Myometrium has rich network of blood vessels; arteries are sometimes found within dilated venous channels, AJSP 2002;26:232; myometrium is PLAP positive

Before puberty: endometrial tissue is inactive and composedof tubular glands, dense fibroblastic stroma, thin bloodvessels

After menopause: inactive (no proliferation or secretion), thin, often with cystic cavities lined by flat or cuboidal cells, fibrotic stroma

Micro images: normal endometrium and cyclin D1 (figures 1A/1B)

Anatomical divisions of uterus

Fundus: cephalad to line connecting the insertion of fallopian tubes

Cornua: lateral regions of fundus associated with intramural fallopian tubes

Isthmus/lower uterine segment: portion of corpus connecting with cervix

Cervix: lower 1/3 of uterus; at and below level of internal cervical os

Uterine cavity: 6 cm long, triangular shape, lined by endometrial mucosa / endometrium, then myometrium, then serosa, which extends to peritoneal reflection

Basalis layer is retained; functionalis layer (superficial 1/2 to 2/3) is shed monthly

Functionalis is divided into spongiosum (near basalis) and compactum (near surface)

Stroma is composed of stromal cells, vessels, stromal granulocytes (T cells, macrophages), foamy cells

Drains to parametrial, paracervical, internal iliac, external iliac, common iliac, periaortic and inguinal lymph nodes

Note: menstruating tissue is replaced by cells from basalis, isthmus and ostio of tubes

Bifid uterus

Gross images: image1

Persistent mullerian duct syndrome

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Rare form of male pseudohermaphroditism caused by lack of regression of Mullerian ducts in phenotypically and genotypically male individuals

Mullerian ducts normally regress in male fetus at 8 weeks due to anti-Mullerian hormone (AMH), which binds to anti-Mullerian type 2 receptor, causing disappearance of Mullerian ducts at 10 weeks of fetal age; mutations of either AMH or receptor block duct regression

<200 cases described in English literature

Usually associated with unilateral cryptorchidism and contralateral hernia

Rarely is bilateral cryptorchidism, pelvic uterus, 2 testes embedded in broad ligament

Associated with testicular germ cell tumors

Case report: clear cell adenocarcinoma of remnant uterus in clinically normal 67 year old man, AJSP 2002;26:1231

Dating of endometrium

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To date endometrium, should see surface endometrium, but date based on most advanced area

Must biopsy uterine corpus above the level of the isthmus; must also biopsy functionalis as basalis layer does not respond to progesterone

Dating has low interobserver agreement

Difficult to date in patient with IUD or on hormones or if endometrium is non-uniform

Proliferative phase

Length varies from 10-20 days, “ideal” is 14 days; during this phase, glands become more tortuous due to epithelial proliferation, in response to estrogen production and estrogen receptors on epithelium

Early proliferative (days 4-7): thin surface epithelium, straight short glands, compact stroma, minimal mitotic activity, large nuclei

Micro image: image1

Mid proliferative (days 8-10): columnar surface epithelium; longer curving glands, variable stromal edema, numerous mitotic figures

Late proliferative (days 11-14): undulant surface epithelium, tortuous glands with prominent mitotic activity and pseudostratification; dense stroma, subnuclear vacuoles in less than 50% of glands

Ovulation: presence of subnuclear vacuoles in 50% of glands is evidence of ovulation; must biopsy functionalis layer, not basal layer

To rule out anovulatory cycles, should biopsy 2 days before menstruation

Secretory/luteal phase

Traditionally assumed to be 14 days, but may vary

Progesterone secretion inhibits endometrial proliferative active and induces secretory activity

Note: secretory material in glands is NOT specific for secretory epithelium; seen also in disordered proliferative and hyperplastic endometrium and carcinoma

Gross: lush, polypoid, no necrosis; may be hemorrhagic if close to day 28

Day 15: no changes from late proliferative; aka interval endometrium; presence of scattered nuclear vacuoles is NOT specific for ovulation (must be 50% or mor)

Days 16-17 - “piano key” appearance; subnuclear vacuoles (day 16), vacuoles at level of nuclei (day 17)

Micro image: image1

Day 18: luminal vacuoles, smaller size, nuclei approach base of cell

Day 19: intraluminal secretion begins

Days 20-21: maximal secretion

Micro image: image1

Day 22: maximal stromal edema in luteal phase; best time for implantation (“day 22, I'm ready for you”)

Day 23: prominent spiral arterioles (thickened walls, coiling, endothelial proliferation)

Day 24: perivascular pre-decidualization (stromal cell hypertrophy with accumulation of cytoplasmic eosinophilia); serrated / tortuous glands

Day 25: predecidualization below surface endometrium

Day 26: confluence of predecidual tissue; stromal granulocytes (probably lymphocytes) appear

Day 27: prominent stromal granulocytes; focal necrosis and hemorrhage

Day 28: prominent necrosis and hemorrhage, aka shedding (glandular and stromal breakdown); predecidual stroma and glandular exhaustion; nuclear dust at base of glandular epithelium; condensed stroma with overlying papillary-syncytial change; intravascular fibrin thrombi; stromal granulocytes

Note: don’t confuse shedding (nuclear crowding, squamoid appearance, focal cytoplasmic acidophilia) with malignancy

Note: shedding in perimenopausal women with bloody background is consistent with anovulatory cycle

Note: endometrial tissue within vessels does not imply malignancy

Dyssynchronous endometrium

Glands and stroma out of synchronization by at least 2 to 3 days

Luteal phase defect

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Due to inadequate progesterone production

Associated with infertility and spontaneous abortions

Lag of histologic endometrial date of 3+ days from actual post-ovulatory date (some say 2+ days)

Must be found in 2 consecutive cycles to be clinically significant

Meaning of this diagnosis has been questioned due to substantial variability present in late luteal phase of menstrual cycle, the usual time to obtain an endometrial biopsy

Micro: either immature endometrium or persistence of proliferative changes; may see dyssynchronous endometrium (dissociation between endometrial glands and stroma)

Pregnancy related changes

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Similar changes seen with intrauterine pregnancy, ectopic pregnancy, progesterone therapy

Arias-Stella reaction

Exaggerated gestational hyperplasia; endometrial glands are enlarged with abundant clear or eosinophilic cytoplasm and marked nuclear changes (large, hyperchromatic, pleomorphic, smudged) with rare mitotic figures; decidualized stroma; changes usually focal, may occur in cervix, endocervical polyps, adenomyosis, endometriosis, post- abortion curettings (20-70%), pregnancies, moles, choriocarcinoma (endometrial nuclei may be gigantic in moles and choriocarcinoma)

DD: clear cell carcinoma (post-menopausal so not pregnant, mitotic figures, coarsely granular chromatin, no decidual reaction unless patient on progesterone), in situ endometrial carcinoma

Decidua

Bland nuclei, minimal atypia, abundant cytoplasm

Gestational hyperplasia

Gross: lush decidua; placental fragments; gestational sac

Micro: early - prominent glandular secretion, stromal edema and predecidual reaction, all simultaneous; implies fertilized ovum has implanted

later - glands are tubular, not coiled; glandular cells have inclusion-like cleared chromatin resembling HSV infection (see below); may see intermediate trophoblasts or villi

DD: late secretory changes in cycling endometrium

Placental site nodules

Aka implantation site reaction

Usually regresses after delivery or abortion

Micro: numerous extravillous (intermediate) trophoblasts, with large, atypical nuclei arranged in a syncytium, often with mitotic figures, that may invade blood vessels (to keep them patent during pregnancy); also cytotrophoblasts and syncytiotrophoblasts; chronic inflammatory cells

Positive stains: hPL (intermediate trophoblasts), hCG (syncytiotrophoblasts, cytotrophoblasts)

DD: leiomyosarcoma, placental site trophoblastic tumor (large masses of intermediate trophoblasts, no villi), choriocarcinoma (laminar pattern of syncytiotrophoblasts and cytotrophoblasts with extensive hemorrhagic necrosis, no villi)

Viral-like inclusions

Optically clear nuclei, resembling viral inclusions, present during pregnancy

Due to replacement of chromatin by fine filamentous network that is biotin immunoreactive

Endometrial curettage and biopsy

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D & C (dilatation and curettage) and endometrial biopsy are methods of choice for sampling localized lesions

Fractional curettage: separate sampling from endometrial and endocervical cavities during same procedure; do endocervix first to minimize contamination

Note: report endocervical extension of a tumor only if normal endocervical glands and carcinoma are present in the SAME fragment

Asherman’s syndrome: intrauterine adhesions after D & C, causing amenorrhea; usually postpartum or post-termination, may be due to subclinical uterine infection

Endometrial biopsy: to evaluate infertile or dysmenorrheic patients; sensitive if done properly

Helpful clinical information: patient’s age, date and characteristics of last and current menstrual period, use of hormones/steroids, chief complaint, physical findings

Exogenous hormones

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Current oral contraceptives

Small doses of estrogen and progesterone

Micro: endometrial glandular arrest with small, straight and inactive glands, no mitotic figures, no secretion; glands lined by immature epithelial cells, nuclei lack thick nuclear membrane or coarse chromatin seen in proliferative endometrium; cytoplasm has randomly distributed vacuoles and smooth, well defined apical border; glands may have dense eosinophilic secretion (abortive secretion); stroma initially edematous, then decidual with granulocytic infiltrates; vessels are thin, later become dilated, lack changes of spiral arterioles (thickening, coiling) at day 23; also endocervical microglandular hyperplasia and squamous metaplasia

Prolonged use: disappearanceof abortive glandular secretion, atrophy of glands and stroma

Micro images: image1

Ovulation Induction Therapy
Treatment for ovulation failure (irregular or infrequentovulation or chronic anovulation due to deficient gonadotropinsor their inability to stimulate follicle maturation)

In polycystic ovary disease patients, may see endometrial hyperplasia with secretory changes of the glands and stroma, or rarely carcinoma

Micro: dyssynchronous endometrium (stromal maturation [day 22-23] more advanced than glandular maturation [day 16-17])

Micro images: image1

Estrogens alone for hormone replacement therapy

Used for hormone replacement therapy (post-menopausal, premature ovarian failure, post-oophorectomy, Turner’s syndrome)

Causes hyperplasia, some with atypia, in 15% of postmenopausal women; also increased risk (4-8x) of endometrial carcinoma, usually superficial and well differentiated with excellent prognosis; also increased risk of breast neoplasms

Adding progesterone protects the endometrium, reduces risk of hyperplasia and carcinoma

Compared to oral contraceptives, uses lower dosages and different estrogens

Micro: proliferative or weakly proliferative endometrium, often with stromal breakdown; endometrial hyperplasia (simple or complex, with or without atypia), occasional squamous metaplasia (squamoid morules), stromal foam cells; endometrial polyps with hyperplastic changes

These changes may persist after therapy ends

Micro images: image1, image2

Combined hormone replacement therapy

Variable changes, often with mixed proliferative and secretory endometrium

Micro: glands may be crowded or hyperplastic with edematous, hyperplastic or decidualized stroma; also tubal, eosinophilic, mucinous, or papillary metaplasia; also changes of shedding

Micro images: image1

DD: carcinoma

Lupron for leiomyomas

Gonadotropin releasing hormone agonist, that usually reduces size of uterine leiomyomas by suppressing estrogen stimulation and inducing a temporary menopause

Micro: leiomyomas initially show edema and necrosis, then hyalinization and mild lymphocytic infiltrate; endometrium becomes weakly proliferative, later inactive, later atrophic

Progestational agents

Used for endometrial hyperplasia and neoplasia, particularly in young women who don’t want hysterectomies or are poor surgical candidates

Micro: lack of glandular proliferation (no mitotic activity), presence of secretory changes inglands, decidual stroma. The endometrialtissue appears quiescent, with no mitotic activity

