International neuroblastoma pathology classification for prognostic evaluation of patients with peripheral neuroblastic tumors

Shimada, Hiroyuki; Umehara, Shunsuke; Monobe, Yasumasa; Hachitanda, Yoichi; Nakagawa, Atsuko; Goto, S.; Gerbing, Robert B.; Stram, Daniel O.; Lukens, John N.; Matthay, Katherine K.

doi:10.1002/1097-0142(20011101)92:9<2451::aid-cncr1595>3.0.co;2-s

Cited by 277 publications

(201 citation statements)

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“…In conclusion, the present findings confirm previous reports indicating that MKI is in NTs a reliable morphological marker of clinical behaviour and identifies favourable and unfavourable NTs (Shimada et al, 1995(Shimada et al, , 1999b(Shimada et al, , 2001Ambros et al, 2002). Our results also show that karyorrhectic cells represent the end-stage of a cascade of events leading to morphologically recognisable apoptosis, although none of these individual events is able by itself to determine the clinical relevance of the entire apoptotic process.…”

Section: Discussionsupporting

confidence: 91%

“…Our results show that a high MKI is associated with advanced stage, NB histological category, MYCN amplification and poor outcome, thus confirming previous findings reported by Shimada et al (1995Shimada et al ( , 1999bShimada et al ( , 2001) and Ambros et al (2002). However, when the levels of expression of key genes involved in apoptosis were compared to either MKI and clinicobiological features, no significant associations were found.…”

Section: Discussionsupporting

confidence: 91%

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Morphological and molecular assessment of apoptotic mechanisms in peripheral neuroblastic tumours

et al. 2006

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Multiple defects in apoptotic pathways have been described in peripheral neuroblastic tumours (NTs). Mitosis -karyorrhexis index (MKI) is a reliable morphological marker identifying favourable and unfavourable NTs. The extent to which apoptotic processes contribute to determine the clinical significance of MKI is still undefined. Apoptosis was investigated in a series of 110 peripheral NTs by comparing MKI to immunohistochemical and molecular apoptotic features. High MKI was found in 55 out of 110 NTs (50%) and was associated with advanced stage (P ¼ 0.007), neuroblastoma (NB) histological category (P ¼ 0.024), MYCN amplification (Po0.001), and poor outcome (P ¼ 0.011). Overall survival probability was 45% in patients with high MKI compared to 73% in patients with low MKI. In the same 110 NTs, the expression of Bcl-2, Bcl-X L , Bax and Mcl-1 was studied by immunohistochemistry, but no significant associations were found with clinicohistological features. Microarray analysis of apoptotic genes was performed in 40 out of 110 representative tumours. No significant association was found between the expression of apoptotic genes and MKI or clinicohistological features. Proliferative activity was assessed in 60 out of 110 representative tumours using Ki67 immunostaining, but no significant correlations with MKI or clinicobiological features were found. In NTs, the combination of apoptosis and proliferation as expressed by MKI is a significant prognostic parameter, although neither of them is per se indicative of the clinicobiological behaviour and outcome.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 91%

Morphological and molecular assessment of apoptotic mechanisms in peripheral neuroblastic tumours

et al. 2006

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“…3,4 Features associated with a poor outcome include: age 418 months, 2 unfavorable histopathology, 5 amplification of the MYCN oncogene, [6][7][8] diploid DNA content, and specific segmental chromosomal aberrations such as loss of heterozygosity at 1p and 11q, gain of 17q. 3,9 Currently, the pathology of neuroblastoma is graded according to the International Neuroblastoma Pathology Classification [10][11][12] that separates histologic subtypes of neuroblastoma into favorable and unfavorable categories. One uncommon subtype is nodular ganglioneuroblastoma, which represents 5-10% of neuroblastic tumors.…”

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confidence: 99%

“…One uncommon subtype is nodular ganglioneuroblastoma, which represents 5-10% of neuroblastic tumors. [12][13][14] Nodular ganglioneuroblastoma is a composite tumor, with a predominance of differentiated Schwannian-type stroma associated with one or more macroscopically visible nodules of neuroblastoma showing neuropil formation but lacking this Schwannian stroma (referred to as 'stroma-poor'). Less common variants without visible nodules have more recently been included under the category of nodular ganglioneuroblastoma.…”

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confidence: 99%

“…15,16 In the original version of this classification system, this subtype was categorized with the unfavorable histology group, and those patients had a 46.8% event-free survival and 59.1% overall survival. 12 More recently, it was shown that nodular ganglioneuroblastoma can be subcategorized as favorable or unfavorable according to the histopathology of the stroma-poor component, using the same criteria as for other stroma-poor neuroblastomas. 15,16 By this system, unfavorable tumors outnumber favorable ones B2:1, with an event-free survival of 29-32% for unfavorable nodular ganglioneuroblastoma compared with 86% for favorable, and overall survival of 33-40% and 90-95%, respectively.…”

