Issue 24 || September 2023

WHAT’S NEW

IN PATHOLOGY?

KERATINOCYTIC/

EPIDERMAL TUMORS

• Keratoacanthoma is kept separate from

squamous cell carcinoma (SCC). Con-

tinued recognition that keratoacantho-

ma likely represents an SCC variant

with self-resolving potential (Fig. 1).

• Adenosquamous carcinoma has been

removed as an SCC subtype. It is

thought to represent squamoid eccrine

ductal carcinoma; discussed with

adnexal neoplasms.

• Merkel cell carcinoma (Fig. 2) desig-

nated a neuroendocrine carcinoma of

skin. In non-Merkel cell polyomavirus

(MCPyV)-associated cases, TP53 and

RB1 mutations seen in other neuroen-

WHAT’S NEW IN

DERMATOPATHOLOGY

2023: WHO 5TH EDITION

UPDATES

Jonathan Ho, MD

1,2

Chico J Collie, MD

Department of Pathology, The University of the West

Indies, Mona Campus, Jamaica W.I.

Division of Dermatology, Department of Medicine,

The University of the West Indies, Mona Campus,

Jamaica W.I.

Corresponding Author:

Jonathan D. Ho, MBBS, DSc, Dip Dermpath

Departments of Pathology and Medicine,

The University of the West Indies, Mona

Campus, Jamaica W.I.

E-mail: jonathan.ho@uwimona.edu.jm

ORCID

Jonathan Ho

https://orcid.org/0000-0002-8752-8769

Chico J Collie

https://orcid.org/0009-0005-5922-5516

Abstract

The 5th edition WHO Classication of

Skin Tumors (2022) has introduced

changes to nomenclature and diagnostics.

Important differences are discussed

below. Changes in each category of skin

tumor have been detailed, with particular

emphasis on meaningful advances in our

understanding of the molecular patho-

genesis of the skin’s diverse tumor land-

scape.

docrine carcinomas are identied.

Origin cell remains unclear.

MELANOCYTIC

NEOPLASMS

• Advanced understanding of the molec-

ular pathways in melanocytic lesions

have led to denition changes. Re-

strained proliferation of activated

oncogenes by tumor suppressor genes

leads to nevi, while additional muta-

tions and escape from tumor suppressor

gene control result in intermediate/

malignant neoplasms (Annu R

Pathol 2014;9:239-271).

Fig. 1. Keratoacanthoma. This crateriform squamous cell carcinoma variant possesses self-resolving potential.

Thick glassy epithelium (yellow dot) may regress via thinner basophilic epithelium (green dot) as shown in the

image.

Sponsored by an unrestricted grant from

The University of the West Indies, Mona - Department of Pathology

• Nevi: clonal neoplasms with a single

mutation, no other pathogenic chang-

es, bland cytologic appearance and

benign behavior.

• Melanocytomas: intermediate neo-

plasms between nevi and melanomas

harboring > 1 driver mutation. Display

atypical histopathologic features and

potential for local recurrence. Second

mutations affect specic pathways

resulting in reproducible clinical and

microscopic features.

• Some melanocytomas (previously

designated “nevi”) have been renamed

to reect respective specic pathway

aberrations and their intermediate

status.

- Wnt-activated deep penetrating/

plexiform melanocytoma (Fig. 3)

- Pigmented epithelioid melanocytoma

(PEM, also known as PRKAR1A-in-

activated melanocytoma)

- BAP1-inactivated melanocytoma

- Spitz melanocytoma (previously

atypical Spitz tumor)

- Microphthalmia-associated transcrip-

tion factor (MITF) pathway-activated

melanocytic tumors, see below

• Immunohistochemistry can aid in

diagnosis:

- Loss of expression of PrkAr1a in some

PEM

- Diffuse nuclear

-catenin, nuclear

LEF1 in Wnt-activated deep pene-

trating/plexiform melanocytoma (Am

J Surg Pathol 2020;44:1413-1418).

- Loss of nuclear BAP1 expression in

BAP1-inactivated melanocytoma

• MITF pathway-activated melanocytic

tumors are a newly introduced set of

melanocytomas with cytoplasmic clear-

ing and fusion genes resulting in

overactive MITF functioning (Am J

Surg Pathol 2021;45:962-968; Vir-

chows Arch 2021;479:841-846). Main

differentials include clear cell sarcoma,

PEComa, melanoma and carcinomas.

Two variants are described

- Clear cell tumor with melanocytic

differentiation and ACTIN::MITF

Translocation (CCTMAM)

Cutaneous nodule

Dermal based +/- subcutis. Marked

cytoplasmic clearing. Low/high-

grade nuclear features but mitoses

are inconspicuous and the lesion

lacks ulceration or perineural inva-

sion. MART-1, HMB45, S100,

MITF positive. Pankeratin negative.

