Children's Doctor


A Disease of Extremes

Yael P. Mossé, MD

LL is a 10-week-old, ex-full-term female who presents to the ED with hepatomegaly. One week earlier, she developed a fever at home. Her primary pediatrician diagnosed otitis media and started her on amoxicillin. On follow-up examination a few days later, her ear has improved, but she is found to have massive hepatomegaly, not noted during previous visits. An initial ultrasound confirmed the liver to be 108 mm without any focal masses, and she is immediately sent to the ED.

In the ED, the patient is afebrile with normal vitals. She is in the 35th percentile for weight and 25th percentile for length. On exam, she is a well-appearing child whose only notable finding is a liver palpated down to the level of the umbilicus. Her abdomen is otherwise soft and nontender. The patient has a history of intermittent abdominal distention and arching with feeds that was diagnosed as GERD. Her  pediatrician started her on Zantac, but she still has arching and persistent gas pains. In the ED, labs show a mild leukocytosis and thrombocytosis, normal coagulation profile, and normal CRP. Her liver-function tests show only a mild transaminitis. Epstein-Barr virus and cytomegalovirus PCRs are negative. While in the ED, the patient has a brief oxygen desaturation to 85% with perioral cyanosis but quickly recovers without oxygen. An EKG indicates borderline left ventricular hypertrophy but is otherwise normal.

Discussion: Neuroblastoma is an embryonal cancer of the autonomic nervous system that generally occurs in young children, with a mean age of diagnosis of 17 months. The tumors arise in sympathetic nervous tissues, typically in the adrenal medulla or paraspinal ganglia, and can present as mass lesions in the neck, chest, abdomen, or pelvis. The clinical presentation is varied, ranging from a child with an asymptomatic mass to one critically ill from a locally invasive primary tumor and/or widely disseminated disease. The incidence of neuroblastoma is 10.2 per 1 million children younger than 15 years, and it is the most common cancer diagnosed during the first year of life.

Neuroblastoma is a fascinating disease because of its diverse and often dramatic clinical behaviors. On one hand, it accounts for a disproportionate amount of childhood cancer morbidity and mortality, but on the other, it shows the highest proportion of human cancer cases that spontaneously and completely regress. Over the past decade, we have witnessed substantial progress in curing the less aggressive form of the disease, mainly due to improved risk-stratification at diagnosis. However, cure rates for patients with high-risk disease have shown only modest improvements despite dramatic escalations in the intensity of therapy.

Though 99% of neuroblastoma cases occur sporadically, the disease can be inherited in an autosomal dominant fashion. Our recent findings on mutations in the ALK oncogene and the homeobox gene PHOX2B have allowed us to identify the majority, if not all, of the mutations that lead to familial neuroblastoma. Thus, genetic testing for mutations in these two genes should be considered in patients with a family history of the disease or other clinical factors, such as bilateral adrenal primary tumors suspicious for a highly penetrant transmissible mutation. This test is available at CHOP’s Molecular Diagnostic Laboratory.

For patients with tumors showing favorable biological features, the aim is reduction of therapeutic intensity. Multiple studies have found that even widely disseminated neuroblastomas may spontaneously and completely regress.

While we classically regard neuroblastoma as either a benign or malignant disease, some patients fall in between, with intermediate-risk disease. The current approach is moderate intensity of chemotherapy, and radiation therapy is typically avoided. For patients with tumors showing adverse prognostic features, standard treatment has been intensification of chemoradiotherapy, but more recently the focus is on exploiting key oncogenic features found in the tumor microenvironment. The current treatment schema for these patients includes an induction regimen of 6 cycles of chemotherapy, surgical resection of the primary tumor, myeloablative therapy with stem cell rescue, and external beam radiation to the primary tumor bed, followed by a maintenance phase of immunotherapy combined with cis-retinoic acid (CRA). A recent randomized phase 3 trial of an intensive immunocytokine regimen combined with CRA showed a dramatic improvement in 2-year event-free survival. These data establish a new treatment paradigm.

