Primary Neuroendocrine Neoplasia of the Liver.

ABSTRACT: The presence of primary neuroendocrine tumors in the liver is still a matter of controversy. We present a case of a somatostatin-receptor-positive mass of the liver in the 68Ga-DOTATOC PET/CT. No other primary tumor was found after conventional imaging, endoscopically, and after liver-segment resection. Immunohistochemically, a constellation of findings was found to be compatible with a primary neuroendocrine neoplasm of the liver.

Prior Resection of the Primary Tumor Prolongs Survival After Peptide Receptor Radionuclide Therapy of Advanced Neuroendocrine Neoplasms.

OBJECTIVE: The aim of the study was to compare impact on survival after resection of primary tumors (PTs) after peptide receptor radionuclide therapy (PRRT). BACKGROUND: PRRT is a highly effective therapeutic option to treat locally advanced or metastatic neuroendocrine neoplasms (NENs). METHODS: We retrospectively analyzed the data of 889 patients with advanced NEN (G1-G3, stage IV) treated with at least 1 cycle of PRRT. In 486 of 889 patients (55%, group 1), PT had been removed before PRRT. Group 2 constituted 403 patients (45%) with no prior PT resection. Progression-free survival (PFS) and overall survival (OS) was determined by 68Ga SSTR-PET/CT in all patients applying RECIST and EORTC. RESULTS: Most patients had their PT in pancreas (n = 335; 38%) and small intestine (n = 284; 32%). Both groups received a mean of 4 cycles of PRRT (P = 0.835) with a mean cumulative administered radioactivity of 21.6 ±â€Š11.7 versus 22.2 ±â€Š11.2 GBq (P = 0.407). Median OS in group 1 was 134.0 months [confidence interval (CI): 118-147], whereas OS in group 2 was 67.0 months (CI: 60-80; hazard ratio 2.79); P < 0.001. Likewise, the median progression-free survival after first PRRT was longer in group 1 with 18.0 (CI: 15-20) months as compared to group 2 with 14.0 (CI: 15-18; hazard ratio 1.21) months; P = 0.012. CONCLUSIONS: A previous resection of the PT before PRRT provides a significant survival benefit in patients with NENs stage IV.

A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors.

We introduce and validate a new precision oncology framework for the systematic prioritization of drugs targeting mechanistic tumor dependencies in individual patients. Compounds are prioritized on the basis of their ability to invert the concerted activity of master regulator proteins that mechanistically regulate tumor cell state, as assessed from systematic drug perturbation assays. We validated the approach on a cohort of 212 gastroenteropancreatic neuroendocrine tumors (GEP-NETs), a rare malignancy originating in the pancreas and gastrointestinal tract. The analysis identified several master regulator proteins, including key regulators of neuroendocrine lineage progenitor state and immunoevasion, whose role as critical tumor dependencies was experimentally confirmed. Transcriptome analysis of GEP-NET-derived cells, perturbed with a library of 107 compounds, identified the HDAC class I inhibitor entinostat as a potent inhibitor of master regulator activity for 42% of metastatic GEP-NET patients, abrogating tumor growth in vivo. This approach may thus complement current efforts in precision oncology.

Results and adverse events of personalized peptide receptor radionuclide therapy with 90Yttrium and 177Lutetium in 1048 patients with neuroendocrine neoplasms.

INTRODUCTION: Peptide receptor radionuclide therapy (PRRT) of patients with somatostatin receptor expressing neuroendocrine neoplasms has shown promising results in clinical trials and a recently published phase III study. METHODS: In our center, 2294 patients were screened between 2004 and 2014 by 68Ga somatostatin receptor (SSTR) PET/CT. Intention to treat analysis included 1048 patients, who received at least one cycle of 90Yttrium or 177Lutetium-based PRRT. Progression free survival was determined by 68Ga SSTR-PET/CT and EORTC response criteria. Adverse events were determined by CTCAE criteria. RESULTS: Overall survival (95% confidence interval) of all patients was 51 months (47.0-54.9) and differed significantly according to radionuclide, grading, previous therapies, primary site and functionality. Progression free survival (based on PET/CT) of all patients was 19 months (16.9-21), which was significantly influenced by radionuclide, grading, and origin of neuroendocrine neoplasm. Progression free survival after initial progression and first and second resumption of PRRT after therapy-free intervals of more than 6 months were 11 months (9.4-12.5) and 8 months (6.4-9.5), respectively. Myelodysplastic syndrome or leukemia developed in 22 patients (2.1%) and 5 patients required hemodialysis after treatment, other adverse events were rare. CONCLUSION: PRRT is effective and overall survival is favorable in patients with neuroendocrine neoplasms depending on the radionuclide used for therapy, grading and origin of the neuroendocrine neoplasm which is not exactly mirrored in progression free survival as determined by highly sensitive 68Ga somatostatin receptor PET/CT using EORTC criteria for determining response to therapy.

