Issue 25 || December 2023

WHAT’S NEW

IN PATHOLOGY?

summarize the notable changes to blad-

der, prostate, testis, and penis based on

the 5th edition of the WHO.

URINARY TRACT

Inverted urothelial papilloma

• This is reserved for almost exclusively

inverted lesions and continues to be in

a separate section.

• Use of the descriptor “inverted” in

other papillary tumors with inverted

histology (non-invasive papillary

urothelial carcinoma and papillary

urothelial neoplasm of low malignant

potential) is discussed within each

respective section in the WHO.

Non-invasive papillary urothelial

carcinoma, low-grade

• Papillary urothelial hyperplasia and

urothelial proliferation with undeter-

mined malignant potential (tented

architecture with short, non-branching

papillae covered by mildly atypical

urothelium) are no longer regarded as

distinct entities but are considered

early low-grade non-invasive papillary

carcinoma.

Non-invasive papillary urothelial

carcinoma, high-grade

• To address grade heterogeneity, there

are now new proposed criteria for

reporting papillary tumors.

– A tumor with ≥ 5% high-grade compo-

nent is diagnosed as “high-grade”.

WHAT’S NEW IN

GENITOURINARY

PATHOLOGY 2023:

WHO 5TH EDITION

UPDATES FOR URINARY

TRACT, PROSTATE,

TESTIS, AND PENIS

Bonnie Choy, MD

Maria Tretiakova, MD, PhD

Debra L. Zynger, MS, MD

Department of Pathology Northwestern University

Feinberg School of Medicine, Chicago, IL, USA

Department of Laboratory Medicine and Pathology,

University of Washington, Seattle, WA, USA

Department of Pathology, The Ohio State University

Wexner Medical Center, Columbus, OH, USA

Corresponding Author:

Debra L. Zynger, MS, MD

Department of Pathology, The Ohio State University

Wexner Medical Center, Columbus, OH, USA

E-mail: debra.zynger@osumc.edu

ORCID

Bonnie Choy

https://orcid.org/0000-0002-3670-3715

Maria Tretiakova

https://orcid.org/0000-0002-0819-9638

Debra L. Zynger

https://orcid.org/0000-0003-1038-5699

Abstract

The 5th edition WHO Classication of

Urinary and Male Genital Tumours

(2022) introduced many signicant

changes relevant to urologic daily prac-

tice, mainly to renal tumors which was

covered in the What’s New newsletter in

September 2022. In this newsletter, we

– A tumor with < 5% high-grade

component is diagnosed as “low-

grade with < 5% high-grade

component”.

Urothelial carcinoma in situ

• Urothelial dysplasia is no longer

discussed in its own section but contin-

ues to be used as a diagnostic term for

lesions that fall short of carcinoma in

situ, despite the lack of reproducible

criteria.

Invasive urothelial carcinoma

• Presence of TERT promoter mutations

can help to: 1) distinguish urothelial

carcinoma from a non-neoplastic prolif-

erative process and 2) establish urothe-

lial origin.

• Advanced urothelial carcinoma with

FGFR3 alterations may be eligible for

treatment with anti-FGFR agents,

while mutations in ERCC2 and other

DNA damage repair genes may deter-

mine those likely to benet from

cisplatin-based chemotherapy.

• Predictors of response to immune

checkpoint inhibitors include PDL1

expression in tumor and host immune

cells, tumor mutation burden, and

microsatellite instability/mismatch

repair defect status.

• Terminology is standardized to charac-

terize genetic alterations as “variants,”

distinct morphologies as “histologic

patterns,” and unique morphologies

with prognostic signicance as tumor

“subtypes.”

• Muscle-invasive bladder carcinoma is

divided into 6 molecular subgroups

with differing prognosis: luminal-pap-

illary (24%), luminal non-specied

(8%), luminal-unstable (15%), stro-

ma-rich (15%), basal-squamous (35%),

and neuroendocrine-like (3%).

PROSTATE

Prostatic intraepithelial

neoplasia

• Low-grade prostatic intraepithelial

neoplasia has no increased risk of cancer

detection and it is not possible to

reliably differentiate from benign

glandular hyperplasia; thus it was

removed as a reportable entity.

Intraductal carcinoma of the

prostate (IDC-P)

• The cribriform growth pattern of

high-grade prostatic intraepithelial

neoplasia (HGPIN) is no longer re-

garded as a distinct entity but rather a

spectrum of intraductal proliferation

that falls between HGPIN and IDC-P;

it is increasingly being referred to as

atypical intraductal proliferation

(AIP), although there is no consensus

on the best terminology.

• IDC-P may represent two distinct enti-

ties: 1) the majority are late events

associated with invasive high-grade

carcinoma spreading into non-neoplas-

tic prostatic ducts and acini and 2) a

small subset which arises from a HG-

PIN precursor and may represent

carcinoma in situ.

• The presence of IDC-P should be

reported but whether to incorporate

areas of IDC-P into Gleason grading

remains controversial, with diverging

recommendations by leading societies.

Prostatic acinar adenocarcinoma

• PIN-like carcinoma is now discussed

as a subtype of acinar adenocarcinoma

(Fig. 1). It generally has favorable

behavior and has the recent distinctive

molecular nding of frequent activat-

ing mutations in the RAF/RAS path-

way.

