1. ENDOMETRIAL TUMORS
By Najla El BIZRI
PGY2
January 11th
, 2012

2. Histology of the Endometrium

3. • The uterus is a flattened pear-shaped organ
approximately 7 cm long in the non-pregnant state.
• Its mucosal lining, the endometrium,
provides the environment for fetal development;
• The thick smooth muscle wall, the myometrium,
expands greatly during pregnancy and provides
protection for the fetus and a mechanism for the
expulsion of the fetus at parturition.

4. • The endometrium is variable in thickness measuring
between 1 mm and 5 mm at different stages of the
menstrual cycle.
• The myometrium makes up the bulk of the uterus
measuring up to about 20 mm in a woman of
reproductive age.

5. In women of child-bearing age, the endometrial lining of
the uterine cavity consists of a:
- Pseudostratified columnar ciliated epithelium forming
numerous simple tubular glands supported by the cellular
endometrial stroma.
Surface Epithelium
Cilia or microvilli
Stromal cells

6. • Under the influence of
oestrogen and progesterone
secreted during the ovarian
cycle, the endometrium
undergoes regular cyclical
changes so as to offer a
suitable environment for
implantation of a fertilised
ovum.
• The cycle of changes in the
endometrium proceeds
through 3 distinct phases:
– Menstruation
– Proliferation
– Secretion

7. • The thinner superficial layer, which has a
compact stromal appearance, is known as the
stratum compactum.
• The broad intermediate layer is characterised
by a stroma with a spongy appearance and is
called the stratum spongiosum.
• The deepest or basal layer, the stratum
basalis, adjacent to the myometrium,
undergoes little change during the menstrual
cycle and is not shed during menstruation.
• The compact and spongy layers exhibit
dramatic changes throughout the cycle and
both are shed during menstruation;
hence they are jointly referred to as the
stratum functionalis.

8. Menstrual Phase
• Spasmodic constriction of
the spiral arterioles 
Ischemia  degeneration of
the Stratum Functionalis
• Leakage of blood into the
stroma
• Stromal cells disaggregate
• Endometrial glands collapse
• Apoptotic bodies can be
seen
1

9. Proliferative phase
• As the glands, stroma and
vessels proliferate, the
endometrium gradually
becomes thicker.
• The straight tubular form of
the endometrial glands can
be seen.
• Mitotic figures in the
epithelium and in the
stroma.
• Coiled and closely packed
tubular glands
• The stroma is somewhat
edematous at this stage
2

10. Secretory phase
• The coiled appearance of the glands is
now more pronounced.
• The glycogen accumulates to form
vacuoles in the basal aspect of the cells
 displacing the nuclei towards the
centre of the tall columnar cells = Basal
vacuolation (day 16).
• Late secretory phase:
saw-tooth appearance of the glands
that contain copious thick glycogen-
and glycoprotein-rich secretions.
• Cytoplasmic vacuoles seen on the
luminal aspect of the cell.
• Mitotic figures are absent.
• Endometrial stromal granulocytes can
be found at this stage.
3

11. Postmenopausal endometrium
• The endometrium is thin, consisting
only on the stratum basalis, and
the glands are sparse and inactive.
• In some women, the glands become
dilated to form cystic spaces, with
flattened epithelial lining.
• The glandular epithelial cells are
cuboidal or low columnar with no
mitotic figures or secretory activity.
• The stroma is much less cellular ;
contains more collagen fibers; no
mitotic activity seen.

12. TUMORS OF THE UTERINE
CORPUS

13. EPITHELIAL
MESENCHYMAL
MIXED

14. Epithelial tumors and related
lesions

15. Endometrial Carcinoma

16. Definition
• A primary malignant epithelial tumor, usually
with glandular differenciation, arising in the
endometrium that has the potential to invade
the myometrium and to spread to distant
sites.

17. Epidemiology
• Endometrial carcinoma is the most common
gynecologic malignancy in developed countries.
• The highest incidence rates are in the United
States and Canada, but in recent years there has
been a decline in incidence and mortality.
• It typically occurs in elderly individuals, 80% of
the patients being postmenopausal at the time
of diagnosis.
• However, it can occur in any age group and has
even been reported in association with
intrauterine pregnancy.

18. • It is currently believed that endometrial
carcinomas can be divided in 2 distinct types on
the basis of their pathogenesis:
– one – 80-85% of cases– occurring as a result of excess
estrogenic stimulation (estrogen dependant
neoplasms) and developing against a background of
endometrial hyperplasia.
– and the other (non-estrogen dependant neoplasms)
developing de novo (10-15% of cases).

19. • Patients at high risk for the first category
include the obese, diabetic, hypertensive,
and infertile; those with failure of ovulation
(including Stein–Leventhal syndrome) and
dysfunctional bleeding; long-standing
estrogen users; breast cancer patients treated
with tamoxifen ; those with severe degrees of
endometrial hyperplasia; and – to a much
lesser degree – those with functioning
granulosa cell tumors and thecomas.

20. Characteristics of Type I and Type II EC

21. Endometrial hyperplasia
• The endometrium is uniquely endowed througout the
female reproductive lifespan with a complex, regular
cycle of periodic proliferation, differenciation, break-
down and regeneration. This high cellular turnover,
conditioned by ovarian hormones and growth factors,
has many opportunities for losing its regulatory
controls.
• Endometrial hyperplasia encompasses conditions that
range from benign estrogen-dependant proliferations
of glands and stroma to monoclonal outgrowths of
genetically altered glands.

22. Endometrial hyperplasia and
Carcinoma
• Clinicopathologic and epidemiologic studies
have supported the malignant potential of
endometrial hyperplasia and the concept of a
continuum of proliferative glandular lesions,
culminating, in some cases, in carcinoma.
• Molecular studies have confirmed this
relationship, since endometrial hyperplasia
and carcinoma share specific molecular
genetic alterations.

