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)