Neuroblastoma of the retroperitoneum.

Neuroblastomas are undifferentiated cancer foci that develop from germinal nerve cells of the sympathetic NS. Neuroblastoma of the retroperitoneum is considered the most frequent extracranial cancer in pediatric practice and occurs in 14% of the total pediatric oncopathology population. The problem is congenital and is often accompanied by various developmental anomalies. The disease is detected usually in the period from 2 to five years of age, less often - up to adolescence. Treatment is predominantly surgical. [1]

Epidemiology

Retroperitoneal neuroblastoma is an exclusively pediatric cancer. There are only a few known cases in which the tumor was diagnosed in patients older than 13-14 years of age. The pathology occurs in about 14% of all pediatric cancers.

Neuroblastoma is known to occur in eight children out of a million under the age of 15. At the same time, every second patient is a child under two years of age. Unfortunately, when the symptoms of the disease appear, 70% of patients have already metastasized. More than 90% of patients diagnosed with neuroblastoma are children under the age of six.

The most common localization of the tumor process:

• about 70% of cases - retroperitoneal space, with lesions of cerebral layers of adrenal glands and ganglia of sympathetic NS;
• about 20% posterior mediastinum;
• much less frequently - head and neck, presacral region.

Metastasis occurs predominantly to regional or distant lymph nodes, bone marrow, bone and liver, skin, much less frequently - to the central nervous system and respiratory organs.

Causes of the retroperitoneal neuroblastoma.

The primary causes of retroperitoneal neuroblastoma formation raise many questions to date. It is known that the tumor starts on the background of malignant degeneration of immature cells of the sympathetic NS. Doctors believe that failures in the normal development of germinal nerve cells occur even before the baby comes into the world. Pathology can begin its development from the moment of chromosome change and/or gene mutation.

Scientists have found a variety of genetic abnormalities in tumor cells. These abnormalities are diverse, indicating that it is impossible to isolate any particular specific change in gene material that would be seen in all sick babies. Presumably, neuroblastoma formation occurs as a result of a series of gene and epigenetic transformations. It should also be taken into account that in most patients the tumor has nothing to do with hereditary pathologies.

Only in some cases the disease affects several generations, manifesting itself as neuroblastoma or similar types of malignant neoplasms. Statistics state that such cases are no more than 1-2%. In a part of patients, the formation of the tumor is due to syndromes predisposing to it. In particular, we can talk about Hirschprung's disease, Undine syndrome (congenital central hypoventilation syndrome).

However, in most babies, the development of cancer is still associated with spontaneous mutations or other genomic disorders affecting the hereditary material of somatic cells. The relationship with smoking during pregnancy, taking certain medications, and other external influences is not observed in all cases, so this issue is still at the research stage.

Risk factors

The risks of the disease are equal in approximately all children. Scientists do not provide precise information on this, as retroperitoneal neuroblastoma is still under active study. Presumably, certain chronic infectious diseases such as human immunodeficiency virus, Epstein-Barr virus, and malaria may be risk factors. These factors are particularly prevalent in low- and middle-income countries.

Nevertheless, in the vast majority of cases, neuroblastoma develops spontaneously, without any obvious cause. In some patients, there is an association with genetic abnormalities.

There is a theory of negative influence of a whole group of factors at once, which are conditionally called "parental". This group includes:

• ionizing radiation exposure to the mother during pregnancy;
• Consumption of pesticide-laden foods by a pregnant woman;
• smoking (including hookahs);
• drug addiction, excessive use of alcoholic beverages and diuretics during pregnancy.

Other risk factors also contribute to the possible development of retroperitoneal neuroblastoma:

• prematurity, premature birth of the baby;
• use of assisted reproductive technologies.

The last of the above factors has no scientific confirmation at the moment and belongs to the category of "theoretical assumptions".

Pathogenesis

The pathogenetic mechanism of retroperitoneal neuroblastoma is not well understood. There is information that the neoplasm originates from germinal nerve cells that have not had time to mature by the time the infant is born. The presence of such immature cells in early infants is not always a factor in the occurrence of neuroblastoma. The presence of these structures in infants from newborn to three months of age is acceptable. After this time, neuroblasts "mature" and continue to function normally, but if pathology develops, they continue to divide, contributing to the formation of neuroblastoma.

