Uterus (excludes Cervix)
Last revised 26 January 2010
Last major update January 2010 – IN PROGRESS
Copyright © 2003-2010, PathologyOutlines.com, Inc.
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Table of Contents
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 (7th ed)
American Journal of Surgical Pathology (AJSP)
Archives of Pathology and Laboratory Medicine (Archives)
Human Pathology (Hum Path)
Modern Pathology (Mod Path)
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
Corpus is upper 2/3 of uterus above level of internal cervical os
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
Normal uterus: anterior; posterior; secretory endometrium
Micro: may have lymphoid follicles
Micro images: normal endometrium and cyclin D1 (figures 1A/1B)
AFIP images: early proliferative phase #1 - small, round, regular glands are widely separated by a stroma without edema, which contains small, regularly distributed blood vessels; #2 - (same patient) glands have slight pseudostratification, occasional mitotic figures, and a few clear cells; the stromal cells are uniform and small, with round-to-ovoid nuclei and occasional mitotic figures
Anatomical divisions of uterus
Fundus: cephalad to line connecting the insertion of fallopian tubes
Cornua: lateral regions of fundus associated with intramural fallopian tubes
Isthmus/lower uterine segment: portion of corpus connecting with cervix
Cervix: lower 1/3 of uterus; at and below level of internal cervical os
Uterine cavity: 6 cm long, triangular shape, lined by endometrial mucosa / endometrium, then myometrium, then serosa, which extends to peritoneal reflection
Basalis layer is retained; functionalis layer (superficial 1/2 to 2/3) is shed monthly
Functionalis is divided into spongiosum (near basalis) and compactum (near surface)
Stroma is composed of stromal cells, vessels, stromal granulocytes (T cells, macrophages), foamy cells
Drains to parametrial, paracervical, internal iliac, external iliac, common iliac, periaortic and inguinal lymph nodes
Note: menstruating tissue is replaced by cells from basalis, isthmus and ostio of tubes
Bifid uterus
Gross images: image1
ENDOMETRIUM, LATE PROLIFERATIVE PHASE
ENDOMETRIUM,
EARLY SECRETORY PHASE
In this
illustration, the glands exhibit a regular tortuosity and are clearly oriented
from the base to the surface of the endometrium. Subnuclear glycogen vacuoles
are clearly visible at this magnification.
ENDOMETRIUM,
EARLY SECRETORY PHASE
The glands of
this day-17 endometrium contain prominent subnuclear glycogen vacuoles
underlying a single row of nuclei in the endometrial glands.
ENDOMETRIUM,
MIDSECRETORY PHASE
These
regularly tortuous glands in this day-20 endometrium contain secretions that
are largely intracellular apical, and partially intraluminal.
ENDOMETRIUM,
LATE SECRETORY PHASE
The glands of
this day-25 endometrium are markedly regressed, and the superficial compacta has
a diffusely predecidualized stroma.
ENDOMETRIUM,
LATE SECRETORY PHASE
This
high-power photomicrograph of a day-25 endometrium shows a spiral arteriole cut
in multiple profiles and surrounded by predecidual stroma. Note the admixture
in the stroma of large decidualized cells and smaller endometrial granulocytes.
MENSTRUAL
ENDOMETRIUM
This
low-power photomicrograph shows the typical fragmentation, stromal collapse,
and the bloody necrotic background of a menstrual specimen.
MENSTRUAL
ENDOMETRIUM
This
photomicrograph shows the balls of endometrial stroma that, taken out of
context, are occasionally mistaken for endometrial carcinoma or sarcoma.
LYMPHOID AGGREGATE IN PROLIFERATIVE ENDOMETRIUM
This is a normal finding and should not be interpreted as evidence of endometritis.
Persistent mullerian duct syndrome – Uterus chapter
Rare form of male pseudohermaphroditism caused by lack of regression of Mullerian ducts in phenotypically and genotypically male individuals
Mullerian ducts normally regress in male fetus at 8 weeks due to anti-Mullerian hormone (AMH), which binds to anti-Mullerian type 2 receptor, causing disappearance of Mullerian ducts at 10 weeks of fetal age; mutations of either AMH or receptor block duct regression
<200 cases described in English literature
Usually associated with unilateral cryptorchidism and contralateral hernia
Rarely is bilateral cryptorchidism, pelvic uterus, 2 testes embedded in broad ligament
Associated with testicular germ cell tumors
Case report: clear cell adenocarcinoma of remnant uterus in clinically normal 67 year old man, AJSP 2002;26:1231
Dating of endometrium – Uterus chapter
To date endometrium, should see surface endometrium, but date based on most advanced area
Must biopsy uterine corpus above the level of the isthmus; must also biopsy functionalis as basalis layer does not respond to progesterone
Dating has low interobserver agreement
Difficult to date in patient with IUD or on hormones or if endometrium is non-uniform
Proliferative phase
Length varies from 10-20 days, “ideal” is 14 days; during this phase, glands become more tortuous due to epithelial proliferation, in response to estrogen production and estrogen receptors on epithelium
Early proliferative (days 4-7): thin surface epithelium, straight short glands, compact stroma, minimal mitotic activity, large nuclei
Micro image: image1
Mid proliferative (days 8-10): columnar surface epithelium; longer curving glands, variable stromal edema, numerous mitotic figures
Late proliferative (days 11-14): undulant surface epithelium, tortuous glands with prominent mitotic activity and pseudostratification; dense stroma, subnuclear vacuoles in less than 50% of glands
Ovulation: presence of subnuclear vacuoles in 50% of glands is evidence of ovulation; must biopsy functionalis layer, not basal layer
To rule out anovulatory cycles, should biopsy 2 days before menstruation
Secretory/luteal phase
Traditionally assumed to be 14 days, but may vary
Progesterone secretion inhibits endometrial proliferative active and induces secretory activity
Note: secretory material in glands is NOT specific for secretory epithelium; seen also in disordered proliferative and hyperplastic endometrium and carcinoma
Gross: lush, polypoid, no necrosis; may be hemorrhagic if close to day 28
Day 15: no changes from late proliferative; aka interval endometrium; presence of scattered nuclear vacuoles is NOT specific for ovulation (must be 50% or mor)
Days 16-17 - “piano key” appearance; subnuclear vacuoles (day 16), vacuoles at level of nuclei (day 17)
Micro image: image1
Day 18: luminal vacuoles, smaller size, nuclei approach base of cell
Day 19: intraluminal secretion begins
Days 20-21: maximal secretion
Micro image: image1
Day 22: maximal stromal edema in luteal phase; best time for implantation (“day 22, I'm ready for you”)
Day 23: prominent spiral arterioles (thickened walls, coiling, endothelial proliferation)
Day 24: perivascular pre-decidualization (stromal cell hypertrophy with accumulation of cytoplasmic eosinophilia); serrated / tortuous glands
Day 25: predecidualization below surface endometrium
Day 26: confluence of predecidual tissue; stromal granulocytes (probably lymphocytes) appear
Day 27: prominent stromal granulocytes; focal necrosis and hemorrhage
Day 28: prominent necrosis and hemorrhage, aka shedding (glandular and stromal breakdown); predecidual stroma and glandular exhaustion; nuclear dust at base of glandular epithelium; condensed stroma with overlying papillary-syncytial change; intravascular fibrin thrombi; stromal granulocytes
Note: don’t confuse shedding (nuclear crowding, squamoid appearance, focal cytoplasmic acidophilia) with malignancy
Note: shedding in perimenopausal women with bloody background is consistent with anovulatory cycle
Note: endometrial tissue within vessels does not imply malignancy
Dyssynchronous endometrium
Glands and stroma out of synchronization by at least 2 to 3 days
Luteal phase defect – Uterus chapter
Due to inadequate progesterone production
Associated with infertility and spontaneous abortions
Lag of histologic endometrial date of 3+ days from actual post-ovulatory date (some say 2+ days)
Must be found in 2 consecutive cycles to be clinically significant
Meaning of this diagnosis has been questioned due to substantial variability present in late luteal phase of menstrual cycle, the usual time to obtain an endometrial biopsy
Micro: either immature endometrium or persistence of proliferative changes; may see dyssynchronous endometrium (dissociation between endometrial glands and stroma)
Pregnancy related changes – Uterus chapter
Similar changes seen with intrauterine pregnancy, ectopic pregnancy, progesterone therapy
Arias-Stella reaction – Uterus chapter
Exaggerated gestational hyperplasia; endometrial glands are enlarged with abundant clear or eosinophilic cytoplasm and marked nuclear changes (large, hyperchromatic, pleomorphic, smudged) with rare mitotic figures; decidualized stroma; changes usually focal, may occur in cervix, endocervical polyps, adenomyosis, endometriosis, post- abortion curettings (20-70%), pregnancies, moles, choriocarcinoma (endometrial nuclei may be gigantic in moles and choriocarcinoma)
DD: clear cell carcinoma (post-menopausal so not pregnant, mitotic figures, coarsely granular chromatin, no decidual reaction unless patient on progesterone), in situ endometrial carcinoma
Decidua – Uterus chapter
Bland nuclei, minimal atypia, abundant cytoplasm
Gestational hyperplasia – Uterus chapter
Gross: lush decidua; placental fragments; gestational sac
Micro: early - prominent glandular secretion, stromal edema and predecidual reaction, all simultaneous; implies fertilized ovum has implanted
later - glands are tubular, not coiled; glandular cells have inclusion-like cleared chromatin resembling HSV infection (see below); may see intermediate trophoblasts or villi
DD: late secretory changes in cycling endometrium
Placental site nodules – Uterus chapter
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 – Uterus chapter
Optically clear nuclei, resembling viral inclusions, present during pregnancy
Due to replacement of chromatin by fine filamentous network that is biotin immunoreactive
Fetus 10th week of pregnancy
Gestational endometrium
Stark glands increased with hoses star Lumina.
