Epithelial and mesenchymal tumors of uterine corpus

Prakriti GuptaDNB Pathology

Sir Gangaram Hospital, New Delhi

1. Epithelial tumors and related lesions2. Mesenchymal tumors3. Mixed epithelial and mesenchymal4. Gestational trophoblastic tumors5. Miscellaneous tumors6. Hematopoetic and lymphoid tumors

Epithelial tumors and related lesions Endometrial carcinoma Endometroid carcinoma• Villoglandular• Secretory • Ciliated• Variant with squamous differentiation Mucinous Serous Mixed Transitional Squamous Small cell Undifferentiated

Endometrial hyperplasiaNon atypical• Simple• ComplexAtypical• Simple • ComplexEndometrial polypTamoxifen related changes

Mesenchymal tumorsEndometrial stromal tumors

• Endometrial stromal nodule • Endometrial stromal sarcoma, low grade • Undifferentiated endometrial sarcoma

Smooth muscle tumours Leiomyoma, not otherwise specified Histological variants• Mitotically active variant• Cellular variant • Haemorrhagic cellular variant• Epithelioid variant • Myxoid • Atypical variant • Lipoleiomyoma variant

Smooth muscle tumour of uncertain malignant potential Leiomyosarcoma • Epithelioid variant • Myxoid variant

Growth pattern variants• Diffuse leiomyomatosis• Dissectiing leiomyoma• Intravenous leiomyomatosis • Metastasizing leiomyoma Miscellaneous mesenchymal tumours

Mixed endometrial stromal and smooth muscle tumour• Perivascular epithelioid cell tumour• Adenomatoid tumour • Other malignant mesenchymal tumours• Other benign mesenchymal tumours

Mixed epithelial and mesenchymal tumours• Carcinosarcoma (malignant müllerian mixed

tumour; • metaplastic carcinoma) • Adenosarcoma • Carcinofibroma • Adenofibroma • Adenomyoma Atypical polypoid variant

Gestational trophoblastic disease

Trophoblastic neoplasms• Choriocarcinoma • Placental site trophoblastic tumour • Epithelioid trophoblastic tumour Molar pregnancies• Hydatidiform mole • Complete• Partial • Invasive • Metastatic Non-neoplastic, non-molar trophoblastic lesions• Placental site nodule and plaque• Exaggerated placental site

Miscellaneous tumours• Sex cord-like tumours• Neuroectodermal tumours• Melanotic paraganglioma• Tumours of germ cell type• Others

Lymphoid and haematopoetic tumours• Malignant lymphoma (specify type)• Leukaemia (specify type)

Secondary tumours

Endometrium

• The endometrium and the myometrium are of mesodermal origin

Classification of endometrial hyperplasia

Hyperplasia without atypia• Simple hyperplasia without atypia• Complex hyperplasia without atypia

Atypical hyperplasia• Simple atypical hyperplasia (very rare)• Complex atypical hyperplasia

Stroma Atypical endometrial hyperplasia

Well differentiated endometrial carcinoma

Altered fibroblastic Stroma (desmoplastic response

unaltered, same as that of normal endometrium

parallel, densely arranged fibroblasts with more fibrosis than normal endometrial stroma, that disrupts the usual glandular pattern

Stromal cells Basophilic ,naked nuclei appearance

spindle , eosinophilic, wavy

Confluent glandular aggregates without interveningstroma reflect stromal invasion

Complex papillary patterns represent stromal invasionif multiple, branching, fibrous processes lined by epithelium

are present

Tamoxifen related changes

• Enlarged uterus• Endometrial cysts• Polyps – large, sessile, wide base, honeycomb • Bizzare stellate glands• Epithelial and mesenchymal metaplasias• Periglandular stromal condensation ( cambium

layer)• Malignancy – 3%

Endometrial carcinoma

Endometrioid adenocarcinoma• Villoglandular• Secretory• Ciliated cell• Endometrioid adenocarcinoma with squamous differentiation

Serous carcinomaClear cell carcinomaMucinous carcinomaSquamous carcinomaMixed types of carcinomaUndifferentiated carcinoma

Modified World Health Organization and International Society ofGynecological Pathologists Histologic Classification of

Endometrial carcinoma

Feature Type I Type II

Unopposedestrogen

Present Absent

Menopausal status Pre- andperimenopausal

Postmenopausal

Precursor lesion Atypicalhyperplasia

Endometrialintraepithelialcarcinoma

Tumor grade Low High

Myometrialinvasion

Variable, often minimal Variable, oftendeep

Histologicsubtypes

Endometrioid Serous and clear cell

Behavior Indolent Aggressive

Genetic alterations PTEN mutation MicrosatelliteinstabilityK-ras mutation

P53 mutation

incidence 80-85% 10-15%

Endometrioid adenocarcinoma

Glandular or villoglandular structures lined by simple to pseudostratified columnar cells.