Note: hyperplasia and carcinoma may persist in sampled or unsampled endometrium

DD: pregnancy (glands not atrophic), sarcoma (nuclear atypia)

Tamoxifen

Used for breast cancer treatment/prevention

Binds to estrogen receptors with both agonist and antagonist effects

Associated with endometrial carcinoma (well to poorly differentiated, may have irregular glandular changes) and MMMT

Gross: uterine size up to 1 kg

Gross images: image1

Micro: polypoid endometrial proliferation with glandularhyperplasia (simple, complex, with or without atypia), mucinous and squamous metaplasia, fibrotic stroma, diffuse smooth muscle hyperplasia, leiomyomas,adenomyosis; also inactive or atrophic changes

Micro images: image1, carcinoma

Hormonal therapy in the past

Associated with pulmonary emboli, thrombophlebitis (intimal thickening with endothelial proliferation)

Less likely now due to smaller hormonal doses

Reference: Mod Path 2000;13:285

Endometritis

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Endocervix normally forms barrier to ascending infection

Acute endometritis

Limited to post-delivery or miscarriage

Due to retained products of conception or instrumentation

Must see microabscesses plus infiltration and destruction of glandular epithelium, as neutrophils are common in cycling endometrium

Chlamydia

Associated with severe acute/chronic inflammation

Chronic endometritis

In women with pelvic inflammatory disease (PID), postpartum, post-abortion (retained tissue), IUD, tuberculosis (miliary or TB salpingitis), symptomatic bacterial vaginosis

Probably not associated with Chlamydia trachomatis infection

15% have unknown cause (may be chlamydia, give antibiotics)

Note: lymphoid follicles are normal in functional layers of endometrial mucosa and do not constitute chronic endometritis

Micro: spindly stroma with edema; focal early breakdown with surface neutrophils; associated with weakly proliferative glands; plasma cells are characteristic, but one plasma cell is probably not enough; usually also histiocytes, lymphocytes and lymphoid follicles are present; usually significant glandular alterations make dating impossible; also focal necrosis or focal calcification

Myometrium usually spared unless inflammation severe

DD: hyperplasia

CMV

May be granulomatous

Coccidiomycosis

May be secondary to resolved primary lung infection

Giant cell arteritis

May involve uterus as isolated finding or part of generalized giant cell arteritis

Granulomas

Due to sarcoid, tuberculosis, CMV, post-laser ablation for post-menopausal bleeding

Hematometra

Blood within uterine cavity, usually due to cervical occlusion

Endometrial mucosa is replaced by lipid laden histiocytes (xanthogranulomatous endometritis)

Called “ceroid containing histiocytic granuloma” if histiocytes contain yellow-brown cytoplasmic pigment

Intrauterine device (IUD)

2/3 have abnormal endometrium at biopsy; often focal or extensive chronic endometritis, necrosis, squamous metaplasia

May be associated with PID and tubo-ovarian abscesses

Infection rate is 13%

Actinomyces common

Pyometra

Pus in endometrial cavity

Due to obstruction and infection; occasionally due to carcinoma, more commonly due to benign cervical stricture

Sarcoidosis

Granulomas usually spread to myometrium (in contrast to TB)

Tuberculosis

Rare in US; common in other countries, where it causes infertility

Plasma cells and white blood cells may be present due to secondary infection; acid fast bacilli present in tubercles or culture

Granulomas tend to accumulate in superficial functional layers of endometrium, so biopsy during late secretory phase

Xanthomatous endometritis

Associated with cervical stenosis and pyometra, usually in elderly

Micro: contains sheets of foamy cells

Endometrial metaplasia

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Must evaluate metaplasia separately from hyperplasia

Tends to be associated with adenocarcinoma and is more common in women at high risk for endometrial carcinoma

Clear cell metaplasia (mesonephric / mesonephroid)

Tall cells, apical nuclei, clear cytoplasm; no atypia

DD: clear cell adenocarcinoma

Eosinophilic (oxyphilic) metaplasia

Estrogen-induced, resembles atypical hyperplasia except there is no atypia

Intestinal metaplasia

Rare

Mucinous metaplasia

Resembles endocervical mucosa; benign features

Associated with hyperestrogen states, endometrial polyps

May produce mucometra if cervical stenosis present

Mucin pools are associated with neutrophils

Papillary proliferation / papillary change

Rare, usually post-menopausal women

Usually benign behavior

Polypectomy or curettage appears to be adequate treatment, AJSP 2001;25:1347

More aggressive treatment may be needed for extensive complex papillary proliferations

Gross: 0.7 cm to 3.0 cm in size, 2/3 occur in endometrial polyps

Micro: focal areas of fibrovascular cores without atypia, usually near endometrial surface

Either simple or complex papillary patterns; often metaplastic epithelial changes

DD: well differentiated / low grade papillary adenocarcinoma, surface syncytial change

Squamous metaplasia

Occurs in normal or hyperplastic endometrium, polyps, leiomyomas

Usually diffuse (adenoacanthosis) or in morules (rounded aggregates of bland cells with indistinct cytoplasmic borders)

Usually in pre-menopausal women, with exogenous hormones or with polycystic ovary disease; also associated with foreign-body reactions, chemical irritants, endometritis

Note: central necrosis of morules is common, and not specific for malignancy

Ichthyosis uteri: complete replacement of endometrium by squamous epithelium

DD: well differentiated endometrial adenocarcinoma with squamous metaplasia

Stromal metaplasia

Formation of smooth muscle, cartilage, bone

DD: retained fetal parts

Syncytial change

Aka papillary syncytial change, surface syncytial change

Reparative change in endometrial biopsies and curettings from patients with uterine bleeding

Associated with anovulatory dysfunctional bleeding, endometrial hyperplasia, estrogen usage, or other hormonal treatment

Micro: denuded endometrial surface produced by breakdown or breakthrough bleeding covered by sheet-like plaque of regenerating epithelial cells, often eosinophilic, without discrete cell boundaries; nuclear debris, neutrophils, rounded clumps of endometrial stromal cells usually present; usually no papillae with fibrovascular cores; may resemble microglandular hyperplasia due to small glandular lumina or pseudolumina

Micro images: image1, image2

Reference: Mod Path 2000;13:309

Tubal (ciliated cell) metaplasia

Markedly increased ciliated cells (non-metaplastic endometrium have some ciliated cells), resembles fallopian tube; often seen with endometrial hyperplasia and other hyperestrogenic states

Micro images: image1

Reference: Mod Path 2000;13:309

Adenomyosis

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Endometrial glands and stroma deep in myometrium

Causes menorrhagia, pelvic pain during menstruation; rarely causes rupture during pregnancy

15% of uteri

May be a type of diverticulosis

May be involved by hyperplasia or carcinoma

Gross: numerous small cysts in enlarged and globular uterus, associated with myometrial hypertrophy and trabeculated smooth muscle; cannot be shelled out; in elderly women, uterus may appear atrophic;

Gross images: image1

Micro: stroma plus marker glands deep in myometrium (at least one low power field from endomyometrial junction, which is usually irregular); often smooth muscle hypertrophy present around glands; usually consists of basal layer of endometrium that may be connected with mucosa; usually proliferative endometrium, although only 25% is proliferative during secretory phase; microscopic foci may be in vascular spaces resembling endometrial stromal sarcoma

Micro images: imag #1; #2; #3

DD: endometrial stromal sarcoma (no glandular tissue, invades myometrium in tongues, no muscular hypertrophy, unusual to contain diffuse small regular glands )

Endometriosis

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Endometrial tissue outside the uterus; closely related to adenomyosis

Women 20-30 years old, up to 10% of all women affected

Consists of functional layers of endometrium that go through menstrual changes, although is more proliferative than normal endometrium

Causes pain, infertility (1/3 of women are infertile)

Causes: regurgitation (retrograde menstruation), metaplasia, angiolymphatic dissemination (to lungs, nodes); metaplastic change of secondary mullerian system represented by pelvic mesothelium

Sites: Ovaries > uterine ligaments > rectovaginal septum > pelvic peritoneum > scar

Rarely in lymph nodes, usually with cuboidal epithelium, no stroma, limited to capsule, resembles tubal epithelium; call endosalpingiosis

May undergo malignant transformation (endometrioid > clear cell, endometrial stromal sarcoma, MMMT)

Organizing hemorrhage may cause adhesions, ovarian chocolate cysts

Treatment: hormones, surgery

Diagram

Gross: blue cystic nodules surrounded by fibrosis; rarely polypoid masses simulating a neoplasm

Gross images: image1, image2, image3

Micro: contains at least two of three features - endometrial glands, endometrial stroma, hemorrhage

may be a dense fibrous mass; may undergo mucinous metaplasia aka endocervicosis or myxoid change

Associated with perineurial invasion

Micro images: image1, image2

Cytology images: contributed by Dr. Carmen Luz - sheet of endometrial epithelium in FNA from abdominal wall; sheet of endometrial epithelium besides a group of endocervical epitelium and endometrial stroma from an endometrial direct cytology; round endometrial epithelial group with slight atypia

DD: well differentiated adenocarcinoma if endocervicosis present; pseudomyxoma peritonei if myxoid change

Dysfunctional uterine bleeding (DUB)

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Definition: bleeding >5 days of unknown cause in women of child bearing age; a clinical term, not a pathologist term

Known causes: endometriosis, submucous myoma, endometrial polyp (5-15%), cancer (5-15% of postmenopausal bleeding), precocious puberty, anovulatory cycle, pregnancy complication, physical lesion (leiomyoma, adenomyosis, endometrial hyperplasia), endocrine disorder, ovarian lesion (granulosa-theca tumor), metabolic disturbance (obesity, malnutrition), exogenous hormones, drugs with hormonal side effects, luteal phase defect, chronic inflammation, ectopic pregnancy, idiopathic stromal predecidualization in postmenopausal women

May be due to degenerative changes in uterine blood vessels associated with atrophy

Can classify based on ovulatory or non-ovulatory cycles:

If patient ovulates, may be due to inadequate proliferative phase, inadequate secretory phase, irregular shedding or membranous dysmenorrhea

Inadequate proliferative phase: disparity between clinical menstrual cycle date and microscopic changes (usually delayed morphologic changes of proliferation)

Inadequate secretory phase: discrepancy of 2+ days between microscopy and clinical cycle date; biopsy shows underdeveloped secretory endometrium or secretory and proliferative endometrium in same specimen; also irregular shedding; due to low progesterone; associated with infertility, amenorrhea; treated with hormones

Irregular shedding: bleeding 7 days or more, due to lag in shedding of secretory endometrium, which is normally completed by day 4 of menstruation; should do biopsy on day 5+ of menstruation; biopsy shows retained secretory endometrium, fragmented menstrual endometrium, proliferative endometrium; occurs in 10-17% of DUB cases; associated with luteal phase defect

Membranous dysmenorrhea: rare, endometrial cast passed during menstruation, resembles decidua; may be due to exogenous progesterone

Anovulatory cycle: proliferative endometrium during chronological secretory phase; usually causes endometrial hyperplasia

Micro: fibrin clumps in endometrial stroma (not present in normal menstrual stroma), stromal crumbling (fragmented pieces with dense stromal cellularity); exogenous hormones cause predecidual stroma, edema, wimpy tubular glands of different sizes

Endometrial hyperplasia

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Proliferation of glands of irregular size and shape with an increase in the gland to stroma ratio compared with proliferative endometrium

Usually in perimenopausal women

Usual predecessor to endometrial carcinoma, particularly younger women or those with well differentiated endometrioid adenocarcinoma, although most with hyperplasia do NOT develop carcinoma

Risk of developing carcinoma is greater with complex or atypical changes

Even among experts, discordance is common on hyperplasia vs. no hyperplasia in endometrial biopsies of women on hormone replacement therapy, AJSP 2002;26:1269

