Precursors of Endometrial CarcinomaBy :Elham Mirzaian,(Ap-cp)
Tehran University of Medical Sciences
Atypical hyperplasia/EIN
In 1986, Kurman and Norris, subdivided
endometrial hyperplasia into two categories based
on the both architectural and cytologic features
In the sense of dividing the hyperplasia into simple
and complex on the basis of the architecture and
subdividing each into typical and atypical on the
basis of their cytology
More recently, a new classification for EH
was proposed based on histopathologic,
molecular genetic changes and
computerized morphometric analysis (EIN
system)
The 2014 WHO classification proposal combined
EIN criteria with former WHO terminology
Atypical hyperplasia/Endometrioid intraepithelial
neoplasia
Synonyms: CA,SA,EIN
WHO 2020
Endometrial atypical
hyperplasia/endometrioid intraepithelial
neoplasia
Not recommended:
Complex atypical endometrial hyperplasia
Simple atypical endometrial hyperplasia
Endometrial intraepithelial neoplasia
EAH/EIN is present in ∼1.4% of
endometrial biopsies
Similar to nonatypical hyperplasia,
EAH/EIN usually occurs around
menopause
Patients present with abnormal uterine
bleeding (postmenopausal bleeding,
hypermenorrhea, dysmenorrhea,
intermenstrual bleeding)
Obesity, anovulatory cycles, and
exogenous hormones are associated with
both endometrioid carcinoma and
hyperplasia
In addition, the risk of EH is associated
with increasing body mass index (BMI) and
nulliparity
Atypical endometrial
hyperplasia/endometrioid intraepithelial
neoplasia (EIN) is considered the direct
precursor to endometrioid carcinoma
GROSS FINDINGS
Macroscopically, EAH/EIN may appear as
abundant tan tissue with a polypoid or
indistinct appearance
Focal lesions are not grossly visible
In biopsy or curettage specimens there
may be more voluminous amounts of
tissue in the submitted sample especially
in postmenopausal patients where scant
tissue is the norm
MICROSCOPIC FINDINGS
EAH/EIN is characterized by crowded
glands lined by cytologically altered cells
with little intervening stroma, and typically
seen as a discrete expansile focus that is
distinct from the surrounding endometrium
The histologic criteria for EIN, are:
1. Glandular crowding with little intervening stroma (gland-to-stroma ratio greater than 1 )
2. Maximum linear dimension exceeding 1 mm in greatest dimension (usually encompassing >5–10 glands)
3. Cytologically altered tubular or branching glands with different cytology between architecturally crowded focus and background
In most cases, the altered cytomorphology
of the crowded area is seen as large round
nuclei with inconspicuous nucleoli,
increased nuclear-to-cytoplasmic ratio and
loss of axial polarity
The mitotic rate varies
The neoplastic epithelium can display
squamous morular, tubal, secretory,
eosinophilic, mucinous, or papillary
metaplasia
Gland Crowding With Morphology Distinct From Surrounding Endometrial Glands
EAH/EIN subjected to treatment with high-dose
progesterone levels may display a variety of
changes (architectural and cytologic)
Pathologic assessment in this setting requires
adequate clinical information, including time since
initial diagnosis and duration of progestin treatment
Ideally, the first diagnostic sample should be
compared with the follow-up specimen
Atypical endometrial hyperplasia/endometrioid intraepithelial neoplasia treated with
progestins
Progestin Effect
Atypical hyperplasia. Branching and tubular glands are crowded with very
little intervening stroma
Atypical hyperplasia. Nuclei are rounded and have vesicular chromatin
Atypical hyperplasia. Nuclei are rounded, have vesicular chromatin, and
display stratification and loss of polarity
Hyperplasia with tubal metaplasia and atypia :
loss of polarity and stratification are beyond those attributable to metaplasia
DIFFERENTIAL DIAGNOSIS
EAH/EIN requires distinction from benign
conditions including nonatypical
endometrial hyperplasia, normal
endometrium, endometrial polyp,
endometrial metaplasia, and certain
endocervical reactive proliferations
Of note, areas of gland crowding
suspicious but insufficient for the diagnosis
of EAH/EIN can be encountered in all
these situations
If there is clinical and/or pathologic
concern for neoplasia, it is advisable to
report this finding
We render the diagnosis of “endometrium
