SSTR2A Expression Research Articles

High Expression of Somatostatin Receptors 2A, 3, and 5 in Corticotroph Pituitary Adenoma.

The development of somatostatin analogs for the treatment of pituitary Cushing's disease has been based on somatostatin receptor expression analyses of small cohorts of pituitary adenomas. Additionally, the classification of pituitary adenomas has recently changed. To enable progress with this treatment option, we assessed somatostatin receptors in a large cohort of corticotroph and other pituitary adenomas according to the new WHO classification of endocrine tumors. Paraffin-embedded tumor samples of 88 corticotroph pituitary adenomas and 30 nonadenomatous pituitary biopsies were analyzed after processing into tissue microarrays and immunohistochemical staining for SSTR 1, SSTR2A, SSTR3, SSTR4, and SSTR5. For comparison, 159 other noncorticotroph pituitary adenomas were analyzed. SSTR3 expression was higher in corticotroph adenomas compared to PIT-1-positive, gonadotroph, and nonfunctioning pituitary adenomas (p < 0.0001, p = 0.0280, and p < 0.0001, respectively). This was also the case for the expression of SSTR5 (p = 0.0003, p < 0.0001, and p < 0.0001, respectively). SSTR2A expression was higher compared to gonadotroph and nonfunctioning pituitary adenomas (p = 0.0217 and 0.0126, respectively) while PIT-1-positive adenomas showed even higher SSTR2A expression (p < 0.0001). SSTR2A and SSTR5 were both expressed higher in nonadenomatous pituitary biopsies than in pituitary adenomas (p = 0.0126 and p = 0.0008, respectively). There are marked expression differences of SSTR1-5 as well as changes in expression in recurrent disease that need to be addressed when looking for other possible substances for the treatment of Cushing's disease. SSTR2A, SSTR3, and SSTR5 seem to be most suitable biomarkers for a targeted therapy with somatostatin analogs.

Somatostatin receptor SSTR2A and SSTR5 expression in neuroendocrine breast cancer

Neuroendocrine breast cancer (NEBC) is a group of rare tumors, which could benefit from therapy targeting the somatostatin receptors (SSTRs). In particular, SSTR2A and SSTR5 are potential targets given their consistent expression in gastrointestinal and pancreatic primary and metastatic neuroendocrine cancers. Currently, there are no studies describing the expression of SSTRs in NEBC. The purpose of our study was to characterize the immunohistochemical expression of SSTR2A and SSTR5 in a cohort of NEBC.Thirty-one primary NEBC cases were analyzed, and SSTR2A and SSTR5 immunohistochemistry performed and scored using the modified immunoreactive score proposed by Remmele and Stanger.All patients were females with a mean age of 66.6 years (SD = 14). 77% of cases were histological grade 2. SSTR2A showed a weak positivity in 11 cases (35.5%), moderate positivity in 6 cases (19.4%) and strong positivity in 5 cases (16.1%). Nine cases were negative for SSTR2A (29%). SSTR5 showed a weak positivity in 16 cases (51.6%), moderate positivity in 6 cases (19.4%), while no cases showed strong positivity. Nine cases were negative for SSTR5 (29%). Five cases were negative for both SSTR2A and SSTR5.A weak to moderate SSTR2A and SSTR5 expression was observed in 50–70% of the cases. A subset of NEBCs with strong SSR2A expression may benefit from SSTRs targeted therapy. These results need further validation in a larger series including metastatic NEBC, to provide potential therapeutic targets for patients with advanced disease.

SSTR2A expression in medullary thyroid carcinoma is correlated with longer survival

