Neuroblastoma

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

ICD-10 code

C47. Malignant neoplasm of peripheral nerves and autonomic nervous system.

The term "neuroblastoma" was introduced by James Wright in 1910. At present, neuroblastoma is understood to be an embryonic-type tumor originating from the progenitor 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 with urine.

Epidemiology of neuroblastoma

Neuroblastoma accounts for 7-11% of all malignant tumors in children, it ranks fourth in the frequency of occurrence among solid neoplasms of childhood. The incidence is 0.85-1.1 per 100 000 children under the age of 15 years. Depending on age, this indicator varies considerably: in the first year of life it is 6: 100 000 children (the most common tumor in children under one year old), at the age of 1-5 years - 1.7: 100 000. At the age of 5-10 years - 0.2 : 100 000, among children older than 10 years the incidence is reduced 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. At autopsy of children who died from other causes before the age of 3 months, neuroblastomas are detected in 1 case for 259 autopsies.

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

As for other congenital tumors, neuroblastoma is characterized by a combination with malformations. 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 the amplification of N-myc indicates a poor prognosis in all age groups.

[1], [2], [3], [4], [5],

How is neuroblastoma manifested?

Neuroblastoma is a tumor that synthesizes hormones capable of secreting catecholamines - epinephrine, norepinephrine and dopamine, as well as their metabolites - vanillinmindal (VMA) and homovaniline (HVA) acids. In 95% of cases, the hormonal activity of neuroblastoma is greater, the higher the degree of its malignancy. Effects of excreted hormones cause specific clinical symptoms of neuroblastoma - crises in the increase of arterial

Neuroblastoma develops in the localization 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 the neuroblastoma in the adrenal glands reflects the common embryogenesis of the ganglion cells of the sympathetic nervous system and chromaffinocytes of the adrenal medulla.

Frequency of localizations of neuroblastoma

• Adrenal - 30%
• Paravertebral islet 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, the first sign of a tumor may be the Bernard-Horner syndrome and the opcoclonus-manycone. Or the syndrome of "dancing eyes". The latter is a hyperkinesis of eyeballs in the form of friendly fast, irregular, non-uniform movements in amplitude, usually in the horizontal plane, most pronounced at the beginning of fixation of the glance. It is believed that the basis of olskolonus-myoclonus is the immunological mechanism. Patients with myoclonus opsonkilusom, as a rule, are detected tumors of low degree of malignancy and a relatively favorable prognosis. Myclo-nosone is often combined with neurological disorders, including delayed psychomotor development.

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

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

Clinical Neuroblastoma Masks

• "Rickets" - Increased abdomen, deformation of the chest, intoxication, decreased appetite, weight loss, sweating.
• Intestinal infection - gastroenterocolitis, pancreatitis, diarrhea and vomiting, intoxication, hyperthermia, weight loss
• Vegetative-vascular dystonia in sympathetic type - Hyperthermia, blood pressure increase crises, tachycardia, dry skin, emotional lability
• Bronchial asthma, bronchitis, SARS, pneumonia - Dyspnoea attacks, wheezing in the lungs
• Meningitis, cerebral palsy - paralysis of limbs, dysfunction of pelvic organs

[6], [7]

Clinical staging

The most commonly used now is the staging of neuroblastoma according to the INSS system.

• Stage 1 - localized, macroscopically removed completely, without or with detection of tumor cells along the line of resection. Identified ipsilateral lymph nodes are not microscopically affected. Immediately adjacent to the tumor lymph nodes, removed along with the primary tumor, can be affected by malignant cells.
• Stage 2A - localized, macroscopically removed not completely. Ipsilateral lymph nodes that do not adhere directly to the tumor are not microscopically affected by malignant cells.
• Stage 2B - localized with or without macroscopically complete removal. Ipsilateral lymph nodes that do not adhere directly to the tumor are microscopically affected by malignant cells. The enlarged contralateral lymph nodes are not microscopically affected by the tumor.
• Step 3:
  • the primary unchanged, passing through the middle line
  • a localized primary tumor that does not pass through the midline,
  • when the tumor affects the contralateral lymph nodes;
  • A tumor located along the middle line and bilaterally sprouting
  • in the tissue (unremovable), or with lesion of the lymph nodes tumor.
• Stage 4 - any primary tumor with dissemination to distant lymph nodes, bones, bone marrow, liver, skin and / or other organs, except for cases falling under the definition of stage 4S.
• Stage 4S is a localized primary neuroblastoma (as defined for stages 1, 2A, 2B) with dissemination limited to the skin, liver and / or bone marrow. This stage is established only for children under 1 year, with the proportion of malignant cells in bone marrow aspirate not exceeding 10% of all cellular elements. A more massive lesion is assessed as stage 4. The results of MIBG scintigraphy should be negative in patients with metastases detected in the bone marrow.

[8], [9], [10], [11], [12], [13], [14]

Classification

Histological structure and histological classification

The histological marker of the tumor is the detection of typical "rosettes" formed by malignant cells.

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

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

• undifferentiated neuroblastoma:
• low-grade neuroblastoma;
• differentiated neuroblastoma;
• ganglionairblasgoma.

A benign variant is ganglioneuroma.

In domestic practice, the traditional four-degree gradation of neurogenic tumors for their malignancy still retains its significance. In this case, malignant forms are represented (as the malignancy decreases) by the following varieties of neuroblastoma:

• sympathomy:
• sympatoblastoma;
• ganglioneuroblastoma.

A benign variant is ganglioneuroma.

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

[15], [16], [17], [18], [19], [20], [21]

How is neuroblastoma recognized?