Often overdiagnosed

Causes: prolonged estrogenic stimulation with reduced progestational activity (usually near menopause or associated with anovulatory cycles), polycystic ovarian disease (Stein-Leventhal syndrome), ovarian granulosa cell tumors (functional), ovarian cortical stromal hyperplasia, estrogen replacement therapy without progestational agents

Disregard cystic changes since they are secondary and can be found without hyperplasia, although presence of cysts usually means hyperplasia is mild

Treatment: progestins (causes sheets of luteinized stroma and dilated glands resembling Swiss cheese) or hysterectomy (for complex atypical hyperplasia only)

Gross: lush, polypoid endometrium

Gross images: image1

Micro: gland to stroma ratio should be 3:1 (i.e. stroma is 1/3 of volume or less); usually associated with proliferative endometrium (pseudostratification or stratification), may have secretory features if patient receiving progesterone; stroma should also be hyperplastic

Metaplasia common: squamous, ciliated cell, mucinous; grade hyperplasia separate from metaplastic changes

DD: polyps, endometritis, artifacts, metaplasia, normal endometrium

Reference: Mod Path 2000;13:309

Disordered proliferative endometrium

Associated with anovulatory cycles, common in perimenopausal and menopausal women; also exogenous estrogen therapy

Resembles normal exuberant proliferative endometrium, but without uniform glandular development (some glands cystically dilated, others have shallow budding)

Increase of cystically dilated glands, but relatively normal ratio of glands to stroma

Sternberg indicates this diagnosis is “insufficient for diagnosis of hyperplasia”, although WHO calls a form of simple hyperplasia

Metaplastic changes (ciliated epithelium) are common

May see endometrial breakdown and hemorrhage with thrombosed, thin walled vessels

Simple hyperplasia

Aka cystic hyperplasia or mild hyperplasia

Usually evolves to cystic atrophy, ~5% to adenocarcinoma without atypia, ~7% to carcinoma with atypia

Usually lacks atypia

Gross: increased endometrial volume, qualitatively different from normal cycling endometrium

Micro: changes in glands and stroma so that glands are not particularly crowded; glands usually round, but may be irregular with cystic dilation; lining epithelium is pseudostratified or mildly stratified; occasional mitotic figures (less than proliferative endometrium); cellular stroma with variable mitotic activity, uniformly distributed blood vessels

Micro images: image1, image2

DD: endometrial polyps (fibrotic stroma with dilated, thick-walled blood vessels), cystic atrophy (glands lined by reduced epithelium, stroma is dense and atrophic), disordered proliferative endometrium (few widely scattered cystic glands, less than hyperplasia), artifacts (fragmented endometrium with artifactually compressed glands-image; telescoping of glands-image), chronic endometritis (may have reactive glandular changes causing crowding, abnormal glandshapes, and variable atypia; but has plasma cells, stromal spindling andedema, surface neutrophils)

Reference: Mod Path 2000;13:309

Complex hyperplasia

Increase in number and size of endometrial glands with crowding of stroma, budding

By definition, some normal stromal cells are present between adjacent glands

~16% without atypia progress to carcinoma; ~47% with atypia progress to carcinoma

Complex pattern may be secretory with eosinophilic metaplasia

High grade (with atypia): rounding of nuclei and formation of nucleoli; stratification, scalloping, tufting, loss of polarity, cytomegaly, hyperchromatism, pleomorphism, mitotic figures; may resemble adenocarcinoma but no stromal invasion or desmoplasia; 23% progress to endometrial adenocarcinoma

Micro images: without atypia

Reference: Mod Path 2000;13:309

Atypical Hyperplasia
If diagnosed at biopsy or curettage, 15%-50% of immediatehysterectomy specimens will have adenocarcinoma, some myoinvasive

Micro: cytologic atypia, usually focal, in a background of complex and rarely simple hyperplasia; usually cellular dyspolarity,irregular stratification, anisocytosis, nuclear rounding, nucleomegaly, hyperchromatism,chromatin clumping, and enlarged nucleoli; may have marked cytoplasmic eosinophilia or eosinophilicnecrotic debris within the atypical cells

Should contrast “atypical” gland with adjacent “non-atypical” glands

Sternberg suggests calling “borderline” if unable to rule out well differentiated carcinoma

Micro images: complex hyperplasia with atypia, atypia

DD: metaplastic changes, atypical hyperplasia with secretory changes resembles secretory carcinoma

Reference: Mod Path 2000;13:309

Atypical secretory hyperplasia

Resembles day 17 endometrium but with atypia

Treatment: conservative

DD: Arias Stella

Endometrial intraepithelial neoplasia (EIN)

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Relatively new classification system (Gynecol Oncol 2000;76:287) for a precursor to endometrioid endometrial adenocarcinoma

An alternative to the WHO system of complex or simple hyperplasia with or without atypia

Most EIN cases are monoclonal and thus premalignant

Criteria for EIN includes:

(a) a larger glandular area than stromal area (volume percent stroma < 55%)

(b) cytology differs between the crowded glandular focus and the background glands

One must also exclude progesterone related effects (wait 2-4 weeks after cessation of hormones), benign mimics (disordered proliferative endometrium or atrophy) and carcinoma.

May predict disease progression more accurately than WHO system (Cancer 2005;103:2304)

May better classify patients into high and low risk subgroups (Mod Pathol 2005;18:324)

Case report: 45 year old woman with menometrorhagia (Case #60)

Micro images: image #1; #2; #3; #4; #5

References: www.endometrium.org, J Clin Pathol 2002;55:326

Sternberg’s pattern approach to diagnosis

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See Sternberg, S: Diagnostic Surgical Pathology (3rd Ed); Lippincott Williams & Wilkins, 1999

Based on low power diagnosis

Pattern 1: glands with nonneoplastic endometrial stroma; must evaluate gland to stroma ratio, glandular and stromal features, appearance of vessels and pattern uniformity

Includes normal endometrium, gestational changes, atrophy, hyperplasia, carcinoma, polyps, metaplasia

Gland to stroma ratio

1:1 associated with normal cycling endometrium, dysfunctional uterine bleeding, infertility

> 1:1 associated with menstruation, late secretory phase, hyperplasia, carcinoma

< 1:1 associated with normal decidua, atrophy, monophasic stromal proliferations

Glandular features

Must evaluate cytologic features and architecture of glands to determine if atrophy, weakly proliferative endometrium, proliferative endometrium, presence of cytologic atypia, secretory endometrium (early, mid-, late), Arias-Stella reaction, disintegrating glands / shedding, budding or branching of glands

Stromal features

Usual stroma in proliferative phase has spindled or oval nuclei with minimal cytoplasm; in secretory phase or pregnancy has decidual changes of large round/oval nucleus, abundant eosinophilic or clear cytoplasm

Vasculature

In proliferative phase, vessels are delicate branching network throughout stroma

Secretory phase vessels have thicker walls, are coiled (aka spiral arteries)

Thick walled vessels in fibrotic stroma are characteristic of endometrial polyps

Pattern uniformity

Cycling endometrium has uniform pattern throughout, except for lower uterine segment / isthmus (spindled stromal cells separated by collagen, hybrid endocervical-endometrial glands) and stratum basalis layer (unresponsive to hormones, appears weakly proliferative throughout menstrual cycle)

Pattern 2: biphasic proliferations of glands and abundant / possibly neoplastic stroma

Includes endometrial polyps, adenofibroma, atypical polypoid adenomyoma, MMMT, adenosarcoma, sarcoma, endometrial stromal neoplasms, adenomatoid tumor

Pattern 3: predominantly monophasic spindle-cell proliferations

Includes smooth muscle neoplasms, endometrial stromal tumors, spindled epithelial neoplasms, pure heterologous uterine sarcomas, undifferentiated sarcoma

Epithelial neoplasms typically express CD10, EMA, keratin vs. smooth muscle neoplasms express smooth muscle actin, desmin, h-caldesmon

Pattern 4: Sheet-like proliferations of large, round, undifferentiated cells

Includes undifferentiated malignancies such as high grade adenocarcinoma, MMMT, undifferentiated sarcomas, extension of cervical primary, metastatic carcinoma, melanoma, leukemia, lymphoma; lobular carcinoma of breast looks deceptively bland

Pattern 5: Extensive necrosis, inflammation, disintegration

Necrosis suggests malignancy; also cervical stenosis, pyometra, xanthomatous endometritis

Inflammatory cells common in post-partum endometrium; also bacterial infection

Disintegration associated with menstruation, hyperplasia; may mimic carcinoma due to stromal collapse

Pattern 6: Scanty samples that suggest inadequate sample

May be due to atrophy or obstructing lesion that shields endometrium from sampling

Miscellaneous

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Atrophy

Normal in prepubertal girls, perimenopausal or menopausal women

Low cuboidal or columnar epithelium with no mitotic figures

Glands usually tubular or cystic, may be closely packed

Stroma appears inactive with variable collagenization and minimal mitotic activity

DD: basalis endometrium, lower uterine segment, endometrial lining of submucous myoma, polyp, progesterone effect

Dyssynchronous endometrium

Discordance between glands and stroma; usually both in secretory phase; also proliferative endometrium and secretory stroma

Microglandular hyperplasia

Clusters of small glands without atypia

Shedding

Aka glandular and stroma breakdown

Common in perimenopausal women

Micro: condensation of endometrial stroma under surface endometrium and nuclear dust

Associated with predecidualized stroma and glandular exhaustion; cannot assess architectural changes

May see signet ring cells (benign) if prolonged shedding

DD: small cell carcinoma

Weakly proliferative endometrium

Normal in prepubertal girls, perimenopausal or menopausal women

Proliferative glands (columnar or cuboidal epithelium with pseudostratification, elongated and densely basophilic nuclei), but relatively reduced number of mitotic figures

Glands usually tubular or cystic, may be closely packed

Stroma also appears inactive, with variable collagenization and minimal mitotic activity

Epithelial tumors

Adenoacanthoma

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Endometrioid adenocarcinoma with well differentiated squamous differentiation

Squamous component is benign

Similar prognosis to other well differentiated adenocarcinomas

Prognosis is dependent on glandular, not squamous component, so call adenocarcinoma with squamous differentiation

Micro images: image1

Reference: Mod Path 2000;13:309

Adenomyoma

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Aka adenomyomatous polyp

Gross: hard consistency, gray color

Micro: endometrial polyp with smooth muscle fibers not connected to vessel walls

Adenosquamous carcinoma

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Endometrioid adenocarcinoma with malignant appearing squamous elements representing at least 10% of tumor

Adenoacanthoma and adenosquamous carcinoma may represent a continuum of squamous metaplasia

Similar prognosis to adenocarcinoma when compared by stage and grade (i.e. squamous component does not affect prognosis)

Micro: squamous component should be definite, based on keratinization, intercellular bridges or 3 out of these 4 criteria: (a) sheet-like growthwithout gland formation or pallisading, (b) sharp cell margins,(c) eosinophilic and thick or glassy cytoplasm, and (d) a decreasednuclear:cytoplasmic ratio compared with foci elsewhere inthe same tumor)

Micro images: image1, image2, CD44

Positive stains : CD44 in squamous component (Archives 2000;124:212)

Reference: Mod Path 2000;13:309

Atypical polypoid adenomyoma

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Aka atypical polypoid adenomyofibroma, APA

Biphasic polypoid lesion with atypical endometrial hyperplasia and usually squamous metaplasia

Uncommon (< 150 cases reported), associated with Turner’s syndrome

Mean age 40 years, range 21-73 years

Symptoms of dysfunctional uterine bleeding

May persist or recur, but does not metastasize; may have increased risk for later carcinoma; may be contiguous with adenocarcinoma; Archives 2002; 126:864

Treatment: conservative polypectomy and curettage or simple hysterectomy in peri/postmenopausal women, but with follow up

