he 5th Edition of the WHO Clas-
sication of Tumours: Digestive
System Tumours “blue book” was
released in mid-2019. Key updates
are below.
General updates
The classication of digestive neuro-
endocrine neoplasms is revised. They
are categorized as neuroendocrine
tumors (NETs, formerly “carcinoids”)
or neuroendocrine carcinomas
(NECs) based primarily on histology.
NETs can be grade 1, 2 or 3, with
a Ki67 of less than 3% qualifying as
grade 1 (formerly 0 - 2%). Mitotic
rate is counted per 2 mm
, not per 10
high power elds.
NECs are always high grade and
therefore do not require numerical
grading. Mixed adenoneuroendo-
crine carcinoma (MANEC) has been
replaced with the more inclusive
conceptual term of mixed neuroendo-
crine-nonneuroendocrine neoplasm
(MiNEN); the actual diagnosis should
indicate the lesion’s components.
Carcinoma grading is generally now
two tier (low grade and high grade).
Poorly cohesive carcinoma is a
diagnostic term incorporated into
most organ system chapters, with
signet ring cell carcinoma considered
a subtype.
Hematolymphoid lesions, mesen-
chymal lesions and syndromes have
been separated into their own respec-
tive chapters.
There is now a separate chapter
on “other tumors” covering mucosal
melanoma, germ cell tumors and
Gastroesophageal junction
carcinomas have been incorporated
into the esophagus chapter.
Undierentiated carcinoma is
separated into its own entity rather
than a squamous cell carcinoma
subtype. Lymphoepithelioma-like
carcinoma is considered a subtype of
this entity.
Undierentiated carcinoma is now
its own separate entity with many
subtypes (large cell carcinoma with
rhabdoid phenotype, pleomorphic
carcinoma, sarcomatoid carcinoma
and carcinoma with osteoclast-like
giant cells).
Micropapillary adenocarcinoma
is added as an aggressive subtype of
Gastroblastoma is added as an
Small bowel /
Ampullary carcinomas have
been incorporated into the small
bowel chapter, though the chapter
distinguishes between ampullary and
nonampullary carcinomas.
Intra-ampullary papillary-tubular
neoplasm has been added as a
subtype of ampullary adenoma.
Low grade appendiceal mucinous
neoplasm (LAMN) is formalized as a
separate entity rather than a form of
appendiceal adenocarcinoma.
High grade appendiceal mucinous
neoplasm (HAMN) is added as a
diagnostic entity similar to LAMN but
showing high grade dysplasia.
Goblet cell carcinoid is renamed
goblet cell adenocarcinoma, with
a new grading system. High grade
examples represent what was
previously termed “adenocarcinoma
ex goblet cell carcinoid” (Figure 1).
Tubular carcinoid and L-cell
carcinoid are renamed tubular NET
and L-cell NET, respectively.
Sessile serrated adenoma / polyp
is renamed to sessile serrated lesion,
with the reasoning that they are not
always polypoid on colonoscopy. Only
one unequivocally distorted crypt is
now needed to make this diagnosis.
Adenoma-like adenocarcinoma
is added as a subtype of colorectal
carcinoma (CRC) with a good
prognosis. Adenosquamous
carcinoma is also now considered a
CRC subtype.
Cribriform-comedo type
adenocarcinoma is removed as a CRC
Spindle cell carcinoma is renamed
to carcinoma with sarcomatoid
Rather than grading CRC based
on the predominant component,
Issue 12 || February 2020
By Raul S. Gonzalez, M.D.
Figure 1: Goblet cell carcinoid of
the appendix is renamed goblet cell
Sponsored by an unrestricted grant
from Mayo Clinic Laboratories
the WHO now recommends grading
based on the least dierentiated
component, regardless of amount.
Liver / Intrahepatic
bile ducts
Several subtypes of hepatocellular
carcinoma (HCC) have been
added: steatohepatitic, clear cell
(formerly a “cytological variant”),
chromophobe and neutrophil-rich.
The lymphoepithelioma-like subtype
is renamed to lymphocyte-rich.
