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.
y Squamous intraepithelial lesions and
squamous cell carcinomas are now
classied as HPV-associated and HPV-
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
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
DE-VIL has been associated
with p16 negative / p53 normal
carcinomas, including verrucous
and conventional squamous cell
DE-VIL is characterized by negative
or patchy p16 and wild-type p53
(heterogeneous staining).
y Carcinomas in both squamous and
glandular categories are now classied
as HPV-associated and HPV-
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
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
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
Issue 14 || March 2021
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.