PurposeMedullary thyroid carcinoma (MTC) derives from the parafollicular C-cells of the thyroid gland. Somatostatin receptors (SSTRs) are expressed in various neuroendocrine tumours including MTC. The aim of this study was to evaluate SSTR2A as a prognostic factor for MTC, to study distribution of SSTR2A expression within tumours and to compare expression of SSTR2A between primary tumours and corresponding lymph node metastases.MethodsPatients who underwent surgery between 1988 and 2014 for MTC from five tertiary referral centres in The Netherlands were included. In total, primary tumours of 114 patients and lymph node metastases of 34 patients were analysed for expression of SSTR2A using a tissue microarray, and correlated with clinicopathological variables and survival.ResultsThe mean age of patients was 45.5 years (SD 16.2), 55 patients were male (49.5%). Primary tumours of 58 patients (50.9%) showed SSTR2A expression. In multivariate Cox-regression analysis, SSTR2A positivity correlated independently with better overall survival (OS) (HR 0.3; 95% CI 0.1–1.0). In stage IV MTC patients, 10-year survival rates for SSTR2A-negative and positive patients were 43% and 96%, respectively. In 53.9% of patients with lymph node metastases, expression in primary tumour and lymph node metastases differed.ConclusionSSTR2A expression is correlated with longer OS in MTC, especially for stage IV patients, suggesting that SSTR2A expression might be a useful prognostic factor in MTC. The SSTR2A status of the primary MTC does not predict expression in lymph node metastases.

Frequent expression of somatostatin receptor 2a in olfactory neuroblastomas: a new and distinctive feature

Olfactory neuroblastoma (ONB) is a malignant neuroendocrine neoplasm with a usually slow course, but with considerable recurrence rate. Many neuroendocrine tumors have shown good response to the treatment with somatostatin analogs and somatostatin radioreceptor therapy. In ONBs, there are scarce data on somatostatin-based treatment and the cellular expression of somatostatin receptors (SSTR), the prerequisite for binding and effect of somatostatin on normal and tumor cells. The aim of our study was to investigate the immunohistochemical expression of SSTR2A and SSTR5 in a cohort of 40 ONBs. In addition, tissue microarrays containing 40 high-grade sinonasal carcinomas as well as 6 sinonasal lymphomas, 3 rhabdomyosarcomas, and 3 Ewing sarcomas were evaluated. Volante system was applied for staining evaluation. Thirty cases (75%) were immunopositive for SSTR2A and 3 (7.5%) for SSTR5. Among the 30 SSTR2A-positive ONBs, 19 tumors (63.3%) scored 2+ and 11 (36.7%) scored 3+. All SSTR5-positive ONBs scored 2+. Neither sinonasal carcinomas nor sinonasal small round blue cell neoplasms expressed SSTR2A or SSTR5. The frequent expression of SSTR2A provides a rationale for radioreceptor diagnosis and therapy with SST analogs in ONBs. SSTR2A expression in ONBs is a helpful adjunct in the differential diagnosis of ONBs.

SOMATOSTATIN RECEPTORS AS POTENTIALTHERAPEUTIC TARGETS IN THE TREATMENT OF ADVANCED ADRENOCORTICAL CANCER. A CASE REPORT

Background. Adrenocortical cancer (ACC) is a rare malignancy of the adrenal cortex. Therapeutic options for advanced ACC are limited. It is necessary to study new and more effective drug combinations and tumor biological targets. The purpose of the study was to determine the expression of somatostatin receptor subtypes 2A and (SSTR 2A and SSTR 5) using immunohistochemical (IHC) analysis of tumor tissue samples in patients with ACC, as well as to study the feasibility of using prolonged analogues of somatostatin in the treatment of advanced ACC. Material and methods. The expression of SSTR 2A and SSTR 5 was analyzed using imunohistochemistry of tumor tissue samples from 20 patients with advanced ACC. Results. The negative (0) IHC status of SSTR 2A and SSTR 5 was determined in 10 patients (50 %). A different staining intensity of SSTR 2A and SSTR 5 expression was found in tumor cells of 10 patients (50 %). The low SSTR expression was associated with low membrane immunoreactivity and high SSTR expression was associated with moderate and strong immunoreactivity. High level of somatostatin receptor expression was detected in 7 patients (35 %). Conclusion. The detection of SSTR 2A and SSTR 5 expression in tumor tissue of patients with advanced ACC, as well as the study of feasibility of using prolonged somatostatin analogs are promising in the treatment of patients with high receptor expression, however, further research is required.