23. Schematic diagram depicting the development
of type I EC arising in the setting of hyperplasia
PTEN hMLH1 KRAS
MI
B-Catenin
PIK3CA
•Mild glandular
crowding
•Cystic glandular
dilatation
•Mild ↑in
Gland/Stroma ratio
•Increased glandular
crowding and
branching
•Glands remain distinct
and nonconfluent

24. Simple hyperplasia w/o atypia
The endometrial glands vary
from dilated to compact
Are bridged by a large
squamous morule
Pseudostratified columnar
epithelium
Elongated nuclei lacking atypia

25. Complex hyperplasia w/o atypia
The endometrial glands show
branching and budding
There’s glandular crowding;
however, cytological atypia is
absent

26. Complex atypical hyperplasia
Nuclear enlargment
Loss of axial polarity and prominent
nucleoli
Unusual nuclear shapes
Irregularity in the nuclear membranes
Cleared or dense chromatin
 Tortuous glands with epithelial
tufts
(reflecting abnormal polarity)
protruding into the lumens
 Cytologic atypia

27. Complex atypical hyperplasia vs.
Carcinoma
• CAH has considerable morphologic overlap with
well-differenciated ADC, and an accurate
distinction may not be possible w/o
hysterectomy.
• 23-48% of women with CAH have a carcinoma
when hysterectomy is performed shortly after
the endometrial biopsy or curettage.
• Currently, CAH is managed by hysterectomy, or,
in young women, a trial of progestin therapy and
close follow-up.

28. Clinical features
• Endometrial carcinoma:
– Can be an incidental finding in specimens submitted
for other reasons:
• Endometrial biopsy for infertility
• Hysterectomy for uterine prolapse
– In the great majority of cases, they present clinically
with:
• Abnormal uterine bleeding
• Post-menopausal bleeding
• Menometrorrhagia
• Endometrioid carcinoma may manifest as:
• Obesity
• Infertility
• Late menopause

29. Associated conditions
• Stein-Leventhal Sd WD EC
• Gonadal dysgenesis WD EC
(Turner Sd)
• HNPCC Tumors of non
(Lynch Sd) endometrioid histology
• Pelvic irradiation Endometrioid or
serous types

30. Imaging
• Transvaginal ultrasound (US) is the imaging
technique of choice for the assessment of the
endometrium in symptomatic patients.
• In postmenopausal women without hormonal
replacement , an endometrial thickness of 5mm is
regarded as the upper normal limit.
• However, endometrial thickening is a nonspecific
finding since it may be due to edometrial
hyperplasia, polyps or carcinoma.
• The final diagnosis needs to be determined by
endometrial sampling.
• MRI is the best imaging technique for
preoperative staging of endometrial carcinoma
proven by endometrial sampling.

31. Macroscopy
• Endometrial carcinoma usually arises in the uterine
corpus, but some cases originates in the lower
uterine segment.
• The macroscopic appearance is that of a single
dominant mass, usually occurring in an enlarged
uterus, although occasionally the uterus is small or
the tumor presents as a diffuse thickening of most
of the endometrial surface.
• EC is seen more frequently on the posterior than on
the anterior wall.

32. Polypoid mass Highly infiltrating mass
Papillary serous
carcinoma filling the
endometrial cavity.

33. • Endometrial carcinoma can develop in any
anatomic region of the mucosa.
• Tumors developing in younger women have a
greater tendency to involve the lower uterine
segment (isthmus).
• Tumors thought to have arisen in the isthmus are
included among the endometrial rather than the
cervical carcinomas.
• Small carcinomas restricted to a cornu can be
missed by a biopsy or even a D&C.

34. • An estimate of the extent of the tumor may
be requested preoperatively or operatively in
order to determine the extent of the surgical
procedure to be performed.
• In occasional cases, no tumor may be visible
macroscopically, with carcinoma identified
only at histologic examination.

35. Tumor spread and staging

36. *FIGO no longer includes stage 0 (Tis)
**Endocervical glandular involvement should only be considered as stage I and no longer
as stage II
Tumor spread and staging

39. Previous vs. Current Classification of
Endometrial carcinoma and MMMT (2008)
• In endometrial carcinoma:
• The previous FIGO IA/pT1a and FIGO IB/pT1b will be merged to FIGO
IA/pT1a.
• The former category FIGO IC/T1c will be into FIGO IB/T1b.
• The category FIGO IC/pT1c will not longer been used.
• Additionally, there will be no separate classification for the involvement
of the endocervical glands by endometrial carcinoma. This feature will be
incorporated in stage FIGO I/T1 disease.
• The new category FIGO II/T2 will be defined as endocervical stromal
involvement.
• There will be a new category, termed T3c/IIIC, which includes regional
lymph node involvement. Stage T3c1/IIIC1 will be defined as pelvic lymph
node involvement and stage T3c2/IIIC2 para-aortal lymph node
involvement with or without pelvic lymph node disease.
• In the TNM system, regional lymph node involvement can alternatively be
classified as N1.

40. • The MMMT will be staged like endometrial
carcinoma.
Previous vs. Current Classification of
Endometrial carcinoma and MMMT (2008)

41. • Uterine sarcomas were staged previously as endometrial cancers, which
did not reflect clinical behavior.
• Therefore, a new corpus sarcoma staging system was developed based on
the criteria used in other soft tissue sarcomas.
Uterine Sarcomas (Leiomyosarcoma, Endometrial Stromal Sarcoma, and
Adenosarcoma)
IA Tumor limited to uterus < 5 cm
IB Tumor limited to uterus > 5 cm
IIA Tumor extends to the pelvis, adnexal involvement
IIB Tumor extends to extra-uterine pelvic tissue
IIIA Tumor invades abdominal tissues, one site
IIIB More than one site
IIIC Metastasis to pelvic and/or para-aortic lymph nodes
IVA Tumor invades bladder and/or rectum
IVB Distant metastasis
Adenosarcoma Stage I Differs from Other Uterine Sarcomas
IA Tumor limited to endometrium/endocervix
IB Invasion to < ½ myometrium
IB Invasion to > ½ myometrium

42. Histopathology

43. Endometrioid carcinoma
• Represents 80% of EC
• A primary endometrial adenocarcinoma
containing glands resembling those of the
normal endometrium.
• Represents a spectrum of histologic
differenciation from a very well
differenciated carcinoma difficult to
distinguish from atypical complex hyperplasia
to minimally differenciated tumors.

44. Characteristic features
• Presence of glandular or villo-glandular
structures lined by simple to pseudostratified
columnar cells that have their long axes arranged
perpendicular to the basement membrane with
at least some elongated nuclei that are polarized
in the same direction.
• As the glandular differenciation decreases and is
replaced by solid nests and sheets of cells, the
tumor is classified as less well differenciated
(higher grade).

