Causes and risks
The reasons for the appearance of the tumor are not fully understood. Neuroblastoma occurs when normal neuroblasts do not mature into nerve cells. Instead, they continue to grow and divide uncontrollably. It is believed that these immature (embryonic) nerve cells begin to mutate even before the birth of a child, when chromosomes begin to change and/or a failure in the regulation of gene function occurs. As current research confirms, in most children the disease is not hereditary. Only about 1% of neuroblastoma cases are hereditary, most often due to mutations in a gene called ALK (or anaplastic lymphoma kinase gene) or in the PHOX2B gene. To date, there are no clinical studies proving that external factors (environment, harmful working conditions of the child’s parents, taking any medications, smoking and drinking alcohol during pregnancy) can cause the disease.
Stages of the disease
Doctors distinguish four stages of neuroblastoma:
First stage : neuroblastoma is localized in the area of the primary lesion.
Second stage : the tumor leaves the primary lesion, but has not yet reached the other side of the spine.
Third stage : The tumor affects both sides of the spine and lymph nodes.
Fourth stage : neuroblastoma spreads metastases to distant soft tissues, bones, and lymph.
Clinical picture of neuroblastoma
Neuroblastoma can occur in any anatomical region where the sympathetic nervous system is located: adrenal glands, cervical, thoracic and abdominal sympathetic divisions, paraganglia.
The most common location of neuroblastoma is the retroperitoneal space (the tumor is equally often diagnosed in the adrenal glands and paravertebral retroperitoneal ganglia). In 15% of children, neuroblastoma is localized in the posterior mediastinum. Less commonly, tumors occur in the pelvis (6%) and neck (2%) (Fig. 1).
Rice. 1. Localization of neuroblastoma
In the early stages of the disease, many children may not have any symptoms. Their tumor is discovered by chance, for example, during a routine ultrasound examination of infants during medical examination. As a rule, complaints in children appear when the tumor has already grown significantly and puts pressure on neighboring organs, disrupting their function, or when the tumor has metastasized.
Common symptoms of the disease include the following: weight loss, weakness, bone and joint pain, and intractable diarrhea.
Most manifestations of the disease and their severity depend on the location of the tumor and its relationship with neighboring organs and tissues. Thus, patients under 2 years of age with retroperitoneal localization are characterized by an increase in abdominal size, fever and weight loss. Neuroblastoma of the retroperitoneal space is palpated through the anterior abdominal wall in the form of a tuberous, non-displaceable tumor node (Fig. 2). In older children, the disease can manifest as pain caused by metastatic bone lesions, respiratory disorders, an increase in the size of the abdomen, and the appearance of constipation. In patients with large retroperitoneal tumors, a developed network of saphenous veins and expanded edges of the chest can be found.
Rice. 2. Neuroblastoma of the retroperitoneum
Localization of the tumor in the cervicothoracic region of the sympathetic spine causes Horner's syndrome (constriction of the pupil, different pupil sizes, redness and/or drooping of the upper eyelid and slight elevation of the lower). Other changes in the eye area may include hemorrhages in the skin or mucous membrane, “bruising” on the eyelids and under the eyes. In the later stages of the disease, black circles sometimes appear around the eyes (spectacle-shaped hematoma) (Fig. 3).
Rice. 3.1. Symptom of "glasses"
Rice. 3.2. Symptom of “glasses” with metastases in the orbit
Damage to the posterior mediastinum can cause a dry cough, respiratory distress, chest deformation, and frequent regurgitation. When the tumor is localized in the pelvic cavity, dysfunction of the pelvic organs (periodic urinary incontinence, defecation disturbance), and edema of the lower extremities are noted.
When the tumor spreads into the spinal canal and compresses the spinal cord, weakness in the legs, unsteady gait, paralysis of the lower extremities, as well as dysfunction of the pelvic organs (urinary retention or involuntary urination, constipation) may develop.
Rarely, in approximately 2-4% of all cases, children have a cerebellar syndrome associated with neuroblastoma (“opsoclonus-myoclonus” or Kinsburne encephalopathy), characterized by uncoordinated, irregular movements of the trunk and limbs, myoclonus and chaotic movements of the eyeballs.
Neuroblastoma is a hormone-producing tumor capable of secreting physiologically active substances - catecholamines - adrenaline, norepinephrine and dopamine. In urine, as a rule, the excretion of their metabolites – vanillylmandelic and homovanillic acids – is increased. In 95% of cases, the higher the degree of malignancy, the greater the hormonal activity of neuroblastoma. The effects of secreted hormones cause specific clinical symptoms of neuroblastoma - a sharp increase in blood pressure, diarrhea (caused by the secretion of vasoactive intestinal polypeptide), sweating, emotional lability, periodic fever.
