Specialty Spotlight with Siva: Little Lumps, Big Questions

Dr. Kade Goepferd: This is Talking Pediatrics, a clinical podcast by Children’s Minnesota, home to the Kid Experts, where the complex is our every day. Each episode, we bring you intriguing stories and relevant pediatric health care information as we partner with you in the care of your patients. Our guests, data, ideas and practical tips will surprise, challenge, and perhaps change, how you care for kids.

Welcome to Talking Pediatrics. I’m your host Dr. Kade Goepferd. Today’s segment is Specialty Spotlight with Siva where we delve into the complexities of pediatric medical and surgical subspecialties with pediatric otolaryngologist and facial plastic surgeon, Dr. Siva Chinnadurai.

Dr. Siva Chinnadurai: Welcome to Specialty Spotlight with Siva. Today my guest is Dr. Lane Miller. He’s a pediatric oncologist at Children’s Minnesota with five years of experience. He completed his pediatric residency at Oregon Health Science University and a fellowship in pediatric hematology oncology and bone marrow transplantation at Emory University where he also obtained a master’s in clinical research. Today, Dr. Miller and I are going to discuss how to approach new lumps or bumps in children and an overview of lymphoma and leukemia.

Thank you so much for joining us and welcome to the show, Dr. Miller.

Dr. Lane Miller: Yes, thank you so much for having me. It’s an honor to be here. I’ve loved listening to the podcast over the last couple of years.

Dr. Siva Chinnadurai: Now this is a big topic, a scary topic for many parents and maybe a source of uncertainty for primary care providers when first encountering some of these concerning findings. When a primary care provider sees a child with a newly discovered lump or bump, say a swelling in the neck or somewhere else, what are some of the initial steps that they should take in evaluating this child?

Dr. Lane Miller: When it comes to lumps and bumps, especially in the neck and head area, we’re oftentimes talking about lymph nodes. There are a couple of other odd scenarios that you probably oftentimes see in your practice, cysts and congenital malformations and oftentimes infections. But there is such an extensive catalog and list of potential diagnoses that could be malignant, could be dangerous, could be entirely benign when it comes to lumps and bumps that really history, examination are critically important. Then sometimes there’s a role for laboratory evaluation and imaging just in the general pediatric setting before a patient’s ever referred to a specialist.

Dr. Siva Chinnadurai: The majority of these lumps and bumps, like you’ve talked about, at least the ones that are concerning enough for people to bring in their kids, are lymph nodes. As you mentioned, when we have lymphadenopathy in kids, there can be a lot of different reasons why that pops up. Are there things, key elements in the history or physical that help at the time of that initial evaluation kind of points you down to more benign or a more malignant pathway of concern?

Dr. Lane Miller: Definitely. The history is so important in getting an understanding of what co-occurring symptomatology, what has occurred in the last week or so, or maybe even longer, in relation to the swelling. Also, we’re very, very curious on the location of the swelling, how that’s changed over time. Are we talking about multiple regions of the body? Are we talking about one nodal area? Has the swelling been painful to the child or has it slowly progressed over time?

Then we’re very interested in constitutional systemic symptoms like fever, weight loss. We actually have strict definitions for what is abnormal weight loss in this case, prolonged fever without another etiology to explain it, night sweats, pulmonary symptoms, gastrointestinal symptoms. We’re interested in all of that. Oftentimes just knowing that history can allow for reassurance for a family, allow us to go on with observation of the patient without any other diagnostics and avoid referrals. But sometimes red flags do pop up in that history taking and the physical exam that lead to some of the more extensive diagnostics.

Dr. Siva Chinnadurai: As you talked about, maybe a painful bump, maybe something that’s just shown up really acutely, maybe after an illness is a little less worrisome, something that’s not quite so abrupt that’s been growing over time, something that’s less painful is maybe a little bit more worrisome. You had mentioned some thresholds for weight loss. What are the thresholds you use to elevate your concern, or?

Dr. Lane Miller: Well, the standard definition is weight loss of more than 10% of your body weight without the intention to lose that weight. Oftentimes when I see a patient who’s had lymphadenopathy for several weeks, especially if it’s a teenager, you can just ask them, “How much do you think you weigh?” They’ll tell you, “Well, I weigh 150 pounds on a good day.” I’ll say, “Wait, well, you weigh 135 today and have you been attempting to lose that weight? Does this seem to make sense with how your lifestyle has been over this time, or is this a shocker to you?” Or parents can tell you what the most recent weight was at a pediatrician visit or what they think their child’s weight is and you can have an understanding and make that calculation.

