Somatostatin Receptor Expression Research Articles

P-37 MEDIASTINAL PARAGANGLIOMA AS A CAUSE OF HYPERTENSION IN A YOUNG PATIENT:A CASE REPORT

Abstract Introduction Paragangliomas, tumors that arise from extraadrenal chromaffin cells, are rarely found in the mediastinum. It is important to diagnose and remove paragangliomas because of its critical symptoms such as hypertension and can be curable with resection. Clinical Case A 18-year-old man, has no known disease, presented with episodes of palpitations, sweating associated with hypertension.The patient’s blood pressure measured at office was 180/110 mmHg. Electrocardiographic monitoring showed only nonspesific ST-T waves changes. Other secondary causes of hypertension were excluded. Suspecting of pheochromocytoma, 24-hour urinary metanephrine and normetanephrine levels were examined, the normetanephrine level was found to be elevated (1367,78 mcg/24 hour; normal range 88-444), whereas metanephrine level was normal (102,16 mcg/24 hour; normal range 52-341). Plasma metanephrine level was normal (58 ng/L; normal range 0-90).However plasma normetanephrine level was elevated (163,1 ng/L; normal range 0-90).The ratio of serum aldosterone level to the plasma renin activity was normal. 1 mg dexamethasone suppression test was normal. There was no adrenal mass in the abdominal MRI, but a mass measuring 4,3x 3,2 cm was seen in the right paravertebral area of the thorax in the area included in the cross-sections. In Ga-68 Dota-tate positron emission tomography (PET),a mass lesion of 43x30 mm in size, showing intense somatostatin receptor expression (SUV-max: 31.9) was detected in the right paravertebral area at the level of the 8th thoracic vertebra, which was evaluated as paraganglioma. For more than 1 month, the patient had been prepared for the surgery administering combination doxazosine and propronol after the treatment with only doxazosin. The patient was consulted to the thoracic surgery department. Phentolamine was provided before surgery. The mass was resected via thoracotomy. In histological evaluation, widespread zelballen and pseudorosette structures were observed. There was no comedonecrosis, and there was no vascular and capsular invasion. Ki 67 proliferation index was 4-5 %. On immunohistochemical staining, the mass tested positive for synaptophysin and chromagranin and negative for cytokeratins. One month after surgery normetanephrine (147,85 mcg/24h; normal range: 88-444) and metanephrine (102,16 mcg/24 h; normal range 52-341) levels were normal. The patients blood pressure was stabilized at 120/70 mmHg and heart rate was 80 bpm. In the genetic analysis of the patient, the NDUFA6 gene was detected and mitechondrial complex 1 deficiency was associated with nuclear type 33 disease and the patient was accepted as a carrier. Screening with 24 hour urine metanephrine and normetanephrine was recommended to patient’s family members. Conclusion Since, there are no definite microscopic criteria for the distinction between benign and malignant tumors, radical excision is necessary. The symptoms are curable with resection of tumor, long term follow up for recurrence is important.Figure 1:Gallium-68 Dota-Tate PETShowing the mass(SUV-max:31.99)

Small Bowel Leiomyoma Mimics Neuroendocrine Tumor on 68Ga-DOTATATE PET/CT.

A 57-year-old man with a 3-month history of lower abdominal pain and rectal bleeding with black stools underwent urgent abdominal CT, which revealed an ovoid hyperdense lesion in the ileum in the right iliac fossa. The prime differential was a midgut neuroendocrine tumor. Thus, the patient was referred for a 68Ga-DOTATATE PET/CT scan, which demonstrated intense activity in this lesion with no evidence of somatostatin receptor expression elsewhere. Surgical small bowel resection later revealed a small bowel leiomyoma, which was confirmed on immunohistochemistry analysis. This case demonstrates that leiomyomas can express somatostatin receptors and can be a false-positive on 68Ga-DOTATATE PET/CT scan.

SSTR2-Targeted Theranostics in Hepatocellular Carcinoma.

