Neuroblastoma ( NB ) is a type of cancer that develops in certain types of neural networks. The most common starts from one of the adrenal glands, but can also develop in the neck, chest, abdomen, or spine. Symptoms may include bone pain, lumps in the abdomen, neck, or chest, or a painless, bluish lump beneath the skin.
Sometimes, neuroblastoma may be caused by mutations inherited from one's parent. Environmental factors have not been found to be involved. The diagnosis is based on tissue biopsy. Sometimes it can be found in infants with ultrasound during pregnancy. At diagnosis, the cancer usually has spread. Cancer is divided into low, middle, and high-risk groups based on the child's age, stage of cancer, and what kind of cancer it is.
Treatment and outcomes depend on a person's risk group. Treatment may include observation, surgery, radiation, chemotherapy, or stem cell transplantation. Low-risk infections in infants usually have good results with surgery or just observation. In high-risk diseases, the likelihood of long-term survival, however, is less than 40% despite aggressive treatment.
Neuroblastoma is the most common cancer in infants and the third most common cancer in children after leukemia and brain cancer. About one out of every 7,000 children is affected at a time. Approximately 90% of cases occur in children younger than 5 years and rarely occur in adults. Cancerous deaths in children, about 15% are caused by neuroblastoma. The disease was first described in the 1800s.
Video Neuroblastoma
Signs and symptoms
The first symptoms of neuroblastoma are often unclear, making diagnosis difficult. Fatigue, loss of appetite, fever, and joint pain are common. Symptoms depend on the location of the primary tumor and metastasis if present:
- In the abdomen, a tumor can cause a swollen stomach and constipation.
- Tumors in the chest can cause respiratory problems.
- Tumors that suppress the spinal cord can cause weakness, resulting in the inability to stand, crawl, or walk.
- Bone lesions in the legs and hips can cause pain and limp.
- Tumors in the bone around the eyes or orbital can cause different bruising and swelling.
- Bone marrow infiltration can cause pallor due to anemia.
Neuroblastoma often spreads to other parts of the body before any symptoms appear, and 50 to 60% of all cases of neuroblastoma present with metastasis.
The most common location for the originating neuroblastoma (ie, primary tumor) is in the adrenal gland. This occurs in 40% of local tumors and in 60% of cases the disease is widespread. Neuroblastoma can also develop anywhere along the chain of the sympathetic nervous system from the neck to the pelvis. Frequencies in different locations include: neck (1%), chest (19%), abdomen (30% nonadrenal), or pelvis (1%). In rare cases, no primary tumor can be distinguished.
Rare but characteristic presentations include transverse myelopathy (tumor spinal cord compression, 5% of cases), treatment-resistant diarrhea (vasoactive tumor vein peptide secretion, 4% of cases), Horner syndrome (cervical tumor, 2.4% of cases) opsoclonus myoclonus syndrome and ataxia (alleged paraneoplastic cause, 1.3% of cases), and hypertension (catecholamine secretion or renal artery compression, 1.3% of cases).
Maps Neuroblastoma
Cause
The cause of neuroblastoma is not well understood. Most cases are sporadic and non-conventional. Approximately 1-2% of cases occur in the family and have been associated with specific gene mutations. Familial neuroblastoma in some cases is caused by a rare germline mutation in the anaplastic lymphoma kinase (ALK ) gene. Germline mutations in the PHOX2A or KIF1B gene have been implicated in familial neuroblastoma as well. Neuroblastoma is also a hallmark of type 1 neurofibromatosis and Beckwith-Wiedemann syndrome.
MYCN amplification of oncogenes in tumors is a common finding in neuroblastoma. The amplification rate shows the bimodal distribution: between 3- to 10-fold, or 100 to 300-fold. The presence of these mutations is highly correlated with advanced stage disease.
The duplicated segment of the LMO1 gene in neuroblastoma tumor cells has been shown to increase the risk of developing an aggressive form of cancer.
Neuroblastoma has been associated with variation of the number of copies in the NBPF10 gene, resulting in a 1q21.1 removal syndrome or 1q21.1 duplicate syndrome.
Several risk factors have been proposed and are the subject of ongoing research. Due to the typical early onset, many studies have focused on parental factors around conception and during pregnancy. Factors studied included occupations (ie exposure to chemicals in certain industries), smoking, alcohol consumption, use of medications during pregnancy, and birth factors; However, the results can not be concluded.
Other studies have examined the possibility of association with atopy and exposure to early life infections, the use of hormones and fertility drugs, and the use of hair dye in mothers.