High interlaboratory and interobserver agreement of somatostatin receptor immunohistochemical determination and correlation with response to somatostatin analogs

Monoclonal antibodies to somatostatin receptors 2A (SSTR2A, UMB-1) and 5 (SSTR5, UMB-4) were reported to be highly reliable for immunohistochemical detection of these receptors in neuroendocrine neoplasms. However, the standardization of either the immunohistochemical procedure and the methods of evaluation has yet to be established. Fifty-two tissues from 38 patients with neuroendocrine neoplasm were retrieved from 2 institutions in Italy and Japan. The tissues were immunostained using 3 staining methodologies: 1 automated and 2 manual protocols from the Italian and Japanese institutions. The slides were independently evaluated by 3 observers (2 experienced pathologists and 1 medical student) using 3 scoring systems (Volante-Score, HER2-Score, and H-Score). The scores obtained from the staining methods were highly correlated with each other (r>0.85, P<.0001). Especially, the Volante- and HER2-Scores were highly concordant (r≥0.95, P≤.0001). Very high interobserver agreement was obtained irrespective of the method used and the experience of the evaluator, with the best concordance obtained by experienced pathologists evaluating automated system-stained slides (SSTR2A, r>0.97; SSTR5, r>0.96). HER2- and H-Scores were reliable to represent the characteristics of the patients. SSTR2A expression evaluated by the HER2-Score was significantly associated with clinical efficacy to somatostatin analogs (P=.04). SSTRs determination is an easily standardizable tool in different laboratories and is highly reproducible irrespective of the method of evaluation used. Given the positive association with clinical efficacy to somatostatin analogs, as well as the simple and widespread use, HER2-Score can be proposed as a standard evaluation procedure of SSTR2A and SSTR5 expression in neuroendocrine neoplasms.

Silent somatotroph tumour revisited from a study of 80 patients with and without acromegaly and a review of the literature.

Silent somatotroph tumours are growth hormone (GH) immunoreactive (IR) pituitary tumours without clinical and biological signs of acromegaly. Their better characterisation is required to improve the diagnosis. Twenty-one silent somatotroph tumours were compared to 59 somatotroph tumours with acromegaly. Tumours in each group were classified into GH and plurihormonal (GH/prolactin (PRL)/±thyroid-stimulating hormone (TSH)) and into densely granulated (DG) and sparsely granulated (SG) types. The two groups were then compared with regards to proliferation (Ki-67, p53 indexes and mitotic count), differentiation (expression of somatostatin receptors SSTR2A-SSTR5 and transcription factor Pit-1) and secretory activity (% of GH- and PRL-IR cells). The silent somatotroph tumours represented 2% of all tested pituitary tumours combined. They were more frequent in women than in men (P = 0.002), more frequently plurihormonal and SG (P < 0.01), with a lower percentage of GH-IR cells (P < 0.0001) compared to those with acromegaly. They all expressed SSTR2A, SSTR5 and Pit-1. The plurihormonal (GH/PRL/±TSH) tumours were mostly observed in women (sex ratio: 3/1) and in patients who were generally younger than those with acromegaly (P < 0.001). They were larger (P < 0.001) with a higher Ki-67 index (P = 0.007). The silent somatotroph tumours are not uncommon. Their pathological diagnosis requires the immunodetection of GH and Pit-1. They are more frequently plurihormonal and more proliferative than those with acromegaly. A low secretory activity of these tumours might explain the normal plasma values for GH and insulin-like growth factor 1 (IGF1) and the absence of clinical signs of acromegaly.

Expression of somatostatin receptor 2A in medullary thyroid carcinoma is associated with lymph node metastasis.

Medullary carcinoma (MTC) is an aggressive tumour that derives from the thyroid parafollicular calcitonin-secreting cells (C cells). Lymph node metastasis may occur early in disease pathogenesis and is one of the most important negative prognostic parameters. Surgery is the only curative therapy while chemotherapeutic options are limited. Neuroendocrine differentiated C cells may express somatostatin receptors (SSTR), which have a wide range of biological actions including inhibitory effects on cell survival and angiogenesis and antiproliferative effects on cancer cell lines. Moreover, they are a potential target for various somatostatin analogues. Aim of this study was to analyse the protein expression of SSTR2A and 5 in MTCs with or without the presence of lymph node metastases in correlation with various clinicopathological parameters. This retrospective immunohistochemical analysis included 97 patients with medullary thyroid carcinomas. Protein expression was detected by immunohistochemistry for somatostatin receptors 2A and 5. Various clinicopathological parameters, such as Ki-67 proliferation index or presence of desmoplasia, were included for statistical analysis. SSTR2A protein expression significantly correlated with the presence of lymph node metastases (p = 0.009), locally advanced MTCs staged according to the TNM (p < 0.001) and degree of desmoplasia (p = 0.029). Although SSTR5 protein expression significantly correlated with advanced stages of MTCs (p = 0.023) and degree of desmoplasia (p = 0.020), no correlation was found with the presence of lymph node metastases. Our results provide additional information concerning the aggressiveness of MTCs and reveal that a high SSTR2A and SSTR5 expression might be a poor prognostic feature.