While the clinical use of radiolabeled somatostatin analogs is well established in neuroendocrine tumors, there is growing interest in expanding their application to other somatostatin receptor 2 (SSTR2)-expressing cancers. This study investigates the potential utility of SSTR2-targeted theranostics in hepatocellular carcinoma (HCC). SSTR2 expression in HCC cell lines and clinical samples was evaluated using qRT-PCR, Western blot analysis, and a public dataset. 67Ga-DOTATATE uptake was measured, 177Lu-DOTATATE cytotoxicity was assessed, and 68Ga-DOTATATE tumor targeting was evaluated in HCC animal models and a patient via PET/CT imaging. SSTR2 expression was confirmed in HCC cell lines and clinical samples. Radioligand uptake studies demonstrated SSTR2-mediated 67Ga-DOTATATE uptake. 177Lu-DOTATATE treatment reduced cell proliferation and enhanced the anti-tumor efficacy of the multikinase inhibitor sorafenib. 68Ga-DOTATATE PET/CT scans successfully identified tumors in HCC animal models and spinal metastases in a patient with HCC. These findings provide evidence that SSTR2-based theranostics could have significant implications for the detection and treatment of HCC.

Central Nervous System Tumor-Embryonal Tumors Type With Neuroendocrine Differentiation.

The central nervous system (CNS) tumor with embryonal tumors type is a rare type of CNS tumor with lack of unifying genetic alterations or diagnostic markers. The CNS tumor-embryonal tumors (CETs) have limited therapeutic options with high probability of adverse events associated with conventional treatment. Identification of somatostatin receptor expression and/or prostate-specific membrane antigen expression in CET patients by using PET/CT imaging may be helpful for deciding therapeutic approaches in these patients as theranostics. We present a 56-year-old woman who complained of headache, diminution of vision, and diagnosed CET and demonstrated high SSTR expression on PET/CT imaging, indicating peptide receptor radionuclide therapy could be effective therapeutic option in this case.

Targeted Peptide Receptor Radionuclide Therapy With 177 Lu-DOTATATE Alters Joints Inflammation.

High and frequent expression of somatostatin receptors in differentiated neuroendocrine neoplasms has paved the way for receptor-based, targeted peptide receptor radionuclide therapy especially for nonoperable or metastatic disease. Besides tumors, radiation, in one form or another, has been tested to treat inflammatory disease as well, and this goes back to the early 1990s when the first case of pneumonia treated with radiation showed complete resolution. Currently, radiotracers help in not only in vivo inflammation detection, characterization, and staging but also, and more importantly, for selection of treatment in individual patients. The same concept could be applied to treatment of infection, by coupling the radioisotopes to ligands that target sterile or nonsterile inflammation. In our case, targeted peptide receptor radionuclide therapy showed remarkable resolution of inflammatory joint disease.

[89Zr]Zr-DFO-TOC: a novel radiopharmaceutical for PET imaging of somatostatin receptor positive neuroendocrine tumors

BackgroundNeuroendocrine tumors (NETs) are clinically diverse types of tumors that can arise anywhere in the body. Previous studies have shown that somatostatin receptors (SSTRs) are overexpressed on NET cell membranes relative to healthy tissue, allowing for tumor targeting through radiolabeled somatostatin analogs (SSAs). This work aims to develop a novel 89Zr-labeled tracer incorporating the SSA, octreotide (TOC), for positron emission tomography (PET) imaging of SSTR + NETs and predictive dosimetry calculations, leveraging the excellent nuclear (t½ = 3.27 days, β+ = 22.3%, β+avg = 395.5 keV) and chemical characteristics (+ 4 oxidation state, preferential coordination number of 7/8, favorable aqueous chemistry) of 89Zr. In combination with 89Zr, the known radiochemistry with the chelator deferoxamine (DFO) gives reason to believe that this radiopharmaceutical incorporating an octreotide conjugate will be successful in studying the suitability of detecting SSTR + NETs.ResultsRadiochemical tracer assessment indicated that amounts as low as 0.1 nmol DFO-TOC can be effectively radiolabeled with 89Zr, while maintaining ≥ 95% radiochemical yield. The stability of the compound was found to maintain radiochemical yields of 89.6% and 88.7% on the benchtop and in mouse serum, respectively, after 9 days. Receptor binding and competitive receptor blocking assays compared AR42J (high SSTR expression), PC-3 (moderate SSTR expression), and PANC-1 (minimal SSTR expression) cell lines at time points up to 6 days. In vitro studies demonstrated highest uptake in AR42J cells, and statistically significant differences in tracer uptake were seen after 1 h. Internalization assays showed maximum internalization after 3 h for all cell lines.ConclusionsIn this work, [89Zr]Zr-DFO-TOC was synthesized with radiochemical yields ≥ 95% and was found to remain stable in vitro at extended time points. In vitro cell studies demonstrated a statistically significant difference between receptor binding and blocking experiments. The development of this work shows potential to positively impact patient care through the predictive dosimetry calculations for the FDA-approved therapeutic agent [177Lu]Lu-DOTA-TATE, while allowing for imaging at extended timepoints and should be studied further.

