localization, and are highlighted in

this newsletter.

MATURE T-CELL AND

NK-CELL LEUKEMIAS

• T-prolymphocytic leukemia (T-PLL)

• T-large granular lymphocytic leuke

mia (T-LGLL)

• Adult T-cell leukemia/lymphoma

(ATLL)

• Aggressive NK-cell leukemia (ANKL)

• Sezary syndrome

This group includes entities that

mostly present in a leukemic phase.

T-PLL requires monoclonal T-cell

lymphocytosis (> 5

/L), T-cell

monoclonality and aberrations in

TCL1A or MTCP1.

T-LGLL with STAT3 mutations is

associated with cytopenias, spleno

megaly and autoimmune diseases.

ATLL has shown new immune eva

sion mechanisms: CTLA4::CD28,

ICOS::CD28, REL truncations, varia

tions of CD274, and alterations in

HLA-A and HLA-B. ANKL is associ

ated with mutations in the JAK/

STAT pathway, epigenetic modiers

and immune checkpoints. Although

Sezary syndrome is much closer to

mycosis fungoides, it is discussed here

because of its leukemic presentation,

mimicking the other leukemic pro

cesses.

Issue 23 || June 2023

WHAT’S NEW IN

HEMATOPATHOLOGY

2023: UPDATES ON

MATURE T-CELL

NEOPLASMS IN THE 5TH

EDITION OF THE WHO

CLASSIFICATION

Mario L. Marques-Piubelli, MD

Roberto N. Miranda, MD

Department of Translational Molecular Pathology,

The University of Texas MD Anderson Cancer Center,

Houston, TX, USA

Department of Hematopathology, The University of

Texas MD Anderson Cancer Center, Houston, TX, USA

Corresponding Author: Roberto N. Miranda, MD

Department of Hematopathology, The University of

Texas MD Anderson Cancer Center, Houston, TX, USA

E-mail: roberto.miranda@mdanderson.org

ORCID

Mario L. Marques-Piubelli

https://orcid.org/0000-0002-6324-2096

Roberto N. Miranda

https://orcid.org/0000-0002-8467-5464

Abstract

The overview of the upcoming Blue

Book of the 5th edition of the World

Health Organization Classication of

Hematolymphoid Tumors was pub

lished in Leukemia in June 2022. The

updates on mature T-/NK-cell lym

phomas and leukemias are organized

in nine groups based on cell of origin,

morphology, clinical scenario, and

PRIMARY CUTANEOUS

T-CELL LYMPHOID

PROLIFERATIONS AND

LYMPHOMAS (CTCL)

• Primary cutaneous CD4+ small or

medium T-cell lymphoproliferative

disorder

• Primary cutaneous acral CD8+

lymphoproliferative disorder

• Mycosis fungoides

• Primary cutaneous CD30-positive

T-cell lymphoproliferative disorder:

lymphomatoid papulosis

• Primary cutaneous CD30-positive

T-cell lymphoproliferative disorder:

primary cutaneous anaplastic large

cell lymphoma

• Subcutaneous panniculitis-like

T-cell lymphoma

• Primary cutaneous gamma/delta

T-cell lymphoma

• Primary cutaneous CD8-positive

aggressive epidermotropic cytotoxic

T-cell lymphoma

• Primary cutaneous peripheral T-cell

lymphoma (PTCL), NOS

These are well-known disorders as

noted in previous WHO editions, 9

in total. The most signicant change

is the removal of the umbrella term of

PTCL from which 4 different entities

have been derived, including PTCL,

NOS to emphasize that the CTCL are

still difcult to classify (Leukemia

2022;36:1720-1748). It is expected

WHAT’S NEW

IN PATHOLOGY?

that the publication of the 5th edition

will abound with underlying molecu

lar mechanisms for each of the disor-

ders in this group. The diagnostic

criteria for each entity are well dened

from previous editions. It is acknowl

edged that mycosis fungoides has a

range of clinical and histologic sub

types, and it is of interest that its

folliculotropic subtype has divergent

outcomes when comparing early with

advanced stage cases. Because of

overlapping clinical, pathologic and

immunophenotypic features of these

9 entities, clinical correlation is more

valid than ever for achieving the most

accurate diagnosis.