45. The NEOPLASTIC GLANDS are lined by Columnar cells
Uniform nuclei

46. Back to back glands
Complex folds
Stromal disappearance
INVASION is indicated by:

47. WD Endometriod carcinoma vs.
Atypical Complex Hyperplasia
WD endometriod carcinomaACH
Stromal disappearance
Stromal desmoplastic response
Tumor necrosis

48. Grading of type I (endometrioid and
mucinous) endometrial carcinoma
ARCHITECTURE
- Grade 1 : <5% non-squamous, non-morular growth pattern
- Grade 2: 6-50% non squamous, non-morular growth pattern
- Grade 3: >50% non squamous, non-morular growth pattern
• Note: squamous/morular components are excluded from th
grading.
CYTOLOGY
• Bizarre nuclear atypia should raise the grade by one
(i.e. from 1  2 or 2  3) but may also signify type II
differenciation (serous or clear cell).

49. Well differenciated Moderately differenciated
Poorly differenciated
50%
35%
15%

50. The BIZARRE NUCLEAR ATYPIA Raises the tumor grade
But should also prompt
consideration of a serous carcin

51. • The frequency and extent of myometrial
invasion by carcinoma are directly related to
the microscopic grade of the tumor.
• High-grade tumors are also significantly
associated with cervical involvement and
lymphovascular invasion.

52. • Care should be exercised to distinguish true
myometrial extension by carcinoma
– from expansion of the endometrial–myometrial junction
– from atypical or malignant changes involving preexisting
foci of adenomyosis.
• It has been proposed that CD10 immunostaining can
help in this distinction by highlighting the endometrial
stroma associated with the adenomyosis when
present.
– However, a warning has been sounded to the effect that
CD10 immunoreactivity can also be found around foci of
invasive adenocarcinoma.
!

53. • Extension of the endometrial carcinoma into
the cervix occurs in over 10% of cases,
– usually by direct invasion,
– but supposedly also by implantation following
D&C.
• This extension may be grossly evident or
become apparent only on microscopic
examination; it may involve the surface only,
the fibrous stroma, or both.

54. Variants of endometrioid
adenocarcinoma

55. Variant with squamous differenciation
• 20-50% or more of endometrioid carcinoma
• Contain varying amounts of neoplastic epithelium
showing squamous differenciation.
• Although the distinction between endometrioid
ADC with and w/o squamous differenciation is
not clinically important, the recognition of
squamous differenciation is nevertheless essential
because the squamous or morular elements
should not be considered part of the solid
component that increases the grade of an EC.

56. The criteria for squamous
differenciation:
1) Keratinization demonstrated with standard
staining techniques
2) Intercellular bridges and/or
3) 3 or more of the following 4 criteria:
a. Sheet-like growth without gland formation or
palisading
b. Sharp cell margins
c. Eosinophilic and thick or glassy cytoplasm
d. A decreased nuclear to cytoplasmic ratio as
compared with foci elsewhere in the same tumor.

57. ADENOACANTHOMA
• The squamous
component exhibits well
differenciated elements.

58. The squamous
component has
markedly atypical
cytologic features.
Worse
prognosis???
ADENOSQUAMOUS
CARCINOMA

59. Villo-glandular (Papillary) variant
• Is the next most commonly
involved variant (25%).
• Involves part of low grade
endometrioid CA but not the entire
tumor.
• Numerous villous fronds are seen.
• ΔΔ:
These features contrast to the
more complex papillary
architecture and high grade
nuclear features that are typical of
serous and clear cell ADC growing
in a papillary pattern.

60. • The glandular lumina may contain cell debris similar to that seen in
colorectal carcinoma and colloquially known as ‘dirty necrosis’.
Such debris is associated with high-grade histology, myometrial
invasion, and extension into the isthmus.
• The stroma of endometrial adenocarcinoma usually has a
desmoplastic quality, but occasionally it may be almost completely
absent, even in the presence of a diffusely infiltrating tumor.
• It may contain collections of foamy cells, probably the result of tumor necrosis
and a good marker for the presence of carcinoma.However, these cells can also be
seen in hyperplasia and in the absence of proliferative epithelial changes.
Their immunophenotype corresponds to that of histiocytes rather than
endometrial stromal cells. They are fat positive and mucin negative, in contrast to
the mucin-positive macrophages sometimes seen in the stroma of benign
endometrial polyps.

61. Secretory variant
• Occasionnal endometrioid ADC are composed of
glands lined by epithelium with voluminous, usually
subnuclear, glycogen vacuoles reminiscent of early
secretory endometrium.
• These tumors have minimal nuclear atypia.
• It’s not believed to be a specific type of endometrial
carcinoma but rather the expression of a pattern that
may be present diffusely or focally in a well-
differentiated endometrioid carcinoma, usually as a
result of progesterone stimulation.

62. Cells with abundant clear to finely granular cytoplasm
ΔΔ: clear cell carcinoma
Secretory
variant

63. Ciliated cell variant
• Although occasional ciliated cells may be seen
in many endometrioid adenocarcinomas, the
diagnosis of the ciliated cell variant is made
only when the ciliated cells line the majority
of the malignant glands.
• Defined in this manner, this is a rare variant,
and the glands often have a strong
resemblance to tubal epithelium.
• ΔΔ: ciliated cell metaplasia (much more common)

64. Ciliated cell
variant
*
*
* *

65. Mucinous adenocarcinoma
• 10% of EC
• A primary adenocarcinoma of the
endometrium in which most of the tumor cells
contain prominent intracytoplasmic mucin.
Both endometrioid and clear cell
adenocarcinoma may have large amounts of
intraluminal mucin, but only mucinous
adenocarcinoma contains the mucin within
the cytoplasm.

66. Mucinous
adenocarcinoma
 Voluminous intra-cytoplasmic mucin
 Visible with HE staining
 Also demonstrated with mucicarmine stain
CK7 +
CK20-
CDX2-

67. • Some mucinous ADC
have a
microglandular
pattern :
Microglandular
carcinoma
ΔΔ:
May be difficult to distinguish from
microglandular hyperplasia of the
endocervix in a biopsy specimen.

68. Mucinous ADC of endometrium vs.
Primary mucinous ADC of cervix
• The diagnosis is difficult in a biopsy or curettage
specimen but is crucial for therapy; it rather depends on
differential biopsy and fractional curettage.
• IHC is useful in determining the site of origin:
• Vimentin +
• ER + = ENDOMETRIAL CA
• CEA –
• Vimentin –
• ER – = ENDOCERVICAL CA
• CEA +

69. Mucinous
metaplasia
Rare mucinous
adenocarcinomas of
the endometrium
may show intestinal
differenciation,
containing numerous
goblet cells.

