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Background
This is one of the most common childhood tumors, part of the small round blue cell tumors of childhood. About 85-90% of all tumors arise in children less than five years of age. In about 20% of cases, there is a strong hereditary predisposition. About 25-35% of cases arise within the adrenal medulla. The rest can arise within the sympathetic ganglion chain which runs alongside the vertebral column. They are broadly classified under the Ewing's sarcoma/primitive neuroectodermal family of tumors. The presentation of the tumor depends upon the location, age, and associated clinical syndromes. Presentations include weight loss, fever, gastrointestinal tract disturbances, and anemia.
OUTLINE
LABORATORY/
RADIOLOGIC/CHARACTERIZATION Radiographs Retroperitoneal tumors cause displacment of the kidneys
Calcifications in 50% of tumors
Metastatic lesions are osteolytic, usually in skull, femur, or humerusLaboratory Markers
Screening for neuroblastoma in North America. Preliminary results of a pathology review from the Quebec Project.Takeuchi LA, Hachitanda Y, Woods WG, Tuchman M, Lemieux B, Brisson L, Bernstein M, Brossard J, Leclerc JM, Byrne TD, et al.
Department of Pathology, Childrens Hospital Los Angeles, CA 90027, USA.
Cancer 1995 Dec 1;76(11):2363-71 Abstract quote BACKGROUND. The Quebec Neuroblastoma Screening Project was initiated to assess clinical and biologic aspects of neuroblastomas detected by screening infants born in the province of Quebec from May 1, 1989, to April 30, 1994.
METHODS. Infants were screened for preclinical detection of neuroblastoma by determination of catecholamine metabolites, vanillylmandelic acid (VMA), and homovanillic acid (HVA). Patients with tumors discovered through this screening as well as patients in the same birth cohort with clinically detected tumors were referred to Quebec Oncology Centers for further investigation, diagnosis, and treatment. Pathology specimens were submitted to Childrens Hospital Los Angeles for central review. Tumors were histopathologically classified according to the Shimada system.
RESULTS. As of August, 1993, 340,000 infants were screened at 3 weeks and 245,000 of them were retested at 6 months of age. Thirty-one tumors were detected through this screening and removed. Histologic material was available for 27 cases: 14 were detected at 3 weeks of age and 13 at 6 months of age. Twenty-six patients had tumors with favorable histology (FH), and one patient had a Stage I tumor with unfavorable histology (UH). At the time of this writing, all mass screening patients are alive, including one child with relapsed disease. During this period, 48 tumors were detected clinically in the same birth cohort, 40 of which were evaluated histologically. Of these 40 cases, 28 of 29 tumors diagnosed in patients up to age 12 months indicated an FH, whereas 9 of 11 tumors diagnosed in patients older than age 12 months indicated a UH. All patients with FH tumors are alive including a child with relapsed disease. The single patient with UH diagnosed before age 12 months died of disease. Of the nine patients with UH diagnosed after age 12 months, four died of disease, one relapsed, and four are alive (including one treated with bone marrow transplantation) after variable follow-up periods.
CONCLUSIONS. The tumors detected by mass screening, similar to those tumors detected through clinical examination before age 12 months, were predominantly FH with good prognosis. However, those tumors that were missed by screening and were detected clinically after the patient was 12 months of age were predominantly UH, with serious clinical problems. This subgroup of patients not detectable by the current screening system presents an immediate and important clinical challenge that should be addressed in future studies.
80-90% of patients have elevated norepinephrine or epinephrine or metabolites of VMA, HVA, or MHPG
VMA/HVA ratio of >1.5 improved prognosis
Synthesized by tumor and coats surface of T lymphocytes leading to E rosette inhibition, present in advanced neuroblastoma Detection of Minimal Residual Disease RT-PCR and flow cytometry has been utilized PCR Quantification of MYCN, DDX1, and NAG Gene Copy Number in Neuroblastoma Using a Real-Time Quantitative PCR Assay
Katleen De Preter, M.Sc., Frank Speleman, Ph.S., Valérie Combaret, Ph.D., John Lunec, Ph.D., Geneviève Laureys, M.D., Ph.D., Bert H.J. Eussen, Nadine Francotte, M.D., Julian Board, Andy D.J. Pearson, M.D., Anne De Paepe, M.D., Ph.D., Nadine Van Roy, Ph.D. and Jo Vandesompele, M.Sc.
