Epidemiology and risk factors
Neuroblastoma is the third most common solid tumor in children developing outside the central nervous system. In girls, this neoplasm is less common than in boys, yet it carries a more favorable prognosis.
The etiology is based on hereditary predisposition: germline mutations are hypothesized, rendering cells susceptible to secondary somatic mutations.
Risk factors and associations:
- Increased incidence in twins and siblings.
- Association with genetic disorders: Beckwith–Wiedemann syndrome and neurofibromatosis.
Macroscopic picture
The tumor forms a node of varying size, which on cross-section presents as soft, grayish tissue resembling brain tissue in appearance. Large nodes frequently develop secondary changes that make the structure heterogeneous: areas of necrosis, hemorrhage, and calcification.
Relationship to surrounding tissues:
- The tumor may be sharply demarcated and enclosed by a thin capsule.
- Marked infiltrative growth with rapid invasion into adjacent structures is possible: kidneys, renal and inferior vena cava, aorta.
Microscopic Structure and Differentiation
The histological picture of neuroblastoma directly depends on its degree of maturity. The tumor is prone to heterogeneity — areas of varying differentiation degrees may coexist within a single node.
- Poorly differentiated neuroblastoma (accounting for the majority of cases). It is represented by small lymphocyte-like cells with dark (hyperchromatic) nuclei and scanty cytoplasm. The cells form solid, continuous sheets.
- More differentiated tumors. The cells acquire eosinophilic neurofibrillar processes and are located within an increasing volume of fibrillar stroma. The appearance of pseudorosettes is characteristic — structures where cells form a wreath around central eosinophilic accumulations of neurofibrils.
- Ganglioneuroma. This is a fully differentiated tumor. It consists of large, mature ganglion cells (with broad eosinophilic cytoplasm, large vesicular nuclei, and distinct nucleoli). The cells are surrounded by bundles of connective tissue, nerve fibers, and Schwann cells (lemminocytes).
On electron microscopy, neuroblastoma cells reveal specific markers: neurosecretory granules and processes with microtubules.
International Staging System
Staging is performed based on the results of pathomorphological examination of surgically removed tissue:
- Stage 1: The tumor is confined to the organ of origin, no metastases, complete resection.
- Stage 2a: Unilateral tumor extending beyond the organ of origin, but does not cross the midline. No metastases, gross total resection.
- Stage 2b: Unilateral tumor of any size, completely or incompletely resected, but regional lymph node metastases are present.
- Stage 3: Unresectable tumor crossing the midline; OR unilateral tumor with contralateral lymph node metastases; OR midline tumor with bilateral lymph node metastases.
- Stage 4: Presence of distant hematogenous metastases and distant lymph node involvement.
- Stage 4S: Tumor size corresponds to stages 1 and 2, but hematogenous metastases are present in the skin, liver, and bone marrow. Diagnosed exclusively in infants under 1 year of age.
Briefly: answers to topical questions
Which biochemical markers (catecholamine metabolites) are determined in the urine for the diagnosis of neuroblastoma?
For the diagnosis of neuroblastoma, the following biochemical markers and catecholamine metabolites are determined in the urine:
- Vanillylmandelic acid (VMA) — a catecholamine metabolite.
- Homovanillic acid (HVA) — a catecholamine metabolite.
- Norepinephrine — a catecholamine.
- Dopamine — a catecholamine.
An elevated concentration of these substances in the urine is observed in approximately 90% of patients with neuroblastoma, serving as an important diagnostic criterion.
Amplification of which oncogene is a major adverse prognostic factor in neuroblastoma?
An important adverse prognostic factor in neuroblastoma is the amplification of the N-myc oncogene.
An increase in N-myc copy number in neuroblastoma correlates with a poor prognosis; sources indicate that N-myc amplification is found in 38% of cases. In disseminated disease, up to 300 copies of N-myc may be detected, which is uncharacteristic for a benign course. Not only the amplification, but also the level of gene expression has prognostic significance.
To which organs and tissues (besides the liver and skin) does stage 4 neuroblastoma most frequently metastasize hematogenously?
In addition to the liver and skin, stage 4 neuroblastoma most frequently metastasizes hematogenously to the bone marrow and bones (skeleton).
- Bone marrow — a typical localization, involvement of which is also characteristic of the specific stage 4S in infants under 1 year of age.
- Bones — a frequent site of metastasis, causing bone and joint pain.
Less frequently, hematogenous metastasis may involve the lungs and brain. Stage 4 is also characterized by the presence of metastases in distant lymph nodes.
To memorize stage 4S, associate the letter "S" with the word "Small" (small patient) — the stage occurs exclusively in infants under 1 year of age. Despite distant metastases (skin, liver, bone marrow), the primary focus remains localized (stages 1-2).
Class and exam questions
What are pseudorosettes and what are they characteristic of?
These are specific microscopic structures in which tumor cells form a ring around a central cluster of eosinophilic neurofibrils. They are characteristic of differentiating neuroblastomas.
Why does a diagnosis of "ganglioneuroma" require the examination of multiple histological sections?
Neuroblastomas often have a heterogeneous structure. To diagnose a benign ganglioneuroma, it is necessary to exclude the presence of poorly differentiated malignant areas within the tumor by examining material from different zones of the node.
What favorable outcomes are possible in neuroblastoma?
Neuroblastoma is characterized by two unique outcomes: spontaneous regression (especially when small in size) and maturation of tumor cells into a benign ganglioneuroma.
What else to study on this topic
- Mechanisms of spontaneous regression of neuroblastomas
- Differential diagnosis of small round cell tumors in children
- Ultrastructure of neurosecretory granules and microtubules
- Pathogenesis of Beckwith–Wiedemann syndrome
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