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GIT Dysplasias
Concept Working definition
Disorders of cell growth & differentiation Unequivocal neoplastic epithelium confined to

THE EXPANDING SPECTRUM OF GI

associated with an increased malignant potential the basement membrane [Riddell]

DYSPLASTIC LESIONS LGD

Prototype:
adenomatous
HGD

dysplasia

Gregory Y. Lauwers, MD
Gregory.Lauwers@Moffitt.org
H. Lee Moffitt Cancer Center & Research Institute
Tampa, FL
Inflammation / Metaplasia Dysplasia Adenocarcinoma

The Spectrum Non-Intestinal Dysplasia is Expanding!

But with the passage of time, more biopsies, more
patient data, more information ….the categorization
of different subtypes of dysplasia is improving…so our NON
BASAL GLAND PYLORIC TYPE OXYNTIC TYPE NON
ADENOMATOUS CONVENTIONAL
ability of a correct and biologically accurate diagnosis FOVEOLAR DYSPLASIA DYSPLASIA IBD RELATED
TYPE DYSPLASIA
not only expands but becomes more complex

ESOPHAGUS / STOMACH STOMACH STOMACH COLON

DUODENUM

Types of Dysplasia for Today’s Discussion

Foveolar Dysplasia

Basal Gland Dysplasia

Pyloric Type Dysplasia

Serrated Dysplasia FOVEOLAR DYSPLASIA

TALL CELLS W/ PALE EOSINOPHILIC CYTOPLASM DUE TO THE APICAL NEUTRAL MUCIN.
Oxyntic Gland Adenoma MUC5AC[+]; MUC6 [+] CELLS MAY BE SEEN AT THE BOTTOM OF GLANDS.

IBD Related Non-Conventional Dysplasia

1
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Foveola dysplasia in BE: prevalence of 46% Note: 41

resections w/

(HGD:58%) (Adjacent IM: 53%) dysplasia w

or w/o
associated
inv. ACA

Foveolar Type Adenomatous type

LGD HGD
Adenomatous & Hybrid Dysplasia:
Prevalence:27%.(HGD:91%;100%) (Adjacent IM: 100%/82%%)
M odern Pathology; 2010-23:834-843

A Closer Look: Non-adenomatous Type Dysplasia

• Prevalence: 6.7%
• 94% the cases are associated
with typical dysplasia
[HGD>LGD]
• High rate DNA abnormalities

Rucker-Schmidt et al. Am J Surg Pathol 2009;33(6):886-93

GASTRIC FOVEOLAR DYSPLASIA

Non-adenomatous Type Dysplasia in BE
10 Year Follow-up
• Cuboidal to low
Maximum dx upon Follow-up columnar cells
• Clear/light
Dysplastic Variant N Low-grade High-grade Carcinoma
eosinophilic
cytoplasm
Nonadenomatous 18 0% 78% 17%
• Round to oval
nuclei
Adenomatous 24 25% 54% 21%

Low-grade 13 46% 31% 23%

High-grade 11 82% 18%

Rucker-Schmidt et al. Am J Surg Pathol 2009;33(6):886-93

2
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Foveolar type dysplasia - low grade Foveolar type dysplasia - high grade
Prevalence of Foveolar GED:
Park DY. AJSP 2008

22% (adenomatous: 45%,hybrid 33%) (n=69)

Muc5AC

• Foveolar GED is often depressed/flat and associated w/ HGD (p= 0.046).

• HGD associated w/ MUC5AC expression regardless of the type (p=0.026)

MUC5AC

Gastric Foveolar Dysplasia: Issues to be Settled

Interobserver variability
Low diagnostic reproducibility – particularly LGD vs reactive changes

Progression rate
Foveolar-type dysplasia: a high-risk lesion?? Controversial
(probably because of the lower reproducibility of the diagnosis)
Ø IMC / invasive very well-differentiated GCA of the foveolar-type are closely similar
to hyperplastic foveolar epithelium [very low N/C ratio and surface maturation].

Surveillance
No specific surveillance guideline available

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Esophageal Basal
Gland Dysplasia

• Prevalence: 7.3%
• 87% have prior or
concurrent
dysplasia or CA
• Association
particularly
significant w/
BASAL GLAND/CRYPT DYSPLASIA regard to the assoc.
w/ HGD (P=0.004).
‘NEOPLASTIC EPITHELIUM WITH DYSPLASTIC FEATURES LIMITED TO THE BASE OF THE
PITS/GLANDS WITHOUT INVOLVEMENT OF THE SURFACE EPITHELIUM’.

Molecular Anomalies &

Natural History of Basal Gland/ Crypt Dysplasia Can we-reliably-recognize BCD?
DNA abnormalities in basal crypt cells 40 bx: 10 BE,9 BCD,10 LGD,9 HGD,2 IMCa
[selected by index pathologist]
• 5 GI pathologists.
• K for IOV for entire cohort :0.44 (moderate)
• [IMC (K=0.65)-LGD (K=0.31)]

No differences in reproducibility of Basal Crypt

Dysplasia (K=0.44)-LGD (K=0.31) or HGD (K=0.46)

Compared w/ BE, BCD shows:

↑ prevalence rate of p53 positivity (60% vs.13%, When disagreement w/ index diagnosis of BCD
P<0.02) (n=17/45 readings), most diagnosed either LGD or
↑ total & basal crypt Ki-67 proliferation rate
HGD rather than BE w/o dysplasia
(P<0.001) (similar to LGD or HGD)
Clonal identity (CDKN2A mutations)

Zhang X Am J Surg Pathol 08; Lomo LC Am J Surg Pathol 06; Khan S. J. Pathol 2013;231; Srivastava A. USCAP 2011 Metaplastic atypia
Coco et al, 2011 Am J Surg Pathol

Recurring issue w/ basal crypt dysplasia

Level 2

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Pyloric Gland Adenoma (<3% of all polyps)

Oberhuber G. Virchows Archiv; 2000; 437:581-90

PYLORIC TYPE DYSPLASIA

CUBOIDAL to TALL CELLS W/ GROUND GLASS EOSINOPHILIC CYTOPLASM.