70. Grading of mucinous adenocarcinomas
• They are graded in the same way as
endometrioid adenocarcinomas, but in
practice almost all of them are grade 1.
Prognosis
• Similar of that of low-grade endometrial ADC:
favorable.

71. Serous adenocarcinoma
• 5% of EC.
• A primary adenocarcinoma of the
endometrium is characterized by a complex
pattern of papillae with cellular budding and
not infrequently containing psammoma
bodies.
• Was first characterized as a common
endometrial tumor only in the early 1980s.
• It clinically typifies type II endometrial
carcinoma.

72. Serous
adenocarcinoma
Broad papillary stalks are covered by secondary and even tertiary
microapapillae
Cells and nuclei are generally rounded rather than columnar
 Lack a perpendicular orientation to the BM.

73. Serous
adenocarcinoma
Prominent myometrial invasion
Extensive necrosis
MNG cells
Psammoma bodies: 30% of cases
High nuclear grade
Apically rather than basally located, with
large macronucleoli
Atypical and bizarre mitoses
Are high grade
by definition
Usually not
graded

74. • Immunohistochemically, strong and diffuse
staining for P53 is one of the most
characteristic features of serous carcinoma.
• This is usually associated with patchy p16
expression and lack of hormone receptors.
p53 +
ER-
PR-

75. Clear cell adenocarcinoma
• 4% of EC.
• An adenocarcinoma composed mainly of clear
or hobnail cells arranged in solid, tubulocystic
or papillary patterns or a combination of
these patterns.
• Is the other major type II carcinoma of the
endometrium.
• Is less common than serous adenocarcinoma.

76. Clear cell
adenoarcinoma
A predominantly solid pattern
Occasional poorly formed tubules
Clear, glycogen-filled cells; occasionally: eosinophilic (oncocytic)
cytoplasm
Distinct cell walls

77. Clear cell
adenoarcinoma
 Hobnail cells
Large, highly pleiomorphic nuclei, often with bizarre and
multinucleated forms
Psammoma bodies
Are high
grade by
definition
Usually
not graded

78. • Patients with clear cell adenocarcinoma are
frequently diagnosed in advanced clinical
stages, and thus, have a poor prognosis.
• Clear cell adenocarcinoma limited to the
uterine corpus has a considerably better
prognosis than serous adenocarcinoma of the
same stage

79. • Precursor lesion for serous and clear cell ADC :
Endometrial intra-epithelial carcinoma
= Endometrial carcinoma in situ
= Surface serous carcinoma
– Characterized by:
Noninvasive replacement of benign endometrial surface
and glandular epithelium by highly malignant cells that
resemble those of invasive serous carcinoma.
• Clinically, EIC has a significance very similar to that of invasive
serous ADC since it can also be associated with disseminated
disease outside the uterus (usually in the peritoneal cavity).

80. p53
Aneuploidy
Serous adenocarcinoma has a tendancy to develop deep
myometrial invasion and extensive lymphatic invasion, and
patients commonly present with extrauterine spread at the
time of diagnosis.
Schematic diagram of type II
endometrial carcinoma

81. Mixed adenocarcinoma
• Is a tumor composed of an admixture of :
– a type I (endometrioid carcinoma,
including its variants, or mucinous carcinoma)
– and a type II carcinoma (serous or clear cell)
in which the minor type should comprise at least 10%
of the total volume of the tumor.
• The % of the minor tumor should be stated in the
pathology report.
• It’s generally accepted that 25% or more of a
type II tumor implies a poor prognosis.

82. Squamous cell carcinoma
• A primary carcinoma of the endometrium
composed purely of squamous cells of varying
degrees of differenciation.
• Only 70 cases reported in the litterature.
• Occurs in post-menopausal women.
• Its histological appearance is essentially
identical to that of squamous cell carcinoma
of the cervix and similarly includes a rare
verrucous variant.

83. Differential diagnosis
• Δ Δ:
– Cervical squamous cell carcinoma extending into
the endometrium
– Squamous differenciation of an endometrioid
carcinoma
• Rare prognosis; the verrucous variant may be
more favorable.

84. Squamous cell
carcinoma
Well differenciated squamous perls
Reactive stroma with inflammatory cells

85. Transitionnal cell carcinoma
• A carcinoma in which 90% or more is
composed of cells resembling urothelial
transitionnal cells.
• Lesser quantities of transitionnal cell
differenciation would qualify the tumor as
mixed carcinoma with transitionnal cell
differenciation.
• Extremely uncommon: fewer than 15 cases
reported.

86. Transitionnal cell carcinoma
Papillae lined by low grade stratified transitional type
epithelium

87. • Macroscopy:
polypoid or papillary with a mean size of 3.5 cm.
• Often grade 2 or 3; papillary configuration.
• Always admixed with another type of carcinoma, most
often endometrioid, but may be clear cell or serous.
• Only the transitionnal cell component invades the
myometrium deeply.
• All endometrial transitionnal cell carcinomas are
negative for CK20, but half are positive for CK7.

88. • ΔΔ:
– Metastatic transitionnal cell carcinoma from the
ovary and bladder
• Unlike primary endometrial tumors, those
metastatic to the endometrium are pure
transitionnal cell tumors.
• The CK7 positive, CK20 negative immunoprofile
also supports mullerian rather than urothelial
differentiation.

89. Small cell (neurooendocrine)
carcinoma
• An endometrial carcinoma resembling small
cell carcinoma of the lung.
• Comprises less than 1% of all carcinomas.
• LMWCK+, NSE+, Vimentin+ (50%), sometimes
Chromogranin and Synaptophysin +
• The behavior is very aggressive.

