Clinical presentation, diagnosis, and staging evaluation of neuroblastoma

INTRODUCTION — The term neuroblastoma is commonly used to refer to a spectrum of neuroblastic tumors (including neuroblastomas, ganglioneuroblastomas, and ganglioneuromas) that arise from primitive sympathetic ganglion cells and, like paragangliomas and pheochromocytomas, have the capacity to synthesize and secrete catecholamines. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology" and "Clinical presentation and diagnosis of pheochromocytoma".)

Neuroblastomas, which account for 97 percent of all neuroblastic tumors, are heterogeneous, varying in terms of 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 (including patient age, tumor stage and histology, and genetic and chromosomal abnormalities). For example, most infants with disseminated disease have a favorable outcome following treatment with chemotherapy and/or surgery, although the majority of children older than one year of age with advanced-stage disease die from progressive disease despite intensive multimodality therapy. This clinical complexity likely derives from the developmental origins of neuroblastoma, which arises due to developmental arrest of maturing components of the embryonic neural crest [3].

Neuroblastoma has been associated with central hypoventilation, Hirschsprung disease, and neurofibromatosis type 1 (neurocristopathy syndrome), and as a familial disorder associated with mutations in the anaplastic lymphoma kinase (ALK) gene. These are discussed separately. (See "Epidemiology, pathogenesis, and pathology of neuroblastoma".)

The clinical presentation, diagnosis, and staging evaluation of neuroblastoma will be presented here. The epidemiology, pathogenesis, pathology, treatment, and prognosis of neuroblastoma are presented separately. (See "Epidemiology, pathogenesis, and pathology of neuroblastoma" and "Treatment and prognosis of neuroblastoma".)

Olfactory neuroblastoma, a malignancy of the olfactory epithelium, which has a different cell of origin, presentation, and treatment than neuroblastoma, is also discussed separately. (See "Olfactory neuroblastoma (esthesioneuroblastoma)".)

CLINICAL PRESENTATION — Neuroblastomas can arise anywhere throughout the sympathetic nervous system. The adrenal gland is the most common primary site (40 percent), followed by abdominal (25 percent), thoracic (15 percent), cervical (5 percent), and pelvic sympathetic ganglia (5 percent) (image 1) [4]. Less commonly, tumors arise within the central or autonomic nervous systems [1]. In approximately 1 percent of cases, a primary tumor cannot be identified. Neuroblastoma metastasizes to lymph nodes, bone marrow, cortical bone, dura, orbits, liver, and skin, and less frequently to pulmonary and intracranial sites (image 2 and image 3) [5].

Presenting symptoms — The presenting symptoms reflect the location of the primary tumor and the extent of metastatic disease, if present. Patients with localized disease can be asymptomatic, whereas children with advanced disease appear ill at presentation, usually with systemic symptoms.

Signs and symptoms of neuroblastoma may include [6-8]:

●Abdominal mass (retroperitoneal or hepatic)

●Abdominal pain or constipation

●Proptosis

●Periorbital ecchymoses ("raccoon eyes," from periorbital ecchymosis caused by orbital metastases)

●Horner syndrome (miosis, ptosis, anhidrosis)

●Cord compression (lower extremity weakness, changes in reflexes, ascending paralysis)

●Unexplained back pain, dysuria, constipation

●Palpable nontender subcutaneous nodules

●Opsoclonus myoclonus syndrome

●Otherwise unexplained secretory diarrhea (from paraneoplastic production of vasoactive intestinal polypeptide [VIP])

●Systemic symptoms (fever, weight loss)

●Bone pain

●Anemia

●Heterochromia iridis (different colors of the iris or portions of the iris)

●Hypertension

●Additional clinical evidence for neuroblastoma (eg, adrenal mass on ultrasound examination, elevated urine catecholamines)

Abdominal tumors — Approximately two-thirds of primary neuroblastomas arise in the abdomen; among these, approximately two-thirds are from the adrenal glands [2,7]. Abdominal tumors can present with abdominal pain or fullness, abdominal mass, hypertension, or rarely intestinal obstruction. When the primary tumor arises from the organs of Zuckerkandl (a pair of embryonic organs that persist until shortly after birth and are located near the aortic bifurcation), the child may have symptoms related to compression of the bowel or bladder (eg, constipation, reduced bladder capacity, enuresis) [2]. Large abdominal tumors also can compress venous or lymphatic drainage, leading to scrotal and lower extremity edema. A sudden and dramatic increase in tumor size with abdominal distention and discomfort can result from spontaneous hemorrhage into the tumor [2].

