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Small Intestinal Neuroendocrine Tumor: A Rare Malignancy with Favorable Outcome
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Small intestinal neuroendocrine tumor (SI-NET) is the most common small bowel tumor in Europe and USA, with an annual incidence of around 0.3-1.3/100000 persons. SI-NETs are the most common type of gastroenteropancreatic NETs (GEP-NETs), and they are known for their ability to produce hormones such as tachykinins and serotonin, as well as for their favorable long-term prognosis in comparison to gastrointestinal adenocarcinoma. The overall aim of the thesis was to investigate unknown or unclear aspects of SI-NET disease, in connection with prognosis, treatment and follow-up. Paper I confirmed several known negative prognostic factors and also showed, for the first time, that para-aortal lymph node metastases and peritoneal carcinomatosis were associated with worse survival by multivariable analyses. Locoregional surgery was associated with a low post-operative mortality, and a prolonged long-term survival by multivariable analysis. In Paper II we continued to investigate peritoneal carcinomatosis and found it be a risk factor not only for death, but also for emergency re-surgery. Furthermore, genetic analyses of samples from primary tumors in patients with and without peritoneal carcinomatosis showed a difference in the DNA between these two groups. In Paper III the outcome after liver surgery and/or radiofrequency ablation of liver metastases was investigated. To summarize, no difference in survival was seen in patients treated with surgery/radiofrequency ablation in comparison with matched controls. However, a superior radiological response of liver metasases and lower U-5-HIAA values were seen in patients subjected to liver surgery and/or radiofrequency ablation compared to matched controls. Paper IV compared ultrasonography, computed tomography and 11C-5HTP-PET in the follow-up after radiofrequency ablation of NET liver metastases. The study concluded that 11C-5HTP-PET depicted all residual tumors after RFA and that it, if used, should be combined with computed tomography for easier interpretation, as RFA areas are not clearly distinguishable with 11C-5HTP-PET alone. Paper V studied gallstone complications after somatostatin analog treatment in SI-NET patients, and concluded that there was a rather high risk to be subjected to a cholecystectomy due to biliary colic, cholecystitis, cholangitis or pancreatitis after primary surgery in somatostatin analog treated patients.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. , 78 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 844
Keyword [en]
Neuroendocrine tumor, peritoneal carcinomatosis, single nucleotide polymorphism array, liver metastases, radiofrequency ablation, liver surgery, positron emission tomography, somatostatin analogs, cholecystectomy
National Category
Surgery
Research subject
Surgery
Identifiers
URN: urn:nbn:se:uu:diva-185071ISBN: 978-91-554-8548-1 (print)OAI: oai:DiVA.org:uu-185071DiVA: diva2:571727
Public defence
2013-01-25, Rosensalen, Entrance 95/96, Uppsala University Hospital, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2012-12-21 Created: 2012-11-19 Last updated: 2013-02-11Bibliographically approved
List of papers
1. Long-Term Results of Surgery for Small Intestinal Neuroendocrine Tumors at a Tertiary Referral Center
Open this publication in new window or tab >>Long-Term Results of Surgery for Small Intestinal Neuroendocrine Tumors at a Tertiary Referral Center
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2012 (English)In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 36, no 6, 1419-1431 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

Small intestinal neuroendocrine tumors (SI-NETs) are uncommon, with an annual incidence of about 1 per 100,000 individuals. The primary tumor (PT) is generally small, but nevertheless the majority of patients have mesenteric lymph node metastases and liver metastases at diagnosis. Our aim was to identify prognostic factors for survival and to evaluate outcome after surgery in SI-NET patients.

