
Uterus (excludes Cervix)
Last revised 14 April 2009
Last major update January 2003
Copyright © 2003-2009, PathologyOutlines.com, Inc.
Bold and underlined topics are hypertext links
Normal, persistent mullerian duct syndrome, endometrial dating, luteal phase defect, pregnancy related changes, endometrial biopsy, exogenous hormones, endometritis, endometrial metaplasia, adenomyosis, endometriosis, dysfunctional uterine bleeding, endometrial hyperplasia, EIN, Sternberg’s pattern approach, miscellaneous
Epithelial tumors: adenoacanthoma, adenomyoma, adenosquamous carcinoma, atypical polypoid adenomyoma, ciliated carcinoma, clear cell carcinoma, endometrial carcinoma-general, endometrial polyp, endometrioid carcinoma, giant cell carcinoma, glassy cell carcinoma, melanoma, minimal deviation carcinoma, mixed carcinoma, mucinous carcinoma, oxyphilic carcinoma, PEComa, secretory carcinoma, serous carcinoma, small cell carcinoma, squamous cell carcinoma, villoglandular carcinoma
Stromal tumors: adenofibroma, adenomatoid tumor, adenosarcoma, endometrial stromal nodule, endometrial stromal tumors-general, endometrial stromal sarcoma, inflammatory pseudotumor, leiomyoma, leiomyosarcoma, malignant leiomyoblastoma, malignant mixed mullerian tumor, metastases, mixed mullerian neoplasms-general, plexiform tumor, post-operative spindle cell tumors, sarcoma, smooth muscle tumors of uncertain malignant potential (STUMP), stromomyoma, uterine tumors resembling ovarian sex cord tumors
Miscellaneous tumors: leukemia/lymphoma, other
Features to report, grossing, staging
AJCC Cancer Staging Manual (6th Ed)
American Journal of Surgical Pathology (AJSP), Jan 1999 to Jan 2003
Archives of Pathology and Laboratory Medicine (Archives), Jan 1999 to Jan 2003
Human Pathology (Hum Path), Jan 1999 to Dec 2002
Modern Pathology (Mod Path), Jan 1999 to Jan 2003
Rosai, J: Ackerman’s Surgical Pathology (8th Ed); Mosby-Year Book, Inc., 1996
Sternberg, S: Diagnostic Surgical Pathology (3rd Ed); Lippincott Williams & Wilkins, 1999
WebPath: The Internet Pathology Laboratory for Medical Education
Please refer to these primary references for more detailed discussions and photographs
Uterus is hollow, pear shaped, 40-80 g, 7-8 cm
Peritoneal reflection is lower posteriorly than anteriorly because bladder is anterior; this is used to orient uterus
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 composed of tubular glands, dense fibroblastic stroma, thin blood vessels
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)
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
Gross images: image1
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
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
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
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
Glands and stroma out of synchronization by at least 2 to 3 days
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)
Similar changes seen with intrauterine pregnancy, ectopic pregnancy, progesterone therapy
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
Bland nuclei, minimal atypia, abundant cytoplasm
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
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
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
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
Micro images: image1
Ovulation Induction Therapy
Treatment for ovulation failure (irregular or infrequent ovulation
or chronic anovulation due to deficient gonadotropins or 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
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
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
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 in glands, decidual stroma. The endometrial tissue 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 glandular hyperplasia (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
Endocervix normally forms barrier to ascending infection
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
Associated with severe acute/chronic inflammation
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
May be granulomatous
Coccidiomycosis
May be secondary to resolved primary lung infection
May involve uterus as isolated finding or part of generalized giant cell arteritis
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
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)
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
Associated with cervical stenosis and pyometra, usually in elderly
Micro: contains sheets of foamy cells
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
Estrogen-induced, resembles atypical hyperplasia except there is no atypia
Intestinal metaplasia
Rare
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
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
Reference: Mod Path 2000;13:309
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
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
DD: endometrial stromal sarcoma (no glandular tissue, invades myometrium in tongues, no muscular hypertrophy, unusual to contain diffuse small regular glands )
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
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
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
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
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
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
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
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 gland shapes, and variable atypia; but has plasma cells, stromal spindling and edema, surface neutrophils)
Reference: Mod Path 2000;13:309
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 immediate hysterectomy
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 eosinophilic necrotic 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
Resembles day 17 endometrium but with atypia
Treatment: conservative
DD: Arias Stella
Endometrial intraepithelial neoplasia (EIN)
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
(c) the premalignant area is at least 1 mm
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
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)
Includes endometrial polyps, adenofibroma, atypical polypoid adenomyoma, MMMT, adenosarcoma, sarcoma, endometrial stromal neoplasms, adenomatoid tumor
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
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
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
May be due to atrophy or obstructing lesion that shields endometrium from sampling
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
Discordance between glands and stroma; usually both in secretory phase; also proliferative endometrium and secretory stroma
Microglandular hyperplasia
Clusters of small glands without atypia
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
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
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
Aka adenomyomatous polyp
Gross: hard consistency, gray color
Micro: endometrial polyp with smooth muscle fibers not connected to vessel walls
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 growth without gland formation or pallisading, (b) sharp cell margins, (c) eosinophilic and thick or glassy cytoplasm, and (d) a decreased nuclear:cytoplasmic ratio compared with foci elsewhere in the same tumor)
Micro images: image1, image2, CD44
