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Clinical and immunohistochemical studies of small bowel carcinoid tumours
Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Small bowel carcinoid tumours arising from enterochromaffin cells in the jejunum and ileum are neuroendocrine tumours (NETs) characterized by secretion of serotonin, tachykinins and other bioactive substances. These substances may lead to the typical carcinoid syndrome as well as pronounced fibrosis locally and in the heart. Although the most frequent histological subtype of malignancy in the small bowel, small bowel carcinoids are rare and therefore difficult to study. We found that previous studies either described selected patients at referral centres, or were based on limited data from large registries. The main objective of this thesis was to investigate small bowel carcinoid patients from a geographically defined cohort with no selection bias.

PAPERS I AND II

The aims of papers I and II were to investigate the incidence, histopathological characteristics, stage atdiagnosis, symptomatology, surgical treatment, prognostic factors and survival of small bowel carcinoid.All patients resident in Jönköping County when diagnosed with small bowel carcinoid between 1960 and2005 were eligible for inclusion. After thorough review of medical records and reexamination of availabletumour specimens, 145 patients were included.

A higher incidence of small bowel carcinoid than previously described was found: 1.12 per 100,000 persons and year. The incidence increased during the study period. Symptoms were most often uncharacteristic: the carcinoid syndrome was seen in only 13% of symptomatic patients. Many small bowel carcinoid tumours presented as surgical emergencies without preceding symptoms, often as intestinal obstruction (35%) caused by mesenteric fibrosis. The majority of small bowel carcinoid tumours had metastasized to the mesentery or the liver at diagnosis. Disease-specific survival after 5 years was 75.0% and after 10 years 63.5%. Independent prognostic factors for worse disease-specific survival were higher age at diagnosis, more advanced disease stage at diagnosis and incomplete tumour resection. Completeness of resection was of particular importance in patients with regional metastases.

PAPER III

There are previous case reports describing small bowel carcinoid in two first-degree relatives, but it is unknown whether this represents hereditary disease forms or chance. Paper III was the first article to describe metastasizing ileal carcinoid tumours in three consecutive generations − strongly suggestive of a hereditary disease form.

PAPER IV

We recently demonstrated expression of cocaine- and amphetamine-regulated transcript (CART) in several types of NETs, including small bowel carcinoid. The aim of paper IV was to investigate whether content of CART in small bowel carcinoid tumours is associated with tumour characteristics, symptoms and survival. CART expression was examined in all available tumour specimens from the patients in Papers I and II − 97 patients were included.

Presence of CART IR tumour cells was associated with histological grade, but not with stage or age. CART expression in small bowel carcinoid tumours was not associated with clinical symptoms. Increasing levels of CART IR in small bowel carcinoid tumour cells was associated with worse disease-specific survival. CART was also found to increase cell viability in an enteroendocrine cell line in vitro. The results suggest that CART could be used as a prognostic biomarker and that CART is a potential anti-tumour treatment target.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2011. , 90 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1265
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-71888ISBN: 978-91-7393-055-0 (print)OAI: oai:DiVA.org:liu-71888DiVA: diva2:455192
Public defence
2011-12-03, Originalet, Qulturum, Länssjukhuset Ryhov, Jönköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2011-11-09 Created: 2011-11-09 Last updated: 2011-11-16Bibliographically approved
List of papers
1. Epidemiology of Small Bowel Carcinoids in a Defined Population
Open this publication in new window or tab >>Epidemiology of Small Bowel Carcinoids in a Defined Population
2010 (English)In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 34, no 7, 1500-1505 p.Article in journal (Refereed) Published
Abstract [en]

Background: This retrospective study describes the epidemiology of small bowel carcinoids in a geographically defined population, with no other selection bias.

Methods: All patients (n = 145) resident in Jönkoping County when diagnosed with carcinoid in the jejunum or ileum from 1960 to 2005 were included. Medical records were reviewed in detail, and tumor specimens were histopathologically and immunohistochemically reexamined when required (n = 44).