MUC6[+]; +/_MUC5 [+] IMMUNOREACTIVITY.

Tubulo-villous Pyloric gland adenoma Tubular Pyloric gland adenoma

LGD
Pyloric Gland Adenoma
Classic Immunophenotype
51% co-expressed MUC5AC in an intermixed pattern

HGD

Choi WT. Histopathology 2018;

Gastric Pyloric Gland Adenoma

WHAT IS KNOWN
Older pts (mean age: 70 yrs)
Females > males (3:1)
Oxyntic mucosa
AIG
Cases associated with FAP; Lynch Sd.
Previously reported 53% w/ HGD
Choi WT. Histopathology 2018;
WHAT IS NEW
Antrum (6%), pylorus (3%)
36% in normal mucosa
55% LGD [avg:1.7 cm]; 37% HGD
[avg:3.4 cm]
TVA more commonly associated w/ in
HGD (52%) than LGD
Recurrence: 7% at 1yr after polypectomy
Duodenal Pyloric Gland Adenoma

5
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Duodenal Pyloric Gland Adenoma [n=42]

LGD (n=25) HGD (n=17)
Gastric heterotopia (%) 4 (16) 4 (23.5)

Tubular (%) 17 (68) 7(37.5)

Architecture
Tubulovillous (%) 8 (32) 10 (62.5)

Pyloric (%) 5 (21.7) 4 (28.6)

MUC staining pattern
Mixed (%) 18 (78.3) 10 (71.4)
SERRATED DYSPLASIA
Recurrence 1 1 RARE IN BOTH ESOPHAGUS AND STOMACH
Associated carcinoma 0 4

Miller G et al. Histopathology 2019

Esophageal Serrated Dysplasia

Serrated Dysplasia: Progression to Cancer

Association with
Progression to
Dysplasia Conventional Conventional cancer
LGD HGD
Conventional LGD (N=22) 1 (5%)

Conventional HGD 12 (75%)

(N=16)
Serrated Dysplasia (N=6) 3(50%) 3(50%) 3 (50%)
Srivastava et al, U SCA P 2010

214 patients

Gastric Serrated Adenocarcinoma Arising from

Serrated Adenoma W/ HGD Gastric Serrated Dysplasia
• 15 cases reported in English literature.
• Harbors invasive carcinomas in 74.3% of cases.
[vs 6.8~30% of cases in conventional adenoma]
• KRAS mutations and BRAF mutations [unlike
colorectal serrated adenomas].

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ORIGINAL ARTICLE

Gastric Adenocarcinoma of Fundic Gland Type

(Chief Cell Predominant Type): Proposal for a New Entity
of Gastric Adenocarcinoma Uyema H AJSP. 2010;609-619.

Hiroya Ueyama, MD,*w Takashi Yao, MD,* Yutaka Nakashima, MD,z Katsuya Hirakawa, MD,y
Yumi Oshiro, MD,J Minako Hirahashi, MD,z Akinori Iwashita, MD,# and Sumio Watanabe, MDw

Key Words: gastric cancer, chief cell differentiation, pepsinogen-I,

Abstract: Only a few cases of gastric adenocarcinoma of fundic H+/K+-ATPase
gland type have been reported. Gastric adenocarcinoma with
chief cell differentiation (GA-CCD) has been recently reported (Am J Surg Pathol 2010;34:609–619)

OXYNTIC GLAND ADENOMA as a new variant of gastric adenocarcinoma. However, its

clinicopathologic features are uncertain. To elucidate them, GA-
CCDs exhibiting pepsinogen-I expression (10 lesions: Group A)
and randomly selected gastric adenocarcinomas of differentiated
type (111 lesions: Group B) were evaluated in this study. Cell G
astric adenocarcinoma of the intestinal type by
Lauren classification is very similar to that of the
12,18
differentiation by MUC2, MUC5AC, MUC6, CD10, pepsino- differentiated type by Nakamura classification. With
gen-I, H+/K+-ATPase and chromogranin A, cell proliferation recent advances in mucin histochemistry and immuno-
Lympho-vascular invasion & nodal metastases. Ueo T. Dig Endosc. 2014;26(2):293-294
by Ki-67, and overexpression of p53 protein were evaluated histochemistry, it has been clarified that intestinal-type
immunohistochemically. In Group A, all GA-CCDs were adenocarcinoma by Lauren classification contains the
2,8,15,21,22,26,29
located in the upper third of the stomach. Tumors were small, gastric phenotype.
with the average maximum diameter ranging from 4 to 20 Although differentiated adenocarcinomas with the
(average, 8.6) mm. Histologically, GA-CCDs were well-differ- gastric phenotype including the foveolar type and pyloric
entiated adenocarcinomas composed of pale gray-blue, baso- gland type have been reported, there are only a few cases
philic columnar cells with mild nuclear atypia, resembling chief of adenocarcinomas
27,28
with differentiation of fundic
cells. Immunohistochemically, scattered positivity for H+/K+- glands. Several cases of parietal cell carcinoma have
ATPase was observed in addition to expression of pepsinogen-I been reported. However, differentiation of parietal cells
and MUC6, indicating focal differentiation toward parietal cells. was confirmed by staining for H+/K+-ATPase in only 1
28
In Group B, pepsinogen-I was very focally expressed in 2 cases. case. Other cases of parietal cell carcinoma could be
As these 2 cases exhibited different clinicopathological and termed oncocytic adenocarcinomas, + +
because immunohis-
histologic features, they cannot be categorized as GA-CCD. tochemical staining of H /K -ATPase characteristic for
1,13,25
Mild atypism, no lymphovascular invasion, low proliferative parietal cells were not carried out, or were negative.
activity, no overexpression of p53, and no recurrence indicated With regard to gastric adenocarcinoma with chief cell
less aggressiveness of GA-CCD. GA-CCD is rare, but it has differentiation, (GA-CCD) only 1 case27has been reported
distinct clinicopathological characteristics, especially in terms of in a recent paper by Tsukamoto et al.
tumor location, histologic features, phenotypic expression, and We collected samples from 10 cases of GA-CCD
low-grade malignancy. We propose gastric adenocarcinoma of and elucidated the associated clinicopathologic features,
fundic gland type (chief cell predominant type) as a new entity of cell differentiation,Hand +/K biologic
+ATPbehavior.
ASE PEPSINOGEN
gastric adenocarcinoma.

