Ductal Adenocarcinoma

Epidemiology:

• 60-80y (80%)
• black > white
• risk factors:
• smoking doubles the risk
• DM
• Chronic pancreatitis
• Up to 10% have a family history
• Mostly unknown genetic contributors
• FAMMM (familial atypical multiple mole melanoma) syndrome
• CDKN2A (9p) mutation
• p16-Leiden deletion of 19 bp has particular high risk of pancreatic CA (15% lifetime)
• Melanoma
• Pancreatic carcinoma
• Fanconi anemia genes:
• BRCA2 (13q)
• Ashkenazi Jew
• FANCC
• FANCG
• FANCN (PALB2)
• BRCA1
• Peutz-Jegher (highly increased risk):
• STK11 mutation
• Hereditary pancreatitis:
• PRSS1 (cationic trypsinogne gene)
• SPINK1 (serine peptidase inhibitor)
• Lynch syndrome
• DNA mismatch repair genes (ex. MSH2 and MLH1)
• ABO blood group
• O is lower risk than A or B

Common sites:

• Head of pancreas (60%)
• Body of pancreas (15%)
• Tail of pancreas (5%)
• Diffuse pancreas involvement (20%)

Gross features:

• Hard
• Stellate
• Gray-white
• Poorly-defined
• Obstruction of distal CBD (lesions of the head of the pancreas)
• Marked distention of the biliary tree
• Cancers of the body and tail are generally larger (not detected early)
• Extension through retroperitoneal space
• Lymph nodes:
• Peripancreatic, gastric, mesenteric, omental, portahepatic

Histologic features:

• Ductal adenocarcinoma:
• Mucin-secreting glands (vast majority)
• Abortive tubular structures or cell clusters
• Highly invasive with extensive peripancreatic tissue invasion
• Features to differentiate well-differentiated CA vs. reactive glands:
• Perineural invasion of surrounding tissues often
• Vascular invasion
• Gland immediately adjacent to a muscular vessel without intervening acini
• Haphazard arrangement of glands (rather than lobular)
• Incomplete glands
• Intense desmoplastic response
• 4-fold variation in nuclear size
• Irregular, jagged-edged glands
• Cuboidal to columnar epithelial cells
• Anaplastic
• Mucinous noncystic carcinoma:
• Adenosquamous carcinoma:
• Focal squamous differentiation
• Signet-ring cell carcinoma:
• Grade 3
• Undifferentiated (anaplastic) carcinoma:
• Grade 4
• Undifferentiated carcinoma with osteoclast-like giant cells
• Mixed ductal-endocrine carcinoma:
• Grading (same as rest of GI tract):
• Grade 1 – well-differentiated – > 95% glands
• Grade 2 – moderately-differentiated – 50-95% glands
• Grade 3 – poorly-differentiated – < 50% glands

Immunophenotype:

Marker:	Sensitivity:	Specificity:
SMAD4 (neg) (?poor prognosis)	55%	High specificity for cancer
DPC4	-/+
CK17	+/-
pVHL (neg)		Sensitive and specific for RCC (and clear cell CA ovary / uterus)
Maspin	+
S100P Placental S100	+	Also positive in urothelial carcinoma
IMP3	+
MUC5AC	+	Also may be positive in other upper GI ADC

Molecular features:

• chromosome instability
• losses:
• 18q (SMAD4) (90%)
• Homozygous (35%)
• Mutation in other allele (20%)
• 17p (90%)
• Mutation in the other allele (75%)
• 1p (60%)
• 9p (CDKN2A) (85%)
• Homozygous deletion (40%)
• Loss of one allele and mutation in the other (40%)
• Promoter methylation (15%)
• BRCA2 (7%) (13q)
• One allele is germline mutation in almost all of these cases
• STK11 (LKB1) (19p) (5%)
• LOH and intragenic mutation
• Homozygous deletion
• TGFBR1 (ALK5) (9q) (4%)
• Homozygous deletion
• TGFBR2 (3p) (4%)
• Homozygous deletion
• Amplification:
• MYB (6q)
• AKT2 (19q)
• NCOA3 (AIB1) (20q)
• Mutations:
• 60 mutations per cancer by whole exon sequencing
• Most thought to be passenger with no direct role in the cancer
• KRAS (12p) (>90%)
• CDKN2A (p16 tumour suppressor gene) (95%)
• SMAD4 tumour suppressor gene (55%) (?poor prognosis)
• TP53 (50-70%)
• MKK4
• STK11
• TGFBR I and II
• FANC pathway genes (?increased sensitivity to treatment by DNA-crosslinking agents or poly (ADP-ribose) polymerase (PARP) inhibitors)
• FANCC
• FANCG
• FANCN
• KRAS2
• promoter methylation:
• CDKN2A (15%)
• microsatellite instability (4%)
• medullary histology
• expression:
• ERBB2 overexpression (70%)

Other features:

• high mortality rate – 5-year survival < 5%
• precursor lesions are pancreatic intraepithelial neoplasias (PanINs)
• migratory thrombophlebitis (Trousseau sign) (10%)

References:

• Robbins 2005
• WHO Classification (2010)
• Lin F, Liu H. Immunohistochemistry in Undifferentiated Neoplasm / Tumor of Uncertain Origin. Arch Pathol Lab Med. 2014;138:1583–1610.