pancreatic cancer: the abcs of the ajcc and who...tubuloacinar or pseudorosette arrangements •...

04/09/2018

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Pancreatic Cancer: The ABCs of the AJCC and

WHO Aatur D. Singhi, MD PhD

Assistant Professor University of Pittsburgh Medical Center

Department of Pathology [email protected]

Objectives

• Case presentation

• Discuss pancreatic cancer and clinical relevant subtypes

• Review AJCC 8th edition staging of exocrine and endocrine pancreatic neoplasms

• 2017 WHO classification of pancreatic neuroendocrine neoplasms

Case Presentation

• 78-year-old female presenting with a 1 day history of jaundice and cola-colored urine.

• The patient had elevated serum liver transaminases and elevated serum pancreatic enzymes.

• These findings prompted an abdominal computed tomography (CT) scan.

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Liver

Kidneys

Head of the Pancreas

Liver

Kidneys


Area of Necrosis

Liver

Kidneys


Pancreatic Mass (5.6 cm)

Bile Duct

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Synaptophysin

Chromogranin A

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Adenocarcinoma

• Definition- invasive gland-forming epithelial neoplasm

• Clinical presentation- diagnosis late in the course • Pathology- varies • Precursor lesions- pancreatic intraepithelial

neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN)

• Evolution’s role- in both familial and sporadic • Surgery- only hope for cure (~15% are resectable) • Outcome- universally poor

Common Bile Duct

Duodenum

Pancreatic Duct

Duodenum

Pancreatic Duct

Common Bile Duct

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Pancreatic Duct

Pancreatic Duct

Pancreatic intraepithelial neoplasia (PanINs): Most pancreatic cancers evolve through PanINs:

(From Wilentz RE, lacobuzio-Donahue CA, et al: Loss of expression of DPC4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in

neoplastic progression. Cancer Res 2000; 60:2002)

Low-grade PanIN High-grade PanIN

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Low-Grade Low-Grade

High-Grade Low-Grade

Pancreatic intraepithelial neoplasia (PanINs): Most pancreatic cancers evolve through PanINs:

Haphazard

growth

Well-differentiated

Moderately-differentiated Poorly-differentiated

Histologic Grades of

Adenocarcinoma

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Variants of Pancreatic Ductal

Adenocarcinoma

Adenosquamous Carcinoma

• A malignant epithelial neoplasm of the pancreas

with significant components of both glandular

and squamous differentiation

• The squamous component should comprise at

least 30% of the neoplasm

• Account for 3-4% of the malignancies of the

exocrine pancreas

• Partial response to cisplatinum based

chemotherapeutic regimens

Squamous

Differentiation

Glandular

Differentiation

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Colloid Carcinoma

• An infiltrating adenocarcinoma characterized by

mucin producing neoplastic epithelial cells

suspended (“floating”) in large pools of extracellular

mucin

• The colloid component should comprise at least

80% of the neoplasm

• 1-3% of the malignancies of the exocrine pancreas

• Grossly soft gelatinous

• Almost always associated with an IPMN

• 5-year survival rates as high as 57%

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Perineural

Invasion

Colloid Carcinoma

• An infiltrating adenocarcinoma characterized by

mucin producing neoplastic epithelial cells

suspended (“floating”) in large pools of extracellular

mucin

• The colloid component should comprise at least

80% of the neoplasm

• 1-3% of the malignancies of the exocrine pancreas

• Grossly soft gelatinous

• Almost always associated with an IPMN

• 5-year survival rates as high as 57%

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Hepatoid Carcinoma

• A malignant epithelial neoplasm in which a significant component shows hepatocellular differentiation

• Only a handful have been reported

• Large polygonal cells with abundant eosinophilic cytoplasm

• The cells form trabecula and may have a sinusoidal vascularity

• Immunolabeling is similar if not the same as hepatocellular neoplasms

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Adapted from https://www.cancer.gov/types/pancreatic

T3: Tumor extends beyond the pancreas


T3: Tumor extends beyond the pancreas

Medullary Carcinoma

• A malignant epithelial neoplasm characterized

by poor differentiation, pushing borders, a

syncytial growth pattern and necrosis

• May have prominent intratumoral lymphocytes

• Many, but not all, carcinomas with medullary

histology have microsatellite instability

• Family history of cancer (Lynch syndrome)

• Trend towards longer survival and response to

immune checkpoint inhibitors

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Medullary Carcinoma

• A malignant epithelial neoplasm characterized

by poor differentiation, pushing borders, a

syncytial growth pattern and necrosis

• May have prominent intratumoral lymphocytes

• Many, but not all, carcinomas with medullary

histology have microsatellite instability

• Family history of cancer (Lynch syndrome)

