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