he 5th edition of the World Health

Organization of Tumours of Female

Reproductive Organs was published in

2020. This is a compilation of the most

important changes in the vulva, cervix

and uterus.

VULVA

y Squamous intraepithelial lesions and

squamous cell carcinomas are now

classied as HPV-associated and HPV-

independent.

y p16 overexpression is a reliable

surrogate marker of HPV infection. A

second marker with prognostic utility

is p53. Thus, squamous neoplasms are

now classied in three main groups:

p16 overexpressed / p53 normal, p16

negative / p53 abnormal and p16

negative / p53 normal.

y HPV-independent (p16 negative),

p53 abnormal carcinomas have been

associated with worse progression-free

and overall survival compared to HPV-

associated carcinomas as well as p16

negative / p53 normal carcinomas.

y HPV-associated squamous

intraepithelial lesions (formerly

known as vulvar intraepithelial

neoplasia of the usual / classic type)

represent the majority (90%) of

precursors. They are referred to as low-

grade (LSIL, equivalent to uVIN1) and

high-grade (HSIL, equivalent to uVIN2

and uVIN3).

• HSIL is characterized by p16

overexpression and wild-type

p53 (with strong staining in mid-

epithelial layers and negative or

patchy basal / parabasal staining).

y The most common HPV-independent

lesion is dierentiated vulvar

intraepithelial neoplasia (dVIN).

Its presumed rapid progression to

invasive carcinoma and the diculties

in its diagnosis likely explain why

dVIN represents only <10% of

squamous intraepithelial lesions.

• dVIN is characterized by negative

or patchy p16 and mutant-type

p53 expression (the latter could be

full-thickness strong, basal strong,

completely negative or cytoplasmic

staining).

y Another, far less common form of

HPV-independent lesion is the now

called dierentiated exophytic vulvar

intraepithelial lesion (DE-VIL). This

lesion demonstrates verruciform

acanthosis, hypogranulosis and

cytoplasmic pallor (Figure 1). Unlike

HSIL and dVIN, DE-VIL lacks cytologic

atypia.

• DE-VIL has been associated

with p16 negative / p53 normal

carcinomas, including verrucous

and conventional squamous cell

carcinoma.

• DE-VIL is characterized by negative

or patchy p16 and wild-type p53

(heterogeneous staining).

CERVIX

y Carcinomas in both squamous and

glandular categories are now classied

as HPV-associated and HPV-

independent.

y More than 90% of squamous cell

carcinomas of the cervix are secondary

to HPV infection. There is emerging

evidence showing that the HPV-

independent subgroup (~7%) has

worse outcome.

y There are currently no morphologic

clues to distinguish between HPV-

associated and HPV-independent

squamous cell carcinomas.

y Adenocarcinoma in-situ also now

has two recognized categories: HPV-

associated (frequently referred to

as “usual”) and HPV-independent.

Currently, only gastric-type AIS and

atypical lobular endocervical glandular

hyperplasia belong to the latter

category. They feature foamy clear

to eosinophilic mucinous cytoplasm,

distinct cell borders, nuclear atypia

and intraglandular growth (tufting,

micropapillary, cribriform) (Figure 2).

y HPV-independent adenocarcinomas, in

particular gastric-type adenocarcinoma,

have worse clinical behavior than HPV-

associated adenocarcinomas.

y HPV-associated endocervical

adenocarcinomas represent 85-90% of

all adenocarcinomas. Their histologic

hallmark is the presence of conspicuous

apical mitoses and apoptosis.

• They are characterized by p16

overexpression (strong and diuse,

nuclear and cytoplasmic staining),

normal p53 staining and negative to

weak ER/PR staining.

• The usual subtype is the most

common, dened as having

50%

of cells with intracytoplasmic mucin,

with the remaining having non-

mucinous cytoplasm.

• The mucinous subtype, dened

as having

50% cells with

intracytoplasmic mucin, can feature

endocervical-type mucinous

epithelium or intestinal-type

epithelium.

• Invasive stratied mucin-producing

carcinoma is a novel subtype,

characterized by solid nests of

multilayered mucinous epithelium

resembling stratied mucin-

producing intraepithelial lesion

(SMILE). This subtype appears to

WHAT’S NEW

IN PATHOLOGY?

Issue 14 || March 2021

THE LATEST

NEWS IN

GYNECOLOGIC

PATHOLOGY

PART ONE

By Carlos Parra-Herran, MD and

Jennifer Bennett, MD

Figure 1: Dierentiated exophytic vulvar

intraepithelial lesion (DE-VIL).

Sponsored by an unrestricted grant from ELITechGroup

Figure 2: Adenocarcinoma in situ,

gastric type.

have a worse outcome compared to

other HPV-associated subtypes.

y Gastric-type adenocarcinoma

represents the most common type of

HPV-independent adenocarcinoma

(~10% of all adenocarcinomas). It

includes the formerly called minimal-

deviation adenocarcinoma / adenoma

malignum.

• It features epithelium with foamy

clear to eosinophilic mucinous

cytoplasm and prominent cell

borders.

