To Örebro University

In Sweden, approximately 400-500 individuals are diagnosed yearly with a neuroendocrine tumor (NET). Primary tumors can arise from all organs in the body, but most commonly from the gastrointestinal (GI) tract (75%) or the lungs (20%). The small intestine (Si) is the most common primary site (35%). The tumor is often diagnosed when metastatic disease has already developed (85% of cases), and spreading is mostly located in the abdominal lymph nodes or liver. Extra-abdominal metastases may also occur. Unlike other tumors, patients with NET and metastatic disease survive for many years. The tumor is diagnosed through a combination of disease-specific biomarkers, radiology and histopathological examination from a biopsy or surgical specimen. 68Ga-DOTATOC-positron emission tomography (PET) and concomitant diagnostic computed tomography (CT) have frequently been used in recent years, due to the high specificity and sensitivity for NET cells.

The aim of this thesis was to evaluate the clinical utility of a commonly used biomarker in patient serum, and to assess the prevalence and importance of metastases to abdominal lymph nodes and extra-abdominal distant metastatic sites with a specific interest in Si-NET and pancreatic NET (pan-NET). Finally, the prognostic impact of disease burden from bone metastases in patients with Si-NET has also been studied.

The first study included one of the most used biomarkers in NET disease and the association between changes in serum 5-HIAA and tumor burden on CT/MRI scan. We also validated the clinical utility of 5-HIAA analysis in patient serum compared to traditional urinary measurement establishing the use of serum analysis at Örebro University Hospital, being less time-consuming and more convenient for patients. In the second study, we assessed the prognostic role of risk factors in patients with locoregional Si-NET, with a specific interest in recurrent disease, and also aimed to define a surgical cut-off for harvested mesenteric lymph nodes to accurately stage these tumors. A minimum of five harvested mesenteric lymph nodes appears to be critical in surgical management. In the third study, we further studied the prevalence of extra-abdominal metastases evident on 68Ga-DOTATOC-PET/CT. The study concluded that metastases to the bones, left supraclavicular lymph nodes, heart, orbit and breast and, in patients with Si-NET, to the pancreas probably occurred more frequently than previously described. Patients with Si-NET harboured extra-abdominal metastases both more frequently and in different locations compared to patients with pan-NET. In the fourth study, we evaluated the prognostic role and clinical symptoms of bone metastases (BM) in patients with Si-NET. In conclusion, the presence of BM, higher extent of BM (>5BM) and synchronous BM at NET diagnosis were independent negative prognostic factors of survival.

Introduction: The prevalence of Bone metastases (BM) in small intestinal neuroendocrine tumours (Si-NET) ranges from 6-23 % and has increased due to new radiology modalities. The aim of our study was to evaluate the overall survival (OS) and the associated symptoms, in particular bone-related pain and fractures in Si-NETpatients with BM.

Method: Retrospective cohort study between 2010-2023 including 138 Si-NET patients with BM detected at 68 Gallium-DOTATOC-PET/CT, treated and followed at Uppsala University Hospital in Sweden. Patients were grouped into two groups according to their number of BM; ≤ BM or > 5 BM. We also included 77 sex and age matched control patients with Si-NET and liver metastases, matched to 77 Si-NET patients with BM and liver metastases.

Result: Of 138 patients, 14 % were treated for BM related pain and 4% patients had a fracture related to Si-NET BM. OS of patients with >5 BM was shorter compared to patients with ≤5 BM (5-year OS 21 % vs 58%; p-=0.028). Concurrent carcinoid heart disease was present in 22% of Si-NET patients with BM, more frequently found inthose with > 10 BM (40%). In the case-control group, OS was 30 % in the case group with BM compared to the control group 64 % (p-value <0.01).

Discussion: Fractures are rare and bone-related pain treatment is needed in 14 % of patients with BM. Presence of > 5 BM is associated with shorter OS and increased risk of carcinoid heart disease. The presence of BM also impair the prognosis, compared to control patients with comparable abdominal metastastic burden.

Introduction: The prevalence of bone metastases (BM) in small intestinal neuroendocrine tumors (Si-NET) ranges from 5 to 23 %.

Aim(s): The aim of our study was to evaluate the overall survival (OS) and the associated symptoms, in particular bone-related pain and fractures in Si-NET patients with BM, which previously have been sparsely described. 

Materials and methods: This is a retrospective cohort study between 1st of January 2010 and 20th of March 2023. We included 133 Si-NET patients with BM detected at 68Gallium-DOTATOC-octreotate PET/CT (68Ga-SSA-PET/CT). Patients were treated and followed at a tertiary referral hospital in Sweden, Uppsala University Hospital. Patients’ characteristics were collected including data on BM-related symptoms, fractures and treatment with analgetics due to bone-related pain. Patients were divided into two groups, those with 1-5 BM or > 5 BM.

