Neuroblastoma Flashcards
All of the following are bad prognostic factors of neuroblastoma except:
A. Age more than one year.
B. Stage IV-S.
C. When adrenal gland is the site of development.
D. Elevated serum ferritin level.
E. Stroma poor Shimada histology.
B. Stage IV-S
In 1971, D’Angio, Evans, and Koop reported a number of patients with a “special” variant of metastatic neuroblastoma, termed IVS (now referred to as 4S [INSS] or MS [INRG]). These patients are infants who typically had a single, small primary tumor but had extensive metastatic disease in the liver, skin nodules (“blueberry muffin” lesions), and small amounts of disease in the bone marrow (<10% of the mononuclear cells).
Patients with 4S neuroblastoma are quite remarkable because the large amount of disease generally undergoes spontaneous regression, even without treatment, and the infants ultimately have no evidence of disease.
Only supportive therapy has been recommended for this stage of neuroblastoma because of the high incidence of spontaneous regression and the good prognosis.
Most of these patients have a tumor with favorable biology (singlecopy MYCN, favorable Shimada histology, and DNA index >1). Therefore, they are assigned to the low-risk classification and receive no therapy.
However, despite the generally benign course of their malignancy, these infants can die of complications caused by the initial bulk of their disease. Limited chemotherapy, local irradiation, or minimal resection can be used to treat infants with life-threatening symptoms of hepatomegaly. Decompressive laparotomy with creation of a Silastic pouch may be needed for those with significant hepatomegaly that causes either respiratory compromise secondary to diaphragmatic elevation or obstruction of the inferior vena cava. This procedure may help avoid lifethreatening events until shrinkage of the liver is achieved by either spontaneous regression or therapy.
As proposed in the ANBL1232 protocol, patients younger than 18 months who are asymptomatic and have tumors with favorable biology are observed.
If patients are symptomatic, age is considered as the next criteria: patients younger than 3 months receive immediate chemotherapy (with full staging within 1 month) with plans to perform the tumor biopsy when they are stable, whereas patients 3–18 months old undergo a tumor biopsy and proceed through a response-based algorithm to determine the length of treatment.
ANBL1232 will also prospectively study an objective scoring system in which values will be assigned to symptoms and laboratory results to generate a clinical score. The trial will evaluate gastrointestinal symptoms, respiratory compromise, venous return, renal compromise, and hepatic dysfunction.
The rare infant with MS disease and either unfavorable Shimada histology or a DNA index of 1 (or if the biology is not known) are treated as having intermediate-risk disease.
Those with MS disease that is MYCN amplified are treated as having high-risk disease.
Neuroblastoma which is localised primary tumour with dissemination limited to skin, liver, and/or bone marrow in infants younger than 1 year of age is labelled as:
A. Stage I.
B. Stage II.
C. Stage III.
D. Stage IV.
E. Stage IV-S.
E. Stage IV-S
What is the DNA index of a tumor?
Normal human cells contain two copies of each of 23 chromosomes; thus, a normal diploid cell has 46 chromosomes.
The majority (55%) of primary neuroblastomas are triploid or “near-triploid/hyperdiploid” and contain between 58 and 80 chromosomes; the remainder (45%) are either neardiploid (35–57 chromosomes) or near-tetraploid (81–103 chromosomes).
The DNA index of a tumor is the ratio of the number of chromosomes present to a diploid number of chromosomes (i.e., 46).
Therefore, diploid cells have a DNA index of 1.0, whereas near-triploid cells have a DNA index ranging from 1.26 to 1.76.
Neuroblastomas that are neardiploid or near-tetraploid usually have structural genetic abnormalities, most frequently chromosome 1p deletion and MYCN amplification.
Near-triploid or hyperdiploid tumors are characterized by almost three complete haploid sets of chromosomes with few structural abnormalities.
Importantly, patients with near-triploid tumors typically have favorable clinical and biologic prognostic factors and excellent survival rates, as compared with those patients who have near-diploid or near-tetraploid tumors.
This association is most important for infants with advanced disease as the prognostic significance of tumor ploidy appears to be lost in patients older than 2 years.
Currently, ploidy affects only the risk group assessment of very limited subgroups of patients with neuroblastoma.
