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Ghosal, S., Das, S., Pang, Y., Gonzales, M. K., Huynh, T.-T., Yang, Y., . . . Pacak, K. (2020). Long intergenic noncoding RNA profiles of pheochromocytoma and paraganglioma: A novel prognostic biomarker. International Journal of Cancer, 146(8), 2326-2335
Open this publication in new window or tab >>Long intergenic noncoding RNA profiles of pheochromocytoma and paraganglioma: A novel prognostic biomarker
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2020 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 146, no 8, p. 2326-2335Article in journal (Refereed) Published
Abstract [en]

Many long intergenic noncoding RNAs (lincRNAs) serve as cancer biomarkers for diagnosis or prognostication. To understand the role of lincRNAs in the rare neuroendocrine tumors pheochromocytoma and paraganglioma (PCPG), we performed first time in-depth characterization of lincRNA expression profiles and correlated findings to clinical outcomes of the disease. RNA-Seq data from patients with PCPGs and 17 other tumor types from The Cancer Genome Atlas and other published sources were obtained. Differential expression analysis and a machine-learning model were used to identify transcripts specific to PCPGs, as well as established PCPG molecular subtypes. Similarly, lincRNAs specific to aggressive PCPGs were identified, and univariate and multivariate analysis was performed for metastasis-free survival. The results were validated in independent samples using RT-PCR. From a pan-cancer context, PCPGs had a specific and unique lincRNA profile. Among PCPGs, five different molecular subtypes were identified corresponding to the established molecular classification. Upregulation of 13 lincRNAs was found to be associated with aggressive/metastatic PCPGs. RT-PCR validation confirmed the overexpression of four lincRNAs in metastatic compared to non-metastatic PCPGs. Kaplan-Meier analysis identified five lincRNAs as prognostic markers for metastasis-free survival of patients in three subtypes of PCPGs. Stratification of PCPG patients with a risk-score formulated using multivariate analysis of lincRNA expression profiles, presence of key driver mutations, tumor location, and hormone secretion profiles showed significant differences in metastasis-free survival. PCPGs thus exhibit a specific lincRNA expression profile that also corresponds to the established molecular subgroups and can be potential marker for the aggressive/metastatic PCPGs.

Keywords
lincRNA, pheochromocytoma, paraganglioma, molecular subtypes, biomarkers
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-408131 (URN)10.1002/ijc.32654 (DOI)000489677900001 ()31469413 (PubMedID)
Available from: 2020-04-14 Created: 2020-04-14 Last updated: 2020-04-14Bibliographically approved
Pettersson, O., Fröss-Baron, K., Crona, J. & Sundin, A. (2020). Tumor Contrast-Enhancement for Monitoring of PRRT Lu-177-DOTATATE in Pancreatic Neuroendocrine Tumor Patients. Frontiers in Oncology, 10, Article ID 193.
Open this publication in new window or tab >>Tumor Contrast-Enhancement for Monitoring of PRRT Lu-177-DOTATATE in Pancreatic Neuroendocrine Tumor Patients
2020 (English)In: Frontiers in Oncology, ISSN 2234-943X, E-ISSN 2234-943X, Vol. 10, article id 193Article in journal (Refereed) Published
Abstract [en]

Background: Therapy monitoring of cancer treatment by contrast-enhanced CT (CECT), applying response evaluation criteria in solid tumors criteria version 1. 1 (RECIST 1.1) is less suitable for neuroendocrine tumors (NETs) which, when responding, tend to show stabilization rather than shrinkage. New methods are needed to further classify patients in order to identify non-responders at an early stage and avoid unnecessary adverse effects and costs. Changes in arterial tumor attenuation and contrast-enhancement could be used to identify the effect of therapy, perhaps even in early stages of treatment.

Methods: Patients with metastatic pancreatic NETs (PNETs) receiving peptide receptor radionuclide therapy (PRRT) with Lu-177-DOTATATE underwent CECT at baseline, mid-treatment (PRRT cycles 3-5) and at follow-up, 3 months after the last PRRT cycle. At baseline CECT, the liver metastasis with the highest arterial attenuation was identified in each patient. The fold changes in arterial tumor attenuation (Hounsfield Units, HU), contrast-enhancement (HU), and transversal tumor area (cm(2)) between CECT at baseline, mid-treatment and follow-up were calculated. Correlation of the tumor metrics to outcome parameters such as progression-free survival (PFS) and time to best response was performed.

