Neuro Endocriene Neoplasma’svan de tractus digestivus
Wat zijn de issues in 2018
MLF (Loes) van Velthuysen, Patholoog, ErasmusMC
▪ Geen conflict of intrest
NEN morphologic spectrum
▪ Grading (55%)
▪ Typing (30%)
▪ Staging (15%)
Diagnoses
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
2008-2010 2011-2012
NEC NEN, no grade
NET Large cell, NOS
Small Cell
IKNL-PALGA
NEC not lung 2008-2012
N=831
NEN >50% Chromogranin or
Synaptophysin positive
NEC: Ki67 >20% or Mitotic
Count: >20/10HPF
Survival
0 2 4 6 8
0
20
40
60
80
100Small cell
Large Cell NOS
NET
NEC
NEN, no grade
Years
Su
rviv
al
Issues with NEN
▪ Grading
▪Beware of inflammation
▪Grade 3 NET vs NEC
▪ Typing
▪Gastric NEN
▪MiNEN (MANEC)
▪ Staging
▪TNM8/ ENETS
NEN in the Netherlands (2001-2008); IKNL; N=5343; C.Korse et al Eur.J.Cancer 2013
http://nationaalkompas.nl/--------/kanker/----/cijfers--------incidentie-----2010-kopie/
NEN are rare tumorsIncidence per year in the Netherlands
NEN: 670 / year
Small Cell Cancer: 1720 / yearColon cancer: 12000 / year Breast cancer: 13000 / year
History of classification of NEN
• 1963 WHO: according to embryological origin: foregut, midgut, hindgut
• 1980 WHO: according to hormone production: Carcinoid (serotonin), Gastrinoma, etc
• 2000 WHO: based on differentiation, localisation, diameter, invasion depth
• 2004 WHO: lung grading based on mitotic index and necrosis
• based on paper from Travis et al 1998 Am.J.Surg.Pathol. N=200
• 2010 WHO: based on proliferation (mitosis and Ki-67 index)
Grade Mitosis / 2mm2
Typical carcinoid <2
Atypical carcinoid 2-10
LCNEC, SCLC >10
WHO 2010 Ge and Pancreas (GEP) NEN
Lung 2004
Grade Mitosis / 2mm2 Ki-67
NET G1 <2 <= 2
NET G2 2-20 3-20
NEC (G3) >20 >20
Grade Mitosis / 2mm2
Typical carcinoid <2
Atypical carcinoid 2-10
LCNEC, SCLC >10
Grade Mitosis / 2mm2
Ki-67 %/500-
2000 nuclei
NET G1 <2 < 3
NET G2 2-20 3-20
NEC/NETG3 >20 >20
WHO 2017 Pancreas (GEP) NEN
Mitosis and Ki-67 index are continuous
variables thus grading is artificial!
Mitosis and Ki-67index are both
strongly correlated with survival
irrespective of cut-off value
Using 2 variables has a function of
dubble check
MLF van Velthuysen et al Neuroendocrinology 2015
Mitosis and Ki-67
index in 362 NEN
Mib-1 Eyebal vs Image analyse
Erasmus MC ervaring, N=189
0
10
20
30
40
50
60
70
80
90
0,00 10,00 20,00 30,00 40,00 50,00 60,00
Image analyse
Eye
ba
ll
124 +/- 2%
82 +/- 1%
53 x eyeball hoger 2-28%; 7x meer dan 10%
12 x eyeball lager 2-11%; 1x > 10%
134/189 geen noemenswaardig verschil
22/189 verschil in graad
graad 1>1% verschil discordant andere graad discordant andere graad maar < 1% verschil
graad 2> 4% verschil discordant andere graad discordant andere graad maar < 4% verschil
graad 3> 10% verschil discordant andere graad discordant andere graad maar < 10% verschil
Issues with NEN
▪ Grading
▪Beware of inflammation
▪Grade 3 NET vs NEC
▪ Typing
▪Gastric NEN
▪MiNEN (MANEC)
▪ Staging
▪TNM8/ ENETS
Ki-67 and inflammation
Issues with NEN
▪ Grading
▪Beware of inflammation
▪Grade 3 NET vs NEC
▪ Typing
▪Gastric NEN
▪MiNEN (MANEC)
▪ Staging
▪TNM8/ ENETS
NEC
Grade 3 NET
Typing: When Neuroendocrine?