An abdominal mass may be detected in an asymptomatic child by the primary care clinician during a routine examination. The mass is typically, but not always, non-tender, fixed, and firm. Such masses may also be detected initially using abdominal ultrasound. (See 'Staging studies' below.)

In a review of malignant abdominal masses diagnosed at a children's hospital, the mass was detected by the primary care provider during a well-child or brief acute-care visit in 11 percent of cases, highlighting the importance of the abdominal examination in all patients [6].

Thoracic tumors — Primary thoracic tumors may be detected incidentally on radiographs obtained in the evaluation of other complaints (eg, respiratory symptoms, trauma) [2] (see 'Paravertebral tumors' below). Mediastinal tumors can cause tracheal deviation or narrowing with resultant stridor, although high thoracic and cervical masses may be associated with a Horner syndrome (ptosis, miosis, and anhidrosis) [2] (see "Horner syndrome"). Large thoracic tumors, usually associated with mechanical obstruction, may cause the superior vena cava syndrome [9]. (See "Malignancy-related superior vena cava syndrome".)

Paravertebral tumors — Because neuroblastomas may arise from paravertebral sympathetic ganglia (paraganglia), primary tumors (usually in the retroperitoneum or mediastinum) are able to invade the spinal canal through the neural foramina, creating a so-called "dumbbell" tumor (image 1). The subsequent epidural spinal cord compression, an oncologic emergency, can cause pain, motor or sensory deficits, or loss of bowel and/or bladder control. The subtle and gradual onset of such neurologic symptoms in young children can make diagnosis difficult. (See "Clinical features and diagnosis of neoplastic epidural spinal cord compression".)

Involvement of the cervical paravertebral sympathetic chain and inferior cervical (stellate) ganglion can result in the Horner syndrome (ipsilateral ptosis, miosis, and anhidrosis) [10,11] (see "Horner syndrome"). Heterochromia iridis (different colors of the iris or portions of the iris) is common among infants who have congenital Horner syndrome, but also occurs in acquired cases [12]. In one retrospective review of 405 cases of neuroblastoma, unilateral Horner syndrome was present in 14 children (3 percent) and was the presenting sign in nine (2 percent) [13].

Infants with isolated or acquired Horner syndrome should undergo careful examination for cervical and abdominal masses, as well as a measurement of urinary catecholamine metabolites, vanillylmandelic acid (VMA) and homovanillic acid (HVA) [12,14]. Radiologic evaluation of the head, neck, and chest is warranted for those who have acquired Horner syndrome, or whose Horner syndrome is associated with other signs (eg, increasing heterochromia, cervical mass, other cranial nerve palsies). (See 'Is there a role for neuroblastoma screening?' below.)

In a retrospective review of 23 infants with an isolated Horner syndrome, urinary VMA was measured in 21, and radiographic imaging (computed tomography [CT] or magnetic resonance imaging [MRI]) of the chest and neck undertaken in 12 [12]. Previously undetected pathology was found in two infants (one with cervical neuroblastoma and another with a benign ganglioneuroma of the left pulmonary apex); a third had been diagnosed with abdominal neuroblastoma before presenting for evaluation of Horner syndrome. Four infants were thought to have birth trauma as an explanation for their Horner syndrome, and no underlying cause was identified among the remaining 16; no additional pathology developed among these patients after a mean 9.3 years of follow-up.

Catecholamine secretion — As neuroblastoma is derived from neural crest cells that are destined to form components of the peripheral sympathetic nervous system, they frequently express both the norepinephrine transporter gene (NAT, making them metaiodobenzylguanidine [MIBG] avid) and the enzymes required for catecholamine metabolism. (See 'Staging studies' below.)