Results: We included 133 patients, 64 were women (48%), 74 (56 %) had < 5 BM while 59 (44%) had > 5 BM. Synchronous BM were encountered in 54 patients (41%) at NET diagnosis. Eighteen patients were treated for BM related pain and two had a fracture related to SI-NET BM. Five-year OS was 42 % (median OS 38 months, range 1-209 months). The OS of patients with >5 BM was shorter compared to that of patients with ≤5 BM (5-year OS 21 % vs 58%; p-=0.028) at univariable log-rank analysis. Concurrent carcinoid heart disease was present in 29 Si-NET patients with BM (22%) and was more frequently found in those with > 10 BM (40%).

Conclusion: The number of BM seems to affect OS, as presence of > 5 BM is associated with shorter OS. More extensive bone tumor burden with >10 BM, isl inked with the presence of carcinoid heart disease. Fractures are rare and bone-related pain treatment is needed in up to 14 % of patients. 

Metastases outside the liver and abdominal/retroperitoneal lymph nodes are nowadays detected frequently in patients with neuroendocrine tumours (NETs), owing to the high sensitivity of positron emission tomography (PET) with Gallium-68-DOTA-somatostatin analogues (68Ga-SSA) and concomitant diagnostic computed tomography (CT). Our aim was to determine the prevalence of extra-abdominal metastases on 68Ga-DOTATOC-PET/CT in a cohort of patients with small intestinal (Si-NET) and pancreatic NET (Pan-NET), as well as that of pancreatic metastasis in patients with Si-NET. Among 2090 patients examined by 68Ga-DOTATOC-PET/CT at two tertiary referral centres, a total of 1177 patients with a history of Si- or Pan-NET, were identified. The most recent 68Ga-DOTATOC-PET/CT report for each patient was reviewed, and the location and number of metastases of interest were recorded. Lesions outside the liver and abdominal nodes were found in 26% of patients (n = 310/1177), of whom 21.5% (255/1177) were diagnosed with Si-NET and 4.5% (55/1177) Pan-NET. Bone metastases were found in 18.4% (215/1177), metastases to Virchow's lymph node in 7.1% (83/1177), and lung/pleura in 4.8% (56/1177). In the subset of 255 Si-NET patients, 5.4% (41/255) manifested lesions in the pancreas, 1.5% in the breast (18/255), 1.3% in the heart (15/255) and 1% in the orbita (12/255). In Si-NET patients, the Ki-67 proliferation index was higher in those with ≥2 metastatic sites of interest, than with 1 metastatic site, (p <0.001). Overall, extra-abdominal or pancreatic metastases were more often found in patients with Si-NET (34%) than in those with Pan-NET (13%) (p <0.001). Bone metastases were 2.6 times more frequent in patients with Si-NET compared to Pan-NET patients (p <0.001). Lesions to the breast and orbita were encountered in almost only Si-NET patients. In conclusion, lesions outside the liver and abdominal nodes were detected in as many as 26% of the patients, with different prevalence and metastatic patterns in patients with Si-NET compared to Pan-NET. The impact of such metastases on overall survival and clinical decision-making needs further evaluation.

Introduction: Neuroendocrine metastases to the orbita, heart, breast, bone, Virchow's lymph node, and pancreas are rarely encountered in small intestinal (SI-NETs) and pancreatic NETs (P-NETs).

Aim(s): We aimed to assessthe prevalence of rare metastatic locations in patients with well-differentiated SI-NETs and P-NETs, who had undergone 68Ga-DOTATOC-PET/CT at diagnosis and/or follow-up.

Materials and methods: In this retrospective analysis of 753 SI-NET patients and 418 P-NET patients treated at two tertiary referral centers, rare metastases were evident in 26.5% (310/1171) of the patient cohort.

Results: Among patients with rare metastases (n=310), 45 % were women and median age at metastases diagnosis was 70 years (43-90). Median Ki-67 was 7% (1-70); 106 were G1 tumors, 142 G2, 11 G3 and 51 of unknown grade. Rare metastatic sites were present in bone 18 % (215/1171), Virchow's lymph node 6 % (75/1171) and 4 % (42/1171) in the lung/pleura. Metastases to the pancreas, breast, heart and orbita were only encountered in SI-NET primaries with a frequency of 5 % (41/753), 2 % (17/753), 2 % (14/753) and 2 % (12/753) respectively. Concomitant liver metastases were present in 86 %. Uncommon metastases were more frequent in SI-NET as compared with P-NET primaries, 255/753 [34%] vs. 55/418 [13%], p ˂0.00001. Bone metastases were present in 23 % (175/753) of SI-NET and 10 % (40/418) of p-NET primaries.

