neonatal neuroblastoma presentation

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Introduction, epidemiology, pathophysiology, clinical presentation, neuroblastoma treatment, radiotherapy, chemotherapy, autologous stem cell transplant, immunotherapy, conclusions, acknowledgment, clinical presentation, evaluation, and management of neuroblastoma.

AUTHOR DISCLOSURE

Drs Sharma, Mer, Lion, and Vik have disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.

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Richa Sharma , Jesse Mer , Alex Lion , Terry A. Vik; Clinical Presentation, Evaluation, and Management of Neuroblastoma. Pediatr Rev April 2018; 39 (4): 194–203. https://doi.org/10.1542/pir.2017-0087

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Pediatricians play a pivotal role in the diagnosis of neuroblastoma and as such should be aware of the elusive signs and symptoms to provide clinical surveillance, appropriate referral, and medical support as part of the patient’s multidisciplinary team.

After completing this article, readers should be able to:

Identify signs and symptoms of neuroblastoma.

Identify patients who require emergency care for a life-threatening presentation.

Discuss the basics of clinical presentation, diagnostics, and management of neuroblastoma.

Pediatric cancers occur in 171 per 1 million children in the United States each year and are the leading cause of disease-associated death in children. ( 1 ) Neuroblastoma is not only the most common cancer in infancy but also the most prevalent solid tumor outside the cranium, ( 2 ) and it sometimes requires the most aggressive treatment plan in pediatric oncology. Therefore, pediatricians should be familiar with clinical presentations that should prompt appropriate and timely referral. In this review, we present neuroblastoma, which exemplifies several principles of pediatric oncology, including its multidisciplinary treatment approach.

The annual incidence of neuroblastoma is approximately 700 cases in North America. ( 1 ) In a review of national cancer registries from 2001 through 2009, a diagnosis of neuroblastoma or ganglioneuroblastoma was found in approximately 6% of the cases. ( 1 ) Neuroblastoma is more common in the white population (9.7 per 1 million) than in the African American population (6.8 per 1 million) ( 2 ) and more common in males (8.5 per 1 million) than in females (7.6 per 1 million). ( 3 ) Although the median age at diagnosis of neuroblastoma is 18 months, ( 4 ) there is a wide age range, from in utero diagnosis to individuals in their 20s. ( 5 ) Research studies have interrogated several exposures, including viruses, chemicals, radiation, and drugs. No strong causality has been found to support a role of environmental risk factors in the pathogenesis of neuroblastoma.

Neuroblastoma arises from abnormal growth of embryonic neural crest cells that normally make up the sympathetic ganglia and the adrenal medulla. ( 6 ) As in all cancers, this aberrant growth is caused by gene mutations. Serving as a starting point, the gene mutation may be germline (occurring in sperm or eggs, thereby hereditable) or somatic (in other cells of the body, which become a tumor).

In some cases, hereditable gene mutations predispose to neuroblastoma. A germline mutation in the ALK oncogene accounts for less than 2% of all neuroblastoma cases and is known as familial neuroblastoma. Familial neuroblastoma often presents with severe clinical features, such as younger age at diagnosis, bilateral adrenal tumors, and multifocal primary neuroblastoma. ( 7 ) A PHOX2B loss-of-function mutation can result in neuroblastoma as one feature of congenital central hypoventilation syndrome. ( 8 )( 9 ) A neurocristopathy syndrome is a rare, heritable group of conditions that result from abnormal neural crest cell development and must be considered when seeing a child with simultaneous occurrence of Hirschsprung disease, congenital hypoventilation syndrome, and congenital neuroblastoma.

In contrast, somatic mutations account for more than 98% of neuroblastoma cases. ( 10 ) Several genetic alterations have been identified, including gene amplification, chromosomal alterations, and gene polymorphisms. The most important biomarker in neuroblastomas, the MYCN gene, is amplified in approximately 20% of cases. ( 11 ) The ALK oncogene has also been shown to have gain-of-function somatic mutation in approximately 14% of neuroblastomas. ( 12 ) Both MYCN and ALK amplifications are associated with aggressive tumor phenotype and poor prognosis. Recurrent gain or loss of specific chromosomal segments is found in almost all high-risk neuroblastomas. The most important alterations include gain of 17q and loss of 11q and 1p. ( 6 ) Ongoing research efforts are underway to better understand genes that are housed in the aforementioned chromosomal regions, which are associated with aggressive neuroblastomas. Finally, the number of whole chromosomes in a cell, also known as ploidy, is another prognostic marker. Tumor cells can have more (hyperploidy) or less (hypoploidy) than the normal number of copies of whole chromosomes. As with neuroblastomas and most other pediatric cancers, hyperploidy is a more favorable prognostic sign than hypoploidy. ( 13 ) Conclusively, there is a great variety of genetic alterations possible, leading to a wide spectrum of clinical behavior of neuroblastomas. The following cases show the dramatic extremes of presentation.

Katie is a 4-month-old healthy girl who is brought to her pediatrician by her mother with a concern of “projectile vomiting” for 3 days. Katie’s mother is worried that she may have pyloric stenosis just as her older brother did when he was an infant. The mother denies sick contacts. Urinary output has been adequate, and Katie is gaining weight adequately. Katie’s vital signs and physical examination findings are normal. A complete abdominal ultrasound is negative for pyloric stenosis. However, it is positive for an incidental finding of a 2-cm heterogeneous mass in the right retroperitoneal space. The mass may be arising from the adrenal gland, and it contains areas of calcification, with partial vascularity on Doppler, and is not causing mass effect. On consultation, a pediatric oncologist would like to see Katie in her clinic today, with plans to obtain a complete blood cell (CBC) count, basic metabolic panel, liver enzyme levels, coagulation profile, and random urinary catecholamine levels.

This case demonstrates 1 side of the clinical spectrum, in which a neuroblastoma may be discovered as an incidental radiologic finding. The symptoms, which brought her to the pediatrician, may very well be unrelated to the neuroblastoma. In addition, a small neuroblastoma may not be palpable on physical examination. The location of the mass on imaging gives a clue to the diagnosis. Although Katie’s tumor is located in the most common site, the adrenal gland, a neuroblastoma can occur anywhere along the sympathetic nervous system. These sites include the adrenal glands (>50%), the abdominal paraspinal ganglia (24%), the thoracic paraspinal ganglia (20%), the neck (3%), and the brain (rarely).

The CBC count shows a white blood cell (WBC) count of 10,200/μL (10.2 ×10 9 /L ), with 56% neutrophils and 44% lymphocytes. The hemoglobin level is 12 g/dL (120 g/L), and the platelet count is 250×10 3 /μL (0.25×10 9 /L).   Her electrolyte, liver enzyme, and fibrinogen levels and coagulation profile are all normal. Her urinary vanillylmandelic acid (VMA) level is 722 mg/g creatinine (reference range, <25.0 mg/g creatinine) and urinary homovanillic acid (HVA) level is 960 mg/g creatinine (reference range, <35.0 mg/g creatinine). The oncologist explains the laboratory values to the mother and states that the increase in urinary catecholamine levels combined with the ultrasonography findings raise concern for a neuroblastoma.

A diagnosis of neuroblastoma is suggested by laboratory, radiologic, and histologic findings ( Table 1 ). Katie’s CBC count is normal, without findings of neutropenia, anemia, or thrombocytopenia, which most likely excludes bone marrow involvement. Abnormal liver enzyme levels and coagulation panel values are generally secondary to liver metastasis, which is not the case for Katie. Both VMA and HVA are catecholamine metabolites that are secreted by neuroblastoma cells and are elevated in 90% to 95% of patients with neuroblastomas. Of note, spot or random urinary catecholamine levels are sufficient to make the diagnosis, and a 24-hour urine collection for catecholamine levels is not needed. Although radiologic studies such as ultrasonography or chest radiography are initially used, magnetic resonance imaging (MRI) (preferred) or computed tomography (CT) is required to better evaluate disease burden ( Fig 1 ).

Laboratory, Radiology, and Pathology Evaluation for Neuroblastoma ( 6 )

CT, computed tomographic; IHC, immunohistochemical; MRI, magnetic resonance imaging.

A. Chest radiograph shows a soft tissue mass at the right lung base. B. Computed tomographic scan shows a large right paraspinal mass with partial enhancement, large areas of necrosis, and scattered calcifications. C. Growth of tumor through interpendicular spaces. D. T2-weighted magnetic resonance image demonstrates tumor neuroforaminal invasion in a classic “dumbbell” pattern.

An abdominal MRI demonstrates a 2-cm heterogeneous mass with calcifications arising from the right adrenal medulla. No lymph node or perivascular involvement is noted.

Although Katie’s laboratory and MRI findings are favorable for localized disease, a metastatic evaluation is necessary for the management of a neuroblastoma. Indeed, metastatic disease to the bone marrow, liver, and skin is found in approximately 50% of patients during the initial presentation. These patients often present with constitutional symptoms such as fever, malaise, pallor, and fussiness. In addition, there may be refusal to walk/crawl, localized pain, and abdominal distention. A “blueberry muffin rash” is a cutaneous manifestation of a neuroblastoma in infants, representing tumor spread to subcutaneous tissue. These cutaneous nodules are purpuric lesions that blanch on palpation. When examining purpuric subcutaneous nodules, leukemic infiltrates and extramedullary hematopoietic centers must be included in the differential diagnosis because the location and appearance are similar. Orbital findings, including heterochromia irides and periorbital ecchymosis, or “raccoon eyes,” are secondary to metastatic spread to the retrobulbar region and are rare but suggestive findings for a neuroblastoma.

