Prognostic value of PD-L1 expression in bronchopulmonary neuroendocrine tumours.

Programmed death protein 1 (PD-1) and its ligand, PD-L1, have emerged as promising therapeutic targets for many types of cancer that overexpress PD-L1. However, data on PD-L1 expression levels in bronchopulmonary neuroendocrine neoplasms (BP-NEN) are limited and contradictory. In the present study, a total of 298 archived, formalin-fixed, paraffin-embedded BP-NEN samples from 97 patients diagnosed with typical carcinoid (TC), atypical carcinoid (AC), small cell lung cancer (SCLC), or large cell neuroendocrine carcinoma of the lung (LCNEC) were evaluated for PD-L1 expression by immunohistochemistry using the highly sensitive monoclonal anti-PD-L1 antibody 73-10. PD-L1 expression levels were semiquantitatively estimated by tumour grading. Of the 298 BP-NEN samples, 85% were positive for PD-L1 expression. PD-L1 immunostaining predominantly localized to the plasma membrane of both tumour cells and tumour-infiltrating immune cells. SCLC and LCNEC exhibited significantly higher PD-L1 expression levels than TC or AC. PD-L1 expression levels were also higher in patients with lymph node or distant metastases, in patients who smoked, and in patients who died during the follow-up period. Moreover, PD-L1 expression levels correlated positively with tumour grading, Ki-67 index and the expression of the chemokine receptor CXCR4 and negatively with the levels of somatostatin receptor 1 and chromogranin A. High tumour PD-L1 levels were associated with poor patient outcomes. In conclusion, PD-L1 expression is common in BP-NEN, increases with malignancy, and is associated with poor prognosis. Therefore, targeting the PD-1/PD-L1 axis could be a promising strategy for treating BP-NEN. PD-L1 may also represent a useful prognostic biomarker for this tumour entity.

Different somatostatin and CXCR4 chemokine receptor expression in gastroenteropancreatic neuroendocrine neoplasms depending on their origin.

Somatostatin receptors (SST), especially SST2A, are known for their overexpression in well-differentiated gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN). The chemokine receptor CXCR4, in contrast, is considered to be present mainly in highly proliferative and advanced tumors. However, comprehensive data are still lacking on potential differences in SST or CXCR4 expression pattern in GEP-NEN in dependence on the place of origin. Overall, 412 samples from 165 GEP-NEN patients, comprising both primary tumors (PT) and metastases (MTS), originating from different parts of the gastrointestinal tract or the pancreas were evaluated for SST and CXCR4 expression by means of immunohistochemistry using monoclonal antibodies. SST2A was present in 85% of PT with a high intensity of expression, followed by SST5 (23%), CXCR4 (21%), SST3 (10%), SST1 (9%), and SST4 (4%). PT displayed higher SST2A and chromogranin A (CgA) expression levels than MTS. In both PT and MTS lower SST2A and CgA expression levels were found in tumors originating from the appendix or colon, compared to tumors from other origins. Tumors derived from appendix or colon were associated with significantly worse patient outcomes. Positive correlations were noted between SST2A and CgA as well as between CXCR4 and Ki-67 expression levels. SST2A and CgA negativity of the tumors was significantly associated with poor patient outcomes. All in all, SST2A was the most prominent receptor expressed in the GEP-NEN samples investigated. However, expression levels varied considerably depending on the location of the primary tumor.

Somatostatin and CXCR4 expression patterns in adenocarcinoma and squamous cell carcinoma of the lung relative to small cell lung cancer.