Center for Medical Genetics (KDPFS, ADP, NVR, JV), and Department of Pediatric Hemato-Oncology (GL), Ghent University Hospital, Ghent, Belgium; Molecular Oncology Unit (VC), Centre Léon Bérard, Lyon, France; Cancer Research Unit (JL, JB), Department of Child Health (AP), University of Newcastle, Newcastle upon Tyne, United Kingdom; Department of Clinical Genetics (BE), Erasmus University, Rotterdam, The Netherlands; and Department of Pediatrics (Hemato-Oncology section) (NF), Cliniques Saint-Joseph Espérance, Montegnée, Belgium
Mod Pathol 2002;15:159-166 Abstract quote
Amplification of the proto-oncogene MYCN is a strong adverse prognostic factor in neuroblastoma patients in all tumor stages. The status of the MYCN gene has become an important factor in clinical decision making and therapy stratification. Consequently, fast and accurate assessment of MYCN gene copy number is of the utmost importance and the use of two independent methods to determine MYCN status is recommended.For these reasons we have developed and evaluated a real-time quantitative PCR (Q-PCR) assay as an alternative for time-consuming Southern blot analysis (SB), and as a second independent technique in parallel with fluorescence in situ hybridization (FISH) analysis. Advantages of Q-PCR are a large dynamic range of quantification, no requirement for post-PCR sample handling and the need for very small amounts of starting material. The accuracy of the assay was illustrated by measurement of MYCN single gene copy changes in DNA samples of two patients with 2p deletion and duplication, respectively. Two different detection chemistries i.e., a sequence specific TaqMan probe and a generic DNA binding dye SYBR Green I were evaluated and shown to yield similar results. Also, two different calculation methods for copy number determination were used i.e., the kinetic method and the comparative CT method, and shown to be equivalent.
In total, 175 neuroblastoma samples with known MYCN status, as determined by FISH and/or SB, were examined. Q-PCR data were highly concordant with FISH and SB data. In addition to MYCN copy number evaluation, DDX1 and NAG gene copy numbers were determined using a similar Q-PCR strategy. Survival analysis pointed out that DDX1 and/or NAG amplification has no additional adverse effect on prognosis.
CLINICAL AND GENETIC TYPES OF NEUROBLASTOMA (J Pediatr Hematol Oncol 1997;19:93)
FEATURE TYPE 1 TYPE 2 TYPE 3 DNA Ploidy Hyperdiploid or near-triploid Near-diploid or near-tetraploid Near-diploid or near-tetraploid N-myc Normal Normal Amplified 1p allelic loss <5% 25-50% 80-90% TRK-A expression High Low Low or absent Age <1 year >1 year >1 year Stage 1,2, or 4S 3 or 4 3 or 4 3-Year survival 95% 25-50% <5%
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION General Distribution follows the sympathetic ganglia, usually in paramidline position between the skull and pelvis
Adrenal medulla and organ of Zuckerkandl6-8 cm in diameter
VARIANTS Blueberry muffin baby 1/3 of neonates present with blue-red cutaneous metastases Myoclonus-oposclonus syndrome Rapid alternating eye movements and myoclonic movements of the extremities Adult Neuroblastoma of the Retroperitoneum and Abdomen Clinicopathologic Distinction From Primitive Neuroectodermal Tumor
Tadashi Hasegawa, M.D.; Takanori Hirose, M.D.; Alberto G. Ayala, M.D.; Shigemi Ito, M.D.; Utano Tomaru, M.D.; Yoshihiro Matsuno, M.D.; Tadakazu Shimoda, M.D.; Setsuo Hirohashi, M.D.
From the Department of Pathology (T.H., S.H.) and Clinical Laboratory (U.T., Y.M., T.S.), National Cancer Center Research Institute and Hospital, Tokyo, Japan; the Department of Pathology (T.H.), Saitama Medical School, Saitama, Japan; and the Department of Pathology (A.G.A., S.I.), University of Texas M.D. Anderson Cancer Center, Houston, Texas, U.S.A.