• Trend towards longer survival and response to

immune checkpoint inhibitors

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Undifferentiated Carcinoma

• A malignant epithelial neoplasm with a

significant component showing no glandular

structures or other features to indicate a definite

direction of differentiation

• Range from pleomorphic epithelioid

mononuclear cells containing abundant

eosinophilic cytoplasm admixed with bizarre

frequently multinucleated tumor giant cells, to

relatively monomorphic spindle cells

• Mean survival of 5 months after diagnosis

Anaplastic giant

cell carcinoma

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Sarcomatoid

carcinoma

Undifferentiated Carcinoma

• A malignant epithelial neoplasm with a

significant component showing no glandular

structures or other features to indicate a definite

direction of differentiation

• Range from pleomorphic epithelioid

mononuclear cells containing abundant

eosinophilic cytoplasm admixed with bizarre

frequently multinucleated tumor giant cells, to

relatively monomorphic spindle cells

• Mean survival of 5 months after diagnosis

Undifferentiated Carcinoma with Osteoclast-like Giant Cells

• Malignant epithelial neoplasm composed of

large benign appearing multinucleated giant

cells admixed with atypical neoplastic

mononuclear cells

• The atypical mononuclear cells variably express

markers of epithelial differentiation

• The osteoclast-like giant cells express markers

of histiocytic/macrophage differentiation (benign)

• Highly aggressive neoplasms with a mean

survival of only 12 months

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Macrophage

marker (CD68)

Undifferentiated Carcinoma with Osteoclast-like Giant Cells

• Malignant epithelial neoplasm composed of

large benign appearing multinucleated giant

cells admixed with atypical neoplastic

mononuclear cells

• The atypical mononuclear cells variably express

markers of epithelial differentiation

• The osteoclast-like giant cells express markers

of histiocytic/macrophage differentiation (benign)

• Highly aggressive neoplasms with a mean

survival of only 12 months

How is Pancreatic Cancer Staged?

• AJCC (7th Edition):

– T-staging is prognostically significant

– Problematic areas for pathology include identifying extension beyond the pancreas

– >70% of resected pancreatic cancers are T3

Allen PJ et al. Annals of Surgery 2016.

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AJCC 8th Edition Staging

• Size rather than tumor extension

• Primary tumor (pT) – pTX Primary tumor cannot be assessed

– pT0 No evidence of a primary tumor

– pTis High-grade dysplasia (carcinoma in situ)

– pT1 Tumor size ≤ 2 cm

– pT2 Tumor size > 2 cm and ≤ 4 cm

– pT3 Tumor size > 4 cm

– pT4 Tumor involves the celiac axis, superior mesenteric artery and/or common hepatic artery

Tis: High-grade dysplasia (carcinoma in situ)


pT1: Tumor ≤ 2 cm in size

pT1a: ≤ 0.5 cm pT1b: > 0.5 cm and < 1 cm pT1c: 1 – 2 cm

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• Size rather than tumor extension

• Primary tumor (pT)

– pT1 Tumor size ≤ 2 cm

– pT1a Tumor size ≤ 0.5 cm

– pT1b Tumor size > 0.5 cm and < 1.0 cm

– pT1c Tumor size 1.0 to 2.0 cm

• pT1a through pT1c is primarily for pancreatic adenocarcinomas arising from IPMNs



pT2: Tumor > 2 cm but < 4 cm in size


pT3: Tumor ≥ 4 cm in size

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Tumor extends beyond the pancreas (doesn’t matter – still based on tumor size)

Tumor extends beyond the pancreas (into the spleen) is staged based on size


pT4: Tumor involves the celiac axis, superior mesenteric artery &/or common hepatic artery

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• Regional lymph nodes (pN)

– pNX Unable to assess regional lymph nodes

– pN0 No regional lymph node involvement

– pN1 Metastasis in 1 to 3 regional lymph nodes

– pN2 Metastasis in 4 or more regional lymph

nodes


Regional lymph nodes

• Regional lymph nodes (N) – Superior to the pancreatic head/uncinate and

body/tail – Inferior to the pancreatic head/uncinate and

body/tail – Anterior pancreaticoduodenal and proximal

mesenteric – Posterior pancreaticoduodenal and proximal

mesenteric – Pancreatic head/uncinate: stomach pylorus

(infrapyloric and subpyloric), hepatic artery, common bile duct and celiac

– Pancreatic body/tail: tail of pancreas, splenic hilum and pancreaticolienal



N1 and N2: Regional lymph node involvement

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• Distant Metastases (pM)

– pM0 No distant metastasis

– pM1 Distant metastasis

**Note: M1 disease is typically a contraindication for surgical resection, so frequently a pathologic M0.




• T- and N-staging are prognostically significant Allen PJ et al. Annals of Surgery 2016.

