eosinophilic cells with brisk inammation

mimicking Warthin tumor or predominant

vacuolated cells mimicking clear cell RCC.

• Many tumors previously diagnosed as type 2

PRCC now constitute independent entities.

Clear cell papillary renal cell tumor

(CCPRCT)

• Renamed from carcinoma to tumor due to

uniformly indolent behavior.

• Low-stage, low-grade tumor with tubulo-

papillary and cystic architecture composed of

clear cells with linearly aligned luminally

oriented nuclei.

• Co-express CK7 and CAIX (cup-like), often

positive for HMWCK, but negative for CD10,

and lack recurrent cytogenetic abnormalities or

VHL gene alterations.

Chromophobe RCC (ChRCC)

• ChRCC can have non-conventional morphol-

ogy with trabecular, alveolar, papillary, micro-

cystic or cystic architecture, but all these

phenotypes typically maintain CK7/CKIT

co-expression, characteristic chromosomal

monosomies and favorable prognosis.

Diagnostic recommendations

• An unequivocal diagnosis of multilocular cystic

neoplasm of low malignant potential (MCN-

LMP), CCPRCT and oncocytoma should not

be made on needle biopsy alone because of

limited sampling and overlapping features with

malignant counterparts.

NEW CATEGORY OF

MOLECULARLY DEFINED

RENAL TUMORS

This heterogeneous group of tumors often shows

signicant morphologic overlap with other renal

tumors. Denitive diagnosis requires molecular

studies like NGS, RNAseq, FISH or RT-PCR

(Mod Pathol 2021; 34: 1167-1184, Mod Pathol

2021; 34: 1392-1424).

Issue 19 || September 2022

WHAT’S NEW IN KIDNEY

TUMOR PATHOLOGY

2022: WHO 5TH EDITION

UPDATES

Maria Tretiakova

Department of Laboratory Medicine and Pathology,

University of Washington, Seattle, WA, USA

Corresponding Author: Maria Tretiakova, MD, PhD

Department of Laboratory Medicine and Pathology,

University of Washington, Seattle, WA, USA

E-mail: mariast@uw.edu

ORCID

Maria Tretiakova

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

Abstract

The 5th edition WHO Classication of Urinary

and Male Genital Tumours (2022) introduces

signicant changes relevant to daily practice,

especially in the completely restructured renal

cell tumor chapters. Herein we highlight the

most important diagnostic updates of known

kidney tumor types, new and molecularly dened

entities and emerging/provisional entities.

UPDATES IN ESTABLISHED

RENAL TUMORS

Papillary renal cell carcinoma (PRCC)

• Subclassication into type 1 and type 2 is no

longer recommended.

• PRCC has classic morphology (papillae with

vascular cores, foamy histiocytes and psam-

moma bodies) but can exhibit other appear-

ances, including predominant solid phenotype,

biphasic pattern with squamoid alveolar cells,

TFE3-rearranged RCC (formerly named

MiTF family Xp11 translocation RCC)

• Heterogeneous tumors in younger patients

with mixed papillary and solid architecture,

psammoma bodies and clear to eosinophilic

cytoplasm.

• Express nuclear TFE3 and variably melanocytic

markers and cathepsin K.

• TFE3 rearrangement with > 20 different gene

partners creates fusion subtypes with variable

tumor morphology, immunoprole and clinical

behavior.

TFEB-rearranged RCC

• Tumor has either translocation or amplication

of TFEB on t(6;11).

• TFEB-translocation RCC is a low-stage

indolent biphasic neoplasm with nests of large

clear cells and smaller cells clustered around

basement membrane material.

• TFEB-amplied RCC is an often high-grade

and high-stage tumor with frequent oncocytic

and papillary morphology affecting older

patients (Fig. 1).

• Both subtypes consistently express nuclear

TFEB, cathepsin K and melanocytic markers.

ELOC (formerly TCEB1)-mutated RCC

(novel entity)

• Uncommon indolent clear cell tumor with solid

and papillary growth patterns and nodular

appearance due to traversing bromuscular

bands and septa.

• Morphologically mimic conventional clear cell

and tuberous sclerosis-associated RCCs.

PathologyOutlines.com

WHAT’S NEW

IN PATHOLOGY?

Sponsored by an unrestricted grant from Roche

Fig. 1. TFEB-ampliﬁed RCC.

often is multifocal and bilateral, exhibiting a

checkerboard mosaic pattern and harboring

mutations in FLCN.

• Eosinophilic vacuolated tumor (EVT) is

characterized by solid growth, cytoplasmic

vacuolization, entrapped tubules and large

vessels, prominent nucleoli, CK7-/CKIT+

immunoprole and mutations in mTOR

pathway genes.

