To Örebro University

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. 

Introduction: Fine-needle aspiration cytology (FNAC) is an effective tool in the diagnostic work-up of patients with thyroid nodules. The aim of our study was to assess the diagnostic sensitivity of FNAC in thyroid cancer (TC) in Sweden by correlating the findings of preoperative FNAC with those obtained through final histology of the surgical specimen.

Methods: A Swedish nationwide cohort of patients having surgery for TC (n = 2519) from the Scandinavian Quality Register for Thyroid, Parathyroid and Adrenal surgery between 2004 and 2013 was obtained. Data was validated through scrutinizing patient FNAC and histology reports.

Results: Among the 2519 cases operated with a final diagnosis of TC, the diagnosis was substantiated and validated through the histology report in 2332 cases (92.6%), included in the present study. Among these, 1679 patients (72%) were female and the median age at TC diagnosis was 52.3 years (range 18-94.6). In 353 cases (15.1%) FNAC was not performed at all; whereas in the remaining 1965 cases, the diagnostic sensitivity of FNAC was 81.6%. In lesions > 1 cm, FNAC diagnostic sensitivity reached 86.5%, whereas in lesions < 1 cm, FNAC yielded a sensitivity of 61.5%. Approximately 85% of FNACs (n = 1981/2332) were performed using ultra-sonographic (US) guidance. In TC lesions > 1 cm, the diagnostic sensitivity of US-guided FNAC (n = 1504) was 86.9% as compared to 76.9% in clinically applied FNAC without US utilization (n = 118).

Conclusions: FNAC is performed in most patients operated for TC in Sweden (85%) and retains its value as a tool in TC diagnostic work-up with an overall sensitivity of 82%, reaching 87% in lesions > 1 cm, that harbor clinically relevant TC.

Introduction: Lithium-associated hyperparathyroidism (LHPT) was first reported in 1973. It remains unclear if this is a specific endocrinopathy or separate simultaneous medical conditions. Definitive management for lithium-treated patients with calcium dysfunction has yet to be established (1).

Method: We conducted this systematic review of all available studies in English which provide patient material from the adult population (>18 years) illustrating lithium’s association in the development of hypercalcaemia and/or hyperparathyroidism. A predefined review protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD 395676). The search used five major databases: Medline, EMBASE, Cochrane Library, PsycINFO, and Web of Science, between 1973 to January 2023, using the keywords hyperparathyroidism, lithium, hypercalcaemia, hypocalcaemia. Review articles and abstracts were excluded.

Result: Of the initial 5418 searches, 169 articles were included for final analysis. Prevalence of hypercalcaemia is reported in approximately 20-30% of lithium-treated patients. Lithium gives moderate increases in calcium levels, with or without elevations in parathyroid hormone. Paradoxically, lithium may be skeletal protective. Multiglandular disease is more common in LHPT than in pHPT, most often consisting of hyperplastic glands. In surgical cases, bilateral exploration is often preferred. Follow-up times are relatively short. No randomised surgical studies exist.

Discussion:

• LHPT appears to be a common endocrinopathy.• Lithium patients with tendency to calcium dysfunction should be carefully monitored.• More radical surgery may lead to health benefits.• Randomized controlled trials should be conducted to identify optimal treatment in patients with LHPT.

PURPOSE: To assess the impact of fine-needle aspiration cytology (FNAC) in the extent of surgery in patients with thyroid cancer (TC) and the associated surgical morbidity in primary and completion setting.

METHODS: A Swedish nationwide cohort of patients having surgery for TC (n = 2519) from the Scandinavian Quality Register for Thyroid, Parathyroid and Adrenal surgery between 2004 and 2013 was obtained. Data was validated through scrutinizing FNAC and histology reports.

RESULTS: Among the 2519 cases operated for TC, the diagnosis was substantiated and validated through the histology report in 2332 cases (92.6%). Among these, 1679 patients (72%) were female, and the median age at TC diagnosis was 52.3 years (range 18-94.6). Less than total thyroidectomy (LTT) was undertaken in 944 whereas total thyroidectomy (TT) in 1388 cases. The intermediate FNAC categories of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/ FLUS), as well as suspicion for follicular neoplasm (SFN) lesions were more often encountered in LTT (n = 314, 33.3%) than TT (n = 63, 4.6%), whereas FNACs suspicion for malignancy and/or malignancy were overrepresented in TT (n = 963, 69.4%). Completion thyroidectomies were undertaken in 553 patients out of 944 that initially had LTT. In 201 cases with cancer lesions > 1 cm, other than FTC (Follicular TC)/ HTC (Hürthle cell TC) subjected to primary LTT, inadequate procedures were undertaken in 81 due to absent, Bethesda I or II FNAC categories, preoperatively. Complications at completion of surgery in this particular setting were 0.5% for RLN palsy (n = 1) and 1% (n = 2) for hypoparathyroidism 6 months postoperatively. The overall postoperative complication rate was higher in primary TT vs. LTT for RLN palsy (4.8% [n = 67] vs. 2.4% [n = 23]; p = 0.003) and permanent hypoparathyroidism (6.8% [n = 95] vs. 0.8% [n = 8]; p < 0.0001).