• Epithelial: expression of cytokeratin
– usually only keratin 8
• Neuroendocrien: expression of proteins of
neuroendocrine granulae
–Chromogranine
–Synaptofysine
– NOT CD56
Issues with NEN
▪ Grading
▪Beware of inflammation
▪Grade 3 NET vs NEC
▪ Typing
▪Gastric NEN
▪MiNEN (MANEC)
▪ Staging
▪TNM8/ ENETS
Gastric NET
Issues with NEN
▪ Grading
▪Beware of inflammation
▪Grade 3 NET vs NEC
▪ Typing
▪Gastric NEN
▪MiNEN (MANEC)
▪ Staging
▪TNM8/ ENETS
Ki67 of NE- component drives MANEC prognosis
▪ 1995 – 2015: all MANEC of 11 Italian centres
▪ M.Milione et al: Endocr Relat Cancer March 28, 2018
MiNEN (MANEC)
▪ Mixed (Adeno) Neuro Endocrien Neoplasma
2 componenten nl Adenocarcinoom en NEC, tenminste 30%
Conclusions: Five of the 6 MANECs presented an overlapping mutational
profile in both components, suggesting a monoclonal origin of the two MANEC
components. Neuroendocrinology 2014;100:310–316; M Scardoni et al
Issues with NEN
▪ Grading
▪Beware of inflammation
▪Grade 3 NET vs NEC
▪ Typing
▪Gastric NEN
▪MiNEN (MANEC)
▪ Staging
▪TNM8/ ENETS
TNM7 = ENETS
TNM8
TNM7 vs ENETS
TNM8 vs ENETS
PA- biopt-GEPNEThttp://richtlijnendatabase.nl/richtlijn/neuro-endocriene_tumoren/pathologie_diagnostiek.html
▪ Classificatie en gradering volgens WHO 2010/17
▪ Chromogranine en synaptofysine (% positiviteit, tenminste 50%)
▪ Aantal mitosen per 2 mm2
▪ % MIB-1 (Ki67) positieve tumorcellen
▪ NET van de maag: type (primair of secundair)
PA- resectie-GEPNET extrahttp://richtlijnendatabase.nl/richtlijn/neuro-endocriene_tumoren/pathologie_diagnostiek.html
▪ Diameter tumor
▪ Diepte ingroei in de wand (bij holle organen)
▪ Afstand tot dichtstbijzijnde snijvlak
▪ Appendix:
▪ diepte invasie in de meso-appendix.
▪ Ligging in appendix: top versus basis
▪ Mesenteriale massa bij dunnedarm NET (en UNP?)
▪ Lymfklier status
Samenvatting
▪ > 50% van de tumorcellen Neuroendocrien
▪ Chromogranine en/of synaptofisine
▪Niet CD56
▪ Graderen; Ki-67 (mib-1) en mitosen
Mitosen, Mib, chromo en synapto in aantal-%,
NIET in categorieen!
▪ Maag: primair of secundair (type)
▪ TNM :
▪Voor NET anders dan voor carcinoom
▪ Let op mesenteriale metastase
Thanks to: Clinical Chemistry, Medical Registration and Medical Oncology of the AvL, Arjen van de Pol, PALGAFrans Prins, Pathology, LUMC
ca b
Mit gr 1 Mit gr 2 Mit gr 3
Ki-67 gr 1 151 30 (d)
Ki-67 gr 2 44 (a) 60 2
Ki-67 gr 3 11 (b) 32 (c) 32
Survival correlates with highest index
MLF van Velthuysen et al Neuroendocrinology 2015
Mitosis and Ki-67 index in 362 NEN
Mitosis and Ki-67 index in 362 NEN
ICC total = 0.86; ICC within each grade 0.15 – 0.18
Mit gr 1 Mit gr 2 Mit gr 3
Ki-67 gr
1 151 30 (d)
Ki-67 gr
2 44 (a) 60 2
Ki-67 gr
3 11 (b) 32 (c) 32
a
b c
d
MLF van Velthuysen et al Neuroendocrinology 2015