Laparoscopic versus open distal pancreatectomy-a propensity score-matched analysis from the German StuDoQ|Pancreas registry.

PURPOSE: The aim of this study was to assess intraoperative, postoperative, and oncologic outcome in patients undergoing laparoscopic distal pancreatectomy (LDP) versus open distal pancreatectomy (ODP) for benign and malignant lesions of the pancreas. METHODS: Data from patients undergoing distal pancreatic resection were extracted from the StuDoQ|Pancreas registry of the German Society for General and Visceral Surgery. After propensity score case matching, groups of LDP and ODP were compared regarding demography, comorbidities, operative details, histopathology, and perioperative outcome. RESULTS: At the time of data extraction, the StuDoQ|Pancreas registry included over 3000 pancreatic resections from over 50 surgical departments in Germany. Data from 353 patients undergoing ODP (n = 254) or LDP (n = 99) from September 2013 to February 2016 at 29 institutions were included in the analysis. Baseline data showed a strong selection bias in LDP patients, which disappeared after 1:1 propensity score matching. A comparison of the matched groups disclosed a significantly longer operation time, higher rate of spleen preservation, more grade A pancreatic fistula, shorter hospital stay, and increased readmissions for LDP. In the small group of patients operated for pancreatic cancer, a lower lymph node yield with a lower lymph node ratio was apparent in LDP. CONCLUSIONS: LDP needed more time but potential advantages include increased spleen preservation and shorter hospital stay, as well as a trend for less transfusion, ventilation, and mortality. LDP for pancreatic cancer was performed rarely and will need critical evaluation in the future. Data from a prospective randomized registry trial is needed to confirm these results.

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

INTRODUCTION: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

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.

Somatostatin receptor immunohistochemistry in neuroendocrine tumors: comparison between manual and automated evaluation.

BACKGROUND: Manual evaluation of somatostatin receptor (SSTR) immunohistochemistry (IHC) is a time-consuming and cost-intensive procedure. Aim of the study was to compare manual evaluation of SSTR subtype IHC to an automated software-based analysis, and to in-vivo imaging by SSTR-based PET/CT. METHODS: We examined 25 gastroenteropancreatic neuroendocrine tumor (GEP-NET) patients and correlated their in-vivo SSTR-PET/CT data (determined by the standardized uptake values SUVmax,-mean) with the corresponding ex-vivo IHC data of SSTR subtype (1, 2A, 4, 5) expression. Exactly the same lesions were imaged by PET/CT, resected and analyzed by IHC in each patient. After manual evaluation, the IHC slides were digitized and automatically evaluated for SSTR expression by Definiens XD software. A virtual IHC score "BB1" was created for comparing the manual and automated analysis of SSTR expression. RESULTS: BB1 showed a significant correlation with the corresponding conventionally determined Her2/neu score of the SSTR-subtypes 2A (rs: 0.57), 4 (rs: 0.44) and 5 (rs: 0.43). BB1 of SSTR2A also significantly correlated with the SUVmax (rs: 0.41) and the SUVmean (rs: 0.50). Likewise, a significant correlation was seen between the conventionally evaluated SSTR2A status and the SUVmax (rs: 0.42) and SUVmean (rs: 0.62). CONCLUSION: Our data demonstrate that the evaluation of the SSTR status by automated analysis (BB1 score), using digitized histopathology slides ("virtual microscopy"), corresponds well with the SSTR2A, 4 and 5 expression as determined by conventional manual histopathology. The BB1 score also exhibited a significant association to the SSTR-PET/CT data in accordance with the high affinity profile of the SSTR analogues used for imaging.