MATERIALS AND METHODS

From the *Department of Human Pathology; wDepartment of Gastro-

Pepsinogen I
enterology, Juntendo University School of Medicine, Tokyo;
zDivision of Pathology; yDivision of Gastroenterology, Japanese
Red Cross Fukuoka Hospital; zDepartment of Anatomic Pathology,
Pathological Sciences, Graduate School of Medical Sciences, Kyushu
University; #Department of Pathology, Fukuoka University Chi-
kushi Hospital, Fukuoka; and JDepartment of Pathology, Japanese
Red Cross Matsuyama Hospital, Matsuyama, Japan.
Correspondence: Takashi Yao, MD, Department of Human Pathology,
Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-Ku,
Tokyo, Japan, 113-8421 (e-mail: tyao@juntendo.ac.jp).
Copyright r 2010 by Lippincott Williams & Wilkins
Samples and Tissue Collection
Group A
GA-CCDs are defined as neoplastic lesions, mainly
composed of highly differentiated columnar cells mimick-
ing the fundic gland cells, mainly chief cells, with nuclear
atypia. They grow in irregularly anastomosing glands
and acini, and have the ability to invade the stroma.
In addition to the histologic similarity, differentiation
MUC-6
toward the chief cells was confirmed by immunohistochem- MUC-5AC
ical staining with pepsinogen-I (a marker for chief cells).

Am J Surg Pathol ! Volume 34, Number 5, May 2010 www.ajsp.com | 609

H+/ K+ ATP ase

In the West…

Ki-67

P53 ORIGINAL ARTICLE

Gastric Adenocarcinoma With Chief Cell Differentiation

A Proposal for Reclassification as Oxyntic Gland
Polyp/Adenoma Singhi A AJSP. 2012;1030-1035.

Aatur D. Singhi, MD, PhD,* Audrey J. Lazenby, MD,w and Elizabeth A. Montgomery, MD*

that arise in patients from multiple ethnic backgrounds. Consid-

Abstract: Gastric adenocarcinoma with chief cell differentiation
(GA-CCD) has been reported as a new, rare variant of gastric
adenocarcinoma. Only 12 cases in Japanese patients have been
described to date, but they demonstrate distinct clinicopathologic
features. To further characterize these lesions, we have collected 10
additional cases. Patients ranged in age from 44 to 79 years (mean,
64.2 y) with a relatively equal sex distribution (6 women and 4
men). Stratified by race, 4 patients were Hispanic, 2 were White,
2 were African American, 1 was Asian (Chinese), and the race
was unknown for 1 patient. All patients presented with gastro-
ering that patients within this study and those reported previously
have had neither true recurrence nor progression of disease, these
lesions are best regarded as benign. Consequently, the term GA-
CCD is contradictory and we prefer the descriptive term “oxyntic
gland polyp/adenoma” until further studies can clarify the
pathogenesis of these lesions and their natural history.
Key Words: fundic gland polyp, oxyntic gland adenoma, chief
cell hamartoma
(Am J Surg Pathol 2012;36:1030–1035)

7
esophageal reflux that prompted an endoscopic examination. The
majority of GA-CCDs were identified in the fundus (7 of 10, 70%)
and the remaining in the cardia (n = 3). Grossly, they were solitary
and polypoid, ranging in size from 0.2 to 0.8 cm (mean, 0.4 cm).
Histologically, all cases were centered in the deep mucosa, with
G astric adenocarcinoma is one of the most common
cancers worldwide, accounting for over 934,000 cases
annually. Approximately 700,000 people succumb to this
focal involvement of surface foveolar epithelium in 3 (30%) cases
malignancy each year, and the 5-year survival rate in the
but not the submucosa. The tumors consisted of clustered glands
United States is 24%.3 It constitutes a heterogenous group
and irregular branching cords of oxyntic epithelium. Thin wisps of
radiating smooth muscle separated the epithelium, but desmo-
of tumors with variable clinical and pathologic features.
Many classification systems for gastric adenocarcinoma
 2/13/22

72 yo ♂ : 3 mm gastric polyp

A morphologic continuum:
Anastomosing glands (55%);
Mild atypia (58%)
Desmoplasia (16%)
Necrosis (8%)

Oxyntic Gland Neoplasm Can Present An Heterogenous Morphology 2019

Tumors with typical morphology (chief cell predominant)

• mucosal or submucosal OXYNTIC GLAND ADENOMA
• mild or focal moderate nuclear atypia

Tumors with atypical features (= submucosal invasion)

• morphologic component (chief mucus neck cells/ foveolar) ADENOCARCINOMA OF
• marked atypical proliferation FUNDIC GLAND TYPE
• larger 26.8 mm average (5/6x)
• 50% had LVI
Parietal + Chief Cells Chief Cells [predominant] Mucus Neck Cells • One case with K-ras mutation in addition to GNAS

Journal of Pathology
J Pathol 2013; 229: 579 – 587 ORIGINAL PAPER
Published online 4 February 2013 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/path.4153
48% 41%
Frequent GNAS and KRAS mutations in pyloric gland adenoma
of the stomach and duodenum
Akiko Matsubara,1 Shigeki Sekine,2* Ryoji Kushima,1 Reiko Ogawa,2 Hirokazu Taniguchi,1 Hitoshi Tsuda1 and
bs_bs_banner