MATERIAL AND METHODS:

We included 603 consecutive patients (325 men; age at diagnosis 63 ± 11 years [mean ± SD]) with histopathologically verified SI-NET, who were diagnosed between 1985 and 2010. Hospital charts were reviewed and were scrutinized for carcinoid heart disease (CHD), flush and/or diarrhea, proliferation by Ki-67 index, mesenteric lymph node metastases (m.lgllm), distant abdominal lymph node metastases (da.lgllm), liver tumor load (LTL), extra-abdominal metastases (EAM), locoregional resective surgery, as well as debulking of LTL, and adverse events after surgery.

RESULTS:

Median overall survival (OS) was 8.4 years; 5-year OS was 67%, and 5-year relative survival was 74%. Independent prognostic factors by univariate and multivariate analysis were age at diagnosis, CHD, m.lgllm, da.lgllm, LTL, EAM, peritoneal carcinomatosis (PC), and proliferation. Locoregional resective surgery was associated with increased survival on crude and multivariate analysis. The 30-day mortality in our institution after initial locoregional resective surgery was 0.5% (1/205).

CONCLUSIONS:

For the first time, m.lgllm and da.lgllm, LTL, PC, and EAM are demonstrated to be independent prognostic factors by multivariate analysis. Locoregional removal of the PT/m.lgllm. was a positive prognostic factor by crude and adjusted analysis and may influence survival.

National Category
Cancer and Oncology Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-163767 (URN)10.1007/s00268-011-1296-z (DOI)000304096800031 ()21984144 (PubMedID)
Available from: 2011-12-14 Created: 2011-12-14 Last updated: 2013-02-11Bibliographically approved
2. Peritoneal carcinomatosis from small intestinal neuroendocrine tumors: Clinical course and genetic profiling
Open this publication in new window or tab >>Peritoneal carcinomatosis from small intestinal neuroendocrine tumors: Clinical course and genetic profiling
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2014 (English)In: Surgery, ISSN 0039-6060, E-ISSN 1532-7361, Vol. 156, no 6, 1512-1522 p.Article in journal (Refereed) Published
Abstract [en]

Background. One-fifth of all patients with small-intestinal neuroendocrine tumors (SI-NETs) present with or develop peritoneal carcinomatosis (PC). Our aim was to determine the prognosis and genetic profiles of tumors in patients with PC compared with tumors in patients without PC. Methods. We included SI-NET patients (cases with PC, n = 73, and controls without PC, n = 468) who underwent operation between 1985 and 2012. The Lyon prognostic index was used to correlate the amount of PC to survival. DNA samples from patients with (n = 8) and without (n = 7) PC were analyzed with a single-nucleotide polymorphism array (HumanOmni2.5 BeadChip, Illumina) to investigate genetic disparities between groups. Results. Patients with PC had poorer survival (median 5.1 years) than controls (11.1 years). An advanced postoperative Lyon prognostic index was a negative prognostic marker for survival by multivariable analysis (P = .042). Patients with and without PC clustered differently based on loss of heterozygosity and copy number variation data from single-nucleotide polymorphism array of the primary tumors (P = .042). Conclusion. SI-NET patients with PC have poor survival, which diminishes with increasing PC load after surgery. Clustering based on copy number variation and loss of heterozygosity data suggests different genotypes in primary tumors comparing patients with and without PC.

National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-185070 (URN)10.1016/j.surg.2014.08.090 (DOI)000345255700031 ()25456945 (PubMedID)
Available from: 2012-11-19 Created: 2012-11-19 Last updated: 2016-12-20
3. Outcome after surgery and radiofrequency ablation of liver metastases in small intestinal neuroendocrine tumors: A propensity score matched treatment-control study
Open this publication in new window or tab >>Outcome after surgery and radiofrequency ablation of liver metastases in small intestinal neuroendocrine tumors: A propensity score matched treatment-control study
(English)Manuscript (preprint) (Other academic)
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-185069 (URN)
Available from: 2012-11-19 Created: 2012-11-19 Last updated: 2013-11-06
4. 11C-5-hydroxytryptophan positron emission tomography after radiofrequency ablation of neuroendocrine tumor liver metastases
Open this publication in new window or tab >>11C-5-hydroxytryptophan positron emission tomography after radiofrequency ablation of neuroendocrine tumor liver metastases
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2012 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 39, no 6, 883-890 p.Article in journal (Refereed) Published
Abstract [en]