Endometrial curettage and biopsy – Uterus chapter
D & C (dilatation and curettage) and endometrial biopsy are methods of choice for sampling localized lesions
Fractional curettage: separate sampling from endometrial and endocervical cavities during same procedure; do endocervix first to minimize contamination
Note: report endocervical extension of a tumor only if normal endocervical glands and carcinoma are present in the SAME fragment
Asherman’s syndrome: intrauterine adhesions after D & C, causing amenorrhea; usually postpartum or post-termination, may be due to subclinical uterine infection
Endometrial biopsy: to evaluate infertile or dysmenorrheic patients; sensitive if done properly
Helpful clinical information: patient’s age, date and characteristics of last and current menstrual period, use of hormones/steroids, chief complaint, physical findings
Exogenous hormones – Uterus chapter
Current oral contraceptives
Small doses of estrogen and progesterone
Micro: endometrial glandular arrest with small, straight and inactive glands, no mitotic figures, no secretion; glands lined by immature epithelial cells, nuclei lack thick nuclear membrane or coarse chromatin seen in proliferative endometrium; cytoplasm has randomly distributed vacuoles and smooth, well defined apical border; glands may have dense eosinophilic secretion (abortive secretion); stroma initially edematous, then decidual with granulocytic infiltrates; vessels are thin, later become dilated, lack changes of spiral arterioles (thickening, coiling) at day 23; also endocervical microglandular hyperplasia and squamous metaplasia
Prolonged use: disappearance of abortive glandular secretion, atrophy of glands and stroma
Micro images: image1
Ovulation Induction Therapy – Uterus chapter
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
Estrogens alone for hormone replacement therapy
Used for hormone replacement therapy (post-menopausal, premature ovarian failure, post-oophorectomy, Turner’s syndrome)
Causes hyperplasia, some with atypia, in 15% of postmenopausal women; also increased risk (4-8x) of endometrial carcinoma, usually superficial and well differentiated with excellent prognosis; also increased risk of breast neoplasms
Adding progesterone protects the endometrium, reduces risk of hyperplasia and carcinoma
Compared to oral contraceptives, uses lower dosages and different estrogens
Micro: proliferative or weakly proliferative endometrium, often with stromal breakdown; endometrial hyperplasia (simple or complex, with or without atypia), occasional squamous metaplasia (squamoid morules), stromal foam cells; endometrial polyps with hyperplastic changes
These changes may persist after therapy ends
Combined hormone replacement therapy – Uterus chapter
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 – Uterus chapter
Gonadotropin releasing hormone agonist, that usually reduces size of uterine leiomyomas by suppressing estrogen stimulation and inducing a temporary menopause
Micro: leiomyomas initially show edema and necrosis, then hyalinization and mild lymphocytic infiltrate; endometrium becomes weakly proliferative, later inactive, later atrophic
Progestational agents – Uterus chapter
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 – Uterus chapter
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 – Uterus chapter
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
Acute endometritis – Uterus chapter
Limited to post-delivery or miscarriage
Due to retained products of conception or instrumentation
Must see microabscesses plus infiltration and destruction of glandular epithelium, as neutrophils are common in cycling endometrium
Chlamydia – Uterus chapter
Associated with severe acute/chronic inflammation
Chronic endometritis – Uterus chapter
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
CHRONIC
ENDOMETRITIS WITH REACTIVE GLANDULAR PROLIFERATION
The spindled
stroma contains a massive lymphoplasmacytic infiltrate. Endometrial glands are
irregularly distributed and variable in size and shape but are also infiltrated
by the inflammatory cells.
CMV – Uterus chapter
May be granulomatous
Coccidiomycosis – Uterus chapter
May be secondary to resolved primary lung infection
Giant cell arteritis – Uterus chapter
May involve uterus as isolated finding or part of generalized giant cell arteritis
Granulomas – Uterus chapter
Due to sarcoid, tuberculosis, CMV, post-laser ablation for post-menopausal bleeding
Hematometra – Uterus chapter
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) – Uterus chapter
2/3 have abnormal endometrium at biopsy; often focal or extensive chronic endometritis, necrosis, squamous metaplasia
May be associated with PID and tubo-ovarian abscesses
Infection rate is 13%
Actinomyces common
Pyometra – Uterus chapter
Pus in endometrial cavity
Due to obstruction and infection; occasionally due to carcinoma, more commonly due to benign cervical stricture
Sarcoidosis – Uterus chapter
Granulomas usually spread to myometrium (in contrast to TB)
Tuberculosis – Uterus chapter
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
Endometrial tuberculosis
Below the picture Endometriumdrüsen. Top cheesy necrosis with giant cell.
Xanthomatous endometritis – Uterus chapter
Associated with cervical stenosis and pyometra, usually in elderly
Micro: contains sheets of foamy cells
Endometrial metaplasia – Uterus chapter
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) – Uterus chapter
Tall cells, apical nuclei, clear cytoplasm; no atypia
DD: clear cell adenocarcinoma
Eosinophilic (oxyphilic) metaplasia – Uterus chapter
Estrogen-induced, resembles atypical hyperplasia except there is no atypia
Intestinal metaplasia – Uterus chapter
Rare
Mucinous metaplasia – Uterus chapter
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 – Uterus chapter
Rare, usually post-menopausal women
Usually benign behavior
Polypectomy or curettage appears to be adequate treatment, AJSP 2001;25:1347
More aggressive treatment may be needed for extensive complex papillary proliferations
Gross: 0.7 cm to 3.0 cm in size, 2/3 occur in endometrial polyps
Micro: focal areas of fibrovascular cores without atypia, usually near endometrial surface
Either simple or complex papillary patterns; often metaplastic epithelial changes
DD: well differentiated / low grade papillary adenocarcinoma, surface syncytial change
Squamous metaplasia – Uterus chapter
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 – Uterus chapter
Formation of smooth muscle, cartilage, bone
DD: retained fetal parts
Syncytial change – Uterus chapter
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
Tubal (ciliated cell) metaplasia – Uterus chapter
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
Micro images: image #1; #2; #3
DD: endometrial stromal sarcoma (no glandular tissue, invades myometrium in tongues, no muscular hypertrophy, unusual to contain diffuse small regular glands )
Adenomyosis uteri
Cystic cavities corresponding to adenomyosis.