The main starting point for the disease is cellular mutations, which appear under the influence of certain provoking factors: their exact characteristics are not yet known. Scientists say that there is a correlation between the risks of tumorigenesis, growth defects and congenital immune deficiency. In about 1.5% of cases, retroperitoneal neuroblastoma is hereditary, transmitted in an autosomal dominant manner. Hereditary pathology is characterized predominantly by an early onset (the peak picture is noted in the period of 6-8 months of age) and the formation of several malignant elements at once.

If we talk about the pathognomonic genetic abnormality, for retroperitoneal neuroblastoma, it is the loss of part of the short arm of the first chromosome. In every third patient, an increase in the number of DNA copies and expression of the N-myc-oncogene are noted in malignant structures. In this situation, the prognosis of the disease is considered particularly unfavorable, which is associated with the rapid expansion of the focus and its resistance to ongoing chemotherapy.

Microscopic examination reveals spherical small structures with a dark-stained nucleus. Tumor tissue is abundant with calcifications and areas of hemorrhages. [2]

Symptoms of the retroperitoneal neuroblastoma.

Most infants with retroperitoneal neuroblastoma are completely asymptomatic for a long time. The tumor is detected accidentally during a preventive medical examination, or during an X-ray or ultrasound examination ordered for other indications. Most often, the symptomatology makes itself known only at the stage of rapid tumor growth or metastasis.

The clinical picture of the disease is diverse and depends on the size of the tumor focus and the presence of metastases. Sometimes the neoplasm can even be palpated. Many children visually notice a strongly bloated abdomen, or a peculiar abdominal swelling. There may be such nonspecific signs as pain and a feeling of heaviness in the abdomen, frequent constipation followed by diarrhea. With compression of the urinary organs, urinary stasis is possible, and with the localization of the pathological focus closer to the spine, its sprouting into the spinal canal is possible. As a result, the baby has neurological symptoms in the form of pain, paresis and partial paralysis.

Somewhat less often as a result of hormonal imbalance against the background of rapid tumor growth in babies increases blood pressure, often bothers diarrhea.

The spread of metastases to the bone system (long tubular bones of the limbs, skull and eye bones) is accompanied by bone pain. Older children begin to limp when walking, and young children refuse to stand or walk. Severe damage to the bone marrow makes itself known by the development of anemia, thrombocytopenia, leukopenia. The child's immunity is severely impaired and bleeding occurs frequently.

Neuroblastoma of the retroperitoneum in children

In the retroperitoneal zone there are also some organs and a developed vascular network. In particular, these include the adrenal glands and kidneys, ureters and pancreas, colon and duodenum, vena cava and abdominal part of the aorta, blood and lymphatic vessels. With the development of neuroblastoma, the risks to the individual are maximum, especially since this tumor occurs predominantly in infants and young children.

In most cases, the neoplasm is detected in babies before they reach the age of two, and sometimes the problem can be detected during fetal ultrasound.

More often the development of retroperitoneal neuroblastoma starts in the adrenal gland. The tumor process rapidly progresses, spreads metastases, and in infants often soon regresses just as rapidly. In some cases, spontaneous "maturation" of neuroblastoma cells is observed, which leads to its transformation into ganglioneuroma.

The first alarming sign of pediatric pathology is a pronounced enlargement of the abdomen, which causes pain and abdominal discomfort. Palpatory palpation is possible to palpate the neoplasm - dense, which is difficult to dislodge.

As the pathologic process spreads, dyspnea and coughing occur, swallowing becomes difficult, and the thorax becomes distorted. If the cerebrospinal canal is affected, there are paresthesias of the lower extremities, general weakness, partial paralysis, impaired function of the intestine and urinary system. Against the background of compression of the vascular network, edema appears. If the tumor spreads to the liver, the organ enlarges, and when the skin is affected, spotty reddish-blue foci appear on them.

Sick children under one year of age have a much better chance of a favorable outcome. The prognosis is significantly worse if the child develops a retroperitoneal tumor.

Signs that parents should look out for:

• increased fatigue of the baby, unreasonable weakness, pale skin, the appearance of dark circles near the eyes;
• Stable fever without signs of infection, increased sweating;
• Increased lymph nodes (intra-abdominal, inguinal);
• stable abdominal bloating;
• alternation of constipation and diarrhea, abdominal pain like colic;
• poor appetite, occasional nausea, underweight;
• bone pain.

