Neuroblastoma

Neuroblastoma is a congenital tumor that develops from embryonic neuroblasts of the sympathetic nervous system.

The term "neuroblastoma" was introduced by James Wright in 1910. Currently, neuroblastoma is understood as an embryonic tumor arising from the precursor cells of the sympathetic nervous system. One of the important differential diagnostic characteristics of the tumor is increased production of catecholamines and excretion of their metabolites in the urine.

Epidemiology of neuroblastoma

Neuroblastoma accounts for 7-11% of all malignant tumors in children, it ranks fourth in frequency among solid neoplasms of childhood. The incidence is 0.85-1.1 per 100,000 children under 15 years of age. Depending on age, this indicator varies significantly: in the first year of life, it is 6:100,000 children (the most common tumor in children under one year), at the age of 1-5 years - 1.7:100,000, at the age of 5-10 years - 0.2:100,000, among children over 10 years old, the incidence decreases to 0.1:100,000.

The incidence of neuroblastoma is 6-8 people per 1 million children per year, or 10 cases per 1 million live births. In autopsies of children who died from other causes before the age of 3 months, neuroblastomas are detected in 1 case per 259 autopsies.

The typical age of disease manifestation is about 2 years, although neuroblastoma can be diagnosed starting from the neonatal period. In 2/3 of cases, neuroblastoma is diagnosed before the age of 5.

Like other congenital tumors, neuroblastoma is characterized by a combination with developmental defects. With this tumor, chromosomal abnormalities are possible - aneuploidy of tumor DNA and amplification of the N-myc oncogene in tumor cells. Aneuploidy of tumor DNA is associated with a relatively favorable prognosis, especially in the younger age group, while amplification of N-myc indicates a poor prognosis in all age groups.

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How does neuroblastoma manifest itself?

Neuroblastoma is a tumor that synthesizes hormones, capable of secreting catecholamines - adrenaline, noradrenaline and dopamine, as well as their metabolites - vanillin-mandelic (VMA) and homovanillic (HVA) acids. In 95% of cases, the hormonal activity of neuroblastoma is greater, the higher the degree of its malignancy. The effects of excreted hormones cause specific clinical symptoms of neuroblastoma - crises of increased arterial

Neuroblastoma develops in the localization sites of the ganglia of the sympathetic nervous system, located on both sides of the spine along the axis of the body and from the adrenal medulla, while the localization of neuroblastoma in the adrenal glands reflects the commonality of embryogenesis of the cells of the ganglia of the sympathetic nervous system and the chromaffinocytes of the adrenal medulla.

Frequency of neuroblastoma localizations

• Adrenal gland – 30%
• Paravertebral space - 30%
• Posterior mediastinum – 15%
• Pelvic area – 6%
• Neck area – 2%
• Other localizations – 17%.

Most often, neurogenic tumors originate from the adrenal gland, paravertebral retroperitoneal space, and posterior mediastinum. When localized in the neck area, the first sign of a tumor may be Bernard-Horner syndrome and opsoclonus-multiclonus. or "dancing eyes" syndrome. The latter is hyperkinesis of the eyeballs in the form of concomitant rapid, irregular, uneven in amplitude movements, usually occurring in the horizontal plane, most pronounced at the beginning of gaze fixation. It is believed that olsoclonus-myoclonus is based on an immunological mechanism. Patients with opsoclonus-myoclonus are usually diagnosed with low-grade tumors and a relatively favorable prognosis. Opsoclonus-myoclonus is often combined with neurological disorders, including psychomotor retardation.

Neuroblastoma is characterized by hematogenous (to the lungs, bone marrow, bones, liver, other organs and tissues) and lymphogenous metastasis pathways. When localized in the posterior mediastinum and retroperitoneal space, in some cases the tumor grows through the intervertebral openings into the spinal canal, which leads to compression of the spinal cord with the development of limb paresis and dysfunction of the pelvic organs. Sometimes paralysis is the first sign of the disease. In some cases, thoracoabdominal tumors develop - with paravertebral growth of neuroblastoma from the retroperitoneal space into the mediastinum or vice versa.

The clinical picture of neuroblastoma depends on its localization and prevalence, the degree of its malignancy and tumor intoxication. The difficulty of timely diagnosis of neuroblastoma is due to the presence of a large number of masks in this disease.