90. The tumor is red and fleshy,
and has a soft consistency.
Macroscopically, they
present as bulky
(sometimes polypoid),
ill-defined, and
invasive tumors

91. Small cell
carcinoma
Small cells
High N/C ratio

92. Diffuse pattern of growth.
Small cell
carcinoma

93. Endometrioid +
Small cell
carcinoma
A common combination

94. Undifferenciated carcinoma
• Are those lacking any evidence of differenciation.
• It grows in the form of solid sheets of epithelial
cells without any signs of differentiation.
• ΔΔ: It is important to distinguish it from a grade 3
endometrioid adenocarcinoma because of its
worse prognosis.
• The association of undifferentiated carcinoma
with low-grade endometrioid adenocarcinoma is
regarded as a form of tumor dedifferentiation

95. Rare types of endometrial carcinoma
Glassy cell carcinoma is a special type of adenosquamous carcinoma; its
appearance is similar to that of its more common cervical counterpart.
Giant cell (adeno)carcinoma is a rare pleomorphic form of high-grade
endometrial adenocarcinoma featuring poorly cohesive sheets and
nests of bizarre multinucleated giant cells. It may be combined with
better differentiated areas showing endometrioid or clear cell
carcinoma features.
Endometrial carcinoma with trophoblastic (choriocarcinomatous)
differentiation should be distinguished from the tumor just mentioned
and from gestational choriocarcinoma.The multinucleated
syncytiotrophoblast-like cells present in the tumor are strongly
immunoreactive for human chorionic gonadotropin (hCG).The
nontrophoblastic areas are more likely to have a serous than an
endometrioid morphology.A related and even rarer phenomenon is that
of endometrial carcinoma secreting alpha-fetoprotein.

96. • Oxyphilic cell carcinoma is a rare variant of endometrioid carcinoma characterized by a
predominant or exclusive component of large eosinophilic (oxyphilic) cells.
• Endometrioid carcinoma with sertoliform (sex cord-like) differentiation similar to that
more commonly seen in ovarian endometrioid tumors has been reported. This
phenomenon is to be distinguished from the uterine tumors resembling ovarian sex-cord
tumors. The term corded and hyalinized endometrioid carcinoma has been proposed to
indicate its two most characteristic morphologic features.
• Hepatoid adenocarcinoma has been reported as arising from the endometrium, in
association with alpha-fetoprotein production.
• Signet ring cell adenocarcinoma has been described as a primary uterine tumor.Before
making this diagnosis, all attempts should be made to rule out the alternative possibilities
of metastasis (particularly from breast and stomach) and of vacuolated decidual cells and
stromal histiocytes simulating signet ring cells.
• Lymphoepithelioma-like carcinoma looks like its homonym in other sites. The few reported
cases have not shown evidence of Epstein–Barr virus infection.
• Rhabdoid tumor of the uterus represents, in at least some of the cases, a dedifferentiated
form of endometrial adenocarcinoma, as is strongly suggested by its occasional coexistence
with a conventional adenocarcinoma appearance.
• Mesonephric (adeno)carcinoma of the endometrium, i.e., a tumor truly derived from
wolffian remnants and, therefore, unrelated to the clear cell carcinoma described above
presenting as a myometrial mass.

97. Endometrial polyps

98. Definition
• A benign nodular protrusion above
the endometrial surface consisting of
endometrial glands and stroma that is
typically at least focally fibrous and
contains thick-walled blood vessels.
• Histologically, they are pedunculated
or sessile lesions with a fibrous
stroma in which characteristic thick-
walled, tortuous, dilated blood
vessels are found. The glandular
component is patchly distributed and
shows dilated, occasionnally crowded
glands lined with an atrophic
epithelium.

99. Endometrial polyps
The glands are cystic and
contain mucoid material
The stroma is fibrous, and the
vessels are prominent
Endometrial polyp with
complex hyperplasia.

100. • The large majority of endometrial polyps are
not true neoplasms but probably represent
circumscribed foci of hyperplasia, possibly due
to a decreased expression of hormone
receptors in the stromal component.
• The glands and stroma of the polyp are
unresponsive to progesterone stimulation
and retain their integrity throughout the
menstrual cycle.

101. Endometrial polyp vs. Endometrial Hyperplasia
• In material obtained from D&C, where usually only fragments of the
polyp are obtained, the distinction with endometrial hyperplasia is
made by examining the stroma.
– In endometrial hyperplasia, the stromal cells are active, with large
vesicular nuclei and occasional mitotic figures,
– whereas the stroma of a polyp is composed of spindle (fibroblast-like) cells,
contains abundant extracellular connective tissue, and has large blood
vessels with thick walls.
• On occasion, however, the stroma is more cellular and mitotically active, i.e.,
similar to that of endometrial hyperplasia.
• Some polypoid lesions exhibit either simple or complex hyperplastic papillary
endometrial proliferations, and it is a matter of individual choice whether to
regard them as localized forms of endometrial hyperplasia or endometrial
polyps with hyperplastic changes.

102. • Furthermore, endometrial polyps with a typical
appearance often coexist with endometrial
hyperplasia.
• All of these observations point to a shared
pathogenesis for these two lesions.
• In the presence of atypical complex hyperplasia
or carcinoma in a polyp, the performance of a
hysterectomy should be considered – especially
in postmenopausal women – even if the changes
appear restricted to the polyp.

103. • Malignant transformation of endometrial
polyps is an exceptional but well-documented
occurrence.
• Some of these cases present in the form of in-
situ or invasive serous carcinomas.

104. Adenomyomatous polyps
• Endometrial polyps having
smooth muscle fibers in
addition to the customary
glands and stroma are
designated as
adenomyomatous polyps
(polypoid adenomyomas).

105. Atypical polypoid adenomyoma
• An important variation on the
theme is the atypical polypoid
adenomyoma (atypical
polypoid adenomyofibroma).
• These tend to occur in
premenopausal women
(average age, 40 years) and
present with abnormal
uterine bleeding. Some are
associated with Turner
syndrome.

106. • Microscopically, they are identified by the
fact that the glands occurring between the
endometrial stroma and smooth muscle
exhibit varying degrees of hyperplasia and
atypia, sometimes approaching the
appearance of carcinoma in situ (‘of low
malignant potential’).
• The danger is to misdiagnose them as
adenocarcinomas with myometrial invasion.
• CD10 immunostaining is helpful in this differential
diagnosis, in that it is negative in the stromal
component of polypoid adenomyoma but often
positive in the cells immediately surrounding the
muscle-invasive glands (so-called fringe-like staining
pattern).
• The behavior is generally benign, but cases have
been seen with local recurrences, carcinomatous
transformation, and coexistent endometrial or
ovarian endometrioid carcinoma.

107. Endometrial mesenchymal
tumors

108. MESENCHYMAL

109. Endometrial stromal tumors
• Tumors composed of endometrial stroma
tend to occur in middle-aged women
(average age, 45 years) and often present with
vaginal bleeding.

