Comparison of immunoreactive score, HER2/neu score and H score for the immunohistochemical evaluation of somatostatin receptors in bronchopulmonary neuroendocrine neoplasms.

AIMS: Due to the growing number of somatostatin receptor (SSTR) targeting analogues and radiopeptides used for the diagnosis and therapy of neuroendocrine neoplasms (NEN), the assessment of SSTR subtype status has increasingly gained predictive value. In pathology, the SSTR protein levels are detected routinely by immunohistochemistry (IHC); however, a lack of a standardized evaluation system persists. Thus, in the present investigation, three well-established semi-quantitative scoring systems [immunoreactive score (IRS), human epidermal growth factor receptor 2 (HER2)/neu score, H score] used commonly for SSTR-IHC evaluation in NEN were compared. METHODS AND RESULTS: A total of 240 formalin-fixed, paraffin-embedded tumour samples from 90 patients with bronchopulmonary NEN were examined by IHC and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) for SSTR1, 2A, 3, 4 and 5 expression. Using both methods, SSTR1, 2A and 5 were the most frequently expressed subtypes. For all SSTR subtypes, all three scores correlated well with each other and with qRT-PCR data. However, the IRS was the most meaningful score with the best correlation to mRNA levels. CONCLUSIONS: Because a unified IHC scoring system for SSTR analysis is needed urgently to optimize the theranostics of NEN, among the scores tested, the IRS seems to be the most suitable according to our results. It provides sufficient accuracy combined with high practicability.

Somatostatin receptors in bronchopulmonary neuroendocrine neoplasms: new diagnostic, prognostic, and therapeutic markers.

CONTEXT AND OBJECTIVES: Gastroenteropancreatic neuroendocrine neoplasms are known for their overexpression of somatostatin receptors (SSTRs), which provide the molecular basis for diagnostic and therapeutic interventions. In contrast, few data on the SSTR expression profile exist for bronchopulmonary neuroendocrine neoplasms (BP-NEN). DESIGN AND SETTINGS: A total of 240 formalin-fixed, paraffin-embedded specimens from 26 typical carcinoid (TC), 30 atypical carcinoid (AC), and 34 small cell lung cancer (SCLC) patients were examined retrospectively by immunohistochemistry (IHC) using specific rabbit monoclonal antibodies and evaluated by the immunoreactive score. Adjacent slides from 20 samples of each tumor type were subjected to additional RT-quantitative PCR mRNA analysis. RESULTS: With different expression patterns, SSTRs were present in most of the tumor sections, at both the protein and mRNA levels. The RT-quantitative PCR data correlated with the IHC scores. SSTR1 was detected in approximately 65% of the TC and AC, but hardly in the SCLC, whereas both SSTR2A and SSTR5 were present in approximately 45% of each entity. Furthermore, the SSTR1 expression level was positively correlated with patient survival. CONCLUSIONS: Our results suggest that SSTRs can be used as novel diagnostic, prognostic, and therapeutic markers of BP-NEN. The differences in the SSTR expression profile between the three types of BP-NEN may help to set a diagnostic cutoff and predict patient prognosis. Similar to TC and AC, our results also revealed a previously unappreciated high level of SSTR2A expression in SCLC within a subgroup of patients. However, in most cases, pan-somatostatin analogs may represent an additional therapeutic option.

Analysis of somatostatin receptor 2A immunohistochemistry, RT-qPCR, and in vivo PET/CT data in patients with pancreatic neuroendocrine neoplasm.

OBJECTIVE: Gallium 68 somatostatin receptor (SSTR) positron emission tomography/computed tomography (PET/CT) is one of the most sensitive imaging methods for pancreatic neuroendocrine tumors. The aim of the study was to correlate the receptor density generated from the static PET/CT (maximum standard uptake values [SUVmax], mean standard uptake values [SUVmean]) with subtype 2A SSTR (SSTR2A) immunohistochemistry and reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) gene-expression data. METHODS: Thirty-nine tumor specimens (17 primary pancreatic tumors [PTs], 22 metastases [MTS]) of 19 patients with PET/CT scans preoperatively were evaluated. Subtype 2A SSTR expression was quantified immunohistochemically (immunoreactive score [IRS]) and on messenger RNA (mRNA) level by RT-qPCR. RESULTS: The PT and MTS did not differ significantly in their SUVmax (P = 0.07) but displayed a dissimilarity with respect to their SSTR2A expression (mean [SD] IRS PT, 8.8 [3.6] vs mean [SD] IRS MTS, 5.1 [4.5]; P = 0.02).The SUVmean was highly significantly correlated to SSTR2A mRNA expression (C = 0.85, P < 0.001) and moderately to SSTR2A protein expression (C = 0.53, P = 0.05). Moreover, the SUVmax correlated moderately with SSTR2A protein expression (C = 0.44, P = 0.03) and mRNA expression (C = 0.64, P = 0.042). CONCLUSIONS: The SUVmax and SUVmean are reliable ex vivo parameters for in vivo quantification of SSTR expression in pancreatic neuroendocrine tumors. Both immunohistochemistry and RT-qPCR are comparable methods for SSTR2A quantification. The PT and MTS differ significantly in their SSTR2A expression. This fact should be taken into account when treating patients with somatostatin analogs or peptide receptor radionuclide therapy.

Differential expression and prognostic value of the chemokine receptor CXCR4 in bronchopulmonary neuroendocrine neoplasms.

INTRODUCTION: For many tumors, the overexpression of the chemokine receptor CXCR4 is associated with increased malignancy and poor patient outcomes. However, comprehensive data for neuroendocrine neoplasms of the lung are still lacking. METHODS: CXCR4 expression was evaluated in a panel of bronchopulmonary neuroendocrine neoplasms (BP-NEN) comprising typical carcinoids (n = 26), atypical carcinoids (n = 30), and small cell lung cancers (SCLC, n = 34). Samples were analyzed by immunohistochemistry using the novel monoclonal rabbit anti-human CXCR4 antibody UMB-2 and by qRT-PCR. The expression was correlated with clinical data and overall patient survival. RESULTS: CXCR4 was predominantly localized at the plasma membrane of the tumor cells. CXCR4 was expressed with a high intensity in almost all of the 30 SCLC samples. In contrast, it was detected infrequently and with low intensity in the typical carcinoid and atypical carcinoid samples. There was a significant correlation between the immunohistochemistry and qRT-PCR data. Additionally, there was a significant negative relationship between CXCR4 expression and overall survival. CONCLUSIONS: With increasing malignancy, BP-NEN clearly differ in the extent of CXCR4 expression. As in other tumor entities, CXCR4 overexpression significantly correlates with negative patient outcome. Due to its particular high expression rate in SCLC, CXCR4 may serve as a promising new target for diagnostic and pharmacological intervention as well as for peptide receptor-based radionuclide therapy.