INFLAMMATORY CONDITIONS AND NEOPLASMS OF THE GALLLADDER
N. Volkan Adsay, MD
Professor and Vice-Chair
Director of Anatomic Pathology
Emory University
Atlanta, GA
Overview
• Normal gallbladder and incidental findings pertinent to daily practice
• Inflammatory conditions and benign lesions
• Neoplasms of gallbladder and EHBD
NORMAL GALLBLADDER AND INCIDENTAL FINDINGS
Layering of the GB is very different than that of the GI tract: Staging problems
Stomach
GB
Sm.
Intestine
Reactive cystic duct
Dysplasia
Luschka’s ducts
Luschka’s ducts
A‐R sinuses
A‐R sinuses or Carcinoma ?
BENIGN- ARs
CARCINOMA
BENIGN- ARs
BENIGN- ARs
CARCINOMA
Adenomyomatous nodules
Metaplasia and Hyperplasia
“Primary hyperplasia”?
“Spongiform hyperplasia”
Pyloric metaplasia: 60% of GBs
Polypoid PG metaplasia (not PG adenoma)
Polypoid PG metaplasia (not PG adenoma)
If forms nodules > 3 mm, additional sampling of
especially the container contents
“Pyloric gland adenoma”: Tm > 1 cm
NON‐NEOPLASTIC
GB POLYPS
Non‐neoplastic polyps
•Seen in 3 % of cholecystectomies. •Most are incidental microscopic lesions with a mean size of 0.4 cm; ONLY 6.5% are clinically significant (>1cm)
•When all clinically significant (>1 cm) polyps are considered, NNPs constitute only 5% of the group.
•A lot of things form lumps and bumps in the GB.
•The vast majority of the true polyps are:
1)Cholesterol polyps; 2) Fibromyoglandular
polyps
Granulation tissue polyp
Lymphoid polyp
Cholesterol
polyp
Cholesterol
polyp
Cholesterol
polyp
~60%, NO
cholesterolosis in the
background GB
Dysplasia
can be
seen in
Cholstrl
Polyps >
1cm
Fibromyoglandular
polyp *
* The term we use for such lesions
Most FMGPs are small
(< 0.5 cm)
Inflammatory Conditions
Acute cholecystitis
Acute cholecystitis
Reperative atypia Reperative atypia vs CIS
Chronic cholecystitis
FEA/LGD
• 2‐4 more sections
SP report: Difficulties
• Accept the fact that gallstones without cholecystitis may be responsible for symptoms
• No significant histopathologic alteration (no gallstones)
• “Minimal” chronic cholecystitis ?
• Chronic “active” cholecystitis
• Lack of definition for specific types like “eosinophilic” and “follicular”
 One pattern, however, warrants special attention…
Hyalinizing cholecystitis
MEDICOMYTHOLOGY:
“PORCELAIN GALLBLADDER”
Porcelain GB
Textbooks / Medical Schools (since 1880’s; including chapters written by Y.T.):
• Porcelain = Extensively calcified • Diffuse mural calcifications
• Very high incidence of carcinoma
– Cancer risk of up to 40 X
– 60% of PGBs develop carcinoma
Porcelain GB
• Recent studies : Totally different picture
– Porcelain GB is exceedingly uncommon
• 2001, Radiology literature: – 44 in 25K (Stephen et al)
– 15 in 10K (Towfigh et al)
– Carcinoma is very uncommon in PGB
• 2 cases and 0 cases in those studies
– If it occurs , it occurs in cases with “mucosal‐
punctate calcifications” rather than those with diffuse mural
Pathologic analysis:
• 4321 cholecystectomies analyzed systematically
• Targeted search of Wayne State, Emory and Univ of
Frontera (Temuco, Chile)
Results:
 10 diffusely calcific (complete PGB); NONE had ca
 106 cases of Hyalinizing Cholecystitis (proposed term)
 with minimal (65%) or no calcifications
 38 had invasive carcinoma;  Odds‐ratio 4.6
 < Half had calcifications