INTESTINAL T-CELL AND

NK-CELL LYMPHOID

PROLIFERATION AND

LYMPHOMAS

• Indolent T-cell lymphoma of the

gastrointestinal tract

• Indolent NK-cell lymphoprolifera

tive disorder (LPD) of the gastroin-

testinal tract

• Enteropathy-associated T-cell lym

phoma

• Monomorphic epitheliotropic

intestinal T-cell lymphoma

• Intestinal T-cell lymphoma, NOS

There may be an increased frequency

of reported intestinal lymphoma,

likely due to its recognition as a

distinct group. The category of intes

tinal LPD and lymphomas includes 2

indolent disorders. The indolent

T-cell lymphoma (Fig. 1) has been

observed to have signicant morbidity

over time, including dissemination.

Alterations in the JAK/STAT path

way and mutations of epigenetic

modiers are more common in CD4+,

CD4+/CD8+, and CD4-/CD8- sub

Fig. 1. Expansion of the lamina propria by small-sized and mature-appearing lymphocytes in indolent T-cell

lymphoma of the gastrointestinal tract.

Fig. 2. Bone marrow core biopsy involved with HST-

CL shows hypercellularity displaying small and hy-

polobated megakaryocytes, morphologically consis-

tent with dysmegakaryopoiesis, raising the possibility

of underlying myelodysplastic syndrome.

Fig. 3. CD3 immunostaining shows that the lympho-

cytes have a sinusoidal pattern characterized by

clusters of lymphocytes in a cord-like pattern in HSTCL.

sets. The indolent NK-cell LPD

seems to behave more as an enteropa

thy, have no aggressive behavior and

carry JAK3 mutations. Lesions are

well circumscribed and small, but

cells show moderate atypia, therefore

NK-cell LPD can be confused with

extranodal NK/T-cell lymphoma

which is associated with EBV. The

other entities in the group of intesti

nal lymphomas remain unchanged.

HEPATOSPLENIC T-CELL

LYMPHOMA (HSTCL)

This rare lymphoma is difcult to

diagnose due to its well-known pro

tean presentation, histopathology

(Fig. 2, 3), phenotype and clinical

aggressiveness; it is also a diagnosis

that may portend allogenic stem cell

transplant as the only means of

achieving cure. Not only young, but

also adult patients can be affected.

HSTCL usually presents at stage IV.

The diagnosis can be missed in a bone

marrow that mimics a myelodysplas

tic syndrome, and the spectrum of

tumor cells may resemble blasts of

acute leukemia. TCR

γδ

is expressed in

~75% of cases, TCR

αβ

is expressed in

~20% and TCR is silent in 5% of cases.

ANAPLASTIC LARGE CELL

LYMPHOMAS (ALCL)

• ALK+ ALCL

• ALK- ALCL

• Primary cutaneous CD30-positive

T-cell lymphoproliferative disorder:

primary cutaneous ALCL (see also

CTCL)

• Breast implant-associated ALCL

These lymphomas have in common a

pleomorphic cytomorphology, uni

form and strong expression of CD30

and conspicuous absence of T-cell

lineage markers. Four entities are

recognized, 2 systemic and 2 site-

specic forms. The systemic entities

are divided by the presence of ALK

gene rearrangement, as ALK+ and

ALK- ALCL. Patients with ALK+

ALCL are usually young, while ALK-

ALCL (Fig. 4) patients are adults and

elders. Patients with ALK+ have

better outcomes than patients with

ALK- ALCL. ALK- ALCL can have

DUSP22 or TP63 rearrangements,

with the latter conveying the worst

outcomes. Of interest, cases with

DUSP22 rearrangements show a

uniform cytomorphology, with dough

nut-like cells and LEF1 expression.

The site-specic forms of ALCL

include the primary cutaneous ALCL

that is grouped together with primary

Fig. 5. Cytologic preparation of an effusion around a breast implant in a case of BIA-ALCL shows large and

atypical cells with irregular nuclear contours, inconspicuous nuclei and abundant cytoplasm with small inclusions.

Fig. 6. Breast capsule with BIA-ALCL shows large

and neoplastic cells conﬁned to the luminal space in

a necrotic background.

Fig. 7. CD30 immunostaining shows diffuse and

strong cytoplasmic and nuclear positivity in the BIA-

ALCL cells.

cutaneous T-cell LPD and lympho-

mas, and breast implant-associated

ALCL (BIA-ALCL). BIA-ALCL (Fig.

5–7) is associated with textured

implants and has an excellent out

come if surgically excised with nega-

tive margins. Patients with non-

resectable disease require chemo- or

immunotherapy.

