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Original Research |

Metachronous Hormonal Syndromes in Patients With Pancreatic Neuroendocrine Tumors: A Case-Series StudyMHSs in Patients With PNETs

Louis de Mestier, MD; Olivia Hentic, MD; Jérôme Cros, MD, PhD; Thomas Walter, MD; Guillaume Roquin, MD; Hedia Brixi, MD; Catherine Lombard-Bohas, MD; Pascal Hammel, MD, PhD; Marie-Danièle Diebold, MD, PhD; Anne Couvelard, MD, PhD; Philippe Ruszniewski, MD, PhD; and Guillaume Cadiot, MD, PhD
[+] Article, Author, and Disclosure Information

From Robert-Debré University Hospital, Reims, France; Beaujon University Hospital, Clichy, France; Edouard-Herriot University Hospital, Lyon, France; Angers University Hospital, Angers, France; and Xavier-Bichat University Hospital, Paris, France.

Acknowledgment: The authors thank Ms. Janet Jacobson for editorial assistance in the preparation of the manuscript.

Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-2132.

Reproducible Research Statement:Study protocol, statistical code, and data set: Not available.

Requests for Single Reprints: Guillaume Cadiot, MD, PhD, Department of Hepato-Gastroenterology and Digestive Oncology, Robert-Debré University Hospital, Avenue du Général Koenig, 51092 Reims Cedex, France; e-mail, gcadiot@chu-reims.fr.

Current Author Addresses: Drs. de Mestier and Brixi and Prof. Cadiot: Department of Hepato-Gastroenterology and Digestive Oncology, Robert-Debré University Hospital, Avenue du Général Koenig, 51092 Reims Cedex, France.

Dr. Hentic and Profs. Hammel and Ruszniewski: Department of Gastroenterology and Pancreatology, Beaujon University Hospital, 100 Boulevard du Général Leclerc, 92118 Clichy Cedex, France.

Dr. Cros: Department of Pathology, Beaujon University Hospital, 100 Boulevard du Général Leclerc, 92118 Clichy Cedex, France.

Drs. Walter and Lombard-Bohas: Department of Digestive Oncology, Edouard Herriot University Hospital, Pavillon E, 5 Place d'Arsonval, 69437 Lyon Cedex 03, France.

Dr. Roquin: Department of Hepato-Gastroenterology, Angers University Hospital, 4 Rue Larrey, 49933 Angers Cedex 9, France.

Dr. Diebold: Department of Pathology, Robert-Debré University Hospital, Avenue du Général Koenig, 51092 Reims Cedex, France.

Dr. Couvelard: Department of Pathology, Bichat University Hospital, 46 Rue Henri Huchard, 75877 Paris Cedex 18, France.

Author Contributions: Conception and design: L. de Mestier, O. Hentic, T. Walter, H. Brixi, P. Ruszniewski, G. Cadiot.

Analysis and interpretation of the data: L. de Mestier, O. Hentic, J. Cros, T. Walter, C. Lombard-Bohas, P. Hammel, M. Diebold, P. Ruszniewski, G. Cadiot.

Drafting of the article: L. de Mestier, O. Hentic, T. Walter, P. Hammel, P. Ruszniewski, G. Cadiot.

Critical revision of the article for important intellectual content: L. de Mestier, O. Hentic, J. Cros, T. Walter, C. Lombard-Bohas, A. Couvelard, P. Ruszniewski, G. Cadiot.

Final approval of the article: L. de Mestier, O. Hentic, J. Cros, T. Walter, G. Roquin, H. Brixi, C. Lombard-Bohas, P. Hammel, M. Diebold, A. Couvelard, P. Ruszniewski, G. Cadiot.

Provision of study materials or patients: L. de Mestier, O. Hentic, J. Cros, T. Walter, H. Brixi, C. Lombard-Bohas, P. Hammel, M. Diebold, P. Ruszniewski, G. Cadiot.

Statistical expertise: L. de Mestier, G. Cadiot.

Administrative, technical, or logistic support: L. de Mestier, G. Cadiot.