Endometriosis – Uterus chapter
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
Dysfunctional uterine bleeding (DUB) – Uterus chapter
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
Micro images: endometrial curette of perimenopausal bleeding of hormonal effect: characteristic atrophic glands and decidualized stroma #1; #2; #3; #4
Endometrial hyperplasia – Uterus chapter
Proliferation of glands of irregular size and shape with an increase in the gland to stroma ratio compared with proliferative endometrium
Usually in perimenopausal women
Usual predecessor to endometrial carcinoma, particularly younger women or those with well differentiated endometrioid adenocarcinoma, although most with hyperplasia do NOT develop carcinoma
Risk of developing carcinoma is greater with complex or atypical changes
Even among experts, discordance is common on hyperplasia vs. no hyperplasia in endometrial biopsies of women on hormone replacement therapy, AJSP 2002;26:1269
Often overdiagnosed
Causes: prolonged estrogenic stimulation with reduced progestational activity (usually near menopause or associated with anovulatory cycles), polycystic ovarian disease (Stein-Leventhal syndrome), ovarian granulosa cell tumors (functional), ovarian cortical stromal hyperplasia, estrogen replacement therapy without progestational agents
Disregard cystic changes since they are secondary and can be found without hyperplasia, although presence of cysts usually means hyperplasia is mild
Treatment: progestins (causes sheets of luteinized stroma and dilated glands resembling Swiss cheese) or hysterectomy (for complex atypical hyperplasia only)
Gross: lush, polypoid endometrium
Gross images: image1
Micro: gland to stroma ratio should be 3:1 (i.e. stroma is 1/3 of volume or less); usually associated with proliferative endometrium (pseudostratification or stratification), may have secretory features if patient receiving progesterone; stroma should also be hyperplastic
Metaplasia common: squamous, ciliated cell, mucinous; grade hyperplasia separate from metaplastic changes
DD: polyps, endometritis, artifacts, metaplasia, normal endometrium
Reference: Mod Path 2000;13:309
Disordered proliferative endometrium – Uterus chapter
Associated with anovulatory cycles, common in perimenopausal and menopausal women; also exogenous estrogen therapy
Resembles normal exuberant proliferative endometrium, but without uniform glandular development (some glands cystically dilated, others have shallow budding)
Increase of cystically dilated glands, but relatively normal ratio of glands to stroma
Sternberg indicates this diagnosis is “insufficient for diagnosis of hyperplasia”, although WHO calls a form of simple hyperplasia
Metaplastic changes (ciliated epithelium) are common
May see endometrial breakdown and hemorrhage with thrombosed, thin walled vessels
Simple hyperplasia – Uterus chapter
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
SIMPLE
HYPERPLASIA
Small and
large glands are lined by proliferative-type endometrial epithelium and are
widely separated by cellular endometrial stroma.
SIMPLE
HYPERPLASIA
Another case
at the same magnification as figure 33 shows essentially the same features.
SIMPLE HYPERPLASIA
Higher
magnification shows three cystic glands lined by proliferative~type endometrial
epithelium without atypia and separated by cellular stroma.
SIMPLE
HYPERPLASIA OF THE ENDOMETRIUM AT INITIAL CURETTAGE
Compare with
figures 61 and 62, which represent repeat curettage from the same patient after
1 year of progestin therapy. (Figures 60-62 are from the same patient)
PARTIAL
RESPONSE OF SIMPLE HYPERPLASIA TO PROGESTIN THERAPY
These glands
differ from those seen at the same magnification in figure 60 (before hormonal
therapy) in that they are slightly smaller, less crowded, and are lined by a
single layer of cells rather than the proliferative-type epithelium seen in
figure 60. This pattern may be characterized as regressed hyperplasia.
COMPLETE
RESPONSE OF SIMPLE HYPERPLASIA TO PROGESTIN THERAPY
Another field
of the same specimen shows inactive glands in a decidualized stroma. This
pattern is characteristic of the response to progestational agents, but the
preexisting condition (simple hyperplasia in this case) can no longer be
specified by an examination of material such as this.
Complex hyperplasia – Uterus chapter
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
COMPLEX
HYPERPLASIA
The nuclei in
these glands are uniform in size and shape and show normal polarity with their
axes perpendicular to the basement membrane. All glands are separated by
stromal cells.
COMPLEX
HYPERPLASIA WITH MORULAR METAPLASIA
This specimen
from a 28-year-old woman with clinical features of the Stein-Leventhal syndrome
shows complex hyperplasia with extensive morular metaplasia. The glands around
the periphery of this large focus of spindle-celled morular metaplasia lack
cytologic atypia and are separated by at least thin wisps of residual
endometrial stroma.
COMPLEX
HYPERPLASIA WITH FOCAL WELL-DIFFERENTIATED ENDOMETRIOID ADENOCARCINOMA
The
endometrioid adenocarcinoma takes the form of several ovoid masses consisting
of a number of confluent endometrial glands, some with a cribriform pattern.
Many other glands are separated by unremarkable endometrial stroma. See figure
50 for higher magnification. (Figures 49 and 50 are from the same patient)
COMPLEX
HYPERPLASIA WITH FOCAL WELL-DIFFERENTIATED ENDOMETRIOID ADENOCARCINOMA
This is a
detail of one of the microscopic foci of endometrial carcinoma seen in figure
49. This type of lesion would not be expected to invade the myometrium (as
exemplified by these photomicrographs, which were taken from a hysterectomy
specimen).
Atypical Hyperplasia – Uterus chapter
top Home
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
Atypical secretory hyperplasia – Uterus chapter
Resembles day 17 endometrium but with atypia
Treatment: conservative
DD: Arias Stella
ATYPICAL
HYPERPLASIA (COMPLEX)
The
irregularly shaped glands in this case are very closely packed but are still
separated by residual endometrial stroma. See figure 41 for cytologic detail.
(Figures 40 and 41 are from the same patient)
ATYPICAL
HYPERPLASIA (COMPLEX)
Higher
magnification of another field from figure 40 demonstrates mild cytologic
atypia at the lower right, characterized by increased nuclear roundness,
clearing of nuclear chromatin, and occasional prominent nucleoli.
ATYPICAL
HYPERPLASIA (COMPLEX)
The glandular
epithelium here is extremely atypical, but residual endometrial stroma
separates all glands in this field. Because of the severity of the atypia, a
specimen such as this should be examined thoroughly to rule out the concomitant
presence of carcinoma.
ATYPICAL HYPERPLASIA (COMPLEX)
Endometrial intraepithelial neoplasia (EIN) – Uterus chapter
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
Sternberg’s pattern approach to diagnosis – Uterus chapter
See Sternberg, S: Diagnostic Surgical Pathology (3rd Ed); Lippincott Williams & Wilkins, 1999
Based on low power diagnosis
Pattern 1: glands with nonneoplastic endometrial stroma; must evaluate gland to stroma ratio, glandular and stromal features, appearance of vessels and pattern uniformity
Includes normal endometrium, gestational changes, atrophy, hyperplasia, carcinoma, polyps, metaplasia
Gland to stroma ratio
1:1 associated with normal cycling endometrium, dysfunctional uterine bleeding, infertility
> 1:1 associated with menstruation, late secretory phase, hyperplasia, carcinoma
< 1:1 associated with normal decidua, atrophy, monophasic stromal proliferations
Glandular features
Must evaluate cytologic features and architecture of glands to determine if atrophy, weakly proliferative endometrium, proliferative endometrium, presence of cytologic atypia, secretory endometrium (early, mid-, late), Arias-Stella reaction, disintegrating glands / shedding, budding or branching of glands
Stromal features
Usual stroma in proliferative phase has spindled or oval nuclei with minimal cytoplasm; in secretory phase or pregnancy has decidual changes of large round/oval nucleus, abundant eosinophilic or clear cytoplasm
Vasculature
In proliferative phase, vessels are delicate branching network throughout stroma
Secretory phase vessels have thicker walls, are coiled (aka spiral arteries)
Thick walled vessels in fibrotic stroma are characteristic of endometrial polyps
Pattern uniformity
Cycling endometrium has uniform pattern throughout, except for lower uterine segment / isthmus (spindled stromal cells separated by collagen, hybrid endocervical-endometrial glands) and stratum basalis layer (unresponsive to hormones, appears weakly proliferative throughout menstrual cycle)
Pattern 2: biphasic proliferations of glands and abundant / possibly neoplastic stroma
Includes endometrial polyps, adenofibroma, atypical polypoid adenomyoma, MMMT, adenosarcoma, sarcoma, endometrial stromal neoplasms, adenomatoid tumor
Pattern 3: predominantly monophasic spindle-cell proliferations
Includes smooth muscle neoplasms, endometrial stromal tumors, spindled epithelial neoplasms, pure heterologous uterine sarcomas, undifferentiated sarcoma
Epithelial neoplasms typically express CD10, EMA, keratin vs. smooth muscle neoplasms express smooth muscle actin, desmin, h-caldesmon
Pattern 4: Sheet-like proliferations of large, round, undifferentiated cells
Includes undifferentiated malignancies such as high grade adenocarcinoma, MMMT, undifferentiated sarcomas, extension of cervical primary, metastatic carcinoma, melanoma, leukemia, lymphoma; lobular carcinoma of breast looks deceptively bland
Pattern 5: Extensive necrosis, inflammation, disintegration
Necrosis suggests malignancy; also cervical stenosis, pyometra, xanthomatous endometritis
Inflammatory cells common in post-partum endometrium; also bacterial infection
Disintegration associated with menstruation, hyperplasia; may mimic carcinoma due to stromal collapse
