4. Mesodermal origin, formed secondary to fusion of
mullerian ducts between 8th and 9th weeks.
Upto 20th week of gestation, single layer of columnar
epithelium supported by thick layer of fibroblastic
stroma
After 20th week, surface epithelium invaginates in to
underlying stroma forming glandular structures that
extend toward the underlying myometrium.
At birth, surface and glands are lined by low
columnar to cuboidal epithelium.
During reproductive period undergoes cyclic
morphological changes in response to hormones.
In post menopausal life it is thin with relatively few
glands in lined by cuboidal epithelium that is devoid
of proliferative or secretory activity (inactive and
atrophic endometrium).
5.
6. Radial arteries of the myometrium penetrate the
endometrium at regular intervals and give rise to
basal arteries.
These divide into horizontal branches providing
the blood supply to basal layer and vertical
branches supplying the functionalis layer which
are known as spiral arterioles.
Sub endothelial elastica is present in the
myometrial arteries but not in endometrial
arteries, except for the basal portion.
Veins and lymphatics are closely associated with
the endometrial arteries and glands,
respectively. Uterine lymphatics drain from
subserosal uterine plexuses to the pelvic and
periaortic lymph nodes.
7.
8.
9.
10. Proliferative phase
Cellular blue appearance at low power
Round to tubular glands
Even, regular spacing between glands
Pseudostratified columnar cells in glands
Numerous mitotic figures in glands and stroma
Interval phase (Day 16)
Mitoses present, but not as numerous as in
proliferative phase
Less than 50% of cells in a gland with continuous and
well developed subnuclear vacuoles
11. Secretory phase
Relatively pink appearance at low power
Convoluted, irregularly shaped glands
Single layer of columnar or cuboidal cells in glands
Early secretory phase (Day 17 - 19)
Day 17: Continuous and well developed subnuclear
vacuoles in > 50% of a gland, rare mitoses
Day 18: Sub- and supranuclear vacuoles (piano keys) with
nuclei in the center of cell
Day 19: Nuclei at base of cell, supranuclear vacuoles,
start of luminal secretions
Mid secretory phase (Day 20 - 22)
Day 20: Maximal intraluminal secretions, stromal cells
with hyperchromatic nuclei and high N:C ratio
Day 21: Increased stromal edema
Day 22: Peak stromal edema
12. Late secretory phase (Day 23 - 27)
Day 23: Predecidua surrounds spiral arterioles.
Day 24: Predecidua bridges multiple vessels
Day 25: Thin band of predecidua beneath endometrial
surface
Day 26: Thick band of predecidua beneath surface
Day 27: Abundant predecidua expanding downward
from endometrial surface, increased number of
stromal granulocytes
Menstrual phase - Endometrial stromal breakdown:
dense round aggregates of stromal cells admixed with
inflammatory cells and blood
13. Gestational changes
Decidual change: stroma gains abundant
eosinophilic cytoplasm, appears polygonal with
distinct cell borders
Arias-Stella reaction in glandular cells
Nuclear enlargement and hyperchromasia
Abundant eosinophilic vacuolated cytoplasm
Hobnail appearance with cells protruding into
glandular lumen
23. Arias stella reaction showing enlarged nuclei, sub and
supra nuclear vacuoles, intraglandular papillary epithelial
tufts, stromal decidualisation.
24.
25.
26. Contraceptives –
1. Progestogen only – depending upon dose and
duration 3 effects can be seen
• Decidual pattern – decidualised stroma (large cells
with large round nucleus, abundant eosinophillic
cytoplasm).
• Secretory pattern – mild tortuous secretory glands
lined by columnar cells with basal nuclei and scant
eosinophilic intraluminal secretions.
• Inactive pattern – widely spaced small inactive
tubular glands with scant cytoplasm with minimal to
absent luminal secretions.
2. Combined – widely spaced glands which lack mitosis
or pseudostratification, sparsely cellular stroma.
27. Tamoxifen (selective estrogen receptor modulator)
1. Diffuse endometrial thickening with cysticaly dilated
glands
2. Polyp are common after prolonged treatment
3. Proliferation of gland and stroma is common.
4. Can cause hyperplasia and carcinoma.
Hormone replacement therapy –
1. Estrogen only – proliferative endometrium
2. Progestogen only - mild tortuous secretory glands
lined by columnar cells with basal nuclei and scant
eosinophilic intraluminal secretions.
