Subgrouping of Unfavorable Histology Neuroblastomas With Immunohistochemistry Toward Precision Prognosis and Therapy Stratification

Ikegaki, Naohiko; Shimada, Hiroyuki

doi:10.1200/po.18.00312

Cited by 13 publications

(14 citation statements)

References 62 publications

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“…Recently, we have described an immunohistochemistry-based sub-classification of the UH neuroblastoma, which subcategorizes them into UH and Extremely Unfavorable Histology (EUH) subsets (7). As shown in Figures S1A, B, the EUH subset includes (i) MYCdriven neuroblastoma expressing high MYC and/or MYCN protein (8), (ii) Neuroblastoma with TERT overexpression due to genomic rearrangements (9)(10)(11), and (iii) Neuroblastoma of the ALT group due to ATRX loss (12,13).…”

Section: Introductionmentioning

confidence: 99%

“…As shown in Figures S1A, B, the EUH subset includes (i) MYCdriven neuroblastoma expressing high MYC and/or MYCN protein (8), (ii) Neuroblastoma with TERT overexpression due to genomic rearrangements (9)(10)(11), and (iii) Neuroblastoma of the ALT group due to ATRX loss (12,13). The remaining tumors of the UH is called the Null group, which does not have the above three characteristics of the EUH tumors (7). The MYC-driven neuroblastoma group includes both MYCN-amplified and non-amplified tumors with high MYCN and MYC expression, respectively, and they are among the worst tumors that ultimately kill the patients.…”

Section: Introductionmentioning

confidence: 99%

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Clinical Relevance of CD4 Cytotoxic T Cells in High-Risk Neuroblastoma

2021

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Neuroblastoma is the most common extracranial childhood solid tumor. The majority of high-risk neuroblastoma is resistant/refractory to the current high intensity therapy, and the survival of these patients remains poor for the last three decades. To effectively treat these extremely unfavorable neuroblastomas, innovative immunotherapy approaches would be the most promising. In this article, we discuss the identity of tumor-infiltrating effector cells and immunosuppressive cells in high-risk neuroblastoma. Neuroblastoma is unique in that it expresses little or no classical HLA Class I and II. In contrast, high-risk neuroblastomas express the stress-responsive non-classical Class I, HLA-E molecule. HLA-E is the ligand of activating receptors NKG2C/E that are expressed on memory NK cells, CD8+T cells and CD4 CTLs. By examining a comprehensive RNA-seq gene expression dataset, we detected relatively high levels of CD4 expression in high-risk neuroblastoma tissues. The majority of CD4+ cells were CD3+, and thus they were likely tumor-associated CD4+T cells. In addition, high-level of both CD4 and NKG2C/E expression was associated with prolonged survival of the high-risk neuroblastoma patients, but CD8 levels were not, further suggesting that the CD4+ NKG2C/E+ T cells or CD4 CTL conferred cytotoxicity against the neuroblastoma cells. However, this T cell mediated- “protective effect” declined over time, in part due to the progressive formation of immunosuppressive tumor microenvironment. These observations suggest that to improve survival of high-risk neuroblastoma patients, it is essential to gain insights into how to enhance CD4 CTL cytotoxicity and control the immunosuppressive tumor microenvironment during the course of the disease.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Clinical Relevance of CD4 Cytotoxic T Cells in High-Risk Neuroblastoma

2021

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“…They can be divided into three subgroups depending on their maturity: neuroblastomas, ganglioneuroblastomas and ganglioneuromas. 2,3 Neuroblastomas are the most undifferentiated and aggressive, ganglioneuroblastomas have intermediate malignant potential and ganglioneuromas, although very rarely have been reported to metastasize, are considered to be benign tumors. 4 Ganglioneuromas typically affect children and young adults.…”

Section: Discussionmentioning

confidence: 99%

Oncovascular Resection of a Ganglioneuroma Involving the Coeliac Trunk and Hepatic Artery—A Case Report

Lawrie

Whitley

Rokošný

et al. 2021

Vasc Endovascular Surg

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A large tumorous mass completely surrounding and compressing the coeliac trunk was identified on computed tomography in a young woman with a six-month history of progressive abdominal pain. The tumor was excised along with the coeliac trunk and the proximal parts of its branches. The hepatic artery was reconstructed with an aorto-hepatic autogenous bypass. Postoperatively the patient had neurogenic diarrhea, which subsided on medical treatment. Seven months after surgery the patient is in a good state of health and living a normal life.

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“…Other molecular mechanisms that account for UH without MYCN amplification include: segmental chromosome aberrations (1p deletion, 11q deletion, and 17q gain), MYC overexpression, ALK mutation/amplification and/or high ALK protein expression, ATRX mutation, and TERT rearrangement 39‐41 . More recently, Ikegaki and Shimada proposed four subgroups in UH neuroblastomas for precision medicine: 42 the MYC subgroup, TERT subgroup, ALT subgroup, and Null subgroup. These subgroups are immunohistochemically identified by their protein makers, which may be potential therapeutic targets (Table 1).…”

Section: Subgrouping Of Unfavorable Histology Neuroblastoma and Precimentioning

confidence: 99%

Biological categories of neuroblastoma based on the international neuroblastoma pathology classification for treatment stratification

Nakazawa

2021

Pathology International

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The International Neuroblastoma Pathology Classification (INPC), which distinguishes a favorable histology (FH) and an unfavorable histology (UH), is one of the most powerful prognostic factors in patients with neuroblastoma. FH that shows spontaneous regression or age‐appropriate tumor differentiation/maturation, is common in infants and has mutual interaction with Schwann cells via the NGF/NTRK1 pathway and gain of whole chromosome 17. In contrast, UH is prevalent in older children and is molecularly heterogeneous. MYCN amplification is the most frequent genomic abnormality in tumors with UH. MYCN‐amplified tumors demonstrate characteristic histology, the same as MYC‐positive neuroblastoma. Chromosome 1pLOH is often associated with MYCN amplification, but on the other hand, chromosome 11qLOH rarely occurs in combination with MYCN amplification. 11qLOH has an inferior prognostic impact in UH without MYCN amplification. The high expression of ALK protein is a negative prognostic factor in both ALK mutated or amplified tumors and FH, but not in UH. Abnormal maintenance/elongation of telomeres; overexpression of telomerase reverse transcriptase (TERT) and the alternative lengthening of telomeres (ALT) phenotype due to ATRX mutation, are another molecular event in UH. The INPC, incorporating immunohistochemistry for MYCN, MYC, ALK, TERT and ATRX, represents a practical and implementable approach to create the biological category for the future management of patients with this unique disease.

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Subgrouping of Unfavorable Histology Neuroblastomas With Immunohistochemistry Toward Precision Prognosis and Therapy Stratification

Cited by 13 publications

References 62 publications

Clinical Relevance of CD4 Cytotoxic T Cells in High-Risk Neuroblastoma

Clinical Relevance of CD4 Cytotoxic T Cells in High-Risk Neuroblastoma

Oncovascular Resection of a Ganglioneuroma Involving the Coeliac Trunk and Hepatic Artery—A Case Report

Biological categories of neuroblastoma based on the international neuroblastoma pathology classification for treatment stratification

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