Pattern 6: Scanty samples that suggest inadequate sample
May be due to atrophy or obstructing lesion that shields endometrium from sampling
Miscellaneous – Uterus chapter
Atrophy
Normal in prepubertal girls, perimenopausal or menopausal women
Low cuboidal or columnar epithelium with no mitotic figures
Glands usually tubular or cystic, may be closely packed
Stroma appears inactive with variable collagenization and minimal mitotic activity
DD: basalis endometrium, lower uterine segment, endometrial lining of submucous myoma, polyp, progesterone effect
Dyssynchronous endometrium – Uterus chapter
Discordance between glands and stroma; usually both in secretory phase; also proliferative endometrium and secretory stroma
Microglandular hyperplasia – Uterus chapter
Clusters of small glands without atypia
Shedding – Uterus chapter
Aka glandular and stroma breakdown
Common in perimenopausal women
Micro: condensation of endometrial stroma under surface endometrium and nuclear dust
Associated with predecidualized stroma and glandular exhaustion; cannot assess architectural changes
May see signet ring cells (benign) if prolonged shedding
DD: small cell carcinoma
Weakly proliferative endometrium – Uterus chapter
Normal in prepubertal girls, perimenopausal or menopausal women
Proliferative glands (columnar or cuboidal epithelium with pseudostratification, elongated and densely basophilic nuclei), but relatively reduced number of mitotic figures
Glands usually tubular or cystic, may be closely packed
Stroma also appears inactive, with variable collagenization and minimal mitotic activity
Epithelial tumors
Adenoacanthoma – Uterus chapter
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
Adenosquamous carcinoma – Uterus chapter
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
Atypical polypoid adenomyoma – Uterus chapter
Aka atypical polypoid adenomyofibroma, APA
Biphasic polypoid lesion with atypical endometrial hyperplasia and usually squamous metaplasia
Uncommon (< 150 cases reported), associated with Turner’s syndrome
Mean age 40 years, range 21-73 years
Symptoms of dysfunctional uterine bleeding
May persist or recur, but does not metastasize; may have increased risk for later carcinoma; may be contiguous with adenocarcinoma; Archives 2002; 126:864
Treatment: conservative polypectomy and curettage or simple hysterectomy in peri/postmenopausal women, but with follow up
Gross: resembles endometrial polyp; single, well-circumscribed, polypoid mass; often in lower uterine segment; usually confined to endometrium with pushing margin; remaining endometrium is often unremarkable
Gross images: image1 (figure 1)
Micro: biphasic with hyperplasic and atypical endometrial glands (complex architecture, often severe cytologic atypia), separated by fascicles of bland smooth muscle and fibrous stroma; squamous metaplasia present (90%) and often extensive; minimal mitotic activity (<3 per 10 HPF); no desmoplasia
Micro images: image1 (figures 2-4), image2, image3
Positive stains: trichrome (smooth muscle); low Ki-67 proliferative activity
DD: adenocarcinoma with muscular invasion (has desmoplasia, older women, grossly invasive, large with hemorrhage and necrosis), MMMT (older women, stromal also malignant, diffuse atypia, increased mitotic activity)
Reference: Mod Path 2000;13:328, Mod Path 2000;13:309
APA of low malignant potential
Glands have features of well differentiated adenocarcinoma
May extend into superficial myometrium
Minimal deviation adenocarcinoma
Poorly differentiated endometrioid adenocarcinoma
Solid tumor masses infiltrating the myometrium.
Partly solid and partly gland forming tumor masses infiltrating the myometrium.
Solid tumor masses infiltrating the myometrium.
Solid tumor mass with several mitotic figures.
Serous papillary adenocarcinoma of the uterus
Ciliated carcinoma – Uterus chapter
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
WELL-DIFFERENTIATED
ENDOMETRIOID ADENOCARCINOMA (CILIATED VARIANT)
Irregular
glands invading deeply in the myometrium are lined predominantly by ciliated
cells (see figure 78 for detail). (Figures 77 and 78 are from the same patient)
Fig. 1-78 AFIP 3rd Series, Vol. 3
WELL-DIFFERENTIATED
ENDOMETRIOID ADENOCARCINOMA (CILIATED VARIANT)
One of the
invading glands from the tumor illustrated in figure 77 is lined predominantly
by ciliated cells. In the absence of myometrial invasion or other clear-cut
evidence of malignancy, most proliferations of this sort would be difficult to
diagnose as carcinoma.
Clear cell carcinoma – Uterus chapter
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
CLEAR
CELL ADENOCARCINOMA
A solid sheet
of tumor cells with voluminous clear cytoplasm characterizes this tumor focus.
CLEAR
CELL ADENOCARCINOMA
The tumor in
this field shows a predominantly papillary growth pattern.
CLEAR
CELL ADENOCARCINOMA
The growth
pattern in this field is tubuloglandular. Nuclear pleomorphism is apparent.
Both clear and hobnail cells are present.
CLEAR
CELL ADENOCARCINOMA
The
tubuloglandular growth pattern on the left in this field blends with a more
solid pattern on the right.
CLEAR
CELL ADENOCARCINOMA
In this
example, a solid focus of tumor is composed of cells with pleomorphic,
hyperchromatic nuclei, each with one or more prominent nucleoli. Voluminous
clear cytoplasm is present.
CLEAR
CELL ADENOCARCINOMA
This field
shows cellular stratification, voluminous clear cytoplasm, and bizarre,
occasionally multiple, nuclei resembling Arias-Stella change. However, at lower
magnification, this was an obviously invasive malignant tumor.
Endometrial carcinoma-general – Uterus chapter
Most common gynecologic malignancy in US (33K cases/year, 4K deaths); incidence is increasing
Usually (80%) arises in postmenopausal women with symptoms of bleeding
Associated with obesity, diabetes, hypertension, infertility, failure of ovulation (Stein-Leventhal syndrome), dysfunctional uterine bleeding, prolonged estrogen use, tamoxifen use (perhaps through imbalance in apoptosis/proliferation), complex endometrial hyperplasia, Muir-Torre syndrome (AJSP 2001;25:936, OMIM)
Stein-Leventhal syndrome: often have hyperplasia that regresses with medical therapy; rarely have a non-lethal, well differentiated carcinomas with minimal muscular invasion
Turner’s syndrome: rarely have well differentiated adenocarcinoma; often with prolonged estrogen therapy, 2/3 have squamous differentiation
Tamoxifen use for breast cancer: may have high-grade tumors with poor prognosis
Major types of endometrial carcioma are endometrioid and serous
Must distinguish muscular invasion (should be deep or have granulation tissue response) from expansion of endometrial-myometrial junction or involvement of adenomyosis (no granulation tissue response, residual normal glands and stroma, glands surrounded by hyperplastic myometrium)
Poorly differentiated tumors are associated with bilateral diffuse uveal melanocytic proliferation and blindness, AJSP 2001;25:212
Spread/metastases: cervix (direct extension or implantation after D & C), ovary, vagina and lung, liver, bone, CNS, skin; nodal metastases to pelvic and para-aortic nodes
8% accompanied by simultaneous ovarian carcinoma, usually with same histology; consider as endometrial metastasis if ovarian tumor is small, bilateral, multinodular with surface implants and angiolymphatic invasion within ovarian stroma
Consider as simultaneous primaries if both tumors are FIGO grade 1/well differentiated and endometrial tumor is not myoinvasive
Rarely see foreign body granulomas in peritoneum in response to desquamated keratin; not considered metastatic disease
Recurrence: vaginal vault, pelvis
Cytology: only 50% sensitive for adenocarcinoma, 60% with cervical scrapings, 75% with vaginal pool material; normal endometrial cells in a cervical cytologic specimen suggests hyperplasia or carcinoma
FIGO grading (excludes serous or clear cell, which are considered high grade):
FIGO 1: resembles microglandular hyperplasia; composed primarily of well formed glands; <5% nonsquamous solid component
FIGO 2: 6-50% nonsquamous solid component
FIGO 3: more than 50% nonsquamous solid component; lacks well formed glands, which differentiates it from serous endometrial carcinoma
Raise grade from 1 to 2 or from 2 to 3 if notable nuclear atypia inappropriate for grade (particularly pleomorphism and prominent nucleoli); others say marked atypia
Note: if marked atypia, tumor may be serous without typical papillary architecture (usually p53+)
Alternative proposal for dividing endometrioid tumors into low grade or high grade based on assessment of amount of solid growth (50% or less vs. 50%+), pattern of invasion (infiltrative vs. expansive), and presence of tumor cell necrosis (yes vs. no) at AJSP 2000;24:1201
High grade if 2 of above features (<50% solid growth, infiltrative growth pattern, tumor cell necrosis)
Note: adenocarcinoma in situ is not considered a valid concept for endometrium
Endometrium intraepithelial neoplasia: questionable if this concept is helpful to pathologists
Treatment: Total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAHBSO), possibly with nodal dissection; progesterone causes regressions in well differentiated tumors, although not curative
Prognostic factors: histologic type, FIGO stage (includes depth of invasion, regional nodal metastases, tumor spread), tumor grade, angiolymphatic invasion (particularly for stage 1 tumors), ER, p53 / HER2 (may not be independent), ploidy
Survival: 5 year survival for patients treated 1993-1995 by stage: 1 - 95%, 2 - 85%, 3-65%, 4-20%
Gross: lush, polypoid endometrium with yellow necrotic areas
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
NECROTIC
ENDOMETRIAL CARCINOMA
In this
pretherapy curettage specimen, only rare neoplastic cells (center) were seen in
voluminous necrotic debris. Better microscopic evidence must be sought before
making a definitive diagnosis of carcinoma.