Results: Fifty-two patients were included (27 men, 25 women), median age 60 years (range 29-80), median Ki-67 8% (range 1-30). Six patients had grade 1 PNETs, forty had grade 2 and four had grade 3 tumors. As an internal control, it was first tested and established that the tumor contrast-enhancement was not merely related to that of the abdominal aorta. The mean +/- SD arterial attenuation of the liver metastases was similar at baseline, 217 +/- 62 HU and at mid-treatment, 238 +/- 80 HU and then decreased to 198 +/- 62 HU at follow-up, compared to baseline (p = 0.024, n = 52) and mid-treatment (p = 0.0004, n = 43). The transversal tumor area decreased 25% between baseline and follow-up (p = 0.013, n = 52). Tumor contrast-enhancement increased slightly from baseline to mid-treatment and these fold changes correlated with PFS (R-2 = 0.33, p = 0.0002, n = 37) and with time to best response (R-2 = 0.34, p < 0.0001, n = 37).

Conclusions: Early changes in contrast-enhancement and arterial attenuation in PNET liver metastases may for CECT monitoring of PRRT yield complementary information to evaluation by RECIST 1.1.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2020
Keywords
therapy monitoring, neuroendocrine tumor, computed tomography, contrast-enhancement, NET, CT, PRRT, Lu-177
National Category
Cancer and Oncology Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-409912 (URN)10.3389/fonc.2020.00193 (DOI)000523685100001 ()32154181 (PubMedID)
Available from: 2020-05-07 Created: 2020-05-07 Last updated: 2020-05-07Bibliographically approved
Backman, S., Bajic, D., Crona, J., Hellman, P., Skogseid, B. & Stålberg, P. (2020). Whole genome sequencing of apparently mutation-negative MEN1 patients. European Journal of Endocrinology, 182(1), 35-45
Open this publication in new window or tab >>Whole genome sequencing of apparently mutation-negative MEN1 patients
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2020 (English)In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 182, no 1, p. 35-45Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE:Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant syndrome usually caused by loss-of-function mutations in the MEN1-gene. However, a minority of patients who fulfill the criteria for MEN1 are not found to harbor MEN1-mutations. Besides, some of these individuals, present with a subtly different phenotype suggestive of sporadic disease. The aim of the present study was to investigate the genetic architecture of mutation-negative MEN1. DESIGN:Fourteen patients with a clinical diagnosis (n=13) or suspicion (n=1) of MEN1 who had negative genetic screening of the MEN1 gene were included. METHODS:Constitutional DNA from the included patients, as well as tumor DNA from six of the patients, was subjected to whole genome sequencing. Constitutional variants were filtered against population databases and somatic variants were studied under a tumor-suppressor model. RESULTS:Three patients carried pathogenic variants (two splice-site variants, one missense variant) in MEN1 that had not been detected during routine clinical sequencing, one patient carried a pathogenic variant in CASR and one patient carried a gross deletion on chromosome 1q which included the CDC73 gene. Analysis of matched tumor DNA from six patients without mutations did not detect any recurrent genes fulfilling Knudson's two-hit model. CONCLUSION:These results highlight the possibility of germline mutations being missed in routine screening, the importance of considering phenocopies in atypical or mutation-negative cases. The absence of apparent disease-causing mutations suggests that a fraction of MEN1 mutation negative MEN1 cases may be due to the chance occurrence of several endocrine tumors in one patient.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-401244 (URN)10.1530/eje-19-0522 (DOI)000505970300008 ()31658439 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2020-01-07 Created: 2020-01-07 Last updated: 2020-01-29Bibliographically approved
Paulsson, J. O., Backman, S., Wang, N., Stenman, A., Crona, J., Thutkawkorapin, J., . . . Juhlin, C. C. (2020). Whole‐genome sequencing of synchronous thyroid carcinomas identifies aberrant DNA repair in thyroid cancer dedifferentiation. Journal of Pathology, 250(2), 183-194
Open this publication in new window or tab >>Whole‐genome sequencing of synchronous thyroid carcinomas identifies aberrant DNA repair in thyroid cancer dedifferentiation
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2020 (English)In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 250, no 2, p. 183-194Article in journal (Refereed) Published
Abstract [en]