Follicular dendritic cell sarcoma: clinicopathologic study of 15 cases with emphasis on novel expression of MDM2, somatostatin receptor 2A, and PD-L1.

Follicular dendritic cell sarcoma (FDCS) is a rare low-grade neoplasm with the phenotype of FDC cells. This rare sarcoma has been well known for being mistaken for a variety of neoplasms (mainly meningioma), particularly at extranodal sites. Diagnosis of FDCS mainly relies on characteristic histologic appearance supplemented by immunohistochemistry and electron microscopy. In this study, we reviewed 15 FDCSs retrieved from our consultation files and stained them for newly reported or novel markers (PD-L1, Rb1, MDM2, and somatostatin receptor 2A [SSTR2A]) in addition to conventional FDC markers. Patients were 7 men and 7 women (1 unspecified) with a mean age of 47 years (20-75 years). The tumor site was lymph nodes (6) or spleen (2), both (1) and extranodal sites of head and neck (4) or abdominal cavity (2). Treatment was variable combinations of surgery and aggressive chemotherapy/radiotherapy. Four of 8 patients with follow-up died of disease within 1 to 10 years. All tumors expressed at least 1 FDC marker: CD21 (8/13), CD23 (2/13), CD35 (8/12), CNA.42 (13/14), Clusterin (8/13), Fascin (15/15) and D2-40/podoplanin (7/14). Epstein-Barr virus (EBER-1/2 in situ hybridization) was performed successfully in 10 conventional variants; all were negative. Five of 14 cases (36%) stained strongly for SSTR2A with a distinctive membranous pattern. Residual lymphoid follicles surrounding some of the tumors stained similarly for SSTR2A. Seven (54%) of 13 assessable cases showed moderate to strong membranous staining for PD-L1 in greater than 5% of the neoplastic cells. The Rb1 antigen was lost in 4 (28%) of 14 cases. MDM2 stained less than 5% to 20% of the tumor cells in 5 (36%) of 14 cases; 2 of them showed amplification by fluorescence in situ hybridization (FISH). CDK4 was negative except for weak staining in 1 of 14 cases. This study adds to the existing few clinicopathologic series on FDCS and represents the first study to show MDM2 amplification in this entity. Our results regarding frequent SSTR2A expression in FDCS are novel and might be of potential diagnostic and therapeutic relevance. SSTR2A expression in FDCS represents a further confusing factor when thinking of meningioma which uniformly expresses this receptor. FDCS occurring within the retroperitoneum and/or the abdominal cavity may closely mimic dedifferentiated liposarcoma, particularly if MDM2 positive and/or amplified and should thus be carefully assessed for expression of FDC markers.

Small Cell Carcinomas of the Bladder Highly Express Somatostatin Receptor Type 2A: Impact on Prognosis and Treatment--A Multicenter Study of Urooncology Society, Turkey.