ENDOMETRIAL
CARCINOMA (VAGINAL SMEAR)
This vaginal
smear from a postmenopausal woman shows a cluster of small adenocarcinoma cells
on the background of numerous superficial cells, indicating estrogenic
activity.
ENDOMETRIAL
ADENOCARCINOMA WITH BULKY OR PUSHING PATTERN OF MYOMETRIAL INVASION
This is an
example of the bulky or pushing pattern of myometrial invasion. This tumor
(left) invades deeply into the myometrium (right), but the junction between
tumor and subjacent myometrium is well demarcated. It is difficult to determine
the depth of myometrial invasion without adjacent endometrial-myometrial
junction available on the same slide for comparison.
ENDOMETRIAL
ADENOCARCINOMA INVADING MYOMETRIUM
This poorly
differentiated tumor stimulates a marked stromal response of loose edematous or
myxoid tissue with fibroblastic proliferation, which separates the nests of
carcinoma from the surrounding myometrium. This is the most common pattern of
myometrial invasion by carcinoma.
ENDOMETRIAL
CARCINOMA INVADING MYOMETRIUM
In this
illustration, well-differentiated endometrial glands infiltrate singly through
the myometrium, with minimal surrounding reactive stroma.
ENDOMETRIAL
CARCINOMA EXTENDING INTO MYOMETRIUM IN ADENOMYOSIS
This pattern
should not be confused with true myometrial invasion, with its attendant
unfavorable prognostic implications. The focus of carcinoma in adenomyosis
(long arrow) is characterized by its sharply defined rounded border, the lack
of a stromal response around it, and the persistence of a benign gland at the
arrow. A focus of adenomyosis without carcinoma is present deeper in the
myometrium (short arrow).
ENDOMETRIAL
CARCINOMA WITH INVASION OF ENDOCERVIX
This
photomicrograph shows carcinoma invading endocervical stroma, a feature
necessary for the diagnosis of true cervical invasion.
Endometrial polyp – Uterus chapter
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 – Uterus chapter
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
Endometrial polyp
Uteruscavums expansion of the polyps in the fundus adherent.
Polyp filling the uterine cavum.
Partially cystic endometrial polyps.
Endometrial polyp with complex hyperplasia and atypia
Cystic polyp with partly extended, partly irregular and stored very densely glandular tubes.
ENDOMETRIAL
POLYP
Another small
polyp found in a curettage specimen demonstrates the same microscopic features
noted in figures 16 and 17.
ENDOMETRIAL
POLYP
This polyp is
composed of relatively few glands, fibrotic stroma, and dilated, thick-walled
blood vessels.
ENDOMETRIAL
POLYP
In this
illustration, dilated, thick-walled vessels are seen adjacent to a cystically
dilated gland (top) lined by a single layer of flattened epithelium.
ENDOMETRIAL
POLYP
These
dilated, thick-walled vessels are a higher magnification of those seen in
figure 17. (Figures 23 and 17 are from the same patient)
ENDOMETRIAL POLYP
ENDOMETRIAL STROMAL SARCOMA ARISING IN AN ENDOMETRIAL POLYP
ENDOMETRIAL
POLYP WITH PSEUDOSARCOMATOUS STROMAL ATYPIA
At this
magnification, the polypoid nature of the lesion can be seen, as well as a
suggestion of scattered enlarged and hyperchromatic nuclei. See figure 30 for
higher magnification. (Figures 29 and 30 are from the same patient)
ENDOMETRIAL
POLYP WITH PSEUDOSARCOMATOUS STROMAL ATYPIA
Higher
magnification of the polyp illustrated in figure 29 shows large, often
multinucleate cells with large hyperchromatic nuclei. These findings were
limited to this polyp in a hysterectomy specimen, and mitotic figures were
absent. The lesion never became more cellular than it is in this field. No
densely cellular cuffs were noted around endometrial glands.
Endometrioid adenocarcinoma – Uterus chapter
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
ENDOMETRIAL
ADENOCARCINOMA
Note the
large numbers of stromal foam cells in this illustration.
ENDOMETRIAL
ADENOCARCINOMA
Note the
large numbers of stromal foam cells in this illustration.
Fig. 1-88 AFIP 3rd Series, Vol. 3
Well differentiated (FIGO grade 1) – Uterus chapter
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
WELL-DIFFERENTIATED
ENDOMETRIOID ADENOCARCINOMA
The glands
illustrated here lack cytologic atypia but are confluent, with no intervening
stroma.
WELL-DIFFERENTIATED
ENDOMETRIOID ADENOCARCINOMA
In this
illustration, several large masses of glands show a confluent or cribriform
pattern, whereas others are separated by a desmoplastic stroma.
WELL-DIFFERENTIATED
ENDOMETRIOID ADENOCARCINOMA
This
illustration shows a confluent glandular pattern.
WELL-DIFFERENTIATED
ENDOMETRIOID ADENOCARCINOMA VERSUS ATYPICAL (COMPLEX) HYPERPLASIA
The glands in
this field show both architectural and cytologic atypia but are still separated
by thin wisps of mostly acellular stroma. Obvious carcinoma was seen in an
adjacent microscopic field (see figure 55). (Figures 54 and 55 are from the
same patient)
WELL-DIFFERENTIATED
ENDOMETRIOID ADENOCARCINOMA
This
microscopic field, a few millimeters away from the field seen in figure 54,
shows the desmoplastic or scirrhous stromal response of invasive carcinoma.
Focal stromal necrosis is also present.
WELL-DIFFERENTIATED ENDOMETRIOID ADENOCARCINOMA
WELL-DIFFERENTIATED
ENDOMETRIOID ADENOCARCINOMA (GRADE I)
This
illustration shows small, round, regular glands growing in a confluent pattern.
WELL-DIFFERENTIATED
ENDOMETRIOID ADENOCARCINOMA
This
illustration is photographed at the same magnification as figure 63 but is from
a different case. The findings are essentially identical. (Figures 64 and 65
are from the same patient)
WELL-DIFFERENTIATED
ENDOMETRIOID ADENOCARCINOMA
At higher
magnification, the tumor is composed of confluent glands lined by slightly
stratified cells with uniform but somewhat rounded nuclei, many with single
prominent nucleoli. (Figures 65 and 64 are from the same patient)
WELL-DIFFERENTIATED ENDOMETRIOID ADENOCARCINOMA
Visible in
this illustration are confluent glands lined predominantly by a single row of
cells with large, round, normochromatic nuclei that are somewhat variable in
size and irregularly distributed.
