Issue 26 || March 2024

WHAT’S NEW

IN PATHOLOGY?

The term “variant” has been replaced by

“subtype” to avoid confusion with genetic

variants; the former was historically widely

used in thyroid pathology

Gene fusion notation has been revised

according to the HUGO Gene Nomencla

ture Committee recommendations, replac-

ing the hyphen (-) or forward-slash (/) with

a double colon (::)

All key entities are supplied with a list of

essential and desirable diagnostic criteria

Nonneoplastic (tumor-like) lesions are

included as a part of the classication, for

differential diagnosis purposes and conve

nience of readers

Tumors not specic to particular organs/

systems (e.g., mesenchymal, hematolym

phoid, metastasis) are combined in separate

chapters, representing such entities from the

entire volume (i.e., endocrine)

Size and area

- Tumor size is reported in mm, not cm

- For mitotic count, tumor area is measured

in mm

and not in high-power elds (10

HPF are approximated as 2 mm

; detailed

conversion tables are available); this is

aimed for standardization and reects

adoption of digital pathology tools

• Thyroid tumors

The new WHO classication divides

follicular cell-derived neoplasms into

benign, low-risk, and malignant

Invasive encapsulated follicular variant of

papillary thyroid carcinoma (IEFVPTC) is

now a distinct entity and no longer a

subtype of papillary thyroid carcinoma

(PTC)

- IEFVPTC has a RAS-like mutational and

transcriptomic prole similar to that of

follicular adenoma (FA) and follicular

thyroid carcinoma (FTC)

- Classic PTC and the inltrative follicular

subtype of PTC are BRAF-like tumors

A grading concept (Table 1) is introduced

for differentiated and medullary thyroid

carcinomas (MTC)

WHAT’S NEW IN THYROID

PATHOLOGY 2024:

UPDATES FROM THE NEW

WHO CLASSIFICATION AND

BETHESDA SYSTEM

Andrey Bychkov

, Chan Kwon Jung

Department of Pathology, Kameda Medical Center,

Kamogawa, Japan

Department of Hospital Pathology, College of Medicine,

The Catholic University of Korea, Seoul, Korea

Corresponding Author:

Andrey Bychkov, MD, PhD, FRCPath

Department of Pathology, Kameda Medical Center,

Kamogawa, Japan

E-mail: bychkov.andrey@kameda.jp

ORCID

Andrey Bychkov

https://orcid.org/0000-0002-4203-5696

Chan Kwon Jung

https://orcid.org/0000-0001-6843-3708

Abstract

In line with the release of the 5th edition WHO

Classication of Tumors of Endocrine Organs

(2022) and the 3rd edition of the Bethesda System

for Reporting Thyroid Cytopathology (2023), the

eld of thyroid pathology and cytopathology has

witnessed key transformations. This digest brings

to the fore the rened terminologies, newly

introduced categories, and contentious method-

ological considerations pivotal to the updated

classication.

2022 WHO CLASSIFICATION

Changes in terminology and volume

structure

• Adopted in all WHO 5th edition volumes

(2019–2023; the iteration cycle of the Blue

Books is every 5 years)

- The new tumor type, high-grade follicular

cell-derived non-anaplastic thyroid carci

noma, has 2 histologic subtypes: tradition-

al poorly differentiated thyroid carcinoma

(PDTC) based on Turin criteria and a new

subtype, differentiated high-grade thyroid

carcinoma (DHGTC)

The new WHO thyroid classication has

been effective since its online release in

March 2022 and should be adopted by prac

ticing pathologists

- Pathologists are responsible for educating

clinicians about relevant changes and new

terminology

- Detailed and illustrated reviews are

available in subscription (Endocrine

Pathology 2022;33(1):27-63) and open

access (Endocrinology and Metabolism

2022;37(5):703-718; Endocrine

2023;80(3):470-476; Endocrine-Related

Cancer 2023;30(2):e220293) journals

Benign and low-risk neoplasms

• Thyroid follicular nodular disease (FND) was

introduced to describe a multifocal benign

proliferation with nodular hyperplasia

This terminology reects the complex blend

of nonclonal/hyperplastic and clonal/

neoplastic proliferations

Clinically ts to multinodular goiter; also

known as adenomatous nodules/hyperplasia

• Follicular adenoma with papillary architec

ture

Typically an autonomous hyperfunctioning

nodule with intrafollicular papillary growth

Differentiated from conventional follicular

adenoma by its specic gene (EZH1, TSHR

or GNAS) mutations

• A new group of low-risk follicular cell-de

rived neoplasia, coded borderline by ICD-O

(/1)