Yae Kanai2
1Pathology
2
PathologyInternational
and Clinical 63: 318–325
2013;Laboratories, National Cancer Centre Hospital, Tokyo, Japan doi:10.1111/pin.12070
Kushima
Molecular Pathology Division, National Cancer Centre Research R. Tokyo, Japan
Institute, Relationship between PPI usage and
Pathology International 2013
*Correspondence to: Shigeki Sekine, Molecular Pathology Division, National Cancer Centre Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo
OGA?
Original
104 Article
– 0045, Japan. e-mail: ssekine@ncc.go.jp
Gastric adenocarcinoma of the fundic gland type shares
common genetic and phenotypic features with pyloric
Abstract
Fundic gland and pyloric gland neoplasia 325
gland adenoma
Gastric and duodenal adenomas exhibit a significant morphological and phenotypical diversity and are classified
into intestinal-type, foveolar-type and pyloric gland adenomas. We analysed the mutations in GNAS , KRAS , BRAF
and CTNNB1 and the expressions of 2 mismatch
Singhi AD, Lazenbyrepair (MMR)EA.
AJ, Montgomery proteins in 80 gastric and 32 duodenal adenomas with
Gastric adenocarci-
histologically distinct subtypes, as well
noma aswithin
chief71
cell gastric A proposal for reclassifica- Activating GNAS mutations were found
adenocarcinomas.
differentiation:
in 22 of the 35 pyloric gland adenomastion as(PGAs;
oxyntic gland
63%) polyp/adenoma.
but inAm J Surgof
none Pathol
the2012;foveolar-type or intestinal-type adenomas
36: 1030–35.

GNAS
or the adenocarcinomas. Fourteen3 PGAs (41%), two foveolar-type adenomas (9%), five intestinal-type adenomas
Chen ZM, Scudiere JR, Abraham SC, Montgomery E. Pyloric
(9%) and one adenocarcinoma (1%) had KRAS mutations. BRAF mutations were absent in all the adenomas and
Ryoji Kushima,1 Shigeki Sekine,2 Akiko Matsubara,1 gland adenoma: An entity distinct from gastric foveolar3 type

IBD RELATED NON CONVENTIONAL DYSPLASIA

Hirokazu Taniguchi,1 Masahiro Ikegami and
adenocarcinomas that were examined. CTNNB1
adenoma. Am J Surgmutations were
Pathol 2009; 33: only found in two intestinal-type adenomas (4%).
186–93.