Am J Surg Pathol 2001;25:918-924 Abstract quote
Adult neuroblastoma (ANB) is a rare and poorly recognized entity among a histologically defined group of small, round-cell tumors arising in the retroperitoneum and abdomen. Eight cases of ANB were compared with seven cases of primitive neuroectodermal tumor (PNET) in these locations to identify clinicopathologic features that could be used to distinguish between the two lesions. The ANB study group included four men and four women 22–74 years of age (mean 38 years). Five patients with ANB presented with inflammatory symptoms or elevated levels of catecholamines and their metabolites. Five of the ANB tumors were classified as undifferentiated and three as poorly differentiated with a background of neuropil. These cases often showed immunoreactivity for multiple neural markers such as CD56, chromogranin A, synaptophysin, neurofilament, and neuron-specific enolase, but were negative for CD99, cytokeratins, desmin, myogenin, smooth muscle actin, muscle-specific actin, CD34, S-100 protein, and CD45. In contrast, all of the PNETs were positive for CD99, and four (57%) were also positive for cytokeratins. Two cases of ANB of the undifferentiated subtype had ultrastructural features characteristic of neuroblastoma and lacked a chimeric transcript (EWS-FLI1or ERG), which is specific for PNET. All five patients with the undifferentiated subtype of ANB and six of the seven patients with PNET died of their disease within 3 years of discovery of the lesion.
Our results show that ANB, although rare, should be considered in the differential diagnosis of patients with small, round-cell tumors in the retroperitoneum and abdomen. Appropriate immunohistochemical studies and laboratory examination enable pathologists to distinguish ANB from other differential diagnoses, especially PNET.
HISTOLOGICAL TYPES CHARACTERIZATION General Neuroblasts with varying stages of differentiation
Classification systems use a combination of different systems and histologic parametersHomer-Wright rosettes
INPC (International Neuroblastoma Pathology Committee)
Neuroblastoma (Schwannian stroma-poor) Undifferentiated type-No ganglionic differentiation
Poorly differentiated type <5% differentiating cells
Differentiating type >5% differentiating cellsGanglioneuroblastoma, nodular Composite Schwannian stoma/rich stroma-dependent and stroma poor Ganglioneuroblastoma, intermixed Schwannian stroma-rich Ganglioneuromna (Schwannian stroma dominant) Maturing
MatureVARIANTS CHROMAFFIN CELL DIFFERENTIATION
Unusual chromaffin cell differentiation of a neuroblastoma after chemotherapy and radiotherapy: report of an autopsy case with immunohistochemical evaluations.
Miyauchi J, Kiyotani C, Shioda Y, Kumagai M, Honna T, Matsuoka K, Masaki H, Aiba M, Hata J, Tsunematsu Y.
Department of Clinical Laboratory, National Children's Hospital, Tokyo, Japan.
Am J Surg Pathol. 2004 Apr;28(4):548-53. Abstract quote
Neuroblastomas are derived from neural crest cells that are capable of multilineage differentiation. Ganglionic neuronal differentiation of childhood neuroblastoma is seen with increasing age, leading to more differentiated tumors called ganglioneuroblastomas or ganglioneuromas. Despite the fact that neuroblastomas most often arise from the adrenal medulla, chromaffin-cell differentiation in neuroblastomas is not widely recognized. Tumor cells with a chromaffin-cell nature have only been detected using histochemical techniques in neuroblastoma cell lines or focal areas of certain in vivo tumors.
We describe a neuroblastoma that exhibited an unusual differentiation toward chromaffin cells in a patient that had been treated with surgery, intensive chemotherapy, and radiotherapy. Although a biopsy specimen of the retroperitoneal primary tumor was extensively necrotic, possibly because of a previous chemotherapy regimen, surgically resected metastatic tumors of bilateral ovaries were viable and diagnosed as poorly differentiated neuroblastomas according to the International Neuroblastoma Pathology Classification system. However, metastatic tumors of bilateral lungs examined at the time of autopsy exhibited histologic features similar to those of a pheochromocytoma/paraganglioma, and immunohistochemical examinations demonstrated that these tumors were composed of extra-adrenal chromaffin cells.