Degradation of norepinephrine, epinephrine, and dopamine lead to the final end products VMA and HVA. Elevated levels of VMA and HVA can be detected in the serum and urine of approximately 70 to 90 percent of patients with neuroblastoma [15]. Testing for these products using high-performance liquid chromatography or other methods can thus be a highly sensitive and specific aid in making the diagnosis of a variety of neuroendocrine tumors including pheochromocytoma and neuroblastoma [16,17]. (See 'Urine catecholamines' below.)

Paraneoplastic syndromes — Several unique paraneoplastic syndromes can be associated with both localized and disseminated neuroblastomas.

Opsoclonus myoclonus — Opsoclonus-myoclonus syndrome (OMS), also known as opsoclonus-myoclonus-ataxia (OMA), is a paraneoplastic syndrome that occurs in 1 to 3 percent of children with neuroblastoma. Almost 50 percent of children with OMA have an underlying neuroblastoma; neurologic symptoms precede tumor diagnosis in about half of these. The disorder is believed to have an autoimmune pathogenesis.

The characteristic symptoms of OMA are rapid, dancing eye movements, rhythmic jerking (myoclonus) involving limbs or trunk, and/or ataxia.

All children with OMA must be evaluated for neuroblastoma [18]. If the initial evaluation is unrevealing, it should be repeated in several months.

The pathogenesis, clinical features, evaluation, treatment, and prognosis of paraneoplastic OMA are discussed in detail separately. (See "Opsoclonus-myoclonus-ataxia syndrome", section on 'Pediatric syndrome'.)

Secretion of VIP — Autonomous tumor secretion of vasoactive intestinal polypeptide (VIP) is another paraneoplastic syndrome that is rarely associated with neuroblastoma. VIP secretion can cause abdominal distension and intractable secretory diarrhea with associated hypokalemia [19]; these symptoms usually resolve after removal of the tumor [20].

The diagnosis of a VIP-secreting tumor is established by the presence of an otherwise unexplained high-volume secretory diarrhea and a serum VIP concentration in excess of 75 pg/mL. A single elevated VIP level should be confirmed by additional testing. VIP-producing tumors are more often the less aggressive ganglioneuroblastomas and ganglioneuromas rather than undifferentiated neuroblastomas [21]. (See "VIPoma: Clinical manifestations, diagnosis, and management".)

Metastatic disease — Neuroblastoma metastasizes by both lymphatic and hematogenous routes. Regional lymph node involvement is found in 35 percent of children who have apparently localized disease [2]. Involvement of lymph nodes outside the cavity or region of origin (ie, abdomen, thorax, pelvis) is considered to represent disseminated disease.

Hematogenous spread extends most often to bone, bone marrow, skin, and liver. Metastatic involvement of the liver is common in infants and can cause respiratory compromise [2]. Neuroblastomas also may spread to lung and brain parenchyma, but this usually occurs as a manifestation of relapsing or end-stage disease [22].

Metastatic spread to the bones and bone marrow can cause pain (especially with ambulation), blood count abnormalities, and fever [2,23-25]. In young children, who cannot complain of pain, bone pain may manifest as a limp or unexplained irritability. Tumor infiltration of the periorbital bones, typically unilateral, can cause the characteristic periorbital ecchymosis ("raccoon eyes"), ptosis, and proptosis. In one retrospective review of 405 cases of neuroblastoma, proptosis or periorbital ecchymosis was present in 15 percent [13].

Metastatic spread to the skin manifests as papules or subcutaneous nodules that can be distributed over the entire body. These lesions are present in approximately one-third of children with congenital neuroblastoma and are typically described as firm, bluish-red, and non-tender [26-28]. The lesions have a distinctive response to rubbing, characterized by central blanching with a surrounding halo of erythema that persists for 30 to 60 minutes [27,28]. The differential diagnosis of skin nodules is presented below. Rigorous evaluation is important to determine the etiology of the nodules so that the child can be appropriately treated. Children with skin nodules that are biopsy-proven to be neuroblastoma should undergo a full tumor evaluation by an oncologist.