mutation
Hitoshi Tsuda 1
*
Notably, 13 of the 14 KRAS -mutated gastric
4 Kushima and
R, Vieth duodenal
M, Borchard F, Stolte PGAs had
M, Mukaisho concurrent GNAS mutations. The loss of the
K, Hattori
MMR proteins, which is indicative ofT. Gastric-type
microsatellite well-differentiated
2 adenocarcinoma andobserved
pyloric
1
Pathology and Clinical Laboratory Division, National Cancer Center Hospital,instability, Departmentwas
gland adenoma of the stomach. Gastric Cancer 2006; 9: 177–
of Molecular in one PGA (3%), 12 foveolar-type
Pathology,
National Cancer adenomas Center (52%), one
Research Instituteintestinal-type
andare3Department 84. adenoma
of Pathology, (2%) and
Jikei five adenocarcinomas
University School of Medicine,(7%). These observations indicate
Figure 8 GNASthat mutations
eachin the histological
GAFGs. Missense mutations
subtype of gastric
Tokyo,byJapan 5 Vieth M,and Kushimaduodenal
R, Borchardadenomas
F, Stolte M. Pyloric has agland distinct genetic background. In particular,
indicated the arrowheads. Sequencing was performed using a
reverse primer.
the present study identified the frequent adenoma:presence of activating
A clinico-pathological GNAS
analysis of 90 cases. mutations, which are often associated with
Virchows
KRAS mutations, as a characteristicArch 2003; 442:
genetic 317–21. of PGAs of the stomach and duodenum.
feature
6 Matsubara A, Sekine S, Kushima R et al. Frequent GNAS and
Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
KRAS mutations in pyloric gland adenoma of the stomach and
aberration in PGAs. We anticipate that the absence of KRAS duodenum. J Pathol 2013; 229: 579–87.
Gastric adenocarcinoma
Keywords:
mutations might be pyloric of the
gland
a potentially fundic
adenoma;
useful gland type
characteristic (GAFG) duodenum;
stomach,
for dis- and
7 Montgomery Key EA, words:
GNAS; chief
Voltaggio cell, gastric
L.KRAS
Biopsy adenocarcinoma
Interpretation of the Gas- of the fundic
pyloric gland
criminating between adenoma
GAFGs(PGA) have however,
and PGAs, been recognizedtrointestinal
recently consider- glandTract Mucosa. Volume 2: Neoplastic. Philadelphia,
type, GNAS, mucous neck cell, pyloric gland adenoma
PA: Wolters Kluwer/Lippincott Williams & Wilkins, 2012; 85–8.
as the
ing raresmall
typesnumber
of neoplasia.
of GAFGs We analyzed
performed in comparative
the present immu- 8 Lennerz JK, Kim SH, Oates EL et al. The transcription factor
Received
nohistochemical 22 August 2012; Revised 8 November
GAFGs and 12MIST1Accepted
2012; 24 gastric
November 2012
study, further analysesand aregenetic
required analyses of 3prospect.
to confirm this is a novel human
Gastric adenocarcinoma chief cell of
marker
the whose
fundic expres-
gland type (GAFG)
PGAs.
GAFG All
and of
PGAs theare 3 GAFGs
currently were
thought to diffusely
be entirely positive
dis- forsion is lost in metaplasia, dysplasia, and carcinoma. Am J
No conflicts of interest were declared. (chief cell predominant type) is a recently proposed subtype
pepsinogen-I,
tinct tumors. However, MIST1 based and MUC6,
on their indicating
common the inpredomi-Pathol 2010; 177: 1514–33.
localization 9 Hattori of gastric
T, Fujita adenocarcinomas.
S. Tritiated 1,2
thymidine autoradiographicGAFGstudy is composed
on of irregu-
nantly
the fundicchiefgland cell/mucous
area, partially neck cell differentiation
overlapping immunohis- of thesecellular migration in the gastric gland of the golden hamster. Cell
tumors. A profiles
Introduction
tochemical small numberand sharedof H.K-ATPase-positive
genetic alterations,parietal
we cellsTissue larly branching and anastomosing tubules lined by pale gray-
Res 1976; 172: 171–84. These adenomas exhibit the histological and immuno-
were also 10 Hanby blue, basophilic columnar cells withmucousmild nuclear atypia,
suggest thatscattered.
GAFGs andPGAs PGAsinvariably
are closelyexhibited diffuse MUC6
related lesions AM, Poulsom R, Playford RJ, Wright NA. The
histochemical features of small intestinal epithelium
neck cell in the humanchief
resembling gastriccells.
corpus: A distinctive,
Cells positivefunctional
for H.K-ATPase differ-
and TFF2 expression,
characterized by a mucous consistent with thecellpyloric
neck cell/chief lineagegland dif-cell lineage. and consist of intestinal-type epithelial cells, includ-
Gastrointestinal adenomas are benign polypoid J Pathol 1999;
epithe- 187: 331–7.
ferentiation of these tumors.
phenotype. Ten of the 12 PGAs also unex- entiating towards parietal cells
C, Finziing have E.also been reported to beand Paneth cells (Figure 1A, B,
lial neoplasms that may have some and
11 Cornaggia
malignant
M, Capella C, Riva absorptive,
G, Solcia Electron goblet
pectedly exhibited focal expression of pepsinogen-I scatteredpoten-
immunocytochemical inlocalization
some GAFGs.. of pepsinogen
1,2
H) [3]. I (PgI) in chief
However, Themolecular analyses
immunohistochemical expression of intesti-
tial
MIST1,[1,2].suggesting Gastric
that PGAsadenomasoften show focal are chiefknown
cellcells, mucous to neck exhibit
cells and transitional mucous-neck/chief
cells offocusing
the humanonfundic GAFG has Histochemistry
never
nal been reported
epithelial 85: previously.
markers, such as MUC2 and CD10, has
differentiation ACKNOWLEDGEMENT
significant andphenotypic
phenotypically diversity
resemble mucous andneck can be classified mucosa. 1986;
5–11. Pyloric gland adenoma also (PGA) isbeen anotherdescribed
rare type of gastric
[3,9]. A previous study reported
cells rather
into than pyloric glands.and
morphologically The mutation analyses
immunophenotypically12 Bredemeyer AJ, Geahlen dis-JH, Weis VG et al. The gastric epi-
The authors activating
revealed thank Dr Jason GNAS Millsmutations,
(Washingtonwhich University
have2010beenthelial tumor whichniche has an incidence
been increasingly recognized ofas24% for the malignant transformation
a distinct
tinct subtypes. According to the World
progenitor cell Health and differentiation of the zymogenic
School
reportedof Medicine, St. Louis, MO,
to be frequently USA) forin
detected hisPGAs,
generous in gift variant
the(chief) cell
two of gastric lineage. ofDev
gastric-type
Biol 2009; 325: of
adenoma. gastric
211–24.
3–5
PGA intestinal-type
is composed of adenomas [2].
Organization
ofGAFGs.
the anti-MIST1 (WHO)
antibody,and andPGAs classification,
Ms Sachiko Miura and Ms distinct 13 Ramseyclosely adenomas
VG, Doherty Foveolar-type adenoma has long been recognized
While GAFGs are morphologically packedJM, Chen CC,glands
pyloric-type Stappenbeck
lined byTS, cuboidal/columnar
are Kina
Chizu primarily
for their classified
skilful technical into This
assistance. two study categories:Konieczny intestinal-
SF, Mills JC. The maturation of mucus-secreting
as a prototype of gastric-type adenomas and is com-
lesions, our observations showed their partially overlappinggastric cells withprogenitors
epithelial round nuclei and pale or eosinophilic cytoplasm. 3–5
type
was andin gastric-type
supported part by aprofiles
grant for and[3].
the Gastric-type
Development of adenomas caninto digestive-enzyme
prised
secreting
immunohistochemical shared presence ofzymogenic cells requires
Recently, Mist1. Development
we reported that 2007; of
frequent 134:
GNAS foveolar-type
211– and KRAS muta- epithelial cells with an apical
be
Cancer
GNAS further
Research
mutations, subclassified
and inaaddition
grant for to their into
Scientific Research
common foveolar-type
from
occurrence in22. and pyloric mucin are cap (Figure genetic 1C, D) [7]. Immunohistochemically,
gland 14 Landis tions occurring at high frequencies
AM, Bourne HR, characteristic
fundicadenomas (PGAs) on these[3]. by Inthe contrast
the CA, to gastric
theMinistry of Health, Labour,Based
and Welfare, and Masters SB, Spada A, Pace Vallar
gland mucosa. observations, we
features
L. GTPase of PGAs
inhibiting mutations ofactivate
foveolar-type
the stomach
the alphaand chainduodenum.
of Gs
adenoma
6 is positive for MUC5AC (a
National
adenomas, Cancer Center
the Research and
histological Development Fund
diversity of duodenal
suggest that both GAFGs and PGAs are closely relatedand stimulate adenylyl cyclase in human ade- marker pituitary of gastric foveolar epithelium) and negative for
(23-A-11),
lesions Japan.
nomas is less well
characterized by a recognized.
mucous neck cell/chief Most cell duodenal Currently,
Nature 1989; 340:adeno-
GAFGs and PGAs aretumours.
thought to be entirely
692–6. MUC6 (a pyloric gland-type mucin) [7,10]. Foveolar-
mas
lineageexhibit
phenotype.intestinal-type differentiation 15 Freda[4], distinct
PU, but
Chung types
some
WK, of tumors.N However,
Matsuoka et al. Analysis it isof becoming
GNAS increasingly
mutations in 60that
growth hormone
type adenoma
secreting pituitary
usually exhibits low-grade dysplasia and
studies haveREFERENCES also reported the presence clear GAFG inand PGA sharetumors:someCor- clinicopathological
relationof PGAs
with clinical and pathological is thought
characteristics and surgi-to be associated with a low risk of malignant
the duodenum [5 – 7]. On the other hand, features:
foveolar-type
cal outcome based on both
highlylesions
sensitive typically
transformation
GH a nd IGF-I arise
criteriainforthe fundic
[2,7]. gland
2007; 10:
1 Ueyama H, Yao T, Nakashima Y et al. Gastric adenocarcinoma
adenomas have been rarely reported inremission. themucosa, Pituitary occur
duodenum. in 275–82.
older patients, and
PGA is a relativelyconsistently express rare type of adenoma that has
Correspondence:
of fundic gland typeRyoji Kushima,
(chief MD, PhD,
cell predominant type):Pathology
Proposal foranda Clinical
16 Lee SH, Jeong1–6 EG, Soung YH, Lee JW, Yoo NJ, Lee SH.
Intestinal-type
new entity of gastric adenoma
adenocarcinoma. Am J Surg is
Patholthe
2010; most Absence MUC6.
common of GNAS Furthermore,
andade-EGFL6 while
been
mutations in GAFG
common ishuman
increasinglyregarded as arecognized
low- as a distinct variant of
Laboratory Division, National Cancer Center Hospital, 5-1-1Tsukiji,