An I-123 metaiodobenzylguanidine (mIBG) scan is used to look for metastatic disease ( Table 1 ). It uses a radiolabeled molecule that possesses structural similarity to noradrenaline and is taken up by neuroblastoma cells. Although mIBG is 99% specific for metastatic neuroblastomas, 10% of neuroblastomas are not mIBG-avid, which can then be detected using positron emission tomography and CT scan. ( 14 )

An I-123 mIBG scan showed uptake in the tumor but was negative for metastatic disease. The oncologist explains that a right-sided abdominal mass in an infant, such as Katie, with elevated urinary catecholamine levels without systemic findings evident on laboratory evaluation is most likely to be a neuroblastoma. Fortunately, Katie is in the favorable age range (<18 months) where she is highly likely to have spontaneous regression of her neuroblastoma. After detailing Katie’s low-risk features, the oncologist converses with the mother and recommends monitoring as the best option for Katie.

Approximately half of all neuroblastomas found in infants spontaneously regress. ( 4 )( 6 ) In infants younger than 6 months, there are a few factors that ensure 98% event-free survival with observation alone. These factors include location (primary adrenal location, without metastases), size (<5 cm), clinical aggressiveness (<50% increase in tumor size during the screening phase), and laboratory evidence (<2-fold increase in urinary catecholamine levels starting from the time of diagnosis through the entire observation period). ( 15 ) Observation consists of sequential abdominal ultrasonography and urinary catecholamine levels at 6 and 12 weeks, followed by serial screening every 3 months for the first year and every 6 months for the second year. Surgical evaluation and histologic assessment are necessary if the tumor grows during the screening period. This mild presentation is contrasted by the opposite side of the clinical spectrum, as seen in the following 2 cases.

Chase is a 3-year-old boy who presents to the pediatrician’s office with worsening hip pain, leg pain, and back pain for 3 weeks. He has numbness in both legs, and his mother has noted shortness of breath when he is active. Vital signs are normal in the office. Significant physical examination findings include decreased breath sounds over the right lung, a large nontender abdominal mass, and 1+ Achilles reflex bilaterally. Chase’s gait is weak and altered, with dragging of his right leg and frequent falls when taking a few steps. Laboratory results include a WBC count of 9,200/μL (9.2×10 9 /L) with a normal differential count, a hemoglobin level of 13.4 g/dL (134 g/L), and a platelet count of 420×10 3 /μL (0.42×10 9 /L) . Electrolyte levels are normal aside from an elevated creatinine level of 1.2 mg/dL (106 μmol/L). Liver enzyme levels and results of coagulation studies are normal. Emergency transport is arranged to take Chase to a pediatric hospital emergency department because of concern for spinal cord compression.

As in this case, a neuroblastoma may present with a clinical sign specific to the location of tumor invasion. Neuroblastoma is one of the most common neoplastic causes of spinal cord compression in children. Common features of spinal cord compression include pain, numbness, and limb weakness. Given that all these signs and symptoms can be subtle in a child, a high index of suspicion is necessary. Sphincter dysfunction, presenting as loss of bowel or bladder function, and loss of deep tendon reflexes are relatively uncommon but ominous signs of spinal cord compression requiring immediate neurosurgical evaluation. An MRI is the most sensitive modality for identifying spinal cord pathology.

A chest radiograph is obtained and demonstrates a large soft tissue mass displacing the right lung ( Fig 1A , ). A contrast abdominal CT scan shows a large lobulated partially enhancing mass with calcifications ( Fig 1B , ). The tumor has displaced nearby structures and collapsed the right lung, with bony destruction of adjacent ribs and the vertebral column ( Fig 1C , ). Spinal MRI depicts the tumor growing through the neuroforamina of the lower thoracic spine and compressing the spinal cord ( Fig 1D   ).

Imaging studies can confirm spinal cord compression. A multidisciplinary approach, involving pediatric oncology and neurosurgery, is required to manage spinal cord compression secondary to a solid tumor. ( 16 ) When spinal cord compression is identified, dexamethasone is given with the intent to reduce spinal cord edema while the pediatric oncologist determines definitive therapy. In severe cases, surgical decompression or radiotherapy is used. There is some evidence that the most important component of managing spinal cord compression due to tumor is starting chemotherapy.

Although not seen in this case, pediatricians should also be familiar with 2 syndromes that should raise suspicion for a neuroblastoma. When a neuroblastoma impinges on the oculosympathetic tract, Horner syndrome becomes evident with ptosis, miosis, and anhydrosis. Opsoclonus myoclonus syndrome (OMS) is a paraneoplastic syndrome characterized by rapid multidirectional eye movements, involuntary muscle spasms, and irritability. Although the exact mechanism of OMS remains unknown, an autoimmune reaction is currently the leading hypothesis. Studies have shown the presence of autoantibodies against neuronal and cerebellar Purkinje cells in patients with OMS associated neuroblastoma.

Given the high mortality rate, the painful adverse effects of chemotherapeutic agents, and the long-term effects of high-risk neuroblastoma treatment, palliative care is a key component of comprehensive patient care. More than end-of-life care, palliative care involves control of symptoms while helping the patient live each day to the fullest. Palliative care often starts with the pediatrician, who has the deepest relationship with the patient and family. The pediatrician not only starts the palliation process, which involves quality of life discussions, establishing advance care goals, and providing social, physical, and spiritual support for the patient and family, but also provides an important link to the palliative care specialist.

Kurt is a 5-year-old boy who presents to the clinic with fever, fussiness, and decreased activity for 2 weeks. Kurt has lost 2.2 lb (1 kg) since his last visit 4 months ago. On physical examination Kurt is febrile (102.7°F [39.3°C]) and tachycardic. He appears pale and listless. He has bilateral cervical lymphadenopathy, abdominal distention with some tenderness, and petechiae on his extremities. Kurt refuses to stand and starts crying. The CBC count shows a WBC count of 3000/μL (3×10 9 /L) ,   with an absolute neutrophil count of 800/μL (0.80×10 9 /L), a hemoglobin level of 6 g/dL (60 g/L), and a platelet count of 13×10 3 /μL (0.013×10 9 /L).

The constellation of pancytopenia, fever, and weight loss raises a concern for a malignancy involving the bone marrow. Because a neuroblastoma commonly metastasizes to the bone marrow, it can present similarly to acute leukemia. A word of caution regarding the abdominal examination is warranted. The presence of ascites may make it difficult to palpate the margins of an abdominal mass. The other frequent abdominal tumor in children is a Wilms tumor. Due to concern for rupture of a Wilms tumor, ( 17 ) it is recommended that the abdominal examination not entail deep palpation. In this case, it is sufficient to know that there is no concern for a surgical abdomen and that follow-up imaging to rule out an abdominal mass is needed.

A CT scan of the chest, abdomen, and pelvis shows a large right adrenal mass with widespread lymphadenopathy notably in the right iliac chain, as well as with the right inguinal lymph nodes. The spleen is enlarged. The mIBG scan shows extensive axial and appendicular skeletal uptake ( Fig 2   ). The oncologist performs bilateral bone marrow aspirates and biopsies, which show small clusters of round blue cells, separated by a fibrillar matrix (Homer-Wright rosettes). The small round blue cells are atypical mononuclear cells with irregular nuclei, clumped chromatin, and mostly indistinct nucleoli. Molecular studies from the tumor biopsy show MYCN amplification, gain of 17q, and hypoploidy. Histopathologic review of the tumor and lymph node biopsy samples demonstrate a stroma-poor, poorly differentiated neuroblastoma.

Anterior (A) and posterior (B) I-123 metaiodobenzylguanidine whole body views show abnormal uptake in the bilateral humeri, femurs, and axial skeleton, including the calvarium. There is also uptake in the right upper quadrant consistent with a known neuroblastoma tumor.

Given the wide variance in neuroblastoma behavior, from spontaneous regression (case 1) to metastatic disease (case 3), a rational treatment plan requires risk stratification. Prognostic variables taken into account for stratification are 1) age at diagnosis, 2) stage of disease, 3) molecular alterations, and 4) histopathologic analysis of the tumor. In case 3, Kurt’s age at presentation already places him as a high-risk case. Genetic alterations, including MYCN amplification, hypoploidy, and the presence of chromosomal alterations, are poor prognostic features. The unfavorable histologic appearance of the tissue biopsy is in concordance with these molecular findings. Given these features, Kurt’s case presents as a classic example of a high-risk neuroblastoma, which will require the most aggressive therapy. A detailed discussion of staging and risk stratification of neuroblastoma is beyond the scope of this review, but a brief stratification scheme is provided in Table 2 , and excellent reviews have recently been published elsewhere. ( 6 )( 18 )( 19 )

International Neuroblastoma Risk Group (INRG) Staging Classifications ( 19 )

A discussion of treatment for high-risk neuroblastoma encompasses all modalities currently in use for pediatric cancer, which include surgery, chemotherapy, radiotherapy, autologous stem cell transplant, and immunotherapy/biological therapy.

Surgery was the only treatment available for solid tumors, such as neuroblastomas, before radiotherapy and chemotherapy were used. Because surgery was felt to be definitive treatment, and some neuroblastomas were not able to be surgically resected at the time of diagnosis, the first chemotherapy regimens were designed with an intent to make these tumors operable. ( 20 ) Most patients with low-risk neuroblastoma, such as a child with localized disease, favorable histologic findings, nonamplification of MYCN , and age younger than 12 months, are, indeed, cured with observation or surgery, when appropriate. ( 21 )( 22 ) However, with high-risk neuroblastoma behavior now elucidated, surgery is an ancillary part of the multimodal treatment. For example, after chemotherapy results in shrinking of the tumor, a second-look surgery is often performed for resection of the tumor. Of note, in a patient with MYCN amplification, micrometastases precipitate local recurrence and distant relapse, thereby making surgery alone insufficient for these patients.