with focal gland crowding,” accompanied
by a note recommending follow-up and
repeated sampling in 3–6 months
EAH/EIN VS Nonatypical hyperplasia
Common to EAH/EIN and nonatypical
hyperplasia is the presence of glandular
crowding
The distinction relies on the presence of
altered cellular differentiation in the
crowded glands that is significantly
different from the background
endometrium
A helpful clue is the diffuse nature of
nonatypical hyperplasia, in contrast to the
(usually) focal or multifocal expansile
distribution of EAH/EIN
Although PTEN and PAX2 are lost in most
EAH/EIN lesions, foci with absent
expression can also be encountered in
bona fide indolent benign endometria and
nonatypical hyperplasia, and the use of
these markers for diagnostic purposes is
not advocated
Similar to nonatypical hyperplasia, benign
endometrium during the proliferative and secretory
phases can mimic EAH/EIN
Attention to the presence of artifacts (e.g.,
telescoped glands showing duble lumens) and
awareness of the pattern of normal physiologic
changes is helpful in reaching the correct diagnosis
Artifacts, such as telescoping," should not be misinterpreted as EIN. Although
the glands look crowded, notice that they are fragmented and appear folded on
top of one another
endometrial polyps can have areas of increased
glandular density which can be misdiagnosed as
EAH/EIN involving a polyp
As in the nonpolypoid endometrium, comparison
between crowded and noncrowded glands within
the polyp is imperative
Epithelial metaplasia can involve
neoplastic and normal endometrium
Although in most instances this distinction
is straightforward,one important exception
is the presence of complex patterns,which
shoud be classified cautiously with
recommendation for follow-up,especially if
the process is extensive
Endocervical tissue with reactive changes,
particularly florid squamous metaplasia and
microglandular hyperplasia may be observed in
endometrial samplings
Since these lesions have increased glandular
density, they can simulate EAH/EIN
It is important to recognize the endocervical origin
of the fragment(s) usually evident by the presence
of significant acute and chronic inflammatory cells
and a distinct basal layer of reserve cells
underneath immature metaplastic squamous and
endocervical epithelium
Cervical microglandular hyperplasia. Unlike endometrial intraepithelial neoplasia, this
lesion is characterized by a visible basal reserve cell layer underneath the columnar
epithelium
Atypical hyperplasia must be distinguished
from an atypical polypoid adenomyoma
and from well-differentiated
adenocarcinoma
Atypical hyperplasia VS well-
differentiated carcinoma
There are three useful criteria, any of which
identifies stromal invasion:
(1) an irregular infiltration of glands associated with an
altered fibroblastic stroma (desmoplastic response)
(2) a confluent glandular pattern in which individual
glands, uninterrupted by stroma, merge at times
creating a cribriform pattern
(3) an extensive papillary pattern
Despite this, uncertainty in this differential persists
in some cases, which for reporting purposes can be
described as “at least EAH/EIN,” or EAH/EIN
bordering on well-differentiated endometrial
endometrioid carcinoma,”
or “EAH/EIN, cannot rule out well-differentiated
endometrial endometrioid carcinoma” because both
conditions will, in general, receive the same
treatment
Lastly, endocervical adenocarcinoma of
both human papillomavirus (HPV)-related
and HPV-unrelated types can colonize the
endometrium and manifest clinically with
bleeding, thus simulating EAH/EIN
Atypical hyperplasia with foci of well differentiated endometrioid carcinoma
Well-differentiated endometrioid carcinoma
Crowded atypical glands with early glandular confluence are surrounded by eosinophilic
spindled stromal cells which constitute a desmoplastic stromal reaction, indicating
stromal invasion by carcinoma
Treatment
The standard treatment for EAH/EIN is
surgical (simple hysterectomy and bilateral
salpingo-oophorectomy)
Hormonal treatment with high-dose
progestins is a valid temporary alternative
for whom desire to retain their uterus for
fertility purposes
Serous Endometrial Intraepithelial
Carcinoma
Serous carcinoma is the prototypic
endometrial carcinoma that is usually not
related to estrogenic stimulation and