The genetics underlying thyroid cancer dedifferentiation is only partly understood and has not yet been characterised using comprehensive pan‐genomic analyses. We investigated a unique case with synchronous follicular thyroid carcinoma (FTC), poorly differentiated thyroid carcinoma (PDTC), and anaplastic thyroid carcinoma (ATC), as well as regional lymph node metastases from the PDTC and ATC from a single patient using whole‐genome sequencing (WGS). The FTC displayed mutations in CALRRB1, and MSH2, and the PDTC exhibited mutations in TP53DROSHAAPCTERT, and additional DNA repair genes – associated with an immense increase in sub‐clonal somatic mutations. All components displayed an overrepresentation of C>T transitions with associated microsatellite instability (MSI) in the PDTC and ATC, with borderline MSI in the FTC. Clonality analyses pinpointed a shared ancestral clone enriched for mutations in TP53‐associated regulation of DNA repair and identified important sub‐clones for each tumour component already present in the corresponding preceding lesion. This genomic characterisation of the natural progression of thyroid cancer reveals several novel genes of interest for future studies. Moreover, the findings support the theory of a stepwise dedifferentiation process and suggest that defects in DNA repair could play an important role in the clonal evolution of thyroid cancer.

Keywords
thyroid carcinoma, dedifferentiation, whole-genome sequencing, clonality, DNA repair
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-401241 (URN)10.1002/path.5359 (DOI)000499618000001 ()31621921 (PubMedID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceKnut and Alice Wallenberg FoundationSwedish Research CouncilSwedish Cancer SocietySwedish Society for Medical Research (SSMF)Swedish Society of Medicine
Note

De 3 första författarna delar förstaförfattarskapet

Available from: 2020-01-07 Created: 2020-01-07 Last updated: 2020-04-20Bibliographically approved
Crona, J. & Beuschlein, F. (2019). Adrenocortical carcinoma: towards genomics guided clinical care. Nature Reviews Endocrinology, 15(9), 548-560
Open this publication in new window or tab >>Adrenocortical carcinoma: towards genomics guided clinical care
2019 (English)In: Nature Reviews Endocrinology, ISSN 1759-5029, E-ISSN 1759-5037, Vol. 15, no 9, p. 548-560Article, review/survey (Refereed) Published
Abstract [en]

Adrenocortical carcinoma (ACC) is an aggressive and rare neoplasm that originates in the cortex of the adrenal gland. The disease is associated with heterogeneous but mostly poor outcomes and lacks effective pharmaceutical treatment options. Multi-omics studies have defined the landscape of molecular alterations in ACC. Specific molecular signatures can be detected in body fluids, potentially enabling improved diagnostic applications for patients with adrenal tumours. Importantly, pan-molecular data sets further reveal a spectrum within ACC, with three major subgroups that have different disease outcomes. These new subgroups have value as prognostic biomarkers. Research has revealed that the p53-RB and the WNT-beta-catenin pathways are common disease drivers in ACC. However, these pathways remain difficult to target by therapeutic interventions. Instead, a unique characteristic of ACC is steroidogenic differentiation, which has emerged as a potential treatment target, with several agents undergoing preclinical or clinical investigations. Finally, a large proportion of ACC tumours have genetic profiles that are associated with promising therapeutic responsiveness in other cancers. All these opportunities now await translation from the laboratory into the clinical setting, thereby offering a real potential of improved survival outcomes and increased quality of life for patients with this serious condition.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-393685 (URN)10.1038/s41574-019-0221-7 (DOI)000480419200011 ()31147626 (PubMedID)
Funder
Swedish Cancer SocietyGerman Research Foundation (DFG), CRC/Transregio 205/1Wallenberg FoundationsTore Nilsons Stiftelse för medicinsk forskning
Available from: 2019-09-25 Created: 2019-09-25 Last updated: 2019-09-25Bibliographically approved
Vyakaranam, A. R., Crona, J., Norlén, O., Hellman, P. & Sundin, A. (2019). C-11-hydroxy-ephedrine-PET/CT in the Diagnosis of Pheochromocytoma and Paraganglioma. Cancers, 11(6), Article ID 847.
Open this publication in new window or tab >>C-11-hydroxy-ephedrine-PET/CT in the Diagnosis of Pheochromocytoma and Paraganglioma
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2019 (English)In: Cancers, ISSN 2072-6694, Vol. 11, no 6, article id 847Article in journal (Refereed) Published
Abstract [en]

