UTERINE CORPUS

EPITHELIAL TUMORS AND RELATED LESIONS

ENDOMETRIAL CARCINOMA ENDOMETRIAL HYPERPLASIA ENDOMETRIAL POLYP TAMOXIFEN-RELATED LESIONS

MESENCHYMAL TUMORS
Endometrial stromal and related tumors Smooth muscle tumors Miscellaneous mesenchymal tumors

MIXED EPITHELIAL AND MESENCHYMAL TUMORS

Carcinosarcoma (MMMT) Adenosarcoma Carcinofibroma Adenofibroma Adenomyoma

MISCELLANEOUS TUMORS
Sex cord-like tumors Neuroectodermal tumors Melanotic paraganglioma

Lymphoid and hematopoietic tumors

Malignant lymphoma Leukemia

ENDOMETRIAL CARCINOMA
A primary malignat tumor, usually with

glandular differentiation, arising in the endometrium that has the potential to invade into the myometrium and to spread to distant sites

GROSS FINDINGS

MICROSCOPIC

FINDINGS

Grading of type I (endometrioid and mucinous) endometrial carcinoma:

Grade 1: 5% non-squamous, non-morular growth

pattern
Grade 2: 650% non-squamous, non-morular growth

pattern
Grade 3: > 50% non-squamous, non-morular growth

pattern

ENDOMETRIAL CARCINOMA PATHOLOGIC FEATURES

Mucinous adenocarcinoma: > 50% of cells with intracytoplasmic mucin Serous carcinoma: irregular, branching papillae with budding and prominent stratifi cation of pleomorphic cells. Rarely, glandular architecture Clear cell carcinoma: cells arranged in tubulocystic, papillary, and solid patterns, frequently with clear and hobnail cells Mixed adenocarcinoma: composed of different types of carcinoma representing > 10% each

Squamous cell carcinoma: exclusively composed of squamous cells

Transitional cell carcinoma: similar morphology to tumors of the urinary tract Small cell carcinoma: similar to small cell carcinoma of the lung Undifferentiated

ENDOMETRIOID ADENOCARCINOMA, GRADE I

ENDOMETRIOID ADENOCARCINOMA, GRADE II

ENDOMETRIOID ADENOCARCINOMA, GRADE III

Endometrioid Adenocarcinoma with Squamous Differentiation

Villoglandular Endometrioid Adenocarcinoma

Secretory Endometrioid Adenocarcinoma

Mucinous Adenocarcinoma

Serous Adenocarcinoma

Papillary Serous Adenocarcinoma

Clear Cell Adenocarcinoma

Mixed Cell Adenocarcinoma

Squamous Cell Carcinoma

Transitional Cell Carcinoma

Small Cell

Carcinoma

Undifferentiated Carcinoma

ENDOMETRIAL HYPERPLASIA

ENDOMETRIAL POLYP

TAMOXIFEN-RELATED LESIONS
Lesions that develop in the endometrium in

patients undergoing long term tamoxifen therapy Bizarre stellate shape of glands and the frequent epithelial and stromal metaplasias Malignant transformation in 3 % of cases

ENDOMETRIAL INTRAEPITHELIAL NEOPLASIA (EIN)

Essential diagnostic criteria of endometrial intraepithelial neoplasia (EIN)
EIN Criteria 1. Architecture 2.Cytological alterations 3. Size more than 1 mm Comments Gland area exceeds that of stroma, usu in a localized region Cytology differs bet. Architecturally crowded focus and background Maximum linear dimension should exceed 1 mm. smaller lesions have unknown natural history.