The Investigation of Somatostatin Receptors as a Potential Target in Breast Phyllodes Tumours.

Somatostatin receptors (SSTRs) are expressed in most neuroendocrine neoplasms, particularly in gastroenteropancreatic neuroendocrine tumours, and have been utilised as diagnostic markers and therapeutic targets. The radioiodinated somatostatin analogue 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid- Tyr3-octreotate (DOTATATE) has been employed for SSTR targeting for either diagnostic or therapeutic purposes depending on the labelling with 68Gallium or 177Lutetium, respectively. SSTR expression is reported in a subset of breast adenocarcinoma and breast neuroendocrine carcinomas; however, minimal knowledge exists regarding their expression in fibroepithelial (biphasic) breast lesions such as fibroadenoma and phyllodes tumours. Aggressive ends of the spectrum, i.e., "cystosarcoma phyllodes", may present a management challenge with recurrences and metastases, and SSTRs could be a promising therapeutic target for these types of tumours. Gene and protein expressions of SSTRs in primary human fibroepithelial lesions of the breast are investigated using RT-PCR and immunoblotting. Localisation of the SSTR-positive cells was determined with immunohistochemistry and immunofluorescence. Both fibroadenoma and phyllodes tumours express SSTRs. Immunohistochemical analyses suggested that this expression is in the stromal, not epithelial, component by demonstrating that SSTR stained in the areas overlapping with α-smooth muscle actin-positive myoepithelial cells around blood vessels and capillary structures. This study is the first in the literature to demonstrate SSTR positivity in mammary fibroepithelial neoplasms. Once validated, these findings may also have significant implications for managing the treatment of these tumours.

Expression of Somatostatin Receptors in the Small Intestine during Postnatal Ontogenesis.

The expression of somatostatin receptors (SSTRs) of types 1, 2, and 5 was studied in the small intestine of rats from different age groups (1, 10, 20, 30, 60 days, and 2-year-old) using Western blotting. The expression of SSTR1, SSTR2, and SSTR5 increased in the first 30 days of life, but decreased in older rats compared to 2-month-old animals. These findings suggest that there is differential expression of SSTRs during age-related development of the small intestine. Further studies will determine the role of individual SSTRs in the growth and development of target organs.

Inter- and intra-tumoral heterogeneity on [68Ga]Ga-DOTA-TATE/[68Ga]Ga-DOTA-TOC PET/CT predicts response to [177Lu]Lu-DOTA-TATE PRRT in neuroendocrine tumor patients