A neuroblastoma is sensitive to radiotherapy, which has been used in combination with chemotherapy in many earlier neuroblastoma treatment plans. ( 23 ) However, radiotherapy carries a risk of late effects, including diabetes mellitus ( 24 ) and decreased height potential. ( 25 ) More importantly, radiotherapy carries an increased risk of secondary malignancy in neuroblastoma survivors. ( 26 ) This has led to stem cell preparative regimens, which avoid total body irradiation by giving larger doses of chemotherapy. Given the discovery of intermediate-risk neuroblastoma being cured with chemotherapy and/or surgery alone, radiotherapy now is mostly reserved for high-risk neuroblastoma. ( 27 )

Chemotherapy remains essential for patients with intermediate- and high-risk neuroblastoma. As with most cancers, to reduce the risk of selecting out cancer populations that become resistant to a single drug, multiagent regimens are used. Common chemotherapeutic agents considered include cyclophosphamide or ifosamide, cisplatin or carboplatin, vincristine, doxorubicin or adriamycin, etoposide, topotecan, and busulfan. The length of treatment has been reduced, and more moderate chemotherapy can be used for intermediate-risk patients. ( 28 ) Higher-dose chemotherapy with increased risk of toxicity is prescribed for children with high-risk neuroblastomas. The advent of stem cell transplant has enabled further intensification of chemotherapy for high-risk patients.

Stem cell rescue is accomplished with the patient’s own peripheral blood stem cells, infused after a preparative regimen that suppresses the bone marrow. The myeloablative regimen continues to evolve, with variations involving the chemotherapeutic agents used, the number of sequential transplants performed, and perhaps most important for long-term adverse effects, whether radiation is used. In randomized controlled trials, autologous stem cell transplant decreases the risk of relapse by approximately 10%. ( 27 )( 29 )

Fifty percent of children treated for high-risk neuroblastomas, despite achieving initial remission, will relapse. ( 30 ) To this end, a maintenance phase was developed involving isotretinoin, anti-GD2 antibody therapy, and cytokines, including granulocyte-macrophage colony-stimulating factor (sargramostim) and interleukin-2 (IL-2). Most familiar to pediatricians in its use for severe acne, isotretinoin is a vitamin A derivative. Also known as 13- cis- retinoic acid, isotretinoin acts on neuroblastomas by decreasing tumor cell proliferation and causing differentiation into nonmalignant cells. The attractive aspects of this drug are its ease of administration (given orally) and its relative tolerability. In fact, it can be given for an extended period, even for years. ( 31 ) In randomized controlled trials, isotretinoin alone reduces relapse risk at least by 10%, presumably by reducing minimal residual disease, an index used to describe the lowest residual disease burden after chemotherapy that is compatible with a cure, in addition to being used to define relapse.

Given its tolerability, isotretinoin can be combined with more intense maintenance therapy, namely, anti-GD2 antibody therapy. GD2 is one of the few disialoganglioside antigens expressed by most high-risk neuroblastoma cells. ( 32 ) The chimeric monoclonal antibody ch14.18 targets the GD2 protein, killing residual neuroblastoma cells via antibody-dependent immune activity. ( 33 ) This immune activity is augmented by giving the patient injections of granulocyte-macrophage colony-stimulating factor and by coupling the GD2 antibody with an infusion of IL-2. Given that GD2 is also expressed by peripheral nerve fibers, aggressive pain control is required during its infusion. In addition, the patient must be monitored during the infusion for capillary leak syndrome, which is a severe adverse effect of IL-2. Despite its severe potential adverse effects, the addition of anti-GD2 antibody and IL-2 to isotretinoin has reduced early relapse by approximately 20%, earning its place as part of the current standard therapy for high-risk neuroblastomas.

Neuroblastoma is a complex disease with diversity of presentation, clinical course, and treatment. Few other diseases may be treated with either intense multimodality treatment or mere observation. When signs and symptoms are recognized early, the pediatrician can help improve outcomes by making a timely referral to the oncologist. Although low-risk groups are highly likely to be cured, the pursuit to improve outcomes for high-risk patients continues. Despite multimodality therapy, cure rates for children with high-risk neuroblastomas remain approximately 50%. More research is needed to delineate treatment targets and new modalities of therapy.

On the basis of strong evidence, ( 2 ) a neuroblastoma is the most common extracranial solid tumor that requires multifaceted treatment, including observation, surgery, chemotherapy, radiotherapy, autologous stem cell transplant, and immunotherapy.

Based on strong evidence, ( 10 ) neuroblastoma is mostly due to somatic mutations that cause abnormal growth of neural crest cells of the adrenal medulla and sympathetic ganglia.

On the basis of consensus, pediatricians play a pivotal role in the diagnosis of neuroblastoma. A high index of suspicion is required given the wide spectrum of clinical presentation by neuroblastoma. Neuroblastoma should be considered in children with findings of abnormal breathing, especially when associated with Hirschsprung disease, an abdominal mass, ambulating difficulties, bowel/bladder dysfunction, fever, malaise, bone pain, or abnormal skin findings.

Based on strong evidence, ( 6 ) increased urinary catecholamine levels are highly sensitive for detecting a neuroblastoma, and further evaluation, including laboratory, radiographic, and histologic analyses, are necessary to confirm the diagnosis of a neuroblastoma and to guide medical therapy.

To view teaching slides that accompany this article, visit   http://pedsinreview.aappublications.org/content/39/4/194.supplemental .

We are indebted to the patients and families treated at Riley Children’s Hospital.

complete blood cell

computed tomography

homovanillic acid

immunohistochemical

interleukin-2

metaiodobenzylguanidine

magnetic resonance imaging

opsoclonus myoclonus syndrome

vanillylmandelic acid

white blood cell

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Neonatal neuroblastoma

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At the time the article was created Aneta Kecler-Pietrzyk had no recorded disclosures.

At the time the article was last revised Jeremy Jones had no recorded disclosures.

Neonatal neuroblastoma is a type of congenital neuroblastoma , an embryonal tumor arising from the sympathetic nervous system. In the majority of cases (45%), the tumor is localized in the adrenal gland. 

Epidemiology

Neonatal neuroblastoma accounts for less than 5% of all cases and carries a favorable prognosis, with most cases being low/intermediate risk for metastatic disease and recurrence.

Clinical presentation

Around 20% of neonatal neuroblastomas present with spinal cord compression due to intraspinal tumor extension. 

Catecholamines are within normal limits or only slightly elevated in cases of neonatal neuroblastoma.

• 1. Interiano RB, Davidoff AM. Current Management of Neonatal Neuroblastoma. Current pediatric reviews. 11 (3): 179-87. Pubmed
• 2. Fisher JP, Tweddle DA. Neonatal neuroblastoma. Seminars in fetal & neonatal medicine. 17 (4): 207-15. doi:10.1016/j.siny.2012.05.002 - Pubmed

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Neuroblastoma

What is neuroblastoma in children?

Neuroblastoma is a cancerous tumor. It grows in nerve tissue of babies and young children. The cancer cells grow in young nerve cells of a baby growing in the womb. These cells are called neuroblasts. It’s is the most common cancer in babies under age 1. It’s rare in children older than age 10. 

Neuroblastoma affects:

• Nerve fibers along the spinal cord
• Clusters of nerve cells (ganglia) along the nerve fibers
• Nerve-like cells in the adrenal glands

In most cases, neuroblastoma starts in the adrenal glands or the nerve fibers in the abdomen. Other common places for it to grow include the nerve fibers near the spine in the chest, neck, or lower belly (pelvis). 

What causes neuroblastoma in a child?

What are the symptoms of neuroblastoma in a child.

The symptoms vary depending on the size and location of the tumor and if it has spread. Symptoms can also occur a bit differently in each child.                                                                                                             

Symptoms of a tumor in the belly (abdomen) can include:

• A lump in the abdomen
• Swelling in the abdomen
• Loss of appetite
• Weight loss
• Swelling of the legs
• Swelling of the scrotum
• Feeling full

Symptoms of a tumor in the chest can include:

• A lump in the chest
• Swelling in the face, neck, arms, or chest
• A change in mental state
• Coughing or trouble breathing
• Trouble swallowing
• Drooping eye lids and other eye changes
• Changes in feeling or movement of the arms or legs

Symptoms of a neuroblastoma that has spread to other parts of the body can include:

• Enlarged lymph nodes
• Bone pain or limping 
• Weakness, numbness, or inability to move arms or legs
• Bruising around the eyes
• Bulging eyes
• Lumps on the head
• Feeling tired or weak
• Frequent infections
• Easy bruising or bleeding

A neuroblastoma may release hormones. This is called paraneoplastic syndrome. It can cause symptoms such as:

• Constant diarrhea
• High blood pressure
• Fast heart rate
• Flushing or redness of skin

A neuroblastoma can also cause opsoclonus-myoclonus-ataxia syndrome. This can lead to symptoms such as:

• Quick eye movements
• Muscle twitching
• Trouble with coordination

The symptoms of neuroblastoma can be like other health conditions. Make sure your child sees a healthcare provider for a diagnosis.

How is neuroblastoma diagnosed in a child?

You may take your child to the healthcare provider because of a lump, swelling, or other symptoms. Most of the time, neuroblastoma has spread by the time it is diagnosed. Your child's healthcare provider will ask about your child's medical history and symptoms. He or she will examine your child. Your child may be referred to a specialist in diagnosing and treating cancer in children (pediatric oncologist).Your child may have tests such as:

• Blood and urine tests.  Blood tests check for signs of disease in the body. Your child may also have urine and blood tests to check for hormones released by the tumor.
• Ultrasound exam (US).  Sound waves and a computer are used to create images. An ultrasound may be done to check your child's belly (abdomen), kidneys, or to guide a needle in a biopsy
• X-ray.  X-rays may be done to check your child's chest or bones
• CT scan.  X-rays and a computer are used to make images of the body.  Scans of the belly (abdomen), lower belly (pelvis), or chest may be done. Contrast dye may be used. A CT scan may also be used to guide the needle in a biopsy.
• MRI scan.  An MRI uses large magnets, radio waves, and a computer to make detailed pictures of the body. This test is used to check the brain and spinal cord.
• Bone scans.  A small amount of dye is injected into a vein. The whole body is scanned. The dye shows up in areas of bone where there may be cancer.
• Positron emission tomography (PET) scan.  For this test, a radioactive sugar is injected into the bloodstream. Cancer cells use more sugar than normal cells, so the sugar will collect in cancer cells. A special camera is used to see where the radioactive sugar is in the body. A PET scan can sometimes spot cancer cells in different areas of the body, even when they can’t be seen by other tests. This test is often used in combination with a CT scan. This is called a PET/CT scan.
• Metaiodobenzylguanidine (MIBG) scan.  A small amount of radioactive iodine called MIBG is injected into a vein. The dye travels through the blood and attaches to cancer cells. Scans may be taken over a few days.
• Bone marrow aspiration or biopsy.  Bone marrow is found in the center of some bones. It’s where blood cells are made. A small amount of bone marrow fluid may be taken. This is called aspiration. Or solid bone marrow tissue may be taken. This is called a core biopsy. Bone marrow is usually taken from the pelvic bone. This test may be done to see if cancer cells have reached the bone marrow.
• Tumor biopsy.  A sample of the tumor is taken. It may be taken with a needle or by a surgical cut (incision). It is checked under a microscope for cancer cells. A biopsy is needed to diagnose neuroblastoma. 