Dr. Siva Chinnadurai: What about some of the initial imaging or laboratory tests? What are good timeframes to get those tests and what are the right tests to get at the primary care office?

Dr. Lane Miller: As you mentioned before, a lot of lymphadenopathy that we see is benign reactive. It’s in the context of some sort of viral prodrome or concurrent viral symptomatology or maybe a localized infection, a pharyngitis, scalp issues, dental issues. That seems clear cut. It can be either observed or managed with antibiotics and observed further.

What we really worry about are cases with red flag symptoms, fevers for over a week without any explaining etiology behind it, this weight loss that we talked about. Very much worry about generalized non-tender adenopathy. I worry about adenopathy that is growing over a period of four to six weeks while potentially all viral symptoms have resolved or there were no viral symptoms to begin with. Very much worry about supraclavicular adenopathy as far as location goes. These are all things that can be determined at the first meeting with the patient.

If you meet any of those criteria at the time of meeting, I think it really does make sense to go ahead with a basic laboratory evaluation. Depending on where the lymph nodes are, potentially a chest film, just a simple plain film to look for deeper mediastinal masses or nodes.

Dr. Siva Chinnadurai: What lab tests do you get as your first volley there, a CBC maybe? What else?

Dr. Lane Miller: Right, a CBC with a white cell differential is absolutely the most important because here we are looking primarily for leukemia, acute leukemia. Acute leukemia can be life-threatening if unmanaged, even just for days. It’s not something you want to miss. In general in our world, it’s relatively common. I know it is rare in the grand scheme of things, but we do see a fair amount of it. It can be caught on a very simple screening test, or at least the suspicion can be raised for it. That is helpful. If you have the capacity to send blood for a peripheral smear evaluation to a hematopathologist, which we have here at Children’s, then that’s excellent as well. That can usually be done in 24 hours.

Other markers that can be helpful in the blood would be markers of rapid cell turnover. A lot of these lymphomas and leukemias will release toxins into the bloodstream like potassium, uric acid, lactase dehydrogenase. We can pick them up in the bloodstream and give us an indication of whether or not this is a rapidly progressing process. Inflammatory markers, infectious studies can also be helpful like Epstein-Barr virus, serologies, cytomegalovirus.

Dr. Siva Chinnadurai: If we see some of these alarming things, you had mentioned that something like an acute leukemia can result in some life-threatening problems even in a really short period of time, what are some red flags where you say this is something where we immediately need to get this child into the specialist? Then what’s the best place to go? Is that straight to the oncology clinic or to a surgical subspecialist for a biopsy? How do you manage those acute referrals and maybe the multidisciplinary approach to how to manage those things acutely?

Dr. Lane Miller: With acute leukemia, our biggest concern is what hyperleukocytosis or high white blood cell count that’s unmanaged can do to the body. These are large, rigid, sticky cells that can clog up the vasculature in the lungs and in the brain, in the CNS and can cause clots, strokes, pulmonary issues, myocardial infarction. It can be very serious, and the spontaneous lysis of these cells and the release of potassium and uric acid you can imagine can be really damaging, especially to the kidneys. We oftentimes see acute kidney as a presenting symptom.

If we are seeing a white blood cell count that’s significantly elevated, usually above 50,000 I consider significantly elevated, it’s important that that patient get into the emergency room right away. Contact our service and we can help guide so that the emergency room is aware of the patient and the story and exactly what labs to draw. Then we can make our pathologist aware that a specimen is coming in and they should look out for it so we get a pretty quick turnaround on a diagnosis.

As far as localized mass effect of lymph nodes, we’re really mostly worried about airway compromise in mediastinal disease, so tracheal compromise. We also sometimes see vascular compression that can lead to something called superior vena cava syndrome or spinal cord compression. Acute pulmonary or neurologic symptoms or facial swelling would all be emergencies to get the patient into the emergency room right away.

Our clinic oftentimes can expedite clinic visits with one of us if it’s not an absolute emergency to get the patient into the emergency room that day. Just call our service. If it’s an ambiguous case and it makes more sense to bring the patient into clinic, we can usually accommodate that.

Dr. Siva Chinnadurai: Now if we dive a little bit more maybe into some of these specific diagnoses, we’ve talked about the child presenting with a lump or bump, and say we have some of those more concerning features, it’s not an emergency, it’s more concerning features and we get into see you and get a excisional biopsy and a diagnosis of a lymphoma as confirmed for this child, can you tell the listeners about the most common types of lymphoma?