BackgroundIndices of tumor heterogeneity on somatostatin receptor PET/CT scans may potentially serve as predictive biomarkers of treatment efficacy in neuroendocrine tumor (NET) patients undergoing [177Lu]Lu-DOTA-TATE PRRT.MethodsNET patients who underwent [177Lu]Lu-DOTA-TATE therapy at the University of Iowa from August 2018 to February 2021 were retrospectively evaluated. Radiomic features on the pre-PRRT somatostatin receptor PET/CT were evaluated using a custom MIM Software® LesionID workflow. Conventional PET/CT metrics of tumor burden, such as somatostatin receptor expression and tumor volume, were calculated in addition to the indices of tumor heterogeneity for each lesion (intra-lesional) and then summarized across all lesions throughout the body (inter-lesional). Endpoints included post-PRRT 24-month time to progression (TTP) and overall survival (OS). Cox regression models were used to assess the predictive ability of the imaging factors on post-PRRT 24-month TTP and OS. LASSO-penalized Cox regression was used to build a multivariable model for each outcome.ResultsEighty patients with a mean age of 65.1 years were included, with most (71.3%) completing 4 cycles of PRRT. Median TTP was 19.1 months, and OS at 60 months was 50%. A large degree of variability between patients was evidenced for imaging features related to somatostatin receptor expression. On multivariable analysis, total receptor expression and mean liver-corrected SUVmean were selected for 24-month TTP. The model was not able to significantly predict progression (C-statistic = 0.58, 95% CI 0.50–0.62). Total receptor expression and mean skewness were selected for OS. The resulting model was able to significantly predict death (C-statistic = 0.62, 95% CI 0.53–0.67), but the predictive ability was limited, as evidenced by the low C-statistic.ConclusionsOur exploratory analysis provides preliminary results showing that imaging indices of inter- and intra-tumor heterogeneity from pretreatment PET/CT images may potentially predict treatment efficacy in NET patients undergoing [177Lu]Lu-DOTA-TATE therapy. However, prospective evaluation in a larger cohort is needed to further assess whether a comprehensive characterization of tumor heterogeneity within a patient can help guide treatment decisions.

Metanephrine mirage: distinguishing the phaeocopies, a case report and literature review

BackgroundWe present one of only seven reported cases of a catecholamine-secreting adrenal neuroblastoma in an adult. The case is used as a platform to discuss key biochemical, genomic and imaging considerations that are central to the successful, targeted management of catecholamine-secreting adrenal tumours.Case presentationA 63-year-old male was urgently reviewed at a tertiary hospital endocrinology outpatient clinic for a 12 cm right-sided adrenal incidentaloma. Plasma normetanephrine and 3-methoxytyramine levels were approximately 10 times the upper limit of normal at 9272 pmol/L (< 900) and 1023 pmol/L (< 110), respectively.The adrenal mass appeared to be inseparable from the liver on imaging, and thus was suspected to be an invasive malignant phaeochromocytoma. FDG positron emission tomography (PET)/CT demonstrated moderate to intense metabolic activity within the right adrenal mass. [68 Ga]Ga-DOTATATE (Ga-TATE) PET-CT demonstrated patchy, heterogenous somatostatin receptor (SSTR) expression in the adrenal lesion, at most Krenning 3 (intensity above liver).The patient underwent a right adrenalectomy and segment 6/7 liver resection. Histopathology revealed a 130 mm diameter neuroblastoma of the differentiating subtype with a low Mitosis-Karyorrhexis Index. There was lymphovascular invasion and tumour focally present at the resection margin, but no tumour in one periadrenal lymph node, and no tumour invasion in the adherent liver. Immunohistochemistry revealed ALK positivity (+ 3) and wild type ATRX.At nine months following adrenalectomy, the plasma normetanephrine level has reduced to 991 pmol/L (< 900). Post-operative GaTate PET/CT shows no definite abnormal SSTR-expressing lesions in the surgical bed or elsewhere. The patient has completed adjuvant radiotherapy and is a candidate for ALK-targeted therapy if required for recurrence in the future.ConclusionsNeuroblastomas may be misdiagnosed as phaeochromocytomas given the ability to secrete catecholamines and similarities in radiological appearance. Differentiating neuroblastomas from phaeochromocytomas and paragangliomas (PPGL) is critical, but clinically difficult. Genomics are central for management; diagnosing ALK-positive neuroblastoma triggers consideration of ALK-targeted therapy, which is not relevant for PPGL. A critical eye is required for the accurate diagnosis and management of malignant adrenal incidentalomas.