This case confirms that neuroblastomas in childhood can transform into pheochromocytoma/paraganglioma-like tumors under special conditions.IN SITU Small microscopic foci confined to adrenal and discovered incidentally at autopsy
1/200 infants dying from unrelated causes
SPECIAL STAINS/
IMMUNOPEROXIDASECHARACTERIZATION Special stains Immunoperoxidase NSE, neurofilament protein, S100
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES Small round blue cell tumors Ewing's sarcoma family of tumor arising in the adrenal gland—Possible diagnostic pitfall in pediatric pathology: Histologic, immunohistochemical, ultrastructural, and molecular study
Keisuke Kato, MD
Yoshikazu Kato, MD
Rieko Ijiri, MD
Kazuaki Misugi, MD, PhD
Ikuko Nanba, MT
Jun-Ichi Nagai, MT
Noriyuki Nagahara, MD, PhD
Hisato Kigasawa, MD
Yasunori Toyoda, MD
Toshiji Nishi, MD
Yukichi Tanaka, MD, PhDHum Pathol 2001;32:1012-1016 Abstract quote
We present an adrenal Ewing's sarcoma family of tumor (ESFT) arising in an 11-year-old Japanese boy. Although intensive chemoradiotherapy and radical surgery were performed, the patient died of obstinate disease 1 year and 3 months after the initial presentation. The primary site (adrenal gland) with radiologic findings (with foci of calcification), high titer of serum neuron specific enolase, and sheets of monotonous primitive rounded cells on histology mostly favored neuroblastoma. However, a diagnosis of ESFT was confirmed by immunohistochemical profile, including MIC2-positivity and molecular study disclosing EWS-FLI1 chimera gene verified by direct sequencing.
Recognition of adrenal ESFT and use of newly developed diagnostic techniques are required for differential diagnosis of undifferentiated small round cell tumor of the adrenal gland.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS Young age <1 yr
Favorable histologic type
Low stage (1,2, 4S)
No N-myc amplification
Hyperdiploid or near-triploid DNA content
No allelic loss of 1p
High expression of TRK-A
Normal serum ferritin, NSE, and lactate dehydrogenase
High urinary VMA/HVA ratioClinicopathologic Study of Mass-Screened Neuroblastoma With Special Emphasis on Untreated Observed Cases
A Possible Histologic Clue to Tumor RegressionRieko Ijiri, M.D.; Yukichi Tanaka, M.D.; Keisuke Kato, M.D.; Kazuaki Misugi, M.D.; Hirokazu Nishihira, M.D.; Yasunori Toyoda, M.D.; Hisato Kigasawa, M.D.; Toshiji Nishi, M.D.; Maho Takeuchi, M.D.; Noriko Aida, M.D.; Takashi Momoi, M.D.
From the Divisions of Pathology (R.I., K.K., Y.T., K.M.), Oncology (H.N., Y. Toyoda), Hematology (H.K.), Radiology (M.T., N.A.), and Surgery (T.N.), Kanagawa Children's Medical Center; and the Division of Development and Differentiation (T.M.), National Institute of Neuroscience, Kanagawa, Japan.
Am J Surg Pathol 2000;24:807-815 Abstract quote Spontaneous regression and maturation of neuroblastoma (NB) are well documented and occur frequently in infants, including those detected by mass screening.
To seek histologic clues for regression/maturation in mass-screened NB, clinicopathologic features of 12 tumors that were resected after 2 to 18 months of untreated observation were reviewed. Unobserved screened and age-matched unscreened patients were also studied.
To evaluate the possible important role of apoptosis, apoptotic cells were detected by in situ deoxyribonucleic acid (DNA) nick end labeling and immunohistochemical stain for activated caspase-3. Nests with a varying degree of reduced cellularity (``less cellular'' and ``hypocellular'' nests) were common in patients younger than 18 months of age, and were rare in older patients. Two characteristic cells, which have not been focused previously, were frequent, especially in the hypocellular nests. One showed amorphic eosinophilic cytoplasm with pyknotic nuclei and the other contained plump cytoplasm with well-maintained nuclei. These cells were also observed in 89% of the unobserved screened NBs and 79% of the age-matched unscreened patients with good outcome, whereas they could not be confirmed in any of the age-matched unscreened NBs with poor outcome. The amorphic and plump cells were negative for activated caspase-3 and in situ DNA nick end labeling.
From these results, the authors hypothesize that these cells most likely represent a degenerative process, in either a state before the activation of caspase-3 or a caspase-independent form of cell death. The presence of less cellular and hypocellular nests with amorphic/plump cells may serve as one of the important clues in predicting tumor prognosis.
CASPASE-DEPENDENT APOPTOSIS
- Increased Occurrence of Caspase-Dependent Apoptosis in Unfavorable Neuroblastomas.