Conclusion: In conclusion, rare metastases are more frequent in SI-NET than p-NETs. The variety and pattern of rare metastases seems different between SI-NETs and P-NET primaries, as orbita, heart, breast and Virchow's lymph node deposits were only encountered in SI-NETs patients; and bone metastases were approximately twice more often inthis group. 

We aimed to assess the prognostic impact of tumor- and patient-related parameters in patients with stage I-III small intestinal neuroendocrine tumors (SI-NETs), who underwent locoregional resective surgery (LRS) with curative intent. We included 229 patients with stage I-III SI-NETs diagnosed from June 15, 1993, through March 8, 2021, identified using the SI-NET databases from five European referral centers. Mean ± SD age at baseline was 62.5 ± 13.6 years; 111/229 patients were women (49.3%). All tumors were well-differentiated; 160 were grade 1 (G1) tumors, 51 were G2, two were G3 and 18 tumors were of unspecified grade (median Ki-67: 2%, range 1%-50%). One-hundred and sixty-three patients (71.2%) had lymph node (LN) involvement. The median number of retrieved lymph nodes was 10 (0-63), whereas the median number of positive LNs was 2 (0-43). After a mean ± SD follow-up of 54.1 ± 64.1 months, 60 patients experienced disease recurrence at a median (range) of 36.2 (2.5-285.1) months. The 5- and 10-year recurrence-free survival (RFS) rates were 66.6% and 49.3% respectively. In univariable analysis, there was no difference in RFS and overall survival (OS) between LN-positive and LN-negative patients (log-rank, p = .380 and .198, respectively). However, in stage IIIb patients who underwent mesenteric lymph node dissection (MLND) with a minimum of five retrieved LN (n = 125), five or more LN metastases were associated with shorter RFS (median RFS [95% CI] = 107.4 [0-229.6] vs. 73.7 [35.3-112.1] months; log-rank, p = .048). In addition, patients with G2 tumors exhibited shorter RFS compared to patients with G1 tumors (median RFS [95% confidence interval (CI)] = 46.9 [36.4-57.3] vs. 120.7 [82.7-158.8] months; log-rank, p = .001). In multivariable Cox-regression RFS analysis in stage IIIb patients, the Ki-67 proliferation index (hazard ratio = 1.08, 95% CI = 1.035-1.131; p < .0001) and the number of LN metastases (hazard ratio = 1.06, 95% CI = 1.001-1.125; p = .047) were independent prognostic factors for RFS. In conclusion, LRS with a meticulous MLND and a minimum number of five harvested LNs appears to be critical in the surgical management of SI-NET patients with locoregional disease. In patients who underwent LRS and MLND, the Ki-67 proliferation index and the LN metastases count were independent predictors of RFS.

Small intestinal neuroendocrine tumors (SI-NETs) may rarely metastasize to the left supraclavicular lymph nodes, also known as Virchow's node metastasis (VM). Data on prevalence, prognostic significance, and clinical course of disease for SI-NET patients with VM is limited. In this retrospective analysis of 230 SI-NET patients treated at two tertiary referral centers, we found nine patients with VM (prevalence 3.9%). Among those, there were 5 females and median age at SI-NET and VM diagnosis was 61 and 65 years, respectively. Two patients had G1 tumors and five G2, while two tumors were of unspecified grade (median Ki67: 7%, range 2-15%). Four patients presented with synchronous VM, whereas five developed metachronous VM after a median of twenty-four months (range: 4.8-117.6 months). Hepatic metastases were present in seven patients, extrahepatic metastases (EM) in eight (six para-aortic distant lymph node metastases, one lung and one pancreatic metastasis), whereas peritoneal carcinomatosis (PC) in two patients. We used a control group of 18 age- and sex-matched SI-NET patients from the same cohort with stage IV disease but no extra-abdominal metastases. There was no difference in best-recorded response to first line treatment according to RECIST 1.1 as well as progression-free survival (PFS) between patients with VM and those in the control group (Chi-square test p = 0.516; PFS 71.7 vs. 106.9 months [95% CI 38.1-175.8]; log-rank p = 0.855). In addition, median overall survival (OS) of SI-NET patients with VM did not differ from those in the control group (138.6 [95% CI 17.2-260] vs. 109.9 [95% CI 91.7-128] months; log-rank p = 0.533). In conclusion, VM, although relatively rare in patients with SI-NETs, is more often encountered in patients with G2 tumors and established distant para-aortic lymph node metastases. The presence of VM in SI-NET patients does not seem to impact patients' survival outcomes and treatment responses, when compared to age- and sex-matched SI-NET patients with stage IV disease confined in the abdomen.