3. Combined – mostly inactive/atrophic endometrium,
less common secretory or proliferative pattern
28.
29.
30.
31. cervix acts as a barrier to the entry of microorganisms into the
endometrial cavity
most type of endometritis results from ascending infection
During menses, abortion, parturition and instrumentation, the
cervical barrier is breached allowing normal vaginal flora access
to the endometrial cavity.
Based on the type of inflammatory infiltrate endometritis is
classified as acute or chronic.
Most acute endometritis are caused by hemolytic streptococci,
Staphylococcus, Neisseria gonorrhea, Clostridium welchii.
Criteria for histologic diagnosis of acute endometritis - moderate
to large number of neutrophils in a non bleeding endometrium,
aggregates of neutrophils in the stroma (micro abscess).
Diagnosis of chronic endometritis - plasma cells but lymphocytes,
macrophages may be present. plasma cell contain an eccentric
nucleus with a characteristic clumped chromatin pattern and a
paranuclear pale staining area representing the golgi apparatus
with amphophilic cytoplasm.
Presence of eosinophils associated with plasma cells.
common causes of chronic endometritis are PID, TB, IUD.
36. Clinical term for uterine bleeding that lacks an underlying
structural abnormality.
Normal cyclical proliferation, differentiation and shedding of
endometrium requires that all involved pituitary and ovarian
hormones be released at proper time in right amounts.
Any disturbance of this finely tuned system may result in
dysfunctional uterine bleeding.
Causes of DUB are
38. Anovulatory cycle
It’s a common cause of DUB.
Failure of ovulation results in excessive endometrial
stimulation by estrogens that is unopposed by
progesterone.
Under these circumstances, the endometrial glands
undergo mild architectural changes that usually
resolve due to a subsequent ovulatory cycle.
Repeated anovulation may result in bleeding.
Anovulation can also be the result of thyroid disease,
a functioning ovarian tumor, polycystic ovaries,
generalized metabolic disturbances like obesity,
malnutrition.
39. defined by the presence of ectopic endometrial tissue at a site
outside the uterus. It occurs in the following sites in descending
order - Ovaries, uterine ligaments, recto-vaginal septum, pelvic
peritoneum, serosa of large and small bowel and appendix,
mucosa of cervix, vagina and fallopian tubes, laparotomy scars.
It can cause infertility, painful menstruation, pelvic pain. It
principally is a disease of women in active reproductive life most
often in the 3rd and 4th decades.
Pathogenesis of endometriosis is explained by many theories such
as –
The regurgitation theory proposes that endometrial tissue
implants at ectopic sites via retrograde flow of menstrual
endometrium.
The benign metastasis theory holds that endometrial tissue from
the uterus can spread to distant sites via blood vessels and
lymphatic channels.
the metaplastic theory suggests that endometrium arises directly
from coelomic epithelium from which the mullerian ducts and
ultimately the endometrium itself originate during embryonic
development.
The extrauterine stem or progenitor cell theory proposes that
progenitor cells from the bone marrow differentiate into
endometrial tissue.
40.
41. When endometriotic lesions are widespread,
organizing hemorrhage causes extensive fibrous
adhesions between tubes, ovaries and other
structures and obliterates the pouch of Douglas.
Ovaries may become markedly distorted by large
cystic masses filled with brown fluid resulting from
previous hemorrhage, these are referred to clinically
as chocolate cysts or endometriomas.
The diagnosis of endometriosis is readily made when
both endometrial glands and stroma are present.
When endometrial tissue is present in the
myometrium, it is called as Adenomyosis.
42. Image showing cut section of ovary containing red-
brown fluid in a cystic area.
43. Endometriotic cyst of the ovary showing abundant
hemosiderin-laden macrophages and fresh hemorrhage in
endometrial stroma.
44.
45. Atrophy is most commonly seen in postmenopausal
women due to estrogen withdrawal.
Microscopically endometrium is composed of a thin
layer of endometrial glands lined by attenuated layer
of inactive epithelial cells surrounded by thin stroma.
No mitotic activity is present.
46. Atrophic endometrium with detached glands composed of low
columnar to cuboidal cells. At places thin stroma is seen.
47. Metaplasia is the presence of any type of glandular
epithelium other than the normal columnar type. It is a
common finding in peri-menopausal and post-menopausal
women and is often associated with abnormal uterine
bleeding or recent use of exogenous hormonal therapy.
Tubal metaplasia: Consists of foci of normal tubal
epithelium within the endometrial glands, including
ciliated, non ciliated secretary and intercalated cells.