How are neuroblastic tumors classified in the International Neuroblastoma Pathology Classification (INPC)?
Neuroblastomas are, by definition, Schwannian stroma poor (<50% of the tumor tissue) and can be subtyped as undifferentiated, poorly differentiated, or differentiating.
Undifferentiated tumors require supplemental diagnostic methods such as immunohistochemistry, electron microscopy, or cytogenetics to make the diagnosis of neuroblastoma. Moreover, neuropil is not present.
In poorly differentiated tumors, <5% of tumor cells have features of differentiation, and neuropil is present.
Differentiating tumors demonstrate >5% of tumor cells differentiating toward ganglion cells.
Additional factors that contribute to the prognostic distinction of stroma-poor neuroblastic tumors (neuroblastoma) as favorable or unfavorable subtypes include the MKI, which is defined as the number of tumor cells in mitosis or karyorrhexis per 5000 neuroblastic cells (i.e., low MKI, <100 cells; intermediate, 100–200 cells; high, >200 cells) and the patient’s age (<1.5 years, 1.5–5 years, >5 years).
It has been hypothesized that neuroblastic cells with maturational potential require a latent period before demonstrating histologic evidence of differentiation. Therefore, there is a certain allowance for mitotic and karyorrhectic activities of neuroblastic cells in tumors in infants and younger children.
Stroma-rich neuroblastic tumors are classified as either ganglioneuroblastomas or ganglioneuromas.
Ganglioneuroblastomas contain cells that are transitioning toward differentiation but are not completely differentiated/mature. Also, less than 50% of the total volume is made up of neuroblastic cells.
Ganglioneuroblastomas can be further divided into intermixed and nodular subtypes, depending on the distribution of the neuroblastic cells. The distinction is important because of the significantly worse prognosis associated with the latter subtype, in which the neuroblastic clones that comprise grossly distinct nodules appear to be responsible for the aggressive phenotype for this subtype.
Ganglioneuromas contain either maturing or mature cells and lack any neuroblastomatous component. Most stroma-rich tumors (ganglioneuroblastoma, intermixed and ganglioneuroma, maturing subtype) are classified as favorable by the INPC.
However, the pathologic/prognostic classification of the ganglioneuroblastoma, nodular subtype, is based on the morphologic evaluation of the neuroblastomatous nodule(s), and can, therefore, be unfavorable.
Tumors that fit the criteria for ganglioneuroma, mature subtype, with abundant Schwannian stroma and fully mature ganglion cells, in the absence of neuroblasts, are considered benign, and are generally not considered for enrollment in protocols for neuroblastic tumors.
Despite this, ganglioneuromas can be quite large and infiltrative, and attempts at removal can be associated with significant complications. In addition, survival does not seem to be influenced by extent of resection.
Therefore, aggressive attempts at resection of ganglioneuromas are not recommended.
What are some genetic events in the pathophysiology of neuroblastomas?
1) Majority (55%) or neuroblastomas are near-triploid/hyperdiploid, containing 58-80 chromosomes (versus the normal diploid cell of 46).
2) Amplification of MYCN proto-onco gene (increased rates or DNA synthesis and cell proliferation, shortening G1 phase of the cell cycle).
Overall, approximately 25% of primary neuroblastomas in children have MYCN amplification, with MYCN amplification being present in 40% with advanced disease but only 5–10% with low-stage disease.
3) Presence and loss of a tumor suppression gene, as suggested by 1p deletions (70% of advanced staged neuroblastomas), and 11q deletions (40% of cases).
4) Mutations
- Activating mutations of ALK, a tyrosine kinase receptor (proto-oncogene activation)
- Loss of function mutations in homeobox gene PHOXB2 on 4p13 (associated with familial neuroblastoma, when occuring with Hirschsprung and central hypoventilation).
- Inactivating mutations of ATRX, a transcriptional regulator (High stage tumors in older patients)
What is the most common primary site for neuroblastomas?
Retroperitoneal neuroblastoma of adrenal origin (50%)
Retroperitoneal neuroblastoma of paraspinal ganglion origin (25%)
Thoracic (posterior mediastinal neuroblastoma) (20%)
Pelvic neuroblastoma (organ of Zuckerkandel) (4%)
Cervical neuroblastoma (1%)
What is the clinical presentation of Neuroblastoma?