Results: The annual age-adjusted incidence of small bowel carcinoids was 1.12 (95% confidence interval 0.95-1.31) per 100,000 persons. Median age at diagnosis was 69 years. The predominating presenting symptom was uncharacteristic abdominal pain (50%), whereas a smaller number suffered from typical flushes (13%). Surprisingly, 14% presented with overt gastrointestinal hemorrhage. Most of the patients diagnosed based on their symptoms had metastases at diagnosis (44% regional, 40% distant). Metastasized tumors by definition belong to World Health Organization (WHO) histopathologic group 2; and when reexamined, most (83%) of the localized tumors were also found to belong to WHO group 2.

Conclusions: In comparison to previous reports, a higher age-adjusted incidence of small bowel carcinoids was observed, and the patients were clearly older at the time of diagnosis. Even with metastatic disease, the presenting symptoms were usually uncharacteristic, and the carcinoid syndrome was infrequently seen.

Place, publisher, year, edition, pages
Springer Science Business Media, 2010
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-58284 (URN)10.1007/s00268-010-0519-z (DOI)000279103400016 ()
Available from: 2010-08-10 Created: 2010-08-09 Last updated: 2017-12-12Bibliographically approved
2. Survival and prognostic factors in patients with small bowel carcinoid tumour
Open this publication in new window or tab >>Survival and prognostic factors in patients with small bowel carcinoid tumour
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2011 (English)In: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 98, no 11, 1617-1624 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Previous studies of small bowel carcinoid tumours usually presented overall or relative survival. This study, in addition, evaluated disease-specific survival in a cohort of patients in a geographically defined population.

METHODS: Patients diagnosed with carcinoid of the jejunum or ileum in Jönköping County between 1960 and 2005 were eligible for inclusion. Available tumour specimens were re-examined to confirm the diagnosis. Medical records and pathology reports were reviewed in detail.

RESULTS: A total of 145 patients were included in the study. One hundred and thirty-five patients underwent surgery in connection with the diagnosis. Resection was considered complete (R0) in 74 patients (54·8 per cent). Only two localized tumours recurred, whereas no patient with distant metastases was cured. Patients with regional metastases who underwent R0 resection had a better survival than patients with incomplete resection (P = 0·005), and a majority of patients remained recurrence-free. Median overall survival was 7·2 years and median disease-specific survival 12·3 years. In multivariable analysis, age 61-74 years (hazard ratio (HR) 3·78, 95 per cent confidence interval 1·86 to 7·68), age 75 years or more (HR 3·96, 1·79 to 8·74), distant metastases (HR 14·44, 1·59 to 131·36) and incomplete tumour resection (HR 2·71, 1·11 to 6·61) were associated with worse disease-specific survival. Later time period of diagnosis (HR 0·45, 0·24 to 0·84) was associated with better disease-specific survival.

CONCLUSION: Age, disease stage and complete resection were identified as independent prognostic factors for survival in patients with small bowel carcinoid tumours. The importance of achieving R0 resection is therefore emphasized.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2011
National Category
Surgery
Identifiers
urn:nbn:se:liu:diva-71884 (URN)10.1002/bjs.7649 (DOI)000296193400019 ()21858790 (PubMedID)
Available from: 2011-11-09 Created: 2011-11-09 Last updated: 2017-12-08Bibliographically approved
3. First Report on Metastasizing Small Bowel Carcinoids in First-Degree Relatives in Three Generations
Open this publication in new window or tab >>First Report on Metastasizing Small Bowel Carcinoids in First-Degree Relatives in Three Generations
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2010 (English)In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 91, no 4, 318-323 p.Article in journal (Refereed) Published
Abstract [en]