Conclusion:
• Hyalinizing cholecystitis with minimal or no calcifications (incomplete PGB) have a high risk of CA, but complete PGB
does not
Carcinoma arising in hyalinizing cholecystitis
If you see glands in hyalinizing cholecystitis, you should suspect
carcinoma because:
1.Epithelium is often denuded entirely
2.Aschoff-Rokitansky is very uncommon
If present, CIS in hyalinizing cholecystitis is denuding, clinging or
micropapillary types
Carcinoma arising in hyalinizing cholecystitis
NECROSIS
Signs of carcinoma in
hyalinizing cholecystitis
HYALINIZATION
Gallbladder Dysplasia
GB Dysplasia
• Incidence: Parallels high GB cancer‐risk geography
– 3% in Australia, >15% in Mexico and Chile
– Our database in the US, < 2%
• Clinical significance: Estimated >10,000 cases seen in surg path (~ 1 mil cholecystectomies in the US) http://digestive.niddk.nih.gov/statistics/statistics.aspx
• Association: Injury/inflammation
– Gallstones
– Long h/o sclerosing cholangitis (or other inflammatory conditions)
– Anomalous union of ducts
– Choledochal cyst
Dysplasia: Spectrum of complexity
Micropapillary/tufting patterns
Tall papillary
Denuding / clinging HGD
Denuding HGD in the
setting of hyalinizing
cholecystitis
(incomplete porcelain
gallbladder)
Cell lineages of GB dysplasia
Biliary
Cuboidal
(n=222; 70%)
Biliary
Pencillate
(n=43; 13%)
Intestinal
(n=20; 6%)
Gastric
(n=33; 10%)
Gastric type had a trend for higher incidence of invasion and worse prognosis
Reactive atypia vs HGD/CIS
Macro‐nuclei and macro‐nucleoli: HGD
Low vs High-grade?
HGD or CIS or Intramucosal Ca (Tis) OR invasive (T1a)
Diagnostic issue: Early invasion ?
Non-invasive(Tis) OR invasive (T1a)
Pseudoinvasive appearance of HGD/CIS
(Illustration: Virtual, by Photoshop pasting)
Approach to Focal epithelial atypia
•
If it is microfocal (in the background of abundant intact/uninvolved mucosa) , it is probably not HGD
– HGD is like wild‐fire
•
Submit 2‐4 additional cassettess*
(Renshaw et al AJCP, 2012; our letter to the editor)
Approach to GB dysplasia 2. If it is convincingly HGD, refer to “early gallbladder cancer” (EGBC) data
Early Gallbladder Cancer is a concept introduced in
high GBC incidence regions, especially Chile
87
SRI LANKA
TAILANDIA
IRLANDA
GRECIA
KOREA
ISLANDIA
INGLATERRA
MAURITIUS
ESCOCIA
ESTADOS UNIDOS
BULGARIA
IRLANDA NORTE
NORUEGA
PORTUGAL
NUEVA ZELANDIA
AUSTRALIA
KUWAIT
CANADA
ESPAÑA
MALTA
FRANCIA
ISRAEL
HONG-KONG
ITALIA
BELGICA
YUGOSLAVIA
DINAMARCA
LUXEMBURGO
SUIZA
HOLANDA
FINLANDIA
SUECIA
ALEMANIA
AUSTRIA
JAPON
CHECOLOVAKIA
ALEMANIA
HUNGRIA
CHILE
Gallbladder Cancer Mortality
Females
USA
Chile
0
100
200
300
400
Chile vs US: 9‐fold difference 500
600
SAMPLING PROTOCOL EMPLOYED BY J.C. ROA ET AL. (CHILE)
1. Every GB is photographed.
2. If a grossly visible lesion is identified as seen here, or if the initial full
thickness section shows any suspect lesions, the entire specimen is submitted
and mapped according to an established protocol
“Early Gallbladder Cancer”
Ti
s
T1b ?
T1a ?
Stage
1
0,9
Early
0,8
Probability
0,7
0,6
p= 5X 10-9
0,5
0,4
Advanced
0,3
0,2
Extra GB
0,1
0
0
50
100
150
200
Survival in months
Juan Carlos Roa et al., Temuco, Chile
250
Involvement of RAS
is associated with
adverse outcome in
EGBC (Roa et al)
“CIS” of GB
• SEER database of the U.S.