Positive stains : CD44 in squamous component (Archives 2000;124:212)
Reference: Mod Path 2000;13:309
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
Glands have features of well differentiated adenocarcinoma
May extend into superficial myometrium
Rare, subtype of well-differentiated endometrioid adenocarcinoma
Good prognosis
Occasionally have abundant solid areas (FIGO grade 2)
Micro: neoplastic glands composed predominantly or exclusively of ciliated cells with stromal invasion; minimal atypia
DD: ciliated cell metaplasia
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
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
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
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 adjacent glands; 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
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
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
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
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
Rare, high grade with bizarre, pleomorphic, multinucleated giant cells
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
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
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
At least 10% of a second type
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)
Large eosinophilic cells
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
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
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
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
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
DD: Cervical squamous cell carcinoma
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
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)
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
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
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
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
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 or tongues of neoplastic stromal cells between smooth muscle bundles of the surrounding normal myometrium; may have angiolymphatic invasion (clumps of tumor cells present in 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
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
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
Lymphocytes, plasma cells and neutrophils forming a mass
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
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
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
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
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
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
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
Edema fluid, collagen deposition
Simulates leiomyomatosis or myxoid leiomyosarcoma
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
May simulate lymphoma due to intense lymphocytic infiltrate
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
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
Fills endometrial cavity, emerges from cervical canal as polypoid growths
Has ulcerated surface
May grossly appear malignant
Resembles schwannoma
More common in GI tract than uterus
Tumor is separate from uterus, acquires vascular connections from omentum, pelvic wall, other sites
Make diagnosis with great caution, because smooth muscle neoplasms arising in retroperitoneum and GI tract with recurring or metastatic potential are notorious for being bland and having no/few mitotic figures
3% of leiomyomas
Presents with abdominal pain, fever, vomiting
Associated with pregnancy, birth control pills
Gross images: image1
Micro: extensive coagulative necrosis
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
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
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
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
Compared to benign tumors, are mitotically active, larger and infiltrative
No hyalinization or necrosis present
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)
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
Biphasic epithelial and mesenchymal proliferations
Benign (both components): adenofibroma, adenomyoma, atypical polypoid adenomyoma
Malignant (one component): adenosarcoma
Malignant (both components): MMMT (carcinosarcoma)
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
Similar to vaginal tumors
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
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
Atypia:
Classify as none/mild or moderate/severe, based on nuclear pleomorphism, nuclear size, nuclear membrane irregularities, chromatin density, nucleoli size/prominence
No/mild atypia: uniform nuclei that may be enlarged, but with smooth nuclear contours, evenly distributed 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 abnormal mitotic figures, call moderate atypia
Severe atypia: obvious pleomorphism, numerous cells with enlarged bizarre nuclei with dense chromatin; frequent giant cells, often multinucleated, enlarged and sometimes atypical nucleoli
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 for patients
with uterine smooth muscle tumors
Must distinguish coagulative tumor cell necrosis and hyalinizing necrosis
Coagulative tumor cell necrosis: abrupt transition between necrotic cells 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 smooth muscle tumors - DON’T IGNORE
Micro image: coagulative tumor cell necrosis
Hyalinizing necrosis: zone of hyalinized collagen between dead cells and preserved cells, reminiscent of infarcted region organized by granulation tissue; eosinophilic collagen matrix common; if dead 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 in submucous leiomyomas features acute inflammatory cells and a peripheral reparative process, whereas ghost outlines of nuclei are usually inconspicuous or absent
Leiomyomas: no coagulative tumor cell necrosis, no significant atypia, 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 muscle neoplasms with a low mitotic index but with uncertainty about the histologic type (standard vs. myxoid or standard vs. epithelioid); combination of standard smooth muscle differentiation, marked diffuse severe atypia, low mitotic index and uncertainty about whether coagulative tumor cell necrosis is present; moderate to severe atypia plus uncertain mitotic index because possible mitotic figures 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)
Aka combined smooth muscle-stromal tumor
Tumor mass containing up to 1/3 smooth muscle component
Benign
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
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
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)
Case report at Hum Path 2001;32:884
Highly aggressive tumors in adults; rapidly fatal
Rare, <20 cases
Case report of 46 year old women with urothelial carcinoma and benign ovarian Brenner tumor at Hum Pathol;32:230
Rare tumor, usually in ages 0-5
Case report of uterine Wilm’s tumor in 42 year old woman at Archives 2001;125:1081
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)
No gross pathology
Anterior and posterior cervix
Anterior and posterior endomyometrium
Each ovary (cortex, hilar region) and fallopian tube
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
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