The Classification of Pancreatic Neuroendocrine Neoplasms...

The Classification of Pancreatic

Neuroendocrine Neoplasms: WHO 2017

Günter Klöppel, N. Volkan Adsay, Carlo Capella, Anne

Couvelard, Ralph H. Hruban, David S. Klimstra, Paul

Komminoth, Stefano La Rosa, Jean-Yves Scoazec, Nobuyuki

Ohike, Robert Y. Osamura, Aurel Perren, and Guido Rindi

Definition: “Neoplasm”

Overarching term to encompass all of the pancreatic

entities with significant neuroendocrine differentiation

(tumors, carcinomas, mixed carcinomas)

Classification of Pancreatic Neuroendocrine

Neoplasms (WHO 2004)

Microadenoma (<0.5 cm)

Well differentiated endocrine tumor

Benign behavior: confined to pancreas, <2 cm, non-angioinvasive, </= 2

mitoses per 10 HPF, </= 2% Ki67-positive cells

Uncertain behavior: confined to pancreas >/= 2 cm, >2 mitoses per 10 HPF,

> 2% Ki67-positive cells, OR angioinvasive

Well differentiated endocrine carcinoma

Low grade malignant: invasion of adjacent organs or metastases

Poorly differentiated endocrine carcinoma

High grade malignant: >10 mitoses per 10 HPF

Kloppel et al. Ann NY Acad Sci 2004; 1014: 13-27

Classification of Pancreatic Neuroendocrine

Neoplasms (WHO 2004): Issues

Combined staging (organ-confined, size) and grading (proliferative rate)

parameters

Used both “tumor” and “carcinoma” to refer to the same entity

Changed diagnosis with disease progression

Used “carcinoma” for both well and poorly differentiated neoplasms

Provided no prognostic stratification for advanced disease

“Benign behavior” and “uncertain behavior” were NOT!

2006 ENETS Grading of GEP-NETs

Grade Mitoses Ki-67 Index

G1 <2 / 10 H.P.F. < 2%

G2 2-20 / 10 H.P.F. 3-20%

G3 >20 / 10 H.P.F. >20%

Poorly Differentiated (High Grade ) Neuroendocrine Carcinoma

Pancreatic NETs:

Overall Survival by Grade

Rindi et al., J Natl Cancer Inst 2012; 104: 764

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

T1 Tumor limited to the pancreas and size </= 2 cm

T2 Tumor limited to the pancreas and size > 2 cm

T3 Tumor extends beyond the pancreas but without

involvement of the celiac axis or SMA

T4 Tumors involves the celiac axis or the SMA (unresectable

primary tumor)

TNM Staging System for Pancreatic

Neuroendocrine Neoplasms (AJCC/UICC 2009)

T – PRIMARY TUMOR

Classification of

Pancreatic Neuroendocrine Neoplasms

(WHO 2010)

Well differentiated

Well differentiated neuroendocrine tumor, Grade 1 (NET G1)

Well differentiated neuroendocrine tumor, Grade 2 (NET G2)

Poorly differentiated

Poorly differentiated neuroendocrine carcinoma, Grade 3 (NEC G3)

TNM should be performed in all cases

WHO Grading of GEP-NETs (2010)

Grade Mitoses Ki-67 Index

G1 <2 / 10 H.P.F. < 2%

G2 2-20 / 10 H.P.F. 3-20%

G3 >20 / 10 H.P.F. >20%

High Grade (Poorly Differentiated) Neuroendocrine Carcinoma

Virchows Archiv 2007, 451:757-762

Neuroendocrinology 2008, 87:1-64

WHO Grading of GEP-NETs:

Provisions

Count mitoses in 50 high power fields

Assess Ki67 based on counting 2000 (500) cells

Assess Ki67 in “hot spots”

If mitotic rate and Ki67 are discordant, assign higher

grade

What about G2 / G3 discordance??

(well differentiated tumor vs. poorly

differentiated carcinoma)

Ki67 = 45%

Mitotic rate = 8 / 10 HPF

Well Differentiated PanNET

Mitotic rate = 12 / 10 HPF

Ki67 = 55%

Poorly Differentiated Neuroendocrine Carcinoma

Chromogranin Ki67

Mitoses <1/10 HPF Mitoses 13/10 HPF

Progression of Low Grade to High Grade Neuroendocrine Tumor

Ki67 = 2%

G1

Ki67 = 45%

G3

Tang et al., Clin Cancer Res 2016; 22: 1011

Poorly Differentiated Neuroendocrine Carcinoma of Pancreas

Gene Small Cell Large Cell

NEC

W.D.