Molecular imaging of late somatostatin receptor-positive metastases of renal cell carcinoma in the pancreas by 68Ga DOTATOC PET/CT: a rare differential diagnosis to multiple primary pancreatic neuroendocrine tumors.

Ga somatostatin receptor PET/CT, currently the most sensitive imaging modality for well-differentiated neuroendocrine tumors, is based on the molecular imaging of somatostatin receptors (SSTRs) that are expressed in different tumor entities such as neuroendocrine neoplasms, lymphomas, meningiomas, or renal cell cancer (RCC). Most neuroendocrine neoplasms show a high expression of SSTR subtypes 2A and 5, whereas the overexpression of SSTR2A in RCC is mainly seen in peritumoral vessels. Here we report a case with strongly SSTR-positive pancreatic lesions detected by Ga DOTATOC PET/CT, which histologically turned out to be ultralate metastases of a RCC.

High uptake of (68)Ga-DOTATOC in spleen as compared to splenosis: measurement by PET/CT.

AIM: The aim of this study is to ascertain the high somatostatin receptor (SSTR) uptake in spleen and to compare the uptake in spleen and splenosis using SSTR PET/CT using( 68)Ga-DOTATOC. MATERIALS AND METHODS: SUV(max) of spleen on (68)Ga-DOTATOC SSTR PET/CT (acquired for initial staging) in 10 patients with known neuroendocrine neoplasm of pancreatic tail was analyzed. All patients underwent left pancreatectomy and splenectomy. Diagnosis of splenosis was confirmed on CT, and SUV(max) was noted on follow-up SSTR PET/CT. RESULTS: SUV(max)was 28.8 ± 12.5 in normal spleen and 10.5 ± 4.3 in splenosis. CONCLUSION: The high uptake of( 68)Ga-DOTATOC (which has a high affinity to SSTR 2) in the spleen as compared to splenosis, which has a different histology, suggests white pulp as the probable site of high SSTR 2 expression.

Intraoperative somatostatin receptor detection after peptide receptor radionuclide therapy with (177)Lu- and (90)Y-DOTATOC (tandem PRRNT) in a patient with a metastatic neuroendocrine tumor.

AIM: The aim of this chapter is to present the results of the first intraoperative somatostatin receptor detection after peptide receptor radionuclide therapy (PRRNT) with (90)Y- and (177)Lu-DOTATOC using a handheld gamma probe and comparison with the findings of preoperative (68)Ga-DOTATOC PET/CT in a patient with a metastatic neuroendocrine tumor (NET) of the ileum. MATERIALS AND METHODS: A 56-year-old female patient, treated twice by PRRNT, was admitted for the third cycle and subsequent surgery. Before operation, the following studies were performed for restaging after the second cycle of PRRNT: (99m)Tc-MAG3 + TER, (99m)Tc-DTPA + GFR, abdominal ultrasonography, MRI of the abdomen, (68)Ga-DOTATOC PET/CT as well as (18)F-fluoride PET/CT. Serum tumor markers were measured before and after PRRNT. Tandem PRRNT was performed using 3000 MBq (90)Y-DOTATOC and 6000 MBq (177)Lu-DOTATOC. Whole-body scintigrams were obtained at 23 and 43 h. Five days after PRRNT, the patient was operated using a handheld gamma probe. Immunohistochemistry and histopathology of the resected tissue were performed. RESULTS: Tandem PRRNT was very well tolerated by the patient. Before PRRNT, (68)Ga-DOTATOC PET/CT revealed the primary tumor in the ileocoecal region as well as bilobular liver metastases and a right iliac bone lesion (osteoblastic on (18)F-fluoride PET/CT). Compared with the previous findings, there was good therapy response (partial remission of the tumor lesions). No nephrotoxicity was observed. Serum chromogranin A (836 µg/l, n < 100) and serotonin (852 µg/l, n < 200) were strongly elevated. Posttherapy scans showed intense uptake in metastases and the primary tumor. Intraoperative gamma probe detected-in addition to the known lesions-bilateral ovarian metastases not visualized by (68)Ga-DOTATOC PET/CT. Bilateral adnexectomy, right hemicolectomy, excision of hepatic metastases in S3, and partial resection of peritoneum were performed. Histopathology confirmed metastases in both ovaries. CONCLUSIONS: Gamma probe-guided surgery after (177)Lu PRRNT is feasible and appears to be more sensitive than (68)Ga-DOTATOC PET/CT. This technique might aid the surgeon in achieving more complete tumor resection through intraoperative detection of very small lesions (<5 mm) directly after PRRNT.