Pheochromocytomas (PCC) and paragangliomas (PGL) may be difficult to diagnose because of vague and uncharacteristic symptoms and equivocal biochemical and radiological findings. This was a retrospective cohort study in 102 patients undergoing C-11-hydroxy-ephedrine (C-11-HED)-PET/CT because of symptoms and/or biochemistry suspicious for PCC/PGL and/or with radiologically equivocal adrenal incidentalomas. Correlations utilized CT/MRI, clinical, biochemical, surgical, histopathological and follow-up data. C-11-HED-PET/CT correctly identified 19 patients with PCC and six with PGL, missed one PCC, attained one false positive result (nodular hyperplasia) and correctly excluded PCC/PGL in 75 patients. Sensitivity, specificity, positive and negative predictive values of C-11-HED-PET/CT for PCC/PGL diagnosis was 96%, 99%, 96% and 99%, respectively. In 41 patients who underwent surgical resection and for whom correlation to histopathology was available, the corresponding figures were 96%, 93%, 96% and 93%, respectively. Tumor C-11-HED-uptake measurements (standardized uptake value, tumor-to-normal-adrenal ratio) were unrelated to symptoms of catecholamine excess (p > 0.05) and to systolic blood pressure (p > 0.05). In PCC/PGL patients, norepinephrine and systolic blood pressure increased in parallel (R-2 = 0.22, p = 0.016). C-11-HED-PET/CT was found to be an accurate tool to diagnose and rule out PCC/PGL in complex clinical scenarios and for the characterization of equivocal adrenal incidentalomas. PET measurements of tumor C-11-HED uptake were not helpful for tumor characterization.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
pheochromocytoma, paraganglioma, PET-CT, C-11-hydroxy-ephedrine, adrenal incidentaloma
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-390633 (URN)10.3390/cancers11060847 (DOI)000475351200111 ()31248124 (PubMedID)
Available from: 2019-08-21 Created: 2019-08-21 Last updated: 2019-09-10Bibliographically approved
Vyakaranam, A. R., Crona, J., Norlén, O., Granberg, D., Garske-Román, U., Sandström, M., . . . Sundin, A. (2019). Favorable Outcome in Patients with Pheochromocytoma and Paraganglioma Treated with 177Lu-DOTATATE.. Cancers, 11(7), Article ID 909.
Open this publication in new window or tab >>Favorable Outcome in Patients with Pheochromocytoma and Paraganglioma Treated with 177Lu-DOTATATE.
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2019 (English)In: Cancers, ISSN 2072-6694, Vol. 11, no 7, article id 909Article in journal (Refereed) Published
Abstract [en]