Staging and grading of neuroblastoma

Once neuroblastoma has been diagnosed, a stage is assigned. Staging is the process of seeing if the cancer has spread, and where it has spread. Staging also helps to decide the treatment. Doctors use two different staging systems for neuroblastoma: the International Neuroblastoma Staging System (INSS) and the International Neuroblastoma Risk Group Staging System (INRGSS).

The INSS system divides tumors into stages 1 through 4. It’s assigned after surgery has been done to remove the tumor. Stage 1 is early cancer. It's only in the place where it started and only on one side of the body. For neuroblastoma, this means the tumor can be fully seen and removed by surgery. Stages 2 and 3 are more complex. The tumor is harder to remove and cancer cells may have spread. Stage 4 means cancer cells from the tumor have spread to other parts of the body far from the primary tumor.

The INRGSS system divides tumors into 4 stages labeled L1, L2. M, and MS. Surgery does not need to be done before assigning one of these stages. They are based on how the tumor looks based on scans called image-defined risk factors (IDRFs) and biopsies. They are used to predict how much of the tumor can be taken put with surgery. The L groups means the cancer is confined to one part of the body. The M group means it has spread beyond where it first started to distant organs. MS is used in children younger than 18 months with cancer that has spread only to the skin, liver, or less than 10% of the bone marrow, or all three.

Grading is used to describe how abnormal the cancer cells look when seen through a microscope. The more abnormal the cells are, the faster they grow. Staging and grading help the healthcare team plan treatment for your child.

Other factors considered

The healthcare team also looks at:

• The location of the main tumor
• Genetic changes in the tumor cells
• The age of your child

Your child’s healthcare team will tell you more about the stage and grade of your child’s cancer. The stages of neuroblastoma are very complex. Be sure to ask the healthcare provider to explain the stage of your child's cancer to you in a way you can understand. Also be sure to ask the healthcare provider if you have any questions.

How is neuroblastoma treated in a child?

Treatment will depend on the stage and other factors. The cancer can be treated with any of the below:

• Surgery.  Surgery is often done to remove as much of the tumor as possible (resection). Surgery may not be possible if the cancer has spread.
• Chemotherapy.  These are medicines that kill cancer cells or stop them from growing. They may be given into the vein (IV), injected into tissue, or taken by mouth. They may be given before or after surgery. Or they may be the main treatment if surgery is not possible. The medicine is given in cycles, with rest periods in between.
• Radiation therapy.  These are high-energy X-rays or other types of radiation. They are used to kill cancer cells or stop them from growing. Radiation may be outside of the body (external) or inside the body (internal). Radioactive iodine (MIBG) is given into a vein (IV). Your child will stay in the hospital for this treatment.
• High-dose chemotherapy/radiation with a stem cell transplant.  Young blood cells (stem cells) are taken from the child or from someone else. This is followed by a large amount of chemotherapy medicine and/or radiation. This causes damage to the bone marrow. After the chemotherapy or radiation, your child will get stem cells to renew the bone marrow.
• Immunotherapy.  This treatment helps the body's immune system attack cancer cells. It is also used when there is a high risk of cancer returning.
• Retinoid therapy.  Retinoid medicine may be given after high-dose chemotherapy/radiation and stem cell transplant. It may be used when there is a high risk of cancer returning. It will reduce the chance of relapse or recurrence.
• Supportive care.  Treatment can cause side effects. Medicines and other treatments can be used for pain, fever, infection, and nausea and vomiting.
• Clinical trials.  Ask your child's healthcare provider if there are any treatments being tested that may work well for your child. 

With any cancer, how well a child is expected to recover (prognosis) varies. Keep in mind:    

• Getting medical treatment right away is important for the best prognosis. 
• Ongoing follow-up care during and after treatment is needed.
• New treatments are being tested to improve outcome and to lessen side effects.

What are the possible complications of neuroblastoma in a child?

A child may have complications from the tumor or from treatment, such as:

• Bleeding or infection after surgery
• Hair loss, mouth sores, nausea, vomiting, diarrhea, increased infections, easy bruising and bleeding, and feeling tired from chemotherapy
• Burns, hair loss, and feeling tired from radiation
• Nausea and diarrhea from radiation to the belly (abdomen)
• Problems with growth and development
• Heart and lung problems
• Changes in sexual development
• Problems with the ability to have children (fertility) in the future
• Return of the cancer
• Growth of other cancers
• A high risk of serious bleeding (consumption coagulopathy) (rare)

How can I help my child live with a neuroblastoma?

A child with a neuroblastoma needs ongoing care. Your child will be seen by oncologists and other healthcare providers to treat any late effects of treatment and to watch for signs or symptoms of the tumor returning. Your child will be checked with imaging tests and other tests. And your child may see other healthcare providers for problems from the tumor or from treatment. Your child may need therapy to help with movement and muscle strength. This may be done by physical and occupational therapists.                                                     

You can help your child manage his or her treatment in many ways. For example:

• Your child may have trouble eating. A dietitian may be able to help.
• Your child may be very tired. He or she will need to balance rest and activity. Encourage your child to be active. This is good for overall health. And it may help to lessen tiredness.
• Get emotional support for your child. Find a counselor or child support group can help.
• Make sure your child attends all follow-up appointments.

When should I call my child’s healthcare provider?

Call the healthcare provider if your child has:

• Symptoms that get worse
• New symptoms
• Side effects from treatment

Key points about neuroblastoma in children

• Neuroblastoma is a cancerous (malignant) tumor that begins in nerve tissue of infants and very young children. 
• The symptoms of neuroblastoma vary greatly depending on size, location of the tumor and whether it has spread. Common symptoms are a lump or swelling.
• Neuroblastoma is diagnosed with blood and urine tests, imaging tests, and biopsy.
• Treatment of neuroblastoma may include surgery, chemotherapy, radiation therapy, high-dose chemotherapy/radiation with stem cell transplant, and other medicines.
• Continuous follow-up care during and after treatment is necessary

Tips to help you get the most from a visit to your child’s healthcare provider:

• Know the reason for the visit and what you want to happen.
• Before your visit, write down questions you want answered.
• At the visit, write down the name of a new diagnosis, and any new medicines, treatments, or tests. Also write down any new instructions your provider gives you for your child.
• Know why a new medicine or treatment is prescribed and how it will help your child. Also know what the side effects are.
• Ask if your child’s condition can be treated in other ways.
• Know why a test or procedure is recommended and what the results could mean.
• Know what to expect if your child does not take the medicine or have the test or procedure.
• If your child has a follow-up appointment, write down the date, time, and purpose for that visit.
• Know how you can contact your child’s provider after office hours. This is important if your child becomes ill and you have questions or need advice.

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INTRODUCTION

Neuroblastomas, which account for 97 percent of all neuroblastic tumors, are clinically heterogeneous, varying in location, histopathologic appearance, and biologic characteristics [ 1 ]. They are most remarkable for their broad spectrum of clinical behavior, which can range from spontaneous regression to maturation to a benign ganglioneuroma, or aggressive disease with metastatic dissemination leading to death [ 2 ]. Clinical diversity correlates closely with numerous clinical and biological factors, although its molecular basis remains largely unknown. For example, most infants with disseminated disease have a favorable outcome after treatment with chemotherapy and surgery, while about half of children over the age of 18 months who have advanced neuroblastoma die from progressive disease despite intensive multimodality therapy.

The treatment and prognosis of neuroblastoma will be reviewed here and is meant to be an overview for the general oncologist. Due to the rarity of this disease, patients should be managed in a setting where appropriate expertise in the treatment of neuroblastoma is available.

The epidemiology, clinical presentation, and diagnosis of neuroblastoma are presented separately, as is a discussion of neuroblastomas arising in the olfactory epithelium. (See "Epidemiology, pathogenesis, and pathology of neuroblastoma" and "Clinical presentation, diagnosis, and staging evaluation of neuroblastoma" and "Olfactory neuroblastoma (esthesioneuroblastoma)" .)

STAGING SYSTEM

Neuroblastoma pp 191–203 Cite as

Neonatal Neuroblastoma

• Dominique Plantaz 3 &
• Claire Freycon 3  
• First Online: 13 August 2019

1096 Accesses

Neonatal neuroblastoma accounts for less than 5% of all cases of neuroblastoma and presents a favorable prognosis with most patients being stratified into low or very low risk of recurrence and some in intermediate and very rarely in high risk. Owing to the unique potential for spontaneous regression of this tumor type, all groups have sought to reduce therapy burden given to neonates and use a watch-and-wait approach for many of these patients, particularly for those with prenatal detection of an adrenal tumor. Ongoing studies also seek to reduce therapy for some intermediate-risk patients to lessen exposure to surgical intervention and chemotherapy risk in this very fragile population. In this review, we discuss the epidemiology, clinical presentation, staging, biology, and treatment for neonates with neuroblastoma.

