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First Report on Metastasizing Small Bowel Carcinoids in First-Degree Relatives in Three Generations
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
Department of Clinical Pathology, Ryhov Hospital, Jönköping, Sweden.
Karolinska Institute, Department of Molecular Medicine and Surgery, Clinical Genetic Unit, Stockholm, Sweden.
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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

Place, publisher, year, edition, pages
2010. Vol. 91, no 4, 318-323 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-65612DOI: 10.1159/000299790OAI: diva2:397200
Available from: 2011-02-13 Created: 2011-02-13 Last updated: 2011-11-16Bibliographically approved
In thesis
1. Clinical and immunohistochemical studies of small bowel carcinoid tumours
Open this publication in new window or tab >>Clinical and immunohistochemical studies of small bowel carcinoid tumours
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.


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.


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.


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.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1265
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-71888 (URN)978-91-7393-055-0 (ISBN)
Public defence
2011-12-03, Originalet, Qulturum, Länssjukhuset Ryhov, Jönköping, 13:00 (Swedish)
Available from: 2011-11-09 Created: 2011-11-09 Last updated: 2011-11-16Bibliographically approved

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