Collection and assembly of data: L. de Mestier, O. Hentic, J. Cros, T. Walter, G. Roquin, H. Brixi, C. Lombard-Bohas, A. Couvelard, P. Ruszniewski, G. Cadiot.


Ann Intern Med. 2015;162(10):682-689. doi:10.7326/M14-2132
Text Size: A A A

Background: Pancreatic neuroendocrine tumors (PNETs) may evolve and cause hormonal hypersecretion–related symptoms that were not present at the initial diagnosis, termed metachronous hormonal syndromes (MHSs). Their setting, characteristics, and outcomes are not well-described.

Objective: To describe MHSs in patients with sporadic PNETs.

Design: Retrospective, multicenter study.

Setting: 4 French referral centers.

Patients: Patients with PNETs who developed MHSs related to hypersecretion of insulin, gastrin, vasoactive intestinal peptide, or glucagon between January 2009 and January 2014.

Measurements: Tumor extension, biological markers, and treatments at initial PNET diagnosis and MHS onset. Pathologic specimens were evaluated centrally, including Ki-67 index and hormone immunolabeling.

Results: Of 435 patients with PNETs, 15 (3.4%) were identified as having MHSs involving the hypersecretion of insulin (5 patients), vasoactive intestinal peptide (5 patients), gastrin (2 patients), or glucagon (4 patients). Metachronous hormonal syndromes developed after a median of 55 months (range, 7 to 219) and in the context of PNET progression, stability, and tumor response in 8, 6, and 1 patients, respectively. The median Ki-67 index was 7% (range, 1% to 19%) at PNET diagnosis and 17.5% (range, 2.0% to 70.0%) at MHS onset. Immunolabeling of MHS-related peptides was retrospectively found in 8 of 14 of pathologic PNET specimens obtained before MHS diagnosis. Median survival after MHS onset was 28 months (range, 3 to 56). Seven patients with MHSs died during follow-up, all due to PNETs, including 4 patients with insulin-related MHSs.

Limitation: Retrospective data collection and heterogeneity of pathologic specimen size and origin.

Conclusion: Metachronous hormonal syndromes were identified more often in the context of PNET progression and increased Ki-67 indices. Patients with insulin-related MHSs may have decreased survival rates.

Primary Funding Source: None.

Figures

Grahic Jump Location
Figure 1.

Change in Ki-67 index from initial PNET diagnosis to MHS onset for 9 patients with multiple pathologic specimens.

MHS = metachronous hormonal syndrome; PNET = pancreatic neuroendocrine tumor.

Grahic Jump Location
Grahic Jump Location
Figure 2.

Ki-67 index evolution and insulin immunolabeling between biopsy samples of the primary tumor performed at initial diagnosis (A to C) and biopsy samples of metastases performed at the onset of insulin secretion occurring after 30 mo of follow-up (D to F).

Samples from patient 4 in Table 4. Panels A and D represent hematoxylin–eosin–saffron staining (original magnification, ×20), panels B and E represent Ki-67 immunolabeling (original magnification, ×20), and panels C and F represent insulin immunolabeling (original magnification, ×20). MHS = metachronous hormonal syndrome; PNET = pancreatic neuroendocrine tumor.

Grahic Jump Location
Grahic Jump Location
Figure 3.

Evolutions of Ki-67 index, insulin, and vasoactive intestinal peptide immunolabeling from surgical samples of the primary tumor performed at the initial diagnosis of an insulin-secreting PNET (A to D) and surgical samples of primary tumor performed at the onset of vasoactive intestinal peptide secretion occurring after 65 mo of follow-up (E to H).

Samples from patient 4 in Table 4. Panels A and E represent hematoxylin–eosin–saffron staining (original magnification, ×20), panels B and F represent Ki-67 immunolabeling (original magnification, ×20), panels C and G represent insulin immunolabeling (original magnification, ×20), and panels D and H represent vasoactive intestinal peptide immunolabeling (original magnification, ×20). MHS = metachronous hormonal syndrome; PNET = pancreatic neuroendocrine tumor.

Grahic Jump Location

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