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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 singhiad@upmc.edu
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
Head of the Pancreas
Area of Necrosis
Liver
Kidneys
Head of the Pancreas
Pancreatic Mass (5.6 cm)
Bile Duct
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Pancreatic Mass (5.6 cm)
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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
Adapted from https://www.cancer.gov/types/pancreatic
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)
Adapted from https://www.cancer.gov/types/pancreatic
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
AJCC 8th Edition Staging
Adapted from https://www.cancer.gov/types/pancreatic
pT2: Tumor > 2 cm but < 4 cm in size
Adapted from https://www.cancer.gov/types/pancreatic
pT3: Tumor ≥ 4 cm in size
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Adapted from https://www.cancer.gov/types/pancreatic
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
Adapted from https://www.cancer.gov/types/pancreatic
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
AJCC 8th Edition Staging
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
AJCC 8th Edition Staging
Adapted from https://www.cancer.gov/types/pancreatic
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.
AJCC 8th Edition Staging
Adapted from https://www.cancer.gov/types/pancreatic
AJCC 8th Edition Staging
• 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
Head of the Pancreas
Pancreatic Mass (5.6 cm)
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
Small Cell Carcinoma
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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Ki-67 Index Differentiation Grade Mitotic Count
Well-differentiated Low-grade (G1) < 3% < 2 / 10 HPF
H&E Ki-67
Ki-67 and Mitotic Index
Ki-67 Index Differentiation Grade Mitotic Count
Well-differentiated Intermediate-grade
(G2) 3 – 20% 2 – 20 / 10 HPF
H&E Ki-67
Ki-67 and Mitotic Index
Ki-67 Index Differentiation Grade Mitotic Count
Well-differentiated or Poorly-differentiated
High-grade (G3) > 20% > 20 / 10 HPF
H&E Ki-67
Ki-67 and Mitotic Index
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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.
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
• If Ki-67 and mitotic counts are discordant, it is recommended to assign a higher grade
Ki-67 and Mitotic Index
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Tang, LH et al. AJSP. 2012. 36:1761-1770.
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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
• If Ki-67 and mitotic counts are discordant, it is recommended to assign a higher grade
Ki-67 and Mitotic Index
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
Well-differentiated Neuroendocrine
Tumor (G3)
or
Poorly-differentiated
Neuroendocrine Carcinoma (G3)
Pancreatic: NETs vs. NECs
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%
Pancreatic: NETs vs. NECs
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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Pancreatic: NETs vs. NECs
Pancreatic: NETs vs. NECs
ATRX
Pancreatic: NETs vs. NECs
ATRX
Pancreatic NET
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Pancreatic: NETs vs. NECs
ATRX RB
Pancreatic NET
Pancreatic: NETs vs. NECs
ATRX RB
Pancreatic NET Pancreatic NEC
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Other Sites: NETs vs. NECs
Well-differentiated Neuroendocrine
Tumor (G3)
or
Poorly-differentiated
Neuroendocrine Carcinoma (G3)
How is a
Gastroenteropancreatic
Neuroendocrine Carcinoma
(NEC) Staged?
Primary tumor (pT)
Regional lymph nodes (pN)
Distant metastases (pM)
How is a
Gastroenteropancreatic
Neuroendocrine Carcinoma
(NEC) Staged?
Primary tumor (pT)
Regional lymph nodes (pN)
Distant metastases (pM)
Staged as other malignancies arising from
that site (e.g. pancreatic adenocarcinoma)
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How is a
Gastroenteropancreatic
Neuroendocrine Tumor (NET)
Staged?
Primary tumor (pT)
Regional lymph nodes (pN)
Distant metastases (pM)
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)
Adapted from https://www.cancer.gov/types/pancreatic
pT1
pT1: Tumor limited to the pancreas,
< 2 cm
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Adapted from https://www.cancer.gov/types/pancreatic
pT2
pT2: Tumor limited to the pancreas,
2 to 4 cm
Adapted from https://www.cancer.gov/types/pancreatic
pT3
pT3: Tumor > 4 cm or extending into the
duodenum or common bile duct
Adapted from https://www.cancer.gov/types/pancreatic
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?
Regional lymph nodes (pN)
– pNX Unable to assess regional lymph nodes
– pN0 No regional lymph node involvement
– pN1 Regional lymph node involvement
Distant metastases (pM)
– 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
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