4. Exclude benign mimics and cancer

MESENCHYMAL TUMORS
Endometrial stromal and related tumors Smooth muscle tumors Miscellaneous mesenchymal tumors

MESENCHYMAL TUMORS
Endometrial stromal and related tumors
Endometrial stromal sarcoma, low grade Endometrial stromal nodule Undifferentiated endometrial sarcoma

MESENCHYMAL TUMORS
Endometrial stroma

Smooth muscle
Blood vessels Admixture of these Leiomyosarcoma and Endometrial stromal tumors

Most common malignant mesenchymal tumors of the uterine corpus

Low-Grade Endometrial Stromal Sarcoma

Low-grade malignant endometrial stromal tumor Cells reminiscent of proliferative-phase endometrial

stroma
(+) Myometrial and vascular invasion and late

recurrences

Low-Grade Endometrial Stromal Sarcoma

Low-Grade Endometrial Stromal Sarcoma

Endometrial Stromal Nodule

Well-circumscribed noninvasive endometrial stromal

tumor
Cells reminiscent of proliferative-phase endometrial

stroma

Endometrial stromal nodule

Endometrial stromal nodule

SMOOTH MUSCLE TUMORS

Benign or malignant neoplasms composed of

cells demonstrating smooth muscle differentiation

LEIOMYOSARCOMA
A malignant neoplasm composed of cells

demonstrating smooth muscle differentiation Solitary intramural masses; usually not associated with leiomyomas 8.0 cm in average size Fleshy, poorly defined margins Zones of hemorrhage and necrosis

DIAGNOSTIC CRITERIA FOR LEIOMYOSARCOMA

STANDARD SMOOTH MUSCLE DIFFERENTIATION EPITHELIOID DIFFERENTIATION
Rounded cells with central nuclei and clear to eosinophilic cytoplasm Any coagulative tumor cell necrosis In the absent of tumor cell necrosis the diagnosis requires diffuse, moderate to severe cytological atypia and a mitotic index of more than 5 mf/10hpf

MYXOID DIFFERENTIATION
Spindle-shaped cells set within an abundant myxoid matrix

Histology

Fascicles of cigar-shaped spindled cells with scanty to abundant eosinophilic cytoplasm

Criteria for leiomyosarc oma

Any coagulative tumor cell necrosis

Any coagulative tumor cell necrosis In the absent of tumor cell necrosis the diagnosis requires diffuse, moderate to severe cytological atypia and a mitotic index of more than 5 mf/10hpf

In the absence of tumor cell necrosis, the diagnosis requires diffuse, moderate to severe cytological atypia & a mitotic index of more than 10mf/10 hpf. When the mitotic index is less than 10mf/10hpf, the chance of recurrence is low (less than 2-3%) and the tempo of recurrence is slow. This group is labeled atypical leiomyoma with low risk of recurrence.
In the absence of coagulative tumor cell necrosis and significant atypia a high mitotic index is compatible with a benign clinical course. When the mitotic index exceeds 15 mf/10hpf the term mitotically active leiomyoma with limited experience can be used The category leiomyoma with limited experience is also used for smooth muscle neoplasms that have focal moderate to severe atypia

Comments

Focal epithelioid differentiation may be mimicked by crosssectioned fascicles od standard smooth muscle

The very common perinodular hydropic degeneration should not be included in this group

LEIOMYOSARCOMA

LEIOMYOSARCOMA

LEIOMYOMA
A benign neoplasm composed of smooth

muscle cells with a variable amount of fibrous stroma Typically multiple, spherical and firm White to tan, whorled trabecular texture

LEIOMYOMA histological variants:

Cellular Hemorrhagic cellular and hormone induced changes Epithelioid Myxoid Atypical leiomyoma (pleomorphic, bizarre, or symplastic

leiomyoma)
Lipoleiomyoma

LEIOMYOMA growth pattern variants:

Diffuse leiomyomatosis Dissecting leiomyoma Intravenous leiomyomatosis Benign metastasizing leiomyoma

MIXED EPITHELIAL AND MESENCHYMAL TUMORS

Carcinosarcoma
Neoplasm composed of an admixture of

malignant epithelial and mesenchymal components

Carcinosarcoma - Gross

Carcinosarcoma - Microscopic
admixture of high-grade malignant epithelial and mesenchymal components High-grade endometrioid carcinoma (more common) Homologous or heterologous (50%) sarcomatous component Homologous sarcomatous component resembles endometrial stromal sarcoma, leiomyosarcoma, malignant fi brous histiocytoma, or undifferentiated sarcoma Rhabdomyosarcoma, benign-appearing cartilage or chondrosarcoma, and less frequently osteosarcoma or liposarcoma as heterologous elements