8
nomatous
34: 609–19. polyp in the upper gastrointestinal
Chuoku 104-0045 Tokyo, Japan. Email: ryoji.kushima@gmail.com cancers.grade
Pathology malignancy
tract 2008;[8].
40: 95–7. that gastric-type
occasionally shows submucosal[6,7]. PGA occurs in both the
adenoma
*Present address: Department of Pathology, National Defense growth, some authors have questioned the malignant poten-
Copyright © 2012 Pathological
Japan. Society of Great Britain and J Pathol 2013; 229: 579 – 587
Medical College, Tokorozawa, tial ofIreland.
GAFGs based on their clinically benign nature and
Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk www.thejournalofpathology.com
Disclosure: The authors declare that they have no conflict of even suggested that GAFGs should be re-classified as
interest.
oxyntic gland polyps/adenomas.2,7 Based on these findings,
Received 11 March 2013. Accepted for publication 14 May 2013.
© 2013 The Authors
we examined the potential relationships between GAFG and
Pathology International © 2013 Japanese Society of Pathology and PGA, paying special attention to their genetic and phenotypic
Wiley Publishing Asia Pty Ltd features.

© 2013 The Authors

Pathology International © 2013 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
 2/13/22

6 new categories of unconventional dysplasia

Novel Classification of Dysplasia in IBD
Noam Harpaz, John Goldblum, Neil Shepherd, Robert Riddell, Carlos Rubio, Michael Vieth, Robert Odze
Icahn School of Medicine at Mount Sinai, New York, NY; Cleveland Clinic, Cleveland, OH; Gloucestershire Cellular Pathology Laboratory, Gloucester,
United Kingdom; Mount Sinai Hospital, Toronto, Canada; Karolinska Institutet, Stockholm, Sweden; Institute of Pathology, Bayreuth Clinic, Bayreuth,

– Dysplasia with terminal epithelial differentiation

Germany and Brigham and Women's Hospital and Harvard Medical School , Boston, MA

Type 1. Conventional adenoma-like. Growth

BACKGROUND RESULTS (cont.)

pattern: tubular, tubulovillous, or villous. Crowded
crypts. Cell features: Nuclei are "adenoma-like"
slightly enlarged, hyperchromatic, elongated or
pencillate, and often stratified up to the surface.
The classificationsystemfor diagnosis andgrading of dysplasia inIBD, originally proposedin Diagnostic agreement for each dysplasia category was also excellent. At least 4 participants were in

– Hypermucinous dysplasia
Goblet cells are variable, but usually 1-2+.
Intervening cells have enterocyte-like features or a
1983 by Riddell et al. (Hum Pathol. 1983;14:931-68), has been widely adopted as the agreement in 25/35 cases (71%), and ≥5 participants were in agreement in 18 cases (51%). small amount of microvesicular mucin or a mucin
cap. Some have prominent Paneth cells or
standard for clinical and research purposes, but there has been little subsequent effort to Diagnostic agreement was highest for Types 2, 5 and6 (Fig. 2), withmeanagreement by 6, 4.7 and endocrine cells.

addresstherecentlyrecognizedmorphological andbiological diversityof dysplasiainIBD. The 4.7participants(86%, 67%, 67%), respectively(Table). Type 2. Hypermucinous. Growth pattern: Villous
often with tapering at the surface. Non-crowded
aims of this study were todetermine the morphological spectrumof dysplasia inIBDandto Dysplasia types 5 and 6 have not been formally described hitherto. They are characterized by non- crypts. Nuclei are small, slightly enlarged, oval-
shaped, inconspicuous nucleoli, and often oriented
develop a reproducible and consistent classification system in order to facilitate future polypoid growth pattern, non-crowded, evenly distributed crypts, and cytoplasmic features that basally along the basement membrane, without
significant stratification. The size and degree of
studiesontheirbiologyandnatural history. either simulatetherepertoireof normal colonic epithelial cells (Type5) or aredevoidof goblet cells atypia of nuclei decrease towards the surface of the

– Incomplete goblet cell maturation / goblet cell

villi, variable number of goblet cells and intervening
(Type6). columnar cells with mucinous differentiation
(foveolar-like mucin cap, microvesicular or both).
Fewenterocyte-like cells.
Type 3. Sessile serrated polyp-like. Growth pattern:

