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Incontrast,patients inthesecond group(typeII)tend tobe elderly,and typicallyhave no
historyof hyperestrogenism. Inthesecases, the surrounding nonneoplasticendometrium is
almost always atrophic or only weakly estrogen supported, but there may be an in situ
componentwithhigh-gradecytologicfeatures.Thecarcinomasthatdevelopinthisgroup
of patients are usually of the special variant type with a poorprognosisorarehighgradeendometrioidneoplasmsthatarehighstagewithdeepmyoinvasion.Theytendto
beER-negativeandPR-negative,stronglyexpressp53,andshowhighKi-67labeling.
Amolecularclassificationofendometrialcarcinomahasbeenproposedbased ondata
from The Cancer Genome Atlas Group (TCGA). Characterized by mutation rates and
somaticcopy-numberalterations,therearefourdistinctmolecularsubtypesofendometrial
cancer: ultramutated POLE, hypermutated microsatellite unstable, copy-number low, and
copy-number high. The ultramutated subtype characterized by mutations in the
exonucleasedomain of DNA polymerase-epsilon (POLE), is associated with a favorable
prognosis.Thehypermutatedsubtypehashighmicrosatelliteinstability(MSI-high)andis
associated with an intermediate prognosis. The copy-number low (also referred to as
subtype with no specific molecular profile) has been associated with an intermediate
prognosis. In contrast, the copy-number high subtype, which is characterized by TP53
mutations, and associated with mainly serous carcinoma histologic subtype, is associated
withthemostunfavorableprognosis(40).
Mostendometrialadenocarcinomasareofendometrioidtype.Inthesetumors,malignant
glands are lined by stratified, often elongated nuclei, reminiscent of benign endometrial
epithelium. A distinct architectural subtype of endometrioid carcinoma exhibits a
villoglandulararchitecture, in which there are long, slender papillae lined by relatively
bland cells with cigar-shaped nuclei (Fig. 6.38). This carcinoma is typically a low-grade
tumor,andthemainreasonforrecognizingthissubtypeisthatitshouldnotbeconfusedwith
serouscarcinomaoftheendometrium,whichispapillary,buthasamuchworseprognosis.
Well-DifferentiatedEndometrioidAdenocarcinomaversusAtypical
HyperplasiaorMetaplasia
Several morphologic definitions of well-differentiated endometrioid adenocarcinoma have
been published over the years, and they differ in various respects (41,42). Most require a
certainlevelofcytologicatypiaorarchitecturalcomplexity.Architecturalcomplexityusually
takestheformofoneormoreofthefollowing:extensivebuddingandbranchingofglands,
papillary structures with superimposed secondary structures (buds or secondary papillae),
and a cribriform pattern (Fig. 6.39). Expert disagreement over cases in this gray zone is
common. This disagreement impedes clinical decision making in only a small subset of
patients, including those with comorbidities or those for whom uterine conservation is
important.
EndometrioidAdenocarcinomawithSquamousElements
Squamous elements are very common in endometrioid adenocarcinoma of all grades
(Fig. 6.40). The presence of squamous differentiation does not affect the prognosis. Of
importance,thesquamousareas(benignormalignant),whichtypicallyformsheets,areruled
outwhendeterminingarchitecturalgrade(seebelow).
Other subtypes of endometrioid adenocarcinoma include the rare secretory carcinoma and
ciliated carcinomas. These are well differentiated and have a favorable prognosis. These
morphologicpatternscanbeseenfocallyinanotherwiseordinaryendometrioidcarcinoma.
MucinousAdenocarcinoma
Puremucinous adenocarcinoma(Fig. 6.41) is usually low grade and low stage and is
frequentlyseeninwomentreatedwithtamoxifen.Ifthispatternisseeninanendometrial
sampling, the anatomic origin—cervix or endometrium—may be in doubt. Strategies for
illuminatingthisissuearesetoutinTable6.5.
SerousCarcinoma
Serouscarcinomamakesupbetween5and 10%ofallendometrialcarcinomasandis
knownforitsaggressivebehavior(43–45).Ittypicallyaffectspostmenopausalwomenand
arisesinthesettingofendometrialatrophy.Thehallmarksofthiscarcinomaareatendency
for myometrial invasion, extensive lymphatic space invasion, and early, clinically
inapparentdisseminationbeyondthe uterus (most ofteninthe form of diffuseperitoneal
involvement).Microscopically,thetumoriscomposedofcomplexpapillaryfronds,linedby
highlymalignantcellspossessingprominent,eosinophilicnucleoli(Fig.6.42).Uterineserous
carcinomasmayexpress ER and/or PR, but the expression levelsaregenerallylower than
those seen in low-grade endometrioid carcinomas; uterine serous carcinomas are strongly
immunoreactive for p53. Serous carcinoma of the endometrium is not graded but is
regardedasahigh-gradetumorbydefinition.
Figure 6.38 Villoglandular carcinoma. Delicate, elongated papillae (analogous to villous
structuresinvillousadenomasofthelargebowel)arelinedbysmall,complex,epithelialbuds.
