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.