CONCLUSIONS: FNAC results appear to affect surgical planning in TC as intermediate FNAC categories lead more often to LTT. Overall, inadequate procedures necessitating completion surgery are encountered in up to 15% of TC patients subjected to LTT due to absent, inconclusive, or misleading FNAC, preoperatively. However, completion of thyroidectomy in this setting did not yield significant surgical morbidity. Primary LTT is a safer primary approach compared to TT in respect of RLN palsy and permanent hypoparathyroidism complication rates; therefore, primary TT should probably be reserved for lesions > 1 cm or even larger with suspicion for malignancy or malignant FNAC.

INTRODUCTION: The purpose of this study was to evaluate longitudinal changes in Ki-67 indices of SI-NETs and assess the impact of these in overall survival (OS).

METHODS: We screened 551 patients with SI-NETs diagnosed from 1993, through 2021, identified using the SI-NET databases from five European referral centres. Only patients with well-differentiated tumours and available baseline tumour samples and follow-up re-biopsies were included. For tumour grading, apart from 2017 WHO classification system, we applied a recently proposed SI-NET site-specific modified histopathological grading system with Ki-67 cut-offs of 5 and 10%. Uni- and multivariable regression analyses were used to determine whether there was a difference between OS in SI-NET patients stratified by increment of Ki-67 indices over time and/or progression to a higher grade.

RESULTS: We included 45 patients. Median Ki-67 index at SI-NET diagnosis was 2% (range: 0.5-15%). Thirty-three patients had Ki-67 indices &lt;5% (70.2%), 6 had Ki-67: 5-10% (12.8%), and 8 had Ki-67 ≥10% (17%). Mean time to re-biopsy was 48.8 months (SD: ±162.5). At re-biopsy, the median change in Ki-67 index (absolute value; follow-up minus time of diagnosis) was 1% (range: -10 to +38%). An increase in Ki-67 occurred in 20 patients (42.6%); in 14 patients, the change in Ki-67 resulted in progression to higher tumour grade following the modified grading system. Patients with an increment in Ki-67 ≥1% had a median OS of 32.9 months versus 80.5 months in patients without (HR = 5.6, 95% CI: 1.42-22.02; p = 0.014). When applying the novel modified histopathological grading system for SI-NETs, patients with grade progression had a median OS of 32.9 months versus 53.7 months in those without (HR = 4.61, 95% CI: 1.22-13.54; p = 0.022). At multivariable analysis, grade progression was confirmed as an independent predictor for death (HR = 7.2, 95% CI: 1.58-32.82; p = 0.011).

CONCLUSIONS: Metachronous increment in Ki-67 indices and related grade progression over time following a site-specific modified histopathological grading system with Ki-67 cut-offs of 5 and 10% is observed in approximately 1/3 of SI-NETs subjected to re-biopsy and it is associated with worse survival outcomes.

Introduction: Prevalence of distant stage disease and overall mortality rates vary considerably among patients with multiple endocrine neoplasia type 1 (MEN1).

Aim(s): To study the metastatic potential of MEN1 different components, and the associated mortality rates.

Materials and methods: We included patients with clinical and/or genetic diagnosis of MEN1, followed at the Endocrinology Unit, First Department of Propaedeutic and Internal Medicine, Laiko General Hospital of Athens, Greece.

Results: We included 123 patients; 56 were women (45.9%). MEN1 first manifestation, commonly hyperparathyroidism, appeared at <25 years of age in 46 patients (38%), between 25-40 years in 49 (39,8%) and >40 years in 23 patients (19,4%). Among patients with pNETs (n=79), 23 had grade 2 and one grade 3 tumors, respectively. Fifteen patients (19%) had secretory pNETs for either insulin or gastrin. PNET distant metastases, mainly to the liver, were present in seven patients (8.9%). Overall, atypical lung (AC) and thymic carcinoids (TC) were encountered in three and seven patients, respectively (two of these had ACTH dependent Cushing’s syndrome); AC and/or TC distant metastases were encountered in all ten patients, harbouring these primaries. Overall, 12 patients with stage IV disease manifested disease progression according to RECIST criteria, with a mean duration of disease for pNETs 14 years and for AC and TC 8 years and died. The mortality was associated with the disease progression in 11 patients, and one died because of sepsis.