Neuroblastoma metastasizes most often to the bone marrow, bones, distant lymph nodes, liver or skin, and rarely to the brain or lungs. Signs of distant metastases can be detected in the form of exophthalmos, hemorrhages in the orbits, and tumor nodes on the head.
Among the features of the course of neuroblastoma are the following:
- Regression is the ability of a tumor to spontaneously or induced by minimal chemotherapy or radiation therapy to decrease (involution). As a rule, this occurs in children under 1 year of age with stage IVS of the disease.
- Reversion is the ability of a tumor to transform from more malignant forms into benign ganglioneuromas (spontaneously or induced).
- In some cases, the tumor process has the opposite direction: a tendency towards an aggressive course and rapid metastasis.
Clinical manifestations
Typical symptoms:
- Palpable tumor
- Temperature increase
- Diarrhea due to the production of vasoactive intestinal peptides
- Bone pain, especially 2 in the hips
- Cerebellar ataxia
- Nystagmus
- Periorbital edema and ecchymosis of the upper eyelid in retrobulbar neuroblastoma
- Hypertension
- Symptoms of arousal
- Tachycardia
- Headache
- Developmental delay
- Bugler syndrome.
Diagnosis of neuroblastoma
Laboratory methods
In a clinical blood test, if the bone marrow is damaged, a decrease in blood parameters may be observed: anemia, leukoneutropenia, thrombocytopenia.
Neuroblastoma-specific markers can also be determined in the blood serum: neuron-specific enolase (NSE), levels of catecholamine metabolites, lactate dehydrogenase (LDH) and ferritin.
An easy-to-perform specialized test for diagnosing neuroblastoma is to determine the level of vanillylmandelic and homovanillic acids in a urine test. They are also called the “urinary catecholamine metabolite test.” This analysis can be carried out by collecting the child’s urine over the course of a day or in a single portion of urine.
Before starting specific therapy, the diagnosis is always verified; The diagnosis of neuroblastoma is made by histological examination of a biopsy of the primary tumor or metastases, or by a combination of the presence of tumor cells in the bone marrow and an increased level of daily excretion of catecholamines.
Molecular genetic research
To determine the degree of malignancy of neuroblastoma, a number of genetic studies are performed: MYCN mutation, deletion of chromosomes 1p or 11q. The presence of these mutations is an unfavorable prognosis factor for the disease.
Instrumental methods
Ultrasonography
The ultrasound method of examination allows us to detect the presence of a tumor and its location in relation to the internal organs. Ultrasound allows you to assess the degree of local and distant spread of the malignant process and reveals metastatic damage to the liver and lymph nodes (Fig. 4).
Rice. 4. Ultrasound of the formation of the right adrenal gland
Computed tomography of the abdominal cavity and retroperitoneum
Computed tomography provides more detailed information about the anatomical relationship of the tumor to surrounding tissues and organs and allows one to assess the structure of the tumor (Fig. 5).
Rice. 5. CT scan of a neurogenic formation in the retroperitoneal space on the right
Magnetic resonance imaging of the abdominal organs, retroperitoneum and spine
MRI of the abdominal cavity and retroperitoneal space is a safe and highly informative research method that allows not only to clarify the location of the tumor, the exact size of the tumor and its relationship with surrounding tissues, but also to identify metastatic foci in the liver and abdominal cavity. MRI also makes it possible to assess the condition of the bone structures and soft tissues of the spinal column and spinal canal (Fig. 6).
Rice. 6. MRI of a neurogenic formation in the retroperitoneal space on the left
Radioisotope research
One of the most informative specific methods for topical diagnosis of neuroblastomas is scintigraphy with metaiodobenzylguanidine (MYBG) labeled with 123I. MyBG is similar in chemical structure to catecholamines in the body. This substance is concentrated in those tumors that produce catecholamines. MYBG is labeled with a radioactive isotope of iodine (for example, 123I) in a dose that is safe for life, and the finished drug is injected intravenously into the bloodstream. Accumulating in tumor cells, it emits radiation. These signals are recorded by a special camera and translated into an image. Thus, the method makes it possible to detect not only the primary tumor, but also the presence of regional and distant metastases (Fig. 7).
Rice. 7. Scintigraphy with metaiodobenzylguanidine (visualizes a primary paravertebral tumor with metastases to the skull bones)
Bone scintigraphy is a method of scanning skeletal bones using intravenous administration of a radiopharmaceutical. The radiotracer accumulates in areas affected by tumor cells in the bones, as seen in gamma camera images. Thus, this research method allows us to identify possible metastases of skeletal bones.