110. • Endometrial stromal tumors have been divided
according to the type of margins into:
(1) a benign category (endometrial stromal nodule)
having pushing margins
(2) a malignant category (endometrial stromal sarcoma)
having infiltrating margins.
• Low-grade
• High-grade

111. Endometrial stromal nodules
• They appear grossly as
solitary sharply
circumscribed, round or
oval, fleshy nodule of soft
consistency and a
characteristic yellow-to-
orange color.
• Median diameter = 4cm
(0.8-15cm)
• 2/3: purely intramural
• Others involve both
endometrium and
myometrium.

112. Clinical features
• Median age = 47 years (23-75y)
• Do not share the same RF as endometrial ADC.
• They do not invade veins, lymphatics, or the
myometrium.
• The prognosis is excellent.
• A hysterectomy may be required if the lesion has not
been completely excised.

113. Circumscribed, bulging, yellow
nodule in the myometrium.
Bland ovoid cells without discernable
cytoplasm proliferating in a plexiform
pattern supported by small arterioles.
Closely packed cells Tumor cells strongly immunoreactive
for CD10

114. • Focal marginal irregularity in the form of finger-
like projections that do not exceed 3 mm is
acceptable.
• ΔΔ: - Low grade ESS
Infiltrative margin
- Highly cellular leiomyoma
Focal typical neoplastic smooth muscle bundles
Large thick-walled vessels
Strong immunoreactivity with desmin and h-caldesmon
Absence of reactivity with CD10

115. Endometrial stromal sarcomas (ESS)
• Traditionally designated endolymphatic stromal
myosis
• Infiltrate the myometrium and have a particular
tendency to permeate lymph vessels.
• Extension to the serosa is seen in ~ half of the cases.
• The local invasion may extend into the broad
ligament, tubes, and ovaries.

116. Myoinvasive low grade ESS
with finger-like projections into the
normal myometrium

117. Extensive myometrial permeation by sharply defined
tumor islands with pointed edges.

118. • The proposal had been made to subdivide ESS
into low-grade and high-grade types on the
basis of their mitotic count :
– <10 mitoses/10 (HPF) LOW GRADE
– ≥10 mitoses/10 (HPF) HIGH GRADE
However, more recent series have not supported such a sharp
distinction, the tendency at present being to designate the
whole group as ESS, to regard mitotic activity as one of the
morphologic factors to evaluate for prognostic purposes.

119. LOW GRADE ESS HIGH GRADE ESS
(Undifferenciated Sarcoma)
<10 mitoses/10 (HPF) >10 mitoses/10 (HPF)
Atypical mitotic figures
Plexiform vasculature No plexiform vasculature
Minimal cytologic atypia Cytologic atypia and
pleiomorphism present
Indolent; low propensity for
local recurrence
Highly aggressive; distant
metastasis common.
A small minority of cases share features of low grade ESS and
undifferenciated sarcoma, and their classification is controversial.

120. Low-grade ESS showing
diffuse permeation of the
myometrium in the form of
small nodules bulging on
the cut surface.
The cut surface has a softer
consistency than the usual
leiomyoma.
Cystic and myxoid
degeneration as well as
necrosis and hemorrhage
are seen occasionally.

121.  Huge polypoid mass within the endometrial cavity.
(This pattern of growth is unusual in this tumor type)

122. Low grade ESS
 Uniform, oval small cells resembling those of the proliferative
phase endometrial stroma, individually enveloped by reticulin
fibers.
 A rich network of thin-walled arteriolar type (plexiform) small
vessels resembling spiral arterioles of the late secretory
endometrium encircle the proliferating cells.

123. Low grade endometrial stromal sarcoma (ESS)
Worm-like, soft, yellow masses focally
replacing the myometrium
Irregular tongues of neoplastic
stromal cells between smooth
muscle bundles of the
surrounding normal myometrium
A tongue of tumor protrudes into
a vascular space
Extensive lymphatic invasion is
the hallmark of the tumor

124. Proliferation of
endometrial stromal cells
lacking atypia around spiral
arteriole-like blood vessels .
Sex cord-like pattern
alpha-inhibin +
CD99 +
CK +
Desmin +

125. • Perivascular hyalinization and a stellate
pattern of hyalinization occur in some cases.
• Reticulin stains usually reveal a dense
network of fibrils surrounding individual cells
or small groups of cells.
• Focal rhabdoid differenciation has been
described in one case.

126. Immunoprofile of Endometrial
Stromal Tumors
• Endometrial stromal nodule and Low grade
ESS:
– Positive for: Vimentin, CD10, actin (focally).
– Negative for: Desmin and h-caldesmon (usually
but not always).
• Low grade ESS:
– Positive for ER and PR (almost always).

127. Treatment
• Hysterectomy is the treatment of choice
• Because some of the tumor cells are positive
for progesterone receptors, hormonal
therapy following excision is a treatment
option.

128. • The natural history of ESS is characterized by
slow clinical progression, repeated local
recurrences (in the pelvis, ovary, intestinal
wall, and anterior abdominal wall).

129. • Before making a diagnosis of
primary extrauterine
endometrial stromal tumor, one
should make an effort to rule
out a metastasis from a uterine
lesion, knowing that these
metastases are often solitary
and that they can occur years or
decades after the excision of the
original tumor.
• A remarkable case has been
described involving the placenta.
ESS metastatic to wall of
large bowel
ESS metastatic to the lung
Primary or metastasis?

130. Gross appearance of High-grade ESS
Polypoid, fleshy, grey to
yellow endometrial mass
Displace the myometrium in
contrast to the infiltrative pattern
of low grade ESS.