These symptoms do not always indicate the presence of retroperitoneal neuroblastoma in the baby. Often such manifestations are a consequence of other, relatively less dangerous diseases. However, if the above signs are detected, it is still better to consult with a doctor and find out the exact cause of the ailment. This will allow timely treatment and improve the outcome of the pathology.

Stages

Topographic staging is consistent with INSS criteria:

1. Neuroblastoma localized, up to 50 mm in the most expanded area. The lymphatic system is not affected. There is no metastasis.
2. Single neuroblastoma, at least 50 mm and not more than 100 mm in the most expanded area. The lymphatic system is not affected. No distant metastases.
3. Solitary neuroblastoma, neoplasia of 50 mm or more than 100 mm. Regional lymph nodes may contain metastases. No distant metastases.
4. It has subcategories A, B and S.

• Stage IV-A is characterized by the presence of neoplasia, a single retroperitoneal neuroblastoma less than 50 mm or greater than 100 mm in size, with absence or presence of metastases to regional lymph nodes and no distant metastasis (no lymphatic lesion can be identified).
• Stage IV-B indicates the presence of multiple synchronous tumors of synchronous growth, with absence or presence of metastases to regional lymph nodes, with absence or presence of distant metastases (could not be determined).
• Stage IV-S is characteristic of early infants and suggests spontaneous self-healing of neuroblastoma, its involution, including after the tumor has reached a sufficiently large size and metastasized.

Complications and consequences

Neuroblastoma of the retroperitoneum always proceeds differently. Variants of its course depend on many factors, but especially unfavorable consequences are observed in case of untimely, delayed detection of the neoplasm. Unfortunately, it often happens that the disease is detected when it has already spread to nearby structures and the lymphatic system, or even to distant organs. But there are also known variants with a positive bioclinical course: for example, in infants, neuroblastoma is prone to spontaneous maturation to benign formation (differentiation) and spontaneous disappearance.

In children over one and a half years of age, neuroblastomas tend to progress rapidly and spread unimpeded through the body - via the blood and lymphatic systems. Metastases are detectable:

• 90% of the time in the bone marrow;
• 60% in the bones;
• 20% in distant lymph nodes;
• 17% in the liver;
• Less commonly in the brain, skin, and lungs.

Some neuroblastomas mature partially, with the formation of more and less malignant structures. Such neoplasms are referred to as ganglioneuroblastomas. Their enlargement is relatively slow, in contrast to purely malignant tumors. A fully mature tumor is called a ganglioneuroma.

If we talk about spontaneous regression, it often occurs in infants of early age. At the same time, retroperitoneal neuroblastoma is often detected only at the stage of metastasis to the liver. At first, such metastatic foci rapidly increase and even begin to press on nearby organs, and the number of daughter foci is a real danger. However, after some time, these foci spontaneously collapse (sometimes under the influence of low-dose chemotherapy).

Spontaneous involution is seen predominantly in stage 4S babies, but can also occur in older children with localized stage I-III neuroblastoma. [3]

Diagnostics of the retroperitoneal neuroblastoma.

Oncomarkers of retroperitoneal neuroblastoma are catecholamine metabolites (vanillimindal and homovanillic acid) in plasma and urinary fluid (optimal technique) and neuron-specific enolase. LDH and ferritin levels are also investigated as a definite risk parameter, although their elevation and thrombocytopenia do not reflect the specificity of the disease.

To assess the condition of the medullary structures, a medullary puncture and subsequent morphologic and immunohistochemical analyses or real-time polymerase-chain reaction are performed. Puncture is performed into the posterior and anterior ridges of the wings of the iliac bone.

Mandatory are considered to be:

• histologic examination;
• molecular genetic diagnosis;
• as well as instrumental imaging techniques.

Instrumental diagnostics is prescribed to examine the primary tumor focus and nearby lymph nodes. For this purpose, ultrasound, computed tomography and magnetic resonance imaging (if possible, using three projections, without and with contrast injection) are prescribed.

Initial diagnosis should necessarily begin with contrast MRI. If hepatic metastasis is suspected, targeted ultrasound is performed.

Meta-iodine-benzyl-guanidine is considered a specific scintigraphic oncomarker. If there are signs of metastasis, technetium scintigraphy is performed.

Other ancillary diagnostic procedures include:

• echocardiogram;
• Kidney ultrasound;
• colonoscopy.