• Prostate cancers harboring homologous

recombination repair defects may re-

spond to poly (ADP-ribose) polymerase

(PARP) inhibition, while those with

mismatch repair defects may respond to

immune checkpoint inhibitors.

Adenoid cystic (basal cell)

carcinoma of the prostate

• Adenoid cystic carcinoma of the pros-

tate is now the preferred diagnostic

term, renamed from basal cell carcinoma,

to avoid confusion with the skin tumor.

TESTIS

Noninvasive germ cell neoplasia

• Gonadoblastoma has been moved from

the category called “tumor containing

both germ cell and sex cord-stromal

elements” into the category “noninva-

sive germ cell neoplasia”.

Fig. 1. PIN-like prostatic adenocarcinoma. A. It is comprised of large discrete glands with ﬂat or tufted pseu-

dostratiﬁed epithelium. B. Immunostaining with HMWCK highlights lack of basal cells in PIN-like carcinoma focus.

Germ cell tumors derived from

germ cell neoplasia in situ

• Teratoma is regarded as containing a

somatic-type malignancy if the compo-

nent that resembles a neoplasm has

overgrowth of at least a 5 mm focus

(consistent with the previous denition

of 1 eld at 4x magnication).

• Somatic malignancy composed of

immature neuroectoderm was formerly

referred to as primitive neuroectoder-

mal tumor (PNET) but has been

renamed to teratoma with embryon-

ic-type neuroectodermal tumor (Fig.

2). This helps avoid confusion with the

unrelated tumor, Ewing sarcoma.

Germ cell tumors unrelated to

germ cell neoplasia in situ

• Well-differentiated neuroendocrine

tumor is renamed testicular neuroen-

docrine tumor, prepubertal-type.

Sex cord stromal tumors

• The recently proposed Leydig cell

tumor Scaled Score (LeSS), in which

Leydig cell tumor is classied as high

or low risk based on size, mitoses,

necrosis, inltrative pattern, and

vascular invasion, is mentioned in the

WHO but is noted to require further

validation (Fig. 3).

• Leydig cell tumor can be FH decient

and this may merit FH testing, partic-

ularly in high risk tumors in which

mutations may occur more frequently.

• Sertoliform cystadenoma of the rete

testis has been moved from being

classied as an adenoma within the

tumors of the collecting duct and rete

testis, to being a part of Sertoli cell

tumor.

• The signet ring pattern of Sertoli cell

tumor is now listed as a separate tumor

called signet ring stromal tumor (Fig.

4). It is composed of signet ring cells

which do not contain mucin, is positive

for vimentin and

-catenin, and is

negative for inhibin. These tumors

appear to have indolent behavior.

• Myoid gonadal stromal tumor has

been changed from a provisional entity

to a conrmed entity. This tumor

features densely packed, bland spindle

cells positive for SMA and S100. Re-

ported tumors have indolent behavior.

Paratesticular mesothelial

tumors

• Well-differentiated papillary mesothe-

lioma is renamed to well-differentiated

papillary mesothelial tumor.

Fig. 2. Teratoma with embryonic-type neuroectodermal tumor. The area with exclusive somatic malignancy

spanned over 3 cm.

Fig. 3. Leydig cell tumor with lymphovascular invasion, categorized as high risk by LeSS.

PENIS

• The terminology for squamous cell

carcinoma groupings has been changed

from non-HPV-related to HPV-inde-

pendent and from HPV-related to

HPV-associated.

• Papillary basaloid carcinoma, warty

basaloid carcinoma, pseudohyperplastic

carcinoma, pseudoglandular carcinoma,

carcinoma cuniculatum, and mixed

squamous cell carcinoma have been

removed as distinct subtypes.

• Pseudohyperplastic and pseudoglandu-

lar patterns are now a part of squamous

cell carcinoma, usual type.

• Carcinoma cuniculatum pattern is now

a part of verrucous carcinoma.

Dr. Choy has been an author for PathologyOutlines since 2020 and a part of

the editorial board since 2021 as the Prostate and Cytopathology subspecialty

section editor. She is currently an Assistant Professor and Associate Program

Director of the Pathology Residency and Cytopathology Fellowship at North-

western University where she practices GU Pathology and Cytopathology.

Dr. Tretiakova has been an author for PathologyOutlines since 2015, part of

the PathologyOutlines editorial board since 2019, and Deputy Editor in

Chief for GU Pathology since 2021. She is currently a Professor and Director

of the GU Fellowship and Immunohistochemistry Laboratories at the Uni-

versity of Washington where she primarily practices GU Pathology.

Dr. Zynger has been an author for PathologyOutlines since 2013, a part of

the editorial board since 2013, and is the subspecialty section editor for Adre-

nal, Penis, and Testis. She is currently a Professor and Director of Urologic

Pathology at The Ohio State University where she primarily practices GU

Pathology.

Meet the Authors

Fig. 4. Signet ring stromal tumor. A. The tumor has large cytoplasmic vacuoles. B. Inhibin is negative. C.

-catenin has diffuse nuclear and cytoplasmic expression. D. Vi-

mentin is diffusely positive.