131. • Poorly differentiated endometrial sarcoma shows a
marked degree of nuclear pleomorphism and
atypicality.
• They lack the typical growth pattern and
vascularization of low grade ESS
Atypical tumor cells
Abnormal mitotic figures

133. Combined smooth muscle-stromal
tumor
• Certain number of mesenchymal uterine tumors
show features of both endometrial stromal and
smooth muscle differentiation.
• If the latter is sizable (1/3 or more of the tumor
mass), the neoplasm is referred to as combined
smooth muscle–stromal tumor.
• A further variation on the theme is represented
by the exceptional case exhibiting both smooth
and skeletal muscle differentiation;
ΔΔ MMMT

134. • Exceptionally, an endometrial stromal tumor
may be seen in a uterus that also contains an
endometrial adenocarcinoma.
• As a matter of fact, the two tumors can collide
with each other.
• ΔΔ MMMT

135. MIXED

136. Mixed epithelial and mesenchymal
tumors
= Malignant Mullerian Mixed Tumor
= Malignant Mesodermal Mixed Tumor
= Metaplastic Carcinoma

137. Malignant mixed müllerian tumors
(MMMTs)
• MMMTs are practically always seen in postmenopausal
patients.
• They present with uterine bleeding and enlargement, followed
by abdominal mass and pelvic pain.
• Their most common location is the posterior uterine wall in the
region of the fundus.
• Grossly, they present as large, soft, polypoid growths involving
the endometrium and myometrium, sometimes protruding
from the cervix to present as an upper vaginal mass.
• Foci of necrosis and hemorrhage are common.
• The most important diagnostic method is uterine curettage,
but in 25% of cases, the diagnosis is made following
hysterectomy.

138. MMMT of uterus resulting in a huge polypoid
mass.
• Uterine carcinomas are
usually polypoid , bulky,
necrotic and hemorrhagic
neoplasms that fill the
endometrial cavity and deeply
invade the myometrium.
• If cartilage or bone forms a
significant portion of the
neoplasm, the neoplasm may
have a hard consistency.

139. • Microscopically, the distinctive feature of MMMTs
is the admixture of carcinomatous and sarcoma-
like elements, resulting in a characteristic biphasic
appearance.
• The carcinomatous component is usually of
glandular type, whether endometrioid, clear cell,
or papillary serous ; or non-glandular (squamous or
undifferenciated CA).
• As a rule, it has a poorly differentiated appearance
and is of a high-grade nature; therefore, a careful
search for stromal elements should be carried out
whenever such patterns are found in an
endometrial biopsy, particularly if accompanied by
extensive necrosis and hemorrhage.

140. • The appearance of the sarcomatous component is
the basis for the division of these neoplasms into a
homologous and a heterologous variety.
• HOMOLOGUS: the malignant stroma is composed either of
round cells resembling those of the endometrial stroma or
of spindle cells resembling leiomyosarcoma or
fibrosarcoma.
• HETEROLOGUS: specific heterologous mesenchymal
elements (such as skeletal muscle, cartilage, bone, or
adipose tissue) are also present.

141. Sarcomatous
elements
Poorly
differenciated
malignant glands
Solid aggregates
of malignant
epithelium with
central squamous
differenciation
Sarcomatous
elements

142. Mesenchymal
component
resembling
leimyosarcoma
Mesenchymal
component
resembling
osteosarcoma

143. • In general, both carcinomatous and sarcomatous
components are easily identified, although in some
cases, one or other element may form a minor
component that may be only identified following
extensive sampling of the neoplasm.
• Any uterine neoplasm composed of high grade
sarcoma, especially when heterologous elements are
present, should be extensively sampled in order to
R/O a carcinosarcoma.
• In most instances, the 2 elements are sharply
demarcated, but in some they appear to merge with
transitional forms between the 2 elements.
• Occasionally, a carcinosarcoma may be identified in
an otherwise benign endometrial polyp.

144. Glandular + mesenchymal components of MMMT.
Heterologous elements = cartilage.

145. • MMMTs are highly aggressive neoplasms; worse
than that of poorly differenciated endometrial
carcinoma.
• Extension into the pelvis, lymphatic and vascular
permeation, and distant lymph-borne and blood-
borne metastases are all common.
• Tumors having only homologous stromal
elements have been found to have a better
prognosis than those with heterologous
elements.
• MMMTs have been associated with chronic
estrogenic stimulation.
• MMMTs can arise in extrauterine locations, the
most common sites being ovary and pelvic
structures.

146. • The MMMT will be staged like endometrial
carcinoma.

147. Immunoprofile
• In general:
– The epithelial elements are immunoreactive with
anti-CK antibodies.
– The mesenchymal elements with Vimentin; they
may show focal staining with anti-CK antibodies,
supporting an epithelial origin of this component.
• Desmin, myoD1, myoglobin and sarcomeric actin
staining may highlight a rhabdomyosarcomatous
mesenchymal component.
• Cartilaginous elements usually stain with S-100 protein.

148. Mixed epithelial and mesenchymal
tumors

149. Müllerian adenosarcoma
• It is regarded as a low-grade variant of MMMT.
• Like the latter, it usually presents in elderly
individuals as a bulky polypoid growth filling the
endometrial cavity, less commonly as an intramural
nodule.
• Shows lesser degree
of hemorrhage and
necrosis than MMMTs.
• Association with
tamoxifen therapy and
prior pelvic radiation.

150. Its distinguishing feature is the fact that the epithelial
(glandular) component appears benign, giving to the
lesion a sometimes striking similarity to phylloides
tumor of the breast.

151.  Leaf-like pattern.
 Isolated glands often dilated and
compressed into thin slits.
 Stromal condensation surrounding the
glands and clefts.

152. Mixed epithelial and mesenchymal
tumors

153. Carcinofibroma
• The mesenchymal component is usually
fibrous, although occasional cases with a
heterologous mesenchymal component have
been described and have been designated as
carcinomesenchymoma.

154. Mixed epithelial and mesenchymal
tumors

155. Uterine adenofibromas
• Uterine adenofibroma
• Papillary adenofibroma
• Papillary cystadenofibroma
• Lipoadenofibroma
• Adenomyomatosis
• Δ Δ Criteria found to be useful in distinguishing müllerian
adenosarcomas from müllerian adenofibromas include
– 2 or more stromal mitoses per 10 HPF
– marked stromal cellularity
– and significant stromal cell atypia.
have been traditionally regarded
as the benign counterparts of
müllerian adenosarcoma.

156. Papillary adenofibroma of uterus.

157. Spread and metastasis
• The two obvious sites of direct spread are the
myometrium and the cervix, both of these having
important prognostic connotations.
• The invasion of the endocervix by endometrial
carcinoma should be distinguished from the atypical
reactive endocervical proliferation that may
accompany a uterus affected by endometrial
carcinoma, possibly related to prior endometrial
sampling.