Predictive value of 68[Ga]Ga-DOTA-TATE PET/CT volumetric parameters in assessing treatment response to long-acting somatostatin analogues in patients with well-differentiated neuroendocrine tumours

BackgroundOver the past decade, numerous treatment options have emerged for patients with locally advanced and metastatic neuroendocrine tumours (NETs). Nevertheless, the optimal timing of treatment interventions remains uncertain, given the highly variable disease course observed in these patients, even when patients have the same tumour stage and grade. The aim of the study was to evaluate the predictive role of standardized uptake values (SUVs) and volumetric parameters obtained from pretreatment [68Ga]Ga-DOTA-TATE for response to SSA therapy in patients with NET. In this retrospective study, we included 42 patients (21 women, 21 men; age range: 46–84 years) with histologically confirmed, metastatic, NET (G1 13, G2 28 cases); median Ki-67 index 5%, range 1–16) who received long acting SSA as a first line treatment and underwent [68Ga]Ga-DOTA-TATE PET/CT before SSA treatment. For all [68Ga]Ga-DOTA-TATE avid lesion SUVmax, SUVmean, somatostatin receptor expression tumour volume (STV), total lesion somatostatin receptor expression (TLD, STV multiplied by SUV mean) and Tmean/Smean (SUVmean of tumours/metastases divided by SUVmean of normal spleen) were measured. Finally, the sum of STV (total STV, TSTV) and TLD (total TLD, TTLD) was calculated for each patient and used in the analysis.ResultsDuring the study period, 14 patients had stable disease (33.3%) and 28 patients experienced progression (66.7%), among whom 12 patients died. The median progression-free survival (PFS) and overall survival (OS) were 26.5 and 46.5 months, respectively. In the univariate and multivariate analysis, in the whole population study, Tmean/Smean ratio (HR 1.88, 95% CI 1.06–3.35, p = 0.03), Ki-67 index (HR 1.14, CI 1.03–1.26, p = 0.01) and pre-treatment chromogranin A serum concentration (HR 1.01, CI 1.0–1.03, p = 0.01) were significantly associated with PFS. Among patients with small intestinal NETs, TSTV (< 125.85 cm3 vs. ≥ 125.85 cm3, p = 0.023) and TTLD (< 4168.95 vs. ≥ 4168.95, p = 0.026) were significantly associated with PFS in the univariate analyses. No significant correlation was found between measured volumetric parameters and OS.ConclusionVolumetric parameters of pretreatment 68[Ga]Ga-DOTA-TATE PET/CT may be useful in prediction of the response to SSA (used in monotherapy as a first-line therapy) in patients with NET.

Toxicity manifestations encountered in peptide receptor radionuclide therapy setting.

Peptide receptor radionuclide therapy (PRRT) has demonstrated immense promise as a treatment for patients with neuroendocrine tumors (NET) who have somatostatin receptor (SSTR) expression. PRRT significantly reduces tumor growth, stabilizes the disease, and prolongs survival in a significant percentage of patients with metastatic/advanced NET. It produces an important beneficial effect on the quality of life (QOL) and effectively alleviates symptoms in patients with NET. Overall, PRRT is typically well-tolerated and most of the side effects are usually transient and subside on their own. It is, however, crucial to be cognizant of the potential toxicities associated with this treatment. This awareness will enable physicians to promptly detect, effectively manage, and prevent these toxicities by identifying high-risk factors in NET patients. This review provides an in-depth overview for clinicians managing NET about the toxicity of PRRT. The toxicities are stratified into acute, subacute, and long-term based on their onset following PRRT. Potential high-risk factors in order to treat effectively and prevent these toxicities in NET patients are presented including the management strategy. This review also discusses novel insights, perspectives, and recent advancements in predicting, preventing, and managing toxicity associated with PRRT, while offering prospective future research directions to minimize clinical toxicity and maximize the therapeutic benefits of PRRT as a treatment strategy for NET patients.