Small cell carcinoma (SmCC) is a rare and aggressive neuroendocrine carcinoma of the bladder. Neuroendocrine carcinomas expressing somatostatin receptors (SSTR) in other viscera such as lung, pancreas, and gastrointestinal system respond to therapy with somatostatin analogs. In the present study, expressions of SSTRs 1 to 5 including type 2A are investigated by immunohistochemistry (IHC) and their relationship with clinicopathologic factors was evaluated. Hundred primary bladder SmCC cases were collected from 12 centers in Turkey. Forty-three cases were pure SmCC. Other cases had mostly papillary urothelial carcinoma as a second component. The percentage of the SmCC component ranged from 5% to 100%. SSTR-2A expression was membranous, whereas the other receptors showed cytoplasmic staining. The percentages of positive cases for SSTR-1, SSTR-2A, SSTR-3, SSTR-4, and SSTR-5 were 4% (3/75), 61.4% (54/88), 2.4% (2/84), 24.4% (20/82), and 6.25% (5/80), respectively. The percentage of SmCC component was positively correlated with the percentage of SSTR-2A expression (P=0.003) while negatively correlated with patient age (P=0.032). SSTR-2A expression was correlated with survival as a bad prognostic factor (P=0.018). SSTR-1, SSTR-3, SSTR-4, and SSTR-5 expressions did not show any statistical significance with any parameter. In conclusion, although the limited number of cases with adequate term follow-up, SSTR-2A expression could be a prognostic factor and somatostatin analogs therapeutic candidate for SmCCs of the bladder as these tumors show high percentage of SSTR-2A expression.

Somatostatin receptor expression in small cell lung cancer as a prognostic marker and a target for peptide receptor radionuclide therapy.

Despite initial responsiveness to both chemotherapy and radiotherapy, small cell lung cancer (SCLC) commonly relapses within months. Although neuroendocrine characteristics may be difficult to demonstrate in individual cases, a relevant expression of somatostatin receptors (SSTR) on the cell surface has been described. We aimed to evaluate the prognostic value of SSTR-expression in advanced SCLC. We further examined pre-requisites for successful peptide receptor radionuclide therapy (PRRT).21 patients with extensive stage SCLC were enrolled. All patients underwent positron emission tomography/computed tomography (PET/CT) with 68Ga-DOTATATE to select patients for SSTR-directed therapy. PET scans were visually and semi-quantitatively assessed and compared to SSTR2a and SSTR5 expression in biopsy samples. Peak standardized uptake values (SUVpeak) of tumors as well as tumor-to-liver ratios were correlated to progression-free (PFS) and overall survival (OS).In 4/21 patients all SCLC lesions were PET-positive. 6/21 subjects were rated “intermediate” with the majority of lesions positive, the remaining 11/21 patients were PET-negative. PET-positivity correlated well with histologic SSTR2a, but not with SSTR5 expression. Neither PET-positivity nor SUVpeak were predictors of PFS or OS. In 4 patients with intensive SSTR2a-receptor expression, PRRT was performed with one partial response and one stable disease, respectively.SSTR-expression as detected by 68Ga-DOTATATE-PET and/or histology is not predictive of PFS or OS in patients with advanced SCLC. However, in patients exhibiting sufficient tracer uptake, PRRT might be a treatment option given its low toxicity and the absence of effective alternatives.

Factors predicting pasireotide responsiveness in somatotroph pituitary adenomas resistant to first-generation somatostatin analogues: an immunohistochemical study.

To gather data regarding factors predicting responsiveness to pasireotide in acromegaly. SSTR2a, SSTR3, SSTR5, AIP, Ki-67 and the adenoma subtype were evaluated in somatotroph adenomas from 39 patients treated post-operatively with somatostatin analogues (SSAs). A standardized SSTR scoring system was applied (scores 0-3). All patients received first-generation SSAs, and 11 resistant patients were subsequently treated with pasireotide LAR. None of the patients with negative or cytoplasmic-only SSTR2a expression (scores 0-1) were responsive to first-generation SSAs, as opposed to 20% (score 2) and 50% of patients with a score of 3 (P=0.04). None of the patients with an SSTR5 score of 0-1 were responsive to pasireotide, as opposed to 5/7 cases with a score of 2 or 3 (P=0.02). SSTR3 expression did not influence first-generation SSAs or pasireotide responsiveness. Tumours with low AIP were resistant to first-generation SSAs (100 vs 60%; P=0.02), while they had similar responsiveness to pasireotide compared to tumours with conserved AIP expression (50 vs 40%; P=0.74). Tumours with low AIP displayed reduced SSTR2 (SSTR2a scores 0-1 44.4 vs 6.7%; P=0.006) while no difference was seen in SSTR5 (SSTR5 scores 0-1 33.3 vs 23.3%; P=0.55). Sparsely granulated adenomas responded better to pasireotide compared to densely granulated ones (80 vs 16.7%; P=0.04). The expression of SSTR5 might predict responsiveness to pasireotide in acromegaly. AIP deficient and sparsely granulated adenomas may benefit from pasireotide treatment. These results need to be confirmed in larger series of pasireotide-treated patients.