Ratio of the ciliated to non ciliated cell is cyclical and
depends on hormonal influences.
Ciliated cell metaplasia: Is the most common form of
metaplasia. It is composed of layer of ciliated columnar
cells with round to oval nuclei and abundant pale
eosinophilic cytoplasm. Ciliated cell metaplasia is a normal
response of endometrial epithelium to various hormonal
exposures. It is most commonly found in perimenopausal
endometrium and is associated with endometrial polyps,
anovulatory cycles and exogenous hormonal therapy.
48. Squamous metaplasia: Often caused by chronic
irritation and often takes the form of squamous
morules or rounded, swirling nest of squamous
cells.
Eosinophilic metaplasia: Glandular epithelium with
abundant eosinophilic cytoplasm and central round
to Oval nucleus. It is believed to be a degenerative
change.
Mucinous metaplasia: It is morphologically similar
to endocervical mucinous epithelium in that it
consists of columnar epithelium with basally
located Oval nuclei and abundant apical mucin.
50. Squamous morular metaplasia showing nests of bland,
immature squamous cells without characteristics features of
squamous differentiation (intercellular bridges,
keratinization)
51. Eosinophilic metaplasia showing eosinophilic cells with
granular cytoplasm found singly and in small clusters within
glandular lumen.
52. These are local overgrowths of endometrial glands
and stroma that are covered by epithelium and
protrude into the endometrial cavity. Polyps are
present in about 20% to 25% of women and are
frequently found in peri and postmenopausal periods.
Grossly polyps appear as broad based to
pedunculated lesions; some pedunculated polyps can
extend into the endocervical canal, and even through
the os.
Microscopically polyps are composed of endometrial
glands within a spindled or fibrous stroma; the
presence of thick walled blood vessels within the
fibrous stroma is the most common key to the
diagnosis.
Adenomyomatous polyp- foci of adenomyosis may
become enlarged into polypoid projections.
53. Atypical polypoid adenomyoma- Characterized
histologically by crowded, irregular endometrial glands
with a complex architecture and cytologic atypia, in
stroma that is predominantly composed of smooth
muscle. This lesion has high rate of recurrence after
incomplete surgical removal. If left untreated there is
risk of progression to endometrioid adenocarcinoma.
54. Uterus has been opened anteriorly through cervix and
into the endometrial cavity. A small polyp is seen high in
fundus projecting into lumen.
58. Defined as abnormal proliferation of endometrial
glands relative to stroma, resulting in increased
gland to stroma ratio when compared to normal
proliferative endometrium.
Hyperplasia associted with prolonged estrogenic
stimulation of the endometrium can be due to
the following conditions –obesity, pcos,
functioning granulosa cell tumor of ovary,
estrogen replacement therapy.
Inactivation of the PTEN tumor suppressor gene
is common genetic alteration in both
endometrial hyperplasia and carcinoma.
59. Hyperplasia without atypia:
increased gland to stroma ratio with variable size of
glands, cystic dilation. Focal back to back glands may
be seen.
Caused by persistent eostrogen stimulation.
Atypical Hyperplasia:
Complex pattern of proliferating glands displaying
nuclear atypia.
Glands are commonly back to back.
Cells are rounded and lose normal perpendicular
orientation to basement membrane.
Nuclei have open vesicular chromatin and
prominent nucleoli.
60. Hyperplasia without atypia showing increased number of
glands which are closely apposed and have minimal
complexity
61. Atypical hyperplasia showing packed glands (back to
back arrangement) showing minimal stroma, complex
contours and atypical epithelial lining
62. Endometrial Intraepithelial Neoplasia (EIN)
It is characterized by markedly atypical nuclei lining the
surfaces and glands of atrophic endometrium. Nuclear enlarged
with granular or vesicular chromatin, frequently display
enlarged eosinophilic nucleoli. Numerous mitotic figures are
seen. This lesion is also referred as Carcinoma in situ.
EIN Criterion
Architecture - Gland area exceeds that of stroma, usually in a
localized region.
Cytological Alterations - Cytology differs between
architecturally crowded focus and background.
Size greater than 1mm - Minimum linear dimension should
exceed 1mm.
Exclude mimics - Basalis, normal secretory, polyps, repair,
lower uterine segment, cystic atrophy, menstrual collapse etc.