Differential diagnosis

The differential diagnosis should be made primarily with other embryonal neoplasms characteristic of early childhood, including:

• with primitive rhabdomyosarcoma;
• Ewing's sarcoma;
• lymphoblastic lymphoma;
• acute leukemia (with metastatic lesions in the bone marrow);
• sometimes with nephroblastoma and central nervous system oncopathology.

Treatment of the retroperitoneal neuroblastoma.

Treatment tactics are determined depending on the age of the patient, the characteristics of the particular neuroblastoma and the stage of the pathology. Thanks to information about these factors, it is possible to assess the risks and develop a treatment regimen.

The main therapeutic tactics are considered to be:

• Surveillance tactics.
• Operative treatment.
• Chemotherapy.
• Massive chemotherapy with stem cell protection.
• Radiation treatment.
• Immunotherapy.

Observational tactics are used only in low-risk infants: regression of the neoplasm has been described in isolated, albeit rare, cases.

If there are no contraindications, surgery is performed, which in many cases guarantees complete removal of cancerous structures. If there are metastases, this approach is much more complicated and requires the use of additional methods.

Chemotherapy is considered the main way to eliminate neuroblastoma, especially in patients at high intermediate risk. Chemotherapy destroys malignant cells and blocks their division and growth. In addition, chemotherapy is given after surgery to remove residual tumor particles and prevent neuroblastoma from growing again.

Massive chemotherapy with stem cell transplantation is indicated for metastatic lesions. Stem cells are taken from the patient and saved for further transplantation. After high-dose treatment with chemopreventive drugs, the patient is transplanted with stem cells, thus protected from massive chemotherapy.

Radiation therapy is given as support and adjunct to other therapies.

Immunotherapy - treatment with monoclonal antibodies - involves the use of special proteins that attach to malignant cells. As a result, tumor structures are recognized and destroyed.

Medications

Chemotherapy drugs used as part of chemotherapy include:

• Carboplatin is a platinum analog that slows and blocks the growth of malignant tumors. It can be used in patients with intolerance to Cisplatin. In turn, Carboplatin treatment is capable of triggering severe allergic reactions and hypersensitivity states. Among other side effects: nausea, bleeding, renal disorders, hearing impairment, in women - malfunction of the monthly cycle. Dosage and frequency of use are established by the attending doctor individually.
• Cyclophosphamide is used both as part of chemotherapy and to prepare patients for hematopoietic stem cell transplantation. Treatment with Cyclophosphamide often negatively affects the function of the urinary system. To avoid complications, taking the drug should be combined with the use of large amounts of fluid, as well as the use of the preventive drug Mesna. In addition, regular urine tests are required during treatment. Other most likely side effects: coloring of nail plates, hair loss, burning sensation during urination. The drug is taken strictly at the same time on an empty stomach, without chewing and crushing the capsules. Dosage is individual.
• Doxorubicin is an antitumor drug for complex therapy of retroperitoneal neuroblastoma. It has serious risks for cardiac activity, so treatment should be regularly monitored by a cardiologist. With already existing heart disorders, Doxorubicin is not prescribed! Among other side effects: change in the color of urine, the appearance of ulcers in the mouth, hair loss. Dosage is determined strictly individually.
• Etoposide - is used as part of complex chemotherapy. The regimen and dose depends on the characteristics of neuroblastoma, the age of the baby and the method of administration chosen by the attending physician. The most probable side symptoms: lower blood pressure, impaired hepatic function, hair loss. During treatment with Etoposide, grapefruit and grapefruit drinks should not be consumed.
• Topotecan is an antitumor agent for complex therapy, during which the patient should regularly monitor blood parameters to assess kidney and liver function and monitor the concentration of the drug in the blood. Depending on this concentration, the doctor can adjust the dosage. Possible side effects: diarrhea, increased risk of infection, anemia, a strong feeling of fatigue, deterioration of hepatic function. In most cases, Topotecan is taken once a day at the same time. The dose is determined by the attending doctor.
• Cisplatin is a chemotherapeutic agent, an analog of platinum. In the course of treatment, it is mandatory to regularly check blood counts, kidney and liver function, monitor the intake of large amounts of fluids, control diuresis, as well as the microelemental composition of the blood. Among the long-term consequences of Cisplatin administration: hearing impairment up to its loss, inhibition of sexual development, renal disorders, formation of peripheral neuropathy or secondary cancer. Additionally with Cisplatin are prescribed antiemetics, as well as preparations of magnesium, potassium, calcium, phosphorus. Doses and duration of administration are determined individually.
• Vincristine is a common antitumor drug that can provoke tissue damage, both by contact and by IV administration. Possible side effects include abdominal and jaw pain, constipation, muscle pain and weakness, paresis and paresthesias of the hands and feet, and bone and joint pain. Remote effects include peripheral neuropathy. Treatment with Vincristine can not be combined with the use of grapefruit and juice from it. Additionally, the doctor may prescribe a laxative drug, which should be taken throughout the entire period of chemotherapy.