The diagnosis of neuroblastoma is based on the morphological verification of the diagnosis. The previous conservative examination is based on the following stages.

• Diagnosis of the primary tumor focus (ultrasound, radiography, RCC and MRI of the lesion, excretory urograph).
• Evaluation of its biological activity: the determination of catecholamine excretion in the urine, it should be borne in mind that, although the content of homovaniline and vanillinmundic acids has a significant diagnostic value, in the domestic practice the measurement of adrenaline, noradrenaline and dopamine content, serum content of neuron-specific enolase (NSE).
• Diagnosis of possible metastases: chest CTG, myelogram, radioisotope study of the skeleton, scintigraphy with methyl iodobenzylguanide (MIBG), ultrasound of the abdominal cavity, retroperitoneal space, other areas of possible metastatic localization.

Mandatory and additional studies in patients with suspected tumor of a neurogenic nature

Compulsory diagnostic tests

• Complete physical examination with assessment of local status
• Clinical analysis of urine
• Biotic blood test (electrolytes, total protein, liver tests, creatinine, urea, lalate dehydrogenate, alkaline phosphate, phosphate-calcium metabolism) Coagulogramia
• Ultrasound of the affected area
• Ultrasound of the abdominal cavity
• PICT (MPT) areas of injury
• Radiography of the chest cavity in five projections (straight, two side, two oblique)
• Urine analysis for the excretion of homovaniline, vailymiindalic acids, epinephrine, norepinephrine, dopamine
• Determination of the content of neuron-specific enolase
• Bone puncture from two points
• Radioisotopic examination of the skeleton
• MIBG scintigraphy
• ECG
• Echocardiography
• Audiograms
• The final step is a biopsy (or complete removal) to verify the histological diagnosis. It is advisable to make biopsy prints for cytological examination

[22], [23], [24], [25], [26], [27], [28]

Additional research

• If there is a suspicion of lung metastasis, the RVT of the thoracic cavity
• If there is a suspicion of brain metastases - EchoEG and PKT of the brain Sighting radiography of bones with a suspicion of bone metastases
• Ultrasound color duplex scanning of the affected area
• Angiography
• Consultation of a neurosurgeon and neurologist with tumor germination into the spinal canal and / or heurological disorders

[29], [30], [31], [32], [33],

Differential diagnostics

In the differential diagnosis of neuroblastoma of the retroperitoneal space, attention should be paid to the signs that are distinguishable from nephroblastoma in excretory urography, such as the preservation of the contrasted cup-and-pelvic system, the displacement of the kidney by volume formation, the exclusion of the ureter by tumor formation, the lack of a connection with the kidney and, in some cases, visible border between the kidney and tumor formation.

[34], [35], [36], [37], [38], [39], [40], [41],

How is neuroblastoma treated?

Modern complex treatment of neuroblastoma includes chemotherapy, radiotherapy on the primary tumor and metastases and the surgical removal of primary neuroblastoma and metastases if they are resectable.

At the manifestation of the clinical picture of neuroblastoma with neurological disorders (lower flaccid paraparesis, impairment of the functions of the pelvic organs), an early decompression of the spinal cord is necessary, since several weeks after the manifestation of neurologic symptoms irreversible changes occur in the spinal cord and restoration of the lost nervous functions is impossible. There are two different strategies for decompression of the spinal cord. One of them provides for the speedy implementation of laminectomy with the removal of the tumor component from the vertebral canal, while on the basis of the histological examination of the operating material confirm the diagnosis of neuroblastoma. The disadvantage of the surgical method of decompression is the risk of spinal cord trauma, spinal instability, and the development of kyphoscoliosis. An alternative strategy is to biopsy / remove the main component of the tumor and carry out, in the presence of morphological confirmation of the diagnosis of neuroblastoma. Course of chemotherapy to achieve regression of the intravertebral component of the tumor and restoration of the functions of the lower extremities and pelvic organs. However, however, decompression with the help of chemotherapy may prove ineffective in the case of individual tumor resistance to cytostatics.

When the neuroblastoma is localized, anterior or posterolateral thoracotomy is performed in the region of the posterior superior mediastinum, in the case of localization in the retroperitoneal space, a medial lalarotomy with possible additional incisions. When the tumor is localized in the adrenal gland, in some cases, transverse laparotomy is more convenient. The neuroblastic pre-sacral region is removed from the perineal or peritoneal-perineal approach.

When removing neuroblastoma, you need to pay attention to the "legs" of the tumor - the strands that go from it towards the intervertebral openings. The "legs" must be isolated and removed as far as possible from the tumor. The pulmonary metastases of neuroblastoma, when resectable, are removed from thoracotomy or sternotomy access.

In cases of unsuccessful tumors, the correct tactics that provide a favorable outcome will be the carrying out of radical chemoradiotherapy and performing an operation in the volume of subtotal resection or an extended biopsy.

In neuroblastoma, polychemotherapy is performed using chemotherapy drugs such as vincristine, cyclophosphamide, ifosfamide, cisplatin, carboplatin, etopind, doxorubicin, dacarbazine. With recurrence of neuroblastoma, tumor metastasis in the bone and bone marrow, the presence of amplification of the NMYC gene, 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 younger than 2 years, in the absence of amplification of the NMYC gene. Depending on the stage, the best outcomes are observed with localized forms of neuroblastoma: at stage I 90% of patients survive, while II - 70%. At III - 50%. At stage IV single patients survive. At the III and IV stages of the disease the best prognosis in children under 1 year. At stage 4S, the survival rate exceeds 90%.

[42], [43]