Prenatal diagnosis — Obstetrical ultrasound examination is often used to detect neuroblastoma in the prenatal setting. As the ease and accuracy of third-trimester imaging with obstetrical ultrasound has improved, and the indications for these studies have broadened, the incidence of prenatal diagnosis of neuroblastoma has risen steadily [29-31]. Prenatally detected adrenal masses typically are found during ultrasound examinations performed after 32 weeks gestation, with the earliest observed at 18 weeks [32]. More than 55 cases of antenatal neuroblastoma have been reported in the literature since the original report in 1983 [31,33]. One hundred children per year in North America are diagnosed with neuroblastoma either prenatally or at younger than three months of age. Because most of these tumors are present antepartum, the incidence of prenatal diagnosis is likely to continue to rise.

If an adrenal tumor was detected on prenatal ultrasound performed for unrelated reasons and the fetus was otherwise progressing normally, repeat ultrasound after delivery should be performed. Urine catecholamines also may be helpful in distinguishing a neuroblastoma from other potential masses including adrenal hemorrhage and vascular malformations, although a negative result does not exclude the diagnosis.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of neuroblastoma includes a variety of neoplastic and non-neoplastic conditions and varies according to tumor location. Distinguishing these conditions from neuroblastoma may be particularly difficult in patients whose tumors do not produce catecholamines or who do not have an obvious primary tumor [2].

When the tumor arises in a suprarenal location, Wilms' tumor and hepatoblastoma should be considered. In thoracic and retroperitoneal locations, lymphoma, germ cell tumors, and infection should be considered. Metastatic involvement of the bone marrow must be distinguished from lymphoma, small cell osteosarcoma, mesenchymal chondrosarcoma, the Ewing sarcoma family of tumors, primitive neuroectodermal tumors (PNETs), undifferentiated soft-tissue sarcomas such as rhabdomyosarcoma, and leukemia, particularly megakaryoblastic leukemia. If the spinal canal is involved, either as a metastatic lesion or by extension of the primary tumor, the differential diagnosis should extend to other neurodevelopmental tumors such as desmoid tumors, epidermoid tumors, and teratomas, as well as astrocytomas [34].

Opsoclonus-myoclonus syndrome may occur in association with other conditions besides neuroblastoma [35-45]:

●Tumors – Hepatoblastoma

●Infections – Poliovirus, parainfluenza virus, coxsackie virus B3 and B2, Epstein-Barr virus, St. Louis encephalitis virus, salmonella, Lyme disease, rickettsia, syphilis, psittacosis, and human immunodeficiency virus (HIV)

●Ingestions – Lithium, phenytoin, amitriptyline, diazepam, cocaine

●Toxic exposures – Toluene, thallium, organophosphates, chlordecone, strychnine

●Metabolic derangements – Biotin-responsive multiple carboxylase deficiency, hyperosmolar nonketotic coma

The differential diagnosis of skin nodules in newborns and infants includes dermoid and other cysts, subcutaneous fat necrosis, benign tumors (eg, infantile myofibromatosis, congenital self-healing reticulohistiocytosis), and other malignant tumors (eg, infantile fibrosarcoma, rhabdomyosarcoma, and congenital leukemia). Biopsy may be required for definitive diagnosis. (See "Skin nodules in newborns and infants".)

The causes of secretory diarrhea are listed in the table (table 1).

DIAGNOSTIC AND STAGING EVALUATION — In children with suspected neuroblastoma, the diagnostic evaluation is best performed at a pediatric cancer center where pediatric oncologists, surgeons, and radiologists familiar with neuroblastoma can be closely involved in the planning and coordination.

Diagnostic evaluation — All patients with suspected neuroblastoma should undergo a complete history and physical examination. Most patients will undergo laboratory evaluations including routine blood counts, serum chemistries, and tests of liver and kidney function. Evaluation of urine or serum catecholamine metabolite levels, vanillylmandelic acid (VMA), and homovanillic acid (HVA) should be obtained to assist in diagnosis and monitoring of disease response, since levels are elevated in greater than 70 to 80 percent of patients with neuroblastoma.