Baby LL was found to have stage 4S neuroblastoma with bilateral adrenal masses. She initially required chemotherapy due to her massive hepatomegaly in order to trigger disease regression. Genetic testing is ongoing in light of her young age at diagnosis and the presence of bilateral adrenal tumors.

Joann Spinale, MD, wrote the “Make the Diagnosis” section in the last issue on which this article is based.

References and Suggested Readings
Mossé YP, et al. Identification of ALK as a major familial neuroblastoma predisposition gene.
Nature. 2008; 455:930-935.

Brodeur GM, Maris JM. In: Pizzo PA, Poplack DG, eds.
Principles and Practice of Pediatric Oncology. Philadelphia: J.B. Lippincott Co; 2006:933-970.

A Malignant Brain Tumor

Kristina Cole, MD, and Peter Phillips, MD

LB is an 8-month-old, full-term infant who came to her pediatrician with a 2-week history of vomiting and irritability. She had been afebrile with no other symptoms, but her mother reported that she could no longer sit independently or pull to a stand. On exam, her pediatrician noted normal vital signs, a crying female infant with macrocephaly, a bulging fontanel, and downward deviation of her eyes with visible sclera between the iris and lid. LB was immediately transported to the CHOP PICU, where a CT and MRI revealed a cerebellar tumor causing obstructive hydrocephalus. (Fig. 1.) The spine MRI was negative. The next day, LB was taken to the operating room. A neurosurgeon placed a ventricular drain to relieve the hydrocephalus and removed the tumor, found to be medulloblastoma. One month after her surgery, LB began her first of 6 cycles of inpatient chemotherapy, 3 of which would include stem cell replacement.


Figure 1: A sagital (A) and axial (B) postcontrast MRI scan demonstrating a large cerebellar mass with associated obstructive hydrocephalus.

Discussion: LB was diagnosed with medulloblastoma (also known as a posterior fossa primitive neuroectodermal tumor, or PNET). It accounts for only 13% of pediatric brain tumors (age 0-14 years) but is the most common malignant solid tumor of childhood, with approximately 700 children diagnosed in the U.S. each year. About half of the patients are younger than 5 years. The presenting symptoms relate to the location of the tumor in the  cerebellum. Patients with medulloblastoma often present with signs of increased intracranial pressure due to obstruction of the fourth ventricle. In  children, like LB, whose sutures have not fused, there may be increased head circumference and a bulging fontanel. Other symptoms include nausea and vomiting, headache, and lethargy. There may be papilledema on fundoscopic exam. Because of the location in the cerebellum, patients may have an unsteady gait, ataxia, and/or dysmetria.

Once a young patient is diagnosed with medulloblastoma, multimodality treatment is necessary—if untreated, medulloblastoma is fatal. The treatment team includes neurosurgeons, rehabilitation physicians, radiation oncologists, neuro-oncologists, specialized nurses, and neuropsychologists.

Patients are divided into risk groups on the basis of age, degree of surgical resection, and extent of tumor dissemination. Treatment starts with the best surgical resection possible.

Children older than 3 years who have a total resection of their tumor without dissemination along the neuro-axis are considered average-risk, while those with residual tumor and/or dissemination are high-risk. Both average- and high-risk patients are treated with focal radiation to the site of the original tumor along with a lower dose of radiation to the entire brain and spine. Those with high-risk disease are treated with a higher dose of craniospinal radiation. After radiation, patients are treated with almost a year of chemotherapy. Clinical trials are under way to determine if shorter, more intense chemotherapy with stem cell rescue may be more effective.

Children younger than 3 years are not treated with radiation because of the profound neurocognitive damage it would cause. Instead, they are treated with intense, high-dose inpatient chemotherapy regimens.

Survival depends on age and risk group. Children younger than 3 years at diagnosis have the worst prognosis, likely due to the fact that they are more likely to have disseminated disease, and radiation is not used or is delayed. Children who are older than 3 with average-risk medulloblastoma have a 5-year survival greater than 80%. Survival of patients with high-risk disease is approximately 60%.