• It is negative for hormone receptors,

but often expresses HIK1083 (a

marker of pyloric-type epithelium).

p53 can show mutant-type

expression, and p16 can be strong

and diuse.

y Other recognized types of HPV-

independent adenocarcinoma are clear

cell and mesonephric. Endometrioid

and serous carcinomas of the cervix

are exceedingly rare, and their

diagnosis requires rst exclusion of an

endometrial and tubo-ovarian primary.

UTERUS-EPITHELIAL

y An algorithm for applying The Cancer

Genome Atlas (TCGA) classication

system (POLE-mutated, microsatellite

instable, copy number low and

copy number high/TP53-mutated)

is provided. Surrogate markers for

molecularly classifying endometrial

carcinomas include targeted POLE

sequencing, and MSH6, PMS2 and p53

immunohistochemistry.

y Molecular features in serous

carcinomas have been updated to

include ERBB2 (HER2) amplication

in 30% of tumors; such patients

have been shown to benet from

trastuzumab therapy.

y The category of mucinous carcinoma,

dened by mucinous cells involving

> 50% of the tumor, has been

eliminated.

y Novel subtypes of endometrial

carcinoma including mesonephric-

like carcinoma and gastric

(gastrointestinal)-type mucinous

carcinoma have been added.

• Mesonephric-like carcinoma

is characterized by a variety

of architectural patterns, focal

intraluminal eosinophilic secretions

and nuclei resembling papillary

thyroid carcinoma with mild to

moderate atypia (Figure 3). They are

often GATA-3, TTF-1, calretinin, and

CD10 (luminal) positive, with ER

negative or at most focally positive.

Many harbor KRAS mutations and

gain of chromosome 1q.

• Gastrointestinal-type mucinous

carcinoma is composed of mucin-

secreting glands (+/- goblet cells)

with low-grade atypia and may be

mismatch repair protein-decient.

y Carcinosarcoma is now considered

a subtype of endometrial carcinoma

rather than a mixed epithelial and

mesenchymal tumor.

UTERUS-MESENCHYMAL

y Fumarate hydratase-decient

leiomyoma has been added as

a subtype of leiomyoma and is

characterized by staghorn vessels,

alveolar-pattern edema, scattered

bizarre nuclei, ovoid nuclei sometimes

arranged in chains, eosinophilic

cytoplasmic (rhabdoid) inclusions

and prominent eosinophilic nucleoli

surrounded by perinucleolar halos

(Figure 4). It may harbor somatic

or germline fumarate hydratase

mutations, the latter being diagnostic

of hereditary leiomyomatosis and

renal cell carcinoma (HLRCC)

syndrome.

y Specic diagnostic criteria for myxoid

leiomyosarcoma are proposed:

presence of any cytological atypia,

tumor cell necrosis or > 1 mitoses/10

HPF.

y IFITM1 has been included as a novel

immunohistochemical stain that is

often strongly and diusely positive in

endometrial stromal nodules and low-

grade endometrial stromal sarcomas.

y Novel subtypes of high-grade

endometrial stromal sarcoma

include those with BCOR alterations

(ZC3H7B-BCOR fusions or BCOR

internal tandem duplication), which

have a morphology overlapping

with other myxoid mesenchymal

neoplasms.

• ZC3H7B-BCOR sarcomas are

positive for cyclin D1, CD10 and

BCOR (~50%), with variable ER/PR.

• BCOR internal tandem duplication

sarcomas are positive for cyclin D1

and BCOR, variably express CD10

and desmin, and are negative for ER,

PR, SMA and caldesmon.

y Molecular alterations for uterine tumor

resembling ovarian sex cord tumor

(UTROSCT) include NCOA1-3, ESR1

or GREB1 fusions.

y Modied gynecologic-specic criteria

for predicting PEComa behavior with

elimination of the “benign” category

are proposed.

y Inammatory myobroblastic tumor

has been added as a distinct entity

and a subset with malignant behavior

is recognized. The most common

ALK fusion partners include IGFBP5,

THBS1 and TIMP3.

y NTRK-rearranged spindle cell

neoplasm is a novel low-grade

sarcoma most common in the cervix.

It is positive for S100, CD34 and TRK,

negative for ER, PR, CD10, SMA and

desmin, and harbors NTRK fusions.

Figure 4: Fumarate hydratase decient

leiomyoma.

Figure 3: Mesonephric-like endometrial

carcinoma.

Meet the Authors

r. Parra-Herran has been part

of the Pathology Outlines

editorial board since 2016. He is

originally from Colombia and

started his academic pathology

career in Canada. He is currently

aliated with Brigham and

Women’s Hospital and Harvard

Medical School as a pathologist and

associate professor of pathology.

r. Bennett has been part

of the Pathology Outlines

editorial board since 2019 and was

appointed deputy editor-in-chief of

gynecologic pathology in 2020. She

is currently an assistant professor

at the University of Chicago

Medical Center. Her research

primarily focuses on the integration

of morphology and molecular

features, particularly in uterine

mesenchymal neoplasms.

The authors did not receive any

compensation from EliTech Group.