Includes noninvasive follicular thyroid

neoplasm with papillary-like nuclear

features (NIFTP), tumors of uncertain

malignant potential (FT-UMP and WDT-

UMP), and hyalinizing trabecular tumor

Extremely low risk of metastatic spread or

recurrence and excellent prognosis, but not

categorized as benign

• NIFTP

Diagnostic criteria not changed, including

<1% papillae cutoff

Newly added subtypes: oncocytic NIFTP,

subcentimeter NIFTP

Oncocytic tumors

• The term “Hürthle cell” has been replaced

with “oncocytic cell,” updating the names of

the related adenoma (OA) and carcinoma

(OCA)

Hürthle cell is a historical misnomer, a term

that originally described not oncocytic cells

but C cells in dogs

Oncocytic terminology is consistently used

across other locations (e.g., kidney, salivary)

Nevertheless, “Hürthle cell carcinoma”

remains an acceptable term because of wide

use by clinicians

• Not a standalone group like in the previous

edition but separate entities in benign

(adenoma) and malignant (carcinoma)

tumors. Nonetheless, both OA and OCA

share similar molecular mechanisms, such as

alterations in mitochondrial genes.

Encapsulated follicular

cell-derived carcinomas

• FTC and IEFVPTC, despite their identical

genomic proles (RAS-like) and clinical

behaviors, remain separate, but the future

edition may combine them into a single

diagnostic category, the follicular-patterned

differentiated thyroid carcinoma

• FTC, IEFVPTC, and OCA are categorized

into 3 subtypes: minimally invasive (capsular

invasion only), encapsulated angioinvasive,

and widely invasive (entirely obliterated or

with focally intact tumor capsule and/or

gross invasion through the gland)

Foci of vascular invasion in encapsulated

angioinvasive carcinomas should be count

ed, with <4 and ≥4 foci continuing to be

designated as limited and extensive angioin

vasion, respectively

Widely invasive FTCs are rare and require

ruling out PDTC and DHGTC

Papillary thyroid carcinoma

• PTC diagnosis requires a set of distinctive

nuclear features, plus either papillary or solid/

trabecular architecture or inltrative growth

in follicular-patterned tumors

Unlike in the previous editions, the impor

tance of PTC nuclear features is now

overshadowed by the molecular signature

This category is reserved only for the BRAF-

like neoplasms

- IEFVPTC is moved out, being a RAS-like

tumor

- The tumor formerly known as cribri

form-morular PTC no longer belongs to

PTC and is now listed among thyroid

tumors of uncertain histogenesis (see

below)

• 13 histologic subtypes exist based on pre

dominant pattern or other morphologic

features

• PTC with follicular pattern

The macrofollicular variant is no longer a

subtype of PTC

The only PTC subtype with a follicular

pattern is now inltrative follicular PTC

- Advanced inltrative follicular PTC may

have morphological overlap with widely

invasive IEFVPTC when the capsule of the

latter is almost completely lost, but the

genetic signature is different (BRAF-like

versus RAS-like)

• Papillary microcarcinoma

No longer considered a histopathological

subtype

Now required to be subtyped by the pattern

(e.g., classic PTC, 6 mm)

• Solid/trabecular PTC, which is more com

mon in children than in adults, is diagnosed

when >50% of the tumor has a solid,

trabecular or nested growth pattern (unlike

the “all or nearly all” cutoff in the previous

edition)