Correlation of monoclonal and polyclonal somatostatin receptor 5 antibodies in pancreatic neuroendocrine tumors.

AIMS: To evaluate the frequency of somatostatin-receptor 5 (SSTR 5) in pancreatic neuroendocrine tumors by using monoclonal and polyclonal antibodies. MATERIAL AND METHOD: we analyzed 66 proven pancreatic neuroendocrine tumors immunohistochemically with monoclonal (clone UMB-4) and polyclonal SSTR 5-antibodies. Immunoreactive score (IRS) and DAKO-score Her2/neu were evaluated. RESULTS: Immunohistochemistry analysis demonstrated for the IRS a significant higher staining of all specimen using the monoclonal antibodies ( IRS SSTR5 poly vs IRS SSTR 5 mono; 20.0% vs 30.3% p < 0.001) by a correlation of 0.21; p = 0.04. For the HER2 score there was also a significant higher staining in the monoclonal group (Her2 SSTR 5 poly vs Her2 SSTR 5 mono; 21.5% vs 28.8% p < 0.001) by a correlation of 0.20; p = 0.08. CONCLUSION: Both antibodies are useful in staining of SSTR, although UMB-4 demonstrated a 10% higher SSTR 5 staining. Due to the previous underestimated expression rate of SSTR 5, current standards in diagnostics and therapy should be reconsidered. The increasing usage of long-acting pansomatostatin receptor analogues will rise the adverse effects connected to SSTR5 binding.

Comparing of IRS and Her2 as immunohistochemical scoring schemes in gastroenteropancreatic neuroendocrine tumors.

UNLABELLED: Neuroendocrine tumors (NET) are known for an overexpression of somatostatin receptors (SSTR). In light of very few and partially contradictory publications, the present study aims to achieve a definite immunohistochemical (IHC) quantification and assessment of the distribution of all five SSTR-subtypes on NET and to evaluate an implementable scoring system, comparing the immunoreactive score of Remmele and Stegner (IRS) to the Her2-score. In 21 patients 40 different tumor tissues were IHC analysed using polyclonal antibodies for SSTR1 and 3-5 and the monoclonal antibody UMB-1 for SSTR2A. SSTR expression was quantitatively evaluated according to HER2-score and IRS, correlated among each other and to the maximum standardized uptake value (SUVmax) in tumor lesions as measured by PET/CT using 68Ga-DOTA-NOC. RESULTS: According to the IRS, the expression of SSTR2A and 3 predominated equally with 84%, followed by SSTR4 (44%) and SSTR1 and 5 (32%). With the Her2-scoring system the most frequent subtype was found to be SSTR2A (68%), followed by SSTR3 (64%), SSTR1 (44%), SSTR5 (40%), and SSTR4 (36%). The IRS-classification and the Her2-score were found to be statistically comparable, and their correlation is highly significant for each SSTR assessment (p<0.01). CONCLUSION: The results of the analyses revealed heterogeneous expression patterns. SSTR2A and 3 were highly expressed, demonstrating the importance of SSTR for diagnostics and therapy. Relatively high frequency of SSTR3 and 4 on NET give reasons to try pansomatostatin analogues for therapy rather than concentrating only on the SSTR2A. Statistically, none of the immunohistochemical scores was superior. However, due the heterogeneity of the cytoplasmic staining justice we propose the IRS as a uniform scoring scheme for IHC NET diagnostic.

Role of PET/CT in the functional imaging of endocrine pancreatic tumors.