Bone marrow examination (myelogram and trephine biopsy) is used to determine the presence of tumor cells in the bone marrow.
What diseases have symptoms similar to neuroblastoma in a child?
Wilms tumor
- less pronounced vascularization of the tumor;
- slight contrast enhancement;
- originates from the kidney parenchyma;
— calcifications in the tumor are rare;
- the tumor does not grow along the posterior wall of the aorta or inferior vena cava;
-tumor thrombi in the renal veins.
Hemorrhage into the adrenal gland
— typical ultrasound morphology with different echostructure depending on the time after hemorrhage
— reduction in size;
- lack of vascularization.
Retroperitoneal teratoma
— contains adipose tissue and calcifications;
- clearly demarcated tumor without signs of malignant growth;
- less pronounced vascularization;
- negative scintigraphy using metaiodobenzylguanidine.
Treatment of neuroblastoma
Taking into account various scenarios for the development of disease outcome (from spontaneous regression to death from progression), risk-adapted principles are proposed in the treatment of neuroblastoma. Patients are stratified according to risk factors before treatment (usually clinical and molecular genetic data) and based on tumor response during treatment (response-adapted). When identifying risk groups before starting treatment, the following prognostic criteria are used: stage of the disease, age at diagnosis, results of molecular genetic data - MYCN amplification and deletion of the short arm of 1p (Fig. 8).
Rice. 8. Stratification of patients into risk groups according to the presence of unfavorable prognosis factors
Neoadjuvant (preoperative) polychemotherapy
- The need for polychemotherapy is determined by the stage of the disease and the presence or absence of unfavorable clinical and biological factors (n-myc amplification, short arm 1p deletions).
- Polychemotherapy allows you to reduce the size of the primary tumor to make surgery safer and more radical.
- The basic drugs for the treatment of neuroblastoma are vincristine, cyclophosphamide, anthracyclines, ifosfamide, platinum drugs, etoposide.
Features of surgical treatment
- For localized stages of the disease, treatment may be limited to complete removal of the tumor.
- In stages III-IV of the disease, the surgical stage is carried out after preoperative (neoadjuvant) polychemotherapy, which is aimed at reducing the size of the tumor with the aim of subsequent radical removal of the tumor.
- In cases where complete tumor removal is impossible, treatment is supplemented with radiation therapy in the postoperative period.
Adjuvant (postoperative) polychemotherapy
Drug treatment should be started 5-7 days after surgery. In the absence of indications for 2nd line polychemotherapy, treatment regimens use the same basic drugs as for neoadjuvant therapy.
Radiation therapy
- Radiation therapy is used to destroy any tumor cells that cannot be removed by surgery and/or that were not destroyed by previous therapies.
- If the operation is non-radical and involves the presence of an active residual tumor, the residual tumor tissue, the lymph nodes involved in the process, and the areas of communication of the tumor with surrounding organs and tissues are irradiated.
- Irradiation is carried out daily, starting from the 5-7th day after surgery.
- According to indications, irradiation of metastatic foci is carried out (for therapeutic, sometimes for analgesic purposes).
If there are unfavorable prognostic factors, in particular the detection of a MYCN oncogene mutation in the tumor, high-dose chemotherapy with autologous hematopoietic stem cell transplantation is recommended.
For patients with a high risk of relapse (advanced stages of the disease with the presence of unfavorable molecular genetic markers), “maintenance” differential therapy with 13-cis-retinoic acid and passive immunotherapy with anti-GD2 monoclonal antibodies is recommended.
Immunotherapy
Immunotherapy is a new treatment for neuroblastoma that is used to destroy cancer cells. Disialoganglioside GD2 is an antigen molecule expressed by neuroblastoma cells, making it an ideal target for antibody immunotherapy: the antibody acts against this molecule. Immune system cells may contribute to the death of neuroblastoma cells.
At the National Medical Research Center of Oncology named after. N.N. Petrov performs all stages of treatment, including minimally invasive operations (laparoscopic and thoracoscopic), tandem transplantation and passive immunotherapy.
By intensifying therapy in children with high-risk neuroblastoma (with the inclusion of tandem high-dose polychemotherapy in consolidation and passive immunotherapy in post-consolidation), it was possible to increase survival results by 20%.
Almost completed protocol
Maryana
Now Maryana has six courses of “chemistry” behind her, between which there was a fear that the child would not survive, and then that perhaps five would be enough. Treatment of such cancer is a kind of game of catch-up with the disease.
After the second course, the tumor significantly decreased, and the bone marrow cleared. It has become possible to take cells for transplantation. After the fourth chemotherapy, a very tiny tumor was removed, and after the sixth, a bone marrow was transplanted. For a long time there were not enough cells for the second transplantation, which was required according to the protocol. But then the transfer was completed surprisingly quickly - in 21 days.