Patients with neuroblastoma usually present with signs and symptoms that reflect the primary site and extent of disease, although localized disease is often asymptomatic.
As 75% of neuroblastoma occurs in the abdominal cavity, an abdominal mass detected on physical examination is a common clinical feature, as is the complaint of abdominal pain.
Other primary sites of neuroblastoma include the posterior mediastinum (20%), the cervical region (1%), and the pelvis (4%) (organ of Zuckerkandel) (Fig. 65.3).
Respiratory distress or dysphagia may be a reflection of a thoracic tumor.
Altered defecation or urination can be caused by mechanical compression from a pelvic tumor or by spinal cord compression from a paraspinal tumor. Spinal cord compression may also manifest as an altered gait.
A tumor in the neck or upper thorax can produce Horner syndrome (ptosis, miosis, and anhydrosis), enophthalmos, and heterochromia of the iris.
Acute cerebellar ataxia has also been observed, characterized by the dancing-eye syndrome, which includes opsoclonus, myoclonus, and chaotic nystagmus. Two-thirds of these cases occur in infants with mediastinal primary tumors.
Additional signs and symptoms that reflect excessive catecholamine or vasoactive intestinal polypeptide (VIP) secretion include diarrhea, weight loss, and hypertension.
More than 40% of patients have metastatic disease at diagnosis. These patients are often quite ill and have systemic symptoms caused by widespread disease.
Neuroblastoma in older patients has a pattern of metastatic disease in which metastases to the bone marrow, lymph nodes, and bone predominate. These metastases may manifest as bone pain from cortical metastases or anemia from marrow infiltration.
The brain, spinal cord, heart, and lungs are rare sites of metastases, except with end-stage disease. Metastatic disease also may be associated with darkened areas around the eyes, referred to as “raccoon eyes,” as a result of retroorbital venous plexus spread. This is an ominous physical sign, as is the presence of a limp in children without a history of head or extremity trauma.
What are the necessary laboratories for suspected neuroblastoma?
The diagnosis of neuroblastoma is generally made by histopathologic evaluation of the primary or metastatic tumor tissue, or by the demonstration of tumor cells in the bone marrow together with elevated levels of urinary catecholamines.
LABS
1) Lactate Dehydrogenase
High serum levels of LDH reflect high proliferative activity or a large tumor burden, and an LDH level higher than 1500 IU/L appears to be associated with a poor prognosis. Thus, LDH can be used to monitor disease activity or the response to therapy.
2) Ferritin
High levels of serum ferritin (>150 ng/mL) may also reflect a large tumor burden or rapid tumor progression. Elevated serum ferritin is often seen in advanced-stage neuroblastomas and indicates a poor prognosis. Levels often return to normal during clinical remission.
3) Catecholamine Metabolites Neuroblastoma is characterized by the relatively unique capacity for secretion of catecholamine products, the metabolites of which can be detected in the urine of more than 90% of patients with neuroblastoma. Thus, a urine specimen is of clinical value in diagnosing neuroblastoma and determining the response to therapy. Documentation of elevated urinary catecholamines is required if the diagnosis of neuroblastoma is being made solely by the identification of neuroblasts in the bone marrow. Urinary levels of these two catabolites can also be used as markers of tumor progression or relapse and serve as a surrogate prognostic indicator. Random urine samples are preferable to 24-hour urine estimations for younger children.
What are the necessary imaging studies for suspected neuroblastoma?
IMAGING
1) Standard Radiographs
Chest radiography can be a useful tool for demonstrating the presence of a posterior mediastinal mass, which in a child is usually a thoracic neuroblastoma. A Pediatric Oncology Group (POG) study demonstrated that a mediastinal mass was discovered on incidental chest radiographs in almost half of patients with thoracic neuroblastoma who had symptoms seemingly unrelated to their tumors. Abdominal radiography is less often the modality by which a neuroblastoma is discovered. However, as many as half of abdominal neuroblastomas are detectable as a mass with fine calcification.