Dr. Lane Miller: As far as the types of lymphoma, there are many. We tend to break it down into two big umbrella terms of Hodgkin’s lymphoma and non-Hodgkin’s lymphoma. Really Hodgkin’s lymphoma was first described by a physician back in the early 19th century who was describing a very discrete subset of rigid lymph nodes that had clonal proliferation of these B cells that had a characteristic histopathological appearance. We call them Reed-Sternberg cells and tended to happen in adolescents, young adults and have a fairly good prognosis with treatment.

Everything else is lumped under this non-Hodgkin’s lymphoma diagnosis. That includes many types of lymphomas, mature B-cell lymphomas like Burkitt’s, lymphoma diffuse large B-cell lymphoma, some of our acute lymphoblastic lymphomas that are very similar in biology to leukemias. That would be our T-cell lymphomas and leukemias. Everything that I just mentioned, these are very rapidly progressing tumors, high mitotic index, doubling time. Then there’s some other rarer lymphomas, MALT lymphomas, marginal zone lymphomas that also fall in that non-Hodgkin’s classification. Most lymphomas are Hodgkin’s lymphoma that we see.

Dr. Siva Chinnadurai: What’s that breakdown between, say in your practice, how many people are coming in the Hodgkin’s type lymphoma?

Dr. Lane Miller: Of all lymphomas, Hodgkin’s makes up about three out of five.

Dr. Siva Chinnadurai: In the diagnosis of Hodgkin’s lymphoma, what are you guys looking at in terms of prognosis? You mentioned these are highly treatable, tend to have a better prognosis. Could you speak more to that?

Dr. Lane Miller: Really all types of lymphomas in pediatrics have made an unbelievable amount of progress over the last decades. Hodgkin’s, in particular, used to be managed with very, very intense chemotherapy that was gonadotoxic, cardiotoxic, toxic to the lungs, often involved radiation. Even over the five years that I’ve been here, I’ve seen a tremendous amount of progress in terms of how we are continuing to cure these patients without using as much toxic chemotherapy.

The overall survival rates for Hodgkin’s in adolescents are very close to 100%. We see it often as how do we get you to that long-term survival? It may take a couple of different attempts at chemotherapy regimens or immunotherapy regimens, but we’re in a very fortunate space where we have so many options.

Dr. Siva Chinnadurai: You’ve hit on just an amazing point in your field in pediatric care in general, which is just that the progress and the rate of progress has just been so amazing achieving these higher and greater remission rates and survival rates, as you said, approaching 100% in some of these diseases. I think so important to that, so vital to that is the close relationship that a lot of our medical specialists, but most especially in your department have with research infrastructure, with partnering with clinical trials, new novel drug development. Can you talk about the relationship that oncologists here have in clinical trials and how you select patients out to get involved in some of these new treatments and what are the focus of these treatments?

Dr. Lane Miller: I think that’s completely true. I think the reason we have made so much unbelievable progress in childhood leukemia and lymphoma and other areas of oncology over the last 50 or 60 years is because a rare disease that would otherwise be very difficult to study, researchers all over the world have been able to collaborate and bring their patients together and ask and answer very big questions by conducting randomized controlled trials, large phase three trials and early phase trials.

We are a Children’s Oncology Group center here at Children’s Minnesota and one of the largest referrers to this consortium in the country. We have many open clinical trials through the Children’s Oncology Group that is also enrolling at hundreds of other institutes in the United States and abroad. All of that data is being gathered and assessed and being used to make future decisions for children. It tends to happen fairly quickly.

I mean, we may be asking a clinical question about immunotherapy one day and two and a half, three years later, it has become the standard of care as part of upfront therapy for that child. In my experience, in other aspects of medicine, that process tends to take a lot longer. It’s really something to watch.

As far as when to enroll a child in a clinical trial, when we open something here, we as a group, we discuss whether or not this is a trial we’re enthused about and we want to open it and we would want to offer to our patients. Most of the time we do do that. If a trial is open and it’s applicable to a patient in their given scenario, we’ll offer it to a family and explain why we think it’s of benefit to them. Every now and then, it may make more sense, based on what we know from the literature in a patient-specific scenario, not to enroll on a trial. In fact, I just did that a couple of days ago and opted not to enroll a child when there was an open clinical trial.

We do have other consortia that we work with, the therapeutic advances of childhood leukemia or a TACL consortia. We work closely with St. Jude’s and Stanford.

Then as far as early phase trials go, we work with other institutions to send patients to those institutions. The University of Minnesota is a great example. They do much of our cellular therapy for our patients, which is a very exciting field. Mayo as well. CHOP in Philadelphia, and we’ve worked with many other centers and have great relationships.