• Aggressive histologic subtypes of PTC: (1)

tall cell, (2) hobnail, (3) columnar cell

Tall cell PTC

- Tall cell is dened as being at least 3 times

taller than their width (unlike 2–3 to 1 in

the previous edition) as well as having

dense eosinophilic cytoplasm and distinct

cell membranes

- At least 30% of the tumor should be

composed of tall cells

Hobnail PTC

- Cutoff of hobnail cells is not explicitly

stated; supposed to remain ≥30%

- True hobnail cells should not be confused

with hobnail-like degenerative atypia

frequently seen in cystic PTC

Diffuse-sclerosing subtype is no longer

considered aggressive PTC

Aggressive PTCs are typically seen in older

patients, show angiovascular invasion,

advanced pathological stage and increased

Table 1. Histopathological grading scheme

Tumor type Tumor necrosis Mitoses per 2 mm

Ki67 index

PDTC Present ≥3 Not required

DHGTC Present ≥5 Not required

MTC

High-grade Present ≥5 ≥5%

Low-grade Absent <5 <5%

Fig. 1. Differentiated high-grade thyroid carcinoma. (A) High-grade FTC with necrosis (left) and mitosis (upper right). (B) High-grade PTC with mitotic activity.

mitotic activity

- In contrast, aggressive (by histologic

pattern) PTCs with an indolent clinical

course occur at a younger age, are usually

encapsulated or well circumscribed and

show low proliferation rate

Included in the ATA clinical risk stratica

tion system

Differentiated high-grade thyroid

carcinoma (DHGTC)

• This new category includes follicular cell-de-

rived carcinomas with high-grade features,

emphasizing the signicance of mitoses and

necrosis in differentiated thyroid carcinomas

(Fig. 1) and the lack of anaplastic foci

Necrosis may extend from focal and come

do-like to large areas; it should be distin-

guished from degenerative changes (e.g.,

cystic and oncocytic tumors)

Mitosis is counted in hot spots, per 2 mm

area

Unlike in MTC (see below), Ki67 is not

used for grading

• If an FTC or PTC has a mitotic count ≥ 5 per

2 mm

and/or necrosis, it is classied as

DHGTC

Most DHGTC develop from PTC, usually

aggressive subtypes

Recorded in diagnosis as “high-grade PTC

(FTC/OCA)”, followed by subtype

Fig. 3. High-grade MTC is identiﬁed by combination of mitotic activity (A, center) and tumor necrosis (B).

If an FTC with areas of solid or trabecular

growth has a mitotic count of ≥3 per 2 mm

and/or necrosis, it is diagnosed as PDTC

Anaplastic thyroid carcinoma (ATC)

• By denition, ATC is composed of undifferen-

tiated cells but may have focal features of

thyroid follicular differentiation and/or a

pre-existing differentiated thyroid carcinoma

• Primary squamous cell carcinoma of the thyroid

is now considered a histologic pattern of ATC

and not a standalone entity

• BRAF V600E detection by immunostaining

(Fig. 2) and/or genotyping should be performed

due to the availability of targeted therapy

Thyroid C cell-derived carcinoma

• MTC remains the archetypal neuroendocrine

neoplasm of the thyroid

Driven predominantly by RET and RAS

alterations

No known benign counterpart

• Grading (high versus low): based on mitotic

count, Ki67, and tumor necrosis

High-grade MTC (Fig. 3) must display at

least one of the following features: mitotic

count ≥5 per 2 mm

, tumor necrosis, Ki67

proliferation index ≥5%

High-grade MTCs are associated with lower

disease-specic survival and recurrence-free

survival rates; they constitute 10–20% of all

cases

Ki67 proliferation index should not rely

solely on eye-balling (approximate count);

instead, formal manual count or automated

image analysis is recommended

Grading of MTC is reserved for surgical

specimens

Salivary gland-type carcinomas of

the thyroid

• Salivary gland-type carcinomas of the thyroid

consist of mucoepidermoid carcinoma and

secretory carcinoma, previously known as

mammary analogue secretory carcinoma

(MASC)

• Secretory carcinoma and mucoepidermoid

carcinoma have specic gene fusions, ET

V6::NTRK3 fusion and CRTC1::MAML2

fusion, respectively

Thyroid tumors of uncertain

histogenesis

• A new category, thyroid tumors of uncertain

histogenesis, includes sclerosing mucoepider

moid carcinoma with eosinophilia (SMECE)

and cribriform-morular thyroid carcinoma

(CMTC); additional studies are needed to

further rene these neoplasms

• The previous classication, dated 2017,

considered SMECE a subtype of salivary

gland-type carcinomas of the thyroid gland

Fig. 2. BRAF-mutant ATC (A) detected by VE1 immunostaining (B).