2) Ultrasonography
Although ultrasonography (US) is the modality most often used during the initial assessment of a suspected abdominal mass, its sensitivity and accuracy are less than that of computed tomography (CT) or magnetic resonance imaging (MRI) for demonstrating a neuoblastoma.
3) Computed Tomography
CT can demonstrate calcification in almost 85% of neuroblastomas, and intraspinal extension of the tumor can be determined on contrast-enhanced CT. Overall, contrast-enhanced CT has been reported to be 82% accurate in defining neuroblastoma extent, with the accuracy increasing to nearly 97% when performed with a bone scan.
4) Magnetic Resonance Imaging
MRI is becoming the most useful and most sensitive imaging modality for the diagnosis and staging of neuroblastoma. MRI appears to be more accurate than CT for detection of stage 4 disease.
The sensitivity of MRI is 83%, and that of CT is 43%, and the specificity of MRI is 97%, and that of CT is 88%.
Metastases to the bone and bone marrow, in particular, are better detected by MRI, as is intraspinal tumor extension.
When considering skeletal metastases alone, MRI and bone scan have been shown to be equivalent.
Encasement of major vessels is better defined by MRI than CT, especially with MR angiography.
MRI in the coronal plane is suitable for routine assessment of the whole body from the neck to the pelvis. Evaluating the utility of whole-body MRI, perhaps performed in conjunction with a functional imaging study such as positron-emission tomography (PET), is being considered for future clinical staging studies.
CT and MRI are not very accurate for staging localized disease. However, the sensitivity of T1- and T2-weighted MRIs is 100% for detecting neuroblastomas in infants identified by mass screening.
5) Metaiodobenzylguanidine Imaging
Metaiodobenzylguanidine (MIBG) is transported to and stored in the chromaffin cells in the same way as norepinephrine. The MIBG scintiscan is the preferred imaging study for evaluating the bone and bone marrow involvement by neuroblastoma.
In addition, monitoring MDP-avid neuroblastomas by bone scintigraphy often results in false-positive imaging for months after tumor remission. Thus, 99m TcMDP bone scanning is a second choice if MIBG imaging is not available or does not visualize known disease.
Iodine-131 (131 I) or iodine-123 (123 I) can be used to label MIBG. 123 I-MIBG supplies a reduced absorbed radiation dose and superior spatial resolution.
The reported sensitivity of MIBG in the detection of neuroblastomas with metastases to the bone and bone marrow is 82%, and the specificity is 91%. Primary tumors and lymph node metastases are also detectable.
MIBG can demonstrate more sites of tumor involvement in bone and bone marrow than either bone scintigraphy or standard radiography. However, false-negative MIBG scans have been seen in patients in which the bone scintigraphy was positive.
What is the role of bone marrow examination in the diagnosis of neuroblastoma?
Marrow biopsy is a routine method for detecting bone marrow involvement. Both aspiration and trephine biopsy should be performed, although the latter has better diagnostic value.
To collect more accurate information, taking specimens from multiple sites is recommended.
Immunohistochemical staining with antibodies such as antiganglioside GD2 , S-100, neuron specific enolase (NSE), and ferritin is also useful to help reduce the number of falsenegative cases.
Because biopsy is invasive and painful, noninvasive alternatives are being evaluated.
Studies have suggested the superiority of MRI and MIBG scintigraphy over bone marrow biopsy in detecting bone marrow infiltration by neuroblastoma. However, the specificity of these modalities requires further evaluation.
What are the stages of Neuroblastoma based on the International Neuroblastoma Staging System (INSS)?
1: Localized tumor with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph nodes negative for tumor microscopically (nodes attached to and removed with the primary tumor may be positive)
2A: Localized tumor with incomplete gross excision; representative ipsilateral nonadherent lymph nodes negative for tumor microscopically
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
3: Unresectable unilateral tumor infiltrating across the midline,* with or without regional lymph node involvement or
Localized unilateral tumor with contralateral regional lymph node involvement or
Midline tumor with bilateral extension by infiltration (unresectable) or by lymph node involvement
4: Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, or other organs (except as defined for stage 4S)
4S: Localized primary tumor (as defined for stage 1, 2A, or 2B), with dissemination limited to skin, liver, and bone marrow † (limited to infants younger than 1 year old)
—
*The midline is defined as the vertebral column. Tumors originating on one side and crossing the midline must infiltrate to or beyond the opposite side of the vertebral column.