Endocrine pancreatic tumors (EPTs) are a heterogeneous group of neoplasms with variable clinical and biological features and prognosis, ranging from very slow-growing tumors to highly aggressive and very malignant ones. As other neuroendocrine tumors, EPTs are characterized by the presence of neuroamine uptake mechanisms and/or peptide receptors at the cell membrane and these features constitute the basis of the clinical use of specific radiolabeled ligands, both for imaging and therapy. The more widespread use of hybrid machines, i.e., positron emission tomography/computed tomography (PET/CT), allows to perform imaging with high resolution and high diagnostic accuracy especially for small lesions, and to correlate anatomic location with function. The recent WHO recommendations for classification and prognostic factors help the selection of tracers likely to show a positive image on PET; therefore, tracers exploiting specific metabolic patterns ((18)F-DOPA and (11)C-5-HTP) or specific receptor expression ((68)Ga-DOTA-peptides) are suited to well-differentiated tumors, while the use of (18)F-FDG is preferred for poorly-differentiated neoplasms with high proliferative activity and loss of neuroendocrine features. In differentiated EPTs, (11)C-5-HTP performs better than (18)F-DOPA even though its use is hampered by its complex production and limited availability and experience; (68)Ga-peptides are indicated for all type of gastroenteropancreatic (GEP) neuroendocrine tumors, regardless of their functional activity. In addition, (68)Ga-DOTA-peptides play a distinctive role in planning peptide receptor radionuclide therapy.

Radioguided surgery in neuroendocrine tumors using Ga-68-labeled somatostatin analogs: a pilot study.

BACKGROUND: Previous studies of the intraoperative use of a hand-held gamma probe to localize metastases and primary tumors have shown improved assessment of tumor spread and changes in surgical management based on additional information gained by radioguided surgery (RGS). PURPOSE: The aim was to test the feasibility and advantages of doing RGS using a gallium-68 labeled with somatostatin receptor analogs in the intraoperative detection of neuroendocrine tumors. METHODS: Ga-68 somatostatin receptor PET/CT imaging was performed preoperatively in 9 patients with gastroenteropancreatic neuroendocrine tumors. Statistical analyses were performed to find out the correlation between the pathologic size of the tumor lesions and the maximum standardized uptake value on PET/CT as well as the target/nontarget ratio (T/NT) of gamma probe counts. Thereafter, the impact of the planned operation procedure and the lesion-based sensitivity of tumor detection (surgical palpation vs. PET/CT vs. gamma probe) had been observed. RESULTS: Overall, 72 locations in 9 patients were examined intraoperatively using gamma probes. The gamma probe detected 94% of the whole histologically quantified lesions, whereas the PET/CT allocated 69% and surgical palpation, 50%. RGS resulted in change in the operative procedure in 56%. There was a significant correlation between the maximum standardized uptake value and tumor size (0.74; P < 0.005). CONCLUSION: Hand-held gamma probe surgery using gallium-68-labeled somatostatin analogs is a feasible and an attractive option for real-time detection of small metastases and primaries of neuroendocrine tumors.

Treatment of bone loss in patients with chronic liver disease awaiting liver transplantation.

BACKGROUND: Most of the patients awaiting liver transplantation already have osteopenia or even osteoporosis by end-stage liver disease.In a retrospective study, we investigated the effect of pre-treatment with oral monthly ibandronate (150 mg), vitamin D3 (800 IU/day) and calcium (1 g/day) for osteopenia and osteoporosis caused by end-stage liver disease in patients before and after liver transplantation (LT). METHODS: The bone mineral density (BMD) of the lumbar spine (LS) and the femoral neck was measured prospectively pre- and post-LT in 31 patients with existing pre-transplant osteopenia. Patients had osteopenia of the LS prior to LT (T-score -1.8 ± 1.5) so that the treatment medication was initiated immediately after the diagnosis. RESULTS: The study group showed a permanently increased BMD with significant differences (g/cm²) from baseline up to 12 months post LT at the lumbar spine (LS: pre-LT 0.80 ± 0.11 g/cm², three months: 0.90 ± 0.08 (P <0.005); six months: 0.95 ± 0.11 (P < 0.008); 12 months: 1.00 ± 0.09 -0.85 (P <0.012). CONCLUSION: The combined pre- and post-operative treatment with oral ibandronate had significantly improved bone mineral density of the lumbar spine at 3, 6 and 12 months post LT. The immediate post-operative bone loss after LT can be significantly avoided by pre-treatment of liver transplant candidates affected by osteopenia.

