Elfi B Conemans1, Lodewijk A A Brosens2, Gabriela M Raicu-Ionita2, Carolina R C Pieterman3, Wouter W de Herder4, Olaf M Dekkers5, Ad R Hermus6, Anouk N van der Horst-Schrivers7, Peter H Bisschop8, Bas Havekes9, Madeleine L Drent10, H Th Marc Timmers11, G Johan Offerhaus2, Gerlof D Valk3, Menno R Vriens12. 1. Department of Endocrine Surgical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, The Netherlands. 2. Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. 3. Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, The Netherlands. 4. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. 5. Departments of Endocrinology and Metabolism and Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. 6. Department of Endocrinology, Radboud University Medical Center, Nijmegen, The Netherlands. 7. Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 8. Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands. 9. Department of Internal Medicine, Division of Endocrinology, Maastricht University Medical Center, Maastricht, The Netherlands. 10. Department of Internal Medicine, Section of Endocrinology, VU University Medical Center, Amsterdam, The Netherlands. 11. Molecular Cancer Research, Regenerative Medicine Center, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands. 12. Department of Endocrine Surgical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address: mvriens@umcutrecht.nl.
Abstract
BACKGROUND: The prognostic value of WHO grade in pancreatic neuroendocrine tumors (PanNETs) in patients with Multiple Endocrine Neoplasia Type 1 (MEN1) is unknown. METHODS: We performed a cohort study using the Dutch National MEN1 database, which includes >90% of the Dutch MEN1 population with data collected between 1990 and 2014. Formalin-fixed paraffin embedded tissue blocks from the largest resected PanNET per patient were collected. MIB1 staining was performed and KI67 labeling index (LI) was determined by manual eye-counting under a microscope and by digital image analysis. Mitotic count was evaluated from hematoxylin & eosin stains. Association between WHO grade and (time until) development of liver metastases was calculated. RESULTS: Sixty-nine MEN1 patients who underwent pancreatic surgery were included. Ten patients (14%) developed liver metastases and all had PanNETs ≥3 cm. WHO G1, G2 and G3 PanNETs were seen in 83% (n = 57), 16% (n = 11) and 1% (n = 1) respectively. In non-functioning PanNETs >2 cm, liver metastases occurred in 80% of WHO G2 PanNETs (4/5) compared to 23% (5/22) in WHO G1 PanNETs (p = 0.03) when WHO grade was based on mitotic count only. This significant association was not seen for WHO grade based on Ki67 LI. After five years, liver metastases in non-functioning PanNETs were not seen in tumors ≤2 cm, in 10% of the large WHO G1 (according to mitotic count only) tumors and in 60% of large WHO G2 tumors (p-value 0.000). CONCLUSION: High mitotic count is correlated with poor prognosis in MEN1 patients with large non-functioning PanNETs.
BACKGROUND: The prognostic value of WHO grade in pancreatic neuroendocrine tumors (PanNETs) in patients with Multiple Endocrine Neoplasia Type 1 (MEN1) is unknown. METHODS: We performed a cohort study using the Dutch National MEN1 database, which includes >90% of the Dutch MEN1 population with data collected between 1990 and 2014. Formalin-fixed paraffin embedded tissue blocks from the largest resected PanNET per patient were collected. MIB1 staining was performed and KI67 labeling index (LI) was determined by manual eye-counting under a microscope and by digital image analysis. Mitotic count was evaluated from hematoxylin & eosin stains. Association between WHO grade and (time until) development of liver metastases was calculated. RESULTS: Sixty-nine MEN1patients who underwent pancreatic surgery were included. Ten patients (14%) developed liver metastases and all had PanNETs ≥3 cm. WHO G1, G2 and G3 PanNETs were seen in 83% (n = 57), 16% (n = 11) and 1% (n = 1) respectively. In non-functioning PanNETs >2 cm, liver metastases occurred in 80% of WHO G2 PanNETs (4/5) compared to 23% (5/22) in WHO G1 PanNETs (p = 0.03) when WHO grade was based on mitotic count only. This significant association was not seen for WHO grade based on Ki67 LI. After five years, liver metastases in non-functioning PanNETs were not seen in tumors ≤2 cm, in 10% of the large WHO G1 (according to mitotic count only) tumors and in 60% of large WHO G2 tumors (p-value 0.000). CONCLUSION: High mitotic count is correlated with poor prognosis in MEN1patients with large non-functioning PanNETs.
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