† Marrow involvement in stage 4S should be minimal (i.e., <10% of total nucleated cells identified as malignant on bone marrow biopsy or on marrow aspirate). More extensive marrow involvement would be considered to be stage 4. The metaiodoberuylguanidine scan (if performed) should be negative in the marrow.
What are the most important variables that predict relapse In neuroblastoma?
Treatment of children with neuroblastoma is based on risk stratification that takes into account clinical and biologic variables predictive of relapse.
The most important clinical variables appear to be age at the time of diagnosis and stage at diagnosis.
The most powerful biologic factors at this time appear to be MYCN status and the histopathologic classification.
In addition, other biologic and molecular variables continue to be evaluated and the allelic status at chromosomes 1p36 and 11q23 has been used to dictate the duration of therapy for certain patients.
Taken together, these variables defined the COG risk stratification used for recent clinical trials.
On the basis of these clinical and biological variables, infants and children with neuroblastoma have been categorized into three risk groups predictive of relapse: low, intermediate, and high risk.
The probability of prolonged disease-free survival for patients in each group is >95%, >90%, and <30%, respectively.
What are image defined risk factors for primary resection of localized neuroblastoma?
Neck
- Tumor encasing major vessel(s) (e.g., carotid artery, vertebral artery, internal jugular vein)
- Tumor extending to base of skull
- Tumor compressing the trachea
- Tumor encasing the brachial plexus
Thorax
- Tumor encasing major vessel(s) (e.g., subclavian vessels, aorta, superior vena cava)
- Tumor compressing the trachea or principal bronchi
- Lower mediastinal tumor, infiltrating the costovertebral junction between T9 and T12 (may involve the artery of Adamkiewicz supplying the lower spinal cord)
Abdomen
- Tumor infiltrating the porta hepatis and/or the hepatoduodenal ligament
- Tumor encasing the origin of the celiac axis and/or the superior mesenteric artery
- Tumor invading one or both renal pedicles
- Tumor encasing the aorta and/or vena cava
- Tumor encasing the iliac vessels
- Pelvic tumor crossing the sciatic notch
Dumbbell tumors with symptoms of spinal cord compression: Any location
Infiltration of adjacent organs/structures: Diaphragm, kidney, liver, duodenopancreatic block, and mesentery
L1 (Absence of IDRF):
Localized tumors without any image-defined risk factors (L1) in patients younger than 1 year of age at the time of presentation and with a tumor <5 cm by imaging studies are eligible for observation-only on the COG study.
Patients may have non-adrenal tumors confirmed by either an MIBG scan or elevated levels of catecholamine metabolites, and may be observed up to 96 weeks without a biopsy. If these patients show disease progression, surgical resection once off protocol is recommended. Patients who are not eligible for observation or who decline enrolment should have their tumor resected. If the tumor is resected completely, as should be possible with most L1 tumors, no adjuvant therapy would be given, regardless of the tumor biologic factors.
L2 (Presence of IDRF):
Patients younger than 18 months with INRG stage L2 tumors (at least one image-defined risk factor) are also potentially eligible for observation-only on the COG study ANBL1232. However, in these patients, a biopsy is required, and only those patients who are asymptomatic and whose tumor has favorable histologic and genomic features can be observed. Patients older than 18 months would generally be considered intermediate risk unless their tumor had unfavorable histology or if MYCN was amplified.
For patients with metastatic disease, those under 1 year of age whose tumor is not MYCN amplified will be considered intermediate risk; those whose tumors are MYCN amplified are classified as high risk.
Patients who are 12–18 months of age with metastatic disease and any unfavorable biologic risk factor (MYCN amplification, SCA, DI, INPC) will also be classified as high risk. Only if none of these risk factors are present will the patient be classified as intermediate risk.
All patients over 18 months of age at the time of diagnosis with metastatic neuroblastoma will be classified as having high-risk disease.
A 4-year-old boy presented with spontaneous raccoon eyes. There was no history of trauma or coagulopathy. On examination, he had a non-tender abdominal lump. Which of the following is the strongest predictor of poor prognosis in this child?
