The Classification of Pancreatic Neuroendocrine Neoplasms: WHO 2017 - - PowerPoint PPT Presentation

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

• f 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% 43% 44% PD- PanNEC 56% 72%

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

50 100 150 25 50 75 100

Months Percent survival 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