METHODS CONCLUSIONS Serrated. Non-crowded crypts. Cell features: Small

round-to-oval, slightly elongated and basally located
nuclei, slightly stratified at the base with evidence of

SevenGI pathologists, all withparticular researchexpertiseinIBD, contributedatotal of 200 Wesuccessfully organizedandclassifiedaspectrumof morphologic dysplasiainIBDinto7 distinct maturation at the surface, nuclear hyperchromasia

depleted dysplasia
with occasional inconspicuous nucleoli, goblet cells

electronic images of dysplasiainIBDfromtheir collections. Twopathologists (N.H. andR.O.) categories. The system was validated and shown to result in excellent agreement by expert GI 1-2+ on average, with occasional crypt Paneth cells
and endocrine cells. Slightly distorted crypt

collated and reviewed all of the images and separated them into distinct morphologic pathologists. This classificationsystemshouldprovideabasis for further studies of thebiologyand architecture, some
reminiscent of a SSA/P.
architectural features

categories basedonavarietyof architectural andcytologicfeatures. After this was complete,
all of the participants received either 1 or 2 illustrative images of each of the morphologic
categories (see below) accompanied by a written description of its salient morphologic
features (Fig. 1). This “atlas” served as a guide for evaluating a test cohort of 36 cases of
natural historyof thevarioussubtypesof dysplasia. Type 4. Traditional serrated adenoma-like. Growth
pattern: Serrated. Non-crowded crypts. Cell
features: enlarged slightly elongated and slightly
stratified nuclei at the base, hyperchromatic, 1-2+
Table. Result of the classification of dysplasia into seven categories
goblet cells and intervening non-goblet eosinophilic
cells with microvesicular mucin or a mucin cap. The

– Sessile serrated polyp/adenoma-like dysplasia

nuclei have mostly open chromatin and prominent
dysplasiainIBDselectedbyN.H. andR.O. M e a n o b s e rve r
nucleoli. Overall, features reminiscent of TSA with
abundant eosinophilic columnar and variable
Eachparticipant alsoreceivedaquestionnaireand1or 2images of eachof thetest cases and D ys p la s ia c a te g o ry
Test cases a g re e m e n t cytoplasmic mucinous differentiation.

was asked(1) togradeeachcasefor dysplasiaaccordingtotheRiddell criteria, (2) toindicate N N (% ) Type 5. Dysplasia with terminal epithelial
whether it was similar toother cases seenintheparticipant’s routineIBDpractice, and(3) to differentiation. Growth pattern: Tubular. Non-
crowded crypts. Cell features: Nuclei small round-
gradeeachcaseaccordingtotheatlasclassificationif possible. 1 C o n ve n tio n a l a d e n o m a -lik e 14 4 .3 (6 1 ) to-oval, slightly irregular, mostly non-stratified,
hyperchromatic, with occasional inconspicuous
Any image
study. Thus,graded negative
thefinal for dysplasia by more
testcohortconsistedof than 2IBDdysplasia.
35casesof participants was excluded fromthe 2 H yp e rm u c in o u s 3 4 .7 (6 7 ) nucleoli, goblet cells 1-2+ (on a 4-point scale of 1=0-
25%, 2=25-50%, 3=50-75%, 4=75-100%), occasional
crypt Paneth cells and endocrine cells (not seen in

– Traditional serrated adenoma-like dysplasia

3 S e s s ile s e rra te d p o lyp -lik e
4 T ra d itio n a l s e rra te d a d e n o m a -lik e
5 “T e rm in a l e p ith e lia l d iffe re n tia tio n ”
6 3 .2 (4 5 ) this example). Predominant cells are enterocyte-like
cells and goblet cells.
2 4 .0 (5 7 ) Type 6. Goblet cell deficient. Growth pattern:
Tubular. Non-crowded crypts. Cell features: oval-
6 4 .7 (6 7 ) to-slightly enlarged or elongated hyperchromatic
nuclei with mild stratification at the bases of the

RESULTS 6 G o b le t c e ll-d e fic ie n t 2 6 .0 (8 6 )

crypts but with evidence of some maturation at the
surface. Cells are enterocyte-like and mildly
eosinophilic. There is a complete or near-complete
absence of goblet cells. At the surface, some nuclei
7 S e rra te d N O S 1 5 .0 (7 1 )
Sevencategoriesof dysplasiawererecognized: are slightly smaller in size and show evidence of

– Serrated dysplasia NOS

degeneration and eosinophilia.
Type1: conventional adenoma-likedysplasia U n c la s s ifie d 1 3 .0 (4 3 )

Type2: hypermucinousdysplasia Type 7. Serrated, NOS. Growth pattern: serrated.

Type3: sessileserratedpolyp/adenoma-likedysplasia Non-crowded crypts. Mildly enlarged, mostly non-
stratified vesicular nuclei with prominent nucleoli.
Type4: traditional serratedadenoma-likedysplasia Entrocyte-like epthelial cells with eosinophilic
cytoplasm. Goblet cells 1-2+ (rare in this example)

Type5: dysplasiawith“terminal epithelial differentiation” A B C

Type6:
Type7: gobletcell-deficientdysplasia
serrateddysplasiaNOS Fig. 1. Morphologic dysplasia categories. Each participant was
The overall diagnostic agreement for dysplasia was excellent Twenty-nine test cases (83%) initially provided these images with a written description of their
were diagnosed as definite dysplasia by ≥6 participants and 32 cases (91%) by ≥5 salientmorphological features.

• Diagnostically challenging / Unknown risk stratification

participants.
In response to the question as to whether the case was considered familiar based on the Fig. 2. Examples of test cases provided to participants for
participant’sroutineIBDpractice, anaffirmativeresponsewasgivenbyall 7participantsfor classification. These categories yielded the highest degrees of
32(94%) casesandby6of 7for34(100%) cases. agreement among the participants. A. Dysplasia with terminal
epithelial differentiation. B. Hypermucinous dysplasia. C. Goblet
cell-deficientdysplasia.

