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
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