Biopsy — The diagnosis of neuroblastoma is definitively confirmed on histology using biopsy. Care must be taken to ensure that adequate diagnostic material is obtained for complete characterization of primary tumor. The nature and extent of the initial diagnostic procedure for a child with suspected neuroblastoma should be decided only after consultation with a pediatric surgeon and oncologist who are familiar with the diagnosis and treatment of neuroblastoma.

In most patients, diagnostic tissue is usually obtained by incisional or image-guided core needle biopsy of the primary tumor [46]. A bone marrow biopsy/aspirate may be used to diagnose patients suspected to have metastatic disease involving the bone marrow. Based on the choice of biopsy technique, these principles are followed:

●Incisional or image-guided biopsy technique – A hollow needle guide should be placed through the skin and soft tissue superficial to the mass to avoid the need for multiple needle passes through uninvolved structures. A minimum of 25 to 30 passes with a 14- or 16-gauge core biopsy needle should be obtained. Real time pathology consultation should confirm that viable tissue is present. The hollow guide should be injected with fibrin glue sealant as the guide is withdrawn to minimize bleeding and tumor seeding of the track.

●Bone marrow biopsy/aspirate – Bone marrow disease is evaluated by aspiration and biopsy of the bone marrow, usually at the posterior iliac crests. Two separate sites are assayed, resulting in four samples (two aspirations, two biopsies). It must contain at least 1 cm of marrow, excluding cartilage, to be considered adequate. If any of the four assays demonstrate tumor cells (picture 1), the bone marrow is considered positive for disease [47]. All four assays must be without evidence of tumor for the bone marrow to be considered clear. In a subset of cases, bone marrow biopsy may not be sufficient to guide therapy because it does not provide information about the histologic grade of the primary tumor.

Tumor tissue or bone marrow, if positive for tumor, must be evaluated for histology (favorable or unfavorable), status of the gene MYCN, DNA ploidy, and loss of heterozygosity (LOH) at 1p or 11q, preferably at a centralized laboratory if the treating institution does not routinely perform these analyses. Proper handling of the tissues after biopsy is crucial in determining treatment. Thus, biopsy should be undertaken with the guidance of a pediatric oncologist or pediatric surgical oncologist whenever possible. (See "Treatment and prognosis of neuroblastoma", section on 'Risk stratification'.)

Urine catecholamines — Neuroblastoma tumor cells take up and metabolize catecholamines, and the resulting degradation products can be detected in serum and urine. Urinary HVA and VMA levels are useful for both diagnosis and for monitoring disease activity over time. Screening programs for neuroblastoma using urine catecholamines are discussed below. (See 'Is there a role for neuroblastoma screening?' below.)

Diagnostic criteria — Minimum criteria for establishing a diagnosis of neuroblastoma have been agreed upon by an international consensus panel [47]. A definitive diagnosis of neuroblastoma requires one of the following:

●An unequivocal histologic diagnosis from tumor tissue by light microscopy, with or without immunohistochemistry, electron microscopy, or increased urine (or serum) catecholamines or their metabolites

●Evidence of metastases to bone marrow on an aspirate or biopsy with concomitant elevation of urinary or serum catecholamines or their metabolites

Staging studies — In patients with suspected neuroblastoma, it is mandatory to obtain complete staging studies before beginning treatment. The goal of these studies is to evaluate the extent of disease. These findings, in turn, determine the clinical and pathologic stage, treatment, and prognosis. The evaluation is best completed at a pediatric cancer center where pediatric oncologists and radiologists familiar with neuroblastoma can be closely involved in the planning and coordination [48]. (See "Treatment and prognosis of neuroblastoma".)

The following studies are necessary for optimal staging:

●CT or MRI – While ultrasound is often the initial radiologic study in the evaluation of a child with an abdominal mass, evaluation of the primary tumor site and nodal sites of metastatic disease by computed tomography (CT) or magnetic resonance imaging (MRI) must also be performed in suspected cases of neuroblastoma. Extension of imaging into chest and pelvis may be required in cases of retroperitoneal primary disease that can extend into these cavities, as well as to assess for potential metastatic sites of disease.