typically occurs in the setting of
endometrial atrophy
Serous carcinoma is frequently associated
with a putative precursor lesion, termed
“serous endometrial intraepithelial
carcinoma” (SEIC)
The origin of serous endometrial intraepithelial
carcinoma (SEIC) is debated
Polypoid carcinoma associated with SEIC (P-SEIC)
compared with usual endometrial serous carcinoma
without SEIC (UESC):
P-SEIC:WT1 +
P-SEIC was associated with more bilateral ovarian
involvement and showed lower rates of myometrial
invasion
SEIC is characterized by markedly atypical
nuclei, identical to those of invasive serous
carcinomas, lining the surfaces and glands
of atrophic endometrium. The lesion can
be very small and focal and is often
present on the surface of a polyp
SEIC often has a slightly papillary contour and
some cells display hobnail morphology and
smudged, hyperchromatic nuclei
The nuclei are enlarged and frequently display
enlarged eosinophilic nucleoli. Numerous mitotic
figures, including atypical ones, are present
SEIC. Markedly atypical cells lining the surface epithelium have enlarged
vesicular nuclei with prominent nucleoli and prominent hobnail morphology
SEIC. Surface epithelium and underlying glands involved by SEIC are
highlighted by diffuse/strong nuclear expression of p53; normal glands are
negative
More recently a lesion has been described,
termed endometrial glandular dysplasia,
which also exhibits cytologic atypia with
serous features but lacks the marked
atypia associated with SEIC
It has been proposed that this lesion
represents the precursor of SEIC and
serous carcinoma
Differential Diagnosis
The distinction of extensive SEIC from early serous
carcinoma has not been well defined
Crowded glands involved by SEIC within a polyp or
within the endometrium should be classified as
extensive SEIC when the proliferation lacks a
confluent glandular pattern, demonstrates no
evidence of stromal desmoplasia (stromal
invasion), and is less than 1 cm in greatest
dimension
When either glandular confluence or stromal invasion is present and the proliferation exceeds 1 cm in greatest dimension, the lesion qualifies as serous carcinoma
Lesions with glandular confluence or stromal invasion but measuring less than 1 cm can be subclassified as minimal uterine serous carcinoma
Extensive SEIC/minimal uterine serous carcinoma.
An endometrial polyp involved by SEIC on its surface, as well as in the adjacent endometrium
(left), contains crowded glands measuring less than 1 cm but verging on being confluent,
suggesting early stromal invasion
It is important to note, however, that metastatic
serous carcinoma can be found in other sites in the
genital tract and in the abdomen in the absence of
demonstrable invasion in uteri with SEIC, indicating
that SEIC is capable of metastasizing without first
invading the stroma of the endometrium
metastasis to the perituneum are found in 20 to 40
percent of cases,even when obvious stromal or
myometrial invasion is not present
SEIC must be distinguished from benign
metaplastic endometrial lesions that can mimic the
nuclear changes seen in SEIC, which include
eosinophilic cell change, hobnail change, tubal
metaplasia and PSM
Immunohistochemistry for Ki-67, a proliferation
marker, is very useful for distinguishing SEIC from
eosinophilic cell change and tubal metaplasia
In addition, SEIC is usually diffusely and strongly
positive for p53
PSM: Increased expression of p53, diffuse p16
expression, low ki67
patients with a diagnosis of SEIC in an
endometrial biopsy or curettage specimen
should undergo careful surgical staging at
the time of hysterectomy
Atypical Polypoid Adenomyoma
Atypical polypoid adenomyoma is a
biphasic polypoid lesion composed of
endometrioid-type glands in a myomatous
or fibromyomatous stroma
Since the stroma may be fibromyomatous
rather than overtly myomatous, some
prefer the designation atypical polypoid
adenomyofibroma
Most patients are premenopausal or
perimenopausal, (average age 40 years)
and present with abnormal uterine
bleeding, usually in the form of
menorrhagia
Atypical polypoid adenomyoma is most
commonly located in the lower uterine
segment, although some cases involve the
fundus, uterine body, or endocervix
In most cases, the lesion has an obvious
polypoid gross appearance,average size
