Clinical Trials Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 28, 2017; 23(32): 5925-5935
Published online Aug 28, 2017. doi: 10.3748/wjg.v23.i32.5925
Characterizing gastrointestinal stromal tumors and evaluating neoadjuvant imatinib by sequencing of endoscopic ultrasound-biopsies
Per Hedenström, Bengt Nilsson, Akif Demir, Carola Andersson, Fredrik Enlund, Ola Nilsson, Riadh Sadik
Per Hedenström, Riadh Sadik, Division of Medical Gastroenterology, Department of Internal Medicine, Sahlgrenska University Hospital, S-413 45 Gothenburg, Sweden
Bengt Nilsson, Department of Surgery, Sahlgrenska University Hospital, S-413 45 Gothenburg, Sweden
Akif Demir, Carola Andersson, Fredrik Enlund, Ola Nilsson, Department of Clinical Pathology and Genetics, Sahlgrenska University Hospital, S-413 45 Gothenburg, Sweden
Author contributions: Hedenström P, Nilsson B, Nilsson O and Sadik R designed the research; Hedenström P, Nilsson B, Demir A, Andersson C, Enlund F, Nilsson O and Sadik R performed the research; Enlund F and Sadik R contributed new analytic tools; Hedenström P and Sadik R analyzed the data; Hedenström P wrote the paper.
Supported by The Health and Medical Care Committee of the Regional Executive Board, Region Västra Götaland, No. VGFOUREG-564381, No. VGFOUREG-665681 and No. VGFOUREG-373551; Sahlgrenska University Hospital, No. LUA-ALF 73830; and The Swedish Society of Medicine, No. SLS-404261 and No. SLS-325061.
Institutional review board statement: This study was reviewed and approved by the Regional Ethical Review Board of Gothenburg (Study code: Dnr 573-09/Dnr 1092-11).
Clinical trial registration statement: This study was registered at ClinicalTrials.gov (NCT02360839).
Informed consent statement: Written and verbal informed consent was obtained from the participating study subjects.
Conflict-of-interest statement: Per Hedenström, Bengt Nilsson, Akif Demir, Carola Andersson, Fredrik Enlund, Ola Nilsson, and Riadh Sadik declare no potential conflicts of interest relevant to this article.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Riadh Sadik, Associate Professor, Division of Medical Gastroenterology, Department of Internal Medicine, Sahlgrenska University Hospital, Blå Stråket 3, S-413 45 Gothenburg, Sweden. riadh.sadik@vgregion.se
Telephone: +46-31-3421000 Fax: +46-31-827458
Received: January 25, 2017
Peer-review started: February 1, 2017
First decision: April 5, 2017
Revised: April 26, 2017
Accepted: June 18, 2017
Article in press: June 19, 2017
Published online: August 28, 2017
Processing time: 214 Days and 23.6 Hours
Abstract
AIM

To evaluate endoscopic ultrasound (EUS)-guided biopsies for the pretreatment characterization of gastrointestinal stromal tumors (GIST) to personalize the management of patients.

METHODS

All patients with lesions suspected to be GIST who were referred for EUS-sampling at a tertiary Swedish center were eligible for inclusion 2006-2015. During the observational study phase (2006-2011), routine fine-needle-aspiration (EUS-FNA) was performed. In 2012-2015, we converted to an interventional, randomized protocol with dual sampling EUS-FNA and fine-needle-biopsy-sampling (EUS-FNB) for all lesions. c-KIT- and DOG-1-immunostaining was attempted in all samples and a manual count of the Ki-67-index was performed. FNB-sampled tissue and the resected specimens were subjected to Sanger sequencing of the KIT and platelet-derived growth factor alpha (PDGFRA) genes.

RESULTS

In all, 64 unique patients with GIST were included, and of these, 38 were subjected to pretreatment dual sampling. EUS-FNB had a higher diagnostic sensitivity when compared head-to-head with EUS-FNA (98% vs 58%, P < 0.001) and was more adequate for Ki-67-indexing (Ki-67EUS) (92% vs 40%, P < 0.001). Sequencing of EUS-biopsies was successful in 43/44 (98%) patients, and the mutation profiles (KIT-mutation 73%, PDGFRA-mutation 18%, wild-type 7%) were fully congruent with those detected in the corresponding resected specimens. In imatinib-naïve patients, the Ki-67EUS was comparable with the Ki-67-index in the corresponding surgical specimens (Ki-67SURG) (2.7% vs 2.9%, P = 0.68). In patients treated with neoadjuvant imatinib who also carried mutations indicating sensitivity, the Ki-67EUS was higher than the Ki-67SURG (2.5% vs 0.2%, P = 0.005), with a significant reduction in the Ki-67-index of -91.5% (95%CI: -82.4 to -96.0, P = 0.005).

CONCLUSION

EUS-guided biopsy sampling is accurate for the pretreatment diagnosis and characterization of GISTs and allows the prediction and evaluation of tumor response to neoadjuvant imatinib therapy.

Keywords: Endosonography; Fine-needle biopsy; Gastrointestinal stromal tumor; KIT; Platelet-derived growth factor alpha; Tumor proliferation rate; Ki-67 index; Neoadjuvant treatment; Imatinib

Core tip: Personalization of the management and treatment of gastrointestinal stromal tumors (GIST) requires an extensive characterization of individual tumors. Information on the tumor proliferation rate and the KIT- and platelet-derived growth factor alpha (PDGFRA)-mutation profile is essential. While endoscopic ultrasound (EUS)-FNA is reported to be suboptimal for the diagnosis of GIST, EUS-guided biopsy sampling (EUS-FNB) has not been evaluated for the characterization of GISTs. This prospective, long-term study showed that EUS-FNB was safe and highly accurate for the pretreatment diagnosis of GISTs, for the sequencing of KIT and PDGFRA, and for the assessment of the tumor proliferation rate (Ki-67-index). By obtaining this information, we managed to guide and evaluate neoadjuvant imatinib therapy in patients with GIST.