Gross: resembles endometrial polyp; single, well-circumscribed, polypoid mass; often in lower uterine segment; usually confined to endometrium with pushing margin; remaining endometrium is often unremarkable

Gross images: image1 (figure 1)

Micro: biphasic with hyperplasic and atypical endometrial glands (complex architecture, often severe cytologic atypia), separated by fascicles of bland smooth muscle and fibrous stroma; squamous metaplasia present (90%) and often extensive; minimal mitotic activity (<3 per 10 HPF); no desmoplasia

Micro images: image1 (figures 2-4), image2, image3

Positive stains: trichrome (smooth muscle); low Ki-67 proliferative activity

DD: adenocarcinoma with muscular invasion (has desmoplasia, older women, grossly invasive, large with hemorrhage and necrosis), MMMT (older women, stromal also malignant, diffuse atypia, increased mitotic activity)

Reference: Mod Path 2000;13:328, Mod Path 2000;13:309

APA of low malignant potential

Glands have features of well differentiated adenocarcinoma

May extend into superficial myometrium

Ciliated carcinoma

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Rare, subtype of well-differentiated endometrioid adenocarcinoma

Good prognosis

Occasionally have abundant solid areas (FIGO grade 2)

Micro: neoplastic glands composedpredominantly or exclusively of ciliated cells with stromal invasion; minimal atypia

DD: ciliated cell metaplasia

Clear cell carcinoma

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Usually post-menopausal patients

Not related to DES exposure

Histologically resembles vaginal and ovarian clear cell carcinomas

High grade tumor - not FIGO graded

Associated with endometrial hyperplasia

Probably not due to mesonephric remnants but are mullerian

Micro: large clear cells with glycogen, distinct margins, papillary formations and hobnail cells; enlarged angulated nuclei with enlarged irregular nucleoli with at least focal cytoplasmic clearing; cytoplasm also eosinophilic; papillary, glandular or sheet-like architecture

May have colloid like material in tubules

Micro images: p53 staining (figure 6)

DD: metastatic renal cell carcinoma

Endometrial carcinoma-general

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Most common gynecologic malignancy in US (33K cases/year, 4K deaths); incidence is increasing

Usually (80%) arises in postmenopausal women with symptoms of bleeding

Associated with obesity, diabetes, hypertension, infertility, failure of ovulation (Stein-Leventhal syndrome), dysfunctional uterine bleeding, prolonged estrogen use, tamoxifen use (perhaps through imbalance in apoptosis/proliferation), complex endometrial hyperplasia, Muir-Torre syndrome (AJSP 2001;25:936, OMIM)

Stein-Leventhal syndrome: often have hyperplasia that regresses with medical therapy; rarely have a non-lethal, well differentiated carcinomas with minimal muscular invasion

Turner’s syndrome: rarely have well differentiated adenocarcinoma; often with prolonged estrogen therapy, 2/3 have squamous differentiation

Tamoxifen use for breast cancer: may have high-grade tumors with poor prognosis

Major types of endometrial carcioma are endometrioid and serous

Must distinguish muscular invasion (should be deep or have granulation tissue response) from expansion of endometrial-myometrial junction or involvement of adenomyosis (no granulation tissue response, residual normal glands and stroma, glands surrounded by hyperplastic myometrium)

Poorly differentiated tumors are associated with bilateral diffuse uveal melanocytic proliferation and blindness, AJSP 2001;25:212

Spread/metastases: cervix (direct extension or implantation after D & C), ovary, vagina and lung, liver, bone, CNS, skin; nodal metastases to pelvic and para-aortic nodes

8% accompanied by simultaneous ovarian carcinoma, usually with same histology; consider as endometrial metastasis if ovarian tumor is small, bilateral, multinodular with surface implants and angiolymphatic invasion within ovarian stroma

Consider as simultaneous primaries if both tumors are FIGO grade 1/well differentiated and endometrial tumor is not myoinvasive

Rarely see foreign body granulomas in peritoneum in response to desquamated keratin; not considered metastatic disease

Recurrence: vaginal vault, pelvis

Cytology: only 50% sensitive for adenocarcinoma, 60% with cervical scrapings, 75% with vaginal pool material; normal endometrial cells in a cervical cytologic specimen suggests hyperplasia or carcinoma

FIGO grading (excludes serous or clear cell, which are considered high grade):

FIGO 1: resembles microglandular hyperplasia; composed primarily of well formed glands; <5% nonsquamous solid component

FIGO 2: 6-50% nonsquamous solid component

FIGO 3: more than 50% nonsquamous solid component; lacks well formed glands, which differentiates it from serous endometrial carcinoma

Raise grade from 1 to 2 or from 2 to 3 if notable nuclear atypia inappropriate for grade (particularly pleomorphism and prominent nucleoli); others say marked atypia

Note: if marked atypia, tumor may be serous without typical papillary architecture (usually p53+)

Alternative proposal for dividing endometrioid tumors into low grade or high grade based on assessment of amount of solid growth (50% or less vs. 50%+), pattern of invasion (infiltrative vs. expansive), and presence of tumor cell necrosis (yes vs. no) at AJSP 2000;24:1201

High grade if 2 of above features (>50% solid growth, infiltrative growth pattern, tumor cell necrosis)

Note: adenocarcinoma in situ is not considered a valid concept for endometrium

Endometrium intraepithelial neoplasia: questionable if this concept is helpful to pathologists

Treatment: Total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAHBSO), possibly with nodal dissection; progesterone causes regressions in well differentiated tumors, although not curative

Prognostic factors: histologic type, FIGO stage (includes depth of invasion, regional nodal metastases, tumor spread), tumor grade, angiolymphatic invasion (particularly for stage 1 tumors), ER, p53 / HER2 (may not be independent), ploidy

Survival: 5 year survival for patients treated 1993-1995 by stage: 1 - 95%, 2 - 85%, 3-65%, 4-20%

Gross: lush, polypoid endometrium with yellow necrotic areas

Gross images: image1, image2

Micro: stromal invasion is required; usually present in the form of stromal disappearance (i.e. back to back, cribriform or confluent glands), stromal desmoplasia (stroma has myofibroblasts, edema, inflammatory cells, myxoid change),stromal necrosis (stroma replaced by necrotic and inflammatory debris), or combinations of these findings between adjacentglands; may be prominent atypia in high grade lesions or minimal atypia in low grade lesions; presence of stromal foam cells between glands, representing altered endometrial stromal cells, is suggestive but not diagnostic of carcinoma

Myometrial invasion: often overdiagnosed due to uneven endomyometrial junction or involvement of adenomyosis (foci of adenomyosis usually rounded not angulated, adenomyosis involved by carcinoma often has residual benign glands, is surrounded by normal myometrium, and other foci are uninvolved)

Micro images: image1, image2, involvement of adenomyosis vs. myometrial invasion

Positive stains: CK 7, CK8/18, CK19; vimentin (65%), CEA (areas of squamous metaplasia), CA125, ER, PR, PTEN (80%), cyclin D1 (40%)

Molecular: K-ras mutations in infiltrative tumors with desmoplastic stroma; 25% aneuploid (usually high stage and grade)

DD: hyperplasia (carcinoma favored if marked pleomorphism with loss of polarity, complex ramification of disorderly arranged glands, extensive papillary formations, confluent glandular pattern with solid or cribriform appearance, desmoplastic stroma; intraglandular cellular bridges without stromal support; neutrophils and nuclear debris within glandular lamina); serous carcinoma (papillary plus high grade features; high grade endometrioid carcinomas lack well formed glands or tubules; endometrioid carcinoma may be papillary but has low grade nuclear features)

Superficial portions of tumor may show microglandular patterns resembling hyperplasia and other metaplastic patterns

Reference: Mod Path 2000;13:309

Endometrial polyp

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Grossly pedunculated mass composed of cystically dilated glands with fibrous stroma and thick walled blood vessels

Asymptomatic or associated with bleeding

May represent circumscribed foci of endometrial hyperplasia

Glands are unresponsive to progesterone stimulation

Either hyperplastic (1/3 are associated with endometrial hyperplasia) or functional / secretory (normal microscopic findings but grossly resembles a polyp)

Associated with tamoxifen therapy for breast cancer - may have severe atypia

Note: must examine carefully for serous carcinoma focus

Gross: multicystic cut surface; sessile or pedunculated

Gross images: image1

Micro: large, thick walled blood vessels, fibrous stroma with spindled, fibroblast-like cells, abundant extracellular connective tissue, polypoid shape, attenuated surface endometrium on 3 sides, cystic change; glands are proliferative or inactive but usually peripheral; rarely has atypical stromal cells

Micro images: image1, image2

DD: basalis endometrium or lower uterine segment, hyperplasia (stromal cells have large vesicular nuclei and mitotic figures)

Reference: Mod Path 2000;13:309

Polyp with atypical (bizarre) stromal cells

Usually an incidental finding

Mean 56 years, range 45-82 years; present with post-menopausal bleeding

Not associated with endometrial carcinoma

Benign behavior

Atypia probably represents degenerative changes

Micro: moderate to severe nuclear atypia due to large, hyperchromatic nuclei and occasional multinucleation; hyperchromasia due to “smudging”, as with symplastic leiomyomas; no prominent nucleoli; no mitotic activity; giant cells often within loose fibrous background; atypical cells scattered throughout the polyp

Positive stains for atypical cells: vimentin, ER, PR, androgen receptor, CD10 (38%)

DD: adenosarcoma (stromal hypercellularity, periglandular stromal cuffing, cambium layer, polypoid or leaf-like projections into glandular lumina, >3 mitoses/10 high power fields), MMMT (malignant appearing epithelial component, stromal component has mitotic figures), endometrial stromal sarcoma (tan to yellow, tightly packed spindled cells without significant glandular elements, smaller capillary type vessels distributed evenly; infiltrates into myometrium; usually no atypical cells)

Reference: AJSP 2002;26:505

Endometrioid adenocarcinoma

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Aka type 1 endometrial carcinoma

80% of endometrial carcinomas

Relatively indolent tumors that arise in background of endometrial hyperplasia

Both carcinoma and hyperplasia are linked to prolonged estrogenic stimulation without progestational agents; both are also associated with estrogen secreting tumors

Associated with estrogen replacement therapy (usually well differentiated and endometrioid with good prognosis); rare if ovarian dysgenesis or castration

Rates much higher in white vs. black women

Local or diffuse, invades through myometrium

Most women have Stage I disease, moderate or well differentiated tumors

5 year survival - Stage 1 (90%), Stage 2 (30-50%), Stage 3/4 (20%)

Case report with separate leiomyosarcoma at Archives 2000;124:1539

Prognostic factors: mitotic index/MIB-1 index for stage 1A/1B, low grade tumors, Mod Path 2002;15:365
Gross: usually large uterus if myometrial invasion; uterus may be normal sized even with myometrial invasion if tumor begins in cornu

Gross images: with leiomyosarcoma

Micro: endometrial-type glands of varying differentiation/atypia with no intervening stroma between glands; may have papillary growth pattern; stroma present is usually desmoplastic, may have foamy cells due to tumor necrosis (not specific for carcinoma, derived from stroma not histiocytes; fat positive, mucin negative); adjacent endometrium often hyperplastic or atrophic

Vascular invasion is associated with chronic inflammation around lymphatics

May have trophoblastic differentiation with hCG+ cells

Commonly has squamous metaplasia (aka adenoacanthoma)

Micro images: with leiomyosarcoma#1, #2

DD of papillary tumors: papillary endometrioid carcinoma (low grade nuclei), villoglandular endometrioid carcinoma, serous carcinoma (high grade), ciliary metaplasia, papillary change, shedding endometrium with papillary syncytial metaplasia, progesterone treatment

Reference: AJSP 2000;24:1201

Well differentiated (FIGO grade 1)