- Clear cell tumor with melanocytic

differentiation and MITF::CREM

translocation (CCTMMC)

Cutaneous nodule

Dermal based +/- subcutis

Fig. 2. Merkel cell carcinoma (primary cutaneous neuroendocrine carcinoma of skin). The tumor demonstrates

round blue cells with a characteristic ﬁnely dispersed “salt and pepper” chromatin pattern. Both Merkel cell

polyomavirus associated and non-associated cases exist.

Fig. 3. Wnt-activated deep penetrating/plexiform melanocytoma. This tumor lacks maturation with descent,

displays nested/plexiform melanocytes with visible nucleoli, some nuclear pleomorphism, nuclear pseudoinclu-

sions, and melanophages. Expresses nuclear

-catenin and LEF1.

Marked cytoplasmic clearing (high-

grade areas may lack clear cell

change). Perineural invasion and

increased mitotic rate described. No

ulceration or vascular invasion

reported.

Diffuse MART1, S100, SOX10 and

MITF. Patchy HMB45. Pankeratin

negative.

• Language endorsements for lesions

lacking clear diagnostic criteria

- Supercial atypical melanocytic

proliferation of uncertain signicance

(SAMPUS) and intraepidermal

atypical melanocytic proliferation of

uncertain signicance (IAMPUS) for

lesions falling short of radial growth

phase or in-situ melanoma, respec-

tively. These designations imply

virtually no risk of distant spread.

- Melanocytic tumor of uncertain

malignant potential (MELTUMP) for

neoplasms where vertical growth

phase of melanoma is the main

alternative and thus the uncertainty

lies in potential metastatic risk.

ADNEXAL TUMORS

• Updates in molecular pathology of

adnexal tumors

- Most poromas and some porocarcino-

mas harbor gene fusions

YAP1::MAML2 or YAP1::NUTM1 (J

Clin Invest 2019;129:3827-3832).

Immunohistochemistry with NUT

identies those with NUTM1 rear-

rangements

- Some hidradenomas exhibit CRT-

C1::MAML2 fusion gene.

- ALPK1 mutations activating NF-

pathway in some spiradenomas and

spiradenocarcinomas (mutually

exclusive from CYLD mutations).

- ETV6::NTRK3 translocation and

NFIX::PKNI fusion in cutaneous

secretory carcinoma.

• Cutaneous NUT carcinoma newly

introduced (provisional)

- Rarely described BRD3::NUTM1 or

NSD3::NUTM1 rearranged tumors

(Am J Surg Pathol 2021;45:1582-

1584).

- Dermal, inltrating neoplasm ar-

ranged in islands, cords and/or nests.

- Glandular and squamoid differentia-

tion with abrupt keratinization.

- Vesicular nuclei, prominent nucleoli.

- Positive NUT immunohistochemis-

try; CEA/EMA highlight ductules.

- Metastatic potential

• Cribriform carcinoma is renamed as

cribriform tumor; denite malignant

potential is unclear.

TUMORS OF THE NAIL UNIT

• Newly introduced section encompass-

ing:

- Onychomatricoma (Fig. 4)

- Onychopapilloma

- Ungual brokeratoma

- Onychocytic matricoma

- Subungual keratoacanthoma

TUMORS OF HEMATOPOIETIC

AND LYMPHOID ORIGIN

• Dendritic cell neoplasms

- Introduction of mature plasmacytoid

dendritic cell proliferation (MPDCP)

associated with myeloid neoplasm.

- MPDCP is a proliferation of plasma-

cytoid dendritic cells with low-grade

cytology occurring in patients with

known myeloid neoplasms (most

commonly chronic myelomonocytic

leukemia and acute myeloid leukemia).

• Histiocytic neoplasms

- ALK-positive histiocytosis: A histio-

cytic neoplasm that may histological-

ly resemble juvenile xanthogranuloma

and is characterized by ALK gene

rearrangement and positive ALK

immunohistochemistry.

- Indeterminate dendritic cell tumor

replaces indeterminate dendritic cell

“histiocytosis”. The denitive cell of

origin remains unclear.

- BRAF V600E mutations in Langer-

hans cell histiocytosis increase risk of

relapse, severe clinical manifestations

and treatment failure (J Clin Oncol

2016;34:3023-3030). Patients may

benet from targeted BRAF inhibitor

therapy.

Fig. 4. Onychomatricoma. Note typical papillomatous projections of matrical-type epithelium with deep

V-shaped invaginations. Subjacent spindle cell proliferation expresses CD34.

