Original article
Outcome after pancreatectomy for neuroendocrine neoplams according to the WHO 2017 grading system: A retrospective multicentric analysis of 138 consecutive patients

https://doi.org/10.1016/j.clinre.2019.08.010Get rights and content

Highlights

  • The WHO 2017 grading system is a useful tool for patient prognosis after and the tailoring of therapeutic strategy.

  • The WHO 2017 grading system, age and distant metastasis were independent predictors of worse survival.

  • Symptomatic panNET, lymph node metastasis were independently associated with disease recurrence.

  • PanNET G3 has an intermediate prognosis between panNET G2 and PNEC.

  • Progress in diagnosis tools to distinguish panNET G3 vs. PNEC are required.

Summary

Aim

The aim of this study was to evaluate the new World Health Organization (WHO) 2017 grading system and the others clinicopathological factors in pancreatic neuroendocrine tumor (panNET) operated patients.

Methods

Histological staging was based on the WHO 2017 grading system. Outcome after surgery and predictors of overall survival (OS) and disease free survival (DFS) were evaluated.

Results

A total of 138 patients underwent surgical resection with a severe morbidity and mortality rates of 14.5% and 0.7% respectively. Five years OS differed according to WHO 2017: 95% among 58 patients with NETG1, 82% in 68 patients with NETG2, 35% in 7 patients with NETG3 and 0% in 5 patients with NECG3 (P < 0.0001). Independent predictors of worse OS were age > 60 y.o (P = 0.014), synchronous metastasis (P = 0.005) and WHO 2017 with significant differences between NETG1 versus NETG2 (P = 0.005), NETG3 (P < 0.001) and NECG3 (P < 0.001). Independent predictors of worse DFS were symptomatic NET (P = 0.038), pN+ status (P = 0.027) and WHO 2017 with significant differences between NETG1 versus NETG3 (P = 0.014) and NECG3 (P = 0.009).

Conclusion

The WHO 2017 grading system is a useful tool for patient prognosis after panNET resection and the tailoring of therapeutic strategy. Surgery could provide good results in NETG3 patients.

Introduction

Neuroendocrine neoplams of the pancreas (panNET) are neoplasms that originate from the endocrine portion of the pancreas. These tumors, which newly affect 2–3 per 100,000 individuals per year, constitute only about 1% to 2% of all pancreatic neoplasms [1], [2]. PanNET can be classified as functioning and non-functioning [3]. At least 50% of panNET are non-functioning and hence asymptomatic. Prognosis of panNET depends on clinico-pathological factors including tumor size, differentiation and proliferative index that give an indication of the biological aggressiveness of the tumor and likelihood of lymph node involvement [4], [5], [6]. Complete surgical resection plays an important role in the curative treatment of patients with panNET. Several guidelines exist for the treatment of functioning and non-functioning panNET [7], [8]. It is generally accepted that tumors > 2 cm and functioning tumors should be resected but the management of non-functioning tumors < 2 cm remains controversial. Further controversy exists as to the surgical approach (open vs. laparoscopic) and the lymphadenectomy. PanNET are associated with synchronous liver metastasis in 30–80% of patients and require dedicated multidisciplinary staff discussion [9]. The prognostic classification of NET has been challenging due to their relative rarity. The WHO 2010 grading system adopted the Ki-67 index and/or mitotic index to divide digestive system NEN into 3 main types: NET G1, NET G2 NEC G3. Several studies leading to the new WHO 2017 grading system had reported that NEC G3 is a heterogeneous category that can be separated into two subcategories with significantly different prognosis and more importantly, therapeutic strategies seem to be distinct [10], [11], [12], [13]. The new WHO 2017 classification (dividing G3 tumors in well differentiated NET G3 or poorly differentiated NEC G3) validation is ongoing for its ability to predict disease-free survival (DFS) and overall survival (OS) for panNET [14].

Therefore, we aimed to explore the clinicopathological characteristics, short-term and survival outcome on the basis of 138 consecutive patients with panNET, as well as to evaluate the prognostic value of the proposed new WHO 2017 classification.

Section snippets

Patient selection and study design

This was a retrospective review of a prospectively maintained database including all consecutive patients requiring a pancreatic resection for panNET at 3 tertiary referral centers for pancreatic surgery in France, between January 1998 and December 2017. The 3 centers were Digestive Surgery Units of Montpellier, Nimes and Institute of Cancer of Montpellier. The University Institutional Review board approved the study (No.: 2019_IRB-MTP_01-02), which was registered on Clinicaltrials.gov registry

Patient characteristics

A total of 138 patients underwent pancreatic resection for panNET in our 3 centers. The age at surgery was 56 (13–77) years, and 48.5% (67/138) were female. ASA score at diagnosis was I/II in 86.5% of the patients. Diagnosis was incidental in 57 (41%) patients. panNET was sporadic in 132 patients (96%) and associated to Multiple Endocrine Neoplasia syndrome type 1 in 5 (3.5%) patients and Von Hippel-Lindau in 1 (0.5%) patients. Primary locations were equally distributed in the pancreas: head

Discussion

This study, which involved three centers with the same clinical RENATEN network, has many strengths: only panNET patients were included, standardization of work-up across our centers and systematic pathological review by 2 TENpath labeled experts. Pancreatic neuroendocrine neoplasms were majority non-functioning, sporadic, single lesion of 31 mm in median size, non-metastatic with homogenous stage distribution. Our findings confirm several specific issues related to the management of panNET and

Funding

The authors have no source of funding to disclose for this study.

Authors’ contributions

All authors declare that has participated sufficiently in the work to take public responsibility for appropriate portions of the content, as defined in to the guidelines of the International Committee of Medical Journal Editors (ICMJE).

R.S., A.C., M.D., J.R., B.R., M.P., E.A. and J.M.F. were responsible for study concept and design. R.S., A.C., M.D., M.B., I.R., B.G., A.H., S.O., F.P., B.R., F.B., J.R., F.Q., P.E.C., M.P., E.A. and J.M.F. contributed for acquisition and interpretation of data.

Disclosure of interest

The authors declare that they have no competing interest.

Acknowledgments

We thank RENATEN LR and the University of Montpellier for its support. We thank Lorenzo Ferre, Cyprien Toubert, John Chauvat and Françoise Guillon for data collection and their advice. We are grateful to Jacqueline Butterworth for editorial assistance. We thank the residents, fellows, and nurses of our division for the care they provided to these patients.

The data will not be made publicly available, but is available from the authors on request.

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