Extensive, complex epithelial growth pattern with little intervening stroma

Usually budding and branching of large glands causing papillary structures

May be villoglandular on low power

May have true papillae (DD: clear cell carcinoma, serous carcinoma), but without atypia

Mild to moderate atypia is allowed or only focal

Some are myoinvasive

Often has benign squamous differentiation (adenoacanthoma), focal mucinous, secretory or ciliated features

Usually stage 1, with 95% relapse-free survival rate

Treatment: hysterectomy plus radiation therapy if penetrate 50% of myometrium

Micro images: image1, image2, image3, image4, p53 staining (figure 5A)

Reference: Mod Path 2000;13:309

Moderate differentiation (FIGO grade 2)

6%-50% of nonsquamous tumor is composed of sheet-like tumor cells without glandular features

Tumor cells have moderate pleomorphism, prominent nucleoli

Treatment: hysterectomy plus radiation therapy if myoinvasive

Micro images: image1

Poorly differentiated (FIGO grade 3)

>50% of nonsquamous tumor is composed of sheet-like tumor cells without glandular features

Tumor cells have high grade features

Glands poorly formed when present

May contain malignant squamous cells; angiolymphatic invasion common

Giant cell carcinoma

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Rare, high grade with bizarre, pleomorphic, multinucleated giant cells

Glassy cell carcinoma

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Rare, type of adenosquamous carcinoma, similar to cervical counterpart

Case report of 60 year old women at Archives 2001;125:816

Micro: diffuse solid sheets of tumor cells, with eosinophilic, ground-glass cytoplasm, distinct cell walls, large nuclei, prominent nucleoli; frequent mitotic figures; heavy eosinophilic and lymphocytic infiltrate common; usually some glandular component; most authors require 30%-100% of glassy cells for diagnosis

Micro images: image1

EM: intermediate filaments, polyribosomes, tonofibrils, and desmosomes

Positive stains: variable keratin, EMA and CEA

Melanoma of uterus

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Very rare, either as primary or metastatic tumor

Uterine metastases may derive from primaries in skin (Gynecol Oncol 2004;93:252), uvea (Pathol Oncol Res 2006;12:184) or hard palate (Can J Surg 2002;45:461)

Melanoma may metastasize to uterine polyps, including adenomyomas (Int J Surg Pathol 2005;13:223).

Some uterine melanomas may originate in the cervix (see Cervix chapter)

Poor prognosis in uterus or cervix, whether tumor is primary or secondary

Primary uterine tumors may arise from lentigo or blue nevus (Diagn Gynecol Obstet 1981;3:269).

Case reports: Case of the Week #109

Micro images: #1; #2; #3; MART1; HMB45; S100; CAM5.2; CK7; CK20

Minimal deviation endometrial carcinoma

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Rare, in cervix and uterine isthmus

Case report at Hum Path 2002;33:856 with typical endometrioid adenocarcinoma involving 75% of endometrium, and minimal deviation endometrial carcinoma involving entire cervix, focal body and isthmus

FIGO grade 1, nuclear grade 1

Low Ki-67/MIB1 staining

Gross: usually no gross tumor

Micro: proliferation of mildly atypical endometrial glands with no/minimal desmoplastic stromal reaction; minimal atypia; FIGO grade 1 and nuclear grade 1

DD: adenomyosis

Mixed

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At least 10% of a second type

Mucinous carcinoma

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Adenocarcinoma with abundant mucin secretion (>50% of tumor)

May have enteric features

May have microglandular pattern with eosinophilic mucinous intraluminal secretion and acute inflammation, simulating microglandular hyperplasia

Mucin should be a predominant component of the tumor, since scattered mucin is present in ordinary endometrial adenocarcinoma

DD: mucinous metaplasia (no atypia), endocervical adenocarcinoma (depends on differential biopsy and fractional curettage, no associated endometrial hyperplasia or metaplasia, no foam cells)

Oxyphilic cell carcinoma

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Large eosinophilic cells

Perivascular epithelioid cell tumor (PEComa)

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Rare tumor, < 20 cases report

Mean age 54 years (range, 40-75 years)

Present with abnormal uterine bleeding and uterine mass

Member of family of lesions composed, in part, of perivascular epithelioid cells

Other members are some angiomyolipomas, lymphangioleiomyomatosis, clear cell “sugar” tumor of lung, clear cell myomelanocytic tumor of ligamentum teres/falciform ligament, abdominopelvic sarcoma of perivascular epithelioid cells (tumors in bold described in soft tissue outline)

May be associated with tuberous sclerosis complex

May recur after hysterectomy

Consider as tumor of uncertain malignant potential, AJSP 2002;26:1

Micro: cells are epithelioid, with clear to eosinophilic granular cytoplasm, perivascular distribution

Positive stains: HMB45, MelanA/Mart1, focal muscle markers

Secretory carcinoma

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Subtype of well differentiated endometrioid adenocarcinoma, usually due to progesterone stimulation

Micro: resembles day 17 endometrium (subnuclear vacuoles) plus late secretory pattern in uninvolved endometrium; minimal atypia

DD: clear cell carcinoma

Serous carcinoma

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Aka papillary serous carcinoma, endometrial type 2 tumor

Aggressive (high recurrence rate, low survival rate)

Compared to endometrioid carcinoma, is less common, older age, same rates in black vs. white women, associated with p53 mutations (considered an early event), usually clinically understaged

Not associated with estrogen secretion as endometrioid tumors are; may follow radiation therapy for cervical carcinoma

Associated with endometrioid adenocarcinoma or clear cell carcinoma or ovarian serous carcinoma

Associated with endometrial polyps and is often polypoid

40% with Stage I disease die of disease, 60% will get retroperitoneal involvement

2/3 have malignant pap smears since buds and tufts break off

25% have primary endocervical involvement

Drop metastases to vagina common

May have superficial endometrial tumor with extensive peritoneal disease, suggesting tubal or angiolymphatic invasion

Resembles ovarian serous carcinoma, and spreads throughout abdomen in a similar manner; may metastasize to bladder, simulating a bladder primary

Transtubal spread common, may create ovarian implants, omental tumor nodules

Considered high grade and is not graded using FIGO

Note: if one gland is serous, consider tumor to be aggressive (others say must be 25% of all tumor)

Gross: uterus small for a high grade tumor

Micro: usually well formed papillae (thick and thin) or tubules with “lobster claw” appearance containing highly pleomorphic tumor cells containing prominent nucleoli, small detached buds and tufts; frequent mitotic activity and necrosis, prominent myometrial invasion; may have glandular pattern and resemble villoglandular carcinoma on low power; usually marked desmoplastic response resembling carcinosarcoma; angiolymphatic invasion common; 40% have psammoma bodies

Associated with endometrial atrophy, not hyperplasia; abrupt transition from normal to serous carcinoma is common

Positive stains: p53 (useful for differentiating from endometrioid carcinoma)

Negative stains: ER, PR

Molecular: most are aneuploid

DD: clear cell carcinoma (may have overlapping features, distinction not important since management is the same)

Endometrial intraepithelial carcinoma

Rare finding without invasive carcinoma; may be associated with extrauterine disease

Replacement of benign surface endometrium and underlying glands with high-grade malignant cells resembling serous carcinoma; no evidence of invasion

Often involves benign endometrial polyps with extensive replacement of surface epithelium and glands

Usually cured by hysterectomy if NO extrauterine involvement by careful staging

May be precursor of invasive serous carcinoma

Positive stains: p53, Ki-67

References: AJSP 2000; 24:797; AJSP 2000;24:726

Minimally invasive serous carcinoma

No myometrial invasion

Usually cured if NO extrauterine involvement by careful staging

May have minimal disease involving ovarian surface epithelium, serous adenofibroma or omentum

Similar behavior as endometrial intraepithelial carcinoma if 1 cm or less of tumor

DD: eosinophilic metaplasia, complex hyperplasia with atypia, clear cell carcinoma

Small cell carcinoma

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Aggressive

Note: 25-50% of typical endometrial adenocarcinomas contain some endocrine cells

Gross: bulky, ill-defined

Micro: resembles cervical counterpart; may see coexisting ordinary adenocarcinoma or be part of mixed mullerian tumor; cells may be small, intermediate or large

Positive stains: neuron specific enolase

Negative stains: chromogranin (usually)

EM: dense core secretory granules

Squamous cell carcinoma

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Rare, associated with pyometra or mucinous glands of heterotopic cervical origin

DD: Cervical squamous cell carcinoma

Villoglandular carcinoma

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Variant of well-differentiated endometrioid adenocarcinoma

Micro: dominant pattern is well differentiated papillary structures; cells resemble classic glandular endometrioid pattern with uniform columnar cells, bland nuclei perpendicular to basement membrane; thin and simple papillary structures without broad fibrovascular cores; no prominent exfoliation; often bland squamous elements

DD: serous adenocarcinoma, clear cell adenocarcinoma,

Stromal tumors

Adenofibroma

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Uncommon, related to papillary adenofibroma, cystadenofibroma, lipoadenofibroma, adenomyomatosis

May be found in cervix, ovary, round and broad ligaments, pelvic wall

Usually post-menopausal women

Usually benign, rarely recurs

Criteria to determine malignant potential is similar to phylloides tumors

Difficult diagnosis based on curettings because adenosarcoma has variable cellularity

Malignant (adenosarcoma): 2 or more stromal mitotic figures/10 HPF, marked stromal cellularity, significant stromal cell atypia

Gross: firm, knobby, papillary, multicystic; no necrosis

Micro: benign counterpart of adenosarcoma with benign glands and stroma, but occasionally invades myometrium and pelvic veins, so distinction not sharp; cleft like papillary architecture; surface epithelium often extends deeply into stroma; prominent cystic spaces; variable epithelial lining (epithelioid, mucinous, serous)

DD: adenosarcoma (has stromal condensation around epithelium, cellular and mitotically active stroma)

Adenomatoid tumor

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Mesothelial origin, similar to tumors of fallopian tube

Benign behavior

Gross: usually close to cornua and serosa; small; often yellow; may not be well circumscribed

Micro: irregular aggregates of cuboidal / flattened cells in adenoid. angiomatoid, solid or cystic patterns; cystic tumors resemble lymphangiomas but no lymphocytes within cystic spaces; often associated with smooth muscle hypertrophy; minimal/no atypia; usually minimal mitotic figures

Adenosarcoma

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Also called mullerian adenosarcoma

A low grade MMMT, usually in elderly

Rosai considers these tumors to be a variant of endometrial stromal sarcoma with capacity to form glands, including sex-cord-like differentiation

May require a hysterectomy to rule out since has focal adenofibroma-like areas

25% are myoinvasive

15%-25% recur if no stromal overgrowth

Case reports: 42 year old woman

Gross: bulky, polypoid and multicystic, sometimes fleshy neoplasm filling endometrial cavity; less hemorrhage and necrosis than MMMT

Micro: epithelial and stromal elements with stromal hypercellularity; resembles phylloides tumor of breast; epithelial component appears benign; stromal elements resemble low grade endometrial stromal sarcoma but less bizarre and less undifferentiated; 20% have multinucleated giant cells and heterologous elements (skeletal muscle); glands usually large and dilated with periglandular stromal cuffing, cambium layer (stromal condensation) beneath surface epithelium and adjacent to glands in 80%; polypoid or leaf-like projections into glandular lumina; 4+ mitotic figures/10 high power fields

May also have extensive stromal fibrosis, suggesting benign appearance

Micro images: image1

DD: adenofibroma (lacks hypercellular stroma, no cambium layer, low mitotic index), endometrial stromal sarcoma with glands (no dilated glands, no periglandular stromal condensation, no intraluminal polypoid protrusions, smaller glands, often intravascular growth, tongue-like infiltration, arborizing vessels)

References: Mod Path 2000;13:328

Adenosarcomas with stromal overgrowth

Resembles malignant phylloides tumor, aggressive, 45%-70% recur, usually in pelvis