Aim: The aim was to assess the feasibility of C-11-5-hydroxy-tryptophan positron emission tomography ( C-11-5-HTP-PET) in the follow-up after radiofrequency ablation (RFA) of liver metastases from neuroendocrine tumors (NETS). Background: Contrast-enhanced computed tomography (CECT) and contrast-enhanced ultrasound (CEUS) are commonly used to evaluate the liver after RFA of NETs. In general, C-11-5-HTP-PET is more sensitive in the visualization of NETs, but no studies have investigated its role after RFA.

Methods: Six consecutive patients with liver metastases from NETs were subjected to RFA treatment. All patients underwent baseline imaging before RFA and on two occasions (1-2 and 6-11 months) after RFA. The imaging consisted of C-11-5-HTP-PET, CEUS and CECT on all three occasions.

Results: Thirty RFA areas were evaluated, and residual tumors (RTs) were depicted in eight areas (22%). C-11-5-HTP-PET depicted RTs after RFA with maximum sensitivity (100%) and specificity (100%), using radiological follow-up as the gold standard. C-11-5-HTP-PET detected five out of eight RTs earlier than CECT or CEUS. In general, the sensitivity of C-11-5-HTP-PET exceeded that of CECT and CEUS for early visualization of NET liver metastases.

Conclusion: C-11-5-HTP-PET can be used in the follow-up after RFA for the purpose of detecting RT, and it provides additional information to CEUS and CECT by detecting new lesions.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-181929 (URN)10.1016/j.nucmedbio.2011.12.013 (DOI)000307041000018 ()
Available from: 2012-10-02 Created: 2012-10-02 Last updated: 2013-02-11Bibliographically approved
5. Prophylactic Cholecystectomy in Midgut Carcinoid Patients
Open this publication in new window or tab >>Prophylactic Cholecystectomy in Midgut Carcinoid Patients
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2010 (English)In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 34, no 6, 1361-1367 p.Article in journal (Refereed) Published
Abstract [en]

Patients with midgut carcinoid (MGC) tumors are commonly treated with somatostatin analogs. Adverse effects of these drugs include impairment of gallbladder function, formation of gallstones, and cholecystitis. Prophylactic cholecystectomy has been advocated, but data to support this recommendation are sparse. We have analyzed a cohort of 235 patients with MGC focusing on the risk for gallstone formation and complications thereof. Forty-eight of the 235 patients had been cholecystectomized before surgery for MGC. Of the remaining 187 patients, 144 were treated with somatostatin analogs. Eighteen of the 187 patients had their gall bladder removed during the primary carcinoid surgery. Twenty-two of the 144 somatostatin-analog-treated patients developed complications, such as gallbladder empyema (n = 1), cholangitis (n = 2), acute cholecystitis (n = 6), acute pancreatitis (n = 1) or acute pancreatitis and cholecystitis (n = 1), or biliary colic (n = 11). Ninety-two of the 144 were examined during surgery, by computed tomography, or by ultrasound, most for reasons other than gallbladder-related indications, and 63% (58/92) of these examinations revealed gallstones. Of the 43 patients not treated with somatostatin analogs, only 3 patients suffered from biliary colic and underwent cholecystectomy. In our study the incidence of gallstone-related complications seems to be higher than in the general population. We recommend that prophylactic cholecystectomy is liberally performed during laparotomy for MGC if patients are planned to undergo treatment with somatostatin analogs.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-136429 (URN)10.1007/s00268-010-0428-1 (DOI)000277714300031 ()20130865 (PubMedID)
Available from: 2010-12-13 Created: 2010-12-13 Last updated: 2015-06-16Bibliographically approved

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