Conclusion: Spread metastatic disease is encountered in all MEN1-associated AC and TC tumors and in a subset of pNETs, approximately 9%. These MEN1 components account for the disease associated mortality at a 10% rate in our Greek MEN1 cohort.

Background: We aimed to identify optimal grading Ki-67 cut-offs to delineate differences in prognosis of patients with small intestinal neuroendocrine tumours (SI-NETs) in terms of overall- and event-free survival rates.

Methods: We included 551 patients with SI-NETs diagnosed from June 15th, 1993, through March 8th, 2021, identified using the SI-NET databases from five European referral centers.

Results: Median age at baseline was 62.3(17-90) years; 252 patients were women (45.7%). All tumours were well-differentiated; 326 were G1 tumours (59.2%), 169 G2(30.7%), only 8 G3(1.5%), while 48 tumourswere of unspecified grade (8.7%). The median Ki67 was 2%(1-70%). 247 patients(44.8%) had distant metastases at baseline (stage IV), 217locoregional disease (41.1%; stage III), whereas 29(7.1%) and 25(4.5%) presented at stages II and I, respectively. Within a mean(SD) follow-up of 51.5(52.9) months, 94 patients(17.1%) died, whereas overall 188 experienced disease recurrence, progression and/or death(34.1%). The median OS was 214.7(95%CI: 152.7-276.6) months and the median EFS was 79.8(95%CI: 68.2-91.5) months, respectively. In multivariable Cox-regression OS analysis, age (HR=1.07, 95%CI: 1.04-1.09; p<0.001), Charlson Comorbidity Index(HR=1.1, 95%CI: 1.03-1.17; p=0.006) and the proposed modified histopathological Ki67 grading system(K67:5-10% group: HR=2.4, 95%CI: 1.3-4.5; p=0.007 and K67≥10% group: HR=5.1, 95%CI: 2.9-9.2; p<0.001) were independent predictors for death. Pertinent EFS analysis, confirmed age(HR=1.04, 95%CI: 1.02-1.05;p<0.001) and the proposed modified histopathological Ki67 grading system(K67≥10% group: HR=4; 95%CI:2.5-6.2;p<0.001) as independent predictors for recurrence, progression and/or death.

Conclusions: Ki-67 proliferation index is an independent predictor of EFS and OS. A modified site-specific histopathological grading system applying Ki-67 cut-offs of 5% and 10% seems more optimal to predict differences in SI-NET patient prognosis

CONTEXT: One of the major prognostic indices in neuroendocrine tumours (NETs) is Ki67 proliferation index.

OBJECTIVE: To identify optimal grading Ki-67 cut-offs to delineate differences in prognosis of patients with small intestinal NETs (SI-NETs).

DESIGN, SETTING, PARTICIPANTS: Multicentre retrospective cohort analysis of 551 SI-NET patients diagnosed from 1993 through 2021 at five European referral centres with a mean(±SD) follow-up time of 51.5(±52.9) months.

MAIN OUTCOME MEASURES: Overall- and event-free survival (OS and EFS) rates.

RESULTS: Median age at baseline was 62.3(range:17-90) years; 252(45.7%) patients were female. All SI-NETs were well-differentiated with 326 being grade 1(G1; 59.2%), 169G2(30.7%), and only 8G3(1.5), while 48 tumours were of unspecified grade (8.7%). The median Ki67 was 2%(range:1-70%). Two-hundred forty-seven patients (44.8%) had distant metastases at baseline (stage IV), 217 locoregional disease (41.1%; stage III), whereas 29(7.1%) and 25(4.5%) presented at stages II and I, respectively. The median OS was 214.7(95%CI:152.7-276.6) months and the median EFS was 79.8(95%CI:68.2-91.5) months, respectively. In multivariable Cox-regression OS analysis, the proposed modified histopathological Ki67 grading system (K67:5-10% group: HR=2.2, 95%CI:1.15-4.31; p=0.018 and K67≥10% group: HR=5.11, 95%CI:2.87-9.09; p<0.001), age (HR=1.07, 95%CI:1.04-1.09; p<0.001), Charlson Comorbidity Index (HR=1.08, 95%CI:1-1.16; p=0.028) and TNM stage (HR=1.79, 95%CI:1.05-3.06; p=0.034) were independent predictors for death. Pertinent EFS analysis, confirmed the proposed modified histopathological Ki67 grading system (K67≥10% group: HR=4.01, 95%CI:2.6-6.37; p<0.001) and age (HR=1.04, 95%CI:1.02-1.05; p<0.001) as independent predictors for recurrence, progression and/or death.

CONCLUSIONS: Ki-67 proliferation index was a strong and independent predictor of OS and EFS. A modified histopathological grading system applying Ki-67 cut-offs of 5 and 10% could be superior to predict differences in SI-NET patient survival outcomes.

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.