Introduction: Small Intestinal Neuroendocrine Neoplasms (SI-NENs) may rarely metastasize to the left supraclavicular lymph nodes, also known as Virchow’s node metastasis (VM).

Aim(s): Data on prevalence, prognostic significance and clinical course of disease for SI-NEN patients with VM is limited.

Materials and methods: In this retrospective analysis of 231 SI-NEN patients treated at two tertiary referal centers we found nine patients with VM. We used a control group of 18 age-and sex-matched SI-NEN patients from the same cohort with stage IV disease, but no extrahepatic metastases.

Results: VM prevalence was 3.9% (9/231; 5 females, median age at VM diagnosis 65 years). Two patients had G1, 5 G2 tumours and 2 of unspecified grade. Four patients presented with synchronous VM, whereas 3 developed metachronous VM after a median of 24 months (range: 4.8–117.6 months). Hepatic metastases were present in 7 patients, extrahepatic metastases (EM) in 8 (6 para-aortic distant lymph node metastases, 1 lung and 1 pancreatic metastasis) and peritoneal carcinomatosis in 2 patients. There was no difference in best-recorded responses to 1st line treatment according to RECIST 1.1 as well as progression-free (PFS) and overall survival rates (PFS) between patients with VM and those in the control group (Chi-square p=0.516; PFS: 71.7 vs. 106.9 months [95%CI 38.1-175.8]; log-rank p=0.855; OS: 138.6 [95%CI 17.2–260] vs. 109.9 [95%CI 91.7–128] months; log-rank p=0.533).

Conclusion: VM is relatively rare in patients with SI-NENs. It is more often encountered in patients withG2 tumors and EM, mainly to distant para-aortic lymph nodes. Its presence does not seem to impact patients’ survival outcomes and treatment responses, when compared to age-and sex-matched patients with stage IV disease. 

Introduction: There are only few studies on the diagnostic value of serum 5HIAA as compared to the 24-hours urinary sampling method and a lack of evidence on the prognostic significance of its serum levels, as well as the markers' ability to predict changes in disease status.

Aim(s): Our aim was to investigate the clinical utility of serum 5HIAA for diagnostic purposes and disease surveillance in a cohort of patients with well-differentiated neuroendocrine neoplasms (WD-NENs).

Materials and methods: Forty-eight patients with WD-NENs and concurrent serum and urinary 5HIAA testing as well as CT/MRI imaging were included.

Results: A positive correlation between disease stage and serum 5HIAA positivity (Pearson Chi-square p=0.017), and between liver tumor burden and serum 5HIAA levels (Spearman’s rank correlation coefficient: 0.46; p=0.013) was confirmed. Further analysis did not reveal any correlation between RECIST 1.1 responses and >25% changes in serum 5HIAA levels (Fisher ́s exact test p=0.735). The concordance rate of serum and urinary 5HIAA positivity at standardized laboratory cut-offs was 75%. In patients without any impairment of the renal function, the concordance between the two tests was as high as 89% and a sensitivity and specificity of 80% and 88.9%, respectively was evident (Cohen’s kappa coefficient=0.685).

Conclusion: Serum 5HIAA performs well compared to urinary testing for diagnostic purposes and corresponds well to tumor stage and liver tumor burden. However, it is not adequate to predict tumor progression. 

Our aim was to investigate the clinical utility of serum 5HIAA for disease surveillance and diagnostic purposes in a cohort of patients with well-differentiated neuroendocrine neoplasms (WD-NENs). Forty-eight patients with WD-NENs and concurrent serum and urinary 5HIAA testing, as well as CT/MRI imaging, were included. Analysis of matching-pairs did not reveal any association between RECIST 1.1 responses and changes in serum 5HIAA levels (p = 0.673). In addition, no correlation was evident between RECIST 1.1 responses and >10%, >25% or >50% changes in serum 5HIAA levels (Fisher's exact test p = 0.380, p > 0.999, and p > 0.999, respectively). The presence of liver metastases and extensive liver tumor involvement were associated with higher serum 5HIAA levels (p = 0.045 and p = 0.041, respectively). We also confirmed a strong linear correlation between the measurements of serum and urine 5HIAA (n = 24, r = 0.791, p < 0.0001). The concordance rate of serum and urinary 5HIAA positivity at standardized laboratory cut-offs was 75%. In patients with normal renal function tests, the concordance between the two methods was as high as 89%, and a sensitivity and specificity of 80% and 88.9%, respectively, was evident (Cohen's kappa coefficient = 0.685). In conclusion, serum 5HIAA performs well compared to urinary testing for diagnostic purposes, mainly in advanced disease stages, and corresponds well to liver tumor burden. However, it is not adequate to predict tumor progression.