Insulinoma with suspected mutant somatostatin receptor expression according to histological examination.

This case highlights the possibility of an insulinoma expressing an aberrant form of SSTRs resulting in a discrepancy between the preoperative octreotide assessment and postoperative SSTR expression. Insulinoma is a pancreatic disease that causes hyperinsulinemic hypoglycemia. The first-line treatment is surgery; however, somatostatin derivatives are administered in cases where surgery is not a viable option and to prevent preoperative hypoglycemia. Here, we report a case in which preoperative examination indicated a potential tumor with low somatostatin receptor 2 (SSTR2) and SSTR5 expression, whereas postoperative pathological examination indicated strong SSTR expression. We report the case of a 69-year-old Japanese female who experienced hypoglycemia-like symptoms for a decade such as sweating, fatigue, hunger, and confusion with an increase in episode frequency per year. Dynamic computed tomography revealed a 13-mm diameter nodule and aberrant blood flow in the pancreatic tail. Subsequently, the patient was diagnosed with pancreatic insulinoma. A preoperative octreotide test did not relieve hypoglycemia, and no uptake of 111indium-pentetreotide was observed, suggesting an insulinoma with low SSTR expression. However, postoperative histological studies suggested that the intracellular domain of SSTRs were highly expressed, while the extracellular domain may be mutated. We present a rare case of insulinoma expressing an aberrant form of SSTRs resulting in a discrepancy between the preoperative octreotide assessment and postoperative SSTR expression.

Metastatic Mucinous Adenocarcinoma of Unknown Origin Showing 68 Ga-DOTATATE Uptake.

Although the use of 18 F-FDG PET/CT is well established in the evaluation of adenocarcinoma, the performance of 18 F-FDG PET/CT in mucinous adenocarcinoma is not consistent. 68 Ga-DOTATATE uptake can be observed in some non-neuroendocrine tumors as a result of tumor blood flow and somatostatin receptor expression at different levels. For this reason, 68 Ga-DOTATATE PET/CT may have a prospective role in the evaluation of mucinous adenocarcinoma. However, there is no published case of mucinous adenocarcinoma with 68 Ga-DOTATATE uptake. We present a unique case of metastatic mucinous adenocarcinoma of unknown origin on 68 Ga-DOTATATE PET/CT.

Histopathological Evaluation of Somatostatin Receptor 2 Expression in Myocarditis-Rationale for the Diagnostic Use of Somatostatin Receptor Imaging.

Myocarditis is an inflammatory disease of the myocardium and remains to this day a challenging diagnosis. A promising novel imaging method uses the expression of somatostatin receptors (SSTRs) on inflammatory cells to visualize myocardial inflammation. However, little is known about the histopathological correlate of SSTR imaging in different forms of myocarditis. In the present retrospective histopathological study, we systematically analysed the expression of SSTR subtype 2 (SSTR2) on inflammatory cells of 33 patients with biopsy- or explant-proven myocarditis (lymphocytic myocarditis (n = 5), giant-cell myocarditis (n = 11), and cardiac sarcoidosis (n = 17)), and in eight controls (multi-organ donors) without signs of myocardial inflammation and/or scars. In all patients, immunohistochemical staining for SSTR2 was positive in areas with CD68-positive macrophages and multinucleated giant cells. Staining for SSTR2 was most prominent in the presence of multinucleated giant cells. The colocalization of both SSTR2 and CD68 on the same cell could be confirmed using immunofluorescence microscopy. Western blotting confirmed the upregulated expression of SSTR2 in cases of granulomatous inflammation (sarcoidosis) of the skeletal and heart muscle, in comparison with controls. In conclusion, our findings demonstrate the expression of SSTR2 on the protein level on CD68-positive macrophages and multinucleated giant cells in various forms of myocarditis, which provides a clear rationale for the diagnostic use of SSTR imaging in this patient group.

Clinicopathological correlations in 38 cases of gastroenteropancreatic high-grade neuroendocrine neoplasms.