Peptide receptor radiotherapy (PRRT) with 177Lu-DOTATATE has emerged as a promising therapy for neuroendocrine tumors (NETs). This retrospective cohort study aimed to assess the outcome of PRRT for 22 patients with histopathologically confirmed pheochromocytoma (PCC) and paraganglioma (PGL), of which two were localized and 20 metastatic. Radiological response utilized response evaluation criteria in solid tumors 1.1 and toxicity was graded according to common terminology criteria for adverse events version 4. Median 4 (range 3-11) 7.4 GBq cycles of 177Lu-DOTATATE were administered as first-line therapy (n = 13) or because of progressive disease (n = 9). Partial response (PR) was achieved in two and stable disease (SD) in 20 patients. The median overall survival (OS) was 49.6 (range 8.2-139) months and median progression-free survival (PFS) was 21.6 (range 6.7-138) months. Scintigraphic response >50% was achieved in 9/19 (47%) patients. Biochemical response (>50% decrease) of chromogranin A was found in 6/15 (40%) patients and of catecholamines in 3/12 (25%) patients. Subgroup analysis showed Ki-67 <15% associated with longer OS (p = 0.013) and PFS (p = 0.005). PRRT as first-line therapy was associated with increased OS (p = 0.041). No hematological or kidney toxicity grade 3-4 was registered. 177Lu-DOTATATE therapy was associated with favorable outcome and low toxicity. High Ki-67 (≥15%) and PRRT received because of progression on previous therapy could constitute negative predictive factors for OS.

Keywords
pheochromocytoma, paraganglioma, Lu-177-DOTATATE, peptide receptor radiotherapy, PRRT, neuroendocrine tumor, NET, PCC, PGL
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-392835 (URN)10.3390/cancers11070909 (DOI)000479322800020 ()31261748 (PubMedID)
Available from: 2019-09-10 Created: 2019-09-10 Last updated: 2019-10-30Bibliographically approved
Muth, A., Crona, J., Gimm, O., Elmgren, A., Filipsson, K., Askmalm, M. S., . . . Tham, E. (2019). Genetic testing and surveillance guidelines in hereditary pheochromocytoma and paraganglioma. Journal of Internal Medicine, 285(2), 187-204
Open this publication in new window or tab >>Genetic testing and surveillance guidelines in hereditary pheochromocytoma and paraganglioma
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2019 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 285, no 2, p. 187-204Article, review/survey (Refereed) Published
Abstract [en]

Pheochromocytoma and paraganglioma (PPGL) are rare tumours and at least 30% are part of hereditary syndromes. Approximately 20% of hereditary PPGL are caused by pathogenic germ line variants in genes of the succinate dehydrogenase complex (SDHx), TMEM127 or MAX. Herein we present guidelines regarding genetic testing of family members and their surveillance based on a thorough literature review. All cases of PPGL are recommended genetic testing for germ line variants regardless of patient and family characteristics. At minimum, FH, NF1, RET, SDHB, SDHD and VHL should be tested. In addition, testing of MEN1, SDHA, SDHAF2, SDHC, TMEM127 and MAX is recommended. Healthy first-degree relatives (and second-degree relatives in the case of SDHD and SDHAF2 which are maternally imprinted) should be offered carrier testing. Carriers of pathogenic variants should be offered surveillance with annual biochemical measurements of methoxy-catecholamines and bi-annual rapid whole-body magnetic resonance imaging and clinical examination. Surveillance should start 5 years before the earliest age of onset in the family and thus only children eligible for surveillance should be offered pre-symptomatic genetic testing. The surveillance of children younger than 15 years needs to be individually designed. Our guidelines will provide a framework for patient management with the possibility to follow outcome via national registries and/or follow-up studies. Together with improved insights into the disease, this may enable optimisation of the surveillance scheme in order to minimise both anxiety and medical complications while ensuring early disease detection.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
molecular genetics, neuroendocrine tumours, pheochromocytoma
National Category
Medical Genetics Surgery
Identifiers
urn:nbn:se:uu:diva-379423 (URN)10.1111/joim.12869 (DOI)000459577200004 ()30536464 (PubMedID)
Available from: 2019-03-19 Created: 2019-03-19 Last updated: 2019-10-30Bibliographically approved
Crona, J., Lamarca, A., Ghosal, S., Welin, S., Skogseid, B. & Pacak, K. (2019). Genotype-phenotype correlations in pheochromocytoma and paraganglioma: a systematic review and individual patient meta-analysis. Endocrine-Related Cancer, 26(5), 539-550
Open this publication in new window or tab >>Genotype-phenotype correlations in pheochromocytoma and paraganglioma: a systematic review and individual patient meta-analysis
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2019 (English)In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 26, no 5, p. 539-550Article, review/survey (Refereed) Published
Abstract [en]

