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

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

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

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

ENDOMETRIAL CARCINOMA – PATHOLOGIC FEATURES

ENDOMETRIOID ADENOCARCINOMA, GRADE I

ENDOMETRIOID ADENOCARCINOMA, GRADE II

ENDOMETRIOID ADENOCARCINOMA, GRADE III

Endometrioid Adenocarcinoma withSquamous 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 Comments

1. Architecture Gland area exceeds that of stroma, usu in a localized region

2.Cytological alterations Cytology differs bet. Architecturally crowded focus and background

3. Size more than 1 mm 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

MYXOID DIFFERENTIATION

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

Rounded cells with central nuclei and clear to eosinophilic cytoplasm

Spindle-shaped cells set within an abundant myxoid matrix

Criteria for leiomyosarcoma

Any coagulative tumor cell necrosis

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.”

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

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

Comments

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

Focal epithelioid differentiation may be mimicked by cross-sectioned 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 - Microscopicadmixture 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 müllerian tumor

Malignant mixed müllerian tumor

Borderline clear cell adenofi broma

ENDOMETRIUM

Cagadas, Sheila Marie A., MDDepartment 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 SECRETORY

Active growth of glands, stroma,

and vessels influenced by estradiol

produced mainly by GRANULOSA

cells in the ovarian follicles

Reflects the effect of the combined

production of progesterone and

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

Endometrium grows from about 0.5 mm up to 4 to 5.0 mm in thickness

3 stages: Early Mid late

PROLIFERATIVE PHASE

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

Constant Lasting 14 days from the

time of ovulation to the onset of

menstruation

SECRETORY ENDOMETRIUM

SECRETORY ENDOMETRIUM

EARLY SECRETORY PHASE

EARLY SECRETORY PHASE

MIDSECRETORY PHASE

LATE SECRETORY PHASE (DAY 23-24)

ENDOMETRIAL DATING, SECRETORY PHASE

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

17 d Regular vacuolation-nuclei lined up with subnuclear vacuoles

18 d Vacuoles decreased in size; early secretions in lumen; nucleus approaches base of cell

19 d Few vacuoles remain; intraluminal secretion; no pseudostratification, no mitoses

20 d Peak of intraluminal secretions

Mid to late secretory phase, 21-27 d. Stromal changes predominate, variable secretory exhaustion

21 d Marked stromal edema

22 d Peak of stromal edema-cells have ‘naked nuclei’

23 d Periarteriolar predecidual change

24 d More prominent predecidual change

25 d Predecidual differentiation begins under surface epithelium

26 d Predecidua starts to become confluent

27 d Granular lymphocytes more numerous; confluent sheets of predecidua

24-27 d Secretory exhaustion of glands-tortuous with intraluminal tufts (saw-toothed), ragged luminal borders, variable cytoplasmic vacuolization, and luminal secretions

Interval phase, 14-15 d. No datable changes for 36-48 hours after ovulation.

Early secretory phase, 16-20 d. Glandular changes predominate.

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

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

DUALISTIC MODEL OF ENDOMETRIAL CARCINOGENESIS

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 atypia2. Hyperplasia with cytologic atypia

(atypical hyperplasia)• Simple• Complex

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

ENDOMETRIAL HYPERPLASIA

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

Simple ComplexGlands are cystically dilated, occ’l outpouchings with abundant cellular stroma

Glands minimally dilated but focally crowded

Cells lining the glands are pseudostratified and columnar; amphohilic cytoplasm

Stroma densely packed than prolif endometrium

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

•Glands crowded; “back-to back” glandular crowding

•Little intervening stroma

•Highly complex but at times tubular

•Epithelial stratification: 2 to 4 layers

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

•Stromal cells are spindle shaped and become compressed by the glandular proliferation

HYPERPLASIA WITHOUT CYTOLOGIC ATYPIA

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

Simple Complex

Glandular outlines maybe simple with

minimal complexity

Maybe more irregular with intraglandular

tufting

Separated by abundant stroma

Back-to-back glands are absent

Glands show marked structural

complexity with irregular outlines

Back-to-back crowding, epith.

stratification and mitotic activity variable

(+) Papillary infoldings

ATYPICAL HYPERPLASIA

SIMPLE ATYPICAL HYPERPLASIA

Simple Hyperplasia

Without Atypia

With Atypia

COMPLEX ATYPICAL HYPERPLASIA

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

DIFFERENTIAL DIAGNOSIS

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

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

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

Also referred to as ‘carcinoma in situ’ and ‘uterine surface carcinoma’

ENDOMETRIAL INTRAEPITHELIAL 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 LEIOMYOMAMITOTICALLY ACTIVE

LEIOMYOMATypical-appearing

leiomyoma5 or more mitotic figures

(MF) per 10 HPF (5-9 MF/10HPF)No nuclear atypiaLeiomyomas 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