While improvements in therapy have increased the long-term survival of medulloblastoma patients, it comes at a cost in late effects. Radiation effects include neurocognitive dysfunction, hearing loss, cardiotoxicity, infertility, hypothyroidism, and growth delay.

As survival rates for children with average-risk medulloblastoma have improved, there has been a growing emphasis on decreasing the effects of treatment. Multi-institution clinical trials are under way to determine whether a decreased craniospinal dose or decreased margin of the radiation boost can result in fewer late effects while maintaining survival.

Another effort to reduce late effects is through the use of proton beam radiation therapy. Proton therapy offers the promise of fewer acute and late effects because it delivers a more focused treatment area, limiting the toxicity to surrounding normal tissues. Currently there are 5 proton centers treating pediatric patients in the U.S. In the winter of 2010, the Roberts Proton Facility at the University of Pennsylvania will open, and children with medulloblastoma will begin proton therapy in the spring of 2010.

LB is now 2 years old, more than a year off therapy. She has high-frequency hearing loss but is playful, healthy, and meeting all developmental  milestones. She continues to have routine surveillance MRI imaging, audiograms, and follow-up in the Neuro-Oncology and Stem Cell Transplant clinics at CHOP.

References and Suggested Readings
Crawford JR, MacDonald TJ, Packer RJ. Medulloblastoma in
childhood: new biological advances.
Lancet Neurol 2007; 6: 1073-85.

Fossati P, Ricardi U, Orecchia R. Pediatric Medulloblastoma:
Toxicity of current treatment and potential role of proton therapy.
Cancer Treatment Rev 2009; 35: 79-96.

The Most Common Childhood Cancer

Leslie Kersun, MD

MC is a 4-year-old male who has seen his pediatrician 3 times over the past 2 weeks with fever, rhinorrhea, and fatigue. He was thought to
have a viral illness. His symptoms persist, and today, he started limping. His mother decides to bring him again to his pediatrician, as something “isn’t right.”

Discussion: On examination, T, 38.5°C and HR, 120 bpm. He is sitting quietly on his mother’s lap. When asked to get on the exam table, MC asks his mother to lift him as he doesn’t want to walk. MC is pale with small, mobile cervical lymph nodes. Liver and spleen are palpated 2 cm below the right and left costal margins. Testicular exam is normal. He has scattered bruises on his shins and knees.

A diagnosis of acute leukemia cannot be made without a bone marrow evaluation, but his pallor, hesitancy to walk, and hepatosplenomegaly are worrisome.

For most cases (>95%), there is no predisposing cause for the development of acute lymphoblastic leukemia (ALL), the most common childhood cancer. There are associated genetic syndromes, including Down syndrome, Bloom’s syndrome and ataxia telangiectasia. Patients also may be at increased risk after exposure to radiation and certain chemotherapeutic agents.

The most common symptoms reflect bone marrow infiltration with leukemia cells: fever, bleeding (petechiae and purpura), pallor, and bone pain. Lymphadenopathy and hepatosplenomegaly are present in 50% to 75% of patients. Half have an elevated white blood cell count and most present with some degree of anemia. Seventy-five percent present with a platelet count under 100,000. Symptoms vary in duration but are usually present for days to months. Children can present with nonspecific symptoms, which may be confused with nonmalignant conditions including viral infections, idiopathic thrombocytopenic purpura, juvenile rheumatoid arthritis, and aplastic anemia.

Diagnosis is confirmed by bone marrow aspirate and evaluation of the cells by methods including light microscopy, flow cytometry, immunohistochemistry, and cytogenetic analysis. At diagnosis, spinal fluid is evaluated for the presence of leukemia cells.

Age and white blood cell (WBC) count at presentation place patients into standard- or high-risk categories. The standard-risk category includes children between the ages of 1 and 9 years with a WBC count of <50,000. Conversely, infants, children >9 years, or any age patient with aWBC >50,000 at presentation have high-risk disease. Factors that affect prognosis and require therapy intensification include slow treatment response, identification of certain cytogenetic abnormalities of the leukemia cells, and minimal residual disease after 1-2 months of treatment.