Concomitant lung and gastroenteropancreatic neuroendocrine tumors and the value of gallium-68 PET/CT.

Well-differentiated neuroendocrine tumors (NETs) of the lung occur as typical and atypical carcinoids. Little is known about the biology of these tumors in respect of their ability to metastasize or the probability of development of concomitant neuroendocrine tumors. Here we report a patient diagnosed with a second neuroendocrine tumor of the ileum 4 years after curative resection of a typical carcinoid of the left lung. The intestinal neuroendocrine tumor was successfully detected by gallium-68 based somatostatin receptor positron emission tomography (PET)/computed tomography (CT) and surgically removed using gamma probe detection based on the same labeling. This case report underlines the utility of somatostatin receptor PET/CT based detection and follow-up of NETs.

Molecular imaging with 68Ga-SSTR PET/CT and correlation to immunohistochemistry of somatostatin receptors in neuroendocrine tumours.

PURPOSE: Somatostatin receptors (SSTR) are known for an overexpression in gastroenteropancreatic neuroendocrine tumours (GEP-NET). The aim of the present study was to find out if the receptor density predicted by the semi-quantitative parameters generated from the static positron emission tomography (PET/CT) correlated with the in vitro immunohistochemistry using a novel rabbit monoclonal anti-SSTR2A antibody (clone UMB-1) for specific SSTR2A immunohistochemistry and polyclonal antibodies for SSTR1 and 3-5. METHODS: Overall 14 surgical specimens generated from 34 histologically documented GEP-NET patients were correlated with the preoperative (68)Ga-DOTA-NOC PET/CT. Quantitative assessment of the receptor density was done using the immunoreactive score (IRS) of Remmele and Stegner; the additional 4-point IRS classification for immunohistochemistry and standardized uptake values (SUV(max) and SUV(mean)) were used for PET/CT. RESULTS: The IRS for SSTR2A and SSTR5 correlated highly significant with the SUV(max) on the PET/CT (p < 0.001; p < 0.05) and the IRS for SSTR2A with the SUV(mean) (p < 0.013). The level of SSTR2A score correlated significantly with chromogranin A staining and indirectly to the tumour grading. CONCLUSION: The highly significant correlation between SSTR2A and SSTR5 and the SUV(max) on the (68)Ga-DOTA-NOC PET/CT scans is concordant with the affinity profile of (68)Ga-DOTA-NOC to the SSTR subtypes and demonstrates the excellent qualification of somatostatin analogues in the diagnostics of NET. This study correlating somatostatin receptor imaging using (68)Ga-DOTA-NOC PET/CT with immunohistochemically analysed SSTR also underlines the approval of therapy using somatostatin analogues, follow-up imaging as well as radionuclide therapy.

Localization of sporadic neuroendocrine tumors by gene expression analysis of their metastases.

A characteristic of human gastroenteropancreatic neuroendocrine tumors (GEP-NET) is a minute unobtrusive primary tumor which often cannot be detected by common physical examinations. It therefore remains unidentified until the tumor has spread and space-occupying metastases cause clinical symptoms leading to diagnosis. Cases in which the primary cannot be located are referred to as NET with CUP-syndrome (cancer of unknown primary syndrome). With the help of array-CGH (comparative genomic hybridization, Agilent 105K) and gene expression analysis (Agilent 44K), microdissected primaries and their metastases were compared to identify up- and down-regulated genes which can be used as a marker for tumor progression. In a next analysis step, a hierarchical clustering of 41.078 genes revealed three genes [C-type lectin domain family 13 member A (CD302), peptidylprolyl isomerase containing WD40 repeat (PPWD1) and abhydrolase domain containing 14B (ABHD14B)] which expression levels can categorize the metastases into three groups depending on the localization of their primary. Because cancer therapy is dependent on the localization of the primary, the gene expression level of these three genes are promising markers to unravel the CUP syndrome in NET.