Malignant mixed mllerian tumor

Malignant mixed mllerian tumor

Borderline clear cell adenofi broma

ENDOMETRIUM

Cagadas, Sheila Marie A., MD Department of Laboratories

MORPHOLOGY AND PHYSIOLOGY OF THE NORMAL ENDOMETRIUM

40-80 g, 7-8 cm Endometrial dating not highly reproducible A discrepancy of 1-2 days in endometrial dating is acceptable The first day of bleeding = DAY 1 of the cycle

HISTOLOGIC DATING OF THE NORMAL, CYCLING ENDOMETRIUM

In the ovulatory patient, normal

endometrium has two phases:

PROLIFERATIVE
SECRETORY

(LUTEAL/POSTOVULATORY)

PROLIFERATIVE
Active growth of glands, stroma,

SECRETORY
Reflects the effect of the combined

and vessels influenced by estradiol production of progesterone and

produced mainly by GRANULOSA

cells in the ovarian follicles

estradiol by luteinized granulosa

and theca cells of the corpus luteum

DATING ENDOMETRIUM
Normal
Cycle of 28 days

Dating most precise in the secretory phase

Follicular phase highly variable in length

Proliferative phase changes not as discrete as in the

secretory phase

PROLIFERATIVE PHASE

PROLIFERATIVE ENDOMETRIUM

PROLIFERATIVE ENDOMETRIUM

PROLIFERATIVE PHASE
Endometrium grows from about 0.5 mm up to 4 to

5.0 mm in thickness

3 stages:
Early Mid

late

PROLIFERATIVE PHASE CHANGES

Early (4-7 days) Thin regenerating epithelium Short narrow glands with epithelial mitoses Stroma compact with mitoses (cells stellate or spindle shaped) Mid (8-10 days) Long, curving glands Columnar surface epithelium Stroma variably edematous, mitoses frequent Late (11-14 days) Tortuous glands Pseudostratified nuclei Moderately dense, actively growing stroma

SECRETORY ENDOMETRIUM
Constant Lasting 14 days from the time of

ovulation to the onset of menstruation

SECRETORY ENDOMETRIUM

EARLY SECRETORY PHASE

EARLY SECRETORY PHASE

MIDSECRETORY PHASE

LATE SECRETORY PHASE (DAY 2324)

ENDOMETRIAL DATING, SECRETORY PHASE

Interval phase, 14-15 d. No datable changes for 36-48 hours after ovulation. Early secretory phase, 16-20 d. Glandular changes predominate.

16 d

Subnuclear vacuoles (note: scattered small irregular vacuoles can be caused by estrogen alone)

17 d
18 d 19 d 20 d

Regular vacuolation-nuclei lined up with subnuclear vacuoles

Vacuoles decreased in size; early secretions in lumen; nucleus approaches base of cell Few vacuoles remain; intraluminal secretion; no pseudostratification, no mitoses Peak of intraluminal secretions

Mid to late secretory phase, 21-27 d. Stromal changes predominate, variable secretory exhaustion 21 d 22 d 23 d 24 d 25 d 26 d 27 d 24-27 d Marked stromal edema Peak of stromal edema-cells have naked nuclei Periarteriolar predecidual change More prominent predecidual change Predecidual differentiation begins under surface epithelium Predecidua starts to become confluent Granular lymphocytes more numerous; confluent sheets of predecidua Secretory exhaustion of glands-tortuous with intraluminal tufts (saw-toothed), ragged luminal borders, variable cytoplasmic vacuolization, and luminal secretions