CT or MRI of the primary tumor may reveal a heterogeneous mass, possibly containing calcifications (image 4). When the mass is adjacent to the spine, an MRI is particularly helpful for evaluation of spinal canal invasion (image 1).

Additionally, a head CT or MRI should be pursued for patients presenting with proptosis, periorbital ecchymosis, or as clinically indicated by symptoms.

●I123-MIBG scan versus FDG-PET – Patients with a confirmed diagnosis of neuroblastoma should be evaluated for bony metastatic disease. For such patients, I123 MIBG is preferred to FDG positron emission topography (FDG-PET) scan or technetium scan for evaluation of the bone, given its higher sensitivity and specificity for detection of metastatic disease. Among patients with known neuroblastoma, I123 MIBG has a sensitivity of approximately 90 percent [49]. For patients with a negative MIBG (indicating MIBG non-avid disease), FDG-PET scan should be performed [50].

MIBG can be combined with single photon emission computed tomography and CT (SPECT-CT) to better classify lesions that appear on planar MIBG scans, detect additional lesions, and better classify lesions that are near areas of physiologic MIBG uptake (image 5) [51]. I-131 MIBG is an optional imaging reagent for SPECT-CT [52]. Additional imaging modalities and improved sensitivity will continue to improve detection of metastatic disease.

MIBG is a chemical analog of norepinephrine that is selectively concentrated in sympathetic nervous tissues such as neuroblastoma. It can be labeled with radioactive iodine and imaged by scintigraphy. The MIBG scan is both sensitive and specific for neuroblastoma and is recommended at diagnosis and repeat evaluations of the tumor [47,49,53-57]. Because radioactive iodine is used, the thyroid gland must be protected by the simultaneous administration of nonradioactive iodine (eg, potassium iodide). When MIBG is used for treatment, thyroid dysfunction has been reported as a potential complication in up to 64 percent of patients [58-60].

In about 10 percent of patients, bone metastases may be suspected despite a negative MIBG. In such cases, a PET scan is a sensitive tool for evaluating metastatic spread to cortical bone, although it is not routinely recommended over I123 MIBG scans. Plain radiographs are not as sensitive as bone scans because of the degree of cortical bone destruction needed to visualize a lesion on plain film.

●Bone marrow biopsy and aspirate – Evaluation of bone marrow biopsy and aspirate should be obtained as part of staging. Further details on this technique are discussed above (See 'Biopsy' above.)

STAGING SYSTEM — Neuroblastomas are staged using the International Neuroblastoma Risk Group Staging System (INRGSS) (table 2), which was originally developed as part of an international collaboration to define risk based on image-defined risk factors (IDRF). These IDRF connote tumor infiltration or encasement of vital structures and correlate with the ability to achieve complete resection. Pretreatment IDRF are combined with presence or absence of metastatic spread and yield a stage for every patient [61]. The INRGSS staging is then combined with molecular, pathologic, and other clinical characteristics to assign the patient to a specific risk group (figure 1) [61-63]. Further details on staging and risk classification systems for neuroblastoma and their impact on selection of therapy are discussed separately. (See "Treatment and prognosis of neuroblastoma", section on 'Staging system'.)

IS THERE A ROLE FOR NEUROBLASTOMA SCREENING? — Universal screening of infants for neuroblastoma with urine catecholamines is not recommended, as data suggest that this approach does not reduce mortality.

Screening may be considered in cases where there is a familial history of neuroblastoma. If present, analysis for germline mutation of the anaplastic lymphoma kinase (ALK) gene should also be performed. (See "Epidemiology, pathogenesis, and pathology of neuroblastoma", section on 'Molecular abnormalities (prognostic impact)'.)

Because outcome is significantly better for patients with localized disease and younger age, several groups have attempted to develop screening programs for neuroblastoma in infancy by measuring urinary catecholamines [64-67]. The aim of these studies has been to ascertain whether earlier detection would decrease the incidence of high-risk or advanced-stage disease and ultimately improve survival.