Diagnosis
Diagnosis is usually confirmed by a surgical pathologist, taking into account clinical presentation, microscopic findings, and other laboratory tests. This may arise from the neural crest element of the sympathetic nervous system (SNS).
Esthesioneuroblastoma, also known as olfactory neuroblastoma, is believed to originate in the olfactory epithelium and its classification is controversial. However, since this is not a malignancy of the sympathetic nervous system, esthesioneuroblastoma is a distinct clinical entity and does not become confused with neuroblastoma.
Biochemistry
About 90% of cases of neuroblastoma, elevated levels of catecholamines or metabolites found in urine or blood. The catecholamines and their metabolites include dopamine, homovanillic acid (HVA), and/or vanillylmandelic acid (VMA).
Imaging
Another way to detect neuroblastoma is a meta-iodobenzylguanidine scan, taken by 90 to 95% of all neuroblastomas, often called "mIBG-avid". The mechanism is mIBG taken by sympathetic neurons, and is a functioning analog of norepinephrine neurotransmitter. When radio-ionated with I-131 or I-123 (radioactive isotope iodine), it is an excellent radiopharmaceutical for the diagnosis and monitoring of response to treatment for this disease. With a half-life of 13 hours, I-123 is the preferred isotope for sensitivity and image quality. I-131 has an 8-day half-life and at higher doses is an effective therapy as a target of radiation against recurrent and refractory neuroblastoma.
Histology
In microscopy, tumor cells are usually described as small, round and blue patterns, and the rosette (Homer Wright rose) can be seen. Rosat Homer Wright is the tumor cells around the neuropil, do not be confused with pseudorosettes, which are tumor cells around the blood vessels. They also differ from pseudorosettes from ependymoma consisting of tumor cells with glial fibrillary acidic protein (GFAP) -a positive process that tapers toward the blood vessels (so the combination of both). Immunohistochemical stains are used by pathologists to distinguish neuroblastoma from histologic mimics, such as rhabdomyosarcoma, Ewing's sarcoma, lymphoma, and Wilms tumor.
Neuroblastoma is one of the peripheral neuroblastic tumors (pNTs) that have the same origin and exhibit a broad pattern of differentiation ranging from benign ganglioneuromas to stromal ganglioneuroblastoma-rich with mixed or neuroblastic cells in nodules, to highly malignant neuroblastomas. This difference in pre-treatment tumor pathology is an important prognostic factor, along with age and mitosis-karyorrhexis index (MKI). This pathology classification system (Shimada system) describes "beneficial" and "unfavorable" tumors by the International Neuroblastoma Pathology Committee (INPC) established in 1999 and revised in 2003.
Staging
The "International Neuroblastoma Staging System" (INSS) was established in 1986 and revised in 1988 stratification of neuroblastoma according to its anatomical presence at diagnosis:
- Stage 1: Local tumor is limited to the area of ​​origin.
- Stage 2A: Unilateral tumors with gross resection are not perfect; ipsilateral and contralateral lymphocyte nodes that can be identified negatively for the tumor.
- Stage 2B: Unilateral tumor with complete or incomplete gross resection; with a positive ipsilateral lymph node for the tumor; contralateral lymph nodes that can be identified negatively for the tumor.
- Stage 3: The tumor infiltrates across the midline with or without regional lymph node involvement; or unilateral tumor with involvement of contralateral lymph nodes; or midline tumor with bilateral lymph node involvement.
- Stage 4: Disseminate the tumor to distant lymph nodes, bone marrow, bone, liver, or other organs except as defined by Stage 4S.
- Stage 4: Age & lt; 1 year with a local primary tumor as defined in Stage 1 or 2, with limited spread of liver, skin, or bone marrow (less than 10 percent of coronated bone marrow cells are tumors).
Although an international treaty on staging (INSS) has been used, the need for international consensus on risk assignment has also been recognized to compare similar cohorts in research results. Beginning in 2005, representatives of a major pediatric oncology group of cooperatives have met to review data for 8,800 neuroblastoma patients treated in Europe, Japan, the United States, Canada and Australia between 1990 and 2002. The task force has proposed the International Neuroblastoma Risk Group INRG). ) classification system. Retrospective studies revealed a high survival rate of the 12-18 month age group, previously categorized as high risk, and encouraged the decision to reclassify children aged 12-18 months without N- myc (also often referred to as MYCN) amplification into the medium risk category.
The new INRG risk assignment will classify neuroblastoma at diagnosis based on the International Neuroblastoma Risk Management System (INRGSS):
- Stage L1: Local disease without risk factors determined by image.
- Stage L2: Local disease with risk factors determined by the image.
- Stage M: Metastatic disease.