Background/Aims: There is an established association between the multiple endocrine neoplasia type 1 (MEN 1) syndrome and foregut carcinoids. Some registry studies also indicate that offspring to carcinoid patients run an increased risk of developing a carcinoid tumor themselves. However, there are only scattered reports of gastrointestinal carcinoids in two generations. The aim of this study was to describe the clinical characteristics as well as the histopathological, immunohistochemical (IHC) and genetic data of metastasizing ileal carcinoids in three consecutive first-degree relatives. Methods: The histopathological and IHC analyses were performed on newly cut sections of the tumor specimens and included growth pattern, proliferation index (Ki67) as well as expression of established neuroendocrine markers and recently introduced cocaine-amphetamine-regulated transcript (CART). The genetic analyses were focused on establishing whether a connection with the MEN 1 syndrome existed in this family, by means of mutation screening using polymerase chain reaction, multiple ligation-dependent probe amplification, and genotyping using fluorescent-labeled microsatellite markers. Results: Histopathology and IHC revealed that the tumors were virtually identical, with only minor differences in proliferation index and expression of CART. Genetic analyses indicated that the inheritance of the small bowel carcinoids in the family was not linked to the MEN1 gene. Conclusion: Metastasizing small bowel carcinoids have been found in first-degree relatives in three consecutive generations. All three tumors were very similar when characterized by histopathology and IHC. Based on clinical findings and genetic analyses, it seems unlikely, although not completely excluded, that inheritance was linked to the MEN 1 syndrome

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-65612 (URN)10.1159/000299790 (DOI)
Available from: 2011-02-13 Created: 2011-02-13 Last updated: 2017-12-11Bibliographically approved
4. Expression of Cocaine- and Amphetamine-Regulated Transcriptis Associated with Worse Survival in Small Bowel Carcinoid Tumors
Open this publication in new window or tab >>Expression of Cocaine- and Amphetamine-Regulated Transcriptis Associated with Worse Survival in Small Bowel Carcinoid Tumors
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2012 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 18, no 13, 3668-3676 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: Cocaine- and amphetamine-regulated transcript (CART) peptide exerts several regulatory functions acting both as neurotransmitter and hormone. We recently showed that CART is expressed in various neuroendocrine tumors, including small bowel carcinoid. The main objective of the present study was to examine whether CART expression is associated with survival in small bowel carcinoid patients. Secondary aims were to assess if CART expression is associated with other tumor characteristics or clinical symptoms.

Experimental Design: Specimens from 97 patients with small bowel carcinoids were examined for CART expression using immunohistochemistry and in situ hybridization. A CART score was introduced based on the proportion of CART immunoreactive cells. On inclusion, specimens were examined by routine histopathological methods and detailed clinical patient data were retrieved. The effect of CART on cell viability was assessed in vitro using an enteroendocrine cell line.

Results: Expression of CART (P = 0.011), and increasing CART score (P = 0.033) were associated with worse disease-specific survival. Adjusting for age, disease stage and tumor grade in multivariable analysis, CART expression was still associated with worse survival (Low CART hazard ratio (HR) 5.47, 95% confidence interval (CI) 0.71 to 42.46; and High CART HR 9.44, 95% CI 1.14 to 78.14). Expression of CART correlated with higher tumor grade, but not with age or disease stage, neither with weight loss or any other symptom. Supporting our clinical data, we found that CART promoted tumor cell viability in vitro.

Conclusion: Expression of CART in small bowel carcinoid tumors is associated with worse survival.

Place, publisher, year, edition, pages
American Association for Cancer Research, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-71887 (URN)10.1158/1078-0432.CCR-11-2513 (DOI)000307502600019 ()
Note

funding agencies|Futurum-Academy of Healthcare at Jonkoping County Council||Foundation for Clinical Cancer Research in Jonkoping||Swedish Research Council|522-2008-4216K2009-55X 21111-01-4K2007-55X-04499-33-3|Faculty of Medicine at Lund University||Novo Nordisk Foundation||Gyllenstiernska Krapperup Foundation||Fredrik and Ingrid Thuring Foundation||Magnus Bergwall Foundation||Crafoord Foundation||Albert Pahlsson Foundation||

Available from: 2011-11-09 Created: 2011-11-09 Last updated: 2017-12-08Bibliographically approved

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