WELL-DIFFERENTIATED ENDOMETRIAL ADENOCARCINOMA (ENDOMETRIAL ASPIRATE)
Moderate differentiation (FIGO grade 2) – Uterus chapter
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
MODERATELY
DIFFERENTIATED ENDOMETRIOID ADENOCARCINOMA (GRADE II)
In this case,
some solid sheets of tumor cells are seen in addition to glands, and the nuclei
are more variable in size and shape and show more irregularity of nuclear
chromatin than those seen in either figure 65 or figure 67. Because a few solid
foci might be the result of tangential sectioning of glands, the nuclear atypia
helps to characterize this tumor as moderately differentiated. (Figures 66 and
68 are from the same patient)
MODERATELY
DIFFERENTIATED ENDOMETRIOID ADENOCARCINOMA
Another field
of the same tumor illustrated in figure 66 shows anisonucleosis, prominent
nucleoli in some nuclei, and nuclear clearing with clumping of chromatin along
the nuclear membrane. (Figures 68 and 66 are from the same patient)
Poorly differentiated (FIGO grade 3) – Uterus chapter
>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
Endometrial adenocarcinoma and leiomyoma
Yellow-white tumor originating from the endometrium. Sharply delineated leiomyoma.
Endometrioid adenocarcinoma
Bottom: atrophic endometrium. Basophilic tumor forming papillary structures.
POORLY
DIFFERENTIATED ENDOMETRIOID ADENOCARCINOMA (GRADE III)
Only a few
small round glands remain in this field to identify this tumor as
adenocarcinoma of endometrioid type. Most of the tumor grows in solid sheets of
anaplastic cells.
POORLY
DIFFERENTIATED ENDOMETRIOID ADENOCARCINOMA
This field
shows a few malignant glands at the center from which solid sheets of anaplastic
tumor cells stream into a reactive spindled stroma. At the top of the large
lumen in the center of the field, some of the lining cells resemble
syncytiotrophoblastic cells.
POORLY
DIFFERENTIATED ENDOMETRIAL ADENOCARCINOMA (ENDOMETRIAL ASPIRATE)
This
photomicrograph shows large tumor cells with marked anisonucleosis,
hyperchromatism, chromatin clumping, and huge prominent nucleoli. Compare the
size of the tumor cells with those in figure 109 (photographed at the same
magnification).
Giant cell carcinoma – Uterus chapter
Rare, high grade with bizarre, pleomorphic, multinucleated giant cells
UNDIFFERENTIATED CARCINOMA (GIANT CELL TYPE)
Glassy cell carcinoma – Uterus chapter
Rare, type of adenosquamous carcinoma, similar to cervical counterpart
Case report of 60 year old women at Archives 2001;125:816
Micro: diffuse solid sheets of tumor cells, with eosinophilic, ground-glass cytoplasm, distinct cell walls, large nuclei, prominent nucleoli; frequent mitotic figures; heavy eosinophilic and lymphocytic infiltrate common; usually some glandular component; most authors require 30%-100% of glassy cells for diagnosis
Micro images: image1
EM: intermediate filaments, polyribosomes, tonofibrils, and desmosomes
Positive stains: variable keratin, EMA and CEA
Melanoma of uterus – Uterus chapter
Very rare, either as primary or metastatic tumor
Uterine metastases may derive from primaries in skin (Gynecol Oncol 2004;93:252), uvea (Pathol Oncol Res 2006;12:184) or hard palate (Can J Surg 2002;45:461)
Melanoma may metastasize to uterine polyps, including adenomyomas (Int J Surg Pathol 2005;13:223).
Some uterine melanomas may originate in the cervix (see Cervix chapter)
Poor prognosis in uterus or cervix, whether tumor is primary or secondary
Primary uterine tumors may arise from lentigo or blue nevus (Diagn Gynecol Obstet 1981;3:269).
Case reports: Case of the Week #109
Micro images: #1; #2; #3; MART1; HMB45; S100; CAM5.2; CK7; CK20
Minimal deviation endometrial carcinoma – Uterus chapter
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
Mucinous carcinoma – Uterus chapter
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)
MUCINOUS
ADENOCARCINOMA
This invasive
adenocarcinoma contains abundant mucin both within lumina and in the cytoplasm
of the glandular cells.
MUCINOUS
ADENOCARCINOMA
In this
illustration, irregular, confluent malignant glands are lined by
well-differentiated cells containing intracytoplasmic mucin.
Oxyphilic cell carcinoma – Uterus chapter
Large eosinophilic cells
Perivascular epithelioid cell tumor (PEComa) – Uterus chapter
Rare tumor, < 20 cases report
Mean age 54 years (range, 40-75 years)
Present with abnormal uterine bleeding and uterine mass
Member of family of lesions composed, in part, of perivascular epithelioid cells
Other members are some angiomyolipomas, lymphangioleiomyomatosis, clear cell “sugar” tumor of lung, clear cell myomelanocytic tumor of ligamentum teres/falciform ligament, abdominopelvic sarcoma of perivascular epithelioid cells (tumors in bold described in soft tissue outline)
May be associated with tuberous sclerosis complex
May recur after hysterectomy
Consider as tumor of uncertain malignant potential, AJSP 2002;26:1
Micro: cells are epithelioid, with clear to eosinophilic granular cytoplasm, perivascular distribution
Positive stains: HMB45, MelanA/Mart1, focal muscle markers
Secretory carcinoma – Uterus chapter
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
WELL-DIFFERENTIATED ENDOMETRIOID ADENOCARCINOMA (SECRETORY VARIANT)
Fig. 1-76 AFIP 3rd Series, Vol. 3
WELL-DIFFERENTIATED
ENDOMETRIOID ADENOCARCINOMA (SECRETORY VARIANT)
A higher
magnification of the secretory element of figure 75 reveals small, regular
nuclei and abundant vacuolated cytoplasm.
Serous carcinoma – Uterus chapter
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)
SEROUS
CARCINOMA
This
low-power photomicrograph shows the typical broad fibrovascular cores lined by
stratified cells, forming secondary papillae and cellular buds.
SEROUS
CARCINOMA
In this
field, the papillae are small and complex, and the cells are poorly
differentiated.
SEROUS
CARCINOMA
This field
shows a complex papilloglandular pattern with slit-like lumina, as opposed to
the round lumina of endometrioid carcinoma.
SEROUS
CARCINOMA
This is
another field with a complex papilloglandular pattern. Note the exfoliation of
small groups of cells into the lumina.
SEROUS
CARCINOMA
This
illustration shows invasion of myometrial lymphatics. Note the psammoma bodies
within the papillary nests of tumor cells.
SEROUS
CARCINOMA
Extensive
invasion of myometrial lymphatics is evident in this illustration. A moderate
host lymphocytic response is also present.
Endometrial intraepithelial carcinoma – Uterus chapter
Rare finding without invasive carcinoma; may be associated with extrauterine disease
Replacement of benign surface endometrium and underlying glands with high-grade malignant cells resembling serous carcinoma; no evidence of invasion
Often involves benign endometrial polyps with extensive replacement of surface epithelium and glands
Usually cured by hysterectomy if NO extrauterine involvement by careful staging
May be precursor of invasive serous carcinoma
Positive stains: p53, Ki-67
References: AJSP 2000; 24:797; AJSP 2000;24:726
Minimally invasive serous carcinoma – Uterus chapter
No myometrial invasion
Usually cured if NO extrauterine involvement by careful staging
May have minimal disease involving ovarian surface epithelium, serous adenofibroma or omentum
Similar behavior as endometrial intraepithelial carcinoma if 1 cm or less of tumor
DD: eosinophilic metaplasia, complex hyperplasia with atypia, clear cell carcinoma
Small cell carcinoma – Uterus chapter
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
UNDIFFERENTIATED
CARCINOMA (SMALL CELL NEUROENDOCRINE TYPE)
The
resemblance to a small cell carcinoma of the lung is evident in this
illustration.
Squamous cell carcinoma – Uterus chapter
Rare, associated with pyometra or mucinous glands of heterotopic cervical origin
DD: Cervical squamous cell carcinoma
ENDOMETRIOID ADENOCARCINOMA WITH SQUAMOUS DIFFERENTIATION
ENDOMETRIOID
ADENOCARCINOMA WITH SQUAMOUS DIFFERENTIATION
Several
morules appear in this well-differentiated adenocarcinoma. Note that the
glandular component of this case is malignant by the usual criteria. Figures 81
and 82 show details of the morules in this case. (Figures 80-82 are from the
same patient)
ENDOMETRIOID ADENOCARCINOMA WITH SQUAMOUS DIFFERENTIATION
ENDOMETRIOID
ADENOCARCINOMA WITH SQUAMOUS DIFFERENTIATION
This is a
detail of another morule from the same case illustrated in figures 80 and 81.
Note the central necrosis, which does not imply malignant squamous
differentiation.