HYPERMUCINOUS INTESTINAL TYPE CRYPT CELL TYPE

Hypermucinous Dysplasia with increased Goblet cell deficient Crypt Cell Dyspl./
Paneth cell differentiation Terminal epithelial diff.
Architecture Tubulovillous/villous Tubular Tubular Flat

Defining features
Other features
Tall mucinous cells with Intestinal type cells with Intestinal type cells w/ Mostly round-to-oval, non-
elongated, hyperchromatic elongated, hyperchromatic elongated hyperchromatic stratified nuclei
nuclei, minimal nuclear atypia nuclei nuclei
Ø 58 patients with 106 dysplastic or serrated lesions.
• 36 foci of NCD in 26 pts [45%] / 70 foci of traditional dysplasia in 46 pts [78%]
• 46% of pts - NCD only – 54%: NCD+ conventional dysplasias [same segment in all but 3]
Hypermucinous > 50% of the Increased Paneth cell Complete or near- Atypia can be limited to the
lesion differentiation involving at complete absence of crypt base without surface
least 2 contiguous crypts in 2 goblet cells involvement Hypermucinous dysplasia (42%)
different foci (beyond what is – ‘pure’ (14%) or ‘mixed type’ (28%), [traditional dysplasia or other NCD].
present in background mucosa)
Serrated ‘changes’ (42%)
Atypia tends to decrease from Loss of goblet cells, but no Scattered Paneth cells, Loss of goblet cells, but no – TSA-like (28%), SSA-like (3%), and serrated NOS (11%).
the crypts to the surface complete or near-complete but not in multiple complete or near-complete
absence of goblet cells clusters of dysplastic absence of goblet cells Dysplastic lesions w/ increased Paneth cell differentiation (11%)
crypts
Goblet Cell Deficient (5%)
N CD: N on conventional Dysplasia

HETEROGENOUS NATURE OF HYPERMUCINOUS DYSPLASIA

HYPERMUCINOUS DYSPL.-INTESTINAL VARIANT HYPERMUCINOUS DYSPL-FOVEOLAR VARIANT (LG)

Among 49 cases, 39% showed intestinal and 12% foveolar phenotype

Hypermucinous NC are the largest lesions (mean 2.1 cm)

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 2/13/22

HYPERM UCIN OUS DYSPLASIA-M IXED VARIAN T

Lee H. Histopathology 2020

• Variable # of goblet cells & few enterocyte-like cells.

• Small nuclei, slightly enlarged, oval-shaped, and often oriented basally
w/o significant stratification

• Atypia tends to decrease from the crypts to the surface of the villi

49% of cases showed mixed differentiation(n=49)

“Goblet cell deficient” type dysplasia

Faintly eosinophilic cytoplasm & lack of goblet cells

Benign nuclear features

Cells are enterocyte-like and mildly eosinophilic. Complete or near-complete absence of

Tubular growth pattern; Non-crowded crypts. GCs.Slightly enlarged / elongated hyperchromatic nuclei w/ mild stratification.

Dysplasia with increased Paneth cell differentiation

Intestinal type cells w/ elongated, hyperchromatic nuclei. Increased Paneth cell differentiation
(beyond what is present in background mucosa)

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Small round-to-oval nuclei, slightly irregular, mostly non-stratified, hyperchromatic

Dyspl. w/ crypt cell type differentiation

IBD RELATED NON CONVENTIONAL DYSPLASIA

Tubular, non-crowded crypts

Serrated changes / dysplasia in IBD Serrated dysplasia

Ø Prevalence:1.2 % to 1.9 % Aliment Pharmacol Ther 2014;39:1408-17; / Ko. HM Mod Pathol 2015

Hyperplastic polyp
Sessile Serrated Polyp/Adenoma – like
Traditional Serrated Adenoma - like
Serrated dysplasia unclassified
Serrated epithelial changes, NOS Serrated dysplasia in 12-29% vs 6% in non-UC patients
.(R ubio C A . J G astroenterol-H epatol 2007)

Serrated epithelial change (SEC)

Sessile serrated polyp

Targeted NGS of SEC

Serrated dysplasia
Traditional serrated adenoma

Hyperplastic polyp
Not consistently recognized
endoscopically w/ only 22%
seen on targeted bx
Parian A. GIE 2016;84:87 Human Pathology;112,2021,pp 9-19

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Characteristics of IBD non-conventional dysplasia Characteristics of IBD non-conventional dysplasia

Predominantly left sided (63% to 81%) Most lesions are low grade (87%)
52% have an history conventional dysplasia • But goblet cell deficient more often shows HGD (31%) compared to
hypermucinous (15%) and crypt cell dysplasia (0%)
• detected in same segment at a rate of 33%
• Goblet cell deficient dyspl. is more likely to be associated w/ Adenocarcinomas are more likely associated with:
conventional dysplasia [74%] than hypermucinous [43%] and crypt
• Crypt Cell Deficient, Goblet Cell Deficient & Hypermucinous (aneuploidy rate
cell [48%] dysplasia (p=0.044) of 100%, 25%, 80% respectively)
• 58% of hypermucinous dysplasia are polypoid compared to 100% of
crypt cell and 65% of goblet cell dysplasia presenting as flat/invisible. CRCs in patients with only NCD showed:
(p<0.001) • More likely to be poorly differentiated (36%) than those associated w
conventional dysplasia (10%).
Detected in same segment as CRC or immediately adjacent at a rate similar to
conventional dysplasia
Lee H. Histopathology 2020 Lee H. Histopathology 2020
Choi WT. Modern Pathol 2020 Choi WT. Modern Pathol 2020
Choi WT. J of Crohn’s & Colitis 2021 Choi WT. J of Crohn’s & Colitis 2021

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