MENSTRUAL ENDOMETRIUM
Normal period: 4 + 1 days Endometrial mucosa rapidly degenerates Endometrial stromal cells of the basal

layer proliferate

Maintain endometrial integrity

MENSTRUAL ENDOMETRIUM

MENSTRUAL ENDOMETRIUM

PRECURSOR LESIONS OF ENDOMETRIUM

Endometrial carcinoma
most common malignant neoplasm of the female genital

tract

Factors related to development of endometrioid type

of adenocarcinoma:
Obesity

Exogenous hormone use Endometrial hyperplasia

DUALISTIC MODEL OF ENDOMETRIAL CARCINOGENESIS

ATYPICAL HYPERPLASIA
Precursor for the endometrioid type of endometrial

carcinoma

ENDOMETRIAL INTRAEPITHELIAL CARCINOMA

Precursor for serous carcinoma, the most common

nonendometrioid subtype of endometrial carcinoma

ENDOMETRIAL HYPERPLASIA
In the past
Adenomatous hyperplasia Atypical hyperplasia Carcinoma in situ was never clearly defined

Proliferation of glands of irregular size and shape;

increased gland/stroma ratio

Maybe diffuse or focal

2 BROAD CATEGORIES:
1. Hyperplasia without cytologic atypia 2. Hyperplasia with cytologic atypia (atypical hyperplasia)

Simple Complex

ENDOMETRIAL HYPERPLASIA
Less than 2% of hyperplasias without atypia

progress to carcinoma

23% of hyperplasias with cytologic atypia progress to

carcinoma

Increased glandular complexity and crowding

increase likelihood of progression to carcinoma

CLASSIFICATION OF ENDOMETRIAL HYPERPLASIA

Simple hyperplasia Complex hyperplasia (adenomatous) Simple atypical hyperplasia Complex atypical hyperplasia (adenomatous with

atypia)

From World Health Organization

CLINICAL FEATURES
Hyperplasia develops as a result of unopposed estrogenic

stimulation

History of persistent anovulation or exogenous unopposed

estrogen usage

Most hyperplasias that occur in perimenopausal women are

associated with anovulation

Postmenopausal women who develop hyperplasia usually are

on unopposed estrogen hormone replacement therapy

HYPERPLASIA WITHOUT CYTOLOGIC ATYPIA

Simple
are cystically dilated, occl outpouchings with abundant cellular stroma
Glands Glands Glands

Complex
crowded; back-to back glandular crowding
Little

intervening stroma complex but at times tubular stratification: 2 to 4 layers

minimally dilated but focally crowded

Cells

Highly

lining the glands are pseudostratified and columnar; amphohilic cytoplasm

Stroma

Epithelial

densely packed than prolif endometrium

Cells

Mitotic

activity variable; usu. less than 5 mitotic figures/hpf

Stromal

retain their spindle shape but are plump, with enlarged nuclei and indistinct cytoplasm

cells are spindle shaped and become compressed by the glandular proliferation

Simple Hyperplasia without Atypia

COMPLEX HYPERPLASIA WITHOUT ATYPIA

ATYPICAL HYPERPLASIA
Stratified Loss of polarity Increase in N/C ratio Nuclei

Enlarged irregular in size and shape Coarse chromatin clumping Thickened irregular nuclear membrane Prominent nucleoli Nuclei round > oval nuclei

ATYPICAL HYPERPLASIA
Simple
Glandular

Complex
Glands

outlines maybe simple with

show marked structural

minimal complexity
Maybe

complexity with irregular outlines

Back-to-back

more irregular with intraglandular

crowding, epith.

tufting
Separated

stratification and mitotic activity variable

by abundant stroma glands are absent

(+) Papillary infoldings

Back-to-back

SIMPLE ATYPICAL HYPERPLASIA

Simple Hyperplasia

Without Atypia

With Atypia

COMPLEX ATYPICAL HYPERPLASIA

DIFFERENTIAL DIAGNOSIS
Disordered proliferative phase

Focal focal glandular abnormality Irregularly shaped, enlarged glands focally interspersed among normal proliferative glands

Key feature disordered proliferative phase VS. simple hyperplasia

Focal nature of glandular abnormality in disordered proliferative

phase

DISORDERED PROLIFERATIVE ENDOMETRIUM

ENDOMETRIAL POLYP

ENDOMETRIAL AND STROMAL BREAKDOWN

ARIAS-STELLA REACTION

Typically occur in the endometrium; can develop in both endocervical glands and ectopic endometrial glands within the cervix