Choices:
1. MYCN amplification
2. 1p deletion
3.11q deletion
4. ALK amplification
Answer: 1 - MYCN amplification
Explanations:
• Metastatic neuroblastoma secondary to tumoral obstruction of the palpebral vessels) can present as Raccoon eyes. Neuroblastoma can present as periorbital ecchymosis in 5.4% of cases.
• MYCN amplification has been reported in around 25% of neuroblastomas.
• MYCN amplification is generally accepted as the strongest predictor of poor prognosis and rapid tumor progression in neuroblastoma.
•Other poor prognostic features of neuroblastomas include deletions of 1p (30%) and 11q (45%) and an unbalanced gain of 179 (60%).
Amplification of ALK is observed in 1 to 2% of cases of neuroblastomas and ALK is often co-amplified with MYCN.
What are the small round blue cell tumors of childhood?
Neuroblastoma
Ewing’s sarcoma
Lymphoma
Rhabdomyosarcoma
Hepatoblastoma
Wilms tumor
Retinoblastoma
Sherif
What are unique clinical presentations of neuroblastoma?
The range of symptoms and signs of neuroblastoma was presented in the index case. There are also some unique presentations, with which clinicians should be familiar.
Horner’s syndrome may be the presenting sign of cervical or upper thoracic neuroblastoma.
The opsoclonus myoclonus syndrome may be the first presentation of a thoracic (more likely) or an abdominal lesion.
The primary lesion is often small and localized, and these patients are frequently first referred to a neurologist.
Any child with new onset ataxia and non-rhythmic nystagmus should undergo a chest x-ray and abdominal ultrasound to screen for neuroblastoma.
These tumors typically have an excellent oncologic outcome, but the syndrome usually continues after tumor resection and requires treatment with steroids, immunoglobulins, and potentially chemotherapy.
Acute lower extremity paraplegia or paralysis may be a sign of thoracic neuroblastoma involving the spinal cord, often referred to as a dumbbell tumor.
This is an acute neurosurgical emergency that may require emergent laminotomy. However, chemotherapy and radiation have also been effective in acutely relieving cord compression.
INSS stage 4S had been defined as a local stage 1 or 2 neuroblastoma with metastasis to the liver, skin, or bone marrow (<10% involvement), negative MIBG scan in cortical bone and bone marrow, and limited to patients less than 1 year old. This has currently been replaced by INRGSS stage MS, which has extended the age to 18 months and included tumors that infiltrate the midline.
These tumors may present with life-threatening symptoms despite a high likelihood of spontaneous regression without therapy.
Respiratory distress in infants from massive hepatomegaly is a classic presentation of this disease. A decompressive laparotomy and silo placement to treat abdominal compartment syndrome may be urgently indicated.
Single or multiple skin metastases, referred to as the blueberry muffin syndrome, can also be seen in stage MS.
Severe diarrhea with hypokalemia may be the presenting condition of a vasoactive intestinal peptidesecreting neuroblastoma.
Finally, although neonatal screening for neuroblastoma is no longer performed, the proliferation of fetal and neonatal ultrasound has led to the frequent identification of small asymptomatic adrenal masses in neonates. The differential diagnoses of these masses include neuroblastoma, adrenal hemorrhage, and subdiaphragmatic pulmonary sequestrations.
This group of patients has an excellent prognosis and a very high likelihood of spontaneous involution. Observation is therefore recommended for most of these antenatally diagnosed lesions.
Likewise, the approach to localized neuroblastoma (L1) in any body region in children less than 12 months old has become significantly less aggressive.
Under COG protocol ANBL1232, this group is now eligible for observation alone, without biopsy, if the tumor measures less than 5 cm in greatest dimension.
Sherif
What is the latest staging for neuroblastoma?
Staging of neuroblastoma has changed significantly in recent years. The INSS, which relied on imaging for patients who did not receive an upfront resection and on tumor margins and lymph node status for patients who did, is no longer used by COG.
