Pathologie des tumeurs neuroblastiques périphériques

M. PeuchmaurUniv. Diderot Paris7, Sorbonne Paris Cité

Sce de Pathologie, R. Debré, APHP

Missions essentielles

• INPC • diagnostic positif• histopronostic • banque tissulaire

congelée

MKI

défavorable

âge

favorable

•Cell. Schwann•Différenciation cell. tumorales

INPC

2 1 3 4

“Cross” sampling

“Book” sampling

SAMPLING OF NEUROBLASTIC

TUMORSFOR PROGNOSTIC

BIOLOGICAL STUDIES

1

3

2

4

1 cm

If possible, minimum 2 samples (A, B) from different sites.Required for therapeutic protocols in pre-treatment specimens!

If possible, minimum 2 samples (A, B) from different sites.Required for therapeutic protocols in pre-treatment specimens!

Type III

Type I

Type IIA

Type IIB

Tumeurs Neuroblastiques Périphériques

• Ganglioneurome• Ganglioneuroblastome mélangé

(intermixed)• Ganglioneuroblastome nodulaire• Neuroblastome

Arbre pour le Diagnostique TNP3 clefs

• Schwann

• Fond fibrillaire

• cellules differenciées < 5%

Arbre pour le Diagnostique TNP3 clefs

• Schwann

• Oui = stroma riche: GN, GNBi et nod < 5%

• Oui: NB Peu Différencié–Non: NB différenciant

Contingent schawnnien: PrésentDominant / Riche

GanglioNeurome, stroma dominant

GanglioNeuroblastome,stroma riche,« intermixed » ou« mélangé »

Contingent schawnnien: PrésentMixte, riche et pauvre

Nodule

• GanglioNeuroblastome, stroma mixte riche et pauvre,

• nodulaire

Arbre pour le Diagnostique TNP3 clefs

• Schwann• Oui = stroma riche: GN, GNB

– Non = stroma pauvre

Contingent schawnnien: Absent0% à <50%

• Neuroblastome, stroma pauvre

Arbre pour le Diagnostique TNP3 clefs

• Schwann: Non = stroma pauvre

• Fond fibrillaire Absent :

=NB indifférencié 5%• Oui: NB Peu Différencié

–Non: NB différenciant

Neuroblastome, stroma pauvre, indifférencié

• Fond fibrillaire ou neuropile: absent • IHC: TH & autres

Arbre pour le Diagnostique TNP3 clefs

• Schwann: Non = stroma pauvre

• Fond fibrillaire Présent :

• cellules differenciées < 5%• Oui: NB Peu Différencié

–Non: NB différenciant

Neuroblastome, stroma pauvre, peu différencié

• Fond fibrillaire ou neuropile: Présent

• Cellules tumorales différenciées: <5%

Arbre pour le Diagnostique TNP3 clefs

• Schwann: Non = stroma pauvre

• Fond fibrillaire Présent :

• cellules differenciées < 5% i:–Non: NB différenciant

Neuroblastome, stroma pauvre, différenciant

• Fond fibrillaire ou neuropile: Présent

• Cellules tumorales différenciées: >5%

INPC: international neuroblastoma pathology classification

catégories stroma sous-type critères additionnels

neuroblastome stroma pauvre indifférencié MKI

peu différencié mitoses

différenciant calcifications

ganglioneuroblastome mixte, stroma riche nodulaire MK I

et stroma pauvre mélangé mitoses

calcifications

ganglioneurome stroma dominant maturant

mature

TNP NOS

Neuroblastome NOS

histopronostic

bas <2% haut >4%

âge dépendant: <1.5 an, [1.5-5], >5 ans

différentiation:

in- peu- diff.

MKI: bas (<2%), intermédiaire [2%-4%], haut >4%

Prognostic categorization of neuroblastomas and nodular ganglioneuroblastomas (classic and variants, prognosis determined by the nodule) U and red: unfavorable. F and green: favorableAge <1.5 yrs

Undifferentiated Poorlydifferentiated

Differentiating

Low MKI U F F

Intermediate MKI

U F F

High MKI U U U

Undifferentiated Poorlydifferentiated

Differentiating

Low MKI U U F

Intermediate MKI

U U U

High MKI U U U

Undifferentiated Poorlydifferentiated

Differentiating

Low MKI U U U

Intermediate MKI

U U U

High MKI U U U

F

Age 1.5-5 yrs

Age > 5 yrs

Prognostic categorization of ganglioneuroblastomas, intermixed and ganglioneuromas.Any age

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Years Since Enrollment

EF

S R

ate

(%)

Favorable (N = 894)

Unfavorable (N = 665)

P < 0.0001

EFS by Shimada Histology (N = 1559)

Eur J Cancer. 2006;42:1113-9J Clin Oncol. 2012;30:1842-8

Outcome after surgery alone or withrestricted use of chemotherapy for patientswith low-risk neuroblastoma: results ofChildren's Oncology Group study P9641.Douglas R. Strother, et al. J Clin Oncol.2012;30:1842-8

• Excellent survival rates can be achieved in asymptomatic low-risk patients with stages 2a and 2b NBL after surgery alone. Patients with stage 2b disease who have unfavorable histology tumors fare less well.