Occurs in association with pregnancy, including ectopic pregnancies

and gestational trophoblastic disease

Identical to endometrial reaction

Glands lined by vacuolated epithelial cells with hypersecretory features

Enlarged, pleomorphic, hyperchromatic nuclei; often project into the glandular lumen in a hobnail pattern

Mitotic activity rare

ARIAS-STELLA REACTION
Differential Diagnosis

Clear cell carcinoma Mass lesion with stromal invasion and increased mitoses Classic tubular and papillary areas Adenocarcinoma in situ More uniform nuclei, less cytoplasmic vacuolization, and increased mitoses

ARIAS-STELLA REACTION

ARIAS-STELLA REACTION

CLINICAL FEATURES
Persistent anovulation Primary infertility May occur in:
Polyps Endometritis Trauma Vitamin A deficiency

ENDOMETRIAL INTRAEPITHELIAL CARCINOMA

Serous carcinoma is frequently associated with a putative precursor

lesion, termed endometrial intraepithelial carcinoma

Markedly atypical nuclei, sumdged hyperchromatic nuclei Slight papillary contour; hobnail morphology Nuclei enlarged, with granular or vesicular chromatin; enlarged

eosinophilic nucleoli
(+)Numerous mitotic figures

ENDOMETRIAL INTRAEPITHELIAL CARCINOMA

Also referred to as carcinoma in situ and

uterine surface carcinoma

ENDOMETRIAL INTRAEPITHELIAL CARCINOMA

ENDOMETRIAL INTRAEPITHELIAL CARCINOMA

ENDOMETRIAL INTRAEPITHELIAL CARCINOMA

ENDOMETRIAL CARCINOMA

ENDOMETRIAL CARCINOMA

ENDOMETRIAL CARCINOMA

ENDOMETRIAL CARCINOMA

ENDOMETRIAL CARCINOMA

MUCINOUS ADENOCARCINOMA

PAPILLARY SEROUS ADENOCARCINOMA

CLEAR CELL ADENOCARCINOMA

LEIOMYOMA

LEIOMYOMA

SPECIFIC SUBTYPES OF LEIOMYOMA MITOTICALLY ACTIVE

LEIOMYOMA Typical-appearing leiomyoma 5 or more mitotic figures (MF) per 10 HPF (5-9 MF/10HPF) No nuclear atypia Leiomyomas removed during secretory phase of menstrual cycle Leiomyomas removed from women who are taking progestine

CELLULAR LEIOMYOMA
WHO definition- the cellularity is

significantly greater than the surrounding myometrium.

Looks like ordinary- spindled shaped

cells, fusiform shape of nuclei, markedly cellular

Lack tumor cell necrosis Few mitotic figures Lacks cytologic atypia Large thick-walled muscular vessel

LEIOMYOMAS WITH BIZZARE NUCLEI (ATYPICAL LEIOMYOMA)

symplasmic or pleomorphic leiomyoma Contains bizzare tumor cells with variation in size and shape, hyperchromatic nuclei, multinucleated

forms
No increase mitotic activity (MF cannot be in excess of 10 MF/10HPF) Distribution: maybe throughout the leiomyoma or maybe focal

Often seen in patients taking progestin compounds.

No tumor cell necrosis

EPITHELIOID LEIOMYOMA
leiomyoblastoma, clear cell

leiomyoma and flexiform leiomyoma

Fifth decade of life (30-78 y/o) Gross: Solitary, yellow to gray and may contain hemorrhage Softer than the usual leiomyoma, occurs in any part of the uterus (median diameter 6-7 cm.) Microscopic: the cells are round

or polygonal rather than spindle shape, arranged in cluster or cords

Nuclei: round , relatively large, and centrally located

MYXOID LEIYOMYOMA
Soft and transluscent Microscopic: cells are small and uniform abundant amorphous myxoid material the smooth muscle cells

Circumscribed margins
No cytologic atypia or mild Mitotic index <2MF/10HPF

VASCULAR LEIOMYOMA
Contains numerous large

caliber vessel with muscular walls Well defined, circumscribed neoplasms that contain at least foci of typical spindle smooth muscle cells

LEIOMYOSARCOMA