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Plantaz, D., Freycon, C. (2020). Neonatal Neuroblastoma. In: Sarnacki, S., Pio, L. (eds) Neuroblastoma. Springer, Cham. https://doi.org/10.1007/978-3-030-18396-7_10

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Neonatal neuroblastoma

Affiliations.

• 1 Department of Paediatric Oncology, Great North Children's Hospital, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK.
• 2 Department of Paediatric Oncology, Great North Children's Hospital, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK; Newcastle Cancer Centre at the Northern Institute of Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. Electronic address: [email protected].
• PMID: 22673527
• DOI: 10.1016/j.siny.2012.05.002

Neuroblastoma, an embryonal tumour arising from the sympathetic nervous system, is the most common neonatal malignancy accounting for >20% of neonatal cancers. It may present as an antenatal adrenal mass or more commonly with localised or metastatic (4s/Ms) disease, which is usually low risk with a very good clinical outcome. Around 20% of neonatal neuroblastoma presents with spinal cord compression requiring prompt diagnosis and treatment with steroids and chemotherapy to relieve the cord compression. Patients with stage Ms disease without life- or organ-threatening symptoms or adverse genetic features (MYCN amplification or segmental chromosomal abnormalities) can be safely observed for spontaneous regression which may also occur with other localised neonatal neuroblastomas. Universal mass screening for neuroblastoma is not indicated but targeted screening of infants at risk of hereditary neuroblastoma with germline ALK or PHOX2B mutations is appropriate. Future studies will be aimed at observing more patients without adverse genetics or life-threatening features.

Copyright © 2012 Elsevier Ltd. All rights reserved.

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Cholestasis and congenital neuroblastoma in a preterm neonate: a case report

Neuroblastoma (NB) is one of the most common tumor during perinatal period. The clinical features of NB occurring in fetuses and neonates differ from that in the older age groups. Frequently, Congenital neuroblastomas are incidentally detected prenatally. Clinical presentations of NBs in neonates are highy variable.

Case presentation

A 24-day old preterm 32 weeks’ gestation male neonate developed cholestasis that lead to the diagnosis of stage MS neuroblastoma. There was no NB primary site identified.

Conclusions

To the best of our knowledge, this is the first case report of metastatic NB (Stage MS) in a preterm neonate presenting with cholestsis but without any identifiable adrenal or extra-adrenal primary.

Introduction

Neuroblastoma (NB) is a tumor of primordial neuroectodermal cells that develops in the embryonic nervous system throughout the fetal and neonatal periods. It is one of the most common neonatal tumors, with an incidence of 0.61 per 100,000 live births [ 1 ]. Congenital NBs comprise about 5% of the total annually diagnosed neuroblastomas and usually carry a good outcome despite the metastatic invasion. They carry a normal MYCN , neuroblastoma oncogene, copy number and hyperdiploid DNA index [ 2 , 3 ]. Spontaneous regression of the tumor is likely to be seen in neonates.

Neonatal cholestasis is a disorder of hepatobiliary and metabolic dysfunction in neonates. The incidence is about 1 in 2,500 infant [ 4 ]. Neonatal cholestasis has many different causes including viruses, obstructive causes, metabolic diseases, or genetic disorders such as alpha-1-antitrypsin deficiency and Alagille syndrome. The obstructive cause of neonatal cholestasis by a neoplastic invasion of the liver is extremely rare. Our case is unique because it was the cholestasis that lead us to the diagnosis of the malignant neoplasm in this preterm neonate. We report a case of congenital NB that presented as neonatal cholestasis. This case report includes a review of the literature on congenital NBs.

A preterm male neonate was born at 32 weeks gestation to a 26-year-old Gravida 3 Para 2 by vaginal delivery. Apgar scores were 2 and 6 at one and 5 min respectively. Pregnancy was complicated with preterm labor. The family history was negative for congenital anomalies, and there was no history of in-utero exposure to any known teratogens. Physical examination revealed a weight of 1835 g (50th centile), length of 45 cm (5th centile), and head circumference of 30 cm (25th centile). The infant developed respiratory distress syndrome, and surfactant was administered via an endotracheal tube soon after birth. His respiratory illness was uncomplicated. He required only non-invasive respiratory support for 4 days. Enteral feeding was begun on the 2nd day of life (DOL) but was not well tolerated. Bilious gastric aspirates were noted on the 6th DOL. A contrast study of the stomach and small bowel was reported unremarkable. Antibiotics were begun, and enteral feeding was held for 7 days. Enteral feeding was resumed at 2 weeks of life and was well tolerated. On the 2nd DOL, the infant’s total bilirubin was 3.9 mg/dL and the direct bilirubin was 0.3 mg/dL. The peak serum total bilirubin was 9 mg/dL on DOL 7. On the 24th DOL, a liver function test was obtained to assess the infant’s nutritional status. The total serum bilirubin was 3.9 mg/dL, direct serum bilirubin was 2.8 mg/dL and serum alkaline phosphatase was 1,064 international units per liter (IU/L) Ultrasound of the liver revealed multiple echogenic lesions throughout the liver, the largest lesion measuring about 1.7 × 2.1 x 1.8 cm was located in the right liver ( Figure 1 ). An abdominal MRI was performed, which showed multiple T2 hyperintense and T1 hypodense lesions throughout the liver ( Figure 2A–D ). The adrenal glands were normal. The working diagnosis was a primary hepatic tumor. A week later (DOL 31), the total and direct bilirubin were 11 mg/dl and 8 mg/dL, respectively, and alkaline phosphatase was 971 IU/L. The PT and PTT were normal. The alpha-fetoprotein was 404,000 ng/mL, urine VMA 125 mg/24 h and urine HVA was 75 mg/24 h. A whole-body MRI found lesions only in the liver. The infant underwent a liver biopsy on DOL 40. The results revealed a metastatic poorly differentiated neuroblastoma [International Neuroblastoma Risk Group (INRG) stage MS: favorable histology neuroblastoma]. Solid tumor panel confirmed favorable prognosis as suspected on prior findings. His respiratory status worsened, and liver function became more abnormal. He developed hypoglycemia requiring IV glucose supplementation from DOL 50 to DOL 58. Chemotherapy (carboplatin and etoposide) was begun on DOL 67 because of respiratory and hepatic dysfunction. The infant developed neutropenia after the chemotherapy treatment, and G-CSF was administered for 10 days. He remained hospitalized for an additional 40 days after chemotherapy for feeding, hypoglycemia, and respiratory issues. The hypoglycemia was attributed to extensive liver metastasis leading to low glycogen storage and hyperinsulinism. Meta-Iodobenzylguanine (IBG) scan with Single Photon Computed Tomography (SPECT/CT) was performed on DOL 93. There was no evidence of MIBG avid disease. Repeat MRI of the liver showed marked resolution of liver lesions as compared to imaging from DOL 44, that is, before the chemotherapy. He was discharged at 5 months of age.

Gray scale sonogram of the liver shows small and large echogenic mass (arrows) on the left and right lobes against the diffusely abnormal hepatic echogenicity (star) background of normal hepatic echotexture.

Coronal T1-weighted magnetic resonance imaging (MRI).

(A, B) Coronal T1-weighted magnetic resonance imaging (MRI) scan post intravenous contrast agent shows diffusely, heterogeneous enhancement through the liver with distinctly nodular foci of hypointensity (arrows). (C, D) Coronal T2-weighted magnetic resonance imaging (MRI) scan shows diffusely, heterogeneous appearing liver with distinctly nodular foci of hyperintensity (arrows).

The five stages of international neuroblastoma staging system (INSS) was established more than 30 years ago [ 5 ]. They are determined by the location of the tumor at the time of diagnosis. Stage 1: localized tumor with complete gross excision; Stage 2A: localized tumor with incomplete gross excision; Stage 2B: localized tumor with or without complete gross excision, with ipsilateral lymphnodes positive for tumor; Stage 3: Unresectable unilateral tumor invading across the midline, with or without involvement of regional lymph nodes; Stage 4: Any primary tumor that has spread to the distal lymph nodes, bone, bone marrow, liver, skin, and/or other organs; Stage 4S: localized tumor in an infant less than 1 year of age with spread limited to liver, skin, and/or bone marrow [ 6 , 7 ].

In 2004, the international task force developed a new International Neuroblastoma Risk Group (INRG) Staging System (INRGSS) that was designed to stratify patients at the time of diagnosis before any treatment was started for the NB. The criteria for INRG staging include age, histologic category, grade of tumor differentiation, MYCN status, presence/absence of 11q abnormalities, and tumor cell ploidy [ 7 ]. The INRG stages are: L1/L2, L1, L2, M, and MS. Stage L1, localized tumor confined to one body compartment and with absence of image-defined risk factors (IDRFs); Stage L2, locoregional tumor with presence of one or more IDRFs; Stage M, distant metastatic disease (except Stage MS); Stage MS (analogous to INSS stage 4s), metastatic disease confined to skin, liver and/or bone marrow in children less than 18 months of age [ 5 ]. Our patient was Stage 4s by the INSS staging system, whereas as per the INRGSS, he was Stage MS at the time of diagnosis.

Approximately 40% of NB patients are under the age of one, 35% are between the ages of one and two, and 25% are older than two years. Our case has Stage MS, which accounts for around 10% of all diagnosed NB cases [ 7 , 8 ]. The high likelihood of spontaneous regression and generally excellent prognosis, are the hallmarks of Stage MS [ 9 ].

Pepper syndrome is described as primary adrenal NB with extensive liver metastases [ 7 ], and it refers to stage 4S NBs. However, our patient’s adrenal glands were normal. The staging of the NB in our case suggests that it is a variant of Stage 4S. The presentation initially lead us to consider primary hepatic tumors (hemangioma, hepatoblastoma) instead of NB. Even after the radiology images were obtained, the diagnosis was not clear.