- Stage MS: "Special" metastatic disease in which MS is equivalent to stage 4S.
The new risk stratification will be based on the new INRGSS staging system, age (automated at 18 months), tumor level, N-myc amplification, unbalanced 11q abortion, and ploidy into four pre-treatment risk groups: very low, low, medium , and high risk.
Screening
Urinary catecholamine levels may increase in pre-clinical neuroblastoma. The screening of an asymptomatic baby at three weeks, six months, and one year has been done in Japan, Canada, Austria and Germany since the 1980s. Japan began screening children aged six months for neuroblastoma through analysis of homovanillic acid and vanilmandelic acid levels in 1984. Screening was discontinued in 2004 after studies in Canada and Germany showed no reduction in deaths due to neuroblastoma, but rather due to an increase in diagnoses that would disappear without treatment, subjugate the babies to unnecessary surgery and chemotherapy.
Treatment
When lesions are localized, it can generally be cured. However, long-term survival for children with elderly disease older than 18 months is poor despite aggressive multimodal therapy (intensive chemotherapy, surgery, radiation therapy, stem cell transplantation, isotretinoin differentiation agent also called 13- cis -retinoic acid, and often immunotherapy with anti-GD2 monoclonal antibody therapy).
Biological and genetic characteristics have been identified, which, when added to classical clinical staging, have enabled the assignment of patients to risk groups to plan treatment intensities. These criteria include patient age, disease spread rate, microscopic appearance, and genetic features including ploidy DNA and N-myc oncogene amplification (N-myc regulates microRNAs), into low, medium, and high-risk diseases. A recent biological study (COG ANBL00B1) analyzed 2687 neuroblastoma patients and the risk assignment spectrum was determined: 37% of low-risk neuroblastoma cases, 18% were medium risk, and 45% were at high risk. (There is some evidence that high and low risk types are caused by different mechanisms, and not just two different degrees of expression of the same mechanism.)
Therapy for these different risk categories is very different.
- Low-risk illnesses can often be observed without treatment at all or healed by surgery alone.
- Medium-risk diseases are treated with surgery and chemotherapy.
- High-risk neuroblastoma is treated with intensive chemotherapy, surgery, radiation therapy, marrow/hematopoietic stem cell transplantation, biologically-based therapy with 13- cis-secretinoic acid (isotretinoin or Accutane) and antibody therapy is usually given with GM-CSF and IL-2 cytokines.
With current treatments, patients with low and middle risk diseases have an excellent prognosis with rates of cure above 90% for low risk and 70-90% for medium risk. Conversely, therapy for high-risk neuroblastoma over the last two decades causes healing to be only about 30% of the time. The addition of antibody therapy has significantly increased survival rates for high-risk illnesses. In March 2009, preliminary analysis of a Children's Oncology Group (COG) study with 226 high-risk patients showed that two years after stem cell transplant 66% of the group were randomized to receive ch14.18 antibodies with GM-CSF and IL-2 is life-free and disease compared to only 46% in the group that does not receive antibodies. Randomization is stopped so that all patients who register in the trial will receive antibody therapy.
Chemotherapy agents used in combination have been found to be effective against neuroblastoma. Agents commonly used in induction and for transplantation of stem cell transplants are platinum compounds (cisplatin, carboplatin), alkylating agents (cyclophosphamide, ifosfamide, melphalan), topoisomerase II (etoposide) inhibitors, anthracycline antibiotics (doxorubicin) and vinca alkaloids (vincristine). Some newer regimens include topoisomerase I inhibitors (topotecan and irinotecan) in induction that have been found to be effective against recurrent disease.
Prognosis
Between 20% and 50% of high-risk cases do not respond adequately to high-dose induction chemotherapy and are progressive or refractory. Relapse after completing frontline therapy is also common. Further treatment is available in phase I and phase II clinical trials that test new agents and combination of agents against neuroblastoma, but the results remain very bad for high-risk recurrent diseases.
Most long-term survivors living today have low or middle-risk illnesses and milder treatment compared with high-risk illnesses. The majority of victims have long-term effects of treatment. High-risk and high-risk survivors often suffer from hearing loss. Reduced growth, impaired thyroid function, learning difficulties, and a greater risk of secondary cancer affect survivors of high-risk illnesses. It is estimated that two out of three survivors of childhood cancer will eventually develop at least one chronic and sometimes life-threatening health problem within 20 to 30 years after a cancer diagnosis.
cytogenetic profile
Based on a series of 493 neuroblastoma samples, it has been reported that the overall pattern of the genome, which is tested by line-based karyotyping, is a predictor of results in neuroblastoma:
- Tumors that appear exclusively with changes in the number of copies of the total chromosome are associated with excellent survival.
