because a lot of those actually will just regress on their own and won't need any treatment at all.
Dr. Neeta Goli:
And how is it managed at initial diagnosis?
Dr. Tanya Watt:
So depending on kind of extent of disease. So small adrenal mass, less than about five centimeters without any kind of concerning signs or symptoms for metastatic disease, we'll observe with ultrasounds usually starting about every month and then spacing out those ultrasounds and only think about surgical intervention if the mass is growing by about 50% or the patient's having any associated symptoms. If there's evidence of metastatic spread, or if a child has symptoms based on location, then we'll often do surgical resection of the primary tumor. Some of them will need chemotherapy, but a lot of them can get by with just surgical resection.
Dr. Neeta Goli:
What is the long-term monitoring or treatment of congenital neuroblastoma?
Dr. Tanya Watt:
So depending on whether we've needed to do chemotherapy or not, a lot of those patients we'll just watch for two or three years to make sure that we don't see any signs of recurrent neuroblastoma. Most of them will do very well. And the overall survival's about 85-90%. If they do need chemotherapy, based on location or based on metastatic spread, then we will follow them lifelong to look for any long-term side effects from the chemotherapy. Fortunately, most of the chemotherapy that we're able to use in these children is in relatively low doses from my standpoint. And so there are not a lot of long-term side effects, even though we're giving it in neonates.
Dr. Neeta Goli:
And other than chemotherapeutic side effects, are there any other complications or anything that the general pediatrician should be aware of when caring for these children later?
Dr. Tanya Watt:
Some of them based on location of where their tumor is, will have Horner’s syndrome either from diagnosis or from surgical resection. I have some that have developed Harlequin syndrome when they get excited or hot, the one side of their body will become very red and the other side will not. And that's usually just from nerve damage during surgery, doesn't have any long-term complications, just looks bizarre when you're taking care of these children. But most of them do quite well.
Dr. Neeta Goli:
Out of curiosity, is the Harlequin color change, is that typically transient or is that expected to resolve with time?
Dr. Tanya Watt:
It often stays.
Dr. Neeta Goli:
From nerve damage. And how does the prognosis of congenital neuroblastoma differ from that of neuroblastoma diagnosed later in childhood?
Dr. Tanya Watt:
So if you're diagnosed under the age of 18 months with neuroblastoma, it is significantly better outcome than if you're diagnosed over 18 months. As we've discussed, most children in the congenital period are diagnosed with just a single mass and not metastatic disease. But even those who have metastatic disease are able to be treated with relatively low doses of chemotherapy and have excellent long-term survival. So somewhere in the 85-95% range. Unfortunately children over the age of 18 months have a much harder time and do significantly worse. And that's with a lot more intensive chemotherapy. They require autologous stem cell transplants, they require radiation and then immunotherapy, where we use a targeted agent against GD2, that's a protein on neuroblastoma cells.
Dr. Neeta Goli:
Why does the prognosis differ so much?
Dr. Tanya Watt:
We wish we understood better. We've tried to understand. There's not really significant change in the genetics of the tumor so we don't entirely understand it well. There's a lot of study looking at the metabolomics of the cells, trying to understand if there's something different within that process, but today, it is not well understood.
Dr. Neeta Goli:
And then as you mentioned, since congenital neuroblastoma is sometimes just found incidentally, it might not always present symptomatically, and if it might be self-limited anyway, is it possible that the incidence is actually higher than is documented, but we just don't know?
Dr. Tanya Watt:
Yes. I think that's very, very likely. Back in the 1970s, they actually tried to do a screening study in the United States and Japan, and some other spots around the world, where they essentially screened with urine catecholamines all infants, and found a significantly higher incidence of neuroblastomas than they had previously diagnosed. Interestingly, they took all of those children to surgery and found that the long-term outcomes were worse for the children that had gone to surgery because they had complications from their surgical resection that was done so early in life. Whereas otherwise more than likely these tumors would have just regressed on their own. And they found that only about two or three of all the patients that they diagnosed, went on to develop metastatic disease, which was similar to the incidence that they would have seen if they hadn't done the screening.
Dr. Tanya Watt:
So one of the few screening procedures that we have gone through in the oncologic world that failed. And so as a result, we don't screen in the neonatal period. But I think there definitely are probably a lot of children out there that are undiagnosed.
Dr. Neeta Goli:
Good to know. To end the episode today, what's your favorite part of your work day?
Dr. Tanya Watt:
So my favorite part of my work day is seeing my survivor patients. I think that as especially those who have had a lot of complications or we thought weren't going to survive, it's so fun to see them running through the door and telling me about everything they've been up to. Watching them grow up and become great members of society makes the job very, very worthwhile.
Dr. Neeta Goli:
I bet. Thanks for joining us today, Dr. Watt.
Dr. Tanya Watt:
Thank you so much.
Dr. Neeta Goli:
Thanks for listening to Newborn News. We hope you join us next time. If you like what you hear, make sure to subscribe and leave us a review. If you have questions, comments, feedback, or suggestions for future episodes, please email me at NewbornNews@utsouthwestern.edu. As a reminder, this content is educational and is not meant to be used as medical advice. Views or opinions expressed in this podcast are those of myself and my guests, and do not necessarily reflect the views of the university.