Molecular features of HCC subtypes
are emphasized, particularly the
DNAJB1-PRKACA translocation of
brolamellar HCC.
Emphasis is placed on categorizing
intrahepatic cholangiocarcinoma into
large and small duct types.
Hepatoblastoma subtypes have
been reorganized, and calcifying
nested stromal-epithelial tumor is
separated out as a distinct entity
rather than a variant / related
The subtypes of combined HCC-
cholangiocarcinoma are less strictly
dened. Cholangiolocarcinoma is
moved from this classication scheme
and is now considered a type of small
duct cholangiocarcinoma instead.
Primary neuroendocrine neoplasms
of the liver have been formally added.
Gallbladder /
Extrahepatic bile
Grading of biliary intraepithelial
neoplasia (BilIN) is now two tier (low
and high grade) rather than three
Acinar cystadenoma is
ocially renamed acinar cystic
Pancreatic intraepithelial neoplasia
(PanIN) is now two tier. Numerical
grading (PanIN-1A, etc.) is no longer
Intraductal oncocytic papillary
neoplasm (IOPN) is established
as a distinct entity separate from
intraductal papillary mucinous
neoplasm (IPMN), due to a dierent
mutational prole (Figure 2).
The neuroendocrine section is
markedly expanded, including
discussion of each hormone
producing subtype and emphasis on
new molecular data.
Duodenal-type follicular
lymphoma, intestinal T cell
lymphoma NOS, indolent T cell
proliferative disorder of the
gastrointestinal tract and EBV
positive inammatory follicular
dendritic cell sarcoma are added as
distinct entities.
Monomorphic CD56+ intestinal
T cell lymphoma is renamed to
monomorphic epitheliotrophic
intestinal T cell lymphoma.
Malignant gastrointestinal
neuroectodermal tumor is added as
a distinct entity. It may represent the
same entity as clear cell sarcoma-like
tumor of the gastrointestinal tract or
a subtype.
Molecular information on
gastrointestinal stromal tumors
(GISTs) is added, in particular the
succinate dehydrogenase (SDH)
decient subtype.
Epithelioid inammatory
myobroblastic sarcoma is added
as an aggressive subtype of
inammatory myobroblastic tumor
with RANBP2 rearrangement.
New hemangioma subtypes
are specied: anastomosing
hemangioma, diuse hepatic
hemangiomatosis and hepatic small
vessel neoplasm.
Molecular data is added to
epithelioid hemangioendothelioma,
namely the characteristic WWTR1-
Several new polyposis syndromes
are added, including gastric
adenocarcinoma and proximal
polyposis syndrome (GAPPS),
NTHL1 associated polyposis,
polymerase proofreading associated
polyposis (caused by POLD1 or
POLE mutation), AXIN2 associated
polyposis and immune deciency
associated polyposis.
Familial pancreatic cancer
(caused by many potential germline
mutations) is added.
Criteria for serrated polyposis have
been modied: either (1) ≥ 5 serrated
lesions ≥ 5 mm in size proximal to the
rectum, with at least 2 ≥ 10 mm, or
(2) > 20 serrated lesions throughout
the colorectum, with ≥ 5 proximal to
the rectum.
Meet the
Figure 2: IOPN of pancreas is
ocially distinct from IPMN.
aul S. Gonzalez,
M.D. is an
Assistant Professor of
Pathology at Harvard
Medical School and the
Associate Director of
Gastrointestinal Pathology at Beth
Israel Deaconess Medical Center.
He is a Deputy Editor-in-Chief and
gastrointestinal pathology editor for
Pathology Outlines, Reviews Editor
for Histopathology, Membership
Chair for the Rodger C. Haggitt
Gastrointestinal Pathology Society
and Vice Chair for the College of
American Pathologists Surgical
Pathology Committee. He has
authored a liver pathology textbook
and has published more than 60
peer reviewed journal articles. He
has been invited to speak at multiple
national conferences and maintains
active social media pages dedicated
to gastrointestinal pathology. You
can follow Dr. Gonzalez on Twitter
@RaulSGonzalezMD, and join his
Facebook group for gastrointestinal
pathology at https://www.facebook.