Patients may develop metastases and die of disease

May have heterologous sarcoma component, rhabdomyosarcoma most common

Endometrial stromal nodule

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Benign, don’t recur

Hysterectomy may be necessary to evaluate the margin

Gross: classically soft, yellow, solitary, sharply circumscribed neoplasm, confined to uterus, no intravascular component

Micro: usually uniformly well-circumscribed monotonous proliferations of bland endometrial stromal cells; expansive growth pattern (not infiltration) at margin; infiltration, if present, should be at most one to three protrusions 3 mm or less; may have sex cord-like differentiation; usually prominent arterioles; may have infarct-like necrosis; no angiolymphatic invasion; minimal mitotic activity (< 10 per 10 HPF)

Note: foci of smooth muscle metaplasia within the tumor should not be interpreted as myometrial invasion at the edge of the tumor, AJSP 2002;26:567

DD: cellular leiomyoma (grossly soft and yellow but fascicular pattern, large thick-walled blood vessels with muscular walls), low grade endometrial stromal sarcoma (infiltrative margin or angiolymphatic invasion); uterine tumors resembling ovarian sex-cord tumors (less cellular, no prominent arterioles, mature smooth muscle often present)

Endometrial stromal tumor with limited infiltration

Clinical significance unclear since long follow up required to assessed whether these tumors have malignant potential; should sample margins extensively, AJSP 2002;26:567

Endometrial stromal tumors-general

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Average age 45, present with vaginal bleeding

May be benign (stromal nodule with pushing margins) or malignant (infiltrating margins, low or high grade)

May contain separate areas of epithelium-like formations in the form of solid masses, glandular structures or cords resembling sex-cord structures; aka uterine tumors resembling sex-cord structures; tend to behave in benign manner

Tumors with smooth muscle and stromal features should be classified and treated as stromal sarcomas, Mod Path 2000;13:328

Difficult to diagnose as nodule vs. sarcoma based on curettings because invasion cannot be assessed, but consider tumor of some kind if endometrial stroma is present without glands

Gross: (all types) soft, yellow-orange

Micro: (all types) uniform small cells resembling endometrial stroma (blunt, spindled to oval with scant cytoplasm and small uniform nuclei), individually enveloped by reticulin fibers, haphazard arrangement (not fascicular), circle small / thin vessels that resemble spiral arterioles, hyalinization and foamy cells present; may have prominent vasculature resembling hemangiopericytoma;

Positive stains: ER, PR, vimentin, actin; variable keratin

Negative stains: S100, h-caldesmon (AJSP 2001;25:455), desmin

Endometrial stromal sarcoma

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0.2 to 1.5% of uterine malignancies; <10% of uterine sarcomas

Low grade or high grade

Micro: resembles endometrial stromal nodules but with infiltration, defined as irregular, jagged islands ortongues of neoplastic stromal cells between smoothmuscle bundles of the surrounding normal myometrium; may have angiolymphatic invasion (clumps of tumor cells presentin spaces within the myometrium); may have glands without cuff of hypercellular stroma seen in adenosarcoma

Positive staining: CD10, muscle markers in areas of smooth muscle differentiation (muscle specific actin, smooth muscle actin, desmin)

Negative staining: c-kit/CD117, h-caldesmon (AJSP 2001;25:455)

DD: lymphoma, undifferentiated carcinoma, pseudosarcomatous changes in the stroma, cellular leiomyoma, leiomyosarcoma

Low grade

Aka endolymphatic stromal myosis

Slow clinical progression with repeated local recurrence

50% recur (may take 10 years), 15% die of metastases (lung) but may be 20-30 years later

Rarely arise from ovary, vagina, peritoneum

Gross: polypoid mass extending into broad ligament, ovaries, fallopian tubes; lymphatic tumor plugs may appear as yellow, ropy or ball-like masses

Micro: monotonous ovoid to spindly cells with minimal cytoplasm intimately associated with prominent arterioles, closely resembles proliferative endometrial stroma; up to 10-15 mitotic figures per 10 HPF in most active areas; tongue-like infiltration between muscle bundles of myometrium; angiolymphatic invasion common; may exhibit myxoid, epithelioid and fibrous change; may have foam cells or hyalinization

Micro images: image1, H&E and CD10 (figures 1A & 1B), CD10, endometrial stromal sarcoma with glands

Positive stains: ER, PR

Negative stains: mucin, glycogen

DD: stromal nodule (no infiltrative, no angiolymphatic invasion), adenomyosis with sparse glands (usually incidental finding in post-menopausal woman, with small and atrophic stromal cells, typical areas of adenomyosis usually present), menstrual endometrium within vessels (usually glands are otherwise uniformly distributed with bland stroma), metastatic lobular carcinoma (check clinical history, strongly keratin positive), fragmented lymphoid follicles in biopsies or curettings, intravascular leiomyomatosis

References: Mod Path 2000;13:328, Mod Path 2001;14:465

High grade

Some classify as high grade based on higher mitotic counts, but this appears to have no prognostic significance

Undifferentiated

Much less common than low grade endometrial stromal sarcoma

5 year survival of 50% with recurrences in pelvis and metastases to lung

Gross: diffusely involve most of endometrial surface; frequently extends beyond uterus, vascular invasion not as evident as low grade stromal sarcomas

Micro: 10 or more mitotic figures /10 HPF, often abnormal; angiolymphatic invasion common; infiltrative margins, usually extensive myometrial invasion; marked nuclear atypia, enlargement and pleomorphism; tumor cells do NOT resemble endometrial stroma,. no arborizing vasculature; resembles stromal component of MMMT

Inflammatory pseudotumor

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Lymphocytes, plasma cells and neutrophils forming a mass

Leiomyoma

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Aka fibroid

Present in 25% of women during reproductive years

More common in blacks than whites; usually multiple in blacks

In 77% at autopsy; 84% of tumors are multicentric

Clinically apparent lesions are more common in nulliparous, postmenopausal women

Rarely associated with polycythemia, which regresses when tumor is excised

May interfere with pregnancy or block ureters if large

Estrogen responsive; may regress after menopause or castration, enlarge during pregnancy

Difficult to diagnose from D & C, since resembles superficial myometrium

Treatment: myomectomy, leuprolide acetate depot, a GNRH analog that shrinks the tumor

Gross: sharply circumscribed, round, firm, gray-white, “raw silk”, whorled cut surface; often shells out, is bulging and trabeculated; usually within myometrium; may be submucosal or subserosal; may be multiple; Sampling: sample myxoid areas extensively to rule out myxoid leiomyosarcoma; sample all leiomyomas that lack the classic gross appearance of leiomyomas and 3 largest tumors

Gross images: image1, image2

Micro: whorled (fascicular) pattern of smooth muscle bundles separated by well vascularized connective tissue; smooth muscle cells are elongated with eosinophilic or occasional fibrillar cytoplasm and distinct cell membranes; may develop areas of degeneration if large, including hyaline or mucoid change, calcification, cystic change or fatty metamorphosis; variable lymphocytes and mast cells; usually non-infiltrative; thick walled arteries throughout; cleft-like spaces; may have extensive hyaline necrosis if protrude into endometrial cavity; usually less than 5 mitotic figures per 10 high power fields in mitotically most active area; no significant atypia; rarely has focal skeletal muscle differentiation (Hum Path 1999;30:356); tubules or glands are rare

Post-lupron treatment: leiomyomas initially show edema and necrosis, then hyalinization and mild lymphocytic infiltrate

Micro images: image #1; #2

contributed by Dr. Mowafak Hamodat, Eastern Health of Newfoundland and Labrador, St. John’s, Canada - embolized leiomyoma #1; #2; #3; #4; #5; #6; #7

Positive stains: desmin, h-caldesmon, occasional focal CD10

Negative stains: keratin (usually), EMA (usually)

Molecular: changes in 6p, del(7q), +12, t(12;14)

EM: smooth muscle cells with varying degrees of differentiation

DD: endometrial stromal sarcoma with smooth muscle metaplasia, leiomyosarcoma

Variants

Apoplectic leiomyoma

Related to red degeneration, also associated with birth control pills

Micro: stellate zones of recent hemorrhage within nodules of hypercellular smooth muscle, rare mitotic figures; no coagulative tumor necrosis

Benign leiomyoblastoma

Aka clear cell or epithelioid leiomyoma

Micro: round or polygonal cells, with epithelioid, clear cell or plexiform patterns, well defined cell membranes; may have transition to typical smooth muscle; minimal mitotic activity

Positive stains: desmin

EM: smooth muscle origin

Benign metastasizing leiomyoma

Leiomyoma extends into vessels, migrates to lung or lymph nodes

Original tumor must clearly be benign and sampled adequately

Must rule out primary smooth muscle tumor of GI tract, retroperitoneum or other areas

“Metastasis” may respond to hormonal treatment; may occur years after uterine resection

Case report of extensively sampled leiomyoma with subsequent lung low-grade leiomyosarcoma at Archives 1999;123:960

Symptoms: none, bleeding, frequency, pain, infertility

Associated with spontaneous abortion, postpartum hemorrhage

Micro images: leiomyoma and later low-grade leiomyosarcoma of lung

Positive stains: estrogen receptor

DD: low grade leiomyosarcoma

Cellular leiomyoma

Increased cellularity, no atypia, no mitotic figures

Usually has large, thick walled blood vessels

Same behavior as classic leiomyoma

Micro images: H&E and CD10

DD: leiomyosarcoma, endometrial stromal sarcoma

References: Mod Path 2001;14:465, AJSP 2001;25:253

Cotyledonoid leiomyoma

Rare benign tumor characterized by extrauterine bulbous growth continuous with a dissecting myometrial component; resembles placenta

Median 40 years, range 23 to 65 years

Alarming gross appearance, case report at Archives 2002;126:210

Gross: multinodular, fungating tumor adherent to adjacent structures; red-brown with multiple bulbous processes protruding over uterine surface; may dissect myometrium; not soft like malignancies

Gross images: image1 (figures 1A-1C)

Micro: fascicles and nodules of bland smooth muscle cells, prominent hydropic degeneration; no necrosis, no mitotic figures, no atypia

Micro images: image1 (figure 2), image2

Dissecting leiomyomas

Benign smooth muscle tumor associated with dissection of myometrium by fascicles of neoplastic smooth muscle; includes cases of intravenous leiomyomatosis, AJSP 1999;23:1032

DD: leiomyosarcoma, low grade endometrial stromal sarcoma

Disseminated peritoneal leiomyomatosis

Rare, benign lesion of multiple peritoneal nodules < 2 cm that cover peritoneal surface

Nodules composed of fibroblasts and bland smooth muscle cells; decidual cells common

Usually young women, with pregnancy (discovered at caesarean section) or other altered hormonal conditions

Nodules regress spontaneously

Clinical resembles metastases

Should rule out GI or retroperitoneal masses (GIST, leiomyosarcoma) before making this diagnosis

Epithelioid leiomyoma

Nonspindled rounded cells resembling epithelial cells with clear or eosinophilic cytoplasm

Minimal atypia, < 5 mitotic figures/10 HPF, no tumor cell necrosis

Often has areas of classic leiomyoma, so get more sections

Positive stains: keratin, desmin, smooth muscle actin

DD: carcinoma

Hydropic degeneration

Edema fluid, collagen deposition

Simulates leiomyomatosis or myxoid leiomyosarcoma

Intravascular / intravenous leiomyomatosis

Rare, mature smooth muscle grows inside lumen of uterine and pelvic veins or within the chambers of the heart (usually right heart)

May arise from typical leiomyomas

Clinically resembles low grade endometrial stromal sarcoma (minimal atypia, no coagulative tumor cell necrosis, usually 0-5 MF/10 HPF), except that gross involvement of veins is more prominent