(top,lowpower;bottom,highpower)
Figure 6.39 Well-differentiated endometrioid adenocarcinoma. Back-to-back glands with
minimal or no intervening stroma (upper left) and cytologic atypia (note prominent nucleoli,
upper right) are features of usual endometrial carcinoma. Glandular nests with extensive
cribriforming are another common pattern seen in endometrioid adenocarcinoma (lower left
andlowerright).Notethatinthisexample,thecytologicatypiaisnotsignificantlydifferentfrom
thatseeninendometrialhyperplasia(lowerright)andthediagnosisofcarcinomaisbasedon
complexarchitecture.
Mostpapillaryproliferationsoftheendometriumare notserous carcinomas;more frequent
are papillary hyperplasia/metaplasias and endometrioid carcinomas with villoglandular
architecture.Allofthesearebenignorlow-gradeproliferations(Table6.8).Metastaticserous
carcinomatotheendometriummustberuledout.
InSituSerousCarcinoma(EndometrialIntraepithelialCarcinoma)
Thislesionischaracterizedbyreplacementofbenign(oftenatrophic)endometrialepithelium
byhighlymalignantcellsresemblingserouscarcinoma(Fig.6.43) (45).Itis regardedasa
precursorofserouscarcinomaandissometimesseenadjacenttoit(46).
Figure 6.40 Endometrioid adenocarcinoma with squamous elements. A solid area of
benign-appearingsquamouscellsisseeninthelowcenterportionofthefield.
Figure 6.41 Mucinous adenocarcinoma. Confluent and cribriform glands are lined by
mucinousepithelium.(top,lowpower;bottom,highpower)
Figure6.42Serouscarcinomaofthe endometrium.Papillaeandglandsarecomposed of
malignantcellswithmarkednuclearatypia.(top,lowpower;bottom,highpower)
ClearCellCarcinoma
Primary clear cell carcinoma of the endometrium is very uncommon and is
histologically indistinguishable from clear cell carcinoma of the ovary. This neoplasm
combines high-grade cytologic features characterized by enlarged, angulated nuclei and
large,irregularnucleoli,withcytoplasmicclearing(atleastinfocalareas).Thearchitecture
maybe papillary, glandular,or sheetlike. When it is glandular,the tumor cell nuclei often
protrude into the luminal space, giving rise to a hobnail ortombstone appearance (Fig.
6.44). The differential diagnosis includes (i) the hypersecretory change (Arias-Stella
reaction)(Fig.6.45)seeninpregnancyandwiththeuseofprogestationalmedicationand(ii)
theclinicallynonaggressivesecretoryvariantofendometrioidcarcinoma.
Table6.8PapillaryProliferationsoftheEndometrium
AnticipatedClinicalBehavior
ArchitectureofConnective
TissueScaffolding CytologicAtypia
Benign
Papillarysyncytialmetaplasia Epithelialstratificationwitha
papillaryconfiguration
Minimal
Papillarychange Three-dimensionalpapillae Minimal
Villoglandularhyperplasia Sheetsorfolia Minimaltomoderate
TypeICarcinomas
Endometrioidcarcinomawith
villousarchitecture
Sheetsorfolia Moderatetosevere
Endometrioidcarcinomawith
smallnonvillouspapillae
Epithelialstratificationwitha
papillaryconfiguration
Minimaltomoderate
Puremucinouscarcinoma Sheetsorfolia Moderatetosevere
TypeIICarcinomas
Uterineserouscarcinoma Three-dimensionalpapillae Markedlyatypical
SquamousCellCarcinoma
Primarysquamouscellcarcinomaoftheendometriumisveryrareandismuchlesscommon
than extension of a primary uterine cervical carcinoma to the endometrium. Primary
squamouscellcarcinoma oftheendometriummaybe associatedwithcervicalstenosisand
pyometra.
UndifferentiatedandDedifferentiatedCarcinoma
These tumors are characterized by the presence of solid, dispersive sheets of round or
polygonalcells, often with increasedlymphocytes.When accompanied byacomponentof
well-differentiated endometroid carcinoma, they are designated as dedifferentiated
carcinoma.Approximately40–50%areassociatedwithsporadic methylationof MLH1 and
aremicrosatelliteunstable(47).
Figure 6.43 In situ serous carcinoma of the endometrium. High-grade nuclear atypia of
serous carcinoma contrasts with benign, inactive glandular epithelium of the adjacent,
nonhyperplasticendometrium.
Figure 6.44 Clear cell carcinoma of the endometrium. Malignant glands are lined by
anaplastichobnailcellswithclearcytoplasm.(top,lowpower;bottom,highpower)
MixedCarcinoma
Tumorheterogeneityisubiquitousandawell-establishedconsequenceoftumorprogression;
endometrial carcinomas are no exception. When differences between components become
sufficientlystriking, the term mixed is employed. To qualify for this diagnosis,the minor
component(s)shouldcompose10%ormoreofthetumor.