ENDOMETRIOID
ADENOCARCINOMA WITH SQUAMOUS DIFFERENTIATION
In this
tumor, the glandular component is poorly differentiated, and the
nonkeratinizing squamous component is cytologically malignant, focally
spindled, and invades at the top center and bottom center into the surrounding
reactive stroma. This tumor may also be designated adenosquamous carcinoma.
ENDOMETRIOID
ADENOCARCINOMA WITH SQUAMOUS DIFFERENTIATION
In this
adenosquamous carcinoma, the glandular component is poorly differentiated, and
the squamous element is histologically malignant, keratinizing, and invasive.
ENDOMETRIOID
ADENOCARCINOMA WITH SQUAMOUS DIFFERENTIATION
This
adenosquamous carcinoma shows mostly the squamous component, except for a
single malignant gland located slightly above and to the left of center. The
squamous component is judged malignant by the usual cytologic criteria, as well
as by mitotic activity and destructive stromal invasion. More importantly, the
glandular component of this tumor was poorly differentiated.
ENDOMETRIOID
ADENOCARCINOMA WITH SQUAMOUS DIFFERENTIATION
In this case,
the squamous elements are cytologically malignant (adenosquamous carcinoma).
Some of the squamous cells appear to drop off into the surrounding stroma to
create a pseudosarcomatous pattern.
SQUAMOUS
CELL CARCINOMA
No glandular
component was seen in this tumor, and no involvement of the cervix was present.
Fig. 1-105 AFIP 3rd Series, Vol. 3
ADENOCARCINOMA
WITH SQUAMOUS DIFFERENTIATION (ENDOMETRIAL ASPIRATE)
The clumped
tumor cells toward the center of the illustration represent adenocarcinoma, but
the two spindled cells with eosinophilic cytoplasm at the upper left indicate a
squamous component.
Villoglandular carcinoma – Uterus chapter
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,
WELL-DIFFERENTIATED
ENDOMETRIOID ADENOCARCINOMA (PAPILLARY OR VILLOGLANDULAR TYPE)
The tumor
cells are well differentiated but grow in a papillary rather than a glandular
pattern. Compare this and the next three figures with figures 89-94, which
illustrate serous carcinomas growing in papillary patterns. (Figures 69 and 70
are from the same patient)
WELL-DIFFERENTIATED
ENDOMETRIOID ADENOCARCINOMA (PAPILLARY OR VILLOGLANDULAR TYPE)
Low
magnification shows the growth pattern of this tumor. Cellular detail is
illustrated in figure 69. (Figures 70 and 69 are from the same patient)
WELL-DIFFERENTIATED
ENDOMETRIOID ADENOCARCINOMA (PAPILLARY OR VILLOGLANDULAR TYPE)
This is
another case illustrating the villoglandular architecture. See figure 72 for
cellular detail. (Figures 71 and 72 are from the same patient)
WELL-DIFFERENTIATED
ENDOMETRIOID ADENOCARCINOMA (PAPILLARY OR VILLOGLANDULAR TYPE)
Higher
magnification of figure 71 shows typical features of serous papillary
adenocarcinomas: relatively uniform nuclei and a lack of prominent mitotic
activity, marked cellular stratification, cellular buds, and exfoliation of
groups of cells into lumina.
Stromal tumors
Adenomatoid tumor – Uterus chapter
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
Endometrial stromal nodule – Uterus chapter
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 NODULE
Circumscription
with pushing margin is demonstrated in this illustration.
ENDOMETRIAL
STROMAL NODULE
In this
illustration, small uniform cells closely resemble those of proliferative-phase
endometrial stroma.
ENDOMETRIAL STROMAL NODULE
This example
shows regularly distributed small blood vessels that resemble spiral
arterioles.
ENDOMETRIAL
STROMAL NODULE
Note thick
bands of hyalinized collagen in this field.
ENDOMETRIAL
STROMAL NODULE
The starburst
pattern of hyalinized collagen is featured in this figure.
ENDOMETRIAL
STROMAL NODULE
There are
numerous cells with foamy cytoplasm present in this field.
ENDOMETRIAL
STROMAL NODULE
Note the
large focus (upper) of smooth muscle differentiation. This focus was well
within the sharply circumscribed tumor border, distinguishing it from
myometrium invaded by tumor.
ENDOMETRIAL
STROMAL NODULE
Silver
reticulum stain demonstrates reticulin fibers wrapping around individual tumor
cells and emphasizes the whorling pattern around the blood vessels.
Endometrial stromal tumor with limited infiltration – Uterus chapter
Clinical significance unclear since long follow up required to assessed whether these tumors have malignant potential; should sample margins extensively, AJSP 2002;26:567
Endometrial stromal tumors-general – Uterus chapter
Average age 45, present with vaginal bleeding
May be benign (stromal nodule with pushing margins) or malignant (infiltrating margins, low or high grade)
May contain separate areas of epithelium-like formations in the form of solid masses, glandular structures or cords resembling sex-cord structures; aka uterine tumors resembling sex-cord structures; tend to behave in benign manner
Tumors with smooth muscle and stromal features should be classified and treated as stromal sarcomas, Mod Path 2000;13:328
Difficult to diagnose as nodule vs. sarcoma based on curettings because invasion cannot be assessed, but consider tumor of some kind if endometrial stroma is present without glands
Gross: (all types) soft, yellow-orange
Micro: (all types) uniform small cells resembling endometrial stroma (blunt, spindled to oval with scant cytoplasm and small uniform nuclei), individually enveloped by reticulin fibers, haphazard arrangement (not fascicular), circle small / thin vessels that resemble spiral arterioles, hyalinization and foamy cells present; may have prominent vasculature resembling hemangiopericytoma;
Positive stains: ER, PR, vimentin, actin; variable keratin
Negative stains: S100, h-caldesmon (AJSP 2001;25:455), desmin
Endometrial stromal sarcoma – Uterus chapter
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
DIAGNOSTIC
ALGORITHM FOR UTERINE PURE MESENCHYMAL NEOPLASMS
Mitoses need
not be counted to distinguish between low-grade and high-grade tumors, if the
criteria outlined above are observed.
Low grade – Uterus chapter
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
LOW-GRADE
ENDOMETRIAL STROMAL SARCOMA
Dilated and
slit-like thin-walled vessels are prominent in this example.
LOW-GRADE
ENDOMETRIAL STROMAL SARCOMA
This
illustration shows dilated vessels and sex cord-like structures.
LOW-GRADE
ENDOMETRIAL STROMAL SARCOMA
There is
extensive myometrial infiltration in this field. Note also slit-like vascular
or lymphatic spaces around tumor masses, which represent vascular involvement.
LOW-GRADE
ENDOMETRIAL STROMAL SARCOMA
This focus
shows the myometrium being infiltrated by uniform small tumor cells.
LOW-GRADE
ENDOMETRIAL STROMAL SARCOMA
In this
illustration, myometrial lymphatics are expanded and infiltrated by tumor. The
lobulated contour of the intravascular tumor is unusual, resembling that seen
in intravenous leiomyomatosis.
LOW-GRADE
ENDOMETRIAL STROMAL SARCOMA
Nests and sex
cord-like arrangements blend with intervening stromal cells in this example.
High grade – Uterus chapter
Some classify as high grade based on higher mitotic counts, but this appears to have no prognostic significance
HIGH-GRADE
ENDOMETRIAL STROMAL SARCOMA
The round
cells resemble endometrial stromal cells but are large and pleomorphic. The
regular vascular pattern of the low-grade tumors is absent in this field.
HIGH-GRADE ENDOMETRIAL STROMAL SARCOMA
Undifferentiated – Uterus chapter
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
UNDIFFERENTIATED SARCOMA OF THE ENDOMETRIUM
This field
consists of poorly differentiated spindled cells. Mitoses are numerous, and
necrosis is seen at the lower right.
UNDIFFERENTIATED SARCOMA OF THE ENDOMETRIUM
This field is
composed of pleomorphic giant and spindle cells.
Inflammatory pseudotumor – Uterus chapter
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
HYSTERECTOMY
SPECIMEN CONTAINING TWO LEIOMYOMAS
In this
illustration, the tumor at the apex shows the typical well-demarcated, firm,
white, whorled cut surface and is in subserosal location. Projecting into the
endometrial cavity is a submucous leiomyoma that is soft and gray but
nonetheless proved to be benign.
LEIOMYOMA
WITH HYALINIZATION
In this
example, smooth muscle cells are entrapped and isolated within extensive fields
of hyalinized stroma. (Figures 141 and 142 are from the same patient)
LEIOMYOMA
WITH HYALINIZATION
A higher
magnification of the same case seen in figure 141 shows the bland appearance of
the smooth muscle cells and the extensive hyalinization.