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Variants

• Adenosquamous carcinoma

• Colloid carcinoma

• Hepatoid carcinoma

• Medullary carcinoma

• Undifferentiated carcinoma

• Undifferentiated carcinoma with

osteoclast-like giant cells

Liver

Kidneys



Bile Duct

Pancreatic Head Mass:

Sarcoma???

No Glandular Differentiation Identified

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Common Bile Duct

Pancreatic Duct

Ampulla

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Spindled Neoplastic Cells

Residual Pancreatic

Parenchyma

Neuroendocrine tumors/carcinomas

All malignant neoplasms

600

500

400

300

200

100

5.00

4.00

3.00

2.00

1.00

19

73

19

74

19

75

19

76

19

77

19

78

19

79

1

98

0

19

81

19

82

19

83

19

84

19

85

19

86

19

87

19

88

19

89

19

90

19

91

19

92

19

93

19

94

19

95

19

96

19

97

19

98

19

99

20

00

20

01

20

02

20

03

20

04

6.00

Inci

den

ce p

er 1

00,0

00 (

NET

/NEC

)

Inci

den

ce p

er 1

00,0

00

Yao, JC et al. J Clin Oncol. 2008; 26:3063-72.

Desari, A et al. JAMA Oncol. 2017; 3: 1335-1342.

Neuroendocrine Neoplasms

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Rectum

Jejunum/Ileum

Stomach

Colon

DuodenumCecumAppendix

Pancreas

Other

Lung

Neuroendocrine Neoplasms

Gross

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Spleen

Gross

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• Lung (Differentiation):

• Carcinoid and Atypical carcinoid

• Neuroendocrine carcinoma

• Small cell carcinoma

• Large cell carcinoma

• Gastroenteropancreatic (Differentiation):

• Well-differentiated neuroendocrine

tumor (NET)

• Poorly-differentiated neuroendocrine

carcinoma (NEC)

• Small cell carcinoma

• Large cell carcinoma

Differentiation

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Microscopic criteria:

• Various “organoid” histologic patterns:

nesting, trabecular, glandular, gyriform,

tubuloacinar or pseudorosette

arrangements

• Uniform, finely granular, amphophilic-

to-eosinophilic cytoplasm

• Coarsely clumped nuclear chromatin

(“salt and pepper”)

• Resemblance to islets of Langerhans

Carcinoid / Well-Differentiated

Neuroendocrine Tumors

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Microscopic subtypes:

Small cell carcinoma

• Small cells with scant cytoplasm

• Fine chromatin

• Nuclear molding

• Diffuse growth pattern

Large cell carcinoma

• Prominent nesting pattern

• Moderate amphophilic cytoplasm

• Large nuclei with clumped chromatin

• May have prominent nucleoli

Poorly-Differentiated

Neuroendocrine Carcinomas

Small Cell Carcinoma



Large Cell Carcinoma

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Histologic Grade:

• Lung (< 11 mitoses per hpf):

Carcinoid: < 2 mitoses per 10 hpf

Atypical carcinoid

• 2-10 mitoses per 10 hpf

• Tumor necrosis

• Gastroenteropancreatic (mitoses & Ki-67):

Low-grade (G1)

Intermediate-grade (G2)

High-grade (G3)

Carcinoid / Well-Differentiated

Neuroendocrine Tumors

Ki-67 Proliferation Index

Ki-67 and Mitotic Index

Ki-67 Index Differentiation Grade Mitotic Count

Well-differentiated or Poorly-differentiated

High-grade (G3) > 20% > 20 / 10 HPF

Well-differentiated Intermediate-grade (G2)

3 – 20% 2 – 20 / 10 HPF

Well-differentiated Low-grade (G1) < 3% < 2 / 10 HPF

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H&E Ki-67



Well-differentiated Intermediate-grade

(G2) 3 – 20% 2 – 20 / 10 HPF

H&E Ki-67




High-grade (G3) > 20% > 20 / 10 HPF

H&E Ki-67


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0 50 100 150 200 250

Survival Time (mo)

0.0

0.2

0.4

0.6

0.8

1.0

Cu

mu

lati

ve

Su

rviv

al

G1

G2

G3

G1 vs G2

G1 vs G3

G2 vs G3

P=0.040

P<0.001

P<0.001

N=193

1. Rindi G, Klöppel G, Alhman H, et al. Virchows Arch. 2006;449:395-401. 2. Rindi G, Klöppel G, Couvelard A, et al. Virchows Arch. 2007;451:757-762. 3. Pape UF, Jann H, Müller-Nordhorn J, et al. Cancer.

2008;113:256-265.




High-grade (G3) > 20% > 20 / 10 HPF


3 – 20% 2 – 20 / 10 HPF


• If Ki-67 and mitotic counts are discordant, it is recommended to assign a higher grade


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Tang, LH et al. AJSP. 2012. 36:1761-1770.