Congenital NBs may be diagnosed on fetal ultrasonography between 33–36 weeks of gestation [ 4 , 10 ]. Most NBs are found incidentally without maternal or fetal symptoms. But maternal symptoms of catecholamine-related effects e,g, sweating, flushing, and vomiting may be present. Fetal hydrops may occur in the advanced metastatic stage. Neonatal presentation of NB includes abdominal mass/distension, organomegaly, respiratory distress, and sympathetic/catecholamine symptoms (e.g. tachycardia, hypertension). It is important to note that in some cases with congenital NBs, if the NB is not detected antenatally, then the neonate may be asymptomatic and could have a tumor that undergoes spontaneous regression without having been clinically evident. In our case, there was no abdominal distension and no significant hepatomegaly. The ultrasonography was obtained for the evaluation of cholestasis, and such an instance has not been reported previously.

The management of stage MS NB remains inconclusive. Although MS illness without MYCN amplification has a favorable prognosis in infants under the age of 12 months, the presence of stage MS NB in a newborn who is less than 2 months old is associated with a bad prognosis, regardless of the MYCN copy status, because of the complications [ 11 ].

In summary, we report a case of a preterm neonate with cholestasis which lead to the diagnosis of a rare stage MS neuroblastoma.

Acknowledgments

We thank Sylvia Sutton-Thorpe, Chrystal Puvabanditsin, and Christina Puvabanditsin for supporting this effort and preparing the manuscript.

Research funding: None declared.

Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

Competing interests: Authors state no conflict of interest.

Informed consent: Informed consent was obtained from the parents.

Ethical approval: The local Institutional Review Board deemed the study exempt from review.

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• Volume 81, Issue 2
• Neonatal neuroblastoma
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• J Moppett ,
• I Haddadin ,
• A B M Foot on behalf of the United Kingdom Children’s Cancer Study Group
• The Royal Hospital for Sick Children St Michael’s Hill Bristol BS2 8BJ
• Dr J Moppett.

Over nine years, 33 children with neonatal neuroblastoma were registered with the UKCCSG (United Kingdom Children’s Cancer Study Group). Tumours of all stages were found, but stage 4S disease predominated. Five tumours were detected prenatally by ultrasonography. Treatment varied according to tumour stage. The overall survival of the group was 91%. Ten children have had long term complications as a result of their disease, usually as a result of spinal tumour involvement. The good overall prognosis in this age group is encouraging, but the poor neurological outcome of patients with intraspinal extension is of concern.

• neurological outcome
• tumour stage
• neuroblastoma

https://doi.org/10.1136/fn.81.2.F134

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Neonatal tumours—those occurring in the first 28 days of life—are rare. They comprise 2% of all paediatric malignancies, with an incidence of 1.58 to 3.65 per 100000 live births. 1-2 A neonatal unit with 3000 deliveries a year might expect to see a case once every 10 to 20 years. The most common neonatal tumour is neuroblastoma, accounting for 28–39% of tumours in this period, with an estimated incidence of 0.61 per 100 000 live births. 2-5

The prognosis of neuroblastoma is influenced by many factors, the most important of which are age and degree of tumour spread. Overall survival for infants under 12 months of age is 81%, while for children over 12 months it is only 31%. 6 7 Similarly, survival for stage 1 and 2 disease, irrespective of age, is greater than 85%, while stage 4 neuroblastoma has a survival of around 50% in the first year of life and less than 20% in those aged over 1 year. 6 8-10 Biological factors, especially amplification of N-myc (an oncogene located on chromosome 2) and loss of parts of chromosome 1 (1p36-), adversely affect prognosis. 11

With the increasing use of prenatal ultrasonography to detect fetal anomalies, the possibility of early detection of children with neuroblastoma is also increasing, with potential implications for the management of these children.

Our study aimed to review the clinical features and outcome of neonatal neuroblastoma in Great Britain, as recorded by the UKCCSG (United Kingdom Children’s Cancer Study Group).

All newly diagnosed children with malignant disease who present to the 22 centres of the UKCCSG are registered centrally. Analysis of this register revealed 33 cases of neuroblastoma diagnosed in the neonatal period over the 9 years between 1 January 1986 and 31 December 1994, an incidence of 0.52 per 100 000 live births. During this time, a comparison of UKCCSG data with those of the National Registry of Childhood Tumours, showed that 94–97% of neuroblastoma cases were registered with the UKCCSG.

We reviewed the records of these 33 patients and noted information regarding tumour location and stage, histology, clinical presentation, urinary catecholamines, serum and biological markers of disease, treatments received, outcome and complications. Additional questionnaires were sent to the treating physician. Obstetric data were sought wherever possible. Tumours were staged according to the Evans system before 1992, and by the INSS (International Neuroblastoma Staging System) from 1992 onwards.

Kaplan–Meier analysis was used to produce survival curves.

These 33 patients represented 4% of all 860 children with neuroblastoma registered with the UKCCSG during the same period, and 15% of infants under 1 year of age. The mean age at diagnosis was 13.4 days (fig 1 ).

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Numbers of children registered with the UKCCSG over study period.

Prenatal maternal ultrasound scans were documented for 12 of these 33 children. Five scans suggested a possible diagnosis of neuroblastoma prenatally. There were two further abnormal prenatal scans; one was reported to show a cyst on the right kidney, the other reduced fetal movements. Retrospectively, these abnormalities can be attributed to neuroblastoma but were not regarded as suspicious at the time. The remaining five scans (from 17 weeks of gestation to term) were normal (table 1 ).

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Neuroblastoma in the neonatal period; characteristics of 33 tumours 1986–94

Table 1 shows details of the tumours. Histological confirmation of the diagnosis (either primary tumour biopsy or compatible tumour cells in the bone marrow, together with raised urinary catecholamines), was obtained in all but one infant (right sided perirenal mass and liver secondaries together with raised urinary catecholamines). Most tumours were adrenal in origin and they were predominantly stage 4S. Many of the children were asymptomatic, including those with masses found on routine examination of the abdomen (n=6), four of the five children identified prenatally by ultrasound scan, and the infant whose prenatal scan showed a cyst on the right kidney (diagnosed when this ultrasound scan was repeated after birth). The others presented with various symptoms related to the site of their tumour. There was one registered stillbirth.

Biological data were incomplete: urinary catecholamines were documented in 29 of the 33 children, and were raised in all but two. Ferritin concentrations were not recorded in 18 patients, but were raised in all stage 4 and 4S patients for whom results were available, and normal in all others, with the exception of one child with a stage 3 tumour. Lactate dehydrogenase activity was raised in all eight patients in whom it was measured. N-myc amplification was examined in six tumours (one stage 2, five stage 4S) and all had normal copy number.

Treatment depended on the tumour stage (table 1 ). Chemotherapeutic regimens over the span of the review included vincristine and cyclophosphamide, sometimes with the addition of etoposide and cisplatin (OPEC) or carboplatin (OJEC). The eight infants with stage 1 and 2 disease underwent primary surgical resection of their tumour. One patient with stage 2 disease had a local recurrence treated successfully with chemotherapy. The seven stage 3 patients were treated with surgery and chemotherapy (6 patients) or surgery alone (1 patient). One of the stage 4 patients was stillborn. The remaining three patients received chemotherapy, and one patient autologous bone marrow transplantation. One patient with stage 4 disease died of toxicity during initial chemotherapy. Five children with stage 4S disease required no treatment for their disease. Four stage 4S patients had total resection of their primary site; this was the only treatment for three. Six children with stage 4S disease received chemotherapy, and two radiotherapy to relieve respiratory compromise.

Overall survival of the cohort was 91% (confidence limits 86.1–95.9%), with a mean follow up of 48 months (SD 32 months, range 0–105 months, median 52.5 months). There were 3 deaths, including the stillbirth; one had stage 4S and two stage 4 disease. When analysed by stage, the survivals in our study were: stages 1–3, 100%; stage 4, 50% and stage 4S, 93%. Fig 2 shows the Kaplan–Meier survival curves.

Kaplan–Meier survival curve for 33 cases of neonatal neuroblastoma, divided by stage.

Long term complications occurred primarily as a result of intraspinal extension of tumour (table 1 ). Four patients have persisting neurological deficit of varying degrees—either problems with walking or incontinence. Two children also had clinically significant scoliosis. One child has abnormal sweating on one side secondary to laminectomy. The child who underwent bone marrow transplantation now has high tone deafness affecting acquisition of normal speech, and one child has learning difficulties, having had vincristine and cyclophosphamide alone as treatment for stage 4S disease.

Our overall survival for neuroblastoma in the neonatal age group was very good at 91% and better than for any other age group. De Bernardi found an overall survival for infants under 1 year of age of 82%, compared with 31% for children over 1 year of age. 7 He found that those under 6 months of age did better than those between 6 and 12 months (86% vs 78%). Survival of prenatally diagnosed neuroblastoma is around 90%. 12 The survival results for the neonatal age group when analysed by stage are similar to published results for infants with neuroblastoma. 8 13-15

Stage 4S disease comprises a primary tumour at stage 1 or 2, with spread limited to the liver, skin, or bone marrow, in a child under 12 months of age. Differentiating stage 4 and 4S disease can be difficult, which the introduction of the INSS has attempted to address. Stage 4S neuroblastoma is an unusual tumour, because in most patients the disease will spontaneously remit without any treatment. In only 1–2% of patients does the disease progress to stage 4. The major risk for infants with stage 4S disease comes from the systemic effects of the disease, chief among which is respiratory compromise caused by an often massively enlarged liver. 14 15 The risk of respiratory compromise is at its greatest in infants under 6 weeks of age. 6 15 16 Treatment with radiotherapy or chemotherapy may be urgently required, and frequent review of such infants is necessary. Our study confirms the good prognosis of stage 4S disease (93% overall survival). In our series six patients with stage 4S disease were treated (42%), similar to the numbers in other reported series. 14

Two of the three live born stage 4 patients survived following intensive chemotherapy. The one death resulted from renal failure during induction chemotherapy. Including the stillborn child, survival in half of the stage 4 cases is similar to the prognosis of stage 4 disease throughout infancy.