LEIOMYOMA
WITH HYALINIZATION
In this case,
the sharp demarcation of a large field of hyalinization from a more typical
leiomyoma suggests a healed infarct.
LEIOMYOMA
WITH PROMINENT VASCULARITY
Parts of this
tumor would be difficult to distinguish from hemangioma.
Variants
Apoplectic leiomyoma – Uterus chapter
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 – Uterus chapter
Aka clear cell or epithelioid leiomyoma
Micro: round or polygonal cells, with epithelioid, clear cell or plexiform patterns, well defined cell membranes; may have transition to typical smooth muscle; minimal mitotic activity
Positive stains: desmin
EM: smooth muscle origin
Benign metastasizing leiomyoma – Uterus chapter
Leiomyoma extends into vessels, migrates to lung or lymph nodes
Original tumor must clearly be benign and sampled adequately
Must rule out primary smooth muscle tumor of GI tract, retroperitoneum or other areas
“Metastasis” may respond to hormonal treatment; may occur years after uterine resection
Case report of extensively sampled leiomyoma with subsequent lung low-grade leiomyosarcoma at Archives 1999;123:960
Symptoms: none, bleeding, frequency, pain, infertility
Associated with spontaneous abortion, postpartum hemorrhage
Micro images: leiomyoma and later low-grade leiomyosarcoma of lung
Positive stains: estrogen receptor
DD: low grade leiomyosarcoma
Cellular leiomyoma – Uterus chapter
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
CELLULAR LEIOMYOMA
CELLULAR LEIOMYOMA
Cotyledonoid leiomyoma – Uterus chapter
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 – Uterus chapter
Benign smooth muscle tumor associated with dissection of myometrium by fascicles of neoplastic smooth muscle; includes cases of intravenous leiomyomatosis, AJSP 1999;23:1032
DD: leiomyosarcoma, low grade endometrial stromal sarcoma
Disseminated peritoneal leiomyomatosis – Uterus chapter
Rare, benign lesion of multiple peritoneal nodules < 2 cm that cover peritoneal surface
Nodules composed of fibroblasts and bland smooth muscle cells; decidual cells common
Usually young women, with pregnancy (discovered at caesarean section) or other altered hormonal conditions
Nodules regress spontaneously
Clinical resembles metastases
Should rule out GI or retroperitoneal masses (GIST, leiomyosarcoma) before making this diagnosis
Epithelioid leiomyoma – Uterus chapter
Nonspindled rounded cells resembling epithelial cells with clear or eosinophilic cytoplasm
Minimal atypia, < 5 mitotic figures/10 HPF, no tumor cell necrosis
Often has areas of classic leiomyoma, so get more sections
Positive stains: keratin, desmin, smooth muscle actin
DD: carcinoma
Hydropic degeneration – Uterus chapter
Edema fluid, collagen deposition
Simulates leiomyomatosis or myxoid leiomyosarcoma
Intravascular / intravenous leiomyomatosis – Uterus chapter
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 – Uterus chapter
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 – Uterus chapter
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
Intramural lipoleiomyoma
Leiomyoma with lymphoid infiltration – Uterus chapter
May simulate lymphoma due to intense lymphocytic infiltrate
Mitotically active leiomyomas – Uterus chapter
Usually young patients
Also submucous leiomyomas with extensive necrosis that protrude into endometrial cavity
Grossly and microscopically typical for leiomyomas, but 5-15 mitoses per 10 HPF
NO moderate/severe nuclear atypia, NO abnormal mitotic figures, NO tumor cell necrosis
Benign behavior
Myxoid leiomyomas – Uterus chapter
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
LEIOMYOMA
WITH MYXOID DEGENERATION
Only very
attenuated fascicles of smooth muscle cells can be identified in this example.
LEIOMYOMA WITH PROMINENT VASCULARITY AND MYXOID CHANGE
Myoma nascens – Uterus chapter
Fills endometrial cavity, emerges from cervical canal as polypoid growths
Has ulcerated surface
May grossly appear malignant
Pallisading / neurilemoma-like leiomyoma – Uterus chapter
Resembles schwannoma
More common in GI tract than uterus
NEURILEMMOMA-LIKE
LEIOMYOMA
This
leiomyoma contains foci in which tumor cells line up in formations resembling
the Verrocay bodies of neurilemmoma.
Parasitic leiomyoma – Uterus chapter
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
Red degeneration – Uterus chapter
3% of leiomyomas
Presents with abdominal pain, fever, vomiting
Associated with pregnancy, birth control pills
Gross images: image1
Micro: extensive coagulative necrosis
Retroperitoneal – Uterus chapter
Usually women; resemble uterine leiomyomas, although distinct from uterus
May occur years after hysterectomy or synchronous with uterine leiomyomas
May arise from hormonally sensitive smooth muscle; probably soft tissue primaries and not parasitic leiomyomas
Minimal mitotic activity
Benign behavior
Usually ER+, PR+
Reference: AJSP 2001;25:1134
Symplastic / Atypical / Bizarre – Uterus chapter
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
Fibroleiomyoma
Stratum basale of the endometrium. Sharply delineated smooth muscle tumor in the myometrium.
Smooth muscle cells forming orthogonal longitudinal bundles. Collagen fibers.
Smooth muscle cells forming longitudinal bundles. Collagen fibers.
Smooth muscle cells forming bundles. Few inflammatory cells and small vessels.
Smooth muscle cells forming bundles.
Smooth muscle cells forming bundles Reminiscent of schwannoma.
Smooth muscle cells forming bundles Reminiscent of schwannoma.
Smooth muscle cells forming bundles Reminiscent of schwannoma.
Fibroleiomyoma with degenerative changes
Fibroleiomyoma with dystrophic calcification
Numerous basophilic granules, calcospherites, coalescing to a large calcified mass (on the left).
Numerous basophilic granules, calcospherites, coalescing to a large calcified mass (on the left).
Numerous basophilic granules, calcospherites, coalescing to a large calcified mass.
Fibroleiomyoma with dystrophic calcification, lipoleiomyoma
Leiomyosarcoma – Uterus chapter
Rare, probably not derived from leiomyomas
Peaks at ages 40-69 years, mean 54 years
If spread beyond uterus, few survive long term
Tend to recur, 50% metastasize to lung, bone, brain, other; lymph node involvement unusual
5 year survival 40%; anaplastic only 10%; minimal survival if extend beyond uterus;
Gross: bulky, fleshy tumor invading into myometrial wall or polypoid tumor projecting into lumen, hemorrhagic or necrotic; grossly appear invasive / infiltrative; usually 5 cm or more but NOT multiple
Gross images: image1, with endometrioid carcinoma
Micro: hypercellular tumors composed of spindle cells resembling smooth muscle cells with moderate to severe pleomorphism; 10+ mitotic figures per 10 high power fields (HPF) in most mitotically active area with abundant abnormal mitotic figures; don’t interpret small pyknotic nuclei from smooth muscle cells as mitoses; use only definitive mitotic figures; coagulative tumor cell necrosis; rarely contains osteoclast-like giant cells
Micro images: image1, image2, image3, with endometrioid carcinoma#1, #2
Contributed by Dr. Jamie Shutter, George Washington University: low power; medium power; high power; tripolar mitotic figure
Micro images: H&E and CD10 (figures 1C & 1D)
Positive stains: actin, myosin, desmin, h-caldesmon (variable, AJSP 2001;25:253), keratin (epithelioid tumors), p53, focal CD10
Negative stains: CD44v3 (Hum Path 2001;32:1190)
DD: endometrial stromal sarcoma with smooth muscle metaplasia
Reference: AJSP 2001;25:455, Mod Path 2001;14:465
Myxoid leiomyosarcomas – Uterus chapter
Rare, but important variant of uterus and broad ligament
Recur and metastasize regardless of mitotic count
Gross: gelatinous, well-circumscribed
Micro: invasive and infiltrative, highly myxomatous; tumor cells have moderate to marked atypia but variable tumor cell necrosis
Positive stains: high MIB-1 index although may have low mitotic count
Malignant leiomyoblastomas – Uterus chapter
Compared to benign tumors, are mitotically active, larger and infiltrative
No hyalinization or necrosis present
Malignant Mixed Mullerian Tumor (MMMT) – Uterus chapter
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)
Carcinosarcoma
Malignant Mullerian mixed tumor