Clinical masks of neuroblastoma

• "Rickets" - enlargement of the abdomen, deformation of the chest, intoxication, loss of appetite, weight loss, lethargy.
• Intestinal infection - gastroenterocolitis, pancreatitis, diarrhea and vomiting, intoxication, hyperthermia, weight loss
• Vegetative-vascular dystonia of the sympathetic type - Hyperthermia, crises of increased blood pressure, tachycardia, dry skin, emotional lability
• Bronchial asthma, bronchitis, acute respiratory viral infections, pneumonia - Attacks of shortness of breath, wheezing in the lungs
• Meningitis, cerebral palsy - paralysis of the limbs, dysfunction of the pelvic organs

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Clinical staging

The most commonly used staging system for neuroblastoma at present is the INSS system.

• Stage 1 - localized, macroscopically completely removed, with or without detection of tumor cells along the resection line. The identified ipsilateral lymph nodes are not microscopically affected. Lymph nodes immediately adjacent to the tumor, removed together with the primary tumor, may be affected by malignant cells.
• Stage 2A - localized, macroscopically not completely removed. Ipsilateral lymph nodes not directly adjacent to the tumor are microscopically not affected by malignant cells.
• Stage 2B - localized with or without macroscopic complete resection. Ipsilateral lymph nodes not directly adjacent to the tumor are microscopically involved with malignant cells. Enlarged contralateral lymph nodes are microscopically free of tumor.
• Stage 3:
  • non-removable primary, crossing the midline
  • localized primary tumor that does not extend across the midline,
  • if the tumor affects the contralateral lymph nodes;
  • a tumor located in the midline and growing bilaterally
  • in tissue (non-removable), or with tumor damage to the lymph nodes.
• Stage 4 - any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin and/or other organs, except for cases that fall within the definition of stage 4S.
• Stage 4S - localized primary neuroblastoma (as defined for stages 1, 2A, 2B) with dissemination limited to the skin, liver, and/or bone marrow. This stage is assigned only to children under 1 year of age, and the proportion of malignant cells in the bone marrow aspirate should not exceed 10% of all cellular elements. More massive lesions are assessed as stage 4. MIBG scintigraphy results should be negative in patients with detected bone marrow metastases.

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Classification

Histological structure and histological classification

Histological marker of a tumor - detection of typical "rosettes" formed by malignant cells.

There are five degrees of malignancy of tumors originating from nervous tissue: four malignant and one benign.

Malignant forms of neurogenic tumors (in order of decreasing cellular atypism):

• undifferentiated neuroblastoma:
• poorly differentiated neuroblastoma;
• differentiated neuroblastoma;
• ganglioneuroblastoma.

The benign variant is ganglioneuroma.

In domestic practice, the traditional four-stage gradation of neurogenic tumors by their malignancy still retains its significance. In this case, malignant forms are represented (in descending order of malignancy) by the following types of neuroblastoma:

• sympathogonioma:
• sympathoblastoma;
• ganglioneuroblastoma.

The benign variant is ganglioneuroma.

A unique feature of neuroblastoma is its ability to "mature" in rare cases spontaneously, and more often under the influence of chemotherapy, turning from a more malignant to a less malignant and even benign ganglioneuroma. Sometimes, during histological examination of the surgical material, only 15-20% of malignant cells are found in the ganglioneuroblastoma tissue, the rest is represented by ganglioneuroma. However, even such a "mature" ganglioneuroblastoma remains a malignant tumor, capable of distant metastasis, and requires antitumor treatment.

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How is neuroblastoma recognized?

Neuroblastoma diagnostics is based on morphological verification of the diagnosis. Its preceding conservative examination consists of the following stages.

• Diagnostics of the primary tumor site (ultrasound, radiography, CT and MRI of the affected area, excretory urography).
• Evaluation of its biological activity: determination of the excretion of catecholamines in urine, while it should be borne in mind that, although the content of homovanillic and vanillylmandelic acids has significant diagnostic value, in domestic practice it is more accessible to measure the content of adrenaline, norepinephrine and dopamine, and the content of neuron-specific enolase (NSE) in the blood serum.
• Diagnostics of possible metastases: CT of the chest organs, myelogram examination, radioisotope examination of the skeleton, scintigraphy with methyliodobenzylguanidine (MIBG), ultrasound of the abdominal cavity, retroperitoneal space, and other areas of possible metastasis localization.