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High-grade (G3) > 20% > 20 / 10 HPF


3 – 20% 2 – 20 / 10 HPF


• If Ki-67 and mitotic counts are discordant, it is recommended to assign a higher grade


Well-differentiated Poorly-differentiated

0 50 100 150 200 250

0.0

0.2

0.4

0.6

0.8

1.0

Cu

mu

lati

ve

Su

rviv

al

G1

G2

G3

G1 vs G2

G1 vs G3

G2 vs G3

P=0.040

P<0.001

P<0.001

N=193

1. Basturk O, Yang Z, Tang LH, et al. AJSP. 2015; 39:683-90. 2. Tang LH, Untch BR, Reidy DL, et al. Clin Cancer Res. 2016; 22: 1011-1017.

G3: NETs vs. NECs

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G3: NETs vs. NECs Well-differentiated Neuroendocrine Tumors

• Surgical resection with curative is the

most effective treatment

• Medical therapy:

Somatostatin analogues (imaging)

mTOR inhibitors

Alkylating agents

Peptide receptor radionucleotide

therapy

Poorly-differentiated Neuroendocrine

Carcinomas

• Platinum-based chemotherapy

G3: NETs vs. NECs

G3: NETs vs. NECs

Well-differentiated Neuroendocrine

Tumor (G3)

or

Poorly-differentiated

Neuroendocrine Carcinoma (G3)

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Pancreatic: NETs vs. NECs


Tumor (G3)

or




PanNETs

Genes Mutation

Frequency

MEN1 44%

DAXX/ATRX 43%

PIK3CA, PTEN,

TSC1, & TSC2 15%

TP53 3%

RB1 0%

CDKN2A 0%

KRAS 0%

TGFBR1, TGFBR2,

SMAD4 0%


PanNETs

Genes Mutation

Frequency

MEN1 44%

DAXX/ATRX 43%

PIK3CA, PTEN,

TSC1, & TSC2 15%

TP53 3%

RB1 0%

CDKN2A 0%

KRAS 0%

TGFBR1, TGFBR2,

SMAD4 0%

PanNECs

Genes Mutation

Frequency

MEN1 0%

DAXX/ATRX 0%

PIK3CA, PTEN,

TSC1, & TSC2 0%

TP53 95%

RB1 74%

CDKN2A 32%

KRAS 29%

TGFBR1, TGFBR2,

SMAD4 10%

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ATRX


ATRX

Pancreatic NET

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ATRX RB

Pancreatic NET


ATRX RB

Pancreatic NET Pancreatic NEC

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Other Sites: NETs vs. NECs


Tumor (G3)

or



How is a

Gastroenteropancreatic

Neuroendocrine Carcinoma

(NEC) Staged?

Primary tumor (pT)

Regional lymph nodes (pN)

Distant metastases (pM)

How is a


Neuroendocrine Carcinoma

(NEC) Staged?

Primary tumor (pT)



Staged as other malignancies arising from

that site (e.g. pancreatic adenocarcinoma)

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How is a


Neuroendocrine Tumor (NET)

Staged?

Primary tumor (pT)



Different from other malignant neoplasms

at the same organ site

How is a Pancreatic NET

T-Staged? Primary tumor (pT)

– pTX Tumor cannot be assessed

– pT1 Tumor limited to the pancreas, < 2 cm

– pT2 Tumor limited to the pancreas, 2 to 4 cm

– pT3 Tumor limited to the pancreas, > 4 cm, or invading the duodenum or common bile duct

– pT4 Tumor invades adjacent organs (stomach, spleen, spleen, adrenal gland) or wall of large vessels (the celiac axis or superior mesenteric artery)


pT1

pT1: Tumor limited to the pancreas,

< 2 cm

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pT2

pT2: Tumor limited to the pancreas,

2 to 4 cm


pT3

pT3: Tumor > 4 cm or extending into the

duodenum or common bile duct


pT4

pT4: Tumor invades adjacent organs

(e.g. spleen), celiac axis or SMA

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pT4

pT4: Tumor invades adjacent organs

(e.g. spleen), celiac axis or SMA

How is a Pancreatic NET

N- and M-Staged?


– pNX Unable to assess regional lymph nodes

– pN0 No regional lymph node involvement

– pN1 Regional lymph node involvement


– pM1 Distant metastases

– pM1a Metastasis confined to liver

– pM1b Metastasis to at least extrahepatic site

(e.g. lung, ovary, bone, etc.)

– pM1c Both hepatic and extrahepatic metastases

pancreatic cancer: the abcs of the ajcc and who...tubuloacinar or pseudorosette arrangements •...

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