– 5‐yr: All alive
– 10‐yr: 30% dead of (“biliary”) cancer
• Chilean experience (Roa et al)
– 10‐yr: ~10% dead of presumed biliary cancer
– “Recurrence” mostly developed multiple years after cholecystectomy
Possible field effect / defect phenomenon
GB/Biliary tract carcinogenesis
• Inflammation/injury  Carcinoma association
–
–
–
–
–
Hyper‐IgM syndrome : GB ca in teenage years
Gallstones
Parasites
Primary sclerosing cholangitis
Anomalous union
• “Metaplastic” cell lineages (gastric, intestinal)
• Possible field defect / field effect phenomenon
NEOPLASTIC POLYPS and PAPILLARY NEOPLASIA
“Pyloric gland adenoma”
So called “pyloric gland adenoma”
Literature impression (including chapters by Y.T):
•Most common type.
• All benign.
So called “pyloric gland adenoma”
Literature impression:
•Most common type.
•Benign
•HOWEVER, in the largest 2 series
published, average size 0.6 and 0.7
cm.
So called “pyloric gland adenoma”
Invasive ca
High-grade dyspl/CIS
If > 1 cm, carcinomatous
change is common
Reappriasal of neoplastic polyps and papillary neoplasia of the gallbladder
Tumoral IN (papillary/polypoid intramucosal neoplasms) of Gallbladder
Previously, plethora of (> 8) names • Pyloric gland adenoma
• Biliary adenoma
• Intestinal adenoma
• Tubular adenoma
• Tubulopapillary adenoma
• Papillary adenoma
• Papillary neoplasm
• Papillary carcinoma
WHO‐2010
 “1 cm” criteria, not mentioned
 2 categories were recognized
1. Adenoma
• Pyloric gland, intestinal, biliary, tubulopapillary
1. Non‐invasive papillary neopl. (intracystic papillary neopl.)
• Pancreatobiliary, intestinal
“Adenoma” vs “Intracystic papillary neopl.”
in the gallbladder Agreement among experts, very poor (kappa, 017)
Tumoral IN of Gallbladder
Plethora of (> 8) names WHO‐2010
• Pyloric gland adenoma
 “1 cm” criteria, not mentioned
• Biliary adenoma
 2 categories were recognized
• Intestinal adenoma
1. Adenoma
• Tubular adenoma
• Pyloric gland, intestinal, biliary, tubulopapillary
• Tubulopapillary Our proposed unifying term (for > 1 cm):
adenoma
Intracholecystic
• Papillary adenoma papillary‐tubular neoplasm
2. Non‐invasive papillary neoplasm (intracystic papillary neoplasm)
• Papillary neoplasm
• Pancreatobiliary, intestinal
• Papillary carcinoma
Proposed unifying category for GB
> 1cm
 Regardless of phenotype:
ICPN
WHO‐2010
 1cm
 Regardless of phenotype: IPN
WHO‐2010
 1cm  Mucinous: IPMN
WHO‐2010
 1cm  Non‐mucinous
 Tubular: ITPN
Intraepithelial Neoplasia in Gallbladder
Flat (Non-tumoral)
• Microscopic
• Incidental; clinically quiescent Tumoral
• Macroscopic
• Mass-forming; grossly
and clinically manifest
(often symptomatic)
Ipek low-medium power
of a convincing IVPN or
IAPN of GB (Use our
best photo pls
HGD (non-tumoral)
Tumoral IN: ICPN
Spectrum of architectural patterns with overlaps
Papillary
Tubular
Tubulo-papillary
Spectrum of dysplastic changes (variable amounts
and degrees), both within the category, but also in a
given case
Even cases with gastric (“pyloric gland”) pattern can be associated with HGD and/or invasion
Spectrum of lineages (intestinal, biliary, gastric), with frequent overlaps
Intracholecystic papillary tubular neoplasm with high-grade
dysplasia/CIS
Frequency of invasive carcinoma in ICPN Subtypes

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