Helena Leijon

Insulinomas are rare functional pancreatic neuroendocrine tumours, which metastasize in 10% of cases. As predicting the prognosis can be challenging, there is a need for the determination of clinicopathological factors associated with metastatic potential. The aim of this study is to evaluate the glucagon-like peptide-1 receptor (GLP-1R) expression in insulinomas and to analyse its association with clinicopathological features and patient outcome. This retrospective study involves pancreatic tumour tissue samples from fifty-two insulinoma patients. After histological re-evaluation, formalin-fixed paraffin-embedded tissue samples were processed into tissue microarrays and stained immunohistochemically with a monoclonal GLP-1R antibody. Forty-eight of the forty-nine (98%) non-metastatic tumours expressed GLP-1R, while one non-metastatic, multiple endocrine neoplasia type 1 (MEN1)-related tumour and all three of the metastatic tumours lacked GLP-1R expression. The lack of GLP-1R expression was associated with impaired overall survival, larger tumour diameter, higher Ki-67 PI and weaker insulin staining. Somatostatin receptor 1–5 expression did not differ between GLP-1R-positive and GLP-1R-negative insulinomas. In conclusion, the lack of GLP-1R expression is associated with metastatic disease and impaired survival in insulinoma patients. Thus, GLP-1R expression could be a useful biomarker in estimating the metastatic potential of the tumour and the prognosis of surgically treated patients.

Background: Parathyroid carcinoma (PC) is a rare cause of primary hyperparathyroidism (PHPT). Distinguishing PC from other tumours underlying PHPT can be difficult and sometimes malignant diagnosis can be made only after recurrence of the disease. Atypical parathyroid adenomas (APA) have similar histological features as PC but lack signs of invasive growth. The expression of somatostatin receptors (SSTR) 1–5 in parathyroid tumours, commonly expressed in other neuroendocrine tumors, is currently not known. Aim: To examine immunohistochemical expression of SSTRs 1–5 in parathyroid tumours: parathyroid adenomas (PA), APAs and PCs. Methods: Nationwide cohort of PC (n=32), age- and gender-matched PA (n=72) and APA (n=28) were used. TMA blocks were stained with antibodies for SSTR subtypes 1–5 and intensity (0–3) of cytoplasmic, nuclear and membrane expression was scored. Correlations of SSTRs with parafibromin, Ki-67, fibrous septae and biochemical and clinical characteristics were also analysed. Results: Membrane expression was negligible for all receptor subtypes. Expression of SSTR 2-3 was negative. Nuclear SSTR1, nuclear and cytoplasmic SSTR4 and nuclear SSTR5 expression increased- and cytoplasmic SSTR5 decreased with tumour aggressiveness: Expression of nuclear SSTR5 was related to decreased parafibromin expression (P=0.002). Serum calcium and parathyroid hormone concentrations correlated with expression of nuclear SSTR1 (PPP=0.045). Tumor size, fibrous septae and Ki-67 were related to expression of nuclear SSTR1 (P=0.029, PP=0.005) and SSTR5 (P=0.023, PPp-value Nuclear SSTR1 1.5% 15% 41% SSTR4 29% 40% 56% 0.027 Nuclear SSTR4 31% 51% 62% 0.008 Nuclear SSTR5 15% 51% 69% SSTR5 85% 78% 56% 0.02 Conclusion: SSTR1 and SSTR5 expression may have a role in parathyroid tumour pathogenesis.

Context No effective methods for separating primary pheochromocytomas and paragangliomas with metastatic potential are currently available. The identification of specific asparagine-linked glycan (N-glycan) structures, which are associated with metastasized pheochromocytomas and paragangliomas, may serve as a new diagnostic tool. Objective To identify differences in N-glycomic profiles of primary metastasized and non-metastasized pheochromocytomas and paragangliomas. Setting This study was conducted at Helsinki University Hospital, University of Helsinki, and Glykos Finland Ltd and included sixteen pheochromocytomas and paragangliomas, eight primary metastasized pheochromocytomas or paragangliomas and eight non-metastasized tumors. Methods N-glycan structures were analyzed using MALDI-TOF mass spectrometric profiling (MS) of formalin-fixed, paraffin-embedded tissue samples. Main Outcome Measure N-glycan profile of tumor tissue Results Four groups of neutral N-glycan signals were more abundant in metastasized tumors than in non-metastasized tumors: 1) complex-type N-glycan signals of cancer-associated terminal N-acetylglucosamine, 2) multifucosylated glycans (complex fucosylation), 3) hybrid-type N-glycans, and 4) fucosylated pauci-mannose-type N-glycans. Three groups of acidic N-glycans were more abundant in metastasized tumors: 1) multifucosylated glycans, 2) acid ester-modified (sulfated or phosphorylated) glycans and 3) hybrid-type/monoantennary N-glycans. Fucosylation and complex fucosylation were significantly more abundant in metastasized paragangliomas and pheochromocytomas than in non-metastasized tumors for individual tests, but were over the false positivity critical rate, when adjusted for multiplicity testing. Conclusions MALDI-TOF mass spectrometric profiling of primary pheochromocytomas and paragangliomas can identify diseases with metastatic potential based on their different N-glycan profiles. Thus, malignancy-linked N-glycan structures may serve as potential diagnostic tools for pheochromocytomas and paragangliomas.

Pheochromocytomas and paragangliomas are rare, neural crest-originating, neuroendocrine tumors. HuR is an mRNA-binding protein of the ELAV/Hu-protein family, which participates in posttranscriptional regulation of many cancer-associated genes. HuR expression has been connected with aggressive behavior of several malignancies. Cyclooxygenase-2 (COX-2) is also expressed in several malignant tumors, and its expression is regulated by HuR. Tissue microarray of 153 primary pheochromocytomas and paragangliomas was investigated for the expression of HuR and COX-2 proteins by immunohistochemistry using two different HuR antibodies (HuR19F12 and HuR3A). In these tumors, the expression of both intranuclear and cytoplasmic HuR was detectable. Increased cytoplasmic HuR expression was significantly associated with metastatic tumors. Increased COX-2 and MIB-1 expression also was associated with metastatic potential, and moreover, HuR and COX-2 expression correlated with each other. Our data suggest that increased expression of HuR protein is associated with metastatic potential of paragangliomas and pheochromocytomas, and COX-2 seems to be a target of HuR.

Introduction and design: Parathyroid carcinoma (PC) is a rare endocrine malignancy and the diagnosis is difficult. As the incidence seems to be increasing, we examined all cases diagnosed in our country during years 2000–2011 and compared the results to those of atypical parathyroid (AA; n=28) and parathyroid adenomas (A; n=72). All tissue specimens were re-examined. Results: In 2000–2011, 32 patients were diagnosed with PC in Finland, compared to 19 cases in 1980–1999. Preoperatively, PC patients (median age 61 year, range 17–83) had higher ionized calcium and parathyroid hormone (PTH) concentrations compared to AA and A (1.76, 1.56 and 1.44 mmol/l, PPP=0.01) and more often suffered from renal (50% vs 48% vs 22%, respectively, P=0.01) and bone involvement (47% vs 15% vs 38%, respectively P=0.002). Tumor size was larger in PC and AA compared to A (2.95 cm vs 2.0 cm vs 1.6 cm, respectively, PP=0.94). Conclusions: The prevalence of parathyroid carcinoma has increased significantly in Finland. Parathyroid carcinoma associates with significantly more severe PHPT compared to adenoma, and has distinct histopathological findings.