The INRGSS is now used and places patients into four groups based solely on imaging at diagnosis, as follows:
L1 Localized tumor, not involving vital structures as defined by the list of IDRFs; confined to one body compartment
L2 Locoregional tumor with presence of one or more IDRFs
M Distant metastatic disease
MS Metastatic disease in children younger than 18 months with metastases confined to skin, liver, and/or bone marrow (bone marrow involvement should be limited to <10% of total nucleated cells on smears or biopsy)
A number of IDRFs have been specified depending on location of the tumor, as follows:
Neck:
- Tumor encasing carotid and/or vertebral artery and/or internal jugular vein
- Tumor extending to base of skull
- Tumor encasing or compressing the trachea
Cervicothoracic junction:
- Tumor encasing brachial plexus roots
- Tumor encasing subclavian vessels and/or vertebral and/or carotid artery
- Tumor encasing or compressing the trachea
Thorax:
- Tumor encasing the aorta and/or major branches
- Tumor encasing or compressing the trachea and/or principal bronchi
Thoracoabdominal:
- Tumor encasing the aorta and/or vena cava
Abdomen/pelvis:
- Tumor infiltrating the porta hepatis and/or the hepatoduodenal ligament
- Tumor encasing the branches of the superior mesenteric artery at the root
- Tumor encasing the origin of the celiac axis and/or of the superior mesenteric artery
- Tumor infiltrating or encasing one or both renal pedicles
- Tumor encasing the aorta and/or vena cava
- Tumor encasing the iliac vessels
- Pelvic tumor crossing the sciatic notch
This INRGSS stages represent the four main branches of the neuroblastoma risk-stratification system.
As mentioned in the index case, histology, MYCN amplification status, DNA ploidy, and the presence or absence of chromosomal aberrations are then used to designate risk status within each branch, resulting in a neuroblastoma survival tree.
Patients are currently classified as very low, low, intermediate, or high risk.
Sherif
What is the treatment for neuroblastoma?
The treatment of neuroblastoma is multidisciplinary and has been referred to as precision medicine because of all the details that must be provided to optimize and customize treatment for the individual patient.
For each patient, the surgeon has one or more roles that include resection of localized lesions, biopsy of unresectable lesions, resections of advanced lesions following neoadjuvant chemotherapy, appropriate lymph node sampling for staging, and provision of vascular access.
Tissue obtained by the surgeon, whether from biopsy or resection, allows for pathologic, cytogenetic, and molecular analyses. It also provides the information required for risk stratification and further treatment, if any.
The pathologist also has a central role in neuroblastoma risk stratification. The International Neuroblastoma Pathology Classification (INPC) classifies tumors into favorable and unfavorable subtypes based on their histologic type, differentiation, MKI, and patient age.
The histologic types include neuroblastoma, ganglioneuroblastoma, and ganglioneuroma.
Neuroblastoma is a Schwannian stroma-poor tumor (<50% Schwannian stroma) in which primitive cells are present, usually within a neuropil background.
Undifferentiated neuroblastoma lacks neuropil and thus requires immunohistochemistry to differentiate it from other small round blue cell tumors of childhood.
The percentage of differentiating neuroblasts (cells maturing from primitive to ganglion cell-like appearance) separates poorly differentiated (<5% differentiating neuroblasts) from differentiating neuroblastoma (>5% differentiating neuroblasts).
Ganglioneuroblastoma, intermixed, shows >50% Schwannian stroma and nests of neuroblasts in a neuropil background. The nodular subtype of ganglioneuroblastoma contains multiple clones and requires special sampling.
Finally, ganglioneuroma (Schwannian stroma-dominant) contains maturing or mature ganglion cells evenly distributed in Schwannian stroma.
Although ganglioneuroma and ganglioneuroblastoma, intermixed, are considered favorable histology and undifferentiated neuroblastoma is considered unfavorable histology, the INPC classification of poorly differentiated neuroblastoma, differentiating neuroblastoma, and ganglioneuroblastoma, nodular subtype, are modified by the patient age and MKI.
The MKI is determined by calculating the number of mitoses and karyorrhectic cells per 5,000 neuroblastic cells.
In addition to the INPC and INSS, biologic criteria including ploidy and MYCN amplification status are necessary to complete patient risk stratification into low-, intermediate-, and high-risk categories.
Initial biopsy or resection specimens must be sent fresh to the pathologist to ensure that appropriate sampling is performed for biologic testing.
The pathologist also has a role in staging by performing evaluation of sampled lymph nodes and bone marrow biopsies.