Now Maryana is in remission.
He and his mother came to the center for examination and are waiting for the remaining two courses of immunotherapy. Is it possible to get treatment in St. Petersburg ? Head. Department of the National Medical Research Center named after. Petrova Svetlana Kuleva: — To get treatment and even examination at the Petrov National Medical Research Center, a referral for an outpatient appointment is sufficient.
All treatment for neuroblastoma in Russia is included in medical care quotas. Chemotherapy and high-dose therapy are provided only at the expense of the federal budget. The situation with immunotherapy is more complicated - the drug for it is not registered in Russia, so permission to import it must be requested individually for each patient. But at the same time, payment for drugs is made at the expense of charitable foundations. There has not been a single refusal to purchase the drug in the practice of the National Medical Research Center. The hospital prepares all the paperwork for charitable foundations itself. Photo: Dmitry Kolosov
Recommendations after treatment
- After successful treatment of neuroblastoma, the child must undergo medical supervision, which may include examination and consultation with a pediatric oncologist, a blood test for tumor markers (LDH, NSE), a urine test for catecholamine metabolites, ultrasound and CT/MRI, scintigraphy with MYBG and other studies.
- The pediatric oncologist conducts an examination once every 1.5-2 months during the first year after the end of treatment, once every 3 months during the 2nd year, once every 6 months over the next 2 years, then 1 once a year.
- Patients are not removed from the register.
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Authors:
- Izmozherova Rina Igorevna;
- Senchurov Evgeny Mikhailovich;
- Mikhailova Elena Andreevna;
- Ivanova Svetlana Vyacheslavovna;
- Faseeva Natalya Dmitrievna;
- Borokshinova Ksenia Mikhailovna;
- Zhuk Irina Nikolaevna.
Pathological anatomy
Rice.
1. Microscopic specimen of neuroblastoma of the brain: among the neuroblasts with vesicular nuclei, conglomerates of vessels with activation and endothelial hyperplasia are visible (indicated by arrows); hematoxylin-eosin staining; X 450. From Neuroblastomas of the brain, Neuroblastomas of the gray tuberosity and third ventricle, white matter of the cerebral hemispheres, and cerebellum are described. Macroscopically, the tumor looks like a gray-pink node with a diameter of 1 to 1.5 cm: on a section, the tumor tissue is porous, often with cysts. Microscopically, N. consists of cells quite tightly adjacent to each other, in some places with the formation of rosettes consisting of non-processed apolar neuroblasts, identified during impregnation according to Bilypovsky - Gros - Lavrentiev. Tumor cells are represented by neuroblasts of varying degrees of maturity, up to mature ganglion cells with Nisslev granularity in the cytoplasm. The nuclei of tumor cells are vesicle-shaped, varying in size, with a distinct dark-colored nucleolus (Fig. 1). The connective tissue stroma is poorly developed. Mitoses and necrosis occur in the tumor tissue. N.'s growth is infiltrative with shallow germination of surrounding tissue.
N. sympathetic part c. n. With. originate from large sympathetic ganglia and small intramural ganglia of internal organs, as well as from the adrenal medulla. Macroscopically, they look like nodes of various sizes and colors. Foci of necrosis occur in the tumor tissue. According to the degree of maturity among N. of the sympathetic part of c. n. With. There are sympathogoniomas and spmpathoblastomas.
Rice. 2. Microscopic specimen of sympathogonioma: a cluster of hyperchromic lpmocyte-like cells (1) and a pseudorosette (2) are visible; hematoxylin-eosin staining; x 450.
Sympathogonioma is the most malignant, immature, primitive tumor; occurs in newborns and early childhood. Tumor cells have scanty cytoplasm and a rounded dark nucleus resembling a lymphocyte. Sometimes pseudorosettes are found (Fig. 2). These cells are derived from primitive cells called sympathogonia, hence the term “sympathogonoma”.
Rice. 3. Microscopic specimen of sympathoblastoma: true (1) and false (2) rosettes are visible among the tumor cells; hematoxylin-eosin staining; x 450.
Sympathoblastoma is a more differentiated tumor. It contains branched neuroblasts with large bodies of oval, elongated or polygonal shape, with a vesicular nucleus containing clumps of chromatin in the form of spokes in a wheel. The cells are arranged densely, sometimes in the form of strands, columns, or bundles. In some cases, false or true rosettes (Fig. 3) and necrotic foci are found. It is not always possible to differentiate between sympathogoniomas and spmpathoblastomas: such tumors, according to the WHO nomenclature, are designated as neuroblastomas.