Koizumi H, Hamano S, Doi M, Tatsunami S, Nakada K, Shinagawa T, Tadokoro M.
From the Departments of *Diagnostic Pathology and daggerPediatric Surgery, and the double daggerUnit of Medical Statistics, Faculty of Education and Culture, St. Marianna University School of Medicine, Kawasaki, Japan.
Am J Surg Pathol. 2006 Feb;30(2):249-257. Abstract quote
Neuroblastoma frequently shows spontaneous regression in which two distinct types of programmed cell death, ie, caspase-dependent apoptosis and H-Ras-mediated autophagic degeneration, have been suggested to play a key role.
The current study was conducted to determine which of these cell suicide pathways predominated in this tumor regression. Periodic acid-Schiff (PAS) staining and immunostaining for H-Ras and for the full-length and cleaved forms of caspase-3, poly (ADP-ribose) polymerase (PARP), and lamin A were carried out on 55 archival tumor specimens. The incidence of caspase-dependent apoptosis in each tumor was quantified by cleaved lamin A staining and compared with clinicopathologic prognostic factors. Although a recent report has shown that neuroblastic cells undergoing autophagic degeneration were readily detectable by PAS and H-Ras staining, we could not confirm this result in any of our samples with the exception of one tumor. Instead, many of our neuroblastoma samples showed nonspecific PAS and Ras staining in areas of necrosis, suggesting that autophagic "degeneration" indeed corresponds to coagulation necrosis or oncosis.
Unexpectedly, the incidence of caspase-dependent apoptosis was significantly correlated with indicators of a poor prognosis in these tumors, including Shimada's unfavorable histology, MYCN amplification, and a higher mitosis-karyorrhexis index, but not with factors related to tumor regression such as clinical stage and mass screening.
These results indicate that neither caspase-dependent apoptosis nor autophagic "degeneration" may be involved in spontaneous neuroblastoma regression. This suggests that other mechanisms, perhaps such as tumor maturation, may be responsible for this phenomenon.STAGING
Experience with International Neuroblastoma Staging System and Pathology Classification.Ikeda H, Iehara T, Tsuchida Y, Kaneko M, Hata J, Naito H, Iwafuchi M, Ohnuma N, Mugishima H, Toyoda Y, Hamazaki M, Mimaya J, Kondo S, Kawa K, Okada A, Hiyama E, Suita S, Takamatsu H.
Department of Pediatric Surgery, Dokkyo University School of Medicine, Koshigaya Hospital, 2-1-50 Minami-Koshigaya, Koshigaya, Saitama 343-8555, Japan.
Br J Cancer 2002 Apr 8;86(7):1110-6 Abstract quote The International Neuroblastoma Staging System and Pathology Classification were proposed in 1988 and in 1999, respectively, but their clinical value has not yet been fully studied in new patients. Six hundred and forty-four patients with neuroblastoma treated between January 1995 and December 1999 were analysed by these classifications. The 4-year overall survival rate of patients <12 months of age with INSS stages 1, 2A, 2B, 3 and 4S disease was 98.5%, which was significantly higher than the 73.1% rate in stage 4 patients <12 months (P<0.0001).
When patients were > or = 12 months, the 4-year overall survival rate of patients with neuroblastoma at 1, 2A, 2B and 3 stages was 100% and that of patients at stage 4 was 48.5% (P<0.0001). As to the International Neuroblastoma Pathology Classification histology, the 4-year overall survival rate was 98.8% in patients with favourable histology and 60.7% in those with unfavourable histology in the <12 months group (P<0.0001). In the > or = 12 months group, the 4-year oral survival of patients with favourable histology was 95.3% and that of patients with unfavourable histology was 50.6% (P<0.0001). Among biological factors, MYCN amplification, DNA diploidy and 1p deletions were significantly associated with poor prognosis in patients <12 months, as were MYCN amplification and DNA diploidy in patients > or = 12 months of age.
Multivariate analysis showed that the INSS stage (stage 4 vs other stages) and International Neuroblastoma Pathology Classification histology (unfavourable vs favourable) were significantly and independently associated with the survival of patients undergoing treatment, stratified by age, stage and MYCN amplification (P=0.0002 and P=0.0051, respectively).