Dr. Siva Chinnadurai: Lane, if we shift gears a little bit out of lymphoma, earlier you had talked about leukemia and oftentimes some of these accelerated time courses that are associated with leukemia. Is there advice you can offer to a primary care provider in differentiating early some of the common symptoms of childhood illnesses or maybe more severe illness versus something that should raise concern for leukemia?

Dr. Lane Miller: Leukemia can be very tricky to diagnose and oftentimes does require three or four clinic visits before that first blood draw occurs. If that’s the case, it’s usually okay because that means it’s a patient that’s been stable and is not giving you a smoking gun series of symptoms that warrant emergent lab workup.

But the symptoms of leukemia, they do masquerade and look like healthy, normal childhood problems, bruising, bone pain, fevers on and off, fatigue. These things can all occur with viral syndromes or just be part of the maturation growing process.

But I think if these symptoms persist, because leukemia does not get better on its own, it does not regress in any way unless treated, as these symptoms start to progress over the course of one or two weeks, that’s the appropriate time to start doing your laboratory workup. Really that CBC with a white count differential is by far the most important test we can get.

For a patient with pancytopenia or just mild reductions in all cell lines, but the patient is well-appearing and looks great and doesn’t need transfusions, that’s probably a good time to call us and try to get that patient into our clinic fairly soon so that we can do a bone marrow evaluation, which we do offer in our clinic under sedation.

Dr. Siva Chinnadurai: A lot of the comments you made about the advance of targeted therapies, the increase in survivability and the improved prognosis when we were talking about lymphoma, a lot of that’s true in the leukemia space as well. Is that right?

Dr. Lane Miller: It might even be a more remarkable trend in the leukemia space, especially with acute lymphoblastic leukemia. There is actually one form of what we call low risk for relapse, acute lymphoblastic leukemia that has essentially 100% survival and 99% survival without relapse, which is just tremendous. Those patients, we’ve been able to reduce the amount of therapy that they’re getting. It’s a small subset. We still have a lot of work to do on probably the other 95% of acute lymphoblastic leukemia patients and a lot of relapses are very hard to salvage. That’s where a lot of our research is going right now. But overall, we’ve made incredible progress. A lot of that is thanks to the addition of immunotherapy into standard chemotherapy backbones.

Dr. Siva Chinnadurai: With this constantly changing, constantly improving landscape and the close partnership between primary care providers and oncologists, is there anywhere you’d suggest that the listeners look to stay up to date with their latest developments or new guidelines, new treatments in pediatric oncology?

Dr. Lane Miller: Listeners and providers can get a lot of information from the websites of the Children’s Oncology Group, from the American Society of Pediatric Hematology and Oncology and the National Comprehensive Cancer Network, or NCCN, which publishes their guidelines online and gives guidance on workup for lymphomas and leukemias. There are some websites that have more up-to-date information on the world of oncology in pediatrics, FDA approvals and the status of certain drugs, so CureSearch, OncLive. Then really all the major journal websites like JAMA, Nature, Blood, you can find updates regularly on their website. Most of those don’t have a paywall for those.

Dr. Siva Chinnadurai: Well, Dr. Miller, I’ve loved our time talking about this and just hearing more about your field. It’s really just the heart and soul of pediatrics, of specialty medicine. It’s great to hear about not only all the progress that’s been made, but the progress that your field is looking to make in the years to come. Today we’ve talked about the basic approach to a child with a newly discovered mass, the lab tests that we should get, maybe a BMP, a CBC, and a chest X-ray in that setting, and differentiating some timeline factors for leukemia versus more persistent common illnesses of childhood and some of the triggers on a CBC for referral.

Some of the more exciting things we’ve talked about is the huge shift from more systemic, highly toxic chemotherapy and radiation to really targeted therapies, immunotherapies, molecular therapies that not only are better for patients in terms of their side effect profile, but are really conferring these huge jumps in survivability, survival rates. That an important point that I know that you’ve made a few times in our conversations is just that timely diagnosis and the right treatment means that the majority of these types of diseases, even though they’re really scary for everybody involved, are really treatable. The prognosis today is so much better than it was even just a few years ago.

Dr. Miller, it has been great to talk to you and hear about your field.

Dr. Lane Miller: Absolutely. Thank you so much for having me. It’s been really great.

Dr. Kade Goepferd: Thank you for listening to Talking Pediatrics. Come back next time for a new episode with our caregivers and experts in pediatric health. Our showrunner is Cora Nelson. Episodes are produced, engineered and edited by Jake Beaver and Patrick Bixler. Our marketing representatives are Amie Juba and Krithika Devanathan. For information and additional episodes, check us out on your favorite podcast platform or go to childrensmn.org/talkingpediatrics.