- Tumors present with any kind of alteration of chromosome number copies are associated with a high risk of relapse.
- In tumors that exhibit segmental changes, additional independent predictors of overall decrease in survival are N-myc amplification, 1p and 11q removal, and 1q gain.
Previous publications categorized neuroblastoma into three major subtypes based on cytogenetic profiles:
- Subtype 1: favorable neuroblastoma with near triploidi and dominance of numerical gain and losses, most representing non-metastatic NB stages 1, 2 and 4S.
- Subtypes 2A and 2B: are found in unusually large neuroblastomas, stages 3 and 4, with loss of 11q and 17q gain without N-myc amplification (subtype 2A) or with N-myc amplification often along with 1p removal and 17q gain (subtype 2B).
Virtual karyotyping can be performed on fresh or paraffin-embedded tumors to assess the number of copies in this locus. SNP virtual array karyotyping is preferred for tumor samples, including neuroblastoma, as they can detect neutral loss from heterozygosity (obtained by uniparental disomy). Neutral LOH copies can be biologically equivalent to removal and have been detected in the key locus in neuroblastoma. ArrayCGH, FISH, or conventional cytogenetics can not detect neutral copy LOH.
Epidemiology
Neuroblastoma is made up of 6-10% of all childhood cancers, and 15% of deaths from cancer in children. The annual mortality rate is 10 per million children in the age group 0-4 years, and 4 per million in the age group of 4-9 years.
The highest incidence is in the first year of life, and some cases are congenital. Large age ranges, including older children and adults, but only 10% of cases occur in people older than 5 years. A large study in Europe reported less than 2% of more than 4000 cases of neuroblastoma aged over 18 years.
History
In 1864, German physician Rudolf Virchow was the first to describe a tumor tumor in a child as a "glioma". The tumor characteristics of the sympathetic nervous system and the adrenal medulla were then recorded in 1891 by German pathologist Felix Marchand. In 1901, a typical presentation of stage 4 in infants (liver but no bone metastasis) was described by William Pepper. In 1910 James Homer Wright understood the tumor originated from primitive nerve cells, and named it neuroblastoma. He also notes cell-lumped lumps in bone marrow samples that are now called "Homer Wright roses". From the notes, "Homer-Wright" with hyphens is a misnomer, as eponymous refers only to Dr. Wright.
Society and culture
Legislative efforts
US Representative Chet Edwards of Waco, Texas, successfully introduced a law to allocate $ 150 million to cure neuroblastoma and other cancers. The move was signed into law in July 2008 by US President George W. Bush. Edwards was inspired by Erin Channing Buenger's (1997-2009) subsequent illness and death efforts from Bryan, the daughter of one of his constituents, Walter L. Buenger, head of history department at Texas A & amp; M University.
Research
The preclinical model
Neuroblastoma patients derived tumor xenografts (PDXs) have been made by orthotopic implantation of patient tumor samples into immunodeficiency rats. The PDX model has several advantages over the conventional cancer cell line (CCL) s. PDXs neuroblastoma retains the genetic superiority of the appropriate patient tumor and PDX shows infiltrative growth and metastasis to distant organs. The PDX model is more predictive of clinical outcomes than conventional cancer line xenografts. PDX neuroblastoma may therefore serve as a clinically relevant model for identifying compounds that are effective against neuroblastoma.
Treatment
The last focus is to reduce therapy for low and middle risk neuroblastoma while maintaining a survival rate of 90%. A study of 467 middle-risk patients enrolled in A3961 from 1997 to 2005 confirms the hypothesis that therapy can be successfully reduced for this risk group. Those with favorable characteristics (grade and tumor response) received four cycles of chemotherapy, and those with unfavorable characteristics received eight cycles, with a three-year survival free and overall survival stable at 90% for the entire cohort. Future plans are to intensify treatment for patients with 1p36 or 11q23 chromosome abnormalities as well as for those who do not have early response to treatment.
Conversely, the focus of the last 20 years or so to intensify treatment for high-risk neuroblastoma. Variations of chemotherapy induction, operation time, stem cell transplant regimen, various delivery schemes for radiation, and the use of monoclonal and retinoid antibodies to treat minimal residual diseases continue to be examined. A recent phase III clinical trial with randomization has been done to answer these questions to improve the survival of high-risk illnesses:
Refractory and recurrent neuroblastoma
Chemotherapy with topotecan and cyclophosphamide is often used in refractory settings and after relapse.
References
External links
- Neuroblastoma in Curlie (based on DMOZ)
Source of the article : Wikipedia
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