Survival J Natl Cancer Inst 1984;73:405 Histological Type Survival % STROMA RICH Favorable histology 100 92 Unfavorable histology 18 STROMA POOR Favorable histology 84 Unfavorable histology 4.5 N-myc amplification N-myc amplification (%) and 3 Year survival <5% and 90% 5-10% and 80% 30-35% and 30% 25-30% and 50% TREATMENT 1-2% undergo spontaneous regression or maturation
Surgical removal followed by chemotherapyManagement is dicated largely by the clincal stage and the risk for recurrent disease based upon the age, stage, and biological risk factors
Surgery alone Individualized
<4 weeks of age usually have chemotherapy and irradiation prior to surgery
> 4 weeks of age have been further divided into low and high risk groups based upon biological markers:
Low risk-surgery alone
High risk-surgery with adjuvant chemotherapyChemotherapy and second-look surgery
Multiagent therapy (Cyclophosphamide, ifosfamide, doxorubicin, etoposide, cisplatin)Postoperative dose intensive chemotherapy
May consider autologous bone marrow and peripheral blood stem cell transplantationA Midkine Promoter-based Conditionally Replicative Adenovirus for Treatment of Pediatric Solid Tumors and Bone Marrow Tumor Purging.
Adachi Y, Reynolds PN, Yamamoto M, Wang M, Takayama K, Matsubara S, Muramatsu T, Curiel DT.
The Division of Human Gene Therapy, Departments of Medicine, Surgery, and Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294 [Y. A., P. N. R., M. Y., W. M., K. T., D. T. C.].
Cancer Res 2001 Nov 1;61(21):7882-8 Abstract quote
The treatment of advanced neuroblastoma (NB) or Ewing's sarcoma (ES) is one of the major challenges in pediatric oncology. Both malignancies are refractory to conventional therapies and have an extremely poor prognosis. High-dose myeloablative radiochemotherapy with autologous bone marrow or peripheral blood stem cell rescue is one of the most aggressive treatments attempted for these diseases but is often undermined by residual tumor cells contaminating the graft. Thus, in this approach, purging of tumor cells from the graft is key to the prevention of relapse after transplantation.
We investigated a novel approach to eliminate tumor cells from the bone marrow or peripheral blood stem cell graft without causing stem cell damage through the use of a conditionally replicative adenovirus (Ad).
ES and NB are sensitive to Ad infection, and advanced NBs express a high level of the growth/differentiation factor midkine (MK). We confirmed in this study that ES cell lines (SK-ES-1 and RD-ES) are also sensitive to Ad infection and express high levels of MK. In contrast, CD34(+) stem cells are refractory to Ad infection and express very little MK. A conditionally replicative Ad in which the expression of E1 is controlled by the MK promoter achieved good levels of viral replication in NB or ES and induced remarkable tumor cell killing. On the other hand, this virus caused no damage to CD34(+) cells even after 3 h of infection at a dose of 1000 multiplicity of infection.
We concluded that application of this replication-competent Ad to hematopoietic grafts could be a simple but effective procedure to achieve complete tumor cell purging.
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DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
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Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
N-myc-Overexpression of this oncogene has been associated with a poor prognosis.
Neuroblast-Primitive precursor cells comprising this tumor
Rosettes-These characteristic structures are tumor cells surrounding a central space filled with extensions of the cytoplasm. Homer-Wright rosettes are the most common type seen in this tumor.
Staging-International Neuroblastoma Staging System (J Clin Oncol 1993;11:1466)
Stage Definition 1 Localized tumor confined to the area of origin;
Complete gross resection, with or without microscopic residual disease:
Representative ipsilateral lymph nodes negative for tumor2A Localized tumor with incomplete gross excision:
Representative ipsilateral nonadherent lymph nodes negative for tumor2B Localized tumor with or without complete gross excision, with ipsilateral nonadherent lymph nodes positive for tumor
Enlarged contralateral lymph nodes negative for tumor3 Unresectable unilateral tumor infiltrating across the midline, with or without regional lymph node involvement;
Or localized unilateral tumor with contralateral regional lymph node involvement;
Or midline tumor with bilateral extension by infiltration or by lymph node involvement4 Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs except as defined for stage 4S 4S Localized primary tumor (as defined for stage 1, 2A, or 2B), with dissemination limited to skin, liver, and/or bone marrow Basic Principles of Disease
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Last Updated February 14, 2006
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