Exclude Cancer - Carcinoma should be diagnosed if: glands are
mazelike and rambling, there are solid areas of epithelial
growth, or there are significant bridges or cribriform areas.
63. EIN showing closely apposed glands with tufting
intraluminal projections with minimal intervening
stroma
64.
65. Most common invasive cancer of the female genital
tract.
Typically occurs in elderly females, 80% being
postmenopausal during diagnosis.
Risk factors – family history, nulliparity, early
menarche late menopause, obesity, HRT
It is divided in 2 types – type 1 and type 2 each with
distinct risk factors, precursor lesions, genetics and
clinical behaviours.
68. Most common type of endometrial carcinoma accounting for 80-
85% cases.
Most tumors are well differentiated and mimic proliferative
endometrial glands.
Most common mutation act to increase signaling through
PI3K/AKT pathway.
It can take the form of a localized polypoid mass or diffusely
involve endometrial lining. Spread generally occurs by
myometrial invasion followed by direct extension to adjacent
structures/organs.
Clinical Features
Abnormal, dysfunctional or postmenopausal uterine bleeding
Pelvic pain or mass / compression effect on adjacent structures
Abdominal bloating
Dyspareunia, dysuria
General stigmata of malignancy, i.e. weight and appetite loss,
malaise, fatigue
69. Gross description - Mass arising from endometrial surface with
varied appearances / sizes but usually exophytic and friable in
texture.
Microscopic (histologic) description
Architecture
Key feature is confluent or back to back glands lacking
intervening stroma
Cribriform or microacinar configurations
Complex papillary, micropapillary or villoglandular structures
Cytologic features
Resembles proliferative type endometrium with varying features
/ degrees of atypia but cytology must differ from that of
surrounding non-neoplastic glands
Cellular / nuclear enlargement
Nuclear rounding (rather than elongation) with large nucleoli
Loss of polarity
Cytoplasmic eosinophilia
Sharp glandular luminal borders
Foamy histiocytes in residual stroma
70. Its divided into 3 histological grades
Well differentiated : composed almost entirely of well
formed glands.
Moderately differentiated : well formed glands mixed with
areas composed of soild sheets of cells which make up <50%
of tumor.
Poorly differentiated : > 50% of tumor shows solid growth
pattern.
Myometrial invasion
Traverses beyond confines of typically irregular endo-
myometrial junction without intervening rim of benign
marker glands or endometrial stroma
Rounded, smooth pushing invasive front, or
Infiltrative extension of neoplastic glands
Stromal response at invasive front variably consists of
fibroblastic proliferation, edema and inflammatory cells
Ratio of myo-invasion is crucial to staging:
Numerator: depth of furthest invasion
Denominator: myometrial thickness
Following myometrial invasion, direct extension to adjacent
organs and eventually dissemination to regional lymph nodes
occurs.
71. FIGO grading system (based primarily on architecture)
Grade 1: 5% or less nonsquamous solid growth pattern
Grade 2: 6 - 50% nonsquamous solid growth pattern
Grade 3: > 50% nonsquamous solid growth pattern
Nuclear atypia exceeding that expected for the architectural
grade increases FIGO grade by 1.
(atypia here is defined as grade 3 nuclei in >50% of tumor)
Morphologic variants
Altered differentiation / metaplasia:
Squamous or "squamous" morular: usually bland but
occasionally cytologically malignant; former can be
glycogenated which imparts appearance of clear cytoplasm
Mucinous: intracytoplasmic mucin (intraluminal mucin
pooling does not qualify). >50% cells should show mucinous
differentiation.
Secretory: sub / supranuclear vacuolization
Ciliated / tubal: resembles fallopian tube lining; scattered
cells with apical terminal bars and ciliation.
72. Papillary type variants:
Villoglandular
Small nonvillous papillae
Micropapillae
Microglandular hyperplasia-like: microcystic, microacinar
glands with intraluminal neutrophils
Corded and Hyalinized Endometrial Carcinoma (CHEC):
linear cords of carcinoma cells molded by an abundant
myxohyaline background
73. Endometrial carcinoma: Gross specimen of anteriorly
opened uterine cavity showing multiple hemorrhagic
polypoidal growths extending into cavity.
74. Endometroid adenocarcinoma FIGO grade 1: The glands are
well-differentiated and show angulation or branching.
Cytologic atypia is minimal. <5% of solid component. (Low
power)
75. Endometroid adenocarcinoma FIGO grade 1: There is crowding of
well-differentiated glands showing minimal cytologic atypia and
minimal stroma.