Mandatory and additional studies in patients with suspected neurogenic tumor

Mandatory diagnostic tests

• Complete physical examination with assessment of local status
• Clinical urine analysis
• Biotic blood test (electrolytes, total protein, liver function tests, creatinine, urea, lactate dehydrogenase, alkaline phosphate, phosphorus-calcium metabolism) Coagulogramia
• Ultrasound of the affected area
• Ultrasound of the abdominal organs and the peritoneal space
• PICT (MPT) of the affected area
• X-ray of the chest organs in five projections (straight, two lateral, two oblique)
• Urine analysis for excretion of homovanillic, vamilimine acids, adrenaline, noradrenaline, dopamine
• Determination of neuron-specific enolase content
• Bone marrow puncture from two points
• Radioisotope study of the skeleton
• MIBG scintigraphy
• ECG
• EchoCG
• Audiogram
• The final stage is a biopsy (or complete removal) to verify the histological diagnosis. It is advisable to make biopsy prints for cytological examination.

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Additional research

• If metastases to the lungs are suspected - CT of the chest organs
• If brain metastases are suspected - EchoEG and CT of the brain Targeted bone radiography if bone metastases are suspected
• Ultrasound color duplex scanning of the affected area
• Angiography
• Consultation with a neurosurgeon and neuropathologist in case of tumor growth into the spinal canal and/or neurological disorders

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Differential diagnostics

In the differential diagnosis of retroperitoneal neuroblastoma, attention should be paid to such signs that distinguish it from nephroblastoma, revealed during excretory urography, as the preservation of the contrasted renal pelvis system, displacement of the kidney by a volumetric formation, displacement of the ureter by a tumor formation, the absence of a connection between the kidney and it, and in some cases, a visible border between the kidney and the tumor formation.

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How is neuroblastoma treated?

Modern complex treatment of neuroblastoma includes chemotherapy, radiation therapy to the area of the primary tumor and metastases, and surgical removal of the primary neuroblastoma and metastases if they are resectable.

When the clinical picture of neuroblastoma with neurological disorders (lower flaccid paraparesis, dysfunction of the pelvic organs) manifests itself, prompt decompression of the spinal cord is necessary, since irreversible changes in the spinal cord occur several weeks after the onset of neurological symptoms, and restoration of lost nerve functions is impossible. There are two different strategies for spinal cord decompression. One of them involves prompt laminectomy with removal of the tumor component from the vertebral canal, while the diagnosis of neuroblastoma is confirmed based on histological examination of the surgical material. The disadvantage of the surgical decompression method is the risk of spinal cord injury, spinal instability, and development of kyphoscoliosis. An alternative strategy consists of biopsy/removal of the main tumor component and, if the diagnosis of neuroblastoma is morphologically confirmed, a course of chemotherapy to achieve regression of the intravertebral component of the tumor and restoration of functions of the lower extremities and pelvic organs. However, decompression with chemotherapy may be ineffective in the case of individual tumor resistance to cytostatics.

If the neuroblastoma is localized in the posterior superior mediastinum, anterior or posterolateral thoracotomy is performed; if it is localized in the retroperitoneal space, a median laparoscopy with possible additional incisions is performed. If the tumor is localized in the adrenal gland, in some cases a more convenient approach is transverse laparotomy. Neuroblastoma of the presacral region is removed through the perineal or abdominoperineal approach.

When removing neuroblastoma, it is necessary to pay attention to the "legs" of the tumor - the strands extending from it in the direction of the intervertebral foramina. The "legs" must be isolated and removed as distally from the tumor as possible. Pulmonary metastases of neuroblastoma, if resectable, are removed through a thoracotomy or sternotomy approach.

In cases of non-removable tumors, the correct tactics that ensure a favorable outcome will be radical chemoradiation therapy and surgery in the amount of subtotal resection or extended biopsy.

In neuroblastoma, polychemotherapy is carried out using such chemotherapy drugs as vincristine, cyclophosphamide, ifosfamide, cisplatin, carboplatin, etopozand, doxorubicin, dacarbazine. In case of relapses of neuroblastoma, tumor metastasis to bones and bone marrow, the presence of NMYC gene amplification, patients are prescribed high-dose chemotherapy with bone marrow transplantation.

Forecast

The prognosis for neuroblastoma depends on several factors. The prognosis is better for more mature morphological variants, in children under 2 years of age, in the absence of NMYC gene amplification. Depending on the stage, the best outcomes are observed in localized forms of neuroblastoma: at stage I, 90% of patients survive, at stage II - 70%. at stage III - 50%. At stage IV, only a few patients survive. At stages III and IV of the disease, the best prognosis is in children under 1 year of age. At stage 4S, survival exceeds 90%.

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