The increased use of routine prenatal ultrasound over the past few years has resulted in more children with neuroblastoma being diagnosed prenatally. 12 17 18 The survival of these infants has been very good overall. Acharya et al recently reviewed 55 children with prenatally diagnosed neuroblastoma. 12 They found predominantly adrenal tumours with favourable staging and biological features, and an overall survival of 90%. In our series five patients had a prenatal ultrasound scan suggestive of neuroblastoma; two had stage 4S, two stage 4, and only one stage 1 disease. This stage distribution contradicts the findings of other studies where the percentage of stage 1 tumours identified by prenatal ultrasound scan was around 70%. 12 17 On the basis of their stage distributions, both Ho et al and Acharya et al recommend a wait and see policy for treatment of prenatally diagnosed patients, but staging investigations are obviously vital before this policy is adopted. 12 17 The comparable overall survival in our study, despite a lower percentage of stage 1 disease, is probably explained by the large numbers of patients with stage 4S disease who have a similarly good prognosis.

The role of prenatal ultrasonography in the diagnosis of neuroblastoma has many parallels with routine postnatal screening for neuroblastoma, first introduced in Japan over 20 years ago. 19 Screening is performed by measuring urinary catecholamines in all infants. It was hoped that screening would result in earlier diagnosis of neuroblastoma at a less advanced stage, thus leading to improved survival. However, while the prognosis of neuroblastoma diagnosed on screening is very good, an increased incidence of neuroblastoma has been noted in the screened populations, but with no reduction in overall mortality. 19-21 Screening may therefore be identifying tumours that would previously have resolved without treatment. It is not possible to determine from our study whether prenatal ultrasonography is detecting a similar group of tumours, because the numbers involved are small.

The mode of presentation and diagnosis in children with neuroblastoma is very diverse, and this was seen in our study group. The primary site distribution within the neonatal period is similar to that of other ages, with a large proportion arising from the adrenal gland. Six cases (18%) presented asymptomatically, with an abdominal mass noted on routine examination, reinforcing the value of routine neonatal abdominal examination. A palpable abdominal mass in a neonate is most likely to be of renal origin, but the possibility of neuroblastoma cannot be discounted. Three patients (9%) presented with skin nodules associated with stage 4S neuroblastoma. Eleven (33%) presented with diverse symptoms referable to the abdominal and respiratory systems, the true diagnosis coming to light during investigation.

We found six infants (18%) with intraspinal tumour involvement. Although they survived, they have all had long term complications, with varying degrees of flaccid paralysis of the legs, urinary incontinence, or scoliosis. One child had a laminectomy and all received chemotherapy. In comparison, the neurological outcome for intraspinal neuroblastoma when all age groups are included is much better. Plantaz et al found serious neurological sequelae in only six of 42 children with intraspinal tumours (15%). 22 However, four of the six children with ongoing neurological problems in their study had deficits present at birth. 22 Munro et al found a similarly poor neurological outlook for children with congenital paraplegia secondary to neuroblastoma. 23 One of our patients had reduced fetal movements at 28 weeks of gestation on ultrasound scan, and had probably had had spinal cord compression for three months by the time of delivery. Long standing nerve damage is likely to be present in most patients with congenital neuroblastoma and spinal cord involvement, which may explain the poor neurological outcome. In view of the long term deformities often noted following spinal cord surgery and the very poor neurological recovery, caution should be used in considering surgical intervention. As most children with intraspinal disease in our study had stage 3 disease they received moderate dose chemotherapy. Plantaz et al showed that in older children with partial neurological deficits, chemotherapy produced good results. 22 The historical nature of our study and the long timespan over which patients have accrued makes it difficult to interpret the limited serum and biological marker results. Certainly urinary catecholamines are raised in most neonatal patients with neuroblastoma, confirming this as a useful investigation. Urinary catecholamines can be accurately measured on a spot urine. The technically difficult 24 hour urine collection is unnecessary. Ferritin, LDH, and N-myc amplification are useful prognostic indicators in neuroblastoma, and may provide additional information in this age group.

We conclude that the outlook for infants diagnosed with neonatal neuroblastoma is better than for any other age group. However, three particular groups are at greater risk from their disease. Stage 4 disease has a similar outcome to that in older infants with only a moderate chance of survival. Stage 4S disease, while having a good long term prognosis, needs careful observation to detect potentially life threatening complications. The functional outcome of those with neurological deficit secondary to their tumour is not good. Some tumours may be picked up prenatally. The high risk of complications, as well as the good survival rates, should be taken into account when counselling parents.

Acknowledgments

We thank Steve Hibbert and all the staff at the UKCCSG data centre for their help with this study, together with the member consultants of the UKCCSG whose patients form this study group.

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• Parkes SE ,
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• Castleberry RP ,
• Shuster JJ ,
• Altshuler G ,
• Pearson ADJ ,
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Neonatal neuroblastoma 4s with diffuse liver metastases (Pepper syndrome) without an adrenal/extraadrenal primary identified on imaging

Apeksha chaturvedi.

1 Department of Imaging Sciences, University of Rochester Medical Center, Rochester, NY, USA

Philip J Katzman

2 Department of Pathology, University of Rochester Medical Center, Rochester, NY, USA

Arie Franco

We report the imaging appearances of a case of pathologically proven, neonatal neuroblastoma 4S with diffuse hepatic metastatic involvement at presentation. Patient had an abnormal appearing liver both by ultrasound and MR. There was no evidence for associated adrenal tumor by imaging. Lack of an associated adrenal mass led to initial misinterpretation of diffuse hepatic accumulation of MIBG seen with radionuclide scintigraphy. To the best our knowledge, this is the first report of metastatic neonatal 4S neuroblastoma without an adrenal (or extra-adrenal) primary identified either on pre- or post-natal imaging.

CASE REPORT

A one- day old female, born at 39 weeks to a healthy mother did not have any abnormalities found on pre-natal imaging. Shortly after delivery, she was tachypneic and had an enlarged abdomen. This prompted lab work, which was significant for thrombocytopenia and coagulopathy. At this point, she was transferred to our institution.

Lab work on arrival to our hospital was significant for total bilirubin 5.7 mg/dL (normal range 0.3 – 1.9 mg/dL), indirect bilirubin 4.9 mg/dL (normal range 0 – 1.9 mg/dL), INR 2.0 (normal range 0.9–1.2), WBC 21,500/micro liter (normal range in a newborn 9.000–30,000/micro liter), platelets 69,000/micro liter (normal range 140,000 – 450,000/micro liter). Tumor markers were as follows: Alpha fetoprotein (AFP) 97,873 IU/mL (normal range below 10 IU/mL), Urine Vanillyl mandelic acid/Creatinine 540 mg/g and peaked at 809 mg/g, Urine homovanillic acid/Creatinine 554 mg/g and peaked at 723 mg/g.

On imaging, ultrasound revealed a diffusely enlarged, markedly heterogeneous liver with patent vasculature [ Figure 1 ]. Ultrasound appearances were interpreted as being most consistent with a hepatic primary neoplasm such as a diffuse hepatoblastoma. Given her elevated tumor markers, hepatic metastatic neuroblastoma was also offered as a differential diagnosis, although the confounding factor was her normal adrenals.

A one-day-old female with neuroblastoma stage 4s.

Sonogram findings: Gray scale sonogram of the liver (performed with a convex transducer, 3.5 MHz) in transverse view (A) shows a diffusely coarse liver (star) and (B) reveals an echogenic nodule (arrow) against the background of diffusely abnormal hepatic echogenicity.

Follow-up abdominal MR images revealed a markedly enlarged and diffusely heterogeneous liver, with few T2 hyperintense foci interspersed through a background of an overall abnormal hepatic signal. On contrast-enhanced T1-weighted MR images [ Figure 2 ], patchy heterogeneous contrast-enhancement was present. Further work up for malignancy ensued, and bone marrow biopsy was negative. The presence of abnormal tumor markers prompted an MIBG scintigraphy [ Figures 3 , ​ ,4], 4 ], which showed diffuse hepatic accumulation of MIBG. No additional foci of abnormal uptake were identified. Adrenals were normal sized.

MRI findings:

(A) Coronal FIESTA (1.5T, TR - 5.292, TE - 2.088) shows diffusely enlarged, heterogeneous appearing liver with at least two distinctly nodular foci of hyper-intensity (arrows).

(B) Axial T1 post intravenous administration of Gadolinium based contrast agent (0.16 cc of gadoversetamide, 1.5 T, TR - 4.104, TE - 1.284) taken through the mid liver shows patchy, heterogeneous contrast enhancement through the liver.

(C) and (D) are SSFSE (1.5T, TR - 1106.87, TE - 202.24) in axial views that show normal appearing, thin normal adrenal glands bilaterally (arrows).

Planar anterior scintigraphic image acquired at 48 hours following the intravenous administration of 1.6 mCi of I-123-MIBG reveals marked diffuse hepatic accumulation of the radiopharmaceutical (white star). No additional MIBG-avid masses were noted on this study. Also, there was no bone marrow uptake of the radiotracer (marrow aspirate and biopsy were negative).

Planar and sequential single photon emission computed tomography (SPECT) images acquired at 30 minutes, 24 hours, and 48 hours after the intravenous administration of 1.6 mCi of I-123-MIBG demonstrate diffuse hepatic uptake with no additional radiotracer uptake.

Ultimately, a liver biopsy was performed [ Figure 5 ], which was consistent with poorly differentiated neuroblastoma, low MKI, favorable histology per Shimada classification. No n-myc amplification was identified in the tumor by FISH analysis. She was diagnosed with neuroblastoma stage 4s.