78. Endometroid adenocarcinoma – villoglandular type:
consists of finger-like projections lined by tall columnar
cells with bland nuclei.
79. Highly agggressive form of endometrial carcinoma.
Usually arise in setting of atrophy.
Age group is 10 years older than that of endometroid
carcinoma.
These tumors are considered by definition as poorly
differentiated (Grade 3).
Tp53 mutations are seen in >90% of these tumors
Their general poorer prognosis is because of propensity to
exfoliate, travel through fallopian tubes and implant on
peritoneal surface. As a result, they have often spread
outside of uterus at the time of diagnosis.
80. GROSS : generally, small atrophic uterus with large bulky
tumor mass or invading myometrium.
MICROSCOPY :
- precursor lesion is serous intraepithelial carcinoma
consists of malignant cells identical to serous carcinoma
confined to epithelial surface.
- invasive lesions have complex papillary growth pattern
composed of cells with marked cytological atypia including
high N/C ratio, atypical mitotic figures, hyperchromasia
and prominent nucleoli.
- at times, can have glandular pattern which is
differentiated from endometroid carcinoma by marked
cytological atypia.
83. Staging system for endometrial carcinoma:
Stage 1 - confined to corpus uteri
Stage 2 - involves corpus and cervix
Stage 3 - extends outside uterus but not true pelvis
Stage 4 – extends outside true pelvis (involving musocs of
bladder or rectum)
Prognosis depends on – depth of infiltration into
myometrium, grade of differentiation, stage of tumor,
molecular subtypes, lymphatic invasion and age of patient.
84. Occur in mddle aged women (=45 years) and frequently
present with vaginal bleeding.
BENIGN
Endometrial stromal nodule : solitary sharply circumscribed
mass of soft consistency having yellow – orange color. Do not
invade lymphatics, veins or myometrium. On microscopy,
monotonous proliferation of bland stromal cells with
expansile (non infiltrating) margin. Can show necrosis,
hemorrhage, myxoid change.
Low grade stromal sarcoma : poorly circumscribed soft
yellow tan to white nodules extending from endometrium
and invading in myometrium. On microscopy, irregular
cellular islands, forming permeative tongue-like pattern of
myometrial invasion with frequent vascular invasion.
Monotonous oval to spindle cells with minimal cytologic
atypia, vesicular chromatin and scant cytoplasm. Mitotic
count is usually low (< 5/10 high power fields), necrosis is
usually absent.
86. Stromal nodule : Monotonous proliferation of bland spindle
cells resembling proliferative phase endometrial stroma.
87. Low grade stromal sarcoma showing yellow brown
tumor mass and infiltrating tumor nodules
88. Low grade stromal sarcoma showing monotonous spindle to
oval cells with minimal nuclear atypia
89. Malignant
High grade stromal sarcoma : tan pink to yellow tumor
mass, soft and fleshy, can be polypoidal.
On microscopy, Permeative (tongue-like) invasion.
Vaguely nested growth of round cells with scant (small
round blue cell appearance) to moderate eosinophilic
cytoplasm and uniform nuclear atypia. Brisk mitoses (>
10/10 high power fields).
Tumor cell necrosis and lymphovascular invasion common.
50% associated with a low grade spindle cell component
resembling low grade endometrial stromal sarcoma.
90. High grade endometrial stromal sarcoma with
uniformly atypical spindled cells and brisk mitoses.
92. Never take oestrogen alone in HRT or
contraceptive pills, opt for low dose combination
of oestrogen with progesterone
Never let endometrial infections go untreated
Maintain a healthy lifestyle
93. 1. Blaustein’s pathology of female genital tract 7th edition
2. Rosai and Ackerman’s Surgical pathology 1st south asia
edition volume 2 section 6 chapter 33.
3. Robbins and Cotran: Pathologic basis of disease 10th
edition volume 2 chapter 22
4.
5. The Washington manual of Surgical pathology 3rd edition
section 7 chapter 33.
6. Harsh Mohan Textbook of pathology 7th edition chapter 10.
7. Akaev I, Yeoh CC, Rahimi S. Update on Endometrial
Stromal Tumours of the Uterus. Diagnostics (Basel). 2021
Mar 3;11(3):429.
8. Ali RH, Rouzbahman M. Endometrial stromal tumours
revisited: an update based on the 2014 WHO
classification. J Clin Pathol. 2015 May;68(5):325-32.