Surgical treatment

Surgical intervention is prescribed not only for the removal of neuroblastoma, but also to confirm the histological diagnosis and to obtain biomaterial using the shock freezing method for subsequent biomolecular study. In addition, during the operation, the doctor specifies the stage of pathology, based on its prevalence: the expansion beyond the midline, the lesion of the lymphatic system, etc. Is taken into account. About complete resection of retroperitoneal neuroblastoma is thought only when the risks of surgical complications are minimized. It is important for the surgeon to avoid mutilation techniques, including muscle resections, nephrectomy, removal of large intestinal segments, which may provoke short bowel syndrome.

Large-scale interventions with complex techniques are only appropriate in cases of life-threatening conditions, such as patients with compressed nerve trunks, blocked airways or large vessels. The need for such interventions is reviewed by a medical consulium.

If retroperitoneal neuroblastoma compresses cerebrospinal structures, chemotherapy is preferred.

Surgery is more successful after prior chemotherapy, as the risks of capsular rupture are significantly reduced. It is optimal to perform 4-6 chemotherapeutic blocks. In most cases, there is no need for radical complete excision of the neoplasm: residual tumor tissue in certain amounts is allowed.

After a course of radiation therapy, surgery may be complicated by the appearance of fibrosis in the area of the pathological focus, which is provoked by radiation. At the same time, successful resection helps to reduce the irradiated field, or to avoid radiation exposure altogether. On this basis, any surgery should be performed before radiation treatment. [4]

Prevention

To date, there is no specific prevention. Specialists continue to actively research the pathology and search for ways of early diagnosis.

At the same time, doctors recommend that women take measures before pregnancy to ensure normal fetal development and prevent premature birth. The expectant mother should be examined and, if necessary, treated beforehand.

Among other recommendations:

• A pregnant woman should register at the antenatal clinic as early as possible - and especially if she has a history of premature births, spontaneous abortions, or abortions.
• It is undesirable to allow a small term between pregnancies: the recommended interval is at least six months.
• The expectant mother should eat a good and varied diet, drink enough water, avoid emotional overload. Depression, stress, neurosis, etc. Make a negative contribution to the health of both the woman and the fetus.
• It is important to have regular ultrasound monitoring of fetal development during pregnancy.
• At high risk of premature birth, a woman is necessarily hospitalized in the hospital, where preventive measures aimed at preserving pregnancy are carried out.

If the future parents are healthy and the pregnancy itself is without pathologic abnormalities, the development of retroperitoneal neuroblastoma in the child becomes unlikely.

Forecast

The outcome of retroperitoneal neuroblastoma depends on many factors, such as:

• The younger the age of the baby at the time of neuroblastoma detection, the better and more favorable the prognosis;
• The specific characteristics of the neoplasm, such as histologic features, changes in genes, and rates of cell division and growth, are important;
• A favorable outcome is questionable if there is spread of cancer cells to the lymphatic system or other organs;
• hard-to-reach and inoperable neuroblastomas have a poor prognosis;
• a positive response of the tumor site to the therapy is important;
• A positive outcome implies the absence of both metastases and recurrence of the disease. [5]

Survival rate

Overall, patient survival rates are estimated to be approximately 1:2 (49% to 54%).

The survival of children according to stage is as follows:

• Stage I is up to 99-100%.
• Stage II - up to 94%.
• Stage III - 57 to 67% (average about 60%).
• Stage IV - about 15% (children with stage IV S younger than 1 year of age survive in almost 75% of cases).

Retroperitoneal neuroblastoma found in infants less than one year of age has a much better chance of a favorable outcome. Tumors found at an older age and at later stages of development have a worse prognosis. The probability of forming a recurrence is from 5 to 50%, depending on the patient's risk category. Five years after the disease is cured, the risk of tumor recurrence decreases dramatically.