Four large studies from Japan, Canada, Austria, and Europe have screened over 10 million children at either six to seven months or one year of age. The incidence of neuroblastoma diagnosis was compared with historic controls [65], unscreened children from the same country [67], or unscreened populations in other cities [64,66]. All of these studies were remarkably similar:

●Screening led to more neuroblastomas being diagnosed in the screened population; however, the additional tumors were mainly low-stage tumors with favorable biologic features. Many of these tumors presumably would have undergone spontaneous regression and never would have been diagnosed clinically.

●There was no decrease in the incidence of high-risk tumors in children beyond the age of screening (ie, older than one year of age).

●Mortality was not lower in the screened populations.

These observations were supported in a pilot study of observation in Japanese infants with neuroblastoma detected through mass screening [68]. Infants were eligible for inclusion if their tumors were stage I or II (table 3), less than 5 cm in diameter, and did not involve large vessels or organs. Immediate resection was performed for increase in size, elevation of tumor markers, or evidence of metastasis. Spontaneous regression occurred in 13 of 22 cases (59 percent); eight of the remaining tumors were resected for increase in size, elevation of tumor markers, and/or parental request; and one tumor was resected at the parents' request. Among the resected tumors, five had favorable biologic features. All patients survived without recurrence. (See "Treatment and prognosis of neuroblastoma", section on 'Prognostic factors'.)

An adverse impact of screening was suggested in the study from Canada, in which 2 of the 43 patients whose tumors were detected by screening had significant adverse effects because of treatment for their favorable-prognosis neuroblastoma [66]. Another study demonstrated that expectant observation of infants younger than six months with small adrenal masses resulted in favorable event-free and overall survival outcomes for most patients, while also avoiding surgical morbidity [69].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neuroblastomas".)

SUMMARY AND RECOMMENDATIONS

●Clinical presentation – Neuroblastoma should be included in the differential diagnosis of children who present with the following symptoms (see 'Clinical presentation' above):

•Abdominal mass (retroperitoneal or hepatic)

•Abdominal pain or constipation

•Proptosis

•Periorbital ecchymosis ("raccoon eyes")

•Horner syndrome (miosis, ptosis, anhidrosis)

•Cord compression (neurologic compromise of lower extremities)

•Unexplained back pain, dysuria, constipation

•Bladder dysfunction, constipation

•Palpable nontender subcutaneous nodules

•Opsoclonus myoclonus syndrome

•Unexplained secretory diarrhea

•Additional clinical evidence for neuroblastoma (eg, adrenal mass on ultrasound examination, elevated urine catecholamines)

In children with signs or symptoms of neuroblastoma, the diagnostic evaluation is best performed at a pediatric cancer center where pediatric oncologists, surgeons, and radiologists familiar with neuroblastoma can be closely involved in the planning and coordination. (See 'Diagnostic and staging evaluation' above.)

●Confirming the diagnosis – The definitive diagnosis of neuroblastoma is made by histologic confirmation, either from biopsy of tumor tissue or evidence of metastases to bone marrow on aspirate or biopsy with concomitant elevation of catecholamines in the urine. (See 'Diagnostic evaluation' above and 'Diagnostic criteria' above.)

●Staging studies – Staging studies include computed tomography (CT) or magnetic resonance imaging (MRI) scan of the primary site and nodal sites of metastatic disease, bone imaging (preferably with a metaiodobenzylguanidine [MIBG] scan (image 5)), and bilateral iliac crest bone marrow aspirate and biopsy. (See 'Staging studies' above.)

●Staging system – Neuroblastomas are staged using the International Neuroblastoma Risk Group Staging System (INRGSS) (table 2). The INRGSS staging is then combined with molecular, pathologic, and other clinical characteristics to assign the patient to a specific risk group (figure 1), which impacts selection of therapy. (See 'Staging system' above and "Treatment and prognosis of neuroblastoma", section on 'Staging system'.)

●Is there a role for neuroblastoma screening? – Universal screening of infants for neuroblastoma with urine catecholamines is not recommended, as data suggest that this approach does not reduce mortality. (See 'Is there a role for neuroblastoma screening?' above.)