Each neuroblastoma site represents different surgical challenges.
Cervical tumors arise from the cervical sympathetic chain and often abut or surround the carotid sheath, brachial plexus, or phrenic nerve. These tumors typically have a favorable biologic behavior, and sacrifice of major vessels and nerves should be avoided. Cervicothoracic tumors may extend from the base of the neck to the thoracic inlet. Adequate resection may necessitate a trap-door incision or combining a neck incision with a thoracoscopic dissection.
An example of a large right cervical tumor in an 18-month-old boy is shown in Figures 52.8 and 52.9. The tumor bulk was in the right neck but the distal margin extended to the thoracic inlet. A trap-door incision was planned, but was not required, and the tumor was resected completely through the cervical incision. Although 17 of 23 nodes separate from the tumor were positive (INSS stage 2B), MYCN was not amplified. The patient was treated with surgery alone as he was still deemed low risk. Under the current staging system, this patient would be classified as L1—very low risk. However, he would not be eligible for observation due to his age and size of the tumor.
Thoracic tumors often arise from one or more intervertebral foramina and extend laterally, as in the index case. Dissection into the intervertebral foramen to achieve a negative margin is difficult, if not impossible. Bleeding in this area can be difficult to control and may compress the dura. Often this component of the tumor can be “plucked” from the foramen, but the surgeon should not pursue this aggressively, as it is not likely to change the risk grouping or treatment of the patient. A thoracoscopic approach is effective for many of these tumors. However, the tumor should not be fragmented inside the thorax. A large tumor that will require at least a minithoracotomy for removal from the thoracic cavity should be resected by an open approach.
Apical thoracic tumors often abut the subclavian vessels and have to be carefully dissected from these structures. Mobilizing the tumor inferiorly and laterally first to allow gentle retraction away from the vessels helps develop the appropriate plane.
Excision of a primary abdominal tumor can range from a straightforward adrenalectomy for a small primary to a painstaking retroperitoneal extirpation that may last for 24 hours. The surgical goal should be to perform the most complete resection possible, without sacrificing organ or neurologic functioning. Although the extent of surgical resection in high-risk, locally advanced neuroblastoma remains somewhat controversial, the COG currently recommends attempted gross total resection of the primary tumor and locoregional disease in these patients. Many patients with extensive retroperitoneal disease respond dramatically to chemotherapy and can undergo a complete resection, which is typically carried out after the fourth cycle of chemotherapy. The tumor response may be most profound after the first two cycles and subsequently plateau.
Neuroblastoma frequently undergoes tumor necrosis that can make diagnosis of small biopsy specimens quite challenging. It is important to ask for intraoperative consultation at the time of biopsy, not only for tissue sampling for molecular studies, but for assessment of tissue adequacy.
Pathologic estimates of MKI may also be compromised by the presence of significant necrosis in small specimens.
It is not appropriate to histologically reclassify post-treatment specimens; the original INPC is the only one that remains valid for treatment and prognostication.
Despite multiple published series of laparoscopic resections of abdominal neuroblastoma, the role of minimally invasive surgery is not well established. One reason for this may be the requirement for extensive lymph node sampling necessary for INSS staging. With the increasing adoption of the INRG IDRF-based staging, laparoscopic resection may become increasingly used in patients without IDRFs. The laparoscopic approach appears most indicated for small localized tumors, as well as patients who present with large metastatic tumors, and have subsequentlyshown excellent response and have no evidence of disease beyond the primary lesion after treatment with chemotherapy.
External beam radiotherapy is associated with significant toxicity in children, and its use in neuroblastoma is limited to specific situations. Symptomatic patients with risk of organ impairment due to bulky tumor unresponsive to chemotherapy may show response to radiation therapy. Emergency radiotherapy may be administered for neurological symptoms due to spinal cord compression. Some patients with minimal residual disease following surgery and chemotherapy may also be candidates for radiotherapy.
Several novel therapies are available for selected high-risk neuroblastoma patients. These include retinoids, immunotherapy using antiganglioside antibodies,131 I-MIBG, and molecular therapy targeted at inhibition of the anaplastic lymphoma kinase (ALK ) oncogene, among others.
Sherif