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The neuroblastoma and ganglion components of nodular ganglioneuroblastoma are genetically similar: evidence against separate clonal origins

et al. 2015

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Nodular ganglioneuroblastoma is characterized by a macroscopic nodule of neuroblastoma within a ganglioneuromatous component. These two components have been considered to originate from separate clones, with the neuroblastoma clone accounting for the clinical behavior of nodular ganglioneuroblastoma. In order to investigate the clonal origin of the cellular components (neuroblasts, ganglion cells, and Schwann cells) of nodular ganglioneuroblastoma, paraffin-embedded tumor samples from eight cases were analyzed by single nucleotide polymorphism array and in situ hybridization. DNA was extracted separately from neuroblastomatous and ganglioneuromatous areas. By in situ hybridization, MYCN gain (4-10 gene copies/ nucleus) was detected in 7/8 neuroblastoma samples. In ganglioneuromatous regions, gains were also detected in ganglion cells but not in Schwann cells. Single-nucleotide polymorphism array studies identified chromosome losses (11q and 14q) and gains (12, 13q, 17q and 18q) in the neuroblastoma component, whereas the ganglioneuromatous component showed fewer or no genetic alterations. There were no unique copy number changes distinguishing nodular ganglioneuroblastoma from other subtypes of neuroblastoma. By in situ hybridization, ganglion cells but not Schwann cells showed the same alterations detected in neuroblasts. Thus, neuroblasts and ganglion cells in nodular ganglioneuroblastoma are genetically related and may arise from the same clone. In contrast, the Schwann cells have a different origin and may be derived from a nonneoplastic neural crest precursor. Our results suggest that the clinical behavior of nodular ganglioneuroblastoma cannot be explained by the presence of separate clones with distinct genetic signatures.

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Histopathology (International Neuroblastoma Pathology Classification) and MYCN status in patients with peripheral neuroblastic tumors

Goto

Umehara

Gerbing

et al. 2001

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BACKGROUND The International Neuroblastoma Pathology Classification (International Classification), which was established in 1999, is significant prognostically and is relevant biologically for the evaluation and analysis of patients with neuroblastic tumors (NTs). MYCN amplification is a known molecular marker for aggressive progression of NTs. These have been used together as important prognostic factors to define risk groups for patient stratification and protocol assignment. METHODS A total of 628 NTs (535 neuroblastomas [NBs]); 21 ganglioneuroblastoma, intermixed [GNBi]; 9 ganglioneuromas [GN]; and 63 ganglioneuroblastoma, nodular [GNBn]) from the Children's Cancer Group studies were evaluated histologically (favorable histology [FH] tumors vs. unfavorable histology [UH] tumors) according to the International Classification and were tested molecularly for MYCN status (amplified vs. nonamplified). Four tumor subsets (FH‐nonamplified, FH‐amplified, UH‐nonamplified, and UH‐amplified) were defined by histopathology and MYCN status, and their prognostic effects were analyzed. Detailed analysis between morphologic indicators (grade of neuroblastic differentiation and mitosis‐karyorrhexis index [MKI]) and MYCN status was done by using tumors in the NB category. RESULTS There were 339 FH‐nonamplified tumors (5‐year event free survival [EFS], 92.1%); 8 FH‐amplified tumors (EFS, 37.5%); 172 UH‐nonamplified tumors (EFS, 40.9%); and 109 UH‐amplified tumors (EFS, 15.0%). The prognostic effects on patients with tumors in the four subsets were independent from the factors of patient age and disease stage (P < 0.0001). MYCN amplification was seen almost exclusively in tumors of the NB category, and no patients with tumors in either the GNBi category or in the GN category and only two patients with tumors in the GNBn category had amplified MYCN. Among the patients with tumors in the NB category, patients with FH‐nonamplified tumors (309 patients) had an excellent prognosis, and patients with UH‐amplified tumors (107 patients) had the poorest clinical outcome in any age group. The prognosis for children with UH‐nonamplified tumors (111 patients) was poor when they were diagnosed at age > 1.5 years. It was also noted that patients with UH‐amplified tumors (median age, 2.14 years) were diagnosed at a significantly younger age compared with the patients with UH‐nonamplified tumors (median age, 3.55 years). Histologically, MYCN‐amplified tumors lacked neuroblastic differentiation regardless of the age of patients. MYCN amplification also was linked generally to increased mitotic and karyorrhectic activities. However, MKI classes in patients with MYCN‐amplified tumors varied significantly, depending on the age at diagnosis, and younger patients had higher MKI classes. CONCLUSIONS The combination of histopathologic evaluation and MYCN status distinguishes four clinical and biologic tumor subsets in patients with NTs. MYCN amplification seems to be the powerful driving force for preventing cellular differentiation regardles...

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International neuroblastoma pathology classification for prognostic evaluation of patients with peripheral neuroblastic tumors

Cited by 277 publications

References 18 publications

Morphological and molecular assessment of apoptotic mechanisms in peripheral neuroblastic tumours

Morphological and molecular assessment of apoptotic mechanisms in peripheral neuroblastic tumours

The neuroblastoma and ganglion components of nodular ganglioneuroblastoma are genetically similar: evidence against separate clonal origins

Histopathology (International Neuroblastoma Pathology Classification) and MYCN status in patients with peripheral neuroblastic tumors

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