PURPOSE: Lung cancer is highly prevalent and has an especially poor prognosis. Thus, new diagnostic and therapeutic targets are necessary. Two potential targets are somatostatin receptors (SST), which are overexpressed in well-differentiated neuroendocrine neoplasms, and the chemokine receptor CXCR4, which is present mainly in highly proliferative and advanced tumours. Although their expression is relatively well characterized in small cell lung cancer (SCLC), in non-small cell lung cancer (NSCLC), data on SST and CXCR4 expression are scarce and contradictory. METHODS: We comparatively evaluated 83 tumour samples from a total of 57 lung cancer patients, of which 22 had adenocarcinoma (ADC), 21 had squamous cell carcinoma (SQC), and 15 had SCLC. Samples were evaluated for SST and CXCR4 expression using immunohistochemistry with well-characterized rabbit monoclonal antibodies. RESULTS: In the samples investigated, the most prominently expressed receptors were CXCR4 and SST5. Specifically, CXCR4 was detected with high expression intensity in more than 60% of ADC samples, about 90% of SQC, and 100% of SCLC. SST5 was present in about 75% of ADC and SQC samples and in more than 90% of SCLC. Although not noticeably expressed in ADC and SQC samples, SST2 was detected in 50% of SCLC cases, with a subset of patients displaying exceptionally high expression. The comparison of the three tumour entities revealed that SCLC samples had higher SST2, SST5, and CXCR4 expression, but lower SST3 and SST1 relative to ADC or SQC samples. CONCLUSION: CXCR4 may be a promising target for diagnostics and therapy in both SCLC and NSCLC.

Differential somatostatin and CXCR4 chemokine receptor expression in MALT-type lymphoma of gastric and extragastric origin.

PURPOSE: Whereas the different somatostatin receptor (SSTR) subtypes and the chemokine receptor CXCR4 are known to be expressed in a wide variety of human malignancies, comprehensive data are still lacking for MALT-type lymphomas. METHODS: Overall, 55 cases of MALT-type lymphoma of both gastric and extragastric origin were evaluated for the SSTR subtype and CXCR4 expression by means of immunohistochemistry using novel monoclonal rabbit antibodies. The stainings were rated by means of the immunoreactive score and correlated with clinical data. RESULTS: While the CXCR4 was detected in 92 % of the cases investigated, the SSTR subtypes were much less frequently present. The SSTR5 was expressed in about 50 % of the cases, followed by the SSTR3, the SSTR2A, the SSTR4 and the SSTR1, which were present in 35, 27, 18 or 2 %, respectively, of the tumors only. Gastric lymphomas displayed a significantly higher SSTR3, SSTR4 and SSTR5 expression than extragastric tumors. A correlation between CXCR4 and Ki-67 expression was seen in gastric lymphomas, whereas primarily in extragastric tumors SSTR5 negativity was associated with poor patient outcome. CONCLUSIONS: The CXCR4 may serve as a promising target for diagnostics and therapy of MALT-type lymphomas, while the SSTRs appear not suitable in this respect.

Comparative evaluation of three proliferation markers, Ki-67, TOP2A, and RacGAP1, in bronchopulmonary neuroendocrine neoplasms: Issues and prospects.

The classification of bronchopulmonary neuroendocrine neoplasms (BP-NEN) into four tumor entities (typical carcinoids (TC), atypical carcinoids (AC), small cell lung cancers (SCLC), large cell neuroendocrine lung carcinomas (LCNEC)) is difficult to perform accurately, but important for prognostic statements and therapeutic management decisions. In this regard, we compared the expression of three proliferation markers, Ki-67, Topoisomerase II alpha (TOP2A), and RacGAP1, in a series of tumor samples from 104 BP-NEN patients (24 TC, 21 AC, 52 SCLC, 7 LCNEC) using different evaluation methods (immunohistochemistry (IHC): Average evaluation, Hotspot evaluation, digital image analysis; RT-qPCR).The results indicated that all three markers had increased protein and mRNA expression with poorer differentiation and correlated well with each other, as well as with grading, staging, and poor survival. Compared with Ki-67 and TOP2A, RacGAP1 allowed for a clearer prognostic statement. The cut-off limits obtained for Ki-67-Average (IHC) were TC-AC 1.5, AC-SCLC 19, and AC-LCNEC 23.5. The Hotspot evaluation generated equal to higher, the digital image analysis generally lower between-entity cut-off limits.All three markers enabled a clear-cut differentiation between the BP-NEN entities, and all methods evaluated were suitable for marker assessment. However, to define optimal cut-off limits, the Ki-67 evaluation methods should be standardized. RacGAP1 appeared to be a new marker with great potential.