• T-cell and NK-cell lymphoproliferative

disorders and neoplasms

- Primary cutaneous T-cell lymphomas

(PCTCL) are all listed as individual

entities including those previously

labeled “rare subtypes”, i.e., subcuta-

neous panniculitis-like T-cell lym-

phoma, extranodal NK/T-cell lym-

phoma, primary cutaneous CD8+

aggressive epidermotropic cytotoxic

T-cell lymphoma, primary cutaneous

γ/δ

T-cell lymphoma, primary cuta-

neous CD4-positive small or medium

T-cell lymphoproliferative disorder,

and primary cutaneous acral

CD8-positive lymphoproliferative

disorder.

- Cutaneous CD8-positive acral T-cell

lymphoma reclassied as a lymphop-

roliferative disorder. This entity is

indolent with excellent long-term

outcomes.

- “Primary cutaneous peripheral T-cell

lymphoma, not otherwise specied

(NOS)” should be used for cases that

cannot be classied as a known

PCTCL subtype.

- Newly introduced section on inborn

error of immunity-associated lymph-

oproliferative disorders, which are

CD8+ T-cell rich dermal inltrates

+/- granulomatous inammation

associated with inborn immunode-

ciencies. May present as nodules,

papules or ulceronecrotic lesions.

EBV in-situ hybridization must be

negative.

SOFT TISSUE TUMORS

• Introduction of four new entities:

- CRTC1::TRIM11 cutaneous tumor:

dermal-based neoplasm characterized

by well-circumscribed proliferation of

spindled/epithelioid cells with pale

cytoplasm. Arranged in nests/fascicles

and may or may not have a vaguely

palisaded appearance. Diffuse SOX10

expression; variable positivity for

S100 and other melanocytic markers.

CRTC1::TRIM11 fusion. Most

commonly seen on the extremities.

Generally indolent but may recur

locally or metastasize (Am J Surg

Pathol 2019;43:861-863; Histopa-

thology 2023;82:368-371).

- Supercial CD34-positive broblastic

tumor: indolent neoplasm occurring

in the skin and subcutis with a

predilection for the extremities.

Characterized by a mixture of spin-

dled and epithelioid cells with mod-

erate pleomorphism, prominent

nucleoli, nuclear pseudoinclusions

and eosinophilic cytoplasm (granular/

glassy). Admixed mixed inammato-

ry cells are characteristic. Diffuse

CD34, PRDM10, and CADM3

expression. AE1/AE3 positivity

>50%. PRDM10 rearrangement in

>50% of cases (Mod Pathol

2022;35:767-776). Excision is cura-

tive in most cases.

- EWSR1::SMAD3 rearranged bro-

blastic tumor: well-demarcated super-

cial tumor exhibiting intersecting

fascicles of bland broblastic spindle

cells peripherally and relatively

acellular, hyalinized collagen centrally

(may lack clear zones). Diffuse nuclear

ERG positivity; negative for SMA,

EMA, SOX10, CD34, S100. EWS-

R1::SMAD3 fusion present. Benign

tumor; may have local recurrence.

- NTRK-rearranged spindle cell neo-

plasm: group of spindle cell lesions

with frequent NTRK rearrangements,

most commonly seen in children.

Involves the dermis and subcutis with

a spectrum of appearances, including

bland spindle cells in brous septa

entrapping mature fat to highly cellu-

lar lesions with sheets/fascicles of

spindle cells. Foci of high-grade

atypia is possible. Variable CD34,

SMA, S100 positivity. Diffuse pan-

TRK positivity if NTRK fusion present.

• Atypical intradermal smooth muscle

neoplasm remains the preferred termi-

nology for smooth muscle tumors with

cytologic atypia limited to the dermis.

Lesions have limited metastatic poten-

tial and an excellent prognosis once

completely excised.

• Epithelioid brous histiocytoma is

classied as being of uncertain differen-

tiation rather than a dermatobroma

subtype.

GENETIC TUMOR

SYNDROMES

ASSOCIATED WITH SKIN

MALIGNANCIES

Newly introduced section detailing

tumor syndromes with cutaneous neo-

plasms including:

• Familial melanoma

• BAP1 tumor predisposition syndrome

• Xeroderma pigmentosum

• Nevoid basal cell carcinoma syndrome

(Gorlin syndrome)

• Carney complex

• Muir-Torre syndrome

• Brooke-Spiegler and related syndromes

Dr. Jonathan Ho has been an au-

thor for PathologyOutlines.com

since 2021 and the Deputy Editor

for Dermatopathology since Janu-

ary 2023. He is currently a Lecturer

at The University of the West

Indies, Mona Campus, Jamaica

where he practices dermatopatholo-

gy and dermatology and is the

Co-Director of the dermatology

residency program.

Dr. Chico Collie has been a resident

author for PathologyOutlines.com

since 2021. He is the Chief Resi-

dent in Pathology at the University

of the West Indies, Mona Campus,

Jamaica. He is passionate about

surgical pathology, with a subspe-

cialty interest in dermatopathology.

Meet the Authors