Succinate Dehydrogenase B Subunit Immunohistochemical Expression Predicts Aggressiveness in Well Differentiated Neuroendocrine Tumors of the Ileum

Massimo Milione,Flavia Melotti,Sara Pusceddu,Patrick Maisonneuve,Vincenzo Mazzaferro,Patrizia Gasparini,Giuseppe Pelosi,Filippo G. de Braud

doi:10.3390/cancers4030808

Abstract

Immunohistochemical loss of the succinate dehydrogenase subunit B (SDHB) has recently been reported as a surrogate biomarker of malignancy in sporadic and familial pheocromocytomas and paragangliomas through the activation of hypoxia pathways. However, data on the prevalence and the clinical implications of SDHB immunoreactivity in ileal neuroendocrine tumors are still lacking. Thirty-one consecutive, advanced primary midgut neuroendocrine tumors and related lymph node or liver metastases from 24 males and seven females were immunohistochemically assessed for SDHB. All patients were G1 tumors (Ki-67 labeling index ≤2%). SDHB immunohistochemistry results were expressed as immunostaining intensity and scored as low or strong according to the internal control represented by normal intestinal cells. Strong positivity for SDHB, with granular cytoplasmatic reactivity, was found in 77% of primary tumors (T), whilst low SDHB expression was detected in 90% of metastases (M). The combined analysis (T+M) confirmed the loss of SDHB expression in 82% of metastases compared to 18% of primary tumors. SDHB expression was inversely correlated with Ki-67 labeling index, which accounted for 1.54% in metastastic sites and 0.7% in primary tumors. A correlation between SDHB expression loss, increased Ki-67 labeling index and biological aggressiveness was shown in advanced midgut neuroendocrine tumors, suggesting a role of tumor suppressor gene.

Highlights

Ileal neuroendocrine tumors (INETs) are the most common type of neuroendocrine neoplasms in the gastrointestinal tract, with a male prevalence and a median age at the time of diagnosis of 66 years.They are mainly composed of enterochromaffin cells (EC) producing serotonin and substance P [1,2].A distinctive feature of INETs, especially when involving the liver, is their capability of causing distinct clinical syndromes [1,3,4], which can be faithfully monitored measuring the relevant hormones in the bloodstream
Neuroendocrine carcinomas, which show high proliferative activity as reflected by Ki67 labeling index (LI) over 20%, are treated with cisplatin-etoposide combination chemotherapy to small cell lung cancer (SCLC) [7,8], whereas most ileal neuroendocrine tumors are slowly growing neoplasms, which mainly depend on angiogenesis for their maintenance and growth [9,10,11,12,13,14]
Interesting findings of our study were that SDHB expression correlated with the tumor cell differentiation and malignant potential of G1 INETs, and that the percentage of immunoreactive cells was associated with the staining intensity (Table 2)

Summary

Introduction

Ileal neuroendocrine tumors (INETs) are the most common type of neuroendocrine neoplasms in the gastrointestinal tract, with a male prevalence and a median age at the time of diagnosis of 66 years. They are mainly composed of enterochromaffin cells (EC) producing serotonin and substance P [1,2]. Surgical resection can be curative in early stage patients [5,6], but most of them present with liver involvement at the time of diagnosis, so tumor grading and staging according to WHO/AJCC/ENET criteria are likely to play the most important role in the prognostic and therapeutic assessment of INETs [6]. This study was aimed at evaluating the distribution of SDHB by immunohistochemistry (IHC) in INETs and corresponding lymph node or liver metastases in order to explore its diagnostic and prognostic implications

Results and Discussion

Patients

Statistical Analysis

Conclusions