Somatostatin Receptor SSTR-2a Expression Is a Stronger Predictor for Survival Than Ki-67 in Pancreatic Neuroendocrine Tumors.

Somatostatin receptors (SSTR) are commonly expressed by neuroendocrine tumors. Expression of SSTR-2a and SSTR-5 may impact symptomatic management; however, the impact on survival is unclear. The aim of this study is to correlate SSTR-2a and SSTR-5 expression in pancreatic neuroendocrine tumors (PNETs) with survival.This study is designed to determine the prognostic significance of somatostatin receptors SSTR-2a and SSTR-5 in PNETs.This retrospective cohort study included cases of resected PNETs between 1992 and 2014. Clinical data, histopathology, expression of SSTR and Ki-67 by immunohistochemistry, and long-term survival were analyzed.A total of 99 cases were included in this study. The mean age was 57.8 years (18–87 years) and median tumor size was 25 mm (range 8–160 mm). SSTR-2a and SSTR-5 expression was scored as negative (n = 19, 19.2%; n = 75, 75.8%, respectively) and positive (n = 80, 80.1%; n = 24, 24.2%). The median follow-up was 49 months. SSTR-2a expression was associated with improved overall survival, with cumulative survival rates at 1, 3, and 5 years being 97.5%, 91.5%, and 82.9%, respectively. Univariate analysis demonstrated better survival in SSTR-2a positive patients (log rank P = 0.04). SSTR-5 expression was not associated with survival outcomes (log rank P = 0.94). Multivariate analysis showed that positive SSTR-2a expression is a stronger prognostic indicator for overall survival [Hazard Ratio (HR): 0.2, 95% Confidence interval (CI): 0.1–0.8] compared to high Ki-67 (HR: 0.8, 95% CI: 0.1–5.7).Expression of SSTR-2a is an independent positive prognostic factor for survival in PNETs.

Inverse expression of somatostatin and CXCR4 chemokine receptors in gastroenteropancreatic neuroendocrine neoplasms of different malignancy.

Somatostatin receptors (SSTR) are widely distributed in well-differentiated neuroendocrine neoplasms (NEN) and serve as primary targets for diagnostics and treatment. An overexpression of the chemokine receptor CXCR4, in contrast, is considered to be present mainly in highly proliferative and advanced tumors. Comparative data are still lacking, however, for neuroendocrine carcinomas (NEC). SSTR subtype (1, 2A, 3, 5) and CXCR4 expression was evaluated in G1 (n = 31), G2 (n = 47), and low (G3a; Ki-67: 21-49%; n = 21) and highly proliferative (G3b; Ki-67: >50%, n = 22) G3 (total n = 43) gastroenteropancreatic NEN samples by performing immunohistochemistry with monoclonal rabbit anti-human anti-SSTR and anti-CXCR4 antibodies, respectively, and was correlated with clinical data. Both CXCR4 and SSTR were widely expressed in all tumors investigated. CXCR4 expression differed significantly between the G1 and G3 specimens and within the G3 group (G3a to G3b), and was positively correlated with Ki-67 expression. SSTR2A, in contrast, exhibited an inverse association with Ki-67. SSTR2A was highly expressed in G1 and G2 tumors, but was significantly less abundant in G3 carcinomas. Additionally, SSTR1 expression was higher in G3a than in G3b tumors. We observed an elevation in CXCR4 and a decrease in SSTR2A expression with increasing malignancy. Interestingly, 23% of the G3 specimens had strong SSTR2A expression. Because CXCR4 was strongly expressed in highly proliferative G3 carcinomas, it is an interesting new target and needs to be validated in larger studies.