SMECE is presumed to arise from solid cell

nests (ultimobranchial body remnants) and

has genetic alterations, such as MET

hyperploidy and mutations in APC,

NTRK3, and NF1

• CMTC, previously classied as a distinct

variant/subtype of PTC, is now listed as a

cancer type among thyroid tumors of

uncertain histogenesis

CMTC features genetic alterations involved

in the Wnt/beta-catenin pathway, such as

mutations in APC and CTNNB1; no cases

of CMTC with BRAF V600E have been

reported

- Nuclear expression of beta-catenin,

estrogen receptor, and progesterone

receptor

- No colloid formation; often negative for

markers of thyroid follicular cell differenti

ation (thyroglobulin and PAX8)

- Cribriform component is TTF1 positive,

but morulae are negative

Other tumors

The term “thyroblastoma” was introduced

for malignant teratomas or carcinosarcomas

with DICER1 mutations

Extranodal marginal zone lymphoma

(E-MZL) is a new preferred terminology for

MALT lymphoma

Molecular immunohistochemistry

• The role of immunohistochemistry is empha-

sized, necessitating robust methodology with

proper reagents, stringent validation proto

cols, and the use of positive controls

• Important biomarkers: surrogate immunos

tains (VE1, pan-TRK, SP174/RAS, ALK,

PTEN, beta-catenin), theranostic markers

(PDL1) (Cancers 2021;14(1):204)

2023 BETHESDA SYSTEM

• A 3rd edition of the Bethesda System for

Reporting Thyroid Cytopathology (TBSRTC)

was released in July 2023 and contains only

minor updates (Thyroid 2023;33(9):1039-

1044)

• TBSRTC assigns a single, distinct name for

each of its 6 diagnostic categories: (I) nondiag-

nostic, (II) benign, (III) atypia of undetermined

signicance (AUS), (IV) follicular neoplasm, (V)

suspicious for malignancy, (VI) malignant

Alternate names for 3 of the diagnostic catego-

ries (I/unsatisfactory, III/follicular lesion of

undetermined signicance, and IV/suspicious

for a follicular neoplasm) have been eliminated

to avoid confusion

TBSRTC 2023 continues to advise using the

category names and optionally, their corre-

sponding category numbers, e.g. benign

(Bethesda II), follicular neoplasm (Bethesda

IV)

• Each category is associated with an updated

risk of malignancy (ROM) based on new data

since the 2017 edition; clinical management

algorithms for each category have also been

revised

• AUS category is now divided into 2 subgroups

(Fig. 4): AUS-nuclear atypia and AUS-other,

with different implied ROM (higher in

AUS-nuclear) and molecular prole

The term “nuclear atypia” (previously known

as cytologic atypia) refers to mild nuclear alter-

ations, such as slight enlargement, pale

chromatin, and irregular contours

AUS-other includes architectural atypia;

oncocytic atypia; atypia, NOS; atypical

lymphoid cells, rule out lymphoma

• Follicular neoplasm (FN) is dened in 2

scenarios: “typical” FN without nuclear atypia

and “potential NIFTP/EFVPTC” with mild or

focal nuclear atypia

Fig. 4. AUS subtypes. AUS-nuclear atypia with mild nuclear changes (A) versus AUS-other (B).

Dr. Bychkov has been an author for

PathologyOutlines.com since 2015,

a part of the editorial board since

2016, and the subspecialty section

editor for Thyroid in 2017-2022.

He is currently the Director of

Digital Pathology at Kameda

Medical Center, Japan. His research

interests are thyroid histopathology

and digital pathology, and he was a

contributor to the 2022 WHO

classication of endocrine tumors.

Dr. Chan Kwon Jung is a Professor

of Pathology at The Catholic Uni

versity of Korea (Seoul). He is a

practicing endocrine pathologist

and cytopathologist, and was a

contributor to the 2022 WHO

classication of thyroid tumors.

Meet the Authors

• New discussions on pediatric thyroid disease

have been included, supplied with pediatric

ROMs and management algorithms

• Revised terminology in accordance with the

WHO 5th edition

• Two new chapters have been added, acknowl-

edging the importance of clinical perspectives,

imaging ndings, and the expanding role of

molecular testing in thyroid disease