NODAL T-FOLLICULAR

HELPER CELL

LYMPHOMAS (NTFHL)

• Nodal T-follicular helper cell lym-

phoma angioimmunoblastic-type

(nTFHL-AI): formerly angioimmu

noblastic T-cell lymphoma

• Nodal T-follicular helper cell lym

phoma follicular-type (nTFHL-F):

formerly follicular T-cell lymphoma

• Nodal T-follicular helper cell lym

phoma, NOS (nTFHL-NOS);

formerly PTCL with TFH pheno

type that does not meet criteria for

nTFHL-AI or nTFHL-F

This group includes 3 nodal TCL

with T-follicular helper phenotype (≥

2 markers are required for diagnosis:

PD1, ICOS, CXCL13, CD10, BCL6,

CXCR5, SAP, c-MAF and CD200),

derived from gene expression signa

ture of CD4+ lymphocytes. There is

morphologic overlap between these

entities, and the prototype is nTFHL-

AI (Fig. 8, 9). While the 3 entities

Fig. 4. Lymph node involved by ALK- ALCL shows

diffuse replacement of normal architecture by large

and anaplastic lymphocytes with no distinct nucleoli;

some of them have a doughnut-like shape.

have mutations of RHOA and IDH2,

nTFHL-AI has also recurrent muta

tions of TET2 and DNMT3A in

hematopoietic precursors. The diag

nosis of nTFHL is recommended for

small samples and to avoid misclas

sication.

OTHER PERIPHERAL

T-CELL AND NK-CELL

LYMPHOMAS

• PTCL, NOS

This entity remains as a heteroge

neous group of neoplasms and the

diagnosis is performed based on the

exclusion of other described entities.

Two distinct biological groups can be

identied using T-cell markers by

immunohistochemistry: PTCL-

TBX21 (PTCL-TH1) and PTCL-

GATA3 (PTCL-TH2). The PTCL-

TH1 group is usually associated with

a cytotoxic phenotype, while the

PTCL-TH2 group is a more heteroge

neous group and is associated with

poorer outcomes. Although these

important biological mechanisms

have been described, the experts

concluded that there is still insuf

cient data to perform systematic

classication in subtypes (Leukemia

2022;36:1720-1748).

Dr. Marques-Piubelli has been part

of the PathologyOutlines.com

hematopathology editorial board

since 2021. He is an Assistant

Professor in the Department of

Translational Molecular Pathology,

at The University of Texas MD

Anderson Cancer Center.

Dr. Miranda has been part of the

PathologyOutlines.com hematopa-

thology editorial board since 2021.

He is a Professor in the Department

of Hematopathology, The

University of Texas MD Anderson

Cancer Center.

Meet the Authors

Fig. 8. nTFHL-AI with effacement of the nodal archi-

tecture and inﬁltration of the capsule and subcapsu-

lar sinus.

Fig. 9. Positivity for the checkpoint molecule PD-1 in

scattered lymphoma cells supports a T follicular

helper phenotype in a case of nTFHL-AI.

EBV-POSITIVE NK/T-CELL

LYMPHOMAS

• EBV-positive nodal T- and NK-cell

lymphoma (EBV+ NTNKL)

• Extranodal NK-T-cell lymphoma

(ENKTL)

This is a group of mature lymphomas

with NK/T phenotype that are associ

ated with EBV infection. The EBV+

NTNKL is a distinct entity that was

under the PTCL, NOS umbrella in

the previous WHO classication. The

disease is more common in East Asians

and presents with extensive lymph

adenopathy and sometimes extranodal

involvement. Angioinvasion and

coagulative necrosis are usually absent

and there is no clear cut-off for EBV

positivity. The ENKTL is an updated

denomination where the qualier

“nasal-type” is dropped, following

primary tumors found in diverse extra

nodal sites. Importantly, the use of

L-asparaginase-based regimens has

resulted in improved outcomes in

affected patients.

EBV-POSITIVE T- AND

NK-CELL LYMPHOID

PROLIFERATIONS AND

LYMPHOMAS OF

CHILDHOOD

• Chronic active EBV disease (CAE-

BVD)

- Severe mosquito bite allergy

(SMBA)

- Hydroa vacciniforme lymphoprolif

erative disorder (HVLPD) classic

form

- Hydroa vacciniforme lymphoprolif

erative disorder (HVLPD) systemic

form

- Systemic CAEBVD

• Systemic EBV-positive T-cell lym

phoma of childhood

EBV+ NK/T-cell LPD and lympho

mas of childhood comprise an uncom-

mon group of disorders that mostly

affect children of Asian and native

American ethnic ancestry. CAEBVD

has a broad clinical spectrum, which

ranges from localized, mostly cutane

ous forms to systemic disease with

fever, hepatosplenomegaly and

lymphadenopathy. The systemic form

of HVLPD should be distinguished

from systemic CAEBVD, which has a

more aggressive behavior.