As the glandular differentiation decreases and is replaced by solid nests and sheets of cells, the tumour is classified as less well differentiated (higher grade).

Nuclear grade1 nuclei are oval, mildly enlarged,

and have evenly dispersed chromatin

2 Intermediate between 1 and 33 nuclei are markedly enlarged

and pleomorphic, with irregular coarse chromatin,and prominent eosinophilic nucleoli

• 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 grading. Bizarre nuclear atypia should raise the grade by one (i.e. from 1 to 2 or 2 to 3) but may also signify type II

differentiation.

Architectural grade

1 No more than 5% of the tumor is composed of solid masses

2 6–50% of the tumor is composed of solid masses

3 More than 50% of the tumor is composed of solid masses

Villoglandular

Thin, delicate fronds covered by stratified columnar epithelial cells with oval nuclei that generally display mild to moderate (grade 1 or 2) atypia

D/D serous

Secretoryprogestin treatment

Well differentiated glandular pattern

columnar cells, unstratified

subnuclear or supranuclear vacuolization closely resembling day 17–22 secretory endometrium

nuclei are grade 1.

corpus luteum

D/D clear cell

With Squamous differentiation<10% squamous element

Both the glandular and squamous components display grade 2 or 3 nuclear atypia

an increased nuclear cytoplasmicratio

increased mitotic activity

Graded on the basis of glandular component

D/D atypical hyperplasia with squamous metaplasia

Mucinous

Epithelial cells lining the glandsColumnar cells with minimal stratification.Cystically dilated glands filledwith mucin and papillary fronds surrounded by extracellular lakes of mucin, containing neutrophils

Serous complex papillary architecture

short and densely fibrotic or thin and delicate

Cells are cuboidal orhobnail shaped and contain abundant granular eosinophilic or clear cytoplasm

Loosely cohesive marked cytologic atypia nuclear pleomorphism,hyperchromasia, and macronucleoli

Clear cellSolid- masses of clear cells with eosinophiliccells

papillary, tubular and cystic -hobnail-shaped cells with interspersed clear and eosinophilic cells.

Moderate to marked atypia

PAS-positive, diastase resistantintracellular, and extracellular hyaline bodies

Endometroid Serous Clear cell

ER + - -

PR + - -

P53 -/+ + -

P16 - + -

Napsin A - - +

HNF-1 β - - +

Endometrial stromal tumors

Endometrial stromal nodule

Endometrial stromal sarcoma, low grade

Undifferentiated stromal sarcoma

Nature benign Malignant, low grade

Malignant, high grade

age 23-75 , 1/3 rd postmenopausal

42-58, 1/4th premenopausal

55-60

gross Solitary, well deliniated , yellow tan nodule of 0.8 -15 cm. Purely intramural, protrusions upto 3mm

Solitary well deliniated intramural with extensive permeation of myometrium upto serosa

Polypoid , fleshy, grey endometrial mass with hemmorhage and necrosis

Endometrial stromal nodule

ESS, low grade Undifferentiated sarcoma

histology Resemble proliferative phase endometriun supported by a large no. Of thin walled arterioles

Spindled stromal cells in plexiform pattern with a rich network of arterioles infiltrating myometrium

markedly pleomorphic cells with No plexiform pattern or vascular network displacing myometrium

Epitheliod, smooth muscle and sex cord like differentiation

present present absent

Extrauterine extent

absent Cord like in 1/3rd Worm like in vessels of broad ligament and adnexa

Distant metastasis at presentation

Ususal mitosis <3 <3 >10

ESN ESS, low grade

Undifferentiated sarcoma

Somatic genetics

Diploid, low S-fraction

Diploid, low S-fraction

Aneuploid, S-fraction>10%

molecular t(7;17)(p15;q21) JAZF1 - JJAZ1 fusion

t(7;17)(p15;q21) JAZF1 - JJAZ1 fusion

+/-

vimentin + + +/-CD10 + + -ER, PR + + -Desmin and h-caldesmon

-/+ -/+ -

Nuclear B-cateninNuclear WT-1

++

-+

--

ESN with sex cord differentiation

Smooth muscle tumors

Smooth muscle tumours Leiomyoma, not otherwise specified Histological variants• Mitotically active variant• Cellular variant • Haemorrhagic cellular variant• Epithelioid variant • Myxoid • Atypical variant • Lipoleiomyoma variant

Smooth muscle tumour of uncertain malignant potential Leiomyosarcoma • Epithelioid variant • Myxoid variant

