Elsevier

Human Pathology

Volume 85, March 2019, Pages 162-167
Human Pathology

Original contribution
HuC/D expression in small round cell tumors and neuroendocrine tumors: a useful tool for distinguishing neuroblastoma from childhood small round cell tumors

https://doi.org/10.1016/j.humpath.2018.11.004Get rights and content

Highlights

  • HuC/D is an RNA-binding protein that displays a neuron-specific expression.

  • Diffuse and strong expression of HuC/D was observed in neuroblastomas.

  • Diagnostic utility of HuC/D immunohistochemistry for neuroblastoma was demonstrated.

Summary

The RNA-binding protein HuC/D displays a neuron-specific expression and is involved in neuronal differentiation and the maintenance of the nervous system. Here we investigated the diagnostic value of HuC/D in neuroblastomas. We evaluated 85 neuroblastic tumors: 81 neuroblastomas; 3 ganglioneuroblastomas, intermixed; 1 ganglioneuroma, maturing; and 101 other tumors consisting of 34 Ewing sarcomas, 14 nephroblastomas, 11 rhabdomyosarcomas, 15 pulmonary small cell carcinomas, 18 pancreatic neuroendocrine tumors, and 9 pheochromocytomas. Immunohistochemistry for HuC/D, PHOX2B, and tyrosine hydroxylase was performed. The immunoreactivity for HuC/D was semiquantified using the total score (TS; range, 0-8). HuC/D positivity was defined as a TS ≥6. The TS of the neuroblastic tumors (mean TS, 7.94) was significantly higher than those of the other small round cell tumors and neuroendocrine tumors (P < .001) except for the pheochromocytomas (mean TS, 6.89; P = .074). HuC/D was positive in all 85 neuroblastic tumors, 1 (2.9%) Ewing sarcoma, 1 (6.7%) pulmonary small cell carcinoma, and 8 (89%) pheochromocytomas. PHOX2B was positive in all of the neuroblastic tumors and pheochromocytomas. Tyrosine hydroxylase was positive in 80 (94%) neuroblastic tumors, 1 (9.1%) rhabdomyosarcoma, and all of the pheochromocytomas. Therefore, HuC/D serves as a highly sensitive diagnostic marker to distinguish neuroblastomas from other small round cell tumors. The combination of HuC/D and PHOX2B staining may be valuable for the diagnosis of neuroblastic tumors, especially in the assessment of small sections. HuC/D expression in tumors may be related to catecholamine production or a neural crest–derived cell origin.

Introduction

Neuroblastomas are small round cell tumors that arise mostly in the adrenal glands and sympathetic nervous system. They are the most common extracranial solid tumor in children. Spontaneous regression and maturation to a benign ganglioneuroma are the characteristic features of neuroblastomas [1], [2], [3], [4], [5], and it is also known that chemotherapy leads to the maturation of neuroblastoma cells. Neuroblastoma cells are typically positive for neural antibodies (eg, neuron-specific enolase, synaptophysin, chromogranin A, NB84, and S-100 protein) [6], [7], but these antibodies are not specific to neuroblastoma [8], [9]. Tyrosine hydroxylase (TH) was the most widely used sympathoadrenal marker specific for neuroblastoma, but its sensitivity was insufficient (84%) [10], [11]. The protein known as paired-like homeobox 2b (PHOX2B) has recently attracted attention as a sensitive and specific marker for neuroblastoma.

HuC/D, a member of the Hu family, is an RNA-binding protein that displays a neuron-specific expression and is involved in neuronal differentiation and the maintenance of the nervous system [12], [13]. It has also been reported that HuC/D is a credible pan-neuronal marker for the enteric nervous system neurons [14], [15]. However, there are few published studies about HuC/D expression in neuroblastoma.

We conducted the present study to determine the HuC/D expression along with PHOX2B and TH expressions in neuroblastomas, small round cell tumors, and neuroendocrine tumors, and we discuss the potential utility of HuC/D expression as a differential diagnostic tool in neuroblastoma.

Section snippets

Patients and tissue samples

This study was approved by the Ethics Committee of Kyushu University (no. 29-429). We examined 85 paraffin-embedded samples from neuroblastic tumor tissue registered in the Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, between 1996 and 2015. Clinicopathological data were obtained from the patients' medical charts. We also stained (as comparison samples) other small round cell tumors and neuroendocrine tumors, comprising 34 Ewing sarcomas, 14

Clinicopathological characteristics

The clinicopathological features of the patients with neuroblastic tumors and the comparative tumors are summarized in Tables 1 and 2. In the group of neuroblastic tumor cases, all 85 patients were children (median age, 0 years; range, 0-8 years).

HuC/D expression

The results of the immunohistochemical analysis are summarized in Table 3. In regard to extent of staining, 98% (83/85) of the neuroblastic tumors showed a PS value of 5 (Figure A). In these cases, the percentage of positive tumor cells was almost

Discussion

In this study, we evaluated the immunohistochemical HuC/D expression profile in neuroblastic tumors, small round cell tumors, and neuroendocrine tumors. The results showed that HuC/D was expressed more diffusely and strongly in the neuroblastic tumors than in the other tumors, with the exception of the pheochromocytomas.

It is of note that HuC/D was reported to be a useful pan-neuronal marker in both central and enteric nervous system neurons [12], [13], [14], [15]. Few studies have addressed

Supplementary data

The following are the supplementary data to this article.

. Examples of HuC/D staining in other small round cell tumors and neuroendocrine tumors. A, Ewing sarcoma with EWSR1-FLI1 fusion in a 28-year-old woman (TS 6 [PS 3 + IS 3]). B, Mixed-type nephroblastoma in a 1-year-old girl (TS 3 [PS 1 + IS 2]). C, Alveolar rhabdomyosarcoma in the sinonasal region with PAX3-FOXO1 fusion in a 1-month-old girl (TS 2 [PS 1 + IS 1]). D, Pulmonary small cell carcinoma in a 79-year-old man (TS 5 [PS 3 + IS 2]). E,

Acknowledgments

The English language used in this article was revised by KN International (http://www.kninter.com/).

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    Competing interests: The authors declare that there are no conflicts of interest to disclose.

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