Excellent long term prognosis; rare distant metastases, may recur

Gross images: image1

Micro: elongated spindle cells vs. round/oval endometrial stromal cells; rare mitotic figures; hybrids with endometrial stromal sarcoma exist occasionally

Positive stains: ER, PR

Molecular: Breakpoint at 12q, similar to t(12;14) in uterine leiomyomas, Mod Path 2002;;15:351

Leiomyomatosis

Aka infiltrating leiomyoma

Rare, diffuse, multinodular involvement of myometrium by numerous leiomyomas that are otherwise classic

DD: primary myometrial hypertrophy (uterine weight 120g without any myometrial lesion), leiomyosarcoma

Lipoleiomyoma

Combination of leiomyoma and mature adipocytes

Also includes neoplasms composed entirely of mature adipocytes

May be due to adipose metaplasia in leiomyomas

No mitotic activity

Leiomyoma with lymphoid infiltration

May simulate lymphoma due to intense lymphocytic infiltrate

Mitotically active leiomyomas

Usually young patients

Also submucous leiomyomas with extensive necrosis that protrude into endometrial cavity

Grossly and microscopically typical for leiomyomas, but 5-15 mitoses per 10 HPF

NO moderate/severe nuclear atypia, NO abnormal mitotic figures, NO tumor cell necrosis

Benign behavior

Myxoid leiomyomas

Islands of smooth muscle in edematous connective tissue containing large vessels

Not infiltrative, small and bland nuclei (i.e. no atypia), no mitotic activity

Benign

DD: myxoid leiomyosarcoma

Myoma nascens

Fills endometrial cavity, emerges from cervical canal as polypoid growths

Has ulcerated surface

May grossly appear malignant

Pallisading / neurilemoma-like leiomyoma

Resembles schwannoma

More common in GI tract than uterus

Parasitic leiomyoma

Tumor is separate from uterus, acquires vascular connections from omentum, pelvic wall, other sites

Make diagnosis with great caution, because smooth muscleneoplasms arising in retroperitoneum and GI tract with recurring or metastatic potential are notoriousfor being bland and having no/few mitoticfigures

Red degeneration

3% of leiomyomas

Presents with abdominal pain, fever, vomiting

Associated with pregnancy, birth control pills

Gross images: image1

Micro: extensive coagulative necrosis

Retroperitoneal

Usually women; resemble uterine leiomyomas, although distinct from uterus

May occur years after hysterectomy or synchronous with uterine leiomyomas

May arise from hormonally sensitive smooth muscle; probably soft tissue primaries and not parasitic leiomyomas

Minimal mitotic activity

Benign behavior

Usually ER+, PR+

Reference: AJSP 2001;25:1134

Symplastic / Atypical / Bizarre

Contains bizarre multinucleated tumor cells (moderate/severe atypia) but NO mitotic figures (or less than 10 mitotic figures/10 HPF) and NO tumor cell necrosis

Associated with progestin use

Micro images: image1

References: Mod Path 2000;13:328

Leiomyosarcoma

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Rare, probably not derived from leiomyomas

Peaks at ages 40-69 years, mean 54 years

If spread beyond uterus, few survive long term

Tend to recur, 50% metastasize to lung, bone, brain, other; lymph node involvement unusual

5 year survival 40%; anaplastic only 10%; minimal survival if extend beyond uterus;

Gross: bulky, fleshy tumor invading into myometrial wall or polypoid tumor projecting into lumen, hemorrhagic or necrotic; grossly appear invasive / infiltrative; usually 5 cm or more but NOT multiple

Gross images: image1, with endometrioid carcinoma

Micro: hypercellular tumors composed of spindle cells resembling smooth muscle cells with moderate to severe pleomorphism; 10+ mitotic figures per 10 high power fields (HPF) in most mitotically active area with abundant abnormal mitotic figures; don’t interpret small pyknotic nuclei from smooth muscle cells as mitoses; use only definitive mitotic figures; coagulative tumor cell necrosis; rarely contains osteoclast-like giant cells

Micro images: image1, image2, image3, with endometrioid carcinoma#1, #2

Contributed by Dr. Jamie Shutter, George Washington University: low power; medium power; high power; tripolar mitotic figure

Micro images: H&E and CD10 (figures 1C & 1D)

Positive stains: actin, myosin, desmin, h-caldesmon (variable, AJSP 2001;25:253), keratin (epithelioid tumors), p53, focal CD10

Negative stains: CD44v3 (Hum Path 2001;32:1190)

DD: endometrial stromal sarcoma with smooth muscle metaplasia

Reference: AJSP 2001;25:455, Mod Path 2001;14:465

Myxoid leiomyosarcomas

Rare, but important variant of uterus and broad ligament

Recur and metastasize regardless of mitotic count

Gross: gelatinous, well-circumscribed

Micro: invasive and infiltrative, highly myxomatous; tumor cells have moderate to marked atypia but variable tumor cell necrosis

Positive stains: high MIB-1 index although may have low mitotic count

Malignant leiomyoblastomas

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Compared to benign tumors, are mitotically active, larger and infiltrative

No hyalinization or necrosis present

Malignant Mixed Mullerian Tumor (MMMT)

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Aka carcinosarcoma

Biphasic tumor with malignant epithelial and stromal components, usually high grade

Rare, almost always in postmenopausal women

Present with bleeding and uterine enlargement

30% with heterologous MMMT and 13% with homologous MMMT have history of radiation therapy (median 16 years previous), patients tend to be young, tumor spreads quicker to pelvis

Also associated with chronic estrogen stimulation

Peritoneal metastases: may have scanty stromal component, psammoma bodies, form papillary structures resembling ovarian serous carcinoma metastases

Stromal and glandular cells may have same cell of origin

Heterologous differentiation has no prognostic importance

Highly aggressive: 5 year survival - 25-35%

Prognosis: based on stage, not presence of heterologous elements; “hopeless” if extends to uterine serosa; cure possible only if tumor restricted to inner half of myometrium at surgery

Treatment: TAHBSO, pelvic lymphadenectomy; recurs in lung and abdomen

Gross: fleshy, bulky, polypoid, may be friable; may protrude through cervical os; hemorrhage, necrosis common; usually extensive myoinvasion

Micro: biphasic tumor with carcinomatous and sarcoma-like elements; most common epithelial component is glandular (endometrioid, clear cell, serous), usually poorly differentiated; most common sarcomatous components are homologous (endometrial stromal sarcoma, leiomyosarcoma) or heterologous (muscle, cartilage, osteoid, fat); angiolymphatic invasion common

Positive stains: keratin (both components), p53 (usually positive or negative in both components), EMA (often both components)

EM: hybrid epithelial/stromal cells

DD: teratomas (younger ages, skin appendages, glia, thyroid, MMMT rarely contain neuroectodermal elements), botryoid rhabdomyosarcoma (children/teens, cervical or vaginal primaries, no carcinomatous

component), metastatic ovarian serous cystadenocarcinoma (papillae and psammoma bodies present), anaplastic carcinoma (keratin may not differentiate)

Metastases to uterus

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Primaries usually breast, GI, kidney, melanoma

May involve myometrium first

May first appear in endometrial curettings, particularly lobular carcinoma of breast

Metastatic breast carcinoma to tamoxifen-associated polyps has been reported, usually involving lobular carcinoma (Ann Diagn Pathol 2005;9:166, Mod Path 2003;16:395, Gynecol Oncol 2005;97:946, Obstet Gynecol 2003;102:1149, Acta Obstet Gynecol Scand 1993;72:585), so careful histologic evaluation of the endometrium is important

Case reports: Case of the Week #125 (breast metastases to tamoxifen induced polyp)

Micro images: breast lobular carcinoma to tamoxifen induced polyp - #1; #2; #3; ER, PR, GCDFP-15

Mixed mullerian neoplasms-general

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Biphasic epithelial and mesenchymal proliferations

Benign (both components): adenofibroma, adenomyoma, atypical polypoid adenomyoma

Malignant (one component): adenosarcoma

Malignant (both components): MMMT (carcinosarcoma)

Plexiform tumor/tumorlet

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Closely related to uterine tumors resembling ovarian sex-cord tumors

Cells with crumbled nuclei, indistinct cytoplasm arranged in cords or rows

Usually at endomyometrial junction

Appears to have smooth muscle origin by EM

Usually 1 cm or less, but may be large or multiple

Benign

Positive stains: keratin, smooth muscle markers

Postoperative spindle cell tumors

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Similar to vaginal tumors

Sarcoma

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Considered to be variants of MMMT but without an epithelial component, and lacking endometrial stromal features

Must sample thoroughly to rule out MMMT

Poor prognosis

Gross: necrotic fleshy tumor fills uterine cavity

Micro: marked nuclear anaplasia, variable pleomorphism, 20+ mitotic figures/10 HPF; may be undifferentiated; entrapped glands usually small, inconspicuous, not surrounded by condensed stroma as in adenosarcoma

Negative stains: keratin

Smooth muscle tumors of unknown malignant potential

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Aka STUMP

Bell criteria for problematic smooth muscle uterine tumors:

Note: criteria do not apply to extrauterine tumors

Note: must rigidly apply following criteria for atypia, mitotic figures, coagulative tumor cell necrosis

Mod Path 2000;13:328

Atypia:

Classify as none/mild or moderate/severe, based on nuclear pleomorphism, nuclear size, nuclearmembrane irregularities, chromatin density, nucleoli size/prominence

No/mild atypia: uniform nuclei thatmay be enlarged, but with smooth nuclear contours, evenlydistributed chromatin; minimal variation in nuclear size and shape, small nucleoli

Moderate / severe should be detectable at low power

Moderate atypia: large, plump, irregular nuclei with coarse chromatin; if 1-2 enlarged abnormalmitotic figures, call moderate atypia

Severe atypia: obvious pleomorphism, numerous cells with enlargedbizarre nuclei with dense chromatin; frequent giant cells, often multinucleated, enlarged and sometimes atypicalnucleoli

Micro images: marked atypia, moderate atypia

Mitotic figures criteria:

1. hairy extensions of chromatin must be present, extending from a central clot-like dense mass of chromosomes; hairy extensions from an empty center favor a nonmitosis

Count 4 sets of 10 fields in area of highest mitotic activity, and use the highest count

2. no nuclear membrane

3. must rule out lymphocytes, mast cells, stripped nuclei, degenerated cells, precipitated hematoxylin

4. count only definite mitotic figures

Necrosis:
Presence or absence is powerful predictor of outcome forpatients with uterine smooth muscle tumors

Must distinguish coagulativetumor cell necrosis and hyalinizing necrosis

Coagulative tumorcell necrosis: abrupt transition between necroticcells and preserved cells; ghost outlines of nuclei of necrotic cells are often seen in necrotic area, but inflammatory cells are uncommon; common in clinically malignant smoothmuscle tumors - DON’T IGNORE

Micro image: coagulative tumor cell necrosis

Hyalinizingnecrosis: zone of hyalinized collagen between dead cells and preserved cells, reminiscentof infarcted region organized by granulation tissue; eosinophilic collagen matrix common; ifdead nuclei present, nuclei are uniform and chromatin is often faint, compared to nuclear hyperchromasia and pleomorphism in tumor cell necrosis; common in leiomyomas

Micro image: hyalinizing necrosis

Necrosis secondary to ulceration insubmucous leiomyomas features acute inflammatory cells anda peripheral reparative process, whereas ghost outlines of nucleiare usually inconspicuous or absent

Leiomyomas: no coagulative tumor cell necrosis, no significantatypia, but any degree of mitotic activity; can call “with significant mitotic activity” if 5+ mitotic figures/10 HPF, but have benign behavior

Atypical leiomyoma: moderate/severe atypia, < 10 mitotic figures/10 HPF, no coagulative tumor cell necrosis

Leiomyosarcoma: usually hemorrhagic and soft, marked pleomorphism, 15-30 mitotic figures/10 HPF with abundant abnormal mitotic figures; coagulative tumor cell necrosis

STUMP: minimally atypical smooth muscleneoplasms with a low mitotic index but with uncertaintyabout the histologic type (standard vs. myxoid orstandard vs. epithelioid); combination of standardsmooth muscle differentiation, marked diffuse severe atypia,low mitotic index and uncertainty about whether coagulativetumor cell necrosis is present; moderate to severe atypiaplus uncertain mitotic index because possible mitoticfigures may be degenerating nuclei mimicking mitotic figures.