Somatostatin Receptors 2A and 5 Are Expressed in Merkel Cell Carcinoma with No Association with Disease Severity

Background/Aims: Merkel cell carcinoma (MCC) is a rare high-grade neuroendocrine tumour of the skin. It has been speculated that MCCs express somatostatin receptors (SSTRs), but this has never been assessed in a large series of MCCs. The main aim of this study was to assess the expression of SSTR2A and SSTR5 in MCC tumours. The secondary aims were to assess whether expression of SSTR was associated with the Ki67 proliferative index, Merkel cell polyomavirus (MCPyV) status, clinical characteristics and outcome. Methods: Clinical data and tumours were collected from an ongoing cohort of French patients with MCC. Immunohistochemistry was performed with anti-SSTR2A and anti-SSTR5 monoclonal antibodies, and tumours were classified into 3 groups: ‘no expression', ‘low expression' and ‘moderate expression' using an SSTR staining score. Results: SSTR expression was assessed for 105 MCC tissue samples from 98 patients, and clinical characteristics were available for 87 of them. SSTR expression was consistent between the primary skin tumour and the corresponding metastases for SSTR2A and SSTR5 in 3/7 and 6/7 cases, respectively. SSTR2A and SSTR5 were expressed in 58 cases (59.2%) and in 44 cases (44.9%), respectively. Overall, at least one SSTR was expressed in 75 tumours (76.5%). SSTR expression was not associated with clinical characteristics, Ki67 proliferative index, recurrence-free survival or MCC-specific survival. Expression of SSTR2A was associated with MCPyV status in MCC tumours but not SSTR5. Conclusion: SSTRs were expressed in a high proportion of MCCs, although expression was heterogeneous between tumours and was not associated with disease severity.

Expression of Somatostatin Receptors 1-5 and Dopamine Receptor 2 in Lung Carcinoids: Implications for a Therapeutic Role

Objective: The expression of somatostatin receptors (SSTRs) and dopamine receptor 2 (DR2) in neuroendocrine tumors is of clinical importance as somatostatin analogues and dopamine agonists can be used for their localization and/or treatment. The objective of this study is to examine the expression of the five SSTR subtypes and DR2 in lung carcinoids (LCs). Methods: We conducted a retrospective study of 119 LCs from 106 patients [typical carcinoids (TCs): n = 100, and atypical carcinoids (ACs): n = 19]. The expression of all five SSTR subtypes and DR2 was evaluated immunohistochemically and correlated to clinicopathological data. In a subgroup of cases, receptor expression was further analyzed using semiquantitative RT-PCR. Results: SSTR2A was the SSTR subtype most frequently expressed immunohistochemically (72%), followed by SSTR1 (63%), SSTR5 (40%), and SSTR3 (20%), whereas SSTR4 was negative. DR2 was expressed in 74% and co-expressed with SSTR1 in 56%, with SSTR2A in 59%, with SSTR3 in 19%, and with SSTR5 in 37% of the tumors. Receptor expression was not related to the histological subtype, tumor aggressiveness (disease extent/grading) or functionality; however, DR2 was expressed more frequently in ACs than TCs (95 vs. 70%, p = 0.017). In a subset of patients, RT-PCR findings highly suggested that the expression of SSTR2A, SSTR3, DR2, and to a lesser extent that of SSTR1 and SSTR5 is the outcome of increased gene transcription. Conclusions: The high and variable immunohistochemical expression of the majority of SSTRs along with their co-expression with DR2 in LCs provides a rationale for their possible treatment with agents that target these receptors.

Relations Between Pathological Markers and Radioiodine Scan and (18)F-FDG PET/CT Findings in Papillary Thyroid Cancer Patients With Recurrent Cervical Nodal Metastases.

The aim of this study was to investigate relationships between the immunohistochemical results and radioiodine scan and (18)F-FDG PET findings in papillary thyroid cancer (PTC) patients with recurrent cervical nodal metastases. A total of 46 PTC patients who had undergone a radioiodine scan and/or (18)F-FDG PET/CT and a subsequent operation on recurrent cervical lymph nodes were enrolled. Twenty-seven patients underwent (18)F-FDG PET/CT, 8 underwent radioiodine scans, and 11 underwent both scans. In all surgical specimens, the immunoexpressions of thyroglobulin (Tg), sodium-iodide symporter (NIS), glucose transporter 1 (Glut-1), and somatostatin receptor 1 and 2A (SSTR1 and SSTR2A) were assessed, and associations between these expressions and radioiodine scan and (18)F-FDG PET findings were evaluated. Of the 38 patients who underwent (18)F-FDG PET/CT, all patients with weak Tg expression had positive (18)F-FDG uptake, while only 45% of the patients with moderate or strong Tg expression showed positive uptake (p = 0.01). The proportion of patients with positive (18)F-FDG uptake increased as the degree of Glut-1 expression with luminal accentuation increased. Of the 19 patients who underwent a radioiodine scan, the proportion with positive radioiodine uptake was greater among patients with strong NIS and SSTR2A expression than among patients expressing these markers at weak levels (p = 0.04 for all). All three patients with weak Tg expression were negative for radioiodine uptake. The (18)F-FDG uptakes of recurrent cervical nodes are related to strong Glut-1 expression with luminal accentuation and weak Tg expression, whereas radioiodine uptake is related to the strong expressions of NIS and SSTR2A.