Mitotically active leiomyoma

>5 MF/ 10 hpf

If

15 MF/ 10 hpf

Mitotically activeLeiomyoma with limited experience

Cellular

• Cellularity is ‘‘significantly’’ greater than the surrounding myometrium

• < 5% of leiomyomas

Hemorrhagic cellular

Multifocal stellatehemorrhages cellular and containspatchy areas ofhemorrhage and edema. MF mainly within a narrow zone resemblinggranulation tissue around areas of hemorrhage

Atypical leiomyoma• progestins • moderate to severe

cytologic atypia• enlarged

hyperchromatic nuclei with prominent chromatin clumping and smudging

• Large cytoplasmic pseudonuclear inclusions

• Multinucleated tumor giant cells

• 0–4 MF/10 HPF• No tumor necrosis

Epitheloid• Cells are round or

polygonal• Clusters or cords• nuclei are round,

relatively large centrally positioned. There are three basic subtypes Leiomyoblastomaclear cell leiomyoma plexiform leiomyoma

Growth pattern variants

Dissecting Leiomyoma

Benign smooth muscle proliferation with a border marked by the dissection ofcompressive tongues of smooth muscle into the surrounding myometrium and, occasionally, into the broad ligament and pelvis

Intravenous Leiomyomatosis andLeiomyoma with Vascular Invasion

Nodular masses of histologically benign smooth muscle cells growing within venous channels• growth

extends into the vena cava in >10% of patients

Benign Metastasizing Leiomyoma

‘‘Metastatic’’ smooth muscle tumor deposits inthe lung, lymph nodes, or abdomen appear to be derived from a benign leiomyoma of the uterus.MC- Lungs

Disseminated PeritonealLeiomyomatosis

Multiple smooth muscle, myofibroblastic, and fibroblastic nodules on the peritoneal surfacesof the pelvic and abdominal cavities in women of reproductive ageAssociated with pregnancy,granulosa tumororal contraceptive use

Tumor cell necrosis

Cellular atypia mitosis

leiomyoma -

-

None to mild

Diffuse moderate to severeAtypical leiomyoma with low risk of recurrence

< 5≥ 5Mitotically active leiomyoma

STUMP -

-

+

Focal moderate to severe

Diffuse moderate to severeMild

≥5

5-9 atypical MF

<10

Leiomyosarcma(smooth muscle diff)

+

+

Mild

Diffuse moderate to severe

≥ 10

Any level

Myxoid

Epitheloid

leiomyoma leiomyosarcoma

SMA + +

Desmin + +

CD 10 - +/-

PR + -

p16 - +

P53 - +

Ki 67 -/+ +++

Smooth muscle tumorsvs

Stromal tumors

cellular leiomyoma vs ESN

IV TUMOR

IV leiomyoma vs ESS, low grade

Cells

Vasularity

reticulin

Stromal tumors

SmallerLess cytoplasm

Numerous arterioles ( plexiform)

Around individual cells

Smooth muscle tumorsLargerMore cytoplasm

Thick walled vessels

Parallels the fascicles of cells

SMA 0 to ++ ++ to +++

Desmin 0 to + +++

Caldesmon 0 +++

CD 10 + to +++ 0 to +

Mixed epithelial and mesenchymal tumors

Benign epithelium

Malignant epithelium

Benign mesenchyme

AdenofibromaAdenomyoma ( including atypical)

carcinofibroma

Malignant mesenchyme

adenosarcoma carcinosarcoma

Adenofibroma

Adenomyoma

Adenosarcoma

Carcinofibroma

Carcinosarcoma

clinical

Uncommon

elderly

Atypical-premenopausal

15-90yrsIrradiationtamoxifen

uncommon

Postmenopausal Pelvic irradiationtamoxifen

gross Fibrous polyps with cystic spaces

PoypoidalSubmucosalLower uterine segment and upper endocervix

PolypoidFoci of necrosis and hemorrhage--/+ myometrial invasion

Polypoid bulkyNecrosisHemmorrhage Myometrial invasion

Adenofibroma Adenomyoma Adenosarcoma

Carcinofibroma

Carcinosarcoma

histo Club like or papillary lined by epitheliumFibromatous stroma

Benign endometrial gland s in fibromyomatous stroma

Atypical- distorted glands with marked architectural complexityno endometrial stroma around the glandsInterlacing fascicles of benign smooth muscle

leaf like growth like phyllodesMitosis >1/10hpfStromal hypercellularityPeriglandular stromal cuffingAtypia

HomologousHeterologous -10-15%

Epithelial- glandularNon glandular

MesenchymalHomologous-Udiif sarcomaLeiomyosarcomaESS

Heterologous- chondrosarcomarhabdomyosarcoma

Adenofibroma

Adenosarcoma

Periglandular stromal hypercellularity in adenosarcoma

Carcinosarcoma