• Stage 2b, Favorable vs Unfavorable – EFS, p=0.0023

• 90 + 3 (% + SE) vs 72 + 7– OS, p<0.001

• 99 + 1 vs 86 + 5

Favorable Histology (n=427)

P<0.0001

0 2 4 6 8 10 12

PR

OB

AB

ILIT

Y

0.25

0.5

0.75

1.0

YEARS

International Neuroblastoma Pathology Classification adds independent prognostic information beyond the prognostic contribution of ageHideki Sano et al. Eur J Cancer. 2006;42:1113-9

Unfavorable Histology (n=319)

The International Neuroblastoma Risk Group consensu s pre-treatment classification schema

H Intermediate*GNB nodular, poorly differentiated or undifferentiated

NB, poorly differentiated or undifferentiated

H Intermediate*

E LowGNB nodular, differentiatingNB, differentiating

>18m

G Intermediate

D LowAny, except GN maturing or GNB intermixed

<18mL2

A Very LowGN maturingGNB intermixed

L1/L2

Pre-treatment Risk Group

Histological Category/Grade of Tumor Differentiatio nAgemonths

INRG Stage

EFS Rate by Tumor GradeNB & GNB, nod > 18 mo (n=1,270)

TNP: la preuve par 3

• 3 missions– Diagnostic– Pronostic– Banque

• 3 clefs Dg– Schwann– Fond fibrillaire– Cellules différenciées

%

• 3 critères Pc– Différenciation– MKI– Âge

• 3 “nouveautés”– PHOX2B– VBP– Nouvelles entités:

nucléoles, Composite Neuroblastoma

PHOX2B Immunolabeling: A Novel Tool for the Diagnos is of Undifferentiated Neuroblastomas Among Childhood Sma ll-, Round-, Blue-cell Tumors. F. Bielle et al. Am J Surg Pathol 2012, 36:1141-9

Anti-PHOX2B +

Anti-TH neg

Anti-PHOX2B +

Question INRG/LINES, L2: taille des prélèvements

Biopsie représentative ?

On behalf of the Europeran group of PathologistsVirtual Biopsy Project : Proof of concept

1.svs ImageScopeInstaller.exe

A

C

B

D

neuroblastoma poorly differentiated subtype with prominent nucleoli

Negative staining for N-myc proteinNuclear staining for N-myc protein

neuroblastoma poorly differentiated subtype with “salt and pepper” nuclei

“Bull’s eye” tumor

“Conventional” tumor

Composite Neuroblastomas

• to clarify the definition and to attempt to describe groups which could be tested for reproducibility and clinical impact.

n°29

n°1

References1/ Pathologie, INPC

• Shimada H, Ambros IM, Dehner LP, et al. The International Neu roblastoma Pathology Classification (the Shimada system) . Cancer.1999;86:364-372.

• Shimada H, Ambros IM, Dehner LP, Hata J, Joshi VV, Roald B.Ter minology and morphologic criteria of neuroblastic tumors:recommendations by the International Neuroblastoma Patho logy Committee. Cancer. 1999;86 :349-363.

• Peuchmaur M, D'Amore ES, Joshi VV, et al. Revision of the inte rnational neuroblastoma pathology classification. Cance r. 2003;98:2274-81.

• Navarro S, Amann G, Beiske K, Cullinane C, D ’Amore E, Gambini C, Mosseri V, de Bernadi B, Michon J, Peuchma ur M. Prognostic value ofInternational Neuroblastoma Pathology Classification in Localized Resectable Peripheral Neurobkastic Tumors. A hi stopathologic study ofLNESG 94.01 Trial and Protocol. J Clin Oncol 2006,24:695-69 9.

• Monclair T, Brodeur GM, Ambros PF, et al; INRG Task Force. The International Neuroblastoma Risk Group (INRG) staging sys tem: an INRGTask Force report. J Clin Oncol. 2009;27:298-303

• Cohn SL, Pearson AD, London WB, et al; INRG Task Force. The Int ernational Neuroblastoma Risk Group (INRG) classificatio n system: anINRG Task Force report. J Clin Oncol. 2009;27:289-97

• F. Bielle et al. PHOX2B Immunolabeling: A Novel Tool for the D iagnosis of Undifferentiated Neuroblastomas Among Childh ood Small-,Round-, Blue-cell Tumors. Am J Surg Pathol 2012, 36:1141-9

2/ Générales

• Lastowska M, Cullinane C, Variend S, et al; United Kingdom Ch ildren Cancer Study Group and the United Kingdom Cancer Cyto geneticsGroup. Comprehensive genetic and histopathologic study re veals three types of neuroblastoma tumors. J Clin Oncol. 200 1;19 :3080-90.

• Brodeur GM. Neuroblastoma: biological insights into a clin ical enigma. Nat Rev Cancer. 2003;3:203-16.

• Attiyeh EF. Chromosome 1p and 11q deletion and outcome in neu roblastomas. NEJM 2005;353:2243-2253

• Janoueix-Lerosey I, Lequin D, Brugière L et al. Somatic and g ermline activating mutation of the ALK kinase receptor in ne uroblastoma.Nature 2008; 455:967-70.

• Janoueix-Lerosey I, Schleiermacher G, Michels E et al. Over all genomic pattern is a predictor of outcome in neuroblasto ma. J Clin Oncol.2009;27:1026-33

• Janoueix-Lerosey I, Schleiermacher G, Delattre O. Molecul ar pathogenesis of peripheral neuroblastic tumors. Oncoge ne. 2010; 29:1566-79.