Treatment includes multi-agent chemotherapy in distinct phases. The purpose of the induction phase is to induce remission so the leukemia burden is below the detection level of our current tests. Additionally, removal of the majority of ALL cells from the bone marrow allows restoration of normal  hematopoiesis. This phase most often includes a steroid (dexamethasone or prednisone), vincristine, and asparaginase with or without an anthracycline. Induction is followed by consolidation treatment in order to both direct therapy at the central nervous system (CNS) and use agents not employed in induction to eliminate cells with drug resistance. Studies have demonstrated that CNS prophylaxis even for patients without involvement at diagnosis is imperative to decrease the relapse risk in this sanctuary site.

Later phases often include repetition of earlier intensive treatment. Another critical component involves maintenance or lower-intensity chemotherapy for a prolonged period (1.5-2.5 years) to eliminate residual disease.

Treatment for patients with initial CNS or testicular involvement includes directed radiation. CNS radiation is also often recommended for patients known to be at increased risk of CNS relapse. Allogeneic stem cell transplantation is used for high-risk patients both at diagnosis an overall survival to be comparable to those with standard-risk ALL. The majority of survivors grow into healthy adults. Patients should be followed by a physician who is familiar with the potential late effects of their treatment once they are at minimal risk for disease recurrence; usually at least several years off-therapy.

In this type of case, one should obtain a basic laboratory evaluation and chest radiograph as soon as possible—if not feasible in an outpatient office, then in an emergency department. MC was sent to the emergency room and had a WBC count of 49,000, hemoglobin of 8.5 g/dl, and platelets of 75,000. Chemistry panel and chest X-ray were normal. He was started on empiric antibiotics. Bone marrow aspirate demonstrated ALL, and he was started on standard chemotherapy. MC is 8 months into a 3-year treatment plan and has tolerated therapy well.

References and Suggested Readings
Pui C-H, Robinson LL, Look AT. Acute lymphoblastic leukemia.
Lancet. 2008; 371: 1030-1043.

Margolin JF, Steuber CP, Poplack DG. Acute Lymphoblastic
Leukemia In: Pizzo PA, Poplack DG, eds.
Principles and Practice of Pediatric Oncology. Philadelphia: J.B. Lippincott Co;
4th Edition, 2002.

Residents’ Corner

Paul Aronson, MD

Care for the Clinician

As physicians, we remember certain moments throughout our careers. The biggest mistake we made during residency. The injured patient we could not save. The code that left us particularly shaken.

These events haunt us, and they can make us doubt our capabilities as doctors.

Pediatric medicine requires family-centered care—support for the patient as well as the family. But often, one group is left out: clinicians, particularly those who care for children with extensive physical or emotional injuries. They usually lack a structured forum in which they can share their feelings about providing care in these challenging situations.

A series of monthly rounds at CHOP aims to address this need. The Schwartz Center Rounds began in September 2007 to promote understanding among clinicians and other care providers, with the ultimate goal of improving communication between these providers and the families they serve.

The rounds are a multidisciplinary forum that provides an opportunity to focus on the social and emotional aspects of patient care. At a recent rounds, participants discussed how being part of a traumatic medical event affects clinicians over time. Other sessions examined conflicts between the family and the medical team, and coping when a patient dies.

As a resident, I attended a Schwartz Rounds devoted to medical errors. I had been struggling over a mistake, and it was a relief to hear my mentor describe his similar emotional reaction to an error of his own. As many of us shared our stories, the experience was therapeutic, and it was a gentle reminder to keep empathy at the forefront of our practice.

The rounds are sponsored by the Kenneth B. Schwartz Center, a nonprofit organization committed to the national promotion of a healthcare system in which caregivers are compassionate, engaged, and able to address patients’ needs, both medical and emotional. The rounds take place at 182 sites in 30 states, including one Wednesday each month at CHOP. The forum is open to all clinicians, and each discussion is kept confidential.

For more information on Schwartz Center Rounds at CHOP, please contact Elizabeth Steinmiller, MSN, PMHCNSBC, clinical nurse specialist in mental health, and facilitator and coordinator of the rounds, at 215-590-2137 or


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