PanNET

Ductal ACa Small Cell

Lung CA

KRAS 25% 33% 0% >90% 0-10%

CDKN2A 11% 50% 0% 80-95% 0-10%

TP53 100% 90% 4% 75% 80%

SMAD4 0% 10% 0% 55% 0%

RB1 89% 50% 0% 13% 90%

DAXX/ATRX 0% 0% 43% 0%

MEN1 0% 0% 44% 0% 0%

mTOR genes 15% 1%

Genetics of Neuroendocrine Neoplasms

of the Pancreas

Yachida et al., Am J Surg Pathol 2012; 36: 173

Jiao et al., Science 2011; 331: 1199

Predictive and prognostic factors for treatment and

survival in 305 patients with advanced gastrointestinal

neuroendocrine carcinoma (WHO G3)

• Reviewed clinical data on advanced stage G3 NECs, 2000-2009

• Ki67 > 20%

• 252 patients received chemotherapy (platinum-based)

• Median survival = 11 mos.

• Response rate = 31%

• Stable disease rate = 33%

Ki67 < 55% predicted a lower response rate (15% vs 42%, p < 0.001)

Ki67 < 55% predicted a better survival (14 vs 10 months, P < 0.001)

Sorbye et al., Ann Oncol 2013; 24: 152-60

Conclusion:

G3 NETs with Ki67 20-55%

may be well differentiated

biologically!!

(“Well Differentiated PanNET with

an Elevated Proliferative Rate”)

Basturk et al., Am J SurgPathol 2015; 39: 683-690

Survival of High Grade Neuroendocrine

Neoplasms of the Pancreas

Are all G3 Neuroendocrine

Neoplasms the Same?

NO!

Small cell carcinoma vs. Large cell NE carcinoma

Large cell NE carcinoma vs. G3 well differentiated NET

NEC G3 vs. NET G3

Well differentiated NE tumor*

Grade Mitoses Ki-67 Index

G1 <2 / 10 HPF <2%

G2 2-20 / 10 HPF 3-20%

G3** >20 / 10 HPF >20%

*Organoid architecture, “well

differentiated” cytology, absence of non-

neuroendocrine carcinoma components,

may have components of G1 or G2,

usually strong immunoexpression of

general NE markers

**mitoses usually <20/HPF; Ki 67 >20%

but usually <50%

Poorly differentiated NE carcinoma*

Grade Mitoses Ki-67 Index

G3** >20 / 10 HPF >20%

*Small cell carcinoma and large cell NE

carcinoma; less organoid architecture,

classic cytology of small cell and large cell

NE CA, absence of G1 or G2 NE

components, may have non-

neuroendocrine carcinoma components,

less diffuse immunoexpression of general

NE markers

**mitoses >20/10 HPF; Ki67 >20% and

usually >50%

Grading of Pancreatic Neuroendocrine Neoplasms: Proposal

Classification of Pancreatic

Neuroendocrine Neoplasms (WHO 2017)

Determining the Ki67 Labeling Index of NETs

Courtesy of Dr. Laura H. Tang

Ki67 Cutpoints

Grade Ki67 2010 Ki67 2017

G1 <2% <3%

G2 3-20% 3-20%

G3 >20% >20%

What about the G1/G2 cut-point??

Several studies have suggested 5% stratifies outcome better than 3%

HOWEVER:

Statistical basis for defining cut-point is complex

Not all studies support the same cut-point

Currently no significant treatment change for G1 vs. G2

Changes in grading parameters confound historical data interpretation

THERFORE:

Keep G1/G2 cut-point the same

Recommend reporting actual Ki67 index

0 10 20 30 40 50 60 70 80 90 100

Ki67%

WDNET

PDNEC

G3

G3 G2 G1

How to distinguish G3 NEC (esp. large

cell NE carcinoma) from G3 NET?

G3 NET Large Cell NEC

Pancreatic G3 NE Neoplasms

How to distinguish G3 NEC (esp. large

cell NE carcinoma) from G3 NET?

• Clinical clues

• History of well differentiated NET?