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

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). 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. 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. 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.

Phosphaturic mesenchymal tumour - a case report

Aim To describe a case of phosphaturic mesenchymal tumour and advances in the immunohistochemical diagnosis. Case A 36-year-old male presented with progressive fatigue, localised right back pain with movement and bilateral foot pain 7 months following trivial injury over the 7 rib anteriorly while playing rugby. A trial of prednisone was ineffective. Results Biochemistry showed severe hypophosphataemia, urinary phosphate loss, raised alkaline phosphatase, mildly reduced serum calcium and magnesium and normal electrolytes. Sestamibi scan with CT scanning highlighted an area of increased uptake in the right C7 transverse process. Serum analysis showed fibroblast growth factor-23 secreting hormone. Histology showed bland cells with densely granular and eosinophilic background. No osteoclast-like giant cells, calcified matrix, haemorrhage or necrosis was identified. Immunohistochemistry showed tumour cells positive for CD56 and negative for synaptophysin, chromagranin, TTF-1, CD31 and Ki -67. Slides referred to Dr Anthony Gill, Royal North Shore Hospital, Sydney, showed strong positivity to FGF23 and diffuse strong positivity to somatostatin receptor 2A. Discussion Phosphaturic mesenchymal tumour is a rare phosphate wasting tumour associated with oncogenic osteomalacia. They have been erroneously diagnosed as other mesenchymal tumours including hemangiopericytoma and osteosarcoma. Expression of FGF23 and SSTR2A are diagnostic.

Expression of somatostatin receptors, SSTR2A and SSTR5, in 108 endocrine pituitary tumors using immunohistochemical detection with new specific monoclonal antibodies

Medical treatment of endocrine pituitary tumors with somatostatin analogs depends on tumor type and somatostatin receptor (SSTR) expression. Immunohistochemical detection of these receptors using polyclonal antibodies has given conflicting results. We studied the expression of SSTR(2A) and SSTR(5) with new procedures in 108 pituitary tumors. Using 2 new, specific monoclonal antibodies (clone UMB-1 and UMB-4), 2 fixatives (Bouin-Hollande and zinc-formalin) and 2 technical procedures (manual and automated), SSTR(2A) and SSTR(5) expression was studied in 60 GH (growth hormone), 15 ACTH (adrenocorticotropic hormone), 23 FSH/LH (follicle-stimulating hormone/luteinizing hormone), 7 PRL (prolactin), and 3 TSH (thyroid-stimulating hormone) tumors. Only membrane staining was taken into account, and the SSTR expression was considered positive when more than 5% of the cells were immunoreactive. GH tumors were classified as GH or GH/PRL, densely or sparsely granulated, and into 3 groups according to the percentage of SSTR-immunoreactive cells (group 1: <25%; group 2: 25%-75%; group 3: >75%). Almost all GH tumors expressed SSTR(2A) (93%) and SSTR(5) (83%) at high levels (group 3: >75%) in 52% and 37%, respectively. SSTR(2A) expression was significantly higher in densely than in sparsely granulated tumors. Moreover, SSTR(2A) was also expressed in the 3 TSH tumors and weakly expressed in 26% of the FSH/LH tumors, although not in ACTH or PRL tumors. SSTR(5) expression was noted in 2 of the 3 TSH tumors, in only 20% of ACTH tumors, and was absent from FSH/LH and PRL tumors. The immunohistochemical detection of SSTR is a reproducible and specific method that could help direct the choice of postoperative medical treatment.