• Low-grade oncocytic tumor (LOT) is a solid

neoplasm with bland low-grade nuclei, CK7+/

CKIT- immunoprole and mutations in

mTOR pathway genes.

Biphasic hyalinizing psammomatous

RCC

• Rare biphasic tumor with larger cells forming

tubules, papillae and acini and smaller cells

clustered around hyalinized basement mem-

brane material in glomeruloid or nested

pattern.

• It has sclerotic stroma with abundant psam-

moma bodies and bi-allelic loss of NF2.

Papillary renal neoplasm with reverse

polarity

• Formerly considered as a subtype of PRCC.

• Eosinophilic tumor with branching papillary

architecture and reverse polarity of low-grade

nuclei (Fig. 4).

• Positive for GATA3, negative for vimentin and

variable for AMACR.

• Has recurrent mutations of KRAS and lacks

trisomy 7/17.

with brisk mitoses.

• Loss of SMARCB1 (INI1, SNF5, BAF47)

protein expression on immunostaining reects

inactivation of SMARCB1 at 22q11.23 by

chromosome translocations or deletions.

Eosinophilic solid and cystic RCC

• Novel distinct entity in “OTHER RENAL

TUMORS” category

• Originally described in patients with tuberous

sclerosis complex, but can occur sporadically

due to TSC1 or TSC2 mutations.

• Indolent tumor disproportionately affecting

women, with only rare reported metastases.

• Solid and cystic architecture, voluminous eosin-

ophilic cytoplasm and coarse basophilic

granularity.

• CK20 and cathepsin K are positive and there is

a lack of CK7/CKIT expression (Fig. 3).

EMERGING/PROVISIONAL

ENTITIES

• These tumor types are still not part of classica-

tion, but discussed in WHO (Mod Pathol

2021; 34: 1167-1184)

Thyroid-like follicular carcinoma

• Rare kidney tumor composed of tightly packed

follicle-like cysts lled with eosinophilic

colloid-like material and lined by cuboidal cells

with scant cytoplasm and oval to round nuclei.

• Positive for PAX8, CK19 and CK7; negative

for TTF1 and thyroglobulin.

• Recurrent EWSR1::PATZ1 fusion.

Other oncocytic tumors

(oncocytic tumor, NOS)

• These are heterogeneous groups of tumors that

do not fulll criteria for oncocytoma or eosino-

philic variant of chromophobe RCC (or other

specic entities).

• Hybrid oncocytic chromophobe tumor

(HOCT) is an indolent oncocytic neoplasm

with borderline (intermediate) features between

oncocytoma and ChRCC. It can be solitary and

sporadic, but in Birt-Hogg-Dubé syndrome

• Consistently immunoreactive for CK7 and can

be focally positive for HMWCK.

• Develops due to bi-allelic inactivation of

TCEB1 (ELOC) on chromosome 8 encoding for

elongin C of the VHL complex with intact

VHL and mTOR pathway genes.

Fumarate hydratase (FH)-deﬁcient RCC

• Renamed from hereditary leiomyomatosis-

associated RCC.

• Aggressive tumor with mixed papillary, solid,

tubulocystic and cribriform architecture,

composed of high-grade cells with cherry-red

macronucleoli.

• Germline (majority of cases) or somatic FH

gene mutations should be suspected with

immunostaining demonstrating FH protein

loss and/or 2-succinocysteine (2SC) gain.

Succinate dehydrogenase (SDH)-

deﬁcient RCC

• Rare tumor with distinct solid morphology of

bland eosinophilic cells with bubbly inclusions.

• Loss of SDHB protein expression and germline

mutation in SDH gene complex.

ALK-rearranged RCC (novel entity)

• Very rare group of extremely heterogeneous

eosinophilic tumors which develop due to

fusions of anaplastic lymphoma kinase gene

(ALK) at 2p23 resulting in ALK protein

overexpression.

• May show cytoplasmic vacuolization; solid,

papillary or cribriform architecture with mucin

production; psammoma bodies; metanephric-

like, rhabdoid or spindle cell morphology (Fig. 2).

SMARCB1-deﬁcient renal medullary

carcinoma

• Renamed from renal medullary carcinoma.

• Highly aggressive medulla-centered adenocar-

cinoma predominantly affecting patients with

sickle cell trait (hemoglobinopathy) and of

African ancestry.

• Presents as locally advanced or metastatic

disease with fast-growing inltrating tumor

composed of cords, nests, tubules and cribri-

form structures in desmoplastic background

Fig. 2. ALK-rearranged RCC.

Fig. 3. Eosinophilic solid and cystic RCC.

Fig. 4. Papillary renal neoplasm with reverse polarity.

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 at the University of Washington

where she primarily practices GU Pathology.

Dr. Tretiakova is an international expert in

GU pathology and has co-authored several

topics in the WHO 2022 Blue Book.

Meet the Author