Pheochromocytoma and paraganglioma (PPGL) can be divided into at least four molecular subgroups. Whether such categorizations are independent factors for prognosis or metastatic disease is unknown. We performed a systematic review and individual patient meta-analysis aiming to estimate if driver mutation status can predict metastatic disease and survival. Driver mutations were used to categorize patients according to three different molecular systems: two subgroups (SDHB mutated or wild type), three subgroups (pseudohypoxia, kinase signaling or Wnt/unknown) and four subgroups (tricarboxylic acid cycle, VHL/EPAS1, kinase signaling or Wnt/unknown). Twenty-one studies and 703 patients were analyzed. Multivariate models for association with metastasis showed correlation with SDHB mutation (OR 5.68 (95% CI 1.79-18.06)) as well as norepinephrine (OR 3.01 (95% CI 1.02-8.79)) and dopa mine (OR 6.39 (95% CI 1.62-25.24)) but not to PPGL location. Other molecular systems were not associated with metastasis. In multivariate models for association with survival, age (HR 1.04 (95% CI 1.02-1.06)) and metastases (HR 6.13 (95% CI 2.86-13.13)) but neither paraganglioma nor SDHB mutation remained significant. Other molecular subgroups did not correlate with survival. We conclude that molecular categorization accordingly to SDHB provided independent information on the risk of metastasis. Driver mutations status did not correlate independently with survival. These data may ultimately be used to guide current and future risk stratification of PPGL.

Place, publisher, year, edition, pages
BIOSCIENTIFICA LTD, 2019
Keywords
pheochromocytoma, paraganglioma, molecular genetics, driver mutations, meta-analysis
National Category
Cancer and Oncology Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-383282 (URN)10.1530/ERC-19-0024 (DOI)000465198700009 ()30893643 (PubMedID)
Available from: 2019-05-14 Created: 2019-05-14 Last updated: 2019-10-30Bibliographically approved
Botling, J., Lamarca, A., Bajic, D., Norlén, O., Lönngren, V., Kjaer, J., . . . Crona, J. (2019). High-grade progression confers poor survival in pancreatic neuroendocrine tumors.. Neuroendocrinology
Open this publication in new window or tab >>High-grade progression confers poor survival in pancreatic neuroendocrine tumors.
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2019 (English)In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194Article in journal (Refereed) Epub ahead of print
Abstract [en]

INTRODUCTION: Little is known about how Pancreatic Neuroendocrine Tumors (PanNETs) evolve over time and if changes towards a more aggressive biology correlates with prognosis. The purpose of this study was to characterize changes PanNET differentiation and proliferation over time, and to correlate findings to overall survival (OS).

PATIENTS AND METHODS: In this retrospective cohort study we screened 475 PanNET patients treated at Uppsala University Hospital, Sweden. Sporadic patients with baseline and follow-up tumor samples were included. Pathology reports and available tissue sections were re-evaluated with regard to tumor histopathology and Ki-67 index.

RESULTS: Forty-six patients with 106 tumor samples (56 available for pathology re-evaluation) were included. Median Ki-67 index at diagnosis was 7% (range 1-38%), grade 1 n=8, grade 2 n=36, and grade 3 n=2. The median change in Ki-67 index (absolute value; follow-up - baseline) was +14% (range -11 to +80%). Increase in tumor grade occurred in 28 patients (63.6%), the majority from grade 1/2 to grade 3 (n=24, 54.5%). The patients with a high-grade progression had a median OS of 50.2 months compared to 115.1 months in patients without such progression (HR 3.89, 95% CI 1.91-7.94, P<0.001).

CONCLUSIONS: A longitudinal increase in Ki-67 index and increase in tumor grade were observed in a majority of PanNETs included in this study. We propose that increase in Ki-67 index and high-grade progression should be investigated further as important biomarkers in PanNET.

National Category
Cancer and Oncology Clinical Laboratory Medicine
Research subject
Oncology; Pathology
Identifiers
urn:nbn:se:uu:diva-399943 (URN)10.1159/000504392 (DOI)31658459 (PubMedID)
Available from: 2019-12-17 Created: 2019-12-17 Last updated: 2020-02-05Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-0677-4894

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