• Octreotide scan positive?

• FDG-PET positive?

• Morphologic clues

• Lower grade component?

• Non-neuroendocrine component?

• Mitotic rate?

• Molecular clues

• Status of TP53, RB1, DAXX, ATRX, MEN1

Well Differentiated PanNETs (G1-3)

Exhibit a Different Molecular Phenotype from

Poorly Differentiated NECs (G3)

TP53 Rb DAXX /

ATRX MEN1

WD-

PanNET

4% 0 43% 44%

PD-

PanNEC

56% 72% 0 0

Yachida et al., Am J Surg Pathol 2012; 36: 173

Jiao et al. Science 2011; 331: 1199

DAXX

Rb p53

Tang et al., Am J Surg Pathol 2016; 40: 1192

WD-NET PD-NEC PD-NEC

p53 Rb

Initial Consensus

Immunohistochemical

Abnormalities

Other Histologic

Components Confirmed Classification

WD-NET G1/G2 WD-NET WD-NET

WD-NET DAXX G1/G2 WD-NET WD-NET

WD-NET ATRX G1/G2 WD-NET WD-NET

WD-NET G1/G2 WD-NET WD-NET

WD-NET DAXX G1/G2 WD-NET WD-NET

WD-NET G1/G2 WD-NET WD-NET

Ambiguous G1/G2 WD-NET WD-NET

Ambiguous G1/G2 WD-NET WD-NET

Ambiguous DAXX G1/G2 WD-NET WD-NET

Ambiguous ATRX G1/G2 WD-NET WD-NET

Ambiguous DAXX G1/G2 WD-NET WD-NET

Ambiguous G1/G2 WD-NET WD-NET

Ambiguous ATRX WD-NET

Ambiguous DAXX G1/G2 WD-NET WD-NET

Ambiguous DAXX G1/G2 WD-NET WD-NET

Ambiguous G1/G2 WD-NET WD-NET

Ambiguous G1/G2 WD-NET WD-NET

Ambiguous G1/G2 WD-NET WD-NET

Ambiguous G1/G2 WD-NET WD-NET

Ambiguous p53/Rb PD-NEC

Ambiguous p53/SMAD4 Ductal adenocarcinoma PD-NEC

Ambiguous p53/Rb PD-NEC

Ambiguous p53/Rb PD-NEC

Ambiguous p53 PD-NEC

Ambiguous Undetermined

PD-NEC-LCC DAXX G1/G2 WD-NET WD-NET

PD-NEC-LCC Rb PD-NEC

PD-NEC-LCC Ductal adenocarcinoma PD-NEC

PD-NEC-SCC p53 Ductal adenocarcinoma PD-NEC

PD-NEC-SCC Rb PD-NEC

PD-NEC-SCC p53/Rb Ductal adenocarcinoma PD-NEC

PD-NEC Rb PD-NEC

PD-NEC p53 PD-NEC

Classification of 33 High Grade Pancreatic Neuroendocrine Neoplasms by Secondary Evidence

Tang et al., Am J Surg Pathol 2016; 40: 1192

18/19 (95%)

morphologically

ambiguous high grade

pancreatic

NEneoplasms

successfully classified

19/33 (58%) of

high grade (G3)

pancreatic NE

neoplasms were

morphologically

ambiguous

0 50 100 1500

25

50

75

100

Months

Pe

rc

en

t s

urv

iva

l

WD-NET

PD-NEC

p<0.0001

Disease Specific Survival of High Grade Pancreatic Neuroendocrine Neoplasms

(N=20)

(N=12)

Tang et al., Am J Surg Pathol 2016; 40: 1192

Somatostatin Receptor (SSTR2)

Immunohistochemistry

Pancreatic Neoplasms with Mixed

Differentiation

Neuroendocrine (usually poorly differentiated) plus a non-

neuroendocrine component

Mixed ductal neuroendocrine carcinoma

Mixed acinar neuroendocrine carcinoma

Each component >30%

Previous terms

Mixed exocrine-endocrine carcinoma, MEEC (2004)

Mixed adenoneuroendocrine carcinoma, MANEC (2010)

Mixed neuroendocrine non-neuroendocrine neoplasm, MiNEN

Comparison of WHO Classifications of

Pancreatic Neuroendocrine

Neoplasms, 1980-2017