Algorithm: No/mild atypia, no tumor cell necrosis => leiomyoma

Moderate/severe atypia, no tumor cell necrosis, => atypical leiomyoma if <10 mitotic figures/HPF or leiomyosarcoma if 10+ MF/10 HPF

Moderate/severe atypia and tumor cell necrosis => leiomyosarcoma (mitotic figures don’t matter)

Stromomyoma

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Aka combined smooth muscle-stromal tumor

Tumor mass containing up to 1/3 smooth muscle component

Benign

Uterine tumors resembling ovarian sex cord tumors

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Resemble plexiform tumors

Most are benign, with uniform cells, no infiltration, low mitotic index,

Malignant variants behave similar to low grade stromal sarcoma (may recur or metastasize)

Micro: more cellular than endometrial stromal nodules, no prominent arterioles, mature smooth muscle often present; sex cord-like elements are cords, tubules or sheets resembling epithelial cells ,but with scanty cytoplasm, indistinct cell margins and round nuclei; may have abundant eosinophilic or clear cytoplasm

Positive stains: cytokeratin, desmin, inhibin (sex cord elements), CD10 (background stromal cells), CD99 (focal)

Negative stains: CD10 (sex cord-like elements)

Miscellaneous tumors

Leukemia / lymphoma

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Rare to be involved by non-Hodgkin’s lymphoma; rarer still to arise as primary tumor in uterus

More common (7%) to be involved by CLL

Large cell lymphoma and granulocytic sarcoma resemble endometrial stromal sarcoma

Both low stage and high stage have similar mean age (55 vs. 58 years), present with abnormal uterine bleeding, usually diffuse large B cell subtype

Low stage tumors: usually involve cervix, 5 year survival 83%

High stage tumors: usually involve uterine corpus, 5 year survival 29%

Reference: Mod Path 2000;13:19

Other

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Endosalpingiosis

Rarely presents as masses or cysts in uterine serosa, AJSP 1999;23:166

Micro: benign glands and cysts resembling tubal epithelium; may involve cervix, lower uterine segment, corpus

DD: minimal deviation adenocarcinoma, florid tubal metaplasia

Epithelioid trophoblastic tumor

Rare (<50 cases reported), newly designated type of gestational trophoblastic tumor, usually in women ages 15-48 years

Case report in uterus of a 66-year-old woman with hydatidiform mole 17 years previous, AJSP 2000;24:1558

Present with abnormal vaginal bleeding or lung metastases; usually elevated beta hCG, but less than levels of choriocarcinoma

Usually associated with prior hydatidiform mole or choriocarcinoma, up to 18 years prior

Metastases in 25%, death in 10%; similar behavior as placental site trophoblastic tumor

Gross: solid/cystic tumor within myometrium

Micro: circumscribed tumor with pushing border; resembles carcinoma due to cords, nests and sheets containing hyaline material and necrotic debris; mononuclear and epithelioid tumor cells resemble intermediate trophoblast of placenta; have distinct cell borders, eosinophilic cytoplasm, occasional small nucleoli; often peritumoral lymphocytic infiltrate or dystrophic calcification (30%); also occasional syncytiotrophoblastic cells; may have increased mitotic activity

Positive stains: CK7, CK18, AE1/AE3, CAM 5.2; type IV collagen, fibronectin; syncytiotrophoblasts - beta hCG, hPL, inhibin-alpha

DD: choriocarcinoma (cytotrophoblast and syncytiotrophoblast in plexiform pattern with marked central hemorrhagic necrosis; high mitotic activity, diffusely positive for beta hCG, occasional hPL+ cells), placental site trophoblastic tumor (tumor cells weave between muscle fibers and invade blood vessels, diffusely positive for hPL, occasional beta hCG+), squamous cell carcinoma (no dual cell population, keratin pearls, intercellular bridges, negative for beta hCG, hPL, inhibin, CK8)

Malignant extrarenal rhabdoid tumor

Case report at Hum Path 2001;32:884

Highly aggressive tumors in adults; rapidly fatal

Urothelial carcinoma

Rare, <20 cases

Case report of 46 year old women with urothelial carcinoma and benign ovarian Brenner tumor at Hum Pathol;32:230

Wilm’s tumor

Rare tumor, usually in ages 0-5

Case report of uterine Wilm’s tumor in 42 year old woman at Archives 2001;125:1081

Gross/micro image

Features to report for carcinoma

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Editorial note

Tumor size and location

Histologic type

Histologic grade

Depth of invasion (uterine wall thickness, maximum depth of myoinvasion, measured from endomyometrial junction)

Angiolymphatic invasion

Preserve of cervical involvement

Features of uninvolved uterus (hyperplasia, metaplasia)

Margins

Nodal involvement (# positive nodes, # total lymph nodes)

Grossing hysterectomy specimens

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No gross pathology

Anterior and posterior cervix

Anterior and posterior endomyometrium

Each ovary (cortex, hilar region) and fallopian tube

Suspected tumor

Above plus:

Ink serosa and take full thickness endomyometrium and serosa to assess depth of invasion

1 section per 1 cm of tumor, minimum 3 sections

All grossly different appearing regions of tumor

High endocervical canal or lower isthmus

Ink and obtain margins of resection, including vaginal mucosa

Staging - uterine carcinoma

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Classification applies to carcinoma and malignant mixed mullerian tumors only; excludes sarcomas

Use clinical staging only if the surgeon feels systemic regional lymph node sampling is not indicated or if the patient was treated with primary radiation therapy (record as cT, cN, cM). Otherwise use surgical / pathologic staging, assigned at the time of definitive surgical treatment or prior to radiation therapy or chemotherapy.

Stage should not be changed due to disease progression or recurrence or based on response to initial radiation therapy or chemotherapy that precedes primary tumor resection

Primary tumor (T) and FIGO stage

TX - primary tumor cannot be assessed

T0 - no evidence of primary tumor

Tis (FIGO 0) - carcinoma in situ

T1 (FIGO I) - tumor confined to corpus uteri

T1a (FIGO IA) - tumor limited to endometrium

T1b (FIGO IB) - tumor invades less than 1/2 of the myometrium

T1c (FIGO IC) - tumor invades 1/2 or more of the myometrium

T2 (FIGO II) - tumor invades cervix but does not extend beyond uterus

T2a (FIGO IIA) - tumor limited to the glandular epithelium of the endocervix. There is no evidence of connective tissue stromal invasion

T2b (FIGO IIB) - invasion of the stromal connective tissue of the cervix

T3 (FIGO III) - local or regional spread within pelvis as defined below

T3a (FIGO IIIA) - tumor involves serosa or adnexa (direct extension or metastasis) or cancer cells in ascites or peritoneal washings

T3b (FIGO IIIB) - vaginal involvement (direct extension or metastasis)

T4 (FIGO IVA) - tumor extends beyond pelvis to invades bladder mucosa or bowel mucosa (bullous edema is not sufficient to classify a tumor as T4)

Regional lymph nodes (N)

NX - regional lymph nodes cannot be assessed

N0 - no regional lymph node metastasis

N1 (FIGO IIIC) - regional lymph node metastasis to pelvic or para-aortic nodes

Distant Metastasis (M)

MX - distant metastasis cannot be assessed

M0 - no distant metastasis

M1 (FIGO IVB) - distant metastasis (includes metastasis to abdominal lymph nodes other than para-aortic, or inguinal nodes; excludes metastasis to vagina, pelvic serosa or adnexal)

Stage grouping

Stage 0: T1s N0 M0

Stage 1: T1 N0 M0

Stage 1A: T1a N0 M0

Stage 1B: T1b N0 M0

Stage 1C: T1c N0 M0

Stage 2: T2 N0 M0

Stage 2A: T2a N0 M0

Stage 2B: T2b N0 M0

Stage 3: T3 N0 M0

Stage 3A: T3a N0 M0

Stage 3B: T3b N0 M0

Stage 3C: T1-T3 N1 M0

Stage 4A: T4 any N M0

Stage 4B: M1

Histopathology - Degree of differentiation

G1: 5% or less of a non-squamous or non-morular solid growth pattern

G2: 6%-50% of a non-squamous or non-morular solid growth pattern

G3: More than 50% of a non-squamous or non-morular solid growth pattern

Notes on pathologic grading:

1. Notable nuclear atypia, inappropriate for the architectural grade, raises the grade to 3

2. Serous, clear cell and mixed mesodermal tumors are high risk and considered grade 3

3. Adenocarcinomas with benign squamous elements (squamous metaplasia) are graded according to the nuclear grade of the glandular component

End of uterus chapter

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Table of Contents

Corpus is upper 2/3 of uterus above level of internal cervical os

Anatomical divisions of uterus

Bifid uterus

Proliferative phase

Secretory/luteal phase

Dyssynchronous endometrium

Arias-Stella reaction

Decidua

Gestational hyperplasia

Placental site nodules

Prolonged use: disappearance of abortive glandular secretion, atrophy of glands and stroma

Estrogens alone for hormone replacement therapy

Combined hormone replacement therapy

Progestational agents

Acute endometritis

Chlamydia

Chronic endometritis

CMV

Giant cell arteritis

Granulomas

Pyometra

Tuberculosis

Xanthomatous endometritis

Eosinophilic (oxyphilic) metaplasia

Mucinous metaplasia

Squamous metaplasia

Tubal (ciliated cell) metaplasia

Disordered proliferative endometrium

Simple hyperplasia

Complex hyperplasia

Atypical secretory hyperplasia

Pattern 2: biphasic proliferations of glands and abundant / possibly neoplastic stroma

Pattern 3: predominantly monophasic spindle-cell proliferations

Pattern 4: Sheet-like proliferations of large, round, undifferentiated cells

Pattern 5: Extensive necrosis, inflammation, disintegration

Pattern 6: Scanty samples that suggest inadequate sample

Atrophy

DD: basalis endometrium, lower uterine segment, endometrial lining of submucous myoma, polyp, progesterone effect

Dyssynchronous endometrium

Shedding

Weakly proliferative endometrium

APA of low malignant potential

Cytology: only 50% sensitive for adenocarcinoma, 60% with cervical scrapings, 75% with vaginal pool material; normal endometrial cells in a cervical cytologic specimen suggests hyperplasia or carcinoma

Well differentiated (FIGO grade 1)

Minimally invasive serous carcinoma

Rare, associated with pyometra or mucinous glands of heterotopic cervical origin

Adenofibroma

Adenomatoid tumor

Adenosarcoma

Low grade

Undifferentiated

Benign metastasizing leiomyoma

Cellular leiomyoma

Disseminated peritoneal leiomyomatosis

Epithelioid leiomyoma

Hydropic degeneration

Intravascular / intravenous leiomyomatosis

Leiomyoma with lymphoid infiltration

Mitotically active leiomyomas

Myxoid leiomyomas

Myoma nascens

Pallisading / neurilemoma-like leiomyoma

Parasitic leiomyoma

Red degeneration

Retroperitoneal

Symplastic / Atypical / Bizarre

Myxoid leiomyosarcomas

Other

Malignant extrarenal rhabdoid tumor

Urothelial carcinoma

Wilm’s tumor

Suspected tumor

Prolonged use: disappearanceof abortive glandular secretion, atrophy of glands and stroma