Pathologic findings: (A) Two wedge biopsies (one shown here, with capsule present - arrows) and two core biopsies were performed. (B) The tumor has sheets (left) and nests (right) of tumor cells. Tumor cells are seen adjacent to hepatocytes (asterisk) under the capsule (C) and surrounding bile ductules (D, center and right). Tumor is highlighted by a CD56 immunostain (E). Adjacent liver parenchyma and bile ductules are positive for a cytokeratin immunostain while tumor is negative (F). (G) There are occasional Homer-Wright rosettes scattered in the tumor (arrows). The rosetting, the presence of a low mitotic-karyorrhectic index and the patient’s young age (3 weeks) were consistent with a favorable histology of this poorly differentiated neuroblastoma (Original magnifications: A - 12.5; B - 40x; C–F - 200x; E - 400x).

Initial hospital course was complicated by increase in abdominal girth, inability to tolerate oral intake requiring a J-Tube, tachypnea and coagulopathy. Given the progressive increase in abdominal girth and poor feeding, the decision was made to proceed with chemotherapy. Three weeks after initial presentation she was started on chemotherapy, which she received Carboplatin (18.6 mg/kg/dose × 1 dose) and etoposide (4mg/kg/dose × 3 doses). Neupogen was administered for expected neutropenia. She did well with chemotherapy. Tumor markers remained low and follow-up sonography of the liver revealed definite improvement [ figure 6 ]. Eventually her Broviac line, which was placed for chemotherapy and her J – tube were removed. Currently, she is off chemotherapy and meeting appropriate developmental milestones.

Same patient at six-month of age; status post treatment for neuroblastoma stage 4s. Sonogram findings: Gray scale sonogram of the liver (performed with a convex transducer, 3.5 MHz) in transverse view shows normal echotexture of the liver with no evidence of nodularity.

Etiology & Demographics

The etiology of neuroblastoma is not completely known. It is thought to be a failure of the neuroblasts to mature. The disease is sporadic, probably results from unknown gene changes. There are genetic markers that can predict prognosis and guide treatment.

Neuroblastoma is the most common extracranial solid tumor of childhood. It accounts for approximately 7.8% of childhood cancer. Over one-half of patients present with metastatic disease at diagnosis. The International (INSS/INRC) staging of neuroblastoma includes 5 stages according to the localization of the lesions at the time of admission [ 1 , 2 ]:

• Stage 1: Localized tumor with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph node negative for tumor microscopically (lymph nodes attached to and removed with the primary tumor may be positive)
• Stage 2A: Localized tumor with incomplete gross excision; representative ipsilateral nonadherent lymph nodes negative for tumor microscopically
• Stage 2B: Localized tumor with or without complete gross excision, with ipsilateral nonadherent lymph nodes positive for tumor. Enlarged contralateral lymph nodes must be negative microscopically
• Stage 3: Unresectable unilateral tumor infiltrating across the midline, with or without regional lymph node involvement; or localized unilateral tumor with contralateral region lymph node involvement; or midline tumor with bilateral extension by infiltration (unresectable) or by lymph node involvement
• Stage 4: Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin and/or other organs (except as defined in stage 4S)
• Stage 4S: Localized primary tumor (as defined in Stage 1, 2A, or 2B) with dissemination limited to skin, liver, and/or bone marrow (limited to infants age <1 year). In previous staging of neuroblastoma it was stated that stage 4S manifests without radiographic evidence of bone metastases on complete skeletal survey [ 3 ].

Age distribution of neuroblastoma is as follows: 40% of patients are younger than 1 year when diagnosed, 35% are aged 1–2 years, and 25% are older than 2 years when diagnosed [ 4 ]. According to Surveillance, Epidemiology, and End Report (SEER), incidence decreases every consecutive year up to age 10 years, after which the disease is rare. The male-to female ratio is 1.2:1 and the incidence of neuroblastoma is slightly higher in white children than in black children.

Stage 4s neuroblastoma represents approximately 7–10% of all neuroblastoma cases [ 5 ]. Its hallmark is the possibility of spontaneous regression despite a large tumor burden, and an overall good prognosis [ 6 ].

Shimada classification of histopathologic features was developed for patients with neuroblastoma [ 7 ]. Important features of the classification include (1) the degree of neuroblast differentiation, (2) the presence or absence of Schwannian stromal development (stroma-rich, stroma-poor), (3) the index of cellular proliferation, (4) nodular pattern, and (5) age. Using these components, patients can be classified into favorable and unfavorable histology groups.

Clinical & Imaging findings

Clinical manifestations can vary according to the organ involved. At presentation, the infants can be tachypneic, pale, and lethargic. The abdomen is usually distended and hepatomegaly may be the sole clinical finding. Associated skin findings of stage 4S disease include non-tender, bluish ‘blueberry muffin’ subcutaneous nodules [ 8 ]. Urinary catecholamines vanillylmandelic acid (VMA) and homovanillic acid (HVA) are usually elevated. If the liver is involved, serum lactate dehydrogenase (LDH) and liver enzymes may be elevated.

I-123-metaiodobenzylguanidine (MIBG) was developed in the early 1980s to visualize tumors of the adrenal medulla.

MIBG enters the neuroendocrine cells by an active uptake mechanism via the epinephrine transporter and is stored in the neurosecretory granules, resulting in a specific concentration in contrast to cells of other tissues. MIBG scintigraphy is used to image tumors of neuroendocrine origin, particularly pheochromocytomas, paragangliomas and neuroblastomas, although other neuroendocrine tumors such as carcinoids and medullary thyroid carcinoma can be visualized.

I-123-metaiodobenzylguanidine (MIBG) is an indispensable tool in evaluating neuroblastoma, both at initial staging and in assessment of subsequent tumor response to therapy [ 9 ]. There is a physiologic MIBG uptake by the liver. Here, we present a case in which lack of a clearly identifiable adrenal mass on imaging led to misinterpretation of diffuse MIBG accumulation within the liver. Also, the suspicion for neuroblastoma on her ultrasound and MR was low given the normal size and appearance of her adrenals. Majority of reported cases of the 4S subtype of neuroblastoma are newborns with an associated small, localized primary adrenal mass, mostly solid, and rarely (<2% cases) cystic [ 10 ]. In this context, our patient presented an interesting dilemma. Diffuse hepatic uptake of MIBG in context of absence of an associated adrenal lesion led to this being interpreted as a false-negative finding related to normal tracer biodistribution, since liver is a site of catecholamine degradation. However, the subsequent biopsy did confirm metastatic liver involvement by neuroblastic cells. Hepatic metastatic involvement by neuroblastoma on MR presents either as a diffusely infiltrative pattern (seen in infants with stage 4S disease), or focal masses [ 11 ]. Sonographic involvement of the liver present as coarse diffuse increased echogenicity or nodular echogenic appearance. This case presented these typical findings.

Our patient presented with a variant of Stage 4s subtype of neuroblastoma, in whom manifestations of the disease included a diffusely involved liver (Pepper syndrome), with associated respiratory compromise and coagulopathy [ 12 ]. Also, there was no identifiable adrenal mass, either on prenatal or postnatal evaluation. She had favorable histology by the Shimada classification, and no evidence of bone marrow infiltration by neuroblastic cells. 4S neuroblastoma tumors are generally considered low risk and have an excellent prognosis. These may spontaneously regress.

Differential Diagnoses

In case of an adrenal mass the differential diagnosis may include neuroblastoma and other masses that originate from the adrenal gland or the surroundings, such as Mesoblastic nephroma, Wilms’ tumor, Rhabdomyosarcoma, Rhabdoid tumor, adrenal cortical carcinoma, adrenal hemorrhage, and adrenal infection such as an abscess. In our case of neuroblastoma 4s with an absence of an adrenal mass, the differential diagnosis is more intriguing as one needs to consider the disease and evaluate the case with I-123-MIBG scintigraphy and urinary VMA and HVA. The differential diagnosis of our case with liver involvement includes any infiltrative or focal primary or metastatic liver disease, such as hepatoblastoma, leukemia, lymphoma, hemangioblastomatosis, teratoma, and infections.

Neuroblastoma can be differentiated from other tumors with I-123-MIBG scintigraphy and urinary VMA and HVA. Cross sectional images are nonspecific and the differential diagnosis based on imaging is difficult. However, epicenter of a tumor based on imaging and different tumor markers may help in narrowing the differential. Tissue samples are essential in establishing the final diagnosis.

Treatment & Prognosis

Treatment for neuroblastoma varies and depends on the stage of the disease. It may include surgery, radiation therapy, chemotherapy or any combination of these. The outcome observed with the different successive treatment approaches suggests that if infants with stage 4s neuroblastoma do require therapy, a more intensive chemotherapy may be more beneficial [ 5 ]. In one study a more intensive treatment by CE regimen (carboplatin and etoposide), only two chemotherapy courses were required. Results of studies suggest that a prompt initiation of a more intensive treatment may be necessary in order to push the neuroblastic cells towards the regression pathway [ 5 ]. The CE regimen proved to be associated with a high response rate and good clinical tolerance when used as second-line or as first-line therapy, a schedule which has also shown good response rates and clinical tolerance in infants with localized, unresectable neuroblastoma [ 13 ]. The CE regimen is now being proposed as first-line therapy in the NB99 Infant SIOP study for patients with stage 4s neuroblastoma who do require medical intervention. Stage 4s neuroblastoma is associated with an excellent survival rate and with overall survival of 88% [ 5 , 14 ].

The presented case is unique in a sense that a neuroblastoma 4s was diagnosed and confirmed pathologically without any evidence for associated adrenal tumor by imaging.

TEACHING POINT

A case of pathologically proven, neonatal neuroblastoma 4s with diffuse hepatic metastatic involvement at presentation and without adrenal mass is extremely rare. The initial evaluation may lead to erroneous interpretation. Diffuse hepatic uptake of MIBG in context of absence of an associated adrenal lesion may be interpreted as a false-negative finding related to normal tracer biodistribution, since liver is a site of catecholamine degradation.

Summary table for neuroblastoma stage 4s.

Differential diagnosis table for neuroblastoma.

ABBREVIATIONS