Diagnosis and treatment of gastroenteropancreatic high-grade neuroendocrine neoplasms (GEP-HG-NENs), particularly G3 well-differentiated neuroendocrine tumours (NETs) and poorly differentiated neuroendocrine carcinomas (NECs) relies on histopathological morphology, immunohistochemistry, and molecular biological markers, which are lacking especially in cases with ambiguous histomorphology. In this study to contribute to the development of more targeted treatment strategies, we examined various immunohistochemical and molecular biological markers and their association with clinicopathological features in GEP-HG-NENs. We included 38 patients with GEP-HG-NENs in this study, with their retrospective follow-up data. The expression of tumour protein p53 (TP53), RB transcriptional corepressor 1 (RB1), somatostatin receptor 2 (SSTR2), clusterin (CLU), and marker of proliferation Ki-67 (MKI67) was immunohistochemically analysed. KRAS proto-oncogene, GTPase (KRAS) and B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E expression was evaluated using quantitative real-time polymerase chain reaction (qRT-PCR). The relationships between immunohistochemical and molecular biological markers and clinicopathological characteristics were examined using a Cox risk regression model, receiver operating characteristic (ROC) curve, and Kaplan-Meier survival analyses. SSTR2, RB, TP53, and CLU expression differed between NET G3 and NECs, with variations among the NET G3 and small- and large-cell NEC (SCNEC and LCNEC, respectively) groups (p < 0.05). The median MKI67 proliferative index was approximately 40% and 70% in G3 NETs and NECs, respectively. The NET G3 group exhibited a median survival of 25 months, indicating a relatively better prognosis than that of the NECs group (median survival, 11 months). Both Kaplan-Meier survival analysis and the Cox risk regression model indicated a statistical correlation among treatment methods, CLU expression, and prognosis (p < 0.05). The BRAF V600E mutation rate was 32.4% in G3 NETs and SCNEC, demonstrating a significant difference between both types (p = 0.0086). Furthermore, ROC curve analysis highlighted the diagnostic significance of the positive expression of the immunohistochemical markers CLU, SSTR2, and RB in identifying NET G3. To guide more suitable treatment strategies, it is essential to develop and apply valuable and more targeted immunohistochemical and molecular pathological markers for a comprehensive analysis.

68 Ga-DOTATATE and 18 F-FDG PET/CT in a Rapidly Progressing Lymphoma.

68 Ga-DOTATATE PET/CT targeting somatostatin receptors is commonly utilized in the imaging of neuroendocrine tumors. However, other malignancies such as lymphomas (both Hodgkin and non-Hodgkin) also have expression of somatostatin receptors, albeit to a lesser degree compared with the neuroendocrine tumors, and thus can be positive on a 68 Ga-DOTATATE PET/CT. We describe an atypical presentation of an aggressive large B-cell lymphoma mimicking a metastatic neuroendocrine tumor at initial presentation with high somatostatin receptor expression demonstrated on the 68 Ga-DOTATATE PET/CT and a rapidly progressing course on the subsequent 18 F-FDG PET/CT.

Peptide receptor radionuclide therapy for ectopic Cushing's syndrome caused by metastatic neuroendocrine neoplasms.

Metastatic gastroenteropancreatic neuroendocrine neoplasms (GEPNEN) can cause ectopic Cushing's syndrome (ECS). ECS is highly morbid and medical therapy is complex and can be ineffective. Patients unsuitable for bilateral adrenalectomy (BA) have dismal outcomes. Peptide receptor radionuclide therapy (PRRT) is a rational option for hormone and disease control in ECS caused by NEN with high somatostatin receptor (SSTR) expression. To describe the characteristics and outcomes of patients with ECS treated with PRRT. Single-centre, retrospective analysis of imaging, biochemistry and outcomes of seven consecutive patients with ECS caused by metastatic GEPNEN treated with PRRT from 2006 to 2023. Patients were aged 17-75 (female n = 6). The primary site was the pancreas (5/7) and rectum (2/7). Six patients were on medical therapy for ECS at baseline (one had a previous BA). A median of 34.4 GBq of [177Lu]Lu-DOTA-octreotate was given. [90Y]Y-DOTA-octreotate (one patient) and [111In]In-octreotide (one patient) were also used. Five patients had radiosensitising chemotherapy. Five patients had a flare of ECS within 1 week of PRRT cycle 1 (PRRT-C1). Following PRRT-C1, 5/7 patients had complete biochemical resolution of ECS at 1.5-6 months (four ongoing; one recurred after 12 months and had elective BA at 18 months). Best metabolic response on [18F]F-FDG PET/CT: Four patients had a complete metabolic response (CMR), and one had a partial metabolic response. PFS was 3-208 months. Two patients progressed at the first follow-up. The longest ECS remission and CMR continues at >17 years. PRRT can be effective for ECS caused by metastatic SSTR-positive GEPNEN and should be considered in its treatment algorithm.