158. • Lymphovascular invasion is the most important
route of spread of endometrial cancer.
• There is an artifact known as vascular
pseudoinvasion sometimes seen in
laparoscopic hysterectomy specimens and
characterized by conspicuous tumor fragments
in the lumen of thick-walled vessels in the outer
myometrium or in ectatic vessels anywhere in
the myometrium.
• The most common sites of extrauterine spread
in endometrial adenocarcinoma of the
endometrioid type are the pelvic and para-
aortic lymph nodes and the ovaries.

159. • An additional route of spread of endometrial
carcinoma is transtubal,but another warning is in
order.
• On occasion, the keratin present in endometrial
carcinoma with squamous metaplasia desquamates
into the uterine cavity and from there travels via the
fallopian tube to produce implants in the peritoneal
surface, leading to the formation of foreign body
granulomas. This finding should not be regarded as
evidence of metastatic disease in the absence of
viable neoplastic cells. Follow-up data suggest that
these keratin granulomas have no prognostic
significance and that they should be distinguished
from viable tumor implants.
• The most common sites of recurrence of endometrial
carcinoma are the vaginal vault and pelvis.

160. • Papillary serous carcinoma characteristically
spreads throughout the abdominal cavity in a
fashion similar to that of ovarian serous
carcinoma.
• Distant metastases of endometrial carcinoma
are more common in the lung, liver, bone,
central nervous system, and skin.

161. Treatment of endometrial carcinoma
• The usual treatment of endometrial carcinoma is total
abdominal hysterectomy with bilateral salpingo-oophorectomy.
• Whenever feasible, this should be supplemented by surgical
staging (including biopsies of pelvic and para-aortic lymph nodes)
if any of the following is present:
– greater than 50% myometrial invasion,
– grade III tumor,
– cervical involvement,
– extrauterine spread,
– unfavorable histologic component (serous, clear cell, or undifferentiated),
– or palpably enlarged nodes.

162. • Radiation therapy, which until recently was
administered routinely in conjunction with surgery
(either preoperatively or postoperatively),
is no longer favored, except for patients with poor
prognostic factors that put them at a high risk of
recurrence.
• Often obtained for tumors limited to the endometrium
but only rarely for tumors invading the myometrium.
Postradiation recurrent tumors tend to show
↓expression of hormone receptors and
↑expression of P53.

163. • Progestational agents, although usually not curative,
occasionally induce striking temporary regressions in
the primary tumor as well as in the metastases.
– Well-differentiated lesions are more likely to
respond and sometimes to regress completely;
this is in keeping with the fact that an association exists
between microscopic degree of differentiation and
presence of estrogen and progesterone receptors.
– Well-differentiated carcinomas treated with
progestins show a ↓ gland-to-stroma ratio,
↓ glandular cellularity, ↓ or absent mitotic
activity, loss of cytologic atypia, and a variety of
cytoplasmic changes, including mucinous,
secretory, squamous, and eosinophilic metaplasia.

164. • The treatment of papillary serous carcinoma consists of
hysterectomy with bilateral salpingo-oophorectomy,
omentectomy, and surgical staging, the latter including
peritoneal cytology and pelvic and para-aortic lymph
node sampling.
• This is usually followed by adjuvant therapy, except for
the minimally invasive tumors.
• Tumor relapse may appear in the form of local
recrudescence (50%), distant metastases (28%), or both
(21%); the median interval is between 1 and 2 years.
• Local recurrences can be treated successfully with
aggressive radiation therapy.

165. Prognostic Factors
1 Tumor stage, as defined by the FIGO system.This refers to the
surgical stage, since the clinical stage frequently underestimates
the extent of disease.
2 Level of infiltration of the myometrial wall, Tumors with
invasion of over one-half of the myometrium are worse than those
invading less than one-half.
3 Microscopic grade of differentiation, as defined by the FIGO
system.Originally this system was primarily based on architectural
rather than nuclear features, except for the papillary serous and
clear cell types, which are by definition high-grade tumors.
The addition of a nuclear parameter to the FIGO system has
improved its prognostic significance.A relationship exists between
microscopic grade and level of invasion (well-differentiated
tumors being more superficial), but there is also a correlation
between grade and survival within a given stage.

166. 4 Cervical extension. This is associated with a
somewhat worse prognosis.
5 Estrogen dependence.
Tumors associated with – and probably resulting
from – chronic estrogenic stimulation have a
better prognosis than the others.
Along the same lines, adenocarcinomas
associated with hyperplasia in the residual
endometrium have a better prognosis than those
lacking this feature.

167. 6 Microscopic type.
 Among the various morphologic variants, the papillary serous type and clear
cell types are the most aggressive, with a definite tendency for upper abdominal
spread for the former.
 Adenosquamous carcinomas are also highly malignant, but this is probably
only a reflection of the fact that they are poorly differentiated tumors.
 Conversely, the excellent prognosis associated with grade I endometrioid
adenocarcinoma, adenoacanthoma, and secretory carcinoma probably relates to
their well-differentiated nature.
7 Lymph vessel invasion. Tumor permeation of lymph vessels is a poor
prognostic sign.
8 Blood vessel invasion. This is an important prognostic factor in stage I
adenocarcinoma.
9 Hormone receptor status. Multivariate analyses have shown that the estrogen
receptor status is a significant predictor of recurrence and survival.
10 P53 overexpression. This parameter has been found to be associated with

168. 11 HER2/neu expression. Intense overexpression of this oncogene is
said to be associated with a poor overall survival.
12 Epidermal growth factor receptor. Expression of this marker is said
to correlate with a high microscopic grade and a shorter survival rate.
13 DNA ploidy. Aneuploid tumors are associated with high microscopic
grade, high clinical stage, and poor prognosis.
14 Cell proliferation. The degree of tumor cell proliferation, as
determined by S-phase fraction, was found to be a strong predictor of
outcome. High mitotic rate has also been found to be a sign of
aggressiveness in stage I grade I adenocarcinomas.

169. 15 RB gene.
16 Angiogenesis.
17 Others. Parameters said to be indicative of favorable
outcome are vimentin positivity, S100A1 immunoexpression,
Langerhans cell infiltration,low expression of p170 (a cell
cycle-related antigen), and absence of hMLH1 (a mismatch
repair gene).

170. References
• Wheater’s Functional Histology
• Tumors of the Breast and Female Genital
Organs. WHO. 2003
• Rosai and Ackerman’s Surgical Pathology, 10th
ed.
• Robbins and Cotran Pathologic Basis of Disease 8E
• Medscape
• www.pathologyoutlines.com

171. Thank you