2cm, in the form of either a sessile or
broad-based polyp, but sometimes the
polypoid nature is not grossly obvious,
especially in smaller lesions
Atypical polypoid adenomyoma
The diagnosis may be made on endometrial biopsy,
polypectomy, or at hysterectomy
Histology shows architecturally irregular
endometrioid type glands that may be widely
separated and haphazardly arranged or somewhat
crowded and arranged in groups, sometimes with a
vaguely lobular pattern
A true glandular cribriform pattern is unusual but a
pseudocribriform appearance is often noted due to
the presence of squamous morules
Mitoses are absent to rare
Atypical polypoid adenomyoma
The nuclei are usually round, sometimes with
prominent nucleoli, and exhibit mild or, at the most,
moderate cytological atypia. Occasional foci of
ciliated or mucinous epithelium may be present
A characteristic histological feature that is present
in most, but not all, cases is abundant squamous
morule formation. sometimes, the morules exhibit
central necrosis
The margin between the lesion and the
underlying myometrium is usually rounded
and well delineated
In some cases, there is significant
glandular crowding with a back-to-back
architecture and stromal exclusion, such
that there are foci that are virtually
indistinguishable from, and which are best
regarded as, grade I endometrioid
adenocarcinoma
Atypical Polypoid
Adenomyoma. Glandular
elements are
haphazardly distributed in
a myomatous stroma (A)
Glandular crowding with
focal cribriform
architecture is observed
(B)
Squamous morular metaplasia is seen in most cases and can be extensive
Very rarely, there is underlying myometrial
invasion, and/or an endometrioid
adenocarcinoma is present in the
surrounding endometrium
Atypical polypoid adenomyoma is generally a
benign lesion, but there is a risk of recurrence if
curettage or polypectomy is undertaken
Given this risk of recurrence and the small but
definite risk of transition to endometrioid
adenocarcinoma, which was estimated at 8.8%in
one meta-analysis, hysterectomy is the treatment of
choice if the diagnosis is made on biopsy or
polypectomy
In a woman who wishes to retain her uterus and in
whom a confident diagnosis of atypical polypoid
adenomyoma has been made on biopsy or
polypectomy, complete removal by curettage or
polypectomy may be undertaken with close follow-
up and imaging
The most important differential diagnosis of atypical
polypoid adenomyomas is an endometrioid
adenocarcinoma exhibiting myometrial invasion or
with a prominent desmoplastic stroma, an obviously
important distinction since most atypical polypoid
adenomyomas exhibit a benign behavior with a
potential for conservative management
Recognition of the polypoid nature of the lesion
assists in establishing the diagnosis
Marked cytological atypia favors a myoinvasive
adenocarcinoma since in atypical polypoid
adenomyomas, there is usually no more than mild
to moderate cytological atypia
The stromal component of atypical polypoid
adenomyoma grows in short interlacing fascicles, in
contrast to the elongated fibers of the normal
myometrium
The smooth muscle in APA is more cellular and
haphazardly oriented
Immunohistochemistry is of little value in
distinguishing between atypical polypoid
adenomyoma and a myoinvasive endometrioid
adenocarcinoma
It has been suggested that CD10 may be of value,
since this is negative in the stromal component of
atypical polypoid adenomyoma, while the
myoinvasive glands of endometrioid
adenocarcinoma are typically surrounded by CD10-
positive stromal cells
The differential diagnosis can also include a benign
endometrial polyp in which there may be a minor
component of smooth muscle within the stroma.
So-called typical adenomyomatous polyps or
polypoid adenomyomas
They are composed of benign endometrioid-type
glands in a myomatous stroma ( fewer glands
usually without gland crowding and presence of
endometrial stroma around the endometrial glands)
Low-grade adenosarcoma may harbor areas of
smooth muscle metaplasia and glandular crowding
but will also show stromal atypia, periglandular
stromal condensation and leaf-like growth
Rarely, a carcinosarcoma enters into the differential
diagnosis because of the admixture of epithelial
and stromal elements (both the epithelial and
mesenchymal components are obviously
malignant)