8785 Does Somatostatin Receptor Expression Intensity Impact Prognosis in Non Pituitary Neuroendocrine Tumors Treated with Somatostatin Analogues?

Abstract Disclosure: N. Saleh Jouneghani: None. S. Fazeli: None. S. Chang: None. A. Hosseini: None. R. Marandi: None. A. Siddiqui: None. M. Talley: None. B. Salehian: None. Does Somatostatin Receptor Expression Intensity Impact Prognosis in Non Pituitary Neuroendocrine Tumors Treated with Somatostatin Analogues? Introduction: Non-pituitary neuroendocrine tumors (NETs) show different somatostatin receptor subtype (SSTR) expression, but their role in tumor progression and prognosis is not well known. We hypothesized that NETs with higher expression of SSTR2, SSRT5, or co-expression of SSTR2 and SSTR5 will have better outcome when treated with Somatostatin Analogues (SSA). Method: Retrospectively, patients with non-pituitary neuroendocrine tumors, followed for more than one year between 1985 and 2022, and treated with SSA (Octreotide or Lanreotide) who had available tissue were selected. Tissue immunostaining performed for SSTR2 and SSTR5 with use of monoclonal antibodies. Expression analysis of the SSTR2 and SSTR5 were evaluated by the validated semi-quantitatively method, reported by an intensity score of 0 -3. The progression free survival and overall survival were calculated by Kaplan Meier and compared in different subgroups with SSTR expression intensity. Response evaluation was assessed using RECIST v1.1. Results: Of 279 non-pituitary neuroendocrine tumors, 51 meet the criteria and tissue sent for analysis. The median age at diagnosis was 62; male 49%, with median follow up 7 years, 85% stage IV at diagnosis, most common primary tumor was in gut 54% followed by pancreas 33%. Positive SSRT5 tumors had 93% SSRT2 co-expression. There were no significant differences in progression-free survival (PFS) observed between tumors with low or high SSTR2 intensity expression (P=0.62). The presence or absences of SSRT5 expression did not have any impact on PFS (p=0.57) or overall survival (p=0.3). Conclusion: in the patient with non-pituitary neuroendocrine tumors, higher SSTR2 expression intensity or having SSRT5 co-expression, did not correlate with a better PFS or overall survival in response to SSA, in our study. Further prospective studies are needed to clarify if higher expression intensity of SSRTs correlates with better response to SSAs in NETs. Presentation: 6/1/2024

Value of 68 Ga-DOTATATE PET/CT in Follow-up of Renal Cell Carcinoma With Multiple Atypical Metastatic Sites.

The development of late metastatic recurrence after nephrectomy is a well-known characteristic of renal cell carcinoma (RCC). Correct diagnosis is often challenging due to the long time between primary tumor excision and the development of metastases. 68 Ga-DOTATATE PET/CT has the potential to be employed in the follow-up of RCC, because RCC expresses somatostatin receptors. However, limited cases have been reported demonstrating 68 Ga-DOTATATE uptake in the metastases of RCC. Herein, we describe a unique case of RCC with multiple atypical metastatic sites, emphasizing the usefulness of 68 Ga-DOTATATE PET/CT in the evaluation and follow-up of patients with RCC.